Front Cover

Chesley's Hypertensive Disorders in Pregnancy

Copyright Page

Contents

List of Contributors

Preface

1 Introduction, History, Controversies, and Definitions

History (Fig. 1.1)

Signs

Edema

Proteinuria

Hypertension

Hypotheses and Rational Management

Prophylaxis

Classification of the Hypertensive Disorders in Pregnancy

Editors’ Update

Measurement of Blood Pressure

Classifications and Definitions: The American College of Obstetricians and Gynecologists Hypertension in Pregnancy Hyperten ...

Denouement

False Steps in the Study of Preeclampsia

References

2 The Clinical Spectrum of Preeclampsia

Introduction

Clinical Manifestations of Preeclampsia Syndrome

Cardiovascular System

Loss of Pregnancy Hypervolemia

Blood and Coagulation

The Kidney

The Liver

The Brain

Uteroplacental Perfusion

Differential Diagnosis

References

3 Epidemiology of Pregnancy-Related Hypertension

Introduction

Definitions of the Hypertensive Disorders of Pregnancy

Prevalence of Hypertensive Disorders of Pregnancy

Eclampsia

Preeclampsia

Discussion of Differential Frequency Estimates

Risk Factors for Preeclampsia

Cardiovascular Risk Factors

Body Mass Index

Physical Activity

Diet

Vitamin D

Smoking

Family Patterns

First Birth and Other Placental Factors

Clinical Predictors

Natural History

Maternal Morbidity Immediately Related to Preeclampsia

Recurrence of Preeclampsia in Subsequent Pregnancies

Reduced Risk of Later-Life Breast Cancer

Increased Risk of Later Life Cardiovascular Disease

Physiological Mechanisms Linking Preeclampsia to Maternal CVD Risk

Impact on Children

Perinatal Outcomes

Remote Impact on Cardiovascular Function in Offspring of Preeclamptic Pregnancies

Critique of Studies

Conclusion

Acknowledgment

References

4 Genetic Factors in the Etiology of Preeclampsia/Eclampsia

Dedication

Introduction

Biological Pathways of Preeclampsia

Fetal/Placental Components of Preeclampsia

Immunogenetic Factors (see also Chapter 8)

Types of Genetic Studies Conducted

Family Reports

Twin Studies

Segregation Analyses

Linkage Analyses

Association Studies

Genome-Wide Association Studies (GWAS)

Next-Generation Sequencing

A Genomics Approach to Preeclampsia

Essential Variables to Consider

Interacting Genomes

Subgroups

Genomic Ethnicity

Population Size

Gene–Gene Interactions

Epigenetics

Gene–Environment Interactions

Confounding Variables

High-Dimensional Biology

A Predictive Genetic Test

Pharmacogenomics

The Future of Preeclampsia Genetic Research

Conclusions

References

5 The Placenta in Normal Pregnancy and Preeclampsia

APPENDIX: Trophoblast Gene Expression in Normal Pregnancy and Preeclampsia

6 Angiogenesis and Preeclampsia

Introduction

Placental Vascular Development in Health

Placental Vasculogenesis

Maternal Vascular Remodeling

Fetal Circulation and Placental Villous Angiogenesis

Angiogenic Factors and Placentation

Natural Killer Cells and Placental Vascular Development

Angiogenic Imbalance in Preeclampsia

Soluble Antiangiogenic Factors in Preeclampsia

Upstream Pathways and Mechanisms of Preeclampsia

Angiogenesis and the Remote Consequences of Preeclampsia

Role of Angiogenic Biomarkers in Preeclampsia

Therapeutic Strategies for Preeclampsia

Anti-Angiogenic Versus Normal Angiogenic Forms of Preeclampsia

Perspectives

References

7 Metabolic Syndrome and Preeclampsia

Introduction

Metabolic Syndrome

Metabolic Syndrome and Cardiovascular Disease

Obesity

Free Fatty Acids and TNF-α

Renin-Angiotensin System

Adipocyte Hypertrophy and Endoplasmic Reticulum Stress

Pregnancy-Induced Metabolic Changes

Carbohydrate and Lipid Metabolism

Maternal Weight Gain in Pregnancy

Preeclampsia and Metabolic Syndrome

Obesity and Insulin Resistance

Inflammation

Dyslipidemia

Angiogenic Factors

Uric Acid and ADMA

Lifestyle Factors

Later-Life Cardiovascular Risk (also see Chapter 3)

Metabolic Syndrome: a Cause of Placental Dysfunction?

Summary and Perspectives

References

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

Normal Pregnancy

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

9 Endothelial Cell Dysfunction

Introduction

Part I: Endothelial Cell Function and Preeclampsia

Endothelial Cell Dysfunction in Preeclampsia

Circulating Markers of Endothelial Cell Activation

Growth Factor Binding Proteins in Preeclampsia

Part II: Circulating Factors Induce Endothelial Cell Dysfunction

Formed Elements in Blood as Activators of Endothelium

Placental Membrane Microvesicles

Endothelial Progenitor Cells (EPCs)

Immune Complexes: Antiphospholipid and Antiendothelial Cell Antibodies

Cytokines

Circulating Lipids and Lipoproteins

Non-Esterified Fatty Acids

Peroxisome Proliferator-Activated Receptors (PPARs)

Angiogenic Factors

Matrix Metalloproteinases

Endothelin

Relaxin

Angiotensin II

Toll-Like Receptors

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

Oxidative Stress as a Mediator of Endothelial Cell Dysfunction

Eicosanoid/Prostacylin Production

Nitric Oxide

Endothelium-Derived Hyperpolarization

Other Vasodilators

Part IV: Clinical Trials

Aspirin

L-Arginine

Fish Oil

Calcium

Anticoagulants

Summary

Part V: Speculations and Directions of Future Investigations

References

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

BPH/5

Genetic Modification of the Renin-Angiotensin System

STOX1 Overexpression

COMT Knockout

Potential Models with Placental Abnormalities

Summary

References

11 Tests to Predict Preeclampsia

Introduction

Assessing the Quality of Tests to Predict Disease

Placental Perfusion and Vascular Resistance Dysfunction-Related Tests

Roll-Over Test, Isometric Exercise Test, and Angiotensin II Sensitivity Test

Blood Pressure

Transcranial Doppler Velocimetry

Uterine Artery Doppler Velocimetry

Fetal and Placental Unit Endocrinology Dysfunction-Related Tests

Human Chorionic Gonadotropin

Alpha Fetoprotein

Estriol

Inhibin A

Pregnancy-Associated Plasma Protein A

Activin A

Placental Protein 13

A Disintegrin and Metalloprotease 12

Renal Dysfunction-Related Tests

Serum Uric Acid

Microalbuminuria

Urinary Calcium Excretion

Urinary Kallikrein

Podocyturia (See Chapter 16)

Endothelial Dysfunction and Oxidant Stress-Related Tests

Fibronectin

Homocysteine

Endothelial Cell Adhesion Molecules

Circulating Angiogenic Factors

Other Tests

Cell-Free Fetal Deoxyribonucleic Acid

Proteomic, Metabolomic, and Transcriptomic Markers

The Use of Combined Tests

Multivariable Prediction Models Derived from Combinations of Maternal Characteristics and Tests

Perspectives and Conclusions

Acknowledgement

References

12 Prevention of Preeclampsia and Eclampsia

Introduction

Dietary Manipulations

Low-Salt Diet

Fish Oil

Calcium Supplementation

Physical Activity

Diuretics and Antihypertensive Drugs

Antioxidant Vitamins

Antithrombotic Agents

Low-Dose Aspirin

Low-Dose Aspirin Plus Heparin

Statins

Prevention of Eclampsia

Magnesium Sulfate for Mild Preeclampsia

Magnesium Sulfate for Severe Preeclampsia

Effects of Magnesium Sulfate on Maternal Mortality and Morbidity

Effects of Magnesium Sulfate on Perinatal Mortality and Morbidity

Treatment for Eclampsia (See Chapter 20)

Side Effects and Toxicity

Initiation, Dose, Duration, and Route of Administration

Prevention of Long-Term Maternal Health Risks Following Preeclampsia

References

13 Cerebrovascular Pathophysiology in Preeclampsia and Eclampsia

Introduction

Neuroanatomical Findings with Eclampsia

Neuroimaging in Eclampsia

Computed Tomography (CT)

Magnetic Resonance Imaging (MRI)

Diffusion-Weighted MRI and Apparent Diffusion Coefficient

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

Animal Studies

Human Studies

Mechanisms of Seizure During Pregnancy and Preeclampsia

Role of Circulating Factors in Eclampsia

Blood–Brain Barrier

Aquaporins and Cerebral Edema During Pregnancy

Effect of Magnesium Sulfate Treatment

Cerebral Hemorrhage

Cortical Blindness

Remote Cerebrovascular Health Following Preeclampsia and Eclampsia

Visual Functioning

Brain White Matter Lesions

Neurocognitive Functioning

Epilepsy

Stroke

References

14 Cardiovascular Alterations in Normal and Preeclamptic Pregnancy

Introduction

Hemodynamics and Cardiac Function in Normal Pregnancy

Systemic Arterial Hemodynamics in Normal Pregnancy

Venous System in Normal Pregnancy

Systemic Arterial Properties in Normal Pregnancy

Left Ventricular Properties in Normal Pregnancy

Coupling between Left Ventricle and Systemic Arterial Circulation in Normal Pregnancy

Hemodynamics and Cardiac Function in Preeclampsia

Systemic Arterial Hemodynamics in Preeclampsia

Systemic Arterial Properties in Preeclampsia

Left Ventricular Properties in Preeclampsia

Factors that May Explain Vascular Changes in pregnancy

Normal Pregnancy

Preeclampsia

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

Summary

References

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

Introduction

Body Fluid Volumes

Preeclampsia

“Normal Fill” or Resetting of the “Volumestat”

Primary Arterial Vasodilatation (“Underfill”)

Excessive Expansion or “Overfill”

Plasma Volume in Normal Pregnancy and Preeclampsia

Novel Salt Concept

Mineralocorticoids and the Renin-Angiotensin-Aldosterone Axis

Antinaturetic Peptides in Pregnancy

Preeclampsia

Agonistic Anti-AT1 Receptor Antibodies

Agonistic Anti-AT1 Receptor Antibodies in Preeclampsia (AT1-AA)

Signal Transduction and Pathophysiological Role of AT1-AA

AT1-AA in Animal Models of Hypertension During Pregnancy (See also Chapter 10)

AT1-AA Induced Hypertension

Presence of AT1-AA in Other Diseases

Concluding Perspectives

References

16 The Kidney in Normal Pregnancy and Preeclampsia

Introduction

Renal Hemodynamics and Glomerular Filtration Rate During Normal Pregnancy

Renal Clearances of para-Aminohippurate and Inulin

Creatinine Clearance

Postural Influences on Renal Function

Mechanisms for Alterations of Renal Hemodynamics and GFR

Cellular and Molecular Mechanisms of Renal Vasodilatation

Osmoregulation in Normal Pregnancy

Renal Hemodynamics and Glomerular Filtration Rate in Preeclampsia

Summary

Renal Handling of Uric Acid

Normal Pregnancy

Preeclampsia

Summary

Renal Handling of Proteins

Normal Pregnancy

Preeclampsia

Summary

Renal Morphology in Pregnancy and Preeclampsia

Introduction

Gross Morphology

Indications for Renal Biopsy in Pregnancy

References

17 Platelets, Coagulation, and the Liver

Introduction

Platelets

Platelets in Normal Pregnancies and with Preeclampsia

Platelet Activation In Vivo

Summary of Platelet Activation

Platelet Behavior In Vitro

Expression of Platelet Receptors in Pregnancy and Preeclampsia

Platelet Second Messengers

Platelet Angiotensin II-Binding Sites

Coagulation

Coagulation Cascade Factors

Regulatory Proteins and Thrombophilia

Fibrinolytic System

Fibrinolysis in Normal Pregnancy

Fibrinolysis in Preeclampsia

The Liver in Preeclampsia

Clinical Aspects of Liver Involvement

The Liver in HELLP Syndrome

Corticosteroid Therapy for HELLP Syndrome

References

18 Chronic Hypertension and Pregnancy

Introduction

Background

Definition

Diagnosis

Cardiac and Hemodynamic Alterations

Effect of Chronic Hypertension on the Mother

Effects of Chronic Hypertension on Fetal/Neonatal Outcome

Chronic Hypertension with Superimposed Preeclampsia

Effects of Superimposed Preeclampsia on the Mother and Fetus/Neonate

Specific Hypertensive Disorders

Essential Hypertension

Physiology and Pathophysiology of Essential Hypertension During Pregnancy

Blood Pressure Patterns and Hemodynamic Measurements

Hormonal and Biochemical Alterations

Pathophysiology of Superimposed Preeclampsia

Secondary Hypertension

Renal Disease

Renovascular Hypertension

Primary Aldosteronism

Pheochromocytoma

Cushing Syndrome

Postpartum Hypertension

Management Principles

Preconception Counseling

Non-Pharmacologic Management

Pharmacologic Management (see Chapter 19)

References

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

Sympathetic Nervous System Inhibition

Centrally Acting α2-Adrenergic Agonists

Peripherally Acting Adrenergic-Receptor Antagonists

Diuretics

Calcium-Channel Antagonists

Direct Vasodilators

Modulators of the Renin–Angiotensin–Aldosterone Axis

Drug use While Breastfeeding

Evidence from Randomized Trials

Evidence for Antihypertensive Treatment in Mild to Moderate Hypertension

Evidence for Antihypertensive Treatment in Severe Hypertension

Conclusion

References

20 Clinical Management

Introduction

Preeclampsia

Early Diagnosis and Evaluation

Hospitalization Versus Outpatient Management

Antihypertensive Therapy for Mild to Moderate Hypertension

Indications for Delivery

Delayed Delivery with Early-Onset Preeclampsia

Eclampsia

Immediate Management of Seizure

Medical Treatment of Eclampsia

Management of Severe Hypertension

Commonly Used Antihypertensive Agents

Other Antihypertensive Agents

Diuretics

Fluid Therapy

Pulmonary Edema

Plasma Volume Expansion

Neuroprophylaxis – Prevention of Eclampsia

Who Should Be Given Magnesium Sulfate?

Delivery

Blood Loss at Delivery

Analgesia and Anesthesia

Persistent Severe Postpartum Hypertension

Furosemide

References

Index