The Developing Human

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THE DEVELOPING

HUMAN
CLINICALLY ORIENTED EMBRYOLOGY
KEITH L. MOORE
Recipient of the inaugural Henry Gray/Elsevier Distinguished Educator Award in 2007—the
American Association of Anatomists’ highest award for excellence in human anatomy educa-
tion at the medical/dental, graduate, and undergraduate levels of teaching; the Honored
Member Award of the American Association of Clinical Anatomists (1994) for significant
contributions to the field of clinically relevant anatomy; and the J.C.B. Grant Award of the
Canadian Association of Anatomists (1984) “in recognition of meritorious service and out-
standing scholarly accomplishments in the field of anatomical sciences.” In 2008 Professor
Moore was inducted as a Fellow of the American Association of Anatomists. The rank
of Fellow honors distinguished AAA members who have demonstrated excellence in
science and in their overall contributions to the medical sciences. In 2012 Dr. Moore
received an Honorary Doctor of Science degree from The Ohio State University; The Queen
Elizabeth II Diamond Jubilee Medal honoring significant contributions and achievements
by Canadians; and the Benton Adkins Jr. Distinguished Service Award for an outstanding
record of service to the American Association of Clinical Anatomists.

T.V.N. (VID) PERSAUD

Recipient of the Henry Gray/Elsevier Distinguished Educator Award in 2010—the American
Association of Anatomists’ highest award for excellence in human anatomy education at
the medical/dental, graduate, and undergraduate levels of teaching; the Honored Member
Award of the American Association of Clinical Anatomists (2008) for significant contribu-
tions to the field of clinically relevant anatomy; and the J.C.B. Grant Award of the Canadian
Association of Anatomists (1991) “in recognition of meritorious service and outstanding
scholarly accomplishments in the field of anatomical sciences.” In 2010 Professor Persaud
was inducted as a Fellow of the American Association of Anatomists. The rank of Fellow
honors distinguished AAA members who have demonstrated excellence in science and in
their overall contributions to the medical sciences. In 2003 Dr. Persaud was a recipient of
the Queen Elizabeth II Golden Jubilee Medal, presented by the Government of Canada for
“significant contribution to the nation, the community, and fellow Canadians.”

MARK G. TORCHIA
Recipient of the Norman and Marion Bright Memorial Medal and Award and the Silver
Medal of the Chemical Institute of Canada in 1990 for outstanding contributions. In 1993
he was awarded the TIMEC Medical Device Champion Award. In 2008 and in 2014 Dr.
Torchia was a nominee for the Manning Innovation Awards, for innovation talent. Dr.
Torchia’s most cherished award has been the Award for Teaching Excellence in 2011 from
the Faculty of Medicine, University of Manitoba, and being asked to address the graduating
class of 2014.
 THE DEVELOPING
HUMAN CLINICALLY ORIENTED EMBRYOLOGY
10th Edition

Keith L. Moore,
BA, MSc, PhD, DSc, FIAC, FRSM, FAAA
Professor Emeritus, Division of Anatomy, Department of Surgery
Former Professor and Chair, Department of Anatomy and Associate Dean for Basic Medical Sciences
Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Former Professor and Head of Anatomy, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada

T.V.N. (Vid) Persaud,

MD, PhD, DSc, FRCPath (Lond.), FAAA
Professor Emeritus and Former Head, Department of Human Anatomy and Cell Science
Professor of Pediatrics and Child Health
Associate Professor of Obstetrics, Gynecology, and Reproductive Sciences, Faculty of Medicine,
University of Manitoba, Winnipeg, Manitoba, Canada
Professor of Anatomy, St. George’s University, Grenada, West Indies

Mark G. Torchia,
MSc, PhD
Associate Professor and Director of Development, Department of Surgery
Associate Professor, Department of Human Anatomy and Cell Sciences
Director, Centre for the Advancement of Teaching and Learning, University of Manitoba,
Winnipeg, Manitoba, Canada
1600 John F. Kennedy Blvd.
Ste 1800
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THE DEVELOPING HUMAN, TENTH EDITION  ISBN: 978-0-323-31338-4

INTERNATIONAL EDITION  ISBN: 978-0-323-31347-6
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Practitioners and researchers must always rely on their own experience and knowledge in
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Previous editions copyrighted 2013, 2008, 2003, 1998, 1993, 1988, 1982, 1977, and 1973.

Library of Congress Cataloging-in-Publication Data

Moore, Keith L., author.
The developing human : clinically oriented embryology / Keith L. Moore, T.V.N. (Vid) Persaud,
Mark G. Torchia.—10th edition.
   p. ; cm.
Includes bibliographical references and index.
ISBN 978-0-323-31338-4 (pbk. : alk. paper)—ISBN 978-0-323-31347-6 (international edition : alk.
paper)
I. Persaud, T. V. N., author. II. Torchia, Mark G., author. III. Title.
[DNLM: 1. Embryology. QS 604]
QM601
612.6′4018—dc23
   2015001490

Content Strategist: Meghan Ziegler

Senior Content Development Specialist: Jennifer Ehlers
Publishing Services Manager: Patricia Tannian
Senior Project Manager: Kristine Feeherty
Design Direction: Margaret Reid

The cover images show a magnetic resonance image of a 27-week-old fetus in the
uterus (Courtesy Dr. Deborah Levine, Beth Israel Deaconess Medical Center, Boston,
Massachusetts). The photograph of the baby (Kennedy Jackson) was taken 7 days
after her birthday. She is wrapped in a knitted cocoon that symbolizes the uterus.

Printed in the United States of America

Last digit is the print number: 9 8 7 6 5 4 3 2 1

 In Loving Memory of Marion
My best friend, wife, colleague, mother of our five children and grandmother of our nine grandchildren, for her love,
unconditional support, and understanding. Wonderful memories keep you ever near our hearts.

—KLM and family

For Pam and Ron

I should like to thank my eldest daughter, Pam, who assumed the office duties previously carried out by her mother,
Marion. She has also been helpful in so many other ways (e.g., reviewing the text). I am also grateful to my son-in-law,
Ron Crowe, whose technical skills have helped me utilize the new technology when I was improving this book.

—KLM

For Gisela
My lovely wife and best friend, for her endless support and patience; our three children—Indrani, Sunita,
and Rainer (Ren)—and grandchildren (Brian, Amy, and Lucas).

—TVNP

For Barbara, Muriel, and Erik

Nothing could ever mean more to me than each of you. Thank you for your support and your love.

—MGT

For Our Students and Their Teachers

To our students: We hope you will enjoy reading this book, increase your understanding of human embryology, pass all
of your exams, and be excited and well prepared for your careers in patient care, research, and teaching. You will
remember some of what you hear, much of what you read, more of what you see, and almost all of what you experience.

To their teachers: May this book be a helpful resource to you and your students.
We appreciate the numerous constructive comments we have received over the years from both students and teachers.
Your remarks have been invaluable to us in improving this book.
This page intentionally left blank
 Contributors

CONTRIBUTORS FIGURES AND IMAGES (SOURCES)

David D. Eisenstat, MD, MA, FRCPC We are grateful to the following colleagues for the clinical
Professor, Departments of Pediatrics, Medical Genetics images they have given us for this book and also for
granting us permission to use figures from their published
and Oncology, Faculty of Medicine and Dentistry,
works:
University of Alberta; Director, Division of Pediatric
Immunology, Hematology, Oncology, Palliative Care,
Steve Ahing, DDS
and Environmental Health, Department of Pediatrics,
Faculty of Dentistry, University of Manitoba, Winnipeg,
Stollery Children’s Hospital and the University of
Manitoba, Canada
Alberta; Inaugural Chair, Muriel and Ada Hole Kids
Figure 19-20F
with Cancer Society Chair in Pediatric Oncology,
Edmonton, Alberta, Canada
Franco Antoniazzi, MD
Department of Pediatrics, University of Verona,
Jeffrey T. Wigle, PhD
Verona, Italy
Principal Investigator, Institute of Cardiovascular
Figure 20-4
Sciences, St. Boniface Hospital Research Centre;
Associate Professor, Department of Biochemistry and
Dean Barringer and Marnie Danzinger
Medical Genetics, University of Manitoba, Winnipeg,
Figure 6-7
Manitoba, Canada
†Volker Becker, MD
CLINICAL REVIEWERS Pathologisches Institut der Universität, Erlangen,
Germany
Albert E. Chudley, MD, FRCPC, FCCMG Figures 7-18 and 7-21
Professor, Department of Pediatrics and Child Health;
Professor, Department of Biochemistry and Medical J.V. Been, MD
Genetics, University of Manitoba, Winnipeg, Department of Pediatrics, Maastricht University
Manitoba, Canada Medical Centre, Maastricht, The Netherlands
Figure 10-7C
Michael Narvey, MD, FRCPC, FAAP
Section Head, Neonatal Medicine, Health Sciences Beryl Benacerraf, MD
Centre and St. Boniface Hospital; Associate Professor Diagnostic Ultrasound Associates, P.C., Boston,
of Pediatrics and Child Health, University of Massachusetts, USA
Manitoba, Winnipeg, Manitoba, Canada Figures 13-29A, 13-35A, and 13-37A

Kunwar Bhatnagar, MD
Department of Anatomical Sciences and Neurobiology,
School of Medicine University of Louisville,
Louisville, Kentucky, USA
Figures 9-33, 9-34, and 19-10

†Deceased.

vii
viii CONTRIBUT O R S

David Bolender, MD João Carlos Fernandes Rodrigues, MD

Department of Cell Biology, Neurobiology, and Servico de Dermatologia, Hospital de Desterro, Lisbon,
Anatomy, Medical College of Wisconsin, Milwaukee, Portugal
Wisconsin, USA Figure 19-5B
Figure 14-14BC
Frank Gaillard, MB, BS, MMed
Dr. Mario João Branco Ferreira Department of Radiology, Royal Melbourne Hospital,
Servico de Dermatologia, Hospital de Desterro, Lisbon, Australia
Portugal Figures 4-15 and 9-19B
Figure 19-5A
Gary Geddes, MD
Albert E. Chudley, MD, FRCPC, FCCMG Lake Oswego, Oregon, USA
Department of Pediatrics and Child Health, Section of Figure 14-14A
Genetics and Metabolism, Children’s Hospital,
University of Manitoba, Winnipeg, Manitoba, Barry H. Grayson, MD, and Bruno L. Vendittelli, MD
Canada New York University Medical Center, Institute of
Figures 4-6, 9-38, 11-19AB, 11-28A, 12-24, 12-42, 12-43, Reconstructive Plastic Surgery, New York,
14-11, 15-6, 16-13DE, 16-14, 16-15, 17-14, 17-33, 17-36, New York, USA
18-20, 18-21, 18-23, 19-9, 20-3, 20-5, 20-6CD, 20-7, 20-8, Figure 9-40
20-13, 20-14, 20-17, and 20-19A
Christopher R. Harman, MD, FRCSC, FACOG
Blaine M. Cleghorn, DMD, MSc Department of Obstetrics, Gynecology, and
Faculty of Dentistry, Dalhousie University, Halifax, Reproductive Sciences, Women’s Hospital and
Nova Scotia, Canada University of Maryland, Baltimore, Maryland, USA
Figures 19-19 and 19-20A-E Figures 7-17 and 12-23

Dr. M.N. Golarz De Bourne †Jean Hay, MSc

St. George’s University Medical School, True Blue, Department of Anatomy, University of Manitoba,
Grenada Winnipeg, Manitoba, Canada
Figure 11-21 Figure 17-25

Heather Dean, MD, FRCPC Blair Henderson, MD

Department of Pediatrics and Child Health, University Department of Radiology, Health Sciences Centre,
of Manitoba, Winnipeg, Manitoba, Canada University of Manitoba, Winnipeg, Manitoba,
Figures 12-28 and 20-18 Canada
Figure 13-6
Marc Del Bigio, MD, PhD, FRCPC
Department of Pathology (Neuropathology), University Lyndon M. Hill, MD
of Manitoba, Winnipeg, Manitoba, Canada Magee-Women’s Hospital, Pittsburgh, Pennsylvania, USA
Figures 17-13, 17-29 (inset), 17-30BC, 17-32B, 17-37B, Figures 11-7 and 12-14
17-38, 17-40, and 17-42A
†Klaus V. Hinrichsen, MD
David D. Eisenstat, MD, MA, FRCPC Medizinische Fakultät, Institut für Anatomie,
Manitoba Institute of Cell Biology, Department of Ruhr-Universität Bochum, Bochum, Germany
Human Anatomy and Cell Science, University of Figures 5-12A, 9-2, and 9-26
Manitoba, Winnipeg, Manitoba, Canada
Figure 17-2 Dr. Jon and Mrs. Margaret Jackson
Figure 6-9B
Vassilios Fanos, MD
Department of Pediatrics, University of Verona,
Verona, Italy
Figure 20-4
†Deceased.
 C O N T R I B U TORS ix

Evelyn Jain, MD, FCFP Margaret Morris, MD, FRCSC, MEd

Breastfeeding Clinic, Calgary, Alberta, Canada Professor of Obstetrics, Gynaecology, and Reproductive
Figure 9-24 Sciences, Women’s Hospital and University of
Manitoba, Winnipeg, Manitoba, Canada
John A. Jane, Sr., MD Figure 12-46
David D. Weaver Professor of Neurosurgery,
Department of Neurological Surgery, University of Stuart C. Morrison, MD
Virginia Health System, Charlottesville, Virginia, USA Section of Pediatric Radiology, The Children’s Hospital,
Figure 14-12 Cleveland Clinic, Cleveland, Ohio, USA
Figures 7-13, 11-20, 17-29E, and 17-41
Robert Jordan, MD
St. George’s University Medical School, True Blue, John B. Mulliken, MD
Grenada Children’s Hospital Boston, Harvard Medical School,
Figures 6-6B and 7-25 Boston, Massachusetts, USA
Figure 9-42
Linda J. Juretschke, MD
Ronald McDonald Children’s Hospital, Loyola W. Jerry Oakes, MD
University Medical Center, Maywood, Illinois, USA Children’s Hospital Birmingham, Birmingham,
Figure 7-31 Alabama, USA
Figure 17-42B
Dagmar K. Kalousek, MD
Department of Pathology, University of British †Dwight Parkinson, MD
Columbia, Children’s Hospital, Vancouver, British Departments of Surgery and Human Anatomy &
Columbia, Canada Cell Science, University of Manitoba, Winnipeg,
Figures 8-11AB, 11-14A, 12-12C, 12-16, and 20-6AB Manitoba, Canada
Figure 17-14
E.C. Klatt, MD
Department of Biomedical Sciences, Mercer University Maulik S. Patel, MD
School of Medicine, Savannah, Georgia, USA Consultant Pathologist, Surat, India
Figure 7-16 Figure 4-15

Wesley Lee, MD Dr. Susan Phillips

Division of Fetal Imaging, William Beaumont Hospital, Department of Pathology, Health Sciences Centre,
Royal Oak, Michigan, USA Winnipeg, Manitoba, Canada
Figures 13-20 and 13-30A Figure 18-6

Deborah Levine, MD, FACR Srinivasa Ramachandra, MD

Departments of Radiology and Obstetric & Figure 9-13A
Gynecologic Ultrasound, Beth Israel Deaconess
Medical Center, Boston, Massachusetts, USA †Dr. M. Ray
Figures 6-8, 6-15, 8-10, 9-43CD, 17-35B, and cover image Department of Human Genetics, University of
(magnetic resonance image of 27-week fetus) Manitoba, Winnipeg, Manitoba, Canada
Figure 20-12B
E.A. (Ted) Lyons, OC, MD, FRCPC, FACR
Departments of Radiology, Obstetrics & Gynecology, Martin H. Reed, MD, FRCPC
and Human Anatomy & Cell Science, Division of Department of Radiology, University of Manitoba and
Ultrasound, Health Sciences Centre, University of Children’s Hospital, Winnipeg, Manitoba, Canada
Manitoba, Winnipeg, Manitoba, Canada Figure 11-27
Figures 3-7, 3-9, 4-1, 4-13, 5-19, 6-1, 6-10, 6-12, 7-23,
7-26, 7-29, 11-19CD, 12-45, and 13-3

†Deceased.
x CONTRIBUT O R S

Gregory J. Reid, MD, FRCSC Pierre Soucy, MD, FRCSC

Department of Obstetrics, Gynecology, and Division of Pediatric Surgery, Children’s Hospital of
Reproductive Sciences, University of Manitoba, Eastern Ontario, Ottawa, Ontario, Canada
Women’s Hospital, Winnipeg, Manitoba, Canada Figures 9-10, 9-11, and 18-22
Figures 9-43AB, 11-18, 12-39, 13-12, and 14-9
Dr. Y. Suzuki
Michael and Michele Rice Achi, Japan
Figure 6-9A Figure 16-13A

Dr. S.G. Robben R. Shane Tubbs, PhD

Department of Radiology, Maastricht University Children’s Hospital Birmingham, Birmingham,
Medical Centre, Maastricht, The Netherlands Alabama, USA
Figure 10-7C Figure 17-42B

Prem S. Sahni, MD Edward O. Uthman, MD

Formerly of the Department of Radiology, Children’s Consultant Pathologist, Houston/Richmond,
Hospital, Winnipeg, Manitoba, Canada Texas, USA
Figures 8-11C, 10-7B, 10-13, 11-4C, 11-28B, 12-16, Figure 3-11
12-17, 12-19, 14-10, 14-15, and 16-13C
Jeffrey T. Wigle, PhD
Dr. M.J. Schuurman Department of Biochemistry and Medical Genetics,
Department of Pediatrics, Maastricht University University of Manitoba, Winnipeg, Manitoba,
Medical Centre, Maastricht, The Netherlands Canada
Figure 10-7C Figure 17-2

P. Schwartz and H.M. Michelmann Nathan E. Wiseman, MD, FRCSC

University of Goettingen, Goettingen, Germany Pediatric Surgeon, Children’s Hospital, Winnipeg,
Figure 2-13 Manitoba, Canada
Figure 11-17A
Joseph R. Siebert, MD
Children’s Hospital and Regional Center, Seattle, M.T. Zenzes
Washington, USA In Vitro Fertilization Program, Toronto Hospital,
Figures 7-32, 13-36, 16-13B, and 17-16 Toronto, Ontario, Canada
Figure 2-17A
Bradley R. Smith, MD
University of Michigan, Ann Arbor, Michigan, USA
Figures 5-16C, 5-17C, 5-20C, 8-6B, 9-3A (inset), 14-13,
and 18-18B

Gerald S. Smyser, MD
Formerly of the Altru Health System, Grand Forks,
North Dakota, USA
Figures 9-20, 13-45, 17-24, 17-32A, 17-34, 17-37A,
and 18-24
 Preface

W e have entered an era of achievement in the fields of molecular biology, genetics, and
clinical embryology, perhaps like no other. The sequencing of the human genome has been
achieved and several mammalian species, as well as the human embryo, have been cloned.
Scientists have created and isolated human embryonic stem cells, and their use in treating
certain intractable diseases continues to generate widespread debate. These remarkable
scientific developments have already provided promising directions for research in human
embryology, which will have an impact on medical practice in the future.
The 10th edition of The Developing Human has been thoroughly revised to reflect current
understanding of some of the molecular events that guide development of the embryo. This
book also contains more clinically oriented material than previous editions; these sections
are set as blue boxes to differentiate them from the rest of the text. In addition to focusing
on clinically relevant aspects of embryology, we have revised the Clinically Oriented Prob-
lems with brief answers and added more case studies online that emphasize the importance
of embryology in modern medical practice.
This edition follows the official international list of embryologic terms (Terminologia
Embryologica, Georg Thieme Verlag, 2013). It is important that physicians and scientists
throughout the world use the same name for each structure.
This edition includes numerous new color photographs of embryos (normal and abnor-
mal). Many of the illustrations have been improved using three-dimensional renderings and
more effective use of colors. There are also many new diagnostic images (ultrasound and
magnetic resonance image) of embryos and fetuses to illustrate their three-dimensional
aspects. An innovative set of 18 animations that will help students understand the complexi-
ties of embryologic development now comes with this book. When one of the animations
is especially relevant to a passage in the text, the icon has been added in the margin.
Maximized animations are available to teachers who have adopted The Developing Human
for their lectures (consult your Elsevier representative).
The coverage of teratology (studies concerned with birth defects) has been increased
because the study of abnormal development of embryos and fetuses is helpful in understand-
ing risk estimation, the causes of birth defects, and how malformations may be prevented.
Recent advances in the molecular aspects of developmental biology have been highlighted
(in italics) throughout the book, especially in those areas that appear promising for clinical
medicine or have the potential for making a significant impact on the direction of future
research.
We have continued our attempts to provide an easy-to-read account of human develop-
ment before birth and during the neonatal period (1 to 28 days). Every chapter has been
thoroughly reviewed and revised to reflect new findings in research and their clinical
significance.
The chapters are organized to present a systematic and logical approach to embryo devel-
opment. The first chapter introduces readers to the scope and importance of embryology,
xi
xii PREFACE

the historical background of the discipline, and the terms used to describe the stages of
development. The next four chapters cover embryonic development, beginning with the
formation of gametes and ending with the formation of basic organs and systems. The
development of specific organs and systems is then described in a systematic manner, fol-
lowed by chapters dealing with the highlights of the fetal period, the placenta and fetal
membranes, the causes of human birth defects, and common signaling pathways used during
development. At the end of each chapter there are summaries of key features, which provide
a convenient means of ongoing review. There are also references that contain both classic
works and recent research publications.
Keith L. Moore
T.V.N. (Vid) Persaud
Mark G. Torchia
 Acknowledgments

T he Developing Human is widely used by medical, and Reproductive Sciences, University of Manitoba,
dental, and many other students in the health sciences. Winnipeg; Dr. L. Ross, Department of Neurobiology and
The suggestions, constructive criticisms, and comments Anatomy, University of Texas Medical School, Houston,
we received from instructors and students around the Texas; Dr. J. Elliott Scott, Departments of Oral Biology
world have helped us improve this 10th edition. and Human Anatomy & Cell Science, University of
When learning embryology, the illustrations are an Manitoba, Winnipeg; Dr. Brad Smith, University of
essential feature to facilitate both understanding of the Michigan, Ann Arbor, Michigan; Dr. Gerald S. Smyser,
subject and retention of the material. Many figures formerly of the Altru Health System, Grand Forks, North
have been improved, and newer clinical images replace Dakota; Dr. Richard Shane Tubbs, Children’s Hospital,
older ones. Birmingham, Alabama; Dr. Ed Uthman, Clinical Patholo-
We are indebted to the following colleagues (listed gist, Houston/Richmond, Texas; and Dr. Michael Wiley,
alphabetically) for either critical reviewing of chapters, Division of Anatomy, Department of Surgery, Faculty of
making suggestions for improvement of this book, or Medicine, University of Toronto, Toronto, Ontario. The
providing some of the new figures: Dr. Steve Ahing, new illustrations were prepared by Hans Neuhart, Presi-
Faculty of Dentistry, University of Manitoba, Winnipeg; dent of the Electronic Illustrators Group in Fountain
Dr. Albert Chudley, Departments of Pediatrics & Child Hills, Arizona.
Health and Biochemistry & Medical Genetics, University The stunning collection of animations of developing
of Manitoba, Winnipeg; Dr. Blaine M. Cleghorn, Faculty embryos was produced in collaboration with Dr. David
of Dentistry, Dalhousie University, Halifax, Nova Scotia; L. Bolender, Associate Professor, Department of Cell
Dr. Frank Gaillard, Radiopaedia.org, Toronto, Ontario; Biology, Neurobiology, and Anatomy, Medical College of
Dr. Ray Gasser, Faculty of Medicine, Louisiana State Wisconsin. We would like to thank him for his efforts in
University Medical Center, New Orleans; Dr. Boris design and in-depth review, as well as his invaluable
Kablar, Department of Anatomy and Neurobiology, advice. Our special thanks go to Ms. Carol Emery for
Dalhousie University, Halifax, Nova Scotia; Dr. Sylvia skillfully coordinating the project.
Kogan, Department of Ophthalmology, University of At Elsevier, we are indebted to Ms. Meghan K. Ziegler,
Manitoba, Winnipeg, Manitoba; Dr. Peeyush Lala, Content Strategist, for her continued interest and encour-
Faculty of Medicine, Western University, Ontario, agement, and we are especially thankful to Ms. Kelly
London, Ontario; Dr. Deborah Levine, Beth Israel McGowan, Content Development Specialist, for her
Deaconess Medical Center, Boston, Massachusetts; Dr. invaluable insights and many helpful suggestions. Their
Marios Loukas, St. George’s University, Grenada; Dr. unstinting support during the preparation of this new
Stuart Morrison, Department of Radiology, Cleveland edition was greatly appreciated. Finally, we should also
Clinic, Cleveland, Ohio; Professor Bernard J. Moxham, like to thank Ms. Kristine Feeherty, Project Manager; Ms.
Cardiff School of Biosciences, Cardiff University, Cardiff, Maggie Reid, Designer; Ms. Amy Naylor, Art Buyer; and
Wales; Dr. Michael Narvey, Department of Pediatrics Ms. Thapasya Ramkumar, Multimedia Producer, at
and Child Health, University of Manitoba, Winnipeg, Elsevier for nurturing this book to completion. This new
Manitoba; Dr. Drew Noden, Department of Biomedical edition of The Developing Human is the result of their
Sciences, Cornell University, College of Veterinary Medi- dedication and technical expertise.
cine, Ithaca, New York; Dr. Shannon Perry, School of Keith L. Moore
Nursing, San Francisco State University, California; Dr. T.V.N. (Vid) Persaud
Gregory Reid, Department of Obstetrics, Gynecology, Mark G. Torchia
xiii
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 Contents

1 Introduction to Human Menstrual Cycle 23

Phases of Menstrual Cycle 24
Development 1
Developmental Periods 1 Transportation of Gametes 25
Stages of Embryonic Development 2 Oocyte Transport 25
Postnatal Period 2 Sperm Transport 25
Infancy 2 Maturation of Sperms 26
Childhood 2 Viability of Gametes 26
Puberty 2 Sequence of Fertilization 27
Adulthood 4 Phases of Fertilization 29
Significance of Embryology 4 Fertilization 29
Historical Gleanings 4 Cleavage of Zygote 30
Ancient Views of Human Embryology 4 Formation of Blastocyst 33
Embryology in the Middle Ages 5 Summary of First Week 35
The Renaissance 5 Clinically Oriented Problems 36
Genetics and Human Development 7
Molecular Biology of Human 3 Second Week of Human
Development 7 Development 39
Human Biokinetic Embryology 8 Completion of Implantation of
Descriptive Terms in Embryology 8 Blastocyst 39
Clinically Oriented Problems 8 Formation of Amniotic Cavity, Embryonic
Disc, and Umbilical Vesicle 41
2 First Week of Human Development of Chorionic Sac 42
Implantation Sites of Blastocysts 46
Development 11
Gametogenesis 11 Summary of Implantation 46
Meiosis 12 Summary of Second Week 48
Spermatogenesis 12 Clinically Oriented Problems 49
Oogenesis 17
Prenatal Maturation of Oocytes 17 4 Third Week of Human
Postnatal Maturation of Oocytes 17 Development 51
Comparison of Gametes 17 Gastrulation: Formation of Germ
Uterus, Uterine Tubes, and Ovaries 18 Layers 51
Uterus 18 Primitive Streak 52
Uterine Tubes 18 Fate of Primitive Streak 54
Ovaries 18 Notochordal Process and Notochord 54
Female Reproductive Cycles 20 Allantois 58
Ovarian Cycle 20 Neurulation: Formation of Neural
Follicular Development 21 Tube 58
Ovulation 22 Neural Plate and Neural Tube 59
Corpus Luteum 22 Neural Crest Formation 59
xv
xvi CONTENTS

Development of Somites 61 Factors Influencing Fetal Growth 99

Development of Intraembryonic Cigarette Smoking 99
Coelom 62 Multiple Pregnancy 99
Early Development of Cardiovascular Alcohol and Illicit Drugs 99
System 62 Impaired Uteroplacental and
Vasculogenesis and Angiogenesis 62 Fetoplacental Blood Flow 99
Primordial Cardiovascular System 62 Genetic Factors and Growth
Development of Chorionic Villi 63 Retardation 100
Summary of Third Week 64 Procedures for Assessing Fetal
Clinically Oriented Problems 67 Status 100
Ultrasonography 100
Diagnostic Amniocentesis 100
5 Fourth to Eighth Weeks of Human
Alpha-Fetoprotein Assay 101
Development 69
Spectrophotometric Studies 101
Phases of Embryonic Development 69
Chorionic Villus Sampling 101
Folding of Embryo 70
Cell Cultures and Chromosomal
Folding of Embryo in the Median
Analysis 102
Plane 70
Noninvasive Prenatal Diagnosis 102
Folding of Embryo in the Horizontal
Fetal Transfusion 103
Plane 70
Fetoscopy 103
Germ Layer Derivatives 70
Percutaneous Umbilical Cord Blood
Control of Embryonic Development 72
Sampling 103
Highlights of Fourth to Eighth
Magnetic Resonance Imaging 103
Weeks 74
Fetal Monitoring 103
Fourth Week 74
Summary of Fetal Period 103
Fifth Week 75
Clinically Oriented Problems 104
Sixth Week 78
Seventh Week 78
Eighth Week 84
Estimation of Embryonic Age 85
7 Placenta and Fetal Membranes 107
Placenta 107
Summary of Fourth to Eighth
Decidua 109
Weeks 87
Development of Placenta 109
Clinically Oriented Problems 88
Placental Circulation 111
Placental Membrane 113
6 Fetal Period: Ninth Week Functions of Placenta 114
to Birth 91 Placental Endocrine Synthesis and
Estimation of Fetal Age 93 Secretion 117
Trimesters of Pregnancy 93 The Placenta as an Allograft 117
Measurements and Characteristics of The Placenta as an Invasive Tumor-like
Fetuses 93 Structure 118
Highlights of Fetal Period 94 Uterine Growth during Pregnancy 118
Nine to Twelve Weeks 94 Parturition 119
Thirteen to Sixteen Weeks 95 Stages of Labor 119
Seventeen to Twenty Weeks 95 Placenta and Fetal Membranes after
Twenty-One to Twenty-Five Weeks 96 Birth 121
Twenty-Six to Twenty-Nine Weeks 97 Maternal Surface of Placenta 121
Thirty to Thirty-Four Weeks 97 Fetal Surface of Placenta 121
Thirty-Five to Thirty-Eight Weeks 97 Umbilical Cord 124
Expected Date of Delivery 99 Amnion and Amniotic Fluid 126
 C O N T ENTS xvii

Umbilical Vesicle 129 Development of Nasal Cavities 181

Significance of Umbilical Vesicle 130 Paranasal Sinuses 181
Fate of Umbilical Vesicle 130 Development of Palate 182
Allantois 130 Primary Palate 182
Multiple Pregnancies 130 Secondary Palate 182
Twins and Fetal Membranes 130 Summary of Pharyngeal Apparatus, Face,
Dizygotic Twins 131 and Neck 191
Monozygotic Twins 132 Clinically Oriented Problems 191
Other Types of Multiple Births 133
Summary of Placenta and Fetal 10 Respiratory System 195
Membranes 135 Respiratory Primordium 195
Neonatal Period 138 Development of Larynx 196
Clinically Oriented Problems 138 Development of Trachea 198
Development of Bronchi and Lungs 200
Maturation of Lungs 201
8 Body Cavities, Mesenteries,
Summary of Respiratory System 206
and Diaphragm 141
Clinically Oriented Problems 207
Embryonic Body Cavity 141
Mesenteries 144
Division of Embryonic Body Cavity 144 11 Alimentary System 209
Foregut 210
Development of Diaphragm 146
Development of Esophagus 210
Septum Transversum 147
Development of Stomach 211
Pleuroperitoneal Membranes 147
Omental Bursa 211
Dorsal Mesentery of Esophagus 147
Development of Duodenum 214
Muscular Ingrowth from Lateral Body
Development of Liver and Biliary
Walls 148
Apparatus 217
Positional Changes and Innervation of
Development of Pancreas 219
Diaphragm 148
Development of Spleen 221
Summary of Development of Body
Midgut 221
Cavities, Mesenteries, and
Herniation of Midgut Loop 223
Diaphragm 151
Rotation of Midgut Loop 224
Clinically Oriented Problems 153
Retraction of Intestinal Loops 224
Cecum and Appendix 225
9 Pharyngeal Apparatus, Face, Hindgut 233
and Neck 155 Cloaca 233
Pharyngeal Arches 155 Anal Canal 233
Pharyngeal Arch Components 157 Summary of Alimentary System 234
Pharyngeal Pouches 161 Clinically Oriented Problems 239
Derivatives of Pharyngeal
Pouches 161 12 Urogenital System 241
Pharyngeal Grooves 164 Development of Urinary System 243
Pharyngeal Membranes 164 Development of Kidneys and
Development of Thyroid Gland 168 Ureters 243
Histogenesis of Thyroid Gland 169 Development of Urinary Bladder 255
Development of Tongue 172 Development of Urethra 258
Lingual Papillae and Taste Buds 172 Development of Suprarenal Glands 259
Nerve Supply of Tongue 173 Development of Genital System 260
Development of Salivary Glands 174 Development of Gonads 260
Development of Face 174 Development of Genital Ducts 262
xviii CONTENTS

Development of Male Genital Ducts Fetal and Neonatal Circulation 325

and Glands 264 Fetal Circulation 325
Development of Female Genital Ducts Transitional Neonatal Circulation 325
and Glands 264 Derivatives of Fetal Vessels and
Development of Vagina 266 Structures 329
Development of External Development of Lymphatic System 331
Genitalia 267 Development of Lymph Sacs and
Development of Male External Lymphatic Ducts 331
Genitalia 267 Development of Thoracic Duct 331
Development of Female External Development of Lymph Nodes 331
Genitalia 268 Development of Lymphocytes 331
Development of Inguinal Canals 276 Development of Spleen and
Relocation of Testes and Ovaries 278 Tonsils 332
Testicular Descent 278 Summary of Cardiovascular
Ovarian Descent 278 System 332
Summary of Urogenital System 278 Clinically Oriented Problems 334
Clinically Oriented Problems 280

13 Cardiovascular System 283 14 Skeletal System 337

Development of Bone and
Early Development of Heart and Blood
Cartilage 337
Vessels 284
Histogenesis of Cartilage 339
Development of Veins Associated with
Histogenesis of Bone 339
Embryonic Heart 285
Intramembranous Ossification 339
Fate of Vitelline and Umbilical
Endochondral Ossification 340
Arteries 288
Development of Joints 341
Later Development of Heart 289
Fibrous Joints 342
Circulation through Primordial
Cartilaginous Joints 342
Heart 291
Synovial Joints 342
Partitioning of Primordial Heart 293
Development of Axial Skeleton 342
Changes in Sinus Venosus 294
Development of Vertebral
Conducting System of Heart 301
Column 342
Birth Defects of Heart and Great
Development of Ribs 344
Vessels 301
Development of Sternum 344
Derivatives of Pharyngeal Arch
Development of Cranium 344
Arteries 317
Cranium of Neonate 346
Derivatives of First Pair of Pharyngeal
Postnatal Growth of Cranium 347
Arch Arteries 317
Development of Appendicular
Derivatives of Second Pair of Pharyngeal
Skeleton 349
Arch Arteries 317
Summary of Skeletal System 353
Derivatives of Third Pair of Pharyngeal
Clinically Oriented Problems 353
Arch Arteries 318
Derivatives of Fourth Pair of Pharyngeal
Arch Arteries 318 15 Muscular System 355
Fate of Fifth Pair of Pharyngeal Arch Development of Skeletal Muscle 355
Arteries 320 Myotomes 357
Derivatives of Sixth Pair of Pharyngeal Pharyngeal Arch Muscles 358
Arch Arteries 320 Ocular Muscles 358
Pharyngeal Arch Arterial Birth Tongue Muscles 358
Defects 320 Limb Muscles 358
 C O N T ENTS xix

Development of Smooth Muscle 358 Aqueous Chambers 426

Development of Cardiac Muscle 359 Cornea 427
Summary of Muscular System 361 Choroid and Sclera 427
Clinically Oriented Problems 361 Eyelids 427
Lacrimal Glands 428

16 Development of Limbs 363 Development of Ears 428

Internal Ears 428
Early Stages of Limb Development 363
Final Stages of Limb Development 367 Middle Ears 430
Cutaneous Innervation of Limbs 367 External Ears 431
Blood Supply of Limbs 371 Summary of Eye Development 434
Birth Defects of Limbs 372 Summary of Ear Development 435
Summary of Limb Development 377 Clinically Oriented Problems 435
Clinically Oriented Problems 377
19 Integumentary System 437
17 Nervous System 379 Development of Skin and
Development of Nervous System 379 Appendages 437
Development of Spinal Cord 382 Epidermis 437
Development of Spinal Ganglia 384 Dermis 439
Development of Spinal Meninges 385 Glands 440
Positional Changes of Spinal Hairs 445
Cord 387 Nails 446
Myelination of Nerve Fibers 387 Teeth 446
Development of Brain 392 Summary of Integumentary
Brain Flexures 392 System 454
Hindbrain 392 Clinically Oriented Problems 454
Choroid Plexuses and Cerebrospinal
Fluid 396
Midbrain 396
20 Human Birth Defects 457
Classification of Birth Defects 457
Forebrain 396 Teratology: Study of Abnormal
Birth Defects of Brain 403 Development 458
Development of Peripheral Nervous Birth Defects Caused by Genetic
System 412 Factors 458
Spinal Nerves 412 Numeric Chromosomal
Cranial Nerves 412 Abnormalities 459
Development of Autonomic Nervous Structural Chromosomal
System 414 Abnormalities 466
Sympathetic Nervous System 414 Birth Defects Caused by Mutant
Parasympathetic Nervous System 414 Genes 469
Summary of Nervous System 414 Developmental Signaling
Clinically Oriented Problems 415 Pathways 471
Birth Defects Caused by Environmental
18 Development of Eyes and Ears 417 Factors 472
Development of Eyes and Related Principles of Teratogenesis 472
Structures 417 Critical Periods of Human
Retina 419 Development 472
Ciliary Body 423 Human Teratogens 475
Iris 423 Birth Defects Caused by Multifactorial
Lens 425 Inheritance 484
xx CONTENTS

Summary of Birth Defects 484 Transcription Factors 496

Clinically Oriented Problems 485 HOX Proteins 496
PAX Genes 496

21 Common Signaling Pathways Used Basic Helix-Loop-Helix Transcription

Factors 497
During Development 487
Intercellular Communication 488 Epigenetics 497
Gap Junctions 488 Histones 498
Cell Adhesion Molecules 489 Histone Methylation 498
Morphogens 490 DNA Methylation 498
Retinoic Acid 490 MicroRNAs 499
Transforming Growth Factor-β and Bone Stem Cells: Differentiation versus
Morphogenetic Proteins 490 Pluripotency 499
Hedgehog 491 Summary of Common Signaling Pathways
WNT/β-Catenin Pathway 492 Used During Development 500
Protein Kinases 493
Receptor Tyrosine Kinases 493 Appendix 503
Hippo Signaling Pathway 494
Notch-Delta Pathway 494 Index 513
 C H A P T E R

1
Introduction to Human
Development
Developmental Periods 1 Embryology in the Middle Ages 5
Stages of Embryonic Development 2 The Renaissance 5
Postnatal Period 2 Genetics and Human Development 7
Infancy 2 Molecular Biology of Human
Childhood 2
Development 7
Puberty 2
Adulthood 4 Human Biokinetic Embryology 8
Significance of Embryology 4 Descriptive Terms in Embryology 8
Historical Gleanings 4 Clinically Oriented Problems 8
Ancient Views of Human Embryology 4

H uman development is a continuous process that begins when an oocyte (ovum) from a
female is fertilized by a sperm (spermatozoon) from a male (Fig. 1-1). Cell division, cell
migration, programmed cell death (apoptosis), differentiation, growth, and cell rearrange-
ment transform the fertilized oocyte, a highly specialized, totipotent cell, a zygote, into a
multicellular human being. Most changes occur during the embryonic and fetal periods;
however, important changes occur during later periods of development: neonatal period (first
4 weeks), infancy (first year), childhood (2 years to puberty), and adolescence (11 to 19
years). Development does not stop at birth; other changes, in addition to growth, occur after
birth (e.g., development of teeth and female breasts).

DEVELOPMENTAL PERIODS
It is customary to divide human development into prenatal (before birth) and postnatal (after
birth) periods. The development of a human from fertilization of an oocyte to birth is divided
into two main periods, embryonic and fetal. The main changes that occur prenatally are
illustrated in the Timetable of Human Prenatal Development (see Fig. 1-1). Examination of
the timetable reveals that the most visible advances occur during the third to eighth weeks—
the embryonic period. During the fetal period, differentiation and growth of tissues and
organs occur and the rate of body growth increases.
1
2 THE DEVEL O P I N G H U M A N

extrauterine existence requires many critical changes,

Stages of Embryonic Development especially in the cardiovascular and respiratory systems.
Early development is described in stages because of the If neonates survive the first crucial hours after birth, their
variable period it takes for embryos to develop certain chances of living are usually good. The body grows
morphologic characteristics. Stage 1 begins at fertiliza- rapidly during infancy; total length increases by approxi-
tion and embryonic development ends at stage 23, which mately one half and weight is usually tripled. By 1 year
occurs on day 56 (see Fig. 1-1). A trimester is a period of age, most infants have six to eight teeth.
of 3 months, one third of the 9-month period of gesta-
tion. The most critical stages of development occur during
the first trimester (13 weeks), when embryonic and early Childhood
fetal development is occurring. This is the period between infancy and puberty. The
primary (deciduous) teeth continue to appear and are
later replaced by the secondary (permanent) teeth. During
Postnatal Period early childhood, there is active ossification (formation of
This is the period occurring after birth. Explanations of bone), but as the child becomes older, the rate of body
frequently used developmental terms and periods follow. growth slows down. Just before puberty, however, growth
accelerates—the prepubertal growth spurt.
Infancy
This is the period of extrauterine life, roughly the first Puberty
year after birth. An infant age 1 month or younger This is the period when humans become functionally
is called a neonate. Transition from intrauterine to capable of procreation (reproduction). Reproduction is

TIMETABLE OF HUMAN PRENATAL DEVELOPMENT

1 TO 10 WEEKS

Primary follicles Oocyte

EARLY DEVELOPMENT OF OVARIAN FOLLICLE

MENSTRUAL PHASE PROLIFERATIVE PHASE

Day 1 of last normal
menstrual cycle
Antrum Mature Oocyte
follicle Ovulation

COMPLETION OF DEVELOPMENT OF FOLLICLE

Oocyte Oocyte Ovary

CONTINUATION OF PROLIFERATIVE PHASE OF MENSTRUAL CYCLE

AGE
(weeks) 1 Stage 1 2 Stage 2 begins 3 4 Stage 3 begins 5 6 Stage 4 7 Stage 5 begins
Trophoblast
Zona pellucida Implantation begins

Fertilization Zygote divides Morula Early blastocyst Late blastocyst

Embryoblast
SECRETORY PHASE OF MENSTRUAL CYCLE

8 9 10 Cytotrophoblast 11 Maternal blood 12 Extraembryonic 13 Stage 6 begins 14

Lacunar Connecting stalk
Lacunae appear in Amnion Eroded mesoderm
syncytiotrophoblast gland network Primary villi Amnion
Amniotic cavity

Primary Embryonic disc

Bilaminar embryonic Primary umbilical umbilical Coelom
disc vesicle Closing plug vesicle Embryonic disc Prechordal plate

F I G U R E 1 – 1 Early stages of development. Development of an ovarian follicle containing an oocyte, ovulation, and the phases
of the menstrual cycle are illustrated. Human development begins at fertilization, approximately 14 days after the onset of the last
normal menstrual period. Cleavage of the zygote in the uterine tube, implantation of the blastocyst in the endometrium (lining) of the
uterus, and early development of the embryo are also shown. The alternative term for the umbilical vesicle is the yolk sac; this is an
inappropriate term because the human vesicle does not contain yolk.