Pathologyof the

HUMANPLACENTA

FIFTH EDITION

Kurt Benirschke, MDPeter Kaufmann, MD

Rebecca Baergen, MD

Pathologyof the

HUMANPLACENTA

FIFTH EDITIONWith 745 Illustrations, 170 in Full Color

Kurt Benirschke, MD Peter Kaufmann, MD Rebecca Baergen, MD8457 Prestwick Drive Department of Anatomy New York-Presbyterian Hospital–WeillLa Jolla, CA 92037 RWTH Aachen Medical College of Cornell UniversityUSA D-52057 Aachen New York, NY 10021

Germany USA

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Preface

Most obstetricians and pediatricians would agree that the examination of the placenta often helps to explain an abnormal neona tal outcome. As early as in 1892, Ballantyne wrote,

A diseased foetus without its placenta is an imperfect specimen, and a description of a foetal malady, unless accompanied by a notice of the placental condition, is incomplete. Deductions drawn from such a case cannot be considered as conclu-sive, for in the missing placenta or cord may have existed the cause of the disease and death. During intrauterine life the foetus, the membranes, the cord and the placenta form an organic whole, and disease of any part must react upon and affect the others.

Similar thoughts were succinctly detailed in Price’s (1950) discussion of his concept of the prenatal biases as they affected twins. His contribution also admonishes us that placental study is a sine qua non for a more perfect understanding of fetal development. Despite all this understanding of the past and appreciation for placen-tal disease, great resistance still exists to perform the task of placental examination routinely. For many pathologists, therefore, the placenta has remained a mysterious organ.

This book had its beginning in 1967 when Shirley G. Driscoll and Kurt Benirschke wrote the volume on placental pathology for the German Handbook of Pathology,the “Henke-Lubarsch.” Because there seemed to be a need for wider dissemination of the text, this book was reprinted by Springer-Verlag New York but soon became unavailable. Since then, a number of books on placental pathology have been written, in French, English, and German (Philippe, Baldwin, Fox, Lewis and Perrin, Lavery, Gall, Kraus et al., Naeye, Becker and Röckelein, Vogel, Kaplan, and Joshi), and much more interest has been accorded this so readily available but poorly studied organ. The journal Placenta has become a significant outlet for results from sophisticated placental studies. Regular trophoblast conferences are being held in Rochester, New York, and European and international meetings were organized. Much other new information has been obtained, and the continuing enigma of placental nonrejection has been tackled by numerous investigators. In addition, the availability of the pla-centa for biochemical study has stimulated many cell biologists and molecular biolo-gists to use this organ as a convenient source of human tissue. Genetic information now adds to our understanding of the complexity of placental function and other issues. Also, because much interest is developing in comparative placentation, a new Web site may be found at http://medicine.ucsd.edu/cpa.

This fifth edition is being written because so many new findings have come from systematic study in the last few years that updating seemed necessary. Moreover,

v

there is a great need to have documentation for legal purposes as the placenta has become an important aspect of medicolegal adjudication of circumstances around the time of birth. The organization of the previous edition also left some topics uncovered that are now being corrected. Many changes have been made throughout the book. Not only was the text updated, but also a more complete index was created, the order of chapters is presented more logically, and tables are presented more use-fully. The text was written with MSWord. A complete set of diskettes with the refer-ences can be made available from the authors, if the reader desires.

I (K.B.) am indebted to many people, foremost to my wife for her understanding and patience with me and with this task; the publishers and many of its staff members have been gracious and patient; my colleagues at the university, and other persons who have all helped gather data, are gratefully acknowledged. Many students and colleagues have graciously read most chapters and they have made many helpful suggestions and corrections, for which I am appreciative. There are some colleagues, however, whose inspiration have helped more than others: Marjorie Grafe; the dys-morphologists Kenneth L. Jones, his wife Marilyn, and their numerous fellows as well as neonatologist Frank Mannino; and ultraso nographer Dolores Pretorius, who con-tinues to challenge me and requires that I provide explana tions for perinatal deaths and abnormalities. Having examined all placentas of all deliveries in the insti tutions with which I was affiliated over the past five decades, I have gathered a large amount of material to digest. Most of all, however, I am grateful to Dr. Geoffrey Altshuler, Oklahoma City, for many stimulating discussions and endless patience with me and his friendship.

P.K. gratefully acknowledges the scientific cooperation of many former and present coworkers: Mario Castellucci, Ayse Demir, Hans-Georg Frank, Hitoshi Funayama, Gabriele Gaus, Berthold Huppertz, Mahmed Kadirov, Sonja Kertschanska, Gaby Kohnen, Georg Kosanke, Azizbek Nanaev, Frank Reister, and the late Gertfried Schweikhart. Many of my data are based on their material, their findings, and their ideas. Also, many colleagues and friends from other laboratories have contributed by discussion and by offering technical help. In this respect I am particularly grateful to Ramazan Demir, Gernot Desoye, Jean-Michel Foidart, John Kingdom, Hubert Korr, Rudolf Leiser, Peter Ruck, Hobe Schröder, Tullia Todros, and the late Elizabeth Ramsey. In many cases it is virtually impossible to differentiate between their and my ideas.

These chapters do not only require scientific inspiration but also much artistic, technical, and secretarial work. The artistic help of Wolfgang Graulich and the photographic assistance of Gaby Bock as well as of Helga Kriegel are gratefully acknowledged. The histologic and electron-microscopic pictures are based on material processed by Marianne von Bentheim, Barbara Ihnow, Michaela Nicolau, Lian Shen, and Uta Zahn. Perfect secretarial assistance was provided by Jutta Ruppert.

The collaboration of all these coworkers and friends was the basis for my contribu-tion. Last but not least, I am very much indebted to my wife for her support and understanding.

Kurt Benirschke, MDLa Jolla, California

Peter Kaufmann, MDAachen, Germany

Rebecca Baergen, MDNew York, NY

vi Preface

References

Baldwin, V.J.: Pathology of Multiple Pregnancy. Springer-Verlag, New York, 1994.Ballantyne, J.W.: The Diseases and Deformities of the Foetus. Vol. I. Oliver and Boyd,

Edinburgh. 1892.Becker, V. and Röckelein, G.: Pathologie der weiblichen Genitalorgane I. Pathologie der

Plazenta und des Abortes. Springer-Verlag, Heidelberg, 1989.Benirschke, K. and Driscoll, S.G.: The Pathology of the Human Placenta. Springer-Verlag,

New York. 1967.Fox, H.: Pathology of the Placenta. 2nd Edition. W.B. Saunders Co. Philadel phia. 1997.Gall, S.A.: Multiple Pregnancy and Delivery. Mosby, St. Louis, 1996.Joshi, V.V.: Handbook of Placental Pathology. Igaku-Shoin, New York, 1994.Kaplan, C.G.: Color Atlas of Gross Placental Pathology. Igaku-Shoin, New York, 1994.Kraus, F.T., Redline, R.W., Gersell, D.J., Nelson, D.M. and Dicke, J.M.: Placental Pathology.

Atlas of Nontumor Pathology. AFIP, Washington, DC, 2004.Lavery, J.P., ed.: The Human Placenta. Clinical Perspectives. Aspen Publishers, Rockville,

Maryland. 1987.Lewis, S.H. and Perrin, V.D.K., eds.: Pathology of the Placenta. Churchill Livingstone,

New York. 1999.Naeye, R.L.: Disorders of the Placenta, Fetus, and Neonate. Mosby Year Book, St. Louis,

Missouri, 1992.Philippe, E.: Pathologie Foeto-Placentaire. Masson, Paris. 1986.Price, B.: Primary biases in twin studies: review of prenatal and natal differences-producing

factors in monozygotic pairs. Amer. J. Hum. Genet. 2:293–352, 1950.Vogel, M.: Atlas der morphologischen Plazentadiagnostik. Springer-Verlag, Heidelberg, 2nd

Edition, 1995.

Preface vii

Contents

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v

1. Examination of the Placenta . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Macroscopic Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Storage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Photography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Placentas of Multiple Births . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7Fixation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Special Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

2. Macroscopic Features of the Delivered Placenta . . . . . . . . . . 13Fetal Surface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Maternal Surface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13The Terms Fetal Placenta and Maternal Placenta . . . . . . . . . . . . . . . . . . 15References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

3. Microscopic Survey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Typical Histologic Features of the First Trimester Placenta . . . . . . . . . 16Typical Histologic Features of the Third Trimester Placenta . . . . . . . . . 20

Immunohistochemical Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

4. Placental Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30Placental Shapes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32Types of Maternofetal Interdigitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34Maternofetal Barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35Maternofetal Blood Flow Interrelations . . . . . . . . . . . . . . . . . . . . . . . . . . 37Placental Types and Phylogeny . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37Human Placenta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

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5. Early Development of the Human Placenta . . . . . . . . . . . . . . 42Prelacunar Stage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42Lacunar Stage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44Early Villous Stages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

6. Basic Structure of the Villous Trees . . . . . . . . . . . . . . . . . . . . . 50M. Castellucci and P. Kaufmann

Syncytiotrophoblast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50Syncytium or Multinucleated Giant Cells? . . . . . . . . . . . . . . . . . . . . . . 50Syncytial Plasmalemmas and Microvilli . . . . . . . . . . . . . . . . . . . . . . . . 54Syncytiotrophoblastic Cytoskeleton . . . . . . . . . . . . . . . . . . . . . . . . . . . 55Specialized Regions of the Villous Surface . . . . . . . . . . . . . . . . . . . . . 55Syncytiotrophoblast with Prevailing Rough

Endoplasmic Reticulum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55Syncytiotrophoblast with Prevailing Smooth

Endoplasmic Reticulum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57Vasculosyncytial Membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59Syncytial Lamellae Covering Langhans’ Cells . . . . . . . . . . . . . . . . . . . 61Syncytial Knots, Sprouts, and Bridges . . . . . . . . . . . . . . . . . . . . . . . . . . 61Transtrophoblastic Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64Trophoblastic Blebbing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Villous Cytotrophoblast (Langhans’ Cells) . . . . . . . . . . . . . . . . . . . . . . . 65Cytotrophoblast Cell Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66Nematosomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70Endocrine Activities of the Villous Cytotrophoblast . . . . . . . . . . . . . 70

Trophoblast Turnover and Syncytial Fusion . . . . . . . . . . . . . . . . . . . . . . . 72Quantitation of Trophoblast Turnover . . . . . . . . . . . . . . . . . . . . . . . . . 72Why Does Syncytiotrophoblast Survival Depend

on Syncytial Fusion? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72Trophoblastic Differentiation and Apoptosis Cascade . . . . . . . . . . . . 73

Molecular Mechanisms of Syncytial Fusion . . . . . . . . . . . . . . . . . . . . . . . 76Phosphatidylserine Flip as Fusion Signal . . . . . . . . . . . . . . . . . . . . . . . 76Junctional and Adhesion Molecules as Fusion Mediators . . . . . . . . . 76The ADAM Family of Fusogenic Proteins . . . . . . . . . . . . . . . . . . . . . . 76Endogenous Retroviral Envelope Proteins of the HERV Family

(Syncytins) and Their Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77Molecular Control of Syncytial Fusion . . . . . . . . . . . . . . . . . . . . . . . . . 78The Role of Oxygen and Cytokines in Trophoblast Proliferation

and Fusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79The Impact of Trophoblast Turnover on

Syncytiotrophoblast Specialization . . . . . . . . . . . . . . . . . . . . . . . . . . 81Trophoblastic Basement Membrane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82Connective Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

Mesenchymal Cells (V Cells) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82Fibroblasts (VD Cells and VDA Cells) . . . . . . . . . . . . . . . . . . . . . . . . 83Myofibroblasts (VDAG Cells and VDAGM Cells) . . . . . . . . . . . . . . . 84Matrix Components of the Villous Stroma . . . . . . . . . . . . . . . . . . . . . 86

Hofbauer Cells (Villous Macrophages) . . . . . . . . . . . . . . . . . . . . . . . . . . 87First Descriptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87Morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87Occurrence and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90Origin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

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Immunologic Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91Other Free Connective Tissue Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93Basic Structure of the Vessel Walls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

Fetal Capillaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94Large Fetal Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94Vasomotor Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

Fibrinoid of the Villous Trees . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96Perivillous Fibrinoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96Intravillous Fibrinoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

7. Architecture of Normal Villous Trees . . . . . . . . . . . . . . . . . . . . 121Classification of Villous Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

Stem Villi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121Immature Intermediate Villi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126Mature Intermediate Villi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128Terminal Villi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129Mesenchymal Villi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133Immunohistochemistry of Villous Types . . . . . . . . . . . . . . . . . . . . . . . . 134

Differentiation and Maturation of Villous Types . . . . . . . . . . . . . . . . . . 137Development of the Mesenchymal Villi . . . . . . . . . . . . . . . . . . . . . . . . 137Development and Fate of Immature Intermediate Villi . . . . . . . . . . . 138Development of Stem Villi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138Development of the Mature Intermediate Villi . . . . . . . . . . . . . . . . . . 140Development of the Terminal Villi . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140

Angioarchitecture of Villi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140Vascular Arrangement in Immature Villi . . . . . . . . . . . . . . . . . . . . . . . 140Larger Vessels of Stem Villi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141Paravascular Capillary Net of Stem Villi . . . . . . . . . . . . . . . . . . . . . . . 141Arrangement of Vessels in Mature Intermediate and

Terminal Villi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143Sinusoids of Terminal Villi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145

Fetoplacental Angiogenesis as the Driving Force for Villous Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146General Aspects of Placental Vasculogenesis

and Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147Vasculogenesis 1: Origin of Hemangiogenic Progenitor Cells

(Days 15 to 21) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148Vasculogenesis 2: Formation of Endothelial Tubes

(Days 21 to 32) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148Angiogenesis 1: Branching Angiogenesis (Day 32 to Week 25) . . . . 153Angiogenesis 2: Formation of Stem Vessels and Regression of

Capillaries in Stem Villi (Weeks 15 to 32) . . . . . . . . . . . . . . . . . . . . 153Angiogenesis 3: Prevailing Nonbranching Angiogenesis

(Week 25 to Term) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154Oxygen and Oxygen-Controlled Growth Factors as Regulators of

Villous and Vascular Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155The Special Role of Oxygen in the Placenta . . . . . . . . . . . . . . . . . . . . 155Types of Hypoxia and Its Effects on Villous Development . . . . . . . . 155Evidence for Oxygen-Controlled Fetoplacental Angiogenesis . . . . . 157Oxygen-Controlled Angiogenic Growth Factors . . . . . . . . . . . . . . . . . 157The Timing Mismatch Between Changes in Oxygenation and

Morphologic Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158Oxygen and Villous Trophoblast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

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Oxygen and Villous Stroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159Oxygen and Intervillous Circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

Hormones as Regulators of Villous Development . . . . . . . . . . . . . . . . . 160Intervillous Space as Related to the Villous Trees . . . . . . . . . . . . . . . . . 160

Width of the Intervillous Space . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161Organization of Villous Trees . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161Histopathologic Importance of Inhomogeneity of

Villous Trees . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164Fetomaternal Flow Interrelations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165

8. Characterization of the Developmental Stages . . . . . . . . . . . . 174Stages of Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174

Nucleated Red Blood Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189

9. Nonvillous Parts and Trophoblast Invasion . . . . . . . . . . . . . . . 191H.G. Frank and P. Kaufmann

Extravillous Trophoblast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191Historical Aspects and Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . 191Extravillous Trophoblast Is a Tissue of Its Own . . . . . . . . . . . . . . . . . 193Proliferation Patterns of Extravillous Trophoblast and

the Invasive Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194Stages of Extravillous Trophoblast Differentiation Within

the Invasive Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196One Stem Cell Origin for Villous Syncytiotrophoblast and

the Extravillous Trophoblast? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200Cytokines and Hormones Controlling Differentiation

of Extravillous Trophoblast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201Extracellular Matrix Secretion Along the Invasive Pathway . . . . . . . 204Extracellular Matrix Receptors (Integrins) . . . . . . . . . . . . . . . . . . . . . 204Other Cell Adhesion Molecules and Gap Junction Molecules . . . . . 206Proteinases, Activators, and Inhibitors Involved in

Trophoblast Invasion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207Nitric Oxide and Trophoblast Invasion . . . . . . . . . . . . . . . . . . . . . . . . . 209Major Basic Protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209Cell Surface Carbohydrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211MHC Class I Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212Normal Extravillous Trophoblast Cells Are Never Proliferative

and Invasive at One Time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213Oxygen-Mediated Regulation of the Invasive Pathway . . . . . . . . . . . 214Extracellular pH as Trigger of Trophoblast Invasion . . . . . . . . . . . . . 215Trophoblastic Mechanisms Limiting Trophoblast Invasion . . . . . . . . 215Endocrine Activities of Extravillous Trophoblast . . . . . . . . . . . . . . . . 216Does Extravillous Trophoblast Differ from One Nonvillous Part

to the Other? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217Decidua . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

Composition of Decidua . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217Endometrial Stromal Cells and Decidual Cells . . . . . . . . . . . . . . . . . . 218Endocrine and Paracrine Aspects of Decidua . . . . . . . . . . . . . . . . . . . 220Functional Considerations of Decidualization . . . . . . . . . . . . . . . . . . . 221B Cells and T Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

Contents xiii

Endometrial Large Granular Lymphocytes (Endometrial NKCells and uNK Cells) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223

Macrophages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224Glandular Residues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225Decidual Extracellular Matrix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

Fibrinoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 Definition and Historical Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

Types of Fibrinoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227Origin of Fibrinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230Interactions Between Matrix-Type and Fibrin-Type Fibrinoid . . . . . 231Functions of Fibrinoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

Trophoblast Invasion as a Result of Deciduo-Trophoblastic Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233

Calcification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236Chorionic Plate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239

Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239Structure at Term . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239Amnion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239Spongy Layer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240Chorionic Mesoderm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241Extravillous Cytotrophoblast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241Langhans’ Fibrinoid Layer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242

Marginal Zone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243Subchorial Closing Ring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243Trabeculae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244Marginal Sinus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244

Basal Plate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244Trophoblastic Shell and Development of the Basal Plate . . . . . . . . . 244Layers of the Basal Plate at Term . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246

Uteroplacental Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249Number and Position of the Uteroplacental Vessels . . . . . . . . . . . . . 251Importance of Physiologic Changes of Uteroplacental Arteries . . . . 252Stages of Physiologic Changes in Uteroplacental Arteries . . . . . . . . 252Sites and Routes of Endovascular Trophoblast Invasion . . . . . . . . . . 254Trophoblast-Endothelial Adhesion Mechanisms . . . . . . . . . . . . . . . . . 255The Role of Macrophages in the Control of Endovascular

Trophoblast Invasion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256Incompetent Trophoblast Invasion or Exaggerated

Maternal Defense as Causes for Maladaptation of Uteroplacental Arteries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257

Structure of Uteroplacental Veins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258Intramural Fibrinoid of Uteroplacental Arteries and Veins . . . . . . . 260Functional Aspects of Uteroplacental Vessels . . . . . . . . . . . . . . . . . . . 260

Septa, Cell Islands, and Cell Columns . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261Septa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261Cell Islands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264Cell Columns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265

Pathology of Trophoblast Invasion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268Placenta Accreta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268Placenta Increta and Percreta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271Uterine Rupture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273Placenta in Ectopic (Tubal) Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . 275Placenta in Abdominal Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276Cysts and Breus’ Mole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277

xiv Contents

Maternal Floor Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281Decidual Degeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287

10. Involution of Placental Site; Retained Placenta . . . . . . . . . . . 313Involution of the Placental Site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313Subinvolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316Placental Polyps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316Involution of a Remaining Placenta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319

11. Anatomy and Pathology of the Placental Membranes . . . . . 321Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321

Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323Amnion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326Amnionic Epithelium: Different Cell Types or Cell Degeneration . . . 327Cytologic and Functional Aspects of the Amnionic Epithelium . . . . . . 327

Amnionic Fluid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330Chromosomal Determinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331

Cellular Metaplasia and Glycogen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331Amnionic Mesoderm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333

A Medley of Themes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334Clinical and Research Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334

Chorion Laeve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335Intermediate (Spongy) Layer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335Chorionic Mesoderm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335Trophoblast Layer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336Decidua . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337Tensile Properties of the Membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338Pathology of the Membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338

Preterm Rupture of the Membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . 338Cysts, Tumors, and Hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340Amniotic Fluid Embolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342Meconium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345Gastroschisis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354Epidermolysis Bullosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354Amnion Nodosum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355Amnionic Bands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358Extramembranous Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366

12. Anatomy and Pathology of the Umbilical Cord . . . . . . . . . . . 380Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380Amnionic Epithelium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380Wharton’s Jelly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381Structure of Umbilical Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383

Innervation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384Contractility of Umbilical Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385Hyrtl’s Anastomosis, False Knots, and Hoboken Nodes . . . . . . . . . . . . 386Allantois . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388

Omphalomesenteric Duct . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389Spiral Turns of the Cord . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392

Contents xv

Length of the Cord . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394Abnormal Length, Nuchal Cord . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395Site of Cord Insertion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401Furcate Cord Insertion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402Velamentous Cord Insertion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403Placental Surface Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407Nucleated Red Blood Cells (NRBCs) . . . . . . . . . . . . . . . . . . . . . . . . . . . 410Cysts and Edema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411Single Umbilical Artery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413Placental Transfusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415Knots . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416False Knots . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418Strictures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419Rupture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420Hematoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421Varices and Aneurysms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423Thrombosis of the Umbilical Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426Thrombosis of the Placental Vascular Tree . . . . . . . . . . . . . . . . . . . . . . . 428Tumors of the Umbilical Cord . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435

13. Placental Shape Aberrations . . . . . . . . . . . . . . . . . . . . . . . . . . . 452Site of Placental Attachment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452Volumetric Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454Abnormal Shapes (“Errors in Outline”) . . . . . . . . . . . . . . . . . . . . . . . . . 454Placenta Previa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457Placenta Membranacea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462Circumvallate Placenta (Extrachorial,

Circummarginate Placentas) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468

14. Histopathologic Approach to Villous Alterations . . . . . . . . . 473How to Assess Villous Histopathology . . . . . . . . . . . . . . . . . . . . . . . . . . . 473

Assessment of Villous Maturation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473Placental Insufficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476Examination of Fetal Stem Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477Examination of the Fetal Capillary Bed . . . . . . . . . . . . . . . . . . . . . . . . 477Villous Architecture and Fibrinoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478Intervillous Space, Infarcts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479Abruptio Placentae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480

Major Histopathologic Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480Syncytiotrophoblast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480Knotting of the Syncytiotrophoblast . . . . . . . . . . . . . . . . . . . . . . . . . . . 480Langhans’ Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482Vasculosyncytial Membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482Trophoblastic Basement Membrane . . . . . . . . . . . . . . . . . . . . . . . . . . . 482Perivillous Fibrinoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482Intravillous Fibrinoid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483Villous Calcification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483Stem Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483Nucleated Red Blood Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484Villous Capillarization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484Stromal Architecture and Stromal Fibrosis . . . . . . . . . . . . . . . . . . . . . 485