Manual of Obstetrics - PDFCOFFEE.COM (2024)

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MANUAL OF OBSTETRICS Eighth Edition

Editors

Arthur T. Evans, MD

Professor and Chairman Department of Obstetrics and Gynecology University of Cincinnati College of Medicine Cincinnati, Ohio

Emily DeFranco, DO, MS

Associate Professor Department of Obstetrics and Gynecology Division of Maternal-Fetal Medicine University of Cincinnati College of Medicine Cincinnati, Ohio

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Acquisitions Editor: Rebecca Gaertner, Jamie Elfrank Product Development Editor: Morgan Hawk, Ashley Fischer Production Product Manager: Priscilla Crater Manufacturing Manager: Beth Welsh Marketing Manager: Stephanie Manzo Design Coordinator: Teresa Mallon Production Services: SPi Global 8th Edition Copyright © 2014 by Wolters Kluwer Health 2001 Market Street Philadelphia, PA 19103 LWW.com © 2007 by Lippincott Williams & Wilkins, a Wolters Kluwer business (7th Edition); © 2000 by Lippincott Williams & Wilkins (6th edition) All rights reserved. This book is protected by copyright. No part of this book may be reproduced in any form or by any means, including photocopying, or utilizing by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Printed in China Library of Congress Cataloging-in-Publication Data Manual of obstetrics / [edited by] Arthur T. Evans, Emily DeFranco. — 8th edition.    p. ; cm.   Includes bibliographical references and index.   ISBN 978-1-4511-8677-2   I. Evans, Arthur T., editor of compilation. II. DeFranco, Emily, editor of compilation.   [DNLM: 1. Obstetrics—Outlines. 2. Contraception—Outlines. 3. Perinatal Care—Outlines.   4. Pregnancy Complications—Outlines.  WQ 18.2]  RG531  618.2—dc23 2013049597 Care has been taken to confirm the accuracy of the information presented and to describe generally accepted practices. However, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents of the publication. Application of this information in a particular situation remains the professional responsibility of the practitioner. The authors, editors, and publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accordance with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new or infrequently employed drug. Some drugs and medical devices presented in this publication have Food and Drug Administration (FDA) clearance for limited use in restricted research settings. It is the responsibility of health care providers to ascertain the FDA status of each drug or device planned for use in their clinical practice. The publishers have made every effort to trace copyright holders for borrowed material. If they have inadvertently overlooked any, they will be pleased to make the necessary arrangements at the first opportunity. To purchase additional copies of this book, call our customer service department at (800) 639–3030 or fax orders to (301) 824–7390. International customers should call (301) 714–2324. Lippincott Williams & Wilkins customer service representatives are available from 8:30 am to 6:00 pm, EST, Monday through Friday, for telephone access. Visit Lippincott Williams & Wilkins on the Internet: http://www.lww.com. 10 9 8 7 6 5 4 3 2 1

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Dedication To my wife, Catherine, for her support and to our children and grandchildren for making it all worthwhile. Arthur T. Evans, MD

To my mentor, colleague, and friend, Arthur Evans, for trusting me to carry on his work on the Manual of Obstetrics. Emily DeFranco, DO, MS

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Contributors Alfred Abuhamad, MD

Cynthia Bean, MD

Professor and Chair Department of Obstetrics and Gynecology Eastern Virginia Medical School Norfolk, Virginia

Assistant Professor Department of Obstetrics and Gynecology University of Cincinnati College of Medicine General Obstetrician and Gynecologist Department of Obstetrics and Gynecology University of Cincinnati Medical Center Cincinnati, Ohio

Albert Asante, MB, BCh Fellow Department of Obstetrics and Gynecology Mayo College of Medicine Fellow Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology Mayo Clinic Rochester, Minnesota

Kristin L. Atkins, MD Assistant Professor Department of Obstetrics, Gynecology and Reproductive Sciences University of Maryland School of Medicine Medical Director of Labor and Delivery Department of Obstetrics, Gynecology and Reproductive Sciences University of Maryland Medical Center Baltimore, Maryland

Bill Atkinson, MD Clinical Associate Professor Department of Obstetrics and Gynecology Division of Maternal-Fetal Medicine Texas Technical University Health Sciences Center Medical Director, Women’s Service Department of Obstetrics and Gynecology Division of Maternal-Fetal Medicine Covenant Health Lubbock, Texas

John R. Barton, MD Associate Professor Department of Obstetrics and Gynecology University of Kentucky Director, Maternal-Fetal Medicine Perinatal Diagnostic Center Baptist Health Lexington Lexington, Kentucky

Eliza M. Berkley, MD Assistant Professor Department of Obstetrics and Gynecology— Maternal-Fetal Medicine Eastern Virginia Medical School Norfolk, Virginia

Kathleen M. Berkowitz, MD Perinatologist MemorialCare Center for Women Miller Children’s and Women’s Hospital Long Beach Medical Center Long Beach, California

Brett Blake, MD Procedural Dermatology Fellow Department of Dermatology VCU Medical Center Richmond, Virginia

Jennifer Cavitt, MD Associate Professor Department of Neurology University of Cincinnati Medical Center Cincinnati, Ohio

Christian A. Chisholm, MD Associate Professor and Vice-Chair for Medical Education Department of Obstetrics and Gynecology University of Virginia Attending Physician Department of Obstetrics and Gynecology University of Virginia Health System Charlottesville, Virginia

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Contributors 

James T. Christmas, MD

Bonnie J. Dattel, MD, FACOG

Director, Maternal-Fetal Medicine Commonwealth Perinatal Services HCA Physician Services Henrico Doctors Hospital Richmond, Virginia

Professor and Assistant Dean Department of Obstetrics and Gynecology Division of Maternal-Fetal Medicine Eastern Virginia Medical School Norfolk, Virginia Director, Labor and Delivery Women’s Health Sentara Norfolk General Hospital Norfolk, Virginia

Charles C. Coddington, MD Professor of Obstetrics and Gynecology Mayo College of Medicine Consultant Division of Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology Mayo Clinic Rochester, Minnesota

Alan M. Coleman, MD Research Fellow Division of Pediatric, General, Thoracic and Fetal Surgery Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Joseph Collea, MD Professor Department of Obstetrics and Gynecology Division of Maternal-Fetal Medicine Georgetown University Washington, DC

David F. Colombo, MD Assistant Professor Department of Maternal-Fetal Medicine Wexner Medical Center The Ohio State University Columbus, Ohio

Hope M. Cottrill, BM, MD Volunteer Faculty Department of Obstetrics and Gynecology University of Kentucky Physician Medical Director of Robotic Surgery Program Cancer Committee Chair of Quality Improvements Member Institutional Review Board Department of Gynecologic Oncology Services Baptist Health Lexington Lexington, Kentucky

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David D’Alessio, MD Professor Department of Internal Medicine Division of Endocrinology University of Cincinnati Director of Endocrinology University Hospital Section Chief, Endocrinology Cincinnati VA Medical Center Cincinnati, Ohio

Emily DeFranco, DO, MS Associate Professor Department of Obstetrics and Gynecology Division of Maternal Fetal Medicine University of Cincinnati Cincinnati, Ohio

Margarita deVeciana, MD Professor Department of Obstetrics and Gynecology Eastern Virginia Medical School Norfolk, Virginia

Arthur T. Evans, MD Chair and Professor of Obstetrics and Gynecology Division of Maternal-Fetal Medicine University of Cincinnati College of Medicine Cincinnati, Ohio

James E. Ferguson II, MD, MBA William Norman Thornton Professor and Chair Department of Obstetrics and Gynecology University of Virginia Obstetrician and Gynecologist-in-Chief Department of Obstetrics and Gynecology University of Virginia Health System Charlottesville, Virginia

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  Contributors

Kellie Flood-Shaffer, MD, FACOG Associate Professor, Division DirectorGeneral Obstetrics and Gynecology Department of Obstetrics and Gynecology University of Cincinnati College of Medicine Faculty Attending Physician Department of Obstetrics and Gynecology University of Cincinnati Medical Center Cincinnati, Ohio

Todd Fontenot, MD

Kimberly W. Hickey, MD Assistant Professor Department of Obstetrics and Gynecology Uniformed Services University Chief, Maternal-Fetal Medicine Department of Obstetrics and Gynecology Walter Reed National Military Medical Center Bethesda, Maryland

Nicolette P. Holliday, MD

Director of Maternal-Fetal Medicine Baton Rouge Medical Center Baton Rouge, Louisiana

Assistant Professor Department of Obstetrics and Gynecology University of South Alabama Mobile, Alabama

Regina Fragneto, MD

Andra H. James, MD

Professor Department of Anesthesiology University of Kentucky College of Medicine Director of Obstetric Anesthesia Department of Anesthesiology UK Healthcare Chandler Medical Center Lexington, Kentucky

Glen A. Green, MD Associate Professor Department of Pediatrics Eastern Virginia Medical School Neonatologist Division of Neonatology Children’s Hospital of the King’s Daughters Norfolk, Virginia

John M. Nokes Professor and Vice-Chair for Research Department of Obstetrics and Gynecology University of Virginia Attending Physician Department of Obstetrics and Gynecology University of Virginia Health System Charlottesville, Virginia

Donna D. Johnson, MD Professor and Chair Department of Obstetrics and Gynecology Medical University of South Carolina Charleston, South Carolina

Elizabeth A. Kelly, MD

Chairman Department of Obstetrics and Gynecology Texas Tech University Health Sciences Center of the Permian Basin Odessa, Texas

Associate Professor Department of Obstetrics and Gynecology University of Cincinnati Medical Director Division of Community Women’s Health University of Cincinnati Medical Center Cincinnati, Ohio

Wendy F. Hansen, MD

Jamil H. Khan, MD

R. Moss Hampton, MD

Department of Obstetrics and Gynecology Division of Maternal-Fetal Medicine University of Kentucky John W. Greene Jr., MD Chair Department of Obstetrics and Gynecology University of Kentucky College of Medicine Lexington, Kentucky

Associate Professor Pediatrics Eastern Virginia Medical School Medical Director Neonatal Intensive Care Unit Children’s Hospital of The King’s Daughters Norfolk, Virginia

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Contributors 

  vii

David F. Lewis, MD, MBA

Jill G. Mauldin, MD

Professor and Chair Division of Maternal-Fetal Medicine Department of Obstetrics and Gynecology University of South Alabama School of Medicine Mobile, Alabama

Associate Professor Medical Director, Women’s Services Division of Maternal-Fetal Medicine Department of Obstetrics and Gynecology Medical University of South Carolina Charleston, South Carolina

Foong-Yen Lim, MD

Kathleen McIntyre-Seltman, MD

Associate Professor Department of Surgery University of Cincinnati Surgical Director of the Cincinnati Fetal Center Division of Pediatric, General, and Thoracic and Fetal Surgery Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Nancy C Lintner, MS, ACNS, RNC-OB, CPT Clinical Program Coordinator for the Diabetes and Pregnancy Program Division of Maternal-Fetal Medicine University of Cincinnati College of Medicine Cincinnati, Ohio

H. Trent Mackay, MD, MPH Department of Obstetrics and Gynecology Uniformed Services University of the Health Sciences Bethesda, Maryland

Kalyani S. Marathe, MD, MPH Post-Doctoral Clinical Fellow in Dermatology Pediatric Dermatology Department of Dermatology Columbia University Medical Center New York, New York

Samantha Mast, MD Instructor Department of Obstetrics and Gynecology Maternal-Fetal Medicine Fellow University of Kentucky Lexington, Kentucky

Professor Department of Obstetrics Gynecology and Reproductive Sciences Division of Gynecologic Specialties University of Pittsburgh Physicians Pittsburgh, Pennsylvania

Susan C. Modesitt, MD, FACOG, FACS Professor and Director Division of Gynecologic Oncology Department of Obstetrics and Gynecology University of Virginia Charlottesville, Virginia

Michael P. Nageotte, MD Professor Department of Obstetrics and Gynecology Division of Maternal-Fetal Medicine University of California–Irvine Medical Center Orange, California

Tondra Newman, MD Fellow, Maternal-Fetal Medicine Department of Obstetrics and Gynecology University of Cincinnati Medical Center Cincinnati, Ohio

Tifany Nolan, MD Instructor of Clinical Obstetrics and Gynecology University of Cincinnati College of Medicine Cincinnati, Ohio

Errol Norwitz, MD, PhD Professor and Chairman Department of Obstetrics and Gynecology Tufts University School of Medicine Boston, Massachusetts

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  Contributors

David M. Pariser, MD

Reena Shah, MD

Professor Department of Dermatology Eastern Virginia Medical School Norfolk, Virginia

Assistant Professor Department of Neurology University of Cincinnati Medical Center Cincinnati, Ohio

Samuel Parry, MD

Tushar A. Shah, MD, MPH

Associate Professor Department of Obstetrics and Gynecology University of Pennsylvania School of Medicine Chief, Maternal-Fetal Medicine Division Department of Obstetrics and Gynecology Hospital of the University of Pennsylvania Philadelphia, Pennsylvania

Assistant Professor Department of Pediatrics Eastern Virginia Medical School Staff Neonatologist Division of Neonatology Children’s Hospital of The King’s Daughters Norfolk, Virginia

Ruth Anne Queenan, MD, MBA

Director, Maternal-Fetal Medicine Fellowship Program Department of Obstetrics, Gynecology and Reproductive Sciences The University of Texas Medical School at Houston Professor Department of Obstetrics, Gynecology and Reproductive Sciences Memorial Hermann Hospital-Texas Medical Center Houston, Texas

Assistant Professor Department of Obstetrics and Gynecology University of Rochester Chief Department of Obstetrics and Gynecology Highland Hospital Rochester, New York

Raymond W. Redline, MD Professor Department of Pathology and Reproductive Biology Case Western Reserve University Staff Pathologist Department of Pathology University Hospitals Case Medical Center Cleveland, Ohio

Jodi Regan, MD Fellow, Maternal-Fetal Medicine Division of Maternal-Fetal Medicine University of Cincinnati College of Medicine Cincinnati, Ohio

Julian N. Robinson, MD Associate Professor of Obstetrics and Gynecology and Reproductive Biology Department of Obstetrics and Gynecology Brigham and Women’s Hospital Boston, Massachusetts

Baha M. Sibai, MD

Brett H. Siegfried, MD Assistant Professor Department of Pediatrics Eastern Virginia Medical School Neonatologist Division of Neonatology Children’s Hospital of the King’s Daughters Norfolk, Virginia

Nicole A. Smith, MD, MPH Assistant Professor of Obstetrics, Gynecology and Reproductive Biology Department of Obstetrics, Gynecology and Reproductive Biology Brigham and Women’s Hospital Boston, Massachusetts

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Contributors 

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Julie Sroga, MD

James W. Van Hook, MD

Assistant Professor of Obstetrics and Gynecology Division of Reproductive Endocrinology and Infertility University of Cincinnati College of Medicine Cincinnati, Ohio

Professor and Executive Vice Chair, Director Division of Maternal-Fetal Medicine Department of Obstetrics and Gynecology Director, Maternal-Fetal Medicine Department of Obstetrics and Gynecology University of Cincinnati Medical Center Cincinnati, Ohio

Amy Thompson, MD, FACOG Assistant Professor of Obstetrics and Gynecology The Clarence R. McLain Chair of Medical Student Education University of Cincinnati College of Medicine Cincinnati, Ohio

Loralei L. Thornburg, MD

Carri R. Warshak, MD Assistant Professor of Obstetrics and Gynecology Division of Maternal-Fetal Medicine University of Cincinnati College of Medicine Cincinnati, Ohio

Assistant Professor Department of Obstetrics and Gynecology University of Rochester Maternal-Fetal Medicine Division Obstetrician and Gynecologist Department of Obstetrics and Gynecology Strong Memorial Hospital Rochester, New York

Selman I. Welt, BS, MD

Kenneth F. Tiffany, MD

Jason J. Woo, MD, MPH, FACOG

Assistant Professor Department of Pediatrics Eastern Virginia Medical School Neonatologist Division of Neonatology Children’s Hospital of the King’s Daughters Norfolk, Virginia

Amy M. Valent, DO Fellow, Maternal-Fetal Medicine Department of Obstetrics and Gynecology University of Cincinnati College of Medicine Department of Obstetrics and Gynecology University of Cincinnati Medical Center Cincinnati, Ohio

Professor Department of Obstetrics and Gynecology East Tennessee State University Obstetrics Director Department of Obstetrics and Gynecology Johnson City Medical Center Johnson City, Tennessee

Attending Consultant Department of Obstetrics and Gynecology MedStar Washington Hospital Center Washington, District of Columbia

John D. Yeast, MD Vice Chair Department of Obstetrics and Gynecology University of Missouri-Kansas City School of Medicine Vice President of Medical Education and Research Saint Luke’s Hospital of Kansas City Kansas City, Missouri

Catherine Van Hook, MD Associate Professor Department of Obstetrics and Gynecology University of Cincinnati College of Medicine Cincinnati, Ohio

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Preface The eighth edition of the Manual of Obstetrics is changing to meet the digital expectations and needs of health care providers. We all want to have choices for how we access information. Clinical situations and personal preferences dictate different solutions at different times. We began the process to provide access to both print and electronic book formats with the seventh edition of the Manual of Obstetrics. The style and presentation were reformatted to be tighter, more compact, and more accessible. The eighth edition brings this process to completion with convergence of print and digital formats allowing the Manual to be available as a traditional printed book or, for the first time, as an e-book on computers and smart devices. Our goal is to make the Manual available to you in the format that works best for you as you care for your patients. The entire eighth edition of the Manual has been carefully updated. A new chapter, Fetal Therapy, has been added in response to the emergence of the fetus as a bona fide individual patient. This chapter recognizes that the fetus has its own principles of care and standards of management. This rapidly evolving specialty area is truly at the cutting edge of obstetric care. A basic understanding of the capabilities and limitations of fetal care is an important new addition to our standard of obstetric care. Several other chapters have been thoroughly revised and updated. Both of the chapters on endocrine disorders have significant additions including insulin pump therapy for pregestational diabetes, choices for gestational diabetes screening and diagnostic testing, thyroid disease management, and complications of adrenal disease with pregnancy. The Neurologic Diseases chapter has been extensively revised and expanded as has Disease of the Placenta. The Preeclampsia chapter contains the most up-to-date version of the new ACOG definitions of, criteria for, and management of preeclampsia. Finally, the chapter on spontaneous preterm birth includes updated recommendations for screening and treatment of preterm labor and preterm rupture of membranes. It also provides new insight for the contemporary management of cervical insufficiency and the short cervix. For the eighth edition, Dr. Emily DeFranco has joined the Manual of ­Obstetrics as the Associate Editor. Dr. DeFranco is Associate Professor of Obstetrics and Gynecology at the University of Cincinnati College of Medicine. She is an academic clinician-scientist and a specialist in Maternal-Fetal Medicine. Her research focus is spontaneous preterm birth and evidence-based medicine. We have worked together for many years, and it is a great pleasure to have her join the editorial staff of the eighth edition of the Manual. I am confident that Dr. DeFranco will be a significant contributor to the success of the Manual of Obstetrics for many editions to come. We are greatly indebted to the distinguished physicians who serve as our chapter authors. The eighth edition of the Manual of Obstetrics would not be possible without their efforts and thoughtful contributions. We note the passing since the last edition of three of the Manual’s long-standing chapter authors, Dr. Richard Oi, Dr. Gary Karlowicz, and Dr. Thomas Pellegrino. Notably, Dr. Oi was the author of “Disease of the Placenta” since the first edition in 1980. We also recognize, in his well-deserved retirement, Dr. Ken Niswander, the founding author of the Manual and editor of the first three editions. We thank Lippincott Williams & Wilkins (LWW) and their editorial staff for their continued support in the production process. Two individuals have been particularly integral to the creation of the eighth edition. Ashley Fischer, the LWW Product Development Editor, has expertly guided the entire project. Debbie Stormer, my x

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Preface 

  xi

academic assistant, managed the complex process of coordinating chapter development between the authors and editors. Without their combined efforts, the eighth edition of the Manual would not have come to fruition. The Manual of Obstetrics is intended to be used by all levels of obstetric providers. We hope that you will find the eighth edition to be a useful guide for making clinical decisions and a stimulus for excellence in obstetric and fetal care. Arthur T. Evans, MD Emily DeFranco, DO, MS

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Contents Contributors iv Preface x

Part I  Obstetric Care  1 1 Prenatal Care  1

Elizabeth A. Kelly

2 Normal Labor  12

Jodi Regan • Catherine Van Hook

3 Obstetric Anesthesia  41

Regina Fragneto

4 Postpartum Care  64

Tifany Nolan • Amy M. Thompson

5 Contraception, Sterilization, and Abortion  86

Jason J. Woo • H. Trent Mackay

Part II  Obstetric Complications  107 6 Pregnancy Loss and Spontaneous Abortion  107

Charles C. Coddington • Albert Asante

7 Ectopic Pregnancy  122

Julie M. Sroga • Kathleen McIntrey-Seltman

8 Spontaneous Preterm Birth  133

Emily DeFranco • Kristin L. Atkins

9 Third-Trimester Bleeding  153

Loralei L. Thornburg • Ruth Anne Queenan

10 Abnormal Labor  163

Cynthia Bean

11 Hypertensive Disorders of Pregnancy  183

John R. Barton • Baha M. Sibai

Part III  Maternal Complications  196 12 Cardiovascular Disease and Chronic Hypertension  196

Samuel Parry

13 Renal Complications  214

Kimberly W. Hickey • Joseph V. Collea

14 Respiratory Complications  228

Nicole A. Smith • Errol R. Norwitz • Julian N. Robinson

15 Hepatobiliary Complications  238

R. Moss Hampton

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Contents 

16 Gastrointestinal Complications  264

Nicolette P. Holliday • David F. Lewis

17 Endocrine Disorders: Diabetes  279

Margarita de Veciana • Arthur T. Evans • Nancy C. Lintner

18 Endocrine Disorders: Thyroid, Parathyroid, Adrenal, and Pituitary Disease 308

Amy M. Valent • David D’Alessio

19 Hematologic Complications  332

Tondra Newman • David F. Colombo

20 Immunologic Complications  371

Jill G. Mauldin • Donna D. Johnson

21 Vascular Complications  380

Wendy F. Hansen • Samantha Mast

22 Thromboembolic Disorders  389

Christian A. Chisholm • Andra H. James • James E. Ferguson II

23 Infectious Complications  403

Bonnie J. Dattel

24 Neurologic Complications  443

Jennifer Cavitt • Reena Shah

25 Dermatologic Complications  478

Brett Blake • Kalyani Marathe • David M. Pariser

26 Substance-Related and Addictive Disorders in Pregnancy  490

James W. Van Hook

27 Gynecologic Complications  508

Kellie Flood-Shaffer

28 Surgical Problems and Trauma  519

Hope M. Cottrill • Susan C. Modesitt

PART IV  Fetal Assessment  535 29 Genetics, Genetic Counseling, and Genetic Risk Assessment  535

Selman I. Welt

30 Teratogens and Birth Defects  562

Bill Atkinson

31 Obstetric Ultrasound  589

Eliza M. Berkley • Alfred Z. Abuhamad

32 Fetal Monitoring and Testing  605

Kathleen M. Berkowitz • Michael P. Nageotte

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xiv 

  Contents

Part V  Fetal Complications  624 33 Fetal Growth Abnormalities  624

Carri R. Warshak • Todd Fontenot

34 Multiple Gestations  634

John D. Yeast

35 Isoimmunization 645

James T. Christmas

36 Disease of the Placenta  656

Raymond W. Redline

37 Fetal Therapy  670

Alan M. Coleman • Foong-Yen Lim

Part VI  Neonatal Care  689 38 Neonatal Resuscitation  689

Brett H. Siegfried • Kenneth F. Tiffany • Glen A. Green

39 Neonatal Complications  708

Tushar A. Shah • Jamil H. Khan

Index 729

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PART

I

Obstetric Care

1

Prenatal Care Elizabeth A. Kelly

KEY POINTS • Prenatal care is designed to provide preventive care, active intervention for acute medical problems and identification of social determinants with referral to appropriate programs and assistance for two patients. • Advances in technology have allowed the fetus to become a separate and distinct patient. • Patient education is an important component of prenatal care. BACKGROUND • Prenatal care is unique: • It provides care simultaneously to two interdependent patients. • There are many components of prenatal care: • Confirming the diagnosis of pregnancy and establishing the estimated gestational age, which allows the estimated date of confinement to be accurately assigned. • Obtaining a full history and conducting a physical examination with laboratory evaluation. • Conducting regular periodic examinations with ongoing patient education. • Assessing and performing well woman health maintenance and preventative care. • Identifying and addressing pregnancy complications as well as acute medical and psychosocial problems. • All information obtained should be recorded in a concise manner that is accessible to other members of the health care team in the electronic health record. DIAGNOSIS OF PREGNANCY AND ACCURATE DATING • Early pregnancy diagnosis and accurate dating are essential for establishing a prenatal care plan, addressing risk factors, identifying medical complications, and determining appropriate timing of the delivery. • The diagnosis of pregnancy is facilitated by both presumptive and probable signs. • Presumptive signs lead a woman to believe that she is pregnant. • Probable signs are highly suggestive of the diagnosis of pregnancy. • Note that these signs do not differentiate between an ectopic and an intrauterine pregnancy. 1

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  Part I • Obstetric Care

Presumptive Signs • Amenorrhea is often the first sign of possible conception but may result from other factors, such as anovulation, premature menopause, thyroid disease, or elevated prolactin. • Subjective signs and symptoms of early pregnancy include breast fullness and tenderness, skin changes, nausea, vomiting, urinary frequency, and fatigue. • Between 12 and 20 weeks’ gestation, a woman will note an enlarging abdomen and perceive fetal movement. Probable Signs • Uterine enlargement • Softening of the uterine isthmus (Hegar sign) • Vaginal and cervical cyanosis (Chadwick sign) • Pregnancy tests: • Urine pregnancy tests used today are very sensitive and may be positive as early as 5 days after embryo implantation. • Radioimmunoassay for serum testing of the beta subunit of human chorionic gonadotropin (hCG) may be accurate up to a few days after implantation (or even before the first missed period). hCG production is at its maximum between 60 and 70 days of gestation and declines thereafter. • These tests do not differentiate between normal pregnancy, gestational trophoblastic disease, ectopic pregnancy, and abnormal intrauterine pregnancy. • Other bioassay techniques used in the past, such as progesterone withdrawal, are of historic interest only. Positive Diagnostic Signs • Fetal heart tones can be detected as early as 7 weeks from the last menstrual period (LMP) by Doppler technology. The nonelectronic fetoscope detects fetal heart tones at 18 to 20 weeks from the LMP. • Fetal movements (“quickening”) are generally first felt by the patient at approximately 16 to 18 weeks. They are a valuable indication of fetal well-being. • Ultrasound examination will demonstrate an intrauterine gestational sac at 5 to 6 weeks and a fetal pole with movement and cardiac activity at 6 to 8 weeks. Vaginal probe ultrasonography has made these early measurements even more accurate. Fetal age can be estimated by crown–rump length, and the number of fetuses may be identified. After 12 to 14 weeks of gestation, fetal biometric measurements, including biparietal diameter and femur length, can be used to estimate fetal age accurately. In the second trimester, fetal anatomy, placental location, and amniotic fluid volume can be evaluated. There is no evidence that diagnostic ultrasound exposure has adverse effects on the developing human fetus. Estimated Date of Delivery • The expected duration of pregnancy, calculated from the LMP to estimated date of delivery (EDD) is 280 days, or 40 weeks. • Naegele’s rule is used to calculate the EDD: • To the 1st day of the LMP, add 7 days and then subtract 3 months. • Deviations from this calculation may be made for various reasons (e.g., irregular or prolonged menstrual cycles, known single sexual exposure, or known conception date via artificial reproductive technologies, such as in vitro fertilization). • If the date of the LMP is unknown or does not correlate with uterine size at the first visit, ultrasonography should be used to establish the EDD. EVALUATION A complete history and physical examination are performed after the diagnosis of pregnancy is established. An important goal is to develop a trusting, working relationship between the patient and the health care team. (c) 2015 Wolters Kluwer. All Rights Reserved.

Chapter 1 •  Prenatal Care 

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History • Menstrual and contraceptive history: • Reliable menstrual history is the most accurate predictor of EDD. • Gynecologic history: Previous sexually transmitted infections, abnormal Papanicolaou (Pap) smear, gynecologic surgeries, and hospitalization for gynecologic conditions should be recorded. • Obstetric history: • The obstetric history is recorded as gravidity and parity. Gravidity is the total number of pregnancies. Parity is expressed as four serial numbers: term deliveries, premature deliveries, abortions and ectopic pregnancy, and living children. • Details of previous pregnancies, such as character and length of labor, mode of delivery, pregnancy and delivery complications, newborn health, and birth weight, should be noted. Recurrent first-trimester losses may suggest genetic abnormalities in the conceptus or parents while a history of second-trimester losses may suggest genetic abnormalities or cervical insufficiency. • If the patient has had a cesarean delivery, it is important to document the prior uterine scar type to assist with counseling for delivery mode and timing. • Medical and surgical history and prior hospitalizations: • Preexisting medical problems or diagnoses are important for pregnancy risk assessment and management. • Previous surgeries and hospitalizations should be elicited and evaluated. • Environmental exposures, medications taken in early pregnancy, history of reactions to medications, legal and illicit drug use, and allergic history. • Family history of medical illnesses, heritable conditions, genetic abnormalities, mental retardation, congenital anomalies, and multiple gestation. • Social history: • Home environment, family and social support, and history of physical or mental abuse should be assessed and appropriate referrals made. • Assessment of tobacco, alcohol and substance use, abuse, or dependence. • Review of systems as related to pregnancy: nausea, vomiting, abdominal pain, constipation, headaches, syncopal episodes, vaginal bleeding or discharge, dysuria or urinary frequency, swelling, varicosities, and hemorrhoids. Physical Examination • Complete physical examination with attention to specific organ systems as directed by any positive findings in the history: • Measurement of height, weight, blood pressure, pulse and documentation of prepregnancy body mass index (BMI); funduscopic examination; examination of thyroid, lymph nodes, lungs, heart, breasts, and abdomen, with fundal height and presence of fetal heart tones, extremities; and a basic neurologic exam • Pelvic examination: • External genitalia—Evidence of previous obstetric injury should be noted. • Vagina—Under hormonal influence of pregnancy, cervical secretions are increased, thus raising the vaginal pH, which may cause a change in the bacteriologic flora of the vagina. No treatment is necessary unless diagnosis of a specific infection is made (see “Treatment of Common Lesions and Infections” later in this chapter). • Cervix—A Pap test as indicated and testing for Chlamydia and gonorrhea are routinely performed. °°Cervical softening and eversion (ectropion) is normal. °°Nabothian cysts are of no consequence. °°Dilatation of the external os is common in multiparous patients and is a nonpathologic finding. Significant cervical effacement or dilation of the internal os is abnormal, except near term, and may indicate premature labor or cervical insufficiency. (c) 2015 Wolters Kluwer. All Rights Reserved.

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  Part I • Obstetric Care

°°Morphologic cervical changes (ridges, hood, or collar), or vaginal adenosis may indi-

cate DES exposure in utero. These women have a higher incidence of cervical insufficiency and preterm delivery and should be evaluated accordingly. • Uterus—Estimating gestational age by gauging uterine size is one of the most important elements of the initial obstetric examination. °°A normal, nongravid uterus is firm, smooth, and approximately 3 × 4 × 7 cm. The uterus will not change noticeably in consistency or size until 5 to 6 weeks after the LMP, or 4 weeks after conception. °°Gestational age from the LMP is estimated by uterine volume (i.e., 8 weeks, twice normal size; 10 weeks, three times normal; 12 weeks, four times normal). At 12 weeks, the uterus fills the pelvis so that the fundus of the uterus is palpable at the symphysis pubis. By 16 weeks, the uterus is midway between the symphysis pubis and the umbilicus. At 20 weeks, the uterine fundus is at the level of the umbilicus. Thereafter, there is a rough correlation between weeks of gestation and centimeters of fundal curvature when measured from the top of the symphysis pubis to the top of the uterine fundus (MacDonald measurement). °°After correcting for minor discrepancies resulting from adiposity and variation in body shape, a uterine size that exceeds the anticipated gestational age by 3 weeks or more, as calculated from the last normal menstrual period, suggests multiple gestation, molar pregnancy, leiomyomata, uterine anomalies, adnexal masses, or simply an inaccurate date for the LMP. Ultrasonography is the best diagnostic tool for this situation. °°Smaller than expected uterine size for gestational age may indicate inaccurate dating or early pregnancy loss. • Adnexa are difficult to evaluate because the fallopian tubes and the ovaries are lifted out of the pelvis by the enlarging uterus. Any questionable masses should be confirmed by ultrasound evaluation. • Clinical pelvimetry is performed as part of the initial bimanual exam to assess the general adequacy of the pelvis for vaginal delivery. Laboratory Evaluation A history positive for certain illness or abnormalities in other screening tests should be investigated with further tests as indicated. • A routine initial screen includes a complete blood count, ABO blood typing and Rh factor, red blood cell antibody screening, urinalysis and culture, serologic test for syphilis, rubella titer, Pap test as indicated, cervical testing for gonorrhea and Chlamydia, hepatitis B surface antigen, and testing for HIV. • Group B Streptococcus (GBS) (see Chapter 23): • Screening is not indicated in early pregnancy, nor is it based on risk factors. Women with a urine culture positive for GBS do not require screening between 35 and 37 weeks as they will require antibiotic prophylaxis in labor. • All women except those with GBS bacteriuria in the current pregnancy should be screened for GBS at 35 to 37 weeks’ gestation by a culture obtained from a swab of the rectum and the lower third of the vagina. Patients with positive results are treated with appropriate antibiotics during labor. • Specialized screening tests: • Hemoglobin electrophoresis should be used to identify hemoglobinopathies in specific groups of women: °°Sickle hemoglobinopathies, beta-thalassemia, and alpha-thalassemia in persons of African descent °°Beta-thalassemia in persons of Mediterranean descent °°Beta-thalassemia and alpha-thalassemia (if microcytic anemia is present) in persons of Southeast Asian descent (c) 2015 Wolters Kluwer. All Rights Reserved.

Chapter 1 •  Prenatal Care 

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• Screening for Tay-Sachs disease, familial dysautonomia, cystic fibrosis, and Canavan disease should be offered to persons of Ashkenazi Jewish (European Jewish) background. • Cystic fibrosis carrier screening should be discussed with all patients and offered to all who are at risk, with highest risk prevalence in Caucasian women. • Herpes cultures for purposes of screening are not recommended. Cultures may be helpful for confirming diagnosis when active lesions are present; however, they have little value in predicting whether the fetus is at risk. • Urine or blood toxicology screening may be indicated for the evaluation of illicit substance use. • Fetal ultrasound as a routine screening test without indications is not currently considered a standard of care in uncomplicated pregnancies. However, most physicians consider an obstetric ultrasound examination to be an essential part of prenatal evaluation and care for all pregnant women. • Aneuploidy screening for trisomy 13, 18, and 21 can be offered in the first trimester at 10 to 14 weeks’ gestation by early aneuploidy screening. This is a combination of ultrasound nuchal translucency and two serum analytes values (pregnancy associated plasma protein-A (PAPP-A) and free or total beta-hCG). Combined early aneuploidy screening with nuchal translucency and serum analytes provides better screening accuracy for selected trisomies compared to later individual screening tests, such as the second trimester quad screen or ultrasound screening alone. • First plus send trimester screening tests • Aneuploidy screening for trisomy 13, 18, and 21 can also be accomplished through tests which utilize a combination of first trimester and second trimester screening results. The tests depend on the desire of the patient after counseling and the need for additional screening to assist with follow-up counseling. These screening options are integrated screening, stepwise sequential screening, and contingent screening. • Mid-trimester screening tests: • Risk assessment for trisomy 13, 18, and 21 and open neural tube defects (NTDs) can be accomplished through the quadruple serum screening tests. These tests use a combination of serum analyte levels to provide an aneuploidy and NTD risk estimate rather than a definitive diagnosis. The quad screen is the preferred over the triple screen because the combination of maternal serum (MS)-alpha-fetoprotein, beta-hCG, estriol, and inhibin A provides greater sensitivity for aneuploidy detection. Blood should be drawn between the 15th and 20th weeks of gestation (16 to 18 weeks is preferred). Abnormal results are further evaluated by ultrasonography and consultation with a maternal–fetal medicine specialist. • At 24 to 28 weeks, a 1-hour glucola screen (blood glucose measurement 1 hour after a 50-g oral glucose load) is obtained to screen for gestational diabetes. °°A 1-hour glucola screen value >140 mg/dL is considered abnormal and requires definitive testing with a 3-hour 100-g oral glucose tolerance test. °°A universal screening approach may be used in which all pregnant women are screened. °°Alternatively, a screening scheme can be used that excludes women who are at low risk for gestational diabetes by meeting all of the following criteria: --Younger than 25 years of age --Not a member of a racial or ethnic group with high prevalence of gestational diabetes --BMI < 25 --No history of abnormal glucose tolerance --No previous history of adverse pregnancy outcomes associated with gestational diabetes --No known diabetes in first-degree relatives °°Women with a particular risk (e.g., previous gestational diabetes or fetal macrosomia, family history of first degree relative with DM, obesity, glycosemia, polycystic ovarian syndrome [PCOS]) should receive a GCT before 20 weeks gestation. (c) 2015 Wolters Kluwer. All Rights Reserved.

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  Part I • Obstetric Care

• Repeat hemoglobin and hematocrit may be obtained at 26 to 30 weeks to determine whether iron supplementation is needed. • At 28 to 30 weeks, an antibody screen is obtained in Rh-negative women, and an Rho(D) immunoglobulin (RhoGAM) is administered. • Repeat third-trimester screening for gonorrhea, Chlamydia, syphilis serology, and HIV is recommended in populations with increased prevelance of sexually transmitted infections. TREATMENT OF COMMON LESIONS AND INFECTIONS THAT MAY BE ENCOUNTERED ON PELVIC EXAMINATION Bartholin Gland Abscess • A painful, erythematous, cystic enlargement on either side of the lateral vaginal introitus may indicate obstruction and infection of the Bartholin gland. • Treatment includes sitz baths, analgesic, and, when fluctuant, incision and drainage. Cyst formation may result from incomplete resolution of an abscess. Marsupialization after the puerperium may be advisable for recurrent problems. Condylomata Acuminata • Venereal warts are hyperkeratotic, flat, or polypoid lesions found in the vulvar or perineal areas, vagina, or cervix and caused by infection with the human papillomavirus (HPV). Certain viral types are associated with the development of dysplasia and epithelial carcinoma. • Pregnancy may stimulate proliferation of these lesions, which may become friable. Cesarean delivery is indicated if the pelvic outlet is obstructed or if vaginal delivery would result in hemorrhage. • Transmission of HPV to the infant is very rare but may result in respiratory papillomatosis. The mode of transmission is unknown (transplacental, perinatal, or postnatal). Cesarean should not be performed to prevent HPV transmission to the infant. • Treatment options in pregnancy are limited. Herpes Simplex Viral Infections • Characteristic lesions are small, painful, superficial, erythematous vesicles that ulcerate. • Treatment is symptomatic. The safety of the antiviral agents acyclovir, famciclovir, and valacyclovir has not been definitively established, but available data do not indicate an increased incidence in congenital anomalies in women treated with acyclovir. • If lesions are present at the time delivery is indicated, cesarean is recommended. • Acyclovir, famciclovir, and valacyclovir are all FDA category B medications and are all approved for treatment of genital HSV in pregnancy. • Women with recurrent genital HSV in pregnancy should be given suppressive therapy with acyclovir from 36 weeks of gestation until delivery to decrease the risk of acute lesions that will necessitate cesarean delivery. Monilial Vulvovaginitis • Monilial (also known as Candida or yeast) infection with the characteristic curdy, white, itchy discharge is common. Hyphal structures are seen on wet mount. • This infection can be treated safely during pregnancy with nystatin or miconazole nitrate creams or suppositories or fluconazole in the usual dose regimens. Trichomonas vaginalis Infection • Vulvar or vaginal burning or itching with an abnormal discharge is a frequent finding with this infection. Confirmation of the diagnosis is by visualization of the organisms on wet mount. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Metronidazole (Flagyl) is the treatment of choice. Clotrimazole suppositories (one nightly for 1 week) have been used, with an improvement in symptoms but only a 70% cure rate. The sexual partner should be referred for treatment or treated depending on the law in the state where one practices medicine. Bacterial Vaginosis • Bacterial vaginosis (BV) produces an abnormal discharge that may cause puritis. Characteristic clue cells are noted on wet mount, with amine discharge on potassium hydroxide preparation. • Metronidizole or clindamycin may be used for treatment. Treatment of the sexual partner has not been found to be useful in routine cases. • Some studies have suggested an association between BV and preterm labor or P PROM risk in women with a prior history of preterm birth. Treatment has not been shown to reduce the risk, and therefore routine screening for BV in pregnancy is not recommended. Neisseria gonorrhoeae Infection • Symptoms may include dysuria, burning, or vaginal discharge. Many patients are asymptomatic. Gram stain of endocervical specimens is not sufficient to detect infection and is not recommended. • Usual treatment regimens may be administered; however, tetracycline is contraindicated in pregnancy. The sexual partner should be treated or referred for treatment. • It is recommended that women with gonorrheal infection be treated for Chlamydia (see below). Routine cotreatment may also decrease the development of antimicrobial resistant N. gonorrhoeae. Chlamydia trachomatis Infection • Symptoms of the infection from this obligatory intracellular parasite include vaginal discharge. Diagnosis can be made through urine, vaginal, or endocervical specimens. • The infection can be transmitted to the newborn in the form of conjunctivitis or pneumonia. • The recommended treatment regimen is azithromycin 1 g orally. • The sexual partner should be treated or referred for treatment, and a test-of-cure 3 to 4 weeks after therapy should be obtained. COMPLICATIONS Risk Assessment Risk assessment is an important components of prenatal care. It is a continuous evaluation that must take into account aspects of the patient’s medical and social complications. Designation of a pregnancy as low risk or high risk creates specific expectations and requirements for prenatal management. • Low risk implies expectation of a term delivery without maternal or infant morbidity or mortality. • High risk implies a need for increased surveillance, special care, and appropriate referrals. Categories of increased risk that should be identified and given appropriate attention include • Preexisting medical illness • Previous pregnancy complications, such as stillbirth, neonatal or infant mortality, preterm birth, fetal growth restriction, congenital malformations, placental abruption, and maternal hemorrhage • Prepregnancy BMI less than 18.5 or greater than 40 • Onset of complicating events that may transition a low-risk pregnancy to a high-risk pregnancy (c) 2015 Wolters Kluwer. All Rights Reserved.

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  Part I • Obstetric Care

Genetics Referral • Congenital anomalies and genetic abnormalities are major causes of infant morbidity and mortality. • Indications for genetic referral include • Maternal age 35 years or older at the time of the EDD • Family history of congenital anomalies or heritable medical disorders • Developmental delay or mental retardation of a previous child • Ethnic background associated with increased risk of specific heritable diseases • Exposure to teratogens • Three or more prior spontaneous abortions SUBSEQUENT PRENATAL CARE Regular prenatal visits allow ongoing evaluation and assurance that the pregnancy is progressing normally. • For low-risk pregnancies, the recommended frequency of prenatal visits is monthly up to 32 weeks, every 2 weeks up to 36 weeks, and then weekly until delivery. • Standard assessment at each prenatal visit includes maternal weight, blood pressure, uterine size, auscultation of fetal heart tones, and evaluation for proteinuria and glucosuria. After 18 to 20 weeks, the patient should be questioned about fetal movements. At 32 weeks and beyond, the presenting fetal part should be documented. • Ongoing patient education appropriate to the gestational age of the fetus is incorporated into these visits. • All prenatal care information should be recorded on a standardized form. GUIDELINES FOR PATIENTS • Nutrition: A balanced approach is necessary because there are many limitations to our understanding of the nutritional needs of pregnancy. • Suggestions include eating foods from each of the major food groups, consuming adequate liquids (especially water), adding fiber, and ensuring adequate calcium intake. • For a woman whose weight is normal before pregnancy (BMI 18.5 to 24.9), normal pregnancy weight gain is 25 to 35 lb based on IOM recommendations. This is usually achieved by eating a well-balanced diet containing 60 to 80 g of protein, 2400 or more calories, low sugars and fats, high fiber, and at least three glasses of milk or other dairy equivalents daily. An underweight woman is at an increased risk for poor fetal growth, and more weight gain is often required. Excessive weight gain and preexisting maternal obesity (BMI ≥ 30) may be associated with increased risk of fetal macrosomia, cesarean delivery, and gestational diabetes and pre eclampsia. • Routine prescription of prenatal vitamins is probably not necessary. Practically all diets that supply adequate caloric intake for appropriate weight gain will also provide enough minerals. There are two exceptions: °°Folic acid supplementation preconceptually and throughout the first twelve weeks of pregnancy has been shown to decrease the incidence of fetal NTDs. °°Iron supplementation is recommended after 14 weeks’ gestation because increased iron requirements in the latter part of pregnancy may be difficult to meet via a normal diet. • Working during pregnancy: Most women can safely work until term without complications. • Pregnant women may work full time. Activity limitations have not been shown to decrease risk of spontaneous preterm birth in women at high risk and are not routinely recommended for prevention of preterm birth in asymptomatic patients. • Exercise: Women may exercise if they have no complicating factors. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Exercise recommendations should be tailored according to the level of physical activity of the patient before she became pregnant and according to her level of physical fitness. A trained athlete can continue rigorous training during pregnancy but should avoid raising her core temperature or becoming dehydrated. • Smoking should be discontinued during pregnancy. • It is important to counsel patients about antenatal smoking risks and cessation recommendations and to record their compliance. • The potentially harmful effects of cigarette smoking during pregnancy include 1. Intrauterine growth restriction 2. Placenta previa 3. Abruptio placentae 4. Low birth weight 5. Preterm premature rupture of membranes 6. Ectopic pregnancy • An evidence-based team approach to tobacco cessation in pregnancy allows a higher rate of cessation. This approach includes the use of motivational interviewing, the Five A’s, support groups, the use of a quit line and individual counseling with a health educator. • Tobacco cessation before fifteen weeks gestation yields the greatest benefit for the woman and fetus, however quitting at any gestation can be beneficial. • Alcohol use should be discontinued in pregnancy, including social and binge drinking. • There may be a linear relationship between alcohol consumption and fetal damage, which would explain why even limited fetal exposure to alcohol through social or binge drinking can be damaging. • Fetal alcohol syndrome (FAS) is the result of chronic fetal alcohol exposure. °°With alcohol use throughout pregnancy, the risk of FAS is 20% to 40%. °°Variants of FAS may also result from binge drinking or persistent social drinking. °°FAS occurs as a characteristic pattern of physical abnormalities that includes fetal growth restriction and mental retardation. As such, it is an important cause of poor fetal growth and abnormal development. °°FAS includes --Cardiac malformations --Central nervous system anomalies such as microcephaly and NTDs --Micrognathia, cleft lip/cleft palate, and other facial abnormalities --Skeletal and truncal abnormalities including diaphragmatic hernia --Genitourinary malformations • Seat belt use is the same as for the nonpregnant automobile passengers: The lap belt is worn low and snugly across the hip bones; the shoulder harness is worn over one shoulder and under the opposite arm, loosely enough to place a clenched fist between the sternum and the belt. • Sexual intercourse: There are no restrictions for the patient without complications. • Fetal movement is generally discernible by the mother at 18 to 20 weeks’ gestation. • Fetal activity is cyclic in nature and will normally vary in frequency and intensity throughout the day. • Decreased fetal movement is best evaluated by a nonstress test or biophysical profile. • Warning signs of preterm labor • Studies have suggested that patient education regarding the warning signs for preterm labor leads to improved rates of early diagnosis of preterm labor. Self-identification allows these patients to seek the attention of the health care staff earlier in their preterm delivery course. • The following symptoms should prompt the patient to seek medical recommendations for evaluation: 1. Contractions every 10 minutes for one hour 2. Vaginal bleeding 3. Rupture of membranes (c) 2015 Wolters Kluwer. All Rights Reserved.

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  Part I • Obstetric Care

• Somatic problems are a result of a normal pregnancy. After investigating to rule out a serious pathologic condition, treatment may be directed to symptomatic relief. • Headache and backache. Acetaminophen (Tylenol), 325 to 650 mg every 3 to 4 hours, is usually sufficient. • Nausea and vomiting: °°Nausea and vomitting may be relieved by eating frequent, and small meals. °°Severe, persistent symptoms may require hospitalization and intravenous fluids. The antiemetics, promethazine (Phenergan), diphenhydramine (Benadryl), and several other antihistamines (2) are considered safe for use in pregnancy and have no known association with birth defects. °°The first line therapy for nausea and vomitting during pregnancy is pyridoxine. • Constipation: °°A high-fiber diet, increased fluid intake, and regular exercise are recommended. Stool softeners such as docusate sodium (Colace) or psyllium hydrophilic mucilloid (Metamucil) may help. °°Mild laxatives should be used sparingly and only if the prior measures fail. • Varicosities: Support stockings and leg elevation are recommended. • Other important information for patients to know: °°When and where to call if they have questions or problems °°Availability of childbirth classes °°Signs of the onset of labor °°Obstetric analgesic options °°Indications for cesarean delivery °°Home safety °°Infant care and feeding, including breast-feeding °°Access to consumer education (e.g., infant safety products, furniture, car seats) °°Birth control counseling PATIENT EDUCATION • Effective prenatal care requires patient-centered, targeted patient education. • One of the primary goals of prenatal care is to address the social determinants of health. • Each woman’s personal socioeconomic situation and support system must be explored and taken into account as part of her prenatal plan of care. • Empowering women through education allows them to participate in decision making regarding the course of the pregnancy and labor. REFERENCES 1. American College of Obstetricians and Gynecologists. ACOG committee opinion number 558. Integrating immunizations into practice: tetanus, diphtheria, and pertussis vaccination. Obstet Gynecol. 2013;121:897–903. 2. Rasmussen KM, Abrams B, Bodnar LM, et al. Recommendations for weight gain during pregnancy in the context of the obesity epidemic. Obstet Gynecol. 2010;116(5): 1191–1195. 3. DeFranco EA, Stamilo DM, Boslaugh SE, et al. A short interpregnancy interval is a risk factor for preterm birth and its recurrance. Am J Obstet Gynecol 2007;197: 264.e1–264.e6. 4. Hauck FR, Thompson JMD, Tanabe KO, et al. Breastfeeding and reduced risk of sudden infant death syndrome: a meta-analysis. Pediatrics. 2011;128(1):103–110. 5. DeFranco EA, Lian M, Muglia LA, et al. Area-level poverty and preterm birth risk: a population-based multilevel analysis. BMC Public Health. 2008;8:316. 6. Mangesi L, Hofmeyr GJ. Fetal movement counting for assessment of wellbeing (Review). Cochrane Library. 2008;(3). (c) 2015 Wolters Kluwer. All Rights Reserved.

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7. Task Force on Sudden Infant Death Syndrome. SIDS and other sleep-related deaths: expansion of recommendations for a safe infant sleeping environment. Pediatrics. 2011; 128;1030. 8. American Academy of Pediatrics, American College of Obstetricians and Gynecologists. Guidelines for perinatal care. Elk Grove Village, IL: American Academy of Pediatrics; 2002. 9. Behrman RE. Preterm birth: causes, consequences, and prevention. Washington, DC: National Academies Press, 2007. 10. Cunningham FG, Williams JW. Williams obstetrics. New York: McGraw-Hill, 2007. 11. Creasy RK, Gummer BA, Liggins GC. System for predicting spontaneous preterm birth. Obstet Gynecol. 1980;55:692–695. 12. Briggs GG, Freeman RK, et al. Drugs in pregnancy and lactation. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2005.

(c) 2015 Wolters Kluwer. All Rights Reserved.

2

Normal Labor

Jodi Regan and Catherine Van Hook

KEY POINTS • Labor and delivery are normal physiologic processes. • Careful evaluation of both the mother and fetus upon presentation to the labor and delivery suite is important due to the possibility of acute changes in status. • Attention to the principles of normal labor and maternal–fetal physiology is imperative to avoid unnecessary interventions. • Continuous electronic fetal monitoring has not been shown to be beneficial in any prospective, randomized controlled study. Nonetheless, its utilization is customary in many labor and delivery suites (1). • Maternal request is sufficient justification for providing pain relief during labor. • Routine use of episiotomies is not recommended as it has not been shown to improve outcomes. Restricted use is preferable (2,3). BACKGROUND Definition • Labor is the process by which contractions of the gravid uterus expel the fetus. • A term pregnancy delivers between 37 and 42 weeks from the last menstrual period (LMP). • Preterm delivery is birth that occurs before 37 completed weeks of gestational age. • Postterm pregnancy occurs after 42 weeks of gestation and requires careful monitoring secondary to increased perinatal morbidity and mortality (4). • Termination of pregnancy before 20 weeks of gestation is defined as either spontaneous or elective abortion. EVALUATION OF THE LABORING PATIENT • Evaluation of the patient presenting with symptoms of labor includes • History • Physical examination • Selected laboratory tests • Fetal assessment • A clinical impression and management plan are formulated from the information obtained. History

History of the Present Labor

• Contractions: • The onset, frequency, duration, and intensity of uterine contractions should be determined. • Contractions that effect progressive cervical effacement and dilation are usually regular and intense (the patient may no longer be able to walk or talk during these contractions). They may be accompanied by a “bloody show,” the passage of blood-tinged mucus from the effacing cervix. • Braxton-Hicks contractions are commonly experienced by many women during the last weeks of pregnancy. These are usually irregular, mild, not well organized, and do not result in cervical change. • Factors that differentiate true labor from false or prodromal labor are listed in Table 2-1. 12

(c) 2015 Wolters Kluwer. All Rights Reserved.

Chapter 2 • Normal Labor 

Table 2-1

  13

Differentiating True Labor and False Labor

Factors Contractions Interval between contractions Intensity of contractions Location of pain Effect of analgesia Cervical change

True labor Regular intervals Gradually shortens

False labor Irregular intervals Remains long

Gradually increases In back and abdomen

Remains same Mostly in lower abdomen Not terminated by sedation Frequently abolished by sedation Progressive effacement and No change dilation

• Rupture of membranes: • The status of the fetal membranes must be determined if it is not reported as part of the initial presentation. • The patient may present with leaking fluid alone or in conjunction with uterine contractions. The time of occurrence is important, because prolonged membrane rupture increases the risk of chorioamnionitis (5). Color of the amniotic fluid may suggest the presence of meconium or blood. • The patient may report a large gush of fluid with continued leakage, which would lead to a high suspicion for ruptured membranes. • The patient may report merely increased moisture on her underclothes, which leads to uncertainty about whether this moisture represents urine, vaginal secretions, cervical mucus, or amniotic fluid. • Confirmation of rupture of membranes (ROM) may include physical examination, laboratory testing (nitrazine or fern test), ultrasonography, and/or other laboratory screening tests such as AmniSure (6). Vaginal Bleeding

• The extent, if any, of vaginal bleeding should be ascertained. • Spotting or blood-tinged mucus is common in normal labor. • Heavy vaginal bleeding merits complete investigation because it may be abnormal and reflect a significant complication (see Chapter 32). Fetal Movement

• The initial assessment of the patient reporting symptoms of labor should include questions about the level of her fetus’s movement. Most patients are aware of their fetus’s baseline level of activity. • If the patient reports a significant or progressive decrease in fetal movement from her normal baseline, fetal well-being must be ascertained. • Such evaluations can involve fetal monitoring with a nonstress test (NST), a contraction stress test (CST), or biophysical profile (BPP) (see Chapter 32). • Fetal movement-counting protocols (aka “kick counts”) are commonly used in the third trimester as a screen for fetal well-being (7). History of Current Pregnancy

• The history of the present pregnancy should be obtained by interviewing the patient in labor and by reviewing the prenatal record (8). • The prenatal record may be from one’s own institution or from an outside source. The patient, of course, may have had no prenatal care or have no record of it. • If a prenatal record is available, important items should be verified with the patient. (c) 2015 Wolters Kluwer. All Rights Reserved.

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  Part I • Obstetric Care

Gestational Age

• Gestational age is best determined from data in the prenatal record including ultrasound data. • The later the patient presents for initial prenatal care, the more difficult it becomes to accurately determine the estimated gestational age (EGA). • Patients presenting for initial prenatal care at ≥24 weeks of gestation are considered to have inherently unreliable dates. • Important landmarks for determining gestational age include • The 1st day of the LMP—the estimated date of confinement (EDC) is calculated as 40 weeks or 280 days from this date, based on regular 28-day cycles • The date of last ovulation (as determined by an ovulation prediction kit or basal body temperature chart), or the date of conception (if known precisely), with the EDC calculated as 38 weeks from this date • Early ultrasound measurement of crown–rump length at 6 to 12 weeks of gestation (accurate to within 3 days) (9) • The average of multiple biometric measurements on fetal ultrasound between 12 and 20 weeks of gestation (accurate to within 10 days) • Fetal heart tones, first heard with a Doppler instrument at 10 to 12 weeks of gestation or with a fetoscope at 18 to 20 weeks of gestation • Quickening (maternally perceived fetal movement), which first occurs at approximately 18 to 20 weeks of gestation in primigravidas • Uterine size on pelvic examination before 16 weeks of EGA, as determined by an experienced clinician • Accurate dating requires evaluation during the first half of pregnancy. • The patient presenting in labor with an uncertain LMP and no prenatal care may be difficult to date with accuracy. • Uncertain gestational age presents a significant problem because of different management strategies for term, preterm, and postterm pregnancies. In these situations, the only alternative is to use ultrasonography in the labor and delivery suite, realizing that it may, at best, be accurate to within only ±3 weeks of gestation in the last trimester. • Amniocentesis to assess fetal lung maturity can be considered to help guide delivery decisions when gestational age is uncertain. Medical Problems Arising during Gestation

• The patient should be questioned specifically regarding any medical problems arising during the pregnancy. • Hospitalizations should be noted, as well as any new medications prescribed. • A history of genital herpes, bleeding, abnormal placentation, hepatitis B/C, HIV, group B streptococcus (GBS) carrier status, recurrent urinary tract infections and pyelonephritis, or any infectious diseases requiring treatment should be elicited. • A history of glucose intolerance and treatment with diet or insulin should be noted. • If any blood pressure elevation has been recorded during the pregnancy, the time of onset, severity, and treatment should be determined. • Seizure history, noting frequency and medications, is pertinent for obstetric care. • Any drug usage with illicit or prescription drugs should also be discussed. Review of Systems

• An obstetrically oriented review of symptoms should be carried out. • Severe headaches, scotomata, hand and facial edema, or epigastric pain may suggest preeclampsia. • Generalized pruritus may be secondary to intrahepatic cholestasis of pregnancy or hepatitis. • Dysuria, urinary frequency, or flank pain may indicate cystitis or pyelonephritis. (c) 2015 Wolters Kluwer. All Rights Reserved.

Chapter 2 • Normal Labor 

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History of Past Pregnancies

Each past pregnancy and its duration and outcome should be reviewed. • Particular attention should be paid to preterm deliveries, operative deliveries, prolonged or difficult labors, shoulder dystocias (up to 16.7% risk of recurrence) (10,11), malpresentation, hypertensive disorders of pregnancy (4% in the general population with a high recurrence rate) (12), placental abruption (20-fold increased risk of recurrence) (13) or placenta previa (risk increases with age, parity, and prior cesarean deliveries) up to 3% for three or more cesarean deliveries (14), and blood loss requiring transfusion. • Other medical facilities may need to be contacted for records to verify or clarify certain points. Medical History

• All active medical problems should be evaluated and the extent of the disease determined (i.e., epilepsy, hypertension, asthma, diabetes, heart disease, etc.). • The stress of labor can aggravate many medical problems and jeopardize both maternal and fetal well-being and may require appropriate consultations from subspecialists. Psychosocial and Emotional History

• Labor is a stressful physical and psychological event, and understanding the patient’s psychosocial and emotional status and history will help in planning for her care and maintaining her sense of control. • How the patient wishes to be addressed should be determined. • Her preparation and plans for labor and birth should be discussed. • The patient’s labor support person(s) and their preparation should be identified. • Questions about substance and alcohol use or abuse, intimate partner violence, and diagnosis and treatment of psychiatric disorders should be included. This part of the history must be obtained from the patient without any family or support persons present. • Plans for breast-feeding after delivery regardless of mode of delivery should be discussed prior to delivery. Physical Examination • Although active labor is not the optimal setting for a comprehensive physical examination, a focused examination with emphasis on the abdomen and pelvis can be performed between painful contractions. • Any signs of intercurrent medical illness or abnormalities of major organ systems should be elicited and carefully noted. • Special note should be taken of those parts of the physical examination that may generate abnormal findings because of that individual patient’s history. General Examination Vital Signs

• A complete set of vital signs should be taken immediately on admission including a pulse oximeter for oxygen saturation if possible. • Blood pressure should be taken between contractions in the upright or left lateral recumbent position with the patient’s arm at the level of the heart. The appropriate size cuff should be utilized with the cuff length 1.5 times the upper arm circumference or cuff with a bladder enclosing 80% of the arm (15). Abnormal readings should be rechecked. • An elevated body temperature, especially if associated with ruptured membranes, may indicate chorioamnionitis. • An elevated pulse or respiratory rate in the absence of any other abnormality is commonly observed in healthy patients in active labor. Head and Neck

• Funduscopy may be indicated to rule out vascular abnormalities, hemorrhages, or exudates that may suggest such diseases as diabetes or hypertension. • Pale conjunctivae (or nail beds) may suggest anemia. (c) 2015 Wolters Kluwer. All Rights Reserved.

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  Part I • Obstetric Care

• Facial, most notably periorbital, edema can be found—in preeclampsia. • The thyroid gland should be palpated to rule out goiter or other masses and to determine if anesthesia should be involved for any concerns related to airway management. • Distended neck veins suggest congestive heart failure, which, although rare, is a serious complication of labor and should be recognized early so that proper therapy may be initiated. Chest

• Examination of the chest may reveal the presence of a pneumonic process or significant cardiac murmurs (other than the physiologic systolic ejection murmur common in pregnancy) and provides a baseline in case complications such as pulmonary edema develop. • Auscultation of the lungs for rales, crackles, and wheezes is especially important in patients with asthma or hypertension or at risk for pulmonary edema. Abdomen

• An attempt should be made to palpate major abdominal viscera for pain or masses, although this is difficult with a term-sized uterus. • Epigastric tenderness may suggest preeclampsia or HELLP (hemolysis, elevated liver enzyme levels, and a low platelet count) syndrome. Extremities

• Examination of extremities should include an assessment of peripheral edema. • Although mild ankle edema commonly is found near term in normal pregnancies, severe lower extremity or hand edema may suggest preeclampsia. Unilateral edema also may suggest underlying VTE (venous thromboembolism). • A brief neurologic examination should be performed because the presence of deeptendon hyperreflexia and clonus may suggest a lowered threshold for seizure activity. The Gravid Uterus • A general examination includes assessment for the size of the uterus, presence of tenderness, globular masses (i.e., fibroids), estimated fetal weight (EFW), and fetal presentation and lie. • Presence of uterine tenderness may by indicative of chorioamnionitis, uterine rupture, or placenta abruption, all of which require prompt attention. Uterine Size

• After 20 weeks, the size of the uterus is anticipated to correlate with the number of centimeters from the pubis to the top of the fundus in a singleton pregnancy. • Correlation of these findings lessens as the pregnancy approaches term due to variation in fetal size and pelvic engagement. • Significant lack of correlation raises concern for the presence of a fetal growth or amniotic fluid disorder or multiple gestation. Size date discrepancy can also be due to the influence of pelvic engagement. • Ultrasonography is indicated to resolve concerns of size date discrepancy. Leopold Maneuvers

• Leopold maneuvers (Fig. 2-1) are a technique used to palpate the gravid uterus to determine fetal presentation and fetal lie. It can also be used to estimate fetal weight (mentally adjusting for maternal habitus, amniotic fluid, and proportion of fetus engaged in the pelvis). Ultrasound can be used for primary assessment of these clinical factors or as confirmation of the Leopold maneuvers. • The first maneuver determines which fetal pole occupies the uterine fundus (e.g., the breech with a vertex presentation). The breech moves with the fetal body. The vertex is rounder and harder and feels more globular than the breech and can be maneuvered separately from the fetal body. (c) 2015 Wolters Kluwer. All Rights Reserved.

Chapter 2 • Normal Labor 

  17

First maneuver

Second maneuver

Third maneuver

Fourth maneuver

Figure 2-1. Leopold maneuvers to diagnose fetal presentation and position of the fetus. (Gibbs RS, Karlan BY, Haney AF, et al. Danforth’s obstetrics and gynecology. 10th ed. Lippincott Williams & Wilkins, 2008:22–41, Figure 6.)

• With the second maneuver, the lateral aspects of the uterus are palpated to determine on which side the fetal back or fetal extremities, or “small parts,” are located. The back is firm and smooth. • The third maneuver is performed with the examiner facing caudally, and the presenting part is made to move from side to side. If this is not done easily, engagement of the presenting part probably has occurred. • The fourth maneuver reveals the presentation. With the fetus presenting by vertex, the cephalic prominence may be palpable on the side of the fetal small parts, confirming flexion of the fetal head (occiput presentation). Extension of the head (face presentation) is suspected when the cephalic prominence is on the side of the fetus opposite the small parts. Fetal Lie

• The lie of the fetus is a description of the relationship of the long axis of the fetus to the long axis of the mother. The lie is longitudinal with a vertex or breech presentation or otherwise transverse or oblique, as with a shoulder presentation. (c) 2015 Wolters Kluwer. All Rights Reserved.

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  Part I • Obstetric Care

Presentation

• Designates the part of the fetus lowest in the pelvis. • Cephalic denotes the fetal head presenting to the pelvis. • Vertex, presentation of the occipital fontanelle due to flexion of the fetal head to the fetal chest is the most common. • Deflexion of the fetal head leads to sinciput (presentation of anterior fontanelle), brow (bregma), or face presentations. • Breech presentations are classified by presentation of the buttocks with or without the feet. • Frank breech presentation: Both hips are flexed with the knees extended. • Complete breech: Both hips are flexed with one or both knees flexed. • Incomplete breech: One or both hips deflexed with one or both feet or knees below the buttocks. • Footling breech is an incomplete breech with one or both feet located below the buttocks. • Shoulder presentation is found with transverse lie. • Compound presentation is presentation of an extremity with the presenting part. Estimated Fetal Weight

• EFW can be assessed with palpation of the gravid uterus and mentally adjusting for maternal habitus, amniotic fluid, and proportion of fetus engaged in the pelvis. • Discrepancy between the gestational age and anticipated fundal height suggests growth or fluid volume abnormality or multiple gestation. Ultrasound examination will be necessary for resolution. • EFW calculated by ultrasound has a margin of error of up to 20% (9,16). Fetal Heart Tones

• Documentation of the fetal heart tones must be performed on admission. • Continuous electronic fetal heart rate monitoring (CEFM) is performed as an initial evaluation at many institutions. The baseline heart rate, variability, accelerations, and decelerations are carefully assessed, and categorization of the tracing is performed accordingly (1,17,18) (see Chapter 22). • If a reassuring tracing is obtained, the patient may continue to be managed with CEFM or may be a candidate for intermittent fetal heart rate monitoring by auscultation. Pelvic Examination • Inspection and palpation of the perineum and the pelvis are critically important in evaluating the laboring patient. • Information needed includes • Presence or absence of perineal, vaginal, and cervical abnormalities (including herpes or human papillomavirus infections) • Adequacy of the bony pelvis • Integrity of the fetal membranes • Degree of cervical dilation and effacement • Station of the presenting part • The presence of third-trimester vaginal bleeding or preterm premature rupture of the membranes will preclude digital examination of the cervix until further evaluation is performed, which may include bedside ultrasound. Inspection

• The perineum should be inspected for herpetic or syphilitic lesions, large vulvar varicosities, large condylomas, or other altered vulvar anatomy, that is, female genital mutilation. • If there is any question of active genital herpes, a speculum examination of the vagina or cervix is necessary.

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Chapter 2 • Normal Labor 

  19

• Diagnosis of ruptured membranes may sometimes be visually confirmed by inspection, but it is often necessary to perform a sterile speculum examination to determine the status of the fetal membranes. • Using sterile technique, a sterile speculum is inserted into the vagina, and a light source is positioned so the cervix and posterior vagina can be visualized. • Gross pooling of amniotic fluid in the posterior fornix is consistent with the diagnosis of ROM. It is important to note the color and consistency of the fluid, the presence of purulence, blood, or meconium. • Direct transcervical visualization of fetal scalp, feet, umbilical cord, or other fetal parts confirms ruptured membranes definitively. • If uncertain about ROM, any fluid pooled in the posterior vaginal fornix is sampled with a sterile cotton swab, smeared on a glass slide, and viewed with the aid of a microscope. Other laboratory methods for the evaluation of ROM are available, that is, AmniSure (6). °°Ferning of the air-dried fluid under the microscope suggests amniotic fluid (Fig.2-2). °°Ultrasound may be used to evaluate amniotic fluid volume if the status of the membranes is still uncertain after physical and laboratory testing. • If bloody amniotic fluid is noted (port-wine fluid), further investigation to rule out abruptio placentae should be undertaken. • The absence or presence of meconium (fetal stool) in the amniotic fluid should be noted. °°The incidence of meconium-stained amniotic fluid increases with advancing gestational age. • Cultures are obtained when preterm labor or chorioamnionitis is suspected. • With preterm ROM at 32 to 34 weeks, a sample of amniotic fluid from the vaginal pool can be obtained to evaluate fetal lung maturity to assist with management decisions regarding expectant management (19). Palpation of the Cervix

• Palpation of the cervix should be done when the patient is between contractions to ensure accuracy and to minimize the patient’s discomfort. • Dilation of the cervix describes the degree of opening of the internal cervical os. The cervix can be described as undilated or closed (0 cm), fully dilated (10 cm), or any point between these two extremes (0 to 10 cm). • Effacement of the cervix describes the process of thinning that the cervix undergoes before or during labor (Fig. 2-3). • The thick prelabor cervix is approximately 3 cm long and is said to be uneffaced or to have 0% effacement. With complete or 100% effacement, the cervix is paper thin. • As a general rule, primiparous women begin to efface the cervix before dilation begins, whereas multiparous women begin to dilate before significant effacement has been reached. Palpation of the Fetal Presenting Part

• Identification of fetal presentation should be confirmed by digitally palpating the fetal presenting part. The novice often assumes it to be a vertex, but identification must be positively made on every occasion. • Vertex presentation can be confirmed by palpating the suture lines of the fetal skull. If the suture lines cannot be identified with certainty, other presentations must be considered. • Palpation of the fetal buttocks, feet, face, or arms is confirmatory.

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  Part I • Obstetric Care

Figure 2-2. “Ferning” in smear from the vagina suggests that amniotic fluid is present in the vagina.

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Chapter 2 • Normal Labor 

Before labor 0% effacement

Complete effacement 100%

  21

Early effacement 30%

Complete dilation

Figure 2-3. Cervical effacement and dilation in the primigravida. (LifeART image copyright (c) 2013 Lippincott Williams & Wilkins. All rights reserved.)

• Inability to positively identify the presenting part is an indication for expeditious ultrasound examination. • Station refers to the relationship between the fetal presenting part and pelvic landmarks. • When the presenting part is at zero station, it is at the level of the ischial spines, which are the landmarks for the midpelvis. This is important in the vertex presentation because it implies that the largest dimension of the fetal head, the biparietal diameter, has passed through the smallest dimension of the pelvis, the pelvic inlet. • In 1988, the American College of Obstetricians and Gynecologists introduced a classification dividing the pelvis into 5-cm segments above and below the ischial spines: °°If the presenting part is 1 cm above the spines, it is described as −1 station. °°If it is 2 cm below the spines, the station is +2. °°At −5 station, the presenting part is described as floating. °°At +5 station, the presenting part is on the perineum, and it may distend the vulva with a contraction and be visible to an observer. °°In practice, this system has not been widely adopted, and many physicians still describe station on the basis of dividing the maternal pelvis below the spines into thirds. An approximation would be, for example, +4 cm = +2/3. • Position of the presenting part is described as the relationship between a certain landmark on the fetal presenting part and the maternal pelvis (Fig. 2-4), as follows: °°Anterior, closest to the symphysis pubis °°Posterior, closest to the coccyx °°Transverse, closest to the left or right vaginal sidewall (c) 2015 Wolters Kluwer. All Rights Reserved.

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  Part I • Obstetric Care OP

ROP

LOP

LOT

Posterior fontanel Lamboid Biparietal 9.5 cm suture Sagittal suture

Coronal suture

ROT

Anterior fontanel

LOA

ROA OA

Figure 2-4. Vaginal palpation of the large and small fontanelles and the frontal, sagittal, and lambdoidal sutures determines the position of the vertex. Various vertex presentations. LOP, left occiput posterior; LOT, left occiput transverse; LOA, left occiput anterior; ROP, right occiput posterior; ROT, right occiput transverse; ROA, right occiput anterior. (Beckmann CRB, Frank W, et al. Obstetrics and gynecology. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2006.)

°°The index landmark in a vertex presentation is the occiput, which is identified by

palpating the lambdoid sutures forming a Y with the sagittal suture; it is the sacrum in a breech presentation and the mentum (or chin) in a face presentation. °°The designations of anterior, posterior, left, and right refer to the maternal pelvis. Therefore, right occiput transverse implies that the occiput is directed toward the right side of the maternal pelvis. • Breech and face presentations are described in a similar fashion (e.g., right sacrum transverse, right mentum transverse). Evaluation of Pelvic Adequacy • The shape of the maternal pelvis may be visualized as a cylinder with a gentle anterior curve toward the outlet. The curve forms because the posterior border of the pelvis (the sacrum and the coccyx) is longer than the anterior border (the symphysis pubis). The lateral borders (the innominate bones) are more or less parallel in the normal female pelvis. • Dystocia may be encountered when abnormalities of the pelvis are present. Pelvic adequacy can be judged clinically by measuring pelvic diameters at certain levels. • Even when conducted by the most experienced clinicians, clinical pelvic measurements are merely estimations. • Unless the maternal pelvis is grossly contracted, adequacy is proven only by a trial of labor. • Despite this, the pelvis must be evaluated at admission for an estimate of adequacy or documentation of abnormalities. • The maternal pelvis is one of three factors that determine the success of labor. These factors have been referred to as the three P’s: Pelvis, Power, and the Passenger. A macrosomic fetus or inadequate uterine contractions, even with an adequate pelvis, may preclude vaginal delivery. (c) 2015 Wolters Kluwer. All Rights Reserved.

Chapter 2 • Normal Labor 

  23

Inlet

• The inlet of the true pelvis is limited by the symphysis pubis anteriorly, the sacral promontory posteriorly, and the iliopectineal line laterally. • The anteroposterior (AP) diameter of the inlet may be estimated by determining the diagonal conjugate measurement. The diameter (the distance from the sacral promontory to the inner inferior surface of the symphysis pubis) is measured clinically by attempting to touch the sacral promontory with the vaginal examining finger while simultaneously noting where the inferior border of the symphysis touches the examining finger. A measurement greater than 12 cm suggests adequacy. Midpelvis

• The midpelvis is bordered anteriorly by the symphysis pubis, posteriorly by the sacrum, and laterally by the ischial spines. A gently curved concave sacrum increases the adequacy of the midpelvis. • The interspinous diameter is estimated by palpating the ischial spines. An estimated distance less than 9 cm suggests midpelvis contraction. Experience is required to estimate this diameter with accuracy. Outlet

• The outlet is limited anteriorly by the arch of the symphysis pubis, posteriorly by the tip of the coccyx, and laterally by the ischial tuberosities. • This transverse diameter of the outlet can be estimated by placing a clenched fist between the two ischial tuberosities. A measurement of 8 cm or more suggests an adequate diameter. • The AP measurement is estimated by judging the prominence of the tip of the sacrum and by noting the angle made by the pubic rami. A narrow pelvic arch decreases the effective AP diameter. • Dystocia as a result of an abnormal outlet alone is unusual, although with midpelvic inadequacy, the outlet is also usually inadequate. Laboratory Tests All prenatal laboratory tests should be reviewed when the patient is admitted for labor. If the patient has not had any prenatal care, or if the care has been incomplete, prenatal laboratory tests should be drawn at the time of hospital admission. Results of the patient’s routine prenatal labs should be available at the time of presentation of labor (for list of these, see Chapter 1 Prenatal Care). If the set of routine prenatal lab results is not available, these tests should be redrawn at the time of evaluation. • Additional laboratory evaluations, such as testing for sexually transmitted infections (STIs), may be indicated in high-risk populations. Gonorrhea, chlamydia, hepatitis B surface antigen, syphilis, and HIV are among the most routinely assessed STIs in pregnancy. • If the patient is diabetic or of unknown status, fingerstick blood glucose testing is appropriate upon evaluation in labor. • Patients with a history of glucose intolerance or diabetes should have serial blood glucose determinations. Often, this can be done with a glucometer in the labor and delivery suite. • If preeclampsia is a possibility, a complete blood cell count including platelets and an expanded hepatic function panel should be ordered. • Fibrinogen and clotting parameters should be measured if the diagnosis of abruptio placentae is being considered. • If a patient has a history of postpartum hemorrhage, preexisting anemia, grand multiparity, or high likelihood for cesarean, a type and screen can be obtained to facilitate rapid crossmatching of blood. • Cervical cultures and perianal cultures for GBS should be obtained for patients who may be preterm or who have symptoms of chorioamnionitis (20,21). • Other specific laboratory tests should be ordered as required for specific physical findings, diseases, or complications. (c) 2015 Wolters Kluwer. All Rights Reserved.

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  Part I • Obstetric Care

Formulation of Impression and Plan • With the pertinent information from the history, examination, and laboratory testing, a clinical impression is formulated. • The process of deciding which patients require invasive procedures, such as placement of internal fetal monitors or intensive care–level monitoring of maternal vital functions begins with the initial clinical impression. The practitioner must be cognizant of and show respect for the patient’s desires regarding her birthing process, while not compromising the level of care given to the mother and fetus. • The high-risk patient presenting in labor needs detailed counseling regarding the nature of her problems, the rationale for tests and procedures, and any options that are available for her medical management. Any needed specialists should then be involved in the care according to the plan for the medical management. Anesthesia should be appropriately notified of the admission as indicated. MANAGEMENT OF NORMAL LABOR • Pregnancy is not a disease, and labor is the normal physiologic consequence of the completion of pregnancy. Nonetheless, complications can occur, such as nonreassuring fetal status, intrapartum fetal death, dysfunctional labor, uterine rupture, chorioamnionitis, maternal and fetal hemorrhage, and even maternal death. • Management of labor should achieve delivery in a reasonable period of time while providing maternal and fetal support and avoiding any significant compromise to the mother or fetus. Distinguishing Normal from Abnormal Progress in Labor Stages of Labor

• The first stage of labor encompasses the interval of time from the onset of labor until the cervix has become fully dilated (10 cm). This stage is further subdivided into a latent and an active phase. • The latent phase is characterized by slow dilation of the cervix to a point at which the rate of change in cervical dilation begins to increase (active phase of labor). Historically, the latent phase has ended with achievement of 4 cm dilation. Newer evidence supports 6 cm as the onset of the active phase of labor (22,23). • The active phase is characterized by more rapid dilation until 10 cm is achieved. • The second stage of labor begins with complete dilation of the cervix and ends with delivery of the infant. • The third stage of labor denotes the interval from delivery of the infant to delivery of the placenta (afterbirth). Assessment of Progress in Labor • Assessment requires periodic digital examination of the cervix to assess changes in effacement, cervical dilation, and descent of the presenting part. Vaginal examinations should be timed often enough to determine the progress of labor, while still being limited for the sake of patient comfort and to minimize the risk of infection. • Assessment of the strength of the uterine contractions can be done manually, with tocometry or with an internal uterine pressure catheter (IUPC). • Manual assessment relies on experienced labor and delivery staffing. • Tocometry or external monitoring is limited to onset and completion of the contractions and is suboptimal for measurement of strength of contractions in the presence of labor that is not progressing. • IUPC provides direct assessment of onset, completion as well as strength of the contractions. Montevideo units (MVUs) are an objective assessment of uterine contraction strength. During a 10-minute window, the MVU difference between the baseline uterine (c) 2015 Wolters Kluwer. All Rights Reserved.

Chapter 2 • Normal Labor 

  25

tone and the peak of each contraction is added together. Greater than 200 MVUs is considered an adequate contraction pattern (24). • The modern spontaneous labor curve differs from the classic Friedman curve (22), which has been used for decades previously. For nulliparous and multiparous patients, acceleration of cervical dilation occurs with active labor at 6 cm dilation (as opposed to 4 cm previously described in the Friedman curve). Once active labor is entered, the multiparous acceleration is more rapid than that of the nulliparous patient. • Defining the duration of the latent phase of labor is difficult due to its onset prior to arrival to the labor unit. • The number of hours from admission to 6 cm varies by the cervical dilation upon presentation (22). • For a nulliparous patient admitted at 2 cm dilation, the median number of hours to reach 6 cm is 6 hours (with 95% percentile at 15.7 hours). Admission at 3 cm corresponded to reaching 6 cm of dilation by a median of 4.2 hours (95% at 12.5 hours) (22). • Diagnosis of an arrest disorder in the first stage of labor (24): • The patient is 6 cm or more dilated with ROM without cervical change, and • Has had an adequate contraction pattern (greater than 200 montevideo units) for 4 or more hours or • Has had an inadequate contraction pattern for 6 or more hours • The patient may persist in latent labor, making a diagnosis of an arrest of labor prior to 6 cm of dilation difficult and could require extended time, if maternal and fetal status permit (24). • The average second stage of labor is influenced by parity and presence of regional anesthesia. • Absent specific maternal or fetal indications, second-stage arrest is defined as ≥3 hours in a nulliparous woman without an epidural and for ≥4 hours with an epidural. In a multiparous woman, the intervals to define a second-stage arrest disorder are ≥2 hours and ≥3 hours, respectively (22). • Some authorities believe that the second stage should be divided into two phases and that expulsive efforts should not be encouraged until the head has descended well into the pelvis and the patient feels the urge to push (if the feeling is not obliterated by epidural anesthesia). This is often described as allowing the patient to “labor down.” In practice, this theory has shown few clinical differences, especially in high-quality studies (25) (see Chapter 10 regarding management of abnormal labor). Amniotomy Amniotomy, or artificial rupture of the membranes (AROM), is usually accomplished by puncturing the amniotic membranes with a sterile plastic instrument that is guided between two gloved fingers. • Indications for amniotomy may include • Visualizing the amniotic fluid for quantity and evidence of meconium or blood • Gaining direct access to the fetus for placement of internal fetal monitors • Attempting to induce labor or restore (augment) progress in labor • Impending second stage of labor where the provider wants to minimize the risk of exposure to body fluids during the birth • Special considerations for avoidance of amniotomy include • Infection with HIV, hepatitis B or C (8) • Polyhydramnios—initial confirmation of engagement of the fetal head is essential • Preterm gestation without medical indication for delivery • Concern for placenta previa or vasa previa • Noncephalic presentations (i.e., breech, compound). Unstable fetal lie or unengaged fetal vertex (c) 2015 Wolters Kluwer. All Rights Reserved.

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  Part I • Obstetric Care

• Amniotomy is the only definitive way to visualize the amniotic fluid and to gain direct access to the fetal scalp. • The effect of amniotomy on the duration of labor is controversial: • Most studies suggest that amniotomy performed in the active phase of labor significantly shortens labor (4,26,27,28–29). At the National Maternity Hospital in Dublin, amniotomy is performed by protocol once the diagnosis of active labor has been confirmed. • Amniotomy performed during the latent phase of labor in nulliparous women undergoing labor induction has been shown to shorten the duration of time to delivery without increase in adverse maternal or neonatal complications (30). • Risks of amniotomy include possible complications: • Rupture of a fetal vessel traversing the fetal membranes (vasa previa) at the site of amniotomy is rare but can cause fetal exsanguination and death. • Prolapse of the umbilical cord between the presenting part and the cervix or below the presenting part can occur at time of amniotomy and cause severe fetal compromise unless operative delivery is performed rapidly. • The risk of cord prolapse can be minimized by avoiding amniotomy until the fetal head is engaged in the pelvis and is exerting significant pressure against the cervix. Cord prolapse can also occur with spontaneous ROM. • Several studies have suggested that one of the side effects from amniotomy is an increased incidence of variable fetal heart rate decelerations in the active phase of labor (29). However, there were no differences in nonreassuring fetal heart rate patterns nor operative deliveries (29,31,32). • In summary, the various applications for amniotomy have rendered it integral to the practice of modern obstetrics, and it is used frequently at most institutions. • There is little disagreement that amniotomy is indicated as part of induction of labor and as an intervention for protraction and arrest of labor disorders. • The procedure has risks, and these must be weighed against the expected benefits each time artificial ROM is contemplated. • It should be understood that, when amniotomy is performed to hasten labor, no randomized controlled study has proven that an accelerated labor provides better fetal or maternal outcomes than a natural labor without interventions. Mechanisms of Labor in the Vertex Presentation • The process of labor and delivery is marked by characteristic changes in fetal position or cardinal movements in relation to the maternal pelvis. These spontaneous adjustments are made to effect efficient passage through the pelvis as the fetus descends (Fig. 2-5). • Engagement is the descent of the largest transverse diameter, the biparietal diameter, to a level below the pelvic inlet. An occiput below the ischial spines is engaged. • Descent of the head is a discontinuous process occurring throughout labor. Because thetransverse diameter of the pelvic inlet is wider than the AP diameter and because the greatest diameter of the unflexed fetal head is the AP diameter, in most instances, the fetus enters the pelvis in an occiput transverse alignment. • Flexion decreases the AP diameter of the fetal head. It occurs as the head encounters the levator muscle sling, thereby decreasing the diameter by approximately 1.5 to 2.5 cm (occipitomental, 12.0 cm, to occipitofrontal, 10.5 cm). Later, further flexion occurs, reducing the diameter to 9.5 cm (suboccipitobregmatic). • Internal rotation occurs in the midpelvis. The architecture of the midpelvic passageway changes so that the AP diameter of the maternal pelvis at this level is greater than the transverse diameter. The fetus accommodates to this change by rotation of the head from a transverse orientation (occiput transverse) to an AP alignment (usually occiput anterior), thus accomplishing internal rotation. Further descent to the level of the perineum occurs with the head aligned in the AP plane.

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Chapter 2 • Normal Labor 

A

C

E

  27

B

D

F

Figure 2-5. Cardinal movements of labor. (Wolters Kulwer©2013.)

• Extension of the head allows delivery of the head from the usual occiput anterior position through the introitus. Little actual descent occurs with extrusion of the head because the head is delivered by a reversal of the flexion that occurred as it entered the pelvis. The face appears over the perineal body, while the symphysis pubis acts as a fulcrum where it impinges on the occiput.

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  Part I • Obstetric Care

• External rotation occurs after delivery of the head, when the fetal head rotates back or restitutes, toward the original transverse orientation (external rotation or restitution) when the bisacromial diameter (fetal shoulders) is aligned in an AP orientation with the greatest diameter of the pelvic outlet. • The remainder of the delivery proceeds with presentation of the anterior shoulder beneath the symphysis pubis and the posterior shoulder across the posterior fourchette. Intrapartum Fetal Assessment • Some form of evaluation of fetal well-being during labor is recommended to minimize the risk of intrapartum fetal death and intrapartum fetal asphyxia. • The two choices are intermittent auscultation and CEFM. • The clinical decision concerning the use of intermittent auscultation of the fetal heart rate versus continuous electronic fetal monitoring (external or internal) is usually based on risk status of the patient at admission and patient desires. Intermittent Auscultation of the Fetal Heart Rate

• If no risk factors are present at the time of admission, a standard approach to fetal monitoring is to determine and record the fetal heart rate (8). • At least every 30 minutes or just after each contraction in the active phase of the first stage of labor, and • At least every 15 minutes in the second stage of labor • If risk factors are present at admission, or if they become apparent during the course of labor, continuous electronic fetal monitoring should be considered. • At most institutions, some degree of continuous fetal heart rate monitoring is conducted. Because intermittent auscultation is not commonly used, many labor and delivery nurses do not have experience with this method of fetal assessment. • Intermittent auscultation requires a higher registered nurse-to-patient ratio than electronic fetal monitoring, which limits its use in many institutions. Continuous Electronic Fetal Monitoring

• The application and interpretation of CEFM are discussed in Chapter 32. • CEFM was developed to decrease the risk of cerebral palsy, which is now known to be infrequently associated with intrapartum events. • No prospective, randomized controlled studies have clearly demonstrated the value of CEFM. The use of CEFM compared to intermittent auscultation did not reduce the risk of CP in these study populations. However, CEFM was found to increase the incidence of operative delivery (cesarean section and assisted vaginal delivery), decrease the risk of neonatal seizures, and had no effect on reduction of perinatal mortality (1,17,18,32–34). • Two retrospective studies published in the early 1980s compared the outcome of monitored patients with that of premonitoring-era patients in the same institution. These studies showed that the incidence of intrapartum stillbirth, severe birth asphyxia, low Apgar scores, and long-term neurologic damage significantly improved in the monitored group (32). These findings have not been confirmed in prospective investigations. • All patients should be considered for CEFM. • Internal fetal electrodes and intrauterine pressure monitors are used when it is necessary to precisely assess the fetal heart rate pattern and the amplitude, duration, and frequency of uterine contractions. Internal fetal monitors may be used for • Patients who are obese or who are difficult to monitor externally • Patients whose labor has been augmented with oxytocin for arrest disorders • Patients whose external tracing is not reassuring • Patients undergoing trial of labor after a prior cesarean delivery (c) 2015 Wolters Kluwer. All Rights Reserved.

Chapter 2 • Normal Labor 

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Risks and Complications

• Intermittent auscultation imparts no direct risk to the fetus, except that evolving fetal compromise may be not be detected at an early stage. Potentially significant deceleratory fetal heart rate patterns could escape notice when using auscultation, allowing a decompensating fetus to be subjected to continued labor (32,34). • CEFM likewise has no direct ill effect on the mother or fetus. It does tend to restrict patient activity and often results in strict bed rest. The main risk is difficult and/or inaccurate fetal heart rate pattern interpretation, thereby allowing either a compromised fetus to go unrecognized or, conversely and more commonly, precipitating unnecessary intervention in the case of a healthy fetus. • Internal fetal monitoring complications include • Fetal scalp cellulitis but with an incidence of less than 1% in most studies (35). • Even more rare, serious complications include cranial osteomyelitis, generalized gonococcal sepsis, and cerebrospinal fluid leakage with associated meningitis, ocular injury, or disseminated HSV infection (36–39). °°Avoidance of fetal scalp electrode is warranted in those with maternal HIV, hepatitis B or C, or other perinatal infection with concern for vertical transmission. • The benefits must be carefully weighed against the risks. Maternal Preparation, Position, Anesthesia, and Analgesia

Physical Preparation

• General considerations for delivery: • Patients with poor personal hygiene and for whom delivery is not imminent are encouraged to shower. • A constipated patient or one who has hard stool palpable in the rectum can be offered an enema. • Shaving of the perineum is not routinely performed. It has no effect on infection rate in episiotomy and laceration repairs and may increase the patient’s risk of morbidity. • Patients in active uncomplicated labor may be candidates for some clear liquid intake (40)—Intravenous (IV) infusion should be considered in some laboring patients. • An IV catheter facilitates rapid administration of medications, anesthetic agents, and blood if clinically indicated. • IV fluids administered in labor are usually Ringer lactate or 0.45% normal saline with or without 5% dextrose. • Gastric emptying is reduced during pregnancy but especially during labor, and keeping the stomach empty for the possibility of emergency general endotracheal anesthesia should be considered. Maternal Position

• Maternal position in labor has consequences for both maternal comfort and fetal wellbeing. The dorsal supine position with the gravid uterus resting on the aorta and inferior vena cava can cause decreased cardiac output and relative placental hypoperfusion. • Patients in the latent phase of labor frequently are most comfortable if they are allowed to ambulate. No significant risk of fetal compromise exists, as long as an initial monitoring strip is reassuring and the membranes are intact or the presenting part is well applied to the cervix. • A randomized controlled trial (RCT) comparing patients who were ambulatory during the active phase of labor versus those who were confined to bed found no differences in the duration of labor, need for oxytocin, use of analgesia, operative vaginal delivery, or cesarean. Neonatal outcomes were also similar (41). • Patients who have freedom of movement in labor will find positions that are most comfortable to them and thereby improve their tolerability of labor. The patient’s labor support person, doula, or registered nurse is critical in helping the patient become (c) 2015 Wolters Kluwer. All Rights Reserved.

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  Part I • Obstetric Care

c­ omfortably positioned during labor. If it becomes necessary, bed rest on the patient’s side rather than on her back is recommended and allows intermittent or continuous fetal monitoring to be performed. • One study (42) showed that continuous fetal monitoring may be carried out in the ambulatory patient by telemetry with no difference in fetal outcome but significantly less subjective pain compared to control subjects. Analgesia and Anesthesia • Management of discomfort and pain during labor and delivery is a necessary part of good obstetric practice. For a detailed discussion of this topic, see Chapter 3. • The Guidelines for Perinatal Care, published by the American College of Obstetricians and Gynecologists, states that maternal request is sufficient justification for providing pain relief during labor (8). The goal of pain relief in labor is to provide the patient sufficient comfort to experience her birth process fully while avoiding fetal compromise. • The modalities that meet these needs include psychoprophylaxis and alternative pain management strategies, narcotic and analgesic drugs, and regional anesthesia. • The first step in pain management should be antepartum counseling and childbirth education classes regarding the different modalities. These should set realistic expectations for labor pains, review nonpharmacologic techniques, and discuss the controversy regarding the association of epidurals with increased risk for cesarean delivery. Alternative Pain Management Strategies • Alternative pain management strategies include the use of a trained lay support person, such as a doula, and relaxation techniques such as massage and acupressure, therapeutic touch, hydrotherapy, music, aromatherapy, self-hypnosis, and alternative positioning techniques, including use of a birthing ball, and breathing techniques (i.e., Lamaze). • In a number of studies, the use of a doula has been shown to reduce the length of the active phase of labor, reduce requests for narcotic analgesia and regional anesthesia, and reduce the rate of operative interventions including cesarean delivery, while maintaining optimal maternal and fetal outcome (43). • Other studies have shown lower intervention rates for women using certified nurse–­ midwives, particularly when they are able to function in a one-on-one situation with the laboring patient (44). Analgesic Medications and Regional Anesthesia (See Chapter 3) Trial of Labor after Cesarean Delivery

Patients with one or two prior low transverse cesarean deliveries may be offered a trial of labor and vaginal delivery (45–47). Current evidence supports the premise that a properly selected and managed patient undergoing trial of labor after cesarean delivery (TOLAC) is associated with decreased maternal morbidity and a decreased risk of complications with future pregnancy. Candidates for a TOLAC include (45) • Patients who have undergone one or two previous cesarean deliveries with low transverse uterine incision • Patients with pelvis that is clinically adequate for the EFW • Patients with no other uterine scars (i.e., myomectomy or classical hysterotomy) or history of uterine rupture • Patients delivering at a facility capable of performing emergency cesarean delivery which includes availability of support staff (delivering physician, anesthesia, nursing, and pediatrics) as well as blood products (c) 2015 Wolters Kluwer. All Rights Reserved.

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Success Rates for TOLAC

• Reports over the past several years suggest that 60% to 80% of women undergoing trial of labor after previous cesarean delivery achieve a successful vaginal birth (14,45–48). • If the prior cesarean delivery was performed for an arrest disorder, then the probability for success is less than when the first cesarean delivery was for a nonrecurring indication (e.g., breech presentation) (15,45–58). • Factors associated with increased likelihood of success of vaginal birth after caesarean (VBAC) are a prior vaginal birth and spontaneous labor. TOLAC Risks

• The potential of uterine rupture or dehiscence is the complication of greatest concern and the outcome associated with TOLAC that most significantly increases the chance of additional maternal and neonatal morbidity (45–48). • Location of prior incision on the uterus influences the potential chance of uterine rupture. One prior low transverse incision has reported clinically determined uterine rupture rates of approximately 0.5% to 1.0% after TOLAC. In women with two prior cesareans, the risk of uterine rupture increased from 0.9% to 1.7% (46,47). Two large studies that reported the risks for women with two previous cesarean deliveries undergoing TOLAC reported some increased risk in morbidity, but the chances of achieving VBAC appear to be similar compared to women with one prior cesarean delivery (48–50). • The TOLAC candidate should be counseled that the risk of uterine rupture is 0.5% to 1% (46). Additionally, in the event of uterine rupture, there is a 6.2% risk of hypoxic ischemic encephalopathy (HIE) and a neonatal death rate of 1.8% (45–49). If uterine rupture does occur, there is an approximately 4% risk of hysterectomy (48). • Epidural may be utilized as part of TOLAC, and no causal relationship has been shown to decrease the rate of successful VBAC (14,48). • Twins who attempt TOLAC have similar rates of success in VBAC compared to their singleton counterparts (14,45). Therefore, any patient with one prior low transverse cesarean may be counseled regarding the option of TOLAC. • Induction of labor remains an option for those women undergoing a TOLAC, but the usage of cervical ripening agents such as Cervidil or misoprostol should be discouraged secondary to increased risk of uterine rupture (14,45). • In any patient undergoing an induction, the patient should be counseled on the potential increased rate of uterine rupture and the decreased success rate of achieving a successful VBAC (14,45). Procedure

• It is essential that an operating room and surgical staff, anesthesiologist, and blood bank services are immediately available on a 24-hour basis and that obstetricians are on site to respond appropriately to the potential uterine rupture in the patient attempting VBAC. • Patients attempting VBAC are admitted to the labor floor, an IV catheter is placed, and a blood type and screen is obtained to facilitate the possibility of blood component transfusion. Internal monitoring with either an electronic fetal scalp electrode or an intrauterine pressure catheter has not been shown to assist in the prediction of uterine rupture (14,45). • Acute signs and symptoms of uterine rupture may be variable and accurate predictors do not exist. However, any fetal heart rate changes (particularly late or severe variable decelerations), increased uterine contractions, vaginal bleeding, loss of fetal station, or new onset of intense pain require careful evaluation. The most common sign associated with uterine rupture is fetal heart rate changes, which occur in up to 70% of uterine ruptures (14,45). • Manual exploration of the uterus after the third stage of labor has not been shown to improve outcomes (45). (c) 2015 Wolters Kluwer. All Rights Reserved.

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NORMAL DELIVERY Management of Spontaneous Delivery of the Infant Preparation

• As the multiparous patient approaches complete dilation or the nulliparous patient begins to crown the fetal scalp with a push, preparations are made for delivery. If delivery is to take place in a combined labor and delivery room, equipment is opened and materials are readied to receive the newborn. Maternal Position

• The mother’s position on a traditional delivery room table is usually restricted to the dorsal lithotomy position with left lateral tilt (to displace the uterus from the great vessels). This position has been encouraged to allow the clinician adequate access to the perineum. • In a labor and delivery room setting, patients may naturally tend to push and deliver on their sides, sitting, squatting, on all fours, or in the knee–chest position. • Relatively few controlled comparisons have been published reporting the benefits of various delivery positions with or without an epidural. • One study (50) advocated the “half-sitting” position that can be used in a delivery room setting with stirrups. Benefits were that patients found this position more comfortable, it led to fewer operative deliveries, and it had equivalent fetal outcomes to controls. • There are insufficient data to support specific patient positioning recommendations in those patients with epidural anesthesia (51). Procedure

• The perineum need not be prepared in a manner similar to that for a surgical procedure. In fact, povidone iodine (Betadine) has never been shown to be indicated for mucous membranes. Warm water or saline irrigation is sufficient to minimize maternal fecal contamination of the perineum. • If not already addressed, delivery anesthesia is chosen at this time. Many deliveries may be performed without anesthesia if it is the patient’s and clinician’s preference. (A pudendal block or local infiltration may be utilized for the delivery if necessary.) • Restricting the use of episiotomy to specific fetal and maternal indications reduces the risk of posterior perineal trauma. Midline episiotomy may increase the risk of third- and fourth-degree lacerations when compared to mediolateral episiotomy (2,3,52). Maneuvers of Delivery from an Occiput Anterior Position Delivery of the Head

• The fetal head is delivered by extension. As the flexed head passes through the vaginal introitus, the smallest diameter (occipitobregmatic) is presented if the vertex is maintained in a state of flexion. Maintaining flexion and pushing the perineum back over the face and under the chin before the head is allowed to extend appeared to be the least traumatic method in one study (53). Extending the fetal head by lifting the fetal chin with a towel-covered hand on the perineum (Ritgen maneuver) can accelerate the delivery process but may be more traumatic to the perineum. A multicenter RCT showed that there was no difference in risk of perineal trauma between the “hands on” and “hands poised” techniques of delivery. Once the fetal head has been delivered, external rotation and restitution to the occiput transverse position occurs. • Updated NRP 2010 guidelines suggest not using the bulb syringe to suction the nares and oropharynx of the fetus, even in the face of meconium-stained fluid. Allowing the fetus to cry and clear secretions on its own is recommended if the infant is vigorous. However, in the special circumstance of meconium, if the infant is not vigorous, there is insufficient evidence to recommend a change in the current practice that tracheal suctioning should be performed immediately after delivery (54). (c) 2015 Wolters Kluwer. All Rights Reserved.

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• A finger should be insinuated into the vagina along the fetal neck to evaluate for a nuchal cord. If one is present, it can usually be reduced over the vertex or over the body. If this cannot be accomplished easily, the cord should be doubly clamped and divided between the clamps on the perineum and the remainder of the delivery carried out promptly. If multiple loops of cord are encountered, the adjacent clamps should be placed on just a single loop. Delivery of the Shoulders

• Delivery of the anterior shoulder is accomplished by gentle downward traction on the fetal head toward the floor in association with maternal expulsive efforts. Flexion of the maternal thighs against the abdomen (McRoberts maneuver) (55) will often facilitate delivery of the anterior shoulder. With the anterior shoulder delivered, the posterior shoulder is delivered with vertical traction directed upward on the vertex. In general, gentle traction should be exerted coincident with the long axis of the fetus to avoid undue stretching of the brachial plexus. The perineal body should be supported to avoid extensions of the episiotomy or to avoid lacerations. When both shoulders have passed through the introitus, the remainder of the delivery requires little assistance in most cases. Final Steps

• Grasping the infant around the back of the neck and head with one hand and gliding the other hand toward the vagina to the baby’s buttocks, the operator delivers the infant. Care should be taken not to compress the blood vessels of the baby’s neck and to keep the baby’s head downward to facilitate drainage of nasopharyngeal secretions. The infant can usually be cradled in one arm and tucked against the operator’s abdomen, leaving the other hand free to perform the steps that follow. The umbilical cord is then doubly clamped and divided, leaving 2 to 3 cm of cord with the infant. • If the infant appears stable and healthy, an alternative to holding the infant, clamping, and cutting the cord is to place the infant directly into the mother’s arms and onto her abdomen. Delaying the cord clamping and cutting until the cord stops pulsating allows for a placental transfusion to newborn. Neither method, early or delayed cord clamping, has been shown to be superior (54,56). Delay of up to 60 seconds can be considered as it may increase total body iron stores and blood volume; these potential benefits must be weighed against the increased risk of neonatal jaundice (56). The 2010 American Heart Association Neonatal Resuscitation Guidelines suggest cord clamp delay (54). • Examination of the proximal end of the cord will prevent clamping part of an omphalocele or umbilical hernia. • If the infant has not been given to the mother, the infant is transferred to the mother’s abdomen for initial bonding. All efforts should be made to keep the mother and the newborn together for a prolonged period after birth. Breast-feeding can be initiated at this time and should be encouraged in most cases. Most routine newborn care can be given by the nursing staff while the infant is on the mother’s abdomen. If resuscitative efforts are necessary, then the infant should be placed in the appropriate location needed to render such care. Episiotomy • Episiotomy has traditionally been one of the most frequently performed obstetric procedures and has been one of the more controversial (2,3,55). This incision of the perineum enlarges the vaginal orifice at the time of delivery. The incision may be made with scissors or a knife and may be made in the midline (medial episiotomy) or begun in the midline and extended laterally (mediolateral episiotomy). • Routine use of episiotomies has not been shown to improve outcomes for patients and can actually be harmful. Routine or liberal use of episiotomies increases the risk that the (c) 2015 Wolters Kluwer. All Rights Reserved.

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patient will have a surgical incision that is larger than if she experiences a spontaneous laceration at birth (2,3,52). • It is recommended that episiotomies should be used selectively and only when clinically indicated. Complications of Episiotomy

• As with any other surgical procedure, the risks of episiotomy must be compared with the benefits. • Refraining from routine performance of episiotomy in some cases has resulted in an increased incidence of first- and second-degree periurethral and vaginal lacerations. • Although an episiotomy may be simpler to repair than a spontaneous laceration, it is associated with a higher incidence of third- and fourth-degree lacerations. Even when recognized and repaired appropriately, these have lifelong implications, most significantly in regard to continence of flatus and stool (2,3,52,57,58). • Pain and edema are the most frequent postepisiotomy complaints. These usually resolve within a few days, particularly if a regimen of sitz baths several times a day is encouraged in the immediate postpartum period. • Dyspareunia may be noted by some women. Evaluation for abnormal healing, lactationassociated atrophy, or other causes is necessary. • Infection can be one of the most serious complications of episiotomy, leading to significant morbidity and, rarely, maternal mortality (2,3,52,57,58). Method

• Episiotomy timing is important. It should be performed when a 3- to 4-cm diameter of fetal scalp is visible during a contraction. Excessive blood loss can occur if it is performed earlier, whereas if performed too late, excessive stretching of the perineum and vagina may have already occurred. • With adequate local, pudendal, or regional anesthetic in place, the perineum is separated from the fetal head usually by insertion of the provider’s fingers between the perineum and fetal head. Medial episiotomy is performed by incising the triangularly shaped perineum toward the anus and into the vagina. An adequate incision should be made for the episiotomy to be of value. Care must be taken to avoid cutting into the anal sphincter or the rectum, unless this degree of exposure is deemed necessary. If a short perineum is encountered or third- or fourth-degree extension likely, a mediolateral episiotomy should be considered (2,3,52). • Delivery is performed with care taken by the clinician to prevent extension of the episiotomy by applying pressure at the perineal apex with a towel-covered hand. • The critical part of the procedure is the decision to perform the episiotomy. Most deliveries can be performed without episiotomy, and the proposed benefits of episiotomy have never been proven (2,3,52). Delivery of the Placenta Delivery of the placenta can be accomplished by either expectant or active management of the third stage of labor. Expectant Management

• Normally, the placenta separates spontaneously from the uterine wall within approximately 5 minutes of delivery but may take as long as 20 to 30 minutes. No attempt should be made to extract the placenta before its separation. • Separation is indicated by • The fundus changing to a globular shape and firm consistency • The appearance of a gush of blood • Lengthening of the umbilical cord (c) 2015 Wolters Kluwer. All Rights Reserved.

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• When separation has occurred, gentle fundal massage and firm but gentle traction on the cord sometimes will effect rapid delivery of the placenta. • In the Brandt-Andrews maneuver, cephalad stabilizing pressure is exerted with the abdominal hand on the lower segment of the uterus while traction on the cord is simultaneously exerted. The abdominal hand should prevent uterine inversion. • An advantage of expectant management of the third stage is that it does not interfere with the normal delivery processes and requires no special medications or supplies. Disadvantages of this method are that the third stage of labor is longer, and there is possible increased risk of postpartum hemorrhage compared with active management of this stage (59). Active Management

• After delivery of the anterior shoulder, or immediately after birth of the infant, the patient is administered an uterotonic drug to stimulate uterine contraction. • Clamp and cut the cord. • Wait for a strong uterine contraction and then apply controlled cord traction while applying countertraction above the pubic bone. • If the placenta is not delivered, wait until the next contraction. • Advantages of active management of the third stage include decreased length of third stage, decreased maternal blood loss of less than 1000 mL (59), possible lower risk for postpartum hemorrhage and anemia, and decreased need for transfusion. • Disadvantages of this method are increased incidence of maternal diastolic blood pressure, nausea, vomiting, increased pain, and increased use of analgesia from time of birth until hospital discharge (59). Manual Extraction

• If the placenta has not delivered after 30 minutes, or if separation has occurred without delivery of the placenta, manual removal may be performed to reduce excessive blood loss. Intrauterine bacterial contamination is a theoretical risk of manual extraction but is not a common complication. • Procedure: Adequate anesthesia should be assured. One hand should grasp the fundus and hold it downward firmly. Physicians should avoid contamination by using an extended-cuff glove and arm cover. With the other hand, reach into the uterine cavity and gently insinuate the fingers between the placenta and the maternal surface in a circumferential fashion until separation is complete. The placenta can now be removed. Vigorous fundal massage and the use of a uterotonic agent, preferably oxytocin, will minimize subsequent bleeding. • Several studies document an increased risk of postpartum endometritis after manual removal of the placenta during a cesarean section. Although it is a common practice to administer prophylactic antibiotics to patients who deliver vaginally and have manual placental extraction, there is no evidence to support this practice (60). Examination of the Placenta

• The placenta should be examined for missing cotyledons or other evidence of undelivered remnants. • The membranes should be inspected for vessels that run blindly to an edge, suggesting a succenturiate lobe that may not have been removed. • The cut end of the cord should be examined for the presence of two arteries and a vein. The absence of one umbilical artery may suggest a congenital anomaly in the newborn. • When abnormalities of the placenta are suspected, pathologic evaluation is warranted. Active Prophylaxis against Postpartum Atony • Although the fundus usually contracts well after delivery, this is not always the case. A poorly contracted uterus can lead to rapid and severe blood loss. Therefore, it is wise to take measures to avoid excessive blood loss caused by postpartum uterine atony. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Gentle but firm external fundal message should always be part of postpartum management. • It is usually is wise to give an oxytocic agent either intramuscularly with the delivery of the anterior shoulder (10 U oxytocin) or in an IV drip after the delivery of the placenta (10 to 20 U in 1000 mL of isotonic IV fluid). The latter route is preferable because it allows for a more controlled third stage. Oxytocin can cause marked hypotension if administered as an IV bolus. Occasionally, oxytocin is insufficient, and other drugs must be considered. • Misoprostol, 600 to 1000 μg placed in the rectum, is a very effective treatment for excessive bleeding due to uterine atony. However, shivering, pyrexia, and vomiting are more common with misoprostol, this is usually self-limited (61). • Methylergonovine maleate (Methergine), 0.2 mg intramuscularly, often produces sufficient uterine contractility to correct atony. Methylergonovine is contraindicated in patients who are hypertensive (hypertension may be aggravated), who are HIV-positive patients on any of the protease or reverse transcriptase inhibitors (e.g., delavirdine, indinavir, nelfinavir), coronary artery disease, and should be avoided as well in patients who are hypotensive (further peripheral vasoconstriction in a patient in hypovolemic shock may result in digit loss secondary to vascular insufficiency) or have recently received ephedrine for hypotension. Repair of Lacerations and Episiotomy

Lacerations of the Birth Canal

• After delivery of the placenta, the clinician should inspect the birth canal for lacerations. • The vaginal sidewalls and fornices should be palpated and inspected. • Lacerations involving the periurethral tissues can be missed unless the labia minora are separated. • Lacerations usually are linear and cephalad and may be repaired in an interrupted or continuous fashion. • By placing the palm of one hand into the vagina as a retractor, the cervix can be exposed. The anterior lip of the cervix should be examined and elevated to allow visualization of the entire cervix. If a cervical laceration is present, visualization can often be improved by having an assistant exert caudad pressure on the uterine fundus. Use of retractors by an assistant may also be necessary. Exposure of vaginal vault lacerations can sometimes be improved by using the initially placed suture for traction to assure visualization and control of the cephalad apex. • Absorbable synthetic suture has been found to reduce short-term pain and dyspareunia (62). Episiotomy

• The episiotomy is repaired with 2-0 or 3-0 absorbable suture material. Interrupted sutures may be required to approximate the deep tissues of the perineal body. Running interlocking sutures are used to repair the vaginal mucosa, with care being taken to include its apex. The perineum is reapproximated with subcutaneous and subcuticular running sutures with attention to landmarks such as the hymeneal ring. • A laceration extending through the anal sphincter (third degree) should be repaired with interrupted sutures, incorporating the fascia of the muscle for strength. The overlapping technique has not been shown to be more effective than the end-to-end technique. • When the rectal mucosa is involved (fourth degree), it should be reapproximated in two layers with interrupted absorbable suture no more than 0.5 cm apart reinforced with the overlying fascia using a continuous synthetic absorbable suture. Care should be taken to avoid including suture material in the luminal surface of the intact mucosa. The remainder of the repair is routine. Performing fourth-degree repairs in the operating room with assistants and lighting for adequate exposure should be considered. Liberal irrigation with isotonic saline during the repair may also facilitate healing. • Although not extensively studied, the use of a single dose of second-generation cephalosporin or clindamycin, if penicillin allergic, was protective of perineal wound complications (62). (c) 2015 Wolters Kluwer. All Rights Reserved.

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Assisted Delivery • When it is not possible to achieve spontaneous vaginal delivery, operative delivery may be necessary. • This may be either by cesarean delivery or an instrumented vaginal delivery. The latter entails the use of either forceps or a vacuum extractor. • Operative delivery options and considerations are discussed in detail in Chapter 10. PATIENT EDUCATION • Patient education for labor and delivery begins during prenatal care and should include the mother’s key support person(s). • Patients should be strongly encouraged to enroll in childbirth preparation classes. • Throughout the pregnancy, health care providers should reinforce the concept that labor, birth, and breast-feeding are normal physiologic processes. • Patient education may be given to the patient by the clinicians and/or the registered nurses responsible for her care. • Information that patients need includes • Signs and symptoms of labor • How and when to contact the labor and delivery suite • Routines in the labor and delivery suite • Analgesia and anesthesia options • Breast-feeding support immediately after birth • Throughout the labor process, the patient and support person(s) must be kept aware of her progress and status. • Informed consent needs to be obtained from the patient before any interventions, procedures, analgesia, or anesthetics are administered. REFERENCES 1. American College of Obstetricians and Gynecologists. AGOG Practice Bulletin No. 106: intrapartum fetal heart rate monitoring: nomenclature, interpretation, and general management principles. Obstet Gynecol. 2009;114(1):192–202. 2. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 71: Episiotomy. Clinical Management Guidelines for Obstetrician-Gynecologists. Obstet Gynecol. 2006;107(4):957–962. 3. Carroli G, Mignini L. Episiotomy for vaginal birth [Review]. Cochrane Database Syst Rev. 2009;(1):CD00081. 4. Greene MF, Creasy RK, Resnik R, Lockwood CL, Moore T. Creasy and Resnik’s maternalfetal medicine: principles and practice. Cambridge University Press, New York, 2008. 5. ACOG Practice Bulletin No. 8: premature rupture of membranes. Clinical management guideline for obstetrician-gynecologists. Obstet Gynecol. 2007;109(4):107–119. 6. Abdelazim IA, Makhlouf HH. Placental alpha microglobulin-1(Amnisure® test) for the detection of premature rupture of fetal membranes. Arch Gynecol Obstet. 2012;285(4):985–989. 7. ACOG practice bulletin No 9: Antepartum fetal surveillance. Int J Gynaecol Obstet. 2000;68(2):175–185. 8. Guidelines for perinatal care. 7th ed. Washington: American Academy of Pediatrics and the American College of Obstetricians and Gynecologists, 2012. 9. American College of Obstetricians and Gynecologists. ACOG practice bulletin No. 101: Ultrasonography in pregnancy. Obstet Gynecol. 2009;113(2 Pt 1):451–461. 10. Lewis DF, Raymond RC, Perkins MB, Brooks GG, et al. Recurrence rate of shoulder dystocia. Am J Obstet Gynecol. 1995;172:1369–1371. 11. ACOG practice bulletin No 40: Shoulder dystocia. Int J Gynaecol Obstet. 2003;80(1):87–92. 12. Hjartardottir S, Leifsson BG, Geirsson RT, et al. Recurrence of hypertensive disorder in second pregnancy. Am J Obstet Gynecol. 2006;194:916–920. (c) 2015 Wolters Kluwer. All Rights Reserved.

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13. Ananth CV, Savitz DA, Williams MA. Placental abruption and its association with hypertension and prolonged rupture of membranes: a methodologic review and meta-analysis. Obstet Gynecol. 1996;88:309–318. 14. Cunningham FG, Bangdiwala SI, Brown SS, et al. National Institutes of Health Consensus Development Conference Statement vaginal birth after cesarean: new insights March 8–10, 2010. Semin Perinatol. 2010;34(5):351–365. 15. ACOG Committee on Practice Bulletins–Obstetrics. ACOG practice bulletin No 33: diagnosis and management of preeclampsia and eclampsia. Obstet gynecol. 2002;99(1):159–167. 16. Hadlock FP, Deter RL, Harrist RB, et al. Estimating fetal age: computer assisted analysis of multiple fetal growth parameters. Radiology. 1984;152:497–501. 17. Macones GA, Hankins GD, Spong CY, et al. The 2008 National Institute of Child Health and Human Development workshop report on electronic fetal monitoring: update on definitions, interpretation, and research guidelines. Obstet Gynecol. 2008;112(3):661–666. 18. AGOG Practice bulletin No. 116: management of intrapartum fetal heart rate tracings. Obstet Gynecol. 2010;116(5):1232–1240. 19. Mercer BM, Crocker LG, Boe NM, et al. Induction versus expectant management in premature rupture of the membranes with mature amniotic fluid at 32 to 36 weeks: a randomized trial. Am J Obstet Gynecol. 1993;169:775–782. 20. Verani JR, McGee L, Schrag SJ; Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention. Prevention of perinatal group B streptococcal disease-revised guidelines from CDC, 2010. MMWR Recomm Rep. 2010;59(RR-10):1–36. 21. American College of Obstetricians and Gynecologists Committee on Obstetric Practice. ACOG Committee Opinion No. 485: prevention of early-onset group B streptococcal disease in newborns. Obstet Gynecol. 2011;117(4):1019–1027. 22. Zhang J, Landy HJ, Branch DW, et al.; Consortium on Safe Labor. Contemporary patterns of spontaneous labor with normal neonatal outcomes. Obstet Gynecol. 2010;116:1281–1287. 23. Zhang J, Troendle J, Reddy UM, et al.; the Consortium on Safe Labor. Contemporary cesarean delivery practice in the United States. Am J Obstet Gynecol. 2010;203:e1–e10. 24. Spong CY, Berghella V, Wenstrom KD, et al. Preventing the first cesarean delivery: Summary of a joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, and American College of Obstetricians and Gynecologists Workshop. Obstet Gynecol. 2012;120:1181–1193. 25. Tuuli MG, Frey HA, Odibo AO, et al. Immediate compared with delayed pushing in the second stage of labor: a systematic review and meta-analysis. Obstet Gynecol. 2012;120(3):660–668. 26. Fraser WD, Turcot L, Krauss I, et al. Amniotomy for shortening spontaneous labor. Cochrane Database Syst Rev. 2006;(3): CD00015. 27. Rouse DJ, McCullough C, Wren AL, et al. Active-phase labor arrest: a randomized trial of chorioamnion management. Obstet Gynecol. 1994;83:937–940. 28. American College of Obstetrics and Gynecology Committee on Practice BulletinsObstetrics. ACOG Practice Bulletin No. 49: Dystocia and augmentation of labor. Obstet Gynecol. 2003;102(6):1445–1454. 29. Garite TJ, Porto M, Carlson NJ, et al. The influence of elective amniotomy on fetal heart rate patterns and the course of labor in term patients: a randomized study. Am J Obstet Gyneol. 1993;168:1827–1831. 30. Macones GA, Cahill A, Stamilio DM, Odibo AO. The efficacy of early amniotomy in nulliparous labor induction: a randomized controlled trial. Am J Obstet Gynecol. 2012;207(5):403.e1–e5. 31. Ingemarsson E, Ingemarsson I, Svenningson HW. Impact of routine fetal monitoring during labor and fetal outcome with long-term follow-up. Am J Obstet Gynecol. 1981;141:29–38. 32. Mueller-Heubach E, MacDonald HM, Joret D, et al. Effects of electronic fetal heart rate monitoring on perinatal outcome and obstetric practices. Am J Obstet Gynecol. 1980;137:758–763. 33. Hon EH, Petrie RH. Clinical value of FHR monitoring. Clin Obstet Gynecol. 1975;18:(4):1–23. (c) 2015 Wolters Kluwer. All Rights Reserved.

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34. Girvell RM, Alfirevic Z, Gyte GM, et al. Antenatal cardiotocography for fetal assessment. Cochrane Database Syst Rev. 2012;12:DC007863. 35. Wagener MM, Rycheck RR, Yee RB, et al. Septic dermatitis of the neonatal scalp and maternal endomyometritis with internal fetal monitoring. Pediatrics. 1984;74:81–85. 36. Nieburg P, Gross SJ. Cerebrospinal fluid leak in a neonate associated with fetal scalp electrode monitoring. Am J Obstet Gynecol. 1983;147:839. 37. Overturf GD, Balfour G. Osteomyelitis and sepsis: severe complications of fetal monitoring. Pediatrics. 1984;74:81–85. 38. Miyashiro MJ, Mintz-Hittner HA. Penetrating ocular injury with a fetal scalp monitoring spiral electrode. Am J Ophthalmol. 1999;128(4):526–528. 39. Amann ST, Fagnant RJ, Shartrand SA, et al. Herpes simplex infection associated with shortterm use of a fetal scalp electrode. A case report. J Reprod Med. 1992;37(4):372–374. 40. Committee on Obstetric Practice, American College of Obstetricians and Gynecologists. ACOG committee opinion No. 441: oral intake during labor. Obstet Gynecol. 2009;114(3):714. 41. Bloom SL, McIntire DD, Kelly MA, et al. Lack of effect of walking on labor and delivery. N Engl J Med. 1998;339:76–79. 42. Haukkamaa M, Purhonen M, Teramo K. The monitoring of labor by telemetry. J Perinat Med. 1982;10:17–22. 43. Kennell J, Klaus M, McGrath S, et al. Continuous emotional support during labor in a US hospital. JAMA. 1991;265:2197–2201. 44. Butler C, Abrams K, Parker J. Supportive nurse midwife care associated with reduced incidence of cesarean section. Am J Obstet Gynecol. 1993;168:404–413. 45. American College of Obstetricians and Gynecologists. ACOG Practice bulletin no. 115: vaginal birth after previous cesarean delivery. Obstet Gynecol. 2010;116(2 Pt 1):450–463. 46. Landon MB. Vaginal birth after cesarean delivery. Clin Perinatol. 2008;25(3):491–504. 47. Landon MB, Spong CY, Thom E, et al. Risk of uterine rupture during a trial of labor in women with multiple and single prior cesarean delivery. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Obstet Gyncol. 2006;108:12–20. 48. Tahseen S, Griffiths M. Vaginal birth after two caesarean sections (VBAC-2)- a systematic review with meta-analysis of success rate and adverse outcomes of VBAC-2 versus VBAC-1 and repeat (third) caesarean sections. BJOG. 2010;117:5–19. 49. Landon MB, Hauth JC, Leveno KJ, et al. Maternal and perinatal outcomes associated with a trial of labor after prior cesarean delivery. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. N Engl J Med. 2004;351:2581–2589. 50. Marttila M, Kajanoja P, Ylikorkala O. Maternal half-sitting position in the second stage of labor. J Perinat Med. 1983;11:286–289. 51. Kemp E, Kingswood CJ, Kibuka M, Thorton JG. Position in the second stage for labour for women with epidural anaesthsia. Cochrane Database Syst Rev. 2013;(1):CD008070. 52. Coats PM, Chan KK, Wilkins M, Beard RJ. A comparison between midline and mediolateral episiotomies. Br J Obstet Gynaecol. 1980;87(5):408–412. 53. Goodlin RC. On protection of the maternal perineum during birth. Obstet Gynecol. 1983;62:393. 54. Kattwinkel J, Perlman JM, Aziz K, et al. Neonatal resuscitation: 2010 American Heart Association Guidelines for Cardiopulmonary resuscitation and Emergency Cardiovascular Care. Pediatrics. 2010;126(5):e1400–e1413. 55. Gonik B, Stringer CA, Held B. An alternate maneuver for management of shoulder dystocia. Am J Obstet Gynecol. 1983;145:882–884. 56. Committee on Obstetric Practice, American College of Obstetricians and Gynecologists. Committee Opinion No. 543: timing of umbilical cord clamping after birth. Obstet Gynecol. 2012;120(6):1522–1526. 57. Poen AC, Felt-Bersma RJ, Strijers RL, et al. Third-degree obstetric perineal tear: long-term clinical and functional results after primary repair. Br J Surg. 1998;85:1433–143. (c) 2015 Wolters Kluwer. All Rights Reserved.

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58. Anthony S, Buitendijk SE, Zondervan KT, et al. Episiotomies and the occurrence of severe perineal lacerations. Br J Obstet Gynaecol. 1994;101:1064–1067. 59. Begley CM, Gyte GM, Devane D, McGuire W, Weeks A. Active versus expectant management for women in the third stage of labour. Cochrane Database Syst Rev. 2011;(11):CD007412. 60. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 120: use of prophylactic antibiotics in labor and delivery. Obstet Gynecol. 2011;117(6):1472–1483. 61. Badejoko OO, Ljarotimi AO, Awowole IO, Loto OM, Bedejoko BO, et al. Adjunctive rectal misoprostol versus oxytocin infusion for prevention of postpartum hemorrhage in women at risk: a randomized controlled trial. J Obstet Gynaecol Res. 2012;38(11):1294–1301. 62. Hale RW, Ling FW. Episiotomy: Procedure and Repair Techniques. Amer College of Obstetricians and Gynecologists. 2007.

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3

Obstetric Anesthesia Regina Fragneto

KEY POINTS • The physiologic changes of pregnancy are a significant factor in the anesthetic care of women during childbirth and sometimes increase the risks of anesthesia. • Neuraxial anesthesia procedures, including epidural and combined spinal–epidural (CSE) analgesia, provide excellent pain relief during labor and are used in the majority of childbirths in the United States. • Both neuraxial and general anesthesia techniques provide effective anesthesia for cesarean delivery. Historically, anesthesia-related maternal mortality has been greater when general anesthesia is used, but the difference in mortality rate between general and regional anesthesia has narrowed in the United States. • Ensuring maternal safety and maintaining adequate uteroplacental perfusion and fetal oxygenation are the most important goals when anesthesia is administered for nonobstetric surgery during pregnancy. BACKGROUND Obstetric anesthesia is an important component in the care of most women during childbirth. Many women choose to receive neuraxial analgesia while in labor, and all women who undergo cesarean delivery require some type of anesthesia. Anesthesia care is also provided to the many women who require other surgical procedures while pregnant. Pathophysiology • The physiologic changes of pregnancy have a significant impact on the administration of both regional and general anesthesia to women during childbirth. • Sensitivity of nerves to local anesthetics is enhanced during pregnancy (1). • As a result, the local anesthetic dose requirements for both spinal anesthesia during surgery and epidural labor analgesia are decreased in pregnant women (2,3). • The sedative effects of increased progesterone levels and the activation of the endorphin system during pregnancy also decrease general anesthesia requirements. • The minimum alveolar concentration of halogenated volatile anesthetic agents, which is defined as the drug concentration at which 50% of patients do not move when exposed to a noxious stimulus, is decreased by approximately 30% in women during pregnancy (4). • The dose of intravenous propofol needed to induce general anesthesia is also decreased in pregnant women (5). • The physiologic changes of pregnancy may affect the safety of administering anesthesia to pregnant women. • Aortocaval compression from the gravid uterus decreases venous return and can result in significant hypotension when a pregnant woman assumes the supine position, especially during late pregnancy. • The sympathetic block produced by spinal and epidural anesthesia causes vasodilatation that results in a further decrease in venous return. • The sympathectomy induced by neuraxial anesthesia impairs a pregnant woman’s ability to compensate via vasoconstriction for the decreased venous return caused by aortocaval compression. As a result, the degree of hypotension that occurs during neuraxial anesthesia is significantly greater in pregnant compared to nonpregnant women. 41

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• Anesthesia-related maternal mortality is more common during general anesthesia than regional anesthesia although the difference in mortality rate between the anesthetic techniques has declined since 1990. • A study of anesthesia-related maternal mortality in the United States between 1991 and 2002 found that the overall rate was 1.2 per million live births, which was a 59% decrease from 1979 to 1990; and 86% of those deaths occurred during cesarean delivery. • The anesthesia-related case fatality rate for cesarean delivery under general anesthesia was 16.8 per million anesthetics from 1991 to 1996 with a decrease to 6.5 per million anesthetics for 1997–2002. • The anesthesia-related case fatality rate for cesarean delivery under regional anesthesia was 2.5 per million regional anesthetics for 1991–1996 and 3.8 per million anesthetics for 1997–2002. • Therefore, the risk of anesthesia-related mortality was 6.7 times greater for pregnant women receiving general anesthesia compared to regional anesthesia for 1991–1996, but the risk ratio had decreased to 1.7 for the period 1997–2002 (6). • The majority of deaths during general anesthesia resulted from airway management problems, such as failed intubation and aspiration, while high neuraxial block was the most common cause of regional anesthesia-related deaths (6). • The physiologic changes of pregnancy play a significant role in the increased risk of general anesthesia for pregnant women. • Airway edema caused by pregnancy-induced capillary engorgement of the mucosa can distort airway anatomy and contributes to the increased incidence of difficult intubation in pregnant women. • One study found that the incidence of difficult or failed intubation was approximately eight times greater in obstetric patients compared to nonpregnant patients (7). • Respiratory changes of pregnancy, including decreased functional residual capacity and increased oxygen consumption, result in a more rapid development of hypoxemia when apnea occurs (8). Therefore, when difficult intubation is encountered during the induction of general anesthesia, an obstetric patient will become hypoxemic more quickly than a nonobstetric patient. • A variety of physiologic factors contribute to the risk of aspiration in parturients. • Gastric emptying is prolonged during labor (9,10). In addition, anatomic changes resulting from displacement of the stomach by the gravid uterus and decreased lower esophageal sphincter tone, caused by increased progesterone levels, produce an increased incidence of gastroesophageal reflux in pregnant women. • Both delayed gastric emptying and gastroesophageal reflux are risk factors for gastric aspiration during the induction of general anesthesia. • Aspiration is more likely to occur when difficult airway management is encountered and securing of the airway with tracheal intubation is delayed. Epidemiology • The majority of pregnant women in the United States will receive obstetric anesthesia. • All patients undergoing cesarean delivery require anesthesia, and the cesarean delivery rate in the United States continues to rise; it had reached 32.8% of all deliveries in 2010 and 2011 (11). • Approximately 75% of women who deliver at a hospital in the United States with greater than 1500 deliveries per year receive neuraxial analgesia during labor (12). • Finally, based on estimates of the rate of surgery during pregnancy (0.3% to 2.2%), as many as 87,000 pregnant women in the United States undergo anesthesia for non–pregnancy-related surgical procedures each year (13). (c) 2015 Wolters Kluwer. All Rights Reserved.

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EVALUATION History • Before providing obstetric anesthesia care, the anesthesiologist must perform a focused history and physical examination. • Important components of the patient’s medical history include the presence of serious underlying medical conditions—especially cardiovascular, pulmonary, and neurological disorders. The anesthesiologist must also be aware of any current pregnancy complications because the presence of these complications will affect decisions concerning anesthetic management. • Crucial medical history information for the anesthesia care provider includes any available information concerning previous general or regional anesthetics. The anesthesiologist will seek any evidence of technical difficulties with regional or general anesthesia procedures, including a history of failed or difficult intubation. • Adverse reactions to anesthetic drugs and a history of anesthesia-related inheritable disorders in the patient or her relatives, such as malignant hyperthermia and atypical pseudocholinesterase, should be noted. Physical Examination • The anesthesiologist’s focused physical examination of the obstetric patient will include auscultation of the heart and lungs and careful assessment of the airway. • When a neuraxial anesthesia technique is planned, examination of the back is also essential. • Most anesthesiologists would agree that the most important component of the physical examination in healthy pregnant women is airway assessment. Evaluation of the airway includes mouth opening, neck movement, thyromental distance, Mallampati classification, and the upper-lip bite test. • The Mallampati airway classification system evaluates the size of the tongue relative to the size of the oropharyngeal cavity. Patients are assigned an airway class based on the pharyngeal structures that can be visualized when the patient opens her mouth wide and sticks out her tongue (Fig. 3-1). A correlation exists between Mallampati airway class and ease of intubation (14).

Class I

Class II

Class III

Class IV

Figure 3-1. Mallampati classification of the airway based on pharyngeal structures that are visible with mouth open. Class I: the soft palate, uvula, and tonsillar pillars are visualized. Class II: the uvula is only partially visualized, and the tonsillar pillars are not visualized. Class III: soft palate only is visualized. Class IV: not even the soft palate is visualized. (Reprinted from Chestnut DH. Obstetric anesthesia: principles and practice. 3rd ed. Philadelphia: Mosby, 2004, with permission.) (c) 2015 Wolters Kluwer. All Rights Reserved.

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Table 3-1

Risk Factors for Difficult Intubation

Morbid obesity Short neck Increased neck circumference Small mouth opening Mallampati Class III or greater Upper-lip bite test Class III Congenital craniofacial abnormalities Receding chin Protruding maxillary incisors Thyromental distance 10,000

Chapter 7 • Ectopic Pregnancy 

Table 7-3

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Diagnosis of Ectopic Pregnancy by Ultrasonography and Human Chorionic Gonadotropin Levels

Variable Abdominal ultrasonogram Vaginal ultrasonogram Sac in uterus No sac in uterus

b-hCG level (IU/mL)/ conclusion 6000 1500–2000 Probable abortion Nondiagnostic

b-hCG level (IU/mL)/ conclusion >6500 >2000 Normal intrauterine pregnancy Probable ectopic pregnancy

β-hCG, human chorionic gonadotropin.

• A positive result of culdocentesis is one in which nonclotting blood is obtained and is highly suggestive of an ectopic pregnancy in the presence of symptoms and a positive pregnancy test. • A negative result is one in which clear serous fluid is obtained, making an ectopic pregnancy unlikely. • A nondiagnostic test is one in which either no fluid (“dry tap”) or a few milliliters of clotting blood are obtained. A nondiagnostic culdocentesis neither confirms nor rules out an ectopic pregnancy. • Culdocentesis is a readily available, rapid, and low-morbidity procedure; it is also painful, and it has a high frequency of nondiagnostic results. Now that sensitive serum β-hCG screening and vaginal ultrasound are available, culdocentesis is rarely indicated in the diagnosis of ectopic pregnancy. Diagnostic Dilation and Curettage • When an abnormal pregnancy is diagnosed by hormone levels and ultrasound, but the location of the pregnancy is unknown, diagnostic dilation and curettage (D&C) is a cost-effective way to distinguish intrauterine pregnancy failure from ectopic pregnancy. • If chorionic villi are identified on gross or histologic examination, ectopic pregnancy is virtually ruled out. If no products of conception are present, the patient has either an ectopic pregnancy or a completed spontaneous abortion. • Diagnostic D&C in conjunction with a postprocedure β-hCG concentration can be useful. A decline of β-hCG greater than 30% is suggestive of abnormal intrauterine pregnancy where a rise of β-hCG is suggestive of ectopic (9). • Some authorities suggest that diagnostic D&C should always precede medical management, but this is controversial. TREATMENT Catastrophic Presentation Ectopic pregnancies can present as life-threatening emergencies. The patient presenting in shock with an acute abdomen should be stabilized and taken to surgery immediately. • Fluid resuscitation must be carried out immediately. Two large-bore peripheral intravenous lines should be started, and balanced saline solution should be infused rapidly. A Foley catheter should be placed to monitor urine output. In the absence of complicating medical conditions, central venous monitoring is generally not needed. • Laboratory tests needed are minimal. Blood should be drawn for hematocrit and crossmatched for four units of red cells. A β-hCG level should be obtained, but it is not necessary to wait for the results. • Surgical approach. • The patient should be taken to surgery as quickly as possible. In some women with massive hemorrhage and severe shock, it may be necessary to proceed to surgery while the patient is being stabilized. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Either a low midline vertical incision or a Pfannenstiel incision can be used. • After the abdomen has been entered, rapid palpation of the uterus and both adnexa will usually localize the pregnancy. Upward traction on the uterus coupled with digital pressure on the involved tube will stop the bleeding so that fluid resuscitation, including transfusion if needed, can be completed. Only then should the hemoperitoneum be cleared and the involved adnexum stabilized in the operative field. The tube should be clamped across the mesosalpinx, the tube excised, and the mesosalpinx suture ligated. There is no need to remove the ipsilateral ovary. • Hysterectomy is not indicated unless the ectopic pregnancy is interstitial or cornual, and the uterine rupture is so severe that it cannot be repaired. Less Acute Presentation In the hemodynamically stable patient with an ectopic pregnancy, there are three possible strategies for management: expectant, surgical, and medical. • Expectant management: • Many ectopic pregnancies will end in tubal abortion, with cessation of trophoblast growth, separation of the products of conception from the tubal wall, and spontaneous resolution. • The risk associated with expectant management is intraperitoneal hemorrhage, which cannot be predicted. Even women with low and falling β-hCG levels may have significant bleeding. For this reason, expectant management is rarely used. • Patients who are Rh negative should receive Rho(D) immunoglobulin (RhoGAM), even though the risk of sensitization is low. • Surgical management: • Procedure selection. • Surgical options are operative laparoscopy and D&C. • In the stable patient, a short waiting time to assemble personnel and equipment and to ensure safety (e.g., allowing time for gastric emptying) may be appropriate. • The first choice for surgical management is operative laparoscopy with either salpingostomy or salpingectomy. Laparotomy is reserved for specific indications. °°Laparoscopic salpingostomy is the procedure of choice in most circumstances (10). °°Salpingectomy is selected if future fertility is not desired (e.g., ectopic pregnancy after tubal ligation) or if rupture has destroyed the tube. Some authorities argue that salpingectomy is the treatment of choice if the contralateral tube is normal; others reserve salpingectomy only for situations where the tube cannot be salvaged (significant bleeding that cannot be controlled, rupture of the tube, or severely damaged tube). °°Laparotomy should be performed if laparoscopy is unsatisfactory because of extensive adhesions, if the patient becomes unstable, or if there are medical limitations to laparoscopy. Laparotomy is usually performed via a small Pfannenstiel incision (10). • Dilation and curettage is performed only if the pregnancy is undesired or the cervix is widely dilated. If the pregnancy is intrauterine, villi can be identified by floating the uterine contents in saline and searching for characteristic bubble-like structures joined by strands of tissue. Frozen section can also be used to search for villi; however, there are high rates of false-positive and false-negative results with frozen sections, and they may be difficult to obtain in a timely manner. • If the clinical presentation is highly suggestive of ectopic pregnancy, laparoscopy should be performed rather than relying on uterine examination unless products of conception are unequivocally seen. °°When the pregnancy is desired, no instruments should be passed through the cervix until the diagnosis of ectopic pregnancy is verified laparoscopically. °°After insertion of the laparoscope, peritoneal blood is aspirated with a large-bore aspirator. The pelvis is visualized, with lysis of adhesions if necessary to obtain a (c) 2015 Wolters Kluwer. All Rights Reserved.

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clear view. Both tubes should be carefully examined. The ectopic pregnancy usually appears as a fusiform, hemorrhagic swelling within the tube. Sometimes, tubal abortion has already taken place with the pregnancy partially or completely extruded from the fimbriated end of the tube, and the products of conception may be within the blood and clot that has been aspirated. Salpingotomy is performed by making a 1- to 1.5-cm incision in the antimesenteric aspect of the tube, directly over the most distended part of the tube, using unipolar needlepoint cautery. Hemostasis can be enhanced by injection of a dilute solution of vasopressin into the tube or the mesosalpinx. The pregnancy mass is then gently removed, using traction and fluid dissection between the mass and the tube wall. The trophoblastic site is cauterized for hemostasis using fine point cautery. There is no need to suture the salpingostomy site. If bleeding cannot be controlled, laparoscopic salpingectomy should be performed using cauterization and incision of the mesosalpinx, laparoscopic stapling devices, or endoscopic ligatures (10). • After conservative surgery (when the tube is not removed), weekly β-hCG levels should be obtained until they are less than negative (values vary by laboratory). °°Approximately 5% to 10% of women treated with salpingostomy will have persistent trophoblastic activity in the tube, which may result in tubal rupture and/or intraabdominal hemorrhage. °°The risk of persistence is increased with larger pregnancies and higher baseline β-hCG levels. °°If there is concern about the completeness of removal of the pregnancy, postoperative prophylactic methotrexate using the single-dose regimen significantly decreases the rate of persistence. °°Early detection of trophoblastic persistence is facilitated by persistently elevated or rising β-hCG levels. • Medical management: • Medical management has the advantage of avoiding surgery with its attendant risks. Patients who are clinically stable with a small, unruptured ectopic pregnancy may be offered medical management with systemic methotrexate, a folic acid antagonist that preferentially inhibits rapidly replicating cells such as trophoblast. In properly selected patients, methotrexate is 75% to 85% effective in resolving ectopic pregnancy, with the remaining women requiring surgery. • Criteria for medical management include hemodynamic stability, gestational sac less than 3.5 cm in diameter, β-hCG at diagnosis less than 5000 IU, no ultrasound fetal cardiac activity, minimal hemoperitoneum, no underlying liver or renal disease, no blood dyscrasia, not breast-feeding, and ability to have regular follow-up. • A D&C should be performed to rule out a nonviable intrauterine pregnancy because medical treatment is ineffective at emptying the uterus. • Pretreatment complete blood count and platelet count, β-hCG level, and liver and renal function tests should be obtained. • Methotrexate is given in either single-dose or multidose regimens (Table 7-4). The two regimens have been widely studied for treatment of ectopic pregnancy and both are acceptable. °°The multidose regimen has a lower failure rate; however, the risk of complications including diarrhea, abnormal liver function, and stomatitis is greater with the multidose regimen. °°The single-dose regimen is slightly less successful, requiring a second dose in up to 20% of women; however, there is a lower incidence of side effects. The failure rate is approximately 15% with the single-dose regimen when the initial β-hCG level is greater than 5000 IU but drops to approximately 4% with lower initial β-hCG levels. °°The failure rate of either regimen increases when a live embryo, a high initial β-hCG level, or a large adnexal mass is present. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Table 7-4

Methotrexate for Ectopic Pregnancy

Protocol

Single-dose regimen 50 mg/m2 IM

Follow-up

β-hCG days 4, 7, then weekly

Success rate

88% 70% single dose 85% two doses

Side effects

10%–25%

Multidose regimen 1 mg/kg IM days 1, 3, 5, 7 until β-hCG drops Leucovorin 0.1 mg/kg days 2, 4, 6, 8 β-hCG each day until >15% drop, then weekly 93% 10% single dose 25% two doses 50% ≥4 doses 15%–35%

IM, intramuscular; β-hCG, β-human chorionic gonadotropin.

--Follow-up after methotrexate includes measurement of β-hCG on days 4 and 7

after the single dose. * The day 4 level is usually increased over baseline due to lysis of trophoblast. * The day 7 level should be at least 15% less than the day 4 level or the dose may be repeated. * Repeat dosing may also be required if β-hCG levels increase or plateau. * Levels of β-hCG should be followed weekly until reaching a nonpregnant level (threshold will vary by laboratory) (1). * Transient increase in abdominal pain is common in the days to weeks after methotrexate administration. This is thought to be caused by separation of the trophoblast from the tubal wall with varying amounts of intraperitoneal bleeding. Most separation pain can be managed on an outpatient basis; however, significant pain may require hospitalization and observation to rule out rupture and intraperitoneal hemorrhage. * Surgical intervention is rarely required but may be needed to manage severe pain, hemorrhage, or treatment failure.

Unusual Locations • Nontubal ectopic pregnancy. More than 95% of ectopic pregnancies occur in the fallopian tube, usually in the distal half. However, pregnancies can implant in a wide variety of sites, including the ovary, intramyometrial portion of the tube or uterine cornua, lower uterine segment or cervix, prior cesarean section scar, and peritoneal cavity (1). • These pregnancies are usually diagnosed later than are tubal pregnancies, in part because they tend to grow larger and progress further in gestation before causing symptoms. • Catastrophic rupture with hemorrhage and shock is significantly more likely to occur in these nontubal pregnancies. • A thorough evaluation including comprehensive transvaginal ultrasound examination is necessary to diagnose these unusual pregnancies. • Treatment is individualized, and a combination of medical and surgical therapy is often appropriate. • Abdominal pregnancy accounts for approximately 0.003% of all pregnancies and 1.4% of all ectopic pregnancies. It arises either from primary implantation in the abdominal cavity or secondary implantation after tubal abortion. • Women with abdominal pregnancy often can present with advanced gestation age complaining of abdominal pain, unusual fetal lie, or unusually prominent fetal parts (c) 2015 Wolters Kluwer. All Rights Reserved.

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(11). If partial placental separation has occurred, the patient may present in shock with intra-abdominal hemorrhage. • Diagnosis may be difficult to make with ultrasound; CT scanning or magnetic resonance imaging may be required. • Once the diagnosis is established, the patient should be stabilized with fluids, blood typed and cross-matched, and a laparotomy performed. The fetus should be removed, the umbilical cord tied as close as possible to the placenta, and the placenta left in situ. Any attempt to separate the placenta from abdominal organs or the abdominal wall may result in severe blood loss and should therefore be avoided. • Cervical pregnancy arises from implantation in the cervical epithelium instead of the endometrium and account for less than 1% of ectopic pregnancies. • The patient usually presents with heavy vaginal bleeding and a cervical mass. The cervix may be effaced and dilated. It is sometimes difficult to distinguish a cervical implantation from an incomplete abortion with products of conception passing through the cervix. • Ultrasound may help distinguish a small uterine fundus above the pregnancy mass. • The pregnancy can removed with suction curettage, but bleeding from the implantation site is often very heavy. Paracervical injection with dilute vasopressin may aid with hemostasis. Hysterectomy may be necessary if hemorrhage is severe. • Conservative treatment using systemic chemotherapy (typically multiregimen methotrexate) in combination with cervical evacuation and hemostatic techniques (balloon tamponade, uterine artery ligation, cervical sutures) is an option in the stable patient (11). • Ovarian pregnancy implants within the ovarian stroma. Ovarian pregnancies are rare, and the diagnosis is seldom made preoperatively. Management is cystectomy or wedge resection of the ovary with repair of the ovary or oophorectomy if cystectomy cannot be accomplished. Long-Term Prognosis • Women who have had one ectopic pregnancy are at significant risk for future infertility and for recurrent ectopic pregnancies. Regardless of treatment modality, patency of the affected tube can be demonstrated by hysterosalpingogram in approximately 75% of women. • Women who have had an ectopic pregnancy should be educated about the symptoms associated with ectopic pregnancy and should be counseled to seek care immediately upon diagnosis of a subsequent pregnancy, regardless of symptoms. β-hCG levels should be monitored, and an early ultrasound should be performed. PATIENT EDUCATION • Women with known risk factors for ectopic pregnancy should be informed of the risks and symptoms before trying to become pregnant. • When a woman has a suspected or diagnosed ectopic pregnancy, she should receive detailed counseling about the medical and surgical management options. • Patients who select medical management with methotrexate must be informed of the need for close, regular follow-up with monitoring of β-hCG levels. REFERENCES 1. American College of Gynecologists. ACOG Practice Bulletin No. 94: Medical management of ectopic pregnancy. Obstet Gynecol. 2008;111:1479–1485. 2. Silva C, Sammel MD, Zhou L, et al. Human chorionic gonadotropin profile for women with ectopic pregnancy. Obstet Gynecol. 2006;107:605–610. 3. Ankum WM, Mol BW, Van der Veen F, et al. Risk factors for ectopic pregnancy: a metaanalysis. Fertil Steril. 1996;65:1093–1099.

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4. Clayton HB, Schieve LA, Peterson HB, et al. Ectopic pregnancy risk with assisted reproductive technology procedures. Obstet Gynecol. 2006;107:595–604. 5. Barnhart KT, Sammel MD, Rinaudo PF, et al. Symptomatic patients with an early viable intrauterine pregnancy: HCG curves redefined. Obstet Gynecol. 2004;104:50–55. 6. Verhaegen J, Gallos ID, van Mello NM, et al. Accuracy of single progesterone test to predict early pregnancy outcome in women with pain or bleeding: meta-analysis of cohort studies. BMJ. 2012;345:e6077. 7. Barnhart K, Mennuti MT, Benjamin I, et al. Prompt diagnosis of ectopic pregnancy in an emergency department setting. Obstet Gynecol. 1994;84:1010–1015. 8. Nyberg DA, Laing FC, Filly RA, et al. Ultrasonographic differentiation of the gestational sac of early intrauterine pregnancy from the pseudogestational sac of ectopic pregnancy. Radiology. 1983;146:755–759. 9. Shaunik A, Kulp J, Appleby DH, et al. Utility of dilation and curettage in the diagnosis of pregnancy of unknown location. Am J Obstet Gynecol. 2011;204:130.e1–e6. 10. Al-Sunaidi M, Tulandi T. Surgical treatment of ectopic pregnancy. Semin Reprod Med. 2007;25:117–122. 11. Molinaro TA, Barnhart KT. Ectopic pregnancies in unusual locations. Semin Reprod Med. 2007;25:123–130.

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8

Spontaneous Preterm Birth Emily DeFranco and Kristin L. Atkins

INTRODUCTION • Preterm delivery is one of the most serious problems in obstetrics. Prematurity is the leading cause of neonatal morbidity and mortality in the United States (1). Despite advances in research and medical care, the incidence of prematurity in the United States remains among the highest compared to other industrialized nations. • The incidence of preterm birth peaked in 2006 and has slightly declined over the last 7 years. • Spontaneous preterm birth is a multidimensional problem that includes preterm labor, preterm premature rupture of membranes, cervical insufficiency, and short cervix. PRETERM LABOR Key Points • The complex mechanisms leading to preterm labor limit the effectiveness of any single treatment intervention. • Preterm labor is diagnosed clinically by evidence of regular uterine contractions associated with cervical change. • Tocolytic medications may prolong pregnancy for a short period of time (48 to 72 hours). • Antenatal corticosteroids should be administered to women at risk of preterm delivery. • Progesterone supplementation may reduce the rate of recurrent spontaneous preterm delivery in women with a prior spontaneous preterm birth. It may also reduce preterm birth risk in asymptomatic singleton pregnancies with midtrimester cervical shortening. Background Although the causes of preterm labor are not well understood, its clinical impact is clear. Infant prematurity is the leading cause of newborn morbidity, mortality, and health expenditure in the United States. The incidence of serious complications of prematurity increases dramatically as the gestational age at delivery decreases. Neonatal mortality also increases with declining gestational age at delivery (2). The serious complications of prematurity include, but are not limited to, respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, sepsis, and patent ductus arteriosus. The costs related to these complications increase exponentially with the degree of prematurity. The economic burden attributed to preterm birth is estimated to be at least 26 billion dollars annually in the United States, with most of that cost incurred in the care of infant survivors of prematurity (3). Definition

• Preterm labor is defined as regular uterine contractions associated with cervical change occurring from 20 to 36 6/7 weeks of gestational age. Pathophysiology

• The pathophysiologic mechanisms that lead to the onset of preterm labor are complex and multifactorial. Because of this complexity, the identification of an effective intervention for preterm labor has been elusive. 133

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• In addition to mechanisms as yet unknown, preterm labor likely occurs as a result of the concomitant activation or a cascade of the following events (4,5): • Functional progesterone withdrawal • Increase in corticotrophin-releasing hormone • Premature decidual activation • Increased prostaglandin production • Oxytocin initiation • Increased cytokine production Etiology

Numerous factors contribute to the high incidence of preterm delivery, including the increase in pregnancies in women over 35 years of age and the increase in the incidence of multiple gestations due to more frequent use of artificial reproductive technologies (6). There are a multitude of causes of preterm delivery. In general, preterm deliveries can be classified as (a) iatrogenic or indicated due to a significant maternal or fetal complication of pregnancy, (b) spontaneous due to preterm labor, or (c) a result of preterm, premature rupture of membranes (PROM). Spontaneous preterm labor accounts for approximately 50% of preterm deliveries. Iatrogenic prematurity and PROM constitute the remaining 50%, contributing approximately 25% each (7). This chapter focuses on spontaneous preterm birth, which is divided primarily into two categories: preterm labor with intact membranes and PROM. In addition, we review cervical disorders that predispose a pregnant woman to spontaneous preterm birth: cervical insufficiency and asymptomatic short cervix. Epidemiology

• The incidence of preterm delivery remains high, with the most recent estimate being 11.5% (8). Preterm delivery occurs more frequently in black women than in white women, especially at the very early gestational ages of less than 28 weeks (9). Of all etiologies of preterm birth, preterm labor is the major contributor. • Risk factors for preterm labor include (10,11) • Prior preterm delivery • African American race • Low socioeconomic status • Lack of prenatal care • Intense physical exertion or stress • Low body mass index • Extremes of maternal age (younger than 18 or older than 40) • Tobacco use • Substance abuse • Prior induced abortion • Prior cervical surgery • Periodontal disease • Uterine overdistension (i.e., multiple gestation or polyhydramnios) • Vaginal bleeding during pregnancy • Uterine anomaly • Anemia • Reproductive tract infections • Short cervix in the midtrimester of pregnancy • Numerous risk factor scoring systems have been proposed for the prediction of preterm labor. Unfortunately, these scoring systems have not been proven to reliably predict spontaneous preterm birth, and most lack clinically important reference standards (12). (c) 2015 Wolters Kluwer. All Rights Reserved.

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Evaluation

History and Physical

• Symptoms may or may not be present in women presenting with preterm labor. When present, these symptoms may vary greatly. Some of the most common presenting symptoms of preterm labor are • Rhythmic contractions (some women describe this as a feeling of “balling up”) • Lower abdominal cramping • Low back pain • Pelvic pressure • Increase in vaginal discharge • Bloody vaginal discharge (bloody show) • Cervical examination can be performed by any one or a combination of the following tools: • Digital cervical exam: °°A change in dilation and/or effacement of the cervix in the presence of regular uterine contractions is sufficient for the diagnosis of preterm labor. °°Alternatively, regular uterine contractions and a cervix greater than 2 cm dilated or ≥80% effaced upon a single examination are sufficient for the diagnosis. • Visual estimation of cervical dilation and effacement by speculum examination • Ultrasonography of the cervix to measure cervical length (CL) • In some cases where the diagnosis of preterm labor is uncertain, that is, frequent preterm contractions without cervical change or cervical dilation less than 2 cm, a combined approach of cervical length measurement and fFN testing may assist in the diagnosis. This approach has been shown to be reliable for diagnosis of PTL or exclusion of PTL compared to the standard approach of digital cervical exam (13,14). Laboratory Tests

• Rectovaginal culture for group B streptococcus (GBS) (Streptococcus agalactiae) should be obtained. • Wet mount (swab of vaginal secretions mixed with saline placed on a microscope slide). The presence of “clue cells” indicates bacterial vaginosis. The presence of flagellated microorganisms indicates Trichomonas vaginalis infection. • Urinalysis and culture to evaluate for evidence of urinary tract infection or asymptomatic bacteriuria. • Fetal fibronectin test from a swab of cervicovaginal secretions. This test • Can be especially useful if the diagnosis of preterm labor is in question. • Has a high negative predictive value. If negative, the risk of delivering in the upcoming 2 weeks is less than 1% (15). • Has a relatively low positive predictive value if used alone. If positive, the risk of delivering in 1 week is 18% (16). • Has a relatively high positive predictive value for preterm birth within a short period of time if used in combination with cervical length in symptomatic patients (13). • Microscope slide of dried vaginal sidewall secretions (do not use a cover slip) to evaluate for evidence of “ferning,” which is suggestive of the diagnosis of PROM. • This is only necessary if PROM is suspected based on patient’s history or exam. • Avoid contaminating the slide with saline, which may result in the false appearance of ferning. • Cervical mucus may also fern, so close attention should be paid to the collection of the specimen. • A new test, AmniSure, may also be used for diagnosis of PROM. It has high screen accuracy for diagnosis of PROM. • Cervical cultures for Chlamydia trachomatis and Neisseria gonorrhoeae may be collected as clinically indicated. • Drug abuse screen, either serum or urine, as clinically indicated. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Ultrasound

• A thorough obstetrical ultrasound is helpful in evaluating the etiology of preterm labor in order to • Identify obvious fetal malformations. Some major congenital malformations may be a contraindication to tocolysis, and some may warrant aggressive tocolysis. • Identify abnormalities in fetal growth. • Identify abnormalities in amniotic fluid volume (oligohydramnios or polyhydramnios). • Confirm fetal presentation to aid in planning mode of delivery. • Evaluate placenta, identifying its location and noting any abnormalities. • Ultrasound evaluation of the cervix may help to further refine the risk of preterm delivery (15). Short cervical lengths are associated with an increased risk of preterm delivery. • Cervical length of 30 mm or greater is useful to exclude the diagnosis of preterm labor. • Short cervical lengths (less than 25 mm or less than 20 mm, depending on gestational age) may assist in confirming the diagnosis of preterm labor, especially when used in combination with positive fFN result (13). Diagnosis • Preterm labor is a clinical diagnosis. It should be suspected in any gravida with regular preterm uterine contractions and is confirmed with documented cervical change. The previously mentioned objective criteria may also be useful in establishing the diagnosis (fetal fibronectin and ultrasound measurement of cervical length). Treatment

Bed Rest and Hydration

• There is no scientific evidence to prove that bed rest, although commonly prescribed, is useful in preventing or treating preterm labor. The American College of Obstetricians and Gynecologists (ACOG) states that “although bed rest and hydration have been recommended to women with symptoms of preterm labor to prevent preterm delivery, these measures have not been shown to be effective for the prevention of preterm birth and should not be routinely recommended. Furthermore, the potential harm, including venous thromboembolism, bone demineralization, and deconditioning, and the negative effects, such as loss of employment, should not be underestimated” (17). • Hydration, both orally and intravenously, is commonly used in the treatment of preterm labor. Several studies that have evaluated the effect of hydration on preterm labor have demonstrated no benefit (18,19). Tocolytic Medications

• Women who meet criteria for the diagnosis of preterm labor are candidates for tocolytic therapy. There is no clear “first-line” tocolytic medication (17). Little evidence exists that any tocolytic medication can effectively prolong gestation longer than 2 to 7 days (20). However, this short prolongation is usually sufficient to administer corticosteroids for fetal benefit and to transfer the patient to a tertiary care facility before delivery. These interventions have been shown to improve perinatal outcome. • Tocolytic medications are, most often, given to women with preterm labor at less than 34 weeks of gestational age. After 34 weeks of gestation, the risk of complications of tocolytic therapy may outweigh the benefits of prolonging the pregnancy for a short period of time. After a determined period of time (48 hours), tocolytic therapy is usually discontinued because prolonged use of tocolysis may increase the maternal–fetal risk without offering a clear benefit (3). Eighty percent of women with presumed preterm labor subsequently deliver at term (15). Therefore, careful consideration should be given before initiating tocolytic therapy. • There are a number of contraindications to tocolysis including, but not limited to, placental abruption, lethal fetal congenital anomaly, intrauterine infection (chorioamnionitis), severe preeclampsia, and evidence of fetal compromise (3). (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Calcium channel blockers (5,21): • The most common calcium channel blocker used for tocolysis is nifedipine. • Mechanism of action: decreases the influx of intracellular calcium ions into myometrial cells, promoting relaxation (22). • Dosage: 20- to 30-mg loading dose, followed by 10 to 20 mg every 4 to 8 hours orally. • Precautions: use with caution in patients with cardiac disease or renal disease and avoid concomitant use with magnesium sulfate. • Side effects: flushing, headache, dizziness, hypotension, and peripheral edema. • Complications: some side effects can be severe, resulting in the discontinuation of therapy in 2% to 5% of patients. Severe hypotension can occur if used with magnesium sulfate. There are no known adverse fetal effects. • Magnesium sulfate: • Tocolytic agent of choice of many obstetricians and perinatologists in the United States (23). • Mechanism of action: inhibits smooth muscle contractions by inhibiting calcium uptake. • Dosage: 4 to 6 g as intravenous (IV) bolus over 15 to 30 minutes, followed by 2 to 6g/h (24). A common clinical approach is to start with a 6-g IV bolus followed by 3 g/h. The hourly rate is titrated until uterine contractions abate or until a serum level of 5 to 8 ng/dL is reached (25). Magnesium sulfate may be discontinued simply by ceasing IV infusion at any time. Weaning the drug is not necessary (26). Serum magnesium levels will slowly decrease as magnesium is cleared by the kidneys. • Precautions: magnesium sulfate should be avoided in women with myasthenia gravis, cardiac impairment, renal impairment, or with concomitant use of a calcium channel blocker due to the potential of causing profound hypotension (24,27). • Side effects: flushing, nausea, headache, drowsiness, and blurred vision. These are common side effects with therapeutic doses of magnesium and not necessarily evidence of magnesium toxicity. • Complications: °°Monitoring for evidence of magnesium toxicity should be performed at frequent intervals in all patients receiving magnesium tocolysis. --Diminished or loss of deep tendon reflexes with serum magnesium levels of greater than 10 ng/dL. --Respiratory depression (greater than 15 ng/dL). --Cardiac arrest (greater than 18 ng/dL). --Magnesium toxicity can be rapidly reversed with 1 g of IV calcium gluconate. °°Pulmonary edema may occur, especially in women with multiple gestation, multiagent tocolytic therapy, or fluid overload (5). • β-Sympathomimetics (5,28): • Ritodrine is the only medication approved by the Food and Drug Administration (FDA) for tocolysis in the United States. Ritodrine is associated with significant side effects and patient intolerance. Because of these side effects, ritodrine has not been marketed in the United States since 1998. • Terbutaline is currently the most commonly used β-sympathomimetic and is β2 selective. Most studies have shown that it is effective in temporarily arresting preterm labor, but it does not reduce the rate of preterm delivery. • Mechanism of action: stimulation of β receptors (some β2 selective), resulting in uterine smooth muscle relaxation. • Dosage: °°Subcutaneous: 0.25 mg every 20 minutes for 4 to 6 doses. Hold for pulse greater than 120 beats/min. °°Subcutaneous pump: Although available, this method is not recommended due to increased risk of maternal cardiac toxicity and death. The FDA recommends against its use for more than 48 hours. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Precautions: avoid or use with caution in patients with cardiac arrhythmias, diabetes, hyperthyroidism, or hypertension. • Side effects: tachycardia, tremor, decreased appetite, and hypotension. • Complications: pulmonary edema (especially with multiagent tocolysis), cardiac arrhythmias, hyperglycemia, hypokalemia, neonatal cardiac arrhythmias, and hypoglycemia. • Prostaglandin synthase inhibitors (5,29): • Agents available: aspirin, ibuprofen, indomethacin, sulindac, ketorolac. Indomethacin is the most commonly used agent. • Mechanism of action: inhibition of prostaglandin synthetase or cyclooxygenase, blocking prostaglandin production. • Dosage: indomethacin can be administered orally, rectally, or vaginally. Common regimens include a 50- to 100-mg loading dose, followed by 25 mg every 6 to 8 hours. Many obstetricians limit the use to 48 to 72 hours to avoid complications (30). • Precautions: contraindicated in patients with active peptic ulcer disease, sensitivity to nonsteroidal anti-inflammatory drugs, significant renal or hepatic impairment, or hematologic abnormalities (especially thrombocytopenia). • Side effects: nausea and gastrointestinal upset. • Complications: indomethacin use has been associated with several fetal and neonatal complications, including premature closure of the fetal ductus arteriosis (especially at gestational ages greater than 32 weeks) (31), pulmonary hypertension, oligohydramnios, intraventricular hemorrhage, and necrotizing enterocolitis. Most of these reported complications occurred in pregnancies with prolonged administration, and these results should be viewed with caution due to multiple potential confounders (32). • Multiple-agent tocolysis: • No clear evidence exists that combining tocolytic drugs improves efficacy. Combining tocolytic agents potentially increases the risk of maternal and neonatal complications (17). Using multiple tocolytic agents simultaneously should be approached with caution. • Maintenance tocolysis: • No clear evidence exists that maintenance tocolysis increases gestational age at birth, increases birth weight, or effectively prolongs pregnancy (33). Corticosteroids

• Antepartum corticosteroids effectively reduce the incidence of neonatal respiratory distress, intraventricular hemorrhage, necrotizing enterocolitis, and neonatal death in preterm infants. A single course of corticosteroids should be administered to all pregnant women between 24 and 34 weeks of gestation who are at risk of preterm delivery within 7 days (34). • Either betamethasone or dexamethasone may be used. Neither the National Institutes of Health (NIH) nor the American College of Obstetricians and Gynecologists (ACOG) recommend the use of one over the other (35). • Betamethasone, 12 mg intramuscularly (IM) every 24 hours for two doses • Dexamethasone, 6 mg IM every 12 hours for four doses • A single additional dose may be considered if the initial dose was given more than 2 weeks prior and there is additional risk for preterm delivery, as recommended by ACOG. Multiple repeat doses of steroids have not been shown to provide added benefit and may be harmful (35). Magnesium Sulfate for Neuroprotection

• Several studies have been published to evaluate the use of magnesium prior to delivery of a preterm infant to assess the reduction in risk of neonatal complications (36–40). • Meta-analyses of these studies have shown that there is a reduction of the incidence of cerebral palsy in these preterm infants when exposed to magnesium sulfate prior to delivery (41,42). (c) 2015 Wolters Kluwer. All Rights Reserved.

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• ACOG Committee on Obstetric Practice has recognized this reduction in the risk of cerebral palsy and has recommended that institutions choosing to use magnesium sulfate for neuroprotection should “develop specific guidelines regarding inclusion criteria, treatment regimens, concurrent tocolysis, and monitoring in accordance with one of the larger trials” (43). Antibiotics

• There is no evidence that treating women with preterm labor with antibiotics is effective in prolonging pregnancy, and this practice is not recommended (35). • Antibiotic prophylaxis to prevent GBS sepsis in the newborn is recommended in women with preterm labor (44). The Centers for Disease Control and Prevention recommends GBS culture of all women in preterm labor. If the culture is negative within 4 weeks of delivery, prophylaxis is not recommended. Prevention

• Progesterone • Studies have demonstrated that progesterone given to women with a history of spontaneous preterm birth can effectively decrease the incidence of recurrent preterm birth in a subsequent pregnancy (45). The optimal formulation for this indication has not been identified, but the most commonly used agent, based on data from the largest clinical trial, is °°17-Hydroxyprogesterone caproate. °°Dose: 250 mg IM weekly initiated at 16 to 20 weeks of gestational age and continued until 37. °°Other studies have demonstrated that women with a singleton pregnancy and asymptomatic cervical shortening in the midtrimester of pregnancy (less than 20 mm) benefit from vaginal progesterone therapy (45). °°Micronized progesterone 200 mg capsule, one per vagina once daily. °°Progesterone 8% vaginal gel, one applicator daily. Complications of Preterm Labor • There are a number of complications that may be either the cause or the result of preterm labor: • Placental abruption • Intra-amniotic infection (chorioamnionitis) • PROM Patient Education • Incidence of preterm delivery in patients with preterm labor: • Eighty percent of women with presumptive preterm labor go on to deliver at term (15). • Recurrence of preterm labor in future pregnancies: • The incidence of recurrent, spontaneous preterm birth varies greatly in numerous series (from 15% to greater than 50%). • The risk increases with multiple factors, including a history of a very early preterm delivery (i.e., less than 28 weeks of gestational age) (46). PRETERM, PREMATURE RUPTURE OF THE MEMBRANES Key Points • PPROM accounts for 25% to 30% of all preterm deliveries. • The management of preterm PPROM should take into account the risk of pregnancy prolongation (intra-amniotic infection, placental abruption, and fetal compromise) versus the benefits of conservative management (fetal maturation). • Women with PPROM at greater than 34 weeks’ gestation should be delivered. • Antibiotics have been shown to prolong latency in patients with PROM. • Corticosteroids decrease neonatal morbidity when given to women with uncomplicated PPROM. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Background PPROM occurs in approximately 3% of all pregnancies and accounts for 25% to 30% of all preterm deliveries (7,47). PPROM presents a unique management dilemma to obstetricians and perinatologists, who must balance between continued gestation to alleviate the risk of prematurity-related morbidities and the prevention of adverse fetal and maternal outcomes related to membrane rupture. The interval between membrane rupture and delivery is usually short, but it is inversely proportional to the gestational age at which it occurs (earlier gestational ages have longer latencies). When managed conservatively, more than half of women with PROM before 34 weeks deliver within 1 week (47,48). Prolonging pregnancy decreases the incidence of neonatal morbidities associated with prematurity, yet longer latencies may increase the likelihood of developing complications of PPROM such as chorioamnionitis, placental abruption, and umbilical cord compression. Definition

• Preterm rupture of the membranes: rupture of the amniotic membranes before 37 weeks of gestational age. • Premature rupture of the membranes: rupture of the amniotic membranes before the onset of labor, regardless of gestational age. • Prolonged rupture of the membranes: rupture of the amniotic membranes for more than 18 hours. • PPROM: preterm premature rupture of the membranes. • PPROM indicates the addition of prolonged membrane rupture. Pathophysiology

• At term, membrane rupture is considered a normal part of parturition and may occur before or after the onset of labor. It occurs due to a combination of physiologic processes that may be exacerbated by uterine contractions (47). • Preterm rupture of membranes is associated with a higher incidence of intrauterine infection than rupture of membranes at term, especially at very early gestational ages. It is thought that ascending bacteria from the vagina lead to increased cytokine activation and resultant apoptosis in the amniotic membranes, making them more susceptible to rupture (49). • PROM can also occur as a complication of amniocentesis. This is fairly uncommon and occurs in less than 0.5% of amniocentesis procedures. Etiology

• Various factors have been associated with PPROM, including • Infectious causes (amnionitis, cervicitis, and other vaginoses) • Increased uterine volume (polyhydramnios and multiple gestation) • Subchorionic hemorrhage • Cervical conization or cerclage • Fetal anomalies • Low socioeconomic status • Biochemical structural abnormalities (Ehlers-Danlos syndrome) • Maternal trauma • Substance abuse, including smoking Evaluation

History and Physical

• Given the significant adverse effects of PPROM on pregnancy outcome, any patient who presents with a history of leaking fluid from the vagina or has a decreased amniotic fluid volume on US should be carefully evaluated. • Direct digital cervical exam should be avoided until the diagnosis of PPROM is ruled out or a decision to deliver has been made. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Sterile speculum exam is used to document rupture of membranes, using the tests described below. The posterior fornix should be examined for evidence of pooling of amniotic fluid. If pooling is not immediately evident, one may visualize fluid coming through the cervix during a Valsalva maneuver or with coughing. Laboratory Tests

• Fern test • The fern test has traditionally been the most common method to determine rupture of membranes. • Vaginal secretions from the posterior fornix are collected with a sterile cotton-tipped applicator and smeared thinly on a glass slide. After sufficient time to allow for the sample to air dry, it is examined under the microscope for the presence of an arborized (fernlike) pattern. To prevent false-negative readings, the slide must be completely dry. Any evidence of arborization should be read as a positive test. • False-positive tests have been reported with the presence of dried saline and/or cervical mucus. • AmniSure • The AmniSure test is a rapid test for the presence of placental alpha microglobulin-1 (PAMG-1) in the vagina. PAMG-1 is a protein found at high levels within amniotic fluid and extremely low levels within cervical and vaginal fluid. • A sterile Dacron swab is used to collect fluid from the vagina. The sterile swab is placed in the vagina no more than 2 to 3 inches deep and left in place for 1 minute. The swab is then rotated in the testing vial for 1 minute. The test strip is then inserted into the vial with solvent. A positive result will be apparent within 10 minutes. • A positive test confirms the presence of ruptured membranes. This testing may be better than nitrazine and ferning test in the presence of prolonged time from time of rupture of membranes. • This test has a sensitivity of 98.7% to 98.9% and specificity of 87.5% to 100% when compared to the presence of ferning and nitrazine positive (50). • Nitrazine test • The nitrazine test relies on the pH of amniotic fluid (pH 7.0 to 7.5), which is significantly more alkaline than normal vaginal secretions (pH 4.5 to 5.5). • A sample of vaginal secretions is smeared onto nitrazine pH paper. A color change to blue-green (pH 6.5) or blue (pH 7.0) is strong evidence for the presence of amniotic fluid. • False-positive results may occur with the presence of blood, urine, semen, or antiseptic cleansing agents. • Due to quality control concerns, this is becoming a less frequently used test for PROM in labor and delivery units. • Ultrasound is helpful in confirming PPROM and aiding in management decisions. • Amniotic fluid volume by ultrasound helps confirm the diagnosis of PPROM, especially when the fern test or the nitrazine test is equivocal. PPROM is usually associated with a low amniotic fluid volume; however, pockets of fluid larger than 2 × 2 cm are often present. • Determination of the fetal presenting part and estimated fetal weight is helpful in the management of women with PPROM. In the case of PPROM, serial ultrasounds for fetal growth should be performed every 3 to 4 weeks as a measure of fetal well-being. • Amniocentesis • Amniocentesis can be used to confirm the diagnosis of PPROM if all other data are inconclusive. • One ampule of indigo carmine diluted in 10 to 20 mL of sterile saline is infused into the amniotic sac through an amniocentesis needle. A tampon is placed in the vagina. The tampon is then removed after 30 to 40 minutes. Presence of blue dye on the tampon confirms the diagnosis of PPROM. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• The patient should be warned that if the fetus delivers within several days, the baby may be stained with the dye used for evaluation. • Methylene blue should not be used because it is associated with fetal hemolytic anemia, hyperbilirubinemia, methemoglobinemia, and fetal staining. • Amniocentesis may also be used to confirm a diagnosis of intra-amniotic infection. Amniotic fluid glucose concentrations below 16 to 20 mg/dL, a positive Gram stain, or a positive amniotic fluid culture are suggestive of this diagnosis. • Rectovaginal culture for GBS (Streptococcus agalactiae) should be obtained. • Cervical cultures for Chlamydia trachomatis and Neisseria gonorrhea may be collected as clinically indicated. • Amniotic fluid may be sent for fetal lung maturity testing. The sample may be obtained from a vaginal pool or amniocentesis. Diagnosis • Clinical evaluation as described above is essential for the diagnosis of PPROM. • PROM should be suspected when there is a history of leaking fluid from vagina or if a low amniotic fluid volume is detected on ultrasound. Differential Diagnosis

• Ensure that the fetal kidneys and bladder are present and normal appearing. Oligohydramnios may be the result of renal agenesis, a lethal abnormality. The management of these pregnancies is quite different from those complicated by PPROM. • Decreased amniotic fluid volume may also be the result of fetal compromise with reduced renal perfusion due to uteroplacental insufficiency. Clinical Manifestations

• Time from rupture of membranes to delivery is usually brief and is inversely related to gestational age at the time of rupture. However, even with conservative management, 50% of women deliver within 1 week of rupture (47,48). Despite this, these women may benefit from conservative management (51). • A small percentage of cases of PPROM resolve, and the fluid leakage ceases (2.6% to 13%) (52). Treatment • Unless delivery is imminent, the patient should be cared for in a hospital that can provide adequate neonatal care for the infant. This may require transfer to a tertiary care facility. • Delivery of the fetus may be indicated in the following circumstances: • Active labor • Chorioamnionitis (maternal fever, uterine tenderness, maternal or fetal tachycardia) • Nonreassuring fetal testing • Fetal demise • Evidence of placental abruption with significant vaginal bleeding • Advanced cervical dilation and/or fetal malpresentation with increased concern for umbilical cord prolapse • In the absence of any of the above concerns, gestational age is the primary factor in the decision to continue conservative management. Prolongation of pregnancy to allow the fetus to mature is of primary concern. Once the fetus is mature or reaches the gestational age where the intensive care unit staff determines it to be relatively mature, the benefit of continued intrauterine growth is outweighed by the risks of continuing the pregnancy. • After 34 weeks of gestational age, conservative management increases the risk for ­chorioamnionitis, lower umbilical cord gases, and prolonged maternal hospital stay without decreasing perinatal morbidity for the fetus (53). Therefore, these fetuses should be ­delivered at 34 weeks. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Between 32 and 34 weeks, if fetal lung maturity studies are positive, delaying delivery provides no additional benefit. Conservative management in the setting of mature lung indices has been associated with increase risk of chorioamnionitis (54). If fetal lung maturity is not documented and there are no other complications, conservative management is appropriate. • Before 32 weeks, delivery is associated with significant infant morbidity related to the degree of prematurity. Conservative management is recommended if no other complications exist. • When PPROM occurs before the fetus is viable, different considerations are given to the continuation of the pregnancy. The fetus is at risk for a number of complications, including pulmonary hypoplasia and limb contractures, if the pregnancy is continued to viability. The patient with previable PPROM may be offered conservative management or immediate delivery. In the case of conservative management, the patient may be managed on an outpatient basis until viability is reached. She should then return to the hospital for inpatient management and initiation of fetal surveillance when viability is reached. Medications Antibiotics

• One of the best-studied areas in the management of PPROM is the use of antibiotics to prolong gestation. Treatment with antibiotics along with conservative management can potentially • Treat or prevent ascending infection • Prevent chorioamnionitis • Reduce neonatal sepsis • Prolong the latency period • The goal of antibiotic treatment is to provide broad-spectrum antimicrobial coverage, for both gram-positive and gram-negative bacteria (55). • The antibiotic regimen proven to prolong latency and improve perinatal outcome is as follows: • Ampicillin, 2 g, and erythromycin, 250 mg, intravenously every 6 hours the first 48 hours, followed by amoxicillin, 250 mg, and erythromycin, 333 mg, orally every 8 hours for 5 days (56) Corticosteroids

• Because patients with PPROM are at significant risk of perinatal morbidity, antenatal corticosteroids are administered for fetal benefit. A single course reduces the incidence of neonatal respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis (57). • There is no increase in perinatal infection when steroids are given in the treatment of PROM (58,59). • Dosing regimens are the same as when used for any other indication: • Betamethasone, 12 mg IM every 24 hours for two doses or • Dexamethasone, 6 mg IM every 12 hours for four doses Tocolytic Therapy

• There is no evidence that tocolytic therapy prolongs gestation in the context of ruptured membranes. Despite this lack of evidence, some centers use tocolytics in patients with PPROM in an effort to continue the pregnancy long enough to administer steroids and transport the patient to a tertiary care facility. For details of acute tocolytic therapy, refer to the “Preterm Labor” section in this chapter. Procedures

• Surveillance of fetal well-being should be performed at least daily (nonstress test and/or biophysical profile). • Continuous fetal monitoring is preferred if there are signs of umbilical cord compression or other concern for fetal well-being. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• The results of the biophysical profile may be confounded by oligohydramnios or impending labor but are still helpful in management decisions. Complications Maternal

• PROM, especially with prolonged membrane rupture, places the pregnancy at risk for chorioamnionitis from ascending bacteria. This risk increases with decreasing gestational age at time of rupture and with increased latency (60,61). • Postpartum endometritis complicates 2% to 13% of these pregnancies. • The risk of placental abruption is greater than in the general population and is reported to occur in 4% to 12% of pregnancies complicated by PPROM. Fetal

• Fetal morbidity after PPROM is predominantly related to the degree of prematurity. The most common complications of prematurity are respiratory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage, and sepsis. • Other fetal morbidities are associated with maternal infection, umbilical cord compression, placental abruption, and prolonged fetal compression. These place the fetus at an increased risk of death in utero and at an increased risk of perinatal asphyxia. • The risk to the fetus is greatly increased if PPROM occurs before the limit of viability. With prolonged oligohydramnios, there is significant risk for maldevelopment of the alveolar tree (pulmonary hypoplasia) as well as fetal compression resulting in malformations similar to those seen in Potter syndrome. • There is a growing body of literature evaluating the adverse neurologic sequelae of prolonged membrane rupture. At the present time, there is no evidence to discourage conservative management in patients with PPROM if no obvious concomitant complications exist (60). Patient Education • Recurrence of PROM in future pregnancies: • Patients with PROM are at increased risk of PPROM in subsequent pregnancies. • One study found that 32% of patients with a history of PPROM developed recurrent PROM an average of 2 weeks later in their next pregnancy (62). CERVICAL INSUFFICIENCY Key Points • Cervical insufficiency is diagnosed based on a patient’s history of second-trimester pregnancy loss in a prior pregnancy (or pregnancies), typically described as painless cervical dilation in the absence of uterine contractions. • Transvaginal ultrasound can be a useful tool in the evaluation and management of cervical insufficiency. • Cerclage may reduce the risk of midtrimester pregnancy loss and preterm birth in women with a history of cervical insufficiency. • History-indicated cerclage is usually performed at 13 to 14 weeks of gestation. • Ultrasound-indicated cerclage is usually performed when the cervix begins to shorten in the midtrimester between 14 and 24 weeks. • Exam indicated or “rescue cerclage” may be placed when the cervix begins to dilate without labor but is associated with an increased risk of complications. • By definition, primiparous patients cannot be diagnosed with cervical insufficiency during their first pregnancy. Background Definition

• The terms cervical insufficiency and cervical incompetence have been used to describe the inability of the uterine cervix to retain a pregnancy in the absence of contractions or labor. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Traditionally, cervical insufficiency has been defined as recurrent second-trimester loss of pregnancy. These losses are characterized by painless dilation and effacement of the cervix, without contractions or blood loss. Often the membranes protrude into the vagina. Membrane rupture is often followed by rapid delivery of the fetus (63). • Spontaneous preterm labor in the midtrimester of pregnancy (16 to 24 weeks) can present with similar signs and symptoms as cervical insufficiency, and often the two conditions are difficult to definitively distinguish from one another. Pathophysiology

• The pathophysiology of cervical insufficiency is not well understood. • Incompetent cervices have less elastin both morphologically and biochemically when compared with normal cervices (64). They also contain a greater amount of smooth muscle than do competent cervices (65,66). • Cervical insufficiency is also related to the collagen concentration in the cervix. Samples of insufficient cervices during the second trimester had greater collagen extractability and collagenolytic activity (67). Other studies have shown that in the nonpregnant state, clinically insufficient cervices have less collagen (68). Etiology

• Congenital conditions that predispose women to cervical insufficiency include uterine anomalies and diethylstilbestrol exposure. • Trauma to the cervix via conization, forceful dilation and curettage, or obstetric lacerations may increase the risk of cervical insufficiency. Epidemiology

• The incidence of cervical insufficiency varies from 0.05% to 1.8%. Evaluation

History and Physical

• An obstetric history complicated by the delivery of a fetus at 16 to 24 weeks without the presence of contractions raises the suspicion of cervical insufficiency. • Digital exam of the cervix was once the only method available to diagnose cervical insufficiency. However, cervical dilation and effacement are often late manifestations of this pregnancy complication and cannot be relied on for early enough diagnosis to provide an operative intervention, that is, cerclage. Screening and Diagnosis

• Cervical insufficiency can be diagnosed based on (a) history alone or (b) suspicious history plus cervical shortening found on transvaginal ultrasound. • History alone: A history of one or more midtrimester loss(es) at 16 to 24 weeks preceded by no symptoms of preterm labor, placental abruption, or PPROM is highly suggestive of cervical insufficiency. Women with cervical insufficiency often present with prolapsed membranes through a dilated cervix and relatively few other symptoms. • Suspicious history plus midtrimester cervical shortening: Women with a prior term delivery and also a midtrimester loss, or history of only one prior pregnancy complicated by midtrimester loss but with equivocal history (± preterm labor), can present a perplexing management quandary. These women may benefit from midtrimester cervical length screening with cerclage placement when/if the cervix becomes short (69). • Various diagnostic tools have been evaluated to assess cervical competence, including hysterosalpingography and radiographic evaluation of traction on the cervix with a balloon and assessing the ease with which Hegar or Pratt dilators pass through the cervix to varying diameters (70,71). These tools have not been found to be beneficial. • Transvaginal ultrasound cervical length (CL) screening is typically reserved to the midtrimester (14 to 24 weeks) in asymptomatic women. The use of CL screening in symptomatic women with uterine contractions at later gestational ages is described in an earlier section of this chapter, preterm labor evaluation (13). (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Cervical length assessments may be useful after 14 weeks of gestation, but not earlier due to the inability to sonographically distinguish the cervix from the lower uterine segment. • Cervical length of 30 mm or greater assures the physician that the risk of preterm delivery is low and no intervention is necessary. • Identification of a short cervix (less than 25 mm) in the second trimester in women with a prior preterm birth should alert the examiner to the possibility of cervical insufficiency and increased risk of recurrent spontaneous preterm birth. These women benefit from ultrasound-indicated cerclage placement prior to 24 weeks of gestational age (69,72). • Suggested cervical length screening strategy for women with a history suspicious for cervical insufficiency who elect CL screening rather than history-indicated cerclage: °°Initiate TV ultrasound cervical lengths at 14 weeks --If CL ≥ 30 mm, repeat every 2 weeks until 23 6/7 weeks. --If CL 25 to 29 mm, repeat every 1 week until 23 6/7 weeks. --If CL less than 25 mm prior to 24 0/7 weeks, offer cerclage placement. Treatment • History-indicated cerclage may be offered to women with a clinical history consistent with cervical insufficiency. Prior recommendations suggested that “elective cerclage for purely historical factors generally should be confined to patients with three or more otherwise unexplained second-trimester pregnancy losses or preterm deliveries.” In clinical practice, though, many obstetric care providers will counsel patients on the option of historyindicated cerclage based on one or two prior midtrimester losses highly suggestive of CI by recollection of the clinical presentation. This procedure is commonly offered between 13 and 14 weeks, once a living fetus has been documented with ultrasound and no obvious abnormalities are noted on serum screening or ultrasound. • An alternative approach to history-indicated cerclage placement is serial transvaginal ultrasound cervical length screening with ultrasound-indicated cerclage placement if the cervix becomes short (less than 25 mm at less than 24 weeks of gestation). • Cerclage type • Vaginal cerclage is the most common type of cerclage, either McDonald or Shirodkar technique. °°Typically placed during pregnancy between 12 and 24 weeks of gestation. °°There is no evidence to suggest superiority of one technique over the other. Because of easier placement and removal, and comparative efficacy, the McDonald cerclage has become the preferred technique (73). • Abdominal cerclage is usually reserved for women with a prior failed vaginal cerclage (i.e., midtrimester spontaneous pregnancy loss despite history-indicated cerclage placement). Abdominal cerclage may be placed prior to pregnancy or during early pregnancy. • Cerclage technique • Suture type °°The most commonly used sutures for vaginal cerclage are Mersilene 5-mm tape and large-caliber nonabsorbable monofilament such as Prolene. • There is no clear evidence that one suture type has superior efficacy over the other (73). Choice of suture type is left to the preference and experience of the surgeon. The largest clinical trial of ultrasound-indicated cerclage used both suture types, but most patients received Mersilene tape (74). • Perioperative antibiotics • Empiric use of prophylactic antibiotics has not been shown to be useful for historyindicated cerclage. Perioperative antibiotics are often used with ultrasound-indicated and exam-indicated cerclage placement, but there is insufficient evidence to recommend their use routinely (73). (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Prophylactic tocolytic agents °°There is insufficient evidence to support the routine use of perioperative prophylactic tocolytic agents at the time of cerclage placement (73). • Cerclage management • Transvaginal CL screening following cerclage placement °°The role of CL screening after intervention has been provided is uncertain. °°May assist to identify patients at high risk of impending preterm birth (i.e., funneling to the stitch or extremely short CL), who may benefit from corticosteroid therapy. • Removal °°Vaginal cerclage should be removed when there is concern for laceration of the cervix in the event of preterm labor or when the patient reaches 37 weeks of gestation. Abdominal cerclage remains in situ, and cesarean is required when delivery is indicated. The optimal time to remove a cerclage in patients who develop preterm PROM is unclear. Complications • Complications of cervical insufficiency include preterm delivery and PROM. A complete description of these pregnancy complications is available in this chapter. • Cervical cerclage is associated with risk of rupture of membranes, chorioamnionitis, and laceration of the cervix by the suture. Rates of these complications are related to the time at which and the circumstances under which the cerclage was placed. Clinical exam–­ indicated cerclage is associated with a greater risk of complications. Patient Education • Patients with obstetric history consistent with cervical insufficiency or those with a successful vaginal cerclage in a prior pregnancy may benefit from history-indicated cerclage placement in the next pregnancy. • Patients with history of one prior midtrimester loss or later spontaneous preterm birth(s) may benefit from ultrasound-indicated cerclage placement if the cervix shortens prior to 24 weeks of pregnancy. They may be offered cervical length screening from 14 to 23 6/7 weeks of gestation. SHORT CERVIX Key Points • A short cervix identified in the midtrimester of pregnancy is associated with a high risk of spontaneous preterm birth. • Low-risk nulliparous singletons with short cervix noted in the midtrimester of pregnancy (18 to 24 weeks) are at increased risk of preterm birth and benefit from vaginal progesterone therapy. Cerclage is not beneficial in this population. • High-risk singletons with a prior preterm birth and short cervix noted in the midtrimester of pregnancy (16 to 24 weeks) benefit from ultrasound indicated cerclage placement. They are also offered 17-hydroxyprogesterone acetate based on their history. • Twin pregnancies (without prior history of preterm birth or midtrimester loss) with midtrimester cervical shortening are at increased risk of preterm birth but do not benefit from cerclage placement. They may benefit from vaginal progesterone therapy. • Routine midtrimester cervical length screening may be beneficial in all pregnancies at risk of preterm birth and may be considered, but this is not a mandated approach. Background A short cervix identified in the midtrimester of pregnancy is associated with a high risk of spontaneous preterm birth in all populations studied. But, despite the strong association between short cervical length and preterm birth, the majority of women with asymptomatic cervical shortening deliver at later than 35 weeks. Therefore, the purpose of cervical (c) 2015 Wolters Kluwer. All Rights Reserved.

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length screening is to identify populations of patients in which interventions have been proven beneficial such as vaginal progesterone, cerclage, and antenatal corticosteroids. An additional goal of cervical length screening should be to avoid unnecessary interventions in women at low risk of preterm birth. Only extremely short cervical lengths in asymptomatic patients in the midtrimester are associated with a significant risk of impending preterm birth within 2 to 4 weeks. Protocols that incorporate universal cervical length screening have demonstrated a reduction in the frequency of preterm birth and have been found to be cost-effective. Universal CL screening in all pregnant women is currently not mandated by ACOG; however, it is considered a reasonable evidence-based practice pattern. Definition • There is an inverse relationship between preterm birth risk and cervical length: the shorter the cervical length, the higher the risk of preterm birth. • Short cervix is commonly defined as a cervical length of less than 25 mm measured by transvaginal ultrasound in the midtrimester of pregnancy, between 14 and 24 weeks of pregnancy. Pathophysiology • The complex processes leading to spontaneous preterm birth are not clearly understood. Cervical shortening is thought to be an early manifestation of the parturition process and may precede birth by weeks or months. Epidemiology • The prevalence of short cervical length in the midtrimester (20 to 25 weeks) has been reported to be approximately 10% defined as cervical length ≤25 mm and 1.7% CL ≤ 15 mm (75). Evaluation • Midtrimester cervical shortening may be discovered incidentally at the time of ultrasound for other indications or may be diagnosed when performing routine transvaginal ultrasound cervical length screening. • If routine transvaginal ultrasound screening is performed in low-risk populations, a single transvaginal cervical length measurement is typically performed at 18 to 24 weeks of gestation at the time of the fetal anatomic survey. • Cervical length screening in singleton pregnancies with prior history of spontaneous preterm birth at 17 to 34 weeks: • Initiate TV ultrasound cervical length measurement at 16 weeks. °°If CL ≥ 30 mm, repeat every 2 weeks until 23 6/7 weeks. °°If CL 25 to 29 mm, repeat every 1 week until 23 6/7 weeks. °°If CL less than 25 mm, offer cerclage placement. • No further scheduled CL screening after 23 6/7 weeks. • Multifetal gestation, uterine malformation, or prior LEEP (screening and treatment similar to low-risk women). • Single TV US cervical length measurement at 18 to 24 weeks, at time of anatomic survey °°If CL less than 20 mm, consider vaginal progesterone. °°If CL ≥ 20 mm, routine care. °°Cerclage has no role in the treatment of short cervix in these populations and may worsen outcomes in otherwise uncomplicated twin pregnancies. • For screening recommendations in high-risk pregnancies with prior midtrimester loss, see Cervical Insufficiency section. • Short cervix is a diagnosis based on transvaginal ultrasound measurement. If short cervix is suspected by transabdominal imaging, confirmation by transvaginal ultrasound measurement is recommended. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Diagnosis • Short cervix is typically defined as cervical length less than 25 mm between 14 and 24 weeks of gestational age. Shortened cervical length at later gestational ages beyond 24 weeks has a weaker correlation with preterm birth risk and prediction, and effective treatments at these later gestational ages have not been studied. Therefore, diagnosis of short cervix is generally limited to measurements obtained less than 24 weeks. Treatment • Vaginal progesterone • 200 mg micronized progesterone capsules, one capsule inserted vaginally daily from time of diagnosis of short cervix (prior to 24 weeks) until delivery. • Efficacious in low-risk singleton pregnancies with short cervix (less than 20 mm) diagnosed less than 24 weeks to reduce preterm birth risk. • Unclear if it useful in twins, uterine malformation, or prior LEEP with a short cervix in the midtrimester. May be beneficial and has no known risk. • Cerclage placement • For singleton pregnancies with prior spontaneous preterm birth and cervical shortening noted in the current pregnancy of less than 25 mm at less than 24 weeks of gestational age. Patient Education • Women with a prior spontaneous preterm birth may benefit from cervical length screening at 16 and 23 6/7 weeks, with ultrasound-indicated cerclage placement if the cervix shortens less than 25 mm. Weekly 17-OHPC injections are also beneficial to reduce recurrent preterm birth risk in this population. Preconception counseling following a spontaneous preterm birth may be helpful to outline a screening and treatment plan for future pregnancies in these high-risk women. • Low-risk women in their first pregnancy have as high as 10% likelihood of having a short cervix in the midtrimester. Their risk of preterm birth may be reduced by cervical length screening and initiation of vaginal progesterone if short cervix less than 20 mm is identified. Patient education regarding the benefits of cervical length screening in this low-risk population may help to reduce the burden of preterm birth in the United States. REFERENCES 1. Mathews TJ, Menacker F, MacDorman MF. Infant mortality statistics from the 2001 period linked birth/infant death data set. Natl Vital Stat Rep. 2003;52:1–28. 2. McElrath TF, Robinson JN, Ecker JL, et al. Neonatal outcome of infants born at 23 weeks of gestation. Obstet Gynecol. 2001;91:49–52. 3. Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring Healthy Outcomes; Behrman RE, Butler AS, eds. Preterm birth: causes consequences, and prevention. Washington, DC: National Academies Press (US), 2007. 4. Castracane VD. Endocrinology of preterm labor. Clin Obstet Gynecol. 2000;43:717–726. 5. Goldenberg RL. The management of preterm labor. Obstet Gynecol. 2002;100:1020–1037. 6. Wright VC, Schieve LA, Reynolds MA, et al. Assisted reproductive technology surveillance—United States, 2001. MMWR Surveill Summ. 2004;53:1–20. 7. Tucker JM, Goldenberg RL, Davis RO, et al. Etiologies of preterm birth in an indigent population: is prevention a logical expectation? Obstet Gynecol. 1991;77:343–347. 8. Hamilton B, Martin J, Ventura S. Births: preliminary data for 2012. Natl Vital Stat Rep. 2013;62:3. 9. Blakemore-Prince C, Kieke B, Kugaraj KA, et al. Racial differences in the patterns of singleton preterm delivery in the 1988 national maternal and infant health survey. Matern Child Health J. 1999;3:189–197. 10. Pschirrer ER, Monga M. Risk factors for preterm labor. Clin Obstet Gynecol. 2000;43:727–734. (c) 2015 Wolters Kluwer. All Rights Reserved.

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11. Robinson JN, Regan JA, Norwitz ER. The epidemiology of preterm labor. Semin Perinatol. 2001;25:204–214. 12. Honest H, Bachmann LM, Sunduram R, et al. The accuracy of risk scores in predicting preterm birth—a systematic review. J Obstet Gynaecol. 2004;24:343–359. 13. DeFranco EA, Lewis DF, Odibo AO. Improving the screening accuracy for preterm labor: is the combination of fetal fibronectin and cervical length in symptomatic patients a useful predictor of preterm birth? A systematic review. Am J Obstet Gynecol. 2013;208(3):233.e1-6. 14. Ness A, Visintine J, Ricci E, et al. Does knowledge of cervical length and fetal fibronectin affect management of women with threatened preterm labor? A randomized trial. Am J Obstet Gynecol. 2007;197(4):426.e1-7. 15. Peaceman AM, Andrews WW, Thorp JM, et al. Fetal fibronectin as a predictor of preterm birth in patients with symptoms: a multicenter trial. Am J Obstet Gynecol. 1997;177:13–18. 16. Iams JD. Preterm birth. In: Gabbe SG, Neibyl JR, Simpson JL, eds. Obstetrics: normal and problem pregnancies. 4th ed. Philadelphia: Churchill Livingstone, 2002:755–826. 17. American College of Obstetrics and Gynecology. Practice Bulletin number 127. Management of preterm labor. Obstet Gynecol. 2012;119(6):1038–1017. 18. Pircon RA, Strassner HT, Kirz DS, et al. Controlled trial of hydration and bed rest versus bed rest alone in the evaluation of preterm uterine contractions. Am J Obstet Gynecol. 1989;161:775–779. 19. Guinn DA, Goepfert AR, Owen J, et al. Management options in women with preterm uterine contractions: a randomized clinical trial. Am J Obstet Gynecol. 1997;177:814–818. 20. Gyetvai K, Hannah ME, Hodnett ED, et al. Tocolytics for preterm labor: a systematic review. Obstet Gynecol. 1999;94:869–877. 21. Ables AZ, Romero AM, Chauhan SP. Use of calcium channel antagonists for preterm labor. Clin Obstet Gynecol. 2005;32:519–525. 22. McDonald TF, Pelzer S, Trautwein W, et al. Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells. Physiol Rev. 1994;74:365–507. 23. Morgan MA, Goldenberg RL, Shulkin J. Obstetrician-gynecologists’ screening and management of preterm birth. Obstet Gynecol. 2008;112:35–41. 24. Lewis DF. Magnesium sulfate: the first-line tocolytic. Clin Obstet Gynecol. 2005;32:485–500. 25. Madden C, Own J, Hauth JC. Magnesium tocolysis: serum levels versus success. Am J Obstet Gynecol. 1990;162:1177–1180. 26. Lewis DF, Bergstedt S, Edwards MS, et al. Successful magnesium sulfate tocolysis: is “weaning” the drug necessary? Am J Obstet Gynecol. 1997;177:742–745. 27. Anthony J, Johanson RG, Duley L. Role of magnesium sulfate in seizure prevention in patients with eclampsia and pre-eclampsia. Drug Safety. 1996;15:188–199. 28. Lam F, Gill P. Beta-agonist therapy. Clin Obstet Gynecol. 2005;32:457–484. 29. Vermillion ST, Robinson CJ. Antiprostaglandin drugs. Clin Obstet Gynecol. 2005;32: 501–517. 30. Niebyl JR, Witter FR. Neonatal outcome after indomethacin treatment for preterm labor. Am J Obstet Gynecol. 1986;155(4):747–749. 31. Moise KJ. Effect of advancing gestational age on the frequency of fetal ductal constriction in the association with maternal indomethacin use. Am J Obstet Gynecol. 1993;168:1350–1353. 32. Macones GM, Marder SJ, Clothier B, et al. The controversy surrounding indomethacin for tocolysis. Am J Obstet Gynecol. 2001;184:264–272. 33. Agency for Healthcare Research and Quality. Management of preterm labor. Evidence Report/Technology Assessment no. 18. AHRQ Publication no. 01-E021. Rockville, MD: AHRQ, 2000. 34. Antenatal corticosteroids revisited: repeat courses. NIH Consensus Statement. 2000;17: 1–10. 35. American College of Obstetrics and Gynecology. Antenatal corticosteroid therapy for fetal maturation. ACOG Committee Opinion no. 475. Obstet Gynecol. 2011;117:422–424. 36. Mittendorf R, Dambrosia J, Pryde PG, et al. Association between the use of antenatal magnesium sulfate in preterm labor and adverse health outcomes in infants. Am J Obstet Gynecol. 2002;186:1111–1118. (c) 2015 Wolters Kluwer. All Rights Reserved.

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37. Crowther CA, Hiller JE, Doyle LW, et al. Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. Australasian Collaborative Trial of Magnesium Sulphate (ACTOMg SO4) Collaborative Group. JAMA. 2003;290:2669–2676. 38. Marret S, Marpeau L, Zupan-Simunek V, et al. Magnesium sulphate given before very preterm birth to protect infant brain: the randomized controlled PREMAG trial. PREMAG trial group. BJOG. 2007;114:310–318. 39. Rouse DJ, Hirtz DG, Thom E, et al. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. Eunice Kennedy Shriver NICHD Maternal-Fetal Medicine Units Network. N Engl J Med. 2008;359:895–905. 40. Marret S, Marpeau L, Follet-Bouhamed C, et al. Effect of magnesium sulphate on mortality and neurologic morbidity of the very preterm newborn (of less than 33 weeks) with twoyear neurological outcome: results of the prospective PREMAG trial. le groupe PREMAG [French]. Gynecol Obstet Fertil. 2008;36:278–288. 41. Doyle LW, Crowther CA, Middleton P, et al. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev. 2009;1:CD004661. doi: 10.1002/14651858.CD004661.pub3. 42. Costantine MM, Weiner SJ. Effects of antenatal exposure to magnesium sulfate on neuroprotection and mortality in preterm infants: a meta-analysis. Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network Obstet Gynecol. 2009;114:354–364. 43. American College of Obstetricians and Gynecologists. Magnesium sulfate before anticipated preterm birth for neuroprotection. Committee Opinion No. 455. Obstet Gynecol. 2010;115:669–671. 44. Scrag S, Gorwitz R, Fultz-Butts K, et al. Prevention of perinatal group B streptococcal disease. Revised guidelines for CDC. MMWR Recomm Rep. 2002;51(RR-11):1–22. 45. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin no. 130: prediction and prevention of preterm birth. Obstet Gynecol. 2012;120(4):964–973. 46. Mercer BM, Golderberg RL, Moawad AH. The preterm prediction study: effect of gestational age and cause of preterm birth on subsequent obstetric outcome. Am J Obstet Gynecol. 1999;181:1216–1221. 47. Mercer BM. Preterm premature rupture of the membranes. Obstet Gynecol. 2003;101: 178–193. 48. Mercer B, Arheart K. Antimicrobial therapy in expectant management of preterm premature rupture of the membranes. Lancet. 1995;346:1271–1279. 49. Naeye RL, Peters EC. Causes and consequences of premature rupture of the fetal membranes. Lancet. 1980;1:192–194. 50. Cousins LM, Smok DP, Lovett SM, et al. AmniSure placental alpha microglobulin-1 rapid immunoassay versus standard diagnostic methods for detection of rupture of membranes. Am J Perinatol. 2005;22(6):317–320. 51. Mercer BM. Management of premature rupture of membranes before 26 weeks gestation. Obstet Gynecol Clin North Am. 1992;19:339–351. 52. Johnson JWC, Egerman RS, Moorhead J. Cases with ruptured membranes that “reseal.” Am J Obstet Gynecol. 1990;163:1024–1032. 53. Naef RW III, Allbert JR, Ross EL, et al. Premature rupture of membranes at 34 to 37 weeks’ gestation: aggressive versus conservative management. Am J Obstet Gynecol. 1998;178:126–130. 54. Cox SM, Leveno KJ. Intentional delivery versus expectant management with preterm ruptured membranes at 30–34 weeks’ gestation. Obstet Gynecol. 1995;86:875–879. 55. Mercer BM, Moretti ML, Prevost RR, et al. Erythromycin therapy in preterm premature rupture of membranes: a prospective randomized trial of 220 patients. Am J Obstet Gynecol. 1992;166:794–802. 56. Mercer B, Miodovnik M, Thurnau G, et al. Antibiotic therapy for reduction of infant morbidity after preterm premature rupture of membranes: a randomized controlled trial. JAMA. 1997;278:989–995. 57. Harding JE, Pang J, Knight DB, et al. Do antenatal corticosteroids help in the setting of preterm rupture of membranes? Am J Obstet Gynecol. 2001;184:131–139. (c) 2015 Wolters Kluwer. All Rights Reserved.

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58. Lewis DF, Brody K, Edwards MS, et al. Preterm premature ruptured membranes: a randomized trial of steroids after treatment with antibiotics. Obstet Gynecol. 1996;88:801–805. 59. Pattinson RC, Makin JD, Funk M, et al. The use of dexamethasone in women with preterm premature rupture of membranes: a multicentre, double-blind, placebo controlled, randomised trial. S Afr Med J. 1999;89:865–870. 60. Morales WJ. The effect of chorioamnionitis on the developmental outcome of preterm infants at one year. Obstet Gynecol. 1987;70:183–186. 61. Hillier SL, Martius J, Krohn M, et al. A case–control study of chorioamnionic infection and histologic chorioamnionitis in prematurity. N Engl J Med. 1988;319:972–978. 62. Asrat T, Lewis DF, Garite TJ, et al. Rate of recurrence of preterm PROM in consecutive pregnancies. Am J Obstet Gynecol. 1991;165:1111–1115. 63. Bengtsson LP. Cervical insufficiency. Acta Obstet Gynecol Scand. 1968;47:9–35. 64. Leppert PC, Yu SK, Keller S, et al. Decreased elastic fibers and desmosine content in the incompetent cervix. Am J Obstet Gynecol. 1987;157:1134–1139. 65. Buckingham JC, Buethe RA, Danforth DN. Collagen-muscle ratio in clinically normal and clinically incompetent cervices. Am J Obstet Gynecol. 1965;92:232–237. 66. Roddick JW, Buckingham JC, Danforth DN. The muscular cervix—a cause of incompetency in pregnancy. Obstet Gynecol. 1961;17:562–565. 67. Rechberger T, Uldbjerg N, Oxlund H. Connective tissue changes in the cervix during normal pregnancy and pregnancy complicated by cervical incompetence. Obstet Gynecol. 1988;71:563–567. 68. Petersen LK, Uldbjerg N. Cervical collagen in non-pregnant women with previous cervical incompetence. Eur J Obstet Gynecol Reprod Biol. 1996;67:41–45. 69. Berghella V, Mackeen AD. Cervical length screening with ultrasound-indicated cerclage compared with history-indicated cerclage for prevention of preterm birth: a meta-analysis. Obstet Gynecol. 2011;118(1):148–155. 70. Rubovits FE, Cooperman NR, Lash AF. Habitual abortion: a radiographic technique to demonstrate the incompetent internal os of the cervix. Am J Obstet Gynecol. 1953;66:269–280. 71. Anthony GS, Calder AA, MacNaughton MC. Cervical resistance in patients with previous spontaneous mid-trimester abortion. Br J Obstet Gynaecol. 1982;89:1046–1049. 72. Berghella V, Rafael TJ, Szychowski JM, et al. Cerclage for short cervix on ultrasonography in women with singleton gestations and previous preterm birth: a meta-analysis. Obstet Gynecol. 2011;117(3):663–671. 73. Berghella V, Ludmir J, Simonazzi G, et al. Transvaginal cervical cerclage: evidence for perioperative management strategies. Am J Obstet Gynecol. 2013;209(3):181–192. 74. Owen J, Hankins G, Iams JD, et al. Multicenter randomized trial of cerclage for preterm birth prevention in high-risk women with shortened midtrimester cervical length. Am J Obstet Gynecol. 2009;201(4):375.e1-8. doi: 10.1016/j.ajog.2009.08.015. 75. Fonseca EB, Celik E, Parra M, et al.; Fetal Medicine Foundation Second Trimester Screening Group. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med. 2007;357(5):462–469.

(c) 2015 Wolters Kluwer. All Rights Reserved.

9

Third-Trimester Bleeding

Loralei L. Thornburg and Ruth Anne Queenan

KEY POINTS • Third-trimester bleeding complicates about 4% of all pregnancies. • Serious causes include placenta previa, abruption, and vasa previa and can result in significant maternal and/or fetal compromise. • Availability of blood products and support systems is important for optimal patient management. • Absence of placenta previa should be confirmed by ultrasound before proceeding with digital examination of the cervix. VAGINAL BLEEDING Background

Definition

• Third-trimester bleeding is defined as any episode of vaginal bleeding that occurs after 24 completed weeks of pregnancy. • Third-trimester bleeding complicates about 4% of all pregnancies. • Vaginal bleeding during pregnancy is a worrisome symptom to the patient and is usually brought to the attention of her physician at the time that it occurs during pregnancy. Etiology

• In approximately 50% of cases, vaginal bleeding is secondary to placental abruption or placenta previa. Both of these conditions carry significant risk of maternal and fetal morbidity and mortality and therefore must be expeditiously diagnosed. • Once these two life-threatening situations are convincingly excluded as a cause of bleeding, attention can be turned to alternate causes of vaginal bleeding in pregnancy. Evaluation

History

The following information should be obtained: • Is there a history of trauma? • What is the amount and the character of the bleeding? • Is there pain associated with the bleeding? • Is there a history of bleeding earlier in the pregnancy? Physical Examination

• Vital sign measurement, including pulse pressure; normal vital signs are reassuring; however, they can be misleading because hypotension and tachycardia are signs of serious hypovolemia, and generally not present until significant blood loss has occurred. Additionally, mild tachycardia can be a normal finding in pregnancy. • Fetal heart rate and/or category of continuous fetal heart rate tracing. • Physical examination, initially excluding speculum and digital pelvic examination until after ultrasound is complete. • Assessment of uterine activity. 153

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• Ultrasound examination of the uterus, placenta, and fetus (transabdominal first and then transvaginal when indicated). • Speculum and digital pelvic examination once placenta previa has been excluded. Laboratory Tests

• Hemoglobin and hematocrit determination. • Coagulation studies when placental abruption is suspected or when there has been significant hemorrhage, including prothrombin time, partial thromboplastin time, platelet count, fibrinogen level, and fibrin split products. • Red-top tube of blood to perform a bedside clot test. • Blood type and crossmatch. • Anti-D immunoglobulin for those who are Rh(D) negative to protect against sensitization. • Urinalysis for hematuria and proteinuria. • Apt test may be used to determine maternal or fetal source of bleeding. (Mix vaginal blood with an equal part of 0.25% sodium hydroxide. Fetal blood remains red; maternal blood turns brown.) In general, fetal bleeding will be apparent on fetal heart rate tracing and intervention should not be delayed for Apt testing. • Kleihauer-Betke (K-B) test is used to quantify fetal to maternal hemorrhage. However, it is positive in only a small proportion of placental abruptions. While the K-B test is helpful to assure adequate anti-D immunoglobulin dosing, it is generally not helpful for diagnosis of abruption (1,2). PLACENTAL ABRUPTION Background

Definition

Placental abruption (also known as abruptio placentae) occurs when a normally implanted placenta completely or partially separates from the decidua basalis after the 20th week of gestation and before the third stage of labor. Incidence

Placental abruption occurs in approximately 1 in 100 deliveries and accounts for 15% of perinatal mortality (3,4). Classification

Placental abruptions are graded by clinical criteria. Ultrasound is not an accurate or reliable method for diagnosis or classification. Clinically, the classification of abruption can be helpful when deciding on the need for interventions and the need for further monitoring (Fig. 9-1). • Grade 1, mild (40% of abruptions): • Vaginal bleeding is slight or absent (less than 100 mL). • Uterine activity may be slightly increased.

Partial separation (concealed hemorrhage)

Partial separation (apparent hemorrhage)

Complete separation (concealed hemorrhage)

Figure 9-1. Types of placental abruption. (From Beckmann CRB, Ling FW. Obstetrics and gynecology. 6th ed. Lippincott Williams & Wilkins, 2009). (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Uterine activity often described as having closely spaced, low-intensity contractions—a hyperstimulation-type pattern. • No fetal heart rate abnormalities are present. • No evidence of shock or coagulopathy. • Grade 2, moderate (45%): • External bleeding may be absent to moderate (100 to 500 mL). • Uterine tone may be increased. Tetanic uterine contractions and uterine tenderness may be present. • Fetal heart tones may be absent and, when present, often show evidence of fetal distress. • Maternal tachycardia, narrowed pulse pressure, and orthostatic hypotension may be present. • Early evidence of coagulopathy may be present (fibrinogen 150 to 250 dL). • Grade 3, severe (15%): • External bleeding may be moderate or excessive (greater than 500 mL) but may be concealed. • The uterus is often tetanic and tender to palpation. • Fetal death is common. • Maternal shock is usually present. • Coagulopathy is frequently present. Etiology

The cause of placental abruption is unknown, but defective placental vasculature has been postulated to be a contributing factor. In the following conditions, the incidence of placental abruption is increased: (3,5) • Preeclampsia and hypertensive disorders • History of placental abruption (recurrence rate ~10%) • High multiparity • Relatively older maternal age • Trauma, both direct and indirect uterine traumas • Cigarette smoking, in a dose-responsive fashion, which is synergistic with hypertension (5) • Illicit drug use, most notably cocaine use • Excessive alcohol consumption • Preterm, premature rupture of the membranes, where the risk increases with length of latency • Rapid uterine decompression (e.g., after delivery of the first fetus in a twin gestation or rupture of membranes with polyhydramnios) • Uterine leiomyomas, especially if located retroplacentally, rapidly enlarging, or degenerating Diagnosis

Clinical Manifestations

• The diagnosis of placental abruption is made by clinical findings, with the symptoms of vaginal bleeding, abdominal pain, uterine tenderness, and uterine contractions. • Vaginal bleeding is present in 80% of patients and concealed in 20%. • Pain is present in most cases of placental abruption and is usually of sudden onset, constant, and localized to the uterus, low abdomen, and lower back. • Localized or generalized uterine tenderness and increased uterine tone are found with the more severe forms of placental abruption. • The uterus may increase in size with placental abruption when the bleeding is concealed. This may be monitored by serially measuring abdominal girth and/or fundal height. • Amniotic fluid may be bloody. • Shock is variably present. • Fetal compromise is variably present. • Placental abruption may cause rapidly progressive preterm labor and/or preterm premature rupture of membranes. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Laboratory Findings

Laboratory findings that are frequently helpful in the diagnosis include (6) • Consumptive coagulopathy • Placental separation precedes the onset of the consumptive coagulopathy, which in turn progresses until the uterus is evacuated. • Coagulation occurs retroplacentally as well as intravascularly, with secondary fibrinolysis. • Levels of fibrinogen, prothrombin, factors V and VIII, and platelets are decreased. • Fibrin split products are elevated, adding an anticoagulant effect. • Hypofibrinogenemia occurs within 8 hours of the initial separation. Ultrasonography

Ultrasonography is very poorly sensitive in making the diagnosis. • The three locations of placental hemorrhage are • Subchorionic (more common less than 20 weeks) • Retroplacental (more common greater than 20 weeks) • Preplacental (unusual) • Symptoms associated with retroplacental hemorrhage are frequently the most severe. • The sensitivity of ultrasonography in detecting placental abruption is only approximately 25% to 50% at best (7). • If abruption is visualized on ultrasound, the predictive value is high (88%) (7). Treatment

Management

• Mild placental abruption • Close observation is required to assure maternal stability and reassuring fetal status. The facility should be fully capable of immediate delivery should the condition of the patient or fetus deteriorate. • Continuous fetal monitoring should be initiated, although the value of antepartum testing is not established. • Maternal hematologic parameters should be monitored and abnormalities corrected. • A trial of tocolytics may be carefully undertaken with consideration of an immature fetus. Nifedipine is the tocolytic of choice if the blood pressure will tolerate this therapy. • Moderate to severe placental abruption • Careful maternal and fetal monitoring is essential to minimize long-term complications (3). • The vigorous management of shock is outlined in Part V of this manual. • Coagulopathy: °°Fresh whole blood, if available, should be used to replace blood loss because it replaces volume and contains clotting factors. If not, rapid infusion protocols should be followed, which in general advocate starting coagulation factors in a 1:1 (red blood cells [RBC]: fresh frozen plasma [FFP]) ratio after transfusion of four units of packed cells (8). °°Clotting factors may be replaced using cryoprecipitate or FFP. One unit of FFP increases the fibrinogen level approximately 10 mg/dL. Cryoprecipitate contains approximately 250 mg fibrinogen per unit, with 4 g (15 to 20 U) being an effective dose. °°Platelet transfusion may be indicated if the platelet count is less than 50,000 per μL, although this is generally reserved for situations with counts of 20,000 to 30,000 per μL or less. One unit of platelets typically raises the platelet count 5000 to 10,000 per μL; 4 to 6 U is the smallest clinically useful dose. °°Coagulation defects will resolve once delivery occurs, with clotting factors returning to normal within 24 hours and platelets returning to normal within 4 days. °°Heparin is not indicated. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Oxygen should be administered. • Urine output should be monitored with an indwelling bladder catheter. • Antenatal corticosteroids should be given for any fetus less than 34 weeks. • For those infants less than 32 weeks, consider magnesium sulfate for neuroprotection during delivery. Mode and Timing of Delivery

• Delivery should in general be expedited in all but the mildest cases once the mother has stabilized depending on severity and gestational age (2). • Nonsevere abruption between 34 and 36 weeks should be monitored carefully and likely will require delivery. Conservative, observational management may be used for selected patients with mild, resolved bleeding, normal laboratory testing, and category 1 fetal testing. • Nonsevere abruption less than 34 weeks should be monitored carefully and managed conservatively when possible. Conservative, observational management may be done for selected patients with mild, resolved bleeding, normal laboratory testing, and category 1 fetal testing. • As long as maternal and fetal surveillance is reassuring, with adequate progress of labor and appropriate volume replacement, the time interval to delivery is less crucial. • Amniotomy should be performed because it may facilitate delivery and decrease thromboplastin release into the circulation. • Oxytocin augmentation may be used. • Vaginal delivery is preferred. • Cesarean section is indicated in the following cases: • Fetal distress without impending vaginal delivery • Severe abruption, threatening the life of the mother • Failed trial of labor • For abruption with fetal demise, vaginal delivery remains preferable, but mode of delivery should be chosen to minimize maternal risks. Labor is often rapidly progressive in these cases, and amniotomy will allow visualization of the bleeding and facilitate labor progression. Complications • Hemorrhagic shock • Consumptive coagulopathy • Couvelaire uterus, or extravasation of blood into the myometrium causing red discoloration of the serosal surface of the uterus, which is found in 8% of patients • Ischemic necrosis of distant organs, mostly preventable by vigorous volume replacement. • Kidney: acute tubular necrosis and cortical necrosis • Liver • Adrenals • Pituitary • Lung Prognosis Placental abruption is one of the gravest obstetric complications, with perinatal mortality of approximately 30% and morbidity related to both gestational age and degree of asphyxia. Maternal mortality is less than 1% (3,4). PLACENTA PREVIA Background Definition

Placenta previa occurs when any part of the placenta implants in the lower uterine segment in advance of the fetal presenting part. All three types of placenta previa are associated with risk of serious maternal hemorrhage. As pregnancy advances, the degree of placenta previa may change as the uterus elongates, the lower uterine segment develops, and the cervix effaces and dilates (9). (c) 2015 Wolters Kluwer. All Rights Reserved.

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Classification

• Total (complete) placenta previa occurs when the entire internal cervical os is covered by placenta. Central placenta previa is a subtype occurring when the placenta is located concentrically around the internal cervical os. • Partial (incomplete) placenta previa occurs when part of the internal cervical os is covered by placenta. • Marginal placenta previa occurs when the placental edge extends to within 2 cm of the internal cervical os (Fig. 9-2).

A

B

C

D

Figure 9-2. Types of placenta previa. A: Low-lying placenta. B: Marginal placenta previa. C and D: Varieties of complete placenta previa. (From Beckmann CRB, Ling FW. Obstetrics and gynecology. 6th ed. Lippincott Williams & Wilkins, 2009). (c) 2015 Wolters Kluwer. All Rights Reserved.

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Incidence

Placenta previa occurs in approximately 1 in 200 pregnancies. More than 90% of placenta previas diagnosed in the second trimester resolve as pregnancy advances, secondary to differential growth of the placental trophoblastic cells toward the fundus (9). • The cause of placenta previa is unknown. Endometrial damage from previous pregnancies and defective decidual vascularization have been postulated as possible mechanisms (10). Associated Conditions

The following are associated with an increased risk of placenta previa: (11) • Maternal age. Placenta previa is three times more common at age 35 than at age 25. • Increasing parity. • Previous uterine scar. • Prior placenta previa. • Tobacco use. • Multiple gestation. • An increase in the risk of congenital anomalies has been reported, although no single associated anomaly has been identified. Diagnosis

Clinical Manifestations

• Patients with placenta previa characteristically present with sudden onset of painless vaginal bleeding in the second or third trimester. One-third become symptomatic before 30weeks and one-third after 36 weeks, with the peak incidence at 34 weeks. Most often, the initial bleeding resolves spontaneously, recurring later in pregnancy. • One-fourth of patients present with bleeding and uterine contractions without uterine tetany. • Malpresentation occurs in one-third of cases (11). • Coagulation disorders are rare in cases of placenta previa but can occur with large amounts of bleeding. Diagnostic Methodologies

• Sonography is more than 95% accurate in diagnosing placenta previa. Transabdominal ultrasonography should be performed with a full bladder. If placenta previa is suspected, the bladder should be nearly emptied and the scan repeated. Transvaginal ultrasonography is safe and useful in establishing the relationship between the cervix and the placenta, especially in cases of posterior placentation (12). • Magnetic resonance imaging has been used to confirm the diagnosis of placenta previa and to evaluate for associated placenta accreta. Ultrasonography, however, is likely to remain the more accessible and therefore more useful tool (13). • Double-setup examination was frequently used in the past for the final step in diagnosing placenta previa. With the improved sensitivity and specificity of ultrasonography, there are fewer indications for this procedure. If the diagnosis remains uncertain or the patient has persistent mild bleeding in labor, the double-setup examination may be undertaken. The procedure should be done in an operating room with blood products and a team available to conduct immediate delivery should hemorrhage occur. Most commonly, double-setup examination is used to determine the existence of marginal placenta previa. Treatment

Management

Management of placenta previa depends on gestational age and the extent of bleeding. • Immediate delivery • When the pregnancy is ≥36 weeks, the neonate should be delivered by cesarean delivery. • Low vertical uterine incision is probably safer in patients with an anterior placenta previa, especially with prior cesarean deliveries or in cases of suspected accreta. If possible, it is best to avoid incisions through the placenta. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Cesarean delivery should be performed regardless of gestational age if hemorrhage is severe and jeopardizes the mother or fetus. • Expectant management may be used to address fetal immaturity if the following conditions are met: • Bleeding is not excessive. • There are significant risks of prematurity to the fetus. • The patient is hospitalized or in a location where rapid transportation to the hospital is available. • Physical activity is restricted. • Intercourse and douching are not permitted. • Hemoglobin is maintained at 10 mg/dL or greater. • Rh immunoglobulin is administered to Rh-negative, unsensitized patients. • Blood products are available. • Once either fetal lung maturity is documented or the fetus has reached approximately 34 to 36 weeks with documented lung maturity, steps toward prompt delivery should be made. Elective delivery results in less morbidity and lower mortality risk to the mother and fetus than emergent delivery in the context of recurrent bleeding. • Tocolysis may be used with caution in certain patients. Nifedipine is the agent of choice. • Some patients are candidates for outpatient management if the following conditions are met: °°Patient motivation and understanding of the severity of the situation. °°Home environment allows compliance with restrictions. °°The bleeding has stopped and not recurred for multiple days. °°There has not been ≥3 episodes of bleeding. °°The patient is always attended by a responsible adult with access to ready transport to the hospital. Complications • Hemorrhagic shock. • Complications of cesarean delivery. • Transfusion-related complications. • Placenta previa associated with placenta accreta, increta, and percreta; previous uterine scars increase the risk substantially; this complication can lead to excess blood loss and in many cases mandate hysterectomy to control hemorrhage (6). Prognosis Maternal mortality from placenta previa should approach zero. Perinatal mortality is less than 10% and is attributed to prematurity. OTHER CAUSES OF VAGINAL BLEEDING Of the following causes of late-pregnancy vaginal bleeding, only the rarely encountered vasa previa confers significant immediate risk to the pregnancy and to the fetus in particular. Although the other causes may be serious, they carry much less immediate risk. Vasa Previa Vasa previa occurs when fetal blood vessels travel within the membranes, usually as a velamentous insertion, and in so doing, cross the region of the internal cervical os (14). • When labor or cervical dilation occurs with unrecognized vasa previa, catastrophic fetal bleeding will occur. • When these vessels rupture, vaginal bleeding is noted, and evidence of fetal distress is universally present.

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• An Apt test will indicate fetal blood. • Emergent cesarean delivery should be performed when the fetus is alive. • Fetal mortality associated with this condition is greater than 50%. • Vasa previa is potentially diagnosable by ultrasound. During the course of an ultrasound examination of a marginal previa or low-lying placenta, the placental vessels can be visualized traversing the lower uterine segment and the internal cervical os. Color Doppler allows fairly precise identification of these blood vessels and their locations (14). • Antenatal diagnosis of vasa previa by ultrasound allows for timing of delivery by cesarean delivery. Cervical Bleeding • Cytologic sampling is mandatory. • Bleeding can be controlled with cauterization or packing. • Bacterial and viral cultures can be diagnostic. Cervical Polyps • Bleeding is usually self-limited. • Trauma should be avoided. • Cytologic sampling is mandatory. • Polypectomy may control bleeding and yield a histologic diagnosis. Bloody Show Bloody show is characteristically associated with cervical changes and blood-tinged mucus. Heavy bleeding is rare and should prompt the evaluation for other complications. Vulvovaginal Trauma • Patient history frequently elucidates the cause. • Adequate pelvic examination should be performed, including an examination under anesthesia, if necessary. • Penetration of the cul-de-sac necessitates exploratory laparotomy. • Foreign bodies must be removed. • Wounds should be debrided and closed, if clean. • Hematomas should be evacuated. Hemostasis should be obtained. Drains as needed should be placed. • Tetanus prophylaxis is indicated. Hematuria Hematuria as a source of vaginal bleeding can be diagnosed by urinalysis. Management of Hemorrhagic Shock • Management of the patient in shock requires vigilance (2,15). • Vital signs should be monitored. • Urine output must be monitored with an indwelling bladder catheter in place and maintained at greater than 30 mL/h. • If urine output is not maintained, hemodynamic monitoring should be instituted. °°A central venous pressure catheter is adequate if left ventricular function appears normal. °°If left ventricular function is questioned, or urine output is inadequate despite adequate central venous pressure, a Swan-Ganz catheter should be placed. °°Oxygen should be administered. • Adequate replacement of blood volume is mandatory. During the wait for blood, colloid or crystalloid (3 mL for every milliliter of blood lost) should be quickly infused. Blood products should be used when available as appropriate. Use of trauma or massive transfusion protocols may be helpful (15).

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• Hematocrit is not a sensitive indicator of acute blood loss because hemodilution is only half complete at 8 hours. • Electrolytes, calcium, oxygenation, and acid–base status should be carefully monitored. • The underlying event should be identified and treated (16). PATIENT EDUCATION • Patients should be informed that vaginal bleeding, particularly in the third trimester, requires urgent attention. • Patients with placenta previa or vasa previa should be told to avoid intercourse. • Patients should be educated about the recognition and significance of bloody show as an indicator of early labor. • Patients who are Rh(D) negative should be made aware of importance of receiving antiD immunoglobulin to protect against sensitization. REFERENCES 1. Dhanraj D, Lambers D. The incidences of positive Kleihauer-Betke test in low-risk pregnancies and maternal trauma patients. Am J Obstet Gynecol. 2004;190(5):1461. 2. Oyelese Y, Ananth CV. Placental abruption. Obstet Gynecol. 2006;108(4):1005. 3. Tikkanen M. Placental abruption: epidemiology, risk factors and consequences. Acta Obstet Gynecol Scand. 2011;90(2):140–149. 4. Tikkanen M, Luukkaala T, Gissler M, et al. Decreasing perinatal mortality in placental abruption. Acta Obstet Gynecol Scand. 2013;92(3):298–305. 5. Ananth CV, Smulian JC, Demissie K, et al. Placental abruption among singleton and twin births in the United States: risk factor profiles. Am J Epidemiol. 2001;153(8):771. 6. de Lloyd L, Bovington R, Kaye A, et al. Standard haemostatic tests following major obstetric haemorrhage. Int J Obstet Anesth. 2011;20(2):135–141. 7. Glantz C, Purnell L. Clinical utility of sonography in the diagnosis and treatment of placental abruption. J Ultrasound Med. 2002;21(8):837. 8. Duchesne JC, Islam TM, Stuke L, et al. Hemostatic resuscitation during surgery improves survival in patients with traumatic-induced coagulopathy. J Trauma. 2009;67(1):33. 9. Dashe JS, McIntire DD, Ramus RM, et al. Persistence of placenta previa according to gestational age at ultrasound detection. Obstet Gynecol. 2002;99(5 Pt 1):692. 10. Faiz AS, Ananth CV. Etiology and risk factors for placenta previa: an overview and metaanalysis of observational studies. J Matern Fetal Neonatal Med. 2003;13:175–190. 11. Sheiner E, Shoham-Vardi I, Hallak M, et al. Placenta previa: obstetric risk factors and pregnancy outcome. J Matern Fetal Med. 2001;10(6):414. 12. Oppenheimer L; Society of Obstetricians and Gynaecologists of Canada. Diagnosis and management of placenta previa. J Obstet Gynaecol Can. 2007;29(3):261–273. 13. Warshak CR, Eskander R, Hull AD, et al. Accuracy of ultrasonography and magnetic resonance imaging in the diagnosis of placenta accreta. Obstet Gynecol. 2006;108(3 Pt 1):573. 14. Sepulveda W, Rojas I, Robert JA, et al. Prenatal detection of velamentous insertion of the umbilical cord: a prospective color Doppler ultrasound study. Ultrasound Obstet Gynecol. 2003;21(6):564. 15. Burtelow M, Riley E, Druzin M, et al. How we treat: management of life-threatening primary postpartum hemorrhage with a standardized massive transfusion protocol. Transfusion. 2007;47(9):1564. 16. Thachil J, Toh CH. Disseminated intravascular coagulation in obstetric disorders and its acute haematological management. Blood Rev. 2009;23(4):167.

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10

Abnormal Labor Cynthia Bean

KEY POINTS • Dystocia results from abnormalities during labor with the interplay between the power (uterine contractions and maternal expulsive forces), the passenger (fetal size, presentation, and position), and the passage (maternal bony pelvis and soft tissues). • Recognition of risk factors and causes of dystocia are critical for proper treatment. • Appropriate management of dystocia reduces maternal and fetal morbidity and prevents unnecessary cesarean deliveries (CD). BACKGROUND Definitions • Dystocia: difficult labor and childbirth. • Prolonged latent phase (Table 10-1; Fig. 10-1) • Nulliparous patient: greater than 20 hours • Multiparous patient: greater than 14 hours • It is often difficult to determine the start of the latent phase because of increased uterine activity (“false labor”) that may occur days before the onset of spontaneous labor (1). • The latent phase is generally considered complete when cervical dilation reaches 3 to 5 cm. • Protraction disorders—slow progression of labor (Fig. 10-2) (2,3). • Protracted active phase dilation: °°Nulliparous patient: rate of dilation less than 1.2 cm/h °°Multiparous patient: rate of dilation less than 1.5 cm/h • Protracted descent—descent of fetal presenting part during second stage of labor: °°Nulliparous patient: less than 1 cm/h °°Multiparous patient: less than 2 cm/h • Arrest disorders—no progression of labor (Fig. 10-3) (2–4). • Secondary arrest of dilation °°No cervical dilation after 2 hours in active labor with adequate contractions • Arrest of descent: °°No descent of fetal presenting part after 1 hour in the second stage of labor • Prolonged second stage of labor (4–6) • Nulliparous patient without regional analgesia: greater than 2 hours • Nulliparous patient with regional analgesia: greater than 3 hours • Multiparous patient without regional analgesia: greater than 1 hour • Multiparous patient with regional analgesia: greater than 2 hours • Precipitous labor—rapid labor (7) • Delivery of the fetus in less than 3 hours Epidemiology • The leading indication for primary CD in the United States is dystocia or “failure to progress” (8,9). • Approximately 50% to 60% of CD may be attributable to dystocia (9). • Successful management of abnormal labor and adhering to the appropriate definitions of dystocia will help decrease the CD rate. 163

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Table 10-1

Labor Duration

Variable Latent phase   Mean (h)   Upper limit (h) Active phase   Mean (h)   Upper limit (h)   Dilation rate   Lower limit (cm/h) Second stage   Upper limit (h)

Nulliparous women

Multiparous women

6.4 20.1

4.8 13.6

4.6 11.7 0 1.2

2.4 5.2

2.9

1.1

1.5

From Friedman EA. Labor: clinical evaluation and management. 2nd ed. New York: Appleton-Century-Crofts, 1978, with permission.

Pathophysiology • Dystocia results from the abnormal functions and interactions between • Uterine contractions and maternal effort: Power • Fetal size, presentation, and position: Passenger • Maternal bony pelvis and soft tissues: Passage Etiology • Associated risk factors for dystocia include (9–15): • Advanced maternal age • Maternal diabetes mellitus and/or hypertension • Short maternal stature • Maternal pelvic contractures or tumors (leiomyomas) • Infertility or nulligravidity • Premature rupture of membranes (PROM) or oligohydramnios • Chorioamnionitis • High station at complete cervical dilation • Fetal malposition • Prior perinatal death

Figure 10-1. Prolonged latent phase pattern (solid line). Broken line illustrates average dilation curve for nulliparous women. (From Friedman EA. Labor: clinical evaluation and management. 2nd ed. New York: Appleton-Century-Crofts, 1978, with permission.) (c) 2015 Wolters Kluwer. All Rights Reserved.

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Figure 10-2. Protraction disorders of labor. A: Protracted active phase. B: Prolonged descent pattern. Broken lines illustrate average normal dilation and descent patterns. (From Friedman EA. Labor: clinical evaluation and management. 2nd ed. New York: Appleton-Century-Crofts, 1978, with permission.)

• Large for gestational age (LGA)/macrosomia • Epidural analgesia • Physician and/or patient anxiety due to prior or current pregnancy complications can result in prematurely labeling the labor as “failure to progress.” EVALUATION History and Physical • During antepartum visits: • Obtain an accurate history to identify risk factors for dystocia.

Figure 10-3. Arrest disorders of labor. A: Secondary arrest of dilation. B: Prolonged deceleration. C: Failure of descent. D: Arrest of descent. Broken lines illustrate normal dilation and descent curves. (From Friedman EA. Labor: clinical evaluation and management. 2nd ed. New York: Appleton-Century-Crofts, 1978, with permission.) (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Perform a physical examination to assess pelvic anatomy, which may help predict pelvic outlet abnormalities. • Perform Leopold maneuvers to help determine fetal presentation. • During labor: • Perform Leopold maneuvers and/or ultrasound to determine fetal presentation. • Estimate fetal size with abdominal palpation and/or ultrasound. • Perform physical examination to determine: °°Fetal position °°Progress of cervical dilation, effacement, and station Diagnostic Studies • Ultrasound evaluation is frequently used to assess • Estimated fetal weight (EFW) • Amniotic fluid index (AFI) • Fetal presentation and position • Placental location • Uterine anomalies or pelvic tumors • Biophysical profile (BPP) DYSTOCIA—UTERINE FUNCTION Diagnosis • The clinician must first distinguish between the latent and active phases of labor before deciding on treatment. Etiologies

• Causes of uterine dysfunction: • Müllerian anomalies (uterine septum or didelphys) • Pelvic tumors (leiomyomas or large ovarian tumors) • Cervical abnormalities resulting from a loop electrosurgical excision procedure (LEEP), cold knife cone (CKC), cerclage, trauma, or other injuries • Uterine overdistension (LGA/macrosomia, multiple gestation, polyhydramnios) Clinical Manifestations

• Effective contractions are obvious clinically if progression of cervical dilation and effacement occurs. • External monitoring using either palpation or a displacement transducer provides information about the frequency of uterine contractions. • Internal monitoring using an intrauterine pressure catheter (IUPC) provides information about the frequency, duration, and intensity of uterine contractions in millimeters of mercury (mm Hg). • Montevideo units (MVUs) equal the mean amplitude (mm Hg) of contractions multiplied by the number of contractions in 10 minutes. • Two hundred to two hundred and fifty montevideo units are commonly used to define adequate contractions in the active phase of labor (16,17). Treatment

Medications

• Prolonged latent phase recommendations • Augmentation of labor (18–21): °°Oxytocin °°Misoprostol • Therapeutic rest (22): °°Nubain, 10 to 15 mg intramuscularly (IM) °°Morphine, 10 to 20 mg IM °°Vistaril, 100 mg orally (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Active management of labor • Limited to nulliparous women with (9): °°Term pregnancies °°Singleton gestations °°Cephalic presentation °°No evidence of fetal compromise • The Dublin or O’Driscoll protocol (23): °°Patient education on signs and symptoms of labor °°Strict admission criteria—only patients in active labor admitted °°Amniotomy within 1 hour of admission if unruptured °°Strict criteria for recognition of abnormal labor patterns °°Oxytocin infusion if abnormal pattern ascertained: --Six milliunits per minute to start --Six milliunits per minute increase every 15 minutes --Maximum of 40 milliunits per minute or seven contractions in 15 minutes or adequate progress °°Nurse/patient ratio of 1:1 °°Intermittent or continuous monitoring of contractions and fetal heart tones °°CD if undelivered 12 hours after admission or if fetal compromise ascertained °°Protocol resulted in CD rate of 4.8% --A second trial in Ireland using the same protocol showed a doubling of the CD rate over the first trial (24). --Lopez-Zeno et al. (25) repeated the study in the United States and reported a decrease in the CD rate, length of labor, and febrile morbidity (25). --Frigoletto et al. (11) repeated the study and reported no decrease in CD rate but a decrease in labor length and febrile morbidity (11). --The American College of Obstetricians and Gynecologists (ACOG) concluded that active management of labor may shorten labor but has not consistently led to a decrease in the CD rate (9). • Protracted labor and arrest of labor • Use O’Driscoll protocol or Seitchik protocol (26). °°Oxytocin, 5 milliunits per minute with increase every 40 minutes °°Twenty to forty minutes is needed for plasma levels of oxytocin to reach a steady state. --Satin et al. (27) analyzed 1773 cases of augmented labor. Individual patient variables prevented accurate prediction of oxytocin dosage or rate needed to affect adequate labor (27). Procedures

• Amniotomy (28–31) • Benefits °°Reduction in labor duration °°Reduction in abnormal 5-minute Apgar score (less than 5) °°Decreased need for oxytocin °°No increase in CD rate • Risks °°Increase in abnormal fetal heart rate patterns (without increase in CD rate) °°Increase in febrile morbidity Complications • Treatment of tachysystole: (32,33) • Decrease or stop oxytocin. • Administer oxygen. • Increase intravenous fluid rate (IVF). • Administer tocolytics (β2-adrenergic agents such as terbutaline). (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Treatment of fetal heart rate abnormalities (33,34) • Discontinue any labor stimulating agent if possible (stop oxytocin, remove prostaglandin insert). • Administer oxygen. • Change maternal position. • Perform cervical exam (check for umbilical cord prolapse, rapid cervical change, or fetal descent). • Monitor maternal blood pressure (treat hypotension if present with volume expansion and/or intravenous ephedrine). • Assess for uterine tachysystole (treat as above). • May perform amnioinfusion (AI) for recurrent variable decelerations. • Perform CD if abnormality cannot be corrected. • Uterine rupture (22,35) • Occurs in approximately 1 in 2000 deliveries. • Risk factors include prior CD, transfundal uterine surgery, obstructed labor, multiparity, and uterine overdistension. • May occur spontaneously without risk factors. • Clinical manifestations include abnormal fetal heart rate patterns (most common finding), loss of fetal station, abdominal pain, vaginal bleeding, cessation of uterine contractions, and signs of hemodynamic instability. • Can be catastrophic for mother and/or fetus. • Immediate CD should be performed once recognized. • Water intoxication—rare side effect of oxytocin • Postpartum hemorrhage (see Chapter 4 for management) DYSTOCIA—FETAL FACTORS Malpresentations Diagnosis Clinical Manifestations

• Asynclitism (36) • Fetal sagittal suture is not midway between the maternal symphysis and sacral promontory (lateral deflection of the sagittal suture). • Parietal bone is palpated as presenting structure. • Brow presentation (Fig. 10-4) • Partially deflexed cephalic attitude (halfway between full extension and flexion) • Diagnosed by palpation (feel brow, orbital ridges, eyes, frontal sutures, anterior fontanelle) • Occurs in 0.2% of all deliveries • Face presentations (Fig. 10-5) • Fetal head is hyperextended (fetal occiput in contact with fetal back). • Diagnosed by palpation (feel facial features). • Reference point for description is the mentum (chin)—mentum anterior (MA) or posterior (MP). • Occurs in 0.2% of all deliveries. • Breech presentations (36,37) • Higher incidence of congenital anomalies in breech versus cephalic (6.3% vs. 2.4%) • Diagnosed by Leopold maneuvers, vaginal examination, or ultrasound • Affects 3% to 4% of all deliveries • Conditions that predispose to breech presentation: °°Prematurity °°Multiple gestation °°Abnormal placental implantation (fundal–cornual or previa) °°Uterine anomalies or pelvic tumors (c) 2015 Wolters Kluwer. All Rights Reserved.

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Figure 10-4. Brow presentation. (From Obstetrical presentation and position. Ross Clinical Education Aid 18. Columbus, OH: Ross Laboratories, 1975, with permission.)

°°Polyhydramnios or oligohydramnios °°Increased parity

• Three types of breech presentations (Fig. 10-6) °°Frank breech—flexion of hips, extension at knees °°Complete breech—flexion at both hips and knees

Figure 10-5. Types of face presentation. LMA, left mentum anterior; RMP, right mentum posterior; RMA, right mentum anterior. (From Obstetrical presentation and position. Ross Clinical Education Aid 18. Columbus, OH: Ross Laboratories, 1975, with permission.) (c) 2015 Wolters Kluwer. All Rights Reserved.

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Figure 10-6. Types of breech presentation. A: Frank breech. B: Complete breech. C: Footling breech. (From Obstetrical presentation and position. Ross Clinical Education Aid 18. Columbus, OH: Ross Laboratories, 1975, with permission.)

°°Incomplete or footling breech—one or both hips deflexed with fetal knee or foot

below fetal buttock • Transverse lie (Fig. 10-7) °°Diagnosed by Leopold maneuvers or ultrasound °°Occurs in 0.3% of deliveries °°Occurs more commonly in similar situations that predispose to breech presentation (see above) • Compound presentation °°More than one presenting part—an extremity prolapses beside the presenting part (most common is the head and an upper extremity) °°May be delivered vaginally if the vertex precedes the extremity

Figure 10-7. Shoulder presentation. (From Obstetrical presentation and position. Ross Clinical Education Aid 18. Columbus, OH: Ross Laboratories, 1975, with permission.) (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Persistent occiput posterior (OP) position • Diagnosed by vaginal examination • May deliver vaginally (spontaneous, manual rotation, operative vaginal delivery) • Occurs in approximately 5% at delivery (38) • Persistent occiput transverse (OT) position • Usually associated with pelvic abnormality (platypelloid or android pelvis) • May delivery vaginally (spontaneous, manual, or forceps rotation) • Fetal anomalies • Increases in biparietal diameter (BPD) as in hydrocephalus or other central nervous system anomalies can result in dystocia. • Increases in fetal abdominal circumference seen with abdominal tumors, distended bladder, ascites, abdominal organ enlargement, or sacrococcygeal tumors can result in dystocia and fetal malpresentation. • Macrosomia can result in dysfunctional labor and shoulder dystocia (see below). • With the common availability of ultrasound in the United States, most fetal anomalies are diagnosed antenatally, which facilitates prospective decisions for which fetuses will benefit from CD. Treatment • Malpositions • OP and OT descend through the pelvis at greater diameters than occiput anterior (OA) and may impede vaginal delivery. • Manual rotation °°First determine the exact orientation of the head. °°Attempt rotation with effective anesthesia and a skilled operator. • Maternal position change aids in turning fetus °°Knee-to-chest position °°Side-to-side rotation • Forceps rotation °°Should be attempted only by operators experienced in the procedure. °°Potential exists for fetal and maternal morbidity. • Brow and face presentations • As a general rule, brow presentations should convert to face or vertex presentations to deliver vaginally. Spontaneous conversion during labor (usually in the second stage) is common. Persistent brow has a poor prognosis for vaginal delivery and usually requires CD. • MA face presentation can deliver vaginally in an adequate pelvis. • MP cannot be delivered vaginally and must be delivered by CD. Note that conversion from MP to MA may not take place until late in the second stage when pressure from the perineum against the face creates sufficient force to cause the fetus to rotate to MA. • Breech presentation • External cephalic version (ECV) indications (39,40): °°35% to 86% success rate (depends on various factors) °°Gestational age of 37 weeks or later °°Normal AFI °°Reactive nonstress test (NST) prior to attempt and after procedure °°Ultrasound guidance with forward or backward roll °°Ability to perform emergency CD if needed for fetal distress • ECV contraindications (factors that would preclude a vaginal delivery) °°Absolute contraindications: --Placenta previa --Oligohydramnios or PROM --Certain fetal anomalies (increased risk of fetal injury) --Nonreassuring NST or fetal heart rate tracing (c) 2015 Wolters Kluwer. All Rights Reserved.

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°°Relative contraindications:

--Prior CD --Obesity --LGA/macrosomia --Maternal medical conditions (hypertension, diabetes mellitus, etc.)

• Breech delivery (41–43) °°Many centers advocate delivery via CD only. °°Physician must be experienced in vaginal breech delivery. °°Must have ability to perform emergent CD. °°Contraindications: --EFW less than 1500 g --Inadequate pelvis --Incomplete breech --Hyperextended neck --Fetal growth restriction °°ACOG recommends the decision regarding mode of delivery should depend on the experience of the provider. • Techniques for breech delivery °°Allow spontaneous delivery to level of umbilicus if possible. °°Perform Pinard maneuver if needed (atraumatic delivery of the feet). °°Support trunk and lower extremities in a moist sterile towel with the sacrum anterior. °°Place gentle traction on lower extremities until delivery of buttocks. °°Continue downward traction and slight rotation until scapulas visible. °°Deliver arms by sweeping each across chest after anterior rotation of the shoulder. °°Flex fetal head by placing fingers over the maxilla, and with the other hand, use two fingers to hook the fetal neck and grasp the shoulders (Mauriceau-Smellie-Veit maneuver). °°Apply suprapubic pressure to help deliver head. °°Perform episiotomy to maximize space if needed. °°Use modified Prague maneuver if sacrum posterior. °°Use Piper forceps if needed for the aftercoming head (see “Operative Vaginal Deliveries” below). • Transverse lie • ECV may be attempted. • CD required °°Low transverse hysterotomy for back up transverse lie °°Vertical (classical) hysterotomy for back down transverse lie Complications • Increased poor outcomes in breech deliveries (41,44). • Vaginal breech delivery complications include nuchal arms and head entrapment. • Complications associated with ECV include placental abruption, fetal distress, rupture of membranes, fetomaternal hemorrhage, and need for emergent CD. • Increase in umbilical cord prolapse with breech presentation and transverse lie. • Increased rate of CD for all malpresentations. DYSTOCIA—MATERNAL PELVIS Evaluation

Physical Examination

• Gynecoid pelvis: • Round in shape • Most adapted to normal labor and delivery (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Anthropoid pelvis: • Longitudinal oval • Also favorable for vaginal delivery • Android pelvis: • Heart shaped • More commonly associated with abnormal labor • Platypelloid pelvis: • Transverse oval • High incidence of dystocia and malposition of fetus • Typical pelvis is a combination of forms. • Severe malnutrition can affect the growth of the bony pelvis. Diagnostic Studies

• Pelvimetry • Measures pelvic inlet or obstetric conjugate °°Anterior–posterior (AP) is distance between symphysis pubis and sacral promontory °°Transverse diameter (T) measured at widest point between lateral margins • Measures midpelvic plane °°AP is distance between lower margin of symphysis and sacrum at S4-5. °°T is distance between ischial spines. • CT has replaced x-ray as the preferred technique for pelvimetry. Although not widely used in current obstetric practice, CT pelvimetry is helpful for assessing adequacy of the pelvis when considering vaginal delivery of a breech fetus or multiple gestation. Management

• When pelvic abnormalities are suspected, a trial of labor is usually advocated unless obvious deformities are present. SHOULDER DYSTOCIA Diagnosis Clinical Manifestations

• The fetal shoulders fail to deliver after delivery of the fetal head using routine maneuvers. • Impaction of the anterior fetal shoulder behind the pubic symphysis. • Turtle sign: the appearance of and then retraction of the fetal head against the perineum. • The incidence ranges from 0.6% to 1.4% (45). • Risk factors (45,46): • Prior shoulder dystocia • Pregestational or gestational diabetes mellitus • LGA/macrosomia (and prior history of a macrosomic infant) • Maternal obesity • Multiparity • Postterm pregnancy • Prolonged second stage of labor • Operative vaginal delivery (midforceps or midvacuum delivery) • Even though risk factors exist, the majority of shoulder dystocias are unpredictable and unpreventable (45). • The majority of shoulder dystocias occur in fetuses weighing less than 4000 g and without other risk factors. Treatment

Procedures

Prompt action is required to avoid fetal and maternal compromise (47): • Stop maternal pushing and call for HELP—make sure to call for anesthesia and pediatrics. • Have someone mark the clock to keep track of time. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Avoid excessive traction on the fetal head. • Never use fundal pressure. • Cut an episiotomy if needed. • Begin to perform extra maneuvers: • Suprapubic pressure °°Have assistant apply suprapubic pressure against the fetal shoulder °°Helps to dislodge the impacted shoulder from under the pubic symphysis • McRoberts maneuver °°Hyperflexion of maternal hips against abdomen. °°This results in straightening of the lumbosacral angle and anterior rotation of the pubic symphysis. °°This maneuver alone alleviates 42% of shoulder dystocias (48). °°Often used in conjunction with suprapubic pressure. • Rubin maneuvers (two different maneuvers) °°First description—Apply force to the maternal abdomen and rotate fetal shoulders from side to side. This helps move fetal shoulders into a more favorable position to allow delivery. °°Second description—The most accessible fetal shoulder is palpated vaginally, and the shoulder is rotated to the anterior chest (adduction), thus reducing the shoulder–shoulder diameter. • Woods maneuver (delivers the posterior shoulder) °°Palpate the posterior shoulder vaginally and either --Apply pressure to the anterior surface of the posterior shoulder (abduction) to rotate into oblique position (Woods maneuver) or --Apply pressure to the posterior surface of the posterior shoulder (adduction) to rotate it forward (modified Woods maneuver) • Delivery of the posterior arm °°Physician passes hand beneath the fetal posterior shoulder. °°Fetal forearm is flexed by applying gentle pressure to the antecubital fossa. °°Forearm is then grasped and swept across the chest and out. °°Anterior shoulder delivered using suprapubic pressure and gentle downward traction on the fetal head. °°Some advocate that delivery of the posterior arm should be the next maneuver performed if suprapubic pressure and McRoberts maneuver are unsuccessful (49). • Clavicular fracture °°Performed if other maneuvers are unsuccessful. °°Break the clavicle by applying upward pressure against the mid portion of the clavicle (upward pressure is used to avoid vascular injury). °°Reduces shoulder–shoulder diameter. • Zavanelli maneuver (cephalic replacement) °°Use Zavanelli maneuver if all above attempts are unsuccessful. °°Fetal head rotated to OA position and flexed. °°Constant, firm pressure maintained on vertex to push fetal head cephalad as far as possible. °°May need to give uterine relaxants (terbutaline or nitroglycerin). °°Proceed with immediate CD. ACOG Recommendations (45)

• Planned CD may be considered for suspected fetal macrosomia with EFWs greater than 5000 g in nondiabetic women and greater than 4500 g in diabetic women. • There is not any evidence that one maneuver is superior to another in releasing an impacted fetal shoulder or decreasing the chance of injury. However, starting with McRoberts maneuver is a reasonable approach. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Complications • Brachial plexus injury (the no. 1 neonatal complication) • Fracture of the fetal clavicle or humerus • Fetal anoxia or death from prolonged delivery or compressed umbilical cord • Increase in perineal trauma (third- and fourth-degree lacerations) • Maternal femoral nerve injury from overzealous flexion of the maternal hips • Postpartum hemorrhage OPERATIVE VAGINAL DELIVERIES Background Definitions

• Forceps have four components: the handle, lock, shank, and blades. • Each blade has two curves: • Cephalic curve—fits around the fetal head (the lateral curve) • Pelvic curve—corresponds to the axis of the maternal birth canal • Outlet forceps (50) • Fetal scalp visible at introitus without separation of labia. • Fetal skull has reached pelvic floor. • Rotation less than 45 degrees. • Fetal head is at or on perineum. • Sagittal suture is in AP diameter or right OA, right OP, left OA, or left OP position. • Low forceps (50) • Leading point of fetal skull is ≥+2/5 station and not on pelvic floor. • Rotation may be less than or greater than 45 degrees. • Any OA or OP position is acceptable. • Midforceps (50) • Fetal head is engaged—BPD has passed through the pelvic inlet. • Station is less than +2/5. • Forceps types (Fig. 10-8) and usage • Parallel shank (Simpson, DeLee) used for molded vertex. • Overlapping shank (Elliot, Tucker-McLane-Luikart) used for unmolded vertex. • Piper forceps are used for the aftercoming head in breech delivery. • Barton and Kielland forceps are specifically rotational forceps for rotation of 90 degrees such as in OT to OA. • Vacuum extraction (51) • Most vacuums are plastic or silicone cups that use a hand pump to create suction once the cup is applied to the fetal head. Treatment Indications

• Prolonged second stage of labor • Nonreassuring fetal heart rate tracing • Shorten the second stage of labor for maternal benefit (certain cardiac, pulmonary, or neuromuscular conditions) • Maternal exhaustion or poor maternal pushing effort Contraindications

• Fetal bone demineralization disorder • Fetal bleeding disorder • Unengaged fetal head • For vacuum delivery—pregnancy less than 34 weeks of gestation Application Principles: Forceps Prerequisites

• Continuous electronic fetal monitoring throughout the procedure. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Figure 10-8. Commonly used forceps. (From Douglas R, Stromme W. Operative obstetrics. 3rd ed. New York: Appleton-Century-Crofts, 1976, with permission.)

• Fetal head must be engaged. • Cervix completely dilated and effaced. • Position, station, and attitude of fetus ascertained. • Type of maternal pelvis should be ascertained. • Experienced operator present. • Adequate anesthesia established. • Ability to perform an emergent CD. Technique (52)

• Left blade applied first unless right occiput position. • Blades inserted into posterior vagina with handle perpendicular to floor. • Blades swept in an arc from horizontal or oblique angle to midline. • Shanks should fall together and lock without force if application is correct. • Sagittal suture palpated equidistant from each blade. • Posterior fontanelle should be midway between the sides of the blades. • Posterior fontanelle should be one fingerbreadth above the plane of the shanks. Application Principles: Vacuum (52)

• Prerequisites listed for forceps delivery should also be present for vacuum application. • Vacuum is applied to the fetal vertex in the midline avoiding the fontanelles. • Care should be taken to avoid maternal soft tissues beneath the cup. • Suction is applied, and pulls by operator occur during contractions. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Steady traction should be applied in line of the birth canal, avoid torque. • Maximum of three “pop-offs” is recommended to avoid injury. Complications • Fetal • Facial nerve or brachial plexus palsies • Skull fractures • Cephalohematomas or subgaleal hematomas • Intracranial or retinal hemorrhage • Scalp or facial lacerations • Hyperbilirubinemia • Asphyxia or death • Maternal • Perineal, vaginal, and cervical lacerations (urinary/fecal incontinence) • Pelvic hematomas • Hemorrhage • Uterine rupture • Urinary retention RETAINED PLACENTA Background Definition

• Failure of the placenta to deliver within 30 minutes of infant delivery Etiology

• Idiopathic • Abnormal placentation • Placenta accreta—abnormal attachment of the placenta to the uterine wall • Placenta increta—invasion of the placenta into the myometrium • Placenta percreta—penetration of the placenta through the myometrium to or through the uterine serosa Treatment

Procedures

• Gentle traction on the umbilical cord and external uterine massage usually results in delivery of the placenta. • Manual extraction of the placenta. • Sharp curettage under ultrasound guidance if adherent fragments remain. Complications • Hemorrhage (see Chapter 4 for treatment) • Endometrial synechiae from curettage UTERINE INVERSION Background Definition

• Complete inversion: The uterine fundus extends beyond the cervix. • Incomplete inversion: The inverted fundus does not extend beyond the cervix. This may go unrecognized. Etiology

• Uterine inversion occurs as result of fundal implantation of the placenta (53). • Uterine inversion may also result from excessive traction on the umbilical cord.

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Epidemiology

• Uterine inversion occurs in approximately 1 in 2500 deliveries. Diagnosis

Clinical Manifestations

• Postpartum hemorrhage. • Uterine fundus cannot be palpated postdelivery. • Beefy, red mass at or protruding through the vaginal introitus. Treatment

Medications

• Tocolytic drugs such as magnesium sulfate, terbutaline, or nitroglycerin (53,54). • General anesthesia. • Resuscitate with intravenous fluids. • Transfuse with blood products if necessary. Procedures (55)

• Attempt manual replacement. • Place the palm of the hand against the fundus with the fingertips exerting upward pressure circumferentially (keep placenta attached if not already separated to prevent further hemorrhage). • Once the uterus is replaced: °°Manually remove the placenta if needed. °°Keep hand inside the uterus until the uterus contracts around the hand. °°Administer a uterotonic to assist with uterine contraction. • Huntington procedure: laparotomy with serial clamping and upward traction on the round ligaments to allow for elevation of uterus. • Haultain procedure: laparotomy with incision on the posterior lower uterine segment with both upward traction abdominally and manual replacement vaginally. CESAREAN DELIVERY Background

Definitions

• Uterine incision types • Low transverse or Kerr incision (LTCS) °°Most common. °°Incision made transversely in the lower uterine segment. °°Least likely to rupture in subsequent pregnancies. °°Trial of labor acceptable after LTCS (56). °°Majority of scar separations are incomplete (uterine dehiscence). • Low vertical or Kronig incision (LVCS) °°Incision made vertically in the lower uterine segment. °°Trial of labor may be acceptable (56). • Classical (CCS) °°Vertical incision into the contractile portion of the uterus °°Trial of labor not recommended after CCS (56) Epidemiology

• The rate of CD has increased over last 30 years, with the national rate now at 32% (57). • Medicolegal concerns influence the CD rate. Evaluation Indications

• Protraction and arrest disorders (most common reason for primary CD) (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Nonreassuring fetal heart rate tracings • Malpresentation • Placenta previa • Maternal genital herpes infection • Prior CD • Elective repeat CD should be performed at or beyond 39 weeks of gestation unless fetal lung maturity has been demonstrated. • Multiple gestation • Certain maternal comorbidities • Various fetal anomalies Complications Maternal

• Hemorrhage (uterine atony, lacerations, accreta, hematomas) • Injuries to bladder, bowel, ureters, blood vessels, nerves, and cervix • Infection (endomyometritis, wound infection, pelvic abscess, necrotizing fasciitis) • Antimicrobial prophylaxis is recommended for all CDs (58). °°Administer antibiotics within 60 minutes of skin incision. °°Decreases rates of endometritis, wound infection, and febrile morbidity. • Thromboembolic events • Anesthesia complications • Postoperative ileus or bowel obstruction • Wound complications (infection, separation, dehiscence, evisceration) • Placenta accreta and/or previa in subsequent pregnancies Fetal

• Iatrogenic prematurity • Transient tachypnea of the newborn • Fetal lacerations PATIENT EDUCATION • Widespread availability of medical information has allowed patients to become better informed. • ACOG pamphlets and other resources provide written explanations of procedure and options. • Audio–visual tapes allow for viewing of procedures. • Physicians have the responsibility to discuss all treatment scenarios. • Patients identified antenatally at high risk for dystocia should be offered available diagnostic testing that may affect management. • Patients with labor dystocia must be informed of risks and benefits of possible treatments and alternatives. • Patients with a prior CD should be offered both elective repeat CD and trial of labor after cesarean (TOLAC) options, if medically appropriate, with a detailed discussion of all risks and benefits. • All discussions with patients and consent forms should be well documented in the patient medical record. REFERENCES 1. Hendricks CH, Brenner WE, Kraus G. The normal cervical dilation pattern in late pregnancy and labor. Am J Obstet Gynecol. 1970;106:1065–1082. 2. Friedman EA. Labor: clinical evaluation and management. 2nd ed. New York: AppletonCentury-Crofts, 1978. 3. Friedman EA. Primigravid labor; a graphicostatistical analysis. Obstet Gynecol. 1955;6:567. (c) 2015 Wolters Kluwer. All Rights Reserved.

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4. Kilpatrick SJ, Laros RK Jr. Characteristics of normal labor. Obstet Gynecol. 1989;74: 85–87. 5. Zhang J, Yancey MK, Klebanoff MA, et al. Does epidural analgesia prolong labor and increase risk of cesarean delivery? A natural experiment. Am J Obstet Gynecol. 2001;185:128–134. 6. Alexander JM, Sharma SK, McIntire DD, et al. Epidural analgesia lengthens the Friedman active phase of labor. Obstet Gynecol. 2002;100(1):46–50. 7. Hughes EC. Obstetric-gynecologic terminology. Philadelphia: Davis, 1972. 8. Gifford DS, Morton SC, Fiske M, et al. Lack of progress in labor as a reason for cesarean. Obstet Gynecol. 2000;95:589–595. 9. American College of Obstetricians and Gynecologists. Dystocia and augmentation of labor. ACOG Pract Bull. 2003;49. 10. Sheiner E, Levy A, Feinstein U, et al. Obstetric risk factors for failure to progress in the first versus the second stage of labor. J Matern Fetal Neonatal Med. 2002;11:409–413. 11. Frigoletto FD Jr, Lieberman E, Lang JM, et al. A clinical trial of active management of labor. N Engl J Med. 1995;333:745–750. 12. Howell CJ. Epidural versus non-epidural analgesia for pain relief in labour. Cochrane Database Syst Rev. 2003;3:CD003766. 13. Satin AJ, Maberry MC, Leveno KJ, et al. Chorioamnionitis: a harbinger of dystocia. Obstet Gynecol. 1992;79:913–915. 14. Piper JM, Bolling DR, Newton ER. The second stage of labor: factors influencing duration. Am J Obstet Gynecol. 1991;165:976–979. 15. Fraser WD, Cayer M, Soeder BM, et al. PEOPLE (Pushing Early or Pushing Late with Epidural) Study Group. Risk factors for difficult delivery in nulliparas with epidural analgesia in second stage of labor. Obstet Gynecol. 2002;99:409–418. 16. Miller FC. Uterine activity, labor management, and perinatal outcome. Semin Perinatol. 1978;2:181–186. 17. Hauth JC, Hankins GV, Gilstrap LC, et al. Uterine contraction pressures with oxytocin induction/augmentation. Obstet Gynecol. 1986;68:305–309. 18. Rouse DJ, Weiner SJ, Bloom SL, et al. Failed labor induction: toward an objective diagnosis. Obstet Gynecol. 2011;117(2, Part 1):267–272. 19. Hofmeyr GJ. Vaginal misoprostol for cervical ripening and induction of labour. Cochrane Database Syst Rev. 1999;2:1–18. 20. Mercer B, Pilgrim P, Sibai B. Labor induction with continuous low dose oxytocin infusion: a randomized trial. Obstet Gynecol. 1991;77:659–663. 21. Muller PR, Stubbs TM, Laurent SL. A prospective randomized clinical trial comparing two oxytocin induction protocols. Am J Obstet Gynecol. 1992;167:373–381. 22. Gabbe SG, Niebyl JR, Simpson JL, eds. Obstetrics: normal and problem pregnancies. 6th ed. Philadelphia: Saunders, 2012. 23. O’Driscoll K, Foley M, MacDonald D. Active management of labor as an alternative to cesarean section for dystocia. Obstet Gynecol. 1984;63:485–490. 24. Boylan P, Robson M, McFarland P. Active management of labor 1963–1990. Am J Obstet Gynecol. 1993;168:295–300. 25. Lopez-Zeno JA, Peaceman AM, Adashek JA, et al. A controlled trial of a program for the active management of labor. N Engl J Med. 1992;326:450–454. 26. Seitchik J, Amico J, Robinson AG, et al. Oxytocin augmentation of dysfunctional labor. IV Oxytocin pharmacokinetics. Am J Obstet Gynecol. 1984;150:225–228. 27. Satin AJ, Leveno KJ, Sherman ML, et al. Factors affecting the dose response to oxytocin for labor stimulation. Am J Obstet Gynecol. 1992;166:1260–1261. 28. Wei S, Wo BL, Qi HP, et al. Early amniotomy and early oxytocin for prevention of, or therapy for, delay in first stage spontaneous labour compared with routine care. Cochrane Database Syst Rev. 2012;9. 29. Garite TJ, Porto M, Carlson NJ, et al. The influence of elective amniotomy on fetal heart rate patterns and the course of labor in term patients: a randomized study. Am J Obstet Gynecol. 1993;168:1827–1831.

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30. Rouse DJ, McCollogh C, Wren AL, et al. Active phase labor arrest: a randomized trial of chorioamnion management. Obstet Gynecol. 1994;88:937–940. 31. Brisson-Carroll G, Fraser W, Breart G, et al. The effect of routine early amniotomy on spontaneous labor: a meta-analysis. Obstet Gynecol. 1996;87:891–896. 32. Egarter CH, Husslein PW, Rayburn WF. Uterine hyperstimulation after low-dose prostaglandin E2 therapy: tocolytic treatment in 181 cases. Am J Obstet Gynecol. 1990;163: 794–796. 33. American College of Obstetricians and Gynecologists. Intrapartum fetal heart rate monitoring: nomenclature, interpretation and general management principles. ACOG Prac Bull. 2009;106. 34. Hofmeyr GJ. Amnioinfusion for potential or suspected umbilical cord compression in labour. Cochrane Database Syst Rev. 1998;1:CD000013. 35. American College of Obstetricians and Gynecologists. Vaginal birth after previous cesarean delivery. ACOG Pract Bull. 2010;115. 36. Cunningham FG, Leveno KJ, Bloom SL, eds. Williams obstetrics. 23rd ed. New York: McGraw Hill, 2010. 37. Creasy RK, Resnik R, Iams JD, eds. Creasy and Resnik’s maternal fetal medicine: principles and practice. 6th ed. Philadelphia: Saunders, 2009. 38. Gardberg M, Laakkonen E, Salevaara M. Intrapartum sonography and persistent occiput posterior position: a study of 408 deliveries. Obstet Gynecol. 1998;91:746–749. 39. American College of Obstetricians and Gynecologists. External cephalic version. ACOG Pract Bull. 2000;13. 40. Gilstrap LC, Cunninghman FG, Vandorsten JP, eds. Operative obstetrics. 2nd ed. New York: McGraw Hill, 2002. 41. Hannah ME, Hannah WJ, Hewson SA, et al. Planned cesarean section versus planned vaginal birth for breech presentations at term: a randomised multicentre trial. Term Breech Trial Collaborative Group. Lancet. 2000;356:1375–1383. 42. Malloy MH, Onstad L, Wright E. National Institutes of Child Health and Human Development Neonatal Research Network: the effect of cesarean delivery on birth outcome in very-low-birthweight infants. Obstet Gynecol. 1991;77:498–503. 43. American College of Obstetricians and Gynecologists. ACOG Committee Opinion No. 340. Mode of term singleton breech delivery. 2006;108(1):235–237. 44. Gifford DS, Morton SC, Fiske M, et al. A meta-analysis of infant outcomes after breech delivery. Obstet Gynecol. 1995;85:1047–1054. 45. American College of Obstetricians and Gynecologists. Shoulder dystocia. ACOG Pract Bull. 2002;40. 46. Baskett TF, Allen AC. Perinatal implications of shoulder dystocia. Obstet Gynecol. 1995;86:14–17. 47. Naef RW, Morrison JC. Guidelines for the management of shoulder dystocia. J Perinatol. 1994;14:435–441. 48. Gherman RB, Goodwin TM, Souter I, et al. The McRobert’s maneuver for the alleviation of shoulder dystocia: how successful is it? Am J Obstet Gynecol. 1997;176:656–661. 49. Hoffman MK, Bailit JL, Branch DW, et al. A comparison of obstetric maneuvers for the acute management of shoulder dystocia. Obstet Gynecol. 2011;117:1272–1278. 50. American College of Obstetricians and Gynecologists. Operative vaginal delivery. ACOG Pract Bull. 2000;17. 51. Bofill JA, Rust OA, Perry KG Jr, et al. Forceps and vacuum delivery: a survey of North American residency programs. Obstet Gynecol. 1996;88:622–625. 52. Hale RW, ed. Dennen’s forceps deliveries. 4th ed. Washington, DC: American College of Obstetricians and Gynecologists, 2001. 53. Watson P, Besch N, Bowes WA Jr. Management of acute and subacute puerperal inversion of the uterus. Obstet Gynecol. 1980;55:12–16. 54. Catanzarite VA, Moffitt KD, Baker ML, et al. New approaches to the management of acute puerperal uterine inversion. Obstet Gynecol. 1986;68:75–105.

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55. American College of Obstetricians and Gynecologists. Postpartum hemorrhage. ACOG Pract Bull. 2006;76. 56. American College of Obstetricians and Gynecologists. Vaginal birth after previous cesarean delivery. ACOG Pract Bull. 2010;115. 57. U.S. Department of Health and Human Services. Centers for Disease Control and Prevention. National Vital Statistics Report: Births: Final Data for 2010. 2012;61:1–71. 58. American College of Obstetricians and Gynecologists. Use of prophylactic antibiotics in labor and delivery. ACOG Pract Bull. 2011;120.

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11

Hypertensive Disorders of Pregnancy John R. Barton and Baha M. Sibai

KEY POINTS Background • Hypertensive disorders are the most common medical complication of pregnancy, occurring in approximately 7% to 10% of all pregnancies. • Hypertensive disorders are associated with significant maternal and perinatal mortality and have a wide spectrum of presentation, ranging from minimal elevation of blood pressure to severe hypertension with multiple organ dysfunction. • Preeclampsia is a syndrome that only occurs during pregnancy and is defined by hypertension and end-organ manifestations such as proteinuria, thrombocytopenia, and hepatic or cerebral manifestations. Definitions for Hypertensive Disorder of Pregnancy • Gestational hypertension • The National High Blood Pressure Education Program Working Group has recommended that the term “gestational hypertension” replace the term “pregnancy-induced hypertension” to describe cases in which elevated blood pressure without proteinuria develops in a woman after 20 weeks of gestation and blood pressure levels return to normal postpartum (1). • According to the criteria established in pregnant women by the Hypertension in Pregnancy Task Force sponsored by the ACOG, gestational hypertension is defined as a persistent systolic blood pressure level of 140 mm Hg or greater or a diastolic blood pressure level of 90 mm Hg or greater that occurs on two occasions 4 hours apart after 20 weeks of gestation in a woman with previously normal blood pressure (2). • Preeclampsia • A syndrome of gestational hypertension plus end-organ manifestations including proteinuria with proteinuria defined as urinary excretion of 0.3 g protein or more in a 24-hour urine specimen or a protein/creatinine ratio ≥0.3 mg/dL. In the absence of proteinuria, new-onset hypertension with thrombocytopenia (less than 100,000 platelets/mL) or renal insufficiency (serum creatinine concentration greater than 1.1mg/dL) or impaired liver functions (transaminases twice the upper limits of normal concentration) constitute diagnostic criteria of preeclampsia (2). • The previous definition of preeclampsia as hypertension of more than 30 mm Hg systolic or 15 mm Hg diastolic above the patient’s baseline blood pressure is no longer used. • Eclampsia • The development of convulsions or coma in patients with signs and symptoms of preeclampsia in the absence of other causes of convulsions • Chronic hypertension • Patients with a persistent elevation of blood pressure to at least 140/90 mm Hg on two occasions before 20 weeks’ gestation, and patients with hypertension that persists for more than 6 weeks postpartum • Superimposed preeclampsia or eclampsia • The development of either preeclampsia or eclampsia in patients with previously ­diagnosed chronic hypertension 183

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PREECLAMPSIA Background Definition

• Preeclampsia is a syndrome of gestational hypertension as defined above. • There are only two types of preeclampsia: mild and severe. Etiology

Preeclampsia is a disorder of unknown etiology that is peculiar to human pregnancy. Many theories regarding its etiology have been suggested, including • Abnormal placentation • Immunologic phenomena • Coagulation abnormalities • Abnormal cardiovascular adaptation • Dietary factors • Genetic factors • Angiogenesis factors • Vascular endothelial damage • Abnormal prostaglandin metabolism Epidemiology

• Preeclampsia is principally a disease of young, nulliparous women. • The incidence of gestational hypertension is 6% to 17% for healthy nulliparous women and 2% to 4% for multiparous women. • The incidence of mild preeclampsia is 2% to 7% in healthy nulliparous women and 14% in twin gestations. • Seventy-five percent of patients with preeclampsia develop the disorder at ≥37 weeks of gestation. Risk Factors

Although geographic and racial differences in incidence have been reported, several risk factors have been identified as predisposing to the development of preeclampsia: • Nulliparity • Multiple gestation • Previous pregnancy with preeclampsia • Family history of preeclampsia or eclampsia • Preexisting hypertension or renal disease • Pregestational diabetes • Use of donor oocytes • Nonimmune hydrops fetalis • Molar pregnancy • Obesity Diagnosis

Clinical Manifestations

• Preeclampsia traditionally has been described as hypertension and proteinuria. It may, however, present as a spectrum of clinical signs and symptoms, alone or in combination, often making diagnosis difficult. • Hypertension °°Abnormally elevated blood pressure is the traditional hallmark for the diagnosis of preeclampsia. The blood pressure criteria for gestational hypertension and preeclampsia are presented earlier in the chapter. • Proteinuria °°Protein excretion in the urine increases in normal pregnancy from approximately 5mg per 100 mL in the first and second trimesters to 15 mg per 100 mL in the third trimester. (c) 2015 Wolters Kluwer. All Rights Reserved.

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°°Significant proteinuria should be defined as greater than 300 mg per 24-hour urine

sample or protein/creatinine ratio ≥0.3 mg/dL. making a diagnosis of severe preeclampsia, the criterion of proteinuria of greater than 5 g excreted in a 24-hour urine has been discontinued (2). • Early recognition of the development of preeclampsia can allow for more timely intervention to improve maternal and perinatal outcome. This reinforces the reason for frequent antenatal visits late in pregnancy to allow early detection of disease. • Some preeclamptic pregnancies, particularly those with more severe disease, can be associated with reduced uteroplacental blood flow, which may be manifested as poor fetal growth. This can be the primary initial manifestation of preeclampsia and can be seen in both mild and severe forms of the disease.

°°When

Management • Figure 11-1 shows a sample algorithm for the management of a normotensive patient who may be developing subtle signs and symptoms of preeclampsia. • Once the diagnosis of preeclampsia has been made, definitive therapy in the form of delivery is the desired goal because it is the only cure for the disease. • The ultimate goals of the therapy must always be first the safety of the mother and then the delivery of a mature newborn that will not require intensive and prolonged neonatal care. • The decision between expectant management and immediate delivery usually depends on one or more of the following factors: • Severity of the disease process • Fetal condition • Maternal condition • Fetal gestational age • Presence of labor or rupture of membranes MILD PREECLAMPSIA Evaluation • At the time of diagnosis, all patients with preeclampsia should be evaluated regarding maternal/fetal condition.

Normotensive pregnancy

BP ≥ 140 • Excessive weight gain • Epigastric pain 90 • RUQ pain • BP 130–138 80–88 • Nausea & vomiting On 2 • ≤ 1 + proteinuria occasions • Not feeling well

Re-check in 1 to 3 days

• CBC • Platelets • Liver function tests

150 100 ≥ 2 + proteinuria • Headache • Visual symptoms • BP ≥

Hospitalize for maternal/ fetal evaluation

Figure 11-1. A sample algorithm for the management of a normotensive patient who may be developing subtle signs of preeclampsia. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Maternal Evaluation History

Markers for possible severe preeclampsia: • Persistent occipital or frontal headaches • Visual disturbances • Right upper quadrant abdominal or epigastric pain Physical Evaluation

• Blood pressure assessment at diagnosis, then twice weekly by the health care provider. • Urine protein assessment at diagnosis. If significant proteinuria is identified, subsequent proteinuria evaluation is not necessary as the amount or change in the amount of proteinuria will not influence the need for delivery (2). • Weight daily. Laboratory Evaluation

• Hematocrit and platelet count once per week • Liver function tests once per week • Twenty-four–hour urine collection at diagnosis for total protein excretion and creatinine clearance or a protein/creatinine ratio to confirm the diagnosis Fetal Evaluation

• Daily fetal movement assessment (kick counts) • Nonstress test (NST) twice weekly • Biophysical profile if nonreactive NST • Amniotic fluid volume assessment weekly • Ultrasound evaluation of fetal growth every 3 weeks Management • Women with mild disease who achieve a gestational age of 37 weeks should undergo delivery. • Even if conditions for induction of labor are unfavorable, the pregnancy should not continue (beyond 37 weeks’ gestation) because uteroplacental blood flow is suboptimal. • The optimal management of mild preeclampsia remote from term is controversial. In general, there is considerable controversy regarding the need for hospitalization versus outpatient management. The use of antihypertensive drugs is not recommended nor is the use of sedatives and anticonvulsive prophylaxis. • For a patient who has mild preeclampsia with an immature fetus, the goal of therapy should be to °°Retard the hypertensive process so as not to endanger the mother or the fetus °°Allow time for the fetus to mature and increase the potential for neonatal survival • Therapy for patients with mild disease can be conducted by either outpatient management or hospitalization. °°Outpatient management is acceptable for patients who are compliant, who can have frequent office visits including laboratory assessments, and who can perform some form of adequate blood pressure monitoring at home. °°Hospitalization should be required for noncompliant patients and those who show unsatisfactory progress as outpatients. • If outpatient management is used, the regimen described below is recommended for mild preeclampsia. °°A patient is considered a candidate for induction of labor if she has reached 37 weeks’ gestation. °°She is also a candidate for induction if her blood pressure continues to rise despite conservative management. °°Figure 11-2 shows a sample algorithm for the management of a patient with mild preeclampsia. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Mild GHTH – Preeclampsia Maternal and fetal evaluation

• ≥370/7 weeks’ gestation • ≥340/7 weeks’ gestation Labor, PPROM, IUGR • Suspected abruptio • Abnormal M/F testing

Yes

Delivery

No • Inpatient /outpatient • Maternal/fetal testing

• Worsening maternal / fetal condition • Labor/PROM • ≥ 370/7 weeks’ gestation

Yes

Figure 11-2. A sample algorithm for the management of a patient with mild preeclampsia.

°°After 34 weeks’ gestation, rupture of membranes, the spontaneous onset of labor or

the development of intrauterine growth retardation with an estimated fetal weight less than 5th percentile, are indications for delivery.

PATIENT EDUCATION • Close communication between the patient and physician is obligatory for successful outpatient management of mild gestational hypertension and preeclampsia. Patients are instructed to contact their managing physician for one for more of the following symptoms specific to preeclampsia: • Blood pressure above a chosen target level • A severe, long-lasting headache • Epigastric or right upper quadrant abdominal pain • Visual disturbances • Nausea and vomiting • The patient should also be instructed to notify her physician for the following complications of pregnancy, regardless of preeclampsia: • Vaginal bleeding • Leakage of fluid from the vagina • Regular preterm uterine contractions • Decreased fetal movement • Patients should be provided a contact telephone number for the physicians’ call service and the hospital at which they intend to deliver. Patients are instructed that if they are unable to contact their physician and their condition worsens, they should come to their physician’s office or hospital for further evaluation. SEVERE PREECLAMPSIA Background • The clinical course of severe preeclampsia is usually characterized by progressive deterioration in both maternal and fetal status. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• These pregnancies are usually associated with increased rates of perinatal mortality and morbidity. • Most of the fetal or neonatal complications are related to intrauterine fetal growth retardation, placenta abruption, or prematurity. Diagnosis • The criteria for the diagnosis of severe preeclampsia are (adapted from ACOG Practice Bulletin No. 33, 2002)(3). • Blood pressure ≥160 mm Hg systolic or ≥110 mm Hg diastolic on two occasions at least 4 hours apart with the patient on bed rest. • Cerebral or visual disturbances. • Severe and persistent epigastric or right upper quadrant abdominal pain. • Pulmonary edema or cyanosis. • Thrombocytopenia. • Fetal growth restriction. • Of note, the previous criteria for severe disease based on proteinuria (≥5 g) are no longer utilized (2). Management • Because the only cure for severe preeclampsia is delivery, there is unanimous agreement that all patients should be delivered if severe disease develops beyond 34 weeks 0 days’ gestation or if there is evidence of fetal jeopardy before that time. In this situation, appropriate management should include (4,5) • Parenteral magnesium sulfate to prevent convulsions • Control of maternal blood pressure within a safe range • Initiating delivery • Management of patients with severe disease remote from term (less than 34 weeks 0 days) is controversial. • Some institutions consider delivery as the definitive therapy for all cases, regardless of gestational age. • Others recommend prolonging pregnancy in all patients remote from term until one or more of the following is achieved: °°Fetal lung maturity °°Fetal jeopardy °°Maternal jeopardy °°Achievement of 34 weeks 0 days’ gestation • All patients with severe preeclampsia should be admitted to the labor and delivery area for close observation of maternal and fetal condition and provided steroids for lung maturity if less than 34 weeks’ gestation during initial evaluation and with the decision for delivery. • All patients should receive intravenous magnesium sulfate to prevent convulsions (Fig.11-3). SEVERE PREECLAMPSIA IN MIDTRIMESTER • Occasionally, a patient may develop severe preeclampsia at or before 28 weeks’ gestation. • These pregnancies are associated with high maternal and perinatal mortality and pose a difficult management decision for every obstetrician. • Immediate delivery will result in extremely high perinatal morbidity and mortality, whereas an aggressive attempt to delay delivery may cause severe maternal morbidity. As a consequence, in the circumstance of a potentially viable fetus, these pregnancies should be managed in a tertiary care center (5). (c) 2015 Wolters Kluwer. All Rights Reserved.

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Severe preeclampsia 1.2 mg/dL Lactic dehydrogenase >600 U/L Elevated liver functions Serum aspirate aminotransferase >70 U/L Lactic dehydrogenase >600 U/L Low platelets Platelet count II Cyanosis (room air saturation 2 d/wk but less than daily or >2 nights/month

>80%

1 Mild intermittent

2 or fewer days/ week or 2 or fewer nights/month

>80%

Daily medications High-dose inhaled corticosteroid and long-acting inhaled β2-agonist (and if needed, corticosteroid tablets) Alternative: High-dose inhaled corticosteroid and theophylline Low-dose inhaled corticosteroid and long-acting inhaled β2-agonist or medium-dose inhaled corticosteroid (and long-acting inhaled β2-agonist if recurring severe exacerbations) Alternatives: Low-dose inhaled corticosteroid and either theophylline or leuko­ triene receptor antagonist Low-dose inhaled corticosteroid Alternative: Cromolyn, leukotriene receptor antagonist, theophylline No long-term medications A course of systemic corticosteroid for severe exacerbations

From NAEPP Working Group Report on Managing Asthma During Pregnancy. Recommendations for Pharmacologic Treatment: Update 2004. NIH Publication No. 05-3279. Bethesda, MD. Acute Exacerbation

• Obtain history, physical examination, pulse oximetry, FEV1 or PEF, arterial blood gas, and chest x-ray if pneumonia suspected. • Administer oxygen by face mask to achieve O2 Sat greater than 95%. • Start intravenous hydration and nebulizer treatment with: • Albuterol 2.5 to 5.0 mg every 20 minutes for three doses, then 2.5 to 10 mg every 1to4 hours as needed. • Add ipratropium if there is a severe exacerbation. • Add systemic corticosteroids if refractory to above regimen. • Oral “burst” of prednisone 60 to 80 mg/d for 3 to 10 days in outpatient management. • Intravenous prednisone or methylprednisolone 120 to 180 mg/d in three or four divided doses for 48 hours, then 60 to 80 mg/d until PEF reaches 70% of predicted or personal best in inpatient management. • Consider admission to the intensive care unit if poor response (FEV1 or PEF less than 50%, PaCO2 greater than 42 mm Hg, mental status changes) or signs of impending respiratory arrest. • Provide continuous electronic fetal monitoring if fetal viability (≥23 weeks) is present.

(c) 2015 Wolters Kluwer. All Rights Reserved.

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Labor Management

• Continue prenatal asthma medications. • Inhaled β-agonists do not delay the onset or slow the progress of labor. • Both prostaglandins and ergometrine (methergine) can cause bronchospasm and therefore should be avoided if possible. Hemabate, a PGF2 α, should be avoided while local dinoprostone, a PGE2 analog, and misoprostol, a PGE1 analog, can be used safely. Complications • Poorly controlled asthma is associated with increased risks of preeclampsia, prematurity, and low birth weight (9). • Pregnancy does not alter the diagnostic tests for or the treatment of asthma. • Inadequate control of asthma can cause more harmful fetal effects than the medications. INFLUENZA Background Influenza A and B are the two types of influenza that can cause epidemic human illness during the winter months (October to May). Influenza is airborne with an incubation period of 1 to 4 days. It is usually a self-limited respiratory illness lasting a few days, but women in the third trimester have an increased risk of complications. Evaluation • Signs and symptoms include fever, myalgia, headache, malaise, cough, sore throat, and rhinitis (10). Treatment • Immunoprophylaxis is associated with reductions in influenza-related respiratory illness, physician visits, hospitalization, and death. • Inactivated influenza vaccine is preferred and may be given in any trimester (11), postpartum, and during breast-feeding. Postpartum vaccination can protect infants from influenza as children under 6 months of age cannot be vaccinated. • No data or evidence exists of any harm caused by the low level of mercury exposure that might occur from influenza vaccination (11). • Influenza and pneumococcal polysaccharide vaccines can be given concurrently. • The intranasal live attenuated influenza vaccine, marketed as FluMist, should not be used during pregnancy. • The influenza antiviral agent oseltamivir (FDA Category C) can be used in pregnancy when potential benefit justifies the potential fetal risk (10). Complications • Exacerbation of underlying medical conditions (e.g., pulmonary or cardiac disease) • Secondary bacterial pneumonia • Coinfection with other viral or bacterial pathogens PERTUSSIS Background The incidence of pertussis is increasing in the United States. In an effort to decrease the burden of disease in infants, the CDC has updated pertussis immunization guidelines. Recommendations • Women should receive the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) in every pregnancy, ideally in the third trimester (12).

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PNEUMONIA Background Pregnancy does not predispose to pneumonia. The pathogens in pregnancy are the same as those affecting nonpregnant women of reproductive age: • Bacterial: Streptococcus pneumoniae, Haemophilus influenzae, Legionella • Viral: Influenza A, varicella • Mycoplasma Diagnosis • Typical symptoms are cough, dyspnea, sputum production, and pleuritic chest pain. • Signs include fever, tachypnea, rales, dullness to percussion, and bronchial breath. • Chest x-ray may reveal single lobar infiltrate typical of bacterial pneumonias or patchy multilobular infiltrates typical of Mycoplasma or viral infections. • Routine sputum cultures, serological testing, cold agglutinin, and bacterial antigen testing are not recommended. Treatment • Hospitalization for intravenous hydration, oxygen supplementation, and empirical antibiotic treatment is indicated. • Erythromycin monotherapy is effective in most community-acquired pneumonias (13). Cefotaxime or ceftriaxone should be added for • Staphylococcal or Haemophilus pneumonia (suspected or documented) • Coexisting chronic conditions • Respiratory rate of 30 per minute or faster, hypotension, pulse of 125 bpm or faster, temperature of less than 35°C or greater than 40°C, altered mental status • Extrapulmonary disease, sepsis, coagulopathy, or anemia • White blood cell less than 4000 per μL or greater than 30,000 per μL • PaO2 of 60 mm Hg or less and/or CO2 retention • Elevated serum creatinine • Multilobar involvement, cavitation, or pleural effusion • Penicillin can be used if pneumococcal disease is strongly suspected (13). • Strains of S. pneumoniae resistant to penicillin and erythromycin are increasingly common. • Pneumococcal polysaccharide vaccine (PPV-23) is not recommended in healthy pregnant women. However, PPV-23 should be given to pregnant women with immunosuppression, asthma, diabetes mellitus, asplenia, tobacco use, and renal and cardiopulmonary diseases (8). Complications • Women hospitalized for pneumonia may have higher rates of low birth weight, preterm birth, and preeclampsia (14). AMNIOTIC FLUID EMBOLISM SYNDROME Background • Also known as anaphylactoid syndrome of pregnancy, the amniotic fluid embolism syndrome (AFES) occurs in approximately 1 in 20,000 to 30,000 deliveries. • AFES is characterized by unpredictable and unpreventable sudden hypoxemia, cardiovascular collapse, and disseminated intravascular coagulopathy during labor or immediately postpartum resulting in hemorrhage. Seizure activity can be present. Extensive ventilation/perfusion mismatch causes early, significant hypoxemia. Left ventricular dysfunction causes cardiovascular decompensation. • The prevailing theory is that AFES is a profound adverse allergic reaction to the presence of amniotic fluid in the maternal circulation. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Diagnosis • AFES is primarily a clinical diagnosis. • The presence of amniotic fluid contents in the lungs on pathologic examination is not diagnostic of AFES. • Air or pulmonary embolism (PE), anesthetic complications, anaphylaxis, sepsis, hemorrhage, aspiration, and myocardial infarction must be excluded. Treatment • Prompt supportive care with judicious intravascular resuscitation, vasopressors, and mechanical ventilation is essential. Central monitoring may be considered. • Continuous external fetal monitoring is indicated when the fetus is viable. • The risk of recurrent AFES is unknown; however, there are a few case reports describing uncomplicated subsequent pregnancies. Complications • AFES results in substantial morbidity and mortality. Many survivors suffer persistent neurologic impairment. • Neonatal complications such as hypoxic ischemic encephalopathy and stillbirth are also common (15). PULMONARY EDEMA Background Pulmonary edema in pregnancy is usually secondary to • Preeclampsia • Tocolytic therapy • Massive fluid resuscitation • Amniotic fluid embolism • Sepsis • Cardiac disease (peripartum cardiomyopathy, structural disease, myocardial infarction) Diagnosis • Symptoms of dyspnea and orthopnea. • Respiratory examination may reveal rales and crackles. There is evidence of hypoxemia. • Chest x-ray reveals fluffy infiltrates or Kerley B lines. Treatment Basic principles of management of pulmonary edema should be similar to that in nonpregnant women: • Identification and reversal of underlying cause. • LMNOP: lasix (diuresis), morphine (to dilate airways), Na2+ and water restriction, ­oxygen, and position patient upright. • Consider management in an intensive care unit setting. • Antibiotics and inotropic support if indicated. TUBERCULOSIS Background • Tuberculosis case rates in the United States continue to decline, with an estimated 2012 rate of 3.2 per 100,000 population (16). • The majority of cases occur in foreign-born persons. Mexico, Philippines, Vietnam, India, and China are the top countries of origin (16). • Adults aged 15 to 64 years accounted for 73% of reported TB cases (16). • The acid–fast bacillus Mycobacterium tuberculosis is transmitted from person to person through an airborne route. Infectivity is associated with cavitary pulmonary disease, (c) 2015 Wolters Kluwer. All Rights Reserved.

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s­putum AFB smear positivity, and frequency of cough. Of note, patients with sputum AFB smear–negative pulmonary TB can also transmit the infection. Diagnosis • The Mantoux tuberculin skin test (0.1 mL of purified protein derivative, PPD) is a safe and valid screening test at any stage of pregnancy. The degree of induration (not redness) that constitutes a positive PPD in pregnancy varies with risk factors (e.g., ≥5 mm if HIV positive, ≥10 mm if intravenous drug user, and ≥15 mm if low risk). • A chest x-ray may be used to rule out the possibility of pulmonary TB in a person with a positive skin test (including patients previously vaccinated with bacilli Calmette-Guérin, BCG). • Asymptomatic individuals with a positive skin test and a negative chest x-ray have latent tuberculosis infection (LTBI). They have been exposed to TB at some point in the past. These individuals are not contagious but may progress to TB upon bacterial activation. The risk of progression to active disease is highest in the 2 years after seroconversion to positive PPD. • Neither a chest x-ray nor a sputum test for acid–fast bacilli smear can confirm a diagnosis of TB. Only a positive culture for M. tuberculosis can provide a definite diagnosis of TB. • Drug susceptibility should always be obtained from the initial isolates because multidrug-resistant TB is common. Treatment • Treatment should be initiated before the culture results are available whenever the probability of active TB is moderate to high. • The first-line regimen consists of isoniazid (INH), rifampin (RIF), and ethambutol daily for 2 months, followed by INH and RIF daily or twice weekly for 7 additional months. Streptomycin should be avoided due to possible fetal ototoxicity. The fetal risks of using pyrazinamide are unknown; however, the benefits of including pyrazinamide in the treatment of women with HIV or multidrug-resistant tuberculosis outweigh potential fetal risks (16). Such women should also be managed in a laminar flow room with contact and respiratory precautions. • LTBI is treated with daily INH 300 mg for 9 months after the first trimester (12 months if HIV infected). INH therapy can be started during pregnancy (16). • INH should be supplemented with pyridoxine (vitamin B6), daily tablets of 50 mg, to decrease neurotoxicity. • Because pregnancy itself does not increase the risk of LTB1 progression to active TB, some experts recommend delaying treatment in pregnant women without risk factors until 6 weeks postpartum because of an increased risk for hepatotoxicity during the puerperium. • Antituberculosis medications are not contraindicated during breast-feeding. • Routine vaccination with BCG is not recommended due to low risk of infection, variable effectiveness against adult pulmonary TB, and potential interference with tuberculin skin test reactivity (16). Complications • Perinatal complications include low birth weight and, rarely, neonatal tuberculosis. • Congenital infection may occur via hematogenous spread or at the time of delivery. CYSTIC FIBROSIS Background • Cystic fibrosis (CF) is an autosomal recessive condition caused by a mutation of the gene encoding for the cAMP-regulated chloride ion channel, known as the cystic fibrosis transmembrane conductance regulator (CFTR). To date, over 1700 mutations in this single-copy gene have been described. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• The defective CFTR protein produces thickened secretions throughout the respiratory and alimentary tracts, sweat ducts, and the reproductive organs leading to • Undernutrition, due to pancreatic insufficiency, and malabsorption • Respiratory failure due to chronic infection, bronchiectasis, and progressive lung destruction • Diabetes mellitus and cirrhosis due to pancreatic and biliary injury • Reduced fertility: °°In females this is contributed to by the increased tenacity of the cervical mucus plug. °°Male infertility (98%) results from abnormalities of the vas deferens. Treatment • Counseling should be undertaken before conception to address the maternal risks based on the mother’s disease status as well as the risk for having a child with CF. • Genetic counseling in women with CF: • All infants will be obligate carriers of one of their mother’s CFTR alleles. • The father’s carrier status will determine the risk of having an affected child. • The CF carrier detection rates of the standard screening panel of the more common 23 mutations differ among ethnic groups (see Table 14-2); therefore, a negative screen result will reduce but not eliminate the risk of having a fetus affected with CF. For couples where both are carriers, or one is affected by CF, genetic counseling should be offered to assess the value of expanded screening or gene sequencing (17). Genotype and phenotype are poorly correlated. • Routine CF screening: • The American College of Obstetricians and Gynecologists (ACOG) currently recommends that all women, regardless of ethnicity, be offered CF screening either prior to or during pregnancy for a panel that includes at least the most common 23 CFTR gene mutations. • If the woman screens negative, no further testing is necessary. • If the woman screens positive, then the father of the baby should be tested and genetic counseling recommended. • Management of women with CF should include • Nutritional counseling and early screening for diabetes mellitus • Pulmonary function monitoring with spirometric tests before, during, and after pregnancy • Aggressive antibiotic therapy. Pseudomonas aeruginosa is the most common pathogen associated with recurrent infections and chronic airway inflammation. Fluoroquinolones should be avoided due to potential adverse effects on fetal cartilage

Table 14-2

Cystic Fibrosis Detection and Carrier Rates Before and After Testing

Ethnic group Ashkenazi Jewish Non-Hispanic white Hispanic white African American Asian American

Detection rate 94% 88% 72% 64% 49%

Carrier rate before testing 1/24 1/25 1/58 1/61 1/94

Carrier rate after ­negative test result 1/380 1/200 1/200 1/170 1/180

From American College of Obstetricians and Gynecologists. Update on Carrier Screening for Cystic Fibrosis. Committee Opinion No. 486, April 2011. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Complications • Perinatal complications include poor maternal weight gain, irreversible deterioration of pulmonary function, congestive heart failure, prematurity, and perinatal death. • Pulmonary function is the best predictor of maternal long-term survival, and poor lung function increases the risk of preterm delivery (18). • Pulmonary hypertension and cor pulmonale from chronic lung disease are contraindications to pregnancy. • Adequate pancreatic function is associated with a better overall outcome. PULMONARY EMBOLISM (SEE CHAPTER 22, THROMBOEMBOLIC DISORDERS) Background Venous thromboembolic disease (pulmonary embolism [PE] and deep vein thrombosis [DVT]) is a leading obstetric cause of maternal mortality. Etiology • Pregnancy is a thrombogenic state. Thromboembolic events are fivefold more common in pregnant women than in nonpregnant women. • Other predisposing factors include trauma (surgery), infection, obesity, and underlying thrombophilia. Treatment • Some authorities recommend low molecular weight heparin (LMWH) as the treatment of choice for acute thromboembolism (19). Because of its long half-life and resistance to reversal by protamine sulfate, many authorities recommend converting LMWH to unfractionated heparin at 36 weeks, prior to the onset of labor. • Unfractionated heparin must be given intravenously or subcutaneously to maintain a therapeutic aPTT (activated partial thromboplastin time). Target aPTT ranges are laboratory specific but correspond to an anti-Xa level of 0.3 to 0.7 U (19). Heparin does not cross the placenta and, as such, is not teratogenic. Adverse effects include hemorrhage, thrombocytopenia, and osteoporosis. In the setting of acute hemorrhage, protamine ­sulfate can be given to reverse heparin action. • Treatment should be continued for the duration of pregnancy and for at least 6 weeks postpartum. After delivery, anticoagulation can be restarted 6 hours after vaginal delivery and 12 hours after cesarean delivery. Treatment can be transitioned to oral warfarin (which is teratogenic and should therefore be avoided in pregnancy), and women on warfarin can breast-feed. • Alternative therapies (fibrinolytic agents, surgical intervention) are associated with a high incidence of complications in pregnancy and, as such, are best avoided. Prophylaxis • Women with prior unexplained DVT have an increased risk of recurrence in a subsequent pregnancy. In women with a documented thrombophilic disorder, antepartum prophylactic heparin is indicated (5000 to 10,000 units SQ bid). PTT should not increase. The management of women with a prior thrombosis but no thrombophilic disorder is controversial. In the United Kingdom, such women are generally given prophylactic anticoagulation in the postpartum period for at least 6 weeks. The practice in the United States favors prophylactic anticoagulation throughout pregnancy and postpartum (19). Complications Venous thrombotic events are more common in pregnancy and the puerperium, with further increased risk after cesarean delivery. If untreated, 15% to 25% of patients with DVT will have a PE as compared with 4% to 5% of treated patients. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Patient Education • Asthma http://www.nhlbi.nih.gov/health/dci/Diseases/Asthma/Asthma_WhatIs.html • Influenza, pneumonia, and tuberculosis http://www.cdc.gov • Immunizations http://www.cdc.gov/vaccines • Cystic fibrosis www.cff.org REFERENCES 1. De Swiet M. The respiratory system. In: Hytten F, Chambergain G, eds. Clinical physiology in obstetrics. 2nd ed. London, UK: Blackwell, 1991:83. 2. Cunningham FG, Leveno KJ, Bloom SL, et al. General considerations and maternal evaluation. In: Williams obstetrics. 23rd ed. New York: McGraw-Hill, 2009:912–925. 3. Centers for Disease Control and Prevention. National Center for Health Statistics. Health data interactive. Available at: http://www.cdc.gov/nchs/hdi.htm Accessed April 9, 2013. 4. Turner ES, Greenberger PA, Patterson R. Management of the pregnant asthmatic patient. Ann Intern Med 1980;93:905. 5. NAEPP Working Group Report on Managing Asthma During Pregnancy: recommendations for Pharmacologic Treatment. Update 2004. NIH Publication No. 05–3279. Bethesda, MD: U.S. Department of Health and Human Services; National Institute of Health; National Heart, Lung, and Blood Institute, 2004. 6. Park-Wyllie L, Mazzotta P, Pastuszak A, et al. Birth defect after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology 2000;62(6):385–392. 7. Centers for Disease Control and Prevention (CDC). Prevention and Control of Influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2004;53(RR06):1–40. 8. Centers for Disease Control and Prevention (CDC). Updated recommendations for prevention of invasive pneumococcal disease among adults using the 23-Valent pneumococcal polysaccharide vaccine (PPSV23). MMWR Morb Mortal Wkly Rep. 2010;59(34):1102–1106. 9. Mendola P, Laughon K, Mannisto TI, et al. Obstetric complications among US women with asthma. Am J Obstet Gynecol. 2013;208:127 e1–e8. 10. Centers for Disease Control and Prevention, National Center for Immunization and Respiratory Diseases. http://cdc.gov/flu. Accessed April 9, 2013. 11. American College of Obstetricians and Gynecologists. Influenza vaccination and treatment during pregnancy. ACOG committee opinion no. 468. Obstet Gynecol. 2010;116:1006–1007. 12. Lutffiyya MN, Henley E, Chang LF, et al. Diagnosis and treatment of community-acquired pneumonia. Am Fam Physician. 2006;73(3):442–450. 13. Centers for Disease Control and Prevention (CDC). Updated recommendations for Use of Tetanus Toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) in pregnant women- Advisory Committee on Immunization Practices (ACIP), 2012. MMWR Morb Mortal Wkly Rep. 2013;62(7):131–135. 14. Chen YH, Keller J, Wang IT, et al. Pneumonia and pregnancy outcomes: a nationwide population-based study. Am J Obstet Gynecol. 2012;207(4):288.e1–e7. 15. Dedhia JD, Mushambi MC. Amniotic fluid embolism. Contin Educ Anaesth Crit Care Pain. 2007;7(5):152–156. 16. Centers for Disease Control and Prevention (CDC). Reported tuberculosis in the United States, 2012. Atlanta, GA: U.S. Department of Health and Human Services, September 2013. 17. American College of Obstetricians and Gynecologists. Update on Carrier Screening for Cystic Fibrosis. Committee Opinion No. 486, April 2011. 18. Thorpe-Beeston JG, Madge S, Gyi K, et al. The outcome of pregnancies in women with cystic fibrosis—single centre experience 1998–2011. BJOG 2013;120(3):354–361. 19. Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e691S. (c) 2015 Wolters Kluwer. All Rights Reserved.

15

Hepatobiliary Complications R. Moss Hampton

KEY POINTS • Distinguishing between pregnancy-induced liver problems and liver problems related to maternal disease is crucial and often challenging. • Pregnancy-induced liver disease presents significant risks for maternal and fetal morbidity and mortality. • Pregnancy should not adversely affect mild to moderate maternal liver disease. • Pregnancy in patients with portal hypertension and esophageal varices carries a high risk of life-threatening hemorrhage. BACKGROUND It is necessary to understand the characteristic alterations of hepatic function common to pregnancy in order to differentiate normal physiologic changes from abnormalities attributable to disease states. Pathophysiology • There is no change in the size of the liver during pregnancy. • There is no change in blood flow during pregnancy. • Biochemical changes (see Table 15-1) • Serum albumin decreases due to increasing plasma volume. • Increase in alkaline phosphatase level due to increased placental production and increased bone turnover. • Increased production of clotting factors. EVALUATION History and Physical • Common complaints with hepatic dysfunction • Right upper quadrant pain • Nausea and vomiting • Pruritus • Common physical findings with hepatic dysfunction • Jaundice. • Hepatomegaly or splenomegaly. • Palmar erythema and spider angiomata do not correlate with liver disease in pregnancy. Laboratory Tests • Liver function tests: a broad range of serum chemistries that typically includes aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, gamma glutamyl transpeptidase (GGT), 5′-nucleotidase, serum bilirubin, serum albumin, and bile acids • Coagulation studies • Sonography 238

(c) 2015 Wolters Kluwer. All Rights Reserved.

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Table 15-1

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Pregnancy-Related Changes in Laboratory Measures of Hepatic Function

Laboratory measure of hepatic function Albumin Alkaline phosphatase Bilirubin Ceruloplasmin Cholesterol Globulins (α, β) Globulins (γ) γ-Glutamyl transpeptidase Haptoglobins Serum transaminases Total protein Transferrin Triglycerides Clotting factors Fibrinogen (I) Prothrombin (II) Factor V Factor VII Factor VIII Factor IX

Pregnancy-related change Approximately 20% decrease Twice normal No change Elevated (twice normal) Elevated (twice normal) Slight increase Slight increase No change or slight increase No change No change No change or slight decrease (dilutional) Slight increase Gradual rise to term 20% elevation at term Minimal increase 50% elevation 25% elevation Twofold elevation 30% elevation

PREGNANCY-RELATED HEPATIC DISEASE STATES Intrahepatic Cholestasis of Pregnancy Background

• Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder in pregnancy occurring in about 1 in 500 pregnancies. It is the second most common cause of jaundice in pregnancy. Definition

• Pruritus of the trunk and extremities (palms and soles of the feet) beginning in the third trimester is the hallmark of this disease. The itching is often intense and unrelenting. Pathophysiology

• Pruritus is thought to result from deposition of bile salts in the subcutaneous tissue and skin. Etiology

The exact etiology is unknown but theories include • A defect in biliary transport of bile secretion(1) • Receptor changes affecting detoxification of bile acids (2) • A possible link to maternal estrogen and progesterone levels (3) Epidemiology

• The incidence is increased in Scandinavians and Chilean Indians. • The disease is rare in African Americans. • Seasonal variations have been noted, with more cases seen in the fall (November). Evaluation History and Physical

• Pruritus usually begins after 26 weeks (third trimester) and becomes more intense as pregnancy advances. • It is not associated with a rash, but excoriations may be present. • Distribution is typically across the trunk, extremities, palms, and soles. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Pruritus resolves with delivery. • Frequently, a history exists of ICP in a previous pregnancy, another family member, or similar symptoms with oral contraceptive pill use. Jaundice

• Usually mild • Develops in 10% to 25% of patients with ICP (4) • Usually begins 1 to 4 weeks after the onset of pruritus Laboratory Tests

• Serum bile acid levels are increased (4). • Increase in serum bilirubin (predominately conjugated) may be up to six times greater than the upper limit of normal (5). • Transaminases may be elevated 2 to 10 times greater than the upper limit of normal. Genetics

• Possibly an autosomal dominant trait Diagnosis Differential Diagnosis

• Viral hepatitis • Gallbladder disease Clinical Manifestations

• In addition to severe pruritus, the patient may have anorexia, steatorrhea, and dark urine. Treatment

• Treatment is used primarily to relieve symptoms until the fetus is mature enough for delivery. Medications

• Ursodeoxycholic acid (UDCA) is the treatment of choice (10 to 15 mg/kg/d) (3). • Antihistamines for symptomatic relief of pruritus. • Corticosteroids—dexamethasone 12 mg/d. • Cholestyramines—8 to 16 g/d in divided doses. Procedures

• Begin antenatal fetal assessment (biophysical profile or nonstress testing) at the time of diagnosis. • Delivery at 37 weeks of gestation (6). Risk Management

• No test reliably predicts fetal demise (7). • Majority of fetal deaths occur after 37 weeks (6). • Mother should begin supplemental vitamin K at the time of diagnosis. Complications

Long-term maternal complications are not seen with ICP, but there are several pregnancyrelated complications: • Increased perinatal mortality • May be related to maternal serum bile acid level • Fetal mortality rate of 11% to 20% when untreated (6). • Fetal testing is not always predictive of imminent fetal death. • Preterm delivery • Meconium-stained amniotic fluid • Postpartum hemorrhage Patient Education

The pregnant patient should be counselled regarding • The increased risks of preterm labor and delivery • The signs and symptoms of preterm labor (c) 2015 Wolters Kluwer. All Rights Reserved.

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• The increased risk of intrauterine fetal demise (IUFD) and regular fetal movement counts • A 45% to 70% risk of ICP recurring in subsequent pregnancies (4) Hemolysis, Elevated Liver Enzymes, and Low Platelets (HELLP) Syndrome and Preeclampsia (see Chapter 11, Preeclampsia) Background

Preeclampsia affects 5% to 7% of all pregnancies and is characterized by new-onset hypertension and proteinuria. It often has significant hepatic effects including reduced perfusion, abnormal liver function, and edema of the hepatic parenchyma and capsule. A variant of severe preeclampsia is the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. HELLP syndrome affects 5% to 10% of patients diagnosed with preeclampsia and is associated with several significant complications (8). Pathophysiology

The manifestations of preeclampsia and HELLP syndrome are thought to be the results of • Placental hypoperfusion • Endothelial cell dysfunction • Alteration of vasomotor tone • Activation of coagulation cascade • Release of proinflammatory mediators Liver biopsy reveals • Periportal hemorrhage and parenchymal necrosis • Fibrin deposition in sinusoids • Steatosis Etiology

• Exact etiology is unknown; see Chapter 11, Preeclampsia for details. Epidemiology

• Usually seen in older, multiparous Caucasian patients. • Generally occurs in late second or third trimester, although 30% of cases occur postpartum. • HELLP syndrome affects 5% to 10% of pregnancies with severe preeclampsia (8). Evaluation Physical Exam

Presenting signs and symptoms can be vague and variable. The most common symptoms are • Epigastric or right upper quadrant pain • Nausea and vomiting • Malaise • Nondependent edema The physical exam is often consistent with preeclampsia: • Hypertension is usually present but may not be in the severe range. • Significant peripheral edema and sudden weight gain often occur. • Hyperreflexia is typically present. Laboratory Tests

The diagnosis of HELLP syndrome requires evidence of • Hemolytic anemia • Abnormal peripheral smear • Elevated serum bilirubin (greater than 1.2 mg/dL) (9) • Low serum haptoglobin • Elevated lactate dehydrogenase (LDH, greater than 600 U/L) (9) • Significant drop in hemoglobin • Elevated liver enzymes (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Abnormal transaminases (greater than 70 units/L or greater than two times upper limit of normal) (9) • Abnormal bilirubin level • Low platelets • Must be less than 100,000 (9). • Severity of low platelets appears to predict the severity of the disease (10). Diagnosis Differential Diagnosis

• Pancreatitis • Idiopathic thrombocytopenia purpura • Cholecystitis • Appendicitis • Pyelonephritis • Acute fatty liver of pregnancy (AFLP) • Signs and symptoms are similar to HELLP. • AFLP often lacks hypertension and proteinuria. • Liver function tests are not as intensely abnormal. • Hemolytic uremic syndrome (HUS) • Usually seen in children. • There is typically more renal involvement. • In pregnancy, HUS most often occurs postpartum. • Thrombotic thrombocytopenic purpura (TTP) • Neurologic symptoms • Fever Clinical Manifestations

The diagnosis of HELLP should be considered in any patient with preeclampsia or who presents in the late second or third trimester with nausea, vomiting, and abdominal pain, especially if the pain is in the right upper quadrant of the abdomen. Treatment Management

Management of HELLP is the same as that for severe preeclampsia. • Seizure prophylaxis, usually with magnesium sulfate (MgSO4) • Control of blood pressure • Corticosteroids to enhance fetal lung maturity if indicated • Delivery Counseling

• Risk of recurrence with subsequent pregnancies is 2% to 20% (9). Complications

HELLP syndrome has a high rate of significant maternal complications: • Disseminated intravascular coagulopathy (DIC). • Acute renal failure. • Eclampsia. • Abruptio placentae. • Pulmonary edema. • Intracranial hemorrhage. • Postpartum hemorrhage. • Hepatic rupture. • Maternal and fetal mortality is more than 50% when there is rupture of the liver or rupture of a subcapsular liver hematoma (9). • Usually occurs in the anterior aspect of the right lobe of the liver (9). • Surgical emergency. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Fetal morbidity and mortality are related to the degree of prematurity and presence of intrauterine growth restriction. • Maternal mortality rate may be as high as 50% (4). Acute Fatty Liver of Pregnancy Background

AFLP is a rare complication of pregnancy affecting approximately 1 in 10,000 pregnancies. It usually presents after 30 weeks’ gestation and may be associated with significant maternal and fetal morbidity and mortality if not treated aggressively or if it goes unrecognized. Pathophysiology

With AFLP, there is centrilobular, microvesicular fatty infiltration of the hepatocytes. This leads to mitochondrial disruption and widespread hepatic necrosis. Fulminant hepatic ­failure results if treatment (i.e., delivery) is delayed. Etiology

• The exact etiology is unknown. • Recent studies suggest an abnormality in the maternal and fetal metabolism of long-chain fatty acids (LCFA). In 31% to 79% of pregnancies with AFLP, there was a deficiency in fetus had long-chain three-hydroxyacyl coenzyme A dehydrogenase (LCHAD) (11). • LCHAD functions in the mitochondrial trifunctional complex, which is responsible for oxidation of fatty acids (12). With LCHAD deficiency, the fetus is unable to metabolize LCFAs, and excessive LCFA metabolites accumulate in the maternal liver where they are hepatotoxic (2). Epidemiology

• AFLP is more common in • Patients with multiple gestation • Nulliparous patients • Male fetus (3:1 male-to-female ratio) • Preeclampsia is present in about 50% of the cases. Evaluation History and Physical

• Presents in the third trimester of pregnancy (usually greater than 30 weeks’ gestation). • Nausea and vomiting are the most common presenting symptoms (75% of patients) (13). • Abdominal pain is present in 51% of patients (13). • Jaundice is common. • Twenty percent to forty percent of patients will have signs or symptoms of preeclampsia. Laboratory Results

• Liver transaminases are elevated 3 to 10 times normal but usually less than 1000 international units/L. • Bilirubin is often greater than 10 mg/dL. • Serum ammonia is elevated. • Hypoglycemia (a poor prognostic sign). • Alkaline phosphate is elevated 5 to 10 times normal. • Lactic acidosis. • Coagulation profile is often affected. • Hypofibrinogenemia (vitamin K–dependent factors [II, VII, IX, X] are decreased). • Thrombocytopenia (less than 100,000 per μL). • Prolonged prothrombin time (PT) and partial thromboplastin time (PTT). Genetics

• Thought to be an autosomal recessive disorder • G1548C mutation of LCHAD associated with AFLP (14) (c) 2015 Wolters Kluwer. All Rights Reserved.

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Diagnosis

Diagnosis is one of exclusion and is usually made based on laboratory findings, patient symptoms, and clinical exam. Ultrasound, computerized tomography (CT) scan, and magnetic resonance imaging (MRI) scans may be suggestive. Liver biopsy may also be helpful. Decisive action is needed to avoid significant maternal and fetal morbidity and mortality. Differential Diagnosis

• Severe preeclampsia • HELLP syndrome • Hemolytic–uremic syndrome • Thrombotic thrombocytopenia purpura Clinical Manifestations

• Distinguish from severe preeclampsia and HELLP syndrome • Risk for fulminant hepatic failure • Severe maternal hypoglycemia • DIC Treatment

• The definitive treatment of AFLP is delivery. • Management prior to delivery is dependent on the presence or absence of other related problems: • Preeclampsia/eclampsia • Maternal metabolic abnormalities • Hemostatic disorders • Renal failure • Sepsis • Fetal distress • Once the patient is stabilized, delivery should be accomplished. Vaginal delivery may be attempted if both the mother and fetus are stable. Otherwise, cesarean section is used if either is unstable or if delivery must be performed expeditiously. Procedures

Liver transplant may be necessary if patient has extensive liver necrosis. Counseling

• The risk of recurrence with subsequent pregnancies is uncertain. • If there is a family history for AFLP, the patient should consider genetic consultation to evaluate for possible LCHAD abnormalities (15). Complications

• Maternal mortality is 1% to 4% and is often due to • Cerebral edema • Gastrointestinal hemorrhage • Renal failure • Sepsis • Fetal mortality is 10% to 20% (7). • DIC occurs in 75% of cases. • Postpartum hemorrhage risk is increased. • After delivery and initial postpartum recovery, expect the liver function to return to normal. There are no long-term sequelae. Patient Education

Patients should be evaluated for genetic predisposition to LCHAD disorders. • If patient is in an “at-risk” group with future pregnancies, she should • Maintain high-carbohydrate, low-fat diet • Avoid fasting • Avoid nonsteroidal anti-inflammatory drugs, tetracycline, and valproic acid (16) (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Possible risks to the newborn • Child should be screened for fatty acid oxidation (FAO) disorder • Reye syndrome Concurrent Maternal Hepatic Disease and Pregnancy In general, severe maternal hepatic disease precludes pregnancy because these patients are usually amenorrheic. Pregnancy does not seem to adversely impact mild to moderate hepatic disease and vice versa. Viral Hepatitis Viral hepatitis is the most common cause of hepatitis in pregnancy. The course of the disease is usually unaffected by pregnancy. Diagnosis and treatment are generally the same as for the nonpregnant patient. Multiple viruses are involved, and while the symptoms and presentation may be similar, the outcomes, complications, and long-term sequelae vary significantly. Hepatitis A Virus (HAV) Background Etiology

• Single-stranded RNA enterovirus • Usually spread by fecal–oral transmission • Short incubation period of 4 weeks Epidemiology

• Endemic in Africa, Asia, and Central America • Sporadic outbreaks in the United States, usually food borne Evaluation History and Physical

• The patient will present with a flu-like illness including • Malaise and fatigue • Headache and arthralgias • Fever • Pruritus Physical Findings

• Hepatosplenomegaly • Dark urine • Jaundice Laboratory Tests

• Transaminases are elevated. • IgM antibodies to hepatitis A virus (HAV) are diagnostic. Differential Diagnosis

• Hepatitis due to other viruses • B, C, D, or E • Cytomegalovirus (CMV) • Herpes simplex virus (HSV) • Epstein-Barr Virus (EBV) • Chemical hepatitis • Jaundice due to other types of hepatic dysfunction • Increased production of bilirubin • Intrahepatic cholestasis of pregnancy Treatment

Treatment for HAV is supportive as this is usually a self-limited infection. Postexposure prophylaxis with hepatitis immune globulin is effective 80% of the time if given within (c) 2015 Wolters Kluwer. All Rights Reserved.

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2 weeks of exposure. Immunization of pregnant women in endemic areas should be encouraged. There does not appear to be vertical transmission to the fetus. However, if active infection is present at the time of delivery, prophylaxis with immunoglobulin is recommended for the fetus. Complications

• Hepatic failure is reported but rare. Patient Education

• Patients should be vaccinated if they live in endemic areas. • Stress good hand washing. Hepatitis B Virus (HBV) Background Etiology

• Double-stranded DNA virus in the core particle • Long incubation period (up to 180 days) Epidemiology

• Endemic in Southeast Asia and China. • In the United States, hepatitis B virus (HBV) is transmitted by contaminated needles, blood products, or direct mucosal contact with contaminated body fluids. • Chronic carrier state and chronic infection can occur. Evaluation History and Physical

The acute infection may be asymptomatic and anicteric. When obtaining a history, look for risk factors that include • Intravenous (IV) drug use • Multiple sexual partners • History of multiple blood transfusions • Partner with HBV • History of human immunodeficiency virus (HIV) infection Physical Exam

Physical Exam may reveal • Urticarial rash. • Arthralgias and arthritis. • Myalgias. • Hepatomegaly and/or right upper quadrant tenderness. • Jaundice is less common. Laboratory Tests

• All pregnant patients should be screened for HBV infection. • Transaminases are elevated with acute infection. • Tests for the presence of antigen/antibodies to the following: • Viral surface components °°Hepatitis B surface antigen (HBsAg) • Core DNA °°Hepatitis B core antigen (HBcAg) • Enzymatic components of viral core (“C” antigens) °°Usually present with acute infection °°Indicative of high infectivity if present • E antigen °°HBeAg is a marker for infectivity. • Specific antigens and antibodies associated with hepatitis B infection vary over the course of the disease. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Diagnosis Differential Diagnosis

• Hepatitis due to other viruses • A, C, D, or E • CMV • HSV • EBV • Chemical hepatitis • Jaundice due to other types of hepatic dysfunction • Increased production of bilirubin • Intrahepatic cholestasis of pregnancy Treatment

Active treatment for an acute infection is not indicated unless the patient has fulminant hepatic necrosis and acute liver failure. For patients acquiring HBV infection during pregnancy, passive immunization with hepatitis B immunoglobulin (HBIG) may be given up to 48 hours after exposure. Vaccination with anti-HBV vaccines is safe to give during pregnancy (17). Risk Management

• Preventing vertical transmission to the fetus • Ninety-five percent of perinatal transmission occurs intrapartum (5). • Risk of transmission to fetus is highest (80% to 90%) when the mother is infected in third trimester (14) or is HBeAg positive at delivery. • Newborns should receive HBIG within 12 hours of delivery if mother is HBsAg positive. (18) HBV vaccination should be given in the first 6 months. • Cesarean section does not prevent transmission from mother to fetus but does lessen the risk (13). • Breast-feeding is not contraindicated in the immunized newborn (17). • Lamivudine may be given to patients with high levels of HBV DNA during the last month of pregnancy to decrease the risk of vertical transmission (19). Complications

• Chronic active hepatitis with eventual cirrhosis • Chronic HBV infection • Increased risks for hepatocellular carcinoma • Acute liver failure Hepatitis C Virus (HCV) Background Etiology

• Single-stranded RNA virus with an envelope • Blood borne • Percutaneous transmission • Incubation time about 50 days (ranges from 15 to 160 days) Epidemiology

• Most common chronic blood-borne infection in the United States (20). Hepatitis C virus (HCV) affects 1% to 2.5% of the pregnant population in the United States with a higher rate in developing countries. • The risk factors are the same as for hepatitis B although many HCV-positive women have no known risks factors (21). • HCV is a common cause of cirrhosis. • Twenty to fifty percent of symptomatic patients will spontaneously clear the virus. • Asymptomatic patients have a higher rate of chronic infection. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Evaluation History and Physical

The acute infection of hepatitis C is very mild. Patients are often asymptomatic and anicteric, although some may have a history of a recent flu-like illness. The history should focus on identifying risk factors; physical exam should look for signs of cirrhosis. • Palmar erythema and spider angioma can be seen in normal pregnancy. • Splenomegaly may be suggestive of cirrhosis. Laboratory Tests

• Hepatitis C IgM and IgG antibodies. • Hepatitis C RNA levels. • Evaluate viral load • Thrombocytopenia and leukopenia may be suggestive of cirrhosis. • Elevations in transaminase levels are variable. Differential Diagnosis

• Hepatitis due to other viruses • A, B, D, or E • CMV • HSV • EBV • Chemical hepatitis • Jaundice due to other types of hepatic dysfunction • Increased production of bilirubin • Intrahepatic cholestasis of pregnancy Treatment

Hepatitis C infection does not affect the pregnancy and does not require active treatment. If the patient has cirrhosis and/or portal hypertension, procedures to diagnose and treat esophageal varices may be indicated. Use of interferon or ribavirin is contraindicated in pregnancy. Patients who are HCV RNA positive after pregnancy should be actively treated. Universal screening of pregnant patients for hepatitis C is not currently felt to be cost-effective, but debate is ongoing (22). Complications

Vertical transmission is the common route of HCV infection. • Transmission rates range from 1% to 5% (4). • Transmission risk is higher if the mother is HCV RNA positive, HIV positive, or viremic at time of delivery (23). • Higher rate of transmission occur with higher viral loads (greater than 1 million copies per mL) (24). • Prolonged rupture of membranes (greater than 6 hours) increases the transmission rate (5). • Mode of delivery and breast-feeding do not affect the transmission rate. • Fetus passively acquires immunization from mother that may persist up to 12 months (24). Chronic maternal disease after hepatitis C. • Chronic hepatitis. • Hepatocellular carcinoma and/or cirrhosis develops in 20% to 30% of patients (25). • Fulminant hepatitis is rare. Hepatitis E Virus (HEV) Background

This disease is seen primarily in underdeveloped countries of the world. It is the leading cause of acute viral hepatitis worldwide and the most prevalent viral cause of acute liver failure in pregnancy (26). Etiology

• Single-stranded RNA virus • Incubation time from 15 to 60 days (c) 2015 Wolters Kluwer. All Rights Reserved.

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Epidemiology

• Fecal/oral spread similar to HAV. • Parenteral and vertical transmission is implicated. • Endemic to underdeveloped countries in the Far East. • Seasonal variation exists, being more common during monsoon conditions. • Usually self-limited if patient is not pregnant. Evaluation History and Physical

This infection often presents as jaundice in the third trimester. Fever and dark urine are common. Laboratory Tests

• Presence of IgM anti-hepatitis E virus (HEV) antibody and HEV-RNA • Abnormal liver function tests Differential Diagnosis

• Hepatitis due to other viruses • A, B, C, or D • CMV • HSV • EBV • Chemical hepatitis • Jaundice due to other types of hepatic dysfunction • Increased production of bilirubin • Intrahepatic cholestasis of pregnancy Clinical Manifestations

Onset of jaundice is usually in the third trimester in patients without a history of chronic liver disease. Treatment

There is no active treatment for this disease. Fulminant liver failure is common (greater than 50% of cases), and pregnancy seems to increase the severity of the disease. Maternal mortality rates as high as 41% to 54% have been reported (27). An effective vaccine may be available in the near future (29). Complications

Increased rates of • Preterm labor • Premature rupture of membranes • Intrauterine growth restriction • Fetal mortality rate up to 69% has been reported (29) Vertical transmission • Occurs in up to 50% of HEV-RNA–positive mothers (12). • There is significant perinatal morbidity/mortality. Hepatitis G Virus (HGV) and GB Agents Background

These represent a poorly understood group of viruses and virus-like agents that are responsible for transfusion-related hepatitis. Etiology

• Single-stranded RNA virus similar to HCV. • Coinfection with hepatitis A, B, C, and HIV common. • GB group are viral agents of flavi-like viruses. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Epidemiology

• Thought to be transfusion-associated hepatitis • Same risk groups as HBV and HCV • Thought to cause 10% of non-A, non-B hepatitis Evaluation History and Physical

• Symptoms of hepatitis G virus (HGV) are mild and nonspecific. • Physical exam may reveal mild right upper quadrant tenderness. • Clinical significance of infection is uncertain (30). Laboratory Tests

• Polymerase chain reaction (PCR) can detect hepatitis G nucleic acid. • Enzyme-linked immunosorbent assay (ELISA) can detect viral envelope protein. Treatment

• Symptomatic • May cause chronic hepatitis as well as acute disease Complications

• Acute infection is not thought to alter or affect pregnancy. • Vertical and sexual transmission is more common than was previously suspected (32). Cytomegalovirus (CMV) Hepatitis Background

• CMV infection is not uncommon in pregnancy, but hepatitis is rare, except in immunosuppressed patients. Etiology

• DNA herpes virus Epidemiology

• CMV is endemic to most populations, and its prevalence increases with age. Evaluation History

• CMV infection presents with a flu-like illness • Malaise • Fever • Arthralgias • Nausea/vomiting Physical

• Intermittent fever • Sore throat • Cervical adenopathy • Splenomegaly • Jaundice Laboratory Tests

• IgM antibody to CMV • Positive viral culture from serum or urine Diagnosis Differential Diagnosis

• Hepatitis due to other viruses • A, B, C, D, or E • HSV • EBV • Chemical hepatitis. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Jaundice due to other types of hepatic dysfunction. • Increased production of bilirubin. • Intrahepatic cholestasis of pregnancy. • Thirty-three to forty-four percent of patients with acquired immunodeficiency syndrome (AIDS) have CMV hepatitis (33). Treatment

The disease is self-limited with a favorable prognosis. Fulminant hepatitis is rare. Complications

• CMV is the most common in utero viral fetal infection. • Ten percent of infected fetuses are severely affected, resulting in • Intrauterine growth restriction • Ventriculomegaly • Microcephaly • Fetal risks are greatest if infection occurs when less than 22 weeks’ gestation. • There is a long-term risk of developmental problem. Epstein-Barr Virus (EBV) Hepatitis Background Etiology

• DNA herpes virus responsible for mononucleosis Evaluation Presenting Symptoms Suggest Mononucleosis

• Intermittent fever • Malaise • Headache • Sore throat Physical Exam

• Cervical and axillary adenopathy • Splenomegaly present in 75% of cases • Hepatomegaly present in 17% of cases • Jaundice present in 11% of cases Laboratory Tests

• IgM antibodies specific to EBV • IgM antibody specific to EBV nuclear antigen • Rising IgG antibody to EBV Differential Diagnosis

• CMV infection with hepatitis Treatment

• Supportive care • Not associated with known fetal morbidity • Reports of acute liver failure with pregnancy Herpes Simplex Virus (HSV) Hepatitis Background

• While 0.5% to 1.0% of all pregnant women may have an overt herpetic infection during pregnancy, HSV hepatitis is very rare. Etiology

• Double-stranded DNA virus Epidemiology

• HSV is found in all populations. • Spread is by intimate contact. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Once infected, the herpes virus can be found in a dormant state in the neural ganglia. • Reactivation of the virus is common. • Hepatitis is only seen in immunosuppressed patients. Evaluation History and Physical

• Patients may or may not have a previous history of HSV infection. • History of immunosuppression or immune deficiency diseases. • May have painful, ulcerative lesion, often in the genital tract. • Usually presents in the third trimester of pregnancy. • May present with hepatic failure, pneumonia, and encephalitis (33). Laboratory Tests

• PCR assays are very sensitive. • Viral culture of lesion if one is present. • IgG and IgM antibodies for HSV 1 and 2. • HIV testing if status is unknown. • Serum transaminases are usually markedly elevated. • PTT may be prolonged along with thrombocytopenia and normal bilirubin (35). • Liver biopsy should show presence of viral inclusion bodies. Differential Diagnosis

• Hepatitis due to other viruses • Hepatitis A, B, C, D, or E • CMV • EBV • Chemical hepatitis • Intrahepatic cholestasis of pregnancy • AFLP • HELLP Treatment

• Antiviral drugs, such as acyclovir, are the mainstay of therapy (33). • Supportive care, as these patients are usually critically ill. Complications

• Hepatic failure • Maternal and fetal death Hepatic Cirrhosis Background

• Hepatic cirrhosis is the result of a wide variety of insults to the liver resulting in chronic hepatic dysfunction and eventually chronic liver failure. Infection, metabolic disease, inherited disease, and toxic exposures (commonly alcohol or medications) can lead to microarchitectural change with areas of fibrosis and nodular regeneration replacing ­normal hepatic tissue. • Pregnancy appears to have little effect on hepatic function of patients with mild liver dysfunction. • Severe hepatic dysfunction is usually associated with infertility. • Pregnancy-associated maternal morbidity correlates with the prepregnancy disease state and the presence of portal hypertension. Pathophysiology of Cirrhosis and Pregnancy

• Changes in maternal hemodynamics during pregnancy • Increased blood volume • Changes in venous return • Increased cardiac output • Decreased systemic blood pressure (c) 2015 Wolters Kluwer. All Rights Reserved.

Chapter 15 • Hepatobiliary Complications 

Portal Hypertension

• Initiated by increased resistance within the portal venous bed. • Pregnancy may also increase portal pressure due to • Increased blood volume • Increased cardiac output • Mesenteric vasodilation • Increased pressure on the inferior vena cava by the enlarging uterus • Varices develop from portosystemic collateral circulation. Etiology

• Inherited diseases • Wilson disease • Hemochromatosis • Infectious diseases • Hepatitis B and C • Chronic cholestasis • Primary biliary cirrhosis • Autoimmune hepatitis • Toxins • Alcohol (ETOH) consumption • Hepatotoxic drugs (see Table 15-2) Epidemiology Inherited Disease

• Wilson disease • Autosomal recessive disorder • Involves abnormal copper metabolism in the liver • Hemochromatosis • Autosomal recessive disorder • Excessive absorption of iron, which leads to increased storage in the liver • More common in males (8:1 male:female ratio) Table 15-2

Common Hepatotoxic Medications

Mimic viral hepatitis Halothane Isoniazid Methyldopa Phenytoin Sulfonamides Cholestasis Anabolic steroids Androgens (17α) Fatty liver Alcoholic hepatitis Corticosteroids Tetracyclines Valproic acid Other liver disease Acetaminophen Aspirin Carbon tetrachloride

(c) 2015 Wolters Kluwer. All Rights Reserved.

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Infectious Disease

• Hepatitis B—see previous discussion • Hepatitis C—see previous discussion Chronic Cholestasis

• Primary biliary cirrhosis • Bile duct destruction of unknown etiology resulting in cholestasis. • Autoimmune basis of disease is suspected as 90% of patients have elevated antimitochondrial antibodies present in their serum. • This usually affects older patients and is rare in pregnancy. Autoimmune Hepatitis (AIH) Background

• Self-perpetuating hepatocellular inflammation of unknown etiology (35). • More common in females than in males. • Commonly seen in younger age groups. • Thirty percent of patients present with cirrhosis (36). • Patients may also have the diagnosis of Sjögren syndrome or ulcerative colitis (36). Evaluation History

Cirrhosis is a result of long-standing insult to the liver. Therefore, there should be a history of antecedent disease or problems. Patients may complain of malaise, fatigue, weakness, and/or anorexia. Pruritus is often present. Physical

• Jaundice • Ascites • Ecchymoses or excessive bruising • Hepatomegaly and splenomegaly • Right upper quadrant pain and tenderness • Hyperpigmentation of the skin • Kayser-Fleischer rings on the cornea of patients with Wilson disease Laboratory Tests

• Liver function tests will be abnormal. • Elevated bilirubin and transaminase levels • Elevated alkaline phosphatase and GGT • Abnormal coagulation studies °°Prolonged PT and PTT °°Prolonged bleeding time °°Thrombocytopenia Tests for Other Etiologies of Hepatitis

• Test for serum ceruloplasmin levels (less than 20 mg/dL) and urinary copper levels (greater than 100 μg) if Wilson disease is suspected. • Antimitochondrial antibodies to evaluate for primary biliary cirrhosis. • Serum iron levels if hemochromatosis is suspected. • Increases in circulating antibodies, hypergammaglobulinemia, and serum transaminases are seen with autoimmune hepatitis (AIH). Differential Diagnosis

• Diffuse liver disease • Viral hepatitis • AFLP • HELLP (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Metastatic or multifocal cancer of the liver • Vascular congestion of the liver • ICP • Cholelithiasis • Disorders of bilirubin metabolism Clinical Manifestations

Patient presentation ranges from asymptomatic liver disease to acute liver failure. With long-standing disease, an acute gastrointestinal bleed may signify esophageal varices. Hepatic encephalopathy is seen with liver failure. Treatment Medications

• Depends on cause of cirrhosis. • Polyethylene glycol (PEG) alpha-interferon and ribavirin are used to treat hepatitis C but are contraindicated in pregnancy. • Lamivudine is used to treat active HBV infection after 36 weeks of pregnancy. • UDCA is used to treat patients with biliary cirrhosis. • Prednisone and azathioprine are used to treat AIH and should be continued as needed during pregnancy. • D-penicillamine or trientiral chelation therapy is the mainstay of therapy for Wilson disease and should be continued at lower doses during pregnancy as long as the disease process is controlled. • Propranolol lowers portal pressures in patients with esophageal varices. Its use in pregnancy has been associated with fetal bradycardia and intrauterine growth restriction. • Spironolactone and furosemide are used for ascites. • Vitamin K. Procedures

• Endoscopy • All pregnant patients with cirrhosis should have endoscopy, preferably prior to pregnancy, to evaluate for esophageal varices. Variceal banding, sclerotherapy, or balloon tamponade may be used in pregnancy for bleeding varices. • Transjugular intrahepatic portosystemic stent shunting (TIPSS) may also be attempted to control bleeding varices (37). • Abdominal sonography should be done early in pregnancy to screen patients for splenic artery aneurysms. • Liver transplant is possible in pregnancy. Complications of Maternal Portal Hypertension

• Complications occur in 30% to 50% of pregnant women with portal hypertension (5). • Includes variceal hemorrhage, hepatic encephalopathy, hepatic failure, and splenic artery aneurysm. • Bleeding occurs in 20% to 25% of patients with varices, especially if the patient has a history of a prior hemorrhage (4). • Bleeding from esophageal varices occurs most commonly in the second trimester (5). • Maternal straining should be limited in the second stage of labor if varices are present. Hepatic Failure • Occurs when there has been extensive hemorrhage and hypotension. • Rupture of splenic artery aneurysm. • Sixty-nine percent rupture in the third trimester (5). • Presents with sudden pain and hypovolemic shock. • Historically, maternal and fetal mortality rates have been very high. • Spontaneous bacterial peritonitis occurs rarely. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Postpartum hemorrhage • Occurs in 7% to 26% of patients • Usually a result of a coagulopathy and thrombocytopenia Patient Education

• There is a high rate of fetal wastage and spontaneous abortion (up to 33%). • Risk of vertical transmission if hepatitis virus is involved. Hepatic Vein Thrombosis (Budd-Chiari Syndrome) Background Definition

• Obstruction of the large hepatic veins causing congestion and necrosis of centrilobular areas of the liver Etiology

• Myeloproliferative disorders are the most prevalent underlying condition (38). • Hypercoagulable states have been associated with this process. • Underlying acquired or inherited thrombophilia, especially factor V Leiden mutation (38). • Oral contraceptive pill use and pregnancy are also common findings. • Occasionally seen as part of HELLP syndrome. Epidemiology

• Hepatic vein thrombosis is primarily seen in women. • Survival rate of 87% was documented in a recent study (38). Evaluation History

• Right upper quadrant pain • Sudden abdominal distention • Pregnant or immediate postpartum period • History of thrombophilia Physical

• Sudden onset of painless ascites • Hepatomegaly Laboratory Tests

• Elevated alkaline phosphatase, aminotransferases, and bilirubin levels. • Ultrasonographic pulsed-wave Doppler images of the liver is the best imaging modality. • Liver biopsy is not specific. • Abnormal coagulation studies. • Percutaneous hepatic vein catheterization is diagnostic. • Bone marrow evaluation is indicated if polycythemia is suspected. Differential Diagnosis

• Thrombosis of the high inferior vena cava • Venoocclusive disease • Peliosis hepatitis • Myeloproliferative disorders Treatment

• Begin thrombolytics and diuretics. • Medical management of ascites is difficult but should be attempted. • Evaluate for thrombophilias and treat if necessary. • Surgical shunting is possible but associated with high maternal morbidity and mortality rates. • Successful liver transplant has been reported. • Fetal outcomes are dependent on maternal outcomes.

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Liver Transplant and Pregnancy • Liver transplant is becoming more frequent and more successful. Increasing numbers of patients are becoming pregnant. • Graft function is not affected by pregnancy. • Pregnancy should be delayed 1 to 2 years after transplant so that immunosuppressive regimens can be stabilized (39). • Risks associated with pregnancy in liver transplant patients: • Preterm labor and premature rupture of membranes • CMV infection • Worsening hypertension and preeclampsia • Rupture of splenic artery aneurysm • First-trimester abortion • Gestational diabetes • Higher cesarean section rate • Liver transplant during pregnancy should be considered for patients with acute liver failure and otherwise poor survival. • Transplant surgery during pregnancy is complicated by increased risks of hemorrhage, infection, renal failure, and respiratory distress syndrome. • Most immunosuppressive drugs are relatively safe to use during pregnancy. Gallbladder Disease Key Points

• Gallbladder disease and its related problems are common in pregnancy and the postpartum period. • Evaluation and treatment for the pregnant patient with gallbladder disease is essentially the same as for the nonpregnant patient. Background

Gallbladder disease is a common problem in the adult population, and more common in females than in males. Pregnancy seems to be responsible for alterations in gallbladder function that may predispose the pregnant patient to the formation of gallstones. Gallbladder disease is the second most common indication for surgery during pregnancy (40). Pathophysiology

• Increase in gallbladder volume and decrease in gallbladder emptying time mirror changes in maternal progesterone levels. • Incomplete emptying of gallbladder during pregnancy increases risk of gallstone formation and biliary sludge. • Hormonal effects of pregnancy (i.e., estrogen and progesterone) cause increased saturation of bile with cholesterol making it more lithogenic. • Gallstones form when the concentration of cholesterol exceeds the ability of bile to keep it in solution (41). • High rate of spontaneous resolution of gallstones during the postpartum period. Etiology

Most authorities feel that the increasing levels of estrogen and progesterone during pregnancy are the basis for these problems. Epidemiology

• Incidence of biliary tract disease is 0.05% to 0.3% during pregnancy (42). • Asymptomatic gallstones are present on routine sonography of gallbladder in 3% to 11% of pregnant females (43). • Gallstones are more common in multiparous patients.

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Evaluation

• Sonography is the imaging modality of choice for diagnosing cholelithiasis in pregnancy. • Abnormal liver function tests are also suggestive of disease. Acute Cholecystitis Background

• Pregnancy appears to be a predisposing factor to the development to cholelithiasis, and cholecystitis is becoming more common. • Incidence of acute cholecystitis in pregnancy is increased and may be due to • Increasing prevalence of obesity • Marked dietary changes • Changes in ethnicity of population Definition

• Inflammation of the gallbladder occurring acutely, often secondary to previously asymptomatic gallstones Pathophysiology

• Occlusion of the biliary tract, most often due to cholelithiasis, with secondary inflammation and infection Epidemiology

• Affects 5 to 8 patients per 10,000 births (44). • More than 50% of patients will have a history of biliary colic (45). • May present in any trimester. • More common in American Indians and Mexican Americans. Evaluation History

• Sudden onset of nausea, vomiting, and colicky or stabbing pain in the right upper quadrant of the abdomen. • Pain may be localized to the right flank, scapula, or shoulder. • Intolerance to, or exacerbation of, symptoms with fatty food intake. Physical

• The patient appears ill. • Presence of Murphy sign (inspiratory arrest elicited when palpating right upper quadrant while asking the patient for deep inhalation) may be less common in pregnancy. • Fever, tachycardia, and tachypnea may be present. • May have guarding and/or rebound tenderness on abdominal exam. • Jaundice may be severe. Laboratory Tests

• Hyperbilirubinemia • Elevated serum transaminases • Elevated white blood cell count • Cholelithiasis in the gallbladder, thickening of the gallbladder wall, or dilatation of the biliary tract on sonography Differential Diagnosis

• Any cause of cholestatic jaundice • Pyelonephritis • Pancreatitis • Appendicitis • Peptic ulcer disease • Ascending cholangitis • Acute hepatitis • Pneumonia (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Myocardial infarction • Herpes zoster Treatment Medical Management

• Bowel rest • Nasogastric suction in more severe cases • Adequate pain relief • Hydration with IV fluids • Broad-spectrum antibiotics • High rate of relapse in the pregnant patient who is treated medically Procedures

• Cholecystectomy • Second most common surgical procedure during pregnancy. • Ideally should be performed in the second trimester. • Laparoscopic approach is safe during pregnancy. • Percutaneous cholecystostomy may be used if surgery is contraindicated. • Endoscopic retrograde cholecystopancreatography (ERCP) • Appears to be safe during pregnancy. • Fetal radiation exposure reported to be 310 mrads (±164 mrads) in one study (46). • Sphincterotomies, stent passage, and stone extraction have been done safely in pregnancy but not without risks (37). Complications

• Gallstone pancreatitis • Gallbladder perforation • Sepsis • Peritonitis • Preterm labor • Intrauterine fetal demise Disease of the Pancreas Key Points

• Pancreatitis in pregnancy is rare but deserves prompt evaluation and treatment. Background

Basic pancreatic physiology is unchanged by pregnancy. The exocrine function of the gland is, however, increased. Insulin and glucagon secretion is increased to offset the diabetogenic effects of pregnancy. Serum amylase and lipid levels increase with gestational age. Acute Pancreatitis Background

• Affects 1 in 1000 to 1 in 10,000 deliveries (47). • Incidence increases with gestational age. • Most common in late third trimester or postpartum. • In pregnancy, there is a strong correlation with the presence of gallstones. • Acute, severe pancreatitis in pregnancy has approximately a 25% mortality rate (45). Definition

• An inflammatory, autodigestive process of the pancreas Pathophysiology

• Inflammation of the pancreas due to release of pancreatic enzymes • Damages vascular endothelium, ductal and acinar cells. • Microcirculatory changes lead to increased vascular permeability and edema. • Inflammatory response can lead to necrosis and hemorrhage. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• May be acute or chronic. • Symptoms may be mild or severe. • Inflammatory process may involve surrounding tissue and/or organs. • May become secondarily infected and form an abscess or develop a pseudocyst. Etiology

• In pregnancy, 70% of pancreatitis is due to occlusion of the biliary tract by gallstones (48) • Possible damage from bile refluxing into pancreatic ducts • Possible damage from increased pressure within the ducts causing release of pancreatic enzymes • Familial hypertriglyceridemia • Types I, IV, and V • Causes 4% to 5% of pancreatitis in pregnancy (49) • ETOH abuse, although this is less frequent during pregnancy • Hypercalcemia • Medications • Diuretics °°Thiazide °°Furosemide • Salicylates • AIDS therapy • Drugs for inflammatory bowel disease °°Azathioprine °°Valproic acid Evaluation History

• Nausea and vomiting present in more than 70% of patients. • Pain is located in midepigastric region and radiates to the back. • Pain usually presents suddenly and is constant and severe. Physical Exam

• The patient appears ill. • Signs and symptoms of an acute abdomen. • Signs of retroperitoneal hemorrhage in the area of the flank (Turner sign) or in the periumbilical area (Cullen sign) are present with hemorrhagic pancreatitis. • Occasionally the patient may be jaundiced. • Fever. Laboratory Tests

• Elevated serum amylase and lipase levels • Amylase-to-creatinine clearance ratio may be more helpful in pregnancy. • Values do not necessarily reflect the severity of the disease in pregnancy (50). • Leukocytosis • Cholelithiasis on gallbladder sonography • Inflammatory changes of the pancreas on CT scan or MRI • Evidence of hypertriglyceridemia • Pancreatitis occurs when triglycerides greater than 2000 mg/dL (50). Differential Diagnosis

• Peptic ulcer disease with or without perforation • Cholelithiasis • Acute cholecystitis • Intestinal obstruction • Renal colic • Pyelonephritis (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Pancreatic neoplasm • Appendicitis • Aortic aneurysm Clinical Manifestations

These patients can be critically ill and will often need to be cared for in an intensive care setting. Assisted ventilation and hyperalimentation are often needed before the patient recovers. Fetal well-being will depend on the acuity of the mother’s illness and how well she responds to treatment, as well as the gestational age of the fetus. Treatment Medical Management

• Bowel rest. • Adequate hydration with IV fluids to prevent hypovolemia. • Monitor for metabolic changes. • Decreased calcium and magnesium levels • Hyperglycemia • Electrolyte abnormalities • Total parenteral nutrition may be necessary in severe cases. • Antibiotics if secondary infection is present. • Adequate pain management. • Ventilatory support may be necessary in severe cases. • For treating hypertriglyceridemia, gemfibrozil has been reported to be safe and effective in pregnancy (51). Procedure

• ERCP • Cholecystectomy and common bile duct exploration if secondary to gallstones • Endoscopic or percutaneous drainage of pseudocyst if greater than 5 cm (51) • Induction of labor if patient is greater than 34 weeks’ gestation may be considered. Complications

• Hemorrhagic pancreatitis may lead to shock, pleural effusion, acute respiratory distress syndrome, ascites, and ileus. • Hypocalcemia. • Hypovolemia and shock. • Hyperglycemia and subsequent nonketotic coma. • Preterm labor. • Recurrent pancreatitis. • Formation of pancreatic pseudocysts. • Maternal and/or fetal death. Patient Education

• Patients with active or chronic liver, gallbladder, or pancreatic disease should receive appropriate assessment and counseling before conception. • These patients need specific education that, except in selected conditions, hepatobiliary disease is rarely a contraindication to pregnancy. REFERENCES 1. Stieger B, Geier A. Genetic variation of bile salt transporters as predisposing factors for drug induced cholestasis, intrahepatic cholestasis of pregnancy, and therapeutic response of viral hepatitis. Expert Opin Drug Metab Toxicol. 2011;7(4):411–425. 2. Benjaminov FS, Heathcote J. Liver disease in pregnancy. Am J Gastroenterol. 2004;99:2479–2488. 3. Pathak B, Sheibani L, Lee RH. Cholestasis of pregnancy. Obstet Gynecol Clin N Am. 2010;37:269–282. (c) 2015 Wolters Kluwer. All Rights Reserved.

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4. Hay JE. Liver disease in pregnancy. Hepatology. 2008;47(3):1067–1076. 5. Sandhu BS, Sanyal AJ. Pregnancy and liver disease. Gastroenterol Clin N Am. 2003;32:407–436. 6. Williamson C, Hems CM, Goulis DG, et al. Clinical outcome in a series of obstetric cholestasis identified via a patient support group. BJOG. 2004;111:676. 7. Lee RH, Incerpi MH, Miller DA, et al. Sudden fetal death in intrahepatic cholestasis of pregnancy. Obstet Gynecol. 2009;113:528. 8. Martin JN, Rose CH, Briery CM. Understanding and managing HELLP syndrome: the integral role of aggressive glucocorticosteriods for mother and child. Am J Obstet Gynecol. 2006;195:914–934. 9. Barton JR, Sibai BM. Diagnosis and management of hemolysis, elevated liver enzymes, and low platelets syndrome. Clin Perinatol. 2004;31:807–833. 10. Martin JN, Rinehart B, May WL, et al. The spectrum of severe preeclampsia: comparative analysis by HELLP syndrome classification. Am J Obstet Gynecol. 1999;180:1373–1384. 11. Jamerson PA. The association between acute fatty liver of pregnancy and fatty acid oxidation disorders. J Obstet Neonatal Nurs. 2005;34:87–92. 12. Ibdah JA, Bennett MJ, Rivaldo P, et al. A fetal fatty acid oxidation disorder as a cause of liver disease in pregnant women. N Engl J Med. 1999;340:1723–1731. 13. Rajasri AG, Srestha R, Mitchell J. Acute fatty liver of pregnancy (AFLP)—an overview. JObstet Gynaecol. 2007;27:237. 14. Steingrub JS. Pregnancy associated severe liver dysfunction. Crit Care Clin. 2004;20: 763–776. 15. Tran TT. Hepatitis B: treatment to prevent perinatal transmission. Clin Obstet Gynecol. 2012;55(2):541–549. 16. Sorrell MF, Belongia EA, Costa J, et al. National Institutes of Health consensus development conference statement: management of hepatitis B. Hepatology. 2009;49:S4–S12. 17. Van Nunen AB, deMan RA, Heijtinh RA, et al. Lamivudine in the last 4 weeks of pregnancy to prevent perinatal transmission in highly viremic chronic hepatitis B patients. J Hepatol. 2000;32:1040–1041. 18. National Institute of Health (NIH). Management of hepatitis C [Review]. NIH consensus. NIH Consens State Sci Statements. 2002;19(3):1–46. 19. Su GL. Hepatitis C in pregnancy. Curr Gastroenterol Rep. 2005;7:45–49. 20. Plunkett BA, Grobman WA. Routine hepatitis C virus screening in pregnancy: a cost effective analysis. Am J Obstet Gynecol. 2005;192:1153–1161. 21. Polis CB, Shah SN, Johnson KE, et al. Impact of maternal HIV co-infection on the vertical transmission of hepatitis C virus: a meta-analysis. Clin Infect Dis. 2007;44(8): 1123–1131. 22. Mast EE, Hwang LY, Sito DS, et al. Risk factors for perinatal transmission of hepatitis C virus (HCV) and the natural history of HCV infection acquired in infancy. J Infect Dis. 2005;192(11):1880–1889. 23. Centers for Disease Control and Prevention. Recommendation for prevention and control of hepatitis C virus (HCV) and HCV-related chronic disease. MMWR Recomm Rep. 1998;47(RR-19):1–39. 24. Castello G, Scala S, Palmieri G, et al. HCV related hepatocellular carcinoma: from chronic inflammation to cancer. Clin Immunol. 2010;134(3):237–250. 25. Mushahwar IK. Hepatitis E virus: molecular virology, clinical features, diagnosis, transmission, epidemiology, and prevention. J Med Virol. 2008;80:646–658. 26. Kumar A, Beniwal M, Kar P, et al. Hepatitis E in pregnancy. Int J Gynecol Obstet. 2004;85:240–244. 27. Labrique AB, Shigufta SS, Krain LJ. Hepatitis E, a vaccine preventable cause of maternal death. Emerg Infect Dis. 2012;9(18):1401–1403. 28. Khuroo MS, Kanrili S. Aetiology, clinical course and outcome of sporadic acute viral hepatitis in pregnancy. J Viral Hepat. 2003 Jan;10(1):61–69. 29. Fischler B, Lara C, Chen M, et al. Genetic evidence for mother to infant transmission of hepatitis G virus. J Infect Dis. 1997;176(1):281–285. (c) 2015 Wolters Kluwer. All Rights Reserved.

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30. Paternoster D, Serena A, Santin M, et al. GB virus C infection in pregnancy: maternal and perinatal importance of the infection. Eur J Obstet Gynecol Reprod Biol. 2009;144(2):115–118. 31. Creasy RK, Resnik R, eds. Maternal-Fetal Medicine: Principles and Practice. 4th ed. Philadelphia: W.B. Saunders, 1999:1055–1056. 32. Cohen J, Powderly WG. Infectious diseases. 2nd ed. St Louis: Mosby, 2004:1169–1171. 33. Deepah J, James A, Quaglia A, et al. Liver disease in pregnancy. Lancet. 2010;375:594–605. 34. Feldman M. Sleisenger and Fordtran’s Gastrointestinal and Liver disease. 7th ed. Philadelphia: Saunders, 2002:1462–1464. 35. Lee WM. Pregnancy in patients with chronic liver disease. Gastroenterol Clin North Am. 1992;21:889–903. 36. Khan S, Tudur Smith C, Williamson P, et al. Portosystemic shunts versus endoscopic therapy for variceal rebleeding in patients with cirrhosis. Cochrane Database Syst Rev. 2006;4:CD000553. 37. Murad SD, Plessier A, Hernandez-Guerra M, et al. Etiology, management, and outcome of the Budd-Chiari syndrome. Ann Intern Med. 2009;151(3):167–175. 38. Gandhi H, Davies N. Liver transplant and obstetrics. J Obstet Gynaecol. 2004;24:771–773. 39. Jabbour N, Brenner M, Gagandeep S, et al. Major hepatobiliary surgery during pregnancy: safety and timing. Am Surg. 2005;71:354–358. 40. Johnston DE, Kaplan MN. Medical progress: pathogenesis and treatment of gallstones. N Engl J Med. 1993;328(6):412–421. 41. Lu EJ, Curet MJ, Yasser Y, et al. Medical versus surgical management of biliary tract disease in pregnancy. Am J Surg. 2004;188:755–759. 42. Ko CW, Beresford SA, Schulte SJ, et al. Incidence, natural history, and risk factors for biliary sludge and stones during pregnancy. Hepatology. 2005;41:359–365. 43. Ramin KD, Ramsey PS. Disease of the gallbladder and pancreas in pregnancy. Obstet Gynecol Clin North Am. 2001;28:571–580. 44. Cunningham FG, Leveno KJ, Bloom SJ, et al., eds. Hepatic, gallbladder, and pancreatic disorders. Williams obstetrics. 23rd ed. USA: McGraw-Hill, 2010:1073. 45. Tham TCK, Vandervoot J, Wang RCK, et al. Safety of ERCP during pregnancy. Am J Gastroenterol. 2003;98:308–311. 46. Hernandez A, Petrov MS, Brooks DL, et al. Acute pancreatitis and pregnancy: a 10 year single center experience. J Gastrointest Surg. 2007;11:1623–1627. 47. Ramin K, Richey S, Ramin S, et al. Acute pancreatitis in pregnancy. Am J Obstet Gynecol. 1995;173(1):187–191. 48. Neill AM, Hackett GA, Overton C, et al. Active management of acute hyperlipidaemic pancreatitis in pregnancy. J Obstet Gynaecol. 1998;18:174–175. 49. Sharp HT. The acute abdomen during pregnancy. Clin Obstet Gynecol. 2002;45:405–413. 50. Saadi JF. Kurlander DJ, Erkins JM, et al. Severe hypertriglyceridemia and acute pancreatitis during pregnancy: treatment with gemfibrozil. Endocr Pract. 1999;5:33–36. 51. Eddy JJ, Lynch GE, Treacy DE. Pancreatic pseudocysts in pregnancy: a case report and review of the literature. J Perinatol. 2003;23:69–72.

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16

Gastrointestinal Complications

Nicolette P. Holliday and David F. Lewis

KEY POINTS • Most pregnant women have gastrointestinal (GI) complaints during pregnancy. • The majority of pregnant women experience nausea, vomiting, and constipation. • Many pregnant women experience symptoms of gastroesophageal reflux. • Others have more serious GI problems. • Health care providers must become familiar with treatment options for the minor complaints and be able to diagnose patients with serious pathologic conditions in order to optimize maternal and perinatal outcomes. Nausea and Vomiting Background

Most patients complain of mild to severe nausea and vomiting during the first and early second trimesters of pregnancy. Although the etiology remains unclear, rapidly rising human chorionic gonadotropin (hCG) and estrogen levels have been implicated. Epidemiology

As many as 85% of pregnancies are accompanied by nausea and vomiting. The majority of these cases are self-limited and resolve spontaneously. Evaluation Physical assessment should include a complete abdominal examination. Laboratory Tests

• Urinalysis will check for degree of dehydration (ketones, elevated specific gravity) and signs of a urinary tract infection (nitrite, leukocyte esterase). • A chemistry panel is needed to detect and correct any electrolyte imbalances. The potassium concentration is especially important to note. • Thyroid function tests (Free T3, Free T4, and TSH), while typically abnormal when there is nausea and vomiting of pregnancy, may be considered if a patient exhibits signs or symptoms of thyroid disease. • Liver function tests along with amylase and lipase may also be abnormally elevated with nausea and vomiting of pregnancy. A hepatitis panel can be considered in refractory cases or with markedly elevated transaminases in order to rule out some infectious etiologies. • Human chorionic gonadotropin is ordered to screen for possible molar pregnancy. • Ultrasound is ordered to determine whether a molar or partial molar pregnancy exists and to assess for presence of multifetal gestation. Diagnosis

Differential Diagnosis

Numerous illnesses present with nausea and vomiting (see Table 16-1). Clinical Manifestations

In severe or refractory cases, it is extremely important to rule out possible pathologic processes. 264

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Chapter 16 • Gastrointestinal Complications 

Table 16-1

  265

Differential Diagnosis for Nausea and Vomiting in Pregnancy

Acute appendicitis Bowel obstruction Food poisoning Hepatitis Hiatal hernia Hyperthyroidism Molar pregnancy Pancreatitis Peptic ulcer disease Pyelonephritis Renal colic

Treatment Diet

Encourage patients to eat frequent, small meals that are rich in simple carbohydrates (e.g., dry toast, crackers). Medications

Results from the Cochrane database (1) concluded that most drugs used for treating nausea and vomiting during pregnancy are more effective than is placebo. • Bendectin contains both vitamin B6 (FDA class A) and doxylamine (FDA class A). Although it is not available in the United States due to medical–legal concerns, evidence indicates that both drug components appear safe and effective. • Promethazine (Phenergan, FDA class C) and prochlorperazine (Compazine, FDA class C): Oral or rectal use has become very popular in the United States. Initial treatment favors rectal suppositories due to limited gastric absorption caused by emesis (2). • Droperidol (Inapsine, FDA class C) represents a dopamine antagonist that is unresponsive to first-line therapy. Continuous infusion seems more effective in refractory cases (3). • Meclizine (Antivert, FDA class B) and cyclinine (Marezine, FDA class B): These antihistamines are effective when given alone or in combination with vitamin B6 in 80% to 90% of patients. • The promoting agent metoclopramide (Reglan, FDA class B) accelerates gastric emptying. Alternative Therapies

• Ginger (FDA class C): Some evidence suggests that ginger decreases nausea. No adverse effects have been reported (4). • Acupressure: Pressure stimulates the PC-6 site. Large studies have failed to confirm the efficacy of acupressure. • Sensory afferent stimulation: Transcutaneous nerve stimulation (TENS) of P6 on the wrist has been effective (5). Complications • Electrolyte imbalance, especially hypokalemia, may induce cardiac arrhythmias. • Hypovolemia (severe) may lead to uteroplacental insufficiency. • Weight loss accompanied by negative nitrogen balance can result in ketone production. HYPEREMESIS GRAVIDARUM Background This manifests as severe nausea and vomiting with significant metabolic disturbances (6). (c) 2015 Wolters Kluwer. All Rights Reserved.

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Etiology

Although the specific etiology is uncertain, hCG, estrogen, psychological factors, and certain personality traits are associated with hyperemesis gravidarum. Other suggested etiologies include thyrotoxicosis, serotonin anomalies, nutritional dysfunction, and Helicobacter pylori infections (7). Epidemiology

The incidence of hyperemesis gravidarum is 1 in 200 pregnancies (0.5%). Women with a female fetus are more likely to have hyperemesis gravidarum, heavy ketonuria, and higher number of hospital admissions (8,9). Evaluation Laboratory

• Urinalysis: Specific gravity, urine ketones, and bilirubin evaluation. The specific gravity assesses hydration status of the patient, and bilirubin is used to evaluate for hepatitis and hemolysis. • Serum electrolytes: Potassium and creatinine are especially pertinent. • Hepatic functions: These tests evaluate for severe dehydration, and they are also elevated with hepatitis. • Thyroid function tests in patients with signs or symptoms of hyperthyroidism may help rule out thyrotoxicosis (TSH is commonly suppressed in hyperemesis gravidarum). • Fetal ultrasound: This is used to exclude molar or partial molar pregnancy and to assess for multifetal gestation. Diagnosis

Differential Diagnosis

• Please see Table 16-2. Clinical Manifestations

Hyperemesis gravidarum usually manifests between 4 and 10 weeks of gestation and is resolved by 20 weeks of gestation. It is usually well tolerated at its inception but leads to weight loss, dehydration, electrolyte abnormalities, and ketosis. Treatment If hospitalization is required, patients should remain NPO for 24 to 48 hours and have intravenous replacement of isotonic fluids containing dextrose. Electrolytes can be replaced intravenously as clinically indicated. After 48 hours, their diet can be slowly advanced from clear liquids to abundant undersized meals rich in simple carbohydrates, such as dry toast and crackers. Medications

Data from the Cochrane database (1) indicated that most drugs used for treating nausea and vomiting during pregnancy were more effective than placebo. • Bendectin is a combination of vitamin B6 (FDA class A) and doxylamine (FDA class A). Although it is not available in the United States due to medical–legal concerns, evidence indicates that it is safe and effective. • Promethazine (Phenergan, FDA class C) and prochlorperazine (Compazine, FDA class C) are used orally or rectally and are very popular in the United States. Rectal suppositories are recommended for initial treatment because of the lack of gastric absorption resulting from emesis. • Droperidol (Inapsine, FDA class C) represents a dopamine antagonist that is unresponsive as first-line therapy. However, continuous infusion is effective for refractory cases. • Theclizine (Antivert, FDA class B) and cyclinine (Marezine, FDA class B) are antihistamines that are effective alone or in combination with vitamin B6 in 80% to 90% of patients. (c) 2015 Wolters Kluwer. All Rights Reserved.

Chapter 16 • Gastrointestinal Complications 

Table 16-2

Commonly Used Antiemetics in Pregnancy Generic name Buclizine

Proprietary name Bucladin

FDA rating Ca

Cyclizine

Marezine

B

Meclizine Chlorpromazine

Antivert Thorazine

B C

Prochlorperazine

Compazine

C

Promethazine Diphenhydramine Dolasctron Ondansetron

Phenergan Benadryl Anzemt Zofran

Cb Bb B B

Doxylamine

Unisom

A

Benzoquinolizine antihistamine

Benzoquinamide

Emete-con

Dopamine antagonist

Metoclopramide

Reglan

Bb

Apomorphine antagonist

Droperidol

Inapsine

Cb

Class Piperazine antihistamine Derivatives Phenothiazine antihistamine derivatives

Antihistamine SHT3 Antagonistic

  267

a

Dose 50 mg PO q12h IM only: 50 mg q6h, prn 25–50 mg PO q24h PO: 10–25 mg q6h IM: 25 mg q4–6h Suppository: 50–100 mg q8h PO: 5–10 mg q8h IM: 5–10 mg q4h, max 40 mg/24 h Suppository: 25 mg q12h PO: 25 mg q6h PO: 25–50 mg q6h 12.5 mg IV PO: 8 mg PO b.i.d.– t.i.d. IV: 4–8 mg IV q8h Manufacturer recommends against use in pregnancy Manufacturer recommends against use in pregnancy PO: 10–15 mg q6h IM: 10 mg q6h IV: 10 mg q6h, given slowly over 1–2 min IM or slow IV: 2.5–5 mg; use in intractable vomiting

Manufacturer recommends against use in early pregnancy. See Chapter 24 for details of FDA rating categories. b Manufacturer recommends use only if potential benefit justifies potential risk to fetus. FDA, Food and Drug Administration. a

• Promoting agents: Metoclopramide (Reglan, FDA class B) accelerates gastric emptying. • Alternative therapies • Ginger (FDA class C): Some evidence suggests that ginger decreases nausea. Adverse associations have not been reported. • Acupressure: This treatment stimulates the PC-6 site with pressure, but numerous studies have not confirmed its efficacy. • Sensory afferent stimulation: TENS of P6 on the wrist has been effective (5). • Ondansetron (Zofran, FDA class B): This agent is effective for refractory cases. • Steroids: In some trials, limited courses of methylprednisolone have been effective. • This therapy remains controversial (6). • Glycopyrrolate (Robinul, FDA class B): This agent is acceptable for patients with ptyalism. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Additional Therapy for Refractory Cases

• Enteral feedings: This option should be considered for patients with significant weight loss and inability to keep down food for 1 to 2 weeks or longer. It enables normal function of the intestines. • Hyperalimentation: This may be necessary in certain cases to help maintain volume requirements and allow weight gain. This treatment requires placement of a central venous line, which increases the risk of systemic infection and other serious complications. Due to associated risks in pregnancy, this option is generally reserved for cases in which enteral feedings have been unsuccessful. • Vitamins: Intravenous thiamine and multivitamin should be considered in patients unable to tolerate oral intake for 1 to 2 weeks or longer. Complications • Mallory-Weiss tear of esophagus. • Diaphragmatic tear (10). • Vitamin deficiency, including Wernicke encephalopathy (vitamin B deficiency). • Renal damage resulting from hypovolemia. • Intrauterine growth restriction, prematurity, and fetal death have been associated with these disorders (8). GASTROESOPHAGEAL REFLUX DISEASE Background Definition

Reflux esophagitis or dyspepsia results in reflux of gastric contents into the esophagus. Pathophysiology and Etiology

Relaxation of the esophageal sphincter due to elevated progesterone levels and increased intra-abdominal pressure from the expanding uterus are reasons that this condition complicates a large percentage of pregnancies. Epidemiology

As many as 80% of Caucasian and 10% of African American women experience symptoms of gastroesophageal reflux at some point during pregnancy. The incidence of gastroesophageal reflux disease (GERD) is similar across all trimesters of pregnancy (11). There is a correlation with prepregnancy body mass index and GERD symptoms (12). Evaluation A history and physical should include careful examination of the chest and the abdomen. Symptoms include classical substernal or epigastric burning or pain that usually occurs after meals or when supine. Diagnosis Differential diagnosis includes cardiovascular pain (angina), pulmonary causes (pneumonia or pleuritic chest pain), and other etiologies of abdominal pain (cholecystitis, appendicitis, or other intra-abdominal processes). In the second and third trimesters, hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome or hepatic hematoma must also be considered. Treatment

Medications

• Oral antacids such as Maalox or Mylanta decrease gastric acid levels and may be effective in mild cases. • Histamine-2 (H-2) receptor antagonist (FDA class B drugs). • Cimetidine (Tagamet, FDA class B) has antiandrogenic activity, and it is recommended that other H-2 blockers be used initially. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Ranitidine (Zantac, FDA class B). A dose of 150 mg twice a day appears to be effective. • Famotidine (Pepcid, FDA class B). The dosage for GERD is 20 to 40 mg twice a day. • Nizatidine (Axid, FDA class B). The usual dose is 150 mg b.i.d. • Proton pump inhibitors (PPIs) (Omeprazole, FDA class C, Lansoprazole, FDA class B): These drugs control gastric secretions and are excreted in human milk. If used postpartum, breast-feeding should be avoided. Reserve the use of PPIs for cases refractory to H2 blockers because carcinogenic and adverse fetal effects have been reported in animal studies. PEPTIC ULCER DISEASE (PUD) Background Definition

A peptic ulcer is an ulcerative area in the gastric lining. Evidence suggests that the incidence of peptic ulcer disease (PUD) is lower during pregnancy because of decreased gastric acid output and increased protective mucus production resulting from elevated progesterone levels. The incidence of PUD in pregnancy is quite low—this disorder complicates 1 in every 4000 pregnancies. The incidence may be actually higher because the diagnosis is difficult during pregnancy (13). Pregnancy is considered to be protective against PUD. Pathophysiology

Excess acid production and the failure of mucus to protect the underlying mucosa are considered the primary causes. Risk factors include genetic predisposition, older age, smoking, excessive alcohol intake, and use of nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin. H. pylori has been also implicated as a causative agent, and it is present in 85% to 100% of duodenal ulcers (14). Evaluation

History and Physical

Patients usually have long-term GERD. Symptoms suggestive of gastric ulcers include dull, epigastric pain that radiates to the back. Pain improves with eating or antacids. Duodenal ulcers result in sharp or burning epigastric pain. Tests

During pregnancy, direct endoscopic evaluation is the most effective method to confirm PUD. If possible, radiographic evaluations should be avoided because of radiation exposure during an upper GI series. Treatment

Medications

• Oral antacids such as Maalox or Mylanta decrease stomach acid with minimal GI absorption and are safe during pregnancy. Both of these drugs are magnesium-based antacids and are superior to the aluminum-based antacids that predispose patients to constipation. The dosage is 15 to 30 mL taken after each meal and at bedtime. • H2 receptor antagonist (FDA class B drugs). Long-term safety has not been clearly established; however, these agents are commonly used in pregnancy. All four medications are labeled as probably safe in lactation as there is limited information in animals and/ or humans demonstrating no risk/minimal risk of adverse effects to infant/breast milk production. • Cimetidine (Tagamet, FDA class B): Use other H2 blockers initially because cimetidine exerts antiandrogenic activity in some animal models. • Ranitidine (Zantac, FDA class B): A dosage of 150 mg b.i.d. appears to be effective. • Famotidine (Pepcid, FDA class B): The dosage for PUD is 40 mg/d. • Nizatidine (Axid, FDA class B): The usual dose is 150 mg b.i.d. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Proton pump inhibitors (PPIs, FDA class C): Reserve the use of these for cases refractory to H2 blockers. These drugs control the gastric secretions. They have theoretical risks of carcinogenesis risk to the fetus based on animal studies. They should be reserved for cases in which the risk/benefit balance justifies their use. • Sucralfate (Carafate, FDA class B): Inhibits acid adhering to mucosal ulceration. It may also stimulate local production of bicarbonate and inhibit the action of pepsin. This drug causes constipation and should be reserved for difficult cases. • Antibiotic therapy: The combination of bismuth subsulfate and paired antibiotics has been proven to be efficacious in treating peptic ulcers with evidence of H. pylori infection. This treatment is recommended after delivery because the therapy has not been evaluated for safety in pregnancy. Complications Most patients with PUD during pregnancy improve. Complications are rare; however, bleeding, perforation, and obstruction can arise during pregnancy and must be considered. The risk of fetal loss is increased if these complications do occur. There is also an increased risk for low birth weight, small for gestational age infants, and preterm delivery (15). If significant ongoing bleeding from a gastric ulcer occurs, surgical treatment should be considered because of the risk of fetal mortality and maternal morbidity (16). BOWEL DISEASE IN PREGNANCY Gastroenteritis

Background Definition

• Acute onset of diarrhea Etiology

• Both viral and bacterial infections can cause this condition (see Table 16-3). Evaluation Signs and Symptoms

Symptoms include diarrhea associated with fever, abdominal pain and cramping, and bloody or mucoid stooling. During pregnancy, dehydration poses the greatest risk to the fetus. Laboratory Tests

If diarrhea persists for more than 24 to 48 hours, consider workup, unless concerned about Clostridium difficile, and then initiation of testing should begin immediately. Table 16-3 Variable Bacterial infections Bacterial toxins Protozoans Helminths Viruses

Acute Gastroenteritis Organism Campylobacter jejuni, Escherichia coli, Listeria, Salmonella species, Shigella species, Yersinia enterocolitica, Vibrio parahaemolyticus Bacillus cereus, C. difficile, V. cholerae, E. coli, Staphylococcus aureus Entamoeba histolytica, Giardia lamblia, malaria species, Toxoplasma gondii Cestodes (hydatid, Taenia), nematodes (Ancylostoma, Ascaris, Enterobius, Strongyloides), Trematodes (Schistosoma) Cytomegalovirus, herpes, polio, others

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• The absence of leukocytes in a stool smear suggests that a bacterial infection is unlikely. • Stool culture for Campylobacter, Salmonella, Shigella, and enterotoxigenic Escherichia coli. • A stool smear should be obtained to test for enteric parasites such as Giardia and Amoeba. SPECIFIC BACTERIAL INFECTIONS Campylobacter jejuni This usually presents with bloody diarrhea, fever, abdominal pain, and tenesmus. These symptoms usually resolve within 5 days; however, they may persist for up to 4 weeks. • Therapy: Hydration is the most important therapy. The symptoms usually spontaneously resolve, although erythromycin may shorten the duration of illness. Vibrio cholerae This is caused by drinking contaminated water. • Therapy: The symptoms usually spontaneously resolve. Chloramphenicol therapy may be considered for severe cases. This drug is FDA category C. It crosses the placenta and has been associated with gray baby syndrome when used late in pregnancy. Clostridium difficile

Background

Clostridium difficile colitis is usually due to an enterotoxin produced from overgrowth of the organism after antibiotic therapy and leads to pseudomembranous colitis. The symptoms normally present 4 to 10 days after antibiotic therapy but may persist for as many as 6 weeks after therapy. Evaluation Clinical Presentation

Watery diarrhea containing leukocytes and sometimes blood. Diagnosis

Clostridium difficile enterotoxins can be detected in stool studies. The toxins can also be detected via PCR (highly sensitive and specific), EIA (enzyme immunoassay) for GDH (C. difficile gluatamate dehydrogenase), EIA for C. difficile toxins A and B, cell culture cytotoxicity assay (the gold standard), and selective anaerobic culture. The selective anaerobic culture is the most sensitive but does not differentiate between the toxin and nontoxin strains. Diagnosis can also be made by endoscopic or histologic findings of pseudomembranous colitis (17) Treatment Therapy

Vancomycin (FDA class B) is the drug of choice; alternative therapy includes metronidazole (FDA class B). Escherichia coli Results from consuming fecal-contaminated food or water. Two types of E. coli are detected: the first type is caused by endotoxins (Montezuma’s revenge), whereas the second type results from local invasion of bowel mucosa. • Therapy: Enterotoxin-derived infection does not require antibiotic therapy. Severe infection responds to aminoglycoside.

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Salmonella Salmonella is caused by consuming contaminated food. Typhoid fever is rare in the United States. Intra-amniotic and fetal infections are uncommon but have been reported with pregnancy loss. Diagnosis

The usual presentation involves rash, fever, and leukopenia with bradycardia. Therapy

Antibiotics such as chloramphenicol (FDA class C), ampicillin (FDA class B), ­trimethoprim–sulfamethoxazole (FDA class C), or ceftriaxone (FDA class B) should be reserved for severe cases. Chloramphenicol has been associated with “gray baby syndrome,” which is rare (1 in 30,000 patients). This condition, though its existence is controversial, results from use of the drug at term, and the newborns have cardiovascular collapse. Most authorities recommend using chloramphenicol only as a last resort because of this risk. Shigella Caused by bacterial dysentery manifested by bloody, mucoid diarrhea. • Therapy: Health care providers should avoid prescribing medications that inhibit bowel function. Consider using ampicillin (FDA class B) for severe infections, while recognizing that resistance frequently occurs. Consequently, treatment with chloramphenicol or trimethoprim–sulfamethoxazole may be necessary in the most severe cases. Staphylococcus Caused by consuming unrefrigerated dairy products. Usually self-limited and presents as explosive diarrhea accompanied by nausea and vomiting. Dehydration can be a significant problem in these patients. INFLAMMATORY BOWEL SYNDROME Inflammatory bowel disease (IBD) includes Crohn disease and ulcerative colitis. The incidence is 1 in 1000 pregnancies. This syndrome usually develops during the peak reproductive span of 15 to 35 years of age (18–21). Both diseases are associated with rectal bleeding and diarrhea. Fertility does not appear impaired in patients suffering from IBD. Similarly, once pregnant, IBD patients do not appear to suffer increased pregnancy complications (premature birth, miscarriage, or congenital anomalies). Patients have a 30% chance of experiencing recurrent disease some time during pregnancy. This rate is comparable to that observed among nonpregnant populations. The effects of IBD on pregnancy are controversial. Some investigators (22,23) have found increased rates of preterm delivery in ulcerative colitis, whereas others (24–27) found no significantly increased perinatal morbidity. If an exacerbation of IBD complicates a pregnancy, there is an increased likelihood of miscarriage or preterm labor (28). Patients with active disease at conception tend to continue with symptoms during pregnancy while those who conceive while in remission tend to undergo a normal pregnancy course (29). Crohn Disease (Regional Enterocolitis) Background Pathology

Pathologically, it is expressed by transmural involvement that encompasses the colon, small bowel, and rectum. Fistula formation is common, and the bowel usually has “skip” lesions (intermittent affected areas).

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Etiology

The exact etiology of Crohn disease remains unknown; autoimmune, familial, and infections have been implicated. Evaluation Initial Presentation

Lower abdominal pain, low-grade fever, weight loss, and diarrhea are common findings, and there are often bloody stools. The clinical picture can be easily confused with appendicitis. Diagnosis

The diagnosis can be difficult during pregnancy. The mainstay for diagnosis in a nonpregnant state is radiographic evaluation (lower GI series or sigmoidoscopy with direct biopsy). However, radiographic evaluations should be restricted during pregnancy, and sigmoidoscopy requires sedation and may be technically difficult to perform with uterine enlargement. Treatment

Optimal treatment varies depending on disease severity. Mild disease can be treated medically with both antidiarrheal drugs and nutritional support. Severe disease requires the use of either steroids or immunosuppressive drugs, such as azathioprine or ­6-mercaptopurine. The latter drugs should be reserved for the most severe cases. Augmentin is the preferred antibiotic if there are complications that require the use of antibiotics (29). Complications

Preexisting Crohn disease does not alter perinatal outcome. However, new-onset disease during pregnancy may be associated with increased perinatal mortality. Vaginal delivery is not recommended if perineal fistula(s) is present. There is also a higher risk of antepartum hemorrhage—highest risk among those without a flare (30). Thus, careful prenatal evaluation should be completed in these patients in order to plan an appropriate delivery option. Ulcerative Colitis Background

Ulcerative colitis involves the large bowel and is more superficial than is Crohn disease. These ulcers are usually present in the descending colon, sigmoid, and rectum; they do not skip among segments like Crohn disease. Etiology

The etiology of ulcerative colitis remains unclear; autoimmune, familial genetic predisposition and infection have all been implicated. Evaluation Clinical Presentation

Patients with ulcerative colitis usually present with abdominal pain, fever, cramping, bloody diarrhea, weight loss, and tenesmus. Diagnosis

The diagnosis can be difficult during pregnancy. The mainstay for diagnosis in a nonpregnant state is radiographic evaluation (lower GI series) or sigmoidoscopy with direct biopsy. However, radiographic evaluations should be restricted during pregnancy, and sigmoidoscopy requires sedation and may be technically difficult to perform with uterine enlargement.

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Treatment

Treatment includes antidiarrheal drugs, steroids, and sulfasalazine (FDA class B) in select cases. There also has been documented safe use of allopurinol therapy in pregnancy (31). Occasionally, proctocolectomy may be necessary for severe disease or complications. Management

Inflammatory bowel disease is managed similarly in both pregnant and nonpregnant patients. However, special consideration should be given to the medications used because of their limited safety data for the fetus. • Evaluate the causes of diarrhea and rectal bleeding. • Rest the GI tract by maintaining strict NPO (excluding medications) for several days. • If symptoms persist, initiate corticosteroid therapy. Steroids administered by retention enemas followed by oral prednisone are commonly employed. Rule out infections (both bacterial and parasitic) as an etiology before starting steroids. Sulfasalazine (FDA class B) can be given, if necessary. In acute exacerbations during pregnancy, both corticosteroids and sulfasalazine are given in high doses. These drugs appear safe to the fetus. Start intravenous hydration with isotonic solutions containing dextrose. • Parenteral hyperalimentation may be needed in severe cases of IBD. Risk of severe complications of this therapy in pregnancy have been reported and should be considered. • Occasionally, surgery is indicated in patients with IBD. However, advancing gestational age increases the technical difficulty of bowel surgery in pregnancy, especially the last trimester. Medications

• Sulfasalazine (Azulfidine, FDA class B). The drug is metabolized to 5-aminosalicylic acid and sulfapyridine. Three to four gram dosages administered three to six times daily are commonly given. Sulfasalazine should be taken with meals, and extra folate supplementation should be initiated (29). • 5-Aminosalicylic acid (mesalamine, FDA class B or olsalazine, FDA class C) can be given by itself. Usually, these drugs are better tolerated than sulfasalazine (class B). It may be used as initial treatment in mild to moderate disease or to prevent relapse. Specifically, in disease confined to the rectosigmoid areas, topical preparations are recommended (32). • Infliximab (Remicade, FDA class B) can be used as well; however, it is usually discontinued at 30 weeks in quiescent patients to limit neonatal exposure (33). • Corticosteroids appear to be safe during pregnancy, but higher doses more than 15 mg/d have been associated with increased risk of infection and premature delivery (29). • Metronidazole (Flagyl, FDA class B) is used for the treatment of pouchitis (29) Other immunosuppressive drugs such as cyclosporine, azathioprine, or 6-mercaptopurine are sometimes needed in severe cases of IBD (29). Both drugs may potentially cause problems during pregnancy; low birth weight and congenital anomalies have been reported in animal models. However, recent results from a small human study have failed to confirm these animal findings. The decision to use this drug should be made in consultation with the patient while explaining the potential risks and the absence of long-term follow-up data. Methotrexate and thalidomide are contraindicated in pregnancy (29). Complications

Complications include toxic megacolon, strictures, and perforations. This disease does not alter the incidences of perinatal morbidity and mortality, and its clinical course is not affected by pregnancy. The risk of venous thromboembolism is increased in these patients (30). PROTOZOAL ENTERITIS Giardia lamblia Caused by drinking contaminated or untreated water or fecal–oral transmission. This is the most commonly diagnosed protozoal infection in the United States.

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• Symptoms: Can cause acute symptoms or chronic carrier state. The carrier state ­manifests itself by flatulence, epigastric pain, and loose stools. • Diagnosis: Stool evaluations for cysts or trophozoites. • Therapy: Metronidazole (Flaygl, FDA class B) is the drug of choice. The dosage is either 2 g/d for 3 days or 750 mg/d for 5 days. Metronidazole should be avoided in the first trimester due to possible teratogenicity. Entamoeba histolytica This protozoa causes amebiasis. Carriers include cats, dogs, rats, and humans, and infections are acquired by direct contact. Infections have a range of presentations from benign carrier state, severe diarrhea, and severe infection such as hepatic abscess or pulmonary involvement caused by violent strains usually from foreign countries. • Diagnosis: Fresh stool examination for a cyst or trophozoites. Serologic examinations are also available. • Therapy: Metronidazole (FDA class B) is the drug of choice. The usual dosage is 750mg t.i.d. for 5 to 10 days. Chloramphenicol (FDA class C) is an alternative for resistant strains. HELMINTHIC INFECTIONS The most common infection and treatments are Cestodes (Tapeworms) • Diphyllobothrium latum—niclosamide, praziquantel, or paromomycin • Echinococcus species—mebendazole • Taenia saginata or Taenia solium—niclosamide Nematodes (Roundworms) • Ascaris lumbricoides—mebendazole • Ancylostoma duodenale (hookworms)—mebendazole • Enterobius vermicularis—pyrvinium pamoate, mebendazole • Filaria species—mebendazole • Necator americanus (hookworm)—mebendazole • Trichinella spiralis, Trichinella trichura—mebendazole • Trematoda (flatworms)—praziquantel OTHER GASTROINTESTINAL PROBLEMS Bariatric Surgery Surgical procedures for alleviating morbid obesity are now relatively common. Pregnancy may occur following these procedures, and those pregnancy outcomes are comparable to those without bariatric surgery (34). Inadequate nutritional intake or absorption of iron, folate, calcium, vitamins A, B12, and K may occur in these patients. Thus, proper supplemental nutritional and vitamin therapy are needed. These patients should not be given large glucose loads for gestational diabetes screening (glucose challenge test or glucose tolerance test). Fasting and 2-hour postprandial finger stick glucose monitoring may be an alternative screening approach for diabetes in these patients. After the Roux-en-Y procedure, there are reports of increased rates of cesarean section, preterm delivery, and neonatal death compared to pregnancy following laparoscopic adjustable gastric banding (35). Clinicians should maintain clinical suspicion for postoperative complications from this procedure including bowel obstruction and internal hernias (36,37).

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Irritable Bowel Syndrome Irritable bowel syndrome (IBS) is the most commonly diagnosed GI condition and is characterized by altered bowel habits and abdominal discomfort without organic disease. IBS is associated with an increased risk of miscarriage and ectopic pregnancy but not association with preeclampsia or intrauterine fetal demise (38). Lactose Intolerance Some adults are intolerant to lactose. This condition occasionally results in nutritional problems during pregnancy due to decreased calcium intake. Oral calcium supplementation is recommended at a dosage of 1200 mg/d. Lactose intolerance presents as abdominal cramps accompanied by watery diarrhea. Patients complain of pain and clinically have increased intestinal peristalsis. Gluten Allergy/Sensitivity Celiac disease is an autoimmune disorder associated with production of antiendomysium which is an antibody against human tissue tranglutaminase. Women with celiac disease have a shorter reproductive period with later menarche and earlier menopause (39). With undiagnosed celiac disease, women have an increased risk for miscarriage, intrauterine growth restriction, low birth weight babies, preterm birth, and cesarean section compared to patients who receive treatment for celiac disease (39–41). On the other hand, there has been no link to increased neural tube defects, preeclampsia, ectopic pregnancy, and postpartum hemorrhage (39). Of note, the severity of the celiac disease does not relate to the outcome of pregnancy, and the risks can be reduced after diagnosis and treatment (41,42). Constipation Constipation is a common problem during pregnancy. Similar to nonpregnant patients, increased fiber and fluid ingestion are important in the prevention and treatment of this common complaint. If necessary, the use of osmotic laxatives, which mobilize fluid into the intestines, is very effective. Examples include Miralax™ and milk of magnesia. Other medications such as the stool softeners Surfak and Colace are also effective. PATIENT EDUCATION • GI disorders are very common. Patients with these disorders should be identified, counseled, and treated appropriately prior to pregnancy if possible. • Patients can be counseled that most GI disorders do not worsen during pregnancy with the exception of IBD. • Particular attention should be given to proper management of nutrition, which requires patient education and continuous reinforcement. • By promoting compliance with treatment and thus control of the underlying disease, patient education helps achieve optimal perinatal outcomes for these pregnancies. REFERENCES 1. Jewell D, Young G. Interventions for nausea and vomiting in early pregnancy (Review). Cochrane Database Syst Rev. 2003;(4):CD 000145. 2. Hansen WF, Yankowitz J. Pharmacologic therapy for medical disorders during pregnancy. Clin Obstet Gynecol. 2002;45:136–151. 3. Nageotte MP, Briggs GG, Towers CV, et al. Droperidol and diphenhydramine in the management of hyperemesis gravidarum. Am J Obstet Gynecol. 1996;174:1801–1806. 4. Borrelli F, Capasso R, Aviello G, et al. Effectiveness and safety of ginger in the treatment of pregnancy-induced nausea and vomiting. Obstet Gynecol. 2005;105:849–856. 5. Evans AT, Samuels SN, Bertolucci LE. Suppression of pregnancy-induced nausea and vomiting with sensory afferent stimulation. J Reprod Med. 1993;38:603–606. (c) 2015 Wolters Kluwer. All Rights Reserved.

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6. Eliakim R, Abulafia O, Sherer DM. Hyperemesis gravidarum: a current review. Am J Perinatol. 2000;17:207–218. 7. Davis M. Nausea and vomiting of pregnancy: an evidence-based review. J Perinat Neonat Nurs. 2004;18:312–328. 8. Veenendaal MV, van Abeelen AF, Painter RC, et al. Consequences of hyperemesis gravidarum for offspring: a systematic review and meta-analysis. BJOG. 2011;118(11):1302–1313. 9. Rashid M, Rashid MH, Malik F, et al. Hyperemesis gravidarum and fetal gender: a retrospective study. J Obstet Gynaecol. 2012;32(5):475–478. 10. Chen X, Yang X, Cheng W. Diaphragmatic tear in pregnancy induced by intractable vomiting: a case report and review of the literature. J Matern Fetal Neonatal Med. 2012;25(9):1822–1824. 11. Rey E, Rodriguez-Artalejo F, Herraiz MA, et al. Gastroesophageal reflux symptoms during and after pregnancy: a longitudinal study. Am J Gastroenterol. 2007;102(11):2395–2400. 12. Habr F, Raker C, Lin CL, et al. Predictors of gastroesophageal reflux symptoms in pregnant women screened for sleep disordered breathing: a secondary analysis. Clin Res Hepatol Gastroenterol. 2013;37(1)93–99. 13. Michaletz-Onody PA. Peptic ulcer disease in pregnancy. In: Gastrointestinal and liver problems in pregnancy. Gastroenterol Clin North Am. 1992;21:817–826. 14. Peterson WL. Helicobacter pylori and peptic ulcer disease. N Engl J Med. 1991;324: 1043–1048. 15. Chen YH, Lin HC, Lou HY. Increased risk of low birthweight, infants small for gestational age, and preterm delivery for women with peptic ulcer. Am J Obstet Gynecol. 2010;202(2):164. e1–e8. 16. Jones RF, McEwan AB, Bernard RM. Hemorrhage and perforation complicating peptic ulcer in pregnancy. Lancet. 1969;2:350–352. 17. LaMont JT, Calderwood SB, Baron EL. Clostridium difficile in adults: clinical manifestations and diagnosis. In: Basow DS, ed. UpToDate. Waltham, MA: UpToDate, 2013. 18. Korelitz BI. Inflammatory bowel disease in pregnancy. Gastrointestinal and liver problems in pregnancy. Gastroenterol Clin North Am. 1992;21:827–836. 19. Korelitz BI. Inflammatory bowel disease in pregnancy. Pregnancy and gastrointestinal disorders. Gastroenterol Clin North Am. 1998;27:213–223. 20. Botoman VA, Bonner GF, Botoman DA. Management of inflammatory bowel disease. Am Fam Physician. 1998;57:57–68. 21. Katz JA. Pregnancy and inflammatory bowel disease. Curr Opin Gastroenterol. 2004;20: 328–332. 22. Baird DD, Narendranathan M, Sandler RS. Increased risk of preterm birth for women with inflammatory bowel disease. Gastroenterology. 1990;99:987–994. 23. Fedor Kow KM, Persaud D, Nimrod CA. Inflammatory bowel disease: a controlled study of late pregnancy outcome. Am J Obstet Gynecol. 1989;160:998–1001. 24. Baiocco RJ, Korelitz BI. The influence of inflammatory bowel disease and its treatment on pregnancy and fetal outcome. J Clin Gastroenterol. 1984;6:211–216. 25. Nielsen OH, Andreasson B, Bordesen S, et al. Pregnancy in ulcerative colitis. Scand J Gastroenterol. 1983;18:735–742. 26. Porter RJ, Stirrat GM. The effects of inflammatory bowel disease on pregnancy: a casecontrolled retrospective analysis. Br J Obstet Gynaecol. 1986;93:1124–1131. 27. Katz JA, Pore G. Inflammatory bowel disease and pregnancy. Inflamm Bowel Dis. 2001;7:146–157. 28. Hanan IM, Kirsner JB. Inflammatory bowel disease in the pregnant woman. Clin Perinatol. 1985;12:669–682. 29. Vermeire S, Carbonnel F, Coulie PG, et al. Management of inflammatory bowel disease in pregnancy. J Crohns Colitis. 2012;6(8):811–823. 30. Broms G, Granath F, Linder M, et al. Complications from inflammatory bowel disease during pregnancy and delivery. Clin Gastroenterol Hepatol. 2012;10(11):1246–1252. 31. Seinen ML, de Boer NK, von Hoorn ME, et al. Safe use of allopurinol and low-dose mercaptopurine therapy during pregnancy in an ulcerative colitis patient. Inflamm Bowel Dis. 2013;19(3):E37. doil: 10. 1002/ibd.22945. (c) 2015 Wolters Kluwer. All Rights Reserved.

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32. Richter JM, Kushkuley S, Barrett JA, et al. Treatment of new-onset ulcerative colitis and ulcerative proctitis: a retrospective study. Aliment Pharmacol Ther. 2012;36(3):248–256. 33. Zelinkova Z, van der Ent C, Bruin KF, et al.; Dutch Delta Group. Effects of discontinuing anti-tumor necrosis factor therapy during pregnancy on the course of inflammatory bowel disease and neonatal exposure. Clin Gastroenterol Hepatol. 2013;11(30):318–321. 34. Sheiner E, Balaban E, Dreiher J, et al. Pregnancy outcome in patients following different types of bariatric surgeries. Obes Surg. 2009;19(9):1286–1292. 35. Dalfra MG, Busetto L, Chilelli NC, et al. Pregnancy and foetal outcome after bariatric surgery: a review of recent studies. J Matern Fetal Neonatal Med. 2012;25(9):1537–1543. 36. Wax JR, Pinette MG, Cartin A. Roux-en-Y gastric bypass-associated bowel obstruction complicating pregnancy-an obstetrician’s map to the clinical minefield. Am J Obstet Gynecol. 2013;208(4):265–271. 37. Leal-Gonzalez R, De la Garza-ramos R, Guajardo-Perez H, et al. Internal hernias in pregnant women with history of gastric bypass surgery: case series and review of literature. Int J Surg Case Rep. 2013;4(1):44–47. 38. Khashan AS, Quigley EM, McNamee R, et al. Increased risk of miscarriage and ectopic pregnancy among women with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2012;10(8):902–909. 39. Tata LJ, Card TR, Logan RFA, et al. Fertility and pregnancy-related events in women with celiac disease: a population-based cohort study. Gastroenterology. 2005;128:849–855. 40. Martinelli P, Troncone R, Paparo F, et al. Coeliac disease and unfavourable outcome of pregnancy. Gut. 2000;46:332–335. 41. Ludvigsson JF, Montgomery SC, Ekbom A. Celiac disease and risk of adverse fetal outcome: a population-based cohort study. Gastroenterology. 2005;129:454–463. 42. Ciacci C, Cirillo M, Auriemma G, et al. Celiac disease and pregnancy outcome. Obstet Gynecol Surv. 1996;51(11):643–644.

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17

Endocrine Disorders: Diabetes

Margarita de Veciana, Arthur T. Evans and Nancy C. Lintner

KEY POINTS • Screening for gestational diabetes mellitus (GDM) should be undertaken at 24 to 28weeks’ gestation. Patients at high risk for GDM (e.g., obesity, prior history of GDM or glucose intolerance, fetal macrosomia, history of polycystic ovarian syndrome, presence of glycosuria, strong family history of type 2 diabetes) should be screened at the first prenatal visit. • Pregnant women with diabetes may experience periods of hyperglycemia, which can result in fetal hyperglycemia and hyperinsulinemia that is associated with excessive fetal growth and other morbidities. • Poor glycemic control during early pregnancy (organogenesis) is associated with an increased risk for miscarriage. Congenital malformations occur two to four times more frequently in infants born to women with pregestational diabetes. Cardiac, central nervous system (CNS), and skeletal malformations are most common, but there are no malformations that are pathognomonic for diabetes. • Preconceptional counseling and medical management should be offered to all patients with pregestational diabetes or glucose intolerance in order to optimize perinatal outcome with pregnancy. • Women with diabetes complicated by vascular disease (especially nephropathy and retinopathy) are at greatest risk for poor perinatal outcome with an increased risk for preeclampsia, preterm delivery, and fetal growth restriction (FGR). Background Diabetes mellitus (DM) is the most common medical complication of pregnancy. It is a metabolic disorder characterized by hyperglycemia resulting from relative deficiency of pancreatic insulin production, limited insulin release in response to a carbohydrate (CHO) challenge, or impaired effect of insulin at the cellular level. Clinically, it manifests as hyperglycemia and increased fat and protein catabolism. This may result in ketosis, which progresses to ketoacidosis. Epidemiologic studies have shown that the prevalence of DM diagnosed among women of childbearing age has increased dramatically in the United States and that a substantial proportion of the population has undiagnosed DM, abnormal fasting glucose levels, or impaired glucose tolerance (1). The cause is multifactorial and includes genetic and environmental contributing factors. White Classification of DM during Pregnancy

• The White classification was first proposed by Priscilla White, M.D. in 1932. This classification is only used during pregnancy and is based on the duration of diabetes and the secondary vascular and other end-organ complications (2). Although it is somewhat descriptive of risk and health status, it does not differentiate by underlying pathophysiology (Table 17-1). • The American Diabetes Association Expert Committee categorizes patients by underlying pathogenesis (insulin-deficient type 1, insulin-resistant type 2, and GDM) (3). 279

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Table 17-1 Class A1 A2 B C D F H R T

White Classification for Pregnant Women with DM

Criteria Gestational diabetes (GDM) not requiring insulin or oral agents Gestational diabetes requiring insulin or oral agents Onset at ≥20 y of age or duration of 35 years of age, or for any patient with history or clinical symptoms of cardiovascular disease (including hypertension). • Subsequent laboratory tests to consider include • Prenatal genetic screening options as otherwise indicated. This includes first-­trimester early aneuploidy screening (11 to 14 weeks), Tetra marker analyte screening (15 to 20weeks), and maternal blood–free fetal DNA screening. Maternal serum α-fetoprotein (MSAFP), unconjugated estriol (uE3), and inhibin A that are components of some second-trimester Down syndrome screening tests are significantly reduced in women with diabetes such that the MoM values must be adjusted. Maternal DM does not increase the risk for fetal aneuploidy. • Serial HbA1c assessments every 4 to 8 weeks. • Repeat 24-hour urine collection in the second and third trimester if abnormal on initial evaluation (e.g., if the 24-hour total protein is greater than 300 mg or creatinine clearance is less than 50 mL/min) or if increased proteinuria is noted on urine dipstick evaluations. • Common maternal complications to monitor on follow-up visits include • Hypertension (greater than 140/90 mm Hg) °°Chronic if identified in the first 20 weeks’ gestation °°Possibly preeclampsia if identified in the latter part of pregnancy • Discovery of nephropathy, retinopathy, gastropathy, or neuropathy • Preterm labor +/– polyhydramnios • Increased risk for hypoglycemia and DKA Fetal Evaluation

• Growth and Development: • Dating ultrasound to confirm gestational age as soon as possible. • Ultrasound at 11 to 14 weeks’ gestation for nuchal translucency (if indicated). • Ultrasound at 18 to 20 weeks’ gestation to evaluate fetal morphology. • Fetal echocardiogram at 22 to 23 weeks’ gestation to exclude congenital heart disease. • Ultrasound at 28 to 32 weeks’ gestation to assess fetal growth (macrosomia or FGR) and to assess amniotic fluid volume (polyhydramnios or oligohydramnios). • Ultrasound prior to delivery (38 weeks’ gestation) for estimated fetal weight (EFW) may be helpful in delivery planning. • Fetal Well-Being: • Antenatal fetal testing is recommended as surveillance for potential uteroplacental insufficiency and fetal compromise in diabetic pregnancies requiring insulin or oral agent therapy for glycemic control. • Fetal kick counts starting at 26 to 28 weeks’ gestation. • Fetal testing options are contraction stress test (CST), nonstress test (NST), biophysical score (BPS), and modified biophysical profile (MBPP = BPS + amniotic fluid volume). • Testing should start no later than 32 to 34 weeks’ gestation and should continue until delivery. °°Fetal testing should be individualized. Patients with vasculopathy (e.g., class F, R, H, T) or who develop complications during pregnancy (e.g., hypertension, very poor glycemic control, or FGR) may benefit from fetal testing earlier in pregnancy (26 to 32 weeks). (c) 2015 Wolters Kluwer. All Rights Reserved.

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• The following testing schemes are acceptable: °°CST alternating with MBPP every 3 to 4 days (i.e., on a Monday/Thursday or Tuesday/Friday schedule) has been shown to be an effective method of fetal surveillance for diabetic pregnancies specifically. When CST is contraindicated, is not readily available, or yields an equivocal result, then BPS is an appropriate backup test. °°CST and BPS alternating every 3 to 4 days. °°NST and BPS alternating every 3 to 4 days. °°MBPP alone every 3 to 4 days. °°Note that the testing schemes of alternating NST/BPS or MBPP alone are most commonly used for class A1, A2, B, and C DM (e.g., diabetes without vascular complications). Pregestational Diabetes

Maternal Evaluation

• A comprehensive history and physical should be performed. • Initial laboratory tests should include • Routine prenatal blood tests. • HbA1c should be considered if there is any question that DM may be long-standing and undiagnosed. • Twenty-four-hour urine collection for total protein and creatinine clearance. • Thyroid function tests (TSH and free T4, plus free T3 if indicated). °°Baseline preeclampsia labs if patient has concurrent chronic hypertension. • Subsequent laboratory tests to consider: • Serial HbA1c assessments every 4 to 8 weeks can be helpful if compliance with dietary recommendations and self-monitoring of blood glucose (SMBG) is questionable. • CMP including liver function studies. This is of particular importance when using oral agent therapy in order to rule out underlying liver abnormalities. • Serial prenatal assessments for • Preeclampsia • Preterm labor • Fetal growth disorders • Polyhydramnios Fetal Evaluation

• Growth and Development: • Ultrasound at 28 to 32 weeks to assess fetal growth (LGA/macrosomia or SGA/FGR) and to assess amniotic fluid volume (polyhydramnios and oligohydramnios). • Ultrasound prior to the onset of labor for EFW may be helpful in delivery planning. However, EFW values have a variance of ±15% generally and potentially even greater for a macrosomic fetus. • Antenatal fetal surveillance (using a similar testing scheme as outlined above): • GDM A1 not requiring insulin or oral agents does not require testing prior to 40 weeks’ gestation unless hypertension, polyhydramnios, or fetal macrosomia is present. • GDM A2 requiring insulin or oral agents requires testing starting at 32 to 34 weeks’ gestation. • Fetal kick counts should be encouraged starting at 26 to 28 weeks’ gestation. DIAGNOSIS Overt Diabetes • It is not unusual for undetected, pregestational diabetes to be diagnosed during pregnancy. Any woman with suspected DM when prenatal care begins should be tested immediately to establish the diagnosis. Glycosuria is common but not diagnostic nor necessary for the diagnosis. • The IADPSG (International Association of Diabetes in Pregnancy Study Group) Guidelines states that any one of the following criteria establishes the diagnosis of pregestational DM during the first trimester (Table 17-2): (c) 2015 Wolters Kluwer. All Rights Reserved.

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Table 17-2

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Diagnosing Preexisting Diabetes during Pregnancy

Measure of glycemic control FPG HbA1c Random plasma glucose

Consensus threshold (IADSPG) 126 mg/dL (≥7.0 mmol/L) ≥6.5% (DCCT/UKPDS standardized) 200 mg/dL (>11.1 mmol/L) plus confirmation by FPG or HbA1c

Adapted from The International Association of Diabetes and Pregnancy Study Group (18).

• An early HbA1c of 5.7% to 6.5% or an FPG >92 mg/dL and 200 mg/dL (11.1 mmol/L) has DM and should be referred for further management. A 2-hour value of 140 to 199 mg/dL (7.8 to 11.0 mmol/L) represents impaired glucose tolerance (IGT) or “prediabetes” (80% will develop DM within 5 years). Class A2 GDM • Management includes the same recommendations as class A1, although glucose monitoring is different. Monitor glucose levels after delivery with a fasting and a postprandial glucose level when the patient resumes PO intake. • The scheduled split-dose or basal–bolus insulin or oral agent(s) regimen should be discontinued in the immediate postpartum period. • Administer rapid-acting insulin subcutaneously if preprandial glucose is greater than 180to 200 mg/dL (4 to 6 units of rapid-acting insulin subcutaneously is usually adequate). • If preprandial values are persistently greater than 180 to 200 mg/dL, a split-dose or basal–bolus insulin regimen should be resumed. See recommendations for classes B to T insulin-dependent DM regarding calculation of postpartum insulin dose. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• If the patient was taking oral agent(s) for glycemic control prior to delivery, the medication(s) may be resumed during the postpartum period with persistent hyperglycemia. There are limited data on breast-feeding with acarbose, glyburide, and Glucophage; however, this is not considered a contraindication for term infants (33). Class B to T Diabetes Mellitus • The goal in the first 3 to 5 days after delivery is to avoid hypoglycemia and to reduce the risk of DKA, severe hyperglycemia, and insulin reactions rather than achieving euglycemia. Glucose values of 80 to 160 mg/dL are acceptable. Patients with severe vascular complications may benefit from tighter control. • CII is discontinued immediately after delivery unless the patient is experiencing persistent hyperglycemia (e.g., as occurs with infection or DKA). • IV fluids may be administered as either non–glucose containing or 5% dextrose solutions. After a vaginal delivery, glucose infusion is generally not required because PO intake is resumed almost immediately. The postoperative patient will generally tolerate a 5% dextrose solution at 125 to 150 mL/h without insulin therapy because of the dramatic and rapid onset of postpartum insulin sensitivity. When oral intake resumes, the IV dextrose solution should be discontinued. • Glucose control may be followed by measurement of either fasting and preprandial ­glucose values (better for class C and above) or fasting and 1-hour postprandial values. • If repeated, rapid-acting insulin coverage is needed to treat persistent hyperglycemia (greater than 160 mg/dL); a regular schedule of split-dose or basal–bolus insulin should be resumed. The new TDD of insulin should be either approximately 50% of the prepregnancy dose (if the patient was in good control) or 25% to 33% of the end-­ pregnancy dose. The latter is generally chosen because this is usually more accurate and reflects tighter control. When the patient is ready to resume tighter glucose control, additional insulin can be sequentially added and the level of control gradually improved with a final goal of 80 to 110 mg/dL before meals. Once euglycemia is established, the SRAIS may be used to adjust the insulin dose as needed. Recommendations should be individualized. Breast-feeding • Lactation is an antidiabetogenic factor in which glucose is shunted preferentially for use as energy in milk production. This naturally lowers glucose levels in the mother without requiring increased insulin. Breast-feeding women with overt DM need to adjust insulin doses and meal plan to balance their bodies’ requirements with those of milk production. Breast-fed babies have a much lower risk of developing DM than those exposed to cow’s milk protein (34). • Insulin requirements are usually reduced until lactation ceases and then return to normal levels. Breast-feeding may be contraindicated in the patient with severely complicated DM who cannot tolerate the added stress of lactation or if the patient must take a medication that is contraindicated with breast-feeding. • Calories. To ensure adequate nutrition and avoid reactive hypoglycemia, the lactating mother (especially if insulin requiring) should test the blood glucose prior to breastfeeding. If the level is less than 100 mg/dL, the women should eat a snack (100 to 300 cal) with each nursing period, especially overnight. Meal plans should be individualized, as caloric requirements vary. Particular attention should be given to adequate calories at night to support feeding schedules (especially in pregestational DM patients). Ketonuria should be monitored as needed. • Fluids. Adequate fluid intake of 2 to 3 quarts of liquid (primarily water) per day is needed (8 to 12 cups of liquid in a 24-hour period). The nursing mother should drink 6to 8 ounces during each nursing period.

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COMPLICATIONS Diabetic Ketoacidosis (35) • A medical emergency for both mother and fetus. • Pregnant women with type 1 DM are at increased risk. DKA can on rare occasion also occur in patients with type 2 DM or GDM. • Predisposing factors include decreased buffering capacity (respiratory alkalosis of pregnancy), pregnancy hyperemesis, “accelerated starvation” of pregnancy, increased insulin antagonists (HPL, prolactin cortisol), and stress. • Precipitating factors include illness (gastrointestinal, pulmonary, urinary, or soft tissue infections), eating disorders, or poor compliance with insulin administration. • Prompt recognition of DKA and treatment is imperative in order to protect the fetus and optimize perinatal outcome. • Diagnosis of DKA is usually confirmed with presence of hyperglycemia (glucose greater than 200 mg/dL) and positive serum ketones. DKA in pregnancy, however, may occur with glucose values under 200 mg/dL • The fetus is at high risk until maternal metabolic homeostasis is achieved; high plasma glucose levels and ketones are readily transported to the fetus, which may be unable to secrete sufficient amounts of insulin to prevent DKA in utero. • Protocol for management of DKA: • Search for and treat the precipitating cause (e.g., infection, history of noncompliance). • Fluid resuscitation. Most pregnant women with DKA will have lost 7 to 10 L of free water at the time of diagnosis. Give physiologic fluid (0.9% NaCl) at 1000 mL/h for at least 2 hours. After the initial 2 L, change to hypotonic saline (0.45% NaCl) at 250 mL/h (more similar to electrolyte losses during osmotic diuresis) until serum glucose level is between 200 and 250 mg/dL. Once glucose levels are lower than 250 mg/dL, fluid should be changed to a glucose-containing solution (0.45% NaCl with 5% dextrose). Approximately 75% of fluid replacement should occur during the first 24 hours of treatment. A practical way to estimate the total fluid loss is 100 mL/kg actual body weight. • Potassium depletion with acute DKA can be substantial. With correction of metabolic acidosis, K+ ions shift intracellularly leading to a rapid decline in potassium levels. If serum K+ is low or normal, begin KCl (20 mEq/h) and reduce by 50% if patient is oliguric. • Insert a Foley catheter and monitor fluid balance (I&Os) carefully. • Insulin for correction of hyperglycemia. °°Typically start with 10 to 15 units of regular insulin (0.1 unit/kg) as an IV bolus load. °°Then initiate a CII at 5 to 10 units/h until glucose values are under 250 mg/dL. The goal is to normalize glucose values over a 4- to 8-hour period. Use of computer software–directed insulin infusion algorithms (e.g., Glucommander) when available can optimize glycemic control promptly. °°When glucose level is less than 250 mg/dL, the CII rate should be decreased, usually to 2.0 to 4.0 units/h and subsequently down to the maintenance range of 0.5 to 2.0units/h. Ideally, serum blood glucose levels should decline by 50 to 75 mg/dL/h until euglycemia is achieved. °°CII should be continued until metabolic alterations have been corrected and the patient can resume a regular diet and transition to her usual subcutaneous insulin treatment regimen when acidosis has resolved. °°Preparation of CII solution: 200 units of regular insulin added to 1000 mL normal saline (2 units regular insulin/10 mL normal saline). • Laboratory monitoring and additional tests: °°Hourly with CII for DKA: serum glucose, urine ketones, and serum potassium. °°At longer intervals: serum electrolytes, arterial blood gases, BUN, serum creatinine, blood acetone, CBC, serum osmolality. °°Twelve-lead EKG should be checked if K+ levels are significantly abnormal. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Chronic Hypertension • Hypertension is a common comorbidity of diabetes, which may be found in 20% to 30% of women who have had diabetes for more than 10 years (2). • Current evidence suggests that none of the antihypertensive medications commonly used in pregnancy (calcium channel blockers, β-blockers, methyldopa) are teratogenic, but they should only be prescribed or continued during pregnancy if required for optimization of blood pressure control. • β-Blockers (e.g., labetalol) may blunt the sympathetic response that precedes hypoglycemia in women with pregestational diabetes, and their use is relatively contraindicated. • Certain calcium channel blockers (e.g., diltiazem) may have renal protective benefits and may be an ideal choice for the pregnant patient with overt nephropathy and hypertension. • Angiotensin-converting enzyme (ACE) inhibitors are commonly utilized in nonpregnant patients with nephropathy due to their renal protective benefits. It is not clear whether this class of drugs has teratogenic potential in the first trimester, but usage in the second trimester and beyond can significantly decreased fetal renal blood flow resulting in oligohydramnios and fetal compromise (36). Recent data suggest that in the first trimester, fetal risk from ACE inhibitors may result from hypertension itself rather than ACE exposure (37). Use of angiotensin receptor blockers (ARBs) and receptor antagonists probably carries a similar risk, but limited data are available. Preterm Labor • Tocolytics: • Magnesium sulfate is the preferred IV tocolytic agent for women with diabetes. • Indomethacin (oral or rectal in patients at less than 32 weeks of gestation) as well as nifedipine (until fetal lung maturity is established) have been used successfully with close follow-up. • The use of β-sympathomimetics should be approached with extreme caution because of the attendant risk of hyperglycemia and ketosis. • Steroids to enhance fetal lung maturity also increase the risk of hyperglycemia and ketosis. • The benefits from use must be weighed against the possible adverse effects namely hyperglycemia (which may last several days). • When steroid use is felt to be necessary because of the high likelihood of an extremely premature delivery (less than 30 weeks of gestation), the patient should be hospitalized, glucose levels should be monitored closely, and a CII should be initiated if necessary to maintain glycemic control after steroid administration. • Use of steroids between 30 to 34 weeks of gestation should be carefully individualized. • Beyond 34 weeks, the use of steroids is not recommended, as benefits to the fetus do not outweigh risks to the mother. • Bed rest: • If long-term bed rest is required, a 10% reduction in total calories may be necessary to prevent excess weight gain. • Insulin requirement may also increase due to the lack of physical activity. PATIENT EDUCATION Contraception • Hormonal methods currently available include the combination oral contraceptive pill (OCP), combination contraceptive patch or NuvaRing, the progestin-only OCP, Implanon, and the long-acting progestins given intramuscularly. • Virtually all combination hormonal contraceptives contain a low estrogen dosage of ethinyl estradiol (20 to 40 mg), but the formulations of progestins vary widely. • Breast-feeding women with a history of GDM should be aware that using the progestinonly hormonal contraceptives has been associated with an almost threefold increased risk (c) 2015 Wolters Kluwer. All Rights Reserved.

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for developing overt DM in their lifetime, compared to that seen with combination OCP use; the magnitude of this risk appears to correlate with the duration of uninterrupted use (38). • ACOG recommends that oral contraceptive use in women with DM should be limited to otherwise healthy nonsmokers, less than 35 years old, with no evidence of hypertension, nephropathy, retinopathy, or other vascular disease (39). • Metabolically neutral methods include barrier methods and the intrauterine device (IUD). The same contraindications apply as for patients without DM. Recurrence of GDM and Risk of Overt DM • Risk of recurrence of GDM in subsequent pregnancies has been quoted as 30% to 60%. Patients requiring medication therapy in addition to nutrition management for optimization of glycemic control are more likely to develop GDM in subsequent pregnancies. • Up to 60% of women with a history of GDM will be diagnosed with overt diabetics during their lifetime. Therefore, DM screening every 1 to 3 years should be recommended if the postpartum 2-h 75-g OGTT screen is normal. Having a subsequent pregnancy or 10lb increase from the postpartum weight may increase the risk of overt DM later in life. Conversely, a 10-lb reduction from the postpartum weight may reduce lifetime DM risk by as much as 50% (38). Preconception Counseling for Pregestational Diabetes Despite widespread underutilization, preconception care programs have consistently been associated with decreased morbidity and mortality (30). It is thus very important that women with overt DM postpone conception until glycemic control has been optimized. The following guidelines are recommended for preconception care (30): • Glycemic control should be optimized to achieve euglycemia prior to conception (fasting blood glucose 70 to 99 mg/dL, preprandial values less than 100 mg/dL; 1-hour postprandial guanine, substitutes adenine for glutamic acid. • Hb Sb thalassemia (discussed in previous section). Diagnosis • The course of Hgb S disease prior to pregnancy frequently predicts how the woman will do in pregnancy. Avoid hypovolemia and hypoxemia in any trimester (2) • Genetic counseling and prenatal diagnosis should be offered (28,29) • Hemoglobin electrophoresis is the diagnostic test. • Moderate anemia with irreversibly sickled RBCs on peripheral smear. Normal, target, fragmented, and nucleated cells may also be seen. • Hemoglobin electrophoresis shows greater than 80% hemoglobin S and elevated Hgb F. • Solubility test (e.g., Sickledex) is inadequate for distinguishing between genotypes. Clinical Manifestations

• β-Chain synthesis does not reach sufficient levels to cause symptoms until about 6 months of age. • Children with Hgb SS are at increased risk for certain infections: • Sepsis • Meningitis • Pneumonia • Osteomyelitis • Urinary tract infections • Respiratory manifestations are secondary to vasoocclusion or infection. • Acute chest syndrome: pulmonary infiltrate, fever, pleuritic chest pain, and tachypnea. Treat if infectious, otherwise supportive care with hydration, pain relief, adequate oxygen. • Leading cause of death is from acute chest syndrome or pulmonary embolism. • Cardiovascular manifestations are secondary to the condition’s hyperdynamic state. • Cardiomegaly (50% with left ventricular hypertrophy) • Prolonged PR interval • Increased risk for gestational or worsening pulmonary hypertension, preeclampsia, and intrauterine growth restriction (IUGR) • Frequent complications in pregnancy: (30) • Antepartum admission • Thrombotic events • Placental abruption • Vasoocclusive episodes • Postpartum infections • Vasoocclusive target areas: • Extremities • Lungs • Spleen, splanchnic bed • Kidneys • Brain (CVA, moyamoya) • Eyes (retinopathy) (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Perinatal complications include small-for-gestational age (SGA) neonate, preterm labor, and premature rupture of m ­ embranes (30) In efforts to decrease the likelihood of developing pre-eclampsia, a daily lose-dose (81 mg) aspirin may be considered after 12 weeks gestation. Treatment • Folic acid supplementation of 5 mg/day is recommended. • Iron supplementation is not helpful in treating anemia. Most patients have iron overload due to transfusion history (26). • Sickle cell crises must be treated with generous fluid support, oxygen supplementation, pain management, and blood transfusions as indicated. • Hydroxyurea is an antineoplastic agent that encourages production of hemoglobin, and decreases the severity of sickling and frequency of pain crises. Concerns for fetal toxicity, so controversial in pregnancy. • Blood transfusion to treat vasoocclusive crises and anemia: • Partial exchange transfusion targets a concentration of hemoglobin A greater than 40% to 50% and a hematocrit between 25% and 30%. • Evidence has shown a decrease in number of vasoocclusive crises, but no difference in perinatal outcome (31). • Prophylactic transfusions are not recommended but may be performed in setting of severe anemia (Hgb less than 6), acute chest syndrome, preoperative, sepsis, acute renal failure, or protracted pain crisis. • Transfusion therapy risks include 25% rate of alloimmunization, 20% rate of delayed transfusion reaction, iron overload, and 1:2,000,000 risk of HIV (2,31). Procedures

• Careful monitoring for asymptomatic bacteriuria and urinary tract infections is necessary. • Fetal surveillance should be started in the late second to early third trimester with nonstress tests and sonographic evaluation for growth and amniotic fluid index (AFI). • Labor and delivery are managed on the basis of obstetric principles. • Cesarean section should be performed only for obstetric indications. Regional anesthesia is preferred to general anesthesia. • Venous thromboembolism (VTE) prophylaxis postpartum is recommended. • Influenza vaccine should be within a year and penicillin prophylaxis continued. Administer pneumococcal vaccine every 5 years. Patient Education • Limited evidence of good quality to advise one contraception method over another; however, depot medroxyprogesterone acetate has been suggested to decrease the incidence and severity of vasoocclusive crises. No studies evaluate the risk of thromboembolism with combined hormonal contraception (32). • Permanent sterilization should be considered when the patient has completed childbearing. • Termination of the pregnancy because of maternal sickle cell anemia is largely unwarranted and should be considered on an individual basis. Sickle Cell Trait (Hb SA) Evaluation

• Carriers will be heterozygous for the condition and have one abnormal and one normal β-chain (1:12 African Americans) on Hgb electrophoresis. • Family history is important (28) Clinical Manifestations

• Sickle cell trait is associated with increased rates of pyelonephritis in pregnancy (26). • In one study, carriers had a higher incidence of pyelonephritis despite similar rates of asymptomatic bacteria or acute cystitis compared to normal pregnant women. • Urinalysis should be performed at each visit with urine cultures every trimester. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Patients at increased risk of early spontaneous abortion and multiple gestations but appears to have low risk of preterm delivery at less than 32 weeks (30). • In settings of significant hypoxemia, sickle cell trait may be associated with: • Vasoocclusive disease • Sudden death at high altitudes (e.g., when exercising a mile above sea level or when in a suddenly depressurized aircraft) • Severe concurrent illness (26) Hemoglobin SC Disease • Double heterozygous for hemoglobin S and hemoglobin C • Carrier rates for Hgb C trait in African Americans are 1:30. • Normal life span but subject to rapid and severe anemic crisis from splenic sequestration. Also, increased tendency in those affected to experience bone marrow necrosis with fat-forming emboli. • During pregnancy, Hb SC can behave like SS with an increase in IUGR, PP infection, and antepartum admission. However, patients usually have better perinatal outcomes (1). • Similar in presentation to hemoglobin S/β-thalassemia OTHER ABNORMALITIES IN HEMOGLOBIN RESULTING IN HEMOLYTIC ANEMIA HEREDITARY SPHEROCYTOSIS Background • Autosomal dominant disorder arises from a mutation in erythrocytes’ structural proteins, spectrin and ankyrin. It is the most common cause of inherited hemolytic anemia. • The incidence of the disease is estimated at 1 per 5000 among those of European descent. • The expression of the disorder is due to increased erythrocyte osmotic fragility. Mild cases frequently go undetected until pregnancy (2). Evaluation • Hyperproliferative anemia on CBC and microspherocytes are found on peripheral smear. • Increased erythrocyte fragility in hypotonic saline is noted on osmotic fragility testing. • Hemolytic crisis may be incited by infection, trauma, and pregnancy. Treatment • Most affected patients have undergone splenectomy, and pregnancy outcomes are favorable. • If splenectomy has not been previously done, the treatment of the anemia should be supportive with transfusion as necessary (31). • Folic acid supplementation is given. • Patients are also at risk for cholelithiasis from pigmentary gallstones produced by chronic hemolysis. • The pneumococcal vaccine can be safely given in pregnancy. GLUCOSE 6-PHOSPHATE DEHYDROGENASE DEFICIENCY Background Etiology

• This X-linked disorder promotes a defect in the erythrocyte enzyme G6PD, an essential mediator in the G6PD/NADPH pathway. The pathway is also known as the pentose phosphate pathway and functions to protect the erythrocyte from oxidation. • Makes RBC susceptible to a variety of oxidizing agents: • Analgesics • Sulfa drugs • Antimalarials • Quinines (c) 2015 Wolters Kluwer. All Rights Reserved.

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Epidemiology

• A common enzyme deficiency and can be identified in 10% of African American men but in only 3% of African American women. • Greeks, Sardinians, and Sephardic Jews have more severe hemolysis when exposed to oxidizing agents and fava beans (1). • Closely related to favism, fava bean consumption produces a hemolytic reaction. Evaluation • Female heterozygous activity varies (Lyon hypothesis) but usually is intermediate in severity (2). • Pregnant women may be predisposed to miscarriage, IUGR, and hemolytic episodes in the third trimester. • Urinary tract infections may be more common, and it may be prudent to screen patients at risk for the disorder before treatment. • Heterozygotes may experience symptoms if a male fetus is affected by disease. • The affected fetus is at risk for neonatal jaundice from chronic hemolytic anemia. • Hydrops may result • Breast-fed infants may be at risk if exposed to oxidants or fava beans ingestion by the mother (1). Treatment Hemolytic episodes during pregnancy require a prompt discontinuation of the causative medication. • Transfusion support as warranted. Patient Education • Screening by PCR for the defect should be considered before treating a patient at-risk. • Screen the newborn infants at-risk in setting of hyperbilirubinemia. • Genetic counseling should be offered (28) AUTOIMMUNE HEMOLYTIC ANEMIA Background • Warm-reactive antibody (IgG) are directed against Rh factors on the erythrocyte’s surface. • Cold-reactive antibody (IgM), usually anti-I or anti-i, also targets the RBC surface but differs from IgG pathophysiology: • A combination of intra- and extravascular hemolysis. More commonly extravascular hemolysis from complement activation (2) • Demonstrates little affinity at the physiologic temperature of 37°C Etiology

• Most causes in women are idiopathic; however, pregnancy is an associated factor. • Warm antibodies may be seen with malignancy (chronic lymphocytic leukemia [CLL], lymphoma) SLE, viral infection, and drug ingestion (i.e., penicillin, α-methyldopa). • Cold antibodies may be seen with mycoplasma infections, infectious mononucleosis (Epstein-Barr virus [EBV]), and lymphoreticular neoplasms. Diagnosis • Mild to moderate macrocytic anemia with leukocytosis, and reticulocytosis; peripheral smear demonstrates microcytes, poikilocytosis • Positive direct and/or indirect Coombs test • May be seen in conjunction with thrombocytopenia (Evans syndrome) (2) Treatment • Glucocorticoids, intravenous immunoglobulin (IVIG) for severe cases, and supportive transfusion as needed. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Splenectomy is an alternative treatment for warm agglutinins. If refractive to splenectomy and steroid therapy, immunosuppression is the next line of therapy. • Hydration and maintaining body temperature are important with cold-reactive antibodies. • Plasmapheresis or immunosuppression may be required in severe cases. THROMBOCYTOPENIA Background • Platelet counts are decreased in pregnancy. The etiologic mechanism is unclear; possibly related to the physiologic autoimmune state of pregnancy. Severely, low levels should be evaluated for other etiologies. Etiology

• Due to the natural decline in pregnancy, gestational thrombocytopenia is very common in pregnancy. It accounts for approximately two-thirds of thrombocytopenia cases (33). • Patients are usually asymptomatic and platelet counts rarely drop below 70,000 cells/μL. These patients are not at risk for any further sequelae. • Platelet count normalizes within 1 week after delivery, 3 months at the most. • Regional anesthesia usually given at counts greater than 70,000. • Pathogenic thrombocytopenia generally results from inadequate production, increased consumption, or increased destruction of platelets. • Inadequate production from nutritional deficiency, congenital thrombocytopenia, aplastic anemia, and infiltrative bone marrow malignancies are examples. • Increased consumption occurs in disseminated intravascular coagulation (DIC). • Increased destruction as a result of acquired, autoimmune, or viral causes: °°Antibodies directed against the platelets (idiopathic thrombocytopenia purpura [ITP]) °°Thrombotic thrombocytopenia purpura (TTP)/hemolytic uremic syndrome (HUS) °°Certain drugs (heparin, quinidine) °°HIV °°Autoimmune conditions (SLE) °°Antiphospholipid syndrome (APS) ACQUIRED CAUSES OF THROMBOCYTOPENIA Idiopathic Thrombocytopenia Purpura

Etiology

• Most common cause of thrombocytopenia during the early trimesters and most common autoimmune disorder in pregnancy (34). • Thrombocytopenia a result of destruction mediated by antibody binding; destruction outperforms new platelet production. Evaluation Clinical Manifestations

• Based on personal history of bleeding or excessive bruising • Since IgG is selectively transported across the placenta, fetal thrombocytopenia may be present. • Corticosteroid and IVIG are not effective in reducing rate of occurrence. °°Maternal platelet count is not directly proportional to fetal counts; however, procedures to evaluate fetal platelet counts complications outweigh any theoretical benefit of information. These procedures have not been shown to demonstrate reduction of neonatal bleeding episodes. • Fetal complications from ITP are usually mild and transient. • DDX: NAIT (neonatal alloimmune thrombocytopenia), a condition resulting in maternal autoimmunization against fetal platelet antigen. (c) 2015 Wolters Kluwer. All Rights Reserved.

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°°Most

common cause of NAIT is sensitization against HPL 1a (PLAT or Zwa). The clinical ­manifestations are profound; severe thrombocytopenia, ecchymosis, ­petechiae, and intracranial hemorrhage in 10% to 20% of cases (34). °°Cordocentesis is indicated in this condition to determine fetal platelet count. IVIG has been shown to be effective and mode of delivery should be by cesarean. Laboratory Tests

• Platelet count less than 100,000 cells/μL, peripheral smear with enlarged platelets • Antiplatelet antibody assays are not specific enough to be diagnostic and is not recommended for routine monitoring Treatment • Current management focuses on glucocorticoid administration (1 mg/kg/day), IVIG, platelet transfusion prior to surgery or for acute bleeding, and splenectomy in refractory cases (34). • Platelet counts greater than 50,000 cells do not require treatment is experts’ consensus; however, what is unclear is the platelet level for prophylactic replacement in pregnancy. • Counseling prior to steroid treatment should include disclosure about weight gain, bone loss with prolonged usage, worsening hypertension, and onset of hyperglycemia. Steroid effects are usually seen in 3 to 7 days and last for 2 to 3 weeks but are still a short-term therapy. • IVIG reduces antiplatelet antibody production and binding; however, it is associated with high cost, headache, nausea, elevated liver transaminases, transient neutropenia, and a severe anaphylactic reaction in IgA-deficient persons. • If splenectomy is indicated, the procedure is usually performed after the second trimester. • Rituximab, a monoclonal antibody treatment, has been suggested as an alternative first line of therapy for chronic and refractory ITP adult patients. • FDA class C, although some case series demonstrates a safe use of rituximab in pregnancy. °°Further prospective studies are needed to evaluate efficiency and maternal and neonatal safety. Some cancer studies have demonstrated an initial suppression of B-lymphocyte development but a return to normal by 6 months of age. Thrombotic Thrombocytopenia Purpura/Hemolytic Uremic Syndrome

Etiology

• Microangiopathic condition usually developing in the second or third trimester. It initiates a cascade of thrombocytopenia, hemolytic anemia, and end-organ failure. • End-organ damage is secondary to ischemia from numerous consolidations of intravascular platelet plugs. • TTP associated with autoimmune disorders, female sex, recent viral illness, and pregnancy. HUS has also been associated with recent Escherichia coli O157:H7 infection, chemotherapy, and bone marrow transplants. • The condition has a high recurrence rate of 50% in subsequent pregnancies (35). Evaluation Clinical Manifestations

• TTP manifests as a triad with severe thrombocytopenia, CNS disturbances (i.e., headaches, altered consciousness, sensory motor defects, seizures), and hemolytic anemia. Itcan easily be confused for HELLP especially in someone with chronic hypertension. • Lactate dehydrogenase (LDH)-to-aspartate aminotransferase (AST) ratios may be helpful, as concurrent preeclampsia will exhibit two to four times higher AST values and have lower total LDH-to-AST ratios. • Up to 80% will have renal dysfunction confusing the diagnosis further (35). (c) 2015 Wolters Kluwer. All Rights Reserved.

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• HUS manifests as a pentad with severe thrombocytopenia, CNS disturbances, renal dysfunction, fever, and hemolytic anemia. • High maternal and neonatal morbidity. Most occur in the postpartum period as acute renal failure. Chronic kidney insufficiency in 25% of patients and neonatal morbidity is related to maternal status and prematurity. Laboratory Tests

• CBC will demonstrate low hemoglobin and low platelets with a peripheral smear confirming hemolysis with schistocytes, helmet cells. • ADAMTS13, a von Willebrand factor (vWF) protease, that clears abnormal large-sized vWF and prevents intravascular platelet agglutination, has been shown to have decreased activity in TTP. No role for ADAMTS13 has been found in HUS (36). Treatment

• Plasmapheresis is the gold standard of care to remove precipitating factors from serum. • Corticosteroids may also be given to encourage response to the plasmapheresis. • Platelet transfusion is not recommended, as it will perpetuate the condition. If active bleeding present, factor/platelet-deficient fresh frozen plasma (FFP) may be given (33). Disseminated Intravascular Coagulation (DIC) Etiology

• There are many diverse causes of DIC (37). • In abruption placenta, the bleeding diathesis results from consumption of fibrinogen and platelets in the retroplacental clot as well as activation of the fibrinolysis system. • In septic abortion or a retained IUFD, decomposition of the fetus and placenta causes passage of thromboplastic material into the maternal circulation initiating a consumptive coagulopathy. • In a severe intrauterine infection due to gram-negative or anaerobic bacteria, endotoxin activation of the coagulation system perpetuates DIC events. The release of microthrombi can cause end-organ ischemia. • DIC implies a general intravascular activation of the coagulation, platelet, and fibrinolysis systems (34). Evaluation Clinical Manifestations

• The range of presentations is highly variable and depends on the etiology. Laboratory Tests

• Depending on the severity, any of the following can be seen: • Decreased hemoglobin–hematocrit • Decreased platelet count • Prolonged partial thromboplastin time (PTT) • Prolonged bleeding time • Decreased fibrinogen • Elevated fibrin degradation products (FDPs) • Fibrinogen levels will fall precipitously prior to the appearance of significant thrombocytopenia. • The degree of laboratory abnormalities does not always correlate with the clinical picture. Treatment

• Definitive management requires evacuation of the uterus to stop release of tissue thromboplastin and coagulopathy cycle. • In some situations, supportive therapy may be necessary with ventilator support, circulatory support with vasopressors, and replacement of products as needed. • Hypofibrinogenemia is managed by transfusions of FFP or cryoprecipitate. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• In situations of severe thrombocytopenia (platelet count below 50,000 per mL), platelet transfusions are indicated. Preeclampsia Etiology

• Thrombocytopenia may be present in up to 50% of pregnancies complicated by preeclampsia (33). • May develop during the postpartum period • A severe variant of preeclampsia, HELLP syndrome: °°Hemolysis (peripheral blood smears with schistocytes and increased LDH) °°Elevated liver enzyme test (greater than 2 SD or 70 units/L) °°Low platelets (less than 100,000 cells/μL) °°Similar findings in TTP-HUS (35) • Endothelial wall damage causes fibrin deposits (especially in the glomerular capillaries of the kidneys) and arteriolar spasm from platelet release of serotonin and ADP: • Platelet adhesion and consumption • Hemolytic anemia • Generally, consumption of coagulation factors has not been demonstrated. In fact, evidence of hypercoagulability exists with increased fibrinogen levels and elevated fibrin degradation products (35). Treatment Procedures

• Delivery with removal of the placenta is the definitive treatment for preeclampsia–eclampsia. • Thrombocytopenia will spontaneously resolve in the following days after delivery and platelet transfusions are rarely indicated. • Steroid administration’s efficacy to boost platelet recovery is uncertain, but it does appear to temporarily improve laboratory abnormalities. Acute Fatty Liver Etiology

• A very rare cause of thrombocytopenia in pregnancy (1/16,000). Usually presents in the third trimester and is more common in multiple gestations (38). • Fatty infiltrates in the liver and kidney microvascular impair function and create a cascade of disseminated problems. • More than half of cases also have concurrent preeclampsia (35). Evaluation Clinical Manifestations

• Clinical manifestations of nausea/vomiting, epigastric pain, anorexia, and jaundice progress to renal dysfunction (diabetes insipidus), elevated liver enzymes, hypoglycemia, and bleeding. Renal failure, coagulopathy, ascites, and encephalopathy are late findings (35,39). • Active bleeding results from deficiency of coagulation factors secondary to impaired hepatic function and acquired antithrombin deficiency. Laboratory Tests

• CBC with mild leukocytosis (greater than 15,000), low platelets, and moderately elevated LFTs (greater than 300 international units/dL) are evident; significant elevation in alkaline phosphatase and conjugated bilirubinemia, profound hypoglycemia, and metabolic acidosis on blood gas are also demonstrated (35). • Liver biopsy is not required for definitive diagnosis, but histologic finding in AFLP is diffuse low-grade centrilobular microvesicular fatty infiltrates. • Computer tomography (CT) is more sensitive than ultrasound or magnetic resonance imaging (MRI) in detecting fatty infiltration, but all imaging methods lack good predictive value to be used as a definitive modality. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Treatment Procedures

• Expedient delivery necessary for maternal recovery. • Supportive care is the mainstay for treatment in AFLP. The focus is on strict fluid balance, correction of coagulopathy, hypoglycemia surveillance and treatment, and prophylactic broad spectrum antibiotic coverage including antifungal (38). • Plasma exchange is effective short-term therapy to sustain liver function and enable hepatocellular regeneration. Results are transient but allow time until liver transplant (40). • Liver transplant is not necessary in most cases as hepatic function usually recovers spontaneously (38). MECHANISMS OF NORMAL HEMOSTASIS Background • Hemostasis is a complex process involving three interacting systems: • Platelet function • Coagulation factors • Fibrinolysis • Coagulation factors widely vary during pregnancy: • Factor VIII, fibrinogen, VII, and X are all increased. • No consistent changes in V or prothrombin. • Protein S is decreased. • Regulation of the process involves both promotion and inhibition to ensure optimal conditions. Abnormalities in either can lead to a bleeding diathesis or thrombus formation (41). • The relative stasis of circulation leading to “hypercoagulability” and anatomic changes of pregnancy increase the risk of venous thrombosis. PLATELETS Physiology • Vascular damage leads to exposure of thromboplastic elements, vWF, GpV1, or GpIa-IIa (α2β1 integrin), and cause platelets to adhere to exposed collagen. • vWF and platelets interact via the glycoprotein Ib/IX/V complex receptor. • Platelets may also directly adhere to subendothelial tissue by GpIa–IIa or GpV1. • Once adherent to the damaged vasculature, the platelets are activated, assemble together, and prompt the coagulation cascade. • GpV1, TXA2, and ADP all play a role in activation. • Thrombin also plays a role, after binding to protease-activated receptor 1 and 4 (PAR1, PAR-4). • GIIb/IIIa binding with fibrinogen is most important in platelet aggregation. • Factors contained in α-granules promote further aggregation or clotting. • Formation of the platelet plug is the first step in obtaining hemostasis. COAGULATION FACTORS Physiology • Soluble plasma proteins interact to provide fibrin deposits where the platelet plug has formed. • Coagulation enzymes, initially present in proenzyme forms, are activated; this catalyze and amplify activation of other cofactors. • The resulting cascade ultimately leads to formation of thrombin (Fig. 19-1). • Thrombin converts fibrinogen to fibrin, in addition to activating factors V, VIII, VII, XI, and XIII in the cascade. • The soluble fibrin monomers are stabilized by cross-linking into fibrin polymers (mediated by factor XIIIa) and bind to the platelet plugs. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Figure 19-1. The classic coagulation cascade. The intrinsic system is activated by endothelial damage and is reflected by measurement of the partial thromboplastin time (PTT). The extrinsic system is activated by tissue damage and is reflected by measurement of the prothrombin time (PT). Proenzymes are generally cleaved to make the activated form (e.g., II → IIa), and these often catalyze the conversion of other proenzymes.

• The coagulation cascade can be initiated by an intrinsic or extrinsic pathway. The actual process is less separate than implied, and the final product is an interaction between both. • The intrinsic pathway is so named because all necessary elements exist in the plasma. °°The intrinsic pathway contains factors XII, XI, IX, and VIII. • The extrinsic system is activated by factors available from adjacent activated platelets activated on the cell membrane and “extrinsic” to the circulating blood. °°Primary instigator is the exposure of tissue factor (TF) after injury so that it is available to bind circulating factor VII. °°The extrinsic pathway contains tissue thromboplastin and factor VII. • Merging of the intrinsic and extrinsic pathways forms the common pathway, which contains factors X, V, prothrombin time (PT), and fibrinogen and leads to the generation of fibrin. • Main screening tests of the coagulation cascade reflect these pathways: • The PTT reflects the intrinsic system. • The PT reflects the extrinsic system. • Regulation of the system involves a delicate balance of activation and inhibition. • Extrinsic pathway activation is time sensitive. Tissue factor pathway inhibitor (TFPI) binds factor Xa, and the complex inhibits the TF–factor VII complex. The intrinsic pathway is then charged with further coagulation by formation of IXa. • Antithrombin III is the best known inhibitory protein, because of its potentiating interaction with heparin in inhibiting Xa and thrombin. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Z-dependent protein inhibitor–protein Z inhibits Xa as well. • Protein S and protein C inactivate factors Va and VIIIa, mediated by thrombin. • Similar thrombin-mediated mechanism of inhibition by α2-microglobulin and heparin cofactor II. • In normal pregnancy, factors VII, VIII, X, fibrinogen, and vWF are all elevated, resulting in a procoagulant state (42). FIBRINOLYSIS Background Etiology

• Fibrinolysis limits the size of the fibrin clot formed. • The release of tissue plasminogen activator (tPa), in the presence of fibrin, converts plasminogen to plasmin. • Plasmin lyses the fibrin clot into degradation products and along with urokinase-type plasminogen activator (UPA) restores fluidity to the blood. • Inhibitory factors, PAI-1, PAI-2, and TAF1 all play a role to counterbalance. • Defects in this system can lead to thrombotic complications or premature clot dissolution causing delayed bleeding. DISORDERS OF HEMOSTASIS • The ability to maintain hemostasis when challenged by vaginal delivery or cesarean ­section is the physiologic goal during pregnancy. • Patients with congenital disorders predisposing them to hemorrhagic or thromboembolic events may or may not be diagnosed prior to pregnancy (42). Evaluation

History and Physical

• An assessment of the patient’s experience with hemostatic challenges, that is, surgery or trauma, should be obtained during the initial prenatal evaluation. • The pattern of bleeding should guide the appropriate investigation. • Abnormal bleeding after a dental extraction, especially if delayed or a blood transfusion required, may indicate a bleeding disorder. • Platelet deficiency, either in number or in function, will frequently manifest by m ­ ucosal bleeding either spontaneously or with minor challenges (41): °°Epistaxis °°Gingival bleeding °°Gastrointestinal bleeding °°Menorrhagia, especially at menarche • Hemarthrosis or deep muscle hematomas are characteristic of coagulation factor deficiencies. • Bleeding problems may be immediate or delayed even if adequate hemostasis was obtained at the time of surgery. • Disorders of fibrinolysis are suggested in the following situations: • Delayed bleeding • Poor wound healing • Unexplained thromboembolic events • Patients may have an exaggerated response to aspirin or other nonsteroidal anti-inflammatory drugs. Laboratory Tests

• Laboratory evaluation should be triggered by an abnormal bleeding history and focused on those hemostatic elements most likely to be abnormal. • Routine lab studies beyond PT and PTT and platelet count have a very low yield in the absence of an abnormal history and are not necessary before routine procedures. (c) 2015 Wolters Kluwer. All Rights Reserved.

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ACQUIRED DISORDERS OF HEMOSTASIS Etiology • There are multiple sources of disordered hemostasis: • Hepatic dysfunction • Vitamin K deficiency • Anticoagulant medications • Antibodies to coagulation factors • Hematologic malignancies • Platelet disorders • Disseminated intravascular coagulation CONGENITAL DISORDERS OF HEMOSTASIS von Willebrand Disease Background

• The most common congenital bleeding disorder affecting 1% of the population. • Primarily an autosomal dominant condition. • vWF is responsible for platelet adhesion to the damaged endothelial surface. • Deficiency or activity dysfunction leads to platelet dysfunction and resulting bleeding diathesis. • Complexes with factor VIII procoagulant • Factor VIII is also carried by vWF; a deficiency in the vWF will lead to a deficiency in factor VIII (similar to hemophilia). • The etiology of the condition varies. • Type I, a quantitative deficiency of normal factor, is the most common type, accounting for about 80% of cases. • Type II results from a qualitative deficiency and consists of four subtypes (34). °°Type IIA form large and intermediate vWF multimers with a decreased affinity for platelets. °°Type IIB is characterized by increased affinity for GpIB thus platelets and promotes rapid clearance from plasma. --DDAVP is contraindicated and leads to thrombocytopenia. °°Type IIM has a reduced interaction for GpIb on platelets. °°Type IIN is characterized by impaired binding to factor VIII. • Type III is a rare autosomal recessive disease characterized by absent vWF. Evaluation Clinical Manifestations

• Uncertain clinical spectrum ranges from subclinical to severe. • The condition may not become apparent until the patient undergoes surgery or becomes pregnant. • Classically, the signs that lead to the diagnosis of von Willebrand disease are: • Positive family history • Positive personal history of excessive bruising or bleeding, especially at menarche • Peripartum complications may include postpartum hemorrhage, perineal hematomas, surgical site bleeding, and anesthesia complications. Laboratory Tests

• As previously noted, the coagulation factors, vWF and factor VIII, are frequently elevated in pregnancy. Patients with von Willebrand disease will often experience amelioration in their condition because of an elevation in these factors. • If the disease is mild, the elevation may be sufficient to raise both ristocetin cofactor and factor VIII to normal levels. • As the disease becomes more severe, this elevation in the factors may not be sufficient to provide normal hemostasis. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Characteristic of vWD is a prolonged bleeding time and PTT. • Only if the factor VIII level is less than 25% to 30% will the PTT be prolonged. • Similarly, the vWF must be less than 30% to cause a prolonged bleeding time (43). • If both are normal and suspicion continues, then one can check a specific vWF panel, which usually consists of • Plasma vWF antigen • Ristocetin cofactor activity • Factor VIII coagulant activity • Multimeric analysis • Be aware that these factor levels can vary greatly from day to day. • Repeat testing in the third trimester may be required to demonstrate an abnormality. • Patients with von Willebrand disease may also be monitored with serial bleeding times. • If the bleeding time is normal at term and factor VIII coagulant activity is at least 30% to 40%, no special treatment is required (43). • If the bleeding time is elevated to greater than 20 minutes, then therapy should be initiated in the expectation of delivery. • The most important assay for the functional activity of vWF is based on the antibiotic ristocetin to initiate platelet agglutination. • The ristocetin test best approximates the level and function of vWF to cause platelet adhesion in vivo to the damaged endothelial surface. • It also correlates well with clinical bleeding and a prolonged bleeding time. • Electrophoresis may also demonstrate abnormalities in the vWF protein. Treatment Medications

• Desmopressin (DDAVP), a synthetic vasopressin, causes release of stored vWF from the endothelial cells. • No adequate and controlled studies are available regarding DDAVP use in pregnancy, although it has been used without deleterious effects (43). • The max dose of DDAVP is 0.3 μg/kg by slow IV infusion in active bleeding. • Variable response so should test during an in emergent situation. Consider for prophylaxis prior to any procedure if factor VIII or vWF is less than 50 international units/dL. • Daily administration may result in water intoxication, hyponatremia, hypertension, and tachyphylaxis. • vWF concentrate (Humate-P in the United States). • Fifty to sixty units per kilogram is administered over 10 minutes and can be repeated every 12 hours. • The risk of virus transmission is greatly reduced by a pasteurization process. • Indicated for types IIb and III as those are unresponsive to DDAVP. • If neither of these is appropriate or available, then cryoprecipitate 0.24 bags per kg at the onset of labor, followed by 0.12 bags per kg every 12 hours for up to 7 days, may be used in an emergency (Table 19-2). Risk Management

• Patients with von Willebrand disease are candidates for the hepatitis B vaccine because they are at risk for numerous transfusions of blood products. • Newborns born to mothers with severe types are at risk for intracranial hemorrhage (ICH). Delivery mode has not demonstrated an improvement in prevention of this condition, but operative deliveries should be avoided. Male infants’ von Willebrand status should be confirmed prior to circumcision. • If regional anesthesia is performed, DDAVP prophylaxis should be given and the epidural catheter should be discontinued as soon as possible given the risk for postpartum bleeding. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Table 19-2 Plasma product Fresh frozen plasma (1 unit = 250 mL)

Components Plasma, fibrinogen, antithrombin III, all coagulation factors (high concentration of factors V and VIII)

Use Use immediately after thawing or store at 1°C–6°C for up to 24 h

Cryoprecipitate (concentrate of factors as result a slow controlled thaw of FFP)

Fibrinogen, vWF, factor VIII, factor XIII, and fibronectin An assumption of 80 international units of factor VIII and 150 mg of fibrinogen per unit will help determine the number of units needed for transfusion Plasma and all factors except contain decreased levels of fibrinogen, factor VIII, factor XIII, and vWF

Use within 6 h postthawing

Cryoreduced plasma

Stable for up to 5 y (at or below −20°C)

Indications Massive transfusion, bleeding in setting of coagulopathy, heparin reversal, alternatives in specific factor deficiencies Active hemorrhage or preprocedure prophylaxis in patients with significant hypofibrinogenemia ( the 99th percentile), present on two or more occasions, at least 12 wk apart Antiphospholipid antibody syndrome (APS) is present if at least one of the clinical criteria and one of the laboratory criteria that follow are met. Adapted from Miyakis S, Lockshin MD, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295–306.

a

ANTICOAGULANT MEDICATIONS Background Etiology

• Indications in pregnancy for anticoagulation include a preexisting condition, such as a prosthetic heart valve, previously diagnosed inherited thrombophilia, or an acute antepartum thromboembolic event in the current pregnancy (41). • Anticoagulant medications have the potential for significant complications in pregnancy, and their use must be carefully regulated. Clinical practice guidelines during pregnancy are guided by prior history of VTE, presence of an inherited thrombophilia, or additional high-risk factors (55). • Warfarin is an oral vitamin K antagonist. It suppresses the intrinsic coagulation pathway and is largely contraindicated in pregnancy due to teratogenicity and fetal hemorrhagic complications. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Indications for Antiphospholipid Antibody Testing

Recurrent spontaneous abortiona Unexplained second- or third-trimester fetal death Severe preeclampsia prior to 34 wks’ gestation Unexplained venous thrombosisb Unexplained arterial thrombosis Unexplained stroke Unexplained transient ischemic attack or amaurosis fugax Systemic lupus erythematous or other connective tissue disease Autoimmune thrombocytopenia Autoimmune hemolytic anemia Livedo reticularis Chorea gravidarum False-positive serologic test for syphilis Unexplained prolongation in clotting assay Unexplained severe IUGR Three or more SAB with no more than one live birth. Superficial venous thrombosis is not included in the clinical criteria.

a

b

• Warfarin crosses the placenta. Congenital anomalies may occur with exposure anytime during pregnancy but is most common with in utero exposure between 6- and 13-week gestation. Substitution of heparin prior to 6 weeks eliminates the risk of embryopathy. °°Warfarin embryopathy is associated with nasal hypoplasia and/or stippled epiphyses in the first trimester exposure and dorsal/ventral midline dysplasia leading to optic atrophy, mental retardation, spasticity, and hypotonia with exposure in any trimester. In one-third of embryopathy cases, limb hypoplasia is present (56). • Warfarin has been found not to pass into breast milk in nursing mothers, so breastfeeding is safe postpartum. • Use should be restricted to those situations in which long-term therapy with heparin is not possible or has significant deleterious consequences, that is, the presence of mechanical heart valves. • Heparin does not cross the placenta and is the preferred anticoagulation therapy in pregnancy (57). • Unfractionated heparin has the advantage of being reversible. Four hours after discontinuation, the anticoagulation effect is nearly absent. A more rapid reversal can be obtained by use of protamine sulfate. • Recent studies, some of them conducted on pregnant women, suggest that LMWHs are comparable if not superior in safety and efficacy to traditional unfractionated heparin in the treatment and prevention of VTE (56). • Long-term therapy with higher doses of heparin can cause osteoporosis as well as increase the risk of maternal hemorrhage. HEMATOLOGIC MALIGNANCIES • Nonspecific symptoms of the malignancy may delay diagnosis during pregnancy as they are often mistaken for normal physiologic occurrences of pregnancy. • Diagnostic procedures are safe during pregnancy; however, some staging modalities, that is, positron emission tomography (PET) scans, should not be utilized. • Management decisions are difficult and must consider the risk to mother for delay of treatment and fetal risk with treatment. • Expectant management is reasonable in chronic or indolent malignancy. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• In aggressive types or in setting of progressing disease, therapy delay until the second trimester may not be feasible. • Considerations of management (58): • All systemic therapies cross the placenta. • Although increased metabolism is suspected with normal physiologic changes of pregnancy, no current evidence supports adjusted dose in pregnancy. • In the first trimester, the risk of fetal malformation and spontaneous abortions (SAB) are increased. Counseling should involve consideration of pregnancy termination, especially if antimetabolite or alkylating agent is indicated. • In the second and third trimester, treatment appears to be safe in pregnancy. IUGR, prematurity, and neonatal complications of bone marrow suppression and sepsis may occur. • Radiation should be limited to deliver a total fetal dose of less than 0.1 Gy (10 rad). • No long-term adverse effects on childhood malignancies or childhood development are reported. • Specific cytotoxic drugs may be excreted into breast milk and to the fetus, so breastfeeding may be contraindicated. • During the initial year after treatment, conception for subsequent pregnancies may be delayed. • Most treatment protocols are based on experts’ opinion due to the limited pregnancy safety data from randomized trials in this setting. • Prophylaxis for thromboembolism indicated given the extreme increase in hypercoagulability as a result of the pregnancy and compounded by malignancy. • Nutritional support, including total parenteral nutrition, is usually reserved for compromised patients. • Granulocyte colony–stimulating factors (G-CSF) and recombinant erythropoietin may be used for prolonged or severe myelosuppression in pregnancy. • Reproductive counseling should advise to avoid pregnancy in the immediate 2 to 3 years after diagnosis and treatment, as relapse is more common during this time. Progesteroneonly agents are the safest for contraception. LYMPHOMAS • Lymphomas are subdivided into Hodgkin (HL) and non-Hodgkin lymphoma (NHL). Hodgkin Lymphoma (HL) Background

• Forth most common malignancy in pregnancy (1:1000 to 6000) • Concurrent pregnancy frequency is likely a consequence of high prevalence during the reproductive ages, especially the nodular-sclerosing subtype. • Two types of HL: classical HL and nodular lymphocyte–predominant HL. • Classical HL is the most common and consists of four subtypes: nodular sclerosing, mixed cellularity, lymphocyte depleted, and lymphocyte rich. • Nodular lymphocyte–predominant HL is rare and only comprises 5% of patients diagnosed with HL. • Clinical presentation is variable but usually related to spread of the increasing lymphadenopathy of the neck, mediastinum, and axilla. It ultimately progresses below the ­diaphragm and may spread to extralymphatic tissues. • Prognosis and treatment are largely based on the stage at the time of presentation and are similar to nonpregnant women. Potentially curable in most cases even at advanced stages. Etiology

• Still relatively unknown, proposed to be associate with a viral etiology. Genetic, environmental, and autoimmune-related factors have also been discussed. • Those with a prior EBV-related mononucleosis have a two- to threefold risk of developing HL; however, only 20% to 40% of HL tumors contain EBV genome. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Diagnosis

• Giant cells derived mainly from B cells infiltrate the affected tissue. These giant cells are called Reed-Sternberg cells. • Reed-Sternberg cells are only present in up to 1% of affected tissue; therefore, fine needle aspiration may miss abnormal cells. Bone marrow or lymph node biopsy is recommended for diagnostic purposes. • B-cell component relates to the symptoms of fever, night sweats, and greater than 10% weight loss that may develop. • Staging of HL with the Ann Arbor staging system is a description of number and position of lymph nodes involved. • Staging evaluation to determine the extent of disease is primarily radiologic, as laparotomy with splenectomy is now rarely done. • Conventional staging in nonpregnant women is bone marrow biopsy, CT of the chest/ abdomen/pelvis, and PET scan. • Staging in pregnancy is performed by CT of the chest only with abdominal shielding along with MRI for postdiaphragmatic disease. PET scan is withheld until after delivery and likely posttreatment to evaluate treatment response. • Even in setting of disseminated disease, precise staging in pregnancy is unwarranted because multiagent chemotherapy is the first-line therapy at all stages. Treatment

• First-line treatment: ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) • Large case series demonstrate increase in fetal malformations if chemotherapy is administered during the first trimester but no significant adverse outcomes when administered in the second or third trimester (58). • If delaying treatment until the second trimester compromises maternal outcome, termination of pregnancy should be considered and treatment started immediately. • Once favored for early-localized disease above the diaphragm, radiation therapy with abdominal shielding is no longer recommended because of risk of fetal teratogenicity and potential under treatment. Non-Hodgkin Lymphoma (NHL)

Background

• Less common malignancy that occurs on a spectrum from indolent to aggressive lymphomas and includes all other lymphoid malignancies of B-cell, T-cell, NK-cell, or plasma cell origin. • Rising prevalence due to increasing maternal ages, general increase in NHL disease, and growing incidence of HIV-associated NHL. • Approximate classifications: • High-grade aggressive disease: Burkitt’s, primary mediastinal B cell, mantle cell lymphoma, and large B cell • Intermediate-grade aggressive disease: T-cell lymphoma, diffuse B-cell lymphoma °°Diffuse B cell is the most common (30% to 40%) of NHLs and occurs at all ages. • Indolent diseases, that is, follicular or marginal zone lymphoma and multiple myelomas, are seen in older age groups. Diagnosis in pregnancy is associated with a poor prognosis. • In this heterogeneous group of lymphomas, therapy and prognosis are dependent on histology. Cure rates decrease as stage of disease advances. • Some NHL types express hormone-related receptors in reproductive organs, which contribute to disease progression and tumor growth at a higher rate than age-matched nonpregnant women. • Burkitt’s lymphoma is mostly known for this phenomenon and is the second most common NHL. Characterized by rapid tumor growth, increased CNS and bone marrow involvement, and increased risk for tumor lyses and relapse. (c) 2015 Wolters Kluwer. All Rights Reserved.

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°°Burkitt’s lymphoma is responsible for almost half childhood lymphomas. Although a

lower incidence in adults is noted, the median age in adults (30 years) makes occurrence in pregnancy possible. • The overall 5-year relative survival rate in NHL is 69.3% (59). Etiology

• Multifactorial as environmental, genetics, and chronic immune stimulation may all play a role in development (60). Diagnosis

• Lymphoma does not affect the course of pregnancy, and the pregnancy does not impact the course of the lymphoma. • Presentation varies based on subtype, and involvement of extranodal sites is more common than HL (61). • Diffuse lymphoma presents with B symptoms, lymphadenopathy, mediastinal mass, and extranodal site involvement. • Burkitt’s presents with signs and symptoms of intra-abdominal masses consequential of extranodal site involvement. • Large B-cell lymphoma commonly manifests as superior vena cava syndrome or progressive dyspnea, from a large mediastinal mass with dense fibrosis. • Diagnosis is performed by bone marrow or lymph node biopsy. • Staging is similar to Hodgkin’s: Ann Arbor system with same staging modalities. Treatment

• NHL’s first-line treatment is usually chemotherapy. • CHOP (cyclophosphamide, adriamycin, vincristine, prednisone) therapy is most widely used in conjunction with radiotherapy or monoclonal antibodies. • Rituximab is an anti-CD20 monoclonal antibody that has been shown to improve outcomes in indolent or aggressive malignancies with weekly administration. °°Retrospective case series described 153 pregnancies exposed to rituximab mainly in the second or third trimester of pregnancies; serious complications were related to maternal and neonatal immunosuppression with subsequent infection. Not associated with increase in congenital malformations (62). °°Recommendations to delay pregnancy during and up to 12 months following treatment is related to the potential depletion of maternal and fetal B cells up to 6 months. • Therapeutic component of radiation may be delayed until after delivery. • More aggressive forms of chemotherapy used in Burkitt’s (CODOX-M/IVAC) contain agents that are not usually recommended in pregnancy. These regimens should be considered as less potent agents are not as affective in promoting remission. Treatment with relapse is usually ineffective (58). • Profound and prolonged myelosuppression may result and stem cell transplantation maybe indicated. • Expectant management early in pregnancy is reasonable in indolent cases, but is usually treated with chemotherapy in later trimesters. • Palliative steroids to alleviate B symptoms are appropriate in women who desire treatment delay until later gestational age. LEUKEMIA Background • Leukemia is divided into chronic and acute and then subdivided into histologic categories. • Two-thirds are myeloid and one-third are lymphoid in origin. • Use of cell surface markers, histochemical staining, and careful examination of the leukemic cells in peripheral blood and bone marrow allow for a precise determination of category. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Increased rates of abortion, fetal growth restriction, preterm delivery, and perinatal mortality (usually related to preterm delivery) have been demonstrated in leukemia-affected pregnancies; A function of disease-related effects of coagulopathy, maternal anemia, and decreased placental perfusion. • Maternal response to therapy is the most influential factor on pregnancy outcomes and perinatal mortality. • Metastasis of maternal leukemia to the placenta or fetus is very rare (63). • The fertility of patients with acute disease is diminished; however, for those in remission after childhood treatment, the fertility rates are good especially if treated prior to puberty. • Oral contraception is the method of choice because ovulation is suppressed and menstrual flow is diminished, thus preventing menorrhagia in patients both with acute disease and in remission. Epidemiology • The incidence is estimated to be less than 0.9 to 1.2 cases per 100,000 women per year (64). Acute Leukemia Background

• Three common types in pregnancy: acute lymphocytic leukemia (ALL), acute promyelocytic leukemia (APML), and acute myeloid leukemia (AML) • ALL is more common in childhood. °°Diagnosis in adults has a grave prognosis. ALL in pregnancy are usually survivors with a previous diagnosis. °°Most likely to present with lymphadenopathy. • AML comprises the majority of acute leukemia in pregnancy. • APML is a variant of AML associated with translocation between chromosomes 15:17. °°May present with life-threatening hemorrhage and increase likelihood of developing DIC. • All are rapid progressing (63). Diagnosis

• Diagnosis is usually by peripheral blood smear evaluation, bone marrow biopsy with flow cytometry, and cytogenetic analysis. An increased total leukocyte count with neutropenia, anemia, and thrombocytopenia are common findings. Treatment

• Given the dismal prognosis of leukemia in the absence of therapy and lack of documented side effects of chemotherapy in utero, chemotherapy should not be withheld or significantly delayed regardless of gestational age at diagnosis (58). • In the first trimester, the patient should be offered termination with subsequent induction of chemotherapy. °°Reports of limb deformities and cardiac dysfunction are available following firsttrimester therapy. • If abortion is refused or diagnosis is made after the start of second trimester, chemotherapy should be started immediately. • Delivery planning is imperative to allow greater than 3 weeks between last treatment and delivery for bone marrow recovery and fetal drug excretion. After 32 weeks, consider delivery and then therapy induction. • Management is based on the type of leukemia (61). • AML usually treated with cytarabine and an anthracycline. °°Anthracyclines, daunorubicin and idarubicin, are associated with higher incidence of pregnancy complications including IUGR, neonatal pancytopenia, prematurity, and IUFD. °°Doxorubicin, an anthracycline used in breast cancer, has a better pregnancy profile and maybe considered as the choice for gestation. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• APL receives ATRA: retinoic acid, an anthracycline, and cytarabine. °°Cardiac and neurologic malformations increase with use of ATRA in the first trimester. °°Delay in starting an anthracycline along with ARTA increases risks of relapse and ATRA resistance. • ALL treatment is usually modified to avoid the use of methotrexate, so various regimens have been employed. • Methotrexate is associated with aminopterin syndrome, cranial dysostosis, micrognathia, and ear anomalies (61). Chronic Leukemia Background

• The diagnosis is usually chronic myelogenous leukemia (CML) if encountered in pregnancy, as CLL tends to target individuals over 50 years (61). • CML makes up 10% of all types of leukemia (63). • Characterized by the presence of the oncogene, BCR/ABL, which promotes and maintains the leukemic clone °°Ninety-five percent of patients have the balanced translocation of t (9:22), which produces the BCR-ABL oncogene. • Slow progressing malignancy, whose course is unaffected by pregnancy Diagnosis Clinical Manifestation

• CML undergoes three clinical phases: chronic phase, accelerated phase, and a blast phase (blast crisis). • Ninety percent of CML are diagnosed in chronic phase with increased neutrophils, normal platelets, and low blast ratio in bone marrow biopsy (63). • In early CML, 50% are asymptomatic. Others may experience indiscriminate ­symptoms or symptoms associated with leukocytosis (WBC greater than 100,000 cells/μL) (63). • May induce leukostasis, tumor lysis syndrome, and disseminated intravascular coagulopathy • Leukostasis, a condition of hyperviscosity, manifests as headaches, tinnitus, or dyspnea. • Diagnosis made with peripheral blood smear (neutrophilia with marked immature myeloid cells), followed by bone marrow biopsy and cytogenetic analysis to evaluate for gene mutation (61). Treatment

• Imatibinib, a tyrosine kinase inhibitor, targets BCR/ABL oncogene in CML and is now first-line treatment (58). • Animal studies have demonstrated a teratogenic effect. Retrospective case series support that the frequency of congenital malformations was higher in women exposed to imatibinib at various gestational ages (65,66). • Remission is dependent on continuation of therapy and may be achieved in 18 months. • Risk of relapse is higher with discontinuation. • Alternative therapies, interferon and hydroxyurea, cytogenetic response is inferior to imatibinib. Hydroxyurea has consistently been found to be teratogenic and should not be used. Interferon does not cross the placenta and is a viable option for those wanting to discontinue imatibinib during pregnancy (58). • If the patient suffers a blast crisis, chemotherapy is necessary, and management of the pregnancy should be similar to that of acute leukemia. • Leukophoresis is an alternative for a rapid, short-term cytoreduction in symptomatic leukocytosis. This should be followed by induction of imatibinib (66). (c) 2015 Wolters Kluwer. All Rights Reserved.

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MYELOPROLIFERATIVE NEOPLASMS • Comprised of essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) and is also known as the Philadelphia-negative myeloproliferative neoplasms (MPN) • Peak incidence is 50 to 70 years of age. However, ET has a second peak in reproductive age, and 15% of PV occurs less than 40 years of age, so a concurrent pregnancy is possible (67). • The condition is a result of a mutation in hemopoietic stem cells inducing RBC overproduction. It follows a chronic course and may transform to acute leukemia. • JAK2V617F mutation is found in a majority of PV cases and approximately half of ET and PMF. It is unclear if isolated complications result from the mutation being present in pregnancy (68). • Pregnancy compounds the prothrombotic nature of MPN, so most major complications are thrombosis-related. • ET and PV have similar perinatal complications: fetal loss especially in the first trimester, placental abruption, IUGR, postpartum thrombotic events, or hemorrhage. PMF seems to share only the increase in fetal loss, as there are no reports of maternal or adverse pregnancy complications (67). • Contraceptive counseling is imperative in women with MPN. In the event of an unplanned pregnancy, the significant fetal and maternal risk should be clearly outlined. Management • Aspirin has demonstrated decreased thrombosis formation in this condition. • Aspirin should be continued in pregnancy in the absence of a contraindication. • LMWH should be considered in the setting of additional risk factors and dosed according to indication. • Venesection or cytoreductive therapy with interferon-α therapy as needed to maintain platelet counts less than 400,000 and packed cell volume (PCV) less than 0.42 to 0.45 (67). • May experience drastic increase during postpartum period in platelets and RBCs • Monitor blood counts closely in pregnancy with monthly CBCs and fetal surveillance for growth. REFERENCES 1. Lee A, Okam M. Anemia in pregnancy. Hematol Oncol Clin North Am. 2011;25(2):241–259. 2. Kilpatrick SJ. Anemia and pregnancy. In: Creasy RK, Resnik R, Iams JD, eds. Maternalfetal medicine principles and practice. 6th ed. Philadelphia: W.B. Saunders, 2009:869–884. 3. McLean E, Cogswell M, Egli I, et al. Worldwide prevalence of anaemia, WHO Vitamin and Mineral Nutrition Information System, 1993–2005. Public Health Nutr. 2009;12(4):444–454. 4. Adebisi OY, Strayhorn G. Anemia in pregnancy and race in the United States: Blacks at risk. Fam Med. 2005;37:655–662. 5. Kozuki N, Lee A, Katz J. Moderate to severe, but not mild, maternal anemia is associated with increased risk of small-for-gestational-age outcomes. J Nutr. 2012;142(2):358–362. 6. Tzur T, Weintraub A, Sergienko R, Sheiner E. Can anemia in the first trimester predict obstetrical complications later in pregnancy? J Matern Fetal Neonatal Med. 2012;25(11):2454–2457. 7. Murray-Kolb LE, Beard JL. Iron deficiency and child and maternal health. Am J Clin Nutr. 2009;89:946S–950S. 8. U.S. Preventive Services Task Force. Routine iron supplementation during pregnancy. [Review.] JAMA. 1993;270:2848–2854. 9. Andersson O, Hellstrom-Westas L, Andersson D, et al. Effect of delayed versus early umbilical cord clamping on neonatal outcomes and iron status at 4 months: a randomized ­controlled trial. BMJ. 2011;343:d7157. (c) 2015 Wolters Kluwer. All Rights Reserved.

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10. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin Number 95: Anemia in pregnancy. Obstet Gynecol. 2008;112:201–207. 11. Mei Z, Cogswell ME, Looker AC, et al. Assessment of iron status in US pregnant Women from the National Health and Nutrition Examination Survey (NHANES), 1999–2006. Am J Clin Nutr. 2011;93:1312–1320. 12. Walsh T, O'Broin S, Geary M, et al. Laboratory assessment of iron status in pregnancy. Clin Chem Lab Med. 2011;49(7):1225–1230. 13. Breymann C, Honegger C, Holzgreve W, et al. Diagnosis and treatment of iron-deficiency anaemia during pregnancy and postpartum. Arch Gynecol Obstet. 2010;282:577–580. 14. Akesson A, Bjellerup P, Bremme K, et al. Soluble transferrin receptor: longitudinal assessment from pregnancy to postlactation. Obstet Gynecol. 2002;99:260–266. 15. Pena-Rosas JP, Viteri FE. Effects and safety of preventive oral iron or iron plus folic acid supplementation for women during pregnancy. Cochrane Database Syst Rev. 2009;(4):CD0004736. 16. Reveiz L, Gyte GM, Cuervo LG, et al. Treatments for iron-deficiency anaemia in pregnancy. Cochrane Database Syst Rev. 2007;2:CD003094. 17. Cogswell ME, Parvanta I, Ickes L, et al. Iron supplementation during pregnancy, anemia, and birth weight: a randomized controlled trial. Am J Clin Nutr. 2003;78:773–781. 18. Siega-Riz AM, Hartzema AG, Turnbull C, et al. The effects of prophylactic iron given in prenatal supplements on iron status and birth outcomes: a randomized controlled trial. Am J Obstet Gynecol. 2006;194:512–519. 19. Cao C, O’Brien K. Pregnancy and iron homeostasis: an update. Nutr Rev. 2013;71(1):35–51. 20. Krafft A, Breymann C. Iron sucrose with and without recombinant erythropoietin for the treatment of severe postpartum anemia: a prospective, randomized, open-label study. J Obstet Gynaecol Res. 2011;37(2):119–124. 21. Lassi Z, Salam R, Haider B, et al. Folic acid supplementation during pregnancy for maternal health and pregnancy outcomes. Cochrane Database Syst Rev. 2013;(3):CD006896. 22. Shetty A, Anwar S, Acharya S. Aplastic anaemia in pregnancy. J Obstet Gynaecol. 2011;31(1):77–78. 23. Choudry VP, Gupta S, Gupta M, et al. Pregnancy associated aplastic anemia: a series of 10 cases with review of literature. Hematology. 2002;7:233–238. 24. Marsh J, Ball S, Yin J, et al. Guidelines for the diagnosis and management of aplastic anaemia. Br J Haematol. 2009;147(1):43–70. 25. Kwon J, Lee Y, Shin J, et al. Supportive management of pregnancy-associated aplastic anemia. Int J Gynaecol Obstet. 2006;95(2):115–120. 26. American College of Obstetricians and Gynecologists. Practice Bulletin No. 78: Hemoglobinopathies in pregnancy. Obstet Gynecol. 2007;109(1):229–237. 27. Leung T, Lao T. Thalassemia in pregnancy. Best Pract Res Clin Obstet Gynaecol. 2012;26(1):37–51. 28. American College of Obstetricians and Gynecologists. ACOG Committee Opinion Genetic screening for hemoglobinopathies No. 238. Int J Gynaecol. 2001;74(3):309–310. 29. Barrett A, McDonnell T, Chan K, et al. Digital PCR analysis of maternal plasma for noninvasive detection of sickle cell anemia. Clin Chem. 2012;58(6):1026–1032. 30. Yu C, Stasiowska E, Stephens A, et al. Outcome of pregnancy in sickle cell disease patients attending a combined obstetric and haematology clinic. J Obstet Gynaecol. 2009;29(6):512–516. 31. Rogers D, Molokie R. Sickle cell disease in pregnancy. Obstet Gynecol Clin North Am. 2010;37(2):223–237. 32. Haddad L, Curtis K, Legardy-Williams J, et al. Contraception for individuals with sickle cell disease: a systematic review of the literature. Contraception. 2012;85(6):527–537. 33. Bockenstedt P. Thrombocytopenia in pregnancy. Hematol Oncol Clin North Am. 2011;25(2):293–310. 34. Lockwood CJ, Silver R. Coagulation disorders in pregnancy. In: Creasy RK, Resnik R, Iams JD, eds. Maternal-fetal medicine principles and practice. 6th ed. Philadelphia: W.B. Saunders, 2003:825–854. 35. Sibai B. Imitators of severe preeclampsia. Obstet Gynecol. 2007;109(4):956–966. (c) 2015 Wolters Kluwer. All Rights Reserved.

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36. George J. ADAMTS13, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome. Curr Hematol Rep. 2005;4(3):167–169. 37. Letsky EA. Disseminated intravascular coagulation. Best Pract Res Clin Obstet Gynaecol. 2001;15:623–644. 38. Dey M, Reema K. Acute fatty liver of pregnancy. North Am J Med Sci. 2012;4(11):611–612. 39. Fesenmeier M, Coppage K, Lambers D, et al. Acute fatty liver of pregnancy in 3 tertiary care centers. Am J Obstet Gynecol. 2005;192(5):1416–1419. 40. Seyyed Majidi M, Vafaeimanesh J. Plasmapheresis in acute fatty liver of pregnancy: an effective treatment. Case Re Obstet Gynecol. 2013;2013:615975. 41. American College of Obstetricians and Gynecologists. Inherited thrombophilias in pregnancy. Practice Bulletin No. 113. Obstet Gynecol. 2010;116:212–222. 42. Brenner B. Haemostatic changes in pregnancy. Thromb Res. 2004;114:409–414. 43. Mannucci PM. Treatment of von Willebrand’s disease. N Engl J Med. 2004;351:683–694. 44. Giangrande PLF. Management of pregnancy in carriers of haemophilia. Haemophilia. 1998;4:779–784. 45. Yang MY, Ragni MV. Clinical manifestations and management of labor and delivery in women with factor IX deficiency. Haemophilia. 2004;10:483–490. 46. Nachman RL, Silverstein R. Hypercoagulable states. Ann Intern Med. 1993;199:819–827. 47. Kujovich JL. Thrombophilia and pregnancy complications. Am J Obstet Gynecol. 2004;191:412–424. 48. Lockwood CJ. Thromboembolic Disease in pregnancy. In: Creasy RK, Resnik R, Iams JD, eds. Maternal-fetal medicine principles and practice. 6th ed. Philadelphia: W.B. Saunders, 2003:855–867. 49. Hallak M, Senderowicz J, Cassel A, et al. Activated protein C resistance (factor V Leiden) associated with thrombosis in pregnancy. Am J Obstet Gynecol. 1997;176:889–893. 50. Dizon-Townson DS, Nelson LM, Jang H, et al. The incidence of the factor V Leiden mutation in an obstetric population and its relationship to deep venous thrombosis. Am J Obstet Gynecol. 1997;176:883–886. 51. Ridker PM, Miletich JP, Buring JE, et al. Factor V Leiden mutation as a risk factor for recurrent pregnancy loss. Ann Intern Med. 1998;128:1000–1003. 52. Wells PS, Blajchman MA, Henderson P, et al. Prevalence of antithrombin deficiency in healthy blood donors: a cross-sectional study. Am J Hematol. 1994;45:321–324. 53. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295–306. 54. Carp HJA. Antiphospholipid syndrome in pregnancy. Curr Opin Obstet Gynecol. 2004;16:129–135. 55. Bates S, Greer I, Pabinger I, et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 suppl):844S–886S. 56. Ageno W, Crotti S, Turpie AGG. The safety of antithrombotic therapy during pregnancy. Expert Opin Drug Saf. 2004;3:113–118. 57. Pabinger I, Grafenhofer H. Anticoagulation during pregnancy. Semin Thromb Hemos. 2003;29:633–638. 58. Rizack T, Mega A, Legare R, et al. Management of hematological malignancies during pregnancy. Am J Hematol. 2009;84(12):830–841. 59. Howlader N, Ries L, Mariotto A, et al. Improved estimates of cancer-specific survival rates from population-based data. J Natl Cancer Inst. 2010;102(20):1584–1598. 60. Mills GB. Immunology of cancer in pregnancy. In: Allen HH, Nisker JA, eds. Cancer in pregnancy. Mt. NY: Futura, 1986. 61. Cohen J, Blum K. Evaluation and management of lymphoma and leukemia in pregnancy. Clin Obstet Gynecol. 2011;54(4):556–566. 62. Decker M, Rothermundt C, Holländer G, et al. Rituximab plus CHOP for treatment of diffuse large B-cell lymphoma during second trimester of pregnancy. Lancet Oncol. 2006;7(8):693–694. (c) 2015 Wolters Kluwer. All Rights Reserved.

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63. Pejovic T, Schwartz PE. Leukemias. Clin Obstet Gynecol. 2002;45:866–878. 64. Catanzarite VA, Ferguson JE II. Acute leukemia and pregnancy: a review of management and outcome, 1972–1982. Obstet Gynecol Surv. 1984;39:663. 65. Pye S, Cortes J, Apperley J, et al. The effects of imatinib on pregnancy outcome. Blood. 2008;111(12):5505–5508. 66. Apperley J. Issues of imatinib and pregnancy outcome. J Natl Compr Canc Netw. 2009;7(10):1050–1058. 67. Barbui T, Finazzi G. Myeloproliferative disease in pregnancy and other management issues. Hematol Am Soc Hematol Educ Prog. 2006;246–252. 68. Harrison C, Robinson S. Myeloproliferative disorders in pregnancy. Hematol Oncol Clin North Am. 2011;25(2):261–265.

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20

Immunologic Complications

Jill G. Mauldin and Donna D. Johnson

KEY POINTS • Immunologic diseases are common in pregnancy. • The complications encountered during pregnancy are related to the type of autoimmune disease. • Most patients can have a successful pregnancy outcome with a multidisciplinary team approach to their care and careful monitoring. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) Background • A disease of fluctuating immune dysfunction. • Disease manifestations vary within a patient as well as across populations of patients. • Pregnancy complicated by systemic lupus erythematosus (SLE) is not uncommon as SLE has a predilection for females of childbearing years. • Ten times more common in women than men. • More common in African Americans than Caucasians. Evaluation • If a patient with SLE is contemplating pregnancy or is pregnant, assessment of her disease is important. Ideally, preconceptional assessment and counseling should be performed because of the potential for adverse impact on pregnancy outcome. • Renal insufficiency is an important risk factor for maternal and fetal complications. • Renal function is more important than precise renal histology. • Urinalysis, creatinine clearance, and 24-hour urine are important for counseling and pregnancy prognosis. • Presence or absence of hypertension should be documented. • Autoimmune antibodies associated with SLE flares and adverse outcomes should be assessed preconceptionally and in the first trimester. • ANA • Anti-dsDNA • Lupus anticoagulant • Anticardiolipin antibodies • Anti-SS-A • Anti-SS-B • Baseline complement levels (C3, C4, and CH50) should be drawn. • Important to evaluate the complete blood count and platelets in the first trimester (1). Diagnosis • Rarely diagnosed for the first time during pregnancy. • Diagnosis requires a thorough history, physical exam, and laboratory tests. • Clinical manifestations: malar rash, discoid rash, photosensitivity, oral ulcers, polyarthritis, serositis, renal disorder, neurologic disorder (seizures, psychosis, organic brain 371

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syndrome, and stroke), and hematologic disorders (hemolytic anemia, leukopenia, ­lymphopenia, and thrombocytopenia). • Immunologic tests associated with SLE: antinuclear antibodies, anti-SSA (Rho), antiSSB (La), anti-RNP, anti-Sm, anti-dsDNA, and antiphospholipid antibodies. • Four or more of the above clinical or laboratory features must be present to establish the diagnosis of SLE (2). • The natural history of the disease is for flares to occur. • Diagnosis of a flare in pregnancy may be difficult (3). • Fatigue, joint aches, or changes in the skin may mark a flare or may be symptoms of normal pregnancy. • Some laboratory findings used to assess disease activity, such as sedimentation rate, platelet counts, and hemoglobin, are altered by pregnancy. • May be confused with preeclampsia. Treatment • Is the same in pregnancy as in the nonpregnant state with a few caveats. • Caution should always be exercised when using drugs in pregnancy because limited data are available for many drugs. • The benefit of treatment should clearly outweigh any potential risk to the fetus. • Immunosuppressive agents • Glucocorticoids/corticosteroids, such as prednisone and hydrocortisone: °°Are inactivated by the placenta. °°Are associated with cleft lip in animals but never documented in humans °°Place patients at higher risk for gestational diabetes and hypertension (3) • Glucocorticoids/corticosteroids, such as dexamethasone and betamethasone: °°Cross the placenta and should be used only if there is the intent to treat the fetus °°Should be avoided because of the concern of fetal growth • Azathioprine: °°Is generally considered safe to use °°Has been associated with fetal cytopenias and intrauterine growth restriction in some reports (3) • Antimalarial agents, such as hydroxychloroquine: °°In the past, these drugs have been discontinued during the pregnancy due to concerns of ophthalmologic damage. °°More recent reports have not revealed any congenital, ophthalmologic, or auditory abnormalities. °°Discontinuation in pregnancy may precipitate a flare (4). • Cyclophosphamide °°An alkylating agent. °°First trimester use should be avoided if possible as it may be teratogenic. °°Second and third trimester usage appears safer but may be associated with intrauterine growth restriction (1). • Methotrexate °°An abortifacient °°Associated with specific malformations such as craniosynostosis, cleft palate, and ear and eye abnormalities (3) • Nonsteroidal anti-inflammatory agents (NSAIDs): • Do not appear to be teratogenic • May be used in very limited amounts and for a short duration but should particularly be avoided in the third trimester • Associated with premature closure of the ductus arteriosus and may lead to primary pulmonary hypertension • Associated with fetal oliguria and subsequent oligohydramnios (1) (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Antihypertensive agents • Important to have good blood pressure control during pregnancy, especially if the patient has preexisting renal disease. • Antihypertensive therapy is discussed in detail in Chapter 12. • Angiotensin-converting enzyme (ACE) inhibitors should be stopped once pregnancy is diagnosed. • Use of ACE inhibitors in the second and third trimesters is associated with severe and irreversible fetal renal abnormalities (1). Complications Maternal

• Pregnancy may be inadvisable in situations such as uncontrollable hypertension, rapid deterioration of renal function, or severe neurologic or cardiopulmonary involvement due to the increased risk of maternal morbidity and mortality. • Whether or not flares are more common in pregnancy is still debatable (1,3,5). • Features of SLE that appear to be protective of flares and subsequent progression of disease in pregnancy are quiescent disease for 6 to 12 months preconceptionally, normal renal function, nephritis in complete remission, and normal blood pressure before conception. • A serum creatinine of greater than 1.6 mg/dL is associated with an increased risk of hypertension, proteinuria, and further renal impairment (6). • Multidisciplinary management is often necessary to ensure the best maternal and fetal outcome. Pregnancy

• Preterm delivery • Rate is 24% to 59% compared to 5% to 15% in the general population. • Most common causes are preeclampsia, nonreassuring fetal status, and possibly a higher incidence of premature rupture of the membranes. • Major cause of perinatal morbidity and mortality. • Increases the risk of cesarean section (5). • Preeclampsia • Two-thirds of patients with preexisting renal disease will develop preeclampsia compared to only 14% of patients with SLE without renal involvement. • It may be impossible to distinguish a lupus flare from preeclampsia. • Clinical signs of active SLE, such as inflammatory arthritis, rash, adenopathy, and rising anti-dsDNA titers, favor the diagnosis of lupus nephritis (1). Fetal

• Increased fetal loss rate • Includes both first spontaneous abortions and intrauterine fetal demise. • Median loss rate is 29% in SLE patients compared to 15% in the general population. • Creatinine greater than 1.6 mg/dL is associated with a fetal loss rate of 45%. • Antiphospholipid antibodies are also associated with increased fetal wastage (6). • Late second- and third-trimester losses may be reduced with antenatal fetal testing (see Chapter 32). • Educate patients regarding fetal kick counts at 28 weeks (1). • Intrauterine growth restriction • May be detected by the use of serial growth ultrasounds. • Congenital heart block • Most strongly associated with anti-SS-A (Ro) (1). • Affects less than 2% of the offspring of antibody-positive patients (5). • Can be detected by auscultation with Doppler or ultrasound. • Characterized by persistent fetal bradycardia leading to congestive heart failure and hydrops fetalis (7). (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Mortality is at least 20%. • Surviving infants will require a pacemaker. • Considered the only nonreversible component of neonatal lupus erythematosus. Neonatal

• Neonatal lupus erythematosus • Clinical manifestations include photosensitive rash, thrombocytopenia, and liver function abnormalities. • Anti-SS-A (Ro) and to a lesser extent anti-SS-B (La) antibodies are associated with neonatal lupus erythematosus. • In patients with these antibodies, approximately 25% of their offspring will develop this neonatal condition (5). • Neonatal lupus erythematosus is transient and disappears by 6 months of life (7). ANTIPHOSPHOLIPID SYNDROME (APS) Diagnosis • The diagnosis of antiphospholipid syndrome (APS) must include one clinical criterion and one laboratory test (5,8). • Nonobstetrical clinical criteria include • One or more episodes of arterial, venous, or small vessel thrombosis in any tissue or organ. °°Thrombosis must be confirmed by imaging, Doppler studies, or histopathology. °°For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall. • Obstetrical clinical criteria include • One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation. • One or more premature births of morphologically normal neonates at or before 34 weeks due to severe preeclampsia or placental insufficiency. • Three or more unexplained consecutive spontaneous abortions before 10 weeks of gestation. • Laboratory criteria • Anticardiolipin antibodies °°Medium or high titer of immunoglobulin IgG or IgM isotype in the blood on two occasions, at least 12 weeks apart. • Anti-β2 glycoprotein 1–dependent antibodies: °°Should be measured by standard enzyme-linked immunosorbent assay °°May be IgG or IgM isotype in the blood on two occasions, at least 12 weeks apart • Lupus anticoagulant antibodies °°The name of the antibody is misleading as many patients do not have SLE and have difficulty with thrombosis, not bleeding. °°Should be present in the blood on two occasions, at least 12 weeks apart. °°Should be detected in accordance with the guidelines of the International Society of Thrombosis and Hemostasis in the following steps: --Prolonged phospholipid-dependent coagulation demonstrated on a screening test, such as activated partial thromboplastin time, kaolin clotting time, or dilute Russell viper venom time --Failure to correct the prolonged coagulation time on the screening test by mixing with normal, platelet-poor plasma --Shortening or correction of the prolonged coagulation time on the screening test by the addition of excess phospholipids --Exclusion of other coagulopathies, such as factor VIII inhibitor, or heparin (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Anticardiolipin, lupus anticoagulant, and anti-β2 glycoprotein 1–dependent antibodies can be found in healthy patients, so testing should be limited to patients with clinical features of APS. • Primary APS usually occurs in patients without clinical evidence of other autoimmune disorders. • Secondary APS occurs in patients with autoimmune or other diseases (5). Treatment • The goal of therapy is to improve maternal and fetal outcome by prevention of pregnancy losses, preeclampsia, and intrauterine growth restriction and to prevent arterial or venous thrombosis. • Although large, controlled, randomized trials are lacking, low-dose aspirin and heparin remain the mainstays of therapy in patients with prior obstetrical complications (9). • The patient may be given aspirin prior to conception. • Patients with obstetrical complications or prior thrombosis may be treated with prophylactic regimens of anticoagulation (10). • Standard heparin °° 5000 units every 12 hours in the first trimester and 10,000 units in the last two trimesters • Low molecular weight heparin °°Enoxaparin 40 mg or dalteparin 5000 units once a day • Treatment with heparin and low-dose aspirin reduces the risk of pregnancy loss. • In pregnancy, antenatal fetal testing and serial growth ultrasounds are indicated. • Iatrogenic preterm delivery is often indicated (9). • Postpartum management depends on whether or not a patient has had a thrombotic event. • If a patient has had a prior thrombosis, prophylactic anticoagulation is recommended and warfarin is acceptable. • If a patient has only a poor obstetrical history, management is more controversial. °°Prophylactic anticoagulation therapy is suggested for 6 weeks after delivery by some experts. Complications • Thrombotic • Arterial and venous thromboses are the most common complications of APS. • Overall prevalence of thrombosis in individuals with APS is 30%. • The annual rate of the first event is 1%. • The annual rate of recurrence in all APS patients not receiving anticoagulation is 10% to 29% (11). • Obstetrical • Recurrent pregnancy loss °°Preembryonic and embryonic loss --These losses occur between conception and the 4th week (preembryonic period) and the 5th through the 9th week (embryonic period). --As many as 10% to 20% of these patients will test positive for lupus anticoagulant or anticardiolipin antibodies (12). --Recurrent pregnancy loss is defined as three or more consecutive losses in this time period (5). °°Fetal period --Ranges from 10th week of gestation until term. --Fetal death criteria apply only to morphologically normal fetuses. --Approximately 80% of patients with APS have had one fetal death compared to fewer than 25% of patients without APS. °°In patients with prior fetal deaths, antepartum fetal testing is indicated. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Preeclampsia °°The median rate of gestational hypertension and preeclampsia is 32% to 50% (8). °°A common indication for delivery in patients with APS. °°The rate of preeclampsia is not reduced by treatment with heparin, aspirin, or steroids. • Placental insufficiency °°Characterized by poor fetal growth or fetal distress. °°Occurs in approximately 30% of patients with APS. °°One of the primary indications for preterm delivery. °°Serial growth ultrasounds can detect early growth aberrations (8). IMMUNE THROMBOCYTOPENIA PURPURA (ITP) Background • This is a common autoimmune disorder encountered during pregnancy. • The most common reason for significant thrombocytopenia in the first trimester (13). • Female to male prevalence is 3:1. • Seventy percent of women diagnosed with this are less than 40 years of age. Diagnosis • Common signs and symptoms include petechiae, ecchymoses, easy bruising, menorrhagia, epistaxis, and gingival bleeding. • There are no definitive symptoms, signs, or diagnostic tests for immune thrombocytopenia purpura (ITP). The diagnosis is one of exclusion. • Immune thrombocytopenia purpura is suspected if the first-trimester platelet count is less than 100,000 mm3 and declines during pregnancy. • The differential diagnosis for thrombocytopenia in pregnancy is extensive. • Gestational thrombocytopenia is the most common cause. °°Accounts for 74% of pregnant women with thrombocytopenia. °°Diagnosis of exclusion. and 150,000 mm3. °°The typical woman has platelet counts between 100,000 3 Women with platelet counts less than 70,000 mm are less likely to have gestational °° thrombocytopenia. °°Usually occurs in the late second or third trimester. °°The patient has no prior history suggestive of thrombocytopenia such as ecchymoses. • Preeclampsia can be associated with low platelet count. °°Usually accompanying hypertension and proteinuria • Infection, such as human immunodeficiency virus or malaria, can cause thrombocytopenia. • Some drugs are associated with thrombocytopenia: °°Heparin, sulfonamides, penicillin, rifampin, and quinine • Thrombocytopenia can be caused by diseases such as SLE, APS, and thrombotic thrombocytopenic purpura (13). Treatment • Treatment is recommended in patients with platelet counts less than 30,000 mm3 or with active bleeding. • As a pregnant patient approaches term, the platelet count should be 50,000 mm3 to ensure adequate hemostasis at delivery (13). Medications

• Corticosteroids may be used. • Efficacious and inexpensive. • 1 to 2 mg/kg/d is usually started. (c) 2015 Wolters Kluwer. All Rights Reserved.

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°°Once the platelet count reaches 75,000 to 100,000 mm , the dose is reduced to 3

maintain the platelet count in this range.

°°Side effects include hypertension and glucose intolerance (13).

• High-dose intravenous immunoglobulin (IVIg) • The typical dose is 1 to 2 g/kg infused over 6 to 8 hours (13). • IVIg is effective in two-thirds of patients. • The effect persists for 4 weeks. • IVIg is more expensive than corticosteroids but has fewer side effects that are usually mild including headache, chills, and nausea. Procedures

• Splenectomy • Considered when refractory to corticosteroids and IVIg (13) • Ideally performed in the second trimester • Platelet transfusion • Recommended when a patient is actively bleeding or when the platelet count is less than 20,000 mm3 Complications • Maternal hemorrhage from vaginal lacerations or cesarean section • Can be minimized if the platelet count is greater than 50,000 mm3 • Neonatal thrombocytopenia • Occurs in 3% to 4% of newborns. • Bleeding complications are uncommon in newborns with mildly depressed platelet counts. • Intracranial hemorrhage, a very serious complication, occurs in less than 1% of infants. • Maternal platelet count correlates poorly with neonatal platelet counts. • The best method of obstetrical management to prevent fetal intracranial hemorrhage is controversial. °°Determination of the fetal platelet count prior to delivery is not recommended. --Current methods of assessing fetal platelet counts can be unreliable and are associated with mortality risks of 1% to 2% (which is at least as high as the risk of neonatal thrombocytopenia). --Fetal scalp sampling. * This technique is difficult in early labor because the presenting part is usually at a high station. * Sampling can lead to a falsely low platelet count as clumping of the platelets can be problematic. * The fetus has already been subjected to the potential ill effects of labor before the platelet count is determined. --Percutaneous umbilical blood sampling has been utilized to determine fetal platelet counts. * It provides an accurate platelet count. * It is expensive and requires personnel and equipment that are not available at most hospitals. * Has largely been abandoned because the complication rate may be as high as 4.6% (fetal hemorrhage) (14). °°Most authors advocate performing a cesarean section only for obstetrical indications since the incidence of intracranial hemorrhage is so low. --At the root of the controversy is that cesarean section has not been proven to reduce the incidence of intracranial hemorrhage. --A cesarean section does contribute to increased cost and maternal morbidity (14). --Intracranial hemorrhage may actually precede intrapartum events (15). (c) 2015 Wolters Kluwer. All Rights Reserved.

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RHEUMATOID ARTHRITIS (RA) Background • Systemic, chronic inflammatory disorder characterized by symmetrical polyarthritis. • Relatively common occurring in 1% to 2% of the population. • Three times more common in females than males. • The incidence of the disease increases with age. Diagnosis • Classic symptoms are pain and swelling in more than one joint. • Upper extremities are usually affected first. • Rheumatoid factor autoantibody is present in 80% to 90% of patients. Treatment • Anti-inflammatory agents are used and are discussed above under SLE. • Amelioration of symptoms occurs in three-fourths of pregnancies. • If a patient’s symptoms improve, the initial relief occurs in the first trimester and is sustained. Complications • Three recent population-based studies found women with rheumatoid arthritis to have a significantly higher risk of preeclampsia and cesarean delivery (5). SCLERODERMA Background • Scleroderma is an uncommon autoimmune disorder that usually affects women in the fourth decade of life. • Scleroderma may be divided into two forms: • CREST (Calcinosis, Raynaud phenomenon, esophageal hypomotility, sclerodactyly, and telangiectases) is the localized form. • Systemic or generalized form: °°Involves the skin, joints, gastrointestinal tract, lungs, heart, and kidneys Evaluation • Systemic scleroderma can cause damage to multiple organs. • Pulmonary: fibrosis °°Vital capacity should be assessed with pulmonary function tests as these patients are at risk for restrictive lung disease. • Cardiac: cardiomyopathy °°Use echocardiogram to estimate the ejection fraction. • Gastrointestinal: malabsorption and reflux °°Weight and nutritional parameters can be determined. • Kidneys: renal insufficiency °°Renal function should be measured before conception. • Hypertension: renal, cardiac, vascular, and CNS effects Complications • Gastrointestinal reflux • May be treated with histamine blockers or proton pump inhibitors • Renal crisis • Antihypertensive therapy may be used to ameliorate. • The most effective antihypertensive therapy is an ACE inhibitor. °°Because of the high associated maternal and fetal mortality, the profound benefit of using an ACE inhibitor may outweigh the fetal risk (16). (c) 2015 Wolters Kluwer. All Rights Reserved.

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SJÖGREN SYNDROME Background • Sjögren syndrome is a rare autoimmune disorder. • Characterized by dry eyes and mouth. Complications • Sjögren syndrome is associated with intense and varied autoantibodies. • These patients can have anti-SS-A (Ro) and anti-SS-B (La), either of which may lead to a congenital heart block in the offspring (17). Patient Education • Patients with immunologic disorders should receive education about the effect of their specific disease on pregnancy and the effect of pregnancy on their disease. • Ideally, patients with underlying immunologic disorders will seek preconception counseling. REFERENCES 1. Baer AN, Witter FR, Petri M. Lupus and pregnancy. Obstet Gynecol Surv. 2011;66:639–653. 2. Petri M. Treatment of systemic lupus erythematosus: an update. Am Fam Physician. 1998;57:2754–2760. 3. Lockshin MD, Sammaritano LR. Lupus pregnancy. Autoimmunity 2003;36:33–40. 4. Costedoat-Chalumeau N, Amoura Z, Huong, DLT, et al. Safety of hydroxychloroquine in pregnant patients with connective tissue diseases. Review of the literature. Autoimmun Rev. 2005;4:111–115. 5. Borchers AT, Naguwa SM, Keen CL, et al. The implications of autoimmunity and pregnancy. J Autoimmun. 2010;34:J287–J299. 6. Mascola MA, Repke JT. Pregnancy and rheumatic disease: obstetric management of the high-risk lupus pregnancy. Rheum Dis Clin North Am. 1997;23:119–132. 7. Shillingford AJ, Weiner S. Maternal issues affecting the fetus. Clin Perinatol. 2001;28:31–70. 8. Branch DW, Holmgren C, Goldberg JD. Antiphospholipid syndrome: ACOG Practice Bulletin, #132. Obset Gynecol. 2012;120:1514–1521. 9. Empson M, Lassere M, Craig JC, et al. Recurrent pregnancy loss with antiphospholipid antibody: a systematic review of therapeutic trials. Obstet Gynecol. 2002;99:135–144. 10. Bates SM, Greer IA, Middeldorp S, et al. VTE, Thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141 (2 suppl):e691S–e736S. 11. Galli M, Barbui T. Antiphospholipid syndrome: definition and treatment. Semin Thromb Hemost. 2003;29:195–203. 12. Geis W, Branch DW. Obstetric implications of antiphospholipid antibodies: pregnancy loss and other complications. Clin Obstet Gynecol. 2001;44:2–10. 13. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115:168–186. 14. Stavrou E, McCrae KR. Immune thrombocytopenia in pregnancy. Hematol Oncol Clin N Am. 2009;23:1299–1316. 15. Silver RM. Management of idiopathic thrombocytopenic purpura in pregnancy. Clin Obstet Gynecol. 1998;41:436–448. 16. Lidar M, Langevitz P. Pregnancy issues in scleroderma. Autoimmun Rev. 2012;11(6–7): A515–A519. 17. Mecacci F, Pieralli A, Bianchi B, et al. The impact of autoimmune disorders and adverse pregnancy outcome. Semin Perinat. 2007;31:223–226.

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21

Vascular Complications Wendy F. Hansen and Samantha Mast

VASCULAR COMPLICATIONS Key Points • The most common times for presentation of rupture or dissection of aneurysms during pregnancy are the third trimester, labor, or the puerperium. • Intracranial hemorrhage (ICH) complicates approximately 3.7 to 9.0 per 100,000 pregnancies, and maternal mortality approaches 40%. • The reported mortality for cerebral infarction is nearly 10%. • Pregnant women with mechanical prosthetic heart valves are at high risk for thrombosis and thromboembolism and require close monitoring and therapeutic levels of anticoagulation. • The optimal regimen for anticoagulation that minimizes both maternal and fetal risks is yet to be determined. ANEURYSMS OF THE AORTA AND ITS BRANCHES Background Definition

• An aneurysm is the presence of a focal dilatation of all three layers of a vessel wall, in direct communication with the lumen, due to congenital or acquired weakness in the vessel wall. • Dissection is present when an intimal tear occurs in a major vessel, allowing formation of an aneurysm. • The three most common sites for intra-abdominal aneurysms: (a) aorta, (b) iliac arteries, and (c) spleen. Pathophysiology

• All of the following factors have been reported to play a role in the risk of aortic dissection and rupture of arterial aneurysms during pregnancy: • Congenital disorders including Marfan syndrome, Ehlers-Danlos syndrome, Turner syndrome, Loeys-Dietz syndrome, aortic coarctation, and the mucopolysaccharidoses (1). • Takayasu arteritis, a chronic progressive granulomatous vaso-occlusive disorder of unknown etiology that primarily affects women of childbearing age (2). • Trauma, infection, or cocaine abuse (1) • Increased wall pressure in the proximal aorta, especially in late pregnancy, which may occur due to cardiovascular changes associated with pregnancy such as increased cardiac output, stroke volume, and blood volume (3) • Changes in progesterone concentrations may alter vessel wall integrity. Epidemiology

• In the absence of Marfan syndrome or Ehlers-Danlos syndrome, arterial aneurysms are uncommon in people less than 40 years of age. • The most common times for presentation of dissection or rupture during pregnancy are the third trimester, labor, or the puerperium. • Splenic artery aneurysms are four times more common in females than males, and 80% are discovered incidentally (4). 380

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Evaluation

History and Physical

• Common symptoms of aortic aneurysm rupture or dissection include • Sudden onset of chest or abdominal pain, often described as severe or “tearing.” Pain may radiate to midscapular area or be migratory. • Nausea, vomiting, light-headedness, and other vasovagal symptoms. • Pain or tingling in extremities. • Neurologic symptoms such as syncope. • The rupture of a splenic artery aneurysm will be associated with severe left upper quadrant pain or epigastric pain, left shoulder or flank pain, and hemodynamic instability (4). • Physical findings with dissection or ruptured aneurysm may include • Tachycardia, hypotension, or hypertension • Anxiety • Decreased pulses and blood pressure differences between extremities Diagnosis • Symptoms of aneurysmal rupture may mimic more common conditions, so a high index of suspicion is necessary. As this condition threatens maternal and fetal well-being, rapid diagnosis is imperative. • Various imaging modalities are used to diagnose dissection and aneurysm rupture. Modalities that utilize ionizing radiation are not contraindicated (5). • Magnetic resonance image (MRI) without contrast is the recommended first-line imaging study during pregnancy. • Computed tomography (CT) of the chest (with shielding of the uterus) results in little fetal radiation exposure and has sensitivity equivalent to MRI. • Chest radiography may show mediastinal widening, but a normal radiograph does not exclude the diagnosis. • Echocardiography will demonstrate abnormalities of the thoracic aorta and is useful if the patient is clinically unstable. • Abdominal ultrasound does not require radiation, but in late pregnancy, the gravid uterus may impede imaging of the abdominal aorta and its branches. Treatment • Immediate management should be aimed at maternal stabilization, including aggressive treatment of hypertension, if present, with an intravenous beta-blocker; administration of oxygen by face mask to optimize placental gas exchange; obtaining blood products for possible transfusion; and close maternal and fetal observation. • Ascending aortic dissections (type A) require emergent surgical repair. Mortality rate may be as high as 1% to 3% per hour over the first several hours and up to 25% in the first 24 hours (1). • Descending aortic dissections (type B) may initially be treated medically. When aortic dissection is diagnosed before the third trimester, surgical repair should be performed, but if the diagnosis is made in the third trimester and the dissection is stable, expectant management is preferred. Repair should be undertaken after cesarean delivery, either at or near term, or if maternal condition worsens (1). • Splenectomy is the treatment of choice for a ruptured splenic artery aneurysm. Asymptomatic splenic aneurysms detected before or during pregnancy should be treated before term (6). Complications • Aortic rupture is frequently catastrophic, and mortality is high. As many as 50% of aortic dissections in women younger than 40 occur during pregnancy and the postpartum period, although pregnancy itself is unlikely to represent an independent risk factor (7).

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• Splenic artery aneurysms are associated with 75% maternal mortality and 95% fetal mortality; combined maternal and fetal survival is rare (6). • Renal artery aneurysms are rare. Rupture leads to retroperitoneal hemorrhage and is associated with a high mortality rate. This entity should be considered among the causes of retroperitoneal hemorrhage in pregnancy (8). PREGNANCY-RELATED STROKE • Rare but potentially devastating event estimated to occur in 34 per 100,000 deliveries with an estimated mortality rate of 1.4 per 100,000 deliveries (9,10). • Risk factors for pregnancy-related stroke include age greater than 35 (OR 2.0), African American race (OR 1.5), migraines (OR 16.9), thrombophilia (OR 16.0), lupus (OR 15.2), heart disease (OR 13.2), hypertension (OR 2.61 to 10.39), thrombocytopenia (OR 6.0), sickle cell disease (OR 9.1), diabetes (OR 2.5), substance abuse (OR 2.3), smoking (OR 1.9), anemia (OR 1.9), and postpartum hemorrhage (OR 1.9) (9). • Pregnancy-related stroke can be pregnancy induced or pregnancy incidental and categorized into two broad types: intracranial hemorrhage and ischemic (11). • Treatment decisions are based on the type of stroke. History and physical are insufficient to answer the question, and imaging with CT or MRI should be done as quickly as possible after symptom onset. • Other rare causes of pregnancy-related stroke include cardioembolism, paradoxical embolism, choriocarcinoma, amniotic fluid embolism, air embolism, and moyamoya disease. INTRACRANIAL HEMORRHAGE Background ICH occurs in 3.7 to 9.0 out of 100,000 pregnancies (12). Approximately half are due to rupture of a saccular aneurysm or of an arteriovenous malformation (AVM), with the other half a consequence of hypertension or trauma. The highest risk for ICH occurs in the postpartum period (13). Definition

• A saccular (berry) aneurysm is an aneurysm commonly found at the bifurcation of major vessels of the circle of Willis, with 85% occurring along divisions of the internal carotid artery. Multiple aneurysms are found in 20% of patients. • An AVM results from congenital anomalies such as arteriovenous fistulae, resulting in direct arteriovenous shunting. They are seen most commonly in the frontoparietal and temporal regions but can occur anywhere in the brain. • Other risk factors for AVM formation include family history of aneurysm, female gender, current cigarette use, or cocaine abuse (13). Pathophysiology

• Controversy exists as to whether the risk of hemorrhage from AVMs is increased during pregnancy, with recent large retrospective cohort studies refuting a theory of increased risk. Any relationship is likely to be coincidental as the most common time for rupture is age 20 to 40 years, the prime childbearing years (13–15). • The risk of rupture of a known AVM in pregnancy is estimated at 3.5%. Reasons given for an increased risk of bleeding include increased cardiac output and increased blood volume. • The risk of rupture of a saccular aneurysm increases as pregnancy advances, possibly due to the increased blood volume of late pregnancy or due to hormonal fluctuations (14). • Maternal hypertension or preeclampsia increases the risk of rupture. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Epidemiology

• AVMs occur in approximately 0.01% of the population (16) and are twice as common in men as in women. • The prevalence of saccular aneurysms in the general population is estimated to be 3.6% to 6% (11). • The risk of ICH due to a ruptured berry aneurysm is estimated as 1:10,000 pregnancies (11). • Risk factors associated with ICH in pregnancy include hypertensive disease (including preeclampsia), coagulopathy, maternal age greater than 35, African American race, tobacco abuse, and increasing parity (13,17). Evaluation

History and Physical

• Symptoms and signs of ICH include a severe headache of sudden onset, meningismus, seizures, altered level of consciousness, vomiting, and focal neurologic deficits. Genetics

• Saccular aneurysms are more common in women with coarctation of the aorta or adult polycystic kidney disease. Diagnosis • Pregnant women in whom ICH is suspected should undergo cranial CT or MRI scanning. Unenhanced CT scanning may reveal blood in the subarachnoid space or within the ventricles; if negative, a contrast-enhanced CT scan should be obtained. • If performed accurately, this imaging method will identify 95% of ICHs, but the detection rate falls to 30% by 96 hours after the event. • If CT indentifies a subarachnoid hemorrhage, angiography for diagnosis and localization of aneurysms is imperative (14). • A lumbar puncture to assess for blood-stained or xanthochromic fluid should follow a negative CT scan. If such fluid is found, cerebral angiography should be performed to identify the site of bleeding. Occasionally, vascular spasm occurs at the site of hemorrhage, and a repeat angiogram may be required. • Abdominal shielding should be employed during all radiographic studies. Treatment

Procedures

• Women known to have a saccular aneurysm or AVM should have definitive management before becoming pregnant. If the patient becomes pregnant before treatment, intervention would be recommended only if expansion or hemorrhage were to occur. Radiosurgery (Gamma Knife) has not been evaluated in pregnancy due to the use of high-dose ionizing radiation (15,16). • It is clear that some women with a stable intracranial AVM will have uneventful pregnancies, and expectant management with neurosurgical consultation is advisable. • If hemorrhage occurs, immediate evaluation is necessary and therapy should be guided by neurosurgical principles. An increased risk of death without treatment and a high incidence of rebleeding argue for the liberal use of surgical intervention. • Surgery is recommended in the presence of coma, space-occupying hematoma, hydrocephalus, or increased intracranial pressure. • Treatment using interventional radiology techniques may be possible in some cases. • Saccular aneurysms less than 4 mm in diameter are usually stable, while those that are more than 5 to 7 mm in diameter are more likely to bleed. • The treatment of saccular aneurysms, whether ruptured or unruptured, should be individualized, with the decision for surgical or medical management based primarily on neurosurgical principles. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• If the gestational age is less than 26 weeks, surgical treatment is almost always indicated. • If the gestational age is more than 26 weeks, the fetal condition should be considered in surgical decision making, and either delivery followed by surgical repair or expectant management may be appropriate. • Surgical management of aneurysmal ICH is associated with lower maternal and fetal mortality (18). • Decision making regarding route of delivery in women with intracranial aneurysms is impaired by limited data. The risk of aneurysm rupture during pregnancy, delivery, and the puerperium is not increased and has been estimated to be 0.05%, similar to the average risk in the general population (15,19). • Cesarean delivery is often recommended because of concerns for increased intracerebral vascular pressure during labor or with Valsalva. There is no evidence that cesarean improves outcomes for mother or fetus and should be reserved for obstetric indications (11,14). • Cesarean delivery is recommended for hemorrhage occurring in the third trimester. • Vaginal delivery is acceptable for women with aneurysms that rupture before the third trimester or those that are treated surgically. A passive second stage of labor and operative vaginal delivery are recommended to avoid the increased intracranial pressure associated with expulsive efforts. Referrals/Counseling

• Some women with ICH during pregnancy will have long-term reduction in decisionmaking capacity or may even be left in a persistent vegetative state. An ethics consultation service may be helpful in guiding decision making in such cases (20). Complications • ICH accounts for 5% to 12% of all maternal deaths (9,11–14). • The maternal mortality from ICH is 20% (13). EMBOLIC STROKE AND CEREBRAL VENOUS THROMBOSIS Background Definitions

• Transient ischemic attack (TIA) is the sudden but short-lived onset of a focal neurologic deficit, caused by brain ischemia. • Stroke, which may be caused either by hemorrhage or by cerebral embolism, is also sudden in onset and focal, but without the rapid resolution seen in TIA. • Cerebral venous thrombosis (CVT) most often involves the superior sagittal sinus but may occur anywhere in the cerebral venous circulation. It occurs more commonly in preeclampsia, sepsis, and when abnormalities of the clotting system are present. Epidemiology

• The overall incidence of cerebral infarction (arterial and venous combined) is approximately 0.9 to 24 per 100,000 deliveries (10,12). • The incidence of embolic stroke is estimated as 4 to 11 per 100,000 deliveries. The occurrence is distributed fairly evenly throughout pregnancy (10,12). • CVT occurs in 0.7 to 24 per 100,000 deliveries and occurs much more commonly in the postpartum period (12). If CVT occurs early in pregnancy, it is likely to recur later in the pregnancy or in the puerperium. Evaluation Any pregnant woman who experiences new-onset or increased frequency of cerebral ischemic symptoms should be hospitalized for diagnostic evaluation and treatment.

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History and Physical

• The symptoms of CVT include headache, vomiting, seizures, lethargy, and drowsiness. • Progressive, atypical headache resistant to analgesia develops in more than 90% of patients and may develop over the course of several days, leading to an average time between symptom onset and diagnosis of 7 days (21). • Physical findings include papilledema, hemiplegia, and altered speech, sensation or vision, including visual field deficits or blindness. Laboratory Tests

• Blood tests include complete blood count, erythrocyte sedimentation rate, serum glucose, coagulation studies, evaluation for thrombophilia, and tests for anticardiolipin antibodies. • The incidence of prothrombotic mutations in patients with CVT may be as high as 40% with many women having multiple mutations (22). Diagnosis • Electrocardiography, echocardiography, and cranial MRI/MRV scanning are indicated, and cerebral angiography should be considered (11). Differential Diagnosis

• The differential diagnosis of cerebral ischemic symptoms includes cerebral embolism, CVT, ICH, mass lesions, seizure disorder, migraine, and eclampsia. Treatment • Labor is not contraindicated, but a passive second stage and operative vaginal delivery are often recommended to avoid increases in intracranial pressure. • Cesarean delivery may be advisable when CVT occurs near term. Medications

• Aspirin in low doses (81 mg/d) is recommended for all women with TIAs, embolic stroke, and current or previous CVT. • Heparin is the anticoagulant of choice in pregnancy due to its inability to cross the placenta. Low molecular weight heparin (LMWH) may provide better safety and efficacy than unfractionated heparin (UFH) in the initial treatment of CVT (23). • Heparin is indicated in women with recurrent TIAs to prevent recurrences. • Intravenous heparin is used in patients with acute embolic stroke or CVT once ICH has been excluded. • Long-term heparin therapy is often advised for women with embolization from a left atrial mural thrombus in the setting of atrial fibrillation. • Heparin is utilized for 6 to 8 weeks postpartum in all women who have had stroke or CVT, as the postpartum period presents a high risk for thrombotic and embolic events. • Although available data are insufficient to develop guidelines, thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) or streptokinase may be employed in pregnant patients who otherwise meet the criteria for use of such agents, including early presentation to the hospital after onset of symptoms, absence of cerebral hemorrhage, and presence of a significant neurologic deficit (24). • In patients with CVT and increased intracranial pressure, the use of dexamethasone or mannitol should be considered to reduce cerebral edema. Referrals/Counseling

• The diagnostic evaluation and treatment planning should be performed in conjunction with a neurologist. • Physical and occupational therapy are helpful in facilitating recovery.

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Complications • The reported mortality of cerebral infarction in pregnancy varies widely, ranging from 0% to 15% (9). • The mortality of CVT temporally related to pregnancy is 0% to 9%, significantly lower than that in nonpregnant patients (25,26). Patient Education • Once a patient has been diagnosed with cerebral infarction, patient education should include smoking cessation, control of hypertension, lipid-lowering therapy, and possibly long-term anticoagulation. • Estrogen-containing oral contraceptives are contraindicated. • Although the risk is low, any of these entities may recur in a future pregnancy, and patient education should include discussion of these risks. Women should be treated with LMWH during future pregnancies (26). MECHANICAL PROSTHETIC HEART VALVES Another serious vascular complication is thrombosis of an artificial heart valve. While cardiovascular complications of pregnancy are covered in Chapter 4, the topic of artificial heart valves is emphasized here due to the high propensity to thromboembolism and the competing needs for maternal and fetal health. Background • Pregnant women with mechanical prosthetic heart valves are at significant risk for thromboembolism (~2.6%) and death (3.3%) (27). Continuous therapeutic anticoagulation with frequent monitoring is required. • Data on the efficacy of anticoagulation in pregnancy are limited to several small case series. The optimal regimen for anticoagulation has yet to be determined. Choice of anticoagulation regimen should be made after a fully informed discussion of risks with the pregnant woman. Treatment

Medications

• Warfarin • Although evidence suggests that warfarin is the most effective anticoagulant in the presence of a mechanical heart valve, there is strong evidence that warfarin is most teratogenic during the 6th to 12th week of gestation, whereas use of warfarin late in pregnancy predisposes to fetal ICH or intrauterine fetal demise (28). • The risk for pregnancy complications in patients treated with sodium warfarin is higher when the mean daily dose exceeds 5 mg daily (29). • LMWH • Should be used with caution for anticoagulation in patients with mechanical prosthetic heart valves, as reports of thrombosis and stroke in both pregnant and nonpregnant women have been published. Careful monitoring of peak and trough levels is required (30). • The use of LMWH during pregnancy is associated with an increased risk of prosthetic valve thromboses (29,30). • While data do not exist from clinical trials to determine the optimal regimen to minimize both maternal and fetal risks, some form of anticoagulation is preferable to no anticoagulation, and one of the following regimens could be considered (29,30): • Adjusted-dose twice-daily LMWH throughout pregnancy with frequently monitored anti-Xa levels 4 hours after subcutaneous injection to maintain the anti-Xa level between 0.7 and 1.2 units/mL. • Adjusted dose UFH every 12 hours to prolong the 6-hour postinjection aPTT at 2.0 to 2.5 times baseline. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• UFH or LMWH (as above) until the 13th week with conversion to warfarin for weeks 13 through 35 (target INR 2.5 to 3.5) when UFH or LMWH is resumed. • In those women deemed to be at highest risk of thromboembolism, may consider warfarin throughout pregnancy until conversion to LMWH or UFH near delivery. • The addition of low-dose aspirin should be considered in high-risk women with prosthetic heart valves (29,30). Patient Education • Patients with known vascular complications require careful preconceptional assessment and counseling. • The safety of pregnancy for these patients should not be presumed until a full assessment has been completed and discussed with the patient. • The occurrence of vascular complications during pregnancy requires extensive patient counseling and education regarding risks and management options. REFERENCES 1. Braverman AC. Acute aortic dissection: clinician update. Circulation. 2010;122:184–188. 2. Hauenstein E, Frank H, Bauer JS, et al. Takayasu’s arteritis in pregnancy: review of the literature and discussion. J Perinat Med. 2010;38(1):55–62. 3. Robinson R. Aortic aneurysm in pregnancy. Dimens Crit Care Nurs. 2005;24:21–24. 4. Al-Habbal Y, Christophi C, Muralidharan V. Aneurysms of the splenic artery—a review. Surgeon. 2010;8(4):223–231. 5. Sahni G. Chest pain syndromes in pregnancy. Cardiol Clin. 2012;30(3):343–337. 6. Ha JF, Phillips M, Faulkner K. Splenic artery aneurysm rupture in pregnancy. Eur J Obstet Gynecol Reprod Biol. 2009;146(2):133–137. 7. Thalmann M, Sodeck GH, Domanovits H. Acute type A aortic dissection and pregnancy: a population based study. Eur J Cardiothorac Surg. 2011;39(6):e159–e163. 8. Soliman KB, Shawky Y, Abbas MM, et al. Ruptured renal artery aneurysm during pregnancy, a clinical dilemma. BMC Urol. 2006;6:22. 9. James AH, Bushnell CD, Jamison MG, et al. Incidence and risk factors for stroke in pregnancy and the puerperium. Obstet Gynecol. 2005;106:509–516. 10. Scott CA, Bewley S, Rudd A, et al. Incidence, risk factors, management, and outcomes of stroke in pregnancy. Obstet Gynecol. 2012;120(2 Pt 1):318–324. 11. Davie CA, O’Brien P. Stroke and pregnancy. J Neurol Neurosurg Psychiatry. 2008;79:240–145. 12. Edlow JA, Caplan LR, O’Brien K, et al. Diagnosis of acute neurological emergencies in pregnant and postpartum women. Lancet Neurol. 2013;12:175–185. 13. Bateman BT, Schumacher HC, Bushnell CD, et al. Intracerebral hemorrhage in pregnancy: frequency, risk factors, and outcome. Neurology. 2006;67:424–429. 14. Khan M, Wasay M. Haemorrhagic strokes in pregnancy and puerperium. Int J Stroke. 2012. [Epub ahead of print] 15. Kim YW, Neal D, Hoh BL. Cerebral aneurysms in pregnancy and delivery: pregnancy and delivery do not increase the risk of aneurysm rupture. Neurosurgery. 2013;72:143–150. 16. Friedlander RM. Arteriovenous malformations of the brain. N Engl J Med. 2007;356:2704–2712. 17. Jung SY, Bae HJ, Park BJ, et al. Parity and risk of hemorrhagic strokes. Neurology. 2010;74(18):1424–1429. 18. Dias MS, Sekhar LN. Intracranial hemorrhage from aneurysms and arteriovenous malformations during pregnancy and the puerperium. Neurosurgery. 1990;27:855–866. 19. Groenestege AT, Rinkel GJE, van der Bom JG. The risk of aneurismal subarachnoid hemorrhage during pregnancy, delivery, and the puerperium in the Utrecht population: casecrossover study and standardized incidence ratio estimation. Stroke. 2009;40:1148–1151. 20. Finnerty JJ, Chisholm CA, Chapple H, et al. Cerebral arteriovenous malformation in pregnancy: presentation and neurologic, obstetric and ethical significance. Am J Obstet Gynecol. 1999;181:296–303. (c) 2015 Wolters Kluwer. All Rights Reserved.

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21. Ferro JM, Cahnao P, Stam J, et al. Prognosis of cerebral vein and dural sinus thrombosis: results of the international study on cerebral vein and dural sinus thrombosis (ISCVT). Stroke. 2004;35:664–670. 22. Klai S, Fekih-Mrissa N, Mrissa R, et al. Maternal cerebral venous thrombosis, uncommon but serious disorder, pathologic predictors and contribution of prothrombotic abnormalities. Fibrinolysis. 2013;24:269–272. 23. Coutinho JM, Ferro JM, Canhao P, et al. Unfractionated or low-molecular weight heparin for the treatment of cerebral venous thrombosis. Stroke. 2010;41:2575–2580. 24. Leonhardt G, Gaul C, Nietsch HH. Thrombolytic therapy in pregnancy. J Thromb Thrombolysis. 2006;21:271–276. 25. Nasr DM, Brinjikji W, Cloft HJ, et al. Mortality in cerebral venous thrombosis: results from the national inpatient sample database. Cerebrovasc Dis. 2013;35:40–44. 26. Saposnik G, Barinagarrementeria F, Brown RD, et al. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42:1158–1192. 27. Sillesen M, Hjortdal V, Vejlstrup N, et al. Pregnancy with prosthetic heart valves—30 years’ nationwide experience in Denmark. Eur J Cardiothorac Surg. 2011;40(2):448–454. 28. Reimold SC, Rutherford JD. Valvular heart disease in pregnancy. N Engl J Med. 2003;349:52–59. 29. Bonow RO, Carabellow BA, Chatterjee K, et al. 2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2008;52(13):e1–e142. 30. Bates SM, Greer IA, Pabinger I, et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy. American College of Chest Physicians evidence based clinical practice guidelines (8th Edition). Chest. 2008;133(6 suppl):844S–866S.

(c) 2015 Wolters Kluwer. All Rights Reserved.

22

Thromboembolic Disorders

Christian A. Chisholm, Andra H. James and James E. Ferguson II

KEY POINTS • The risk of venous thromboembolism during pregnancy and the puerperium is 0.5 to 2.0 per 1000 women, a four-to fivefold increase over the nonpregnant state. • Women with genetic and acquired thrombophilias incur a higher risk of thrombosis during pregnancy. • The risk for venous thromboembolism is approximately similar in all trimesters and postpartum; however, the risk of pulmonary embolism is highest postpartum and, in particular, following cesarean delivery. • The treatment of venous thromboembolism during pregnancy is heparin based; with rare exceptions, warfarin derivatives are contraindicated in pregnancy but not during the puerperium or lactation. VENOUS THROMBOEMBOLISM Background Definition

• Thromboses in the deep venous system or deep vein thrombosis (DVT) and pulmonary embolism (PE) are collectively known as venous thromboembolism (VTE). VTE occurs more frequently in pregnant women, with an incidence of 0.5 to 2.0 per 1000 pregnancies, roughly four to five times higher than in the nonpregnant population. The risk for VTE is further elevated in the postpartum period (1,2). • Pulmonary emboli, which occur in less than 1 in 1000 pregnancies, cause about 10% of maternal deaths in the United States (3). Most PE in pregnancy originates from DVT. Other causes include fat, amniotic fluid, and air emboli. Pathophysiology

• A combination of normal physiologic changes of pregnancy and external influences contributes to the increased risk of VTE by altering all three components of the Virchow triad. • Hormone-related increases in the hepatic synthesis of components of the clotting cascade: fibrinogen, prothrombin, and factors VII, VIII, IX, and X. In the postpartum period, concentrations of factors V, VII, and IX are further elevated. • Relative stasis of flow in the venous circulation, particularly in late pregnancy due to compression of the inferior vena cava by the expanding uterus. • Endothelial injury, most often occurring at delivery and particularly after operative delivery. Medical complications of pregnancy associated with endothelial dysfunction (e.g., preeclampsia) may also increase the risk of VTE. Epidemiology

• Risk factors for VTE in pregnancy (2,4) • Patient characteristics: age greater than 35 years, parity ≥3, African American race, positive family history (first-degree relatives) • Medical conditions: heart disease, blood disorders including sickle cell disease, autoimmune disorders including lupus and antiphospholipid syndrome, hypertension, diabetes, inflammatory bowel disease 389

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• Obesity • History of superficial thrombophlebitis (STP), varicose veins • Smoking • Surgery in pregnancy • Complications of pregnancy: °°Assisted reproduction, multiple gestation, hyperemesis, urinary tract infection, diabetes, antepartum hemorrhage, anemia • Peripartum complications: °°Preeclampsia, stillbirth • Complications of delivery and the puerperium: °°Cesarean delivery (especially emergency cesarean delivery), postpartum infection, postpartum hemorrhage, transfusion Evaluation

History and Physical

• STP may present with inflammation, local edema, and pain, commonly at intravenous (IV) catheter sites. • DVT is associated with pain, erythema, and edema, and most commonly occurs in a lower extremity. • The physical findings include tenderness to palpation of the involved extremity and asymmetric edema resulting in unequal calf circumferences (discrepancy of greater than 2 cm). DVT is more common in the left lower extremity, presumably due to relative compression of the left common iliac vein by the right common iliac artery. • Homans sign (calf tenderness on dorsiflexion of the foot) is neither sensitive nor specific for DVT in pregnancy, as most DVT in pregnancy occurs in the iliofemoral system. • PE may present with dyspnea, substernal or pleuritic chest pain, tachypnea, apprehension, and cough. • Significant emboli may present with cardiovascular collapse, shock, and/or death. • Signs include tachycardia, jugular venous distension, parasternal heave, rales, hemoptysis, fever, diaphoresis, a pleural rub, and an S3 murmur. Laboratory Tests

• In pregnant women suspected of having a PE, the laboratory testing may include • Arterial blood gases: °°Usually reveal arterial hypoxemia (PaO2 less than 70 mm Hg) without hypercarbia (normal PaCO2 in pregnancy = 28 to 32 mm Hg) or an increased alveolar–arterial oxygen gradient (greater than 15). °°PE is unlikely if the PaO2 is greater than 85 mm Hg. • d-dimer is a degradation product formed during the lysis of fibrin by plasmin. °°d-dimer concentrations (measured by ELISA) of less than 500 μg/mL in nonpregnant individuals essentially exclude PE (posttest probability less than 5%) (5). °°d-dimer concentrations are normally increased in pregnancy. Cases of DVT and PE have been reported with negative d-dimer levels; consequently, d-dimers should not be used to exclude DVT and PE in pregnancy (6). Genetics

• Hereditary thrombophilia (one or more) will be identified in at least 20% to 50% of women who experience VTE during pregnancy (2). • Testing for hereditary thrombophilia is appropriate in women with a history of VTE, as results of testing may affect the thromboprophylactic regimen (1). • General population screening for thrombophilia is not recommended, as the prevalence of some of these conditions is high, but the absolute risk of thromboembolism is low (7). • Thrombophilias are discussed elsewhere in this chapter. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Diagnosis

Clinical Manifestations

• STP is diagnosed by physical examination, which will demonstrate inflammation and tenderness, and often a palpable thrombus. • The clinical suspicion of DVT generally requires confirmation by imaging. Imaging Techniques

• The diagnosis of DVT may be confirmed by a variety of imaging modalities (1,6). • Venous ultrasonography has a 95% sensitivity and 96% specificity for the diagnosis of symptomatic proximal DVT in the general population. However, it is less accurate for calf and iliac vein thrombosis (8). Due to the high proportion of DVT occurring above the inguinal ligament, accuracy of ultrasound is likely reduced during pregnancy. Two components of venous ultrasound are utilized in this imaging modality: °°Compression ultrasound: The presence of a thrombus prevents coaptation of the vein walls. °°Duplex Doppler ultrasound: The absence of venous flow in the femoral system as measured by Doppler techniques indicates a proximal occlusion. This is valuable for assessing for the presence of iliac thrombosis. Color Doppler imaging may further enhance the value of this modality. • Occasionally, additional imaging may be required such as magnetic resonance venography or magnetic resonance direct thrombus imaging (Fig. 22-1) (1). • A number of imaging tests used in the evaluation of the patient with suspected of PE involve radiation exposure for the fetus. The total fetal radiation exposure in a woman  Q)  imaging, and pulmonary angirequiring chest radiography, ventilation/perfusion (V/ ography is estimated as 0.5 rad (5 mGy), substantially lower than the 1.0-rad exposure (10 mGy) threshold thought to increase slightly the risk of childhood malignancies (9). These tests should never be withheld in a pregnant woman suspected to have pulmonary thromboembolism, given the mortality of this condition. • Chest radiography will demonstrate vascular congestion, elevation of the hemidiaphragm, atelectasis, and pulmonary edema in up to 70% of patients with PE and will exclude pneumonia as an alternate diagnosis. Chest radiography results in less than 0.001 rad fetal radiation per exposure (less than 0.01 mGy) (9). • Electrocardiography may show tachycardia. The classic findings of acute cor pulmonale (right axis deviation with S1Q3T3 and nonspecific T-wave inversion) usually are seen only in massive PE.  Q)  scan results in a fetal radiation exposure of 0.1 to • Ventilation/perfusion (V/ 0.37mGy (9).  Q scan or perfusion scan alone should be performed next if the chest radiograph °°A V/ is normal (6) (a normal perfusion scan essentially excludes PE, and the additional imaging time and radiation exposure of the ventilation phase can be avoided.)  Q mismatch is very reliable for diagnosing PE in pregnancy (6). of a V/ °°The presence  Q defects may be seen in women with underlying pulmonary disease, °°Matching V/ and angiography may be necessary to diagnose or exclude PE.  Q scan over computed tomographic pulmonary °°The primary reason to choose V/ angiography (CTPA) is the increased radiation exposure to maternal breast tissue with CTPA (approximately a four- to eightfold increase) (6). • CTPA is the diagnostic test of choice if the chest radiograph is abnormal or unavailable (6) (and has become the first-line imaging test for PE in many institutions). Fetal radiation exposure is estimated at 0.006 to 0.096 rad per procedure (0.06 to 0.96 mGy) (9). °° CTPA may be considered diagnostic (posttest probability greater than 85%) when positive and exclusionary (posttest probability less than 1%; negative predictive value ~99%) when negative. °°If venous ultrasonography or additional imaging studies are abnormal, treatment for DVT should be initiated (Fig. 22-2). (c) 2015 Wolters Kluwer. All Rights Reserved.

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Suspect Lower Extremity DVT

Compression Ultrasonography of Lower Extremity(ies)

Results?

No

Negative

Equivocal and/or Suspect Iliac Vessel Process

Still With Concerns?

MRI of Iliac Veins

Positive

Yes Repeat Compression Ultrasonography in 3 Days

Results?

Positive

Negative

Follow

Treat

Figure 22-1. Recommended algorithm for evaluation of the pregnant patient with suspected deep venous thrombosis. Differential Diagnosis

• For a pregnant patient presenting with cardiovascular collapse, the differential diagnosis includes amniotic fluid embolism, hemorrhage, narcotic overdose, myocardial infarction, pulmonary thromboembolism, and tension pneumothorax. Stabilization is usually necessary before undertaking a full diagnostic evaluation. • When the clinical suspicion for pulmonary thromboembolism is high, anticoagulation with intravenous heparin should be initiated even before the diagnosis is confirmed. Treatment • Superficial thrombophlebitis (STP): • STP is treated with warm compresses, analgesia (acetaminophen), elevation, and oral antibiotics (if signs of infection are present). (c) 2015 Wolters Kluwer. All Rights Reserved.

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Suspected PE in Pregnancy

Present

CUS

Absent

Leg Symptoms Negative

CXR Abnormal

CTPA

Positive

Normal

Nondiagnostic

Negative Technically Positive Inadequate

TREAT

STOP

CUS,CTPA

V/Q

Positive Negative

TREAT

STOP

Figure 22-2. ATS/STR diagnostic algorithm for suspected PE in pregnancy. (Reprinted with permission of the American Thoracic Society. Copyright © 2013 American Thoracic Society. From Leung AN, Bull TM, Jaeschke R, et al. An official American Thoracic Society/Society of Thoracic Radiology clinical practice guideline: evaluation of suspected pulmonary embolism in pregnancy. Am J Respir Crit Care Med. 2011;184(10):1200–1208. Official Journal of the American Thoracic Society.)

• As embolism does not occur from the superficial veins, anticoagulation is not necessary. However, it may be useful to manage symptoms. • Risk for DVT is not increased. • DVT in pregnancy is managed with therapeutic-level heparin therapy, most commonly low molecular weight heparin (LMWH). Elevation of the involved extremity and early ambulation after resolution of pain and inflammation are important components of treatment for DVT. • With suspected PE in pregnancy, the initial treatment and monitoring should include (1,10): • Administration of oxygen by face mask • Evaluation for the need for thrombolysis (presence of hypotension or cardiogenic shock) • Intensive monitoring of cardiovascular and respiratory status • Opioid analgesia as needed for pain relief and mild pulmonary vasodilatation • IV unfractionated heparin (UFH) given acutely in doses to prolong the activated partial thromboplastin time (aPTT) to 1.5 to 2.5 times normal, followed by outpatient treatment with adjusted-dose UFH or LMWH (see below) Medications

Pharmacologic interventions to prevent and treat thrombosis in pregnancy rely primarily on the use of UFH or LMWH. • Nomenclature for anticoagulation regimens used during pregnancy (1): • Low-dose prophylaxis: a fixed dose of anticoagulant given subcutaneously one to two times per day without use of routine monitoring to verify a therapeutic prolongation of the aPTT or therapeutic increase in anti-Xa levels, for example: (c) 2015 Wolters Kluwer. All Rights Reserved.

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°°Low-dose UFH °°Low-dose LMWH

• Adjusted-dose prophylaxis: anticoagulation administered to achieve traditional therapeutic effects. °° Adjusted-dose UFH is given two to three times per day subcutaneously or by continuous IV infusion. Typical midinterval aPTT prolongation is 1.5 to 2.5 times normal (2). °°Adjusted-dose LMWH is given subcutaneously (only), and a therapeutic increase in anti-Xa level (0.6 to 1.0 units/mL) (10) 3 to 4 hours after injection is desired. • Unfractionated heparin (UFH) • Traditional method of heparin administration during pregnancy. Consequently, there is extensive experience with this method. • Molecular weight (MW): 3000 to 30,000 (mean 15,000) Da, with a negative charge. • Unreliable pharmacokinetics when administered subcutaneously with only 20% to 30% bioavailability. • Does not cross the placenta. • Binds to and increases the activity of antithrombin, a potent inhibitor of thrombin. • Short half-life of 1.5 hours. With IV administration, there is no detectable level 6 hours after discontinuation. • Therapeutic effect is measured by the aPTT or by anti-Xa levels. • Protamine sulfate is used when emergent reversal of anticoagulation is necessary. Complications

• Osteoporosis—2% risk of vertebral fracture. • Heparin-induced thrombocytopenia (HIT) is rare in pregnancy and likely occurs with less frequency than the 3% rate encountered in nonpregnant patients (10). Administration

• Low-dose UFH: A commonly advocated approach is • 5000 units SQ q12h in the first trimester • 7500 units SQ q12h in the second trimester • 10,000 units SQ q12h in the third trimester °°In general, aPTT does not need to be performed unless the daily dose exceeds 15,000 units/d. The main reason to perform aPTT is to prevent excessive anticoagulation. • Adjusted-dose UFH (SQ): Most often used in long-term treatment after 4 to 5 days of IV UFH. Initial dose of 10,000 units every 8 hours or 140 units/kg every 8 hours with an aPTT performed 4 hours after injection. Large doses (in excess of 30,000 units/d) are common during pregnancy. • Adjusted-dose UFH (IV): Most often used in the acute treatment of a DVT or PE during pregnancy and postpartum. An institutional heparin nomogram should be followed, whether that be standard care (a bolus of 5000 units given over 5 minutes, followed by 1000 to 2000 units/h) or weight based (loading dose of 80 units/kg, followed by 18 units/kg/h) (11). Therapeutic target is aPTT 1.5 to 2.5 times control. An aPTT should be performed 6 hours after the loading dose. • LMWH is increasingly used during pregnancy and is the most commonly used anticoagulant during gestation. There is a relative lack of controlled trials in pregnant women, with resultant unanswered questions about proper dosing and monitoring of anticoagulant levels. However, the potential advantages of LMWH (fewer bleeding complications, less frequent HIT) have made its use common. • Mean MW 3600 to 6500 Da. • Does not cross the placenta. • Anti-Xa levels are generally recognized as the most sensitive method for measuring anticoagulant effect. • Bioavailability is 85% to 90%. • Enoxaparin is available in 40-, 60-, 80-, 100-, 120-, and 150-mg syringes. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Complications

• HIT is very rare. • Risk of osteoporosis is reduced compared to UFH. • Difficult to reverse with protamine sulfate (10). Administration

• In nonpregnant patients, once-daily administration of LMWH may be recommended for acute treatment of thromboembolism; however, alterations in the hemostatic system associated with pregnancy change the pharmacokinetics of LMWH and commonly require twice-daily dosing. LMWH is not given intravenously. Current recommendations include • Low-dose LMWH: There is little consensus concerning the proper dosing regimen. Two regimens commonly reported in the literature are °°Once-daily regimen, for example, enoxaparin 40 mg qd. °°Twice-daily regimen, for example, enoxaparin 30 to 40 mg per q12h. °°The authors recommend the twice-daily approach for LMWH. • Adjusted-dose LMWH: °° A twice-daily regimen: Enoxaparin 1 mg/kg q12h or dalteparin 100 units/kg q12h. Based on the pharmacokinetics of enoxaparin, anticoagulant effect should be measured 3 to 4 hours after injection (12), by peak anti-Xa levels targeting 0.6 to 1.0 units/mL (1). It is not known how often levels should be measured. Recommendations from monthly to each trimester have been made (10). Special Considerations

• LMWH therapy is often changed to UFH at 35 to 37 weeks’ gestation. • Administration of epidural/regional anesthesia within 24 hours of LMWH injection may increase the risk of epidural hematoma, a serious complication. • LMWH should not be given for at least 2 hours after removal of an epidural/spinal catheter (13). • Coumarin: Coumarins such as warfarin (Coumadin) are restricted during pregnancy to very special circumstances such as artificial heart valves because of fetal hazards. Coumarins can be used postpartum. Consequently, pregnancy is one of the few situations where heparin is used for a prolonged period of time. • Warfarin derivatives cross the placenta, are teratogenic between 6 and 12 weeks of gestation, can cause fetal bleeding at any stage of pregnancy, and are associated with a high fetal loss rate. Their use is restricted to the second and early third trimester in certain cases of thrombogenic artificial heart valves as detailed in Chapter 21. Warfarin can be used safely in the postpartum period and during breast-feeding. • Warfarin is an antagonist of vitamin K, thereby decreasing the production of vitamin K–dependent clotting factors II, VII, IX, and X along with protein C (PC) and protein S (PS). • Warfarin is metabolized in the liver and kidneys. The half-life is 20 to 60 hours with a duration of effect of 2 to 5 days. • The anticoagulation effect of warfarin depends on the clearance of the functional clotting factors from the systemic circulation. • The earliest changes in the international normalized ratio (INR) occur 24 to 36 hours after the first dose. The early changes in the INR do not reflect the body’s ability to prevent clot expansion or prevent new thromboses. Rather, the antithrombotic effect—the ability to prevent both clot expansion and new clot formation—depends on the inhibition of factor II (prothrombin), which does not occur until around day 5 of treatment. • Loading doses of warfarin (10 mg/d or more) should not be used, as they do not inhibit thrombosis any more rapidly and may potentiate a hypercoagulable state via early depletion of PC and PS, which have a much shorter half-life than prothrombin: 8 versus 50 hours. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• The paradoxical hypercoagulable state from depletion of PC and PS necessitates the concomitant use of a heparin or other anticoagulant for the first 4 to 5 days of warfarin treatment. • Initial dosing should approximate the chronic maintenance dose, which is 4 to 6 mg/d. Typical target INR is 2.0 to 3.0. • Monitoring: INR monitoring should be performed daily until a therapeutic range is maintained for at least 2 consecutive days. INR monitoring should then be performed two to three times per week until stable. Under very stable circumstances, monitoring can be reduced to once every 4 weeks. • Complications: Maternal bleeding. The risks to the fetus are dose dependent and include intracranial hemorrhage and fetal death. Prophylaxis

Guidelines for prophylaxis of selected patients at high risk of VTE can be found in Table 22-1. Guidelines for cesarean for the peripartum interval include the following: • Any patient receiving thromboprophylaxis during pregnancy should receive thromboprophylaxis postpartum. • Women undergoing cesarean delivery should receive thromboprophylaxis with pneumatic compression devices (1). • Patients with multiple risk factors for DVT or PE should receive thromboprophylaxis with pneumatic compression devices and LMWH (1,10). Complications • Long-term complications of DVT include • Postthrombotic syndrome (pain, edema, and hyperpigmentation) • Deep venous insufficiency • Venous stasis ulcers Patient Education • Women with a confirmed VTE during pregnancy or the puerperium should be advised to avoid estrogen-containing oral contraceptives. GENETIC AND ACQUIRED THROMBOPHILIAS Background Definition

Thrombophilia is “the tendency to the occurrence of thrombosis” and may be genetic or acquired. The most common acquired thrombophilia is the antiphospholipid syndrome and is discussed in Chapter 10. Guidelines for prophylaxis to prevent VTE in patients with genetic thrombophilias are presented in Table 22-1. The most frequently encountered genetic thrombophilias are discussed below: Factor V Leiden (G1691A) Mutation Pathophysiology

• Mutation in nucleotide 1691 (G → A) of the factor V gene’s 10th exon results in a substitution of glutamine for arginine at position 506 in the factor V polypeptide (factor V Q506). • The resultant amino acid substitution impairs the activated PC and PS complexes’ proteolytic inactivation of factor Va leading to an augmented generation of thrombin. • Pregnancy-associated reductions in PS act to enhance factor V Leiden prothrombotic effects. Epidemiology

• Present in 5% to 9% of white European populations; it is much more rare in Asian and African populations. Overall prevalence in the general population of 1% to 15% (7). (c) 2015 Wolters Kluwer. All Rights Reserved.

Chapter 22 • Thromboembolic Disorders 

Table 22-1

  397

Guidelines for Prophylaxis of Selected Pregnant Patients at High Risk of VTE

Patient details Low-risk thrombophiliaa without previous VTE

Low-risk thrombophiliaa with a single previous episode of VTE—not receiving long-term ­anticoagulation therapy High-risk thrombophiliab without previous VTE

Antenatal recommendation Surveillance only or ­prophylactic LMWH or UFH

Low-dose LMWH/UFH or surveillance only

Low-dose LMWH or UFH

High-risk thrombophiliab with a single previous episode of VTE—not receiving long-term ­anticoagulation therapy

Low-dose or adjusteddoseLMWH/UFH regimen

No thrombophilia with previous single episode of VTE associated with transient risk factor that is no longer present— excludes pregnancy- or estrogen-related risk factor No thrombophilia with previous single episode of VTE associated with transient risk factor that was pregnancy- or estrogen-related No thrombophilia with previous single ­episode ofVTE without an ­associated risk factor (idiopathic)—not receiving long-term anticoagulation therapy Thrombophilia or no thrombophilia with two or more episodes of VTE (provoked or not)—not receiving long-term anticoagulation therapy

Surveillance only

Postpartum recommendation Surveillance only or postpartum low-dose LMWH or UFHd if the patient has additional risk factorse Low-dose LMWH or UFH for 4–6 wk postpartum

Low-dose LMWH or UFH for 4–6 wk postpartum Low-dose or adjusteddose LMWH/UFH for 6 weeks (therapy level should be at least as high as antepartum treatment) Low-dose LMWH or UFHc

Low-dose LMWH or UFHc

Low-dose LMWH or UFH for 4–6 wk postpartum

Low-dose LMWH or UFHc

Low-dose LMWH or UFH for 4–6 wk postpartum

Low-dose or adjusted-dose LMWH or UFH

Adjusted-dose LMWH orUFH for 6 wk

(Continued) (c) 2015 Wolters Kluwer. All Rights Reserved.

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Table 22-1

Guidelines for Prophylaxis of Selected Pregnant Patients at High Risk of VTE (Continued)

Patient details

Antenatal recommendation

Thrombophilia or no Adjusted-dose LMWH or thrombophilia with (a) two UFH or more episodes of VTE— receiving long-term anticoagulation therapy— and (b) long-term anticoagulation any indication

Postpartum recommendation Resumption of long-term anticoagulation therapy

Low-risk thrombophilia: factor V Leiden heterozygous; prothrombin G20210A heterozygous; protein C or protein S deficiency. b High-risk thrombophilia: antithrombin deficiency; double heterozygous for prothrombin G20210A mutation and factor V Leiden; factor V Leiden homozygous or prothrombin G20210A mutation homozygous. c Surveillance without anticoagulation is supported as an alternative approach by some experts. d Postpartum anticoagulation with low-dose LMWH 40 mg daily or 30–40 mg every 12hours, using higher doses when additional risk factors are present. LMWH is preferred to UFH except when rapid reversal may be needed. e First-degree relative with a history of thrombotic episode before age 50 y or other major thrombotic risk factors (e.g., obesity, prolonged immobility). LMWH, low molecular weight heparin; UFH, unfractionated heparin; VTE, venous thromboembolism. Adapted from James A. Practice Bulletin No. 123: Thromboembolism in pregnancy. Obstet Gynecol. 2011;118(3):718–729; Bates SM, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed.: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e691S–e736S. a

Evaluation Laboratory Tests

• Tests are DNA based and reliable during pregnancy. Genetics

• Autosomal dominant Diagnosis Clinical Manifestations

• Heterozygosity for factor V Leiden mutation is present in approximately 40% of pregnant patients with thromboembolic disease (7). • Heterozygosity is associated with an absolute thrombosis risk of less than 1.2% during pregnancy and the puerperium in women with no family history of VTE and 3.1% for those with such a history (10). • Homozygosity for the mutation is rare (less than 1%) and confers a 4.8% absolute risk of thromboembolism during pregnancy and the puerperium among women with no family history of VTE and 14.0% with such a history (10). • Compound heterozygosity for factor V Leiden and the prothrombin G20210A mutation is rare (0.01%) and is associated with an absolute risk of thromboembolism during pregnancy of 4.7%. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• This risk is increased to greater than 20.0% for women with factor V Leiden mutations and a prior personal history of VTE (7). Factor II (Prothrombin G20210A) Mutation Pathophysiology

• Mutation in the promoter located in the 3’-untranslated region of the prothrombin gene (G20210A) leads to increased (150% to 200%) circulating levels of prothrombin and an increased risk of thromboembolism. Epidemiology

• Present in 2% to 5% of the general population (7) Evaluation Laboratory Tests

• Tests are PCR based and reliable during pregnancy. Genetics

• Autosomal dominant Diagnosis Clinical Manifestations

• Among pregnant patients with a VTE, the mutation is found in approximately 17% (7). • Heterozygosity is associated with an absolute risk of VTE during pregnancy and postpartum of 1.0% among women with no family history of VTE and 2.6% with such a history (10). • Homozygosity is rare (less than 1%) and is associated with a 3.7% risk of VTE in pregnancy and postpartum among women with no family history of VTE (7,10). • This risk is increased to greater than 17% for women with factor II mutations and a prior personal history of VTE (7). Antithrombin Deficiency Pathophysiology

• Numerous point mutations, deletions, and insertions result in circulating concentrations of antithrombin insufficient to oppose the action of thrombin (factor IIa) and other activated clotting factors, including IXa, Xa, XIa, and XIIa (7). Epidemiology

• Present in 0.02% of the general population (7) Evaluation Laboratory Tests

• Concentrations unchanged during normal pregnancy. • Concentrations reduced in patients with nephrotic syndrome. • Heparin therapy interferes with measurement of antithrombin concentrations. • Two classes of AT deficiency: • Type I (quantitative deficiency) °°Most common °°Concomitant reduction in both antigenic protein levels and activity • Type II (qualitative deficiency) °°Normal antigenic levels but decreased activity Genetics

• Usually autosomal dominant Diagnosis Clinical Manifestations

• Significant lifetime risk of thromboembolism • Present in 1% of pregnant patients with thromboembolism (7) (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Antithrombin concentrations: • Mild deficiency: antithrombin activity 70% to 85%. • Severe deficiency: antithrombin activity less than 60%—VTE risk 0.7% during pregnancy and puerperium in those without a positive family history versus 3.0% with such history. The risk increases to 40% if there is a personal history of prior VTE. • Consider AT concentrates for women with AT deficiency who are pregnant or postpartum and have a personal history of VTE or new-onset or recurrent VTEs, AT levels less than 60% with a compelling family history and those with very low levels of AT (less than 40%) (14). Protein C Deficiency

Pathophysiology

• PC is a vitamin K–dependent anticoagulant that works in conjunction with PS to inhibit factors Va and VIIIa. • Deficiencies in PC result from numerous mutations. • Two primary types are recognized (7). • Type I—both immunoreactive and functionally active PC levels are decreased. • Type II—immunoreactive levels are normal but functionally active levels are decreased. Epidemiology

• Present in 0.2% to 0.4% in the general population (7) Evaluation Laboratory Tests

• Levels remain unchanged or may increase up to 135% during pregnancy. • Liver disease may reduce levels. Genetics

• Autosomal dominant Diagnosis Clinical Manifestations

• In patients without a family history, the risk of thromboembolism during pregnancy is 0.7% and 1.7% for those with a positive family history (10). • In heterozygous individuals with a personal history of VTE, the risk of thromboembolism approximates 4% to 17% if PC levels are less than 60 (7). • Homozygous individuals present with neonatal purpura fulminans at birth and extensive necrosis—pregnant women are unlikely to be encountered. Protein S Deficiency Pathophysiology

• PS is a vitamin K–dependent hepatic glycoprotein that acts as a cofactor for PC by promoting the binding of PC with the platelet surface membrane. • Three phenotypes: • Type I—reduced total and free immunoreactive forms • Type II—normal free immunoreactive levels but reduced APC cofactor activity • Type III—normal total immunoreactive but reduced free immunoreactive levels Epidemiology

• Present in 0.03% to 0.13% of the general population (7) Evaluation

Laboratory Tests

• Free PS levels fall significantly during pregnancy. • Liver disease may reduce levels. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Genetics

• Autosomal dominant Diagnosis Clinical Manifestations

• In patients without a family history, the risk of thromboembolism during pregnancy is 0.5% versus 6.6% for those with a positive family history (10). • In heterozygous individuals with a personal history of VTE, the risk of thromboembolism approximates 0% to 22% if PS free antigen levels are less than 55% (7). • Homozygous individuals present with neonatal purpura fulminans at birth and extensive necrosis—pregnant women are unlikely to be encountered. Other Thrombophilias • Hyperhomocysteinemia has been associated with an increased incidence of VTE in nonpregnant women; however, it does not appear that homozygosity for MTHFR C667T alone leads to an increased risk of VTE during pregnancy (10). • Other thrombophilias exist that appear to exert little independent risk of VTE, and there is insufficient evidence to recommend screening for these thrombophilias (7). This group includes alternative mutations in the factor V gene, a PAI-1 mutation, protein Z deficiency, and activity-enhancing mutations in various clotting factor genes. Patient Education • Reproductive-age patients with VTE outside of pregnancy require detailed evaluation and counseling prior to undertaking pregnancy. • A number of the etiologies for VTE have a genetic basis that requires counseling regarding maternal and fetal risks including the risk of transmission to the fetus. • Women on anticoagulation therapy require education regarding the risks of anticoagulant medications with pregnancy and treatment options prior to and during pregnancy. REFERENCES 1. James A. Practice Bulletin No. 123: Thromboembolism in pregnancy. Obstet Gynecol. 2011;118(3):718–729. 2. James AH. Prevention and treatment of venous thromboembolism in pregnancy. Clin Obstet Gynecol. 2012;55(3):774–787. 3. Berg CJ, et al. Pregnancy-related mortality in the United States, 1998 to 2005. Obstet Gynecol. 2010;116(6):1302–1309. 4. Abdul Sultan A, et al. Risk factors for first venous thromboembolism around pregnancy: a population based cohort study from England. BMJ 2013;347:f6099. 5. Cutts BA, Dasgupta D, Hunt BJ. New directions in the diagnosis and treatment of pulmonary embolism in pregnancy. Am J Obstet Gynecol. 2013;208(2):102–108. 6. Leung AN, Bull TM, Jaeschke R, et al. An official American Thoracic Society/Society of Thoracic Radiology clinical practice guideline: evaluation of suspected pulmonary embolism in pregnancy. Am J Respir Crit Care Med. 2011;184(10):1200–1208. 7. Lockwood C, Wendel G. Practice Bulletin No. 124: Inherited thrombophilias in pregnancy. Obstet Gynecol. 2011;118(3):730–740. 8. Kearon C, Ginsberg JS, Hirsh J. The role of venous ultrasonography in the diagnosis of suspected deep venous thrombosis and pulmonary embolism. Ann Intern Med. 1998;129(12):1044–1049. 9. Groen RS, Bae JY, Lim KJ. Fear of the unknown: ionizing radiation exposure during pregnancy. Am J Obstet Gynecol. 2012;206(6):456–462. 10. Bates SM, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed.: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e691S–e736S. (c) 2015 Wolters Kluwer. All Rights Reserved.

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11. Raschke RA, et al. The weight-based heparin dosing nomogram compared with a “standard care” nomogram. A randomized controlled trial. Ann Intern Med. 1993;119(9):874–881. 12. Casele HL, et al. Changes in the pharmacokinetics of the low-molecular-weight heparin enoxaparin sodium during pregnancy. Am J Obstet Gynecol 1999;181(5 Pt 1):1113–1117. 13. Horlocker TT, et al. Executive summary: regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Third Edition). Reg Anesth Pain Med. 2010;35(1):102–105. 14. James AH, Konkle BA, Bauer KA. Prevention and treatment of venous thromboembolism in pregnancy in patients with hereditary antithrombin deficiency. Int J Womens Health. 2013;2013(5):233–241.

(c) 2015 Wolters Kluwer. All Rights Reserved.

23

Infectious Complications Bonnie J. Dattel

KEY POINTS • Bacterial and viral infections are common in pregnancy with the potential for severe consequences due to the physiologic changes of pregnancy. • Treatment regimens for pregnant women must take into account the physiologic changes of pregnancy, the risks to the fetus, and optimal maternal health. • Women should be screened for common infections during pregnancy and receive appropriate preventive treatment based on the specific organisms identified. URINARY TRACT INFECTIONS Urinary tract infections are frequently encountered medical complications of pregnancy. • The three types of urinary tract infection in pregnancy are • Asymptomatic bacteriuria (ASB) • Cystitis • Pyelonephritis • The uropathogens most commonly isolated in ASB are similar to those in cystitis and pyelonephritis. Escherichia coli is the primary pathogen in 65% to 80% of cases. Other pathogens include Klebsiella pneumoniae, Proteus mirabilis, Enterobacter species, Staphylococcus saprophyticus, and group B β-hemolytic Streptococcus. Asymptomatic Bacteriuria

Background Definition

Asymptomatic bacteriuria is defined as persistent bacterial colonization of the urinary tract without urinary symptomatology. Epidemiology

• ASB occurs in 2% to 7% of pregnant women. • The prevalence of ASB in pregnant and nonpregnant women is similar; therefore, pregnancy is not believed to predispose to ASB. • However, ASB is more likely to become symptomatic and progress to pyelonephritis secondary to the physiologic changes of pregnancy (1). If untreated, 20% to 30% of pregnant women with ASB will develop acute pyelonephritis. Treatment

Treatment should be considered when two clean catch specimens are positive for the same bacteria 105 colony-forming units, or a single catheterized specimen is positive for 102 bacteria of the same species (see Table 23-1). Follow-up

• A negative repeat culture obtained approximately 10 days after completion of therapy is necessary to document successful treatment.

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Table 23-1

ACOG Recommended Oral Therapy for ASB or Acute Cystitis

Agent Trimethoprim–sulfamethoxazole Nitrofurantoin macrocrystals Nitrofurantoin monohydrate/macrocrystals Cephalexin

Dosage 160–180 mg q12h for 3 d 50–100 mg q6h for 3 d 100 mg q12h for 3 d 250–500 mg q6h for 3 d

If antibiotic sensitivities are available: Ampicillin Amoxicillin Trimethoprim Sulfisoxazole

250–500 mg q6h for 3 d 250–500 mg q8h for 3 d 200 mg q12h for 3 d 2-g loading dose, then 1 g q6h for 3 d

Maternal and Fetal Complications

• Acute pyelonephritis increases maternal risk for sepsis, respiratory insufficiency, anemia, and transient renal dysfunction. • ASB increases the risks of preterm labor, preterm birth, and low birth weight. • Therefore, all pregnant women should be screened for ASB early in pregnancy. Pyelonephritis • Acute pyelonephritis is most commonly treated with hospitalization and intravenous antibiotics. • Intravenous therapy is usually continued until the patient is afebrile for 24 to 48 hours and symptomatically improved. The patient can then be changed over to outpatient oral antibiotics to complete a total of 10 days of therapy. • Recommended antimicrobial regimens include • Trimethoprim–sulfamethoxazole, 160/800 mg q12h • Ampicillin, 1 to 2 g q6h, plus gentamicin, 1.5 mg/kg q8h • Ceftriaxone, 1 to 2 mg q24h • A third-generation cephalosporin first-line agent • Suppressive therapy. Women treated for pyelonephritis are placed on antibiotic suppression for the remainder of the pregnancy and periodically screened for recurrence. Choices for suppression are • Nitrofurantoin, 50 to 100 mg hs or • Cephalexin, 250 to 500 mg hs • All other women treated for urinary tract infections should have periodic rescreening for infection with cultures or urine dipstick for nitrates or leukocyte esterase. If infection recurs, patients are treated and then placed on chronic suppression. PNEUMONIA Background

Etiology

• Pneumonia is an infection with inflammation involving the parenchyma, distal bronchioles, and alveoli (2). • Approximately two-thirds of cases of pneumonia are bacterial in origin, with two-thirds of those caused by Streptococcus pneumoniae. This is followed by Haemophilus influenzae and atypical pathogens such as Mycoplasma and Legionella. • Two common viral agents are influenza A and varicella, which can be particularly menacing during pregnancy (2). • Opportunistic infections with fungi and protozoans are especially noted in immunocompromised patients. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Table 23-2

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Microbiologic Isolates from Pregnant Patients (Decreasing Frequency of Occurrence)

No organism isolated Streptococcus pneumoniae or Haemophilus influenzae Atypical bacterial agents Mycoplasma or Legionella Viral agents Influenza A or varicella-zoster virus Fungal/protozoal agents Enteric bacterial Escherichia coli or Klebsiella pneumoniae

Epidemiology

Pneumonia occurs in the pregnant population with a frequency equal to that of the general population. Diagnosis

• Laboratory tests to aid diagnosis of pneumonia include anteroposterior and lateral shielded chest x-ray, sputum Gram stain and culture, blood cultures, and complete blood count with differential. • In bacterial pneumonia, lobar consolidation is usually observed, with pleural effusion present in about 25% of cases. Leukocytosis may be present. Blood cultures are positive in about one-third of cases. • In viral pneumonia, the respiratory symptoms may not be impressive initially, but the pregnant patient can rapidly develop respiratory failure. Chest x-ray findings include a unilateral patchy infiltrate (2). Treatment

• Broad-spectrum antibiotic coverage is recommended. If the patient’s condition worsens, anaerobic and gram-negative coverage can be supplemented. • Once intravenous therapy is discontinued, oral therapy is continued for a total of 10 to 14 days (Tables 23-2 and 23-3).

Table 23-3

Therapy for Pneumonia

Antibiotic therapy for pneumonia • Ampicillin, 2 g IV q6h • Ceftriaxone, 1–2 g IV q24h • Cefotaxime, 1 g IV q6–8 h • Erythromycin, 500 mg to 1 g IV q6h • Azithromycin, 250 mg PO q12h • Gentamicin, 1.5 mg/kg IV initially, then 3 mg/kg/d • Clindamycin, 900 mg IV q8h Antiviral therapy (if needed) • Amantadine (for influenza) • Ribavirin (for influenza) • Acyclovir (for varicella)

(c) 2015 Wolters Kluwer. All Rights Reserved.

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TUBERCULOSIS Background • Tuberculosis (TB) is the leading infectious disease in the world. The majority of patients presenting with TB have pulmonary disease. • Progression of TB is not affected by pregnancy. • There is no evidence to suggest an increased incidence of preterm labor or other adverse pregnancy outcomes in cases of treated TB (3). Treatment • The currently recommended initial treatment of drug-susceptible TB disease in pregnancy is • Isoniazid (INH) and rifampin daily, with the addition of ethambutol initially. • Pyridoxine (50 mg qd) should always be given with INH in pregnancy because of the increased requirements for this vitamin in pregnant women. • If drug susceptibility testing of the isolate of M. tuberculosis reveals it to be susceptible to both INH and rifampin, then ethambutol can be discontinued. • If pyrazinamide is not used in the initial regimen, INH and rifampin must be given for 9 months instead of 6 months. • The treatment of any form of drug-resistant TB during pregnancy is extraordinarily difficult and should be handled by an expert with experience with the disease (2). • The treatment of asymptomatic TB (positive PPD) should be delayed until after delivery unless there is evidence of recent infection. • Because the risk of INH hepatitis is increased in the postpartum period, patients must be monitored closely for hepatotoxicity. Complications for the Fetus

• Congenital infection of the infant also can occur via aspiration or ingestion of infected amniotic fluid. If a caseous lesion in the placenta ruptures directly into the amniotic cavity, the fetus can ingest or inhale the bacilli. Inhalation or ingestion of infected amniotic fluid is the most likely cause of congenital TB if the infant has multiple primary foci in the lung, gut, or middle ear. • The mortality rate of congenital TB has been close to 50%, primarily because of failure to suspect the correct diagnosis. CHORIOAMNIONITIS AND ENDOMYOMETRITIS • In an uncomplicated pregnancy, there is no change in vaginal flora except for a progressive increase in colonization by Lactobacillus. • A pregnancy complicated by bacterial vaginosis, preterm labor, or premature rupture of membranes predisposes the woman to chorioamnionitis. • Postpartum, there are dramatic changes in the makeup of vaginal flora. There is a marked increase in the number of anaerobic species by the third postpartum day. Predisposing factors to anaerobic colonization include trauma, lochia, suture material, and multiple intrapartum vaginal examinations (4,5). Chorioamnionitis Background

Chorioamnionitis is an infection that involves the amniotic cavity and the chorioamniotic membranes. Microscopically, bacteria and leukocytes are noted between the amnion and the chorion. Pathogens

Chorioamnionitis is most commonly the result of ascending contamination of the uterine cavity and its contents by the lower genital tract flora, although systemic infections can infect the uterus via blood (Table 23-4). (c) 2015 Wolters Kluwer. All Rights Reserved.

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Table 23-4

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Chorioamnionitis Organisms

Aerobes Gram negative E. coli Other gram-negative bacilli

Anaerobes Gram negative Fusobacterium sp. Gardnerella vaginalis Bacteroides fragilis Bacteroides sp.

Gram positive Streptococcus agalactiae Enterococcus faecalis Staphylococcus aureus Streptococcus sp.

Gram positive Peptostreptococcus sp. Peptococcus sp. Clostridium sp. Facultative Mycoplasma hominis Ureaplasma urealyticum

Risk Factors

Risk facts for intra-amniotic infection include ruptured membranes before labor, labor duration, preterm labor, internal fetal monitoring, cervical examinations during labor, nulliparity, young age, meconium-stained amniotic fluid, cervical colonization (e.g., with gonorrhea or group B Streptococcus [GBS]), and bacterial vaginosis. Diagnosis

• The diagnosis is made by clinical examination, based on maternal and fetal manifestations of intrauterine infection. • Maternal manifestations include fever, tachycardia, uterine tenderness, foul-smelling amniotic fluid, and maternal leukocytosis (unreliable). • Fetal manifestations include tachycardia and possibly a non–reassuring fetal heart rate pattern. Treatment

• Intravenous antibiotics should be initiated immediately on diagnosis. • Prompt intrapartum administration of broad-spectrum antibiotic therapy (Table 23-5) results in better maternal and fetal outcomes than when therapy is delayed until after delivery.

Table 23-5

Chorioamnionitis: ACOG Recommendations Intravenous Therapy

Intrapartum: • Ampicillin, 2 g q4–6 h • Penicillin, 5 million units q4–6 h plus gentamicin (aminoglycoside), 1.5 mg/kg q8h If cesarean section is performed, then at cord clamp add: • Clindamycin, 900 mg q8h • Metronidazole, 500 mg q12h Alternatively, possible extended-spectrum, single-agent therapy may include (less information regarding efficacy) • Cefotetan, 2 g q12h • Ampicillin/sulbactam, 1.5–3 g q6h, or • Ceftizoxime, 1 g q8h, or • Ticarcillin/clavulanic acid, 3.1 g q4–6 h, or • Piperacillin, 3–4 g q4–6 h (c) 2015 Wolters Kluwer. All Rights Reserved.

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Complications for the Mother and Fetus

• The average interval between diagnosis of chorioamnionitis and delivery is from 3 to 7 hours. • There has never been a defined “critical time interval” after which maternal and neonatal complications increase. Recent studies have indicated that longer diagnosis-to-delivery times do not correlate with worsening prognosis of either mother or newborn. • Because there is little evidence that cesarean delivery offers an advantage over vaginal delivery, route-of-delivery decisions should be based on standard obstetric indications (5). GROUP B STREPTOCOCCUS Background • GBS is a leading cause of neonatal bacterial sepsis in the United States (6). Incidence has been decreasing after the release of revised disease prevention guidelines in 2002. • Streptococcus agalactiae is a gram-positive coccus that colonizes the lower gastrointestinal tract of approximately 10% to 30% of all pregnant women in the United States. Secondary spread to the genitourinary tract commonly ensues. • Colonization of the genitourinary tract creates the risk for vertical transmission during labor or delivery, which may result in invasive infection in the newborn during the first week of life. This is known as early-onset GBS infection and constitutes approximately 80% of GBS disease in newborns. • Invasive GBS disease in the newborn is characterized primarily by sepsis, pneumonia, or meningitis (7). The incidence of invasive GBS decreased from 0.47/1000 LB in 1999 to 2001 to 0.34/1000 LB in 2003 to 2005 (p < 0.001) (6). Evaluation Recommendations for Prophylaxis

The Centers for Disease Control and Prevention (CDC) recommends following a screening-based approach for the prevention of neonatal GBS disease. Screening-Based Approach

• All pregnant women should be screened by culture at 35 to 37 weeks of gestation for anogenital GBS colonization. • Patients should be informed of the screening results and of potential benefits and risks of intrapartum antimicrobial prophylaxis for GBS carriers. • Culture techniques that maximize the likelihood of GBS recovery should be used. Because lower vaginal and rectal cultures are recommended, cultures should not be collected by speculum examination. The optimal method for GBS screening is collection of a single standard culture swab or two separate swabs of the distal vagina rectum. Swabs may be placed in a transport medium if the microbiology laboratory is off-site. The sample should be identified as being specifically for GBS culture. • Laboratories should report the results to the delivery site and to the physician who ordered the test. GBS prenatal culture results must be available at the time and place of delivery. Treatment

• Intrapartum chemoprophylaxis should be offered to all pregnant women identified as GBS carriers by culture at 35 to 37 weeks of gestation. • If the results of GBS culture are not known at the time of labor, intrapartum antimicrobial prophylaxis should be administered if one of the following risk factors is present: • Less than 37 weeks of gestation • Duration of membrane rupture of 18 hours or more • Temperature of 100.4°F (38.0°C) or more • Women with GBS bacteriuria in any concentration in the current pregnancy or who previously gave birth to an infant with an early onset of the disease should receive intrapartum antimicrobial prophylaxis. • Women with negative vaginal and rectal cultures within 5 weeks of delivery do not require intrapartum antibiotics regardless of gestational age. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Oral antimicrobial agents should not be used to treat women who are found to be colonized with GBS during prenatal screening. Such treatment is not effective in eliminating carriage or preventing neonatal disease (8). • Routine intrapartum antibiotic prophylaxis for GBS-colonized women undergoing cesarean section deliveries without labor or membrane rupture is not recommended. Medications Intrapartum chemoprophylaxis

• For intrapartum chemoprophylaxis, intravenous penicillin G (5 million units initially and then 2.5 million units every 4 hours) should be administered until delivery. • Intravenous ampicillin (2 g initially and then 1 g every 4 hours until delivery) is an acceptable alternative to penicillin G, but penicillin G is preferred because it has a narrow spectrum and thus is less likely to select for antibiotic-resistant organisms. • For penicillin-allergic women, clindamycin (900 mg IV q8h until delivery) or erythromycin (500 mg IV q6h until delivery) may be used, although GBS resistance to clindamycin is increasing. (Penicillin G does not need to be administered to women who have a clinical diagnosis of amnionitis and who are receiving other treatment regimens that include agents active against streptococci.) (8) HUMAN IMMUNODEFICIENCY VIRUS Background Etiology

Perinatal transmission of HIV accounts for virtually all new HIV infections in children. Epidemiology

Women presented approximately 20% of the cases of AIDS reported to the CDC through 2003 (9). In the year 2000, an estimated 6000 to 7000 HIV-infected women gave birth, and an estimated 280 to 370 infants were infected in the United States. Of these HIVinfected women, one in eight did not receive prenatal care and one in nine did not have HIV testing before giving birth. The CDC estimates that the number of infants born with HIV each year dropped from 1650 (1991) to fewer than 200 (2004). Treatment Procedures

In 1994, following clinical trials that demonstrated a two-thirds reduction in perinatal HIV transmission with zidovudine (ZDV) therapy for infected pregnant women and their infants, the Public Health Service (PHS) issued guidelines for the use of ZDV during pregnancy. This was followed by recommendations for universal HIV counseling and voluntary testing of pregnant women in July 1995 (10) (Table 23-6).

Table 23-6

Time period Antepartum Intrapartum Neonatal

Zidovudine Therapy for the Prevention of Perinatal Transmission of HIV Therapy 100 mg ZDV five times per day PO after 14 wk of gestation 2 mg/kg body weight ZDV infused IV over 1 h, then 1 mg/kg body weight by continuous infusion until delivery Oral ZDV syrup, 2 mg/kg body weight every 6 h for 6 wk; first dose at 8–12 h of age if possible (may be given IV in newborns unable to take oral feeds)

From Dattel BJ. Antiretroviral therapy during pregnancy: beyond AZT (ZDV). Obstet Gynecol Clin North Am. 1997;24:645–657. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Risk Factors for Transmission

• Transmission of HIV infection from the mother to child is influenced by many factors. • Known correlates of HIV-1 transmission include high maternal plasma viremia, advanced clinical HIV disease, reduced maternal immunocompetence, prolonged duration of time after rupture of the amniotic membranes before delivery, vaginal delivery, direct exposure of the fetus to maternal blood during the delivery process, and prematurity or low birth weight of the newborn (11). • There is no single factor that, by itself, seems to accurately predict whether an individual woman will transmit HIV to her child. Antiretroviral Therapy

• ZDV monotherapy remains the standard for the prevention of vertical transmission of HIV, but it is not adequate for the treatment of pregnant women infected with HIV. • Optimal therapy is two nucleoside analog revised transcriptase inhibitors and a protease inhibitor. This regimen has significant beneficial effects on CD4 counts, viral load, and survival in comparison with ZDV monotherapy (12,13). • These treatment recommendations are based on the following risk for perinatal transmission: • Twenty percent among 396 women who do not receive antiretroviral drugs • Ten percent of 710 women taking ZDV alone • Four percent of 186 women receiving oral antiretroviral drugs • One percent of these taking three drug combinations • ZDV alone is no longer a preferred agent for the treatment of HIV in the nonpregnant patient but is considered a first-line agent during pregnancy. • Nevirapine should not routinely be initiated in treatment-naïve women with CD4 cell carry greater than 250 cells/mm3 because of potential hepatotoxicity and fatal risk. • Recommended regimens include • ZDV + lamivudine + lopinavir/ritonavir or atazanavir/ritonavir • Alternatives include • Zid + lamivudine + nelfinavir. • ZDV + lamivudine + nevirapine if CD4 less than 250. • ZDV + lamivudine + ritonavir-boosted saquinavir on darunavir. • Alternatively, nucleoside reverse transcriptase inhibitors (NRTI)/nonnucleoside reverse transcriptase inhibitors (NNRTIs) with good placental passage (tenofovir, emtricitabine, or abacavir) can be used if ZDV toxicity, such as severe anemia, develops. • Low CD4 counts of less than 200 cells/mm3 suggest more advanced disease. Women with low counts should receive ZDV and a multiple drug regimen (HAART therapy) (12). • Data suggest that patients with low viral loads (i.e., less than 2500 copies of HIV RNA per mL) are at lower risk of disease progression than those with high (2500 to 20,000 copies of HIV RNA per mL) or very high (greater than 20,000 copies of HIV RNA per mL) viral loads, indicating a relationship between increasing viral load and vertical transmission from the mother to fetus/infant. Development of a Treatment Plan

• To develop an appropriate treatment plan, the physician must know the status of the HIV-1–infected pregnant patient’s CD4 count and viral load. • Intrapartum ZDV therapy is not required if viral load is less than 400. OTHER VIRAL DISEASES Influenza Background

Influenza is an acute, communicable infection that occurs primarily in winter months. Because of its high infectivity and frequency of genetic mutation, novel strains of orthomyxovirus influenza, the etiologic agent, often cause major epidemics. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Diagnosis

• Generalized symptoms of headache, fever, myalgia, malaise, cough, and substernal chest pain appear abruptly within 1 to 2 days after infection. • Physical examination may reveal basilar rales. • The chest x-ray may show bilateral interstitial infiltrates. • Gram stains of sputum show insignificant numbers of bacteria and mononuclear cells. • Identification of the virus within exfoliated epithelial cells after reaction with fluorescent conjugates of an influenza antiserum is the only rapid method of definitive diagnosis. • The virus can be cultured from nasopharyngeal washings, nasal swabs, and throat swabs. • Serum antibody is detectable 2 to 3 weeks after infection by hemagglutination inhibition, neutralization, or complement fixation antibody testing. Paired specimens are necessary for the diagnosis. Prognosis

Influenza generally is a self-limited disease, but serious morbidity and mortality do occur. Mother

• Pregnant women are a high-risk group during influenza epidemics. • Increased mortality is caused by viral pneumonia itself and by superimposed staphylococcal and gram-negative enteric pneumonias. • Rates of spontaneous abortion are as high as 25% to 50%. Fetus

• Influenza virus can be transmitted transplacentally to the fetus. • Many studies of large numbers of patients have failed to link influenza and congenital malformations. However, serious maternal illness with hypoxia can cause premature labor and abortion. Treatment

• Hospitalization of pregnant women is required if febrile or with pulmonary symptoms due to high rates of pneumonia especially in the third trimester. • Antiviral prophylaxis should be initiated as soon as possible in pregnant women. Studies from 2009 to 2010 influenza season demonstrated less severe disease and fewer deaths. • Oseltamivir is generally preferred: 75 mg two times per day for 5 days. • Pregnant women who are seriously ill should be hospitalized. • Bacterial superinfection should be treated empirically on the basis of presumed pathogens. Nafcillin and either a third-generation cephalosporin or gentamicin would be adequate initial therapy, which can be modified later on the basis of culture results. • The CDC recommends that all pregnant women receive flu vaccine regardless of gestational age. Measles

Background

Measles (rubella) is a highly contagious, exanthematous, common childhood disease with peak incidence in the spring. Widespread vaccination had reduced the number of cases in the United States. However, worldwide measles remain a significant cause of morbidity and mortality making it the fifth most common cause of death in children under 5 years of age (14). Diagnosis

• Small, irregular, bright red spots (Koplik spots) that are diagnostic of measles appear on buccal and sometimes other mucosal membranes at the end of the 10- to 14-day incubation period. • Catarrhal symptoms of coryza, cough, keratoconjunctivitis, and fever are prominent early in the illness. • The maculopapular rash begins on the face and spreads downward to the extremities. • The rash, which often becomes confluent, fades in the same sequence. • Patients who are partially immune have milder catarrh, fewer Koplik spots, and a more discreet and fainter rash. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Measles virus can be identified by immunofluorescent testing in smears from nasal secretions, sputum, and oropharyngeal surfaces and by culture of these specimens. • Fourfold or greater increases in hemagglutination inhibition, neutralizing, or complementfixing antibodies can be demonstrated in convalescent serum drawn 2 to 3 weeks after infection. Prognosis

Mother

• Morbidity from the respiratory symptoms and rash and mortality from the infrequent complications of encephalitis and myocarditis are the same for pregnant and nonpregnant women. • Spontaneous abortions and premature deliveries are common. Fetus

• Measles virus penetrates the placenta, and newborns have or develop typical exanthematous lesions. • Most reports, but not all, indicate no increase in congenital malformations in infants born to infected mothers (15,16). Treatment Management

• Supportive measures of bed rest, fluids, antipyretics, expectorants, and steam inhalation reduce morbidity. • Immune serum γ-globulin (0.5 mL/kg) given within 6 days after exposure minimizes or prevents measles symptomatology. • Secondary bacterial complications, particularly pneumonia, are treated with appropriate antibiotics. Prevention

• Pregnant women who are exposed to measles and who are susceptible (i.e., do not have antibody) should receive γ-globulin. Infants born to women with active measles should receive γ-globulin (0.25 mL/kg). • Women who have not had measles or documented measles immunity should receive two doses of the live virus vaccine, 1 month apart, at least 30 days before becoming pregnant. Vaccine is contraindicated during pregnancy (see Table 23-7). • Women without documented immunity by history or serology or those patients vaccinated before 1980 should be revaccinated with two doses of the live virus vaccine before becoming pregnant because of waning immunity. Rubella

Background

• Rubella (German measles) is a highly contagious exanthematous disease of childhood and early adulthood. • Despite the availability of effective vaccines, up to 20% of women of childbearing age do not possess rubella antibody (17). Diagnosis

• Fever, cough, conjunctivitis, headache, arthralgias, and myalgias occur after a 14- to 21-day incubation period and a 1- to 5-day prodromal period. • Postauricular, occipital, and cervical lymphadenopathies are prominent early findings. Arthritis is a frequent occurrence in adult women. • The maculopapular rash begins on the face, spreads downward, and subsequently fades in the same top-to-bottom order. • The illness lasts from a few days to 2 weeks. • Rubella virus can be isolated from pharyngeal secretions, blood, urine, and stools.

(c) 2015 Wolters Kluwer. All Rights Reserved.

(c) 2015 Wolters Kluwer. All Rights Reserved. Serologic testing of women in childbearing age should determine need for vaccination

0.25 mL/kg immune serum globulin to exposed susceptible women within 6 d of exposure

Contraindicated

None confirmed; teratogenicity is suspected Contraindicated

Live attenuated virus vaccine

Rubella Low morbidity and mortality; not altered by pregnancy High rate of abortion and congenital rubella syndrome in first trimester

None confirmed

Live attenuated virus vaccine

Measles Significant morbidity; low mortality; not altered by pregnancy Significant increase in abortion rate; no malformations reported

Passive immunization with mumps is not indicated

Contraindicated

None confirmed

Mumps Low morbidity and mortality; not altered by pregnancy Slightly increased fetal mortality in serious infections; no confirmed congenital abnormalities Live attenuated virus vaccine

HbsAg, hepatitis B surface antigen; d, day. Adapted from Leontic EA, Respiratory disease in pregnancy. Med Clin North Am. 1977;61:111.

Indications for vaccination during pregnancy Comments

Recommended for patients with serious underlying disease Amantadine may be of value in influenza A infections, but because of possible teratogenicity, its use should be avoided

Inactivated type A and type B virus vaccines None confirmed

Vaccine

Risk of vaccine to fetus

Influenza Increase in morbidity and mortality, particularly during epidemics Increased rate of abortion; no increase in malformations

Immunization for Viral Infections During Pregnancy

Variable Risk of disease to pregnant women Risk of disease to fetus or newborn

Table 23-7

Not recommended for adults except in epidemics or close contact with a suspected case Salk vaccine indicated for nonimmunized women traveling in endemic areas (see text for details)

Immune serum globulin has failed to prevent hepatitis B in newborns; hepatitis B immune globulin and vaccine should be given to newborns (see text for details)

Recommended for pregnant women at high risk

Hepatitis B Possible increase in severity in pregnant women from nutritionally deprived backgrounds Anoxic fetal damage Hepatitis B is transmitreported; 25% mortality in ted transplacentally, neonatal disease; paralysis sometimes causing but no increase in conneonatal hepatitis; no genital abnormalities increase in congenital defects or abortions Live attenuated virus vac- Recombinant subunit cine (Sabin) or killed virus vaccine (HBsAg) vaccine (Salk) None confirmed Unknown

Poliomyelitis Increased incidence and severity in pregnancy

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• Increases in hemagglutination inhibition, neutralizing, and complement-fixing antibodies are demonstrable 2 to 4 weeks after infection. Most laboratories presently use enzymelinked immunosorbent assay (ELISA) or latex agglutination testing of paired sera to detect recent infection. Prognosis Mother

• Morbidity from the rash, respiratory illness, arthritis, and infrequent encephalitis are the same for pregnant and nonpregnant women. Fatality is rare. • Spontaneous abortion and stillbirth are two to four times more frequent in pregnancies complicated by rubella. Fetus

• Direct infection of the fetus occurs. • If the disease is acquired during the first trimester of pregnancy, the risk of fetal malformation or death ranges from 10% to 34%. • Acquisition of infection later in pregnancy results in fewer and usually less deleterious fetal abnormalities. • Manifestations of congenital rubella include cataracts, blindness, cardiac anomalies (patent ductus arteriosus, ventricular septal defect, pulmonary valve stenosis), deafness, mental retardation, cerebral palsy, violaceous birthmarks, hepatosplenomegaly, thrombocytopenic purpura, hemolytic anemia, lymphadenopathy, encephalitis, and cleft palate (18). Treatment Management

• Supportive measures of bed rest, fluids, and acetaminophen for treatment of headache and arthritis usually suffice for this mild, self-limited illness. • Therapeutic abortion should be considered except in instances in which infection is known to occur in the third trimester of pregnancy. During 2001–2004, the median number reported was 13. Since 2001, only five infants with congenital rubella have been reported. • Epidemiologic evidence suggests rubella is no longer endemic in the United States. Prevention

• Prepubertal and nonpregnant postpubertal women without documented antirubella antibodies should be immunized with live attenuated rubella vaccine. • Women who are vaccinated should not become pregnant for 3 months after vaccination. • Neither accidental immunization of a pregnant woman nor exposure to virus shed by recently immunized children has resulted in fetal infection (see Table 23-7). • Rubella vaccine exposure in pregnancy is not an indication for termination. Mumps

Background

Mumps is a contagious disease of children and young adults (18). Diagnosis

• Fever, myalgia, malaise, and headache of variable severity occur after a 2- to 3-week incubation period. • Parotitis is the most prominent feature, and this finding establishes the diagnosis. • Mastitis and oophoritis can occur in postpubertal women. • The demonstration of immunoglobulin M (IgM) antibody by immunofluorescent techniques or a fourfold or greater increase in serum complement-fixing antibody confirms the diagnosis. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Prognosis Mother

• The morbidity from parotitis and the complications of mastitis, oophoritis, and encephalitis are the same for pregnant and nonpregnant women. • Spontaneous abortions are more frequent in women who are infected during the first trimester of pregnancy. Fetus.  There has been a growing controversy concerning the development of congenital

endocardial fibroelastosis (19).

Treatment Management

• Administer symptomatic treatment to relieve the discomfort of fever and parotitis. • Passive immunization with hyperimmune mumps immunoglobulin is no longer recommended because the drug is not of value. Prevention

Vaccination with live attenuated mumps virus is suggested for nonpregnant postpubertal women who have not had mumps parotitis (see Table 23-7). Poliomyelitis Background

Poliomyelitis, currently a rare illness in pregnancy, was, in the prevaccine era, more common and more severe in pregnant than in nonpregnant women of similar age (20). This increase in incidence was attributed to hormonal changes in pregnancy and to greater exposure to young children. Diagnosis

• Fever, headache, coryza, nausea, vomiting, and sore throat precede the characteristic paralytic phase, which is marked by hyperesthesia, muscle pain, and flaccid paralysis. • Poliovirus can be isolated from feces, serum, and cerebrospinal fluid (CSF). • Increases in neutralizing and complement-fixing antibodies are demonstrable in serum obtained at 2 and 4 weeks after infection. Prognosis Mother

• In the prevaccine era, morbidity and mortality were higher in the pregnant than in the nonpregnant state. • The incidence of abortion is increased. Fetus

• There is no increase in the incidence of congenital abnormalities with intrauterine infection. • Paralysis and growth retardation occur in infants infected in utero. Neonatal poliomyelitis has a mortality of approximately 25%. Treatment Management

• Isolation procedures are required for infected mothers and newborns to prevent spread of the infection through excretory products. • Supportive care to prevent deformities and, if necessary, to maintain adequate maternal ventilation is indicated during the acute illness. Prevention

• If immediate protection against poliomyelitis is needed because of travel to an endemic area, a single dose of oral vaccine is given unless time permits the schedule required for the inactivated vaccine (see Table 23-7). • The inactivated vaccine is recommended for booster injections because the live attenuated oral vaccine has, on rare occasions, caused poliomyelitis in adults. (c) 2015 Wolters Kluwer. All Rights Reserved.

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COXSACKIE VIRUSES Background Coxsackie virus serotypes A and B cause a wide spectrum of brief, self-limited illnesses involving one or more organ systems (20). Diagnosis

• Herpangina, lymphonodular pharyngitis, and rhinopharyngitis indistinguishable from rhinovirus-induced common colds occur in pregnant women infected with coxsackievirus A. Aseptic meningitis is caused by both serotypes. Pleurodynia is caused by infections with coxsackievirus B. • Coxsackievirus can be isolated from pharyngeal secretions and feces, but for practical purposes, culture is rarely performed. • Because of the large numbers of serotypes, serologic proof of infection—demonstration of fourfold or greater increases in neutralizing or complement-fixing antibody—is impractical except in epidemics. Prognosis Mother

• The coxsackievirus-induced illnesses are self-limited and are not associated with significant maternal mortality. • The incidence of abortion is not increased. Fetus

• Coxsackievirus A infections are of no consequence to the fetus. • Coxsackievirus B infections cause serious illness (myocarditis and encephalitis) and fetal mortality in the perinatal period. The most common defect associated with coxsackievirus B infection is tetralogy of Fallot, but definitive evidence linking this or other congenital abnormality to coxsackievirus B infections is lacking. Treatment Management

• Symptomatic treatment is indicated for the mother, and supportive treatment is indicated for the fetus with myocarditis or encephalitis. • Newborns who survive infection usually do not have residual defects. Prevention

No vaccine is available. Varicella (Chickenpox)-Zoster Background

• Varicella is a common childhood illness caused by the varicella-zoster herpes virus that is characterized by cutaneous vesicles that crust and scab. It is transmitted by droplets or by direct contact with an infected person and is highly contagious to susceptible persons after household exposure. • Most cases occur in children so that 95% of adults show serologic evidence of immunity (21). • The mean incubation period of varicella is 15 days, with a range of 10 to 21 days. • Infectivity occurs from 2 days before the onset of skin lesions until 5 days after the lesions have crusted. • Childhood varicella usually is uncomplicated, and although varicella is uncommon in adults, adulthood varicella carries increased risks of death from pneumonia. Diagnosis

• Before the onset of rash, a 1- to 2-day prodromal period of fever, headache, malaise, and anorexia may occur. Prodromal symptoms increase with age. • Characteristic skin lesions appear on the trunk, scalp, face, and extremities. In a normal host, rash progresses in stages over a 1-week period: maculae, papule, vesicle, pustule, and crusted lesion. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• If present, fever lasts 1 to 3 days. All organ systems may be involved. • Pneumonia and hepatitis are the primary serious complications. Treatment Healthy Woman Presenting for Preconceptional Counseling or First Prenatal Visit

• If a woman has a positive history of chickenpox, she is considered immune; therefore, a question about a history of chickenpox should be included during preconceptional counseling and at the initial prenatal visit. • Women with a negative or equivocal history should have a serum varicella titer drawn to determine their immune status (varicella IgG). • Also, because the vaccine may not be as immunogenic as past natural infection, patients who have been vaccinated should have serologic testing for varicella titers. • Because the vaccine consists of a modified live virus, nonimmune women who are not pregnant can receive the vaccine but should avoid pregnancy for 1 month thereafter. • Nonimmune pregnant women should receive the vaccine postpartum; the vaccine is not contraindicated with breast-feeding (22) • There is no risk for pregnant women of acquiring varicella from children with recent varicella vaccination. A Nonimmune Pregnant Woman Exposed to Chickenpox

• A person with chickenpox is infectious from 2 days before the appearance of typical lesions until 5 days after the vesicles crust over. • It is important to note that 85% of adults who do not recall having had chickenpox nevertheless have protective antibody levels. • In a potentially exposed patient, determining her varicella titer first is preferable to administering varicella-zoster immunoglobulin (VZIG), because VZIG is relatively expensive (~$400 for the usual adult dose) and because it is not stocked in local pharmacies. The patient’s serum must be collected within 10 days of the earliest exposure because only by then can it be determined if the antibody detected is an indication of protection from prior exposure versus antibody response to the current exposure. • VZIG must be administered within 96 hours of exposure, and it provides no benefit when administered after the onset of symptoms. VZIG reduces the rates of clinical varicella in exposed persons, but it has not been shown to prevent adverse fetal effects; therefore, VZIG’s only purpose is to prevent or reduce the severity of illness in the mother (22). A Pregnant Woman with Chickenpox

• All patients with suspected varicella infection should be isolated and evaluated with only varicella-immune medical staff in attendance. • The diagnosis is usually clinical. Fever, malaise, and the characteristic rash appear 10 to 21 days after exposure. • The care is isolated palliation. • The most dangerous maternal complication is varicella pneumonia. When varicella pneumonia develops in pregnant women, the morbidity and mortality are comparatively high. Supportive oxygen and ventilator therapy should be used as indicated. There is general agreement that intravenous antiviral therapy should be given to pregnant women with any respiratory embarrassment associated with chickenpox. • Antiviral therapy consists of inhibitors of herpes DNA polymerase (acyclovir, famciclovir, and valacyclovir). There are insufficient data regarding the risk/benefit ratio of giving these antivirals to pregnant varicella patients without pulmonary symptoms (22). Chickenpox in the Immediate Peripartum Period

• When maternal chickenpox breaks out close to the time of delivery, the mother may infect the baby before there has been adequate time for her to produce and transfer protective antibodies across the placenta. These newborns suffer high morbidity and mortality rates. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• If mothers contract chickenpox between 5 days before and 2 days after delivery, their newborns should receive VZIG. Because VZIG does not always prevent neonatal chickenpox in this scenario, acyclovir may be a useful supplement in their management. Pediatric consultation is advised (22). Maternal Complications

• Varicella infection may range from a trivial illness with a few skin lesions to a major life-threatening episode. The infection can result in complications such as pneumonia, encephalitis, visceral dissemination, or hemorrhagic varicella. • Varicella acquired later in pregnancy, particularly in the third trimester, appears to be associated with increased morbidity, with a greater severity of pneumonia, a higher incidence of hospitalization, and an increased requirement for mechanical ventilation, compared to that acquired earlier in pregnancy (23). Fetal Complications

• Fetal involvement has been traditionally divided into three forms: • “Varicella embryopathy” stemming from maternal disease occurring before 20 weeks of gestation • Congenital varicella resulting from maternal infection from 20 weeks of gestation until term, but more commonly close to term • Neonatal disease occurring when the pregnant patient has active lesions around the time of delivery (24) • There is a wide range of fetal anomalies attributed to varicella-zoster. The risk of fetal anomalies correlates with the trimester in which infection occurred • First-trimester infection = 0.5% to 6.5% • Second- and third-trimester infection = 0% to 1.1% (25) Fetal varicella syndrome is associated with maternal infection within the first 20 weeks of gestation. It can include low birth weight as well as dermatologic, neurologic, ophthalmologic, skeletal, gastrointestinal, and genitourinary abnormalities. Herpes Zoster

Endogenous reactivation of latent varicella zoster not associated with significant risk of congenital varicella syndrome. Passage to fetus is rare. Treatment is similar to nonpregnant adults. CYTOMEGALOVIRUS Background Definition

Cytomegalovirus (CMV) is a member of the herpesvirus family of double-stranded DNA viruses. • It is the most common congenital viral infection with birth prevalence of 0.5% (26). • It inserts itself into host cells creating characteristically large cells with prominent intranuclear inclusion bodies. • The replicative cycle of CMV is divided into three periods: immediate-early, early, and late. Monoclonal antibodies against proteins from these three periods have been used to detect the presence of the virus, using rapid viral diagnostic techniques such as the shell vial culture–enhancement system (26). Epidemiology

• On the basis of antibody testing, CMV infects 50% to 60% of women of childbearing age (27). Pregnant women usually acquire CMV infection initially by exposure to body excretions (saliva, urine) of young children or by intimate sexual contact (28). • The virus is present in the urine of approximately 5% of pregnant women. Increased cervical excretion of CMV is seen in the third trimester. • Virus shedding is much more common in women younger than 30 years. Interestingly, the majority of congenital CMV infections occur in infants of women younger than 30 years of age (27). (c) 2015 Wolters Kluwer. All Rights Reserved.

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• CMV is the most common viral cause of intrauterine infection, and it is the major ­infectious factor known to be associated with congenital mental retardation and deafness (29). It has been estimated that the overall burden of congenital CMV infection to the health care delivery system is in excess of $1 billion (30). • The period of greatest risk for fetal disease and subsequent neurologic impairment is the first 22 weeks of gestation. • Fetal infection may follow either primary or recurrent maternal infection. Primary maternal CMV infection is associated with a more serious and a much higher incidence of congenital infection than recurrent maternal CMV infection (31). • Primary maternal CMV infection affects approximately 1% of all pregnancies, and the infection carries a 50% risk of intrauterine transmission, with a 10% risk of symptomatic congenital sequelae at birth or in early infancy (32). • Although the rate of recurrent maternal CMV infection is about 10 times greater than that of primary maternal CMV infection, the risk of intrauterine infection from recurrent maternal CMV infection is only about 1% (26,33). Diagnosis

• Adult infections usually are asymptomatic. Symptomatic infections resemble infectious mononucleosis and present with low-grade fever, malaise, lymphadenopathy, and hepatosplenomegaly. • Laboratory studies show leukocytosis with atypical lymphocytes, abnormalities in hepatocellular function, and a negative heterophile antibody test for mononucleosis. • CMV can be cultured from blood, saliva, urine, and cervical mucus. Because many patients excrete CMV, the demonstration of increases in antibody titers in convalescent serum is the most accurate means of documenting a newly acquired infection. • Identification of the virus can be accomplished with anti-CMV antibodies. Polymerase chain reaction (PCR) can be used to identify the presence of CMV DNA in amniotic fluid, urine, blood, and saliva (27). Prognosis Mother

• CMV infection is self-limited and without any increased morbidity or mortality in pregnancy. • The infection also is not known to increase the incidence of abortion or premature delivery. Fetus

• Infection of the fetus occurs either in utero by transplacental passage of the virus or at birth when the fetus traverses an infected birth canal. • It has been estimated that the prevalence of intrauterine CMV infections is between 0.2% and 2.5% of births. • Abnormalities of variable severity affect approximately 10% of infected infants and include microcephaly, diminished mentation, chorioretinitis, hearing loss, intracranial calcifications, and hepatosplenomegaly. Intrauterine infection can also result in stillbirth. • Additionally, 5% to 20% of asymptomatic congenitally infected infants will experience late manifestations that include neuromuscular disturbances, auditory damage, and visual impairment (27). • Hyperimmunoglobulin therapy of pregnant women with primary CMV is a promising but investigational approach. Treatment Management

Administer symptomatic treatment to relieve discomfort. Ganciclovir, an antiviral agent, is efficacious in the treatment of CMV retinitis and GI disease. Its value in pregnancy is unknown. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Prevention

No vaccine is currently available. Prenatal diagnosis of congenital CMV can be accomplished with serologic testing of amniotic fluid. VIRAL HEPATITIS Background Viral hepatitis (hepatitis A, B, or C) is one of the most serious diseases in the United States and is the most common cause of jaundice during pregnancy (34). • Hepatitis A has an incubation period of 25 to 40 days. Infection is transmitted by the fecal–oral route. Maternal transmission to the fetus does not occur. • Hepatitis B has a 50- to 180-day incubation period and is transmitted by contaminated blood, saliva, breast milk, and semen. Pregnant women who are infected transmit the virus transplacentally to the fetus and at birth. Neonatal hepatitis seldom occurs if the mother is a chronic carrier or acquires hepatitis early in pregnancy; the risk is high when infection occurs late in pregnancy. • Hepatitis C, which occurs in the same settings as hepatitis B, has an incubation period of approximately 9 weeks. Infection with hepatitis C virus (HCV), a small RNA virus, is characterized by persistent viremia. Two studies demonstrate that the risk of vertical transmission is low, with rates of approximately 6% (35). The risk of transmission correlates with the HCV viral titer in the mother (35). Diagnosis

Clinical Symptoms

• Except for fever being more common in hepatitis A and prodromal arthralgias occurring in 20% of patients with hepatitis B, the clinical presentations of both viruses are similar, being marked by anorexia, nausea, and malaise. • Jaundice with hepatic tenderness and enlargement occurs in the first weeks following the onset of symptoms. Pruritus may also be present. • In hepatitis A, the onset of jaundice is associated with rapid improvement in symptoms. Hepatitis B infection causes more prolonged symptomatology and jaundice. • Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) are markedly elevated, signifying hepatocellular damage. The serum bilirubin also is increased significantly, whereas the serum alkaline phosphatase is minimally elevated. Antibody Studies

• Hepatitis A infection is diagnosed by demonstrating hepatitis A IgM antibody or by culturing the virus from stool. • Hepatitis B infection is diagnosed by demonstrating hepatitis B surface antigen (HBsAg) in serum and increases in hepatitis B core antibody (HBcAb) and hepatitis B surface antibody (HBsAb). Hepatitis B e antigen (HBeAg) is present in HBsAg-positive sera, and its persistence is associated with chronic hepatitis and increased infectiousness. • Hepatitis C is diagnosed by detection of antibodies using a second-generation enzyme immunoassay. Confirmation is accomplished using a radioactive immunoblot assay (RIBA). Prognosis Mother

• An increased severity of illness has been reported in pregnant women from nutritionally deprived backgrounds. Whether this association applies in developed countries is uncertain. • Viral hepatitis is associated with an increased risk of premature labor. Fetus

• The risk of fetal infection depends on the timing of the maternal infection. • Hepatitis B virus is transferred from mother to infant in 75% of cases when infection occurs in the last trimester of pregnancy and in only 10% of cases when infection occurs earlier. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Neonatal hepatitis is more common in infants whose mothers are infected in the last trimester. • Congenital defects are not increased in infants born to infected mothers. • Because infection with HCV is chronic, no difference can be determined regarding infection rate of the fetus and the timing of the primary infection. Treatment Management

• Bed rest and diet should accord with the patient’s desires and tolerance. • Hepatitis B immune globulin is recommended for newborns born to HBsAg-positive women, particularly if infections occurring in the second half of pregnancy. HBV vaccine should be given concomitantly with immune globulin with additional doses at 1 and 6 months. • Two indications for use of antiviral therapy during pregnancy: • Treatment of chronic disease in mother • Decrease risk of transmission • Lamivudine and telbivudine are preferred. Prevention

• Human immune serum globulin, 0.02 mL/kg to a total of 2.0 mL, is given as prophylaxis for hepatitis A. • Human immune serum globulin, 0.04 mL/kg to a total of 4.0 mL, is given as prophylaxis for hepatitis B. Alternatively, hepatitis B immune globulin, 0.05 to 0.07 mL/kg, can be given twice, once within 7 days of exposure and again 25 to 30 days after the first injection. • Hepatitis B vaccine is available for individuals at high risk of infection, and pregnancy is not considered a contraindication. • No prophylaxis or treatment is available for pregnant women with HCV infection or their infants. • All newborns now receive their first hepatitis B immunization before discharge from the nursery. RABIES Background Definition

Rabies is an almost invariably fatal infection that is transmitted by exposure to salivary secretions containing the neurotropic virus (36). Etiology

Most human cases result from bites or licks of an infected animal, usually a dog. On occasion, respiratory infection occurs when persons enter caves inhabited by rabid bats. Treatment

• Because prevention is paramount in this disease, which has an incubation period of 10 days to 1 year, the critical decisions relate to prophylaxis. • The following are guidelines for determining prophylaxis: • Dogs and cats that are considered healthy should be observed for signs of rabies. If disease does not develop in 10 days, prophylaxis is unnecessary. If the animal dies, the brain should be examined for the presence of virus. Rabies is proved by identifying viral antigen, by virus isolation, or by finding Negri bodies. If rabies is found, the patient is treated with a single dose of rabies immune globulin, 20 international units/kg, and a course of human diploid cell vaccine, five 1-mL doses IM, to be given on days 0, 3, 7, 14, and 28. Serum for rabies antibody testing should be collected 2 to 3 weeks after the last dose. If no antibody response occurs, a booster dose should be given. • If the animal escapes or is suspected of being rabid, or if the bite is from a wild animal (e.g., skunks, raccoons, or foxes), treatment with rabies immune globulin and human diploid cell vaccine is instituted. (c) 2015 Wolters Kluwer. All Rights Reserved.

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PARVOVIRUS B19 Background Definition

Parvovirus B19 is a common cause of human infection worldwide. Etiology

• The virus is transmitted by the respiratory route. • Parvovirus B19 is present in blood, and although viremia is rare, infection can also be transmitted by blood and blood products (37). Epidemiology

• Women of childbearing age show an average annual seroconversion rate of 1.5%. • There is no evidence of reinfection in immunocompetent individuals. Pathogenesis

Parvovirus B19 has a special predilection for the erythroid system. • It attacks the final stage of the red blood cell line in the bone marrow, causing both hemolysis and red blood cell aplasia, resulting in anemia without reticulocytosis. • Occasionally, the virus may strike all cell lines, resulting in pancytopenia. • The fetus can be severely affected because the half-life of red blood cells in the fetus is 50 to 75 days, and production has to be increased in order to maintain a normal blood volume. Diagnosis

• Parvovirus B19 cannot be cultured directly on traditional culture media. • Maternal serum evaluation for parvovirus B19–specific IgG and IgM is most commonly used for diagnosis of acute infection. • The diagnosis of congenital infection includes neonatal evaluation of IgG-, IgM-, and IgM-specific parvovirus B19 serologies as well as PCR amplification of viral DNA. • Ultrasound Doppler velocimetry to evaluate for fetal anemia (see Chapter 31). Treatment

• Whenever clinical evidence of nonimmune hydrops fetalis is noted on sonogram, or if exposure to the virus is suspected in a pregnant woman, serologic testing should be offered. • Termination of pregnancy should not be recommended to an affected woman because the virus is not related to an increased risk of congenital malformations. • Once the acute maternal infection is proved serologically, serial sonograms are recommended to search for signs of hydrops fetalis as a complication of severe fetal anemia. Follow-up should be continued for 12 weeks after the diagnosis of maternal infection. If signs of fetal hydrops appear after 20 weeks of gestation, a decision should be made whether to manage the case conservatively or to perform diagnostic cordocentesis and intrauterine transfusion as indicated. The parameters to be tested in fetal blood include karyotype, hemoglobin, white blood count, platelet count, as well as specific IgM, IgG, and viral DNA. Should the fetus suffer from severe anemia (hemoglobin less than 8 g/dL), intrauterine transfusion should be considered, preferably during the same procedure. Maternal Complications

• The most common clinical presentation of parvovirus B19 infection is erythema infectiosum or fifth disease. This is a relatively mild influenza-like disease, accompanied by low-grade fever and a characteristic “slapped cheek” rash. • In adults, the most common symptom is arthralgia, which may last for several weeks; occasionally, arthritis appears as polyarthritis or oligoarthritis. • In about 20% of the population, the infection has no clinical manifestations despite positive serologies. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Fetal/Neonatal Complications

• Nonimmune fetal hydrops resulting from intrauterine fetal parvovirus B19 infection is a well-known, though rare, phenomenon. Both aplastic anemia and myocarditis may contribute to the development of fetal hydrops (38). • There is no evidence of increased risk of birth defects in infants with maternal B19 infection. The risk of fetal death from parvovirus B19 infection is calculated at 9% of B19-infected pregnancies. GENITAL INFECTIONS Herpes Simplex Background

• Herpetic infections usually are caused by type 2 virus, but type 1 is responsible for 15% of genital herpes infections. • Both viruses are transmitted by person-to-person contact; approximately 5% of pregnant women have histories of symptomatic disease, and 13% will have clinical reactivation of infection at the time of delivery (39). • Serologic surveys suggest that at least 20% of people have had prior infections with herpes simplex virus (HSV) type 2 (36). Diagnosis

• Herpetic vesicles, 1 to 22 mm in diameter, develop on the genitalia and skin surfaces. These pruritic lesions rupture in 2 to 3 days, forming painful, shallow ulcers. • Accompanying signs and symptoms include low-grade fever, malaise, and regional adenopathy. Jaundice and encephalitis are infrequent complications. • The illness lasts from 7 to 10 days; recurrences are common. • Pregnant women infected for the first time shed virus for 8 to 100 days; patients with recurrences shed virus for 6 to 40 days. Asymptomatic shedding in women with a history of genital herpes occurs on approximately 1% of days; the duration of shedding is 1 to 2 days. • The appearance and distribution of the lesions permit a presumptive clinical diagnosis. Definitive proof of herpes infection requires identification of virus in infected specimens by direct immunofluorescent testing or by culturing virus in tissue cultures. • Specific serologic tests for the HSV-specific glycoprotein G2 have sensitivities of 80% to 98%, but false negatives may occur early in the course of infection. Other serologic evaluations are of limited clinical use because of the lack of IgG-specific tests. Prognosis Mother

• The morbidity from these self-limited infections and the rarity of death, usually from encephalitis, are unaffected by pregnancy. • An increased incidence of abortion and premature delivery is associated with primary genital herpes but not with recurrent infection. Fetus

• Local (skin), central nervous system (CNS), or disseminated herpetic infections develop in 30% to 50% of newborns delivered to mothers with primary herpes and 5% to those with recurrent disease develop infections. • Disseminated infections are associated with high mortality and serious neurologic sequelae in survivors. • Infections in newborns with intrauterine herpes simplex infections are characterized by a rash at birth, congenital malformations, and a less fulminant course. The congenital malformations include microcephaly, encephalitis, chorioretinitis, and cerebral atrophy. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Treatment Management

Acyclovir, valacyclovir, and famciclovir decrease the duration of a primary genital herpes infection and the frequency and duration of recurrent attacks. The benefits of these antiviral agents may outweigh any theoretic risk. Prevention

Patients should be examined closely for genital lesions in the third trimester and at delivery. Cultures for cervicovaginal shedding in patients with chronic recurrent herpes are of limited use late in the third trimester. In women with confirmed primary HSV infection within 6 weeks of delivery, cesarean section should be considered because of the prolonged period of viral shedding and lack of maternal antibody. Women with frequent herpes recurrences should receive antiviral medications in the final months of pregnancy to reduce risk of recurrences and viral shedding. Newborn infants from infected mothers should be isolated and examined for 12 to 14 days for the development of herpetic infection. Infants inadvertently exposed to HSV at delivery should have urine, stool, eye, and throat cultures sent for HSV isolation. If a culture becomes positive, the child should be treated with acyclovir. Close observation for clinical symptoms and signs should be performed. Syphilis

Background

Treponema pallidum, the etiologic agent of syphilis, is transmitted through sexual contact. • In recent years, the incidence of primary and secondary syphilis in the United States has increased with a concomitant increase in congenital infection (39). • The syphilis rate among women increased from 1.1/100,000 cases in 2007 to 1.5/100,000 in 2008. • Infections are transmitted readily from the mother to fetus. Diagnosis Physical Examination

• The chancre of primary syphilis is usually found on vaginal and cervical membranes. Chancres also occur extragenitally, most often in oral and anal regions. The lesions begin as nontender papules and subsequently ulcerate. Healing occurs within 3 to 6 weeks. Clinical features of primary syphilis are infrequently seen in pregnancy. • Manifestations of secondary syphilis appear 2 to 12 weeks after the primary chancre and include skin rashes of various types (e.g., macular, papular, pustular, bullous), which often occur on the palms and soles; condylomas in perigenital areas; alopecia; generalized adenopathy; and low-grade fever. Condyloma latum is the most commonly observed lesion of secondary syphilis in pregnancy. Testing

• Using dark-field microscopy, the diagnosis is established by identifying T. pallidum in specimens from suspicious lesions. • In the absence of a positive dark-field examination, a presumptive diagnosis is made by detecting antibody to reagin (a cardiolipin–lecithin antigen) with the Venereal Disease Research Laboratory (VDRL) or rapid plasma reagin card (RPRC) test. • Because false-positive results occur with these tests, positive results are confirmed with the fluorescent treponemal antibody absorption test (FTA-ABS) or the microhemagglutination assay (MHATP) for antibodies to T. pallidum. The diagnostic accuracy of the FTA-ABS or MHATP test is nearly 100% in cases of secondary syphilis, and the rate of false-positive results is less than 1%. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Clinical Findings

• The manifestations of congenital syphilis may occur at birth, but more often they appear in the first weeks of life. • The most common clinical findings are skin eruptions of the type and distribution observed in adults, osteitis of nasal bones resulting in characteristic saddle nose deformities, periostitis and osteochondritis of long bones, hepatosplenomegaly, frontal bossing, notched incisors, mulberry molars, eighth nerve deafness, and neurosyphilis. Prognosis Mother. The morbidity of primary and secondary syphilis is the same in pregnant and

nonpregnant women.

Fetus.  If the mother is not treated

• Twenty-five percent of fetuses will die in utero. • Twenty-five percent to thirty percent will die shortly after birth. • Forty percent of survivors will acquire syphilis after the 3rd week of life.

Treatment Management

• Treat pregnant patients with primary, secondary, or tertiary syphilis with 1 to 3 weekly injections of 2.4 million units IM of benzathine penicillin G. • Patients allergic to penicillin should have their penicillin allergy confirmed. If they are truly allergic to penicillin, they should be desensitized before each dosage of penicillin (Table 23-8).

Table 23-8 Penicillin V suspension doseb 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Oral Desensitization Protocol for Women with Penicillin Allergy and Syphilisa Dose strength (U/mL)c 1000 1000 1000 1000 1000 1000 1000 10,000 10,000 10,000 80,000 80,000 80,000 80,000

Measured dose (mL)c 0.1 0.2 0.4 0.8 1.6 3.2 6.4 1.2 2.4 4.8 1.0 2.0 4.0 8.0

Total dose (units) 100 200 400 800 1600 3200 6400 12,000 24,000 48,000 80,000 160,000 320,000 640,000

Cumulative dose (units) 100 300 700 1500 3100 6300 12,700 24,700 48,700 96,700 176,700 336,700 656,700 1,296,700

Observe 30 min for allergic signs or symptoms before parenteral administration of penicillin. Then observe for at least 1 h after injection or infusion for signs of urticaria, angioedema, or anaphylaxis. b Interval between doses: 15 min; elapsed time, 3 h, 45 min. c Undiluted penicillin V suspension is 80,000 units/mL. The penicillin V suspension is first diluted to 1000 or 10,000 units/mL and then administered orally in 30 mL of water. a

(c) 2015 Wolters Kluwer. All Rights Reserved.

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• If the serologic titer as measured by serial quantitative VDRL tests does not decrease, a second course of therapy is indicated. Patients with a history of treatment of syphilis should be retreated if doubts exist regarding the adequacy of therapy. • Patients with suspected treatment failure or who are infected with HIV or who have an antibody titer greater than 1:32 should have consideration of a lumbar puncture to ascertain the presence of neurosyphilis (40). • Adequate treatment of infected mothers before the 16th week of gestation prevents congenital syphilis, whereas treatment after the 16th week cures the infection but may not prevent the stigmata of congenital syphilis (41). Prevention

Pregnant women should be tested serologically for syphilis at their first prenatal examination. Gonorrhea

Background

Gonococcal infections are epidemic in the United States, with nearly 400,000 individuals infected annually and a prevalence of 0.5% to 0.7% (42). Infections are transmitted primarily through sexual contact. Diagnosis

• Gonorrhea is an asymptomatic infection in 80% of women. Pain and tenderness in the pelvic region, cervical discharge, dysuria, and fever are the most common findings in patients with symptomatic infection. Pustular skin lesions, migratory arthralgias, and tenosynovitis culminating in a monoarticular septic arthritis indicate disseminated infection. • The diagnosis is established by demonstrating gram-negative diplococci within polymorphonuclear leukocytes from vaginal and cervical exudates. The microscopic impression is confirmed by culturing the exudates on the Thayer-Martin media. Newer laboratory techniques using nucleic acid hybridization permit rapid detection of gonococci in infected urogenital specimens and the identification of Neisseria gonorrhoeae isolated from culture. These techniques also allow detection of N. gonorrhoeae and Chlamydia trachomatis in the same specimen. • Gonococci can be cultured from pharyngeal and rectal swabs, blood, septic joints, and skin pustules. Prognosis Mother

• Women who become infected during the last 20 weeks of gestation or in the puerperium have an increased incidence of gonococcal arthritis. • Women who harbor gonococci in the genital tract may have a flare-up of their latent disease during labor or immediately postpartum. There may be an increased risk of ­gonococcemia in such women. • Abortion may occur because of premature rupture of the membranes secondary to gonococcal infection. • Chronic pelvic inflammatory disease, secondary to gonorrhea, is an important cause of ectopic pregnancy. Fetus

• Neonatal gonorrhea is acquired in utero or during delivery when the fetus traverses an infected birth canal. • Infection in utero results in chorioamnionitis and subsequent neonatal sepsis. • Infections acquired during delivery cause conjunctivitis (ophthalmia neonatorum), otitis externa, and vulvovaginitis. Gonorrhea is transmitted to 30% to 35% of newborns who pass through an infected cervix. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Treatment

The 2005 CDC recommendations for treatment of N. gonorrhoeae during pregnancy are as follows: • Uncomplicated gonococcal infections of the cervix, urethra, and rectum during pregnancy. • Recommended regimens: cefixime, 400 mg orally in a single dose, or ceftriaxone, 125 mg IM in a single dose. • Alternative regimens: spectinomycin, 2 g IM in a single dose, or ceftizoxime, 500 mg IM in a single dose, or cefotaxime, 500 mg IM in a single dose, or cefotetan, 1 g IM in a single dose, or cefoxitin, 2 g IM, with probenecid, 1 g orally in a single dose. • Uncomplicated gonococcal infection of the pharynx during pregnancy: ceftriaxone, 125 mg IM in a single dose. • Gonococcal conjunctivitis during pregnancy: ceftriaxone, 1 g IM in a single dose, and lavage the infected eye with saline solution once. • Disseminated gonococcal infection during pregnancy: • Recommended: ceftriaxone, 1 g IM or IV every 24 hours. • Alternatives: cefotaxime, 1 g IV q8h, or ceftizoxime, 1 g IV q8h, or spectinomycin, 2 g IM q12h. • All regimens should be continued for 24 to 48 hours after improvement begins, at which time therapy may be switched to cefixime, 400 mg orally bid, to complete a full week of antimicrobial therapy. • Gonococcal meningitis and endocarditis during pregnancy: ceftriaxone, 1 to 2 g IV q12h. Therapy for meningitis should be continued for 10 to 14 days. Therapy for endocarditis should be continued for at least 4 weeks. • Ophthalmia neonatorum prophylaxis regimens: • Silver nitrate, 1% aqueous solution in a single application • Erythromycin, 0.5% ophthalmic ointment in a single application • Tetracycline, 1% ophthalmic ointment in a single application Chlamydial Infections Background

Chlamydia trachomatis is a small bacterial microorganism that is an obligatory intracellular parasite. • It is recognized as the most common sexually transmitted disease in the United States, and the cause of nongonococcal urethritis, lymphogranuloma venereum, epididymitis, pelvic inflammatory disease, and conjunctivitis in adults and of inclusion conjunctivitis, pneumonia, otitis media, and vaginitis in infants who are born through infected birth canals (43). • It can be isolated from the genital tract of approximately 25% of sexually active nonpregnant women, approximately 5% of pregnant women, and fewer than 5% of women without a history of sexual contact. Diagnosis

The CDC recommends screening at the initial intake obstetric visit for all patients, with rescreening in the third trimester for high-risk patients or for those thought to have shown poor compliance. • In pregnant women: • Cervical Chlamydia cultures are 100% specific and 80% to 90% sensitive. • Direct fluorescent antibody and enzyme immunoassay tests have high specificity and sensitivity in high prevalence populations, while in groups of women with lower prevalences, culture techniques are more accurate. • Nucleic acid probes have greater than 98% correlation with culture in asymptomatic pregnant women. • Only culture is applicable to all anatomic sites and specimens (44). • Tests of cure are recommended during pregnancy at least 3 weeks after treatment (40). (c) 2015 Wolters Kluwer. All Rights Reserved.

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Treatment

• Treatment recommendations include first-line and alternative therapies. All sexual contacts require treatment, regardless of symptomatology. • The 2005 CDC recommendations for the treatment of Chlamydia in pregnant women call for • Erythromycin base, 500 mg orally qid for 7 days or • Amoxicillin, 500 mg orally tid for 7 days • Alternative regimens consist of °°Erythromycin base, 250 mg orally qid for 14 days °°Erythromycin ethylsuccinate, 800 mg orally qid for 7 days °°Erythromycin ethylsuccinate, 400 mg orally qid for 14 days °°Azithromycin, 1 g orally in a single dose Maternal–Fetal Complications

• The detection of C. trachomatis, especially during pregnancy, is very important because many of the women infected with this pathogen are asymptomatic. • Untreated infection can result in spontaneous abortion, fetal death, premature rupture of membranes, preterm delivery, and postpartum endometritis–salpingitis. Neonatal Complications

• Vertical transmission of C. trachomatis during vaginal delivery has been noted to occur in 50% to 70% of infants born to infected women (45). • Initial C. trachomatis perinatal infection involves mucous membranes of the eye, oropharynx, urogenital tract, and rectum. • Chlamydia is the most frequent identifiable infectious cause of ophthalmia neonatorum. This infection is most often recognized by conjunctivitis that develops 5 to 12 days after birth. • Chlamydia is also a common cause of subacute, afebrile pneumonia with onset from 1 to 3 months of age. Trichomonas Vaginalis Background

• Trichomonas vaginalis causes approximately 25% of vulvovaginal infections. • It is the most prevalent nonviral, sexually transmitted disease. • Risk factors include multiple sexual partners, black race, previous history of sexually transmitted diseases, and coexistent infection with N. gonorrhoeae. Evaluation Clinical Presentation

• Symptomatic patients generally complain of a foul odor, a copious, yellow-gray or green homogeneous frothy vaginal discharge, vulvovaginal irritation, and occasionally dysuria. • Up to 50% of infected women are asymptomatic. Diagnosis

• Diagnosis of trichomonal infection is made by wet-mount preparation for mobile, flagellated organisms and an elevated pH level (greater than 4.5). An abundance of leukocytes usually is noted. • Occasionally, trichomonal infection is diagnosed incidentally in asymptomatic females by Papanicolaou smear. Treatment

Metronidazole, 2 g in a single dose orally, after the first trimester. Sexual partners should also be treated (40). Pregnancy Complications

Trichomoniasis is associated with preterm labor, preterm delivery, low birth weight, and premature rupture of the membranes. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Fetal/Neonatal Complications

• Complications are secondary to preterm delivery. • Vertical transmission of Trichomonas has been described in rare case reports but is believed to be cleared from the newborn once the maternal hormonal milieu has dissipated. Bacterial vaginosis Background

• Bacterial vaginosis, previously known as nonspecific vaginitis or Gardnerella vaginitis, is the most common cause of vaginal discharge. • Between 9% and 41% of pregnant women will have bacterial vaginosis during pregnancy. Diagnosis

• The patient typically complains of a gray, malodorous, fishy-smelling vaginal discharge, although a large percentage of patients will be asymptomatic. • Diagnosis is made by demonstrating three of the following four signs: • Thin, dark or gray, homogeneous, malodorous discharge that adheres to the vaginal walls • Elevated pH level (greater than 4.5) • Positive KOH (whiff/amine test) • Presence of clue cells on wet-mount microscopic evaluation Treatment

• Treatment recommendations include first-line and alternative therapies. • The 2006 CDC-recommended regimen for the treatment of bacterial vaginosis in pregnancy includes • Metronidazole, 5000 mg orally bid for 7 days • Metronidazole gel 0.75%, one full applicator (5 g) intravaginally once a day for 5 days • Clindamycin cream 2% one full applicator (5 g) intravaginally at bedtime for 7 days • Alternative regimens include °°Metronidazole, 2 g orally in a single dose °°Clindamycin, 300 mg orally bid for 7 days °°Clindamycin ovules 100 g intravaginally once at bedtime for 3 days Maternal/Pregnancy Complications

Pregnant women with bacterial vaginosis are at increased risk of preterm labor, preterm premature rupture of membranes, and chorioamnionitis (46). Fetal/Neonatal Complications

The risks are those associated with preterm delivery and chorioamnionitis. FUNGAL INFECTION Vulvovaginal Candidiasis Background

• Approximately 30% of women with a healthy vaginal ecosystem harbor Candida, usually Candida albicans. These patients are asymptomatic, and yeast most likely would not be identified on wet-mount examination (47). • The most common symptom of Candida infection is vulvovaginal pruritus. Also, vulvar burning, which can be exacerbated with micturition or sexual intercourse, is common, along with an increase or change in consistency of the vaginal discharge. Diagnosis

Diagnosis is made by: • Nonmalodorous, thick, white, “cottage cheese–like” discharge that adheres to the vaginal walls • Presence of hyphal forms or budding yeast cells on wet-mount microscopic evaluation • Pruritus (c) 2015 Wolters Kluwer. All Rights Reserved.

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Treatment

The 2005 CDC-recommended regimens for the treatment of vulvovaginal candidiasis include • Fluconazole, 150 mg orally once • Butoconazole 2% cream, 5 g intravaginally for 3 days • Clotrimazole 1% cream, 5 g intravaginally for 7 to 14 days • Clotrimazole, 100-mg vaginal tablet for 7 days • Clotrimazole, 100-mg vaginal tablet, two tablets for 3 days • Clotrimazole, 500-mg vaginal tablet, one tablet in a single application • Miconazole 2% cream, 5 g intravaginally for 7 days • Miconazole, 200 mg vaginal suppository, one suppository for 3 days • Miconazole, 100 mg vaginal suppository, one suppository daily for 7 days • Terconazole 0.4% cream, 5 g intravaginally for 7 days • Terconazole 0.8% cream, 5 g intravaginally for 3 days • Terconazole, 80-mg vaginal suppository, one suppository daily for 3 days Maternal/Pregnancy Complications

Vulvovaginal candidiasis is not associated with an untoward obstetric outcome. Fetal/Neonatal Complications

Vulvovaginal candidiasis is not generally associated with fetal or neonatal complications. However, there have been reports of intra-amniotic fetal Candida infection associated with cervical cerclage and with IUDs retained during pregnancy Recurrent Vulvovaginal Candidiasis • Recurrent vulvovaginal candidiasis is defined as four or more episodes of symptomatic vulvovaginal candidiasis annually. • The optimal treatment is an initial intensive regimen continued for approximately 10 to 14 days, followed immediately by a maintenance regimen for at least 6 months (40). OTHER INFECTIONS OF IMPORTANCE IN PREGNANCY Toxoplasmosis Background

The causative microorganism, Toxoplasma gondii, is a protozoan with infectious cystic forms that are found in cat feces (oocyst) and herbivorous and carnivorous animal tissue (tissue cyst). Infection results from the ingestion of cyst-containing animal tissues or foods contaminated with cat feces and by transplacental transmission when women are infected during pregnancy. Diagnosis

• Asymptomatic lymphadenopathy is the most common manifestation. • More severe infections resemble infectious mononucleosis with fever, myalgias, sore throat, lymphadenopathy, macular rashes, migratory polyarthritis, and hepatosplenomegaly. It may also simulate viral pneumonia. • Meningoencephalitis, the most severe complication, usually occurs in immunocompromised patients. • Chorioretinitis is rare in acquired toxoplasmosis. • The diagnosis is established by identifying the protozoa in tissue sections, smears, or body fluids or by demonstrating eightfold or greater increases in antibody titer using either the Sabin-Feldman dye test or immunofluorescent testing for IgM or IgG antibody. In cases limited to a single test, only elevated IgM antibody titers permit the diagnosis of acutely acquired toxoplasmosis (48). Prognosis Mother

• Maternal morbidity and mortality are unaffected by pregnancy. • Infection increases the incidence of abortion and premature labor to 10% to 15% in women infected in the first and second trimesters of pregnancy. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Fetus

• Manifestations of congenital toxoplasmosis include chorioretinitis (often bilateral), cerebral calcification, mental retardation, convulsions, microphthalmia, hydrocephalus, and microcephaly. • Signs of cerebral palsy and encephalitis can develop days or months after birth. • Toxoplasmosis has also been implicated in stillbirth. • The risk of intrauterine transmission in untreated women who develop acute toxoplasmosis varies by trimester (49): • Twenty-five percent in the first trimester • Fifty-four percent in the second trimester • Sixty-five percent in the third trimester Treatment Management

• The usual treatment of acute maternal toxoplasmosis is spiramycin, followed by pyrimethamine and sulfadiazine for confirmed fetal infections if the pregnancy is continued. Treatment with spiramycin reduces, but does not eliminate, the risk of transmission to the fetus (48). • One management paradigm is to begin spiramycin on diagnosis of maternal infection and perform an amniocentesis for PCR. • A positive PCR would suggest fetal infection and would prompt a change from spiramycin to pyrimethamine and sulfadiazine. • A negative PCR would result in the continuation of spiramycin to reduce the incidence of subsequent fetal infection. • Serial ultrasounds should be considered for the remainder of the pregnancy to rule out obvious fetal involvement. Prevention

• Prevention is of great importance, especially during pregnancy. • Various prenatal programs throughout the world perform routine toxoplasmosis serologic testing (e.g., France, Austria, and Italy). • Universal screening for maternal toxoplasmosis in the United States is currently not practiced secondary to the relatively low prevalence of the disease and the high false-positive rate of serologic screens in commercial labs. • Targeted screening after finding an incidental abnormality on ultrasound consistent with toxoplasmosis infection is commonly practiced (48). • Pregnant women should not eat raw meat products. • If there are cats in the household, hands should be thoroughly washed after handling them, especially before eating; their litter trays should be emptied daily by someone other than the pregnant woman, as oocytes take 2 or 3 days to become infectious (50). Malaria

Background

• Malaria, one of the most common infections of humans, causes significant morbidity and mortality in medically indigent areas of the world. • Acute life-threatening illnesses are invariably caused by Plasmodium falciparum, whereas relapsing chronic infections are caused by P. vivax or, in selected endemic areas, P. ovale, or P. malariae. Diagnosis

• Episodic paroxysms of high, spiking fever, headache, and myalgia distinguish malaria from virtually every other illness. Splenic enlargement is present in chronic infections. • A history of residence in or passage through an endemic area usually is obtained. • In the United States, the possibility of illicit intravenous drug use should be considered because malaria is transmitted by contaminated blood. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Microscopic identification of the parasite in blood smears confirms the diagnosis. • Chronic infections are diagnosed by demonstrating high levels of indirect fluorescent antibody in serum. Prognosis Mother

• Malarial attacks, especially those caused by P. falciparum, are particularly severe in pregnant patients. • Abortions, prematurity, and stillbirths are increased in women who undergo malarial attacks during the first trimester of pregnancy. Fetus

• Malarial parasites can cross the placenta in nonimmune mothers and cause fetal infection. • Congenital malaria results in intrauterine growth retardation. • Infected newborns have fever, jaundice, hepatosplenomegaly, seizures, and, occasionally, pulmonary edema 48 to 72 hours after delivery. Treatment Management

• Nonpregnant patients with infections caused by P. vivax and P. ovale should receive 26.3 mg of primaquine phosphate PO for 14 days. However, because fetal red cells are relatively deficient in glucose-6-phosphate dehydrogenase and glutathione, the fetus is at risk for intravascular hemolysis. Therefore, primaquine is not recommended in pregnancy (12). • Treat pregnant women with malaria caused by P. vivax, P. ovale, and non–chloroquineresistant P. falciparum with 1.0 g of chloroquine phosphate PO for one dose, followed by 0.5 g at 6, 24, and 48 hours. • Relapses are treated with chloroquine. • Primaquine is used after delivery. • Treatment for drug-resistant strains of malaria: • Falciparum malaria resistant to chloroquine is treated with 650 mg of quinine sulfate PO tid for 10 days, combined with pyrimethamine, 50 mg/d PO for 3 days, followed by 500 mg of sulfadiazine PO qid for 5 days. It should be emphasized that pyrimethamine is a highly teratogenic drug. • Some experts recommend Fansidar (pyrimethamine and sulfadoxine) in combination with folinic acid to treat chloroquine-resistant P. falciparum, because quinine is an abortifacient in early pregnancy and can lead to premature labor in later pregnancy. Quinine has been associated with fetal auditory nerve hypoplasia, deafness, visual changes, and limb abnormalities. • Fansidar-resistant malaria is treated with quinine and tetracycline despite the risks of teratogenicity. Prevention

• If travel to an endemic area is required, chloroquine is considered to be the drug for prophylaxis. It can cause retinal and cochleovestibular damage but is generally considered sufficiently safe in pregnancy to be recommended for prophylaxis. • Chloroquine phosphate, 500 mg PO, is given 1 week before leaving and once weekly while the patient must remain in endemic areas. The drug should be continued for 6 weeks after the patient has left the endemic area. • Fansidar is no longer recommended as prophylaxis in areas with chloroquine-resistant P. falciparum as a result of severe drug reactions. It is recommended that Fansidar be carried by travelers to these areas and taken therapeutically at the first sign of illness. • Because safe, effective chemoprophylaxis is unavailable for chloroquine-resistant P. ­falciparum, nonimmune pregnant women should be discouraged from traveling to endemic areas unless absolutely necessary. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Lyme Borreliosis Background

Lyme borreliosis is caused by Borrelia burgdorferi, a tick-borne spirochete (51). The organism is transmitted by the bite of Ixodes ticks, generally during the spring and summer. Diagnosis

• Early infection is characterized by a distinctive rash (erythema migrans) that has advancing serpiginous borders with central clearing. • Later disease can involve the heart, neurologic system, musculoskeletal system (arthritis), and eyes. • The diagnosis is made clinically by noting a history of tick bite followed by a rash consistent with erythema migrans in association with a positive antibody test, with the ELISA being the preferred test. Serologic test results must be interpreted with caution because false-positive and false-negative results occur with all assays. Prognosis Mother

• Infection is similar in pregnant women and nonpregnant women. • Gestational Lyme borreliosis is associated with fetal deaths and miscarriage. Fetus

• Transplacental transmission of B. burgdorferi has been reported and is associated with congenital cardiac malformations and encephalitis. • Serosurveys suggest that although B. burgdorferi can cause an adverse fetal outcome, it is uncommon (51,52). Treatment Management

• Early infection is treated with amoxicillin, 500 mg PO tid for 21 days. Doxycycline is contraindicated in pregnancy. • Arthritis is treated with amoxicillin, 500 mg PO qid, plus probenecid, 500 mg qid, for 30days. The alternative is ceftriaxone, 2 g IV qd for 14 days, or penicillin, 3 million units IV q4h for 14 days. • Severe cardiac or neurologic disease is treated with ceftriaxone, 2 g IV qd for 14 days, or penicillin, 3 million units IV q4h for 14 days. Prevention

• Avoidance of tick bites is the only method of prevention. • There is no vaccine available. Listeriosis

Background

• Listeria monocytogenes is a small facultative, anaerobic gram-positive bacillus and is the only one of its seven species that is pathogenic for humans. • Pregnant women account for 27% of all cases and for 60% of cases among persons 10 to 40 years of age (53). • Infection most likely occurs after ingestion of the organism in food, as many foods are contaminated with L. monocytogenes; it has been recovered from raw vegetables, raw milk, fish, poultry, and meats. • The incubation period for invasive illness ranges from 11 to 70 days, with a mean of 31 days. • L. monocytogenes crosses the mucosal barrier of the intestine, and once the bacillus enters the bloodstream, it may disseminate hematogenously to any site; L. monocytogenes has a predilection for the CNS and the placenta. • It is generally believed that resistance to infection by L. monocytogenes is cell mediated, as evidenced by clinical association between listerial infection and conditions associated with impaired immunity such as lymphomas, pregnancy, AIDS, and corticosteroidinduced immunosuppression. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Diagnosis

Diagnosis requires: • Isolation of L. monocytogenes from CSF, blood, joint fluid, urine, amniotic fluid, placenta, and cervix • Identifying the organism via standard microbiologic techniques Treatment

• For treatment of listeriosis during pregnancy, ampicillin (a 2-week course of 4 to 6 g/d in four equal doses) or penicillin is recommended. Cephalosporins are not adequate therapy against L. monocytogenes (54). Erythromycin has also proved to be efficacious in pregnancy (55). • Because iron is a virulence factor for L. monocytogenes and iron overload states are risk factors for listerial infection, it is recommended to withhold iron replacement therapy until treatment is completed (56). Maternal Complications

• Typical clinical syndromes among pregnant women are sepsis and a mild flu-like illness. Symptoms are often subtle and include malaise, fever, abdominal pain, gastrointestinal complaints, premature contractions, and decreased fetal movements. • Infection can uncommonly result in maternal complications such as meningitis and endocarditis. Fetal/Neonatal Complications

• When in utero infection occurs, the fetus may be stillborn or die within hours of a disseminated form of listerial infection known as granulomatosis infantiseptica, which is characterized by the widespread presence of microabscesses and granulomas that are prevalent in the liver and spleen (57). • Overall perinatal mortality is widely quoted to be between 22% and 30% (53). The chances of perinatal morbidity and mortality are high when listeriosis is contracted in late gestation. • Neonatal disease can cause both an early-onset sepsis, occurring shortly after birth, and a late-onset sepsis, occurring within the first few weeks of life. EMERGING INFECTIONS Avian Flu Background

• Bird flu is an infection caused by an avian (bird) influenza virus. These viruses do not generally infect humans, but several cases of human infection including during pregnancy have been reported since 1997. • The largest risk is for mutation of the avian influenza virus mixed with human virus in patients with human influenza. This would allow the virus to mutate and potentially spread from person to person. • There have been no cases of avian flu reported in the United States. Treatment

• Currently, there is no vaccine available for avian flu. • Worldwide surveillance is taking place and travel to areas with avian flu is discouraged. Severe Acute Respiratory Syndrome Background

• Severe acute respiratory syndrome (SARS) is a recently recognized febrile severe lower respiratory illness caused by infection with a novel coronavirus (SARS-CoV). • The case fatality rate approximates 10%. • Early recognition and application of appropriate infection control measures are critical in controlling outbreaks of SARS. • The vast majority of patients with SARS-CoV has a clear history or exposure to an SARS patient or to a setting in which it can occur and develop pneumonia. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Diagnosis

There are no currently available laboratory tests that can distinguish SARS virus from other respiratory illnesses rapidly enough to direct clinical management. Treatment

• No specific treatment guidelines are currently in existence. • Patients should receive supportive care and treatment with empiric therapy for community-acquired pneumonia. Infectious disease consultation is strongly recommended. West Nile Virus Background

West Nile virus (WNV) is a single-stranded RNS virus. It is a member of the Japanese encephalitis virus antigenic complex. • The main route of human infection is through the bite of an infected mosquito. Mosquitoes become infected when they feed on infected birds. • Humans, horses, and other mammals are not known to commonly develop infectious level viremias. Therefore, there is no documentation of animal-to-person transmission of WNV. • Alternative modes of transmission include breast milk (one probable case reported) and transplacental (mother to child). Epidemiology

• Most patients (four out of five) who are infected with WNV will not develop illness. • Approximately 20% of patients with WNV will develop West Nile fever with the potential for severe illness. Diagnosis Clinical Manifestations

• Symptoms include fever, headache, tiredness, body aches, and an occasional skin rash on the trunk of the body as well as swollen lymph nodes. The symptoms of severe disease include headache, high fever, neck stiffness, stupor, disorientation, coma, tremors, convulsions, muscle weakness, and paralysis. • The illness can be a few days to a few weeks in duration. • Serious illness can occur in people of any age; however, people over the age of 50 or immunocompromised patients are at the highest risk for severe illness. Treatment Antibiotic Selection and Considerations

Except for the additional consideration of fetal toxicity, the selection of antibiotics for treatment in pregnant women is the same as for women who are not pregnant. • Antimicrobial efficacy and toxicity are almost always unaltered in pregnancy. • The two distinctive considerations in pregnancy are the potential toxicity for the fetus or mother of some commonly used antibiotics (e.g., sulfonamides, tetracyclines) and the occasional need for higher drug dosages because of the expanded blood volume, increased renal blood flow, and increased glomerular filtration rate, which reduce drug levels below the therapeutic range (13,47). • Appropriate microbial smears and cultures should be obtained before therapy is initiated to identify pathogens and to determine their antimicrobial susceptibility patterns. If the smear is not helpful diagnostically, treatment is initiated on the basis of an educated guess concerning the likely pathogens for a particular infection (e.g., urinary tract infections are most often caused by E. coli). • Interpretation of culture results from the female genital tract requires knowledge of the normal flora. This flora, which is unchanged by pregnancy, consists of aerobic and anaerobic bacteria and small numbers of fungi, usually Candida sp. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Normal Vaginal Flora of Pregnancy

• Commonly isolated flora include Staphylococcus epidermidis,* Enterococcus faecalis,* Lactobacillus sp., Corynebacterium sp., Bacteroides fragilis,* Fusobacterium sp., Veillonella sp., Peptococcus sp., and Peptostreptococcus sp. • Occasionally isolated flora include Staphylococcus aureus,* Streptococcus sp.,* Clostridium perfringens,* Candida sp., E. coli,* Proteus sp.,* Klebsiella sp.,* Gardnerella vaginalis, Actinomyces sp., and Mobiluncus sp. • Potential pathogens are Pseudomonas sp., Streptococcus pneumoniae, Listeria monocytogenes, Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urealyticum, and Haemophilus aphrophilus. Effects of Selected Antibiotics and Antiviral Agents on Mother and Fetus (Table 23-9)

• Penicillins. Penicillins are safe in pregnancy. There is no increase in maternal toxicity and no known fetal toxicity (5,57). • Cephalosporins. Cephalosporins are safe and do not cause increased fetal toxicity. • Carbapenems. Imipenem is a carbapenem antibiotic related closely to the penicillins. Cilastatin is an inhibitor of a renal dehydropeptidase, which prevents rapid degradation of imipenem. Little is known about its use in pregnancy. Therefore, despite safety in animal studies, it should not be used in pregnancy when alternative therapies are available (58,59). The other carbapenem antibiotic, meropenem, was recently approved for commercial use in the United States. • Monobactam. Aztreonam is a monobactam antibiotic that has only a β-lactam ring. It is considered safe in pregnancy. Patients with allergies to other β-lactam antibiotics often tolerate aztreonam (7,13). • Tetracyclines. Parenteral tetracycline can cause fulminant maternal hepatitis and pancreatitis when administered during the third trimester of pregnancy. Oral tetracycline causes staining and deformity of deciduous teeth as well as inhibition of bone growth in the fetus. Tetracycline should be avoided in pregnancy unless no other appropriate antibiotic is available. • Sulfonamides. Maternal toxicity does not increase with sulfonamides. Fetal toxicity occurs in the perinatal period, when the inability of the neonatal liver to conjugate sulfonamides results in hyperbilirubinemia and kernicterus caused by blockage of the binding sites necessary to conjugate bilirubin. When these drugs are used before the perinatal period, the maternal liver removes sulfonamide from the fetal bloodstream (13). • Chloramphenicol. No increase in maternal toxicity occurs with chloramphenicol. Inability of the neonatal liver to conjugate chloramphenicol results in the “gray-baby syndrome,” which is characterized by gray facies, generalized flaccidity, hypothermia, and cardiovascular collapse (13). • Aminoglycosides. The risk of ototoxicity and nephrotoxicity secondary to use of gentamicin, kanamycin, netilmicin, streptomycin, amikacin, or tobramycin is the same in pregnant and nonpregnant women. Fetal toxicity to the eighth cranial nerve has occurred after prolonged use of streptomycin in treating TB. Streptomycin should not be used unless INH, ethambutol, or rifampin is contraindicated. These drugs may also cause nephrotoxicity in the fetus; therefore, their use should be limited as much as possible (58,59). • Macrolides. Erythromycin, clarithromycin, and azithromycin are the macrolide antibiotics presently available. No increase in maternal toxicity and no known fetal toxicity occur with erythromycin. The estolate form of this drug causes transient, self-limited elevations of serum transaminases, particularly in the latter half of pregnancy, so treatment with this agent is not recommended. Clarithromycin has been associated with toxicity to the fetus in animal studies; therefore, it should not be used in pregnancy except when *Significant Pathogens

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Chapter 23 • Infectious Complications 

Table 23-9

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Antibiotics and Antiviral Agents and Pregnancya

Antimicrobial agent Acyclovir Amantadine Amikacin Amoxicillin–clavulanate Amphotericin B Ampicillin Ampicillin–sulbactam Azithromycin Aztreonam Cefaclor Cefadroxil Cefamandole Cefazolin Cefixime Cefonicid Cefoperazone Ceforanide Cefotaxime Cefotetan Cefoxitin Cefpodoxime Cefprozil Ceftazidime Ceftizoxime Ceftriaxone Cefuroxime Cephalexin Cephradine Chloramphenicol Ciprofloxacin Clarithromycin Clindamycin Cloxacillin Dapsone Dicloxacillin Didanosine Doxycycline Erythromycin Ethambutol Fluconazole Flucytosine Foscarnet Ganciclovir Gentamicin Imipenem–cilistatin Isoniazid Itraconazole Kanamycin Ketoconazole Lorcarbacef Methenamine mandelate Methicillin

Problem in pregnancy Possible Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Yes Possiblef No Possible No Nob Yes Nob Possible Possibleb Possible Nob Nob No Possiblef Nob Nob No

Passes placenta

Harmful to fetus

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

Harmful to newborn No

Possiblec Nob

Possiblec

Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Nob Possible Possiblef

No

Nob Possible Nob Nob Yes Nob Nob Possible Possiblef Possible Possible Possiblec One report unconfirmed Possiblef Possiblec Possibleh Nob Nob

Nob

Nob No Possibled No Possibled Nob,e

Yes Yes Nob No Possible Nob Yes Possible Possible Possiblec,g Possiblec Nob Possiblec Possibleh No

(Continued ) (c) 2015 Wolters Kluwer. All Rights Reserved.

Table 23-9

Antibiotics and Antiviral Agents and Pregnancya (Continued)

Antimicrobial agent Metronidazole Mezlocillin Minocycline Nafcillin Nalidixic acid Netilmicin Nitrofurantoin Norfloxacin Oxacillin Penicillin G Penicillin V potassium Pentamidine Piperacillin Piperacillin–tazobactam Pyrazinamide Pyrimethamine Rifampin Spectinomycin Streptomycin Sulfonamides Tetracycline Ticarcillin/clavulanate Tobramycin Trimethoprim and sulfamethoxazole Vancomycin Zalcitabine Zidovudine

Problem in pregnancy

Passes placenta

Harmful to fetus

Yesb,i No Yes No Yesi No

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

Yesi Nob Yes Nob Yesi Possiblec

Nob Nob

Yes

Nob Nob

Yes Nob

Yes Yes

Yesk Possibleb

No Nom Yes Nob Nob Yes

Yes Yes Yes Yes Yes Yes

Rareb Nob,l Yes Nob Possiblec Yesl,m

Yes Nob No No

Possiblef Possible

Yes Nob Nob

Possiblec Possiblef

Harmful to newborn No Yes No Yesj Possiblec Yes Yes

Yes Yes Possiblec Yes Possiblec

Breast milk levels greater than 50% of maternal serum levels are seen with acyclovir, ampicillin, carbenicillin, chloramphenicol, erythromycin, INH, itraconazole, metronidazole, tetracycline, and sulfonamides. Breast milk levels less than 25% of maternal levels are seen with aztreonam, cefazolin, cefotaxime, cefoxitin, clindamycin, nalidixic acid, nitrofurantoin, methicillin, oxacillin, penicillin G, penicillin V potassium, and pyrimethamine. Blank spaces indicate information not well known. b Not known to be harmful, but no adequate and well-controlled studies have been performed for pregnant women; therefore, should be used during pregnancy only if clearly needed. c Ototoxicity and nephrotoxicity are potential consequences of use. d Safety in infants from birth to 3 months has not yet been established. In older children, the drug’s use has been associated with high incidence of increased eosinophils and elevated serum AST. e Ceftriaxone should not be given to hyperbilirubinemic newborns, especially prematures. f  Teratogenic effects have been seen in animal studies. g Ganciclovir should be used with extreme caution in newborns because of the probability of carcinogenicity. h Has been shown to be teratogenic to rats in high doses (10 times maximum human doses). Has also been shown to be embryotoxic in rats during the first trimester in the same dosage. Dystocia was noted in rats receiving ketoconazole in the third trimester. It probably is excreted in breast milk; therefore, mothers who are on ketoconazole should not breast-feed their children. i A potential carcinogen. j Increased CNS side effects in newborns. k Significant teratogenic effect in the first and probably the second trimesters. Safe in the third trimester if clinically warranted. Used for treatment of toxoplasmosis. l If given in large doses shortly before delivery, hyperbilirubinemia and kernicterus may occur in the newborn. m Not recommended; trimethoprim is a folate antagonist. a

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no alternative therapy is available. Conversely, azithromycin has been shown to be safe to the fetus in animal studies. Although data in humans are limited, azithromycin appears to be a safe agent in pregnancy. • Clindamycin. Maternal or fetal toxicity is not known to increase with clindamycin. Its most common obstetric indication is for postpartum endomyometritis. It is also the drug of choice for group B streptococcal prophylaxis in the penicillin-allergic patient. • Trimethoprim–sulfamethoxazole. Maternal toxicity does not increase with trimethoprim and sulfamethoxazole, but folic acid antagonists may increase anemia. Although unproved clinically, trimethoprim has the potential for teratogenicity; therefore, this drug should not be used unless absolutely indicated (13). • Vancomycin. Vancomycin given either intravenously or orally can be associated with fetal ototoxicity or nephrotoxicity. It is the drug of choice for C. difficile–induced pseudomembranous colitis (13,58). • Fluoroquinolones. Ciprofloxacin and ofloxacin cause chronic arthrosis deformans in animal studies. Therefore, quinolones are contraindicated in pregnant or lactating women (58). • Metronidazole. Although the data suggesting teratogenic effects of metronidazole are equivocal, it is recommended for use only in the second and third trimesters (58). • Anti-tuberculosis agents. These agents include INH, rifampin, ethambutol, streptomycin, pyrazinamide, ethionamide, and cycloserine. Treatment with INH, rifampin, and ethambutol represents a smaller risk to a woman and her fetus than does untreated disease. Congenital malformation rates are not increased. Streptomycin is not recommended for use in pregnancy, and the teratogenicity of other agents is unclear. Their use should be avoided during pregnancy (58,59). • Pyrimethamine. Although no increase in maternal toxicity is known, pyrimethamine should not be used in the first or second trimester because it is potentially teratogenic. If absolutely necessary, pyrimethamine can be used in the third trimester. • Antiherpetic agents. Three oral therapies for the treatment of genital HSV infections are available in the United States: acyclovir, famciclovir, and valacyclovir. Animal studies and use in humans suggest their use is safe. • Antiretroviral agents. Drug registry information has failed to reveal an increase in malformations in children born to mothers taking ZDV, but animal studies have suggested an increase in embryo resorption as well as an increase in development of cancer in the offspring born to pregnant mice treated with high doses of ZDV during pregnancy. Data regarding the safety and efficacy of the newer antiretroviral agents suggest that they are safe especially in the second and third trimesters of pregnancy. One exception is Sustiva (efavirenz), which has been shown to be teratogenic in the first trimester and should be avoided. In managing a pregnant HIV-positive woman, it is important to treat the patient as someone who is HIV positive rather than someone who is pregnant. There is no justification for withholding antiviral or prophylactic therapies to the mother for fear of harming the child because lack of treatment of the mother may increase fetal risk (60). • Reverse transcriptase inhibitors (nucleoside analog and nonnucleoside). These agents include ZDV, didanosine (ddI), zalcitabine (ddC), lamivudine (3TC) (the nucleoside analogs), and nevirapine (nonnucleoside). Once the HIV enters the CD4 cell, the HIV converts its single-stranded RNA genetic information into complementary doublestranded DNA before replication. This requires the viral enzyme reverse transcriptase. The nucleoside analogs (ZDV, ddI, ddC, 3TC) as well as the NNRTIs (nevirapine) inhibit this step of replication (12,61). • Protease inhibitors. These agents include saquinavir, ritonavir, indinavir, and nelfinavir. Once DNA is transcribed from the HIV RNA, it is inserted into cell DNA and instructs the cell to begin making new HIV copies. The viral particles must then “bud” through the host cell wall in order to infect new cells, thereby propagating the infection. The protease inhibitors work at this step by preventing the virus from leaving the host cell (12,57,61). (c) 2015 Wolters Kluwer. All Rights Reserved.

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Causes of Antibiotic Failure

• Human factors • Incorrect diagnosis • Treatment initiated too late • Antibiotic not given or taken improperly because of prescription error or lack of compliance • Drug factors • Inadequate dose or inappropriate dose interval. (Pregnant women may require higher doses than nonpregnant women because of altered pharmacokinetics.) • Inadequate course of therapy. • Wrong route of administration. • Failure of drug to reach the site of infection. • Pathogen factors • Microbial resistance • Bacteria in dormant state • Superinfection • Host factors • New, unrelated infection elsewhere in the body • Rapid degradation of the antibiotic (e.g., acetylation of INH) • Failure to institute appropriate supportive measures (e.g., surgical drainage, debridement, or dilation and curettage) • Impaired host defenses resulting from underlying illness or immunosuppressive therapy Immunization During Pregnancy

• Pregnancy is considered a contraindication for immunization with live attenuated virus vaccines in nonepidemic settings. A nonpregnant woman of childbearing age receiving a live virus vaccine should avoid pregnancy during the subsequent 3 months. • Use of inactivated virus vaccines is considered safe and acceptable in pregnancy. • The specifics of immunization are given in Table 23-9. Patient Education

For the latest and most accurate updates on worldwide infectious diseases and vaccinations, the reader should log onto http://www.cdc.gov REFERENCES 1. American College of Obstetricians and Gynecologists. Antimicrobial therapy for obstetric patients. ACOG Educ Bull. 1998:245. 2. Goodrum LA. Pneumonia in pregnancy. Semin Perinatol. 1997;21:276–283. 3. Riley L. Pneumonia and tuberculosis in pregnancy. Infect Dis Clin North Am. 1997;11: 119–132. 4. Starke JR. Tuberculosis: an old disease but a new threat to the mother, fetus, and neonate. Clin Perinatol. 1997;24:107–127. 5. Casey BM, Cox SM. Chorioamnionitis and endometritis. Infect Dis Clin North Am. 1997;11:203–218. 6. Phares CR, Lynfield R, Farley MM, et al. Epidemiology of invasive group B streptococcal disease in the United States, 1999–2005. JAMA. 2008;299(17):2056–2065. 7. ACOG Committee Opinion. Prevention of early-onset group B streptococcal disease in newborns. Int J Gynecol Obstet. 1996;54:197–205. 8. Special Medical Reports: CDC issues recommendations for the prevention of perinatal group B streptococcal disease. Am Fam Physician. 1996;54:1787–1793. 9. Lindsay MK, Nesheim SR. Human immunodeficiency virus infection in pregnant women and their newborns. Clin Perinatol. 1997;24:161–180. 10. Centers for Disease Control and Prevention. HIV/AIDS Surveillance Report Volume 15, 2003. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. (c) 2015 Wolters Kluwer. All Rights Reserved.

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11. Bulterys M, Lepage P. Mother-to-child transmission of HIV. Curr Opin Pediatr. 1998;10: 143–150. 12. Dattel BJ. Antiretroviral therapy during pregnancy: beyond AZT (ZDV). Obstet Gynecol Clin North Am. 1997;24:645–657. 13. Cooper ER, Charurat M, Mofenson L, et al. Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr. 2002;29(5):484–494. 14. Centers for Disease Control and Prevention (CDC). Global measles mortality, 2000–2008. MMWR Morb Mortal Wkly Rep. 2009;58(47):1321–1326. 15. Siston AM, Rasmussen SA, Honein MA, et al. Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States. JAMA. 2010;303(15):1517–1525. 16. Ali ME, Albar HM. Measles in pregnancy: maternal morbidity and perinatal outcome. Int J Gynecol Obstet. 1997;59:109–113. 17. Nies BM, Lien JM, Grossman JH. TORCH virus-induced fetal disease. In: Reece EA, Hobbins JC, Mahoney MJ, eds. Medicine of the fetus and mother. Philadelphia: JB Lippincott, 1992. Chapter 25. 18. Reef SE, Redd SB, Abernathy E, et al. The epidemiological profile of rubella and congenital rubella syndrome in the United States, 1998–2004: the evidence for absence of endemic transmission. Clin Infect Dis. 2006;43 (Suppl 3):S126–S132. 19. Gibbs RS. Fetal infections from non-TORCH viruses. In: Reece EA, Hobbins JC, Mahoney MJ, eds. Medicine of the fetus and mother. Philadelphia: JB Lippincott, 1992. Chapter 26. 20. Cherry JD. Enteroviruses. In: Remington JS, Klein JO, eds. Infectious diseases of the fetus and newborn infant, 3rd ed. Philadelphia: WB Saunders, 1990:325–366. 21. Glantz JC, Mushlin AI. Cost-effectiveness of routine antenatal varicella screening. Obstet Gynecol. 1998;91:519–528. 22. Skve DV. Varicella in pregnancy. WMJ. 1997;96:44–47. 23. Nathwani D, Maclean A, Conway S, et al. Varicella infections in pregnancy and the newborn: a review prepared for the UK advisory group on chickenpox on behalf of the British Society for the Study of Infection. J Infect. 1998;36(suppl 1):59–71. 24. Katz VL, Kuller JA, McMahon MJ, et al. Varicella during pregnancy: maternal and fetal effects. WMJ. 1995;163:446–450. 25. Birthistle K, Carrington D. Fetal varicella syndrome—a reappraisal of the literature: a review prepared for the UK Advisory Group on Chickenpox on behalf of the British Society for the Study of Infection. J Infect. 1998;36(suppl 1):25–29. 26. Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol. 2007;17(4):253–276. 27. Nigro G, Adler SP, La Torre R, et al. Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med. ;353(131):1350–1362. 28. Lipitz S, Yagel S, Shalev E, et al. Prenatal diagnosis of fetal primary cytomegalovirus infection. Obstet Gynecol. 1997;89:763–767. 29. Hagay ZJ, Biran G, Ornoy A, et al. Congenital cytomegalovirus infection: a long-standing problem still seeking a solution. Am J Obstet Gynecol. 1996;174:241–245. 30. Whitley RJ, Kimberlin DW. Infections in perinatology: treatment of viral infections during pregnancy and the neonatal period. Clin Perinatol. 1997;24:267–283. 31. Carroll ED, Campbell ME, Shaw BNJ, et al. Congenital lobar emphysema in congenital cytomegalovirus infection. Pediatr Radiol. 1996;26:900–902. 32. Revello MG, Zavattoni M, Sarasini A, et al. Human cytomegalovirus in blood of immunocompetent persons during primary infection: prognostic implications for pregnancy. J Infect Dis. 1998;177:1170–1175. 33. Mandelbrot L. Vertical transmission of viral infections. Curr Opin Obstet Gynecol. 1998;10: 123–128. 34. Zeldis JB, Crumpacker CS. Hepatitis. In: Remington JS, Klein JO, eds. Infectious diseases of the fetus and newborn infant, 3rd ed. Philadelphia: WB Saunders, 1990:574–600. 35. Ohto H, Terazawa S, Sasaki N, et al. Transmission of hepatitis C virus from mothers to infants. N Engl J Med. 1994;330:744–750. (c) 2015 Wolters Kluwer. All Rights Reserved.

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36. Arvin AM, Yeager AS. Other viral infections of the fetus and newborn. In: Remington JS, Klein JO, eds. Infectious diseases of the fetus and newborn infant, 3rd ed. Philadelphia: WB Saunders, 1990. 37. Brown KE, Young NS. Parvovirus B 19 in human disease. Annu Rev Med. 1997;48:59–67. 38. Brandenberg H, Los FJ, Cohen-Overbeek TE. Short communication: a case of early intrauterine parvovirus B19 infection. Prenat Diagn. 1996;16:75–77. 39. Centers for Disease Control and Prevalence (CDC). Congenital syphilis—United States, 2003–2008. MMWR Morb Mortal Wkly Rep. 2010;59(14):413–417. 40. Centers for Disease Control and Prevention. 1998 guidelines for treatment of sexually transmitted diseases. MMWR Morb Mortal Wkly Rep. 1998;47(RR-1):1–116. 41. Fiumara NJ. The diagnosis and treatment of infectious syphilis. Compr Ther. 1995;21: 639–644. 42. Wendel PJ, Wendel GD Jr. Sexually transmitted diseases in pregnancy. Semin Perinatol. 1993;17:443–451. 43. Centers for Disease Control and Prevention. Chlamydia trachomatis genital infections— United States, 1995. MMWR Morb Mortal Wkly Rep. 1997;46(9):193–198. 44. Mou SM. Bacterial infections. In: Willett GD, ed. Laboratory testing in OB/GYN. London: Blackwell Scientific Publishing, 1994. 45. Adair CD, Gunter M, Stovall TG, et al. Chlamydia in pregnancy: a randomized trial of azithromycin and erythromycin. Obstet Gynecol. 1998;91:165–168. 46. MacDermott RIJ. Review: bacterial vaginosis. Br J Obstet Gynaecol. 1995;102:92–94. 47. ACOG Technical Bulletin. Vaginitis. Int J Gynecol Obstet. 1996;54:293–302. 48. Bader TJ, Macones GA, Asch DA. Prenatal screening for toxoplasmosis. Obstet Gynecol. 1997;90:457–464. 49. Zargar AH, Masoodi SR, Laway BA, et al. Seroprevalence of toxoplasmosis in women with repeated abortions in Kashmir. J Epidemiol Community Health. 1998;52:135–136. 50. Gordon N. Toxoplasmosis: a preventable cause of brain damage. Dev Med Child Neurol. 1993;35:567–573. 51. Steere AC. Lyme disease. N Engl J Med. 1989;321:586–596. 52. MacDonald AB. Gestational Lyme borreliosis: implications for the fetus. Rheum Dis Clin North Am. 1989;15:657–677. 53. Craig S, Permezel M, Doyle L, et al. Perinatal infection with Listeria monocytogenes. Aust N Z J Obstet Gynaecol. 1996;36:286–290. 54. Schuchat A. A guest editorial: listeriosis and pregnancy: food for thought. Obstet Gynecol Surv. 1997;52:721–722. 55. Dimpfl T, Gloning KP. Listeriosis in pregnancy: letter to the editor. Int J Gynecol Obstet. 1994;45:284–285. 56. Lorber B. Listeriosis: state of the art clinical article. Clin Infect Dis. 1997;24:1–9. 57. Millar LD, Cox SM. Urinary tract infections complicating pregnancy. Infect Dis Clin North Am. 1997;11:13–26. 58. Dashe JS, Gilstrap LC III. Antibiotic use in pregnancy. Obstet Gynecol Clin North Am. 1997;24:617–629. 59. Duff P. Antibiotic selection in obstetric patients. Infect Dis Clin North Am. 1997;11:1–12. 60. Kotler DP. HIV in pregnancy. Gastroenterol Clin North Am. 1998;27:269–280. 61. Andiman WA. Medical management of the pregnant woman infected with human immunodeficiency virus type I and her child. Semin Perinatol. 1998;22:72–86.

(c) 2015 Wolters Kluwer. All Rights Reserved.

24

Neurologic Complications Jennifer Cavitt and Reena Shah

SEIZURES IN THE PREGNANT PATIENT Key Points • Pregnancy is not contraindicated in women with epilepsy (WWE). • Greater than 90% of WWE have favorable pregnancy outcomes. • In most cases, antiepileptic drugs (AED) should be continued during pregnancy. • Both seizures and AED are associated with increased risk of adverse outcomes of pregnancy. • Goal for treatment in pregnancy is seizure freedom with the lowest effective AED dose. • Avoid AED polytherapy when possible. • Valproic acid (VPA) exposure during pregnancy is associated with significantly greater risks than other AED exposures. • Folic acid supplementation is recommended prior to conception and during pregnancy. • Pregnant WWE should be managed jointly by their neurologist and obstetrician. Background Definitions

• A seizure is a sudden, abnormal synchronous electrical discharge of cerebral neurons. • Seizures may be provoked (toxic, metabolic, infectious, etc.) or unprovoked. • Symptoms vary depending on the area of brain involved. °°Brief change in awareness and/or behavior °°Abnormal movement: tonic posture, clonic jerking, myoclonic jerks, loss of muscle tone, etc. °°May be followed by postictal confusion • Epilepsy is defined as ≥2 unprovoked seizures greater than 24 hours apart. • Focal seizures (aka partial seizures) begin in a localized area of the brain and may or may not spread to involve other regions of the brain. Focal seizures may occur with or without impairment of consciousness or awareness; with observable motor or autonomic components, such as twitching or jerking, flushing, or automatic behaviors called automatisms (e.g., lip smacking or picking); or involving subjective sensory or psychic phenomena only (also called an “aura”). Focal seizures may spread to diffuse brain involvement, leading to a convulsion, such as a tonic–clonic seizure (1). • Generalized seizures involve nearly all of the brain at onset and include generalized tonic–clonic (GTC), tonic or atonic (“drops”), myoclonic, and absence seizure types (1). Risk Factors

• Some epilepsy syndromes have a genetic component. • Other epilepsy risk factors include traumatic brain injury, stroke, brain tumor or other cerebral structural abnormality, congenital or developmental neurologic disorder, or degenerative disorder. Epidemiology

• Epilepsy affects approximately 1% of the population (2). • Greater than 1 million WWE of reproductive age in the United States give birth to greater than 24,000 infants each year (3). 443

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Evaluation History

• Proper evaluation of a woman with epilepsy should begin prior to pregnancy. • Essential information includes • Certainty of the diagnosis of epilepsy—is further diagnostic evaluation required? • Is the woman followed regularly by a neurologist? • The seizure type, frequency, intensity, and duration should be assessed. • Identify current AED treatment: °°Evaluate compliance, efficacy, and adverse effects. °°Is she a candidate to discontinue AED prior to conception? • Are there any other associated neurologic disorders? • Does she have any complications related to seizures or AED that occurred in prior pregnancies? • Is she taking supplemental folic acid? • Is pregnancy desired or planned, or is the woman already pregnant? • If pregnancy is not desired, what (if any) is the method of contraception? • If pregnancy is desired (or possible), is she taking supplemental folic acid? • If the woman is pregnant °°What is the stage of gestation? °°Has she continued her AED treatment? °°Has there been any change in seizure frequency or intensity? °°Is she taking supplemental folic acid? Diagnosis

• In women with a well-established epilepsy diagnosis, the diagnosis is ordinarily not an issue for the obstetrician. However, certain important scenarios make diagnosis an issue. • In patients with well-established epilepsy, the appearance of clinical spells different from the patient’s usual seizures may indicate another disorder. • A few patients will experience new-onset seizure disorder during pregnancy. • The differential diagnosis of seizures includes many other kinds of clinical “spells” including: syncope, panic attacks, psychogenic nonepileptic seizures, episodic vertigo, paroxysmal movement disorders, and others. These attacks are sometimes difficult to distinguish from epileptic seizures, and expert consultation may be needed. • Correct diagnosis is important: • Nonepileptic events are not effectively treated with AEDs. • Use of AED for nonepileptic events exposes the mother and baby to risks of AED therapy with no concomitant benefit. • Treatment for the correct diagnosis will be delayed. • If the obstetrician observes an attack, it is important to obtain as detailed a description as possible. Particular attention should be paid to the onset of the attack, its clinical characteristics, its duration, and any postattack symptoms. • If a woman develops a seizure disorder during pregnancy, a complete evaluation should be performed by a neurologist to establish a diagnosis and search for an underlying cause. Treatment

General Principles

• Every effort should be made to maintain seizure control during pregnancy and delivery. • Most WWE require continuing AED treatment prior to, during, and after pregnancy and delivery. • The best AED for a given patient is an AED appropriate for the patient’s seizure type, which provides best seizure control at the lowest dose and with the fewest side effects. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Risks

WWE taking AED are at greater risk of adverse pregnancy outcomes related to teratogenicity, cognitive effects in the children exposed in utero to AED, seizures during pregnancy, and possibly increased rates of some obstetrical complications. Major Congenital Malformations

• The vast majority of WWE will have babies with no malformations. • The most common major congenital malformations (MCM) occurring in infants of WWE on AED include congenital heart disease, cleft lip/palate, neural tube defects, and urogenital defects (3). • The overall risk of MCM in WWE taking AED is approximately 3% to 9%, or approximately two to four times the risk in the general population (3). • Approximately 2% to 8% risk of MCM with any first-trimester monotherapy AED exposure (3) • Approximately 6.5% to 19% risk of MCM with any first-trimester polytherapy AED exposure (3) • MCM risk is significantly higher with first-trimester monotherapy or polytherapy including VPA compared to other monotherapy AED exposure or polytherapy without VPA (3). • First-trimester topiramate (TPM) exposure is associated with a greater risk of cleft lip (4). • Greater risk of MCM is associated with higher first-trimester VPA, lamotrigine (LTG), and phenobarbital (PB) doses. °°VPA doses above approximately 1000 mg/d or levels greater than 70 μg/mL (5) °°LTG doses ≥300 mg/d (6) °°PB doses ≥150 mg/d (6) Cognitive Outcomes in Children of Women with Epilepsy

• In utero exposure to VPA is associated with reduced cognitive abilities measured in children at ages 3, 4.5, and 6 years, and the effect is dose dependent (7–9). • In utero VPA exposure is associated with significantly increased absolute risk (4.4%) of autism spectrum disorders in children compared with those not exposed to VPA (2.4%) (10). • Use of periconceptional folic acid by WWE on AED is associated with significantly higher IQ scores in their children at age 6 years (7). Obstetrical Complications and Perinatal Outcomes

• Rigorous literature reviews have raised concern for possible increased obstetrical complications and adverse perinatal outcomes in WWE. • There may be a modestly increased risk (up to 1.5 times expected) of cesarean delivery for WWE on AED (11). • An increased risk (greater than 2 times expected) of premature contractions and premature labor and delivery (L&D) in WWE who smoke has also been reported (11). • Insufficient evidence exists to support or refute increased risk of preeclampsia, ­pregnancy-related hypertension (HTN), or miscarriage (11). • WWE taking AED are at increased risk of having small for gestational age neonates, approximately 2 times expected rate (5). • There is probably no substantially increased risk (greater than 2 times expected) of perinatal death in newborns of WWE (5). Vitamin K Supplementation

• There is insufficient evidence to support or refute increased risk of neonatal hemorrhagic complications in newborns of WWE on AED or decreased risk when these women are treated with prenatal vitamin K supplementation (12). • Newborns of WWE taking enzyme-inducing AED (EIAED) (phenytoin [PHT], carbamazepine (CBZ), PB, primidone [PRM]) routinely receive vitamin K at delivery, as do all newborns. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Effect of Maternal Seizures on the Fetus

• GTC seizures pose a risk to the fetus, as well as to the mother. • Maternal and fetal hypoxia and acidosis (3). • Fetal intracranial hemorrhage, miscarriage, prolonged fetal heart rate (HR) depression (greater than 20 minutes), and stillbirths have been reported following GTC seizures (3). • Effects to the fetus from nonconvulsive seizures are less clear. • There are case reports of fetal HR decelerations (3). • There is risk of trauma with multiple seizure types, potentially leading to perinatal complications. Seizure Frequency During Pregnancy

• Most WWE (64%) have unchanged seizure frequency during pregnancy (3). • Sixteen percent have fewer seizures in pregnancy compared to baseline. • Seventeen percent have an increase in seizure frequency during pregnancy. • Studies observing seizure frequency in pregnant WWE have not included a control group of nonpregnant WWE with seizure frequency data for comparison. Thus, the influence of pregnancy on seizure frequency is unclear (11). • Seizure freedom ≥9 months prior to conception is associated with high likelihood (84% to 92%) of seizure freedom during pregnancy (11). • There is insufficient evidence to support or refute increased risk of status epilepticus (SE) in pregnancy (11). Laboratory Tests

• AED levels can provide important guidance in managing AED therapy before, during, and after pregnancy. However, physicians should • Evaluate seizure control, not an AED level, to determine AED effectiveness • Be cognizant that drug toxicity is a clinical diagnosis, which may or may not correlate with “toxic” blood levels Contraceptive Management

• Oral contraceptives (OC) per se have no effects on seizure frequency. • Estrogen may lower serum levels of LTG up to 50%, potentially leading to breakthrough seizures (13,14). • EIAED, including PHT, PB, PRM, CBZ, felbamate (FBM), clobazam (CLB), and rufinamide (RUF), may reduce hormone levels, leading to contraceptive failure. Oxcarbazepine (OXC) greater than 1200 mg/d and TPM greater than 200 mg/d have a similar effect. It has been recommended WWE taking these agents should take OC with ≥50 μg estradiol or its equivalent, though no studies have determined whether this improves the risk of contraceptive failure in the setting of EIAED. Transdermal patch and vaginal ring formulations and intramuscular (IM) medroxyprogesterone also have higher failure rates. An 8- to 10-week dosing interval for IM medroxyprogesterone in the setting of EIAED has been suggested, though whether this improves efficacy has not been established (3,14). • Perampanel (PMP) reduces levonorgestrel levels by up to 40% (see Table 24-1). Prepregnancy Management • Any uncertainty about the diagnosis of epilepsy should be resolved. Consultation with a neurologist should be obtained and continued through pregnancy. • If seizure free greater than 2 years on AED with normal imaging, electroencephalography (EEG), and exam, consider whether the patient is a candidate to wean off AED under care of neurologist, dependent on epilepsy syndrome diagnosis. If electing to wean AED, counsel regarding risk of seizure recurrence. This should be accomplished ≥6 months prior to conception. • Consider changing to an alternative to VPA therapy, if possible prior to conception (5).

(c) 2015 Wolters Kluwer. All Rights Reserved.

(c) 2015 Wolters Kluwer. All Rights Reserved.

Abbreviation CBZ

CLB KLO ESX EZG FBM GBP LCM LTG LEV LRZ OXC PMP PB PHT PGB PRM RUF TGB TPM VPA

ZNS

Antiepileptic drug name Carbamazepine

Clobazam Clonazepam Ethosuximide Ezogabine Felbamate Gabapentin Lacosamide Lamotrigine Levetiracetam Lorazepam Oxcarbazepine Perampanel Phenobarbital Phenytoin Pregabalin Primidone Rufinamide Tiagabine Topiramate Valproic acid

Zonisamide

C

C D C C C C C C C D C C D D C D C C D D

Pregnancy class D

No

Yes Yes No Yes Yes No Yes >200 mg/d No

c

Yes No No No Yes No No Yesb No No Yes >1200 mg/d

Interaction with HCa Yes

Loss

Loss Gain

Gain

Gain

Loss Gain Loss Gain

Weight gain or loss Gain

Yes

Yes

Yes Yes

Bone loss association Yes

40%

80%–90% 85% N/A 80% 25% 14 drinks Women: 1 point if >7 drinks 1 point for each of maximum number Men: >4 Women: >3

From National Institute on Alcohol Abuse and Alcoholism (NIAAA). Helping patients with alcohol problems: a health practitioner’s guide. NIAAA, 2003.

(c) 2015 Wolters Kluwer. All Rights Reserved.

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--Recovery treatment is increasing the likelihood of the dependent individual not

wanting and not starting the use of the agent again. • Because addiction is a medical–psychological–social disease, pharmacotherapy alone is rarely successful. • Additional nonpharmacologic treatments of dependence disorders include °°Twelve-step programs °°Treatment of medical complications of addiction °°Treatment of psychiatric comorbidity °°Family therapy • Detoxification and/or pharmacologic management of detoxification/withdrawal of the pregnant addict should generally be a multidisciplinary process, with comanagement by a(n) °°Obstetrician °°Addiction medicine specialist °°Maternal–fetal medicine specialist °°Medical specialist

ALCOHOL Scope and Significance • Maternal alcoholism ranks as one of the leading causes of newborn neurodevelopmental disorders (32). • Up to 1 in 500 live newborns meet the diagnostic criteria for Fetal Alcohol Syndrome (FAS) (33,34). • More than 2.5 million women in the United States are estimated to be alcohol dependent (14). Mechanism of Action • The neurochemistry of alcohol intoxication and dependence is relatively complex and involves activation or modification of the following neurotransmitter pathways (35): • Gama-aminobutyric acid (GABA) • Serotonin • Dopamine • Norepinephrine • Endorphin (opioid) • Glutamate • Seizure activity from alcohol withdrawal occurs due to chronic alcohol-induced upregulation of excitatory neurotransmitters (36,37). • Delirium tremens (DTs) are the most serious manifestation of acute alcohol withdrawal. °°Risk of both maternal and fetal mortality may be appreciable from uncontrolled DTs. °°A major goal of alcohol withdrawal management is prevention of DTs. Detoxification Treatment (22,35) • Benzodiazepines are standard therapy for seizure prevention. • Long-acting agents generally perform better than do short-acting agents and may have a lower predilection for cross addiction. • The teratogenic effects of benzodiazepines are uncertain. • Benzodiazepines may themselves produce a withdrawal syndrome. • Other medications used for acute withdrawal therapy include • Carbamazepine • Valproic acid • Clonidine (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Adjunctive management of detoxification includes • Nutritional therapy • Prevention of Wernicke encephalopathy (22,35,36) from administration of thiamine (100 mg IV) during initiation of treatment and as a continued supplement for several days thereafter Recovery Pharmacotherapy • Naltrexone • Opioid antagonist—attenuates opioid-mediated reinforcement initiated by alcohol consumption • Naltrexone nonpregnant subjects—reduces drinking associated with relapse—not as successful for maintenance of abstinence (38) • Limited data in pregnancy consistent with safety (39–41) • Disulfiram • Induces physical illness with alcohol consumption via alcohol dehydrogenase inhibited production of excessive acetaldehyde metabolites. • Although data are not conclusive, disulfiram should probably not be used during pregnancy (13). TOBACCO Scope and Significance • From 1990 to 2003, the rate of smoking reported by pregnant women decreased from 18.4% to 11% (23,42). • Smoking is associated with several pregnancy-related risks (23): • Intrauterine growth delay • Abruptio placentae • Placenta previa • Ectopic pregnancy • Poor newborn outcome Mechanism of Action • The primary addictive agent in tobacco products is nicotine. • Delivery system chosen by the user offers ritualistic reinforcement of nicotine use. • Nicotine’s central nervous system (CNS) effects are complex (43). • At low doses, nicotine causes sympathetic activation (mild CNS stimulant). • At higher doses, ganglionic activation occurs and may produce mild anxiolytic effects. • Addictive reinforcement is mediated by both the low-dose stimulation and the highdose reduction in anxiety. • Continued tobacco use (without attempts to quit or modulate consumption) may be indicative of increased risk of alcohol or illicit drug use during pregnancy (23). • Dosing kinetics and reinforcement kinetics of nicotine are formidable (44). Pharmacotherapy • Nicotine substitution systems • Provide controlled dosing of nicotine without, or perhaps with less, ritualistic reinforcement. • Allow use of nicotine without harmful inhalation or ingestion of other components of tobacco (e.g., “tar,” carbon monoxide, etc.). • Large-scale clinical trials not performed in pregnancy (23). °°Short-term results not suggestive of hemodynamic effects in mother or fetus and found to demonstrate less overall total nicotine use (45) °°Safety of use data not presently conclusive (c) 2015 Wolters Kluwer. All Rights Reserved.

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°°Evidence still insufficient to show efficacy, although nicotine substitution in preg-

nancy is only therapy yet studied via a randomized controlled trial • Efficacy of nicotine replacement (gum) evidenced by (46): °°Small but significant increase in smoking cessation °°Small but statistically significant increase in newborn birth weight • If the nicotine patch is used, some suggest removing the patch at bedtime to reduce overall exposure of the fetus to nicotine (23). • Bupropion • Adrenergic antidepressant that inhibits neuronal uptake of norepinephrine and dopamine. °°Precise mechanism of action in smoking cessation not certain • Effectiveness (nonpregnant smokers)—approximately two and a half times more effective than nontreated controls after 1 year of initiation of abstinence (25% to 30% without tobacco use). • Effectiveness in pregnancy less well studied: °°Ten of 22 smokers (45%) with successful abstinence in comparison to 14% in the control group (47) • Safety is not conclusively established in pregnancy. °°One recent trial of 136 exposures to bupropion without increased rate of malformations (48) • Maternal side effects include (uncommon) risk of medication-induced seizures. Other Treatments • Brief intervention (“Ask, Advise, Assess, Assist, Arrange”) may be somewhat effective in smoking cessation during pregnancy (49). • Multiple resources are available via phone self-help lines and online (23). • http://www.surgeongeneral.gov/tobacco • http://www.americanlegacy.org OPIATE (NARCOTICS) Scope and Significance • Although not as common as alcohol addiction, opiate addiction is a significant problem for both the mother and the unborn fetus. • Opiate addiction may be through illicit use of prescription narcotics or use of heroin or other “street” narcotics, which is generally parenteral. • Use of prescription narcotics and abuse/dependence are on the rise in the United States. • Illicit use carries concomitant risks associated with how the drug is taken and high-risk behaviors associated with drug seeking. Mechanism of Action • Narcotics act centrally by binding opioid receptors that are present throughout the CNS (50). • Activation of endorphin psychoactive and analgesic pathways produces the euphoria associated with narcotic use. • Rebound from chronic administration-mediated receptor down-regulation induces withdrawal. °°Alcohol withdrawal may be fatal while opioid withdrawal feels fatal to otherwise healthy adults (51). °°Withdrawal in pregnancy may precipitate preterm labor (13). °°A specific neonatal withdrawal syndrome may occur in newborns of opioid-­ dependent gravidas (25). (c) 2015 Wolters Kluwer. All Rights Reserved.

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Detoxification Treatment • It is very difficult for the opiate addict to abstain from narcotic use. • Most addicts who abstain after withdrawal return to illicit use of opiates within 1 year of initial discontinuation. • Pregnant narcotic (heroin) addicts have better outcomes if enrolled in structured methadone maintenance regimens than if treated via abstinence or drug reduction therapy (50,51). • The goal of detoxification treatment is usually to attenuate acute withdrawal by substitution of the addictive opiate of choice with an equivalent cross-tolerant dose of a medically controlled, long-acting narcotic. Recovery Pharmacotherapy • As mentioned previously, it is recommended that long-acting opioid agonists are used for maintenance treatment of opiate-dependent pregnant patients (see subsequent section on agents used). Agents Used for Opiate Dependence Treatment • Methadone • Long-acting opioid agonist receptor saturation attenuates withdrawal and pleasurable effects from use. • Most effective treatment for established narcotic addicts (50,51). • Use in pregnancy demonstrated to be effective. • Most authorities do not recommend discontinuation during pregnancy: °°Fetal withdrawal risk present. °°Maternal relapse occurs more frequently. • Formerly thought to produce a dose-related risk of neonatal addiction—association not currently thought to be clear secondary to increased relapse risk and use of street drugs and methadone together at lower doses (52,53). • Use and dose adjustment management should occur in conjunction with the addiction specialist. °°Requirements may be increased during pregnancy—80 to 150 mg/d or higher is not uncommon. • Fetal effects and risk from methadone use during pregnancy difficult to discern from effects of other substance use or lifestyle risks from addiction (13) • Buprenorphine • Buprenorphine is a mixed opioid agonist–partial antagonist used in the United States since 2002 as a treatment of opiate dependence (54). • Restrictions on use are far less than with methadone. °°Goal of introduction of buprenorphine was to allow wider availability of treatment for narcotic addiction. • Patients may be started on buprenorphine de novo or converted from methadone. °°Because buprenorphine is a mixed agonist–antagonist agent, patients on high doses of methadone (pure agonist) should not be converted to buprenorphine because of the risk of precipitation of withdrawal. • Some data show effectiveness of buprenorphine equivalent to methadone at dosefor-equivalent dose (55). °°Neonatal withdrawal is possible, however. °°Neonatal withdrawal possibly less likely. °°Use during pregnancy should be in comanagement with an addiction specialist. ADJUNCTIVE TREATMENT Pharmacotherapy • Many agents and medications are used for adjunctive therapy of addiction (35), management of complications, or treatment of comorbidities. Examples include, but are not limited to (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Clonidine—treatment of autonomic instability and/or hypertension • Antidepressants—treatment of comorbid psychiatric diagnoses • Mood stabilizers—treatment of comorbid psychiatric diagnoses • Beta-adrenergic–blocking agents—treatment of hypertensive complications • Adjunctive pharmacotherapy is not used to treat drug dependence directly. Rather, such treatments are for control of symptoms or for therapy of other conditions that may affect outcome. • Use of adjunctive treatments during pregnancy must be determined on a case-by-case basis, with the balance of potential benefit of treatment with possible or unknown risk to the pregnancy or the mother. Recovery Treatment • Because addiction is a disease that results in “collateral damage” to one’s family, friends, finances, employment, and spirituality, most feel that successful treatment of addiction requires whole person and family therapy for long-term success. • Completion of predetermined recovery milestones appears to have a positive effect on duration of recovery (56). • Women, and in particular, pregnant women, have faced difficulty in accessing longterm inpatient or outpatient comprehensive treatment for chemical dependence, albeit the current trend is one of increased specific availability of gender-sensitive treatments (57). • As with many other diseases, an eventual desire to recover is crucial to long-term success. • Forced treatment (medical or legal) is generally not successful for long-term results (58). • Because of the high social comorbidity associated with the pregnant dependent patient, multidisciplinary treatment for the addict and her family are necessary for success. • Despite the challenges inherent in the treatment of the pregnant addict, there is tremendous potential for creating positive influences on the lives of several people for each female addict who is successfully treated (the patient, her fetus, other family members). It is to society’s advantage to increase the resources available to addicted pregnant patients. Twelve-Step Program Recovery • The prototype of 12-step recovery is Alcoholics Anonymous (AA) (59). • Empiric spirituality-based program of recovery. °°Program started more than 70 years ago by a recently sober alcoholic stockbroker (Bill W.) and an alcoholic physician (Dr. Bob) • Only requirement for membership is “a desire to stop drinking.” °°No dues or fees required to participate • Twelve-step process is followed through use of sponsor, attendance at group meetings, and helping fellow alcoholics. • Program is available worldwide and is not religious based. • Information for health professionals on AA available (60). • Open gender meetings are the norm for AA, although women-only meetings are available. • In addition to AA, 12-step programs are now present for many other chemical and social addictions. Examples include (but are not limited to) • Narcotics Anonymous • Cocaine Anonymous • Overeaters Anonymous • Debtors Anonymous • Most medical treatment programs of addiction are based, at least in part, on a 12-step format. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Efficacy of 12-step recovery programs for the treatment of chemical dependency in pregnancy has not been definitively studied. • In general, long-term participation in 12-step recovery is a positive predictor for longterm (frequently lifetime) recovery (61). COMPLICATIONS Fetal Alcohol Syndrome • Alcohol is a known teratogen. Postnatal manifestations of prenatal maternal exposure to alcohol are characterized broadly as fetal alcohol effect(s) (FAE) (62). • FAS is the most significant manifestation of maternal alcohol use in pregnancy. • Complete expression of FAS is characterized by (63) • Intrauterine growth delay • Microcephaly • Micropthalmia • Neurobehavioral manifestations (mental retardation, developmental delay, etc.) • Dysmorphic facies: °°Thin upper lip °°Short palpebral fissures °°Flattened philtrum and nasal bridge • FAS is the leading preventable cause of mental retardation in the United States (64). • Incomplete manifestation of FAS is subcharacterized as FAE (65). • Genetic and environmental factors appear to play a part in expression of FAS and FAE. • A safe threshold for alcohol consumption in pregnancy has not been established—it is recommended that women who are pregnant or who plan to become pregnant abstain from alcohol. • Prenatal screening of the fetus for FAE or FAS is not generally possible—intrauterine growth delay may be a relatively nonspecific finding (or it may be caused by other comorbidities such as tobacco use or poor nutrition). Effects of Tobacco Use in Pregnancy • Effects on pregnancy from maternal smoking are far more pronounced than the apparent short-term maternal complications of use. • Smoking during pregnancy increases the rate of the following complications (23,46,49): • Intrauterine growth delay • Abruptio placentae • Placenta previa and accreta • Spontaneous abortion • Preterm labor • Stillbirth—rate in smokers at 10 per 1000 (66) • Risk particularly increased in smoking women with concurrent pregnancy diagnosis of fetal intrauterine growth restriction • Cigarette use during pregnancy does not appear to increase the risk of the following (13,67): • Congenital malformations (identifiable at birth) • Preeclampsia °°May be a function or effect of smoking on gestational age at delivery (preterm birth) • Possible postnatal effects of cigarette use during pregnancy (or postnatal exposure to the newborn from continued maternal use) may include • Increased risk of sudden infant death syndrome (68) • A possible association with neurodevelopmental outcome (69) °°Postnatal outcome data may be confounded by other substance exposures. • Perinatal effects from smoking may be attenuated in those who cannot stop during pregnancy by modulation (reduction) of use while pregnant (23). (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Intrauterine growth delay risk increased by 53% in those who smoked less than one pack per day as compared to 130% in those who smoked more than one pack per day (66). • Patients should be advised to reduce use of tobacco during pregnancy even if they are unable to abstain completely. Effects of Other Substances of Abuse or Dependence in Pregnancy • Marijuana (Cannabis) • Marijuana is the most common illicit drug used in pregnancy (13). • Current evidence does not suggest an association with cannabis use and intrauterine growth delay, in the absence of concomitant tobacco use (70). • No consistent association with congenital malformation and maternal marijuana use in pregnancy. • Recent data may suggest an increased risk of childhood depression in children of prenatal cannabis users (71). • Additional investigation is needed to evaluate fetal risk from maternal marijuana use. • Cocaine • Cocaine functions as a central and peripheral adrenergic agonists. °°Vasoconstriction is a common feature. °°Maternal morbidity and mortality are related to increased blood pressure and resulting cardiovascular, CNS, and uteroplacental effects from vasoconstriction, loss of autoregulation, and vascular bed ischemia. • Cocaine in powdered, injectable, or inhaled (“crack”) delivery systems is a powerfully addictive substance. °°Principle active ingredient of cocaine is benzoylecgonine. °°In those who chronically use cocaine during pregnancy, accumulation of the drug occurs in the fetal compartment (72). --Cocaine’s pKa is alkaline, so the lower fetal pH enhances concentration in the fetal compartment. --Demethylation metabolism, which occurs in the liver, is much slower in the fetus due to hepatic immaturity. • Short-term pregnancy effects from maternal cocaine use include (73) °°Increased perinatal mortality °°Preterm labor °°Preeclampsia °°Abruptio placentae °°Fetal cerebral hemorrhage (74) °°Increased risk of spontaneous abortion • Teratogenic risk from maternal cocaine use is less clear and may be related to the cocaine itself or correlates of cocaine use (64). • Postdelivery developmental effects on the offspring of pregnant women who used cocaine during pregnancy are not as clearly defined as once thought. °°Many authorities feel that previously observed cocaine-induced effects on childhood neurodevelopmental performance may be related to fetal exposure to chaotic environmental influences during childhood or prenatal alcohol or tobacco use in conjunction with illicit cocaine use (75,76). °°Definitive data on offspring effects from prenatal cocaine exposure are not presently conclusive. • Methamphetamines and other related CNS stimulants: • Although the receptor-mediated mechanism of action is different than with cocaine, other CNS stimulants produce similar effects and maternal risk profiles. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Crystal methamphetamine (“ice” or “crank”) is a rapidly growing drug of addiction or abuse. • Direct fetal risks from maternal CNS stimulant use in pregnancy are similar to those risks found with cocaine use (77). • Data are presently inconclusive regarding long-term neurodevelopmental or teratogenic effects from noncocaine CNS stimulants (78). • Hallucinogenic agents: • Lysergic acid diethylamide (LSD), psilocybin, peyote (mescaline), and phencyclidine (PCP) do not demonstrate consistent newborn or developmental effects in offspring of reported users (79). • PCP and MDMA may exhibit appreciable sympathomimetic or anticholinergic effects—fetal risk is at least potentially similar to other CNS stimulants (80). °°Maternal risk from MDMA use may include anticholinergic crisis and dehydration. • Conclusive data regarding pregnancy-related risk from the use of hallucinogens are lacking. • MDMA use during pregnancy is associated with differences in 1 year of life neurodevelopmental scores in exposed offspring (81). • Volatile solvents and inhalants: • Inhalation of industrial solvents are associated with a variety of teratogenic and fetal neurodevelopmental effects (82,83). °°Maternal and/or fetal hypoxia, electrolyte disturbances, and heart rate abnormalities may occur as a result of solvent inhalation. °°Long-term maternal hepatic or CNS dysfunctions are tragic consequences of chronic solvent inhalation. °°A particular toluene embryopathy has been described in the offspring of pregnant women who inhaled the agent during gestation. --The effects are similar to those seen with FAS—embryologic pathophysiology appears to be similar (84). • Dextromethorphan (DM): • DM is a common ingredient in over the counter cough and cold remedies. • In supernormal doses, DM has become popular as a “club drug” of abuse. • Euphoric effects of DM are similar to MDMA. • Ingestion of a recreational dose of DM may lead to significant metabolic consequences (85) °°Acid–base disorders °°Autonomic instability °°Seizures • Inconclusive data regarding normal (nonrecreational) use of DM in pregnancy are not suggestive of a consistent pattern of malformations (86). • Data on the recreational use of DM during pregnancy are limited. PATIENT EDUCATION • Provider recognition and discussion of substance use and chemical dependence are crucial to both moderation of abusive use and self-recognition of addiction by the dependent patient. • Brief intervention may be effective in abuse and low level dependence of alcohol. • Smoking intervention (previously described) and resources enhance the medical treatment of smoking cessation. • Several US government and other foundation resources are available to patients wanting more information about substance abuse/addiction and to those who wish to cease addictive behavior (Table 26-3). (c) 2015 Wolters Kluwer. All Rights Reserved.

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Table 26-3 Smoking

Alcohol Illicit substances Twelve-step recovery

Resources for Patients Surgeon General U.S. Department of Health and Human Services http://www.surgeongeneral.gov/tobacco/prenatal.pdf 800-358-9295. American Legacy Foundation http://www.americanlegacy.org/866-66-START National Institute on Alcohol Abuse and Alcoholism (NIAAA) http:\\www.niaaa.nih.gov/faqs/general-english/default.htm http:\\www.thecoolspot.gov National Institute on Drug Abuse (NIDA) http:\\www.nida.nih.gov/students.html Alcoholics Anonymous http:\\www.alcoholics-anonymous.org Narcotics Anonymous http:\\www.na.org Cocaine Anonymous http:\\www.ca.org

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14. Substance Abuse and Mental Health Services Administration. Summary of findings from the 2000 National Household Survey on Drug Abuse. Publication SMA 01-3549. Rockville: U.S. Department of Health and Human Services, 2001. 15. National Center for Health Statistics. Health, United States, 2004: with chart book on trends in the health of Americans. Hyattsville: National Center for Health Statistics, 2004. Available at: http://www.cdc.gov/nchs/data/hus/hus04.pdf. Accessed October 16, 2005. 16. American Congress of Obstetricians and Gynecologists. Nonmedical use of prescription drugs. ACOG Committee Opinion No. 538. American Congress of Obstetricians and Gynecologists, 2012. 17. Verstraete A. Detection times of drugs of abuse in blood, urine, and oral fluid. Ther Drug Monit. 2004;26:200–205. 18. Maurer H. Position of chromatographic techniques in screening for detection of drugs forensic toxicology and/or doping control. Clin Chem Lab Med. 2004;42:1310–1324. 19. Willette R. The role of the substance abuse professional. In: Graham A, Schultz T, MayoSmith M, et al., eds. Principles of addiction medicine. 3rd ed. Chevy Chase: American Society of Addiction Medicine, 2003:993–1000. 20. American Congress of Obstetricians and Gynecologists. Substance abuse reporting and pregnancy: the role of the obstetrician-gynecologist. ACOG Committee Opinion No. 473. American Congress of Obstetricians and Gynecologists, 2011. 21. Erlich L. A textbook of forensic addiction medicine and psychiatry. Springfield: Charles C. Thomas, 2001. 22. Wunsch MJ, Weaver MF. Alcohol and other drug use during pregnancy: management of the mother and child. In: Ries RK, Fiellin DA, Miller SC, et al., eds. Principles of addiction medicine. 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2009:1111–1124. 23. American Congress of Obstetricians and Gynecologists. Smoking cessation during pregnancy. ACOG Committee Opinion No. 316. American Congress of Obstetricians and Gynecologists, 2005. 24. Sonderregger T. Perinatal substance abuse. Baltimore: Johns Hopkins University Press, 1992. 25. Hoegerman G, Schnoll SH. Narcotic use in pregnancy. Clin Perinatol. 1991;18:51–76. 26. American Congress of Obstetricians and Gynecologists. At-risk drinking and illicit drug use: ethical issues in obstetric and gynecologic practice. ACOG Committee Opinion No. 294. American Congress of Obstetricians and Gynecologists, 2004. 27. Sokol RJ, Martier SS, Ager JW. The T-ACE questions: practical prenatal detection of risk drinking. Am J Obstet Gynecol. 1989;160:863–868. 28. Chan AW, Pristach EA, Welte JW, et al. Use of the TWEAK test in screening for alcoholism/ heavy drinking in three populations. Alcohol Clin Exp Res. 1993;17:1188–1192. 29. National Institute on Alcohol Abuse and Alcoholism (NIAAA). Helping patients with alcohol problems: a health practitioners guide. Rockville: U.S. Department of Health and Human Services, 2003. 30. Chasnoff IF, Wells AM, McGourty RF, et al. Validations of the 4P’s Plus screen for substance use in pregnancy validation of the 4P’s Plus. J Perinatol. 2007;12:744–748. 31. Yonkers KA, Gotman N, Kershaw T, et al. Screening for prenatal substance use: development of the substance use risk profile-pregnancy scale. Obstet Gynecol. 2010;116:827–833. 32. Hoyme HE, May PA, Kalberg WO, et al. A practical clinical approach to diagnosis of fetal alcohol spectrum disorders: clarification of the 1996 Institute of Medicine criteria. Pediatrics. 2005;115:39–47. 33. Bertrand J, Floyd LL, Weber MK. Guidelines for identifying and referring persons with fetal alcohol syndrome. MMWR Recomm Rep. 2005;54(RR-11):1–14. 34. May PA, Gossage JP. Estimating the prevalence of fetal alcohol syndrome: a summary. Alcohol Res Health. 2001;25:159–167. 35. Hillemacher T. Biologic mechanisms in alcohol dependence—new perspectives. Alcohol Alcohol. 2011;46:224–230. 36. Gordon AJ. Physical illness and drugs of abuse. A review of the evidence. Nyack, NY: Cambridge University Press, 2010. 37. Kumar N. Neurologic presentation of nutritional deficiencies. Neurol Clin. 2010;28:107–170. (c) 2015 Wolters Kluwer. All Rights Reserved.

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38. Gastfriend DR. Intramuscular extended release naltrexone. Current evidence. Ann N Y Acad Sci. 2011;1216:144–166. 39. Hulse GK, O’Neill G, Pereira C, et al. Obstetric and neonatal outcomes associated with maternal naltrexone exposure. Aust N Z J Obstet Gynaecol. 2001;41:424–428. 40. Hulse GK, Arnold-Reed DE, O’Neil G. Naltrexone implant and blood naltrexone levels over pregnancy. Aust N Z J Obstet Gynaecol. 2003;43:386–388. 41. Jones HE. Acceptance of naltrexone by pregnant women enrolled in comprehensive drug addiction treatment: an initial survey. Am J Addict. 2012;21:199–201. 42. Hamilton BE, Martin JA, Sutton PD. Births: preliminary data for 2003. Centers for Disease Control and Prevention, National Center for Health Statistics. National Vital Stat Rep. 2004;53(a):1–17. 43. Harmey D, Griffin PR, Keney PJ. Development of novel pharmacotherapeutics for tobacco dependence: progress and future directions. Nicotine Tob Res. 2012;14:1300–1318. 44. Wynn WP III, Stroman RT, Almgren MM, et al. The pharmacist “toolbox” for smoking cessation: a review of methods, medicines, and novel means to help patients along the path of smoking reduction to smoking cessation. J Pharm Pract. 2012;(6):591–599. 45. Oncken CA, Hatsukami DK, Lupo VR, et al. Effects of short-term use of nicotine gum in pregnant smokers. Clin Pharmacol Ther. 1996;59:654–661. 46. Coleman T, Chamberlain C, Davey MA, et al. Pharmacological interventions for promoting smoking cessation during pregnancy. Cochrane Database Syst Rev. 2012;(9):CD010078. 47. Chan B, Einarson A, Koren G. Effectiveness of Bupropion for smoking cessation during pregnancy. J Addict Dis. 2005;24:19–23. 48. Chun-Fai-Chan B, Koren G, Fayez I, et al. Pregnancy outcome of women exposed to Bupropion during pregnancy: a prospective comparative study. Am J Obstet Gynecol. 2005;192:932–936. 49. Fiore MC, Bailey WC, Cohen SJ, et al. Treating tobacco use and dependence. Clinical practice guideline. Rockville: U.S. Department of Health and Human Services, Public Health Service, 2000. 50. Rahimi-Movaghar A, Amin-Esmaeili M, Hefazi M, et al. Pharmacological therapies for maintenance treatments of opium dependence. Cochrane Database Syst Rev. 2013;(1):CD007775. 51. National Consensus Development Panel on Effective Medical Treatment of Opiate Addiction. Effective medical treatment of opiate addiction. JAMA. 1998;280:1936–1943. 52. Sharp C, Kuschel C. Outcomes of infants born to mothers receiving methadone for pain management in pregnancy. Arch Dis Child Fetal Neonatal Ed. 2004;89:33–36. 53. Berghella V, Lim P, Hill M, et al. Maternal methadone dose and neonatal withdrawal. Am J Obstet Gynecol. 2003;189:312–317. 54. U.S. Department of Health and Human Services. Substance abuse and mental health services administration center for substance abuse treatment. Buprenorphine. Rockville: U.S. Department of Health and Human Services, 2005. Available at http://buprenorphine.samhsa.gov/about.html. Accessed October 30, 2005. 55. Jones HE, Kaltenbach K, Heil SH, et al., Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med. 2010;363:2320–2331. 56. Greenfield L, Burgdorf K, Xiaowu C, et al. Effectiveness of long term residential substance abuse treatment for women: findings from three national studies. Am J Drug Alcohol Abuse. 2004;30:537–550. 57. Grella C, Greenwell L. Substance abuse treatment for women: changes in the setting where women received treatment and types of services provided, 1987—1998. J Behav-Health Serv Res. 2004;31:367–383. 58. Jones H, Svikis D, Rosado J, et al. What if they do not want treatment? Lessons learned from intervention studies of non-treatment-seeking, drug-using pregnant women. Am J Addict. 2004;13:342–357. 59. Alcoholics Anonymous. Alcoholics Anonymous. 4th ed. New York: Alcoholics Anonymous World Service, Inc., 2002. 60. Alcoholics Anonymous. AA as a resource for the medical profession. New York: Alcoholic Anonymous World Service, Inc., 1982. (c) 2015 Wolters Kluwer. All Rights Reserved.

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61. McCrady B, Tonigan S. Recent research into twelve step programs. I. In: Ries RK, Fiellin DA, Miller SC, et al., eds. Principles of addiction medicine. 4th ed. Philadelphia: Lippincott Williams & Wilkins, 2009:923–938. 62. Pruett D, Waterman EH, Caughey AB. Fetal alcohol exposure: consequences, diagnosis and treatment. Obstet Gynecol Surv. 2013;68:62–69. 63. Jones KL, Smith DW. Recognition of the fetal alcohol syndrome in early infancy. Lancet. 1973;302:999–1001. 64. Pagliaro L, Pagliaro A. Drugs as human teratogens and fetotoxins. In: Pagliaro L, Pagliaro A, eds. Problems in pediatric drug therapy. 4th ed. Washington: American Pharmaceutical Association, 2002. 65. Smitherman C. The lasting impact of fetal alcohol syndrome and fetal alcohol effect on children and adolescents. J Pediatr Health Care. 1994;8:121–126. 66. ACOG Practice Bulletin No. 102: management of stillbirth. Obstet Gynecol. 2009;113(3):748–761. 67. Hammoud AO, Bujold E, Sorokin Y, et al. Smoking in pregnancy revisited: findings from a large population-based study. Am J Obstet Gynecol. 2005;192:1856–1862. 68. Wisborg K, Kesmodel U, Henriksen TB, et al. A prospective study of smoking during pregnancy and SIDS. Arch Dis Child. 2000;83(3):203–206. 69. Clifford A, Lang L, Chen R. Effects of maternal cigarette smoking during pregnancy on cognitive parameters of children and young adults: a literature review. Neurotoxicol Teratol. 2012;34:560–570. 70. English D, Hulse GK, Milne E, et al. Maternal cannabis use and birth weight: a metaanalysis. Addiction. 1997;92:1553–1560. 71. Gray K, Day N, Leech S, et al. Prenatal marijuana exposure: effect on child depressive symptoms at ten years of age. Neurotoxicol Teratol. 2005;27:439–448. 72. Scanlon J. The neuroteratology of cocaine: background, theory, and clinical implications. Reprod Toxicol. 1991;5:89–98. 73. Cain MA, Bormick P, Whiteman V. The maternal, fetal, and neonatal effects of cocaine exposure in pregnancy, Clin Obstet Gynecol. 2013;56:124–132. 74. Gieron-Korthals M, Hedal A, Martinez C. Expanding spectrum of cocaine induced central nervous system malformations. Brain Dev. 1994;16:253–256. 75. Messinger D, Bauer C, Das A, et al. The maternal life type study: cognitive, motor, and behavioral outcomes of cocaine-exposed and opiate-exposed infants through three years of age. Pediatrics. 2004;113:1677–1685. 76. Mansoor E, Morrow CE, Accomero VH, et al. Longitudinal effects of prenatal cocaine use on mother-child interactions at ages 3 and 5 years. J Dev Behav Pediatr. 2012;33(1):32–41. 77. Pagliaro A, Pagliaro L. Substance use among women. Philadelphia: Brunner/Mazel, 2000. 78. Wouldes T, LaGasse L, Sheridan J, et al. Maternal methamphetamine use during pregnancy and child outcome: what do we know? NZ Med J. 2004:U1180. 79. Pagliaro L. Pharmacopsychology updates: psychotropic teratogens. Psymposium. 1995;6:18–19. 80. Tabor B, Smith-Wallace T, Yonekura M. Perinatal outcome associated with PCP versus cocaine use. Am J Drug Alcohol Abuse. 1990;16:337–348. 81. Singer LT, Moore DG, Min MO, et al. One year outcomes of prenatal exposure to MDMA and other recreational drugs. Pediatrics. 2012;130:407–413. 82. Hannigan JH, Bowen SE. Reproductive toxicology and teratology of abused toluene. Syst Biol Reprod Med. 2010;56:184–200. 83. Arnold G, Kirby R, Langendoerfer S.Toluene embryopathy: clinical delineation and developmental follow-up. Pediatrics. 1994;93:216–220. 84. Pearson MA, Hoyme H, Seaver L, et al. Toluene embryopathy: delineation of the phenotype and comparison with fetal alcohol syndrome. Pediatrics. 1994;93:211–215. 85. Forrester MB. Dextromethorphan abuse in Texas, 2000–2009. J Addict Dis. 2011;30:243–247. 86. Martinez-Frias M, Rodriguez-Pinilla E. Epidemiologic analysis of prenatal exposure to cough medicines containing dextromethorphan: no evidence of human teratogenicity. Teratology. 2001;63:38–41. (c) 2015 Wolters Kluwer. All Rights Reserved.

27

Gynecologic Complications Kellie Flood-Shaffer

KEY POINTS • Pregnancy does not prevent or protect a woman from developing common gynecologic problems and complications. • Untreated gynecologic problems can adversely affect obstetric care and exacerbate obstetric complications. • Treatment of gynecologic problems is frequently the same for the pregnant and the nonpregnant patient with some notable exceptions. EXTERNAL GENITALIA Careful inspection of the external genitalia before pregnancy, as well as at the initial prenatal visit, is crucial to the patient’s health. Counseling about the signs and symptoms of external genital infections, as well as the risks of transmission with exposure to infectious organisms, should also be discussed. Bartholin Abscess Background

• Bartholin cysts are a common occurrence in the reproductive age female, and pregnancy can exacerbate their symptoms. • Although asymptomatic cysts need not necessarily be treated, an abscess of the Bartholin gland usually requires immediate treatment. Diagnosis

• A Bartholin gland abscess typically causes significant pain and inflammation. The diagnosis can often be made based solely on the patient’s complaints. • Patients will complain that they feel a large tender “bump” on their labia and have severe pain with standing, walking, or sitting. • Although the symptoms are fairly classic, a thorough examination and evaluation must be performed (1,2). Treatment

• Drainage via an incision on the mucosal side of the gland is appropriate when the area is fluctuant. Otherwise, warm sitz baths are recommended until the abscess is ready for drainage. • Cultures obtained at the time of initial drainage are useful, as gonococcus is often the etiologic agent, and when suspected, antibiotics are appropriate. • Once the abscess is incised, a Word catheter is placed for 4 to 6 weeks to allow adequate epithelialization of a drainage tract. Packing the incised abscess pocket with narrow gauze is also acceptable. • Recurrent infection or development of recurrent symptomatic cysts warrants subsequent marsupialization (surgical exteriorization of the cyst for drainage). Removal of the gland is not recommended in pregnancy and should be deferred until the puerperium is complete. 508

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Human Papillomavirus and Condylomata Acuminata Background

• Condylomata acuminata or genital warts are very common in both men and women. • They are caused by the human papillomavirus (HPV) of which there are more than 100 subtypes. More than 40 of these subtypes can infect the genital area. Genital warts are usually caused by HPV types 6 and 11 (3,4). • Reinfection and persistent infection are common. Diagnosis

• Condyloma acuminatum has a classic “cauliflower-like” appearance and can protrude from the skin on stalks. The lesions appear fleshy and may cause some minor itching but are not painful. • The clinician must clinically distinguish the very common condylomata acuminata (genital warts) from the rare, wart-like growths of condyloma latum, which is caused by Treponema pallidum (1,2). • During pregnancy, genital warts may proliferate, rapidly enlarge, and become friable and can obstruct the vaginal canal. • HPV, in rare cases, may be transmitted to the newborn, resulting in laryngeal papillomas with respiratory complications. However, delivery by cesarean section is not indicated to prevent fetal intrapartum exposure. Treatment

• Outpatient treatment of genital warts during pregnancy can be safely achieved by • Cryotherapy (liquid nitrogen application or nitrous oxide cryoprobe). • Carbon dioxide laser therapy. • Topical application of 50% to 80% trichloroacetic acid solution. • Imiquimod cream has been used with some success but should be used with caution and only when benefits outweigh risks, as it is a category C drug in pregnancy and may be associated with fetal toxicity. • Podophyllin, podofilox, and sinecatechins are currently not advised for use in pregnancy because of the risks of birth defects, fetal death, stillbirth, and maternal toxicity. • Removal of condyloma via electrocautery or laser therapy is an alternative that may require general or regional anesthesia (see Chapter 3). • Both cryotherapy and carbon dioxide laser therapy appear to be highly effective when used to treat condyloma in pregnancy, with no significant fetal, neonatal, or maternal morbidity. • The recurrence rate of genital warts appears to be the lowest when treated in the third trimester. • Genital warts are not considered an indication for cesarean delivery unless they are so large as to constitute physical obstruction or significant risk for vaginal/cervical lacerations. • There are currently two U.S. Food and Drug Administration (FDA)–approved vaccines shown to be effective in preventing HPV infection in adolescents and young adults. Inadvertent administration of these vaccines during pregnancy has shown no harmful fetal effect, but women with known pregnancy should not be vaccinated (3). Genital Herpes Simplex (See Chapter 23) VAGINITIS (5) Background • Vaginal infections are among the most common reasons for urgent gynecologic office visits. • Speculum examination and microscopic study are essential in the evaluation of pregnant women complaining of vaginal discharge. Both physiologic secretions and rupture of membranes may be misdiagnosed as vaginitis. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Although most vaginal infections are easily treated, these infections may be associated with more serious obstetric complications such as maternal and neonatal infection, preterm premature rupture of membranes (PPROM), or preterm labor. Candidiasis Background

• Candida accounts for approximately 35% of vaginal infections. However, a “yeast infection” is not a sexually transmitted disease. It is a result of the overgrowth of fungal organisms that are present in the normal vaginal flora. • The most common fungal organism is Candida albicans. Other important pathogens include Monilia, Candida tropicalis, and Candida glabrata. • Several factors may predispose a patient to vaginal candidiasis including pregnancy, diabetes, immunosuppressive disorders, use of oral contraceptives or oral corticosteroids, or recent use of broad-spectrum antibiotics. Diagnosis

• Typical symptoms include itching, burning, dysuria, an erythematous vulva, and curdlike (“cottage cheese”) discharge, which tends to adhere to the vaginal mucosa. The vaginal pH remains normal at less than 4.2. The vulva and groin may also exhibit “satellite lesions” or erythematous papules that often cause intense pruritus. • Confirmation of the diagnosis is made with the microscopic observation of hyphae and budding yeast in a 10% potassium hydroxide wet preparation. • Pregnant women, especially those previously infected, are at increased risk for candida vulvovaginitis. The signs, symptoms, and method of diagnosis are the same as for the nonpregnant patient. Treatment

• Clotrimazole and miconazole nitrate topical (intravaginal) treatments are more effective than is nystatin and require fewer treatment days. Because small amounts of these drugs may be absorbed from the vagina, they should be used with caution in the first trimester. Topical azole treatments, applied for 7 days, are the first line for symptomatic candidiasis in pregnancy. • Fluconazole oral medication has been used anecdotally in pregnancy, but caution should be exercised with benefits outweighing risks as it is also a category C drug in pregnancy. Trichomoniasis

Background

• Trichomoniasis accounts for approximately 20% to 25% of vaginal infections. The causative agent is the protozoan Trichomonas vaginalis. • Trichomoniasis is a highly contagious, sexually transmitted infection and is more often seen in young, single patients with multiple sexual partners. • There is evidence that T. vaginalis has been associated with obstetric complications (6). Diagnosis

• Typical signs and symptoms of this venereally transmitted protozoan include an often malodorous, frothy, yellow-green discharge accompanied by intense pruritus and dysuria. • In 25% of cases, there may be red subepithelial abscesses and punctuate hemorrhages noted on the cervix and in the vaginal fornices giving the cervicovaginal epithelium a “strawberry” appearance. • The diagnosis is confirmed microscopically with the observation of motile trichomonads in a wet preparation with normal saline. Vaginal pH is elevated, usually ≥4.5 (1). Treatment

• Metronidazole is the preferred treatment for both the nonpregnant and the pregnant patient. It is administered as either (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Single 2-g oral dose or 250 mg orally three times daily for 7 to 10 days. • Topical metronidazole is not recommended for treatment of trichomoniasis. • The patient’s partner(s) must be referred for treatment. One must suspect, with recurrent infections, that the patient’s partner(s) has failed to receive therapy. • Many studies have examined mother–infant pairs exposed to metronidazole throughout pregnancy with conflicting results. • Metronidazole is known to increase the fetotoxicity and teratogenicity of alcohol in mice, which may be a confounding factor in humans as well. • There are conflicting data regarding a potential increase in facial abnormalities in fetuses exposed to metronidazole in the first trimester. This has led to the recommendation by some experts that its use should probably be avoided early in gestation. Symptomatic treatment such as a dilute povidone–iodine douche or vaginal clotrimazole suppositories, therefore, may be helpful for the first-trimester patient. The Centers for Disease Control and Prevention (CDC), however, recommends that all symptomatic pregnant women with trichomoniasis should be considered for treatment regardless of stage of pregnancy (CDC Sexually Transmitted Treatment Guidelines, 2010; www.cdc.gov). • There are no data to date suggesting any poor outcomes from the use of metronidazole in the second and third trimesters. The manufacturer recommends against using singledose therapy in pregnancy (1,6); however, CDC-recommended treatment is a single 2-g oral dose in pregnancy. Bacterial Vaginosis Background

• Previously named for the presence of Gardnerella vaginalis, bacterial vaginosis (BV) is now understood to be a polymicrobial vaginal infection resulting from the disruption of normal vaginal flora and is comprised of anaerobes, Mobiluncus, Gardnerella, and mycoplasma organisms. • BV in pregnant women has been associated with preterm labor and delivery, PPROM, and maternal and neonatal infections; therefore, treatment is essential to a healthy pregnancy (7). Diagnosis

• Typically, the patient complains of a profuse, thin, grayish-white, yellow, or greenish discharge with a fishy odor. Most patients complain that the odor is worse after intercourse, but they typically do not complain of pruritus. Vaginal pH is ≥4.5 (1,7). • Microscopically, squamous cells studded with coccobacilli (“clue cells”), as well as a decrease or absence of lactobacilli, make this diagnosis. • When vaginal secretions are mixed with a drop of 10% potassium hydroxide solution, the characteristic amine odor (spoiled fish) is released. This is the so-called whiff test and can also help to confirm the diagnosis. Treatment

• Metronidazole, 250 mg orally three times daily or 500 mg orally twice daily for 7 days, is the most effective therapy. Ampicillin has been used with some success but is not recommended for first-line treatment. • Clindamycin is effective but may be more expensive and may cause diarrhea. It may be used as an alternative first-line agent in place of metronidazole. The dose for treatment of BV in pregnancy is 300 mg orally twice daily for 7 days (CDC Sexually Transmitted Treatment Guidelines, 2010; www.cdc.gov). • As noted previously, metronidazole may be avoided in the first trimester for asymptomatic patients. It is commonly recommended that symptomatic infections with BV should be treated in pregnancy because of its association with preterm labor and delivery and PPROM. Data are inconsistent regarding the benefit of treating asymptomatic cases of BV in pregnancy. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Treatment of the sexual partner is not usually recommended but may be considered in recurrent or persistent infections (1,7). CERVICAL DISEASES Cervical Intraepithelial Neoplasia Background

Pregnancy represents an opportunity to screen a wide range of women for preinvasive disease who might otherwise not seek routine exams. Abnormal cervical cytology is encountered in up to 3% of all pregnancies, with severe dysplasia present in 1.3 per 1000 pregnancies. The vast majority of all cervical dysplasias (greater than 99%) are directly associated with the HPV. The American Society for Colposcopy and Cervical Pathology (ASCCP) and American College of Obstetricians and Gynecologists (ACOG) have revised evaluation and treatment guidelines in 2013, and although there is not a large amount of data specific to pregnancy, these guidelines are the standard of care nationally (4,8,9). Diagnosis

• Nonpregnant evaluation of abnormal cervical cytology in pregnancy differs little from that in the nonpregnant woman. • The most notable exception in the 2013 ASCCP Treatment Guidelines is that LGSIL (low-grade squamous intraepithelial lesion) in pregnant women may be evaluated by colposcopy during pregnancy or colposcopy may be deferred to the postpartum period (4). • Eversion of the transformation zone in the pregnant patient may make colposcopic examination of the cervix somewhat easier. If a lesion appears suspicious by presence of dense acetowhite changes, thickened edges, or the presence of atypical vessels, directed biopsies must be done to rule out invasive cancer. • Endocervical curettage is omitted to avoid stimulation of prostaglandin release in the endocervical canal and the theoretical risk of spontaneous abortion in the first trimester or PROM (premature rupture of membranes) or PTL (preterm labor) in the second or third trimesters. • Cone biopsies are not routinely performed in pregnancy because of the risks of spontaneous abortion and hemorrhage. Occasionally, a cone biopsy will be indicated if the full extent of the disease is not seen or if the directed biopsy shows microinvasion. When possible, the cone biopsy should be performed during the second trimester, when the risk for spontaneous abortion is less (10). A prophylactic cerclage may be placed immediately before the cone biopsy, both for assistance with hemostasis and prevention of cervical incompetence; however, there is considerable ongoing controversy as to the obstetric benefits of cerclage in this situation (4,9). Cervical Cancer Although invasive cervical carcinoma has become less prevalent as a result of cytologic screening and eradication of precursor lesions, a large percentage of women with the disease are of reproductive age. • Cervical carcinoma is the most common gynecologic malignancy encountered during pregnancy, occurring in approximately 1 per 2200 pregnancies. Three percent of all cervical carcinomas occur during pregnancy (11). • Pregnancy does not affect the growth of cervical cancer, and stage for stage, survival is the same as for nonpregnant women. • HPV is known worldwide to be a carcinogen for cervical cancer (4,12). Microinvasive Carcinoma • Patients with microinvasive carcinoma (depth of penetration not greater than 3 mm) by cervical biopsy should have a cone biopsy performed to rule out frank invasion as well as possibly providing definitive therapy (10). (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Microinvasive carcinoma by cone biopsy with negative margins and no lymphovascular space invasion may be managed expectantly throughout the pregnancy with periodic Papanicolaou tests and colposcopic exams. • Vaginal delivery can be planned, with cesarean delivery reserved for obstetric indications. Definitive treatment can then be pursued postpartum as indicated. Invasive Cervical Carcinoma Diagnosis

• The diagnosis is based on biopsy, either colposcopically directed or obtained directly from suspicious exophytic lesions. The diagnosis should be considered in any women with unexplained vaginal bleeding, especially if the bleeding occurs after sexual intercourse (11). Treatment

• Treatment recommendations depend largely on the gestational age of the pregnancy at diagnosis. • For stage IB or IIA disease up to 20 weeks, the patient can be treated with radiation therapy (which usually results in a spontaneous abortion) or primary radical hysterectomy with pelvic lymphadenectomy (with the fetus left in situ or evacuated by hysterotomy at the time of the hysterectomy). Surgical therapy may be preferred, especially in younger women, in order to preserve ovarian function. • After 20 weeks, consideration may be given to several cycles of platinum-based chemotherapy, which has shown no adverse fetal effects in the treatment of patients with ovarian cancer (11), while time is gained to permit additional fetal maturation. The fetus can then be delivered by cesarean section, followed by radical hysterectomy with pelvic lymphadenectomy, or radiation therapy. • Radiation therapy is recommended for stage IIB to IIIB disease, again dependent on the gestational age with regard to timing of delivery. After 24 weeks of gestation, steroid administration for fetal lung maturation may be undertaken followed by cesarean section prior to the start of radiation therapy. Ideally, if the health of the mother is not in jeopardy, prolonging the pregnancy as long as possible is preferred for best fetal outcome. • Although no data have consistently shown an increased risk from vaginal delivery through a small stage I or II tumor, one multivariate analysis did find a trend toward worse outcomes after vaginal delivery (11,13). Implants of squamous and adenocarcinoma have also been reported in episiotomy scars. DISEASE OF THE UTERUS Abnormalities of Position • Anterior sacculation of the uterus • Severe anteflexion of the uterus caused by poor abdominal muscle tone or diastasis recti in the late third trimester may result in abnormal presentation and lack of engagement of the presenting part. This abnormality is seen almost exclusively in the grand multiparous but is not uncommon in African American females. • Correction of the abnormal orientation of the fetus with abdominal pressure provided by a well-fitting girdle or other binding support may allow for more effective pushing in the second stage of labor. • Retroflexion • Retrodisplacement of the uterus is common in early pregnancy, but the enlarging uterus nearly always assumes a more anteverted position by 12 weeks of pregnancy. Rarely, the retroflexed enlarging uterus may become incarcerated in the hollow of the sacrum, with resulting edema from venous obstruction, marked pain, and, notably, an inability to void because of urethral “kinking” and obstruction. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Patients with an incarcerated, retroflexed uterus should be placed in the knee–chest position, and the anterior lip of the cervix should be grasped and pulled with a ring forceps. Simultaneously, the posterior surface of the uterus is pushed ventrally by exerting pressure through the posterior fornix. This procedure is painful and typically requires anesthesia. • Prolapse • Complete prolapse of the uterus is rare in pregnancy. With partial prolapse, a ring (with or without support), Smith-Hodge, or Gellhorn pessary may provide relief of symptoms. The pessary should be removed and washed with mild soap and water daily to prevent infection. • Torsion of the uterus • This rare complication of pregnancy is almost always associated with a pathologic condition of the uterus such as leiomyomata or adhesions from previous uterine surgery. • The clinical picture is that of an abdominal catastrophe, with severe abdominal pain or shock, and may be confused with the picture of abruptio placentae. The patient has acute abdominal findings and requires laparotomy. Detorsion may be attempted in early pregnancy. Cesarean section followed by hysterectomy is often required near term. • Fetal morality is very high, with maternal mortality as high as 50%. Leiomyomata Uteri Background

Uterine fibroid tumors are usually asymptomatic in pregnancy but may interfere with conception and may cause early spontaneous abortion. Later in gestation, they may predispose the fetus to abnormal presentation, obstruct labor, and occasionally lead to preterm labor, placental separation, or postpartum hemorrhage. Infarction or degeneration of fibroids may occur, leading to acute abdominal pain, often with fever, leukocytosis, and uterine tenderness. Treatment

• Treatment for symptomatic uterine fibroids in pregnancy is limited to analgesics in most cases. Acute pain associated with degenerating fibroid may be treated with a short course of nonsteroidal antiinflammatory agent. Laparotomy is avoided unless the diagnosis is uncertain. • Fibroid tumors that obstruct labor may necessitate cesarean section. The uterine incision may be difficult or impossible to repair in the presence of massive leiomyomata, and cesarean hysterectomy is occasionally necessary. Hysterectomy may also be indicated for intractable postpartum hemorrhage caused by submucous leiomyomata or severe uterine atony. Under these circumstances, typed and cross-matched blood is to be immediately available in the operating room. DISEASE OF THE FALLOPIAN TUBE Acute Salpingitis Background

• Acute or chronic pelvic inflammatory disease (PID) is very rare in pregnancy. • Other conditions are far more common and should be considered before a diagnosis of PID is entertained. • When PID does occur during pregnancy, it is associated with a high risk for septic abortion or fetal loss; therefore, hospitalization for treatment is recommended (1,2). Diagnosis

• The diagnosis is difficult to make and easily confused with other entities, such as appendicitis, torsion of the adnexa, threatened abortion, and ectopic pregnancy. All of these conditions should be excluded before considering a diagnosis of PID. • Laparoscopy or laparotomy should be performed if the suspicion for appendicitis, torsion, or ectopic pregnancy is high. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• In many cases, infection may have been present before conception. One theory holds that pathogenic organisms may be able to ascend from the cervix to the upper tract early in pregnancy, contrary to the thought that the conceptus acts as a barrier to the development of salpingitis. The presence of gonococcus or Chlamydia should be confirmed by cervical culture. Treatment

• PID during pregnancy should be treated with gentamicin and clindamycin to avoid potential fetal effects of the other treatment regimens recommended by the CDC. • Gonococcal infections worldwide have become increasingly resistant to antibiotic therapy, and CDC guidelines should be regularly referenced for optimal therapeutic management (1). • In subclinical disease, vaginal delivery puts the fetus at risk for contracting gonococcal or chlamydial ophthalmia or chlamydial pneumonia if the mother is not treated prior to delivery. Torsion of the Fallopian Tube Background

• Torsion of the fallopian tube has been described in pregnancy and should be included in the differential diagnosis of abdominal pain during pregnancy. • The patient presents with pain, generally sudden in onset, located in the quadrant of the involved tube and perhaps radiating to the flank or thigh. Tenderness usually is present, but signs of peritoneal irritation are variable. Other symptoms include nausea, vomiting, and bladder or bowel irritability. Maternal temperature, white blood cell count, and erythrocyte sedimentation rate usually are normal or only slightly elevated. Diagnosis

• Differential diagnosis includes • Torsion or degeneration of an ovarian cyst • Torsion or degeneration of a uterine leiomyoma • Ureteral or renal colic • Acute appendicitis • Placental abruption • Inflammatory peritoneal processes • Intraperitoneal bleeding Treatment

• Therapy is surgical. • If the affected tube is beyond recovery, it is excised. There is no reason to remove a normal ovary. • If torsion is incomplete or recent, and if tissue distal to the torsion remains viable, detorsion of the tube with stabilization by suture may be considered. DISEASES OF THE OVARIES The Pelvic Mass in Pregnancy (14) The most important issue in any woman with a pelvic mass is the possibility of a malignant ovarian neoplasm. • Functional cysts are usually less than 8 cm in diameter and should resolve spontaneously by the beginning of the second trimester. • Cystic masses of 8 cm or larger, smaller masses that increase in size or persist, and solid adnexal masses require surgical exploration, ideally in the early second trimester. • Adnexal masses of any kind may precipitate torsion of the mass or the entire adnexa, resulting in acute symptoms and signs, which may be intermittent but may necessitate exploration either during pregnancy or in the puerperium. • Rarely, ovarian masses may obstruct labor, making cesarean section necessary, at which time the neoplasm can be addressed. (c) 2015 Wolters Kluwer. All Rights Reserved.

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CANCER Malignant diseases of the gynecologic organs may occur in pregnancy, most commonly including breast cancer, ovarian cancer, and cervical cancer. Ovarian Cancer Background

• A malignant ovarian neoplasm is encountered one in every 20,000 to 30,000 deliveries. • Of the three types of ovarian cancer (epithelial, stromal, and germ cell), there seem to be a disproportionate number of germ cell tumors in pregnant compared to nonpregnant women, although this difference may partially result from reporting bias. • Fortunately, early-stage, low-grade tumors are the most common (15). Treatment

• Early consultation with a gynecologic oncologist is strongly encouraged. • Thorough surgical staging of the disease is desirable. • There are special considerations for stage IA tumors: • Unilateral salpingo-oophorectomy in women who desire future childbearing may be justified if the tumor is unilateral and localized (stage IA). • Further adjuvant therapy may be required for stage IA malignant germ cell tumors. • Unilateral pelvic and para-aortic lymphadenectomy is recommended for correct evaluation of apparently stage IA dysgerminomas because of their propensity for lymphatic dissemination. • Cancers other than stage IA are treated as in the nonpregnant patient, except in the third trimester (16). • When ovarian cancer is suspected in the third trimester, therapy may be delayed until fetal pulmonary maturity is demonstrated. Cesarean section is then performed along with definitive surgery and staging for the neoplasm (13). Breast Cancer

Background

• The incidence of breast cancer is approximately 1 in 3500 to 10,000 deliveries. Approximately 1.5% to 4.0% of breast cancers coexist with pregnancy, making it an uncommon, but not rare, event (17). • The glandular hyperplasia of the breast that accompanies pregnancy makes recognition of suspicious breast masses difficult. Therefore, breast cancer is often recognized at a later stage than would occur in the nonpregnant state. Diagnosis

• The diagnosis relies on a physical exam because mammograms are not routinely obtained during pregnancy. • The suspicious breast lump is evaluated in the same manner in the pregnant and nonpregnant patient. Tissue diagnosis is obtained by fine needle aspiration of fluid, by tissue core, or by open biopsy. • The role of mammography remains controversial because of the radiographic density of the breast in younger women and during pregnancy (18,19). The radiation dose is negligible, however, and mammography can be used safely, if necessary, especially after the first trimester. Treatment

• Debate continues about the best form of therapy in the nonpregnant state, but modified radical mastectomy appears to be the most common choice during pregnancy. Simple lumpectomy with radiation treatment is less desirable because of fetal radiation exposure. • The role of adjuvant chemotherapy remains controversial because of the potential risks of fetal teratogenesis and mutagenesis. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• When matched for age and stage, there is no difference in survival rates between pregnant and nonpregnant women. It has been suggested that breast cancer has a worse prognosis when diagnosed in pregnancy; however, this opinion probably reflects the tendency to find more advanced stage cancers and/or a higher proportion of high-grade and estrogen receptor–negative cancers in pregnant women. • Survival is not improved by pregnancy termination, but it may be recommended to avoid the risk of fetal exposure to either chemotherapy or radiation therapy (20). PATIENT EDUCATION • Women should understand that they can expect to experience most of the same gynecologic problems during pregnancy that they would when not pregnant. • Women with PID and endometriosis can be informed that they will likely experience an improvement or disappearance of their symptoms during pregnancy. • Pregnant women should receive information about the continued risk for breast and cervical cancer during pregnancy, along with the need to receive appropriate evaluation of any abnormal breast findings or Papanicolaou test/cervical biopsy results. REFERENCES 1. Update to the Centers for Disease Control and Prevention-Sexually transmitted diseases treatment guidelines 2010. MMWR Morb Mortal Wkly Rep. 2010;59(RR-12): 21–22. 2. Sweet RL, Gibbs RS. Infectious diseases of the female genital tract. 5th ed. Philadelphia: Wolters Kluwer/Lippincott Williams and Wilkins, 2009. 3. American College of Obstetricians and Gynecologists. Human Papillomavirus vaccination. ACOG Committee Opinion No. 467. ACOG Obstet Gynecol. 2010;116:800–803. 4. Massad LS, Einstein MH, Huh WK, et al. 2012 updated consensus guidelines for managing abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis. 2013;17(5):S1–S27. 5. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 72: vaginitis. Obstet Gynecol. 2006;107:1195–1206. 6. Cotch, MF, Pastorek JG II, Nugent RP, et al. Trichomonas vaginalis associated with low birth weight and preterm labor. Sex Transm Dis 1997;24(6):353–360. 7. Nelson DB, Macones G. Bacterial vaginosis in pregnancy: current findings and future directions. Epidemiol Rev. 2002;24(2):102–108. 8. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 131: screening for cervical cancer. Obstet Gynecol. 2012;120(5):1222–1238. 9. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 99: management of abnormal cervical cytology and histology. Obstet Gynecol. 2008, reaffirmed 2010;112(16):1419–1444. 10. Demeter A, Sziller I, Csapo Z, et al. Outcome of pregnancies after cold-knife conization of the uterine cervix during pregnancy. Eur J Gynaecol Oncol. 2002;23:207–210. 11. Nevin J, Soeters R, Dehaeck K, et al. Cervical carcinoma associated with pregnancy. Obstet Gynecol Surv. 1995;50:228–239. 12. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12–19. 13. Arment F. Gynecologic cancers in pregnancy. Lancet. 2012:379. 14. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 83: management of adnexal masses. Obstet Gynecol. 2007, reaffirmed 2011;110(1):201–214. 15. American College of Obstetricians and Gynecologists. ACOG Committee Opinion number 280: the role of the generalist obstetrician-gynecologist in the early detection of ovarian cancer. Obstet Gynecol. 2002;100(6):1413–1416. 16. Malfetano JH, Goldkrand JW. Cis-platinum combination chemotherapy during pregnancy for advanced epithelial ovarian carcinoma. Obstet Gynecol. 1990;75:545–547.

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17. American College of Obstetricians and Gynecologists. ACOG Committee Opinion Number 186: role of the obstetrician-gynecologist in the diagnosis and treatment of breast disease. Int J Gynaecol Obstet. 1997;59(2):162–163. 18. Sukumvanich P. Review of current treatment options for pregnancy-associated breast cancer. Clin Obstet Gynecol. 2011;54(1):164–172. 19. Barthelmes L, Davidson LA, Gaffney C, et al. Pregnancy and breast cancer. BMJ. 2005;330:1375–1383. 20. National Cancer Institute: Breast Cancer Treatment and Pregnancy(PDQ). www.cancer. gov. 2012.

(c) 2015 Wolters Kluwer. All Rights Reserved.

28

Surgical Problems and Trauma Hope M. Cottrill and Susan C. Modesitt

TRAUMA IN OBSTETRICS Key Points • The pregnant patient with trauma should undergo evaluation, treatment, and care for her injuries similar to the nonpregnant patient. • While the well-being of the unborn fetus is always important, it should be considered only after the pregnant woman has undergone necessary assessment to allow appropriate stabilization and treatment efforts to begin. • The coordinated care of the pregnant trauma patient and her fetus depends on gestational age as well as maternal and fetal status. • Fetal viability is currently accepted as equal to or greater than 23 to 24 weeks’ gestation. Background Definition

• Trauma is damage to the body caused by an external force. • Trauma can result in fracture, dislocation, sprain, intracranial injuries, internal injuries of chest or pelvis, open wound, blood vessel injury, contusion, crush injury, burn, nerve, and spinal cord injury, and it can be caused by a variety of sources: • Forces of nature: lightning strikes, animal bites • Mechanical forces: motor vehicle collisions (MVCs) or assault • Self-inflicted: attempted suicide Etiology/Epidemiology

• Trauma occurs commonly in pregnancy: • The leading cause of death for women of childbearing age is unintentional injury (accidents) with the majority being MVCs (1). • Falls affect 27% of pregnancies (2). • Women aged 18 to 35 have the highest incidence of intimate partner violence with the risk of physical abuse being 1% to 20% during pregnancy (1,3,4). Evaluation

History and Physical Exam

• MVC • Nature of MVC: Car, motorcycle, direction of collision, vehicle rollover, ejection from vehicle, etc • Speed of MVC: High speed, low speed, stationary • Patient’s location in vehicle and role as passenger or driver • Patient restrained or unrestrained • Loss of consciousness • Alcohol or drugs involved • Physical abuse • Routine screening is recommended at first prenatal visit, then in each trimester, and at postpartum visit. °°Consider use of a questionnaire. 519

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°°Ask the patient about violence away from the partner. °°Document statements in quotations.

• Document any injuries in detail, including diagrams and/or photos. • Assess safety and notify law enforcement officials of suspected abuse. • Falls: Circumstances, area of body struck, and loss of consciousness • Obstetric information: gestational age, obstetric history, and complications Initial Management

• Primary survey (ABCs [airway, breathing, circulation]) • Airway °°Clear foreign bodies and suction as necessary. °°Establish airway with head tilt (cervical spine must be evaluated prior to moving head) and jaw thrust. Apply cricoid pressure prior with positive pressure ventilation and with endotracheal tube placement to decrease aspiration (5). °°Consider inserting an artificial airway device early in resuscitation to decrease the risk of aspiration keeping in mind that a smaller endotracheal tube may be needed for the pregnant patient due to edema (5). °°If no other airway can be obtained, a cricothyroidotomy should be performed (6). • Breathing °°Consider mouth-to-mouth resuscitation or intermittent positive pressure ventilation. °°Supplemental oxygen and monitoring of oxygenation status are standard for the trauma patient until evaluation is complete (6): --Maintain maternal pulse oxygen at ≥95% for pregnancies that are ≥23 to 24 weeks’ gestation (fetal viability). --If the exact gestational age is not known, then the presumption should be that the fetus is viable until proven otherwise. °°If inadequate ventilation is noted, the differential diagnosis includes tension pneumothorax, massive hemothorax, or flail chest with pulmonary contusion (6). These are emergent situations and require immediate intervention. • Circulation °°Control obvious external hemorrhage. °°Obtain intravenous access. °°Modification to basic life support technique at ≥20 weeks’ gestation: Manually displace the gravid uterus to the left or position the patient with a wedge under the right hip or place the woman in a modified left lateral position to prevent compression of inferior vena cava. Perform chest compressions slightly above the center of the sternum to allow for increased abdominal contents and elevated diaphragm (5). °°Advanced cardiopulmonary life support: No additional modification. • Shock °°Physiologic changes of pregnancy alter normal vital sign parameters and can mask hemorrhage (see below). °°Volume resuscitation should be based on other parameters (peripheral perfusion, mental status changes, diaphoresis, pallor, fetal heart rate decelerations) as well as vital signs changes. °°Pneumatic antishock garment may be utilized, but the abdominal portion should not be inflated in pregnancies with fetal viability. °°The underlying etiology of reversible causes of cardiac arrest in the pregnant patient may be related to cardiac disease (myocardial infarction, aortic dissection), iatrogenic magnesium sulfate toxicity, pulmonary embolism, preeclampsia/eclampsia, amniotic fluid embolism, and anesthetic complication (high spinal) (5). • Secondary survey • Further evaluation: Complete the history and physical exam (including bimanual pelvic/speculum exam, exclusion of obvious rupture of membranes, and rectal exam), laboratory values, and radiographic evaluation. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Assessment of fetal status: °°Fetal heart tones °°Ultrasound to evaluate --Intra-abdominal hemorrhage and organ damage --Fetal cardiac activity --Fetal number --Fetal position --Gestational age --Placental location and status --Amniotic fluid volume °°Prolonged electronic monitoring of the fetal heart rate and uterine activity should be performed for the viable fetus when the mother is stable. The length of time necessary for reassurance will vary with the type and severity of the trauma, but the recommended minimum time is 4 hours (7). • Perimortem cesarean section: °°If maternal chest compressions do not produce a pulse, consider emptying the uterus to improve resuscitation. °°The suggested time frame to initiate perimortem cesarean section is 4 minutes. Maternal neurologic damage occurs 6 minutes after cerebral blood flow ceases. Therefore, the goal is to initiate cesarean section in 4 minutes, complete evacuation of the uterus in 5 minutes, and achieve cerebral blood flow in 6 minutes (8). °°If the maternal injuries are fatal and there is a chance the fetus will survive, proceed with cesarean delivery (9). Laboratory Tests

• Complete blood count. • Comprehensive metabolic panel (electrolytes, liver function, and renal function). • Coagulation profile. • Amylase. • Lipase. • Urinalysis. • Urine drug screen and consider blood alcohol level. • Urine pregnancy test in reproductive age females who are not obviously pregnant. • Blood type and screen (or crossmatch if necessary). • Rh status to determine if Rh immune globulin needs to be given to the patient. • Kleihauer-Betke test may be of use, but has significant limitations (10). Radiographic Tests

• Evaluation of the pregnant patient should utilize the same tests as the nonpregnant patient, but radiation exposure to the fetus should be considered. • Focused abdominal sonography for trauma (FAST) has been shown to be efficacious in pregnant patients (11). • Magnetic resonance imaging (MRI) has no radiation exposure or known adverse fetal effects (12). • X-ray and computed tomography (CT) techniques have associated radiation exposure, and parents should be appropriately counseled if time permits (Table 28-1). • The fetus is at greatest risk at 8 to 15 weeks’ gestation for teratogenic effects from radiation exposure (13). • Exposure to less than 5 rad has not been shown to increase fetal loss or anomalies (14). • The pregnant uterus should be shielded whenever possible. Diagnosis

Differential Diagnosis

• The differential diagnosis depends on the nature of the injury, examination of the patient, further history, and observation. For example, someone found unconscious and (c) 2015 Wolters Kluwer. All Rights Reserved.

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Table 28-1

Estimated Fetal Exposure from Radiologic Procedures (13)

Procedure Ultrasound MRI Chest x-ray Abdominal film (single view) Pelvis x-ray CTa scan of head or chest CT scan of lumbar spine CT scan of abdomen CT scan of abdomen CT scan of pelvis

Mean fetal exposure (mGy)b 0 0 2.0 cm or an AFI >5.0 cm

0 Absence of reactivity No episodes of fetal extremity extension/flexion Fewer than three gross body movements within 30 min Absence of sustained ­episode of fetal breathing Less fluid

• The advantage of the BPP is that it evaluates both acute and chronic markers for fetal compromise by combining the NST and amniotic fluid index (AFI), respectively. The BPP requires proficiency in ultrasonography and should be done twice weekly (25). • Each of the five markers is scored as either 0 (absent) or 2 (present). Scores of 8 or 10 signify fetal well-being (Table 32-3). • Primary surveillance and backup tests. • There is no one method of antepartum fetal surveillance that is superior to others. Selection of a method of primary surveillance is based on the cost and availability of services in a particular region. • The use of weekly CST, biweekly NST, biweekly BPP, or biweekly modified BPP should result in perinatal mortality rates of 0.4 to 3 per 1000 live births within 1 week of a normal test (26). • The most common method of primary surveillance currently in use is the modified BPP, which is actually an NST combined with amniotic fluid assessment by ultrasound. When this test is abnormal, a CST or BPP can be performed as a backup test (27). The need for subsequent interventions is determined by the test result, the patient-specific setting, and the clinical judgment of the assessor. FETAL HYPOXIA/ACIDOSIS Differentiating between a truly hypoxic, compromised fetus and a fetus with normal acid– base status that has some abnormal features of FHRM is difficult. The use of standardized guidelines can decrease intraobserver variability and identify a subset of patients in whom obstetric interventions are likely to alleviate fetal acidosis or clinically significant hypoxia. • The principles of FHRM indicate that • The presence of a normal fetal heart rate baseline is a reassuring feature that persists until fetal compromise is firmly established • Loss of variability and presence of decelerations precede the loss of a normal fetal heart rate baseline. Persistently minimal or absent fetal heart rate variability is a strong indicator of fetal compromise (28) • During the intrapartum period, additional information can be acquired with rupture of the membranes and with further tests to identify a truly compromised fetus. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Fetal scalp and acoustic stimulation °°Stimulation of the fetal scalp either digitally at the time of cervical examination or atraumatically with an Allis clamp is a valuable adjunct for intrapartum fetal assessment. °°When accelerations occur following stimulation, fetal acidosis is not present (29). °°In the absence of accelerations, at least 20% of the patients have a fetus with a pH less than 7.20 (30). °°Vibroacoustic stimulation–induced fetal heart rate accelerations are also reassuring of normal fetal pH. Absence of an acceleration after acoustic stimulation is associated with fetal pH less than 7.20 in a significant percentage of cases (31). °°STAN—ST segment waveform analysis. The placement of an internal fetal scalp ­electrode allows for direct assessment of the fetal cardiotocography (CTG) and changes in the ST segment (32). Changes are categorized as normal, intermediary, abnormal, or preterminal. Improvements in neonatal outcome with the STAN ­system appear modest at best (33). • Acid–base determination °°Fetal acid–base determination can be assessed from a fetal scalp blood sample obtained during labor or from cord blood at the time of delivery. It directly measures the type and degree of acidosis present. Due to risks for fetal infection and hemorrhage, fetal scalp sampling procedures are rarely indicated. Fluid obtained from the fetal scalp may not accurately reflect the true acid–base status of the fetus. °°Fetal respiratory acidosis can be differentiated from metabolic or mixed acidosis by measuring the partial pressure of carbon dioxide (PCO2) and base deficit present. The normal fetal PCO2 is 40 to 50 mm Hg. Normal base deficit is approximately 7 mEq/L. Normal pH values decrease slightly as labor progresses. Fetal respiratory acidosis is associated with intermittent umbilical cord occlusion and increased PCO2 levels. The pH is usually in the range of 7.20 to 7.25. A hypoxic fetus produces lactic acid, and the resulting metabolic acidosis is reflected in an increase of the base deficit. °°The U.S. Food and Drug Administration approved fetal pulse oximetry for clinical use in 2000. Currently, the American College of Obstetricians and Gynecologists does not recommend adjunctive use of fetal pulse oximetry during labor (21). Two large randomized trials have been conducted (34,35). Neither was able to demonstrate a reduction in overall cesarean delivery rate, although one study (34) did show a decrease in rate of cesarean delivery for “non-reassuring” fetal status. Treatment

Management

• When an indeterminate or abnormal fetal heart rate pattern is identified, management depends on • Setting (antepartum vs. intrapartum) • Gestational age • Clinical circumstances • If a reversible condition is generating, the abnormal fetal heart rate pattern should be corrected. Reversible conditions (Table 32-1) can be treated with appropriate measures of intrauterine resuscitation. • Irreversible conditions are best treated by expeditious delivery and extrauterine resuscitation by experienced neonatal personnel. • When indeterminate or abnormal fetal heart rate patterns are encountered in the out­ patient setting, backup testing should be performed promptly. • When there are specific fetal concerns about gestational age and the possible need for neonatal intensive care unit services, hospitalization should be arranged at a facility where such services are available. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Transfer of a patient in labor with an indeterminate or abnormal fetal heart rate pattern is difficult and should be approached with great caution, regardless of gestational age or complications. A diagnosis of abnormal fetal status with failure to respond to intrauterine resuscitative measures requires prompt delivery, with neonatal support provided until transport can be arranged. Treatment of Maternal Conditions

• Reversal of an unstable maternal condition can convert an indeterminate or abnormal fetal heart rate pattern to one that is normal. • Uncontrolled diabetes should be treated with insulin, fluid support, and correction of electrolyte abnormalities. • Hypertension should be controlled with short-acting medications. Care should be taken not to overcorrect hypertension, as this can abruptly decrease intrauterine blood flow. • Maternal conditions that are not readily reversible, such as acute or severe abruption, should be treated by delivery. • Correction of intrapartum complications will often improve indeterminate or abnormal fetal heart rate patterns. • Excessive uterine activity should be addressed by decreasing or discontinuing the use of Pitocin. If it is severe or persistent, the administration of a short-acting β-mimetic agent may also be indicated. Both of these actions decrease uterine activity, allowing the fetus to regain metabolic reserve. • Hypotension should be corrected with fluid and vasopressor support. • Fetal heart rate patterns indicative of cord compression can often be improved or alleviated by changing maternal position. The presence of recurrent variable decelerations should prompt consideration to treat with amnioinfusion (21). • Oxygen administration will improve the maternal–fetal oxygen gradient and allow for quicker fetal recovery from hypoxia. Oxygen should be administered at 100% concentration via face mask. • Correction of maternal fever using antipyretics will reverse fetal tachycardia. Treatment of Fetal Conditions

• During labor, fetal conditions are generally treated via management of the mother. The primary decisions regard circumventing or intervening in the normal labor process through cesarean delivery for abnormal or ominous fetal heart rate patterns. The American College of Obstetrics and Gynecology considers the use of FHRM to be associated with a high false-positive rate and increased rate of obstetric interventions. The use of a three-tiered system of categorization of fetal heart rate is recommended to decrease interobserver variability and limit the scope of such intervention to the subset of patients most likely to benefit (21). • Tachycardia. • Sinus tachycardia must be differentiated from supraventricular tachycardia. • Intermittent supraventricular tachycardia is usually of little clinical significance, but persistence of this rhythm is associated with high-output cardiac failure, fetal hydrops, and eventual death. • Digoxin is the most commonly used initial treatment; other available agents include quinidine, verapamil, and propranolol. • β-Mimetics, theophylline, caffeine, and some over-the-counter drugs may induce mild fetal tachycardia. Discontinuation of the drug and substitution of an appropriate alternative medication is indicated when the tachycardia is concerning or prolonged. • Fetal anemia may also cause tachycardia. • Bradyarrhythmia. • Persistent antepartum fetal bradyarrhythmia is generally due to heart block. Sustained, prolonged bradyarrhythmia can lead to heart failure and death. Careful fetal surveillance is required to determine the proper timing of delivery. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Intrapartum fetal bradycardia is indicative of fetal compromise, as discussed earlier in this chapter. Bradycardias that last longer than 3 to 4 minutes require immediate response and progression to delivery. Repetitive bradycardias of 2 to 4 minutes in length require delivery after three or four occurrences. Risk Management • The presumption that antepartum and intrapartum FHRM could prevent stillbirth and neonatal complications due to a compromised intrauterine environment preceded investigations designed to confirm the promise of these interventions. • Ironically, the widespread use of intrapartum electronic FHRM led to an increase in cesarean deliveries, with little evidence to support a concomitant decrease in cerebral palsy or other neonatal complications. It has further led to a widespread popular assumption that we can prevent these complications and that failure to do so must be a result of inadequate implementation of infallible technology. • The dichotomy between public expectation and the observed limitations of FHRM makes this an area of medicolegal risk. Risk management in this area revolves around expeditious response to perceived abnormalities noted in the testing protocols. • In the antepartum and outpatient setting, all fetal surveillance tests should be read the same day as performed. Indeterminate and abnormal results should be investigated promptly. The patient should be informed of the results and of any improvements resulting from further interventions. She should also be informed about how those results will affect her ongoing plan of care. • Intrapartum categorization of the fetal heart rate as Category 1, 2, or 3 should occur on an ongoing basis as labor progresses. The use of standardized definitions can limit the number of unindicated interventions and focus resources on the subset of patients most likely to benefit from those interventions. In cases where a Category 3 FHR pattern cannot be improved, prompt intervention and neonatal resuscitation should be implemented. • The most common complication of fetal heart rate assessment is the overtreatment of a fetus not truly compromised. If appropriate clinical judgment is not employed, this may result in unnecessary interventions, higher cesarean delivery rates, or even premature delivery. PATIENT EDUCATION • Patients who have been identified as at high risk for antepartum or intrapartum complications should be informed of the specific risks involved. • Patients should be informed of the benefits, limitations, and physiologic basis of FHRM. • When antepartum testing is performed, the patient should be aware of the time needed for the test to be completed, the process by which the results are reviewed, and the frequency with which testing will occur. It is helpful to advise the patient that, although the diagnosis of a reassuring test truly is reassuring, the presence of some nonreassuring features does not necessarily indicate that a problem exists. This is particularly true when CSTs are used, as there is a high false-positive rate for this test compared to NST or BPP testing. • Patients should be aware that the identification of indeterminate or abnormal features of the fetal heart rate will be fully and promptly investigated, whether she is in the antepartum or intrapartum setting. REFERENCES 1. Goodlin RC. History of fetal monitoring. Am J Obstet Gynecol. 1979;133:323–352. 2. Vintzileos AM, Nochimson DJ, Antsaklis A, et al. Comparison of intrapartum electronic fetal heart rate monitoring versus intermittent auscultation in detecting fetal acidemia at birth. Am J Obstet Gynecol. 1995;173(4):1021–1024. 3. Ananth CV, Joseph KS, Oyelese Y, et al. Trends in preterm birth and perinatal mortality among singletons: United States, 1989 through 2000. Obstet Gynecol. 2005;105:1084–1091. (c) 2015 Wolters Kluwer. All Rights Reserved.

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4. Chen HY, Chauhan SP, Ananth CV, et al. Electronic fetal monitoring and its relationship to neonatal and infant mortality in the United Sates. Am J Obstet Gynecol. 2011;204: 401.e1–401.e10. 5. Larma JD, Silva AM, Holcroft CJ, et al. Intrapartum electronic fetal heart rate monitoring and the identification of metabolic acidosis and hypoxic-ischemic encephalopathy. Am J Obstet Gynecol. 2007;197:301.31–38. 6. Macones GA, Hankins GDV, Spong CY, et al. The 2008 National Institute of Child Health and Human Development workshop report on electronic fetal monitoring: update on definitions, interpretation, and research guidelines. Obstet Gynecol. 2008;112:661–666. 7. Ananth CV, Chauhan SP, Chen HY, et al. Electronic Fetal Monitoring in the United States: Temporal trends and adverse perinatal outcomes. Obstet Gynecol. 2013;121:927–933. 8. Kontoupoulos EV, Vintzileos AM. Condition specific antepartum fetal testing. Am J Obstet Gynecol. 2004;191:1546–1551. 9. Nichols PL, Chen T-C. Minimal brain dysfunction: a prospective study. Hillsdale, NJ: Lawrence Erlbaum Associates, 1981. 10. Hobel CJ, Hyvarinen M, Oh W. Abnormal fetal heart rate patterns and fetal acid-base balance in low birth weight infants with respiratory distress syndrome. Obstet Gynecol. 1972;39:83. 11. Chan WH, Paul R, Toews J. Intrapartum fetal monitoring, maternal and fetal morbidity and perinatal mortality. Obstet Gynecol. 1973;41:7–13. 12. Tutera G, Newman RL. Fetal monitoring: its effect on the perinatal mortality and cesarean section rates and its complications. Am J Obstet Gynecol. 1975;122:750–754. 13. Paul RH, Huey JR, Yaeger CF. Clinical fetal heart rate monitoring—its effect on cesarean section rate and perinatal mortality: five year trends. Postgrad Med. 1977;61:160–166. 14. Lee WK, Baggish MS. The effect of unselected intrapartum fetal monitoring. Obstet Gynecol. 1976;47:516–520. 15. Alfirevic Z, Devane D, Gyte GM. Continuous cardiotocography (CTG) as a form of electronic fetal monitoring (EFM) during labour. Cochrane Database Syst Rev. 2006;(3):CD006066. DOI: 10.1002/14651858.CD006066. 16. Lees MH, Hill JD, Ochsner AJ III, et al. Maternal and placental myometrial blood flow of the rhesus monkey during uterine contractions. Am J Obstet Gynecol. 1971;110:68–81. 17. Poseiro JJ, Mendez-Bauer C, Pose SV, et al. Effect of uterine contractions on maternal blood flow through the placenta. In: Perinatal factors affecting human development. Scientific Publication 185. Washington: Pan American Health Organization, 1969:161. 18. Druzen M, Ikenoue T, Murata Y, et al. A possible mechanism for the increase in FHR variability following hypoxemia. Paper presented at: The 26th Annual Meeting of the Society for Gynecologic Investigation; March 23, 1979; San Diego, CA. 19. Hammacher K. In: Kaser O, Friedberg V, Oberk K, eds. Gynakologie v Gerburtshilfe. Bd II. Stuttgart: Georg Thieme Verlag, 1967. 20. Dalton KJ, Dawes GS, Patrick JE. The autonomic system and fetal heart rate variability. Am J Obstet Gynecol. 1983;146:456–462. 21. American College of Obstetricians and Gynecologists (ACOG). Intrapartum fetal heart rate monitoring: nomenclature, interpretation, and general management principles. Washington, DC: American College of Obstetricians and Gynecologists (ACOG), 2009 Jul. 11 p. (ACOG practice bulletin; no. 106). 22. Electronic fetal heart rate monitoring: research guidelines for interpretation. National Institute of Child and Human Development Research Planning Workshop. Am J Obstet Gynecol. 1997;177:1385–1390. 23. Piaquadio K, Moore TM. A prospective evaluation of fetal movement screening to decrease the incidence of antepartum fetal death. Am J Obstet Gynecol. 1989;160:1075. 24. Nwosu CE, Welch CR, Manasse PR, et al. Longitudinal assessment of amniotic fluid index. Br J Obstet Gynecol. 1993;100:816–819. 25. Miyazaki F, Nevarez F. Saline amnioinfusion for relief of repetitive variable decelerations: a prospective randomized study. Am J Obstet Gynecol. 1985;153:301–306. 26. Greiss FC Jr, Crandell DL. Therapy for hypotension induced by spinal anesthesia during pregnancy. JAMA. 1965;191:793–796. (c) 2015 Wolters Kluwer. All Rights Reserved.

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27. Nageotte MP, Towers CV, Asrat T, et al. The value of a negative antepartum test: contraction stress test and modified biophysical profile. Obstet Gynecol. 1994;84:231–234. 28. Williams KP, Galerneau F. Intrapartum fetal heart rate patterns in the prediction of neonatal acidemia. Am J Obstet Gynecol. 2003;188(3):820–823. 29. McDonald D, Grant A, Sheridan-Pereira M, et al. The Dublin randomized control trial of intrapartum fetal heart rate monitoring. Am J Obstet Gynecol. 1985;152:524. 30. Haverkamp AD, Thompson HE, McFee JG, et al. The evaluation of continuous fetal heart rate monitoring in high risk pregnancy. Am J Obstet Gynecol. 1976;125:310. 31. Luttkus AK, Norén H, Stupin JH, et al. Fetal scalp pH and ST analysis of the fetal ECG as an adjunct to CTG. A multi-center, observational study. J Perinat Med. 2004;32:486–494. 32. Neilsen J. Fetal electrocardiogram (ECG) for fetal monitoring during labor. Cochrane Database Sys Rev. 2006(3). 33. Clark S, Gimovsky M, Miller F. Fetal heart rate response to fetal scalp blood sampling. Am J Obstet Gynecol. 1982;144:706. 34. Garite TJ, Dildy GA, McNamara H, et al. A multicenter controlled trial of fetal pulse oximetry in the intra-partum management of non-reassuring fetal heart rate patterns. AJOG. 2000;183(5):1049–1058. 35. Klauser CK, Christensen EE, Chauhan SP, et al. Use of fetal pulse oximetry among high-risk women in labor: a randomized clinical trial. Am J Obstet Gynecol. 2005;192:1810–1819.

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PART

V

Fetal Complications

33

Fetal Growth Abnormalities

Carri R. Warshak and Todd Fontenot

KEY POINTS • Aberrations of fetal growth increase the risk of fetal and neonatal morbidity and mortality. • Maternal comorbidities such as obesity, diabetes, hypertension, and other vascular ­diseases predispose to complications from fetal growth abnormalities. Comprehensive management of these conditions may prevent perinatal complications. • Women at risk for growth abnormalities should be screened with sonographic evaluation of fetal growth and well-being and other fetal surveillance as appropriate. Delivery management may be dramatically influenced by fetal growth abnormalities. INTRAUTERINE GROWTH RESTRICTION Background Definitions

• The most commonly used definition for intrauterine growth restriction (IUGR) in the United States is an estimated fetal weight less than the 10th percentile (1,2). Fetuses with lagging abdominal circumference are deemed “at risk” and should be followed closely for development of IUGR. • Estimation of fetal weight is heavily influenced by parental race, fetal gender, genetic influences, maternal body mass index (BMI), and altitude (2,3). • Many fetuses with estimated weights less than the 10th percentile, or with small abdominal circumferences, are constitutionally small, and it is often challenging to differentiate the growth-restricted fetus from the constitutionally small fetus that is meeting its growth potential. Etiology and Pathophysiology • Fetal life is a period characterized by phases of rapid cell proliferation and differentiation (1). IUGR is the result of disruption of this normally proliferative state. IUGR may be symmetrical if the disruption occurs early and globally within the fetus or asymmetrical when the insult occurs later in gestation and preferentially impairs growth of the fetal abdominal circumference. Different etiologic mechanisms lead to varying degrees and patterns of growth restriction. • Pathologic findings on placental examination are the hallmark for the diagnosis of true IUGR versus a constitutionally small fetus. However, for obvious reasons, this 624

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i­nformation is not available to the clinician to aid in the management of the pregnancy. Placental abnormalities associated with IUGR include decreased placental weight, decidual necrosis, and infarction. Histologic changes in placental villi including hypermaturity, villus edema, and infarction are characteristic of placental insufficiency and resultant fetal hypoxia. Massive intervillus fibrin deposition, or “maternal floor infarction,” is a lesion of particular importance because it is associated with high rates of severe fetal compromise and stillbirth and tends to be recurrent with future pregnancies (3). • Maternal, placental, and fetal factors may lead to the development of IUGR. Maternal factors are as follows: • Medical comorbidities: including chronic hypertension, pregestational diabetes, lupus, cardiovascular disease, thyroid dysfunction, nephrotic syndrome, hemoglobinopathies, antiphospholipid antibody syndrome, severe pulmonary conditions, and severe nutritional deficiencies. • Medications used to treat comorbidities may increase the risk of IUGR: °°Antiepileptics °°Warfarin °°Folic acid antagonists °°Possibly beta-blockers • High doses of radiation have been shown to cause symmetrical growth restriction. • Social habits: °°Tobacco use °°Excessive alcohol intake • Cocaine/amphetamine exposures and other drug exposures. • Severe maternal nutrition deficiencies. °°In the adequately nourished woman, regardless of weight, minimal weight gain and even weight loss are unlikely to cause IUGR. °°Women with severe nutritional deficiencies secondary to poor resources, extremely poor diet, or conditions such as severe hyperemesis gravidarum are at risk for IUGR. • Obstetrical complications predispose a pregnancy to an increased risk of IUGR. • Preeclampsia °°Both placental vascular changes and a contracted maternal intravascular volume contribute to restriction in fetal growth. • Multiple gestation °°As many as 30% of twin pregnancies may have IUGR in one or both twins. This is especially true in monochorionic twins and specifically in the setting of twin–twin transfusion syndrome (4). • Recurrent bleeding • Preterm premature rupture of membranes • Placental abnormalities that have been associated with an increased risk of IUGR: • Placenta previa • Subchorionic hemorrhage • Partial/chronic abruption • Aberrant cord insertions • Fetal factors. • Fetal karyotype abnormalities, such as trisomy 21, trisomy 18, trisomy 13, and triploidy, commonly have significant IUGR. • Major fetal malformations are often associated with poor fetal growth. °°Abdominal wall defects, skeletal dysplasias, and others interfere with the ability to accurately estimate fetal weight using ultrasound and may not be associated with true growth restriction. °°Neural tube defects, heart defects, or fetal tumors may be associated with growth restriction both because of increased demand on the fetal cardiovascular system and because of association as part of a fetal syndrome associated with IUGR. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Congenital infections are relatively uncommon causes of growth restriction but should be considered especially when other markers for congenital infection are present. °°Viral infections such as cytomegalovirus, parvovirus, rubella, and HSV are associated with IUGR. °°Protozoan parasites such as Toxoplasma gondii have also been shown to cause IUGR.

Fetal Adaptation

• The fetus with growth restriction secondary to uteroplacental insufficiency with hypoxia adapts to its environment by a variety of mechanisms. • Fetal metabolism is shifted toward anaerobic metabolism, producing lactic acid and altering the acid–base status of the fetus. • Compensatory polycythemia to improve oxygen delivery to tissues that when pronounced may paradoxically decrease tissue perfusion. • Cardiovascular changes that redirect blood flow to vital organs such as the fetal brain, heart, and adrenal glands develop and offer an opportunity to quantitate the degree of fetal impairment. • Decrease in fetal urine output as blood is shunted from the fetal kidneys, leading to a consequent decreased amniotic fluid volume. • Ultimately, the fetus adapts to the hypoxic, hypoglycemic environment by conserving energy, and behavioral changes, as measured by the nonstress test and biophysical profile, become evident. Evaluation • History • A detailed history can help to identify patients at risk for IUGR such that more aggressive surveillance is undertaken. In addition, information gained from a detailed history can help direct the diagnostic evaluation when a fetus with IUGR is discovered. • Physical exam • The fundal height measurement is considered the primary method of screening for IUGR in the general obstetric population. Although it is nonspecific and poorly sensitive, it remains the most common method for screening for IUGR in low-risk patients (2). • Assessing maternal weight gain is not a sensitive or specific method for the detection of IUGR. • When IUGR is identified, a detailed exam for signs of preeclampsia and other medical comorbidities is useful. • Ultrasound • Ultrasound is the primary diagnostic tool for the evaluation of IUGR. °°Equations that use abdominal circumference, biparietal diameter, and femur length have been shown to be the most accurate at estimating the fetal weight (4,5). °°While both first-trimester biometry and second-trimester biometry have been used to predict subsequent small for gestational age (SGA) neonates, second-trimester biometry appears to be superior (6). °°Accurate pregnancy dating is a prerequisite to the ability to accurately diagnose IUGR. °°Customized growth curves may lower the false-positive rate of biometry for the ­prediction of true growth restriction, although such curves are variably used (7,8). • The finding of IUGR on ultrasound should prompt a detailed evaluation of fetal anatomy, quantification of the amniotic fluid volume, and performance of umbilical artery Doppler studies. In appropriately aged fetuses, additional measures of fetal well-being such as a biophysical profile or nonstress test can provide meaningful information regarding the overall status of the fetus. • In fetuses found to have IUGR who remain undelivered, serial ultrasounds at intervals of at least every 2–4 weeks should be considered. In the specific setting of preeclampsia, more regular measurements of the fetus may be indicated, but it is not generally (c) 2015 Wolters Kluwer. All Rights Reserved.

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r­ ecommended to repeat biometry at intervals less than 2 weeks given the inherent error range of biometric measurements. • Laboratory • When IUGR is diagnosed in the midtrimester, consideration for karyotype analysis should be undertaken, particularly if there are associated fetal malformations. Genetic amniocentesis has traditionally been recommended to evaluate for aneuploidy in ­high-risk patients. In patients at moderate or low risk who wish to avoid an invasive procedure, there may be a role for newer cell-free fetal DNA aneuploidy screening. Although ffDNA is useful for the detection of certain karyotype abnormalities, it is not able to detect a wide range of less common karyotype abnormalities, such as triploidy, trisomies of chromosomes other than 21,13, and 18 and partial deletions/duplications/inversions that would be diagnosable with traditional amniocentesis and karyotype analysis via cell culture. • Infectious causes for IUGR are relatively uncommon. Maternal serology and/or ­amniotic fluid evaluation with microbial culture and polymerase chain reaction (PCR) testing should be considered in cases of midtrimester onset IUGR or when ultrasound findings suggestive of congenital infection are present. • Thrombophilias. °°Inherited thrombophilias do not appear to be associated with IUGR (9). °°Acquired thrombophilia as part of the antiphospholipid syndrome does appear to be associated with IUGR, particularly when there is severe IUGR and/or preeclampsia occurring prior to 34 weeks. In this subset of patients testing for lupus anticoagulant, anticardiolipin antibodies and anti–β2-glycoprotein I should be considered (10). • Several biomarkers have been associated with IUGR such as maternal serum α-fetoprotein, endothelin 1, leptin, placental growth factor, urinary S100B, insulin-like growth factors, myoinositol, and D-chiro-inositol (1). At the current time, there are no markers available for diagnostic purposes in the clinical setting of suspected IUGR. MANAGEMENT Fetal Surveillance • Fetal kick counting. • It is an important daily measure of fetal well-being and should be instituted both in the uncomplicated pregnancy and the pregnancy complicated by IUGR. • Various methods of measurement are available, and none are known to be superior. • A variety of antenatal testing options are available to assist in the surveillance of the preterm fetus in pregnancies complicated by IUGR. • The fetal nonstress test, biophysical profile, amniotic fluid volume measurements, and Doppler velocimetry have all been found to be useful in this context. • In the setting of IUGR, decreased amniotic fluid volume (in particular, the absence of a 2-cm pocket of amniotic fluid) has been shown to be associated with significant increase in the risk of stillbirth. • Doppler velocimetry has been shown to be a useful adjunct in predicting perinatal outcomes. Normal results are associated with reduced perinatal mortality in this setting (11–13). • The optimal frequency of testing is unclear, although testing twice per week appears to lower the risk of stillbirth as compared to once per week (14). Treatments • Aspirin. • Aspirin may have a role in prevention of recurrent IUGR, especially in women with thrombophilia or in those that have pregnancies complicated by preeclampsia (15). • There is little support that aspirin started after the development of IUGR influences further growth or improves perinatal outcomes. • Additional nutritional supplementation, high protein diets, zinc supplementation, calcium supplementation, heparin, maternal oxygen therapy, maternal bed rest, and plasma (c) 2015 Wolters Kluwer. All Rights Reserved.

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volume expansion have been studied as potential therapies for IUGR; however, none has been conclusively shown to improve fetal growth or reduce perinatal morbidities or mortality and may come with considerable maternal risk. It is recommended these interventions be considered only in experimental protocols (2). In the setting of maternal hypertensive disease related to chronic hypertension or preeclampsia, bed rest may improve hypertension and prolong latency to delivery. Delivery Management • Preterm IUGR • When patients have significant IUGR and delivery is likely to be indicated prior to 34weeks, consideration for a course of glucocorticoids is warranted (2). This is especially true when significant Doppler abnormalities, such as absent end-diastolic flow or reversal of end-diastolic flow, are present or, in the setting of preeclampsia, remote from term. • Timing of delivery in the preterm fetus found to have IUGR is a complex decision requiring consideration of both risks of prematurity and risks of pregnancy prolongation. The Growth Restriction Intervention Trial (GRIT) randomized women with IUGR to delivery versus expectant management (14,16). These investigators found similar perinatal mortality between groups, with higher stillbirth rate in the delayed delivery group as compared to higher neonatal mortality rate in the group immediately delivered. Two-year follow-up of development in survivors was also comparable (14). However, in the group immediately delivered prior to 31 weeks, a higher rate of morbidity and disability was seen (13% vs. 5% in those expectantly managed). Of note, the mean latency for the expectantly managed group was only 4.9 days and 3.2 days if IUGR was diagnosed at less than 32 weeks, which may explain their similar outcomes. • Term IUGR • Management options for the IUGR fetus at term have also been studied. The DIGITAT Study Group randomized fetuses with IUGR beyond 36 0/7 weeks to induction versus expectant management (17). Fetuses expectantly managed were delivered an average 10days later and were slightly larger; however, there was no difference in the composite adverse neonatal outcome. In addition, there was a similar rate of cesarean section in both groups. Thus, these authors concluded induction did not appear to increase maternal morbidity and cesarean rate; however, there were not significantly increased adverse fetal outcomes with expectant management, and induction may prevent possible neonatal morbidity and stillbirth. Prognosis • The fetuses with IUGR have higher rates of fetal and neonatal complications. Rates of stillbirth are significantly elevated and, in the setting of reversal of end-diastolic flow in umbilical artery Doppler, may be as high as 20%. Conversely, evidence of growth restriction is found in 23% to 65% of stillbirths (13,18). A recent cohort study of all births in the United States in 2005 demonstrated that the risk for IUFD was 58, 43.9, and 26.3 per 10,000 at-risk fetuses at the less than 3rd, less than 5th, and less than 10th percentiles, respectively (19). Other perinatal morbidities include hypoxia, acidemia, polycythemia, hyperbilirubinemia, hypoglycemia, seizures, sepsis, need for ventilation, and hypothermia (13,20,21). Ultimately, these complications lead to an increased risk of long-term neurologic sequelae and increased risk of developmental delay (20). • Efforts to understand “perinatal programming” have greatly expanded (1). It is becoming increasingly clear that intrauterine environmental factors alter the development of organs and tissues in the fetus, leading to susceptibility to childhood and adult disease. Ischemic heart disease, hypertension, cardiovascular disease, obesity, and diabetes have all been demonstrated to be associated with a hypoxic, hypoglycemic intrauterine environment (20). No longer does the concept of “correction” by delivery or “catch-up” in neonatal life appear to be the resolution of IUGR, but in fact, there appear to be long-standing medical effects on the health of the child persistent even into adulthood. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Prevention • When IUGR is caused by modifiable maternal risk factors such as tobacco use, alcohol intake, and potentially medication exposures, patients should be encouraged to reduce or eliminate these exposures to improve perinatal outcome. Smoking cessation programs are associated with a 6% increase in smoking cessation and a 19% reduction in low birth weight and perinatal morbidity and mortality (20). • Optimization of maternal health when concurrent maternal medical comorbidities are thought to be the underlying etiology for the IUGR can reduce the risk for an SGA fetus. In particular, in patients with severe hypertension, SGA can be prevented with aggressive antihypertensive therapy (22). When IUGR occurs in the setting of preeclampsia and maternal obesity, interpregnancy weight loss has been demonstrated to reduce the recurrence risk of preeclampsia (23,24). • Aspirin for the prevention of preeclampsia and IUGR is controversial. Despite ­dozens of trials, a conclusive improvement in outcomes eludes researchers. However, a Cochrane meta-analysis demonstrated a 10% reduction in SGA when aspirin is started early in pregnancy to prevent IUGR (15). Other studies have similarly demonstrated reduction in IUGR when aspirin is initiated early in pregnancy in women at risk for preeclampsia and IUGR (25). Finally, initiation of aspirin therapy when abnormal uterine artery Doppler studies early in pregnancy predict the likely development of IUGR and/or preeclampsia has shown a significant reduction in IUGR (20). • Worldwide, malaria is a major causative factor for IUGR, and prevention of malaria could greatly impact the rate of this pregnancy complication (20). MACROSOMIA Background Definitions

• Fetal macrosomia is a categorical definition used to describe fetuses with an estimated or actual weight above a predefined cutoff. Most consider a fetal weight above 4000 or 4500 g to be macrosomic, with weights above 4500 g being the most commonly used definition (26). • A similar term, large for gestational age (LGA), is used to describe the fetal weight in relation to the gestational age of the fetus, and in general, weights above the 90th percentile are considered LGA (26). • Macrosomia leads to maternal and fetal morbidity. Macrosomia is associated with a near doubling of the risk for cesarean section (27). In addition, maternal pelvic floor injury may be related to delivery of the macrosomic fetus (28). Fetal complications include neonatal intensive care unit (NICU) admission, hypoglycemia, shoulder dystocia, brachial plexus injury, and Erb palsy (27,29–31). Etiology and Pathophysiology • Incorrect dating can falsely identify a fetus as LGA. Therefore, when a fetus is found to be measuring ahead of the clinical dating, reexamination of the accuracy of gestational dating should be undertaken. • Maternal comorbidities such as diabetes and obesity are the most commonly identified causes for fetal macrosomia. Maternal BMI greater than 30 has been found to double the rate of fetal macrosomia (27). Gestational diabetes not only increases the risk of fetal macrosomia but also increases the risk of morbidity in fetuses with macrosomia when compared to nondiabetics (29,32). • Maternal and paternal genetic factors play a role in the predetermination of the fetal size, and therefore, the fetal size appears to be an interplay between genetic predetermination and intrauterine environmental influences. (c) 2015 Wolters Kluwer. All Rights Reserved.

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• Fetal factors can also contribute to fetal size. Male gender has consistently been associated with increased fetal size. Fetal anomalies such as intra-abdominal masses, bladder outlet obstruction, severe ventriculomegaly, and hydrops can also lead to an increased fetal size. Rarely, genetic syndromes, such as Beckwith-Wiedemann or Pallister-Killian syndrome, cause a fetus to grow abnormally large. The prognosis for the fetus in these settings is determined by the underlying causative factor rather than the absolute fetal size. Evaluation

Risk Factors

• Maternal diabetes. • Most important risk factor for the development of fetal macrosomia secondary to both its impact on the rate of fetal macrosomia and its influence on the occurrence of complications in the setting of fetal macrosomia. • Even in women who do not meet the classic criteria for gestational diabetes, increasing insulin resistance has been found to increase the rate of LGA (26,33). • Nondiabetic patients may have additional risk factors for the development of macrosomia: • Prior history of macrosomia • High maternal prepregnancy weight • Male fetus • Gestational age greater than 40 weeks • Ethnicity • LGA maternal birth weight • Tall maternal stature • Maternal age younger than 17 years • Positive glucose screen with a negative glucose tolerance test (26,34) • Excessive maternal weight gain has also been associated with the development of fetal macrosomia, especially in the obese pregnant woman (35,36). Diagnosis

Physical Exam

• Fundal height measurement is used as a general screening tool for assessing fetal growth abnormalities. Near delivery, Leopold maneuvers can be used to roughly estimate the fetal size, but are imprecise. Obesity is a major hindrance to the performance of both of these measurements, in addition to being a major risk factor for the development of macrosomia. For these reasons, ultrasound estimation of fetal weight is performed in women at risk for macrosomia or with suspected macrosomia. Ultrasound

• Ultrasound estimation of fetal weight using biometric measures such as the head circumference, biparietal diameter, abdominal circumference, and femur length is commonly used to evaluate for fetal macrosomia. • Sonographic estimation of fetal weight has a considerable error range, which increases with fetal size. It is likely that high maternal BMI also influences the accuracy of ­ultrasound-obtained estimations of fetal weight. • Measurements of subcutaneous fat in various fetal anatomical landmarks have been found to correlate with postnatal adiposity, but not necessarily with greater accuracy in the prediction of estimated fetal weight from standard ultrasound biometry (37). Laboratory Testing

• Cord blood serum C-peptide is a biomarker that correlates with LGA; however, it has limited clinical utility for diagnostic or management purposes (33). • Maternal testing for gestational diabetes should be performed or repeated as indicated when the fetus is found to be LGA or macrosomic. (c) 2015 Wolters Kluwer. All Rights Reserved.

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Treatment

Medical Management

• Among patients with diabetes, optimizing maternal glycemic control remains one of the cornerstones in prevention of macrosomia. Aggressive glycemic profiling and management with oral hypoglycemic agents or insulin is recommended. • Maternal nutritional counseling may prevent excessive maternal weight gain, especially in the obese woman, and reduce the risk of macrosomia. However, studies evaluating this as a therapeutic option to prevent macrosomia are limited (26). Fetal Surveillance

• The finding of fetal macrosomia alone is not necessarily an indication for antenatal fetal surveillance. However, comorbidities such as maternal diabetes, obesity, postterm pregnancy, and polyhydramnios often prompt initiation into an antenatal fetal surveillance program. Delivery Management

• Induction of labor appears to increase the rate of cesarean delivery, without a reduction in neonatal morbidity (26,38). Therefore, early induction because of suspected macrosomia cannot be recommended. • Although cesarean delivery may reduce the risk of shoulder dystocia and fetal morbidity from a traumatic vaginal delivery, this must be weighed against the increased maternal risks of cesarean delivery with both the current pregnancy and future pregnancies. There are no prospective trials that support reductions in fetal injury with altering mode of delivery among nondiabetic patients with suspected macrosomia. • There are no specific recommendations for the weight at which elective cesarean section should be considered. In general, most experts consider cesarean delivery in diabetic women with estimations of fetal weight beyond 4250 to 4500. In nondiabetics, it is likely that benefits to elective cesarean section are only seen if estimations of fetal weight beyond 5000 g are used to recommend cesarean delivery. • When fetal macrosomia is suspected, it is recommended to avoid operative vaginal deliveries as this may increase the risk of shoulder dystocia and traumatic delivery. Prognosis • Macrosomic fetuses have higher rates of many morbidities and even mortality. In women with diabetes, a birth weight over 4000 g has been shown to increase risks of hypoglycemia, respiratory distress syndrome, shoulder dystocia, and Erb palsy (29). The risk of brachial plexus injury is directly related to fetal weight and has been found to be 2.86% in fetuses weighing over 5000 g (31). Prevention • Optimization of maternal health prior to conception may reduce both prepregnancy weight and occurrence of diabetes and therefore decrease risk of complications from macrosomia. • Strict glycemic control in women found to be diabetic early in pregnancy before the development of fetal macrosomia is likely to reduce complications from fetal macrosomia. REFERENCES 1. Dessi A, Ottonello G, Fanos V. Physiopathology of intrauterine growth retardation: from classic data to metabolomics. J Matern Fetal Neonatal Med. 2012;25(S5):13–18. 2. ACOG Practice Bulletin Number 134. Intrauterine growth restriction. Obstet Gynecol. 2013;121(5):1122–1133. 3. Tyson RW, Staat BC. The intrauterine growth-restricted fetus and placental evaluation. Semin Perinatol. 2008;32(3):166–171. 4. Resnik R. Intrauterine Growth Restriction. Obstet Gynecol. 2002;99(3):490–496. 5. Guidetti DA, Divon MY, Braverman JJ, et al. Sonographic estimates of fetal weight in the intrauterine growth retardation population. Am J Perinatol. 1990;7:5–7. (c) 2015 Wolters Kluwer. All Rights Reserved.

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6. Tuuli MG, Cahill A, Stamilio D, et al. Comparative efficacy of measures of early fetal growth restriction for predicting adverse perinatal outcomes. Obstet Gynecol. 2011;117(6):1331–1340. 7. Mongelli M, Gardosi J. Reduction of false-positive diagnosis of fetal growth ­restriction by application of customized fetal growth standards. Obstet Gynecol. 1996;88(5): 844–848. 8. Bukowski R, Uchida T, Smith GSC, et al. Individualized norms of optimal fetal growth: fetal growth potential. Obstet Gynecol. 2008;111(5):1065–1076. 9. Facco F, You W, Grobman W. Genetic thrombophilias and intrauterine growth restriction: a meta-analysis. Obstet Gynecol. 2009;113(6):1206–1209. 10. Committee on Practice Bulletins—Obstetrics, American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 132. Antiphospholipid Syndrome. Obstet Gynecol. 2012;120(6):1514–1521. 11. Berkley E, Chauhan SP, Abuhamad A; Society for Maternal-Fetal Medicine Publications Committee. Doppler assessment of the fetus with intrauterine growth restriction. Am J Obstet Gynecol. 2012;206(4):300. 12. Alfirevic Z, Stampalija T, Gyte GM. Fetal and umbilical Doppler ultrasound in high-risk pregnancies. Cochrane Database Syst Rev. 2010;(1):CD007529. 13. Thompson JL, Kuller JA, Rhee EH. Antenatal surveillance of fetal growth restriction. Obstet Gynecol Surv. 2012;67(9):554–565. 14. Thornton JG, Hornbuckle J, Vail A, et al.; GRIT study group. Infant well-being at 2 years of age in the Growth Restriction Intervention Trial (GRIT): multicentered randomized controlled trial. Lancet. 2004;364(9433):513–520. 15. Duley L, Henderson-Smart DJ, Meher S, et al. Antiplatelet agents for preventing preeclampsia and its complications. Cochrane Database Syst Rev. 2007;98:253. 16. The GRIT Study Group. A randomized trial of timed delivery for the compromised preterm fetus: short term outcomes and Bayesian interpretation. BJOG. 2003;110:27–32. 17. The DIGITAT Study Group. Induction versus expectant monitoring for intrauterine growth restriction at term: randomized equivalence trial (DIGITAT). BMJ. 2010;341:c7087. 18. Morrison I, Olsen J. Weight-specific stillbirths and associated causes of death: an analysis of 765 stillbirths. Am J Obstet Gynecol. 1985;152:975–980. 19. Pilliod RA, Cheng YW, Snowden JM, et al. The risk of intrauterine fetal death in the smallfor-gestational-age fetus. Am J Obstet Gynecol. 2012;207(4):318. 20. Bergella V. Prevention of recurrent fetal growth restriction. Obstet Gynecol. 2007;110(4): 904–912. 21. McIntire DD, Bloom SL, Casey BM, et al. Birth weight in relation to morbidity and mortality among newborn infants. N Engl J Med. 1999;340:1234–1238. 22. Abalos E, Duley L, Steyn DW, et al. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev. 2007;(1):CD002252. 23. Mostello D, Jen Chang J, Allen J, et al. Recurrent preeclampsia: the effect of weight change between pregnancies. Obstet Gynecol. 2010;116:677. 24. Maggard MA, Yermilov I, Li Z, et al. Pregnancy and fertility following bariatric surgery: asystematic review. JAMA. 2008;300:2286. 25. Bujold E, Roberge S, Lacasse Y, et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started early in pregnancy: a meta-analysis. Obstet Gynecol. 2010;116(2):402–413. 26. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin 22. Fetal Macrosomia. Obstet Gynecol. 2000;96(5):1–12. 27. Ju H, Chadha Y, Donovan T, et al. Fetal macrosomia and pregnancy outcomes. Aust N Z J Obstet Gynaecol. 2009;49(5):504–672. 28. King JR, Korst LM, Miller DA, et al. Increased composite maternal and neonatal morbidity associated with ultrasonographically suspected fetal macrosomia. J Matern Fetal Neonatal Med. 2012;25(10):1953–1959. 29. Esakoff TF, Cheng YW, Sparks TN, et al. The association between birthweight 4000 gm or greater and perinatal outcomes in patients with and without gestational diabetes mellitus. Am J Obstet Gynecol. 2009;200(6):672. (c) 2015 Wolters Kluwer. All Rights Reserved.

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30. Bjorstad AR, Irgens-Hansen K, Daltveit AK, et al. Macrosomia: mode of delivery and pregnancy outcome. Acta Obstet Gynecol Scand. 2010;89(5):664–669. 31. Raio L, Ghezzi F, Di Naro E, et al. Perinatal outcome of fetuses with a birthweight greater than 4500 gm; an analysis of 3356 cases. Eur J Obstet Gynecol Reprod Biol. 2003;109(2):160–165. 32. Gross SJ, West DJ, Scardo JA, et al. Antepartum detection of macrosomic fetus: clinical versus sonographic, including soft-tissue measurements. Obstet Gynecol. 2000;95:639–642. 33. HAPO Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcome. N Engl J Med. 2008;358:1991–2992. 34. Okun N, Verma A, Mitchell BF, et al. Relative importance of maternal constitutional factors and glucose intolerance of pregnancy in the development of newborn macrosomia. J Matern Fetal Med. 1997;6:285–290. 35. Parker JD, Abrams S. Prenatal weight gain advice: an examination of the recent weight gain recommendations of the Institute of Medicine. Obstet Gynecol. 1992;79:664–669. 36. Bianco AT, Smilen SW, Davis Y, et al. Pregnancy outcome and weight gain recommendations for the morbidly obese woman. Obstet Gynecol. 1998;91:97–102. 37. Chauhan SP, West DJ, Scardo JA, et al. Antepartum detection of macrosomic fetus: clinical versus sonographic, including soft-tissue measurements. Obstet Gynecol. 2000;95:639. 38. Gonan O, Rosen DJ, Dolfin Z, et al. Induction of labor versus expectant management in macrosomia: a randomized study. Obstet Gynecol. 1997;89:913–917.

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34

Multiple Gestations John D. Yeast

KEY POINTS • Prematurity is the greatest risk factor for multiple-gestation pregnancies. • Monochorionic placentation creates additional risk for either fetus and requires careful surveillance. • Higher-order multiple gestations also pose significant medical risks for maternal morbidity. BACKGROUND Definition • Incidence with spontaneous ovulation • Twin gestation occurs in 15 out of 1000 pregnancies. °°Monozygotic twin gestation is constant at 3 to 5 in 1000 births. °°Dizygotic twin incidence varies by population group. • Triplet gestation occurs in 3.7 out of 10,000 pregnancies. °°The frequency of triplets is influenced by the same factors as is that of twins. • Higher-order multiple gestation: °°Incidence is less than 5 out of 1,000,000 pregnancies. °°Live birth rate is significantly lower. • Incidence in United States • Vital statistics data often do accurately differentiate spontaneous conceptions from assisted reproductive technology (ART). • Twin gestation: °°Thirty-three out of 1000 births are twins (1). °°There has been a 76% increase in incidence since 1980 (1,2). °°Thirty-three percent of twins result from fertility therapies (2,3). • Triplet gestation and higher-order multiples (triplets/+): °°Triplets and higher-order multiples accounted for 13.8 out of 10,000 pregnancies in 2010. °°During the 1980s, the incidence rose greater than 400%. However, since 1995, the incidence has dropped nearly 30% (1,4). °°Only 7% to 18% of triplets occur spontaneously. °°Less than 7% of higher-order multiples result from spontaneous ovulation (5). • The gradual increase in maternal age over the past 20 years also has had some minor effect on the frequency of multiple-gestation birth. Pathophysiology • Zygosity and placentation • The outcome of multiple gestations, especially twins, correlates well with placentation and, to a lesser extent, zygosity. • The outcome for triplets and higher-order multiples is more influenced by the degree of prematurity. • Patterns of placental relationships remain important to siblings in triplets and higherorder multiples due to the possible combinations of zygosity. 634

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Chapter 34 • Multiple Gestations 

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• Zygosity • Monozygotic twins °°There is a fixed incidence of 30% of monozygosity in spontaneous twins. °°Monozygosity can occur in ART twins, especially after intracytoplasmic sperm injection. • Dizygotic twins °°The rate of dizygotic twins is influenced by --Maternal age --Parity --Race and ethnicity °°There is a 70% incidence of dizygosity in spontaneous twins. °°There is a greater than 95% incidence of dizygosity in ART twins and higher-order multiples. • Placentation • Monochorionic placenta °°Derived from single embryo, identical °°Monochorionic/diamniotic --There is a 68% incidence of monochorionic/diamniotic placentation in monozygotic twins. --Excess preterm birth and perinatal mortality are observed with a single placenta. --The perinatal fetal death rate is as high as 25% (6). °°Monochorionic/monoamniotic --In monozygotic twins, the incidence of monochorionic/monoamniotic placentation is less than 2%. --Up to 50% perinatal mortality is reported due to cord entanglement. • Dichorionic/diamniotic placenta °°Dichorionic placentation may occur in either monozygotic or dizygotic twins and higher-order multiples. °°Dichorionic placentation occurs in monozygotic twins that divide earlier than 3 days after fertilization. °°There is lower perinatal risk than with monochorionic placentation. • Evaluation of the placenta may help determine if same-sex twins are identical. °°Placentation should always be documented --During ultrasound studies --In the delivery room --In the lab, if necessary °°Same-sex twins with separate placentas have a monozygotic/dizygotic risk of 1:5 (Table 34-1).

Table 34-1

The Frequency of Placentation in Twin Pregnancies

Placentation type Diamnionic/dichorionic, fuseda Diamnionic/dichorionic, separatea Diamnionic/monochorionicb Monoamnionic/monochorionicb

Frequency 34.0% 35.2% 29.6% 1.2%

May be mono- or dizygotic. Monozygotic only. Source: Hollenbach KA, Hickok DE. Epidemiology and diagnosis of twin gestation. Clin Obstet Gynecol. 1990;33:3–9.

a

b

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636 

  Part V • Fetal Complications

Table 34-2

Perinatal Outcome for Multiple-Gestation Pregnancy Gestation

Outcome Percent delivering at

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