Pathology of the Human

Kurt Benirschke • Graham J. Burton Rebecca N. Baergen

Pathology of the Human Placenta

Sixth Edition Authors Kurt Benirschke, M.D. Rebecca N. Baergen, M.D. Prestwick Drive Department of Pathology La Jolla, CA and Laboratory Medicine USA New York-Presbyterian Hospital Weill Medical College of Cornell University Graham J. Burton, M.D., D.Sc. New York, NY Physiological Laboratory USA University of Cambridge Centre for Trophoblast Research Cambridge UK

ISBN 978-3-642-23940-3 ISBN 978-3-642-23941-0 (eBook) DOI 10.1007/978-3-642-23941-0 Springer Heidelberg New York Dordrecht London

Library of Congress Control Number: 2012931856

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Springer is part of Springer Science+Business Media (www.springer.com) Preface

It is with great sadness that we report here that Professor Peter Kaufmann died in December 2010 from the cancer that had troubled him for a long time. Professor Graham Burton will ably replace Peter’s contributions in the future. Most obstetricians and pediatricians would agree that the examination of the placenta often helps to explain an abnormal neonatal outcome. As early as in 1892, Ballantyne wrote that: 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 conclusive, 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 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 (1950). Despite all this understanding of the past and appreciation for , great resistance still exists to perform the task of placental examination routinely. For many pathologists, therefore, the pla- centa 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 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, and Sebire; Perrin, Gruenwald, Lavery, Naeye, Becker, and Röckelein; Vogel, Kaplan, Joshi, and Baergen), and much more interest has been accorded to this “so readily available but poorly studied” organ. The journal Placenta founded by Harold Fox has become a signi fi cant outlet for results of sophisticated placental studies. The International Federation of Placenta Associations (IFPA) has been established to promote research interest and to inte- grate the activities of the former Trophoblast Conferences held in Rochester, N.Y., and the European and other regional placenta groups. Much new information has been obtained and the continuing enigma of placental non-rejection has been tackled by numerous investigators without complete resolution. In addition, the availability of the placenta for biochemical study has stimulated many cell biologists and molecular biologists to use this organ as a convenient source of human tissue. Genetic and epigenetic information now add to our understanding of the complexity of placental function, and so forth. Also, because much interest is developing in “Comparative Placentation,” a website may be found at: http://medicine.ucsd.edu/cpa . This sixth edition is being written because so many new fi ndings have come from the sys- tematic study in the last few years that updating seemed necessary. Moreover, there is a great need to have documentation for legal purposes as the placenta has become an important aspect of medico-legal 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 has the text been updated, a more complete index has been created, the order of chapters is presented more logically and tables

v vi Preface are presented more usefully. The text was written with MS Word. A complete set of diskettes with the references can be made available from the authors, if desired. I (KB) am indebted to many people, foremost to my wife for her understanding and patience with me and this task; the publishers with many of its people have been gracious and patient; my colleagues at the university; and other persons who have all helped gather data are grate- fully 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 dysmorphologists Kenneth L. Jones and his wife Marilyn and their numerous fel- lows as well as neonatologist Frank Mannino; and ultrasonographer Dolores Pretorius who continues to challenge me and requires that I provide explanations for perinatal deaths and abnormalities. Having examined all of all deliveries in the institutions with which I was affi liated over the past fi ve 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 stimu- lating discussions and endless patience with me and his friendship. PK gratefully acknowledges the scientifi c cooperation of many former and present cowork- ers. These comprise 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 fi ndings, 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. Unfortunately, since PK was taken ill he turned over the respon- sibility for his chapters to Professor Graham J. Burton of Cambridge, England. We are most grateful to him for accepting this task. These chapters do not only require scienti fi c 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 histological and electron-microscopic pictures are based on material processed by Marianne von Bentheim, Michaela Nicolau, Lian Shen, Barbara Ihnow, and Uta Zahn. Perfect secretarial assistance was provided by Jutta Ruppert. The collaboration of all these coworkers and friends was the basis for my contribution (PK). I (GJB) wish to acknowledge the enormous contribution made by all members of my labora- tory over several decades of placental research. I was introduced to the placenta by Donald Steven, and have had the great pleasure and privilege to work with many academic colleagues, post-doctoral fellows, and students. In particular, I am most grateful to Eric Jauniaux, Stephen Charnock-Jones, Ashley Moffett, Carolyn Jones, and Jeremy Skepper for long and productive collaborations, and for their comments on draft versions of chapters. I also wish to acknowledge the visionary philanthropy of Charlie Loke in endowing the Centre for Trophoblast Research (www.trophoblast.cam.ac.uk ), which has provided a unique foundation for placental research. I (RB) am most grateful to my husband for his patience and support. I am also grateful to a number of colleagues for their helpful suggestions and their inspiration including Ona Faye-Petersen, Debra Heller, and Cynthia Kaplan. I also would like to thank our residents and Pathology Assistants who have assisted with photographs and gathering data, but I would like to particularly thank our fellow Kristina Loukeris for her support and assistance which she graciously provided on a daily basis.

La Jolla, CA, USA Kurt Benirschke, M.D. Dortmund & Aachen, Germany Peter Kaufmann, M.D. Cambridge, UK Graham J. Burton, M.D., D.Sc. New York, NY, USA Rebecca N. Baergen, M.D. Preface vii

Bibliography

Baergen RN (2011) Manual of pathology of the human placenta, 2nd edn. Springer, New York Baldwin VJ (1994) Pathology of multiple . Springer, New York Ballantyne JW (1892) The diseases and deformities of the foetus, vol I. Oliver and Boyd, Edinburgh Becker V, Röckelein G (1989) Pathologie der weiblichen Genitalorgane I. Pathologie der Plazenta und des Abortes. Springer, Heidelberg Benirschke K, Driscoll SG (1967) The pathology of the human placenta. Springer, New York Fox H, Sebire N (2007) Pathology of the placenta, 3rd edn. Saunders, Philadelphia Gall SA (1996) Multiple pregnancy and delivery. Mosby, St. Louis Gruenwald P (ed) (1975) The placenta and its maternal supply line. Effects of insuf fi ciency on the . University Press, Baltimore Joshi VV (1994) Handbook of placental pathology. Igaku-Shoin, New York Kaplan CG (1994) Color atlas of gross placental pathology. Igaku-Shoin, New York Kraus FT, Redline RW, Gersell DJ, Nelson DM, Dicke JM (2004) Placental pathology. Atlas of nontumor pathology. AFIP, Washington, DC Lavery JP (ed) (1987) The human placenta. Clinical perspectives. Aspen Publishers, Rockville Naeye RL (1992) Disorders of the placenta, fetus, and neonate. Mosby Year Book, St. Louis Perrin VDK (ed) (1999) Pathology of the placenta. Churchill Livingstone, New York Philippe E (1986) Pathologie Foeto-Placentaire. Masson, Paris Price B (1950) Primary biases in twin studies: review of prenatal and natal differences-producing factors in monozygotic pairs. Am J Hum Genet 2:293Ð352 Vogel M (1995) Atlas der morphologischen Plazentadiagnostik, 2nd edn. Springer, Heidelberg

Contents

1 Examination of the Placenta ...... 1 1.1 Macroscopic Examination ...... 1 1.2 Storage ...... 1 1.3 Selection ...... 2 1.4 Photography ...... 2 1.5 Examination ...... 2 1.6 Placentas of Multiple Births ...... 6 1.7 Fixation ...... 8 1.8 Stereological Analysis ...... 9 1.9 mRNA and Microarray Analyses ...... 9 1.10 Special Procedures ...... 9 References ...... 10

2 Macroscopic Features of the Delivered Placenta ...... 13 2.1 Fetal Surface ...... 13 2.2 Maternal Surface ...... 14 2.3 The Terms “Fetal Placenta” and “Maternal Placenta” ...... 14 References ...... 15

3 Microscopic Survey ...... 17 3.1 Typical Histological Features of the First Trimester Placenta ...... 17 3.2 Typical Histological Features of the Third Trimester Placenta ...... 23 4 Placental Types ...... 27 4.1 Placental Shapes ...... 28 4.2 Types of Maternal-Fetal Interdigitation ...... 29 4.3 Maternal-Fetal Interface ...... 30 4.4 Maternal-Fetal Flow Interrelations ...... 31 4.5 Placental Types and Phylogeny ...... 32 4.6 Genomic Imprinting ...... 35 4.7 Human Placenta ...... 36 4.8 Animal Models ...... 37 References ...... 37

5 Early Development of the Human Placenta ...... 41 5.1 The Origin of Trophoblast ...... 41 5.2 Prelacunar Stage ...... 41 5.3 Lacunar Stage ...... 44 5.4 Early Villous Stages ...... 45 5.5 Histiotrophic Nutrition ...... 46 5.6 Villus Regression and Formation of the De fi nitive Placenta ...... 48 5.7 The and Yolk Sac ...... 50 References ...... 51

ix x Contents

6 Basic Structure of the Villous Trees ...... 55 6.1 Syncytiotrophoblast ...... 55 6.1.1 Microvillous Surface ...... 55 6.1.2 Basal Surface ...... 61 6.1.3 Organelles...... 61 6.1.4 Nuclei ...... 63 6.1.5 Cytoskeleton ...... 64 6.1.6 Enzymes ...... 64 6.1.7 Glycogen ...... 65 6.1.8 Specialized Regions of the Villous Surface ...... 66 6.1.9 Syncytial Sprouts and Knots ...... 67 6.1.10 Intervillous Bridges ...... 69 6.1.11 Transtrophoblastic Channels ...... 70 6.2 Villous Cytotrophoblast (Langhans’ Cells) ...... 70 6.2.1 Villous Cytotrophoblast Cell Types ...... 71 6.2.2 Cytotrophoblast Fusion ...... 73 6.2.3 Junctional Proteins ...... 74 6.2.4 Endogenous Retroviral Glycoproteins ...... 74 6.2.5 Externalization of Phosphatidylserine ...... 76 6.2.6 Reorganization of the Cytoskeleton ...... 76 6.2.7 Reorganization of the Plasma Membranes ...... 77 6.2.8 Overview ...... 77 6.3 Syncytiotrophoblast Regeneration and Repair ...... 78 6.3.1 Trophoblast Apoptosis ...... 79 6.3.2 Trophoblastic Basement Membrane ...... 80 6.3.3 Connective Tissue ...... 81 6.3.4 Matrix Components of the Villous Stroma ...... 83 6.4 Villous Macrophages (Hofbauer Cells) ...... 84 6.4.1 Origin and Distribution ...... 84 6.4.2 Functions ...... 85 6.5 Other Free Connective Tissue Cells ...... 86 6.5.1 Fetal Vasculature ...... 86 6.5.2 Stem Villous Arteries ...... 86 6.5.3 Fetal Capillaries ...... 87 6.5.4 Vasomotor Control ...... 88 6.5.5 Lymphatics ...... 89 6.6 Fibrinoid of the Villous Trees ...... 89 6.6.1 Perivillous Fibrinoid ...... 89 6.6.2 Intravillous Fibrinoid ...... 89 References ...... 89

7 Architecture of Normal Villous Trees ...... 101 7.1 Classi fi cation of Villous Types ...... 101 7.1.1 Stem Villi ...... 102 7.1.2 Immature Intermediate Villi ...... 104 7.1.3 Mature Intermediate Villi ...... 106 7.1.4 Terminal Villi ...... 106 7.1.5 Mesenchymal Villi ...... 109 7.2 Differentiation and Growth of Villous Types ...... 110 7.2.1 Formation of Mesenchymal Villi ...... 110 7.2.2 Differentiation of Mesenchymal Villi ...... 111 7.2.3 Development of the Terminal Villi ...... 112 7.3 Angioarchitecture of Villi ...... 113 7.3.1 Vascular Arrangement in Immature Villi ...... 113 7.3.2 Larger Vessels of Stem Villi ...... 113 Contents xi

7.3.3 Paravascular Capillary Net of Stem Villi ...... 113 7.3.4 Arrangement of Vessels in Mature Intermediate and Terminal Villi . 115 7.3.5 Sinusoids of Terminal Villi ...... 117 7.4 General Aspects of Placental Vasculogenesis and Angiogenesis ...... 117 7.4.1 Vasculogenesis (Day 15Ð32) ...... 118 7.4.2 Angiogenesis and Vascular Remodeling (Day 32 to Week 40) . . . . . 121 7.5 Molecular Regulation of Vasculogenesis and Angiogenesis ...... 121 7.5.1 Vascular Endothelial Growth Factor ...... 124 7.5.2 Placental Growth Factor ...... 124 7.5.3 Angiopoietins ...... 125 7.5.4 Fibroblast Growth Factor ...... 125 7.5.5 Homeobox Genes ...... 125 7.6 Oxygen and Oxygen-Controlled Growth Factors as Regulators of Villous and Vascular Development ...... 126 7.6.1 Oxygen Sensing by Placental Tissues ...... 128 7.6.2 Evidence for Oxygen-Controlled Fetoplacental Angiogenesis . . . . . 130 7.6.3 Oxygen and Villous Trophoblast ...... 131 7.6.4 Oxygen and Villous Stroma ...... 133 7.6.5 Oxygen and Intervillous Circulation ...... 133 7.6.6 The Lobular Arrangement of the Villous Trees ...... 134 7.6.7 The Intervillous Clefts ...... 136 7.7 Histopathological Importance of Inhomogeneity of Villous Trees ...... 137 7.8 Fetomaternal Flow Interrelations ...... 137 References ...... 138

8 Characterization of the Developmental Stages ...... 145 8.1 Stages of Development ...... 145 References ...... 155

9 Nonvillous Parts and Trophoblast Invasion ...... 157 9.1 Extravillous Trophoblast ...... 157 9.1.1 Origins of Extravillous Trophoblast and Cell Columns ...... 157 9.1.2 Stages of Extravillous Trophoblast Differentiation Along the Invasive Pathway ...... 160 9.1.3 Proliferative Stem Cells ...... 161 9.1.4 Migratory Cells of the Cell Column...... 161 9.1.5 Cytotrophoblastic Shell ...... 162 9.1.6 Invasive Interstitial Extravillous Trophoblast Cells ...... 162 9.1.7 Multinucleated Placental-Bed Giant Cells ...... 164 9.1.8 Endovascular Trophoblast ...... 164 9.1.9 Proteinases, Activators, and Inhibitors Involved in Trophoblast Invasion ...... 165 9.1.10 Cytokines and Hormones Controlling Differentiation and Invasion of Extravillous Trophoblast ...... 166 9.1.11 Nitric Oxide, Carbon Monoxide, and Trophoblast Invasion ...... 169 9.1.12 MHC Class I Molecules ...... 171 9.1.13 Oxygen-Mediated Regulation of the Invasive Pathway ...... 172 9.1.14 Failure of Extravillous Trophoblast Invasion in Pathological ...... 174 9.1.15 Endocrine Activities of Extravillous Trophoblast ...... 175 9.2 Decidua ...... 175 9.2.1 Composition of Decidua ...... 176 9.2.2 Endometrial Stromal Cells and Decidual Cells ...... 176 9.2.3 Endocrine and Paracrine Aspects of Decidua ...... 177 9.2.4 Uterine Natural Killer Cells (UNK Cells) ...... 178 xii Contents

9.2.5 Macrophages ...... 179 9.2.6 Dendritic Cells ...... 180 9.2.7 B Cells and T Cells ...... 180 9.2.8 Regulatory T Cells ...... 180 9.2.9 Endometrial Glands ...... 181 9.2.10 Decidual Extracellular Matrix ...... 181 9.3 Fibrinoid ...... 182 9.3.1 Localization of Fibrinoid Subtypes ...... 182 9.3.2 Functions of Fibrinoid ...... 183 9.4 Calci fi cation ...... 185 9.5 Chorionic Plate ...... 187 9.5.1 Development ...... 187 9.5.2 Structure at Term ...... 188 9.5.3 Amnion ...... 188 9.5.4 Spongy Layer ...... 189 9.5.5 Chorionic Mesoderm ...... 189 9.5.6 Extravillous Cytotrophoblast ...... 189 9.5.7 Langhans’ Fibrinoid Layer ...... 190 9.6 Marginal Zone ...... 190 9.6.1 Subchorial Closing Ring ...... 190 9.6.2 Marginal Sinus ...... 190 9.7 Basal Plate ...... 191 9.7.1 Development of the Basal Plate ...... 191 9.7.2 Layers of the Basal Plate at Term ...... 191 9.8 Uteroplacental Vessels ...... 194 9.8.1 The Anatomy of the Uteroplacental Vasculature ...... 194 9.8.2 Establishment of the Maternal Arterial Circulation ...... 195 9.8.3 Number and Position of the Uteroplacental Vessels ...... 196 9.8.4 Importance of Physiological Changes of Uteroplacental Arteries . . . 196 9.8.5 Stages of Physiological Changes in Uteroplacental Arteries ...... 198 9.8.6 Structure of Uteroplacental Veins ...... 200 9.8.7 Septa ...... 200 9.8.8 Cell Islands ...... 202 9.9 Pathology of Trophoblast Invasion ...... 204 9.9.1 Placenta Accreta ...... 204 9.9.2 Placenta Increta and Percreta ...... 207 9.9.3 ...... 210 9.9.4 Placenta in Ectopic (Tubal) Pregnancy ...... 211 9.9.5 Placenta in ...... 213 9.9.6 Cysts and Breus’ Mole ...... 214 9.9.7 Maternal Floor Infarction ...... 218 9.9.8 Decidual Degeneration ...... 222 References ...... 223

10 Involution of Implantation Site: Retained Placenta ...... 241 10.1 Involution of the Placental Site ...... 241 10.2 Subinvolution ...... 243 10.3 Placental Polyps ...... 244 10.4 Involution of a Remaining Placenta ...... 247 References ...... 248

11 Anatomy and Pathology of the Placental Membranes ...... 249 11.1 Overview ...... 249 11.1.1 Development...... 250 11.1.2 Amnion ...... 253 Contents xiii

11.2 Amnionic Epithelium: Different Cell Types and Cell Degeneration ...... 254 11.3 Cytological and Functional Aspects of the Amnionic Epithelium...... 255 11.3.1 Amnionic Fluid ...... 258 11.3.2 Chromosomal Determinations ...... 259 11.4 Cellular Metaplasia and Glycogen ...... 260 11.5 Amnionic Mesoderm ...... 261 11.5.1 A Medley of Themes ...... 262 11.5.2 Clinical and Research Applications ...... 263 11.6 Laeve ...... 263 11.7 Intermediate (Spongy) Layer ...... 264 11.8 Chorionic Mesoderm ...... 264 11.9 Trophoblast Layer ...... 265 11.10 Decidua ...... 266 11.11 Tensile Properties of the Membranes ...... 267 11.12 Pathology of the Membranes ...... 268 11.12.1 Preterm Rupture of the Membranes ...... 268 11.12.2 Cysts, Tumors, and Hemorrhage ...... 269 11.12.3 Amnionic Fluid ...... 272 11.12.4 Meconium ...... 274 11.12.5 Gastroschisis ...... 283 11.12.6 Epidermolysis Bullosa ...... 284 11.12.7 Amnion Nodosum ...... 285 11.12.8 Amnionic Bands ...... 287 11.12.9 Limb-Body Wall Defect ...... 293 11.12.10 Extramembranous Pregnancy ...... 293 References ...... 295

12 Anatomy and Pathology of the ...... 309 12.1 Development ...... 309 12.2 Amnionic Epithelium ...... 311 12.3 Wharton’s Jelly...... 311 12.4 Structure of Umbilical Vessels ...... 312 12.4.1 Innervation ...... 313 12.4.2 Contractility of Umbilical Vessels ...... 314 12.4.3 Hyrtl Anastomosis, False Knots, and Hoboken Nodes ...... 315 12.4.4 Allantois ...... 317 12.4.5 Omphalomesenteric Duct ...... 318 12.5 Spiral Turns of the Cord ...... 321 12.6 Length of the Cord ...... 324 12.6.1 Abnormal Length, ...... 325 12.6.2 Site of Cord Insertion ...... 330 12.6.3 Furcate Cord Insertion ...... 331 12.6.4 Velamentous Cord Insertion ...... 331 12.7 Placental Surface Vessels ...... 336 12.8 Nucleated Red Blood Cells (NRBCs) ...... 339 12.9 Cysts and ...... 339 12.10 ...... 341 12.11 Placental Transfusion ...... 344 12.12 Knots ...... 345 12.13 False Knots ...... 346 12.14 Strictures ...... 346 12.15 Rupture ...... 348 12.16 Hematoma ...... 349 12.17 Varices and Aneurysms ...... 351 12.18 Thrombosis of the Umbilical Vessels ...... 354 xiv Contents

12.19 Thrombosis of the Placental Vascular Tree ...... 357 12.20 Tumors of the Umbilical Cord ...... 362 References ...... 363

13 Placental Shape Aberrations ...... 377 13.1 Site of Placental Attachment ...... 377 13.2 Volumetric Growth ...... 379 13.3 Abnormal Shapes (“Errors in Outline”) ...... 379 13.4 Placenta Previa ...... 382 13.5 Placenta Membranacea...... 386 13.6 (Extrachorial, Circummarginate Placentas) ...... 387 References ...... 390

14 Histopathological Approach to Villous Alterations ...... 395 14.1 Microscopic Evaluation ...... 395 14.1.1 Assessment of Villous Maturation ...... 395 14.1.2 Placental Insuf fi ciency ...... 397 14.1.3 Examination of Fetal Stem Vessels ...... 398 14.1.4 Examination of the Fetal Capillary Bed ...... 399 14.1.5 Villous Architecture and Fibrinoid ...... 399 14.1.6 Intervillous Space, Infarcts ...... 400 14.1.7 Abruptio Placentae ...... 401 14.2 Major Histopathological Findings ...... 401 14.2.1 Syncytiotrophoblast ...... 401 14.2.2 Knotting of the Syncytiotrophoblast ...... 402 14.2.3 Langhans’ Cells ...... 402 14.2.4 Vasculosyncytial Membranes ...... 403 14.2.5 Trophoblastic Basement Membrane ...... 403 14.2.6 Perivillous Fibrinoid ...... 403 14.2.7 Intravillous Fibrinoid ...... 403 14.2.8 Villous Calci fi cation ...... 403 14.2.9 Stem Vessels ...... 404 14.2.10 Nucleated Red Blood Cells ...... 405 14.2.11 Villous Capillarization ...... 405 14.2.12 Stromal Architecture and Stromal Fibrosis ...... 406 14.2.13 Hofbauer Cells (Macrophages) ...... 406 14.2.14 In fl ammatory Changes ...... 406 14.2.15 Villous Edema or Immaturity ...... 407 References ...... 409

15 Villous Maldevelopment ...... 411 15.1 Three-Dimensional Interpretation of Two-Dimensional Sections ...... 411 15.2 Syncytial Knotting: Artifact or Meaningful Pathological Finding? ...... 411 15.3 Classi fi cation of Villous Maldevelopment ...... 414 15.4 Cases of Villous Maldevelopment ...... 416 15.4.1 Synchronous Villous Immaturity ...... 416 15.4.2 Persisting Villous Immaturity and Rhesus Incompatibility ...... 417 15.4.3 Normal Mature Placenta ...... 417 15.4.4 Preterm Villous Maturation and Villous Hypermaturity ...... 419 15.4.5 Prolonged Pregnancy ...... 419 15.4.6 Placentas at High Altitude and Maternal ...... 420 15.4.7 Intrauterine Growth Restriction ...... 421 15.4.8 Maternal Diabetes Mellitus ...... 423 References ...... 425 Contents xv

16 Erythroblastosis Fetalis and ...... 429 16.1 Erythroblastosis Fetalis ...... 429 16.2 Placental Pathology in Erythroblastosis ...... 430 16.2.1 Nonimmune Hydrops ...... 436 16.2.2 a-Thalassemia ...... 437 16.3 Fetal Hemorrhage ...... 439 16.3.1 Fetal Tumors ...... 440 16.4 Congenital Anomalies and Hydrops Fetalis ...... 443 16.5 Congenital Heart Disease ...... 444 16.6 Cardiac Arrhythmias ...... 445 16.7 Nephrotic Syndrome ...... 445 16.8 Parvovirus Anemia and Other Causes of Myocarditis ...... 446 16.8.1 Hydrop s of Unknown Etiology ...... 450 References ...... 452

17 Transplacental Hemorrhage, Cell Transfer, Trauma ...... 461 17.1 Transplacental Blood and Cell Transfer ...... 461 17.2 Trauma ...... 461 17.3 Placenta in Hemorrhage ...... 466 17.4 Technique for Identi fi cation of Fetal Red Blood Cells ...... 467 17.5 Signi fi cant Transplacental Hemorrhage ...... 471 17.6 Fetal Consequences of Massive Hemorrhage Across the Placenta ...... 473 17.7 Nucleated Fetal Blood Elements Passing Through the Placenta ...... 477 17.8 Mother to Fetus Transfer of Cells ...... 478 References ...... 479

18 Fetal Storage Disorders ...... 487 References ...... 492

19 Maternal Diseases Complicating Pregnancy: Diabetes, Tumors, Preeclampsia, Lupus Anticoagulant ...... 495 19.1 Maternal Diseases ...... 495 19.1.1 Scleroderma ...... 495 19.1.2 Dermatomyositis ...... 496 19.1.3 EhlersÐDanlos Syndrome ...... 496 19.1.4 Rheumatoid Arthritis ...... 496 19.1.5 Acute Fatty Liver of Pregnancy ...... 497 19.1.6 ...... 497 19.1.7 Smoking ...... 499 19.1.8 Hodgkin’s Disease ...... 500 19.1.9 Irradiation ...... 501 19.1.10 Hypercholesterolemia ...... 501 19.1.11 Pruritus Gravidarum ...... 201 19.1.12 Pheochromocytoma ...... 502 19.1.13 Hematological Disorders ...... 502 19.1.14 Endocrine Disorders ...... 505 19.1.15 Diabetes Mellitus During Pregnancy ...... 506 19.1.16 Maternal Neoplasms ...... 509 19.2 Hypertensive Disorders ...... 513 19.2.1 Preeclampsia ...... 513 19.2.2 Animal Models ...... 514 19.2.3 Placental Pathology of Preeclampsia ...... 514 19.2.4 Decidual Arteriopathy ...... 515 xvi Contents

19.2.5 Infarcts ...... 519 19.2.6 Abruptio Placentae ...... 522 19.2.7 Fetal Effects of Abruptio Placentae ...... 526 19.2.8 Other Placental Changes in Preeclampsia ...... 526 19.2.9 Etiology of Toxemia, Pregnancy-Induced Hypertension, or Preeclampsia ...... 529 19.3 Lupus Erythematosus and Lupus Anticoagulant ...... 532 19.3.1 Lupus Erythematosus ...... 532 19.3.2 Lupus Anticoagulant ...... 536 References ...... 539

20 Infectious Diseases ...... 557 20.1 ...... 557 20.1.1 Macroscopic Appearance ...... 557 20.1.2 Microscopic Appearance ...... 559 20.1.3 General Considerations of Chorioamnionitis ...... 572 20.1.4 Speci fi c Microorganisms...... 575 20.2 Leprosy ...... 581 20.3 Tuberculosis ...... 582 20.4 Listeriosis ...... 583 20.5 Actinomyces ...... 586 20.6 Mycoplasma Hominis and Ureaplasma Urealyticum ...... 586 20.7 Chlamydia trachomatis and C. psittaci ...... 587 20.8 Bacterial Vaginosis ...... 589 20.9 Syphilis ...... 589 20.10 Necrotizing Funisitis ...... 592 20.11 Other Spirochetal Diseases ...... 595 20.12 Fungus Infections ...... 595 20.13 Virus Infections and Villitides ...... 599 20.13.1 Cytomegalovirus Infection ...... 599 20.13.2 Herpes Simplex Virus Infection ...... 603 20.13.3 Varicella (Chickenpox) ...... 607 20.13.4 EpsteinÐBarr Virus ...... 608 20.13.5 Smallpox, Vaccinia, Alastrim, and Parvovirus B19 ...... 608 20.13.6 Enteroviruses ...... 609 20.13.7 In fl uenza, Mumps, and Rabies ...... 610 20.13.8 ...... 610 20.13.9 Rubella (German Measles) and Other Viral Infections ...... 612 20.13.10 Rubeola: Measles ...... 612 20.13.11 Human Immunode fi ciency Virus (HIV) Infection ...... 613 20.14 Toxoplasmosis ...... 614 20.15 Kala-Azar ...... 618 20.16 Chagas’ Disease ...... 618 20.17 Babesiosis, Trichomoniasis, Rickettsia, and Ehrlichia ...... 619 20.18 Malaria ...... 620 20.19 Other Parasitic Infections ...... 621 20.20 Villitis of Unknown Etiology (VUE) ...... 622 References ...... 629

21 , Placentas of Trisomies, and Immunological Considerations of Recurrent Reproductive Failure ...... 657 21.1 Anatomical Findings ...... 659 21.2 Summary of Placental Findings in Chromosomally De fi ned . . . . 662 21.2.1 Trisomies ...... 662 21.2.2 Polyploidies ...... 664 Contents xvii

21.2.3 Monosomy X ...... 665 21.2.4 Induced Abortion ...... 666 21.3 Incomplete Abortion ...... 670 21.4 Placenta in Chorionic Villus Sampling ...... 671 21.5 Trisomic Placentas ...... 674 21.5.1 Chemical Markers and Trisomy ...... 676 21.6 Recurrent or Habitual Abortion ...... 677 References ...... 679

22 Molar Pregnancies ...... 687 22.1 Incidence ...... 688 22.2 Genetics ...... 690 22.3 Recurrent Hydatidiform Moles ...... 695 22.4 Complete Hydatidiform Moles ...... 696 22.5 Partial Hydatidiform Mole ...... 700 22.6 Other Attributes ...... 703 22.7 Deportation ...... 705 22.8 Invasive Mole (Chorioadenoma Destruens) ...... 706 22.9 Therapy ...... 708 22.10 Ectopic Moles...... 709 22.11 Complete Mole and Coexistent Fetus ...... 709 22.12 PHM with Twin Gestation ...... 711 References ...... 713

23 Trophoblastic Neoplasms ...... 723 23.1 ...... 723 23.1.1 Intraplacental Choriocarcinoma (Choriocarcinoma “In Situ”) and Choriocarcinoma Coincident with Pregnancy ...... 728 23.1.2 Chorangiocarcinoma ...... 730 23.2 Lesions of Extravillous Trophoblast: Exaggerated Placental Site, Placental Site Nodule, Placental Site Trophoblastic Tumor (PSTT), and Epithelioid Trophoblastic Tumor (ETT) ...... 731 23.3 Ultrastructure of Trophoblastic Tumors ...... 735 23.4 Antigenic Studies of Trophoblastic Tumors...... 735 23.5 Epidemiology of Choriocarcinoma ...... 736 23.6 Endocrine Aspects of GTN ...... 737 23.7 Ectopic : Tumors in Men ...... 738 23.8 Therapy of GTN ...... 739 23.9 Choriocarcinoma in Animals ...... 740 23.10 Choriocarcinoma in Cell Lines and Genetics...... 740 References ...... 741

24 Benign Tumors and Chorangiosis ...... 747 24.1 Chorangiomas ...... 747 24.2 Other Benign Tumors ...... 754 24.3 Chorangiosis and Chorangiomatosis ...... 754 24.4 Mesenchymal Dysplasia and the Beckwith-Wiedemann Syndrome ...... 756 References ...... 756

25 Multiple Pregnancies ...... 761 25.1 Zygosity ...... 761 25.2 The Placenta in the Study of Zygosity ...... 764 25.3 Causes of Multiple Births and Incidence ...... 769 25.4 Third Type of Twin ...... 774 xviii Contents

25.5 Twinning Incidence ...... 776 25.6 Superfetation and Superfecundation ...... 778 25.7 Vascular Anatomy of Twin Placentas...... 778 25.8 Monoamnionic Monochorionic Twin Placenta ...... 784 25.9 Diamnionic Monochorionic Twin Placenta ...... 798 25.10 Diamnionic, Dichorionic Twin Placenta ...... 800 25.11 Vanishing Twin Phenomenon ...... 801 25.12 Fetus Papyraceus ...... 805 25.13 Twin-to-Twin Transfusion Syndrome ...... 811 25.14 Amniopatch ...... 825 25.15 Acardiac Twins ...... 826 25.16 Conjoined Twins ...... 835 25.17 Sacrococcygeal Teratoma, Epignathus ...... 838 25.18 Congenital Anomalies ...... 840 25.19 Cytogenetics and “Heterokaryotypic MZ Twins” ...... 842 25.20 Chimerism, Mosaicism ...... 843 25.21 Whole-Body Chimerism ...... 845 25.22 Triplets and Higher Multiple Births ...... 846 25.23 Twins in Abortion and ...... 851 25.24 Morbidity and Mortality ...... 853 25.25 Hormones in Twin Pregnancy ...... 855 References ...... 855

26 Legal Considerations ...... 883 26.1 Twinning Problems ...... 886 26.2 In fl ammation ...... 888 26.3 The Green Placenta ...... 889 26.4 Vascular Abnormalities ...... 890 26.5 Umbilical Cord ...... 891 26.6 Placental Villous Color ...... 892 26.7 Other Types of Pathology ...... 893 References ...... 895

27 Arti fi cial Reproductive Technology (ART) ...... 897 27.1 Placental Pathology with ART ...... 899 27.2 Monozygosity and Monochorionicity Following ART ...... 900 27.3 Chimerism ...... 901 27.4 Con fi ned Placental Mosaicism ...... 901 27.5 Imprinting ...... 901 27.6 Immunology ...... 902 References ...... 902

Erratum ...... E1

Appendix ...... 907

Index ...... 925