50 Studies Every Obstetrician-Gynecologist Should Know 1

50 Studies Every Obstetrician-Gynecologist
Should Know
50 STUDIES EVERY DOCTOR SHOULD KNOW
50 Studies Every Doctor Should Know: The Key Studies that Form the
Foundation of Evidence Based Medicine, Revised Edition
Michael E. Hochman
50 Studies Every Internist Should Know
Kristopher Swiger, Joshua R. Thomas, Michael E. Hochman,
and Steven Hochman
50 Studies Every Neurologist Should Know
David Y. Hwang and David M. Greer
50 Studies Every Pediatrician Should Know
Ashaunta T. Anderson, Nina L. Shapiro, Stephen C. Aronoff, Jeremiah Davis,
and Michael Levy
50 Imaging Studies Every Doctor Should Know
Christoph I. Lee
50 Studies Every Surgeon Should Know
SreyRam Kuy, Rachel J. Kwon, and Miguel A. Burch
50 Studies Every Intensivist Should Know
Edward A. Bittner
50 Studies Every Palliative Care Doctor Should Know
David Hui, Akhila Reddy, and Eduardo Bruera
50 Studies Every Psychiatrist Should Know
Ish P. Bhalla, Rajesh R. Tampi, and Vinod H. Srihari
50 Studies Every Anesthesiologist Should Know
Anita Gupta, Michael E. Hochman, Elena N. Gutman
50 Studies Every Ophthalmologist Should Know
Alan D. Penman, Kimberly W. Crowder, and William M. Watkins, Jr.
50 Studies Every Urologist Should Know
Philipp Dahm
50 Studies Every Obstetrician-Gynecologist Should Know
Constance Liu, Noah Rindos, and Scott A. Shainker
50 Studies Every Obstetrician-
Gynecologist Should Know
edited by
Constance Liu, MD, PhD

Medical Offficer
Department of Obstetrics and Gynecology
Gallup Indian Medical Center
Gallup, NM, USA
Noah Rindos, MD
Assistant Professor
UPMC Magee-Womens Hospital
Pittsburgh, PA, USA
Scott A. Shainker , DO, MS
The Annie and Chase Koch Chair in Obstetrics and Gynecology,
Director, New England Center for Placental Disorder, Assistant Professor
of Obstetrics, Gynecology, and Reproductive Biology
Division of Maternal-Fetal Medicine, Department of Obstetrics
and Gynecology
Beth Israel Deaconess Medical Center/Harvard Medical School
Boston, MA, USA
1
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Library of Congress Cataloging-in-Publication Data

Names: Liu, Constance, editor. | Rindos, Noah, editor. | Shainker A., Scott, editor.
Title: 50 studies every obstetrician-gynecologist should know /
[edited by] Constance Liu, Noah Rindos, Scott A. Shainker.
Other titles: Fifty studies every obstetrician and gynecologist should know |
50 studies every doctor should know (Series)
Description: New York, NY : Oxford University Press, 2021. |
Series: 50 studies every doctor should know |
Includes bibliographical references and index.
Identifiers: LCCN 2020036319 (print) | LCCN 2020036320 (ebook) | ISBN 9780190947088 (paperback) |
ISBN 9780190947101 (epub) | ISBN 9780190947118 (online)
Subjects: MESH: Pregnancy Complications | Pregnancy | Genital Diseases, Female | Case Reports
Classification: LCC RG525 (print) | LCC RG525 (ebook) | NLM WQ 240 | DDC 618.2—dc23
LC record available at https://lccn.loc.gov/2020036319
LC ebook record available at https://lccn.loc.gov/2020036320
DOI: 10.1093/med/9780190947088.001.0001
This material is not intended to be, and should not be considered, a substitute for medical or other
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Printed by Marquis, Canada

To Chris, Taro, and Hiro: I love you like a zebra loves its stripes. Thanks & love to my
parents: Drs. Wen-Shin and Wan-tzu.
—Constance  Liu
Thank you to Steph, Raspberry, Luca, and Milo for all of your support and love.
—Noah Rindos
To Mom, Lindsay, Molly, and Logan for their unending love and support.
To my father, who would have received such enjoyment from this . . .
—Scott A. Shainker
CONTENTS
Preface from the Series Editor xiii

Preface xv
Contributors xvii
1. Magnesium Sulphate for Seizure Prophylaxis in Women With

Preeclampsia: The MAGPIE Trial 1
Peter Lindner and Shad Deering
2. Low-Dose Aspirin for the Prevention and Treatment of Preeclampsia:
The CLASP Trial 7
Danielle M. Panelli and Deirdre J. Lyell
3. First Trimester Hemoglobin A1 and Risk for Major Malformation and
Spontaneous Abortion 13
Rachel Blake and Chloe Zera
4. Effect of Treatment of Gestational Diabetes Mellitus on Pregnancy
Outcomes: The ACHOIS Trial 20
Alexandra Belcher-Obejero-Paz and Aviva Lee-Parritz
5. Reduction of Maternal–Infant Transmission of HIV Type 1 With
Zidovudine Treatment 26
Eliza Rodrigue McElwee and Pooja K. Mehta
6. The Length of the Cervix and the Risk of Spontaneous Preterm
Delivery 32
Julie Stone and Michael House
viiiContents
7. Intramuscular Progesterone for the Prevention of Recurrent

Preterm Birth 38
Emily A. Oliver and Amanda Roman-Camargo
8. Antibiotics for Preterm Premature Rupture of Membranes 43
Katherine S. Kohari and Christian M. Pettker
9. Fetal Fibronectin in Cervical and Vaginal Secretions as a Predictor of
Preterm Delivery 48
Zachary Colvin and Anna Palatnik
10. Magnesium Sulfate for the Prevention of Cerebral Palsy:
The BEAM Trial 54
Laura Smith and Blair J. Wylie
11. Pelvic Scoring for Elective Induction: The Bishop Score 60
C. Sola Ajewole and Jodi F. Abbott
12. Management of Post-Term Pregnancy: The Post-Term Pregnancy Trial 64
Ashley E. Benson and Brett D. Einerson
13. Planned Cesarean Section Versus Planned Vaginal Birth for Breech
Presentation at Term: The Term Breech Trial 69
Samantha Morrison and Hugh Ehrenberg
14. Induction of Labor Versus Expectant Management for Prelabor
Rupture of Membranes: The TERMPROM Study 74
Adina Kern-Goldberger and Dena Goffman
15. Antepartum Glucocorticoid Treatment for Prevention of the Respiratory
Distress Syndrome in Premature Infants 81
Melissa H. Spiel and John Zupancic
16. Outcomes Associated With Trial of Labor After Cesarean Delivery 86
Hadi Erfani and Alireza A. Shamshirsaz
17. Timing of Elective Repeat Cesarean Delivery at Term and Neonatal
Outcomes 92
Katherine Johnson and Brett C. Young
18. The Natural History of the Normal First Stage of Labor 97
Karin Fox
19. Maternal Morbidity Associated With Multiple Repeat Cesarean
Deliveries 103
Matthew K. Janssen and Steven J. Ralston
Contents ix
20. First-Trimester or Second-Trimester Screening, or Both, for Down

Syndrome: The FASTER Trial 108
Jessica M. Hart and Barbara M. O’Brien
21. Cell-Free DNA Screening for Fetal Aneuploidy: The NEXT Trial 115
Ashley N. Battarbee and Neeta L. Vora
22. Antepartum Assessment of Fetal Well-Being: The Biophysical Profile 121
Jonathan S. Hirshberg and Nandini Raghuraman
23. Diagnostic Tests for Evaluation of Stillbirth 127
Stephanie Dukhovny
24. An Intervention to Promote Breastfeeding: The PROBIT Study 132
Leanna Sudhof and Toni Golen
25. Racial and Ethnic Disparities in Maternal Morbidity and Obstetric
Care 138
Rose L. Molina and Neel Shah
26. The Risk of Pregnancy After Tubal Sterilization: Findings From the U.S.
Collaborative Review of Sterilization the CREST Study 144
Sujata Chouinard and Eve Espey
27. Complications of First-Trimester Abortion: A Report of 170,000 Cases 149
Maryl Sackeim and Sadia Haider
28. Long-Acting Reversible Contraception Versus Pills/Patch/Ring:
The Contraceptive CHOICE Project 154
Antoinette Danvers and Elizabeth B. Schmidt
29. Long-Acting Reversible Contraception (LARC) and Teen Pregnancy:
The Contraceptive CHOICE Project 159
Jaclyn Grentzer
30. Effect of Screening Mammography on Breast Cancer Detection and
Mortality 164
Myrlene Jeudy, Monique Swain, and Mark Pearlman
31. Human Papillomavirus Infection of the Cervix: Relative Risk Association
of 15 Common Anogenital Types 170
Jacqueline M. Mills and Elizabeth A. Stier
32. Transvaginal Ultrasound for Endometrial Assessment of Postmenopausal
Bleeding 175
Alison A. Garrett and Sarah E. Taylor
xContents
33. The Accuracy of Endometrial Sampling in the Diagnosis of Patients With

Endometrial Carcinoma and Hyperplasia: A Meta-Analysis 180
Chelsea Chandler and Alexander Olawaiye
34. Elective Bilateral Oophorectomy Versus Ovarian Conservation at the
Time of Benign Hysterectomy 185
Johnny Yi and Megan Wasson
35. Native-Tissue Anterior Colporrhaphy Versus Transvaginal Mesh for
Anterior Pelvic Organ Prolapse 191
Nick Rockefeller and Peter Jeppson
36. Preoperative Urodynamics Testing in Stress Urinary Incontinence:
The VALUE Trial 197
Linda Burkett and Megan Bradley
37. A Midurethral Sling to Reduce Incontinence After Vaginal Repair:
The OPUS Trial 202
Deepali Maheshwari and Ellen Solomon
38. Uterine-Artery Embolization Versus Surgery for Symptomatic Uterine
Fibroids 207
Kristen Pepin and Sarah L. Cohen
39. Robotic-Assisted Versus Laparoscopic Hysterectomy Among Women
With Benign Gynecologic Disease 212
Chetna Arora and Arnold P. Advincula
40. Endometrial Ablation Versus Hysterectomy: The STOP-DUB Trial 218
Christine Helou and Mandy Yunker
41. Pelvic Organ Function After Total Versus Subtotal Abdominal
Hysterectomy 224
Susan Tsai, Jessica Traylor, and Magdy Milad
42. Prolonged GnRH Agonist and Add-Back Therapy for Symptomatic
Endometriosis 230
Sierra J. Seaman and Hye-Chun Hur
43. Laparoscopic Excision Versus Ablation for Endometriosis-Associated
Pain 235
Laura Newcomb and Nicole Donnellan
44. Clomiphene, Metformin, or Both for Infertility With Polycystic Ovarian
Syndrome: The PPCOS Trial 240
Tana Kim and Zaraq Khan
Contents xi
45. A Randomized Clinical Trial to Evaluate Optimal Treatment for

Unexplained Infertility: The FASTT Trial 246
Stephanie Rothenberg and Joseph Sanfilippo
46. Reproductive Technologies and the Risk of Birth Defects 251
Caitlin Sacha and John Petrozza
47. Biomarkers of Ovarian Reserve and Infertility Among Older Reproductive
Age Women 257
Alexis Gadson and Wendy Kuohung
48. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal
Women: The Women’s Health Initiative 262
Rachel Beverley and Judith Volkar
49. Predictors of Success of Methotrexate Treatment for Tubal Ectopic
Pregnancies 267
Mary Louise Fowler, Paul Hendessi, and Nyia Noel
50. Application of Redefined Human Chorionic Gonadotropin Curves for the
Diagnosis of Women at Risk for Ectopic Pregnancy 272
Paul Tyan and Lauren D. Schiff
Index 279
PREFACE FROM THE SERIES EDITOR
When I was a third-year medical student, I asked one of my senior residents—

who seemed to be able to quote every medical study in the history of mankind—
if he had a list of key studies that have defined the current practice of general
medicine that I should read before graduating medical school. “Don’t worry,” he
told me. “You will learn the key studies as you go along.”
But picking up on these key studies didn’t prove so easy, and I was frequently
admonished by my attendings for being unaware of crucial literature in their
field. More important, because I had a mediocre understanding of the medical
literature at that time, I lacked confidence in my clinical decision-making and
had difficulty appreciating the significance of new research findings. It wasn’t
until I was well into my residency—thanks to considerable amount of effort and
determination—that I finally began to feel comfortable with both the emerging
and fundamental medical literature.
Now, as a practicing general internist, I realize that I am not the only doctor
who has struggled to become familiar with the key medical studies that form the
foundation of evidence-based practice. Many of the students and residents I work
with tell me that they feel overwhelmed by the medical literature and that they
cannot process new research findings because they lack a solid understanding of
what has already been published. Even many practicing physicians—including
those with years of experience—have only a cursory knowledge of the medical
evidence base and make clinical decisions largely on personal experience.
I initially wrote 50 Studies Every Doctor Should Know in an attempt to pro-
vide medical professionals (and even lay readers interested in learning more
about medical research) a quick way to get up to speed on the classic studies
that shape clinical practice. But it soon became clear there was a greater need for
this distillation of the medical evidence than my original book provided. Soon
after the book’s publication, I began receiving calls from specialist physicians in
a variety of disciplines wondering about the possibility of another book focusing
xiv Preface from the Series Editor
on studies in their field. In partnership with a wonderful team of editors from

Oxford University Press, we have developed my initial book into a series, of-
fering volumes in Internal Medicine, Pediatrics, Surgery, Neurology, Radiology,
Critical Care, Anesthesia, Psychiatry, Palliative Care, Ophthalmology, and now
Obstetrics and Gynecology. Several additional volumes are in the works.
I am particularly excited about this latest volume in Obstetrics and Gynecology,
which is the culmination of hard work by a team of editors—Constance Liu,
Noah Rindos, and Scott A. Shainker, who have summarized the most impor-
tant studies in their field. Particularly over the past several years, there has be-
come a solid evidence base in the field of Obstetrics and Gynecology, and Drs.
Liu, Rindos, and Shainker have effectively captured it in this volume. I be-
lieve 50 Studies Every Obstetrician-Gynecologist Should Know provides the per-
fect launching ground for trainees in the field as well as a helpful refresher for
practicing clinicians–physicians, nurse practitioners, and other women’s health
professionals. The book also highlights key knowledge gaps that may stimulate
researchers to tackle key unanswered questions in the field. A special thanks also
goes to the wonderful editors at Oxford University Press—Marta Moldvai and
Tiffany Lu—who injected energy and creativity into the production process for
this volume. This volume was a pleasure to help develop, and I learned a lot about
the field of Obstetrics and Gynecology in the process.
I have no doubt you will gain important insights into the field of Obstetrics
and Gynecology in the pages ahead!
Michael E. Hochman, MD, MPH
PREFACE
We entered the field of obstetrics and gynecology eager to learn, advocate for
patients, and become the physician-scientists we are today. We believe in repro-
ductive rights and evidence-based medicine: together these foster the ability to
provide compassionate and optimal care. We embarked on this project because
we believe that understanding the primary literature is critical for any clinician
who seeks to practice thoughtful, evidence-based medicine. More than just
knowing what to do, we believe clinicians should know why they do it.
This volume, part of the larger series 50 Studies Every Doctor Should Know,
aims to present a foundational understanding of the practice of obstetrics and
gynecology. We interrogated a broad range of literature. While there are certainly
far more than 50 studies we could have included, we employed a rigorous itera-
tive process that prioritized studies that impact current practice and, importantly,
answer the “why” of management. This book is ideal for generalists who seek to
contextualize new evidence, practitioners of women’s health who wish to deepen
their understanding of the literature, trainees who are learning the basics of
management, and even the interested lay person who wants to understand what
studies are guiding their care.
We are grateful for the contributions of the chapter authors across a diverse
range of subspecialties. We thank them for their clinical experience, knowledge,
and ability to make these studies accessible to readers at all levels of experience.
Collectively we represent the diverse field of obstetrics and gynecology: (CL)
a generalist obstetrician-gynecologist serving Native American patients in rural
western New Mexico, (SS) an academic maternal-fetal medicine specialist
in Boston, and (NR) a minimally invasive pelvic surgeon in Pittsburgh. From
residency at Boston Medical Center, our paths have diverged neatly to rep-
resent a range of career choices, but we have this in common: a commitment
to advocating for our patients and an understanding that offering the best care
xviPreface
means continual attention to our foundation of evidentiary learning. We hope

this volume provides additional background for you to achieve the same.
We would like to thank Dr. Michael Hochman for his vision in creating this se-
ries. We are also grateful to Ms. Marta Moldvai and Ms. Tiffany Lu from Oxford
University Press for their editorial support and guidance. We appreciate the
contributions of Justin Dietrich to the family planning section. Finally, we would
like to thank the patients who participated in these clinical trials and studies.
Constance Liu, MD, PhD
Noah Rindos, MD
Scott A. Shainker, DO, MS
CONTRIBUTORS
Jodi F. Abbott, MD, MHCM Ashley N. Battarbee, MD, MSCR

Associate Professor Assistant Professor
Department of Obstetrics and Department of Obstetrics and
Gynecology Gynecology
Boston University School of Medicine University of Alabama
Boston, MA, USA Birmingham, AL, USA
Arnold P. Advincula, MD Alexandra Belcher-Obejero-Paz,
Professor & Division Chief MD, MPH
Division of Gynecologic Specialty Obstetrics and Gynecology Generalist
Surgery Department of Obstetrics and
Columbia University Medical Center Gynecology
New York, NY, USA Lynn Community Health Center
Lynn, MA, USA
C. Sola Ajewole, MD
Resident Physician Ashley E. Benson, MD, MA
Department of Obstetrics and Physician Fellow
Gynecology Department of Obstetrics and
Boston Medical Center Gynecology
Boston, MA, USA University of Utah
Salt Lake City, UT, USA
Chetna Arora, MD
Assistant Professor Rachel Beverley, MD
Department of Obstetrics and Fellow, Reproductive Endocrinology
Gynecology and Infertility
Columbia University Department of Obstetrics,
New York, NY, USA Gynecology, and Reproductive
Sciences
University of Pittsburgh
Medical Center
Pittsburgh, PA, USA
xviiiContributors
Rachel Blake, MD Zachary Colvin, DO

Chief Resident, PGY4 Maternal Fetal Medicine Fellow
Harvard Medical School Medical College of Wisconsin
Boston, MA, USA Milwaukee, WI, USA
Megan Bradley, MD Antoinette Danvers, MD, MSCR
Department of Obstetrics and Assistant Professor
UPMC Magee-Womens Hospital Gynecology and Women’s
Pittsburgh, PA, USA Health
Albert Einstein College of Medicine/
Linda Burkett, MD
Montefiore Medical Center
Physician, Urogynecology
Bronx, NY, USA
Department of Obstetrics,
Gynecology, and REI Shad Deering, MD
UPMC Magee-Womens Associate Dean, Baylor College of
Hospital Medicine, Children’s Hospital
Pittsburgh, PA, USA of San Antonio System Medical
Director, CHRISTUS Simulation
Chelsea Chandler, MD
Institute
Fellow
Department of Obstetrics and
Department of Gynecologic
Gynecology
Oncology
Baylor College of Medicine
Houston, TX, USA
Nicole Donnellan, MD
Sujata Chouinard, MD
Associate Professor
Resident Physician
Department of Obstetrics,
Gynecology, and Reproductive
Gynecology
Sciences
University of New Mexico
Albuquerque, NM, USA
Sarah L. Cohen, MD, MPH
Stephanie Dukhovny, MD
Minimally Invasive Gynecologic
Assistant Professor
Surgeon
Department of Gynecology
Gynecology
Mayo Clinic
OHSU
Rochester, MN, USA
Portland, OR, USA
Contributors xix
Hugh Ehrenberg, MD Alison A. Garrett, MD

Attending Physician Fellow
Department of Maternal Fetal Department of Gynecologic
Medicine Oncology
Voorhees, NJ, USA UPMC Magee-Womens Hospital
Brett D. Einerson, MD, MPH
Assistant Professor Dena Goffman, MD
Department of Obstetrics and Chief of Obstetrics
University of Utah Gynecology
Salt Lake City, UT, USA Columbia University Irving
Medical Center
Hadi Erfani, MD, MPH
New York, NY, USA
Resident
Department of Obstetrics and Toni Golen, MD
Gynecology Assistant Professor
Baylor College of Medicine Department of Obstetrics,
Houston, TX, USA Gynecology, and Reproductive
Biology
Eve Espey, MD, MPH
Beth Israel Deaconess Medical
Professor and Chair
Center/Harvard Medical School
Boston, MA, USA
Gynecology
University of New Mexico Jaclyn Grentzer, MD, MSCI
Albuquerque, NM, USA Independent Provider
Planned Parenthood of Orange and
Mary Louise Fowler, MD, MEng
San Bernardino Counties
Resident Physician
Laguna Beach, CA, USA
Gynecology Sadia Haider, MD, MPH
Boston Medical Center Associate Professor of Obstetrics and
Boston, MA, USA Gynecology
Karin Fox, MD, MEd
Gynecology
University of Chicago
Gynecology
Chicago, IL, USA
Baylor College of Medicine
Houston, TX, USA Jessica M. Hart, MD
Fellow
Alexis Gadson, MD
Department of Maternal Fetal
REI Fellow
Medicine
Women and Infants Hospital/Brown
Beth Israel Deaconess Medical Center
University
Boston, MA, USA
Providence, RI, USA
xxContributors
Christine Helou, MD Matthew K. Janssen, MD

Department of Obstetrics and Department of Maternal Fetal Medicine
Gynecology University of Pennsylvania
Greater Baltimore Medical Center Philadelphia, PA, USA
Towson, MD, USA
Peter Jeppson, MD
Paul Hendessi, MD Division Chief of Urogynecology
Clinical Associate Professor Department of Obstetrics and
Gynecology University of New Mexico
Boston University Albuquerque, NM, USA
Boston, MA, USA
Myrlene Jeudy, MD
Jonathan S. Hirshberg, MD Department of Obstetrics and
Clinical Fellow in Maternal-Fetal Gynecology
Medicine and Surgical Critical Care Kaiser Permanente
Department of Obstetrics and Atlanta, GA, USA
Gynecology/Department of
Katherine Johnson, MD
Surgery
MFM Attending Physician
Washington University
St. Louis, MO, USA
Gynecology
Michael Hochman, MD, MPH University of Massachusetts/UMass
Director of the USC Gehr Family Memorial Medical Center
Center for Health Systems Worcester, MA, USA
Science and Innovation
Adina Kern-Goldberger, MD, MPH
Internal Medicine
Fellow
Keck School of Medicine of USC
Sherman, Oaks, CA
Gynecology
Michael House, MD Hospital of the University of
Associate Professor Pennsylvania
Department of Obstetrics and Philadelphia, PA, USA
Gynecology
Zaraq Khan, MBBS, MCR, FACOG
Tufts Medical Center
Chair, Reproductive Endocrinology
Boston, MA, USA
and Infertility
Hye-Chun Hur, MD, MPH Division of Reproductive
Minimally Invasive Gynecologic Endocrinology and Infertility,
Surgeon Department of Obstetrics and
Gynecologic Specialty Surgery Gynecology
Columbia University Irving Consultant, Minimally Invasive
Medical Center Gynecologic Surgery
New York, NY, USA Rochester, MN, USA
Contributors xxi
Tana Kim, MD Constance Liu, MD, PhD

Reproductive Endocrinologist Medical Officer
Division of Reproductive Department of Obstetrics and
Endocrinology and Infertility, Gynecology
Department of Obstetrics and Gallup Indian Medical Center
Gynecology Gallup, NM, USA
Mayo Clinic
Deirdre J. Lyell, MD
Rochester, MN, USA
Professor
Katherine S. Kohari, MD Department of Obstetrics and
Assistant Professor Gynecology
Department of Obstetrics, Stanford University
Gynecology, and Reproductive Palo Alto, CA, USA
Sciences
Deepali Maheshwari, DO, MPH
Section of Maternal-Fetal Medicine
Fellow
Yale University School of
Medicine
Gynecology
New Haven, CT, USA
University of Massachusetts
Wendy Kuohung, MD Medical School
Associate Professor of Obstetrics and Worcester, MA, USA
Gynecology
Eliza Rodrigue McElwee, MD
Director, Division of Reproductive
Maternal Fetal Medicine Fellow
Endocrinology and Infertility
Gynecology
Gynecology
Medical University of South Carolina
Boston University School
Charleston, SC, USA
of Medicine
Boston, MA, USA Pooja K. Mehta, MD, MSHP
Women’s Health Lead, Cityblock Health
Aviva Lee-Parritz, MD
Assistant Professor, Section of
Chief
Community and Population Medicine
Department of Medicine
Gynecology
Louisiana State University Health
Boston University
Sciences Center
Boston, MA, USA
New Orleans, LA, USA
Peter Lindner, MD
Magdy Milad, MD, MS
Resident Physician
Albert B Gerbie Professor
Gynecology
Gynecology
Walter Reed National Military
Northwestern Feinberg School of
Medical Center
Medicine
Bethesda, MD, USA
Chicago, IL, USA
xxiiContributors
Jacqueline M. Mills, MD, MPP Alexander Olawaiye, MD, FRCOG,

Resident Physician FACOG, FRCS
Department of Obstetrics and Associate Professor
Gynecology Department of Obstetrics, Gynecology,
Boston Medical Center and Reproductive Sciences
Boston, MA, USA University of Pittsburgh School of
Medicine
Rose L. Molina, MD, MPH
Assistant Professor of Obstetrics,
Gynecology, and Reproductive Emily A. Oliver, MBBS, MPH
Biology Maternal Fetal Medicine Fellow
Beth Israel Deaconess Medical Center Thomas Jefferson University Hospital
Boston, MA, USA Philadelphia, PA, USA
Samantha Morrison, MD Anna Palatnik, MD
Chief Resident, PGY4 Assistant Professor
Crozer-Chester Medical Center Medical College of Wisconsin
Upland, PA, USA Milwaukee, WI, USA
Laura Newcomb, MD Danielle M. Panelli, MD
Department of Obstetrics and Clinical Fellow
University of Virginia Gynecology
Charlottesville, VA, USA Division of Maternal-Fetal Medicine
Stanford University
Nyia Noel, MD, MPH
Stanford, CA, USA
Assistant Professor
Department of Obstetrics and Kristen Pepin, MD, MPH
Gynecology Assistant Professor
Boston University School of Medicine Weill Cornell Medical Center
Boston, MA, USA New York
New York, NY, USA
Barbara M. O’Brien, MD
Physician Mark Pearlman, MD
Department of Obstetrics and Professor, Active Emeritus
Beth Israel Deaconess Medical Center Gynecology Department of Surgery
Boston, MA, USA University of Michigan Medical School
Ann Arbor, MI, USA
Contributors xxiii
John Petrozza, MD Amanda Roman-Camargo, MD

Chief, Division of Reproductive Associate Professor
Medicine & IVF Department of Obstetrics and
Gynecology Thomas Jefferson University
Massachusetts General Hospital Philadelphia, PA, USA
Boston, MA, USA
Stephanie Rothenberg, MD
Christian M. Pettker, MD Pacific NW Fertility
Department of Obstetrics, Seattle, WA, USA
Gynecology, and Reproductive
Caitlin Sacha, MD
Sciences
Clinical Research Fellow in
Yale School of Medicine
Reproductive Endocrinology and
New Haven, CT, USA
Infertility
Nandini Raghuraman, MD, MS Department of Obstetrics and
Assistant Professor Gynecology, Massachusetts
Department of Obstetrics and General Hospital
Gynecology/Department of Harvard Medical School
Surgery Boston, MA, USA
Washington University
Maryl Sackeim, MD
St. Louis, MO, USA
Faculty
Steven J. Ralston, MD, MPH Family Planning Division
Chair Kaiser Permanente San Francisco
Department of Obstetrics and San Francisco, CA, USA
Gynecology
Joseph Sanfilippo, MD
Pennsylvania Hospital
Philadelphia, PA, USA
Gynecology
Noah Rindos, MD UPMC Magee-Womens Hospital
Assistant Professor Pittsburgh, PA, USA
Lauren D. Schiff, MD
Gynecology
Assistant Professor of Minimally
Invasive Gynecologic Surgery
Nick Rockefeller, MD Gynecology
Clinical Fellow University of North Carolina School
Female Pelvic Medicine and of Medicine
Reconstructive Surgery Chapel Hill, NC, USA
University of New Mexico
Albuquerque, NM, USA
xxivContributors
Elizabeth B. Schmidt, MD, MSCI, Director, Fetal Surgery Fellowship

FACOG, FACS Co-Chief, Maternal Fetal Surgery
Chief of Family Planning Section
Gynecology Gynecology/Department of
Northwell Surgery
Great Neck, NY, USA Baylor College of Medicine
Children’s Fetal Center, Texas
Sierra J. Seaman, MD
Children’s Hospital
Physician
Houston, TX, USA
Gynecology Laura Smith, MD
Columbia University Irving Medical Clinical Fellow
Center—New York Presbyterian Department of Obstetrics and
Hospital Gynecology
New York, NY, USA Beth Israel Deaconess Medical Center
Boston, MA, USA
Neel Shah, MD, MPP
Assistant Professor Ellen Solomon, MD
Department of Obstetrics, Assistant Professor of Obstetrics and
Gynecology, and Reproductive Gynecology
Biology Division of Urogynecology and Pelvic
Harvard Medical School Surgery
Boston, MA, USA University of Massachusetts, Baystate
Medical Center
Scott A. Shainker, DO, MS
Springfield, MA, USA
The Annie and Chase Koch Chair in
Obstetrics and Gynecology Melissa H. Spiel, DO
Assistant Professor of Obstetrics, Assistant Professor
Gynecology, and Reproductive Department of Obstetrics, Gynecology,
Biology and Reproductive Biology
Beth Israel Deaconess Medical Center/ Harvard Medical School
Harvard Medical School Boston, MA, USA
Boston, MA, USA
Elizabeth A. Stier, MD
Alireza A. Shamshirsaz, MD Professor
Associate Professor, Fetal surgeon/ Department of Obstetrics and
Maternal Fetal Medicine Gynecology
Chair, Fetal Center Steering Committee Boston University School of
Chief, Division of Fetal Therapy and Medicine
Surgery Boston, MA, USA
Contributors xxv
Julie Stone, MD Paul Tyan, MD, MSCR

Fellow Obstetrics and Gynecology Physician
Department of Maternal Fetal Medicine Department of Obstetrics and
Tufts Medical Center Gynecology
Boston, MA, USA Capital Women’s Care
Leesburg, VA
Leanna Sudhof, MD
Attending Physician Judith Volkar, MD
Department of Obstetrics and Assistant Professor
Gynecology University of Pittsburgh
Beth Israel Deaconess Medical Center Medical School
Boston, MA, USA Pittsburgh, PA, USA
Monique Swain, MD Neeta L. Vora, MD
Assistant Professor Associate Professor
Henry Ford Hospital University of North Carolina
Detroit, MI, USA Chapel Hill, NC, USA
Sarah E. Taylor, MD Megan Wasson, DO
Assistant Professor of Gynecologic Associate Professor of Obstetrics and
Oncology Gynecology
Department of Obstetrics, Gynecology, Chair of the Department of Medical
and Reproductive Sciences and Surgical Gynecology
Pittsburgh, PA, USA Mayo Clinic in Arizona
Phoenix, AZ, USA
Jessica Traylor, MD
Physician Blair J. Wylie, MD, MPH
Department of Obstetrics and Director, Division of Maternal Fetal
Gynecology Medicine
Northwestern University Feinberg Department of Obstetrics and
School of Medicine Gynecology
Chicago, IL, USA Beth Israel Deaconess Medical
Center
Susan Tsai, MD
Boston, MA, USA
Assistant Professor
Department of Obstetrics and Johnny Yi, MD
Gynecology Department of Medical and Surgical
Northwestern University Feinberg Gynecology
School of Medicine Mayo Clinic Arizona
Chicago, IL, USA Phoenix, AZ, USA
xxviContributors
Brett C. Young, MD Chloe Zera, MD, MPH

Attending Assistant Professor
Department of Obstetrics and Department of Maternal Fetal Medicine,
Gynecology Obstetrics and Gynecology
Beth Israel Deaconess Medical Beth Israel Deaconess Medical
Center Center/Harvard Medical School
Boston, MA, USA Boston, MA, USA
Mandy Yunker, DO, MSCR John Zupancic, MD, ScD
Associate Professor Associate Chief of Neonatology
Department of Obstetrics and Department of Neonatology
Gynecology Beth Israel Deaconess Medical
Vanderbilt Medical Center Center
Nashville, TN, USA Boston, MA, USA
1
Magnesium Sulphate for Seizure Prophylaxis

in Women With Preeclampsia
The MAGPIE Trial
PETER LINDNER AND SHAD DEERING
“Magnesium sulphate halves the risk of eclampsia, and probably reduces

the risk of maternal death. There do not appear to be substantive harmful
effects to mother or baby in the short term.”
—The Magpie Trial Collaborative Group1
Research Question: Do women with preeclampsia and their babies benefit

from magnesium sulphate?1
Funding: UK Medical Research Council, UK Department for International

Development, UNDP/ UNFPA/ WHO/ World Bank Special Programme of
Research, Development and Research Training in Human Reproduction
Year Study Began: 1998
Year Study Published: 2002
Study Location: 33 countries
Who Was Studied: Pregnant women with singleton or multiple gestations with
preeclampsia (blood pressure >140mmHg systolic and/or >90 mmHg diastolic
2 5 0 S tudi e s E v e r y O bst e trician - G y n e co l ogist S hou l d K now
on 2 separate occasions with documented proteinuria) who had not yet delivered
or were less than 24-hours postpartum.
Who Was Excluded: Patients with a known hypersensitivity to magnesium, his-

tory of myasthenia gravis or those in a hepatic coma at risk of renal failure were
excluded.
How Many Patients: 10,141
Study Overview: This was a randomized, double-blind, placebo-controlled trial.

See Figure 1.1
Pregnant or <24 hours

postpartum women with
preeclampsia
Randomized
Magnesium
Placebo
sulphate
Figure 1.1. Study overview: MAGPIE Trial
Study Intervention: Patients were randomized to receive a loading dose of

either magnesium sulphate or placebo, followed by 24 hours of maintenance
therapy of the same.
Magnesium toxicity was evaluated by serial reflex exams every 30 minutes and
urine output monitored hourly. Magnesium dosing was reduced by half when
there was evidence of toxicity or low urine output. If a patient had an eclamptic
seizure the trial treatment was stopped and nontrial magnesium sulphate was
started.
Follow-Up: Until discharge from the hospital
Endpoints: Primary outcomes: eclampsia, fetal death. Secondary outcomes:

Significant maternal morbidity (as individual, prespecified outcomes and as
a composite), complications of labor including cesarean section, and neonatal
morbidity.
Magnesium Sulphate for Seizure Prophylaxis in Women With Preeclampsia 3
RESULTS
• In the magnesium sulphate group, there was a 58% risk reduction of
eclampsia when compared to the placebo arm. The number needed to
treat to prevent an eclamptic seizure in women with severe preeclampsia
was 63, and 109 for mild preeclampsia.
• There was no difference in the risk of maternal death between the two
groups (relative risk [RR]: 0.55, 95% confidence interval [CI]: 0.26–1.14).
Magnesium sulphate did not affect maternal morbidity compared to the
placebo when evaluating for respiratory depression, respiratory arrest,
pulmonary edema, cardiac arrest, renal failure, or liver failure.
•
There was a lower risk of placental abruption in patients who received
magnesium sulphate prior to delivery. The article cites 12 fewer placental
abruptions per 1000 women.
• Women who received magnesium sulphate during the labor process were
noted to have a 5% higher risk of requiring a cesarean section (RR 1.05,
95% CI 1.00–1.11, p = 0.02).
• There was no difference in length of hospital stay or need for admission to
an intensive care unit between the placebo and magnesium groups.
•
There was no difference in the in utero or neonatal death rate between the
2 groups (RR: 1.02, 95% CI: 0.92–1.14).
• There was no difference in effectiveness of magnesium sulphate when
comparing intramuscular versus intravenous routes of administration.
(See Table 1.1.)
Table 1.1. Summary of Magpie Trial’s Key Findings

Outcome Magnesium Placebo p-value Relative Risk
Sulphate Arm (%) (95%
Arm (%) confidence
interval)
Eclamptic convulsion 0.8 1.9 <0.0001 0.42
(0.29–0.60)
Eclamptic convulsions in severe 1.2 2.8 Not given 0.42
preeclampsia (0.23–0.76)
Eclamptic convulsions in mild 0.7 1.6 Not given 0.42
preeclampsia (0.26–0.67)
Any serious maternal morbidity 3.9 3.6 Not given Not given
Maternal mortality 0.2 0.4 0.11 Not given
Fetal death 12.7 12.4 Not given 1.02
(0.92–1.14)
Cesarean delivery 50 48.0 0.02 Not given

Criticisms and Limitations: The most important limitation of this study

is the evolving definition of preeclampsia with and without severe features.
The Magpie study utilizes a classic definition of preeclampsia. Blood pressure
parameters and definitions of proteinuria have changed slightly since then, as
have qualifying laboratory and clinical characteristics that classify a patient
as severe. Despite these newer definitions, the benefits of magnesium remain
steadfast, and the therapy is still considered first-line treatment in the preven-
tion of eclampsia in women with preeclampsia.
Although the Magpie trial is a large, multicenter, randomized controlled
trial, the magnesium sulphate arm had a significantly higher rate of maternal
side effects such as hot flashes and nausea. Therefore, the presence of these
side effects could have inadvertently unblinded the study. It is estimated that
approximately 20% of the women allocated magnesium sulphate were able to
determine which treatment they were receiving. The clinical significance of this
remains unknown.
The study did not randomize route of administration for magnesium; there-
fore, the assumptions made about equipoise between intramuscular and intra-
venous routes of magnesium should be considered with caution; however, both
routes were used, and it is reasonable to consider the intramuscular route in the
developing world or in clinical scenarios where intravenous access is not available.
Other Relevant Studies and Information:
• A follow-up study by the Magpie Collaborative Group evaluated

long-term maternal and neonatal effects 2 years after receiving
magnesium sulphate. There was no increase in the risk of death or
disability.2
• A meta-analysis that evaluated randomized control trials that
compared magnesium sulphate with either a placebo or other
anticonvulsants was published in 2010. The study came to similar
conclusions as the Magpie trial.3
• Current American College of Obstetricians and Gynecologists (ACOG)
guidelines recommend magnesium sulphate for preeclampsia with
severe features as well as in patients with severe gestational
hypertension.4,5
• The Magpie study demonstrated that magnesium sulfate reduces
eclamptic seizure in patients with mild preeclampsia. However,
subsequent review of available trials do not demonstrate a clear
improvement in maternal or fetal outcomes in this cohort6; thus,
ACOG guidelines do not currently support the universal use of
magnesium sulfate in preeclampsia without severe features.5
Magnesium Sulphate for Seizure Prophylaxis in Women With Preeclampsia 5
Summary and Implications: Magnesium sulphate therapy reduces the risk of

eclampsia by 58% without increasing maternal or fetal morbidity.
CLINICAL CASE: POSTPARTUM MAGNESIUM

SULPHATE THERAPY FOR SEIZURE PROPHYLAXIS
Case History
A 37-year-old G2P1001 at 39+0 weeks estimated gestational age was admitted
to labor and delivery in active labor. Upon assessment she is complaining of a
severe headache that has not resolved despite pain medications and vital signs
demonstrate persistent systolic blood pressure greater than 170 mmHg. Her
prenatal course was complicated by gestational hypertension, and this preg-
nancy was conceived with the aid of in vitro fertilization.
Based on the findings of the Magpie trial, how should this patient be treated?
Suggested Answer
Initiation of magnesium sulfate is considered standard of care for patients with
hypertensive diseases of pregnancy with severe features. In this case, the pa-
tient has severe range hypertension and a persistent headache. The Magpie
trial demonstrated a reduced risk of eclamptic convulsions with magnesium
sulfate. There is no difference in the efficacy of intramuscular magnesium sul-
phate versus intravenous administration, but intravenous administration is
preferred due to irritation with intramuscular administration. In addition to
initiating magnesium sulphate, prompt anti-hypertensive therapy should be
initiated in this scenario.
References
1. Altman D, Carroli G, Duley L, Farrell B, Moodley J, Neilson J, Smith D; Magpie
Trial Collaboration Group. Do women with pre-eclampsia, and their babies, benefit
from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial.
Lancet 2002 Jun 1;359(9321):1877–1890. doi:10.1016/s0140-6736(02)08778-0.
PMID:12057549.
2. Magpie Trial Follow-Up Study Collaborative Group. The Magpie trial: a randomized
trial comparing magnesium sulphate with placebo for pre-eclampsia. Outcome for
women at 2 years. BJOG 2007;114:300–309.
3. Duley L, Gülmezoglu AM, Henderson-Smart DJ, Chou D. Magnesium sulphate and
other anticonvulsants for women with pre-eclampsia. Cochrane Database Sys Rev.
2010;11:CD000025.
4. American College of Obstetricians and Gynecologists, College of Obstetricians and

Gynecologists, Task Force on Hypertension in Pregnancy, Force on Hypertension
in Pregnancy, Task Force on Hypertension in Pregnancy, American College of
Obstetricians and Gynecologists. Hypertension in pregnancy. Report of the
American College of Obstetricians and Gynecologists’ Task Force on Hypertension
in Pregnancy. Obstetrics Gynecol. 2013;122:1122–1131.
5. Gestational Hypertension and Preeclampsia. ACOG Practice Bulletin No. 202.
American College of Obstetricians and Gynecologists. Obstet Gynecol. 2019;
133:el–e25.
6. Sibai BM. Magnesium sulfate prophylaxis in preeclampsia: lessons learned from re-
cent trials. Am J Obstet Gynecol. 2004;190(6):1520–1526. Review. PubMed PMID:
15284724.
2
Low-Dose Aspirin for the Prevention and

Treatment of Preeclampsia
The CLASP Trial
DA N I E L L E M . PA N E L L I A N D D E I R D R E J.   LY E L L
“Low-dose aspirin may be justified in women judged to be especially li-

able to early-onset pre-eclampsia severe enough to need very preterm
delivery.”
—CLASP (Collaborative Low-d ose Aspirin
Study in Pregnancy) Collaborative Group1
Research Question: Does maternal antiplatelet therapy during pregnancy de-

crease the risk of preeclampsia? Secondarily, what are the impacts of aspirin use
on duration of pregnancy, maternal hemorrhage, intrauterine growth restriction,
and other maternal and neonatal outcomes?
Year Published: 1994
Funding: The study was commercially sponsored by the Clinical Trial Service
Unit and the Radcliffe Infirmary switchboard, the UK Medical Research Council,
Sterling Winthrop, Bayer-Europe, and the European Aspirin Foundation. The
authors report that the project was completed independently of the commercial
sponsors with the exception of medication donation.
Years of Study: Women were recruited between January 1988 and December 1992.
Study Location: 213 centers in 16 countries.
Who Was Studied: Women between 12 and 32 weeks of gestation deemed to be

at risk of either preeclampsia or intrauterine growth restriction (IUGR) during
the index pregnancy. Patients either had a history of preeclampsia or IUGR in
a prior pregnancy, chronic hypertension, renal disease, advanced maternal age,
“family history,” or multiple pregnancy and were thus candidates for prophylactic
treatment or had preeclampsia or IUGR in the current pregnancy and were con-
sidered candidates for therapeutic treatment.
Who Was Excluded: Women with an increased risk of bleeding or asthma, an

allergy to aspirin, or a high likelihood of imminent delivery.
Study Overview: This was a randomized, double-blind, placebo-controlled trial.

See Figure 2.1
Pregnant women between 12–

32 weeks at risk for
preeclampsia or IUGR
Randomization
Aspirin Placebo
Figure 2.1. Study overview: the CLASP Trial
After the study was initiated, recruitment goals were expanded to 10,000
(originally 4,000) in order to better be able to detect a 25% decrease in the rare
event of stillbirth or neonatal death. The study had originally only been powered
to detect a 25% decrease in the development of preeclampsia, a 100g increase in
birth weight, and an increase of 1 day in mean duration of gestation.
Study Intervention: Women were randomized to treatment with 60 mg aspirin

daily versus a matching placebo tablet. This dose was chosen as it was thought
to balance side effects and effective inhibition of maternal cyclo-oxygenase-
dependent platelet aggregation.
Low-Dose Aspirin for the Prevention and Treatment of Preeclampsia 9
Follow-Up: 6 weeks postpartum
Endpoints: Primary outcome: a composite of development of proteinuric pree-

clampsia, IUGR, 100g birthweight difference, and 1 day difference in gestational
age at delivery. Secondary outcome: maternal or neonatal bleeding event, still-
birth or neonatal demise.
RESULTS
• A total of 6.7% of women randomized to aspirin developed proteinuric
preeclampsia versus 7.6% of those assigned to the placebo group. This
corresponds to a nonsignificant 12% decrease in the odds of developing
preeclampsia among women who received aspirin. There was a 22%
reduction among those in the “prophylaxis” arm who entered the study
prior to 20 weeks gestation (p = 0.06).
•
Women who received aspirin were significantly less likely to deliver
before 37 weeks than women who received placebo (19.7% vs. 22%,
p = 0.003).
• The mean neonatal birthweight from the aspirin group was 32g greater
than that of the control group (p = 0.05), but there was no significant
difference in IUGR rates.
• There were no significant differences in stillbirths, neonatal deaths,
abruption, antepartum hemorrhage, neonatal intraventricular hemorrhage,
or adverse maternal experiences with neuraxial anesthesia. (See Table 2.1.)
Table 2.1. Study Outcomes

Outcome Placebo (%) Aspirin (%) Odds
Reduction
Prophylactic Proteinuric 7.6 6.7 13% reduction
Group preeclampsia (NS)
Preterm delivery 19.1 17.2 12% reduction
(p = 0.03)
Therapeutic Proteiniuric 7.5 6.9 8% reduction
Group preeclampsia (NS)
Preterm delivery 22.2 19.7 21% reduction
(p = 0.03)
Abbreviation: NS, nonsignificant.

Criticisms and Limitations: Postpartum follow-up information was only avail-

able on 8,915 women; of these, only 66% achieved at least 95% medication ad-
herence. In addition, this trial was powered to detect only a 25% decrease in
stillbirth and neonatal death and as a result had limited ability to detect smaller
degrees of change in these rare outcomes. In addition, this study included two
distinct subpopulations: those receiving prophylactic aspirin and those receiving
therapeutic aspirin. Aspirin may have a differential impact on these two groups;
however, this study was not adequately powered to examine the impact on each
subpopulation alone.
• In recent years, higher doses of aspirin, up to 150 mg, have been shown
to be associated with greater reductions in preeclampsia rates.2,3
• Several meta-analyses have been published evaluating the dose and
timing of initiation of aspirin to elucidate optimal benefit. While results
have been conflicting, there is some evidence to support additional
value in initiation of aspirin prior to 16 weeks gestation.2–5
• The safety of prophylactic aspirin has been affirmed; a US Preventive
Services Task Force (USPTF) review found no increase in placental
abruption, postpartum hemorrhage, or mean blood loss.6 Several
reviews have also affirmed fetal safety, with no demonstrated increase
in fetal anomalies, ductal closure, or intracranial hemorrhage. The
American College of Obstetricians and Gynecologists (ACOG) states
that the data suggesting gastroschisis to be twice as common in women
with aspirin exposure should be interpreted with extreme caution.7
• The authors cautioned that the results of the CLASP trial justified the
use of prophylactic aspirin only in women who are at particular risk of
early-onset pre-eclampsia (before 32 weeks), but available evidence and
safety data since CLASP supports broader application of prophylactic
aspirin to women with moderate risk factors.
• Current recommendations include 81mg aspirin for women at high risk
for the development of preeclampsia and those with multiple moderate
risk factors that likely have compounding risk effect.8
Summary and Implications: This study failed to demonstrate significant

differences in the development of preeclampsia, stillbirth, or neonatal demise
with 60mg aspirin use versus placebo but did identify a trend toward a lower
incidence of preeclampsia at earlier gestational ages. Based on the results from
the CLASP trial and several other studies, the USPTF and ACOG guidelines
Low-Dose Aspirin for the Prevention and Treatment of Preeclampsia 11
currently recommend initiating aspirin therapy after 12 weeks gestation to all

women considered to be at high risk for developing preeclampsia.6–7
CLINICAL CASE
Case History
A 29-year-old healthy G3P1 presents for her first prenatal visit at 12 weeks ges-
tation. She has a history of preeclampsia with severe features in a pregnancy
two years ago, which required delivery at 34 weeks. She is worried about re-
currence of this disease. How would you counsel her regarding antepartum
management?
Suggested Answer
Based on USPTF and ACOG guidelines, this patient should be offered daily
aspirin after 12 weeks of gestation (ideally before 16 weeks), as this has been
shown to reduce rates of preeclampsia and need for preterm delivery as per the
results of CLASP trial and other studies that drive this recommendation. At
this time, both guidelines recommend a dose of 81mg.
References
1. CLASP: a randomised trial of low-dose aspirin for the prevention and treat-
ment of preeclampsia among 9364 pregnant women. CLASP (Collaborative
Low-dose Aspirin Study in Pregnancy) Collaborative Group. Lancet. 1994 Mar
12;343(8898):619–629. PMID:7906809.
2. Rolnik DL et al. Aspirin versus placebo in pregnancies at high risk for preterm pree-
clampsia. NEJM. 2017;377(7): 613–622.
3. McMaster-Fay RA, Hyett JA. Comment on: preventing preeclampsia with as-
pirin: does dose or timing matter? Am J Obstet Gynecol. 2017;217(3):383.
4. Roberge S, Nicolaides K, Demers S, Hyett J, Chaillet N, Bujold E. The role of aspirin
dose on the prevention of preeclampsia and fetal growth restriction: systematic re-
view and meta-analysis. Am J Obstet Gynecol. 2017;216(2):110–120.
5. Meher S, Duley L, Hunter K, Askie L. Antiplatelet therapy before or after 16 weeks’
gestation for preventing preeclampsia: an individual participant data meta-analysis.
Am J Obstet Gynecol. 2017;216(2):121–128.
6. Final update summary: low-dose aspirin use for the prevention of morbidity and
mortality from preeclampsia: preventive medication. U.S. Preventive Services Task
Force. September 2016.
7. Gyamfi-Bannerman C, Manuck T. Low-dose aspirin use during pregnancy. ACOG
Comm Opin 743. 2018;132(1):44–52.
8. Henderson JT, Whitlock EP, O’Connor E, Senger CA, Thompson JH, Rowland MG.
Low-dose aspirin for the prevention of morbidity and mortality from preeclampsia: a
systematic evidence review for the U.S. Preventive Services Task Force. Evidence
Synthesis No. 112. AHRQ Publication No. 14–05207-EF-1. Rockville, MD: Agency
for Healthcare Research and Quality; 2014.
3
First Trimester Hemoglobin A1 and

Risk for Major Malformation and
Spontaneous Abortion
R AC H E L B L A K E A N D C H L O E   Z E R A
“Although the risks for both adverse outcomes were markedly elevated
following a first trimester in very poor metabolic control, there was
a broad range of control over which the risks were not substantially
elevated.”
—G reene et al.1
Research Question: Among women with diabetes, is glycemic control in early

pregnancy associated with congenital malformation?
Funding: Not reported
Study Location: Joslin Diabetes Center and Brigham and Women’s Hospital
Boston, MA
Who Was Studied: All patients with insulin-dependent diabetes presenting at or

before 12 weeks of gestation
Who Was Excluded: Patients with incomplete outcomes data (N = 21)
How Many Patients: 303
Study Overview: This was a prospective study examining the relationship be-
tween first trimester glycosylated hemoglobin A1 levels in patients with pre-
existing insulin-controlled diabetes. See Figure 3.1
Pregnant women with

insulin-dependent diabetes
≤12 weeks’ gestation
Spontaneous abortion Major malformation No major malformation
Figure 3.1. Study overview
Routine ultrasounds were performed on all patients by one author who was
blinded to first trimester HbA1 value. First trimester spontaneous abortion
was defined as serial ultrasound demonstrating empty intrauterine gestational
sac or fetus without cardiac motion or histologic identification of trophoblast.
Malformations were considered major if they were fatal, required surgery, or had
significant “anatomic or cosmetic” impact.
Parametric tests were used to calculate the risk ratios for spontaneous abortion
and major malformations stratified by first trimester HbA1.
Follow-Up: Congenital anomalies assessed by clinical examination prior to

newborn hospital discharge; for subjects with heart murmur identified on new-
born exam, there was a follow-up call to the patient or pediatrician to determine
whether a cardiac anomaly was identified post-discharge.
Endpoints: Primary outcomes were first-trimester spontaneous abortion, and

major congenital malformation (fatal, required surgery to correct, or were of
major anatomic or cosmetic importance).
First Trimester Hemoglobin A1 and Risk for Major Malformation and Spontaneous Abortion 15
RESULTS
• Thirty-five percent of the total patient population had a first trimester
HbA1 greater than 9 standard deviations above the mean, and 14% were
above 12 standard deviations above the mean. (See Table 3.1.)
• Ten patients were lost to follow-up (mean HbA1 12.0%), and nine patients
were known to have transferred their care to other physicians during the
study period (mean HbA1 9.6%).
•
There were a total of 20 major malformations diagnosed, of which 8 were
considered “fatal.” Five of those patients elected termination.
• The most common major fatal malformations were Tetralogy of Fallot,
anencephaly, and diaphragmatic hernia. The most common nonfatal
malformations were ventricular septal defect, unilateral renal agenesis, and
anomalous vertebrae.
• There were no differences in maternal age, White classification, or diabetes
score between those with a fetal malformation or spontaneous abortion
and those without.
• The mean HbA1 value was significantly lower (p <0.005) among
patients in the no major malformations group (9.9%) compared to that
of the major malformations (12.4%) and spontaneous abortion group
(11.6%). There was no significant difference between the HbA1 levels of
patients with major malformations (12.4%) compared to patients with
spontaneous abortions (11.6%).
• There was an association of HbA1 with risk for spontaneous abortion,
particularly ≥11.1%.
• The risk for major malformations was also associated with HbA1 ≥12.8%.
Table 3.1. Results
First Trimester Approximate Risk Ratio (95% CI) Risk Ratio (95%
HbA1 (%) HbA1c (%) for Spontaneous CI) for Major
( James 1981) Abortion Malformation
<9.3 6.5 1.0 (ref) 1.0 (ref)
9.4–11.0 6.6–7.9 0.7 (0.3–1.6) 1.7 (0.4–1.7)
11.1–12.7 8.0–9.3 1.98 (1.03–3.38) 1.4 (0.3–8.3)
12.8–14.4 9.4–-10.8 2.9 (1.4–5.8) 12.8 (4.7–35.0)
>14.4 >10.8 3.0 (1.3–7.0) 13.2 (4.3–40.4)

Criticisms and Limitations: There is likely a bias toward patients with relatively

well-controlled diabetes in this cohort, suggested by the mean HbA1 of 12%
among patients lost to follow-up. Outcome ascertainment may also have been bi-
ased, as women who experienced miscarriage prior to establishing care were not
enrolled, and determination of malformations was limited to prenatal ultrasound
and neonatal exam, with limited infant follow-up.
This study does not include a control group without diabetes, therefore one
cannot compare the risk of malformation or spontaneous abortion between
patients with well-controlled diabetes and those without diabetes. Finally, there
was no adjustment for confounders that are known to be associated with risk
for pregnancy loss and/or congenital anomalies, including maternal obesity,
smoking, and age.
Interpretation of the findings must also be placed in the context of the era
during which this study was conducted. Advances in ultrasound have allowed for
much earlier identification of first trimester pregnancy as well as early assessment
of fetal anatomy. The standard of care for ultrasound-identified structural abnor-
malities now includes prenatal diagnosis with microarray, whereas in this study,
only one amniocentesis is mentioned. Notably, this amniocentesis (performed
for advanced maternal age) identified a fetus with Turner’s syndrome, which was
included in the group with first trimester losses for the purposes of analysis. It
is possible that more genetic and/or structural abnormalities would have been
identified in current clinical practice.
• While early work was conflicting, the majority of data have demonstrated
a correlation between diabetes control in the first trimester and risk for
both spontaneous abortions and major malformations. A small study
showed that the mean glycated hemoglobin A1 concentrations of women
with diabetes were higher among those with spontaneous abortions than
that of women who had continuing pregnancies.2
• Several studies have found that initial glycohemoglobin concentrations
in pregnancy above 12% or median first-trimester preprandial glucose
concentrations above 120 mg/dL are associated with increased risk
when compared to that of women without diabetes.3, 4
• The American Diabetes Associations recommends a prepregnancy A1C of
<6.5% to reduce the risk of congenital anomalies and other complications.5
The American College of Obstetricians and Gynecologists recommends
maintaining glucose control near “physiologic levels” before and
throughout pregnancy for the same reason.6
• Interestingly, numerous studies have demonstrated that the degree

of metabolic control necessary to prevent spontaneous abortions is
greater than that required to avoid major malformations; however,
the risk of either event likely increases in proportion to the degree of
blood sugar elevation.7, 8 Glycemic control in the weeks surrounding
conception seems to be most important with respect to risk for
spontaneous abortion.9 Nonetheless, in all of these studies, normal
outcomes were seen in women with a wide range of glycemic
control.10
• Of note, this study uses Hemoglobin A1, which is the first fraction to
separate on cation exchange chromatography. Subsequent fractions
are designated HbA1a, HbA1b, and HbA1c, respective of their order
of elution. Hemoglobin a1c is currently more commonly used as
a measure of blood sugar control; HgA1 and hga1c are correlated,
but HgA1 generally demonstrates a higher value than the equivalent
hemoglobin a1c.11
Summary and Implications: Despite some limitations, this study demonstrated

an association of major malformations and spontaneous abortions with degree of
glycemic control in the first trimester of pregnancy. Current guidelines from the
American Diabetes Association recommend that women target a normal hemo-
globin A1c (<6.5) prior to pregnancy.9
CLINICAL CASE: FIRST TRIMESTER HBA1

AND RISK FOR FETAL MALFORMATIONS AND
SPONTANEOUS ABORTION
Case History
A 34-year-old G1 with type 1 diabetes presents to your office at 8 weeks ges-
tation with an unplanned but desired pregnancy. She is concerned about her
risk for miscarriage and fetal congenital anomalies, because her HbA1c drawn
last week at her endocrinologist’s office was 8.5%. You look at her continuous
glucose monitor download with her and note that her blood sugars have been
within her target range since she adjusted her pump settings at that visit. She
asks you if could estimate her risk of having a major congenital defect since she
is aware that her risk might be higher than average.
Suggested Answer
This study, like many others, does show an association with risk for preg-
nancy loss and congenital anomalies with elevated first trimester HbA1 values.
However, it is important to note that most women had normal pregnancies,
even within a cohort of women with a wide range of HbA1. These data do not
allow us to estimate what percentage of adverse pregnancy outcomes should
be considered a result of glycemic control alone, as there are miscarriages and
congenital anomalies among women with diabetes that are not attributable to
glycemic control and therefore may even overestimate her individual risk.
It is important when counseling women with diabetes that while they are
at risk for adverse pregnancy outcomes, the majority of women have normal
pregnancies. Even in unplanned pregnancies in which glycemic control is sub-
optimal prior to conception, good glycemic control in the late first trimester
may modify the risk for structural anomalies. A multidisciplinary approach to
optimizing the care for women with diabetes often results in healthy pregnan-
cies with term delivery.
References
1. Greene MF, Hare JW, Cloherty JP, Benacerraf BR, Soeldner JS. First-trimester he-
moglobin A1 and risk for major malformation and spontaneous abortion in diabetic
pregnancy. Teratology. 1989 Mar;39(3):225–231. doi:10.1002/tera.1420390303.
PMID:2727930.
2. Miodovnik M, Mimouni F, Tsang RC, Ammar E, Kaplan L, Siddiqi TA. Glycemic
control and spontaneous abortion in insulin-dependent diabetic women. Obstet
Gynecol. 1986 Sep;68(3):366–369.
3. Miodovnik M, Skillman C, Holroyde JC, Butler JB, Wendel JS, Siddiqi TA.
Elevated maternal glycohemoglobin in early pregnancy and spontaneous abor-
tion among insulin-dependent diabetic women. Am J Obstet Gynecol. 1985 Oct
15;153(4):439–442.
4. Rosenn B, Miodovnik M, Combs CA, Khoury J, Siddiqi TA. Glycemic thresholds for
spontaneous abortion and congenital malformations in insulin-dependent diabetes
mellitus. Obstet Gynecol. 1994 Oct;84(4):515–520.
5. American Diabetes Association. 14. Management of Diabetes in Pregnancy: Standards
of Medical Care in Diabetes-2020. Diabetes Care. 2020 Jan;43(Suppl 1):S183–S192.
doi:10.2337/dc20-S014. PMID:31862757.
6. American College of Obstetricians and Gynecologists’ Committee on Practice
Bulletins— Obstetrics. ACOG Practice Bulletin No. 201: Pregestational
Diabetes Mellitus. Obstet Gynecol. 2018;132(6):e228– e248. doi:10.1097/
AOG.0000000000002960
7. Greene MF. Spontaneous abortions and major malformations in women with dia-
betes mellitus. Semin Reprod Endocrinol. 1999;17(2):127–136.
8. Combs CA, Kitzmiller JL. Spontaneous abortion and congenital malformations in

diabetes. Baillieres Clin Obstet Gynaecol. 1991 Jun;5(2):315–331.
9. Miodovnik, M. Preconceptional metabolic status and risk for spontaneous abortion
in insulin-dependent diabetic pregnancies. Am J Perinatol. 1988 Oct;5(4):368–373.
10. Langer O. A spectrum of glucose thresholds may effectively prevent complications in
the pregnant diabetic patient. Semin Perinatol. 2002 Jun;26(3):196–205.
11. Peterson KP, Pavlovich JG, Goldstein D, Little R, England J, Peterson CM. What is
hemoglobin A1c? An analysis of glycated hemoglobins by electrospray ionization
mass spectrometry. Clin Chemistry. 1998;44(9):1951–1958. PMID 9732983
4
Effect of Treatment of Gestational Diabetes

Mellitus on Pregnancy Outcomes
The ACHOIS Trial
A L E X A N D R A B E L C H E R -O B E J E R O -PA Z A N D
AV I VA L E E -PA R R I T Z
“Our results indicate that treatment of gestational diabetes in the form of

dietary advice, blood glucose monitoring, and insulin therapy as required
for glycemic control reduces the rate of serious perinatal complications
without increasing the risk of cesarean delivery.”
—ACHOIS Trial Group1
Research Question: Does the treatment of woman with gestational diabetes re-
duce the risk of perinatal complications and affect maternal outcomes, mood,
and quality of life?
Funding: National Health and Medical Research Council Australia, the Queen
Victoria Hospital Research Foundation
Study Location: 18 sites in Australia and the United Kingdom

Effect of Treatment of Gestational Diabetes Mellitus on Pregnancy Outcomes 21
Who Was Studied: Patients with singleton or twin pregnancy between 16 and
30 weeks gestation with a glycemic response to a standard oral glucose-tolerance
test that was intermediate between the normal and diabetic response, defined as
(1) having one or more factors for gestational diabetes or (2) a positive 50-g oral
glucose challenge test (>140mg/dL after 1 hour) and having a 75-g oral glucose
tolerance test with a 2-hour value of >140mg/dL to <190mg/dL.
Who Was Excluded: Patients with previously treated gestational diabetes, a gly-
cemic response indicating diabetes, or active chronic systemic disease (with the
exception of essential hypertensive disease).
Study Overview: See Figure 4.1
Women with abnormal glucose screening test
Intervention Group
(dietary advice, blood glucose
Routine Care
monitoring, and insulin
therapy)
Figure 4.1 Study overview: the ACHOIS Trial
Study Intervention: Patients were randomized to either the intervention

group or routine care. Interventions included dietary advice from a qualified
dietitian and instruction on how to self-monitor glucose levels 4 times daily
until they reached target ranges for 2 weeks. Insulin therapy was initiated
based on elevated glucose levels. Patients in the routine care group and their
caregivers were not informed of the diagnosis of glucose intolerance of preg-
nancy and were not provided with intervention or treatment, replicating the
standard of care at the time.
Follow-Up: Enrollment (approximately 29 weeks gestational age) until 3 months

postpartum
Endpoints: Primary infant outcomes: Serious perinatal injury (i.e., death, shoulder

dystocia, bone fracture, and nerve palsy), admission to the neonatal nursery,
and jaundice requiring phototherapy. Primary maternal outcomes: the need for
induction of labor, the need for cesarean birth, maternal physical and mental health
status. Secondary infant outcomes: gestational age at birth, birth weight and other
measures of health. Maternal secondary outcomes: mode of delivery, maternal
weight gain, number antenatal admissions, and other complications.
RESULTS
• Rates of serious perinatal outcomes were significantly lower in the
intervention group (1%) compared to the routine care group (4%).
However, rates of admission to the neonatal nursery were significantly
higher among women in the intervention group (71%) than the routine
care group (61%). Infants in the intervention group were less likely to be
large for gestational age, and less likely to be macrosomic (both p <0.001).
(See Table 4.1.)
• Infants born to mothers in the intervention group had lower birth weights
when compared to those who receive routine care (p <0.0001) and were
born at earlier gestational ages (p =0.01). In addition, they were more
likely to undergo induction of labor (p <0.001).
• Treatment of gestational diabetes did not have any effect on the need for
treating neonatal hypoglycemia.
Table 4.1. Summary of Infant and Maternal Primary and Secondary

Clinical Outcomes in ACHOIS Study
Outcome Intervention Group Routine Care Group Adjusted
(n = 506) (n = 524) p-valuea
Neonatal
Any serious perinatal 7 (1%) 23 (4%) 0.01
outcomeb
Death 0 (0%) 5 (1%) 0.07
Birth weight in g (±SD) 3335±551 3482±660 <0.001
Macrosomiac 49 (10%) 110 (21%) <0.001
Maternal
Induction of labor 189(39%) 150 (29%) <0.001
Cesarean delivery 152(31%) 164 (32%) 0.73
Weight gain in kg (±SD) 8.1±0.3 9.8±0.4 0.01
Preeclampsia 58 (12%) 93 (18%) 0.02
a
Adjusted for maternal age, race or ethnic group, and parity. b Included perinatal death,
shoulder dystocia, bone fracture, and nerve palsy. cDefined as a birth weight of 4kg or
greater.
• In a subgroup analysis of patients who completed quality of life (QOL)

surveys, those in the intervention group had similar or higher QOL
scores than the routine care group, suggesting that receiving a diagnosis of
gestational diabetes did not diminish QOL.
Criticisms and Limitations:
• This study used the World Health Organization definition of gestational

diabetes, which expanded in 1998 from patients with an intermediate
glycemic response to any glycemic response above normal, including
patients with a “diabetic” response. Women with severe glycemic
intolerance, defined here as a glycemic response <198mg/dl (diabetic
range) were not included; thus, the findings of the ACHOIS trial
cannot be generalized to this patient population.
• This study population was recruited over the course of 10 years,
spanning from 1993 to 2003. By the early 2000s, the use of oral agents
for gestational diabetes management was being introduced with
early studies suggesting favorable outcomes. The ACHOIS was not
designed to study this emerging shift in treatment.
• Racial and ethnic groups studied were largely homogenous with White
woman comprising ~75% of the study population, raising questions
about generalizability of the study across ethnic groups as the dynamics
of gestational diabetes is known to be different in different racial
populations, country of origin, and so on.
• The median body mass index of the study for the intervention and
routine care groups was 26.8 and 26, respectively; it may be difficult to
generalize these findings to an obese patient population.
• The results from several other randomized control trials have

further established that glycemic control of woman with mild
carbohydrate intolerance in pregnancy results in a decrease in the rate
of shoulder dystocia,2,3 preeclampsia,2,3 and birthweight greater than
4000g.2-5
• The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study
found greater risk with higher maternal glucose levels for adverse
pregnancy outcomes such as premature delivery, shoulder dystocia,
birth injury, and preeclampsia.6
Summary and Implications: The ACHOIS study is one of the first random-

ized control trials to investigate whether management of gestational diabetes can
improve perinatal outcomes. The trial found that treating gestational diabetes
is associated with improved maternal and fetal outcomes including decrease in
macrosomia, birth trauma, shoulder dystocia, and preeclampsia. This and sub-
sequent studies have shaped current ACOG guidelines, which recommend diet
modification, glucose monitoring, and, if necessary, pharmacologic management
for glycemic control in patients with gestational diabetes.7 Insulin is considered
the preferred treatment over oral medications.
CLINICAL CASE: MANAGEMENT OF GESTATIONAL

DIABETES
Case History
A 26-year-old G2P1001 at 27 weeks and 4 days with history of normal sponta-
neous vaginal delivery presents for the routine prenatal visit. Her oral glucose
tolerance test done prior to this visit suggests a diagnosis of gestational dia-
betes. Based on the ACHOIS study, what are your next steps in management?
Suggested Answer
The ACHOIS and subsequent studies demonstrated improved fetal and ma-
ternal outcomes in women with gestational diabetes with frequent blood sugar
monitoring, proactive diet and exercise management, and initiation of phar-
macologic management should glucose levels continue to be elevated. Patients
should be counseled about the risks of uncontrolled glucose, particularly the
increased risks of preeclampsia, shoulder dystocia, and macrosomia.
References
1. Crowther CA, Hiller JE, Moss JR, et al. Effect of treatment of gestational dia-
betes mellitus on pregnancy outcomes. N Engl J Med. 2005;352(24):2477–2486.
doi:10.1056/NEJMoa042973
2. Bevier WC, Fishcer R, Jovanovic L. Treatment of women with an abnormal glu-
cose challenge test (but a normal oral glucose tolerance test) decreases the risk of
macrosomia. Am J Perinatol. 1999;16:269–275.
3. Landon MB, Spong CY, Thom E, Carpenter MW, Ramin SM, Casey B, et al., Eunice
Kennedy Shriver National Institute of Child Health and Human Development
Maternal-Fetal Medicine Units Network. A multicenter, randomized trial of treat-
ment for mild gestational diabetes. N Engl J Med. 2009;361:1339–1348.
4. Bonomo M, Corica D, Mion E, Goncalves D, Motta G, Merati R, et al. Evaluating

the therapeutic approach in pregnancies complicated by borderline: glucose intoler-
ance: a randomized clinical trial. Diabet Med. 2005;22:1536–1541.
5. Garner P, Okun N, Keely E, Wells G, Perkins S, Sylvain J, et al. A randomized con-
trolled trial of strict glycemic control and tertiary level obstetric care versus routine
obstetric care in the management of gestational diabetes: a pilot study. Am J Obstet
Gynecol. 1997;177:190–195.
6. HAPO Study Cooperative Research Group. Metzger BE, Lowe LP, Dyer AR,
Trimble ER, Chaovarindr U, Coustan DR, Hadden DR, McCance DR, Hod M,
McIntyre HD, Oats JJ, Persson B, Rogers MS, Sacks DA. Hyperglycemia and adverse
pregnancy outcomes. N Engl J Med. 2008 May 8;358(19):1991–2002.
7. ACOG Practice Bulletin No. 190 Summary: gestational diabetes mellitus. Obstet
Gynecol. 2018;131(2):406–408.
5
Reduction of Maternal–Infant Transmission

of HIV Type 1 With Zidovudine Treatment
E L I Z A R O D R I G U E M C E LW E E A N D P O O JA   K . M E H TA
“Our study indicates that substantial reduction in the rate of maternal–

infant transmission of HIV is possible with minimal short-term toxicity
to mother or child.”
—P ediatric AIDS Clinical Trials Protocol 76 Study Group1
Research Question: Does administration of antepartum, intrapartum, and neo-

natal zidovudine safely and effectively reduce the risk of maternal–infant human
immunodeficiency virus type 1 (HIV-1) transmission?
Funding: The trial was supported by the National Institute of Allergy and Infectious
Diseases, the National Institute of Child Health and Human Development, the
Burroughs Wellcome Company in and the Agence Nationale de Recherche sur
le SIDA
Study Location: 59 centers in France and the United States
Who Was Studied: HIV-infected pregnant women between 14 and 34 weeks

gestational age who had a CD4+ T-lymphocyte count above 200 cells per cubic
millimeter and had no existing indication for antiretroviral therapy.
Reduction of Maternal–Infant Transmission of HIV Type 1 With Zidovudine Treatment 27
Who Was Excluded: Pregnant women who demonstrated specific lab abnormal-
ities (anemia, neutropenia, thrombocytopenia, renal impairment, or abnormal
liver function); had received any antiretroviral treatment during the pregnancy;
had previously received immunotherapy, anti-HIV vaccines, chemotherapeutic
agents, or radiation therapy; had pregnancies with life-threatening anomalies
oligohydramnios in the second trimester; had unexplained polyhydramnios in
the third trimester; had evidence of fetal anemia; or had conditions that could
increase fetal concentration of zidovudine or its metabolites.
Study Overview: This randomized, double-blind, placebo-controlled trial was

discontinued at the first interim analysis, which showed that a three-part zidovu-
dine regimen was effective in reducing HIV vertical transmission. See Figure 5.1
HIV-Infected Pregnant Patients

between 14–34 weeks
Randomized
Zidovudine Placebo
Figure 5.1. Study overview; the Pediatric AIDS Clinical Trial Group Protocol 76
Study Group
Study Intervention: Participants were stratified by gestational age. In the zi-

dovudine arm, mothers received a standardized regimen of oral zidovudine
antepartum (100mg 5 times daily) during pregnancy and a weight-based contin-
uous intravenous (IV) zidovudine administration intrapartum. Infants born to
mothers in this arm received a weight-based regimen of zidovudine for the first
6 weeks of life. Participants and their infants in the placebo arm did not receive
antiviral treatment.
Follow-Up: Participants were monitored every 4 weeks until 32 weeks gestation,

and then every 4 weeks until delivery. Sonograms were obtained before study
entry and every 4 weeks after 28 weeks gestation. Women were seen 6 weeks and
6 months after delivery. Infants were followed through 18 months of life.
Endpoints: Primary outcome: Percentage HIV-infected infants at 18 months.

Secondary outcomes: Maternal and infant adverse events (e.g., fetal or neonatal
death) and toxic effects (e.g., anemia, neutropenia, thrombocytopenia, serum
electrolyte abnormalities).
RESULTS
• The median gestational age of the live-born infants was 39 weeks; women
received the study drug for a median of 11 weeks before giving birth. (See
Table 5.1.)
• There was a 67.5% relative reduction in HIV transmission risk from
mother to child in the zidovudine group (p = 0.00006). The study was
discontinued early as this result crossed the predetermined interim
analysis stopping p-value of 0.005.
• An increase in CD4+ lymphocyte values was observed in both study
groups but was greater in the zidovudine group (141 vs. 101 cells per
cubic millimeter, p = 0.02).
•
The hemoglobin concentration at birth of infants in the zidovudine group
was significantly lower than placebo, with maximal difference at 3 weeks
of age and no difference by 12 weeks of age. Zidovudine treatment was not
associated with neonatal death, premature birth, fetal growth, or structural
abnormalities.
• The majority of maternal adverse effects that were reported were
determined to be associated with obstetric complications and occurred in
both placebo and intervention groups.
Table 5.1. Key Study Findings

Zidovudine Placebo
n = 180 n = 183
HIV infected 13 40
Probability of maternal–fetal HIV transmission 8.3% 25.5%
at 18 monthsa
a
Calculated by Kaplan-Meier method.

Criticisms and Limitations: Women were enrolled after the first trimester to

avoid potential impact on fetal organogenesis, due to lack of safety data. This
limited early exposure to zidovudine and may have impacted the rate of HIV
transmission. Furthermore, treatment efficacy may be different in women with
more advanced HIV disease, who may have increased viral load or zidovudine
resistance. HIV initial viral load and viral load response were not assessed in this
study; it is now widely acknowledged that viral load significantly impacts vertical
transmission risk.
A debate emerged after the publication of this trial about the ethics of short-
course zidovudine trials and withholding treatment from pregnant participants
in the placebo arm.
• Further studies have since confirmed greater efficacy of combination

antiretroviral therapy compared to zidovudine when administered
antepartum to pregnant women (regardless of CD4+ T lymphocyte
count and HIV viral load),2 and with postpartum administration to
infants.3 Combination treatment regimens, however, are associated with
a higher risk for neonatal and maternal adverse outcomes, including low
birth weight and elevation in maternal liver enzymes.4
• The French Perinatal Cohort5 evaluated HIV mother-to-child
transmission in more than 11,000 HIV-positive pregnant women. The
study demonstrated no significant reduction in HIV transmission with
the administration of intrapartum zidovudine in the setting of a low
HIV viral load (HIV RNA <1,000 copies/mL). This study suggests
intrapartum antiretroviral therapy is not necessary for preventing
vertical transmission in pregnant women with low viral load and
further emphasizes the benefit of intrapartum therapy in the setting of
higher viral loads.
• Current US treatment guidelines recommend that IV zidovudine
should be administered to women with HIV RNA >1,000 copies/
mL near delivery (or unknown HIV RNA levels), regardless of
antepartum regimen. Antiretroviral therapy is not necessary for
women receiving antiviral therapy with HIV RNA ≤1,000 copies/
mL in late pregnancy and/or near delivery and for whom there are
no concerns about adherence to or tolerance of their regimens but
may be considered taking into account recent adherence, individual
preferences, and provider judgement.6
Summary and Implications: This study demonstrated that a combination of

antepartum, intrapartum, and neonatal antiretroviral therapy reduced peri-
natal transmission of HIV in women with mildly symptomatic disease and no
prior antiretroviral treatment. This hallmark study is the stepping stone to ad-
ditional work supporting the premise that antiretroviral therapy administered
during pregnancy reduces risk of vertical transmission.1
CLINICAL CASE
A 27-year-old G2P1001 at 15 weeks gestational age with intrauterine preg-
nancy presents for antenatal care. She is newly diagnosed with HIV, with an
elevated viral load of 2500 and CD4+ T-lymphocyte count of 235. She is con-
cerned about HIV transmission to her infant. She asks about safety and efficacy
of starting medication to help her and her baby at her current gestational age.
Suggested Answer
This study, as well as several others, demonstrates a significant decrease in ver-
tical HIV transmission with the administration of antiretroviral therapy during
the antepartum, intrapartum, and neonatal periods. Per current guidelines, a
three-drug treatment regimen antepartum is recommended to reduce mother-
to-child transmission, including intrapartum zidovudine administration as in-
dicated based on viral load at the time of delivery.6
This theoretical patient has been newly diagnosed with HIV infection. She
should be started on antiretroviral therapy at the earliest possible opportunity,
which should be continued through delivery to decrease transmission of HIV
to the child. Viral load should be reassessed at least once per trimester and
again prior to delivery to inform decisions about intrapartum zidovudine ad-
ministration and mode of delivery.
References
1. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal–infant trans-
mission of human immunodeficiency virus type 1 with zidovudine treatment.
Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med.
1994;331(18):1173–1180.
2. Cooper ER, Charurat M, Mofenson L, Hanson IC, Pitt J, Diaz C, Blattner W.
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.
3. Nielsen- Saines K, Watts DH, Veloso VG, et al. Three postpartum anti-
retroviral regimens to prevent intrapartum HIV infection. N Engl J Med.
2012;366(25):2368–2379.
4. Fowler MG, Qin M, Fiscus S, Currier J, et al. Benefits and risks of antiretroviral
therapy for perinatal HIV prevention. N Engl J Med. 2016;375:1726–1737.
5. Briand N, Warszawski J, Mendelbrot L, et al. Is intrapartum intravenous Zidovudine
for prevention of mother-to-child HIV-1 transmission still useful in the combination
antiretroviral therapy era? Clin Infect Dis. 2013 Sep;57(6):903–914.
6. Panel on Treatment of Pregnant Women with HIV Infection and Prevention of
Perinatal Transmission. Recommendations for the Use of Antiretroviral Drugs in
Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV
Transmission in the United States. Available at http://aidsinfo.nih.gov/contentfiles/
lvguidelines/PerinatalGL.pdf
6
The Length of the Cervix and the Risk

of Spontaneous Preterm Delivery
J U L I E STO N E A N D M I C H A E L H O U S E
“There is a continuum of cervical performance that is reflected function-

ally by the gestational age of the infant delivered prematurely and ana-
tomically by the length of the cervix.”
—JD Iams et al.1
Research Question: Is a short cervix associated with an increased risk of spon-

taneous preterm birth?
Funding: The Eunice Kennedy Shriver National Institute of Child Health and
Human Development
Year Study Began: 1992–1994
Year Study Published: 1996
Study Location: 10 university-affiliated prenatal clinics in the Maternal Fetal

Medicine Network of the National Institute of the Child Health and Human
Development.
Who Was Studied: Women with singleton pregnancies before 24 weeks’ gesta-
tion were recruited.
The Length of the Cervix and the Risk of Spontaneous Preterm Delivery 33
Who Was Excluded: Patients with multiple gestation, cerclage, placenta previa,
or a major fetal anomaly were excluded.
How Many Patients: 2,915
Study Overview: See Figure 6.1
Cervical length
measured at 22–24
weeks
Cervical length
measured at 28
weeks
Primary Outcome:
Preterm birth
before 35 weeks
Figure 6.1 Study overview
Cervical length and funneling were evaluated as potential variables predic-

tive of preterm delivery. All patients had a real-time transvaginal ultrasound
performed with the bladder emptied between 22–24 6/7 weeks’ gestation (24-week
visit) and again 4 weeks later (28-week visit). Cervical length in centimeters was
recorded. Also, the presence or absence of a funnel was recorded. A digital cer-
vical exam preceded each ultrasound measurement, and the Bishop score was
correlated with cervical length.
Follow-Up: The first study visit occurred between 22–24 6/7 weeks’ gestation.
Subsequent visits were at 2, 4, and 6 weeks afterwards.
Endpoints: The primary outcome was spontaneous preterm birth before 35

weeks’ gestation. Spontaneous preterm birth was defined as preterm birth arising
from preterm labor or preterm premature rupture of the membranes.
RESULTS
• The key finding of the study was that a short cervix is associated with
subsequent preterm birth. The relative risk of preterm birth increased as
cervical length decreased, see Table 6.1 and Figure 6.2.
34 5 0 S t u dies E v er y O bstetrician - G y necologist S ho u ld K now
Table 6.1. Relative Risk of Preterm Birth for Different

Cervical Length Cutoff Values
Short Cervix Length % of Women Relative Risk of Spontaneous
Cutoff (mm) Preterm Birtha
(95% Confidence Interval)
40 75 1.98 (1.2–3.3)
35 50 2.35 (1.4–3.9)
30 25 3.79 (2.3–6.2)
26 10 6.19 (3.8–10.0)
22 5 9.49 (6.0–15.2)
13 1 13.99 (7.9–24.8)
a
Relative risk of preterm birth compared to women with cervical length over 40 mm
(above the 75th percentile).
Relative risk of preterm birth before 35 weeks

16
14
Relative Risk of preterm birth
12
10
0
10 20 30 40
Cervical Length at 24 weeks (mm)
Figure 6.2 The relative risk of preterm birth as a function of cervical length. As cervical
length decreases, the relative risk of preterm birth before 35 weeks increases, indicating
an inverse relationship.
• There were small differences in cervical length between nulliparous and

multiparous women, but the differences were clinically insignificant. Data
for parous and nulliparous women were combined. The mean ± standard
deviation cervical length at 24 weeks was 35.2 ± 8.3mm.
• Among parous women, the number of previous deliveries had no effect on
the length of the cervix.
•
Cervical shortening between 24 to 28 weeks was associated with a modest
increase in preterm birth risk compared to no shortening (relative risk
2.03; 95% confidence interval 1.28–3.22).
• Receiver-operating-characteristic curves suggested cervical length

less than 25mm as a threshold value for clinical use. When the
cervix was less than 25mm at 24 weeks, the sensitivity, specificity,
positive predictive value, and negative predictive value for predicting
preterm birth before 35 weeks was 37.3%, 92.2%, 17.8%, and 97%,
respectively.
•
Funneling was a significant predictor of preterm birth even after
controlling for cervical length. The data on funneling, however,
showed substantial variation among study centers.
Criticisms and Limitations: The pathophysiology of cervical shortening is

difficult to establish. Preterm birth is a syndrome caused by multiple causes.2
Cervical shortening can be the final common pathway of cervical insufficiency,
intrauterine infection/inflammation, and preterm labor. Although the study es-
tablished the association of a short cervix and subsequent preterm birth, it did
not determine the cause of cervical shortening.
• Subsequent studies established that a short cervix measured earlier in

gestation (e.g., 16–18 weeks was associated with preterm birth).3
• Randomized trials used cervical shortening to target patients
appropriate for therapy to prevent preterm birth. In the setting of
a short cervix, both vaginal progesterone4 and cerclage5 have been
evaluated as interventions that may prevent preterm birth.
•
In current practice, measurement of cervical length is a central
feature of the American College of Obstetricians and Gynecologists
management protocol to prevent preterm birth.6
• When transabdominal imaging at the anatomy survey suggests a short
cervix is present, it is recommended to perform a vaginal ultrasound for
improved visualization of cervical length.6
• For women with a history of a spontaneous preterm birth, serial
transvaginal cervical length screening is recommend from 16 to 23
weeks every 1 to 2 weeks.6,7
Summary and Implications: A short cervix is associated with increased pre-

term birth risk.
This study demonstrated an inverse relationship between cervical length
and risk of preterm birth; the shortest cervix conferred the highest risk
36 5 0 S t u dies E v er y O bstetrician - G y necologist S ho u ld K now
of preterm birth. Based on this and other studies, serial cervical length
measurements are recommended for women with a history of spontaneous
preterm birth and for women with a suspected short cervix on transabdominal
ultrasound. If a short cervix is seen, vaginal progesterone and/or cervical cer-
clage may be considered to reduce the risk of preterm birth depending on the
clinical situation.
CLINICAL CASE: THE LENGTH OF THE CERVIX AND

THE RISK OF PRETERM BIRTH
Case History
A 32-year-old G3P0111 presents at 16 weeks for a new prenatal visit. She has
a history of spontaneous vaginal delivery at 31 weeks for preterm labor with
her first child. She has no significant medical or surgical history. She denies any
cramping, vaginal bleeding, or leakage of fluid. Ultrasound confirms a viable
16-week intrauterine pregnancy.
What other measurement should be obtained?
Suggested Answer
The cervical length should be measured using a transvaginal ultrasound. If
cervical length is less than 2.5 cm, cerclage can be offered. If cervical length
is greater than 2.5 cm, serial measurements should be scheduled every 1 to 2
weeks until 23 weeks to assess for cervical shortening.7
References
1. Iams JD, Goldenberg RL, Meis PJ, Mercer BM, Moawad A, Das A, et al. The
length of the cervix and the risk of spontaneous premature delivery. N Engl J Med.
1996;334:567.
2. Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science.
2014;345:760.
3. Owen J, Yost N, Berghella V, Thom E, Swain M, Dildy GA, 3rd, et al. Mid-trimester
endovaginal sonography in women at high risk for spontaneous preterm birth.
JAMA. 2001;286:1340.
4. Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH, 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;357:462.
5. Owen J, Hankins G, Iams JD, Berghella V, Sheffield JS, Perez-Delboy A, 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;201:375.
6. ACOG Practice Bulletin No. 130: prediction and prevention of preterm birth. Obstet
Gynecol. 2012;120:964.
7. Iams JD, Berghella V. Care for women with prior preterm birth. Am J Obstet Gynecol.
2010;203:89.
7
Intramuscular Progesterone for the Prevention

of Recurrent Preterm Birth
E M I LY A . O L I V E R A N D A M A N DA R O M A N - C A M A R G O
“Weekly injections of 17P resulted in a substantial reduction in the

rate of recurrent preterm delivery among women who were at particu-
larly high risk for preterm delivery and reduced the likelihood of several
complications in their infants.”
—PJ Meis et al.1
Research Question: Does 17 alpha-hydroxyprogesterone caproate (17P) pre-

vent recurrent preterm delivery?1
Funding: National Institute of Child Health and Human Development
Year Study Began: 1998a
Study Location: 19 participating centers in the United States
Who Was Included: Pregnant women between 16 and 20 weeks with a history
of spontaneous preterm delivery (between 20 and 36 completed weeks).
The study was started in 1998; data prior to 1999 was not included.
a
Intramuscular Progesterone for the Prevention of Recurrent Preterm Birth 39
Who Was Excluded: Women whose pregnancies were complicated by a mul-

tifetal gestation; known fetal anomaly; who were on progesterone or heparin
treatment; had a cervical cerclage in place or planned, chronic hypertension on
medication, seizure disorder, or plans to deliver at another institution.
Study Overview: This was a randomized controlled trial. See Figure 7.1
Pregnant women with a history

of spontaneous preterm birth
200/7 to 166/7 weeks
Randomized
17-OH-progesterone Placebo
Figure 7.1. Study overview
Study Intervention: Participants were randomized to receive either 17P or an

identically packaged placebo. Both the patients and providers were blinded to the
group assignment. Study treatment was administered intramuscular and weekly,
from 16 weeks up to 36 weeks of gestation. The women continued to receive
standard prenatal care.
Follow-Up: Women were followed until delivery, infants were followed until dis-
charge either from the hospital in which the birth occurred, or if they were trans-
ferred, from the hospital to which they were transferred.
Endpoints: The primary outcome was preterm birth, defined as delivery be-
fore 37 weeks of gestation. Secondary outcomes included: miscarriage, still-
birth, infant outcomes including birthweight less than 2500g, necrotizing
enterocolitis, need for supplemental oxygen, intraventricular hemorrhage,
infant death.
40 5 0 S t udi e s E v e r y O bs t e t rici a n - G y n e co l ogis t S hou l d K now
RESULTS
• Frequency of preterm delivery (<37 weeks) was 36.3% in the progesterone
group versus 54.9% in the placebo group (p <0.001).
• The frequency of delivery before 35 weeks was 20.6% in the progesterone
group versus 30.7% in the placebo group (p = 0.02). The difference in
deliveries before 32 weeks was also statistically significant (11.4% vs.
19.6%, p = 0.02).
•
After adjusting for the number of prior preterm births, the relative risk of
preterm birth was 0.70 (95% confidence interval (CI); 0.57–0.85) in the
progesterone group.
•
There were no statistically significant differences in the rate of miscarriages
and stillbirths.
• There was a significant decrease in birthweight less than 2500g (relative
risk (RR) 0.66, 95% CI: 0.51–0.87) and need for supplemental oxygen
(RR 0.62, 95% CI 0.42–0.92) in the progesterone group. There were no
significant differences in the other neonatal outcomes. (See Table 7.1.)
Table 7.1. Pregnancy Outcomes According to Randomization

Progesterone Placebo Relative Risk (95%
Group (%) Group (%) Confidence Interval)
Preterm delivery before 36.3 54.9 0.66
37 weeks (0.54–0.81)
35 weeks (0.48–0.93)
32 weeks (0.37–0.91)
Birth weight <2500g 27.2 41.1 0.66
(0.51–0.87)
Birth weight <1500g 8.6. 14.6 0.62
(0.36–1.07)
Neonatal death 2.6 5.9 0.44
(0.17–1.13)

Criticisms and Limitations: This study included women with a particularly high

incidence of preterm birth, with 54.9% in the placebo controlled group having a
recurrent preterm delivery. The mean gestational age of the prior preterm birth
was 31 weeks, and half the women had a history of 2 or more preterm births. The
ability to extrapolate these results to other populations remains unknown.
Intramuscular Progesterone for the Prevention of Recurrent Preterm Birth 41
• Several trials of women with a history of prior preterm birth have

also demonstrated a significant reduction in preterm birth <37 weeks
and perinatal mortality with 17P 250 mg IM weekly compared to
placebo.2,5
• Vaginal progesterone has also been studied and generally been
demonstrated to perform more poorly or, at best, no better than 17P.3,4,6
• In 2019 the PROLONG trial (17OHPC to Prevent Recurrent Preterm
Birth in Singleton Gestations) concluded, contrary to Meis et al.,
that patients taking 17P did not have a reduction in preterm birth
or neonatal morbidity. The Meis et al. study differed from the
PROLONG trial in that (a) the incidence of recurrent preterm birth
in the placebo arm was more than 2 times that of the PROLONG
study, and (b) the racial breakdown of the study population was
much more homogenous, with <10% enrollees identified as Black in
the PROLONG trial.7
• ACOG and SMFM guidelines currently recommend 17P to be given
weekly starting between 16 to 20 weeks until 36 weeks for women with
a history of spontaneous preterm birth.8
Summary and Implications: In women with a history of spontaneous preterm

birth, weekly intramuscular 17P, starting between 16 and 20 weeks though 36
weeks’ gestation, decreases the rate of recurrent preterm birth prior to 37 weeks
compared to placebo.
CLINICAL CASE
Case History
A 23-year-old G1P0101 had an uncomplicated pregnancy until around 32
weeks. She presented with back pain and contractions and was found to be
2cm dilated. Shortly after presenting she ruptured her membranes, her con-
tractions worsened and she had a spontaneous preterm vaginal delivery.
The patient returns postpartum and would like to discuss how her next
pregnancy would be managed. Based on the results of this trial, how would
you advise this patient?
42 5 0 S t udi e s E v e r y O bs t e t rici a n - G y n e co l ogis t S hou l d K now
Suggested Answer
This trial showed that in women with a history of spontaneous preterm birth,
administering 17P intramuscularly weekly from 16 weeks’ gestational age until
36 weeks decreased the risk of preterm birth. Therefore, she should be offered
treatment with weekly 17P starting at 16 weeks until 36 weeks.
References
1. Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17
alpha-hydroxyprogesterone caproate. N Engl J Med. 2003;348(24):2379–2385.
2. Johnson JW, Austin KL, Jones GS, Davis GH, King TM. Efficacy of 17 alpha-
hydroxyprogesterone caproate in the prevention of premature labor. N Engl J Med.
1975;293(14):675–680.
3. da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M. Prophylactic administration of
progesterone by vaginal suppository to reduce the incidence of spontaneous preterm
birth in women at increased risk: a randomized placebo-controlled double-blind
study. Am J Obstet Gynecol. 2003;188(2):419–424.
4. O’Brien JM, Adair CD, Lewis DF, et al. Progesterone vaginal gel for the reduction of
recurrent preterm birth: primary results from a randomized, double-blind, placebo-
controlled trial. Ultrasound Obstet Gynecol. 2007;30(5):687–696.
5. Maher MA, Abdelaziz A, Ellaithy M, Bazeed MF. Prevention of preterm birth: a
randomized trial of vaginal compared with intramuscular progesterone. Acta Obstet
Gynecol Scand. 2013;92(2):215–222.
6. El-Gharib MN, El-Hawary. Matched sample comparison of intramuscular versus
vaginal micronized progesterone for prevention of preterm birth. J Matern Fetal
Neonatal Med. 2013;26(7):716–719.
7. Blackwell SC, Gyamfi-Bannerman C, Biggio JR Jr, et al. 17-OHPC to Prevent
Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): a multicenter,
international, randomized double-blind trial. Am J Perinatol. 2020;37(2):127–136.
8. Society of Maternal- Fetal Medicine. Progesterone and preterm birth preven-
tion: translating clinical trials data into clinical practice. Am J Obstet Gynecol. 2012
May;206(5):376–386.
8
Antibiotics for Preterm Premature Rupture

of Membranes
K AT H E R I N E S . K O H A R I A N D C H R I ST I A N M . P E T T K E R
“Antibiotic treatment of expectantly managed women with PPROM . . .

will reduce infectious and gestational age-dependent infant morbidity.”
—BM Mercer et al. 1
Research Question: Should patient’s presenting with preterm prelabor rupture

of membranes (PPROM) be given antibiotics to improve perinatal morbidity
and mortality?
Funding: National Institute of Child Health and Human Development Maternal-

Fetal Medicine Units Network
Year Study Began: 1992
Year Study Published: 1997
Study Location: 11 clinical centers in the United States
Who Was Studied: Pregnant women between 24 weeks and 32 weeks presenting
with PPROM who were being considered for expectant management.
Who Was Excluded: Patients with fever requiring antibiotics, recent antibi-
otic and/or corticosteroid use, allergies to penicillin and/or erythromycin,

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50 Studies Every Obstetrician-​Gynecologist

Constance Liu, MD, PhD

Published in the United States of America by Oxford University Press

© Oxford University Press 2021

All rights reserved. No part of this publication may be reproduced, stored in

You must not circulate this work in any other form

Library of Congress Cataloging-in-Publication Data

Printed by Marquis, Canada

Preface from the Series Editor xiii

1. Magnesium Sulphate for Seizure Prophylaxis in Women With

7. Intramuscular Progesterone for the Prevention of Recurrent

20. First-​Trimester or Second-​Trimester Screening, or Both, for Down

33. The Accuracy of Endometrial Sampling in the Diagnosis of Patients With

45. A Randomized Clinical Trial to Evaluate Optimal Treatment for

When I was a third-​year medical student, I asked one of my senior residents—​

on studies in their field. In partnership with a wonderful team of editors from

means continual attention to our foundation of evidentiary learning. We hope

Jodi F. Abbott, MD, MHCM Ashley N. Battarbee, MD, MSCR

Rachel Blake, MD Zachary Colvin, DO

Hugh Ehrenberg, MD Alison A. Garrett, MD

Christine Helou, MD Matthew K. Janssen, MD

Tana Kim, MD Constance Liu, MD, PhD

Jacqueline M. Mills, MD, MPP Alexander Olawaiye, MD, FRCOG,

John Petrozza, MD Amanda Roman-​Camargo, MD

Elizabeth B. Schmidt, MD, MSCI, Director, Fetal Surgery Fellowship

Julie Stone, MD Paul Tyan, MD, MSCR

Brett C. Young, MD Chloe Zera, MD, MPH

Magnesium Sulphate for Seizure Prophylaxis

“Magnesium sulphate halves the risk of eclampsia, and probably reduces

Research Question: Do women with preeclampsia and their babies benefit

Funding: UK Medical Research Council, UK Department for International

Year Study Began: 1998

Year Study Published: 2002

Study Location: 33 countries

Who Was Excluded: Patients with a known hypersensitivity to magnesium, his-

How Many Patients: 10,141

Study Overview: This was a randomized, double-blind, placebo-controlled trial.

Pregnant or <24 hours

Figure 1.1. Study overview: MAGPIE Trial

Study Intervention: Patients were randomized to receive a loading dose of

Follow-​Up: Until discharge from the hospital

Endpoints: Primary outcomes: eclampsia, fetal death. Secondary outcomes:

Table 1.1. Summary of Magpie Trial’s Key Findings

Criticisms and Limitations: The most important limitation of this study

Other Relevant Studies and Information:

• A follow-​up study by the Magpie Collaborative Group evaluated

Summary and Implications: Magnesium sulphate therapy reduces the risk of

CLINICAL CASE: POSTPARTUM MAGNESIUM

4. American College of Obstetricians and Gynecologists, College of Obstetricians and

Low-​Dose Aspirin for the Prevention and

“Low-​dose aspirin may be justified in women judged to be especially li-

Research Question: Does maternal antiplatelet therapy during pregnancy de-

Study Location: 213 centers in 16 countries.

Who Was Studied: Women between 12 and 32 weeks of gestation deemed to be

Who Was Excluded: Women with an increased risk of bleeding or asthma, an

How Many Patients: 9,364

Study Overview: This was a randomized, double-​blind, placebo-​controlled trial.

Pregnant women between 12–

Figure 2.1. Study overview: the CLASP Trial

50 Studies Every Obstetrician-Gynecologist

Published in the United States of America by Oxford University Press

© Oxford University Press 2021

All rights reserved. No part of this publication may be reproduced, stored in

You must not circulate this work in any other form

20. First-Trimester or Second-Trimester Screening, or Both, for Down

When I was a third-year medical student, I asked one of my senior residents—

Jodi F. Abbott, MD, MHCM Ashley N. Battarbee, MD, MSCR

Rachel Blake, MD Zachary Colvin, DO

Hugh Ehrenberg, MD Alison A. Garrett, MD

Christine Helou, MD Matthew K. Janssen, MD

Tana Kim, MD Constance Liu, MD, PhD

Jacqueline M. Mills, MD, MPP Alexander Olawaiye, MD, FRCOG,

John Petrozza, MD Amanda Roman-Camargo, MD

Julie Stone, MD Paul Tyan, MD, MSCR

Brett C. Young, MD Chloe Zera, MD, MPH

Year Study Began: 1998

Year Study Published: 2002

How Many Patients: 10,141

Figure 1.1. Study overview: MAGPIE Trial

Follow-Up: Until discharge from the hospital

• A follow-up study by the Magpie Collaborative Group evaluated

Low-Dose Aspirin for the Prevention and

“Low-dose aspirin may be justified in women judged to be especially li-

How Many Patients: 9,364

Study Overview: This was a randomized, double-blind, placebo-controlled trial.

Figure 2.1. Study overview: the CLASP Trial

Follow-Up: 6 weeks postpartum

Criticisms and Limitations: Postpartum follow-up information was only avail-

Year Study Began: 1983

Year Study Published: 1989

Who Was Studied: All patients with insulin-dependent diabetes presenting at or

How Many Patients: 303

Follow-Up: Congenital anomalies assessed by clinical examination prior to

Endpoints: Primary outcomes were first-trimester spontaneous abortion, and

Year Study Began: 1993

Year Study Published: 2005

How Many Patients: 1,000

Study Overview: See Figure 4.1

Figure 4.1 Study overview: the ACHOIS Trial

Follow-Up: Enrollment (approximately 29 weeks gestational age) until 3 months

Reduction of Maternal–Infant Transmission

“Our study indicates that substantial reduction in the rate of maternal–

Year Study Began: 1991

Year Study Published: 1994

Study Location: 59 centers in France and the United States

Who Was Studied: HIV-infected pregnant women between 14 and 34 weeks

How Many Patients: 477

Study Overview: This randomized, double-blind, placebo-controlled trial was

Follow-Up: Participants were monitored every 4 weeks until 32 weeks gestation,

Endpoints: Primary outcome: Percentage HIV-infected infants at 18 months.