DRUG SAFETY IN PREGNANCY PETER I. FOLB, M.D., F.R.C.P. Professor of Pharmacology, University of Cape Town; Chief Physician, Groote Schuur Hospital, Cape Town; Chairman, South African Medicines Control Council, South Africa M.N.GRAHAM DUKES, M.D., M.A., LL.M. Professor of Drug Policy Studies, University of Groningen, The Netherlands ELSEVIER AMSTERDAM • NEW YORK • OXFORD
CONTENTS How to use this book i Preface iii 1 Thahdomide 1 1.1 Introduction 1 1.2 Animal data 1 1.3 Human morbidity and mortality 2 1.4 Specific congenital malformations 3 1.5 Other birth defects 5 1.6 Thalidomide-resistant pregnancies 5 1.7 Differential diagnosis of the thalidomide syndrome 5 1.8 Experimental aspects of the thalidomide embryopathy 6 1.9 Summary and conclusions 6 2 Amphetamines 9 2.1 Introduction 9 2.2 Animal data 9 2.3 Clinical studies 10 2.4 Conclusions > 12 3 Tricyclic Antidepressants 15 15 3.1 Introduction 3.2 Animal data 15 3.3 Human studies 15 3.4 Human case reports not included 16 3.5 17 Negative studies 17 3.6 Recommendations for use of antidepressants in pregnancy 17 3.7 Summary 4 Lithium 19 Introduction 4.1 19 4.2 Animal data 19 4.3 Human studies 20
4.4 Negative reports 22 4.5 General considerations 22 4.6 Guidelines for administration during pregnancy 23 4.7 Conclusions 23 27 5 Ethanol 5.1 Introduction 27 5.2 The fetal alcohol syndrome 27 Animal studies 5.3 28 Human congenital malformations 5.4 30 5.5 Complications of pregnancy and labour 31 5.6 Negative study 33 5.7 Combined syndromes 33 5.8 Disulfiram 33 5.8.1 Animal data 33 5.8.2 Congenital malformations 34 5.9 Summary and conclusions 34 6 Cigarette Smoking 37 6.1 Introduction 37 6.2 Adverse effects on the fetus 37 6.3 Placental effects 40 6.4 Passive maternal smoking 41 6.5 Smoking in conjunction with other substances of abuse 41 6.6 Pathogenesis 42 6.7 Summary 42 7 Caffeine 45 45 7.1 Introduction 7.2 Animal data 45 7.3 Negative human studies 46 7.4 Case reports 47 7.5 Pharmacokinetics in the maternal-fetal unit 48 7.6 Reports not included 49 7.7 Summary 49 Drugs of Abuse 53 8.1 Introduction 53 8.2 Cannabis (marijuana) 53 8.2.1 Introduction 53 8.2.2 Animal data 53 8.2.3 Dysmorphogenesis in humans 54 8.2.4 Prenatal complications 54 8.2.5 Cancer risk 55 8.3 Cocaine 56 8.3.1 Animal data 56 8.3.2 Dysmorphogenesis in humans 56 8.3.3 Auditory defects 57
8.3.4 Complications of pregnancy and the perinatal period 57 8.3.5 Disorders of the neonate 59 8.4 Morphine, heroin and methadone 60 8.4.1 Animal studies 60 8.4.2 Adverse neonatal effects 61 8.4.3 Long-term follow-up 63 8.4.4 Negative reports 64 8.5 Lysergic acid diethylamide 65 8.5.1 Animal data 65 8.5.2 Human studies 66 8.5.3 Chromosomal studies 67 8.5.4 Negative human case reports 67 8.5.5 Publications not included 68 8.6 Phencyclidine 68 8.6.1 Animal data 68 8.6.2 Human case report 68 8.7 Summary 68 8.8 Reports not included 69 9 Neuroleptic Agents 73 9.1 Introduction 73 9.2 Animal data 73 9.3 Human teratogenicity studies 73 9.4 Perinatal complications 74 9.5 Postnatal growth and development 75 9.6 Neuroleptic malignant syndrome in the mother 76 9.7 Principles of drug therapy of the pregnant psychotic patient 76 9.8 Summary and conclusions 77 10 Benzodiazepines 79 10.1 Introduction 79 10.2 Animal data , 79 10.3 Human congenital malformations 80 10.4 Nervous system depression of the fetus and neonate 81 10.5 Acute drug withdrawal in the neonate 82 10.6 Negative reports 83 10.7 Publications not included 83 10.8 Maternal intoxication 84 10.9 Recommendations for use in pregnancy 84 10.10 Summary and conclusions 84 11 Anticonvulsants 87 11.1 Introduction 87 11.2 Pathogenesis 87 11.3 Teratogenesis and pregnancy complications - general considerations 88 11.4 Carbamazepine 89 11.4.1 Introduction 89 11.4.2 Dysmorphogenesis 89 11.5 Hydantoins 90 11.5.1 Introduction 90
xu 11.5.2 Fetal hydantoin syndrome 90 11.5.3 Multiple congenital malformations 92 11.5.4 Malignancy associated with the fetal hydantoin syndrome 93 11.5.5 Differential diagnosis of the fetal hydantoin syndrome 94 11.5.6 Negative report 94 11.5.7 Publications not included 94 11.5.8 Pathogenesis of fetal hydantoin syndrome 95 11.6 Phenobarbitone and related barbiturates 96 11.6.1 Introduction 96 11.6.2 Cardiovascular abnormalities 96 11.6.3 Pharmacokinetics 96 11.6.4 Multiple congenital abnormalities 97 11.6.5 Barbiturate withdrawal in the neonate 97 11.7 Sodium valproate (valproic acid; valproate) 97 11.7.1 Animal data 97 11.7.2 Neural tube defects 98 11.7.3 Other congenital malformations 99 11.7.4 Publications not included 102 11.7.5 Pathogenetic mechanisms 102 11.7.6 Conclusions 103 11.8 Combined antiepileptic therapy - 103 11.9 Summary and conclusions 104 12 Opioid Analgesics 111 12.1 Pethidine (meperidine) 111 12.1.1 Case studies 111 12.2 Pentazocine 112 12.3 Morphine 112 12.4 Animal data 113 12.5 Summary 113 13 Non-steroidal Anti-inflammatory Agents, and Paracetamol 115 13.1 Introduction 115 13.2 Animal data 116 13.3 Acetylsalicylic acid (aspirin) 117 13.3.1 Fetal and postnatal effects 117 13.3.2 Platelet function and haemorrhagic complications 118 13.3.3 Uterine tone and function 119 13.3.4 Negative reports 119 13.3.5 Overdose 120 13.3.6 Beneficial effect to the fetus 120 13.4 Indomethacin 121 13.4.1 Fetal and neonatal circulations 121 13.4.2 Renal vasoconstriction and oligohydramnios 121 13.4.3 Primary pulmonary hypertension in the neonate 122 13.4.4 Congenital malformations 123 13.5 Paracetamol 123 13.5.1 Pharmacokinetics 123 13.5.2 Negative studies 123 13.5.3 Acute paracetamol poisoning 124 13.6 Phenylbutazone 125 13.7 Naproxen 125
Xlll 13.8 Treatment of rheumatic diseases in pregnancy 125 13.9 Summary and conclusions 125 14 Anaesthetic Agents [General and Local Anaesthetics] 131 14.1 Introduction 131 14.2 Suxamethonium and congeners 131 14.2.1 Experimental data 131 14.2.2 Negative clinical data 131 14.2.3 Interaction of succinylcholine with hypermagnesaemia 132 14.3 Propofol 132 14.4 Surgical atmospheric pollution 132 14.5 Fetal hazards of general and local anaesthesia 132 14.6 Local anaesthetics 133 14.6.1 Introduction 133 14.6.2 Experimental data 133 14.7 Adverse effects of local anaesthetics in the newborn infant 134 14.8 Maternal complications 135 14.9 Negative reports 136 14.10 Conclusions 137 15 Sympathomimetic Agents 141 15.1 Introduction 141 15.2 Animal data 141 15.3 Congenital malformations 142 15.4 Fetal complications 143 15.5 Maternal complications during pregnancy 143 15.6 Pregnancy complications of anti-asthma therapy 146 15.7 Metabolic disturbances in the maternal-fetal unit 147 15.8 Neonatal complications 148 15.9 Interaction with prostaglandin synthetase inhibitors 148 15.10 Negative reports 149 15.11 Articles considered but not included 149 15.12 Comment . 149 16 Antihypertensive Drugs, and yS-Adrenergic Receptor Blocking Agents 153 16.1 Introduction 153 16.2 a-Methyldopa 153 16.2.1 Perinatal outcome 153 16.2.2 Long-term follow-up 155 16.2.3 Growth and development 155 16.3 Angiotensin-converting enzyme (ACE) inhibitors 156 16.3.1 Introduction 156 16.3.2 Pregnancy outcome 156 16.3.3 Oligohydramnios and neonatal anuria 156 16.3.4 Conclusion 158 16.4 /?-Adrenergic receptor blocking agents 158 16.4.1 Introduction 158 16.4.2 Theoretical considerations 158 16.4.3 Outcome of pregnancy 159 16.4.4 Intrauterine growth retardation 160
160 16.4.5 Perinatal complications 16.4.6 Metabolic effects 161 16.4.7 Allergy 161 16.4.8 Fetal and uteroplacental haemodynamics 161 16.4.9 Negative reports 162 16.4.10 The merits of /J-adrenergic receptor blocking agents in hypertension 162 of pregnancy 16.5 Comment 163 16.6 Hydralazine 163 16.7 Minoxidil 164 16.8 Clonidine and lofexidine 164 16.9 Reserpine 165 16.10 Summary and conclusions 165 17 Diuretics 169 17.1 Introduction 169 17.2 Effects of diuretics in pregnancy 169 17.3 Furosemide 170 17.4 Thiazide diuretics 170 17.5 Triamterene 170 17.6 Negative report 170 17.7 Animal data 171 18 Penicillamine and Gold 173 18.1 Introduction 173 18.2 Gold 173 18.2.1 Animal data 173 18.2.2 Pharmacokinetics 173 18.2.3 Negative studies 173 18.2.4 Congenital malformations 174 18.3 Penicillamine 174 18.3.1 Congenital malformations 174 18.3.2 Negative studies 175 18.4 Comment and conclusions 176 19 Antibiotics and Chemotherapeutic Agents 179 19.1 Introduction 179 19.2 Antibiotics and stillbirth 179 19.3 Aminoglycosides 179 179 19.3.1 Introduction 19.3.2 Experimental data 180 19.3.3 Human vestibular apparatus 180 19.3.4 Pharmacokinetics 180 19.3.5 Comment 181 19.4 Ampicillin 181 181 19.4.1 Pharmacokinetics 19.4.2 Animal data 181 19.4.3 Acute anaphylaxis in the mother 182 19.4.4 Negative human study 182 182 19.5 Cephalosporins 19.5.1 Human studies 182
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