Teratology in the Twentieth Century Plus Ten (eBook)

Preface 6
Contents 7
Introductory Matters 14
Coincidental Discoveries 14
Early Genetic Studies 15
Definition 15
Introduction: Styles 15
Congenital Means Present at Birth 16
Malformations: Abnormalities of Structure 16
Recognition of Malformations 17
Major and Minor Malformations 17
Minor Malformations and Variants 18
Classification 19
Classification by Cause 19
Classification by Type 20
Classification by Pathogenesis 21
Nomenclature 21
Syndromes 22
Frequency 22
Difficulties of Establishing Frequency 23
A Matter of Terms 23
How Often Do Malformations Happen? 24
An Aside 25
Why Investigate Malformation Frequency 25
Ascertainment 26
Underestimating Frequency 26
Overestimating Frequency 27
Biological Factors 27
Pioneering Studies 29
X-Irradiation 29
Animal Studies 29
Human Pelvic Irradiation 30
An Irradiation-Caused Abnormality 30
Eye Abnormalities 31
Dose, Time, and Effects 32
Dose Matters 32
Murphy's Contribution 32
Atomic Radiation 33
The Hiroshima and Nagasaki Bombs 33
Microcephaly and Mental Retardation 33
Rubella 35
The Discovery 35
The German Measles Epidemic 36
Teratological Principles 36
Timing and Malformation Pattern 36
The 1964 Epidemic 37
Time Versus Agent: The 'Critical' Period 38
The Debate 38
Gestational Age and Frequency 40
An Old Disease 40
A Teratogen Disappears 41
Later Studies 42
Other Infectious Diseases 42
Influenza 42
Cytomegalovirus 42
Toxoplasmosis 42
Varicella-zoster Virus 43
Problems Regarding Intrauterine Infection 43
Intrauterine Infection in Animals 44
Pioneering Experimental Studies 45
Vitamin Deficiency 45
Hale and Vitamin A Deficiency 45
Discovery Greeted Skeptically 46
Warkany and Riboflavin Deficiency 47
Searching for the Cause 47
The All-Important Details 48
Cautions and Critics 49
Early Experiments 50
New Needs and New Ideas 50
Vitamin A and Diaphragmatic Hernia 50
The Power of Genetics 52
Basis of Diaphragmatic Hernia 53
The Early Investigators 53
Trypan Blue 54
Trypan Blue's Teratogenic 'Mechanism' 54
Hypoxia 55
A Little Break: Down Syndrome 56
Cortisone Studies and By-Products 56
Relevance to Humans 57
Induced and Spontaneous Malformations 57
Genetics and Individual Responses 58
The Multifactorial/Threshold Concept 58
A New Concept of Embryotoxicity 59
A Variety of Experiments 60
Vitamin Antimetabolites 60
Folic Acid 61
Folic Acid Antimetabolite Human Use 61
New Challenges 63
Infant Mortality and Malformation 63
Teratology Conferences 63
The Teratology Society 64
Thalidomide 66
The Thalidomide Syndrome 67
The Revelation 68
Thalidomide: Safety and Sales 69
Toxicity in Adults 70
Thalidomide in the USA 70
Dose- and Time-Response Relations 71
Thalidomide's Teratogenic Mechanism 72
Teratogenesis Mechanism Continued 73
Postscript: Was Anyone to Blame? 74
The Future? 75
Testing for Teratogenicity 76
Proposals for Drug Testing 76
The Procedure 77
The Dose-Response Curve 77
Teratogens and Mutagens 77
Teratological Detours 80
Bendectin 80
The Product 80
Alleged Teratogenicity 81
Legal Action 82
Blighted Potatoes 82
Were Potatoes the Answer? 83
Animal Studies 84
Avoidance Trials 84
Female Sex Hormones 84
Genital Defects 85
Nongenital Defects 85
Defect Nonspecificity 85
Diethylstilbestrol 86
Fetal Wastage 86
DES Usage 86
The Revelation 86
Dosage and Timing 87
The Registry 87
The Reevaluation 88
Critique 88
Congenital Defects 89
Summary and Conclusion 89
Surveillance of Congenital Malformations 90
Surveillance and Monitoring 90
Monitorings Limited Abilities 91
Epidemiology of Congenital Malformations 93
Epidemiology of Malformation Communities 94
Familial Studies 94
Clefts of the Lip and Palate 94
Neural Tube Defects 95
Human Disease as Teratogen 97
Phenylketonuria 97
Discovery and Basis 97
Pregnancy Outcome 98
Congenital Malformations 98
Dose and Time Matters 98
PKU Varieties 99
Maternal PKU Therapy 99
PKU Frequency 100
Population Malformation Load 100
PKU, Ethnicity, etc. 101
Diabetes Mellitus 102
Pregestational Diabetes Mellitus 102
Perinatal Mortality 102
Spontaneous Abortion 103
Congenital Macrosomia 103
Gestational Diabetes 103
Gestational Diabetic Outcome 104
Pregestational Diabetes Mellitus Resumed 105
Major Malformations in Diabetic Pregnancy 105
Glycosylated Hemoglobin 105
Mortalities Versus Survivors 106
Minor Abnormalities 108
Specific Major Malformations 108
Caudal Dysplasia 108
Central Nervous System Malformations 109
Cardiovascular Malformations 109
Specificity of Teratological Response 110
Dose-Response Relation 111
Conclusion 112
Fever 112
But Is It a Human Teratogen? 112
Environmental Hazards and Disasters 114
Iodine Deficiency 114
The Story of Iodine 115
Cretinism 115
Endemic Goiter 115
Organic Mercury 116
The Epidemic in Minamata 116
Congenital Minamata Disease 117
Source of the Methylmercury 117
The Epidemic in Iraq 117
Matters of Environment and Dose 118
Studies Elsewhere 118
Agent Orange 119
Male Exposure Toxicity 119
Exposure of Vietnamese Nationals 120
Exposure of US Military 120
Ranch Handlers and Reproduction 121
Exposure of Australian Military 121
Nonmilitary Herbicide Exposure 122
Herbicide Exposure and Sex Ratio 122
The Political Dimension 123
The Aftermath 124
Seveso 124
Sellafield 125
Chernobyl 126
Polychlorinated Biphenyls 126
Cola-Colored Babies 127
PCB-Exposed American Children 127
Love Canal: A Study in Political Teratology 128
Love Canal and Chromosomes 130
The Last Word 130
Disease Medication and Teratogenesis 131
Retinoids 131
A Human Teratogen 131
Synthetic Retinoids 132
Isotretinoin 133
The Population at Risk 133
Retinoic Acid Embryopathy 134
Further Threat: Etretinate 135
Acitretin 135
Topical Tretinoin Use 136
Antiepileptic Drugs 136
Therapy of Epilepsy: Fetal Consequences 137
Fetal Hydantoin Syndrome 137
Recognizing Minor Defects 139
Is Epilepsy Teratogenic? 140
Epilepsy and Spontaneous Abortion 141
Major Congenital Malformations 141
Carbamazepine 142
Valproic Acid 143
Altered Antiepileptic Use 144
Later Writings 145
Psychological Effects 145
Summary 146
Animal Studies 146
Lithium 147
Its Discovery 147
Its Teratogenicity 148
Ebstein's Anomaly 148
The Retraction 149
The Finale 150
An Addendum 151
Antihypertensives 151
Folic Acid and Congenital Malformation 152
Maternal Folic Acid Status and NTD 152
Later Concentration Studies 153
The Connection Develops 154
Maternal Vitamin Usage and NTD 155
Folic Acid and NTD Recurrence 155
Randomized Trials 157
MRC Trial 158
Irish Double Blind Trial 159
Texas Trial 159
Folic Acid and NTD Occurrence 160
Atlanta Study 160
NIH Study 161
Boston Study 162
The Debate 162
Two Widely Separated Studies 162
Other Recent Studies 163
Boston Case-Control Study 163
California Study 164
Emigration and Acculturation 165
China Studies 166
Other and Later Reports 168
Has Folic Acid Prevented NTD? 169
Folic Acid Food Fortification 169
Secular Decline 173
Terathanasia 174
Prenatal Diagnosis 175
Has the Secular Decline Continued? 177
Finale 178
Addendum 178
Genes and NTD Risk 179
Alcohol Consumption During Pregnancy 180
Early Seattle Study 180
The Fetal Alcohol Syndrome 180
The FAS Expanded 181
FAS Specificity 182
Diagnosing the FAS 183
Fetal Alcohol Effects 184
The Epidemiological Process 186
Prospective Studies 187
Moderate Drinking 187
The NIH Study 187
Chronological Overview 188
A Palpebral Fissure Parenthesis 189
To Continue 190
Major Malformations 196
Minor Malformations 196
Long-Term Effects on Growth 197
Retrospective Studies 198
Orofacial Defects 199
Limb Defects 200
Conditions in Older Children 201
Critique 203
Alcohol and Neurodevelopment 203
Longitudinal Studies 203
Alcohol and Spontaneous Abortion 206
Summary and Critique 208
Prevalence of the FAS 209
The Fundamental Problem 211
Animal Alcohol Studies 212
Finale 213
B. Franklin on Wine 213
The Accomplishment and the Expectation 214
References 216