Chesley's Hypertensive Disorders in Pregnancy

Chesley’s Hypertensive Disorders in Pregnancy

Fourth Edition

Edited by

Robert N. Taylor, MD, PHD

Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA

James M. Roberts, MD

Senior Scientist, Magee Women’s Research Institute, Professor, Obstetrics, Gynecology, Reproductive Sciences and Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

F. Gary Cunningham, MD

Beatrice and Miguel Elias Distinguished Chair in Obstetrics and Gynecology, University of Texas, Southwestern Medical Center, Dallas, Texas, USA

Marshall D. Lindheimer, MD

Professor Emeritus, Department of Obstetrics and Gynecology and Medicine, and the Committe on Clinical Pharmacology, The University of Chicago, Chicago, Illinois, USA

Table of Contents

Cover image

Title page

Copyright

List of Contributors

Preface

Preface to the Second Edition

Comments Added to the Preface by Editors in 2008

Preface to the Fourth Edition

Chapter 1. Introduction, History, Controversies, and Definitions

History (Fig. 1.1)

Signs

Hypotheses and Rational Management

Prophylaxis

Classification of the Hypertensive Disorders in Pregnancy

Editors’ Update

Denouement

References

Chapter 2. The Clinical Spectrum of Preeclampsia

Introduction

Clinical Manifestations of Preeclampsia Syndrome

Differential Diagnosis

References

Chapter 3. Epidemiology of Pregnancy-Related Hypertension

Introduction

Definitions of the Hypertensive Disorders of Pregnancy

Prevalence of Hypertensive Disorders of Pregnancy

Risk Factors for Preeclampsia

First Birth and Other Placental Factors

Clinical Predictors

Natural History

Impact on Children

Critique of Studies

Conclusion

Acknowledgment

References

Chapter 4. Genetic Factors in the Etiology of Preeclampsia/Eclampsia

Dedication

Introduction

Biological Pathways of Preeclampsia

Types of Genetic Studies Conducted

A Genomics Approach to Preeclampsia

Essential Variables to Consider

High-Dimensional Biology

A Predictive Genetic Test

Pharmacogenomics

The Future of Preeclampsia Genetic Research

Conclusions

References

Chapter 5. The Placenta in Normal Pregnancy and Preeclampsia

Introduction

The Microanatomy of Normal Human Placentation

The Microanatomy of Abnormal Human Placentation in Preeclampsia

The Road to Preeclampsia

Oxygen Tension Regulates Human Cytotrophoblast Proliferation and Differentiation In Vitro

During Normal Pregnancy, Invasive Cytotrophoblasts Modulate their Adhesion Molecule Repertoire to Mimic That of Vascular Cells

In Preeclampsia, Invasive Cytotrophoblasts Fail to Switch their Adhesion Molecule Repertoire to Mimic That of Vascular Cells

The Pathological Consequences of Abnormal Cytotrophoblast Invasion and Failed Spiral Artery Remodeling

Novel Unbiased Approaches for Addressing the Complexities of the Preeclampsia Syndrome

Summary and Future Directions

Appendix Trophoblast Gene Expression in Normal Pregnancy and Preeclampsia

References

Chapter 6. Angiogenesis and Preeclampsia

Introduction

Placental Vascular Development in Health

Angiogenic Imbalance in Preeclampsia

Perspectives

References

Chapter 7. Metabolic Syndrome and Preeclampsia

Introduction

Metabolic Syndrome

Metabolic Syndrome and Cardiovascular Disease

Pregnancy-Induced Metabolic Changes

Preeclampsia and Metabolic Syndrome

Metabolic Syndrome: A Cause of Placental Dysfunction?

Summary and Perspectives

References

Chapter 8. Immunology of Normal Pregnancy and Preeclampsia

Introduction

Maternal Adaptation to a Foreign Fetus

Innate and Adaptive Immunity

Nature’s Transplant

Classical Two-Stage Model of Preeclampsia

Stage 1 Preeclampsia, Interface 1 and Maternal Immune Responses to Trophoblast

Stage 2 Preeclampsia and Interface 2

Endothelial Cells are Inflammatory Cells

Inflammation and the Integrated Stress Response

Widespread Implications of Vascular Inflammation

Cytokines, Chemokines, Growth Factors, Adipokines and Angiogenic Factors

Metabolism and Vascular Inflammation

Acute-Phase Response

Vascular Inflammation in Normal Pregnancy and Preeclampsia

The Continuum between Normal Pregnancy and Preeclampsia

Immunoregulation

T Regulatory Cells, Th17 and T-Cell Memory

Angiotensin II (Ang II), the Immune System and Preeclampsia

Systemic Immunoregulation in Normal Pregnancy and Preeclampsia

Acute Atherosis: A Second Inflammatory Lesion of Preeclampsia

The Role of the Placenta and Non-Placental Factors

Trophoblast Extracellular Vesicles

Maternal Predisposing Factors

Conclusions

References

Chapter 9. Endothelial Cell Dysfunction

Introduction

Part I: Endothelial Cell Function and Preeclampsia

Part II: Circulating Factors Induce Endothelial Cell Dysfunction

Part III: Oxidative Stress: A Point of Convergence for Endothelial Cell Dysfunction

Part IV: Clinical Trials

Part V: Speculations and Directions of Future Investigations

References

Chapter 10. Animal Models for Investigating Pathophysiological Mechanisms of Preeclampsia

Introduction

Models Used to Investigate Links between Placental Ischemia and Endothelial and Cardiovascular Dysfunction

Animal Models Used to Study Role of Angiogenic Factors (See also Chapter 6)

Models Used to Investigate the Role of Immune Mechanisms in Preeclampsia

Genetic Models

Summary

References

Chapter 11. Tests to Predict Preeclampsia

Introduction

Assessing the Quality of Tests to Predict Disease

Placental Perfusion and Vascular Resistance Dysfunction-Related Tests

Fetal and Placental Unit Endocrinology Dysfunction-Related Tests

Renal Dysfunction-Related Tests

Endothelial Dysfunction and Oxidant Stress-Related Tests

Other Tests

The Use of Combined Tests

Multivariable Prediction Models Derived from Combinations of Maternal Characteristics and Tests

Perspectives and Conclusions

Acknowledgement

References

Chapter 12. Prevention of Preeclampsia and Eclampsia

Introduction

Dietary Manipulations

Physical Activity

Diuretics and Antihypertensive Drugs

Antioxidant Vitamins

Antithrombotic Agents

Prevention of Eclampsia

Treatment for Eclampsia (See Chapter 20)

References

Chapter 13. Cerebrovascular Pathophysiology in Preeclampsia and Eclampsia

Introduction

Neuroanatomical Findings with Eclampsia

Neuroimaging in Eclampsia

Pathogenesis of Cerebral Manifestations in (PRE)Eclampsia

Eclampsia as Posterior Reversible Encephalopathy Syndrome (PRES)

Cerebral Blood Flow Autoregulation

Cerebral Blood Flow Autoregulation and Hemodynamics in Pregnancy

Mechanisms of Seizure During Pregnancy and Preeclampsia

Role of Circulating Factors in Eclampsia

Remote Cerebrovascular Health Following Preeclampsia and Eclampsia

References

Chapter 14. Cardiovascular Alterations in Normal and Preeclamptic Pregnancy

Introduction

Hemodynamics and Cardiac Function in Normal Pregnancy

Hemodynamics and Cardiac Function in Preeclampsia

Factors that May Explain Vascular Changes in pregnancy

Pregnancy-Associated Responses and the Assessment of Cardiovacular Disease Risk Later in Life

Summary

References

Chapter 15. The Renin-Angiotensin System, its Autoantibodies, and Body Fluid Volume in Preeclampsia

Introduction

Body Fluid Volumes

Plasma Volume in Normal Pregnancy and Preeclampsia

Concluding Perspectives

References

Chapter 16. The Kidney in Normal Pregnancy and Preeclampsia

Introduction

Renal Hemodynamics and Glomerular Filtration Rate During Normal Pregnancy

Osmoregulation in Normal Pregnancy

Renal Hemodynamics and Glomerular Filtration Rate in Preeclampsia

Renal Handling of Uric Acid

Renal Handling of Proteins

Renal Morphology in Pregnancy and Preeclampsia

References

Chapter 17. Platelets, Coagulation, and the Liver

Introduction

Platelets

Coagulation

The Liver in Preeclampsia

References

Chapter 18. Chronic Hypertension and Pregnancy

Introduction

Background

Specific Hypertensive Disorders

Management Principles

References

Chapter 19. Antihypertensive Treatment

Introduction

Goals of Antihypertensive Drug Therapy

General Principles in the Choice of Antihypertensive Agents

Fetal Safety and Drug Use in Pregnant Women

Choice of an Antihypertensive Drug for Use in Pregnancy

Drug Use While Breastfeeding

Evidence from Randomized Trials

Conclusion

References

Chapter 20. Clinical Management

Introduction

Preeclampsia

Eclampsia

Management of Severe Hypertension

Neuroprophylaxis – Prevention of Eclampsia

Delivery

Persistent Severe Postpartum Hypertension

References

Index

Color Plates

Copyright

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Fourth edition

Copyright © 2015, 2009 Elsevier Inc. All rights reserved.

© 1999 Appleton & Lange A Pearson Education Company

© 1978 Appleton-Century-Crofts as Hypertensive Disorders in Pregnancy by Leon C. Chesley

Cover Figure Legend: Left and middle panels show syncytial knots derived from a preeclamptic placenta, transduced with adenovirus carrying enhanced green fluorescent protein (left panel) and stained for PKH26, a yellow dye that stably integrates into plasma membranes (middle panel). The right panel shows a syncytial knot from a normal placenta stained with MitoTracker® Red, to identify mitochondria. All sections were stained with DAPI (4’,6’-diamidino-2-phenylindole) a blue dye that binds strongly to A-T rich DNA, and identifies the syncytialized nuclei. Courtesy of Augustine Rajakumar, PhD and S. Ananth Karumanchi, MD, Harvard Medical School.

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List of Contributors

Edgardo J. Abalos, MD,     Vice Director, Centro Rosarino de Estudios Perinatales, Rosario, Santa Fe, Argentina

James M. Alexander, MD,     Professor of Obstetrics & Gynecology, Southwestern Medical Center at Dallas, Texas, USA

Phyllis August, MD, MPH

Ralph A. Baer, MD, Professor of Research in Medicine, Professor of Obstetrics & Gynecology, Medicine, and Public Health, Weill Cornell Medical College, New York, New York, USA

Theresa Lang Director of Lang Center for Research and Education, New York Hospital Queens, New York, USA

Marilyn J. Cipolla, PhD,     Professor, Department of Neurological Sciences, Obstetrics, Gynecology and Reproductive Sciences; Pharmacology, University of Vermont, Vermont, USA

Agustin Conde-Agudelo, MD, MPH,     Perinatology Research Branch, Intramural Division, NICHD/NIH/DHHS, Bethesda, Maryland and Detroit, Michigan, USA

Kirk P. Conrad, MD,     Professor, Departments of Physiology and Functional Genomics and Obstetrics and Gynecology, University of Florida, College of Medicine, Gainesville, Florida, USA

F. Gary Cunningham, MD,     Beatrice and Miguel Elias Distinguished Chair in Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas, Texas, USA

Sandra T. Davidge, PhD,     Professor, Departments of OB/GYN and Physiology, Canada Research Chair in Women’s Cardiovascular Health, University of Alberta, Edmonton, Alberta, Canada

Ralf Dechend, MD,     Department of Cardiology, Franz-Volhard-Clinic, Max Delbruck Center for Molecular Medicine, Berlin, Germany

Christianne J.M. De Groot, MD, PhD,     Professor, Department of Obstetrics & Gynecology, Vrije Universiteit (VU) Medical Center, Amsterdam, The Netherlands

Susan J. Fisher, PhD,     The Ely and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Maternal Fetal Medicine, and Department of Anatomy, University of California at San Francisco, San Francisico, California, USA

Eric M. George, PhD,     Assistant Professor of Physiology and Biochemistry, University of Mississippi Medical Canter, Jackson, Mississippi, USA

Joey P. Granger, PhD,     Billy S. Guyton Distinguished Professor, Professor of Physiology and Medicine, Director, Center for Excellence in Cardiovascular-Renal Research, Dean, School of Graduate Studies in the Health Sciences, University of Mississippi Medical Canter, Jackson, Mississippi, USA

Judith U. Hibbard, MD,     Professor and Vice Chair of Obstetrics, Department of Obstetrics & Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

Carl A. Hubel, PhD,     Associate Professor, Magee-Womens Research Institute; Department of Obstetrics and Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine; Department of Environmental and Occupational Health, Pittsburgh, Pennsylvania, USA

Arun Jeyabalan, MD, MS,     Department of Obstetrics and Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Magee-Womens Research Institute, Clinical and Translational Research Institute, University of Pittsburgh, Pennsylvania, USA

S. Ananth Karumanchi, MD,     Associate Professor of Medicine, Obstetrics & Gynecology Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA

Louise C. Kenny, MBChB, PhD,     Senior Lecturer & Consultant-Obstetrician & Gynaecologist, Cork University Maternity Hospital, Cork, Ireland

Babbette Lamarca, PhD,     Associate Professor, Director, Research Division, University of Mississippi Medical Canter, Jackson, Mississippi, USA

Marshall D. Lindheimer, MD,     Professor Emeritus, Department of Obstetrics and Gynecology and Medicine, and the Committee on Clinical Pharmacology and Pharmacogenetics, The University of Chicago, Chicago, Illinois, USA

Keith R. McCrae, MD,     Hematologic Oncology and Blood Disorders, Taussig Cancer Center, Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA

Michael T. McMaster, PhD,     The Ely and Edythe Broad Center of Regeneration Medicine and Stem Cell Research and Department of Cell and Tissue Biology, University of California at San Francisco, San Francisco, California, USA

Roberta B. Ness, MD, MPH,     Dean and M. David Low Chair in Public Health, The University of Texas School of Public Health, Houston, Texas, USA

Sarosh Rana, MD,     Assistant Professor, Obstetrics, Gynecology and Reproductive Biology, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts, USA

Christopher W.G. Redman, MB, BChr,     Professor of Obstetric Medicine, Nuffield Department of Obstetrics and Gynecology, John Radcliffe Hospital, Oxford, London, United Kingdom

Janet W. Rich-Edwards, ScD, MPH,     Associate Professor, Department of Medicine, Connors Center for Women’s Health and Gender Biology, Brigham and Women’s Hospital; Associate Professor, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA

James M. Roberts, MD,     Senior Scientist, Magee-Women’s Research Institute, Professor of Obstetrics, Gynecology, Reproductive Sciences and Epidemiology and Clinical and Traslational Research University of Pittsburgh, Pittsburgh, Pennsylvania, USA

Roberto Romero, MD,     D. Hon. C, Chief, Perinatology Research Branch Program Director of Obstetrics and Perinatology, Intramural Division NICHD, NIH, DHHS, Professor, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, Professor, Department of Epidemiology and Biostatistics, Michigan State University, Michigan, USA

Ian L. Sargent, BSc, PhD,     Professor of Reproductive Science, Nuffield Department of Obstetrics and Gynecology, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom

Sanjeev G. Shroff, PhD,     Distinguished Professor of & Gerald E. McGinnis Chair in Bioengineering and Professor of Medicine, Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

Baha M. Sibai, MD,     Professor, Department of Obstetrics and Gynecology College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA

Anne Cathrine Staff, MD, PhD,     Professor II, Head of the Research Center of Obstetrics and Gynecology, Oslo University Hospital, Oslo, Norway

Isaac E. Stillman, MD,     Associate Professor of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA

Robert N. Taylor, MD, PhD,     Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA

Jason G. Umans, MD, PhD,     MedStar Health Research Institute, the Departments of Medicine and of Obstetrics and Gynecology, Georgetown University; Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, DC, USA

Kenneth Ward, MD,     President and CEO, Juneau Biosciences, LLC, Salt Lake City, Utah, USA

Virginia D. Winn, MD, PhD,     Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, Colorado, USA

Gerda G. Zeeman, MD, PhD,     Department of Obstetrics and Gynecology, Division of Obstetrics and Prenatal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

Preface

Preface to the Second Edition

In 1996, Gary Cunningham, senior author of Williams’ Obstetrics, approached me with the idea of organizing a second edition of Chesley’s Hypertensive Disorders in Pregnancy. This first edition, though published in 1978, was still a major reference text for investigators in the field, often kept locked in drawers for safe-keeping, as this out-of-print classic was difficult to locate. Next we contacted Dr. James Roberts, Director of the Magee-Womens’ Research Institute, whose investigative team is among the leading contributors to the literature on preeclampsia this decade. Of interest, their conference room, dedicated by Leon Chesley, and bearing his name, contains his framed photograph positioned to keep a watchful eye on the quality of their deliberations. With three enthusiastic editors on board the second edition was born.

The 1999 edition is a multi-authored text, reflecting the enormous progress in the field since 1978 (and the editors’ recognition that there are few Leon Chesleys among us today as well!). To stay in the spirit of the initial edition, your editors developed the following strategy. Each chapter would be first-authored by an acknowledged expert in the topic assigned, and would also be co-authored by one of the editors. This was meant to insure the timeliness of the material, increase cohesiveness, minimize redundancy, and above all, to achieve the goals set for the text. We believe that the strategy worked, though it may have been taxing to the co-author editor, especially when the topic deviated several degrees from his own area of expertise.

This edition is aimed both at investigators and practicing physicians. Thus, one will find chapters designed primarily as scholarly assessments of a given research area, and others with didactic advice for the care of pregnant women with hyper tension. Of interest is the considerable variability in focus from chapter to chapter, some authors reviewing the literature, primarily as those cited have presented it, others combining this with commentary, at times almost philosophical (in Chapter 4, an editors’ comment was inserted to tell the reader why!). Some authors tried to mimic the encyclopedic approach (with all encompassing tables) in Chesley’s first edition, others preferred a more concise approach, (but with extensive bibliography). Your editors decided to leave these approaches intact, the co-editor comparing the chapter’s goal and the initial Chesley text in the introductory comments. Finally, Chesley’s Chapter 2 in the first edition, History, is reprinted in its entirety as part of our own first chapter. This historical review is a must read, and we doubt if it will be equaled for quite some time.

We consider Leon Chesley the father of modern research in the hypertensive disorders of pregnancy (some might say of modern research in obstetrics as well). He is now over 90 years of age, having weathered two strokes with mind and sense of humor intact. We visited him several times during the genesis of this edition, receiving his blessing on each occasion. We are proud to honor him with this edition.

Comments Added to the Preface by Editors in 2008

Leon Chesley died shortly after publication of the second edition, and your editors missed those periodic exhilarating visits to Leon that highlighted preparation of that publication. Thus this edition is both a tribute and memorial to him and we worked hard to attain the perfection he always insisted on, and hope that, wherever he is, he is proud of his disciples.

The third edition is patterned after the second but there are changes. In the previous edition normal and abnormal aspects of organ systems were usually separated into distinct chapters, while in this edition each of these topics, such as the cardiovascular system, or kidney, is combined into a single chapter. This led to another small change. In the second edition each chapter, with the exception of the introductory first, was first authored by but one expert coupled to only one of the three editors as co-author, a style designed to ensure continuity and decrease excessive repetition. In the current edition the complexity of several chapters required two experts (now able to bully their editor co-author more effectively!). Finally, there are three new chapters, each devoted to recent and exciting observations in areas unknown or given short shrift in the preceding edition. These topics are angiogenic factors, agonistic antibodies to the angtiotensin II type 1 receptor and immunology and inflammation. Finally, the lead editor (MDL), having celebrated his diamond birthday in 2007 and golden wedding anniversary in 2008, will retire from this chore following this third edition of Chesley’s Hypertensive Disorders in Pregnancy. The field is progressing quickly and developing new giants and the editors assure you that the next edition will meet the standards that Leon set with his first, and we strove to repeat in these last two editions.

Marshall D. Lindheimer, MD

Preface to the Fourth Edition

The third edition of Chesley’s Hypertensive Disorders in Pregnancy, as the two prior ones, was widely acclaimed as an essential scholastic resource and enthusiastically endorsed by clinicians and scientists, alike. In the modern digital era, downloads are the currency of readership. Since its publication in 2009, the third edition of Chesley’s has been one of the most highly downloaded and viewed biomedical references on Science Direct. Hypertension during pregnancy remains amongst the three leading killers of pregnant women and their unborn children; yet surveys show that half of physicians fail to elicit a history of pregnancy hypertension during routine encounters, despite its association with remote cardiovascular disease, and research support remains dismal compared with equally mortal diseases in terms of DALYs (Disability Adjusted Lost Years).

We have optimistic expectations for this fourth edition of the textbook, which witnesses the passing of the torch from lead editor Marshall Lindheimer to me (RNT). With the prior edition, Prof. Lindheimer stated his intention to retire as senior editor, having achieved a number of personal and professional milestones. Fortunately for his colleagues and audience, Marshall generously supported the current effort in his critical role as editor emeritus and spiritual guru of the present edition. It is an honor for me to accept the responsibility to assure that future generations of physicians, physiologists, educators and scholars of preeclampsia will continue to be galvanized by the information and ideas contained in these pages and challenged by the knowledge gaps that remain.

The overall format of the fourth edition follows that of its immediate precursor. We have continued the tradition of presenting Leon Chesley’s masterfully written History chapter in its entirety within Chapter 1. Internationally renowned experts in the field, including several new authors, have been invited to collaborate with the editors to present state-of-the-art chapters designed to summarize and illuminate the horizons of knowledge in each academic domain. Fundamental aspects of the principles that underpin preeclampsia pathogenesis are updated in the first half of the text, with an emphasis on new clinical and conceptual insights and their therapeutic applications in the later chapters.

Lest one forgets the remarkable contributions of our predecessors, we proffer the distinguished photograph below of Leon Chesley, whom all four editors had the inspiring opportunity to claim as a mentor. I was struck by his curious necktie choice, with its kangaroo motif. While making that specific sartorial selection for his pose on the frontispiece, Dr. Chesley might have been wondering: Had humans evolved from marsupials, with their transient embryonic attachment to a simple yolk-sac placenta, would our species have ever developed preeclampsia? You may have to wait for the fifth edition to find out.

Robert N. Taylor

Leon C. Chesley, PhD (1908–2000)

Chapter 1

Introduction, History, Controversies, and Definitions

Marshall D. Lindheimer, Robert N. Taylor, James M. Roberts, F. Gary Cunningham and Leon Chesley†

This chapter contains Leon Chesley’s introduction from his sole-authored first edition, including an in-depth and scholarly review of our knowledge of preeclampsia through the ages. Also included is his lecture, False steps in the history of preeclampsia, presented in September 1975 at an International Workshop; both meeting and lecture considered the impetus for renewed focus on this devastating disease. The chapter also contains an EDITORS’ UPDATE summarizing progress made since Chesley’s single-authored first edition, including the new classification schema in the American College of Obstetricians and Gynecologists’ Hypertension Task Force 2013 recommendations.

Keywords

introduction; history of preeclampsia; classification schema

Leon Chesley’s Hypertensive Disorders in Pregnancy was initially published in 1978.¹ Then, as now, hypertension complicating pregnancy was a major cause of fetal and maternal morbidity and death, particularly in less developed nations. Most of this morbidity was and remains associated with preeclampsia, a disorder with devastating effects in many organ systems, high blood pressure being but one aspect of the disease. The first edition was single authored, written entirely by Dr. Chesley, a PhD in physiology, who originally found employment as a chemist at the Newark New Jersey’s Margaret Hague Maternity Hospital, during the Great Depression of the 1930s. Curious why certain tests were being performed on convulsing pregnant women, he went to the wards, observed, and was stimulated to study that enigmatic disorder preeclampsia, the result being signal contributions published from the late 1930s through the early 1980s. His contributions included major observations in such diverse areas as epidemiology, remote prognosis, vascular and renal pathophysiology, and treatment, all focusing on hypertension in pregnancy. A compendium of his achievements is but one aspect of the initial edition of this text, which for the next two decades was a leading resource for clinicians and investigators who wished to learn more about high blood pressure in pregnant women.

In 1978 a text devoted to the hypertensive disorders in pregnancy could be single authored, due in part to the energy, intellect, and other attributes of Leon Chesley, but also because research in this important area of reproductive medicine was still sporadic and unfocused, and progress regrettably slow. Leon almost singly energized the field, and the editors of this text are among many of those for whom he served as a role model, nurturing three of us in early and mid-career. The initial edition, and other signal events during the 1970s (summarized further later in this chapter as EDITORS’ UPDATE), spurred rapid progress in many areas including prevention trials, observations regarding pathogenesis, and management considerations. Thus, just like the second and third, the fourth edition again aims to be a leading reference text, multi-authored by leaders in the field. Again our stated goal of the previous editions, that this text will do scholarly justice to Dr. Chesley’s 1978 tour de force, remains the major and obvious goal for the fourth edition.

The remainder of this chapter is as follows: We reproduce Dr. Chesley’s original chapter entitled History in its entirety. Unable to improve on it, we add an EDITORS’ UPDATE, and then conclude by republishing Dr. Chesley’s 1975 workshop banquet address False Steps in the Study of Preeclampsia.² That meeting led to the formation of the International Society for the Study of Hypertension in Pregnancy, and Dr. Chesley’s message about how to study preeclampsia remains valid today.

History (Fig. 1.1)

Several German authors, such as von Siebold, Knapp, Kossmann, Fasbender, Fischer, and Bernhart, have written on the history of eclampsia, but all too often they did not document their sources and made errors that live on in second-, third-, and nth-hand reviews.³–⁸

Figure 1.1 This portrait of Francois Mauriceau inaugurated the History chapter in the first edition of this text.

Bernhart wrote that eclampsia was mentioned in the ancient Egyptian, Chinese, Indian, and Greek medical literature.⁸ One of the oldest sources that he cited, without specific reference, was the Kahun (Petrie) papyrus dating from about 2200 BC. His source is likely to have been Menascha.⁹ Griffith had translated Prescription No. 33, on the third page of the papyrus, as: To prevent (the uterus) of a woman from itching (?) auit pound — upon her jaws the day of birth. It cures itching of the womb excellent truly millions of times.¹⁰ Menascha cited Griffith’s paper but rendered the translation (in German) as: To prevent a woman from biting her tongue auit pound — upon her jaws the day of birth. It is a cure of biting excellent truly millions of times.⁹ He suggested that the untranslated word "auit means small wooden stick. In a later book on the Kahun papyrus, Griffith changed his translation to: To prevent a woman from biting (her tongue?) beans, pound — upon her jaws the day of birth.¹⁰,¹¹ Curiously, Menascha did not cite Griffith’s later translation and he included the word auit" from the first version. Possibly the ancient scribe had eclampsia in mind, but that interpretation is tenuous at best.¹²

Bernhart also wrote, again without references, that both the Indian Atharva-Veda and the Sushruta, of old but unknown dates, mention eclampsia. He said that the Atharva-Veda described an amulet to be worn in late pregnancy for warding off convulsions during childbirth.⁸ There are several references to pregnancy in the Atharva-Veda (translated by Whitney).¹² One is a description of a protective amulet to be put on in the 8th month of gestation (Bk. VIII, 6, pp. 493–498), but there is not the remotest indication of any specific disorder such as convulsions. The ceremonial verses are clearly directed toward protecting the woman’s genital organs against demons and rapists, who are characterized by such epithets as after-snuffling, fore-feeling, and much licking (to name the milder ones).

There are two possible references to eclampsia in the Sushruta (English translation edited by Bhishagratna).¹³ In Volume II, Chapter 8, p. 58: A child, moving in the womb of a dead mother, who had just expired (from convulsions etc.) should be delivered by cesarean section. The parenthetic from convulsions etc. was supplied by the editor and comparison with the Latin translation (Hessler)¹³ indicates that it probably was not in the original text. In Chapter 1, p. 11 of Volume II: An attack of Apatànkah due to excessive hemorrhage, or following closely upon an abortion or miscarriage at pregnancy (difficult labor) or which is incidental to an external blow or injury (traumatic) should be regarded as incurable. Again the parenthetic words are editorial explanations and the Apatànkah (convulsions) might well be those associated with severe hemorrhage. By comparison with the Latin translation, the English version seems to have been embellished, for the Latin version specifies only abortion and hemorrhage. An editorial note (pp. 58–60, Vol. II) asserts that the ancient Indians delivered living eclamptic women by cesarean section, but the editor provided no documentation whatever.

Bernhart’s reference to the old Chinese literature was to Wang Dui Me, whose work was translated into German by Lo.¹⁴ The work, originally published in 1832 AD, was thought to be free of any influence of Western medicine but even it if were, there is no indication that it recorded only ancient observations. In several respects it seems to have been contemporary; the author described what Lo translated as Eklampsie and wrote: I use recipe No. 232 ….

Several of the German authors cite Hippocrates as commenting on the susceptibility of pregnant women to convulsions and on their prognosis. None of the quotations appears in The Genuine Works of Hippocrates as translated by Adams, or in any of the half-dozen other translations that I have seen. Some of the quotations can be found in other Greek sources.¹⁵ Earlier translators, for instance, had attributed the Coacae Praenotiones to Hippocrates, but most scholars agree that it was written before Hippocrates’s time. One such quotation, appearing in several German papers is: In pregnancy, drowsiness and headache accompanied by heaviness and convulsions, is generally bad. It comes from the Coacae Praenotiones (Coan Prognosis), XXXI, No. 507. The Greeks of that time recognized preeclampsia, for in the Coan Prognosis, XXXI, No. 523, we find: In pregnancy, the onset of drowsy headaches with heaviness is bad; such cases are perhaps liable to some sort of fits at the same time (translated by Chadwick and Mann).¹⁶ Hippocrates (4th century Be), in his Aphorisms (Sec. VI, No. 30), wrote: It proves fatal to a woman in a state of pregnancy, if she be seized with any of the acute diseases. Galen, in the 2nd century AD commented that epilepsy, apoplexy, convulsions, and tetanus are especially lethal (Vol. 17, pt. II, p. 820, Kühn [ed]).¹⁷ It may be significant that Galen specified convulsive disorders and perhaps he had in mind what we now call eclampsia, which was not to be differentiated from epilepsy for another 1600 years.

Celsus, in the first century AD, mentioned often fatal convulsions in association with the extraction of dead fetuses (Bk. VII, Chapter 29, translated by Lee).¹⁸ In the same connection, Aetios, in the 6th century AD, wrote: Those who are seriously ill are oppressed by a stuporous condition …, Some are subject to convulsions …, and The pulse is strong and swollen (translated by Ricci).¹⁹

There is a possible reference to eclampsia in Rösslin’s Der Swangern Frawen und Hebammen Rosengarten, a book that was the standard text of midwifery in Europe and England for almost two centuries.²⁰ In discussing the maternal prognosis in difficult labor with fetal death, Rösslin listed among the ominous signs unconsciousness and convulsions (Bk. I, Chapter 9, p. 67). The book was largely based upon the older classics, and the relevant section is reminiscent of Celsus, Aetios, and, especially, Paul of Aegina (translated by Adams).²¹ The book was translated into English from a Latin version of what probably was the second edition and appeared in 1540 as The Byrth of Mankinde. Raynalde revised and amplified the second edition of 1545, and the text was little altered thereafter. Ballantyne’s quotation of the relevant paragraph in Book II, Chapter 9, from the edition of 1560 is virtually identical with that published 53 years later (Raynalde), except for the variable and carefree spelling of the times.²²,²³

Gaebelkhouern (variously, Gabelchoverus, Gabelkover) distinguished four sorts of epilepsy in relation to the seats of their causes, which he placed in the head, the stomach, the uterus, and chilled extremities.²⁴ He further specified that only the pregnant uterus causes convulsions, particularly if it carries a malformed fetus. The mothers feel a biting and gnawing in the uterus and diaphragm that leads them to think that something is gnawing on their hearts (epigastric pain?). The description of that symptom is usually credited to Chaussier, 1824, 228 years later).²⁵

Although eclampsia is dramatic, it is not astonishing that there are so few references to it in the older writings, which covered the whole field of medicine. Eclampsia had not been differentiated from epilepsy, and obstetrics was largely in the hands of midwives. Even some relatively modern textbooks of obstetrics have barely noticed eclampsia, and those of Burton and Exton made no mention whatever of convulsions.²⁶,²⁷ In the first edition of Mauriceau’s book, the only comment on convulsions relates to those associated with severe hemorrhage, of which his sister died.²⁸ The literature of eclampsia, for practical purposes, began in France because it was there that male physicians first took up the practice of obstetrics on a significant scale. Viardel, Portal, Peu, and de la Motte each published notable books in the late 17th and early 18th centuries.

In later editions of his book, Mauriceau devoted more and more attention to what we now call eclampsia. Hugh Chamberlen published purported translations of Mauriceau’s later editions, but they seem to have been impostures and really were reissues of the translation of the first edition.²⁹ Such fraud befits a family that kept so important an invention as the forceps secret through three generations for personal profit, and befits the man who sold the secret. In the edition of 1694, and possibly earlier, Mauriceau set forth several aphorisms dealing with the subject. Among them were (No. 228): The mortal danger to mother and fetus is greater when the mother does not recover consciousness between convulsions.³⁰ (No. 229): Primigravidas are at far greater risk of convulsions than are multiparas. (No. 230): Convulsions during pregnancy are more dangerous than those beginning after delivery. (No. 231): Convulsions are more dangerous if the fetus is dead than if it is alive. He attributed the convulsions to an excess of heated blood rising from the uterus and stimulating the nervous system and thought that irritation of the cervix would aggravate the situation. He also believed that if the fetus were dead, malignant vapors arising from its decomposition might cause convulsions. His assigning convulsions to such specific causes carries the implication that he had distinguished eclampsia from epilepsy.

Kossmann wrote that in 1760, before he had bought (gekauft hatte) his title de Sauvages, Bossier first introduced the word eclampsia.⁵ He said that de Sauvages was a typical Frenchman in that he took it badly whenever his title was omitted, that he had mistaken the meaning of the Greek word from which he derived eclampsia, that none of the supporting references that he cited was correct, and that we owe the word to de Sauvages’s slovenly scholarship.

Kossmann was in error. De Sauvages published under that name at least as early as 1739, and there is no indication in the Biographisches Lexikon (Hirsch) that he had not been born as de Sauvages.³¹ He did acquire the title de Lacroix later. De Sauvages differentiated eclampsia from epilepsy in his Pathologia Methodica, the three editions of which were forerunners of his Nosologia that Kossmann cited. He indicated that epilepsy is chronic and that the fits recur over long periods of time; all convulsions of acute causation de Sauvages called eclampsia, spelled with one c in the first and second editions and with two in later publications.³²,³³ He attributed the source of the words to Hippocrates, in the sense of Epilepsia puerilis, which Kossmann considered to be erroneous. In later editions, he cited de Gorris’s Definitionem Medicarum, Hippocrates, and the Coan Prognosis, in none of which the word occurs, according to Kossmann.

Part of the discrepancy is explained by the questionable authorship of many writings that have been attributed to Hippocrates.¹⁵,¹⁶,³⁴ Most scholars do not accept the sixth book of Epidemics as being his, but in Section I, No.5, the word does appear and has been translated as epilepsy, both before and after de Sauvages’s time. Galen (Vol. 17, pt. I, p. 824, Kühn [ed]: 1829) translated εχλαμψιεζ as fulgores (lightning, shining, brilliance) but after four half-pages of discussion as to its significance, concluded that here it means epilepsy.¹⁷ Nearly a century after de Sauvages, Grimm translated the word as Fallsucht (epilepsy).³⁴ The word does not appear in the edition of de Gorris’s definitions that I have seen, but it may be in others.³⁵ Perhaps de Sauvages cited the wrong dictionary, for he is vindicated by another one. Castelli, in his Lexicon Medicum, defined eclampsis as brightness, lightning, effulgence, or shining forth, as in a flashing glance (splendorum, fulgorum, effulgescentium et emicationem, qualis ex oculis aliquando prodeunt).³⁶ He cited several writings attributed to Hippocrates in which the word was used metaphorically to mean the shining vital flame in puberty and the vigorous years of life (emicatione flamme vitalis in pubertate et aetatis vigora). Under Effulgescentia he wrote vide eclampsis. In an earlier edition (1651), eclampsis did not appear, but effulgescentia had several definitions, the first of which is a disorder characteristic of boys, the most familiar being epilepsy (quas Graeci εχλαμψιαζ vocant Hipp. praesertim significant morbum puerorum proprium, aut certe perquam familiarissimum, id est, Epilepsium).³⁷ Castelli, who followed Galen’s discussion just mentioned, wrote that to some the word denoted the temperamental change to warmth, or the effulgent vital flame of youth and early manhood. Others considered the interpretation to be the bodily development and perfection during early adulthood.

Blancard (variously Blancardo, Blankaard) in his Lexicon Medicum, defined eclampsis as effulgio and wrote that some authors had called the circulation eclampsis because they thought that a flashing principle in the heart (luminoso principe in corde) impelled the blood.³⁸ The word disappeared from his later editions.

In the third edition (1759) of Pathologia Methodica, de Sauvages listed several species of eclampsia in relation to such acute causes as severe hemorrhage, various sources of pain, vermicular infestations, and other such factors as had been noted by Hippocrates.³³ One species was Eclampsia parturientium and de Sauvages indicated that Mauriceau had described the disease.

Vogel, Cullen, and Sagar, in their classifications of diseases, adopted de Sauvages’s Ecclampsia parturientium, but dropped one of the two c’s.³⁹–⁴¹ Interestingly, the taxonomists defined both Convulsio gravidarum and Eclampsia parturientium (or parturientes) as different genera and without cross-reference between the two.

Gutsch, a student of J. C. Gehler in Leipsig, may have been the first German obstetrician to take up the word, and for a generation the German use of it seems to have been confined to that center.⁴² Kossmann wrote that the word reappeared in France in 1844, but Ryan said that it was generally used there in his time.⁵,⁴³ That is confirmed by the listing of publications in the Index-Catalogue of the Library of the Surgeon General’s Office (1890), where the word eclampsia appears in the titles of 31 books or monographs from six European countries before 1845; there were many from France.

Ryan recognized the specificity of what he called dystocia convulsiva: He gave as synonyms labor with convulsions, convulsio apoplectica, apoplexia hysterica, apoplexia lactusa, apoplexia sympathetica, and eclampsia.⁴³ When consciousness returned between fits, Ryan called them epileptiform; when coma or stertor supervened, he called them apoplectic or eclamptic convulsions. He wrote that the convulsions may occur during the last 3 months of pregnancy, in labor, or after delivery and that the prognosis is unfavorable as a third of those afflicted are destroyed. Postpartum eclampsia is less dangerous, he said.

Bossier de Sauvages’s use of the word eclampsia as a generic term for convulsions having an acute cause persisted for more than 200 years.³² Stedman’s Medical Dictionary (1957) defined eclampsia as convulsions of an epileptoid character and listed several varieties. Puerperal eclampsia was defined as convulsions of uremic or other origin, occurring in the latter part of pregnancy or during labor; there was no mention of the puerperium. The 20th edition, in 1961, discarded all but the obstetric definition; Coma and convulsions that may develop during or immediately after pregnancy, related to proteinuria, edema, and hypertension. Puerperal eclampsia was described as following delivery, which is technically correct, but a misleading guide to interpretation of much of the literature of the 19th century.

Signs

Edema

Fasbender wrote that Demanet was the first to relate convulsions with edema.⁶,⁴⁴ An anonymous author included Demanet’s entire paper in a review that is more accessible than the origina1.⁴⁵ All six of Demanet’s eclamptic patients were edematous, and he suggested that anasarca be added to the three recognized causes of convulsions, i.e., depletion, repletion, and labor pains. Most eclamptic women have such marked edema that it could not have escaped notice before 1797 and, in fact, several writers had commented on it before then. Mauriceau remarked on the severe edema of one of his patients (Observation No. 90), but he usually did not describe the women other than to specify age and parity.³⁰ De la Motte considered edema to be benign unless associated with convulsions.⁴⁶ Smellie presented his cases as exemplifying methods of delivery and said nothing about the appearance of the patients.⁴⁷ Van Swieten, in his commentary on Boerhaave’s Aphorism No. 1302, specified edema as one of the indications for phlebotomy in women threatened with convulsions.⁴⁸

Proteinuria

Rayer found protein in the urines of three pregnant edematous women.⁴⁹ From his descriptions, it seems probable that the first one had preeclampsia and the other two had Bright’s disease.

Lever is generally credited with the discovery of proteinuria in eclampsia.⁵⁰ He was stimulated to look for it by the clinical resemblance between eclampsia and Bright’s disease, and he found it in nine of ten convulsive women. The description of the postmortem findings in the one woman who did not have proteinuria is suggestive of meningitis and perhaps her convulsions were not of eclamptic origin. Because of the rapid abatement of the proteinuria after delivery, Lever concluded that eclampsia is different from Bright’s disease, although others of his era were not so astute. Lever attributed the proteinuria to renal congestion caused by compression of the renal veins by the bulky uterus. He speculated that such compression might be absent in the upwards of 50 normal women in labor whose urines he found to be normal, unless symptoms have presented themselves, which are readily recognized as precursors of puerperal fits.

Simpson should share credit with Lever, for in the same year he wrote: (I) had publically taught for the last two sessions, viz., that patients attacked with puerperal convulsions had almost invariably albuminous urine, and some accompanying, or rather, preceding dropsical complications.⁵¹ Unfortunately, one of his fatal cases of eclampsia did have chronic nephritis and he found granular kidneys at autopsy, which led him to believe that eclampsia was a manifestation of nephritis.

Hypertension

Old-time clinicians surmised the presence of eclamptic hypertension from the hard, bounding pulse, but confirmation was long delayed for want of methods for measuring the blood pressure. Sphygmographic tracings were interpreted as showing arterial hypertension, but no absolute values could be specified. Mahomed reported that such tracings indicated the presence of hypertension in nearly all pregnant women, and he concluded that Puerperal convulsions and albuminuria were accounted for by the predisposing condition of high tension in the arterial system existing during pregnancy.⁵²,⁵³ The sphygmographic features pointing to hypertension were: (1) the increased external pressure required to obtain optimal tracings, (2) a well-marked percussion wave separated from the tidal wave, (3) a small dicrotic wave, and (4) a prolonged tidal wave. We now know that the hemodynamic changes of normal pregnancy do not include hypertension, but the increased cardiac output changes the character of the pulse. The ancient Chinese recognized the altered pulse perhaps as long as 4500 years ago; in the Yellow Emperor’s Classic of Internal Medicine we find: When the motion of her pulse is great she is with child (translation by Veith).⁵⁴

Ballantyne, from sphygmograms made in two eclamptic and one severely preeclamptic women, concluded that arterial blood pressure is considerably increased.⁵⁵ One of the patients died 10 hours after delivery, and the tracings suggested that after the completion of labor there is a great tendency to complete collapse (of the arterial pressure) and that unless checked will go on till death closes the scene. His description of terminal hypotension is descriptive of many cases of fatal eclampsia, although he generalized too broadly. Galabin wrote: From sphygmographic tracings taken during the eclamptic state, I have found that the pulse is … one of abnormally high tension, like that in Bright’s.⁵⁶ In discussing the management of eclampsia, he wrote: The first treatment should be to give an active purgative. This lowers arterial pressure ….

Despite the efforts of earlier investigators, indirect methods for the measurement of arterial blood pressure did not become available until 1875. The instruments of Marey, Potain, von Basch, and others led to overestimates of the blood pressure but did give relative values. Thus, Lebedeff and Porochjakow, using von Basch’s sphygmomanometer, found that the blood pressure is higher during labor than in the early puerperium.⁵⁷ Vinay, using Potain’s device, observed that the blood pressure was increased in pregnant women with proteinuria (180–200 mm Hg as compared with the normal of up to about 160, by his method).⁵⁸ The discovery of eclamptic hypertension is widely credited to Vaquez and Nobecourt, who remarked that they had confirmed Vinay’s observations published in his textbook 3 years earlier.⁵⁹ Vinay, however, said nothing about the blood pressure in eclampsia and regarded his hypertensive albuminuric patients as having Bright’s disease.⁵⁸ Wiessner reported that the blood pressure fluctuates widely during eclampsia.⁶⁰

Cook and Briggs used an improved model of Riva Rocci’s sphygmomanometer that has not been greatly changed to this day.⁶¹ They observed that normal pregnancy has little effect on the blood pressure until the onset of labor, when it increases with uterine contractions. Women with proteinuria were found to have hypertension, and the authors wrote that the detection of increased blood pressure in a pregnant woman should excite the apprehension of eclampsia. They observed that proteinuria was usually associated with hypertension and thought that the blood pressure was the better guide to prognosis.

The differentiation of preeclampsia–eclampsia from renal disease and essential hypertension was long delayed, and although we now recognize that they are separate entities, the correct diagnosis is often difficult. Although Lever looked for proteinuria in eclamptic women because of their clinical resemblance to patients with glomerulonephritis, he concluded that the diseases are different because eclamptic proteinuria cleared rapidly after delivery.⁵⁰ Others of that era, however, cited his discovery of proteinuria as evidence for the identity of the diseases. Frerichs, in his textbook, wrote that eclampsia represents uremic convulsions and the concept persisted for half a century.⁶² Autopsies of women dying of eclampsia often uncovered no renal abnormalities detectable by methods then available, but that objection was countered by Spiegelberg,⁶³ for example. He wrote, in italics, "True eclampsia depends upon uremic poisoning in consequence of deficient renal excretion." He attributed the deficiency to chronic nephritis aggravated by pregnancy or to disease of the renal arteries secondary to vasospasm. He suggested, as had others before him, that the renal vasospasm arose reflexively from stimulation of the uterine nerves, a hypothesis revived in modern times by Sophian.⁶⁴ The Zeitgeist was reflected in the 1881 issue of the Index-Catalogue of the Library of the Surgeon General’s Office. Under Bright’s disease it specified "see, also, –Puerperal convulsions."

Toward the end of the 19th century the development of cellular pathology and of improved histologic methods led to the detection of a characteristic hepatic lesion and the recognition of eclampsia as an entity, distinct from Bright’s disease (Jürgens; Schmorl).⁶⁵,⁶⁶ The differentiation of the nonfatal, nonconvulsive hypertensive disorders remained confused for many years. The terms nephritic toxemia, Schwangerschaftsniere, and Nephropathie persisted through the 1930s and the term low reserve kidney was introduced as late as 1926.

The recognition of primary or essential hypertension is relatively recent, but its relevance to pregnancy was not appreciated for many years after it had been accepted as an entity. Allbutt observed that middle-aged and older men and especially women often develop hypertension and that the increase in blood pressure is not accompanied by any other evidence of renal disease.⁶⁷ He referred to the condition as senile plethora or hyperpiesis; later it was termed essential hypertension by Frank or hypertensive cardiovascular disease by Janeway.⁶⁸,⁶⁹ The appellation senile had a lingering effect, and obstetricians thought that women of childbearing age were not old enough to have developed essential hypertension.

Herrick and coworkers recognized essential hypertension as an important and frequent component of the hypertensive disorders in pregnancy.⁷⁰–⁷² They showed that what the obstetricians called chronic nephritis in and following pregnancy was more often essential hypertension. Herrick wrote: Viewed largely, then, the toxemias of pregnancy are probably not toxemias. Rather they are evidences of underlying tendencies to disease.⁷⁰ He thought that about a quarter of the cases have renal disease, either frank or brought to light by pregnancy. The rest, he thought, have frank or latent essential hypertension. In some papers, he seemed not to have decided whether eclampsia and severe preeclampsia caused vascular disease or were manifestations of it that were revealed and peculiarly colored by pregnancy. In one of his last papers on the subject (Herrick and Tillman), he wrote: When these are fully delineated it is our opinion that we shall find nephritis concerned in but a small fraction of the toxemias; that the larger number, including the eclampsias, the preeclampsias, and the variously designated milder types of late toxemia … will be found to have unit characteristics based upon cardiovascular disease with hypertension.⁷²

Fishberg, in the fourth edition of his book Hypertension and Nephritis, denied the specificity of preeclampsia–eclampsia, which he regarded as manifestations of essential hypertension.⁷³ Although he retreated from that view in the following edition (1954), he continued to regard eclampsia as a typical variety of hypertensive encephalopathy.⁷⁴

Dieckmann, in his book The Toxemias of Pregnancy, said that about half of the women with hypertensive disorders in pregnancy have either nephritis or essential hypertension, but that primary renal disease accounted for not more than 2%.⁷⁵ That opinion, in which he both followed and led, gained wide acceptance. Herrick’s estimate of the prevalence of chronic renal disease, however, seems to have been closer to the truth. Several studies of renal biopsies have indicated that 10 to 12% of women in whom preeclampsia is diagnosed clinically have the lesions of primary renal disease, usually chronic glomerulonephritis.

Hypotheses and Rational Management

Zuspan and Ward wrote that in the treatment of the eclamptic patient, she has been blistered, bled, purged, packed, lavaged, irrigated, punctured, starved, sedated, anesthetized, paralyzed, tranquilized, rendered hypotensive, drowned, been given diuretics, had mammectomy, been dehydrated, forcibly delivered, and neglected.⁷⁶ Many procedures could be added to the list. Aside from the great variety of medications, surgical approaches have included ureteral catheterization, implantation of the ureters in the colon, renal decapsulation, drainage of spinal fluid, cisternal puncture, trepanation, ventral suspension of the uterus, postpartum curettage, oophorectomy, and so on. I do not rehearse the list in any spirit of levity, for it is important to remember that each of the treatments was rational in the light of some hypothesis as to the cause or nature of eclampsia. That is more than we can say for our present management, which is purely empiric, perhaps too often symptomatic, and in some respects based upon imitative magic.

Eclampsia was not differentiated from epilepsy until 1739, and the distinction was not generally accepted for another century. Merriman discussed dystocia convulsiva and wrote: The cases alone deserving the appellation of puerperal convulsions, which have fallen under my observation, have borne a very exact resemblance to the epilepsy.⁷⁷ Ryan, in his Manual of Midwifery (1831), recognized eclampsia as an entity, but 25 years later his countryman Churchill, in his Theory and Practice of Midwifery (1856), classified gestational convulsions as hysteric, epileptic, and apoplectic.⁴³,⁷⁸ By the time the differentiation from epilepsy was generally accepted, eclampsia had been confused with uremic Bright’s disease, and the proliferation of hypotheses as to its cause was delayed until late in the 19th century.

Hippocrates, in his Aphorisms, Section VI, No. 39, wrote: Convulsions take place either from repletion or depletion (translated by Adams).¹⁵ Hippocrates referred to convulsions generally, as did Galen, who iterated his view (Vol. 18, pt. I, p. 61, Kühn [ed]: 1829).¹⁷ Accordingly, obstetricians divided on the question of which factor accounted for convulsions in childbirth. Mauriceau recommended bloodletting, except in the convulsions associated with severe hemorrhage.³⁰ According to Gutsch, who did not give a reference, van Swieten wrote that depletion was the cause and attributed the convulsions to collapse of the cerebral blood vessels.⁴² Gutsch was completely wrong, but virtually every history of eclampsia has perpetuated his error. Van Swieten, in commenting on Boerhaave’s Aphorism No. 1322, was in agreement with the concept that the sudden reduction in intraabdominal pressure at delivery might lead to a pooling of blood diverted from the brain and thus account for weakness and syncope.⁴⁸ Van Swieten went on to say that if the uterus did not contract, then lying-in women run with blood, and, by the sudden inanition of the (cerebral) vessels, die in convulsions; pretty nearly in the same manner that the strongest animals, when their arteries are cut open by the butcher, their blood being entirely exhausted, are seized with violent convulsions before they die (English translation of 1776).⁴⁸ Clearly, van Swieten was not referring to eclamptic convulsions. In his comments on Aphorisms Nos. 1010, 1295, and 1302, van Swieten indicated unequivocally that cerebral congestion is the cause of what we now call eclamptic convulsions. He attributed the cerebral repletion to compression of the abdominal organs by the large uterus, to blockage of the aorta by the uterus, and to the violent expulsive efforts at delivery, all of which diverted blood to the brain. Accordingly, he wrote: no one can doubt but the letting of blood must prove of the greatest service, especially if these symptoms (including edema) happen near the time of delivery; for then by the violent efforts of labour, the blood may be forcibly thrown into the vessels of the encephalon, and all its functions thereby suppressed; or even a fatal apoplexy may ensue from a rupture of the vessels; convulsions too may often follow (comment on Aphorism No. 1302).

In addition to the factors specified by van Swieten as leading to repletion, other writers had suggested reflex effects arising from stimulation of the uterine nerves and suppression of the menses during pregnancy. The opposite hypothesis, that the convulsions were caused by depletion or cerebral anemia, had its proponents and still lingers on in terms of cerebral vasospasm and edema.

Old-time physicians and barber-surgeons resorted to bloodletting in the treatment of many disorders and they noted the extraordinary tolerance of pregnant women for hemorrhage. By the end of the 18th century the plethora of pregnancy was a widely accepted concept that seems to have tipped the scales in favor of repletion and cerebral congestion as the cause of gestational convulsions. Phlebotomy and purgation, which were the sheet anchors in the management of eclampsia one and two centuries ago, probably were of late origin. Section V of Hippocrates’s Aphorisms specified contraindications to those measures. No. 29: Women in state of pregnancy may be purged, if there be any urgent necessity, from the fourth to seventh month, but less so in the latter case. In the first and last periods it must be avoided. No. 31: If a woman with child be bled, she will have an abortion, and this will be the more likely to happen, the larger the foetus (translated by Adams, 1849). Galen agreed (Vol. 17, pt. II, pp. 652, 821, Kühn [ed]: 1829).¹⁷

Although Celsus, in the first century AD, disputed the adverse effect of bleeding, the doctrine persisted (Bk. II, Chapter 10, translated by Lee).¹⁸ In the 6th century, Aetios reiterated the deleterious effect of phlebotomy; he cited Hippocrates when he recommended bleeding as a means of inducing abortion (Chapter 18, translated by Ricci).¹⁹ Avicenna, in the 11th century, advised against both bleeding and purgation during pregnancy (translated by Krueger).⁷⁹ Maimonides, in the 12th century, seems to have contradicted himself.⁸⁰ His 12th Treatise, Aphorism 5 is: The conditions and complications that mitigate [sic] against bloodletting, although signs of filling may be apparent, are as follows: Convulsive disorders … But Aphorism 22 says: Venesection is an utmost necessity at the very onset: (in) patients suffering from … convulsions … (translated by Rosner and Muntner).

The prime object of phlebotomy was to decrease cerebral congestion and to that end, some physicians preferred bleeding from the temporal artery or jugular vein. Leeches and cups were applied to the scalp, neck, and even face to draw blood away from the brain. Blisters and sinapisms were placed in various areas for the same purpose, and the scalp was shaved for the closer application of cold packs. Sometimes the physician recognized that repeated phlebotomies had so weakened the woman that another would be hazardous, so that rather than subject her to another general hemorrhage, he placed leeches or cups on the head for the local diversion of blood from the brain. Ryan, who attributed eclampsia to cerebral congestion, wrote: In these kingdoms, copious depletion with camphor mixture, ether, etc, are chiefly employed, along with repeated bleeding.⁴³ Ether, which was popular in France, was given in mixtures by mouth or subcutaneously.

Those who believed that the convulsions were caused by irritation of the uterus also used sinapisms, blistering, and the like as counterirritants, and they bled patients from veins in the feet, which they believed to be a revulsive measure.

Later, when a circulating toxin was postulated as the cause of eclampsia, phlebotomy was retained as a rational treatment because it directly removed the noxious substance. To the same end, all of the emunctories were stimulated and the use of diuretic, purgative, emetic, and sudorific drugs became popular. High colonic irrigation and gastric lavage were used for the same purpose. Tincture or extract of jaborandi was used to induce intense sweating and when its most active alkaloid was identified as pilocarpine, that drug came into use. It was tried for a time in Edinburgh, but abandoned when it was found to have doubled the maternal mortality from 30 or 35% to 67%; the women drowned in their own secretions (Hirst).⁸¹ A parallel situation exists today in the common use of potent diuretic drugs, which probably do no real good and are dangerous, though not so dramatically as in the case of pilocarpine.

The concept of eclampsia as a toxemia is more than a century old. The earliest reference that I have found is by William Tyler Smith, who wrote: "It deserves to be borne in mind, that the depurgatory functions ought, in order to preserve health,