Creasy & Resnik’s MATERNAL - FETAL MEDICINE : Principles and Practice [9 ed.]

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Creasy & Resnik’s

MATERNAL-FETAL MEDICINE Principles and Practice

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9 EDITION th

Creasy & Resnik’s

MATERNAL-FETAL MEDICINE Principles and Practice EDITORS

Charles J. Lockwood, MD

Dean, Morsani College of Medicine Senior Vice President, USF Health Professor of Obstetrics and Gynecology Department of Obstetrics and Gynecology University of South Florida; Executive Vice President, Tampa General Hospital Tampa, Florida

Joshua A. Copel, MD

Professor and Vice Chair, Clinical Operations Department of Obstetrics, Gynecology, and Reproductive Sciences Professor of Pediatrics Assistant Dean for Clinical Affairs Yale School of Medicine New Haven, Connecticut

Lorraine Dugoff, MD

Professor Chief, Reproductive Genetics Department of Obstetrics and Gynecology University of Pennsylvania Philadelphia, Pennsylvania

Judette Louis, MD, MPH

Associate Professor and Chair Department of Obstetrics and Gynecology University of South Florida Tampa, Florida

Thomas R. Moore, MD

Professor and Chair Emeritus Department of Obstetrics, Gynecology, and Reproductive Sciences University of California San Diego La Jolla, California

Robert M. Silver, MD

Chair, Department of Obstetrics and Gynecology Professor of Obstetrics & Gynecology and Population Health Sciences University of Utah Health Salt Lake City, Utah

Robert Resnik, MD

Professor and Chair Emeritus Department of Obstetrics, Gynecology, and Reproductive Sciences University of California San Diego La Jolla, California

Elsevier 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 CREASY & RESNIK’S MATERNAL-FETAL MEDICINE: PRINCIPLES AND PRACTICE, NINTH EDITION ISBN: 978-0-323-82849-9 Copyright © 2023 by Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notice Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous editions copyrighted 2019, 2014, 2009, 2004, 1999, 1994, 1989, and 1984.

Executive Content Strategist: Nancy Duffy Content Development Specialist: Jennifer Pierce Publishing Services Manager: Catherine Jackson Specialist: Kristine Feeherty Design Direction: Maggie Reid Printed in India Last digit is the print number:

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For Nancy—Charly Lockwood For Alix—Josh Copel For Bill—Lorraine Dugoff For Mudathiru—Judette Louis For Peggy—Tom Moore For Denise—Bob Silver

CONTRIBUTORS

Sonya S. Abdel-Razeq, MD

Marie H. Beall, MD

Vikki M. Abrahams, PhD

Richard Beigi, MD, MSc

Associate Professor Obstetric, Gynecology, and Reproductive Sciences Yale University New Haven, Connecticut Professor Obstetrics, Gynecology, and Reproductive Sciences Yale School of Medicine New Haven, Connecticut

Reem S. Abu-Rustum, MD

Associate Professor Director of Ultrasound Education and Research Department of Obstetrics and Gynecology University of Florida College of Medicine Gainesville, Florida

Laith Alshawabkeh, MD, MSc

Associate Professor of Medicine Division of Cardiovascular Medicine University of California San Diego Medical Center La Jolla, California

Michael J. Aminoff, MD, DSc

Distinguished Professor of Neurology Department of Neurology University of California San Francisco School of Medicine San Francisco, California

Mert Ozan Bahtiyar, MD

Professor Obstetrics, Gynecology, and Reproductive Sciences Director Yale Fetal Care Center Yale School of Medicine New Haven, Connecticut

C. Noel Bairey Merz, MD

Professor Obstetrics and Gynecology David Geffen School of Medicine at UCLA Los Angeles, California Professor of Reproductive Sciences Department of Obstetrics, Gynecology, and Reproductive Sciences University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania

Vincenzo Berghella, MD

Professor Maternal-Fetal Medicine Obstetrics and Gynecology Sidney Kimmel Medical College Thomas Jefferson University Philadelphia, Pennsylvania

Kristin Bixel, MD

Assistant Professor Obstetrics and Gynecology Division of Gynecologic Oncology The Ohio State University Columbus, Ohio

Daniel G. Blanchard, MD

Professor of Medicine Division of Cardiovascular Medicine University of California San Diego Medical Center La Jolla, California

Lisa M. Bodnar, PhD, MPH, RD

Professor of Epidemiology and Obstetrics & Gynecology Graduate School of Public Health and School of Medicine University of Pittsburgh Pittsburgh, Pennsylvania

Women’s Guild Endowed Chair in Women’s Health Director, Barbra Streisand Women’s Heart Center Erika J. Glazer Women’s Heart Research Initiative Director Director, Linda Joy Pollin Women’s Heart Health Program Barbra Streisand Women’s Heart Center Cedars-Sinai Heart Institute Los Angeles, California

Rupsa C. Boelig, MD, MS

Linda A. Barbour, MD, MSPH

Jennifer M. Brady, MD

Professor of Medicine and Obstetrics and Gynecology Divisions of Endocrinology, Metabolism, & Diabetes and Maternal-Fetal Medicine University of Colorado Anschutz Medical Campus and School of Medicine Aurora, Colorado vi

Assistant Professor Maternal-Fetal Medicine Obstetrics and Gynecology Sidney Kimmel Medical College Thomas Jefferson University Philadelphia, Pennsylvania

Assistant Professor Pediatrics University of Cincinnati College of Medicine Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Contributors

D. Ware Branch, MD

Rebecca K. Chung, MD

Bryann Bromley, MD

David E. Cohn, MD, MBA

Professor Obstetrics and Gynecology University of Utah School of Medicine Salt Lake City, Utah Professor (part time) Obstetrics, Gynecology, and Reproductive Biology Massachusetts General Hospital Harvard Medical School Boston, Massachusetts

Catalin S. Buhimschi, MD, MBA

Department Head Department of Obstetrics and Gynecology University of Illinois at Chicago College of Medicine Chicago, Illinois

Mary Catherine Cambou, MD Medicine University of California Los Angeles Los Angeles, California

Fellow Physician Reproductive Endocrinology and Infertility University Hospitals Cleveland, Ohio Division of Gynecologic Oncology Obstetrics and Gynecology The Ohio State University College of Medicine; Chief Medical Officer Arthur G. James Cancer Hospital and Solove Research Institute Columbus, Ohio

Joshua A. Copel, MD

Professor and Vice Chair, Clinical Operations Department of Obstetrics, Gynecology, and Reproductive Sciences Professor of Pediatrics Assistant Dean for Clinical Affairs Yale School of Medicine New Haven, Connecticut

Mary E. D’Alton, MD

Associate Professor Department of Obstetrics, Gynecology, and Reproductive Sciences Yale School of Medicine New Haven, Connecticut

Chair and Willard C. Rappleye Professor Obstetrics and Gynecology Columbia University Vagelos College of Physicians and Surgeons; Director, Obstetrics and Gynecology Services Columbia University Medical Center New York, New York

Patrick Catalano, MD

Lori B. Daniels, MD, MAS

Katherine Harper Campbell, MD, MPH

Professor Mother Infant Research Institute Department of Obstetrics and Gynecology Tufts Medical Center Tufts University College of Medicine Boston, Massachusetts

Professor of Medicine Division of Cardiovascular Medicine University of California San Diego Medical Center La Jolla, California

Monique E. De Paepe, MD, MSc

Associate Professor Obstetrics and Gynecology University of Pittsburgh and Magee-Womens Research Institute Pittsburgh, Pennsylvania

Perinatal Pathologist Pathology Women and Infants Hospital; Professor Pathology and Laboratory Medicine Alpert Medical School of Brown University Providence, Rhode Island

Christina Chambers, PhD, MPH

Vanja C. Douglas, MD

Janet M. Catov, PhD, MS

Professor Division of Dysmorphology and Teratology Department of Pediatrics University of California San Diego La Jolla, California

Beth Christian, MD

Associate Professor of Internal Medicine Clinical Internal Medicine - Hematology The Ohio State University Columbus, Ohio

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Professor of Neurology Department of Neurology University of California San Francisco San Francisco, California

Patrick Duff, MD

Associate Dean for Student Affairs Department of Obstetrics and Gynecology University of Florida Gainesville, Florida

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Contributors

Lorraine Dugoff, MD

Professor Chief, Reproductive Genetics Department of Obstetrics and Gynecology University of Pennsylvania Philadelphia, Pennsylvania

Jeffrey R. Fineman, MD

Professor Department of Pediatrics University of California San Francisco San Francisco, California

Ariadna Forray, MD

Associate Professor Psychiatry Yale School of Medicine New Haven, Connecticut

Jan M. Friedman, MD, PhD

Professor Medical Genetics University of British Columbia; Senior Clinician Scientist BC Children’s Hospital Research Institute Vancouver, British Columbia, Canada

Rosemary J. Froehlich, MD

Assistant Professor Department of Obstetrics, Gynecology, and Reproductive Sciences Division of Maternal-Fetal Medicine University of Pittsburgh Medical Center Pittsburgh, Pennsylvania

Alessandro Ghidini, MD

Director Antenatal Testing Center Inova Alexandria Hospital Alexandria, Virginia; Professor Obstetrics and Gynecology Georgetown University Medical Center Washington, DC

Kelly S. Gibson, MD

Division Director, Maternal-Fetal Medicine Obstetrics and Gynecology The MetroHealth System; Associate Professor Reproductive Biology Case Western Reserve University Cleveland, Ohio

Jennifer Gilner, MD, PhD

Assistant Professor Obstetrics and Gynecology Division of Maternal-Fetal Medicine Duke University Medical Center Durham, North Carolina

Katherine Laughon Grantz, MD, MS

Research Fellow Epidemiology Branch Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda, Maryland; Faculty, Maternal-Fetal Medicine Women’s and Infants’ Services Washington Hospital Center Washington, DC; Assistant Professor Obstetrics and Gynecology Georgetown University Washington, DC

James M. Greenberg, MD

Professor of Pediatrics University of Cincinnati College of Medicine; Executive Co-Director, Perinatal Institute Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Anthony R. Gregg, MD, MBA

Maternal-Fetal Medicine and Clinical Genetics Obstetrics and Gynecology Prisma Health Columbia, South Carolina

William Grobman, MD, MBA

Professor Obstetrics and Gynecology The Ohio State University Wexner Medical Center Columbus, Ohio

Beth B. Haberman, MD

Professor Pediatrics University of Cincinnati College of Medicine Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Torre L. Halscott, MD, MS

Assistant Professor, Maternal-Fetal Medicine and Critical Care Medicine Gynecology and Obstetrics The Johns Hopkins University School of Medicine Baltimore, Maryland

Christina S. Han, MD

Division Director Maternal-Fetal Medicine, Obstetrics, and Gynecology David Geffen School of Medicine at UCLA Los Angeles, California

Lorie M. Harper, MD, MSCI

Associate Professor and Chief, Division of Maternal-Fetal Medicine Department of Women’s Health Dell Medical School University of Texas at Austin Austin, Texas

Contributors

Joy L. Hawkins, MD

Professor of Anesthesiology University of Colorado School of Medicine Director of Obstetric Anesthesia University of Colorado Hospital Aurora, Colorado

Robert Phillips Heine, MD

Professor and Frank R. Lock Chair Obstetrics and Gynecology Wake Forest University School of Medicine Winston Salem, North Carolina

Anne Kennedy, MBBCh

Chief of Ultrasound Professor of Radiology and Imaging Sciences University of Utah Salt Lake City, Utah

Aliya Khan, MD

Division of Endocrinology and Metabolism McMaster University Hamilton, Ontario, Canada

Sarah J. Kilpatrick, MD, PhD

Associate Professor of Medicine Obstetrics, Gynecology, and Reproductive Sciences University of Pittsburgh Pittsburgh, Pennsylvania

Chair Department of Obstetrics and Gynecology Helping Hand of Los Angeles Endowed Chair Associate Dean for Faculty Development and Diversity Cedars-Sinai Medical Center Los Angeles, California

Andrew D. Hull, BMedSci, BMBS

Sumire Kitahara, MD

Katherine P. Himes, MD, MS

Professor Obstetrics & Gynecology and Reproductive Sciences University of California San Diego La Jolla, California

Meredith A. Humphreys, MD Fellow Obstetrics and Gynecology University of Utah Salt Lake City, Utah

Anjali J. Kaimal, MD, MAS

Associate Professor Obstetrics, Gynecology, and Reproductive Biology and Population Medicine Massachusetts General Hospital Harvard Medical School Boston, Massachusetts

S. Ananth Karumanchi, MD

Michelle A. Kominiarek, MD, MS

Associate Professor Department of Obstetrics and Gynecology Division of Maternal-Fetal Medicine Northwestern University Feinberg School of Medicine Chicago, Illinois

Jeffrey A. Kuller, MD

Professor of Obstetrics and Gynecology Division of Maternal-Fetal Medicine Duke University Medical Center Durham, North Carolina

D. Yvette LaCoursiere, MD, MPH

Professor of Medicine Department of Medicine Harvard Medical School Boston, Massachusetts; Staff Physician Medicine and Biomedical Sciences Cedars-Sinai Medical Center Los Angeles, California

Professor Reproductive Medicine University of California San Diego La Jolla, California

Stephen R. Lapinsky, MBBCh, MSc Professor of Medicine Department of Medicine University of Toronto Toronto, Ontario, Canada

Erin Keely, MD

Professor Department of Medicine University of Ottawa Ottawa, Ontario, Canada

Thomas F. Kelly, MD

Associate Professor of Pathology Associate Director, Hematopathology Fellowship Program Pathology and Laboratory Medicine Cedars-Sinai Los Angeles, California

Robert M. Lawrence, MD

Clinical Professor and Chief, Division of Maternal-Fetal Medicine Obstetrics, Gynecology, and Reproductive Sciences University of California San Diego La Jolla, California

Adjunct Clinical Professor of Pediatrics Department of Pediatrics University of Florida Gainesville, Florida

https://radiologyebook.vn/

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Contributors

Ruth A. Lawrence, MD

Distinguished Alumna Professor Emeritus of Pediatrics and Obstetrics & Gynecology Division of Neonatology Department of Pediatrics; Founding Director Breastfeeding and Human Lactation Study Center; Director (Emeritus) Finger Lakes Children’s Environmental Health Center University of Rochester Rochester, New York

Ann Leung, MD

Professor Department of Radiology Stanford University Medical Center Stanford, California

Professor and Chairman Department of Obstetrics and Gynaecology Royal College of Surgeons in Ireland; Chief Executive Officer/Master Rotunda Hospital Dublin, Ireland

Emin Maltepe, MD, PhD

Professor Pediatrics, Biomedical Sciences, and Developmental & Stem Cell Biology University of California San Francisco San Francisco, California

Giancarlo Mari, MD, MBA Obstetrics and Gynecology Women’s Health Institute Cleveland Clinic Foundation Cleveland, Ohio

Ming Y. Lim, MBBCh

Assistant Professor Department of Internal Medicine University of Utah Salt Lake City, Utah

Joan M. Mastrobattista, MD

James H. Liu, MD

Arthur H. Bill Professor and Chair Reproductive Biology and Obstetrics & Gynecology University Hospitals Case Medical Center Cleveland, Ohio

Adetola Louis-Jacques, MD

Assistant Professor of Obstetrics and Gynecology University of Florida Gainesville, Florida

Stephen J. Lye, PhD

Senior Investigator Lunenfeld-Tanenbaum Research Institute Sinai Health System; Professor of Obstetrics and Gynecology Professor of Physiology University of Toronto Toronto, Ontario, Canada

George A. Macones, MD, MSCE Professor and Chair Department of Womens Health Interim Dean Dell Medical School University of Texas at Austin Austin, Texas

Mala Mahendroo, PhD

Fergal D. Malone, MD

Professor of Obstetrics and Gynecology Ultrasound Clinic Chief Baylor College of Medicine Houston, Texas

Molly McAdow, MD, PhD

Instructor of Obstetrics, Gynecology, and Reproductive Sciences Yale School of Medicine New Haven, Connecticut

Christina J. Megli, MD, PhD

Research Assistant Professor Obstetrics, Gynecology, and Reproductive Sciences University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania

Brian M. Mercer, MD

Chairman Obstetrics and Gynecology MetroHealth System; Professor Reproductive Biology Case Western Reserve University Cleveland, Ohio

Giacomo Meschia, MD

Professor Obstetrics and Gynecology Green Center for Reproductive Biology Sciences University of Texas Southwestern Medical Center Dallas, Texas

Emeritus Professor Pediatrics University of Colorado Aurora, Colorado

Sam Mesiano, PhD

William H. Weir, MD Professor Department of Reproductive Biology Case Western Reserve University; Vice Chair for Research Department of Obstetrics and Gynecology University Hospitals of Cleveland Cleveland, Ohio

https://radiologyebook.vn/

Contributors

Torri D. Metz, MD, MS

Michael P. Nageotte, MD

Associate Professor Obstetrics and Gynecology University of Utah Health Salt Lake City, Utah

Kenneth J. Moise, Jr., MD

Professor Women’s Health Dell Medical School/University of Texas Austin Health; Director Comprehensive Fetal Center at Dell Children’s Hospital Dell Children’s Hospital Austin, Texas

Manju Monga, MD

Professor and Vice Chair (Clinical Affairs) Obstetrics and Gynecology Baylor College of Medicine Houston, Texas

Laura A. Montaney, RDMS, RDCS, BA Sonographer Maternal-Fetal Care and Genetics University of California San Diego Health San Diego, California

Ana Monteagudo, MD

Clinical Professor Obstetrics and Gynecology Carnegie Imaging/Icahn School of Medicine at Mt. Sinai New York, New York

Thomas R. Moore, MD

Professor and Chair Emeritus Department of Obstetrics, Gynecology, and Reproductive Sciences University of California San Diego La Jolla, California

Gil Mor, MD, PhD

Professor and Director C.S. Mott Center for Human Development Wayne State University School of Medicine Detroit, Michigan

Louis J. Muglia, MD, PhD

President and CEO Office of the President Burroughs Wellcome Fund Research Triangle Park, North Carolina; Adjunct Professor Department of Pediatrics University of Cincinnati Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Professor Obstetrics and Gynecology University of California Irvine Orange, California; Associate Chief Medical Officer Miller Children’s and Women’s Hospital Long Beach, California

Vivek Narendran, MD, MRCP (UK), MBA Professor of Pediatrics Perinatal Institute; Director, UCMC-NICU University of Cincinnati Medical Center Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Amy T. Nathan, MD

Associate Professor Pediatrics University of Cincinnati College of Medicine Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio

Karin Nielsen-Saines, MD, MPH

Professor of Pediatrics Department of Pediatrics David Geffen School of Medicine at UCLA Los Angeles, California

Joshua F. Nitsche, MD, PhD

Associate Professor Division of Maternal-Fetal Medicine Department of Obstetrics and Gynecology Wake Forest University School of Medicine Winston Salem, North Carolina

Sarah Gloria Običan, MD

Associate Professor Division Director Department of Obstetrics and Gynecology University of South Florida Tampa, Florida

Anthony O. Odibo, MD, MSCE

Virginia S Lang Professor of Obstetrics and Gynecology Department of Obstetrics and Gynecology Washington University in St. Louis St. Louis, Missouri

Michael Paidas, MD

Professor and Chair Obstetrics, Gynecology, and Reproductive Sciences University of Miami Miller School of Medicine Miami, Florida

Mana M. Parast, MD, PhD

Professor Pathology University of California San Diego La Jolla, California

https://radiologyebook.vn/

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Contributors

Christian Pettker, MD

Professor Department of Obstetrics, Gynecology, and Reproductive Sciences Yale School of Medicine New Haven, Connecticut

Jessica L. Pippen, MD

Maternal-Fetal Medicine Obstetrics and Gynecology The MetroHealth System; Assistant Professor Reproductive Biology Case Western Reserve University Cleveland, Ohio

Professor of Obstetrics and Gynecology Columbia University Irving Medical Center New York, New York

Robert Resnik, MD

Professor and Chair Emeritus Department of Obstetrics, Gynecology, and Reproductive Sciences University of California San Diego La Jolla, California

Drucilla J. Roberts, MD, MS

Lauren A. Plante, MD, MPH

Professor, Departments of Obstetrics & Gynecology and Public Health Sciences Penn State University College of Medicine Hershey, Pennsylvania

Camille E. Powe, MD

Assistant Professor Department of Medicine Department of Obstetrics, Gynecology, and Reproductive Biology Harvard Medical School Massachusetts General Hospital Boston, Massachusetts

Dolores H. Pretorius, MD

Professor of Radiology University of California San Diego University of California Center for Maternal-Fetal Care and Genetics La Jolla, California

John Queenan, MD

Professor and Chairman Emeritus Department of Obstetrics and Gynecology Georgetown University School of Medicine Washington, DC

Aleksandar Rajkovic, MD, PhD

Professor Pathology and Obstetrics, Gynecology, & Reproductive Sciences University of California San Francisco San Francisco, California

Bhuvaneswari Ramaswamy, MD, MRCP Professor Internal Medicine The Ohio State University Columbus, Ohio

Ronald P. Rapini, MD

Uma M. Reddy, MD, MPH

Professor Department of Pathology Harvard Medical School; Pathologist Department of Pathology Massachusetts General Hospital Boston, Massachusetts

Michael G. Ross, MD, MPH

Distinguished Professor Obstetrics and Gynecology David Geffen School of Medicine at UCLA; Distinguished Professor Community Health Sciences Fielding School of Public Health at UCLA Los Angeles, California

Jane E. Salmon, MD

Collette Kean Research Chair Medicine-Rheumatology Hospital for Special Surgery; Professor Department of Medicine Weill Cornell Medical College New York, New York

Lisa Rose Sammaritano, MD Professor of Clinical Medicine Rheumatology Hospital for Special Surgery Weill Cornell Medicine New York, New York

Thomas J. Savides, MD

Interim Chief, Division of Gastroenterology Professor of Medicine University of California San Diego La Jolla, California

Anna Katerina Sfakianaki, MD, MPH

Associate Professor Obstetrics, Gynecology, and Reproductive Sciences University of Miami Miller School of Medicine Miami, Florida

Chernosky Distinguished Professor and Chair Department of Dermatology University of Texas Medical School and MD Anderson Cancer Center Houston, Texas

https://radiologyebook.vn/

Contributors

Thomas D. Shipp, MD

Associate Professor of Obstetrics, Gynecology, and Reproductive Biology Harvard Medical School; Obstetrics and Gynecology Brigham and Women’s Hospital Boston, Massachusetts

Vineet K. Shrivastava, MD

Assistant Clinical Professor Obstetrics and Gynecology University of California Irvine Orange, California; Vice Chair Department of Obstetrics and Gynecology Miller Children’s and Women’s Hospital Long Beach, California

Robert M. Silver, MD

Chair, Department of Obstetrics and Gynecology Professor of Obstetrics & Gynecology and Population Health Sciences University of Utah Health Salt Lake City, Utah

Hyagriv N. Simhan, MD, MS

Professor Obstetrics, Gynecology, and Reproductive Sciences University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania

Mark Steven Sklansky, MD

Professor and Chief Division of Pediatric Cardiology David Geffen School of Medicine at UCLA Los Angeles, California

Marcela C. Smid, MD, MA, MS Assistant Professor Obstetrics and Gynecology University of Utah Salt Lake City, Utah

John M. Thorp, Jr., MD, MSCR

McAllister Distinguished Professor Obstetrics and Gynecology University of North Carolina School of Medicine; Professor Maternal Child Health University of North Carolina School of Public Health Chapel Hill, North Carolina

Ilan E. Timor-Tritsch, MD

Professor, Obstetrics and Gynecology Department of Obstetrics and Gynecology New York University School of Medicine New York, New York

Alan Tita, MD, PhD

Professor Obstetrics and Gynecology University of Alabama at Birmingham Birmingham, Alabama

Methodius G. Tuuli, MD, MPH, MBA

Chace-Joukowsky Professor and Chair Department of Obstetrics and Gynecology Warren Alpert Medical School of Brown University; Chief of Obstetrics and Gynecology Women and Infants Hospital of Rhode Island Providence, Rhode Island

Amy M. Valent, DO, MCR

Assistant Professor of Obstetrics and Gynecology Division of Maternal-Fetal Medicine Oregon Health & Science University Portland, Oregon

Arthur Jason Vaught, MD

Maternal-Fetal Medicine Gynecology and Obstetrics The Johns Hopkins University School of Medicine Baltimore, Maryland

Ronald J. Wapner, MD

Peter Sottile, MD

Assistant Professor Division of Pulmonary Sciences and Critical Care Medicine University of Colorado School of Medicine Denver, Colorado

Mishka Terplan, MD, MPH

Associate Medical Director Friends Research Institute Baltimore, Maryland; Adjunct Faculty Family Medicine University of California San Francisco San Francisco, California

Professor Obstetrics and Gynecology Columbia University Medical Center New York, New York

Randall B. Wilkening, MD Professor of Pediatrics University of Colorado Aurora, Colorado

Isabelle Wilkins, MD

Professor Obstetrics and Gynecology University of Pittsburgh Pittsburgh, Pennsylvania

Ravi I. Thadhani, MD, MPH

Professor of Medicine at Harvard Medical School Chief Academic Officer Massachusetts General Hospital Boston, Massachusetts

https://radiologyebook.vn/

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Contributors

Richard B. Wolf, DO, MPH

Clinical Professor Department of Obstetrics, Gynecology, and Reproductive Sciences Maternal-Fetal Medicine University of California San Diego La Jolla, California

Paula J. Woodward, MD

Professor of Radiology and Imaging Sciences University of Utah Salt Lake City, Utah

Kimberly A. Yonkers, MD

Professor University of Massachusetts Chan School of Medicine Worcester, Massachusetts

Brett C. Young, MD

Assistant Professor Harvard Medical School; Maternal-Fetal Medicine and Obstetrics & Gynecology Beth Israel Deaconess Medical Center Boston, Massachusetts

Blair J. Wylie, MD, MPH

Director, Division of Maternal-Fetal Medicine Department of Obstetrics and Gynecology Beth Israel Deaconess Medical Center; Associate Professor of Obstetrics, Gynecology, and Reproductive Biology Harvard Medical School Boston, Massachusetts

https://radiologyebook.vn/

PREFACE

We are pleased to present the ninth edition of Creasy & Resnik’s Maternal-Fetal Medicine: Principles and Practice. Since the publication of the first edition in 1984, the goal has been to provide a comprehensive text, combining the underlying basic, translational, and clinical science for topics germane to the specialty of perinatology. Chapters include extensive updates and revisions where appropriate. The fetal imaging section was introduced in the seventh edition and was extremely well received, and consequently it has been significantly expanded. In this edition there has been an update of infectious disease topics including COVID-19 and Zika virus, which now constitute four separate chapters. The editors are deeply appreciative of the contributions of Dr. Robert Creasy, whose efforts contributed to the overall success of the first seven editions of the text, and to Dr. Jay Iams, who provided his expertise in editions five through seven. For the ninth edition we enthusiastically welcome Drs. Judette Louis and Lorraine Dugoff to the editorial group. We also express our gratitude to the many contributors to this and previous editions, for having shared their knowledge in a scholarly and meticulous fashion. Dr. Resnik in particular would like to honor Charles Lockwood, his selection as the new editor, as well as Drs. Daniel Blanchard and Lori Daniels for their outstanding chapter “Cardiac Diseases.” We are also indebted to Jennifer Pierce, Content Development Specialist at Elsevier; Kristine Feeherty, Health Content Management Specialist; and Nancy Duffy, Executive Content Strategist. Finally, our special gratitude goes to our families, to whom we dedicate this edition, for their continuing support and patience. Charles J. Lockwood Joshua A. Copel Lorraine Dugoff Judette Louis Thomas R. Moore Robert M. Silver Robert Resnik

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Contents

PART

1 Scientific Basis of Perinatal Biology, 1

1 Human Genetics and Patterns of Inheritance, 2 ANTHONY R. GREGG, MD, MBA

|

JOSHUA A. COPEL, MD |

Applications, 246

MERT OZAN BAHTIYAR, MD

MARIE H. BEALL, MD

5 Multiple Gestation: The Biology of Twinning, 72 MONIQUE E. DE PAEPE, MD, MSC

STEPHEN J. LYE, PHD

SAM MESIANO, PHD

18 Clinical Applications of Three-Dimensional Sonography in Obstetrics, 254

Obstetric Imaging, 273 ANNE KENNEDY, MBBCH

Birth, 102

|

|

LOUIS

|

PAULA J. WOODWARD, MD

20 Fetal Central Nervous System Imaging, 283 ANA MONTEAGUDO, MD |

8 Immunology of Pregnancy, 127 GIL MOR, MD, PHD

| VIKKI M. ABRAHAMS, PHD

9 Maternal Cardiovascular, Respiratory, and Renal Adaptation to Pregnancy, 143 JOAN M. MASTROBATTISTA, MD

|

MANJU MONGA, MD

10 Endocrinology of Pregnancy, 150 JAMES H. LIU, MD

|

REBECCA K. CHUNG, MD

11 The Breast and the Physiology of Lactation, 163 ADETOLA LOUIS-JACQUES, MD | ROBERT M. LAWRENCE, MD | RUTH A. LAWRENCE, MD

12 Maternal Nutrition, 186 LISA M. BODNAR, PHD, MPH, RD |

JOSHUA A. COPEL, MD

19 Role of Magnetic Resonance Imaging in

7 Pathogenesis of Spontaneous Preterm CATALIN S. BUHIMSCHI, MD, MBA J. MUGLIA, MD, PHD

|

REEM S. ABU-RUSTUM, MD | LAURA A. MONTANEY, RDMS, RDCS, BA | DOLORES H. PRETORIUS, MD

6 Physiology of Parturition, 85 |

THOMAS R. MOORE, MD

17 Doppler Ultrasound: Select Fetal and Maternal

4 Amniotic Fluid Dynamics, 66

MALA MAHENDROO, PHD

2 Obstetric Imaging, 231

Anatomy Ultrasound Examination, 232

DRUCILLA J. ROBERTS, MD, MS

|

GEORGE A. MACONES, MD,

16 Performing and Documenting the Fetal

3 Normal Early Development, 42

MICHAEL G. ROSS, MD, MPH

METHODIUS G. TUULI, MD, MPH, MBA | MSCE

PART

JENNIFER GILNER, MD, PHD | ALEKSANDAR RAJKOVIC, MD, PHD | JEFFREY A. KULLER, MD

|

Medicine, 217

JEFFREY A. KULLER, MD

2 Molecular Genetic Technology, 16

MANA M. PARAST, MD, PHD

15 Evidence-Based Practice in Perinatal

KATHERINE P. HIMES, MD, MS

ILAN E. TIMOR-TRITSCH, MD

21 Imaging of the Fetal Face and Neck, 303 KATHERINE HARPER CAMPBELL, MD, MPH (CLEFT LIP AND PALATE) | CHRISTINA S. HAN, MD (CYSTIC HYGROMA; GOITER) | SONYA S. ABDEL-RAZEQ, MD (MICROGNATHIA; ABNORMAL ORBITS)

22 Fetal Thoracic Imaging, 315 ANNA KATERINA SFAKIANAKI, MD, MPH (CONGENITAL DIAPHRAGMATIC HERNIA; CYSTIC LUNG LESIONS, CONGENITAL PULMONARY AIRWAY MALFORMATION, AND BRONCHOPULMONARY SEQUESTRATION; CONGENITAL HIGH AIRWAY OBSTRUCTION) | KATHERINE HARPER CAMPBELL, MD, MPH (PLEURAL EFFUSION)

23 Fetal Cardiac Malformations and Arrhythmias: Detection, Diagnosis, Management, and Prognosis, 322 MARK STEVEN SKLANSKY, MD

13 Fetal Cardiovascular Physiology, 194 JEFFREY R. FINEMAN, MD

|

EMIN MALTEPE, MD, PHD

24 Fetal Abdominal Imaging, 366 RICHARD B. WOLF, DO, MPH

14 Placental Respiratory Gas Exchange and Fetal Oxygenation, 204 GIACOMO MESCHIA, MD

| RANDALL B. WILKENING, MD

25 Fetal Urogenital Imaging, 400 RICHARD B. WOLF, DO, MPH

26 Skeletal Imaging, 433 RICHARD B. WOLF, DO, MPH

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Contents

27 Placenta and Umbilical Cord Imaging, 472 THOMAS R. MOORE, MD

MEREDITH A. HUMPHREYS, MD |

28 Uterus and Adnexae Imaging, 483 ALESSANDRO GHIDINI, MD |

THOMAS R. MOORE, MD

29 First-Trimester Imaging, 489 BRYANN BROMLEY, MD

PART

| THOMAS D. SHIPP, MD

3 Fetal Disorders: Diagnosis and Therapy, 501

30 Prenatal Diagnosis of Congenital Disorders, 502 LORRAINE DUGOFF, MD

|

RONALD J. WAPNER, MD

31 Teratogenesis and Environmental Exposure, 549 CHRISTINA CHAMBERS, PHD, MPH

|

ANJALI J. KAIMAL, MD, MAS

33 Intrapartum Fetal Surveillance, 574 MICHAEL P. NAGEOTTE, MD

|

VINEET K. SHRIVASTAVA, MD

34 Invasive Fetal Therapy, 595 SARAH GLORIA OBIČAN, MD

|

ANTHONY O. ODIBO, MD, MSCE

35 Hemolytic Disease of the Fetus and Newborn, 634 KENNETH J. MOISE, JR., MD

|

JOHN QUEENAN, MD

36 Nonimmune Hydrops, 650 ROSEMARY J. FROEHLICH, MD |

ISABELLE WILKINS, MD

37 Multiple Gestation: Clinical Characteristics and Management, 660

FERGAL D. MALONE, MD | |

MARY E. D’ALTON, MD

4 Disorders at the

Maternal-Fetal Interface, 687

38 Prevention and Management of Preterm Parturition, 688

RUPSA C. BOELIG, MD, MS | HYAGRIV N. SIMHAN, MD, MS | VINCENZO BERGHELLA, MD

42 Stillbirth, 782 UMA M. REDDY, MD, MPH

39 Premature (Prelabor) Rupture of the Membranes, 723

|

KELLY S. GIBSON, MD

40 Clinical Aspects of Normal and Abnormal Labor, 734

JOHN M. THORP, JR., MD, MSCR MD, MS

|

|

ROBERT M. SILVER, MD

43 Placenta Previa and Accreta, Vasa Previa,

Subchorionic Hemorrhage, and Abruptio Placentae, 799 ANDREW D. HULL, BMEDSCI, BMBS | ROBERT M. SILVER, MD

ROBERT RESNIK, MD

|

44 Fetal Growth Restriction, 810 GIANCARLO MARI, MD, MBA |

ROBERT RESNIK, MD

45 Pregnancy-Related Hypertension, 826 LORIE M. HARPER, MD, MSCI | S. ANANTH KARUMANCHI, MD

PART

ALAN TITA, MD, PHD |

5 Maternal Complications, 855

46 Patient Safety and Quality Improvement in Obstetrics, 856

CHRISTIAN PETTKER, MD | WILLIAM GROBMAN, MD, MBA

47 Maternal Mortality, 867 TORRI D. METZ, MD, MS |

KATHERINE LAUGHON GRANTZ,

ROBERT M. SILVER, MD

48 Bacterial and Parasitic Infections in Pregnancy, 879 BLAIR J. WYLIE, MD, MPH

49 Maternal and Fetal Viral Infections, 908 KARIN NIELSEN-SAINES, MD, MPH | MD

MARY CATHERINE CAMBOU,

50 Sexually Transmitted Diseases, 938 ROBERT PHILLIPS HEINE, MD PHD | PATRICK DUFF, MD

|

JOSHUA F. NITSCHE, MD,

51 Maternal-Fetal Infections, 959 CHRISTINA J. MEGLI, MD, PHD |

RICHARD BEIGI, MD, MSC

52 Cardiac Diseases, 973 DANIEL G. BLANCHARD, MD | LORI B. DANIELS, MD, MAS | LAITH ALSHAWABKEH, MD, MSC

53 Coagulation Disorders in Pregnancy, 1013 MING Y. LIM, MBBCH |

BRIAN M. MERCER, MD

D. WARE BRANCH, MD

JAN M. FRIEDMAN, MD, PHD

32 Assessment of Fetal Health, 560

PART

41 Recurrent Pregnancy Loss, 768

ROBERT M. SILVER, MD

54 Thromboembolic Disease in Pregnancy, 1039 MICHAEL PAIDAS, MD |

|

PETER SOTTILE, MD | |

ANN LEUNG, MD

55 Anemia and Pregnancy, 1054 SARAH J. KILPATRICK, MD, PHD

|

SUMIRE KITAHARA, MD

56 Malignancy and Pregnancy, 1070 KRISTIN BIXEL, MD | BHUVANESWARI RAMASWAMY, MD, MRCP | BETH CHRISTIAN, MD | DAVID E. COHN, MD, MBA

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Contents

57 Renal Disorders, 1088 RAVI I. THADHANI, MD, MPH

|

67 Management of Depression and Psychoses in Pregnancy and in the Puerperium, 1317

BRETT C. YOUNG, MD

KIMBERLY A. YONKERS, MD |

58 Respiratory Diseases in Pregnancy, 1106 JESSICA L. PIPPEN, MD

|

68 Substance Use and Addiction in Pregnancy and

KELLY S. GIBSON, MD

the Postpartum Period, 1328

59 Diabetes in Pregnancy, 1132 THOMAS R. MOORE, MD | PATRICK CATALANO, MD

MARCELA C. SMID, MD, MA, MS |

69 The Skin and Pregnancy, 1357

MICHELLE A. KOMINIAREK, MD, MS | MARCELA C. SMID, MD, MS | D. YVETTE LACOURSIERE, MD, MPH

|

LINDA A. BARBOUR, MD, MSPH

62 Other Endocrine Disorders of Pregnancy, 1214 | ALIYA KHAN, MD

|

Pregnancies, 1368

71 Intensive Care Considerations in Obstetrics, 1387 LAUREN A. PLANTE, MD, MPH |

STEPHEN R. LAPINSKY, MBBCH, MSC

JANET M. CATOV, PHD, MS

|

C. NOEL BAIREY MERZ, MD

THOMAS J. SAVIDES, MD

64 Diseases of the Liver, Biliary System, and Pancreas, 1257

TORRE L. HALSCOTT, MD, MS

|

ARTHUR JASON VAUGHT, MD

65 Pregnancy and Rheumatic Diseases, 1277 LISA ROSE SAMMARITANO, MD D. WARE BRANCH, MD

| JANE E. SALMON, MD

|

PART

6 The Neonate, 1409

73 Neonatal Morbidities of Prenatal and Perinatal Origin, 1410

JAMES M. GREENBERG, MD | VIVEK NARENDRAN, MD, MRCP (UK), MBA | JENNIFER M. BRADY, MD | AMY T. NATHAN, MD | BETH B. HABERMAN, MD

Index, 1439

66 Neurologic Disorders, 1293 VANJA C. DOUGLAS, MD

70 Anesthesia Considerations for Complicated

72 Pregnancy as a Window to Future Health, 1401

63 Gastrointestinal Disease in Pregnancy, 1241 THOMAS F. KELLY, MD

RONALD P. RAPINI, MD

JOY L. HAWKINS, MD

61 Thyroid Disease and Pregnancy, 1187

ERIN KEELY, MD

MISHKA TERPLAN, MD, MPH

CAMILLE E. POWE, MD |

60 Pregnancy in Women With Obesity, 1166

AMY M. VALENT, DO, MCR

ARIADNA FORRAY, MD

| MICHAEL J. AMINOFF, MD, DSC

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VIDEO CONTENTS

PART

2 Obstetric Imaging

17 Doppler Ultrasound: Select Fetal and Maternal Applications

Video 17-1 Umbilical Artery Video 17-2 Middle Cerebral Artery Video 17-3 Ductus Venosus Video 17-4 Uterine Artery

23 Fetal Cardiac Malformations and Arrhythmias: Detection, Diagnosis, Management, and Prognosis

Video 23-1 Four-Chamber View Video 23-2 Transverse Sweep Video 23-3 Perpendicular Sweep Video 23-4 Parasternal Short-Axis High Video 23-5 Pulmonary Stenosis Video 23-6 Parasternal Short-Axis Ventricles Video 23-7 Aortic Stenosis Video 23-8 Sagittal Arch Sidedness Video 23-9 Hypoplastic Left Heart Syndrome Video 23-10 d-Transposition of the Great Arteries

24 Fetal Abdominal Imaging Video 24-1 Ascites, Coronal View Video 24-2 Ascites, Color Doppler Video 24-3 Ascites, Sagittal View Video 24-4 Ascites, Axial Sweep Video 24-5 Ascites, With Anhydramnios Video 24-6 Ascites, With Peripheral Edema Video 24-7 Duodenal Atresia, “Double Bubble” Sign Video 24-8 Duodenal Atresia, Late Findings Video 24-9 Duodenal Atresia, Enlarged Stomach Video 24-10 Intestinal Atresia, Late Findings Video 24-11 Jejunal Atresia Video 24-12 Imperforate Anus Video 24-13 Gastroschisis, Axial View Video 24-14 Gastroschisis, Sagittal View Video 24-15 Gastroschisis, Axial Sweep Video 24-16 Gastroschisis, Color Doppler Video 24-17 Gastroschisis, Abdominal Cord Insertion Video 24-18 Omphalocele, Axial Sweep Video 24-19 Omphalocele, Umbilical Vessels Video 24-20 Omphalocele, Color Doppler Video 24-21 Omphalocele With Ascites Video 24-22 Omphalocele in Late First Trimester Video 24-23 Omphalocele With Herniated Liver Video 24-24 Omphalocele With Pentalogy of Cantrell Video 24-25 Abdominal Cyst, Axial View Video 24-26 Renal Cyst Video 24-27 Ovarian Cyst Video 24-28 Neonatal MRI of Abdominal Cyst Video 24-29 Echogenic Subdiaphragmatic Abdominal Lesion

Video 24-30 Fetal Cholelithiasis Video 24-31 Fetal Bowel Obstruction Video 24-32 Echogenic Hepatic Lesion Video 24-33 Echogenic Abdominal Lesion, Shadowing Video 24-34 Pulmonary Sequestration Video 24-35 Limb-Body Stalk Lesion, Embryonic Maldevelopment Video 24-36 Limb-Body Stalk Lesion, Vascular Disruption Video 24-37 Limb-Body Stalk Lesion, Placental Involvement Video 24-38 Limb-Body Stalk Lesion, Cardiac Involvement Video 24-39 Limb-Body Stalk Lesion With Ectopia Cordis Video 24-40 Limb-Body Stalk Lesion With Vertebral Defect Video 24-41 Limb-Body Stalk Lesion, Amnion Disruption Video 24-42 Umbilical Vein Varix at Abdominal Cord Insertion Video 24-43 Umbilical Vein Varix, Axial Sweep Video 24-44 Umbilical Vein Varix, Color Doppler Video 24-45 Umbilical Vein Varix, Split Screen View Video 24-46 Absent Stomach Video 24-47 Color Doppler Imaging of Dilated Esophagus Video 24-48 Normal Posterior Pharynx

25 Fetal Urogenital Imaging Video 25-1 Pyelectasis, Axial View Video 25-2 Pyelectasis With Normal Contralateral Kidney Video 25-3 Pyelectasis, Coronal View Video 25-4 Hydronephrosis Video 25-5 Pyelectasis, Sagittal View Video 25-6 Echogenic Kidneys, MRI Video 25-7 Autosomal Dominant Polycystic Kidney Disease Video 25-8 Autosomal Recessive Polycystic Kidney Disease Video 25-9 Cystic Renal Dysplasia Video 25-10 Meckel-Gruber Syndrome Video 25-11 Unilateral Multicystic Kidney, Sagittal Video 25-12 Unilateral Multicystic Kidney, Axial Video 25-13 Multicystic Kidney, Large Cysts Video 25-14 Multicystic Kidney, Neonatal Imaging Video 25-15 Posterior Urethral Valve, Sagittal View Video 25-16 Posterior Urethral Valve, Axial View Video 25-17 Markedly Enlarged Bladder Video 25-18 First-Trimester Posterior Urethral Valve Video 25-19 Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome Video 25-20 Urinary Ascites Video 25-21 Ureterocele, Axial View Video 25-22 Ureterocele, Sagittal View Video 25-23 Ureterocele, Coronal View Video 25-24 Bilateral Ureteroceles Video 25-25 Hydroureter With Cystic Kidney Video 25-26 Hydroureter With Ureterocele Video 25-27 Bladder Exstrophy, Doppler Imaging

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Video Contents

Video 25-28 Bladder Exstrophy, Absent Bladder and Perineal Mass Video 25-29 Bladder Exstrophy, Perineal Mass Video 25-30 Bladder Exstrophy, Ambiguous Genitalia Video 25-31 Ambiguous Genitalia, Bifid Scrotum Video 25-32 Ambiguous Genitalia, Micropenis Video 25-33 Ambiguous Genitalia, Uncertain Gender Video 25-34 Ambiguous Genitalia, Urine Flow Video 25-35 Ambiguous Genitalia, Bladder Exstrophy Video 25-36 Ambiguous Genitalia, Virilization Video 25-37 Ambiguous Genitalia, Skeletal Dysplasia Video 25-38 Duplicated Renal Collection Video 25-39 Duplicated Renal Collection, Color Doppler Video 25-40 Duplicated Renal Collection, Mild Renomegaly Video 25-41 Duplicated Renal Collection, Ureterocele Video 25-42 Bladder With Ureterocele Video 25-43 Duplicated Renal Collection, Ureterocele Video 25-44 Renal Agenesis, Anhydramnios Video 25-45 Renal Agenesis, Axial View Video 25-46 Fetal Adrenal Glands Video 25-47 Bilateral Renal Agenesis, Color Doppler Video 25-48 Unilateral Renal Agenesis, Color Doppler Video 25-49 Horseshoe Kidney Video 25-50 Ureteromegaly Video 25-51 Ureteromegaly, Color Doppler Video 25-52 Unilateral Ureterovesical Junction Obstruction

26 Skeletal Imaging Video 26-1 Skeletal Dysplasia, Angulated Bones Video 26-2 Skeletal Dysplasia, Short Upper Extremity Video 26-3 Skeletal Dysplasia, Compressible Calvarium Video 26-4 Bell-Shaped Chest Video 26-5 Bell-Shaped Chest With Abnormal Facial Profile Video 26-6 Abnormal Cardiac-to-Thoracic Ratio Video 26-7 Abnormal Hands, Arthrogryposis Video 26-8 Abnormal Hands, Claw-Like Appearance Video 26-9 Clenched Hands Video 26-10 First-Trimester Arthrogryposis Video 26-11 Familial Polydactyly Video 26-12 Polydactyly Video 26-13 Abnormal Posturing, Tailor’s Position Video 26-14 Clubfoot, Metatarsal View Video 26-15 Clubfoot, 5-Toe View Video 26-16 Clubfoot, Plantar Surface Video 26-17 Clubfoot With Open Neural Tube Defect Video 26-18 Bilateral Clubfoot Deformity Video 26-19 Sacrococcygeal Teratoma, Exterior Mass Video 26-20 Sacrococcygeal Teratoma, Internal Mass Video 26-21 Sacrococcygeal Teratoma, First-Trimester Mixed Echogenic Mass Video 26-22 Sacrococcygeal Teratoma, First-Trimester Isoechoic Mass Video 26-23 Caudal Regression, Axial Video 26-24 Caudal Regression, Sagittal Video 26-25 Vestigial Tail Video 26-26 Neural Tube Defect, Meningocele Video 26-27 Neural Tube Defect, Myelomeningocele Video 26-28 Meningocele, Axial View

Video 26-29 Myeloschisis, Axial View Video 26-30 Neural Tube Defect, Coronal View Video 26-31 Neural Tube Defect, Myeloschisis Video 26-32 Neural Tube Defect, Intracranial Findings Video 26-33 Neural Tube Defect, Ventriculomegaly and Chiari Sign Video 26-34 Cloverleaf Skull Video 26-35 Scoliosis Video 26-36 Hemivertebrae Video 26-37 Amniotic Band Syndrome, Absent Digits Video 26-38 Amniotic Bands, Hand Deformity Video 26-39 Amniotic Bands, Ventral Wall Defect Video 26-40 Amniotic Bands With Elevated Alpha Fetoprotein (AFP) Video 26-41 Amniotic Bands Without Involvement of Fetal Extremities

27 Placenta and Umbilical Cord Imaging Video 27-1 Partial Mole With Amniotic Sac Video 27-2 Central Placenta Accreta Bulging Into Bladder Video 27-3 Circumvallate Placenta Video 27-4 Posterior Placenta With Small Anterior Lobe With Connecting Blood Vessels Video 27-5 Vasa Previa

28 Uterus and Adnexae Imaging Video 28-1 Adnexal Mass Video 28-2 Bicornuate Uterus Video 28-3 Uterine Fibroid

29 First-Trimester Imaging Video 29-1 Split Screen Showing an Axial Sweep Through the Fetal Heart in the Later First Trimester Demonstrating the Normal Four-Chamber View and 3VT View in Greyscale and With Color Doppler␣

PART

5 Maternal Complications

52 Cardiac Diseases Video 52-1 Apical Four-Chamber View of a Large Ostium Secundum Atrial Septal Defect Video 52-2A Apical Four-Chamber View in a Case of Muscular Ventricular Septal Defect Video 52-2B Communication Between the Ventricles Is Seen Only With Color-Flow Doppler Examination Video 52-3 Parasternal Short-Axis View Demonstrating a Bicuspid Aortic Valve Video 52-4 Parasternal Long-Axis Image of Tetralogy of Fallot Video 52-5A Apical Four-Chamber View of Ebstein Anomaly Showing Apical Displacement of the Tricuspid Valve as Well as Right Heart Enlargement Video 52-5B Color Image of Ebstein Anomaly Demonstrating Severe Tricuspid Regurgitation Video 52-6 Parasternal Long-Axis Image of Rheumatic Mitral Stenosis Video 52-7A Apical Four-Chamber View of Severe Mitral Regurgitation

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Video Contents

Video 52-7B Another Case of Severe Mitral Regurgitation With a Very Eccentric Regurgitant Jet Video 52-8 Parasternal Long-Axis Image of Severe Left Ventricular Dysfunction in Peripartum Cardiomyopathy Video 52-9A Apical Four-Chamber View of Hypertrophic Obstructive Cardiomyopathy Video 52-9B Parasternal Long-Axis Image of Hypertrophic Obstructive Cardiomyopathy, Showing Systolic Anterior Motion of the Mitral Valve

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Video 52-10 Parasternal Long-Axis Image in Marfan Syndrome Video 52-11A Fluoroscopic Image of a Partially Thrombosed Mechanical Valve in the Mitral Position Video 52-11B Transesophageal Echocardiographic Image Demonstrating Immobilization of the Prosthetic Disk to the Viewer’s Right

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PART

1

Scientific Basis of Perinatal Biology

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1

Human Genetics and Patterns of Inheritance ANTHONY R. GREGG, MD, MBA

| JEFFREY A. KULLER, MD

The Human Genome Project was completed on October 21, 2004, and provided the primary structure (nucleotide sequence) of all chromosomes.1 However, in the nearly 150 years preceding this breakthrough, there were major discoveries that were equally relevant. Gregor Mendel, known as the father of modern genetics, described the most basic modes of inheritance and provided an early understanding of human genetic variability.2 The double helix structure of DNA was described in the middle of the 20th century by James Watson and Francis Crick.3 Genome sequencing, made possible in part by the discovery of the polymerase chain reaction technique by Mullis and colleagues4 and sequencing reactions by Sanger and Coulson,5 helped bring the human genome out of the laboratory to the bedside. In this chapter, we link the principles of meiosis and mitosis to emerging clinical practice in genomic medicine. We illustrate errors in mitosis and meiosis that lead to medical conditions familiar to prenatal diagnosticians and clinical geneticists to establish a framework for understanding genetic mechanisms. We first present an overview of genomic structure (Fig. 1.1), which begins with a description of the nuclear and mitochondrial genome. Using examples to help patients create a mental image of the human genome is helpful. For example, ask patients and their families to think of the human genome as books on a shelf (Box 1.1). An understanding of how these function forms the basis for understanding the concepts of genetic counseling and prenatal testing (see Box 1.1).

DNA Structure Worldwide investment, interest, and contributions toward our understanding of the human genome created the need for a standardized nomenclature. Furthermore, reporting variants within the genome requires uniform reporting criteria.6 Understanding normal and abnormal inheritance patterns necessitates an understanding of DNA structure. The primary DNA structure is the nucleotide sequence. Single-stranded DNA consists of the nucleotides adenine (A), cytosine (C), guanine (G), and thymine (T), named by their respective nitrogen base (i.e., purine [A or C] and pyrimidine [G or T]) joined to a sugar (five carbon deoxyribose) with phosphate groups attached. The single-stranded nucleotide chain is held together by covalent phosphodiester bonds. When laboratories identify variation in primary structure (e.g., DNA sequence), reporting standards require the application of specific criteria to classify variants as pathogenic, likely pathogenic, benign, likely benign, or of uncertain significance.6 Secondary DNA structure describes how DNA strands join one another. Purines and pyrimidines join predictably (A to T and G to C) to form a double strand held together by weak hydrogen bonds (two for A to T and three for G to C). These strands can dissociate to allow recombination (normal human 2

variation and disease). Abnormalities of recombination result in copy number variants (CNVs), also referred to as microdeletions and duplications. The five most common syndromes resulting from CNVs are (1) DiGeorge (22q11.2 deletion),2 (2) 1p36 deletion,7 (3) Prader-Willi (15q11.2-q13 paternal deletion),8 (4) Angelman (15q11.2-q3 maternal deletion),9 and (5) cri du chat (5p deletion).10 Tertiary structure is the orientation of DNA in space as a double helix, facilitated in part by histones. Histones are proteins that permit DNA to wind or unwind depending on their acetylated states. This function of histones changes the transcriptional activity of regions of the genome (epigenetics).␣

Cell Division MEIOSIS Gametes are derived from primordial germ cells specific to the ovary and testes. These primordial germ cells have 2n (46) chromosomes (diploid) but give rise to gametes, which have half that number, n (23) chromosomes (haploid). The process leading to this reduction division is termed meiosis. Meiosis is divided into meiosis I and II. One important distinction is that total DNA goes from 4n to 2n during meiosis I and 2n to n during meiosis II. The configuration of DNA (e.g., tetrad and sister chromatids) represented by chromosomes is also unique (Table 1.1). There are characteristic phases (e.g., prophase, metaphase, anaphase, and telophase) within meiosis I and II. Prophase of meiosis I has five distinct stages (leptotene, zygotene, pachytene, diplotene, and diakinesis). During zygotene, homologous chromosomes (maternal and paternal chromosomes) align at the synaptonemal complex, giving way to a bivalent (two homologous chromosomes) tetrad (each chromosome has two DNA (Nucleotides) Nuclear Genome

Mitochondrial Genome

46 chromosomes (nucleotides)

. 44 autosomes . 13,14,15,21,22 . 2 sexAcrocentric chromosomes

Single, Circular

Genes (~20,000) Regions Regulatory

. Ribosomal RNA (2) . Transfer RNA (22) . mRNA (13)

. . Coding . Noncoding

Genes

promoters enhancers exons introns repeats

Figure 1.1 Basic structure of the nuclear and mitochondrial genomes.

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1

BOX 1.1

COUNSELING PEARLS

• Help patients create a mental image of their genome and weave the story around this picture. • Visualize the genome as a set of books on a shelf (i.e., chromosomes), with each book containing the information that tells every cell of the body how to function. The sperm and egg each have 23 books before conception. After conception, each cell of the body has 46 books.

TYPES OF GENETIC PROBLEMS: • Incorrect number of books (i.e., aneuploidy)—for example, Down syndrome (extra number 21 chromosome) • One book stuck to another book (i.e., translocation)—for example, Robertsonian translocation • Chapter or paragraph duplicated or deleted (i.e., microdeletion or duplication)—for example, DiGeorge syndrome (deletion of chromosome 22q11.2) • Misspelled word (i.e., point mutation)—for example, delta F508 mutation that causes cystic fibrosis • Genetic problems lead to an improper blueprint—cells perform their function improperly, resulting in birth defects, abnormal cell function, developmental delay, and so on

TABLE

1.1

Human Genetics and Patterns of Inheritance

sister chromatids). Homologous recombination occurs during pachytene, when sister chromatids of maternal and paternal homologs exchange segments of DNA, resulting in genetic variability among offspring from the same parents. In females, oogenesis begins in utero but stops during prophase I and is completely dormant by 8 months’ gestation (see Table 1.1). This arrested state occurs during the diplotene stage of prophase I. There are five stages of prophase I (leptotene, zygotene, pachytene, diplotene, and diakinesis). Recombination or “crossing over” occurs during these stages. A prolonged diplotene stage of prophase I ( known as dictyotene) is seen only in oocyte development. In females, meiosis I resumes at puberty, and each month another one or more oocytes (a function of follicular recruitment) resumes to complete the reduction division (2n to n). Meiosis I is completed at the time of ovulation (first polar body is formed), and meiosis II begins, but is once again halted, this time during metaphase. Meiosis II is completed only if fertilization occurs (second polar body is formed). Fertilization most often takes place in the fallopian tube. An important distinction between male and female gamete development is the time in life at which meiosis is initiated and the time course to completion. In males, this is a short process (approximately 64 days), has its onset at puberty, and is continuous throughout a man’s reproductive life.␣

Meiosis in the Developing Oocyte

Interphase (fetal life) Meiosis I

Meiosis II

3

Stages/Phases

DNA

DNA Configuration

Comments

Three stages: G1, S, and G2 Prophase: Five stages: leptotene, zygotene, pachytene, diplotene, and diakinesis

4n

Sister chromatids

4n

Tetrads Chiasmata

Prometaphase

4n

Tetrads Chiasmata

Metaphase

4n

Anaphase

4n

Tetrads Chiasmata Sister chromatids

Telophase

2n

Sister chromatids

Cytokinesis

2n

Sister chromatids

Prophase

2n

Sister chromatids

Prometaphase

2n

Sister chromatids

Metaphase

2n

Sister chromatids

Anaphase

n

Chromosomes

Telophase

n

Chromosomes

Cytokinesis

n

Chromosomes

Kinetochores hold sister chromatids at centromere S-phase content doubles (2n–4n) Nuclear membrane fragments DNA condensation begins Spindle develops Homologous chromosomes form a tetrad Chiasmata appear (regions of recombination between homologous chromosome) Crossing over between homologous pairs Stall during diplotene stage: 8 months’ gestation (primary oocyte) until puberty Nuclear membrane is gone Spindle attached to shared kinetochore DNA is condensed Crossing over between homologous pairs Tetrads randomly align along metaphase plate Crossing over between homologous pairs Homologs are pulled apart Sister chromatids remain together Random segregation toward opposite ends of cell Sister chromatids take a polar position Nuclear membrane starts to form Cell division begins Nuclear membrane and cell division completed Stall: Until ovulation (secondary oocyte and first polar body) Nuclear membrane fragments DNA condensation begins Spindle develops Nuclear membrane is gone Spindle attached to shared kinetochore DNA is condensed Sister chromatids randomly align along metaphase plate Stall: Until fertilization Sister chromatids are pulled apart Random segregation toward opposite ends of cell Chromosomes take a polar position Nuclear membrane starts to form Cell division begins Nuclear membrane and cell division completed Mature ovum and three polar bodies (first polar body also divides)

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4

PART 1 Scientific Basis of Perinatal Biology

MENDEL’S LAWS Mendel used pea plants and flowers as a model for his scientific observations, which remain relevant today. Among these observations are Mendel’s laws of inheritance (Table 1.2), which provide a general description of how genetic variability is accomplished during meiosis. Although Mendel was unaware of recombination, the concept of gametes being uniquely different owing to chance is a tenet conveyed regularly in genetic counseling sessions.␣ MITOSIS Cellular DNA is located in the nucleus and mitochondria. Nuclear DNA within somatic cells is partitioned into 46 individual chromosomes, which defines a euploid cell (2n). Mitotic cell TABLE

Mendel’s Laws of Inheritance

1.2

Law

Principle

Clinical Pathology

Segregation

Alleles of the same gene segregate into separate gametes Genes that yield distinct traits segregate independently when on separate chromosomes Some alleles are dominant, others are recessive, and dominant alleles will express

Nonallelic homologous recombination (unequal crossing over) Nonallelic homologous recombination (unequal crossing over) Aneuploidy rescue

Random assortment

Dominance

Point mutations (e.g., single-gene disorders) Microdeletions/ microduplications (e.g., genes within a locus) Nonallelic homologous recombination Aneuploidy rescue

division (Fig. 1.2) conserves this number as the zygote (fertilized egg) moves into embryonic and fetal stages of development.␣

Errors in Meiosis DNA is the blueprint for developmental processes within cells that allow normal cell function, organ function (including the placenta), and subsequently human development to occur. The blueprint must be acquired in roughly equal amounts from the sperm and egg (ignoring the difference in DNA content between the sex chromosomes). From a genetic perspective, the goal of meiosis is to reduce the 2n content of DNA in the primordial germ cell to 1n in the mature gamete. This reduction division allows for restoration of 2n when a single sperm (n) fertilizes the mature ovum. TRIPLOIDY Anytime the quantity or quality of the blueprint is not preserved, abnormal cell function, organ function (e.g., developmental delay), fetal development (e.g., birth defects), and miscarriage can occur. Triploidy is one of the most common genetic causes of fetal loss (approximately 20%). Estimates are that triploidy occurs in about 2% to 3% of conceptions.11 Triploidy, which can result in a partial mole, can derive through several distinct mechanisms, some of which originate as errors in meiosis (Fig. 1.3). Dispermy is the most common cause and leads to a diandrogenic conception. Another cause is abnormal chromosome segregation (meiosis I or meiosis II) of all chromosomes involving either sperm (diandrogenic) or egg (digynic). Fertilization of the primary oocyte and failure to extrude either polar body are additional digynic mechanisms.␣ NONDISJUNCTION Nondisjunction is an error in meiosis that results from failure of either tetrad separation in anaphase I or sister chromatid

Cell Cycle and Mitosis G2 Growth Organelles

Interphase is: G0 - G1 - S - G2

Nuc. membrane breaks

Chromosome Condensation Polar Position Spindle app., Centrosomes

Prometaphase

Prophase Double helix duplicates Centromeres form Telomeres maintained

§

S phase

Chromosomes max condensed Chromosomes line up

Metaphase sis

*G1 or **G0

G1 or G0

*G1 – dividing cells **G0 – nondividing cells §

Cy

to

kin e

Longest portion of cell cycle

Chromosomes decondense Nuc. membrane reforms Chromosome Separation Telophase

Sister chromatids

Anaphase Figure 1.2 The cell cycle and stages of mitosis. Major events during mitosis are noted.

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separation in anaphase II. Aneuploidy, gain or loss of at least one chromosome, is the result. Aneuploidy of chromosome 21 (i.e., Down syndrome) is associated with advanced maternal age and is the most common aneuploid condition in liveborn children. It usually results from maternal meiosis I nondisjunction events.12 Nondisjunction results in gametes with either too few or too many chromosomes (Fig. 1.4). The proportion of gametes that are monosomic or trisomic after a meiosis I nondisjunction event is 1:1. The gametes derived after meiosis II nondisjunction are present in a 2 (euploid):1 (trisomic):1 (nullisomic) proportion. Characterizing disomy is important. Heterodisomy and isodisomy are terms used to describe the parental origin of the extra chromosome in a trisomic gamete. There are important genetic implications that are based on the parental origin of the nondisjunction. The parent of origin of the extra chromosome can be determined by molecular analysis of DNA that makes up the centromere. When the tetrad fails to disjoin in meiosis I, the subsequent trisomic gamete is considered heterodisomic (homologs originate from a male and a female parent). When Mechanisms of Triploidy

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Secondary oocyte with retained 1st or 2nd polar body (pb) 23 23 pb

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Dispermy

Nondisjunction meiosis I or meiosis II involving all chromosomes 23

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Figure 1.3 Four mechanisms that lead to triploidy.

Human Genetics and Patterns of Inheritance

sister chromatids fail to disjoin in meiosis II, the subsequent trisomic gamete is considered isodisomic (homologs are of male or female origin).␣ IMPRINTING Imprinting refers to gene expression that depends on parental origin. Most genes are expressed from the maternal and paternal chromosome in roughly equal amounts. When normal gene function requires expression from one or the other parent, but not both, one copy must be “turned off.” Genes or genomic regions are turned off through the process of cytosine methylation, histone modification (i.e., histones control tertiary structure by opening and closing DNA making it available or unavailable for transcription), and silencing RNA (small fragments of RNA that influence transcriptional start sites). These are epigenetic mechanisms of gene silencing, meaning that these are reversible ways of controlling gene expression. The first two of these mechanisms takes place during oogenesis and spermatogenesis. During gamete development, imprints are reset. When resetting does not occur as it should, abnormal development is possible. Imprinting control regions exist along stretches of DNA, and variations in these regions can disturb the normal resetting and reimprinting of specific genes or regions of the genome. As noted, biparental gene expression is the norm. When an allele from one parent is deleted, there can be only uniparental gene expression. If that remaining gene is imprinted, there can be an abnormal phenotype because there is no expression of the remaining imprinted gene from the other parent. In the genomic era, the clinician must understand the relationship between imprinting and deletions. Genetic conditions amenable to screening today have expanded beyond the common aneuploidies (e.g., trisomies 21, 18, and 13). Today noninvasive

Oocyte Sperm

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Figure 1.4 Fertilization after normal meiosis and segregation of chromosomes after nondisjunction that occurs in an oocyte during meiosis I and meiosis II. The chromosome number within a zygote and the proportion of zygotes with normal and abnormal chromosome constitution are shown.

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prenatal screening through cell-free DNA is available for several conditions characterized by aberrant imprinting (e.g., PraderWilli syndrome), although the accuracy of this testing, including its positive and negative predictive values, is still unclear.␣ TRISOMIC RESCUE Trisomic rescue is another mechanism that can result in parent-of-origin effect. Once again, an imprinted region of the genome is required. This rescue is a corrective action that occurs in a gamete or somatic cell shortly after fertilization (i.e., early zygote). A gamete or early embryonic cell that was once trisomic owing to nondisjunction events in meiosis or mitosis can extrude the extra chromosome. If successful, the daughter cells that arise from the rescued cell will be euploid. The specific chromosome involved in the trisomy and subsequent rescue is important. When a genomic region or specific gene has a parent-of-origin expression pattern (e.g., is an imprinted region), a medical condition may result when the normally imprinted gene, or region, remains as part of the chromosome that was not extruded and the normally active chromosome is the one extruded.13 Uniparental disomy (UPD) describes the state in which the remaining two homologs (i.e., chromosomes) after trisomic rescue are derived from the same parent. UPD can be either isodisomic or heterodisomic (Fig. 1.5). Whether the abnormal gamete came after a nondisjunction event in meiosis I (heterodisomy) or meiosis II (isodisomy) determines the outcome after a successful rescue. Heterodisomy results in two chromosomes from each grandparent, and when these two chromosomes remain after trisomic rescue, the result is uniparental heterodisomy. Biparental inheritance is the norm; this means that conditions characterized by abnormal imprinting can result. In addition to conditions characterized

sperm

by imprinting, uniparental isodisomy can result in expression of recessive variants. When a parent who is a carrier of a recessive allele has a child with UPD for a chromosome that carries that recessive allele, isodisomy at that locus will result in a child who expresses the recessive trait. This represents an example where one parent is a carrier and one is not but offspring are capable of expressing a recessive condition.14,15 UPD can also arise when a disomic ovum forms after nondisjunction and a sperm that is nullisomic for the same chromosome unite (or vice versa). Meiosis not only aims to preserve blueprint quantity but also ensures that at fertilization an equal amount of blueprint derives from male and female gametes. UPD most often follows meiosis I nondisjunction as tetrads fail to separate, resulting in heterodisomy. However, when a meiosis II nondisjunction occurs, with subsequent failure of sister chromatids to separate, UPD is isodisomic. In this case, trisomy rescue succeeds in establishing blueprint quantity, but the two-parent-of-origin requirement for genes is lacking (i.e., there will be either two identical paternal copies or two identical maternal copies). This can result in a clinically recognizable syndrome (e.g., PraderWilli syndrome [46,XY,upd(15)mat]). When trisomy rescue is successful and the male and female blueprint is preserved, a euploid zygote develops. Successful rescue can follow either meiosis I or meiosis II nondisjunction (see Fig. 1.5). Structural variation (SV) is a nonspecific term that includes large and small changes in the genome. When SV arises from two or more breaks in the genome, it is classified as complex.16 Complex SVs are often large and visible on a standard chromosomal analysis (i.e., karyotype). These include Robertsonian and insertional translocations as well as inversions. Robertsonian translocations occur between acrocentric chromosomes as a result of joining at the centromere. Acrocentric chromosomes (13, 14, 15, 21, and 22) have their

Trisomic rescue

oocyte Mat upd 15 Heterodisomy (Prader-Willi syndrome)

Successful rescue

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Chromosome 15 - Heterodisomy (meiosis I nondisjunction)

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Successful rescue

Figure 1.5 Trisomic rescue. After conception, aneuploidy can occur for any autosome; however, early embryonic death often follows. The early zygote can attempt to rescue itself by eliminating the extra chromosome. Possible outcomes are shown using Prader-Willi syndrome and chromosome 15 as an example. Mat upd, Maternal uniparental disomy.

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centromeres at the end of the chromosome. The short arm of these chromosomes consists of repetitive noncoding nucleotide sequences called satellites as well as genes that encode ribosomal RNA. Patients who carry Robertsonian translocations are phenotypically normal but are at risk to produce aneuploid conceptions (Fig. 1.6). Insertional translocations (Fig. 1.7) and inversions (Fig. 1.8) can result in an abnormal phenotype when carriers produce gametes that are missing a portion of the genome. When the blueprint is lost at the breakpoints or at positional effects (some genes require nearby sequences for normal transcription) required for normal transcriptional activity, the SV transmitted to the offspring will result in an abnormal phenotype. Imbalances in genomic quantity can also result from ring chromosomes that form after breakage of distal ends of the same chromosome and joining of the broken ends. The distal DNA that breaks away is lost through gametogenesis. A normal phenotype is unusual in fetuses and children with a ring chromosome because of loss of genetic material.

Human Genetics and Patterns of Inheritance

7

Marker chromosomes are derived from stray DNA, the origin of which can be difficult to identify. These are uncommon (1 to 2 per 2000 births).17 Two commonly observed markers derive from either chromosome 15, inv dup 15, or 22, inv dup (22)(pter-q11.2). The former is associated with developmental delay when the marker is large. When a person’s chromosome analysis includes three or four copies of the inv dup (22) (pter-q11.2) marker, cat-eye syndrome is the result. The clinical picture of cat-eye syndrome is variable but often includes coloboma (abnormal slit in the iris), from which the name of the syndrome is derived (Table 1.3). CNV is estimated to occur in 1% to 2% of healthy people.18 CNVs are SVs that result in a change in gene dosage. One might think of CNVs as being on a spectrum, with the largest possible CNV being a large piece of a chromosome or even an entire chromosome. Compared with the SVs described earlier (>5 Mb in size), CNVs are as small as 1 kb in size and therefore may not be visible on a conventional karyotype. The presence or absence of

Autosomes: 1 2 3 4 5 6 7 8 9 10 11 12

13, 14, 15 , 1 6 , 1 7 , 1 8 , 1 9 , 2 0 , 21, 22

Sex Chromosomes: X, Y Robertsonian Translocations Common

Rare

1) rob (13q14q) – most common (75%) A. Trisomy 13 rare 1.0% would include 5 to 28 genes, while a comparable pan-ethnic panel would include 40 genes. Although the carrier rate appears high, it should be considered that every individual is suspected to carry a dozen or more deleterious variants and that 0.17% to 2.52% of couples will be at risk of having a child affected by one of the screened conditions. The appropriate extent of screening must be individualized for each patient and take into account both identified genetic risks and personal values after counseling by a qualified professional. Informed patient consent is recommended prior to offering expanded carrier screening and should meet the following ACOG guidelines11,18: 1. Carrier screening of any nature is voluntary, and it is reasonable to accept or decline. 2. Results of genetic testing are confidential and protected in health insurance and employment by the Genetic Information Nondiscrimination Act of 2008.

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TABLE

2.3

Disorders Recommended for Ethnic-Based or Pan-ethnic Carrier Screening by ACOG

Group ALL WOMEN considering pregnancy or currently pregnant

GENETIC DISORDER Spinal muscular atrophy

Cystic fibrosis

Hemoglobinopathy (includes sickle cell disease [Hgb S], αthalassemia, and β-thalassemia)

Family history of fragile X–related disorders or intellectual disability suggestive of fragile X syndrome Ashkenazi Jewish (Eastern and Central European descent; should include Jews of unknown descent)

Fragile X syndrome (related disorders include premature ovarian insufficiency and fragile X–associated tremor/ataxia syndrome)

Tay-Sachs disease (Note: screening also recommended if patient is French Canadian or Cajun descent) Canavan disease Familial dysautonomia Additional Fanconi anemia autosomal group C recessive Bloom syndrome conditions Niemann-Pick for which disease type A screening Mucolipidosis should be type IV considered Gaucher disease in patients Familial of Ashkehyperinsulinism nazi Jewish Glycogen storage descent disease type IA Joubert syndrome Maple syrup urine disease type 1B Usher syndrome

Carrier Frequency Caucasian, 1:35 Hispanic, 1:117 Ashkenazi Jew, 1:41 Asian, 1:53 African-American, 1:66 Caucasian, 1:25 Hispanic, 1:58 Ashkenazi Jew, 1:24 Asian, 1:94 African-American, 1:61 Hgb S African-American, 1:10 Also in high frequency: Mediterranean, Middle Eastern, Southeast Asian, or West Indian descent α-Thalassemia African, 1:3 Mediterranean, 1:30 Southeast Asian, Middle Eastern, 1:20 β-Thalassemia African-American, 1300 disease-associated alleles identified) Most common screen is panel of 23 panethnic variants CBC with RBC indices for all women Hemoglobin electrophoresis if ethnicity-based risk or abnormal RBC indices

Detection Rate (%) Caucasian: 95% Hispanic: 91% Ashkenazi Jew: 90% Asian: 93% African-American: 71% Caucasian: 88% Hispanic: 72% Ashkenazi Jew: 94% Asian: 49% African-American: 65%

DNA-based molecular analysis (Southern blot and PCR) for triplet repeat

Ashkenazi Jew, 1:30 French Canadian, Cajun, 1:30 to 1:50 Non-Jewish groups, 1:300 1:41 1:31 1:89

Biochemical: hexosaminidase A level

98%

DNA variants DNA variants DNA variants

97% 99% 99%

1:100 1:90

DNA variants DNA variants

95%–97% 95%

1:127

DNA variants

95%

1:15 1:52

DNA variants DNA variants

95%

1:71

DNA variants

1:92 1:81

DNA variants DNA variants

1:95 (type III)

DNA variants

ACOG, American College of Obstetricians and Gynecologists; CBC, complete blood count; PCR, polymerase chain reaction; RBC, red blood cell count.

3. Conditions included on expanded carrier screening panels vary in severity. Many are associated with significant adverse outcomes such as cognitive impairment, decreased life expectancy, and need for medical or surgical intervention. 4. Pregnancy risk assessment depends on accurate knowledge of paternity. If the biological father is not available

for carrier screening, accurate risk assessment for recessive conditions is not possible. 5. A negative screen reduces but does not eliminate risk to offspring. This is referred to as residual risk. 6. Because expanded carrier screening includes a large number of disorders, it is common to identify carriers for one or more conditions. In most cases, being a carrier

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of an autosomal recessive condition has no clinical consequences for the individual carrier. If each partner is identified as a carrier of a different autosomal recessive condition, offspring are not likely to be affected. 7. In some instances, an individual may have two pathogenic variants for a condition (homozygous or compound heterozygous) and thus learn through carrier screening that they have an autosomal recessive condition that could affect current or future personal health. Some expanded carrier screening panels include selected autosomal dominant and X-linked conditions and, likewise, an individual may discover predisposition to these conditions. Referral to an appropriate specialist for medical management and genetic counseling is indicated in such circumstances to review the inheritance patterns, recurrence risks, and clinical features. 8. It is important for parents to understand that over 30% of genetic disorders are the result of de novo genetic variants. De novo variants arise in the germline or due to an error of somatic cell division. Therefore these variants will not be detected on parental carrier screens. 9. Downstream prenatal genetic testing on the offspring of carrier-positive parents is not available for all of the genes offered on expanded carrier screening panels. Therefore careful research on which laboratory can perform prenatal testing for a given condition is necessary prior to performing chorionic villus sampling (CVS) or amniocentesis. A recent publication from American College of Medical Genetics and Genomics (ACMG) recommends a tiered system based on carrier frequency19 and defines the gene content in each tier. It is important to note that carrier frequency was used to mean in any ethnic group with reasonable representation in the United States. In this tiered approach, Tier 1 conveys the recommendations previously adopted by ACMG and ACOG, with universal screening for CF and SMA and additional carrier screening dependent on clinical risk assessment. Tier 2 includes genes that have ≥1/100 carrier frequency. Tier 3 includes conditions with a ≥1/200 carrier frequency and includes X-linked conditions. Tier 4 includes genes less common than those in Tier 3, does not have lower limit carrier screening frequency, and can greatly extend the number of conditions screened. Although there are many serious conditions at a carrier frequency of less than 1/200, the problem with Tier 4 screening is that there is less information about the natural history and poor genotype-phenotype correlation for the very rare conditions. ACMG recommends that all pregnant patients and those planning a pregnancy should be offered Tier 3 carrier screening. Tier 3 screening currently encompasses 97 autosomal recessive and 16 X-linked genes, with recommendation for continuous scrutiny and adjustment of this list of genes. This is especially important at the time when emphasis on sequencing genomes from diverse populations will bring additional information on the prevalence and carrier frequency of mendelian disorders.␣ Fetal Genetic Screening and Testing ACOG and the Society for Maternal-Fetal Medicine (SMFM) recommend that all pregnant women be counseled, as early as possible in their prenatal care, about the opportunities for prenatal genetic assessment consisting of either aneuploidy screening or diagnostic testing. This recommendation is not dependent on maternal age or other risk factors.9 Furthermore, the same professional societies, in addition to the American

Molecular Genetic Technology

21

College of Radiology, all recommend prenatal ultrasound for accurate determination of gestational age, fetal number, cardiac activity, placental localization, and diagnosis of major fetal anomalies.20 Fetal structural anomalies or multiple minor sonographic markers identified on ultrasound increase the likelihood of aneuploidy, DNA microdeletions, or other genetic syndromes.21 Prenatal genetic testing should be offered to further evaluate abnormal findings on prenatal ultrasound. Comprehensive discussion of screening modalities and screening or testing indications for pregnancy is presented in Chapter 30. Here we focus on molecular genetic technologies, which are laboratory-based techniques for evaluating DNA sequence variation in an embryo or fetus. The benefits and limitations of the various types of genetic assessment are discussed for each technique. General benefits of genetic testing include identification of disorders for which in utero treatment may provide benefit, optimization of neonatal outcomes by planning appropriate delivery staffing and location, providing family preparation for caring for a child with a genetic disorder, the option of pregnancy termination, future pregnancy planning, and providing reassurance when results are normal.␣

Sources of Parental Genetic Material Genomic DNA is relatively stable; therefore it can be obtained from any cell with a nucleus, even if the cells are no longer viable. Samples for molecular testing can include blood lymphocytes, skin scrapings, hair, cheek cells or saliva, semen, urine, and paraffin tissue blocks. At the individual gene level, diseasespecific testing for families that carry known genetic variants may be performed using standard polymerase chain reaction (PCR) amplification and Sanger DNA sequencing methods (see Hybridization Techniques: Southern Blot, Polymerase Chain Reaction, later). An updated list of relatively common genetic conditions for which DNA-based prenatal diagnosis is available is kept on the Genetic Testing Registry website (www.ncbi.nlm. nih.gov/gtr).␣

Sources of Fetal Genetic Material EMBRYO BIOPSY Advancement of in  vitro fertilization techniques has allowed optimization of methods to remove or biopsy small numbers of cells from an in vitro fertilized embryo for genetic assessment prior to implantation. The techniques available to retrieve preimplantation cells include polar body biopsy of prefertilized oocytes, biopsy of one or two cells (termed blastomeres) from the six- to eight-cell early-cleavage-stage embryo on day 3, or removal of 5 to 12 cells from the trophectoderm of the 5- to 7-day blastocyst.22 In all cases, removal of the cells does not appear to cause any cellular damage, with continued development of the embryo and no increased risk for congenital anomalies.23␣ NONINVASIVE APPROACH: CELL-FREE DNA IN THE MATERNAL CIRCULATION Early attempts at noninvasive genetically based prenatal screening were focused on isolation of intact fetal cells within the maternal circulation. To date, this technology has proven unsuitable for clinical application due to multiple technological

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PART 1 Scientific Basis of Perinatal Biology

obstacles, such as limited numbers of fetal cells, unreliable recovery of fetal cells, and evidence that these cells persist long after pregnancy, thus complicating specificity in the setting of subsequent pregnancies.24 In contrast, identification of fetal-derived cell-free small DNA fragments (30%), a statistic that rises exponentially to 60% by age 40. However, early enthusiasm for this approach has been tempered by several clinical trials.138,139 One large multicenter randomized double-blind controlled trial conducted between 2003 and 2007 comparing IVF with PGT-A to standard IVF in 408 women (age range 35 to 41 years) showed a decreased pregnancy success rate (25% versus 37%) in those receiving PGT-A compared to those who did not.138 Aneuploidy screening may have failed to improve outcomes because many of the embryos that were rejected on the basis of aneuploidy by PGT-A FISH results would have been ultimately normal embryos with successful pregnancy potential (perhaps indicating that biopsy of a single blastomere is not representative of the karyotype of the conceptus due to trisomic rescue).140,141 During the two-, four-, and eight-cell stages of early embryo development, mosaicism with normal and aneuploid cells may be common, but only the small minority of normal cells will endure and give rise to the embryo. Negative results on this cleavage-stage randomized controlled trial did not deter various groups from applying new technologies to biopsy embryos at a later stage of development. The current PGT-A version 2.0 (as opposed to version 1.0, which relied on limited FISH probes) refers to embryo biopsy at the blastocyst stage (day 5 or 6), followed by genome-wide aneuploidy detection via array CGH, quantitative PCR, or massive parallel sequencing and then subsequent frozen elective single-embryo transfer. The advantages of trophectoderm biopsy at a blastocyst stage include (1) the ability to harvest several cells for more DNA to analyze, (2) the blastocyst biopsy is less damaging to the embryo than blastomere biopsy, and (3) there is, in general, less overall aneuploid mosaicism at the blastocyst stage. Massive parallel sequencing (NGS technology) relies on the same principle as ES/GS sequencing (Fig. 2.10) and has recently entered PGT-A to replace array CGH.142 Though array CGH is considered a gold standard, early claims are being made that massive parallel sequencing may also detect clinically significant mosaicism. However, such claims need to be tempered against the facts that only a few cells are being analyzed and the site of biopsy may significantly alter detection of mosaicism; therefore further studies are necessary before massive parallel sequencing can become a standard assay for mosaicism. To date, there have been approximately 100 documented live births after transferring mosaic embryos, and no significant adverse events have been documented.143 However, long-term follow-up is lacking and the significance of PGT-A mosaicism remains unclear. Pre- and post test genetic counseling is essential for patients to understand the risks of transferring mosaic embryos.

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Molecular Genetic Technology

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Deletion 9p, Trisomy 16

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Figure 2.10 Whole-genome profiling by oligonucleotide comparative genomic hybridization microarray performed on biopsy from a 6-day blastocyst and displayed by Agilent CytoGenomics software 4.0. Chromosomes are plotted in a horizontal orientation and are listed at the bottom of a plot. The single-cell recommended analysis method was used to detect aberrations with a minimum size of 5 Mb and minimum log2 ratios of 0.35 for gains and −0.45 for losses. The moving average from an embryonic DNA was compared against the male reference sample (blue line) and the female reference sample (pink line). The gender of an embryo is determined by a copy number of sex chromosomes and by comparison to normal reference male and female DNA. (A) A loss in copy number for the short arm of chromosome 9 (9p deletion) and a gain of all chromosome 16 probes (trisomy 16) were detected in a male embryo. (B) Chromosome 14 gain (trisomy 14) was observed in a female embryo. Arrows indicate location of abnormal loss and gain in copy numbers.

A number of small randomized controlled studies have shown 15% to 20% increased implantation and delivery rates with PGT-A.144–147 Other studies on PGT-A have shown decreased miscarriage rates in women older than 37 years of age who used PGT-A and no effect on individuals younger than 35 years.147 One randomized controlled trial in women of advanced maternal age (38–41 years old) showed benefits of PGT-A in clinical outcome at the first embryo transfer but also in dramatically decreasing miscarriage rates and shortening the time to pregnancy.148 Most recently, a randomized multicenter trial involving 330 women whose embryos underwent PGT-A versus 331 women whose embryos underwent morphologic examination did not show improvement in overall pregnancy outcomes, as analyzed per embryo transfer or per intention to treat. The age of participants ranged from 25 to 40 years. There was a significant increase in ongoing pregnancy per embryo transfer with the use of PGT-A in the subgroup of women aged 35–40 years, but this was not significant when analyzed by the intention to treat.149 The study showed no overall improvement in ongoing pregnancy rates and live birth rate in women aged 25–40 years but did support the use of PGT-A for women aged 35–40 years. In summary, additional multicenter trials with larger numbers of participants are needed to determine the efficacy of this technique in improving pregnancy outcomes. A number of indications have been proposed for PGTA, including recurrent miscarriage, advanced maternal age, diminished ovarian reserve, multiple failed IVF cycles, personal reasons (sex selection), improvement of singleton pregnancy IVF, reduction of twinning, and patient preference for transfer of a euploid embryo. Many couples at risk of carrying a child with a mendelian disorder undergo PGT-A in addition to PGTM. Despite all of the reasons mentioned previously, there is significant controversy regarding the effectiveness of PGT-A due to lack of large multicenter randomized controlled trials, practical problems of obtaining significant numbers of blastocysts in older patients, reports of euploid deliveries from aneuploid embryos, and controversies regarding discrepant karyotype and mosaicism in inner cell mass versus trophectoderm.150 Claims of higher implantation rates after PGT-A are countered by the fact that performing PGT-A is also associated with a subsequent

lower number of embryos for transfer and/or cryopreservation. The lack of consensus regarding the overall clinical utility of PGT-A will hopefully improve with outcomes of additional trials that are underway.142 Nonetheless, the attractiveness of assessing and only transferring seemingly euploid embryos has become commonplace in the United States. Careful counseling of couples regarding the pros and cons of embryo aneuploidy screening is very important. It is also critical to understand the limitations of PGT-A and to communicate these limitations to couples considering this procedure. Errors in PGT-A can arise due to mislabeling of samples, contamination with extraneous DNA, technical problems (amplification failure, array noise), discrepancy between inner cell mass karyotype and trophectoderm karyotype, and mosaicism in the trophectoderm sample. Moreover, PGT-A is a screening test, and the detection rate is not 100%. Screening is limited to whole chromosome gain or loss and will not detect subchromosomal deletions/duplications. PGT-A also does not test for whole chromosome mosaicism, triploidy (three sets of each chromosome), or genetic conditions caused by single-gene variants (such as CF). The false-negative rate for microarray PGT-A is lower than 1%. Every couple, regardless of their ethnic background and family history, has a 3% to 5% risk for birth defects with each pregnancy, and even if the result of PGT-A is normal, the baby could still have one or more birth defects or intellectual disability from causes not detected by PGT-A testing. PGT-A does not replace prenatal testing such as CVS or amniocentesis. Standard prenatal screening or testing should still be made available to patients undergoing IVF, including patients who had PGT-A. Women who do not desire to undergo diagnostic procedures due to associated risk of loss can be offered cfDNA screening with all of the caveats associated with such testing.␣ Preimplantation Genetic Diagnosis Prenatal Genetic Testing for Mendelian Disorders. PGT-M is used to describe genetic testing for mendelian disorders that is performed before an embryo transfer. Three approaches have been utilized for PGT-M to date. The first approach was based on polar body removal, and the genetic status of the oocyte was

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inferred from the results of the polar body assay. In the circumstance in which the polar body has the mutated gene, the oocyte is inferred to be “normal” and therefore an embryo obtained by fertilization of this oocyte would be unaffected with the genetic condition of interest. A second method of PGT-M is blastomere biopsy, in which one or two blastomeres are removed from an eight-cell (day 3) embryo and analyzed for the genetic condition of interest. Only embryos found not to have the genetic variant are transferred into the uterus. This is the method that has been most commonly used to date. Finally, PGT-M can be performed at the blastocyst stage by sampling a portion of the trophectoderm (early placenta). All three approaches appear to be safe, with studies showing no increased risk of birth defects or growth disorders in infants born after PGT-M when compared to infants born after other assisted reproductive technologies. Each technique is associated with some limitations. Polar body testing can result in an erroneous diagnosis because of crossing over occurring during meiosis. This limitation has become rare as newer technologies of direct gene testing have been introduced, replacing earlier studies that used linkage markers. However, its major limitation for recessive disorders is that polar body biopsy only determines the maternal contributions to the embryo. A finding that the embryo will have the maternal variant does not differentiate between a carrier and an affected embryo, thus decreasing the number of embryos that are “unaffected” to only those that receive the normal allele from the mother. Blastomere biopsy is subject to error relating to the requirement for DNA amplification from a single cell by PCR. Erroneous amplification of sperm DNA from the zona pellucida, allele dropout of one of the parental alleles during amplification, or both may lead to false-negative results. However, current molecular technologies using SNPs and short tandem repeats allow simultaneous variant detection and marker analysis, almost completely eliminating the risk of misdiagnosis by sperm contamination. Similarly, SNP microarrays following whole genome amplification provide methods to overcome the allele dropout problem as well. Blastocyst biopsy has the benefit of providing more cells (three to eight cells)136 but requires a longer culture period. Because of the late stage when the biopsy is performed, any genetic testing must be done rapidly, within 24 hours, or the biopsied blastocysts must be cryopreserved for later use. With improved embryo cultured conditions, many groups are performing PGT-M on blastocyst embryos (embryo day 5 or 6), and in many centers, PGT-M is usually performed in conjunction with PGT-A so that euploid and pathogenic variant-free embryos are transferred. In order for PGT-M to be performed, carrier status of the parents and the precise coordinates of the pathogenic variants are required. It is important to understand that currently PGT-M only detects inherited disorders; that is, pathogenic variants present in the parents and transmitted to the offspring. PGT-M will not detect de novo genetic disorders, or variants that are not detectable in parental blood but present in the offspring. Importantly, de novo variants are known to contribute as much as 40% to clinically significant phenotypes detected postnatally and probably contribute even more in prenatal cases. It is critical for couples to understand the scope and limitations of current PGT-M testing. The most common monogenetic disorders evaluated by PGT-M are CF, β-thalassemia, and SMA among the autosomal recessive disorders; myotonic dystrophy, Huntington disease, and Charcot-Marie-Tooth disease among the dominant disorders; and fragile X syndrome, Duchenne

or Becker muscular dystrophy, and hemophilia among the X-linked disorders. Because PGT-M is not 100% accurate, patients should still be offered prenatal diagnosis to confirm that the mendelian condition of concern is not present in the fetus. It is also important to consider ethical considerations when testing for late-onset disorders, such as Huntington disease. An individual whose embryos are undergoing PGT-M for Huntington disease may also request that his or her own carrier status not be disclosed to him or her. A “non-disclosure PGT-M” option exists that enables an at-risk parent to have Huntington disease–free children without finding out their own genetic status. For this to occur, familial mutation of other affected family members needs to be known. The at-risk parents remain blind to their own results, the embryo’s genetic test results, how many successful fertilizations occurred, and how many embryos are implanted. Only the health professionals handling the genetic tests of the embryos are aware of the results. It is ethically acceptable to honor such requests, but this practice is controversial around the world.151,152␣ Preimplantation Genetic Testing for Carriers of Balanced Rearrangements. Structural chromosome rearrangements include balanced alterations, such as translocations, inversions, and insertions, and unbalanced aberrations, also referred to as CNVs, such as deletions, duplications, and supernumerary marker chromosomes. These genomic abnormalities can result in losses, gains, or rearrangements of DNA fragments and impact human reproductive and developmental pathways, leading to infertility and/or a high risk of miscarriage, birth defects, and intellectual disability in offspring. Reciprocal translocations (exchange of DNA segments between two or more chromosomes) and Robertsonian translocations (caused by a fusion of the long arms of two acrocentric chromosomes) are the most common balanced structural chromosome rearrangements, affecting at least 1/500 individuals in the general population,153 and their incidence is likely underestimated.154 Prevalence of balanced chromosomal rearrangements among infertile patients is 8- to 10-fold higher than in the fertile population,154 affecting up to 15% of couples with reproductive problems.155,156 Carriers are usually phenotypically normal but present with a spectrum of reproductive phenotypes ranging from normal gametogenesis to meiotic arrest and subsequent oligo/azoospermia in males or depletion of germ cells and ovarian insufficiency in females. There is also an increased risk of producing chromosomally unbalanced gametes and conceiving an embryo affected by segmental aneuploidies (gains and losses of large DNA segments). Breakpoints of most balanced chromosome rearrangements are unique, making it difficult to assess the reproductive risk of unbalanced progeny. In couples with complex rearrangements (involving at least three chromosomes and three or more chromosome breakpoints) the proportion of affected embryos is very high and may require a large number of fertilized embryos for testing. Preimplantation genetic testing for inherited structural rearrangements (PGT-SR) can be offered to these couples at risk and performed as part of an IVF cycle. Embryos can be tested for the presence of imbalances involving chromosomal segments that are affected by parental rearrangement utilizing FISH, quantitative PCR, array comparative genomic hybridization (aCGH), SNP-based microarray, or NGS technologies. Most of these methods have a resolution and sensitivity to detect

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deletions and duplications that are larger than 5–10 Mb in size; however, the quality and quantity of biopsied samples are the limiting factors.157 Also, for PGT-SR in patients with complex rearrangements or pathogenic microdeletions and microduplications or when rearranged chromosomal segments are cryptic (less than 10 Mb), consultation with laboratory specialists is recommended prior to biopsy to determine techniques and sample type to efficiently identify unaffected embryos. Embryos determined to be negative for segmental aneuploidy may contain a normal karyotype or carry a balanced rearrangement, the same as present in the parent. Both chromosome complements are not expected to be associated with birth defects and, therefore, those embryos might be selected for transfer. Gametes of patients with balanced rearrangements have a higher chance to be affected by aneuploidy for any chromosome due to an interference in the proper segregation of other chromosome pairs, a phenomenon known as interchromosomal effect.157–160 In addition, chromosome rearrangements involving imprinted chromosomes (6, 7, 11, 14, 15, 20), particularly Robertsonian translocations involving chromosomes 14 and 15, are associated with an increased risk for uniparental disomy (UPD) and a liveborn child with an imprinting disorder.161 PGT-SR, utilizing a whole genome SNP-based strategy, is beneficial for a simultaneous detection of inherited segmental aneuploidies as well as additional numerical chromosome abnormalities and UPD. In rare instances, breakpoints of a balanced chromosome rearrangement fall within a gene or a gene regulatory region, affecting its function.162 Parents, carriers of such rearrangements, might be clinically affected or asymptomatic due to incomplete penetrance of the disease, late-onset manifestations, or a gender-limited phenotype and may desire to select karyotypically normal embryos for a transfer. Although challenging, PGT-SR for such purposes can be accomplished by advanced NGS techniques incorporating genotype comparison of the rearranged chromosomes in embryos and family members, high-resolution breakpoint mapping, and/or analysis of long DNA reads spanning the chromosome breakpoints to distinguish carrier from noncarrier embryos.163 Carriers of balanced and unbalanced structural chromosome rearrangements are often uncovered after conventional karyotype or microarray analysis performed as of part of the genetic evaluation of an affected child or for recurrent miscarriage, during prenatal diagnosis of a fetus with abnormal ultrasound findings, or after a fetal loss.164 Genetic testing of an affected offspring is extremely valuable in discovery and characterization of chromosome rearrangements carried by the parents because it allows for selection of effective IVF and PGT approaches. In patients with infertility, karyotype analysis is commonly performed; however, its resolution may not be sufficient to reveal cryptic balanced or unbalanced alterations. In addition, there is growing evidence for the high incidence of CNVs165 and germline mosaicism166 that may affect a patient’s fertility or embryonic or fetal viability. There has been a significant improvement in molecular cytogenetic techniques and NGS bioinformatic methods, enabling precise detection and characterization of chromosome rearrangements in human genomes.167,168 Application of these techniques to patients with unexplained infertility may unravel hidden structural chromosome rearrangements, identify disrupted genes, and aid in the selection of unaffected embryos.␣

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Ethical Issues Surrounding Preimplantation Genetic Testing PGT has raised numerous ethical issues. It allows individuals with adult-onset disorders, such as carriers for the BRCA1 variant, to carry embryos free of the pathogenic variants. PGT for adult-onset conditions is ethically justified both in cases when the condition is serious and for adult-onset conditions of lesser severity or penetrance.169 Significant counseling regarding PGT in such cases should include a detailed review of the adult condition from which the parent suffers, the degree of penetrance and expressivity of such condition, and medical interventions to manage the condition, as well as the overall residual risk of genetic disorders. Penetrance of many pathogenic variants for individual conditions is below 100%, and intrafamily variation is significant and should be understood by the patient. Publicly funded databases such as ClinGen are striving to curate all of the pathogenic variants and provide clinicians with guidelines regarding phenotypes and medical interventions. Another set of ethical considerations arises when individuals want to transfer embryos with genetic anomalies.170 Such requests are rare and may involve individuals who themselves are affected with conditions such as hearing loss and achondroplasia and would like to rear children with a similar phenotype. Extensive and highly individualized counseling in such situations is important, as for any PGT procedure, and should involve discussion about the condition, the full spectrum of the phenotype expressivity and penetrance as well as the potential lethality, and the emotional, physical, and financial effects that such a condition may have on the family unit. If the provider is not willing to assist the patients with their requests, patients should be given the option to seek help elsewhere. Overwhelming numbers of individuals with genetic conditions are born to couples without infertility problems and therefore individuals who seek assisted reproductive services should likewise have the same choices. Nonetheless, in circumstances in which a child is highly likely to be born with a severe condition that is associated with severe handicap and suffering, the physician can refuse to transfer such embryos. Recently, some commercial genetic laboratories have begun to offer polygenic risk score calculations in embryos also known as PGT-P. Polygenic risk scores have been derived from decades of GWAS studies on various medical conditions in children and adults and depend on using trait- and diseaseassociated SNPs to calculate risk. Polygenic risk scores in postnatal populations have the potential to supplement or even replace current disease risk prediction algorithms, although they are not currently used clinically pending further study validating clinical utility. PGT-P in human embryos has been offered for variety of traits including height, eye color, IQ, and susceptibility to diseases such diabetes, cancer, and cardiovascular disease.171,172 However, studies have shown that trait predictions are poor,171 are not accurate in diverse populations, and simply lack longitudinal data to show that such screening is clinically relevant. The use of PGT-P in human embryos is controversial and awaits further input from various stakeholders to address governance of PGT-P. Much controversy has also been generated surrounding the use of newly available genome editing technologies, such as clustered regularly-interspaced short palindromic repeats/ CRISPR-associated protein 9 (CRISPR/Cas9), to edit embryo genomes. Genome editing theoretically can be used to revert a pathogenic variant in the embryo to a benign variant.

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Alternatively, it could be used to “enhance” the embryo, with variants that can, for example, prevent infection with human immunodeficiency virus or provide other advantages. Genome editing is now widely used in animals and plants for various purposes, including pigs that carry variants that allow them to be a nonhuman organ donor or crops that carry variants to grow faster and be disease resistant. Routine application of genome editing to humans is unlikely to occur soon due to various problems, including generation of mosaic embryos, off-target effects (genetic editing at nonprescribed sites) with unintended consequences, and overall safety concerns inherent in new technologies. Research in this arena should be allowed to proceed because there are significant benefits that genetically affected human embryos may derive in the future.␣

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Conclusion The past two decades yielded revolutionary advances in reproductive genetic technology. Curation of human genome sequence information in the years since completion of the Human Genome Project and expanding applications of NGS have provided seemingly endless genotype data, and work is ongoing to translate that information to correlated phenotypes and reduce the burden of VUS. Access to genetic material has also burgeoned, with improved understanding of embryonic development, results of embryo biopsy, and ongoing exploration of data available from cfDNA. With rapidly developing technologies at our disposal, reproductive and obstetrics professionals have a responsibility to connect patients with resources to ensure full understanding of the benefits and limitations of various screening and diagnostic options. Obtaining genetic information prior to conception or birth is fundamental to making informed reproductive decisions, particularly for patients with a personal, family, or obstetric history signifying elevated risk for a genetic disorder. A combination of a long-standing diagnostic method (such as karyotyping) and chromosomal microarray and ES/GS sequencing may be needed to solve diagnostic dilemmas. Understanding the pros and cons of each technology is important when counseling patients about their options.␣

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There is a significant amount of naturally occurring genetic variation in the human genome. Single nucleotide polymorphisms (SNPs) introduce genetic variation at the level of individual base substitutions, and copy number variations (CNVs) represent variation in the “dose” of a relatively large DNA segment (1000 to 500,000 bp or more). The biological implications of genetic variants depend on the gene or genes affected by the change in DNA. The term mutation has been replaced by the term variant, which can be classified as benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Genetic disease ranges from abnormal numbers of whole chromosomes, to phenotypes caused by loss or gain of subchromosomal DNA segments containing several contiguous genes (called microdeletions and microduplications), to single-gene disorders (also called mendelian disorders). Human disease may also have a genetic basis with a more complex genotype-phenotype correlation, such as autism, which may involve multiple genes in addition to environmental influences.

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Genetic screening and testing should be accompanied by patient education, genetic counseling, timely disclosure of test results to patients, and the availability of next steps (such as definitive prenatal genetic testing) in the event of positive results. Carrier screening refers to genetic testing of asymptomatic individuals to determine whether they carry one or more disease-associated genetic variants. Ethnic-based carrier screening is targeted to specific ethnic populations known to be at increased risk for particular disorders. Pan-ethnic carrier screening tests for a select panel of disorders in all patients, regardless of race/ethnicity. It is also known as expanded carrier screening. Genetic risk assessment before or during pregnancy may be indicated based on family history, prior obstetric history, parental age, or ethnic background. Additionally, it is acceptable for any patient, regardless of risk, to choose diagnostic prenatal genetic testing after informed consent. Benefits of genetic testing include optimization of neonatal outcomes by planning appropriate delivery staffing and location, identification of disorders for which in utero treatment may provide benefit, the option of pregnancy termination or preimplantation selection, and providing reassurance when results are normal. The fetus, amniocytes, and chorionic villi each develop from different cell lines in early embryo development. Thus it is possible for tissue samples from each of these sources to have disparate karyotypes resulting from abnormal chromosome segregation. The earlier in development that an abnormal chromosomal segregation event such as nondisjunction or trisomy rescue occurs, the more widespread the mosaicism may be in the differentiated organism (i.e., more likely to affect both the chorion/placenta and the fetus). Later chromosomal segregation events are more likely to be confined to specific cell types, giving rise to clinical findings such as confined placental mosaicism, which leads to discordant karyotypes between chorionic villus sampling (CVS) and amniocentesis. Factors influencing the likelihood of fetal involvement for a mosaic aneuploidy result include the specific chromosome involved and the tissue source where the aneuploidy was detected. CVS and amniocentesis samples can be assessed by direct analysis and by analysis following long-term culture (approximately 1 week). There are benefits and drawbacks to each method, but diagnostic accuracy is maximized when both direct and culture methods are used concurrently. For both CVS and amniocentesis, long-term culture gives more accurate diagnostic capability for fetal karyotype. The molecular resolution of a G-banded karyotype is 5 Mb, which allows detection of chromosome number changes and relatively large structural chromosome rearrangements. Chromosomal microarray analysis (CMA) is a technique that samples across the whole genome with resolution down to a 50- to 100-kb level. CMA allows for detection of CNVs, including microdeletions and microduplications that would not be diagnosed on karyotype. Microarray is recommended for genetic analysis in cases with sonographic fetal anomalies and unexplained stillbirth and can be considered in any patient who chooses to undergo diagnostic prenatal testing.

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Southern blotting involves enzymatic digestion of DNA at unique cut sites, separation of fragment sizes on a gel, and transfer of the fragments to a membrane where they can be probed for the DNA segment of interest. This technique is commonly used to identify large repeat expansions for genes subject to dynamic variations, such as in fragile X syndrome. When PCR is used to amplify specific DNA fragments, multiple diagnostic genetic tests can be performed on minimal amounts of starting material. Next-generation sequencing (NGS) is the revolutionary technology that changed the scale of genetic testing possibilities. NGS, or massively parallel sequencing, is an automated technology that generates millions of simultaneous sequencing reads. NGS can be used to sequence entire genomes or constrained to specific areas of interest, including all protein-coding genes (an exome) or small numbers of individual genes. Current recommendations from ACOG, SMFM and ACMG specify that use of exome sequencing (ES) or genome sequencing (GS) for prenatal diagnosis can be a useful diagnostic when other testing is negative. The diagnostic accuracy of molecular genetic techniques depends on the source of DNA, the percentage of the total genome that is assessed in any given technique, and, for sequencing technology, the depth of sequence assessment (the number of overlapping sequence reads for a given segment of DNA). Noninvasive prenatal screening (NIPS) uses NGS of cfDNA derived from maternal plasma coupled with bioinformatics algorithms to determine fetal ploidy (chromosome count).

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The available tests have a high sensitivity and specificity for common trisomies (21, 18, 13); however, the predictive value of the tests is significantly different depending on the prevalence of aneuploidy in the population being tested. NIPS is an excellent screening tool for common aneuploidies in all risk populations and is superior to other forms of aneuploidy screening. Women whose reports from NIPS are indeterminate or uninterpretable have an increased risk of aneuploidy and should undergo comprehensive ultrasound evaluation and genetic counseling with the option for diagnostic genetic testing. PGT-A is an option for patients with infertility undergoing in vitro fertilization (IVF), with the goal of increasing take-home pregnancy rates by screening for aneuploidy. There is significant controversy regarding the effectiveness of PGT-A in women under 35 years of age, but current data suggest that it is useful in women older than 35 years of age. PGT-M involves genetic testing on embryos prior to implantation from parents with identified risk of transmitting a known genetic or chromosomal abnormality to their offspring. PGT-M can detect only inherited disorders and will not detect de novo genetic variants, which contribute as much as 40% to clinically significant phenotypes. There is also residual risk following PGT-M, such that patients should still be offered prenatal diagnosis for confirmation.

A full reference list is available online at ExpertConsult.com.

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56. Ledbetter DH, Zachary JM, Simpson JL, et al. Cytogenetic results from the U.S. Collaborative Study on CVS. Prenat Diagn. 1992;12:317. 57. Boehm FH, Salyer SL, Dev VG, et al. Chorionic villus sampling: quality control—a continuous improvement model. Am J Obstet Gynecol. 1993;168:1766. 58. Winsor EJ, Akoury H, Chitayat D, et al. The role of molecular microsatellite identity testing to detect sampling errors in prenatal diagnosis. Prenat Diagn. 2010;30:746. 59. Kalousek DK, Howard-Peebles PN, Olson SB, et al. Confirmation of CVS mosaicism in term placentae and high frequency of intrauterine growth retardation association with confined placental mosaicism. Prenat Diagn. 1991;11:743. 60. Mardy A, Wapner RJ. Confined placental mosaicism and its impact on confirmation of NIPT results. Am J Med Genet C Semin Med Genet. 2016;172:118. 61. Wolstenholme J. Confined placental mosaicism for trisomies 2, 3, 7, 8, 9, 16, and 22: their incidence, likely origins, and mechanisms for cell lineage compartmentalization. Prenat Diagn. 1996;16:511. 62. Cassidy SB, Lai LW, Erickson RP, et al. Trisomy 15 with loss of the paternal 15 as a cause of Prader-Willi syndrome due to maternal disomy. Am J Hum Genet. 1992;51:701. 63. Purvis-Smith SG, Saville T, Manass S, et al. Uniparental disomy 15 resulting from “correction” of an initial trisomy 15. Am J Hum Genet. 1992;50:1348. 64. Ledbetter DH, Engel E. Uniparental disomy in humans: development of an imprinting map and its implications for prenatal diagnosis. Hum Mol Genet. 1995;4(Spec No). 1757. 65. Worton RG, Stern R. A canadian collaborative study of mosaicism in amniotic fluid cell cultures. Prenat Diagn. 1984;4(Spec No):131. 66. Kalousek DK, Dill FJ, Pantzar T, et al. Confined chorionic mosaicism in prenatal diagnosis. Hum Genet. 1987;77:163. 67. Goldberg JD, Porter AE, Golbus MS. Current assessment of fetal losses as a direct consequence of chorionic villus sampling. Am J Med Genet. 1990;35:174. 68. Johnson A, Wapner RJ, Davis GH, et al. Mosaicism in chorionic villus sampling: an association with poor perinatal outcome. Obstet Gynecol. 1990;75:573. 69. Wapner RJ, Simpson JL, Golbus MS, et al. Chorionic mosaicism: association with fetal loss but not with adverse perinatal outcome. Prenat Diagn. 1992;12:347. 70. Breed AS, Mantingh A, Vosters R, et al. Followup and pregnancy outcome after a diagnosis of mosaicism in CVS. Prenat Diagn. 1991;11:577. 71. Post JG, Nijhuis JG. Trisomy 16 confined to the placenta. Prenat Diagn. 1992;12:1001. 72. Phillips OP, Tharapel AT, Lerner JL, et al. Risk of fetal mosaicism when placental mosaicism is diagnosed by chorionic villus sampling. Am J Obstet Gynecol. 1996;174:850. 73. Benn P. Trisomy 16 and trisomy 16 mosaicism: a review. Am J Med Genet. 1998; 79:121. 74. Vejerslev LO, Mikkelsen M. The european collaborative study on mosaicism in chorionic villus sampling: data from 1986 to 1987. Prenat Diagn. 1989;9:575. 75. Fassihi H, McGrath JA. Prenatal diagnosis of epidermolysis bullosa. Dermatol Clin. 2010;28:231.

76. Evans MI, Krivchenia EL, Johnson MP, et al. In utero fetal muscle biopsy alters diagnosis and carrier risks in Duchenne and Becker muscular dystrophy. Fetal Diagn Ther. 1995;10:71. 77. Kuller JA, Hoffman EP, Fries MH, et al. Prenatal diagnosis of Duchenne muscular dystrophy by fetal muscle biopsy. Hum Genet. 1992;90:34. 78. Suren A, Grone HJ, Kallerhoff M, et al. Prenatal diagnosis of congenital nephrosis of the Finnish type (CNF) in the second trimester. Int J Gynaecol Obstet. 1993;41:165. 79. Johnson MP, Bukowski TP, Reitleman C, et al. In utero surgical treatment of fetal obstructive uropathy: a new comprehensive approach to identify appropriate candidates for vesicoamniotic shunt therapy. Am J Obstet Gynecol. 1770;170:1994. 80. Klinger K, Landes G, Shook D, et al. Rapid detection of chromosome aneuploidies in uncultured amniocytes by using fluorescence in situ hybridization (FISH). Am J Hum Genet. 1992;51:55. 81. Ward BE, Gersen SL, Carelli MP, et al. Rapid prenatal diagnosis of chromosomal aneuploidies by fluorescence in situ hybridization: clinical experience with 4,500 specimens. Am J Hum Genet. 1993;52:854. 82. Cheong Leung W, Chitayat D, Seaward G, et al. Role of amniotic fluid interphase fluorescence in situ hybridization (FISH) analysis in patient management. Prenat Diagn. 2001;21:327. 83. Sawa R, Hayashi Z, Tanaka T, et al. Rapid detection of chromosome aneuploidies by prenatal interphase FISH (fluorescence in situ hybridization) and its clinical utility in japan. J Obstet Gynaecol Res. 2001;27:41. 84. Tepperberg J, Pettenati MJ, Rao PN, et al. Prenatal diagnosis using interphase fluorescence in situ hybridization (FISH): 2-year multicenter retrospective study and review of the literature. Prenat Diagn. 2001;21:293. 85. Weremowicz S, Sandstrom DJ, Morton CC, et al. Fluorescence in situ hybridization (FISH) for rapid detection of aneuploidy: experience in 911 prenatal cases. Prenat Diagn. 2001;21:262. 86. Technology Transfer Committee, American College of Medical Genetics. Technical and clinical assessment of fluorescence in situ hybridization: an ACMG/ASHG position statement. I. Technical considerations. Test and Technology Transfer Committee. Genet Med. 2000;2:356. 87. Evans MI, Goldberg JD, Horenstein J, et al. Selective termination for structural, chromosomal, and mendelian anomalies: international experience. Am J Obstet Gynecol. 1999;181:893. 88. Pergament E. The application of fluorescence in-situ hybridization to prenatal diagnosis. Curr Opin Obstet Gynecol. 2000;12:73. 89. McDonald-McGinn DM, Emanuel BS, Zackai EH. 2 Deletion Syndrome, in Genereviews(r) 22q11. Seattle (WA): 1993. 90. Society for Maternal-Fetal Medicine, Dugoff L, Norton ME, et al. The use of chromosomal microarray for prenatal diagnosis. Am J Obstet Gynecol. 2016;215:B2. 91. Snijders AM, Nowak N, Segraves R, et al. Assembly of microarrays for genome-wide measurement of DNA copy number. Nat Genet. 2001;29:263. 92. Beaudet AL, Belmont JW. Array-based DNA diagnostics: let the revolution begin. Annu Rev Med. 2008;59:113.

93. Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86:749. 94. Hillman SC, Willams D, Carss KJ, et al. Prenatal exome sequencing for fetuses with structural abnormalities: the next step. Ultrasound Obstet Gynecol. 2015;45:4. 95. Wapner RJ, Martin CL, Levy B, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012;367:2175. 96. Donnelly JC, Platt LD, Rebarber A, et al. Association of copy number variants with specific ultrasonographically detected fetal anomalies. Obstet Gynecol. 2014;124:83. 97. Reddy UM, Page GP, Saade GR, et al. Karyotype versus microarray testing for genetic abnormalities after stillbirth. N Engl J Med. 2012;367:2185. 98. Yatsenko SA, Davis S, Hendrix NW, et al. Application of chromosomal microarray in the evaluation of abnormal prenatal findings. Clin Genet. 2013;84:47. 99. Kearney HM, Thorland EC, Brown KK, et al. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med. 2011;13:680. 100. Giardino D, Corti C, Ballarati L, et al. De novo balanced chromosome rearrangements in prenatal diagnosis. Prenat Diagn. 2009;29:257. 101. Warburton D. De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints. Am J Hum Genet. 1991;49:995. 102. Conlin LK, Thiel BD, Bonnemann CG, et al. Mechanisms of mosaicism, chimerism and uniparental disomy identified by single nucleotide polymorphism array analysis. Hum Mol Genet. 2010;19:1263. 103. Southern EM. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975;98:503. 104. Sutherland GR, Gedeon A, Kornman L, et al. Prenatal diagnosis of fragile X syndrome by direct detection of the unstable DNA sequence. N Engl J Med. 1720;325:1991. 105. Prior TW, Bridgeman SJ. Experience and strategy for the molecular testing of Duchenne muscular dystrophy. J Mol Diagn. 2005;7:317. 106. Mullis K, Faloona F, Scharf S, et al. Specific enzymatic amplification of DNA in vitro: the polymerase chain reaction. Cold Spring Harb Symp Quant Biol. 1986;51(Pt 1):263. 107. Mullis KB, Faloona FA. Specific synthesis of DNA in vitro via a polymerase-catalyzed chain reaction. Methods Enzymol. 1987;155:335. 108. Jama M, Millson A, Miller CE, et al. Triplet repeat primed PCR simplifies testing for Huntington disease. J Mol Diagn. 2013;15:255. 109. Treff NR, Tao X, Ferry KM, et al. Development and validation of an accurate quantitative realtime polymerase chain reaction-based assay for human blastocyst comprehensive chromosomal aneuploidy screening. Fertil Steril. 2012;97:819. 110. Higuchi R, Fockler C, Dollinger G, et al. Kinetic PCR analysis: real-time monitoring of DNA amplification reactions. Biotechnology (N Y). 1993;11:1026. 111. Manickam K, McClain MR, Demmer LA, et al. ACMG Practice Guideline Exome and genome sequencing for pediatric patients

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128. Mazloom AR, Dzakula Z, Oeth P, et al. Noninvasive prenatal detection of sex chromosomal aneuploidies by sequencing circulating cellfree DNA from maternal plasma. Prenat Diagn. 2013;33:591. 129. Poon LC, Musci T, Song K, et al. Maternal plasma cell-free fetal and maternal DNA at 11-13 weeks’ gestation: relation to fetal and maternal characteristics and pregnancy outcomes. Fetal Diagn Ther. 2013;33:215. 130. McCullough RM, Almasri EA, Guan X, et al. Non-invasive prenatal chromosomal aneuploidy testing–clinical experience: 100,000 clinical samples. PLoS ONE. 2014;9:e109173. 131. Norton ME, Jacobsson B, Swamy GK, et al. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med. 2015;372:1589. 132. Van den Veyver IB. Recent advances in prenatal genetic screening and testing. F1000Res. 2016;5:2591. 133. Wapner RJ, Babiarz JE, Levy B, et al. Expanding the scope of noninvasive prenatal testing: detection of fetal microdeletion syndromes. Am J Obstet Gynecol. 2015;212:332e1. 134. Society for Maternal-Fetal Medicine, Norton ME, Biggio JR, et al. The role of ultrasound in women who undergo cell-free DNA screening. Am J Obstet Gynecol. 2017;216:B2. 135. Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. The use of preimplantation genetic testing for aneuploidy (PGT-A): a committee opinion. Fertil Steril. 2018;109(3):429–436. https://doi.org/10.1016/j. fertnstert.2018.01.002. 29566854. 136. Harris BS, Bishop KC, Kuller JA, Alkilany BS, Price TM. Preimplantation genetic testing: a review of current modalities. Fertil Steril Rev. 2021;2:43–56. 137. Preimplantation Genetic Testing: ACOG Committee Opinion. Number 799. Obstet Gynecol. 2020;135(3):e133–e137. https:// doi.org/10.1097/AOG.0000000000003714. PubMed PMID: 32080053. 138. Mastenbroek S, Twisk M, van Echten-Arends J, et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med. 2007;357:9. 139. Twisk M, Mastenbroek S, Hoek A, et al. No beneficial effect of preimplantation genetic screening in women of advanced maternal age with a high risk for embryonic aneuploidy. Hum Reprod. 2008;23:2813. 140. Vanneste E, Voet T, Melotte C, et al. What next for preimplantation genetic screening? High mitotic chromosome instability rate provides the biological basis for the low success rate. Hum Reprod. 2009;24:2679. 141. Vanneste E, Voet T, Le Caignec C, et al. Chromosome instability is common in human cleavage-stage embryos. Nat Med. 2009;15:577. 142. Sermon K, Capalbo A, Cohen J, et al. The why, the how and the when of PGS 2.0: current practices and expert opinions of fertility specialists, molecular biologists, and embryologists. Mol Hum Reprod. 2016;22:845. 143. Practice Committee and Genetic Counseling Professional Group (GCPG) of the American Society for Reproductive Medicine. Clinical management of mosaic results from preimplantation genetic testing for aneuploidy (PGT-A) of blastocysts: a committee opinion.

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Fertil Steril. 2020;114(2):246–254. https://doi. org/10.1016/j.fertnstert.2020.05.014. PMID: 32741460. Forman EJ, Upham KM, Cheng M, et al. Comprehensive chromosome screening alters traditional morphology-based embryo selection: a prospective study of 100 consecutive cycles of planned fresh euploid blastocyst transfer. Fertil Steril. 2013;100:718. Scott Jr RT, Upham KM, Forman EJ, et al. Blastocyst biopsy with comprehensive chromosome screening and fresh embryo transfer significantly increases in vitro fertilization implantation and delivery rates: a randomized controlled trial. Fertil Steril. 2013;100:697. Fiorentino F, Biricik A, Bono S, et al. Development and validation of a nextgeneration sequencing-based protocol for 24-chromosome aneuploidy screening of embryos. Fertil Steril. 2014;101:1375. Chang J, Boulet SL, Jeng G, et al. Outcomes of in vitro fertilization with preimplantation genetic diagnosis: an analysis of the United States assisted reproductive technology surveillance data, 2011-2012. Fertil Steril. 2016;105:394. Rubio C, Bellver J, Rodrigo L, et al. In vitro fertilization with preimplantation genetic diagnosis for aneuploidies in advanced maternal age: a randomized, controlled study. Fertil Steril. 2017;107(5):1122–1129. https:// doi.org/10.1016/j.fertnstert.2017.03.011. Epub 2017 Apr 19. PMID: 28433371. Munné S, Kaplan B, Frattarelli JL, STAR Study Group, et al. Preimplantation genetic testing for aneuploidy versus morphology as selection criteria for single frozen-thawed embryo transfer in good-prognosis patients: a multicenter randomized clinical trial. Fertil Steril. 2019;112(6):1071–1079.e7. https://doi. org/10.1016/j.fertnstert.2019.07.1346. Epub 2019 Sep 21. PMID: 31551155. Gleicher N, Vidali A, Braverman J, et al. Accuracy of preimplantation genetic screening (PGS) is compromised by degree of mosaicism of human embryos. Reprod Biol Endocrinol. 2016;14:54. Asscher E, Koops BJ. The right not to know and preimplantation genetic diagnosis for Huntington’s disease. J Med Ethics. 2010;36(1):30– 33. https://doi.org/10.1136/jme.2009.031047. PMID: 20026690. Ethics Committee of the American Society for Reproductive Medicine. Ethics Committee of the American Society for Reproductive Medicine. Use of preimplantation genetic testing for monogenic defects (PGT-M) for adultonset conditions: an Ethics Committee opinion. Fertil Steril. 2018;109(6):989–992. https:// doi.org/10.1016/j.fertnstert.2018.04.003. PMID: 29935659. Wilch ES, Morton CC. Historical and clinical perspectives on chromosomal translocations. Adv Exp Med Biol. 2018;1044:1–14. https://doi.org/10.1007/978-981-13-0593-1_1. PMID: 29956287. Dong Z, Wang H, Chen H, et al. Identification of balanced chromosomal rearrangements previously unknown among participants in the 1000 Genomes Project: implications for interpretation of structural variation in genomes and the future of clinical cytogenetics. Genet Med. 2018;20(7):697–707. https://doi. org/10.1038/gim.2017.170. Epub 2017 Nov 2. PMID: 29095815; PMCID: PMC5932280.

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155. Stern C, Pertile M, Norris H, Hale L, Baker HW. Chromosome translocations in couples with in-vitro fertilization implantation failure. Hum Reprod. 1999;14(8):2097–2101. https:// doi.org/10.1093/humrep/14.8.2097. PMID: 10438432. 156. Dong Z, Yan J, Xu F, et al. Genome sequencing explores complexity of chromosomal abnormalities in recurrent miscarriage. Am J Hum Genet. 2019;105(6):1102–1111. https:// doi.org/10.1016/j.ajhg.2019.10.003. Epub 2019 Oct 31. PMID: 31679651; PMCID: PMC6904795. 157. Treff NR, Franasiak JM. Detection of segmental aneuploidy and mosaicism in the human preimplantation embryo: technical considerations and limitations. Fertil Steril. 2017;107(1):27–31. https://doi.org/10.1016/j. fertnstert.2016.09.039. Epub 2016 Nov 2. PMID: 27816233. 158. Mateu-Brull E, Rodrigo L, Peinado V, et al. Interchromosomal effect in carriers of translocations and inversions assessed by preimplantation genetic testing for structural rearrangements (PGT-SR). J Assist Reprod Genet. 2019;36(12):2547–2555. https://doi.org/10.1007/ s10815-019-01593-9. Epub 2019 Nov 6. PMID: 31696386; PMCID: PMC6911137. 159. Kirkpatrick G, Ferguson KA, Gao H, et al. A comparison of sperm aneuploidy rates between infertile men with normal and abnormal karyotypes. Hum Reprod. 2008;23(7):1679– 1683. https://doi.org/10.1093/humrep/ den126. Epub 2008 Apr 24. PMID: 18436578. 160. Anton E, Vidal F, Blanco J. Interchromosomal effect analyses by sperm FISH: incidence and

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distribution among reorganization carriers. Syst Biol Reprod Med. 2011;57(6):268–278. https://doi.org/10.3109/19396368.2011.63368 2. PMID: 22092077. Yamazawa K, Ogata T, Ferguson-Smith AC. Uniparental disomy and human disease: an overview. Am J Med Genet C Semin Med Genet. 2010;154C(3):329–334. https://doi. org/10.1002/ajmg.c.30270. PMID: 20803655. Wilch ES, Morton CC. Historical and clinical perspectives on chromosomal translocations. Adv Exp Med Biol. 2018;1044:1–14. https://doi.org/10.1007/978-981-13-0593-1_1. PMID: 29956287. Chow JFC, Cheng HHY, Lau EYL, Yeung WSB, Ng EHY. Distinguishing between carrier and noncarrier embryos with the use of long-read sequencing in preimplantation genetic testing for reciprocal translocations. Genomics. 2020;112(1):494–500. https://doi. org/10.1016/j.ygeno.2019.04.001. Epub 2019 Apr 1. PMID: 30946890. Yatsenko SA, Rajkovic A. Genetics of human female infertility†. Biol Reprod. 2019;101(3):549– 566. https://doi.org/10.1093/biolre/ioz084. PMID: 31077289; PMCID: PMC8127036 . Gajecka M. Unrevealed mosaicism in the nextgeneration sequencing era. Mol Genet Genomics. 2016;291(2):513–530. https://doi.org/10.1007/ s00438-015-1130-7. Epub 2015 Oct 19. PMID: 26481646; PMCID: PMC4819561. Ordulu Z, Kammin T, Brand H, et al. Structural chromosomal rearrangements require nucleotide-level resolution: lessons from nextgeneration sequencing in prenatal diagnosis. Am J Hum Genet. 2016;99(5):1015–1033.

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https://doi.org/10.1016/j.ajhg.2016.08.022. Epub 2016 Oct 13. PMID: 27745839; PMCID: PMC5097935. Hochstenbach R, van Binsbergen E, SchuringBlom H, Buijs A, Ploos van Amstel HK. A survey of undetected, clinically relevant chromosome abnormalities when replacing postnatal karyotyping by whole genome sequencing. Eur J Med Genet. 2019;62(9):103543. https://doi. org/10.1016/j.ejmg.2018.09.010. Epub 2018 Sep. 22. PMID: 30248410. Hochstenbach R, van Binsbergen E, SchuringBlom H, Buijs A, Ploos van Amstel HK. A survey of undetected, clinically relevant chromosome abnormalities when replacing postnatal karyotyping by whole genome sequencing. Eur J Med Genet. 2019;62(9):103543. https://doi. org/10.1016/j.ejmg.2018.09.010. Epub 2018 Sep. 22. PMID: 30248410. Ethics Committee of the American Society for Reproductive Medicine. Use of preimplantation genetic diagnosis for serious adult onset conditions: a committee opinion. Fertil Steril. 2013;100:54. Ethics Committee of the American Society for Reproductive Medicine. Transferring embryos with genetic anomalies detected in preimplantation testing: an ethics committee opinion. Fertil Steril. 2017;107:1130. Karavani E, Zuk O, Zeevi D, et al. Screening human embryos for polygenic traits has limited utility. Cell. 2019;179:1424. Lázaro-Muñoz G, Pereira S, Carmi S, et al. Screening embryos for polygenic conditions and traits: ethical considerations for an emerging technology. Genet Med. 2021;23:432.

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Normal Early Development MANA M. PARAST, MD, PHD

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DRUCILLA J. ROBERTS, MD, MS

Miscarriage, fetal growth restriction, and preeclampsia are pathologies generally arising from events that go awry in the early developmental period. Most fetal malformations arise in early embryogenesis. Thus to accurately diagnose and design effective treatments for these conditions, an understanding of early human development is essential. Normal early placental and embryonic development requires a complex sequence and array of signaling pathways, cell-cell communication, and decidua-embryo and maternal immune cell–embryo crosstalk. This chapter reviews the earliest developmental events of the embryo and placenta.

Preimplantation Development After fertilization, the zygote moves through the fallopian tube to the endometrial cavity for implantation, a process that takes ∼7 days (0–7 days postfertilization). During this time, many events occur in both the zygote and the endometrium to permit successful continuation of the pregnancy. In the zygote, the earliest events occur under relative transcriptional silence, utilizing maternally-derived “stored” proteins and mRNAs (maternal messenger RNAs), which mediate the first two cleavage divisions.1 In the human embryo, zygotic control of cell divisions commences with the third cleavage division, at the four- to eight-cell transition, and is termed embryonic genome activation (EGA).1 Although the zygotic genome is biparental, the contributions to the early zygote from each parent are not equal: a phenomenon called imprinting2 silences transcription from one or the other parent’s allele in select genes, a process with significant implications for early human development, discussed in more detail later in this chapter. Following the third cleavage division and EGA, at 3 days postfertilization, the zygote begins to undergo compaction to form the morula, taking the first morphological steps toward loss of radial symmetry.1 At this stage, cell junctions form, and positional cell polarity begins to develop, with inner and outer cells becoming distinct. Further changes in morphology and gene expression lead to the outer cells becoming trophectoderm (TE) and the inner cells forming the inner cell mass (ICM). Recently, keratins have been identified as one of the earliest asymmetrically inherited fate determinants that play a key role in the specification of outer cells as TE.3 While TE cells are the progenitor of all trophoblast cells (epithelial component) of the placenta, the ICM gives rise, not just to the embryo proper, but also to extraembryonic/primitive endoderm (yolk sac) and extraembryonic mesoderm, which forms the mesenchyme and fetal vascular components of the placenta. An early factor expressed in the zygotic genome is POU homeodomain class 5 transcription factor 1 (POU5F1, also known as octamer-binding transcription factor 4 [OCT4]) (Box 3.1), a critical protein involved in maintenance of pluripotency.4 42

In the early human zygote, all cells express POU5F1 (OCT4) up to, and including, the early blastocyst stage. The first lineage specification factor expressed in the outer cells of the compacted morula is caudal-type homeobox transcription factor 2 (CDX2), which is coexpressed with POU5F1 (OCT4) in cells destined to become TE.4,5 The developing embryo enters the uterine cavity on or about 4 days postfertilization and, shortly before it enters the uterus, undergoes cavitation to form the blastocyst. Although cell fate determination of the TE lineage likely begins at the compacted morula stage, morphologic differentiation of a human ovum into embryonic and TE cells first occurs in a 58-cell blastocyst, around 5 days postfertilization, as first described by Hertig6 and most recently confirmed by single-cell transcriptome analysis.7 In the early blastocyst (5–6 days postfertilization), one can identify the outer shell of TE and the ICM (Fig. 3.1). By the late blastocyst stages (7–8 days postfertilization), the ICM further differentiates into the primitive endoderm/hypoblast (PrE, located nearest the blastocyst cavity) and the epiblast (see Fig. 3.1). The PrE goes on to form the yolk sac, while epiblast is the precursor to both the embryo proper and extraembryonic mesoderm. The molecular controls of these preimplantation events have been best described in the mouse, but with the advent of single-cell analysis7,8 and recent advances in long-term culture of human embryos,5,9 significant differences between murine and human embryogenesis have been identified, which deserve mention here.10,11 For example, in the murine system, the totipotent blastomeres differentiate to TE and ICM by restricted expression of Cdx2 and Pou5f1 (Oct4) transcription factors, respectively. Along with Pou5f1, Nanog (a homeodomain transcription factor) and SRY-box 2 (Sox2, an SRY-related HMG-box transcription factor) (see Box 3.1) are coexpressed in the ICM, all of which are necessary to maintain pluripotency. The inner cell mass then differentiates to the epiblast and primitive endoderm by restricted expression of the transcription factor GATA binding protein 6 (Gata6) to the primitive endoderm (Fig. 3.2). In the human embryo, however, while some of these same factors are expressed, significant differences have been identified. For example, POU5F1 (OCT4) is expressed in all cells of the human blastocyst, including those of the TE, through 6 days postfertilization,4,5,12 where it may play a role in establishment of this lineage.13 Compared to mouse TE, human TE is defined by low levels of CDX2 expression, but significantly higher levels of another transcription factor, GATA3.4,5 In addition to POU5F1 coexpression with low CDX2 levels, the human TE also lacks expression of ELF5 and EOMES, two transcription factors involved in TE lineage identity and maintenance in the mouse.8 Perhaps as a result of all these differences, human TE has been shown to remain non– lineage-restricted with the ability to contribute to NANOG+

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3

BOX 3.1

SYNOPSIS OF SELECT CRITICAL GENETIC FACTORS REGULATING DEVELOPMENTAL PROCESSES

TRANSCRIPTION FACTORS CDX: Caudal-type homeobox transcription factors, important in trophoblast fate determination and later in intestinal epithelial cell differentiation.138 HOX: Homeobox-containing transcription factors highly conserved evolutionarily and across species. The HOX gene complex provides specific regional distinction of the anteriorposterior axis of vertebrate embryos.139 HOX genes are also important in specific organogenesis (e.g., the gynecologic tract140) as well as limb,141 hindbrain,142 and gut143 patterning. Mutations, misexpressions, or deletions of HOX genes are often lethal but can also result in viability with often severe malformations144 (for review, see Goodman and Scambler145). GATA: Family of zinc finger transcription factors that bind GATA motifs. GATA proteins are important in formation of mesendoderm and endoderm, hematopoiesis, heart and lung development, gonadal development, and T-cell differentiation.146 NANOG: A homeodomain transcription factor key in maintaining inner cell mass pluripotency.147 POU/OCT: Homeodomain and octamer domain transcription factors with pivotal roles in embryogenesis, neurogenesis, metabolism, and immunity.148 SOX: Sex determining region Y (SRY)–related high-mobility group (HMG)-box transcription factors conserved throughout eukaryotic species. Important in many developmental regulatory events, including sex determination, neuronal development, and lung and gut patterning.149 TBX: T-box containing transcription factors. The genes (about 17) in the TBX family produce proteins that are essential for the embryonic development of mesodermal derivatives, including the extremities and the fetal heart.150 TBX genes have been implicated in human malformation syndromes and defects, including DiGeorge, Holt-Oram, and some forms of cleft palate (for review, see Packham and Brook151).␣ GENE FAMILIES ENCODING SECRETED PROTEINS BMP: A family of growth factors/cytokines that work as morphogens regulating patterning throughout development.152 Their importance during development is exemplified by the fact that mutations in bone morphogenetic proteins (BMPs) either are embryonic lethal or cause major malformations.153,154 FGF: A conserved family of secreted growth factors (heparinbinding proteins) with 22 family members in humans. Fibroblastic growth factors (FGFs) have multiple roles in embryonic development, including cell fate determination, angiogenesis, branching morphogenesis, and limb patterning.155 SHH: A critical evolutionarily conserved signaling molecule of the hedgehog family. Sonic hedgehog (SHH) is important in many aspects of development as a morphogen, including leftright asymmetry, anterior-posterior axis formation and mesodermal morphogenesis, axial segmentation and limb, gut, neural, and lung development.156,157 Alterations of SHH, or its pathway, are the cause of many cases of holoprosencephaly and its associated cyclopia.158 WNT: A family of signal transduction proteins important in body axis patterning, cell fate determination, cell migration and proliferation, and regeneration.159,160 Wingless-type MMTV integration site family (WNT) proteins play an important role in gynecologic tract development, the endometrial cycle, uterine receptivity, blastocyst attachment and implantation, and trophoblast invasion (for review, see Nayeem and colleagues44). WNT proteins function through canonical (via nuclear β-catenin) or noncanonical pathways.161,162

inner embryonic cells in a reaggregation assay.14 At 7–8 days postfertilization, the human PrE expresses GATA6, as in the mouse, but also strongly expresses SOX17.5 Recent studies have shown that all the above events, which occur through 10 days postfertilization in  vivo, can progress

Normal Early Development

43

relatively normally, in the absence of maternal cues, in vitro.5,9 This is an important finding, particularly since in  vitro fertilization practice now favors later stage embryo transfers.15,16 It appears that implantation rates are superior with transfer of blastocyst-stage embryos, compared to earlier cleavage- and morula-stage embryos.15,17␣

Maternal Factors and Uterine Receptivity Development to the blastocyst stage occurs within the zona pellucida, a semiporous specialized “shell” that functions to hold the blastomeres of the early cleavage embryo together. Nevertheless, the maternal environment can still affect preimplantation development via secretions from the epithelia of the fallopian tube and endometrium. These histotrophic agents are important for the early zygote and must penetrate the zona pellucida.18–20 Following arrival within the uterine cavity, at approximately 6–7 days postfertilization, the late-stage blastocyst hatches from the zona pellucida, orients itself with polar TE (TE cells closest to the ICM) apposed to the luminal endometrial epithelium, and adheres to and then implants into the endometrium (Fig. 3.3). This process involves coordinated endometrial and trophoblastic differentiation and signaling among TE, endometrial epithelium, maternal immune cells, and specialized endometrial stromal cells—the decidua. Once the blastocyst is formed and hatches from the zona pellucida, adhesion molecules and their receptors from endometrial epithelial projections (pinopodes), and from the microvilli or atypical podosomes21 of the TE, interact to facilitate attachment. The process of attachment requires the endometrium to be “receptive.” Receptivity is a process by which the proliferating endometrium undergoes a marked transformation to a nonproliferative tissue rich in secretory factors necessary for blastocyst survival. In menstruating humans, endometrial receptivity is a function of a cyclic response to the ovarian hormones progesterone (P4) and estradiol (E2) in the midluteal phase of the menstrual cycle. The endometrial response to the major surge in P4 and minor surge in E2 results in decreased proliferation of the endometrial stromal and epithelial cells, the marked transformation of the stromal cells to large specialized secretory cells called decidua, and an influx of specialized immune cells. This unique cellular milieu depends on autocrine and paracrine signaling among the cells and interaction with the hatched and activated blastocyst. This receptive endometrium is short lived, and the “window of implantation” is only a couple of days in the human.22 Studies have shown that epithelial-to-mesenchymal signaling is critical for development of the receptive state of the endometrium. P4 hormone exposure induces several specific epithelial and stromal events leading to decidualization and endometrial receptivity (Table 3.1). The specialized decidualized stromal cells express many factors important in conferring receptivity, including prolactin and insulin-like growth factor– binding protein 1 (IGFBP-1).23 One important P4-regulated transcription factor is cyclooxygenase-2 (COX2) which is also influenced by human chorionic gonadotropin (hCG). The COX2 protein is an enzyme important in synthesis of prostaglandins. COX2 is expressed in the endometrial epithelium and subepithelial stroma. COX2 is also important in inducing angiogenesis in receptive endometrium required for normal

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Polar Zona body pellucida

Zygote

Blastocyst cavity Trophectoderm

2-Cell stage

4-Cell stage

8-Cell stage

Morula

Early blastocyst

ICM

Mid blastocyst

Hatched from zona pellucida

Late blastocyst

Maternal mRNA Zygote POU5F1 (Oct4) Zygote POU5F1, Nanog, Sox17 Zygote POU5F1, Cdx2, Gata3 Zygote GATA6, Sox17

Figure 3.1 Stages of mouse preimplantation development, similar to human, beginning with the zygote (fertilized egg). The polar body is the byproduct of the second meiotic division of the oocyte and degenerates during preimplantation development. Cells are colored to highlight gene expression, as designated in the color code list (bottom). ICM, Inner cell mass; mRNA, messenger RNA. Scale = 20 µ. (Modified from Saiz N, Plusa B. Early cell fate decisions in the mouse embryo. Reproduction. 2013;145:R65–R80.)

implantation [reviewed in Staun-Ram and Shalev24]. Another critical factor in inducing endometrial receptivity is a member of the hedgehog family of secreted proteins, Indian hedgehog (IHH), expressed in the endometrial epithelium. Epithelial IHH induces expression of chicken ovalbumin upstream promoter transcription factor 2 (COUP-TFII) in the stromal cells. This signal transduction pathway leads to stromal cell expression of bone morphogenetic protein 2 (BMP2) and wingless-type MMTV integration site family, member 4 (WNT4), both secretory factors necessary for receptivity (reviewed in Large and DeMayo25). Also essential is the expression of two members of the homeobox (HOX) family of transcription factors, HOXA10 and HOXA11. These HOX proteins are required for decidualization, and their expression is regulated by E2 and P4.26 Interestingly, HOXA10 and HOXA11 are embryologically important in uterine formation as well (reviewed in Taylor and coworkers27). Receptivity is also marked by expression of integrins. These transmembrane proteins, important in cell-cell communication, are expressed in response to the E2-responsive leukemia inhibitory factor from the endometrial epithelium. Leukemia inhibitory factor (LIF) is a critically important factor in the process involved in generating endometrial receptivity as well as inducing factors necessary for attachment and implantation. Other factors important in endometrial receptivity are highlighted in Table 3.1. One of the important processes in uterine receptivity is the interaction of the endometrium and trophectoderm with specialized immune cells in the decidua (for reviews, see Sharma28 and Robertson and Moldenhauer29). The normal decidua contains multiple groups of beneficial immune cells, including decidual natural killer (dNK) cells and T-regulatory (Treg) cells. The dNK cells are unique cells that are either recruited from peripheral blood and converted to decidual NK cells by decidualized stromal cell secretion of transforming growth factor-β1 (TGF-β1) and interleukin-15,30 or are differentiated from tissue-resident (immature) NK cells in situ.31 The dNK cells provide important controls for trophoblast

invasion and remodeling of the uterine spiral arteries (reviewed in Lash and colleagues32) as well as aiding in preventing maternal immune rejection of the hemiallograft zygote33 (reviewed in Warning and associates34). Recent single-cell analysis of early gestation decidua indicate heterogeneity of dNK cells, suggesting that distinct subpopulations carry out the different functions in vivo.35 Treg cells are specialized antiinflammatory and immunosuppressive T cells that modulate the immune response. They are increased at the implantation site and mediate tolerance of the semiallogeneic fetus. Deficiencies in both dNK cells and Tregs are thought to play a role in early pregnancy loss.28,29␣

Implantation Implantation begins with attachment of the activated blastocyst to the receptive luminal endometrial epithelium (for reviews, see Cha and coworkers36 and Tu and associates37). This involves the specialized polar TE, cells that border the ICM and have a distinct phenotype (Fig. 3.3), adhering to and then invading into the receptive endometrium. Both E2 and P4 are necessary for the expression of arguably the most important factors for blastocyst attachment, heparin-binding epidermal growth factor–like growth factor (HB-EGF) and its receptors ErbB1 and ErbB4.38 HB-EGF is expressed in both a soluble and a membrane-bound form by the endometrial epithelium in the pinopodia.39 Its receptors are expressed on the polar TE of the blastocyst associated with their microvilli/podosomes. HB-EGF–associated binding of the TE to the endometrium is the critical event in blastocyst attachment.36 HB-EGF plays other roles in implantation, and defects in its regulation are associated with abnormal implantation and preeclampsia.40 Other factors that also play key roles in the attachment process include leukemia inhibitory factor,41,42 endometrial epithelial HOXA10 and HOXA11,43 and canonical WNT signaling in the endometrial epithelium.36,44 Blastocyst-to-endometrium signals45 and epithelial-stromal crosstalk46,47 also function in the initial steps of implantation.

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MURINE Totipotent

Inside cell

Outside cell Hippo Yap

ICM

Tead4 Cdx2

POU5F1 (Oct4) Nanog Sox2

TE Gata6

Nanog

PE

Epiblast

Yolk sac

Embryo

Eomes Psx1 Hand1

AMOT

NICD RBPJ YAP TEAD4

AMOT NF2

TE

LATS

NF2

YAP TEAD4

?

Out Cdx2

Sox2

P

ICM

P YAP

LATS

In RBPJ

TEAD4

Cdx2

Sox2 Sox2

A HUMAN

Inside cell

Totipotent

Outside cell HIPPO YAP

POU5F1 (OCT 4) NANOG Pluripotent SOX17 FOXA2 GATA6

CDX2 TEAD4 GATA3

ICM NANOG POU5F1 (OCT 4) TCFAPZC

PE

Epiblast

Yolk sac

Embryo

TE

CK7

B Figure 3.2 Signaling cascades controlling early cell fate decisions and segregation of trophectoderm (TE) and inner cell mass (ICM) in the compacted morula using the inside-outside cell model. PE, Primitive endoderm. (A) Murine system. (B) Human system. (A, Inset modified from Chazaud C, Yamanaka Y. Lineage specification in the mouse preimplantation embryo. Development. 2016;143:1063–1074.)

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TABLE

3.1

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PART 1 Scientific Basis of Perinatal Biology

Uterine Receptivity Factors Expression Location

Effect on Endometrial Receptivity

ESTROGEN- AND/OR PROGESTERONE-REGULATED FACTORS IHH Epithelium Paracrine signal for epithelial-stromal interaction, stromal cell proliferation HAND2 Stroma Important for decidualization; downregulates epithelial differentiation LIF Epithelium/ Signals to the blastocyst and lumina endometrial epithelium for uterine receptivity and implantation NON–ESTROGEN/PROGESTERONE-RESPONSIVE FACTORS MSX1 Epithelium Increased expression during window of implantation; upstream activator of stromal BMP2 expression and inhibitor of WNTs137 BMP2 Stroma Required for decidualization; also plays a role in embryo spacing (may be a clue to placenta previa) LKF5 Epithelium to Downregulated in epithelium stroma at implantation and upregulated in stroma with decidualization; role in implantation HOXA10, Stroma Crucial for decidualization HOXA11 aBMP2,

Bone morphogenetic protein 2; HAND2, heart- and neural crest derivatives–expressed protein 2; HOXA, homeobox protein HOXA; IHH, Indian hedgehog; KLF5, Kruppel-like factor 5; LIF, leukemia inhibitory factor; MSX1, muscle segment homeobox 1. For review, see Cha J, Sun X, Dey SK. Mechanisms of implantation: strategies for successful pregnancy. Nature Med. 2012;18:1754–1767.

Once attachment has occurred, the cells of the polar TE break through the endometrial epithelium, burrowing underneath and forming a shell of cells, called cytotrophoblast, around the embryo48 (Fig. 3.3). The cells from the cytotrophoblastic shell subsequently differentiate into primitive syncytium, a unique trophoblast cell type with both invasive and secretory functions (see Fig. 3.3, and more detail later).48 The blastocyst continues to invade the endometrium via the primitive syncytium, and a completely interstitial implantation of the blastocyst is usually accomplished by the ninth day of gestation. The entire blastocyst thus comes to assume an interstitial position (i.e., it sinks entirely into the endometrium at the site of attachment). The process may be aided by the collapse of the blastocyst cavity that occurs at this time. The implanted cytotrophoblastic shell encases the blastocyst and comes to be surrounded by endometrium (decidua) on all sides. The portion of decidua lying between blastocyst and myometrium is the decidua basalis; the other portion is the decidua capsularis that eventually fuses with the decidua vera on the opposite side of the uterine cavity to form the decidua parietalis, which in turn becomes part of the chorion laeve (Fig. 3.4) and comes to lie on the outside of the placental membranes. Once within the endometrium, the blastocyst begins gastrulation (further differentiation and development of the embryo proper). Simultaneously, placental growth proceeds in an accelerated manner (in comparison to embryonic growth), which is required for gestation to proceed. It has been estimated that most pregnancy losses that occur in the first trimester are failures of periimplantation events, resulting from problems either with uterine receptivity or with early placentation itself49; therefore successful completion of these events is necessary for embryonic survival. For this reason, we will first focus on events related to placental development, before discussing gastrulation and embryonic development. Once the polar TE has attached and the embryo has invaded into the decidua, marked changes begin to occur, starting with

Secretion-filled lacunae Primitive cytotrophoblast Primary villous development begins

Primitive syncytium

Figure 3.3 Blastocyst attachment. Schematic diagram illustrating the anatomic features of implantation site at approximately 12 days of gestation. (Modified from James JL, Carter AM, Chamley LW. Human placentation from nidation to 5 weeks of gestation. Part II: tools to model the crucial first days. Placenta. 2012;33:335–342.)

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CDX2 TEAD4 GATA3

TE ? Decidua basalis Decidua capsularis Decidua parietalis

Chorion frondosum

? Primitive syncytium ck7 Hcg CT GCM1

Yolk sac

Syncytins

GATA3 TEAD4 p63 VGLL1 HtrA4

Amnion

Chorion laeve

47

MMP9 ST

Mucus plug

hCG KLF4 hPL

formation of the cytotrophoblastic shell. The transition from polar TE to cytotrophoblast involves loss of CDX2 expression, retention of GATA3, and gain of expression of p63 and VGLL1, among other transcription factors (Fig. 3.5).6 Differentiation of TE cells into cytotrophoblast heralds the establishment of a true trophoblast progenitor cell, which will persist throughout gestation and gives rise to subsequent terminally differentiated and specialized progeny, the syncytiotrophoblast and the extravillous cytotrophoblast (described further later). Although a unique molecular signature for human trophoblast stem cells (TSC) has yet to be defined, Okae and colleagues have developed culture conditions for derivation of such cells from both human blastocyst-stage embryos and first-trimester cytotrophoblast, which can maintain self-renewal long-term in vitro.50 As noted, the cells of the cytotrophoblastic shell also differentiate into a specialized multinucleated, invasive cell type, called the primitive syncytium (Fig. 3.3). These cells secrete enzymes that break down surrounding decidual cells and matrix, leading to development of clefts (lacunae), which later coalesce to form the intervillous space. These lacunae are filled with endometrial glandular secretions, into which the primitive syncytium taps, to provide nutritional support for the recently-implanted embryo, a process referred to as histiotrophic nutrition.51 Otherwise, very little is known about the formation or function of primitive syncytium, though it is important to distinguish these cells from true syncytiotrophoblast, which, though multinucleated, are noninvasive cells (see later). The primitive syncytium express the trophoblastic hormone hCG and the pantrophoblast marker cytokeratin 7,5 but not the characteristic marker of invasive extravillous cytotrophoblast, human leukocyte antigen G (HLAG) (see later; M. Parast, unpublished observations). It is not clear what becomes of the primitive syncytium. Both villous and extravillous trophoblastic differentiation proceeds soon after implantation, as described in the next section.␣

HLA-G 4 integrins Gata3

Wnt

Cervical glands Figure 3.4 Late second-trimester gestation demonstrating anatomy of the mature placenta. (Modified from Carlson BM. Human embryology and developmental biology. 5th ed. Philadelphia: Elsevier Saunders; 2014.)

EVT

?

iEVT

eEVT

UPA TIMP MMP 1 5 integrins

Vascular adhesion molecules

Figure 3.5 Pathway of trophoblast differentiation. CT, Cytotrophoblast; eEVT, endovascular extravillous trophoblast; EVT, extravillous trophoblast; iEVT, invasive extravillous trophoblast; ST, syncytiotrophoblast; TE, trophoblast stem cell.

Postimplantation Trophoblast Differentiation The self-renewing cytotrophoblast (CTB) progenitor cell can differentiate down one of two pathways, forming either specialized invasive extravillous cytotrophoblast (EVT), or true syncytial cells, the syncytiotrophoblast (STB), which cover the placenta and serve transport and endocrine functions throughout pregnancy. Both of these cell types are discussed in this section; for additional details, see the review by Farah and colleagues.52 EXTRAVILLOUS CYTOTROPHOBLAST Within anchoring villi, at the junction with the uterus, CTB progenitor cells give rise to extravillous cytotrophoblast (EVT). The role of EVT is to anchor the gestation and access oxygenated maternal blood for the growing embryo. To achieve these ends, EVT need to invade the maternal endometrium and remodel the endometrial vasculature from muscular vessels to highcapacitance slow-flow vessels. At this early time in gestation, the embryo is growing under low oxygen conditions (95%) exhibit intertwin vascular anastomoses crossing the intertwin membrane (Fig. 5.4).53–55 Vascular communications between monochorionic twins can be artery-to-artery (AA), vein-to-vein (VV), or artery-tovein (AV). These intertwin anastomoses can be categorized based on the near-constant anatomic relationships between the different vessel types: chorionic arteries virtually always course superficial to their accompanying veins (see Fig. 5.4). AA and VV anastomoses are superficial; they form a direct communication between homonymous vessels from each twin without penetrating the chorionic plate (see Fig. 5.4A). In contrast to these superficial anastomoses, AV anastomoses occur deep within the parenchyma at the villous capillary level and are recognized by the chorionic penetration of an unpaired artery of one twin in close proximity to an unpaired vein of the opposite twin (see Fig. 5.4B). AV anastomoses are obligatorily unidirectional. AA and VV anastomoses are bidirectional and allow flow in either direction, depending on pressure gradients between twins. Superficial AA and VV anastomoses are thus believed to be able to compensate for flow imbalances generated by nonequilibrated AV anastomoses. Although monochorionicity remains an excellent proof of monozygosity, rare exceptions have been described involving dizygotic monochorionic twinning.11,12 Therefore determination of monochorionic placentation status should be regarded as a screening tool, rather than unequivocal evidence of monozygosity.37 Further genotyping is especially recommended when monochorionic twins have a dissimilar phenotype and following artificial reproduction.37 Definitive zygosity determination relies on genetic markers such as blood

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B

Figure 5.3 Diamniotic-monochorionic twin placenta. (A) Overview showing thin intertwin membrane. Chorionic vessels are noted crossing the intertwin membrane. (B) Closer view of the intertwin membrane. The dividing membrane has been separated to demonstrate two amnion layers without interposed chorion and the exposed bare chorionic plate. Inset, Micrograph of membrane roll of intertwin membrane of diamnioticmonochorionic twin placenta showing two juxtaposed amnion layers without interposed chorion.

B

A

Figure 5.4 Diamniotic-monochorionic twin placenta following vascular dye injection. (A) The chorionic vasculature is injected with dye using the following color code: left twin: artery red, vein green; right twin: artery red, vein yellow. Arteries (red) cross over accompanying veins (green/yellow). Owing to the presence of an artery-to-artery anastomosis (arrow), the arterial beds of both twins share the same color (red). A thin intertwin membrane is visible. (B) Closer view of the central portion of the vascular equator showing two left-to-right artery-to-vein anastomoses between an artery of the left twin (red) and a vein of the right twin (yellow) (arrows).

group testing or, preferably, polymerase chain reaction analysis of variable microsatellite markers using DNA extracted from a skin biopsy specimen, umbilical cord tissue, or buccal smear. Possible pitfalls in interpretation must be taken into account, such as those created by postzygotic mutations and blood mosaicism.37␣

Complications of Monochorionic Twinning and Their Associated Placental Characteristics Monochorionicity is associated with a higher perinatal mortality and with a higher incidence of preterm birth, low birth weight, and prolonged stay in the neonatal intensive care unit compared with dichorionic twin pregnancies. The overall

perinatal mortality is approximately 12% in monochorionic twins compared with 2% to 5% in dichorionic twins, and mortality is even higher in monoamniotic twins.56,57 In addition, monochorionic twin pregnancies are susceptible to a specific set of complications, including TTTS, TAPS, TRAP sequence, discordant growth restriction, and malformations. Because nearly all monochorionic pregnancies have connections between the two choriovascular beds, death of one twin affects the outcome of the surviving co-twin.58 These vascular disruptions are usually seen following the death of one co-twin but may occur in monochorionic twins with two surviving infants. Consequences for the surviving co-twin include survival with cerebral impairment, preterm delivery with its sequelae, or intrauterine death. Many organ systems may be affected including brain (hypoxic-ischemic encephalopathic brain disruptions with microcephaly, hydrocephalus, or porencephaly/hydranencephaly),

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gastrointestinal system (intestinal atresia), and skin (aplasia cutis). Proposed mechanisms to explain injury to the co-twin following twin fetal demise include the embolic theory, in which thromboplastin-like material is transferred through open placental vascular anastomoses to the survivor, and the hypovolemic shockischemic theory, in which blood is shunted into the low-resistance circulation of the dead or dying fetus. In addition to the structural or growth anomalies associated with specific complications of monochorionic twinning such as TTTS, TAPS, TRAP sequence, and conjoined twinning, twin pregnancies are susceptible to other malformations, deformations, or disruptions that may or may not be related to their twin status. Primary structural malformations, chromosomal effects, and genetic syndromes seen in singletons may also occur in twins. The overall odds ratio for congenital anomalies in twins compared with singletons is estimated at 1.3,38 with a significantly higher frequency in monozygotic twins compared with dizygotic twins.38,59 The placental findings in most congenital anomalies are either nonspecific or similar to those seen in singleton pregnancies. TWIN-TO-TWIN TRANSFUSION SYNDROME Definition TTTS is a complication of monochorionic twinning, characterized by chronic fetofetal blood transfusion from one twin (donor) to the other (recipient) through placental vascular communications. This unbalanced shift of blood volume results in hemodynamic imbalance and oligohydramnios in the donor and polyhydramnios in the recipient (so-called twin oligohydramnios-polyhydramnios sequence). TTTS traditionally refers to an often severe, chronic condition and needs to be distinguished from several acute forms of intertwin transfusion. Acute perimortem TTTS occurs following intrauterine death of one monochorionic twin and is caused by exsanguination from the surviving twin into the low-pressure circulation of the dead or dying co-twin. This form of perimortem acute twin-to-twin transfusion is mediated mainly through large-sized AA or VV anastomoses.60 Acute peripartum (or perinatal) TTTS may occur during birth and is caused by acute shifts of blood volume between twins resulting from blood pressure differences associated with uterine contractions, delayed cord clamping, or changes in fetal position around the time of delivery. The clinical presentation of acute peripartum TTTS may range from subtle intertwin differences in hemoglobin levels without obvious effects to frank hypovolemic shock in the donor twin and polycythemia in the recipient.60 Similar to other forms of acute TTTS, acute peripartum TTTS is believed to be facilitated by large superficial AA and VV anastomoses. Acute peripartum TTTS is distinct from the more common postpartum placentofetal (as opposed to twin-to-twin, or fetofetal) transfusion that occurs when cord clamping of one twin directs blood from the entire placenta to the remaining twin through vascular anastomoses.␣ Pathogenesis The pathogenesis of TTTS is incompletely understood. TTTS is a complex and multifactorial condition with both placental and fetal contributions.61 An intuitive, albeit simplistic, model of TTTS proposes that the primary event is flow imbalance from donor to recipient across unbalanced unidirectional AV anastomoses. If this flow imbalance is significant and

Figure 5.5 Placenta of twin pregnancy complicated by twin-to-twin transfusion syndrome. Artery-to-artery anastomoses are absent. Both twins have peripheral (marginal) cord insertion. Artery-to-vein anastomoses are noted from right twin (donor) to left twin (recipient) (arrows). Color code: left twin: artery red, vein black; right twin: artery green, vein yellow. The intertwin membrane was removed before injection.

not fully compensated by bidirectional AA anastomoses, the donor becomes hypovolemic and anemic, whereas the recipient develops polycythemia and hypervolemia. These volume changes are believed to induce modulation of a variety of hormonal and biochemical regulators in both twins. The renin-angiotensin system is upregulated in the donor twin and downregulated in the recipient twin. Both twins are likely exposed to equally high renin levels through their shared circulation, which may contribute to cardiovascular anomalies in some recipient twins.62,63 In addition, concentrations of atrial natriuretic peptide, brain natriuretic peptide, and endothelin-1 are higher in the amniotic fluid of recipient twins compared with donor twins.64 Although their exact mechanisms of action remain incompletely understood, dysregulation of these and other unidentified biochemical and related mediators likely plays a role in a proposed exaggerated hemodynamic response to hypervolemia and hypovolemia in TTTS.␣ Placental Findings TTTS has no pathognomonic placental or choriovascular signature. Nevertheless, several anatomic placental features have been linked to an increased risk for development of TTTS in diamniotic-monochorionic twin gestations.61,65,66 Pregnancies complicated by TTTS have a lower frequency of intertwin AA anastomoses than uncomplicated, nonTTTS monochorionic pregnancies (25% to 57% in TTTS versus >85% in non-TTTS placentas) (Fig. 5.5).61,65,66 The relative paucity of AA anastomoses in TTTS placentas has contributed to the notion that these potentially bidirectional anastomoses have a protective role against the development of TTTS in monochorionic twin gestations by compensating for hemodynamic imbalances created by uneven AV anastomoses.67 Mathematical computer models of TTTS support the protective role of AA anastomoses.68 However, this theory does not account for the presence of AA anastomoses, often large, in a substantial portion of cases with TTTS. In contrast to AA anastomoses, the frequency of VV anastomoses is higher in TTTS pregnancies than in non-TTTS

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pregnancies (38% versus 15% to 25%).61,66,67,69,70 In the subgroup of placentas without AA anastomoses, this difference is even more striking. In the absence of AA anastomoses, the prevalence of VV anastomoses is 32% in TTTS placentas versus 8% in non-TTTS placentas. This suggests that VV anastomoses may play an adverse role in TTTS, especially in the absence of AA anastomoses, perhaps by acting as low-resistance functional AV anastomoses.71 The contribution of AV anastomoses to the onset or continuation of TTTS is less clear. In contrast to AA and VV anastomoses, AV anastomoses are deep and obligatorily unidirectional. In the absence of compensating AA anastomoses, AV imbalance directed from donor to recipient strongly correlates with the development of TTTS.61,66 This specific combination of absent AA anastomoses and severe AV imbalance is virtually diagnostic of TTTS but is seen in only a small minority of TTTS placentas (14%).66 The role of AV anastomoses in the vast remainder of monochorionic gestations is incompletely understood. TTTS has been described even in the absence of identifiable AV anastomoses.61,66,68 It has been speculated that in such cases an AA anastomosis may have been converted into a functional AV anastomosis; for instance, by arterial stenosis.68 In addition to choriovascular features, both peripheral cord insertion and uneven placental sharing have been linked to an increased risk for TTTS development in monochorionic gestations. The reported frequency of peripheral (marginal or velamentous) cord insertion of at least one twin is significantly higher in TTTS gestations than in non-TTTS gestations (approximately 50% versus approximately 30%).66 When cord insertion is discordant, it is virtually always the donor twin that has a peripheral cord insertion.61,66,72 Markedly uneven placental sharing, traditionally defined as greater than 25% intertwin difference in distribution of placental choriovascular territory, is seen in approximately 50% of TTTS gestations versus 25% of non-TTTS gestations61; the donor twin almost always has the smaller share. Diagnosis, clinical characteristics, management, and outcome are described in Chapter 37.␣ TWIN ANEMIA-POLYCYTHEMIA SEQUENCE

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twin to become polycythemic. The chronic, gradual character of intertwin blood transfusion in TAPS is believed to allow time for hemodynamic compensatory mechanisms in the absence of hormonal imbalance, thus preventing the development of oligohydramnios and polyhydramnios in donor and recipient, respectively.75,76 The absence of oligohydramnios and polyhydramnios in TAPS is poorly understood. As mentioned, it has been speculated that the chronic, gradual character of intertwin blood transfusion in TAPS allows time for hemodynamic compensatory mechanisms in the absence of hormonal imbalance, thus preventing the development of oligohydramnios and polyhydramnios in donor and recipient, respectively.75,76 In contrast, development of TTTS has been attributed to larger and more acute intertwin transfusion and is mediated in part by unbalanced hormonal regulation. Hormonal discordance seen in TTTS, such as upregulated renin levels in donor twins and downregulated renin levels in recipients, has thus far not been described in TAPS pregnancies.␣ Placental Findings The typical angioarchitectural pattern associated with TAPS consists of sparse (three or four per placenta, on average) and small-sized (diameter 2 cm with no umbilical cord (text discusses subjectively decreased fluid)

false-positive screening test results, which is the major clinical drawback of using the NST. The most common explanation for a nonreactive NST result is a sleep cycle in a normal fetus that is longer than average.1 A nonreactive result, especially if FHR variability is preserved and there are no decelerations, should not be assumed to indicate fetal compromise. Ultrasound evaluation with a BPP should be available as the backup test. Beyond the BPP, ultrasound provides additional fetal evaluation that may help to diagnose the reason for an apparently abnormal NST result. For example, a repeatedly nonreactive finding for a fetus with normal serial ultrasound assessments may lead to a diagnosis of central nervous system abnormalities, drug exposure, or prior fetal central nervous system injury. Late decelerations or variable decelerations

Fewer than three body or limb movements in a 30-min observation period

Low-velocity movement only Incomplete flexion, flaccid extremity positions, abnormal fetal posture Must score 0 when fetal movement (FM) is completely absent FMs and accelerations not coupled Insufficient accelerations, absent accelerations, or decelerative trace Minimal or absent variability No cord-free pocket >2 cm or multiple definite elements of subjectively reduced amniotic fluid volume

may occur in the context of NST monitoring, with no clear demonstration of contractions. Either pattern should lead to evaluation by ultrasound to exclude FGR and oligohydramnios.␣ BIOPHYSICAL PROFILE The BPP relies on the premise that multiple parameters of well-being are better predictors of outcome than any single parameter.15 Fig. 32.2 shows a detailed evaluation of outcome variables performed during development.16,17 The traditional BPP study includes five variables (Table 32.1), with a total possible score of 10, but several variations have been proposed. The most frequently utilized is the modified BPP, which usually includes fetal heart rate monitoring and amniotic fluid evaluation.18,19

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Assessment of Fetal Health

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Amniotic Fluid Volume. A deepest vertical pocket (DVP) that is less than 2 cm or more than 8 cm suggests oligohydramnios or polyhydramnios, respectively; in this setting, a detailed fetal evaluation is suggested to exclude anatomic and anomalous explanations.23 For moderately increased fluid (i.e., maximum vertical pocket depth of 8 to 12 cm), the most common explanations are idiopathic polyhydramnios, fetal macrosomia resulting from maternal diabetes, and structural abnormalities, and fetal testing is likely to reflect fetal neurologic and acid-base status accurately. For pockets deeper than 12 cm in singleton pregnancies, neurologic issues, structural defects, and chromosomal abnormalities are more likely (especially if associated with fetal growth restriction),24 and the BPP may not predict the neonatal outcome.25 Through the normal range (i.e., maximum vertical pocket depth of 3 to 8 cm), the maximum vertical depth method assigns normal status accurately, although it may not correlate precisely with absolute volumes.␣

A

B Figure 32.3 Fluid pocket verification. (A) Amniotic fluid meets the vertical pocket criteria of the biophysical profile score. (B) Pulsed Doppler demonstrates that this is a vertical pocket of the umbilical cord that contains no measurable amniotic fluid.

These approaches emphasize the principle of multivariable fetal assessment. Biophysical Profile Score Variables Amniotic Fluid Measurement. The physiologic principle connecting decreased amniotic fluid volume to fetal compromise is the understanding that fetal oliguria in an anatomically normal fetus is a consequence of redistribution of fetal blood flow away from the kidneys and is frequently a reflection of uteroplacental insufficiency.20 Many methods of assessing amniotic fluid volume have been suggested. The technique for determining the BPP requires assessment of a single adequate pocket of fluid. With the transducer vertical to the maternal abdomen, the maximum vertical depth of a clear amniotic fluid pocket is recorded. The transducer is then rotated 90 degrees in the same vertical axis, confirming that the measured pocket has true biplanar dimensions. The phrase 2 × 2 pocket does not mean that the pocket is 2 cm deep and 2 cm wide; it refers to the documentation that the pocket is 2 cm deep in at least two intersecting ultrasound planes, avoiding the possibility that a sliver of amniotic fluid is misconstrued as a true threedimensional pocket. Amniotic fluid is measured in real time, and when there is doubt about a true pocket, it is confirmed by pulsed Doppler. Continuous color imaging may lead to the false impression of oligohydramnios (Fig. 32.3).21 This method reflects the relative amount of amniotic fluid and was not meant for determining an absolute physiologic parameter.22␣

Diagnosis of Oligohydramnios. The original criterion for the diagnosis of oligohydramnios was a maximum vertical pocket of only 1 cm. Although this finding highly correlated with FGR, it was so uncommon as to be clinically meaningless. A metaanalysis identified four high-quality randomized controlled trials (RCTs) that compared the amniotic fluid index (AFI) with the single DVP with respect to preventing adverse pregnancy outcome. The limits used were an AFI less than 5 cm and a DVP less than 2 × 1 cm. The trials included 3125 participants, with the primary outcome measure defined as admission to the neonatal intensive care unit. No difference was observed for the primary outcome (risk ratio [RR] = 1.04; confidence interval [CI], 0.85 to 1.26).26 When the AFI was used for fetal surveillance, however, the diagnosis of oligohydramnios was made more frequently (RR = 2.33; CI, 1.67 to 3.24); labor induction was used more frequently (RR = 2.1; CI, 1.6 to 2.76), and there was a higher rate of cesarean deliveries for lack of assurance of fetal well-being (RR = 1.45; CI, 1.07 to 1.97).26 There were no differences in Apgar scores, umbilical artery pH (