DRUG SAFETY IN PREGNANCY PETER I. FOLB, M.D., F.R.C.P. Professor of - - PDF document

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 15 15 16 17 17 17 19 19 19 20 3.1 3.2 3.3 3.4 3.5 3.6 3.7

Introduction Animal data Human studies Human case reports not included Negative studies Recommendations for use of antidepressants in pregnancy Summary 4 Lithium

4.1 4.2 4.3

Introduction Animal data Human studies

5 Ethanol 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 Introduction The fetal alcohol syndrome Animal studies Human congenital malformations Complications of pregnancy and labour Negative study Combined syndromes Disulfiram 5.8.1 Animal data 5.8.2 Congenital malformations Summary and conclusions 4.4 Negative reports 22 4.5 General considerations 22 4.6 Guidelines for administration during pregnancy 23 4.7 Conclusions 23 27 27 27 28 30 31 33 33 33 33 34 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 45 46 47 48 49 49

53

53 53 53 53 54 54 55 56 56 56 57 7.1 7.2 7.3 7.4 7.5 7.6 7.7 Drugs 8.1 8.2 8.3 Introduction Animal data Negative human studies Case reports Pharmacokinetics in the maternal-fetal unit Reports not included Summary

• f Abuse

Introduction Cannabis (marijuana) 8.2.1 Introduction 8.2.2 Animal data 8.2.3 Dysmorphogenesis in humans 8.2.4 Prenatal complications 8.2.5 Cancer risk Cocaine 8.3.1 Animal data 8.3.2 Dysmorphogenesis in humans 8.3.3 Auditory defects

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

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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

16.4.5 Perinatal complications 16.4.6 Metabolic effects 16.4.7 Allergy 16.4.8 Fetal and uteroplacental haemodynamics 16.4.9 Negative reports 16.4.10 The merits of /J-adrenergic receptor blocking agents in hypertension

• f pregnancy

16.5 Comment 16.6 Hydralazine 16.7 Minoxidil 16.8 Clonidine and lofexidine 16.9 Reserpine 16.10 Summary and conclusions 17 Diuretics 17.1 Introduction 17.2 Effects of diuretics in pregnancy 17.3 Furosemide 17.4 Thiazide diuretics 17.5 Triamterene 17.6 Negative report 17.7 Animal data 18 Penicillamine and Gold 18.1 Introduction 18.2 Gold 18.2.1 Animal data 18.2.2 Pharmacokinetics 18.2.3 Negative studies 18.2.4 Congenital malformations 18.3 Penicillamine 18.3.1 Congenital malformations 18.3.2 Negative studies 18.4 Comment and conclusions 19 Antibiotics and Chemotherapeutic Agents 19.1 Introduction 19.2 Antibiotics and stillbirth 19.3 Aminoglycosides 19.3.1 Introduction 19.3.2 Experimental data 19.3.3 Human vestibular apparatus 19.3.4 Pharmacokinetics 19.3.5 Comment 19.4 Ampicillin 19.4.1 Pharmacokinetics 19.4.2 Animal data 19.4.3 Acute anaphylaxis in the mother 19.4.4 Negative human study 19.5 Cephalosporins 19.5.1 Human studies

160 161 161 161 162 162 163 163 164 164 165 165 169 169 169 170 170 170 170 171 173 173 173 173 173 173 174 174 174 175 176 179 179 179 179 179 180 180 180 181 181 181 181 182 182 182 182

19.6 Chloramphenicol and thiamphenicol 182 19.6.1 Animal data 183 19.6.2 Clinical pharmacokinetics 183 19.6.3 Negative human studies 184 19.7 Griseofulvin 184 19.7.1 Animal data 184 19.7.2 Human congenital malformations 184 19.8 Metronidazole and other nitromidazoles 185 19.8.1 Introduction 185 19.8.2 Congenital malformations 185 19.8.3 Negative human studies 185 19.9 Nitrofurantoin and nitrofurantoin macrocrystals 186 19.9.1 Animal data 186 19.9.2 Human pharmacokinetics 186 19.9.3 Negative human studies 186 19.10 Penicillins 187 19.10.1 Negative human studies 187 19.11 Sulphonamides and trimethoprim 188 19.11.1 Introduction 188 19.11.2 Animal data 188 19.11.3 Negative studies in humans 188 19.11.4 Chromosomal studies 188 19.11.5 Conclusions 189 19.12 Tetracyclines 189 19.12.1 Introduction 189 19.12.2 Animal data 189 19.12.3 Human case reports and studies 190 19.12.4 Human pharmacokinetics 191 19.12.5 Maternal hepatotoxicity 191 19.12.6 Reports considered and not included 192 19.12.7 Clinical recommendations 193 19.13 Summary 193 20 Drugs Used in Tuberculosis 199 199 199 199 200 200 200 201 201 201 201 202 202 202 203 205 205 205 20.1 20.2 20.3 20.4 20.5 20.6 20.7 Introduction Streptomycin and dihydrostreptomycin 20.2.1 Ototoxicity 20.2.2 Negative reports Isoniazid 20.3.1 Negative studies 20.3.2 Data considered but not included Rifampicin 20.4.1 Animal data 20.4.2 Fetal toxicity Ethambutol 20.5.1 Negative human studies Chromosomal studies Conclusions 21 Antimalarials 21.1 21.2 Introduction Chloroquine

21.3 Mefloquine 207 21.4 Mepacrine 207 21.5 Proguanil 207 21.6 Pyrimethamine 207 21.6.1 Pyrimethamine with dapsone 208 21.6.2 Pyrimethamine with sulphadoxine (Fansidar) 208 21.7 Quinine 208 21.7.1 Fetal toxicity 208 21.7.2 Quinine action on pancreatic /?-cells 209 21.8 Information not available 209 21.9 Conclusions and clinical recommendations 210 22 Vaccines 211 22.1 Introduction 211 22.2 Bacille Calmette-Guerin (BCG) vaccine 211 22.3 Influenza virus vaccine 211 22.3.1 Neurotoxicity 212 22.3.2 Negative human studies 212 22.4 Measles vaccine (including measles-mumps-rubella MNR vaccine) 213 22.5 Mumps vaccine 213 22.6 Poliomyelitis vaccine 213 22.6.1 Human studies 213 22.7 Rabies vaccine 214 22.8 Rubella vaccine 214 22.8.1 World Health Organization findings and recommendations 214 22.8.2 Use in pregnancy - negative studies 215 22.8.3 Recommendations for rubella immunisation 216 22.9 Smallpox vaccine 216 22.10 TC-83 Venezuelan equine encephalitis vaccine 217 22.11 Yellow fever vaccine 217 22.12 Conclusions and recommendations 217 221 221 221 221 222 222 223 223 223 224 224 224 225 226 226 227 227 228 23.4 General effects of anticoagulation in pregnancy 228 23 Anticoagulants 23.1 Introduction 23.2 Heparin 23.2.1 23.2.2 23.2.3 23.2.4 23.2.5 23.2.6 Osteopenia in the mother Haemorrhagic complications Outcome of pregnancy Toxic epidermal necrolysis A contrary view Summary 23.3 Warfarin sodium 23.3.1 23.3.2 23.3.3 23.3.4 23.3.5 23.3.6 23.3.7 23.3.8 Introduction Fetal warfarin syndrome and warfarin embryopathy Fetal mortality Isolated case reports Differential diagnosis of the fetal warfarin syndrome Pathogenesis of warfarin embryopathy Other publications considered Summary

xvu 23.5 Therapeutic considerations 229 23.5.1 Antithrombin III congenital defect 229 23.5.2 Congenital factor XIII deficiency 229 23.5.3 Valve prosthesis in pregnancy 230 23.5.4 Thromboembolic disease 230 24 Haematinics 233 24.1 Introduction 233 24.2 Animal data 233 24.3 Negative human data 233 24.4 Conclusion 234 25 Drugs Acting on the Gastrointestinal Tract 235 235 235 235 235 235 236 236 236 236 237 237 238 238 26 Antiemetic Agents 241 26.1 Bendectin (Debendox) 241 26.1.1 Introduction 241 26.1.2 Large-scale studies of Bendectin teratogenicity 241 26.1.3 Congenital malformations . 242 26.1.4 Negative human studies 242 26.2 The problem of identifying a low-grade teratogen 243 26.3 Antiemetic agents other than Bendectin 244 26.3.1 Animal data 244 26.3.2 Negative human studies 244 26.4 Atropine and other parasympatholytic agents 245 26.4.1 Pharmacokinetics 245 26.4.2 Congenital malformations 245 26.4.3 Maternal and fetal effects 246 26.5 Prochlorperazine 246 26.5.1 Congenital malformations of the limbs 246 27 Vitamins and the Retinoids 249 27.1 Introduction 249 27.2 Experimental data 250 27.3 Human fetal effects of vitamin A and the retinoids 252 27.4 Other articles considered 257 25.1 25.2 25.3 25.4 25.5 25.6 25.7 Introduction Bismuth Carbenoxolone Cimetidine 25.4.1 Animal data 25.4.2 Human fetal hepatotoxicity Ranitidine Sulphasalazine 25.6.1 Human congenital malformations 25.6.2 Kernicterus 25.6.3 Male infertility 25.6.4 Negative human studies Conclusions

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27.5 Differential diagnosis of retinoid embryopathy 258 27.6 Mechanisms of retinoid teratogenicity 258 27.7 Principles of behavioural teratology reflected by the retinoids 259 27.8 Topical retinoic acids 259 27.9 Recommendations for the use of vitamin A during pregnancy 259 27.10 Vitamin D 260 27.10.1 Introduction 260 27.10.2 Animal data 260 27.10.3 Negative human study 260 28 Corticosteroids 265 28.1 Introduction 265 28.2 Animal data 256 28.3 Negative human studies - congenital malformations 266 28.4 Effects on pregnancy and labour 266 28.5 Neonatal status 267 28.6 Head circumference and brain maturation 268 28.7 Dexamethasone 269 28.8 Conclusions 269 29 Hormonal Contraceptives 273 29.1 Introduction 273 29.2 Congenital malformations 273 29.3 Disturbances of fetal sex expression 276 29.4 Neoplastic change in the infant 277 29.5 Chromosomal abnormalities 277 29.6 Twin pregnancies 278 29.7 Maternal complications 278 29.8 Negative reports 279 29.9 Hormonal pregnancy tests 281 29.10 Comment and conclusions 281 30 Diethylstilboestrol and Related Agents Affecting Fetal Sex Hormone Development 285 30.1 Introduction 285 30.2 Clomiphene 285 30.2.1 Congenital malformations 285 30.2.2 Complications of pregnancy 286 30.2.3 Negative results 286 30.3 Danazol 286 30.3.1 Antigonadotrophic effects 287 30.3.2 Effects on the male fetus 288 30.4 Diethylstilboestrol 288 30.4.1 Introduction 288 30.4.2 Neoplasia of the female genital tract 288 30.4.3 Uterine and vaginal structural abnormalities 289 30.4.4 Disturbances in ovulation and fertility 290 30.4.5 Complications in pregnancy of the offspring 291 30.4.6 Hormonal and menstrual abnormalities 292 30.4.7 Abnormalities in the male offspring 293 30.4.8 Miscellaneous pathological effects 294

30.4.9 A challenge to the evidence 294 30.4.10 Summary 295 30.5 Medroxyprogesterone acetate 295 30.6 Progestogens 296 30.7 Summary 296 31 Spermicidal Agents 301 31.1 Introduction 301 31.2 Animal and experimental data 301 31.3 Human studies 301 31.4 Negative studies in humans 303 31.5 Conclusion 304 32 Thyroid and Antithyroid Drugs 305 32.1 Introduction 305 32.2 Radioactive iodine 306 32.3 Iodine-containing anti-asthmatic medicines 306 32.4 Iodine-containing radiocontrast media 307 32.5 Iodine-containing douche 307 32.6 /J-Adrenergic receptor blocking agents 308 32.6.1 Introduction 308 32.6.2 Negative reports 308 32.7 Propylthiouracil and the thioamides 308 32.7.1 Introduction 308 32.7.2 Effects on the fetal thyroid gland 309 32.7.3 Fetal morbidity 309 32.7.4 Negative results 309 32.7.5 Aplasia cutis 310 32.8 Combined thyroid and antithyroid therapy in pregnancy 311 32.9 Effects of radioactive fallout 311 32.9.1 Introduction 311 32.9.2 Mental deficiency 311 32.10 Management of hyperthyroidism in pregnancy - general principles 312 32.11 Summary and conclusions 312 33 Oral Hypoglycaemic Agents 315 33.1 Introduction 315 33.2 Biguanides 315 33.3 Sulphonylureas (other than tolbutamide) 315 33.3.1 Fetal loss, and outcome of pregnancy 315 33.3.2 Carbutamide 316 33.3.3 Chlorpropamide 317 33.4 Tolbutamide 318 33.4.1 Animal data 318 33.4.2 Transplacental access to the human fetus 318 33.4.3 Adverse effects on the fetus 319 33.5 The relevance of glucose control in pregnancy 319 33.6 Reports not included 320 33.7 Conclusion 321

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34 Prostaglandins 323 34.1 Introduction 323 34.2 Human case reports 323 34.3 Negative human studies 325 34.4 Animal data 325 35 Cytotoxic and Immunosuppressive Agents 327 35.1 Introduction 327 35.2 Anthracyclines 327 35.3 Azathioprine 328 35.4 Busulphan 328 35.5 Chlorambucil 328 35.5.1 Animal data 329 35.5.2 Human reports 329 35.6 Cyclophosphamide (also 4-hydroxycyclophosphamide; dechlorocyclophos- phamide) 330 35.6.1 Animal data 330 35.6.2 Human reports 330 35.6.3 Mutagenesis 332 35.7 Cyclosporin 333 35.7.1 Human experience 333 35.7.2 Pharmacokinetics 334 35.8 Cytosine arabinoside 335 35.9 Methotrexate and aminopterin 335 35.9.1 Introduction 335 35.9.2 Animal data 336 35.9.3 Human embryotoxicity 336 35.10 Podophyllin 337 35.10.1 Negative report 338 35.11 Procarbazine 338 35.11.1 Human case reports 338 35.12 Combined cytotoxic chemotherapy 338 35.13 Pregnancy outcome in patients undergoing immunosuppressive therapy 342 35.14 Acute leukemia in pregnancy 343 35.15 Chemotherapy of gestational trophoblastic tumours 344 35.16 Parenthood in male homograft recipients 344 APPENDIXES Appendix I Abnormal fetal genitourinary system development associated with drugs 349 Appendix II Drugs associated with polydactyly and syndactyly 363 Appendix III Reported association of congenital abnormalities of bones and intrauterine drug exposure 369 Appendix IV Limb reduction deformities associated with drug exposure in utero 385 Appendix V Drug-related anencephaly, exencephaly and spina bifida in hu- mans 395 Appendix VI Human congenital cardiac defects that have been associated with drug exposure in utero 401 Appendix VII Drugs associated with congenital hearing loss and/or microtia 427 Appendix VIII Drugs associated with congenital ocular defects 435

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Appendix IX Drugs associated with oral clefts 447 Appendix X X-irradiation 461 Appendix XI Behavioural teratology 467 Appendix XII The kinetics of drugs during pregnancy - general principles 471 Appendix XIII Evaluation and prediction of drug safety in pregnancy 475 Appendix XIV Attempted suicide with drugs in pregnancy 485 Index of Drugs Index of Side Effects 491 497