Preeclampsia (eBook)

Dr. Shigeru Saito,Professor,Department of Obstetrics & Gynecology, University of Toyama, Toyama, Japan

Preface 6
Contents 7
Part I: Risk Factors for Preeclampsia 9
1: Risk Factors for Preeclampsia 10
1.1 Introduction 11
1.2 Prevalence 11
1.3 Risk Factors 11
1.3.1 Pregnancy-Specific Factors 11
1.3.1.1 First Pregnancy (Nulliparity) 11
1.3.1.2 New Paternity (Primipaternity Hypothesis) 16
1.3.1.3 Limited Sperm Exposure 16
1.3.1.4 Interval between Pregnancies 17
1.3.1.5 Assisted Reproductive Technology 17
1.3.1.6 Multiple Pregnancy 17
1.3.1.7 Hydatidiform Mole 18
1.3.1.8 Fetal Gender 18
1.3.2 Pre-existing Maternal Conditions 19
1.3.2.1 Older Age 19
1.3.2.2 Higher Body Mass Index or Obesity 19
1.3.2.3 Personal or Family History of Preeclampsia 20
Personal History 20
Family History 21
Paternal Factor (So-Called Dangerous Father) 21
1.3.2.4 Ethnicity or Race 21
1.3.2.5 Pre-existing Hypertension (Chronic Hypertension) 21
1.3.2.6 Pre-existing Diabetes Mellitus (Insulin-Dependent Diabetes Mellitus) 22
1.3.2.7 Pre-existing Renal Disease 22
1.3.2.8 Antiphospholipid Antibody Syndrome 23
1.3.2.9 Systemic Lupus Erythematosus 23
1.3.2.10 Infections 24
1.3.3 Environmental Factors 24
1.3.3.1 High Altitude 24
1.3.3.2 Income 25
1.4 Factors for Preventing Preeclampsia 25
1.4.1 Smoking 25
1.4.2 Summer Births 26
1.4.3 Maternal Physical Activity 26
References 27
Part II: Genetic Background in Preeclampsia 33
2: Genetic Background of Preeclampsia 34
2.1 Introduction 35
2.2 Overview of Genetic Factors in the Pathogenesis of Preeclampsia 35
2.3 Maternal Genetic Factors 37
2.3.1 Vasoactive-Related Gene Polymorphism 37
2.3.2 Coagulation-Related Genes 38
2.3.3 Cytokine-Related Genes 39
2.3.4 Others 39
2.4 Paternal/Fetal Genetic Factors 39
2.4.1 Paternal Genetic Factors 39
2.4.2 Fetal Genetic Factors 39
2.5 HLA Polymorphisms 40
2.6 Maternal and Fetal Genotypes 41
2.7 Genome-Wide Association Studies 42
2.8 Future Directions 43
References 43
Part III: Pathological Findings in Preeclampsia 49
3: Trophoblast Invasion: Remodelling of Spiral Arteries and Beyond 50
3.1 Introduction 51
3.2 Extravillous Trophoblast 51
3.2.1 Interstitial Trophoblast 53
3.2.2 Endoglandular Trophoblast 55
3.2.3 Endovascular Trophoblast 55
3.2.3.1 Endoarterial Trophoblast 57
3.2.3.2 Endovenous Trophoblast 58
3.2.4 Endolymphatic Trophoblast 58
3.3 General Considerations on Trophoblast Invasion 58
3.3.1 Deep Invasion 59
3.3.2 Shallow Invasion in the First Trimester 59
3.4 Preeclampsia and Shallow Invasion 60
3.4.1 Placental Blood Flow 61
3.4.2 Preeclampsia and Placental Hypoxia 62
3.4.2.1 Effect of Shallow Trophoblast Invasion 62
3.4.2.2 Placental Perfusion and Oxygenation 62
References 63
Part IV: Pathophysiology of Preeclampsia 66
4: Immunological Maladaptation 67
4.1 Introduction 68
4.2 Role of the Immune System 69
4.3 Epidemiological Evidence of Impaired Tolerance in Preeclampsia 70
4.4 Immunological Changes in Preeclampsia 71
4.4.1 Macrophages and Monocytes 71
4.4.2 Dendritic Cells (DCs) 72
4.4.3 NK Cells 74
4.4.4 Th1/Th2/Th17/Treg Balance 75
4.5 The Immune-Mediated Pathophysiology of Preeclampsia 76
4.6 Immunological Findings in Animal Models of Preeclampsia 78
4.7 Challenges in Treating Preeclampsia with Immune Cells or Immunomodulators 79
References 81
5: Glucose Intolerance and Insulin Resistance: Relevance in Preeclampsia 87
5.1 Introduction 87
5.2 Preeclampsia and the Glucose Tolerance Defect 89
5.3 Preeclampsia Presents a Risk for Future Diabetes Development 91
5.4 Perspective 93
References 96
6: Placental Adenosine Signaling in the Pathophysiology of Preeclampsia 101
6.1 Introduction 102
6.2 Metabolism of Adenosine and Adenosine Signaling via Adenosine Receptors 102
6.3 Detrimental Roles of Adenosine Signaling in Various Chronic Disease States 104
6.4 Evidence Associated with Adenosine Signaling and PE 105
6.4.1 Increased Levels of Adenosine in Maternal and Fetoplacental Circulation in PE Patients 105
6.4.2 Expression of Adenosine Receptors in the Placenta of PE Patients 106
6.5 Identification of Enhanced Placental Adenosine Signaling as a Novel Pathogenic Factor for PE 106
6.5.1 Generation of Genetically Engineered Pregnant Mouse with Placenta-Specific Elevation of Adenosine 106
6.5.2 Dams with Elevated Placental Adenosine Displayed Key Features of PE 108
6.5.3 ADORA2B Activation Is Responsible for the Features of PE Induced by Placental Excess Accumulation of Adenosine 108
6.5.4 Human Evidence of the Accumulated Placental Adenosine and Its Underlying Mechanisms Contributing to PE 109
6.5.5 Elevated CD73 Underlies Increased Placental Adenosine and Contributes to Pathophysiology of PE via ADORA2B Activation 109
6.6 Conclusion and Future Direction 110
References 111
7: Obesity, Adipokines, and Lipokines 115
7.1 Overview 115
7.2 Obesity 116
7.3 Adipokine 117
7.3.1 Tumor Necrosis Factor 118
7.3.2 Leptin 118
7.3.3 Adiponectin 119
7.3.4 Resistin 119
7.3.5 Plasminogen Activator Inhibitor 119
7.3.6 Monocyte Chemoattractant Protein-1 120
7.3.7 Visfatin 120
7.3.8 Interleukin-6 120
7.3.9 Apelin 121
7.4 Lipokine 121
7.4.1 Free Fatty Acids 121
7.4.2 Palmitoleate (Palmitoleic Acid) 122
7.4.3 Retinol-Binding Protein 4 122
7.4.4 Adipocyte Fatty Acid-Binding Protein 122
References 123
8: Autophagy in Preeclampsia 127
8.1 Introduction 128
8.2 The Role of Autophagy in Reproduction 128
8.3 The Role of Autophagy on Trophoblast Functions 131
8.4 The Role of Autophagy in Preeclampsia or FGR: Pros and Cons 133
8.5 Protein Aggregation in Preeclampsia 135
8.6 Cautions for Estimating Autophagy in the Placenta 135
8.7 Future Directions for Autophagy Research on Preeclampsia 137
References 138
9: Animal Models in Preeclampsia 143
9.1 Introduction 144
9.2 Pathology 144
9.3 Animal Models 145
9.3.1 What Kind of Animals? 145
9.3.2 Immune Response 145
9.3.2.1 Administration of Low-Dose Endotoxin 147
9.3.2.2 IL-4 and IL-12 Administration: Th1/Th2 Imbalance Model 147
9.3.2.3 Cytokine Administration/Reduction Models (TNF?, IL-6, IL-10) 147
9.3.2.4 Autoantibodies to Angiotensin II Type I Receptors (AT1-AAs) 147
9.3.3 Trophoblast Invasion 148
9.3.3.1 Doxycycline-Administrated Model 148
9.3.3.2 Storkhead Box 1 (STOX1) 148
9.3.4 Oxygen Dysregulation 148
9.3.4.1 Reduced Uterine Perfusion Pressure (RUPP) Model 148
9.3.4.2 Hypoxia-Inducible Factor 1? (HIF-1?)-Related Models 149
9.3.5 Anti-angiogenesis 150
9.3.5.1 sFLT1 Model Animals 150
9.3.5.2 sENG Model 150
9.3.6 Preexisting Hypertension Model/Spontaneous Model 151
9.3.6.1 Renin Angiotensin-Related Models of Preeclampsia 151
9.3.6.2 The BPH/5 Mouse 151
9.3.7 Others 151
9.3.7.1 Insulin-Induced Models of Preeclampsia 151
9.3.7.2 Stress-Induced Model Animals 152
9.3.7.3 N?-Nitro-l-Arginine Methyl Ester Hydrochloride (l-NAME)-Treated Rat 153
9.3.7.4 Adenosine-Related Placental Dysfunction Model 153
9.4 Challenges and Future Directions 153
References 154
10: The Differences Between Early- and Late-Onset Pre-eclampsia 158
10.1 Introduction: What Is Pre-eclampsia? 159
10.2 Definitions of Early- and Late-Onset Pre-eclampsia 160
10.3 Clinical Features of Early- and Late-Onset Pre-eclampsia 161
10.3.1 Differences in Short-Term Outcomes and Risk of Recurrence 161
10.3.2 Differences in Long-Term Health Outcomes 161
10.4 Epidemiology of Early- and Late-Onset Pre-eclampsia Rates and Risk Factors 162
10.5 Previous Pathophysiological Understanding of Early- and Late-Onset Pre-eclampsia 163
10.6 Two Placental Pathways to Pre-eclampsia 165
10.7 The New Two-Stage Model in Relation to Early- and Late-Onset Pre-eclampsia 168
References 170
Part V: Prediction of Preeclampsia 174
11: sFlt-1/PLGF 175
11.1 Introduction 176
11.2 Anti-angiogenesis Is an Important Mechanism in the Pathogenesis of Preeclampsia 176
11.3 Diagnosis of Preeclampsia with the Use of Angiogenetic Factors 182
11.4 Angiogenic Factors and Prediction of Preeclampsia 186
11.4.1 Early Prediction of Preeclampsia and Screening in the First Trimester 186
11.4.2 Short-Term Prediction in the Second and Third Trimester 188
11.5 The sFlt-1/PlGF Ratio and Clinical Decision-Making 190
References 192
12: Ambulatory Blood Pressure Measurement and Home Blood Pressure Measurement 199
12.1 Introduction 199
12.2 Ambulatory Blood Pressure Measurements 202
12.3 Home Blood Pressure Measurements 203
12.4 Summary 204
References 206
13: MicroRNA 209
13.1 MicroRNAs 210
13.2 Placenta-Derived MicroRNAs 211
13.3 Placenta-Derived Exosomes 213
13.3.1 Placental miRNAs Are Released from the Villous Trophoblast into Maternal Circulation via Exosomes 213
13.3.2 Placenta-Derived Exosomes in Maternal Blood during Normal Pregnancy 214
13.4 Abnormal Expression of miRNAs in the Preeclamptic Placenta 215
13.5 Placenta-Derived Exosomes in Maternal Blood as Predictive Markers for PE 215
13.6 Placenta-Specific miRNAs in Maternal Blood as Predictive Markers for PE 216
13.7 Future Prospects 219
References 219
Part VI: Therapy 225
14: Novel Therapies for Preeclampsia 226
14.1 Introduction 226
14.2 Soluble Anti-Aangiogenic Factors in the Pathogenesis of Maternal Syndrome 227
14.3 Angiogenic Biomarkers 229
14.4 Targeted Therapeutics 230
References 233
15: Pravastatin for Preeclampsia Prevention and Treatment 237
15.1 Lessons from the Mouse 238
15.1.1 Pravastatin Prevents Adverse Pregnancy Outcomes in a Mouse Model of Antiphospholipid Syndrome (APS) 238
15.1.2 Pravastatin Prevents the Onset of Preeclampsia in Mouse Models 240
15.2 C1q KO and CBA/J × DBA/2 Mouse Models 241
15.3 sFlt-1-Induced Mouse Models 242
15.4 From Mice to Women: Pilot Clinical Studies 243
References 247
16: Prevention and Treatment of Stroke and Eclampsia 250
16.1 Introduction 251
16.2 Eclampsia 251
16.2.1 Epidemiology and Pathophysiology 251
16.2.2 Treatment and Prevention 252
16.2.2.1 Initial Emergent Care 252
16.2.2.2 Anticonvulsive Therapy 252
16.2.2.3 Antihypertensive Therapy 254
16.2.2.4 Discriminating Between Eclampsia and Stroke 254
16.2.2.5 Collaboration with Neurosurgeons 255
16.2.2.6 Hypertension During Labor (Labor-Onset Hypertension, LOH) 255
16.2.2.7 HBPM: A Tool for Predicting Eclampsia/Stroke 258
16.2.2.8 Verification of the Validity of the Expression “Eclampsia” 259
16.3 Pregnancy-Associated Stroke 259
16.3.1 Epidemiology and Outcomes 259
16.3.2 Treatment and Prevention 260
16.3.2.1 Cerebral Hemorrhaging 260
16.3.2.2 Subarachnoid Hemorrhaging (SAH) 260
16.3.2.3 Cerebral Infarction 261
16.3.2.4 Cerebral Venous Sinus Thrombosis (CVST) 261
16.3.2.5 Moyamoya Disease 262
16.3.2.6 Arteriovenous Malformations (AVM) 262
16.4 Case Presentation 262
16.4.1 Case 1: Eclampsia During Labor with Labor-Onset Hypertension 262
16.4.2 Case 2: Antepartum Cerebral Hemorrhaging 263
16.4.3 Case 3: Cerebral Hemorrhaging During Labor 263
16.5 Challenges and Future Directions 264
References 264
Part VII: The Risk of Cardiovascular Events in Preeclamptic Cases 268
17: Cardiovascular Disease Following Hypertensive Pregnancy 269
17.1 Introduction 270
17.2 Evidence for Long-Term Cardiovascular Risk 271
17.3 Other Long-Term Risks of Hypertensive Pregnancy 273
17.3.1 Cognitive Dysfunction 273
17.3.2 Chronic Kidney Disease 274
17.3.3 Diabetes 275
17.3.4 Venous Thromboembolism 275
17.3.5 Cancer 275
17.3.6 Cardiovascular Disease in the Offspring 275
17.4 Mechanisms by Which Pre-eclampsia Is Related to Cardiovascular Disease 276
17.4.1 Metabolic Syndrome 276
17.4.2 Sympathetic Nervous System 277
17.4.3 Effects of Pre-eclampsia upon the Heart 278
17.4.4 Changes in Vasculature 278
17.5 Opportunities to Prevent Cardiovascular Complications of Pre-eclampsia and Gestational Hypertension 279
17.5.1 Recognition of Risk 279
17.5.2 Lifestyle, Exercise and Drug Therapy 281
References 282