Copyright 4
Preface 5
References 8
Contents 9
Contributors 11
Chapter 1: Brave New World: The Intrauterine Environment as the Biological Foundation for the Lifespan 13
The Developing Brain 14
Disorders in the Offspring and the Intrauterine Environment 15
Future Research 16
Developmental, Not Only Intrauterine, Environment 16
Public Health Implications of Developmental Programming 17
Manipulating the Environment to \u201cOptimize\u201d Outcomes 17
Intrauterine Environmental Deprivation 17
Fetal Learning 18
Conclusions: View from Mt. Barcroft 18
References 19
Chapter 2: In the Beginning 21
Fetal Neurobehavioral Development 22
Prenatal to Postnatal Continuities 24
Within Domain Relations 24
Cross-Domain Associations 25
Summary 26
References 27
Chapter 3: Maternal Influences on the Developing Fetus 30
Contemporaneous Associations Between Maternal Psychological Functioning and Fetal Neurobehavior 31
Fetal Response to Experimental Manipulation of Maternal State 33
Temporal Associations Between Maternal and Fetal Functioning 36
Relationship Between Maternal Psychological State During Pregnancy and Postnatal Developmental Outcomes 38
Summary and Future Directions 40
References 40
Chapter 4: Implications of Maternal Programming for Fetal Neurodevelopment 44
Programming the Maternal Brain 44
Alterations in Maternal Attachment and Care Giving 45
Alterations in Stress Responsiveness 45
Alterations in Cognitive Performance 47
Alterations in Brain Structure and Function 48
Maternal Programming Effects Are Cumulative and Persistent 48
Maternal Programming Mechanisms 49
Estrogens 50
Oxytocin 50
Glucocorticoids 52
Emerging Possibilities for Fetal Participation in Prenatal Programming of Maternal Brain 52
Placental CRH 53
Fetal Sex 53
Fetal Behavior 54
Fetal Microchimerism 54
Implications for the Study of Prenatal Influences on Neurodevelopment 55
Fetal Programming 55
Rationale for an Integrated Model of Fetal and Maternal Programming 56
References 57
Chapter 5: Maternal Thyroid Function During Pregnancy: Effects on the Developing Fetal Brain 65
Introduction 65
Basic Thyroid Physiology 66
Thyroid Hormones in Pregnancy 68
Thyroid Hormones and Fetal Brain Development 70
A Historical Perspective on Maternal Hypothyroidism 74
Studies on Outcome Following Maternal Hypothyroidism 76
Does Maternal Hypothyroidism Contribute to Childhood Developmental Disorders? 79
Conclusions 80
References 80
Chapter 6: Obstetric Factors Related to Perinatal Brain Injury 88
Introduction 88
Definitions and Epidemiology 88
Pathophysiology 90
Intrapartum Complications 91
Placental Abruption 91
Uterine Rupture 91
Umbilical Cord Prolapse 92
Preeclampsia 93
Fever and Chorioamnionitis 94
Shoulder Dystocia 94
Breech Delivery 95
Intrapartum Identification of Asphyxia 95
Neonatal Markers of Hypoxic Injury 98
Interventions to Reduce Perinatal Brain Injury 100
References 101
Chapter 7: Activation of the Maternal Immune System as a Risk Factor for Neuropsychiatric Disorders 105
Introduction 105
Risk Factors Contributing to Schizophrenia and Autism 106
Maternal Infection: An Environmental Risk Factor 107
Animal Models of Immune Activation 108
Maternal Influenza Infection 108
Maternal Immune Activation 108
Maternal Poly(I:C) Administration 109
Maternal LPS Administration 109
Other Protocols for Maternal Immune Activation 110
Mechanisms Underlying MIA-Induced Behavioral Abnormalities 110
The Immune System in Neuropsychiatric Disorders 113
Immune Activation in the Human Brain 113
Inflammation and Drug Treatment 113
Mechanisms for Chronic Inflammation and Abnormal Behavior 115
Conclusion 117
References 117
Chapter 8: Prenatal Infections and Schizophrenia in Later Life \u2013 Focus on Toxoplasma gondii 124
Introduction 124
Methods for the Study of Perinatal Infections and Risk of Schizophrenia 125
Case Control Studies 125
Prospective Cohort Studies 126
Population-Based Studies 128
Register-Based Studies 128
Perinatal Infectious Disease Exposures Associated with Schizophrenia 129
T. gondii and Risk of Schizophrenia 130
The T. gondii Organism 130
Maternal Antibodies During Pregnancy 132
Toxoplasma Antibodies in Adults 134
Prevention and Treatment 135
Unanswered Questions Relating to Toxoplasma and Schizophrenia 135
Individual Variation in Response to Toxoplasma Infection 136
Genetic 136
Immunogenetic 136
Geographic Differences in Antibody Prevalence 137
Conclusion 138
References 139
Chapter 9: Maternally Acting Alleles in Autism and Other Neurodevelopmental Disorders: The Role of HLA-DR4 Within the Major H 144
Introduction 144
Early Examples of Maternally Acting Alleles 145
Rh Incompatibility 145
Maternal Phenylketonuria 148
More Recent Reports of Maternally Acting Alleles 149
Choice of a Study Design to Document Maternally Acting Alleles 149
Case Control Studies of MHC Gene Alleles and Autism 151
Non-inherited Maternal Alleles in Rheumatoid Arthritis 152
Documentation of Maternally Acting Alleles Using More Direct Study Designs 153
Known Maternally Acting Alleles 154
Reports of HLA-DR4 Studies in Autism 154
The Major Histocompatibility Complex 154
Case\u2013Control Studies of HLA-DR and Autism 155
Case-Parent Study of Autism (Table 9.1, #4) 156
Possible Modes of Action by Which HLA-DR4 Might Contribute to Autism 157
Inflammation and Oxidative Stress 158
Synaptic Pruning and the MHC 159
HLA-DR4, High Relative Birth Weight and Possible Relevance to Autism 160
Maternal Antibodies and Autism 160
Non-inherited Maternal Allele HLA-DR4 in Rheumatoid Arthritis 161
Future Studies of HLA Markers and Autism 161
References 162
Index 168