Pathology of the HUMAN PLACENTA

FIFTH EDITION Kurt Benirschke, MD Peter Kaufmann, MD Rebecca Baergen, MD Pathology of the HUMAN PLACENTA

FIFTH EDITION With 745 Illustrations, 170 in Full Color Kurt Benirschke, MD Peter Kaufmann, MD Rebecca Baergen, MD 8457 Prestwick Drive Department of Anatomy New York-Presbyterian Hospital–Weill La Jolla, CA 92037 RWTH Aachen Medical College of Cornell University USA D-52057 Aachen New York, NY 10021 Germany USA

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9 8 7 6 5 4 3 2 1 springer.com 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 vi Preface 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 ultrasonographer 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, MD La Jolla, California Peter Kaufmann, MD Aachen, Germany Rebecca Baergen, MD New York, NY Preface vii

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. Philadelphia. 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. Contents

Preface ...... v

1. Examination of the Placenta ...... 1 Macroscopic Examination ...... 1 Storage ...... 1 Selection ...... 2 Photography ...... 2 Examination ...... 2 Placentas of Multiple Births ...... 7 Fixation ...... 8 Special Procedures ...... 10 References ...... 11

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

3. Microscopic Survey ...... 16 Typical Histologic Features of the First Trimester Placenta ...... 16 Typical Histologic Features of the Third Trimester Placenta ...... 20 Immunohistochemical Markers ...... 24

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

ix x Contents

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

6. Basic Structure of the Villous Trees ...... 50 M. Castellucci and P. Kaufmann Syncytiotrophoblast ...... 50 Syncytium or Multinucleated Giant Cells? ...... 50 Syncytial Plasmalemmas and Microvilli ...... 54 Syncytiotrophoblastic Cytoskeleton ...... 55 Specialized Regions of the Villous Surface ...... 55 Syncytiotrophoblast with Prevailing Rough Endoplasmic Reticulum ...... 55 Syncytiotrophoblast with Prevailing Smooth Endoplasmic Reticulum ...... 57 Vasculosyncytial Membranes ...... 59 Syncytial Lamellae Covering Langhans’ Cells ...... 61 Syncytial Knots, Sprouts, and Bridges ...... 61 Transtrophoblastic Channels ...... 64 Trophoblastic Blebbing ...... 64 Villous Cytotrophoblast (Langhans’ Cells) ...... 65 Cytotrophoblast Cell Types ...... 66 Nematosomes ...... 70 Endocrine Activities of the Villous Cytotrophoblast ...... 70 Trophoblast Turnover and Syncytial Fusion ...... 72 Quantitation of Trophoblast Turnover ...... 72 Why Does Syncytiotrophoblast Survival Depend on Syncytial Fusion? ...... 72 Trophoblastic Differentiation and Apoptosis Cascade ...... 73 Molecular Mechanisms of Syncytial Fusion ...... 76 Phosphatidylserine Flip as Fusion Signal ...... 76 Junctional and Adhesion Molecules as Fusion Mediators ...... 76 The ADAM Family of Fusogenic Proteins ...... 76 Endogenous Retroviral Envelope Proteins of the HERV Family (Syncytins) and Their Receptors ...... 77 Molecular Control of Syncytial Fusion ...... 78 The Role of Oxygen and Cytokines in Trophoblast Proliferation and Fusion ...... 79 The Impact of Trophoblast Turnover on Syncytiotrophoblast Specialization ...... 81 Trophoblastic Basement Membrane ...... 82 Connective Tissue ...... 82 Mesenchymal Cells (V Cells) ...... 82 Fibroblasts (VD Cells and VDA Cells) ...... 83 Myofibroblasts (VDAG Cells and VDAGM Cells) ...... 84 Matrix Components of the Villous Stroma ...... 86 Hofbauer Cells (Villous Macrophages) ...... 87 First Descriptions ...... 87 Morphology ...... 87 Occurrence and Distribution ...... 90 Origin ...... 90 Contents xi

Immunologic Aspects ...... 91 Other Free Connective Tissue Cells ...... 93 Basic Structure of the Vessel Walls ...... 93 Fetal Capillaries ...... 94 Large Fetal Vessels ...... 94 Vasomotor Control ...... 96 Fibrinoid of the Villous Trees ...... 96 Perivillous Fibrinoid ...... 96 Intravillous Fibrinoid ...... 98 References ...... 99

7. Architecture of Normal Villous Trees ...... 121 Classification of Villous Types ...... 121 Stem Villi ...... 121 Immature Intermediate Villi ...... 126 Mature Intermediate Villi ...... 128 Terminal Villi ...... 129 Mesenchymal Villi ...... 133 Immunohistochemistry of Villous Types ...... 134 Differentiation and Maturation of Villous Types ...... 137 Development of the Mesenchymal Villi ...... 137 Development and Fate of Immature Intermediate Villi ...... 138 Development of Stem Villi ...... 138 Development of the Mature Intermediate Villi ...... 140 Development of the Terminal Villi ...... 140 Angioarchitecture of Villi ...... 140 Vascular Arrangement in Immature Villi ...... 140 Larger Vessels of Stem Villi ...... 141 Paravascular Capillary Net of Stem Villi ...... 141 Arrangement of Vessels in Mature Intermediate and Terminal Villi ...... 143 Sinusoids of Terminal Villi ...... 145 Fetoplacental Angiogenesis as the Driving Force for Villous Development ...... 146 General Aspects of Placental Vasculogenesis and Angiogenesis ...... 147 Vasculogenesis 1: Origin of Hemangiogenic Progenitor Cells (Days 15 to 21) ...... 148 Vasculogenesis 2: Formation of Endothelial Tubes (Days 21 to 32) ...... 148 Angiogenesis 1: Branching Angiogenesis (Day 32 to Week 25) . . . . 153 Angiogenesis 2: Formation of Stem Vessels and Regression of Capillaries in Stem Villi (Weeks 15 to 32) ...... 153 Angiogenesis 3: Prevailing Nonbranching Angiogenesis (Week 25 to Term) ...... 154 Oxygen and Oxygen-Controlled Growth Factors as Regulators of Villous and Vascular Development ...... 155 The Special Role of Oxygen in the Placenta ...... 155 Types of Hypoxia and Its Effects on Villous Development ...... 155 Evidence for Oxygen-Controlled Fetoplacental Angiogenesis . . . . . 157 Oxygen-Controlled Angiogenic Growth Factors ...... 157 The Timing Mismatch Between Changes in Oxygenation and Morphologic Changes ...... 158 Oxygen and Villous Trophoblast ...... 159 xii Contents

Oxygen and Villous Stroma ...... 159 Oxygen and Intervillous Circulation ...... 159 Hormones as Regulators of Villous Development ...... 160 Intervillous Space as Related to the Villous Trees ...... 160 Width of the Intervillous Space ...... 161 Organization of Villous Trees ...... 161 Histopathologic Importance of Inhomogeneity of Villous Trees ...... 164 Fetomaternal Flow Interrelations ...... 164 References ...... 165

8. Characterization of the Developmental Stages ...... 174 Stages of Development ...... 174 Nucleated Red Blood Cells ...... 185 References ...... 189

9. Nonvillous Parts and Trophoblast Invasion ...... 191 H.G. Frank and P. Kaufmann Extravillous Trophoblast ...... 191 Historical Aspects and Nomenclature ...... 191 Extravillous Trophoblast Is a Tissue of Its Own ...... 193 Proliferation Patterns of Extravillous Trophoblast and the Invasive Pathway ...... 194 Stages of Extravillous Trophoblast Differentiation Within the Invasive Pathway ...... 196 One Stem Cell Origin for Villous Syncytiotrophoblast and the Extravillous Trophoblast? ...... 200 Cytokines and Hormones Controlling Differentiation of Extravillous Trophoblast ...... 201 Extracellular Matrix Secretion Along the Invasive Pathway ...... 204 Extracellular Matrix Receptors (Integrins) ...... 204 Other Cell Adhesion Molecules and Gap Junction Molecules . . . . . 206 Proteinases, Activators, and Inhibitors Involved in Trophoblast Invasion ...... 207 Nitric Oxide and Trophoblast Invasion ...... 209 Major Basic Protein ...... 209 Cell Surface Carbohydrates ...... 211 MHC Class I Molecules ...... 212 Normal Extravillous Trophoblast Cells Are Never Proliferative and Invasive at One Time ...... 213 Oxygen-Mediated Regulation of the Invasive Pathway ...... 214 Extracellular pH as Trigger of Trophoblast Invasion ...... 215 Trophoblastic Mechanisms Limiting Trophoblast Invasion ...... 215 Endocrine Activities of Extravillous Trophoblast ...... 216 Does Extravillous Trophoblast Differ from One Nonvillous Part to the Other? ...... 217 Decidua ...... 217 Composition of Decidua ...... 217 Endometrial Stromal Cells and Decidual Cells ...... 218 Endocrine and Paracrine Aspects of Decidua ...... 220 Functional Considerations of Decidualization ...... 221 B Cells and T Cells ...... 222 Contents xiii

Endometrial Large Granular Lymphocytes (Endometrial NK Cells and uNK Cells) ...... 223 Macrophages ...... 224 Glandular Residues ...... 225 Decidual Extracellular Matrix ...... 225 Fibrinoid ...... 226 Definition and Historical Remarks ...... 226 Types of Fibrinoid ...... 227 Origin of Fibrinoids ...... 230 Interactions Between Matrix-Type and Fibrin-Type Fibrinoid . . . . . 231 Functions of Fibrinoid ...... 231 Trophoblast Invasion as a Result of Deciduo-Trophoblastic Interactions ...... 233 Calcification ...... 236 Chorionic Plate ...... 239 Development ...... 239 Structure at Term ...... 239 Amnion ...... 239 Spongy Layer ...... 240 Chorionic Mesoderm ...... 241 Extravillous Cytotrophoblast ...... 241 Langhans’ Fibrinoid Layer ...... 242 Marginal Zone ...... 243 Subchorial Closing Ring ...... 243 Trabeculae ...... 244 Marginal Sinus ...... 244 Basal Plate ...... 244 Trophoblastic Shell and Development of the Basal Plate ...... 244 Layers of the Basal Plate at Term ...... 246 Uteroplacental Vessels ...... 249 Development ...... 249 Number and Position of the Uteroplacental Vessels ...... 251 Importance of Physiologic Changes of Uteroplacental Arteries . . . . 252 Stages of Physiologic Changes in Uteroplacental Arteries ...... 252 Sites and Routes of Endovascular Trophoblast Invasion ...... 254 Trophoblast-Endothelial Adhesion Mechanisms ...... 255 The Role of Macrophages in the Control of Endovascular Trophoblast Invasion ...... 256 Incompetent Trophoblast Invasion or Exaggerated Maternal Defense as Causes for Maladaptation of Uteroplacental Arteries ...... 257 Structure of Uteroplacental Veins ...... 258 Intramural Fibrinoid of Uteroplacental Arteries and Veins ...... 260 Functional Aspects of Uteroplacental Vessels ...... 260 Septa, Cell Islands, and Cell Columns ...... 261 Septa ...... 261 Cell Islands ...... 264 Cell Columns ...... 265 Pathology of Trophoblast Invasion ...... 268 Placenta Accreta ...... 268 Placenta Increta and Percreta ...... 271 Uterine Rupture ...... 273 Placenta in Ectopic (Tubal) Pregnancy ...... 275 Placenta in Abdominal Pregnancy ...... 276 Cysts and Breus’ Mole ...... 277 xiv Contents

Maternal Floor Infarction ...... 281 Decidual Degeneration ...... 284 References ...... 287

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

11. Anatomy and Pathology of the Placental Membranes . . . . . 321 Overview ...... 321 Development ...... 323 Amnion ...... 326 Amnionic Epithelium: Different Cell Types or Cell Degeneration . . . 327 Cytologic and Functional Aspects of the Amnionic Epithelium ...... 327 Amnionic Fluid ...... 330 Chromosomal Determinations ...... 331 Cellular Metaplasia and Glycogen ...... 331 Amnionic Mesoderm ...... 333 A Medley of Themes ...... 334 Clinical and Research Applications ...... 334 Chorion Laeve ...... 335 Intermediate (Spongy) Layer ...... 335 Chorionic Mesoderm ...... 335 Trophoblast Layer ...... 336 Decidua ...... 337 Tensile Properties of the Membranes ...... 338 Pathology of the Membranes ...... 338 Preterm Rupture of the Membranes ...... 338 Cysts, Tumors, and Hemorrhage ...... 340 Amniotic Fluid Embolism ...... 342 Meconium ...... 345 Gastroschisis ...... 354 Epidermolysis Bullosa ...... 354 Amnion Nodosum ...... 355 Amnionic Bands ...... 358 Extramembranous Pregnancy ...... 364 References ...... 366

12. Anatomy and Pathology of the Umbilical Cord ...... 380 Development ...... 380 Amnionic Epithelium ...... 380 Wharton’s Jelly ...... 381 Structure of Umbilical Vessels ...... 383 Innervation ...... 384 Contractility of Umbilical Vessels ...... 385 Hyrtl’s Anastomosis, False Knots, and Hoboken Nodes ...... 386 Allantois ...... 388 Omphalomesenteric Duct ...... 389 Spiral Turns of the Cord ...... 392 Contents xv

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

13. Placental Shape Aberrations ...... 452 Site of Placental Attachment ...... 452 Volumetric Growth ...... 454 Abnormal Shapes (“Errors in Outline”) ...... 454 Placenta Previa ...... 457 Placenta Membranacea ...... 462 Circumvallate Placenta (Extrachorial, Circummarginate Placentas) ...... 464 References ...... 468

14. Histopathologic Approach to Villous Alterations ...... 473 How to Assess Villous Histopathology ...... 473 Assessment of Villous Maturation ...... 473 Placental Insufficiency ...... 476 Examination of Fetal Stem Vessels ...... 477 Examination of the Fetal Capillary Bed ...... 477 Villous Architecture and Fibrinoid ...... 478 Intervillous Space, Infarcts ...... 479 Abruptio Placentae ...... 480 Major Histopathologic Findings ...... 480 Syncytiotrophoblast ...... 480 Knotting of the Syncytiotrophoblast ...... 480 Langhans’ Cells ...... 482 Vasculosyncytial Membranes ...... 482 Trophoblastic Basement Membrane ...... 482 Perivillous Fibrinoid ...... 482 Intravillous Fibrinoid ...... 483 Villous Calcification ...... 483 Stem Vessels ...... 483 Nucleated Red Blood Cells ...... 484 Villous Capillarization ...... 484 Stromal Architecture and Stromal Fibrosis ...... 485 xvi Contents

Hofbauer Cells (Macrophages) ...... 486 Inflammatory Changes ...... 486 Villous Edema or Immaturity ...... 486 References ...... 488

15. Classification of Villous Maldevelopment ...... 491 Three-Dimensional Interpretation of Two-Dimensional Sections . . . . 491 Syncytial Knotting: Artifact or Meaningful Pathologic Finding ...... 491 Interpretation of Syncytial Knotting ...... 491 Artificial Knotting as Related to Villous Shapes in Paraffin Sections ...... 494 Conclusions Concerning Knotting ...... 497 Classification of Villous Maldevelopment ...... 497 Summarizing Diagram of Villous Maldevelopment ...... 497 Villous Maturation Score ...... 500 Cases of Villous Maldevelopment ...... 502 Synchronous Villous Immaturity ...... 502 Persisting Villous Immaturity and Rhesus Incompatibility ...... 502 Normal Mature Placenta ...... 504 Preterm Villous Maturation and Villous Hypermaturity ...... 506 Prolonged Pregnancy ...... 507 Placentas at High Altitude and Maternal Anemia (Preplacental Hypoxia) ...... 508 Intrauterine Growth Restriction with Preserved End-Diastolic Umbilical Flow in the Third Trimester, with or Without Late-Onset Preeclampsia (Uteroplacental Hypoxia) ...... 509 Intrauterine Growth Restriction Combined with Absent or Reverse End-Diastolic Umbilical Blood Flow in the Second Trimester, with or Without Early-Onset Preeclampsia (Postplacental Hypoxia) ...... 511 Preeclampsia ...... 512 HELLP Syndrome (Postplacental Hypoxia) ...... 513 Maternal Diabetes Mellitus ...... 515 References ...... 516

16. Erythroblastosis Fetalis and Hydrops Fetalis ...... 519 Erythroblastosis Fetalis ...... 519 Placental Pathology in Erythroblastosis ...... 520 Nonimmune Hydrops ...... 526 a-Thalassemia ...... 527 Fetal Hemorrhage ...... 529 Fetal Tumors ...... 530 Congenital Anomalies and Hydrops Fetalis ...... 532 Congenital Heart Disease ...... 533 Cardiac Arrhythmias ...... 534 Nephrotic Syndrome ...... 534 Parvovirus Anemia ...... 535 Hydrops of Unknown Etiology ...... 540 References ...... 541

17. Transplacental Hemorrhage, Cell Transfer, Trauma ...... 552 Transplacental Blood and Cell Transfer ...... 552 Trauma ...... 552 Contents xvii

Placenta in Hemorrhage ...... 558 Technique for Identification of Fetal Red Blood Cells ...... 559 Significant Transplacental Hemorrhage ...... 561 Fetal Consequences of Massive Hemorrhage Across the Placenta . . . 563 Other Fetal Blood Elements Passing Through the Placenta ...... 568 Mother-to-Fetus Transfer of Cells ...... 569 References ...... 569

18. Fetal Storage Disorders ...... 577 References ...... 582

19. Maternal Diseases Complicating Pregnancy: Diabetes, Tumors, Preeclampsia, Lupus Anticoagulant ...... 584 Maternal Diseases ...... 584 Hematologic Disorders ...... 592 Endocrine Disorders ...... 596 Diabetes Mellitus During Pregnancy ...... 596 Maternal Neoplasms ...... 600 Hypertensive Disorders ...... 604 Preeclampsia ...... 604 Animal Models ...... 605 Placental Pathology of Preeclampsia ...... 605 Decidual Arteriopathy ...... 606 Infarcts ...... 612 Abruptio Placentae ...... 615 Fetal Effects of Abruptio Placentae ...... 620 Other Placental Changes in Preeclampsia ...... 620 Etiology of Toxemia, Pregnancy-Induced Hypertension, or Preeclampsia ...... 623 Lupus Erythematosus and Lupus Anticoagulant ...... 625 Lupus Erythematosus ...... 625 Lupus Anticoagulant ...... 630 References ...... 634

20. Infectious Diseases ...... 657 Chorioamnionitis ...... 657 Macroscopic Appearance ...... 657 Microscopic Appearance ...... 660 General Considerations of Chorioamnionitis ...... 674 Specific Microorganisms ...... 676 Mycoplasma Hominis and Ureaplasma ...... 687 Chlamydia Trachomatis and C Psittaci...... 689 Bacterial Vaginosis ...... 690 Syphilis ...... 690 Necrotizing Funisitis ...... 694 Other Spirochetal Diseases ...... 696 Fungus Infections ...... 696 Virus Infections and Villitides ...... 700 Cytomegalovirus Infection ...... 700 Herpes Simplex Virus Infection ...... 706 Varicella (Chickenpox) ...... 709 Epstein-Barr Virus ...... 710 xviii Contents

Smallpox, Vaccinia, Alastrim, and Parvovirus B19 ...... 710 Enteroviruses ...... 712 Influenza, Mumps, Rabies ...... 712 Hepatitis ...... 712 Rubella (German Measles) and Other Viral Infections ...... 713 Rubeola (Measles) ...... 714 Human Immunodeficiency Virus Infection ...... 715 Toxoplasmosis ...... 716 Kala-Azar ...... 720 Chagas’ Disease ...... 720 Babesiosis, Trichomoniasis, Rickettsia, and Ehrlichia ...... 722 Malaria ...... 722 Other Parasitic Infections ...... 724 Villitis of Unknown Etiology ...... 724 References ...... 732

21. Abortion, Placentas of Trisomies, and Immunologic Considerations of Recurrent Reproductive Failure ...... 762 Anatomic Findings ...... 764 Summary of Placental Findings in Chromosomally Defined Abortions ...... 768 Trisomies ...... 768 Polyploidies ...... 770 Monosomy X ...... 772 Induced Abortions ...... 772 Incomplete Abortion ...... 777 Placenta in Chorionic Villus Sampling ...... 778 Trisomic Placentas ...... 781 Chemical Markers and Trisomy ...... 782 Recurrent or Habitual Abortion ...... 784 References ...... 787

22. Molar Pregnancies ...... 797 Hydatidiform Moles and Partial Moles ...... 797 Hydatidiform Moles ...... 797 Other Attributes ...... 811 Therapy ...... 815 Partial Hydatidiform Mole ...... 817 References ...... 825

23. Trophoblastic Neoplasms ...... 837 Choriocarcinoma ...... 837 Choriocarcinoma In Situ and Choriocarcinoma Coincident with Pregnancy ...... 843 Chorangiocarcinoma ...... 846 Exaggerated Placental Site: Placental Site Nodule, Placental Site Trophoblastic Tumor, and Epithelioid Trophoblastic Tumor . . . . . 846 Ultrastructure of Trophoblastic Tumors ...... 851 Antigenic Studies of Trophoblastic Tumors ...... 851 Epidemiology of Choriocarcinoma ...... 852 Endocrine Aspects of Gestational Trophoblastic Neoplasia ...... 852 Contents xix

Ectopic Choriocarcinomas; Tumors in Men ...... 853 Therapy of Gestational Trophoblastic Neoplasia ...... 854 Choriocarcinoma in Anamils...... 855 Choriocarcinoma in Cell Lines and Genetics ...... 855 References ...... 856

24. Benign Tumors and Chorangiosis ...... 863 Angiomas ...... 863 Other Benign Tumors ...... 870 Chorangiosis and Chorangiomatosis ...... 871 Mesenchymal Dysplasia and the Beckwith-Wiedemann Syndrome ...... 873 References ...... 873

25. Multiple Pregnancies ...... 877 Zygosity ...... 877 The Placenta in the Study of Zygosity ...... 879 Causes and Incidence of Multiple Births ...... 885 Third Type of Twin ...... 890 Twinning Incidence ...... 891 Superfetation and Superfecundation ...... 893 Vascular Anatomy of Twin Placentas ...... 893 Monoamnionic/Monochorionic Twin Placenta ...... 902 Diamnionic/Monochorionic Twin Placenta ...... 915 Diamnionic/Dichorionic Twin Placenta ...... 917 Vanishing Twin Phenomenon ...... 919 Fetus Papyraceus ...... 923 Twin-to-Twin Transfusion Syndrome ...... 928 Acardiac Twins ...... 941 Conjoined Twins ...... 950 Sacrococcygeal Teratoma and Epignathus ...... 953 Congenital Anomalies ...... 955 Cytogenetics and Heterokaryotypic Monozygotic Twins ...... 956 Chimerism and Mosaicism ...... 957 Whole-Body Chimerism ...... 959 Triplets and Higher Multiple Births ...... 960 Twins in Abortion and Ectopic Pregnancy ...... 967 Morbidity and Mortality ...... 968 Hormones in Twin Pregnancy ...... 971 References ...... 971

26. Legal Considerations ...... 1001 Twinning Problems ...... 1004 Inflammation ...... 1005 The Green Placenta ...... 1007 Vascular Abnormalities ...... 1008 Umbilical Cord ...... 1009 Placental Villous Color ...... 1009 Other Types of Pathology ...... 1010 References ...... 1013 xx Contents

27. Glossary ...... 1016

28. Normative Values and Tables ...... 1019

Index ...... 1027