Drugs During Pregnancy and Lactation
Prelims-N52072.qxd 5/24/07 7:46 PM Page i
This page intentionally left blank
Drugs During Pregnancy
and Lactation
Treatment options and
risk assessment
Second edition
Edited by
Christof Schaefer, Paul Peters, and Richard K. Miller
AMSTERDAM • BOSTON • HEIDELBERG • LONDON • NEW YORK • OXFORD
PARIS • SAN DIEGO • SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO
Academic Press is an imprint of Elsevier
Prelims-N52072.qxd 5/24/07 7:46 PM Page iii
Academic Press is an imprint of Elsevier
84 Theobald’s Road, London WC1X 8RR, UK
30 Corporate Drive, Suite 400, Burlington, MA 01803,USA
525 B Street, Suite 1900, San Diego, California 92101-4495, USA
First edition 2001
Second edition 2007
Copyright © 2001, 2007 Elsevier BV.All rights reserved
No part of this publication may be reproduced, stored in a retrieval system or transmitted
in any form or by any means electronic, mechanical, photocopying, recording or otherwise
without the prior written permission of the publisher
Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in
Oxford, UK: phone (+44) (0) 1865 843830; fax (+44) (0) 1865 853333; email:
Alternatively you can submit your request online by visiting the Elsevier web site at
and selecting
Obtaining permission to use Elsevier material
Notice

toxicology 9
1.6 Effects and manifestations 10
1.7 Pharmacokinetics in pregnancy 12
1.8 Passage of drugs to the unborn and fetal kinetics 13
1.9 Causes of developmental disorders 14
1.10 Embryo/fetotoxic risk assessment 15
1.11 Classification of drugs used in pregnancy 19
1.12 Paternal use of medicinal products 20
1.13 Communicating the risk of drug use in pregnancy 21
1.14 Risk communication prior to pharmacotherapeutic choice 22
1.15 Risk communication regarding the safety (or otherwise) of drugs
already used in pregnancy 23
1.16 Teratology information centers 24
2
Specific drug therapies during pregnancy
2.1 Analgesics and anti-inflammatory drugs 28
Minke Reuvers and Christof Schaefer
2.1.1 Paracetamol (acetaminophen) 28
2.1.2 Aspirin (acetylsalicylic acid) 29
2.1.3 Pyrazolone derivatives 32
2.1.4 Combination analgesic preparations 32
2.1.5 Opioid analgesics in general 33
2.1.6 Morphine 33
2.1.7 Codeine 34
Prelims-N52072.qxd 5/24/07 7:46 PM Page v
2.1.8 Pethidine (meperidine) 34
2.1.9 Fentanyl, alfentanil, remifentanil, and sufentanil 36
2.1.10 Other narco-analgesics and centrally acting analgesics 37
2.1.11 Naloxone 38
2.1.12 Nonsteroidal anti-inflammatory drugs (NSAIDs) 38

2.3.12 Non-selective β-adrenergic agonists 73
2.4 Antiemetics 78
Lee H. Goldstein and Matitiahu Berkovitch
2.4.1 Nausea and vomiting in pregnancy 78
2.4.2 Diet manipulations and treatment 79
2.4.3 Complementary treatment options 80
2.4.4 Acupuncture and acupressure 81
2.4.5 Hypnosis 82
2.4.6 Ginger 82
vi Contents
Prelims-N52072.qxd 5/24/07 7:46 PM Page vi
2.4.7 Antihistamines (H
1
-blockers) 83
2.4.8 Dopamine antagonists 85
2.4.9 Pyridoxine (vitamin B
6
)86
2.4.10 Thiamine (vitamin B
1
)87
2.4.11 Serotonin antagonists 87
2.4.12 Glucocorticoids 88
2.4.13 Other agents with antiemetic properties 89
2.5 Gastrointestinal and antilipidemic agents and spasmolytics 94
Margreet Rost van Tonningen
2.5.1 Gastritis and peptic ulcer during pregnancy 94
2.5.2 Antacids and sucralfate 95
2.5.3 H
2

2.6.3 Other β-lactam antibiotics and β-lactamase inhibitors 126
2.6.4 Macrolide antibiotics 126
Contents vii
Prelims-N52072.qxd 5/24/07 7:46 PM Page vii
2.6.5 Lincomycin and clindamycin 128
2.6.6 Tetracyclines 128
2.6.7 Sulfonamides, trimethoprim, atovaquone, and pentamidine 129
2.6.8 Quinolones 131
2.6.9 Nitrofurantoin and other drugs for urinary tract infections 132
2.6.10 Aminoglycosides 133
2.6.11 Chloramphenicol 134
2.6.12 Metronidazole and other nitroimidazole antibiotics 135
2.6.13 Polypeptide antibiotics 136
2.6.14 Antimycotics in general 136
2.6.15 Nystatin 137
2.6.16 Clotrimazole and miconazole for topical use 137
2.6.17 Other local “conazole” antimycotics 138
2.6.18 Other local antimycotics 138
2.6.19 “Conazole” antimycotics for systemic use 139
2.6.20 Amphotericin B 140
2.6.21 Flucytosine 141
2.6.22 Griseofulvin 142
2.6.23 Terbinafine 142
2.6.24 Malaria prophylaxis and therapy in pregnancy 143
2.6.25 Chloroquine 144
2.6.26 Proguanil 144
2.6.27 Mefloquine 145
2.6.28 Pyrimethamine, sulfadoxine and dapsone 146
2.6.29 Quinine 147
2.6.30 Halofantrine 148

Paul Peters
2.7.1 Vaccination and pregnancy 179
2.7.2 Cholera vaccine 180
2.7.3 Hemophilus influenza b (HIB) vaccine 180
2.7.4 Hepatitis A vaccine 180
2.7.5 Hepatitis B vaccine 181
2.7.6 Human Papilloma Virus (HPV) vaccine 182
2.7.7 Influenza vaccine 182
2.7.8 Measles and mumps vaccines 183
2.7.9 Meningococcal meningitis vaccine 184
2.7.10 Pneumococcal vaccination 184
2.7.11 Poliomyelitis vaccine 184
2.7.12 Rabies vaccine 185
2.7.13 Rubella vaccine 186
2.7.14 Tetanus and diphtheria vaccines 187
2.7.15 Typhoid vaccine 187
2.7.16 Varicella vaccine 188
2.7.17 Yellow fever vaccine 189
2.7.18 Immunoglobulins 189
2.8 Heart and circulatory system drugs and diuretics 193
Corinna Weber-Schöndorfer
2.8.1 Arterial hypertension and pregnancy 194
2.8.2 α-methyldopa 195
2.8.3 β-adrenergic receptor blockers 196
2.8.4 Hydralazine and dihydralazine 198
2.8.5 Nifedipine and other calcium antagonists 200
2.8.6 ACE inhibitors 203
2.8.7 Angiotensin-II receptor antagonists 205
2.8.8 Clonidine 207
2.8.9 Diazoxide 208

2.9.8 Fibrinolysis 247
2.9.9 Streptokinase 247
2.9.10 Other fibrinolytics 248
2.9.11 Inhibitors of fibrinolysis 249
2.9.12 Volume expanders 249
2.10 Antiepileptics 254
Elisabeth Robert-Gnansia and Christof Schaefer
2.10.1 Epilepsy and antiepileptic drugs in pregnancy 255
2.10.2 Benzodiazepines 257
2.10.3 Carbamazepine 260
2.10.4 Ethosuximide and other succimides 261
2.10.5 Oxazolidine anticonvulsants 262
2.10.6 Phenobarbital and primidone 263
2.10.7 Phenytoin 266
2.10.8 Sultiam 268
2.10.9 Valproic acid 269
x Contents
Prelims-N52072.qxd 5/24/07 7:46 PM Page x
2.10.10 Felbamate 273
2.10.11 Gabapentin 273
2.10.12 Lamotrigine 274
2.10.13 Levetiracetam 276
2.10.14 Oxcarbazepine 277
2.10.15 Pregabalin 278
2.10.16 Tiagabine 278
2.10.17 Topiramate 279
2.10.18 Vigabatrin 279
2.10.19 Zonisamid 280
2.11 Psychotropic drugs 288
Hanneke Garbis and Patricia R. McElhatton

Contents xi
Prelims-N52072.qxd 5/24/07 7:46 PM Page xi
2.13 Antineoplastic drugs 335
Corinna Weber-Schöndorfer and Christof Schaefer
2.13.1 Cancer and pregnancy 335
2.13.2 Classification of the drugs used for chemotherapy 338
2.13.3 Vinca alkaloids and structural analogs 339
2.13.4 Podophyllotoxin derivatives 340
2.13.5 Nitrogen mustard agents 340
2.13.6 Nitrogen mustard analogs 341
2.13.7 Other alkylating agents 342
2.13.8 Cytotoxic anthracycline antibiotics 343
2.13.9 Other cytotoxic antibiotics 345
2.13.10 Folate antagonistic antimetabolites 346
2.13.11 Purine-derived antimetabolites (purine antagonists) 349
2.13.12 Pyrimidine-derived antimetabolites (pyrimidine antagonists) 350
2.13.13 Taxanes 352
2.13.14 Platin compounds 352
2.13.15 Other antineoplastic drugs 354
2.13.16 Enzymes and antibodies exerting antineoplastic effects 355
2.13.17 Antineoplastic drugs with endocrine effects 357
2.13.18 Cytostatic drugs of plant origin 358
2.13.19 Occupational handling of cytostatic drugs 358
2.14 Uterine contraction agents, tocolytics, vaginal therapeutics,
and local contraceptives 368
Herman van Geijn
2.14.1 Prostaglandins 368
2.14.2 Oxytocin 371
2.14.3 Ergot alkaloids (see also Chapter 2.1) 372
2.14.4 Tocolytics in general 372

2.15.16 Antiestrogens, antiandrogens, and danazol 409
2.15.17 Mifepristone (RU486) 410
2.15.18 Clomiphene 411
2.16 General and local anesthetics and muscle relaxants 423
Asher Ornoy
2.16.1 Halogenated inhalation agents for general anesthesia 424
2.16.2 Ether (diethyl ether) 426
2.16.3 Nitrous oxide 427
2.16.4 Injectable anesthetics 427
2.16.5 Local anesthetics 431
2.16.6 Epidural and spinal analgesia/anesthesia in pregnancy 432
2.16.7 Muscle relaxants 433
2.16.8 Occupational exposure to inhalation anesthetics 434
2.17 Dermatological medications and local therapeutics 441
Paul Peters and Christof Schaefer
2.17.1 Typical skin changes during pregnancy 441
2.17.2 Anti-infective agents 442
2.17.3 Antiseptics and disinfectants 444
2.17.4 Astringents 447
2.17.5 Polidocanol 448
2.17.6 Camphor and menthol 448
2.17.7 Coal tar and slate oil preparations 448
2.17.8 Local immunomodulators and neurodermatitis therapy 449
2.17.9 Keratolytics 449
2.17.10 Retinoids for acne and psoriasis therapy 452
2.17.11 Photochemotherapy and fumaric acid 456
2.17.12 Sex hormones and cyproterone acetate 456
2.17.13 5-Fluorouracil 457
Contents xiii
Prelims-N52072.qxd 5/24/07 7:46 PM Page xiii

2.18.10 Vitamin E (tocopherol) 476
2.18.11 Vitamin K 476
2.18.12 Multivitamin preparations 477
2.18.13 Iron 477
2.18.14 Calcium 478
2.18.15 Fluoride 479
2.18.16 Strontium 479
2.18.17 Biphosphonates and other osteoporosis drugs 480
2.18.18 Iodide 481
2.18.19 Trace elements 481
2.19 Herbs during pregnancy 485
Henry M. Hess and Richard K. Miller
2.19.1 The safety of herbs during pregnancy 485
2.19.2 Counseling a pregnant woman about herbs 486
2.19.3 General concepts regarding the use of herbs during
pregnancy 488
2.19.4 Herbs used as foods 489
2.19.5 Essential oils that are safe during pregnancy 489
2.19.6 Herbs frequently used during pregnancy 490
2.19.7 Herbs controversially used during pregnancy 491
2.19.8 Herbs contraindicated during pregnancy 491
xiv Contents
Prelims-N52072.qxd 5/24/07 7:46 PM Page xiv
Contents xv
2.20 Diagnostic agents 502
Elisabeth Robert-Gnansia
2.20.1 X-ray examinations 502
2.20.2 Ultrasound 505
2.20.3 Magnetic resonance imaging 506
2.20.4 Barium sulfate 507

2.23.3 Chloroprene (chlorbutadiene) 574
2.23.4 Cyanide 575
2.23.5 Photographic/printing chemicals 575
Prelims-N52072.qxd 5/24/07 7:46 PM Page xv
2.23.6 Pesticides 576
2.23.7 Phenoxyacetic acid derivatives and chlorinated
dibenzo-dioxins 581
2.23.8 Metals 583
2.23.9 Hazardous waste landfill sites 590
2.23.10 Radiation associated with the nuclear industry 592
2.23.11 Video display terminals (VDTs) 594
2.23.12 Mobile phones 596
2.23.13 Other sources of electromagnetic radiation 596
2.23.14 Electric shocks and lightning strikes 598
3
General commentary on drug therapy and drug risk
during lactation
Ruth Lawrence and Christof Schaefer
3.1 The advantages of breastfeeding versus the risks of maternal
medication 609
3.2 The passage of medications into the mother’s milk 612
3.3 Infant characteristics 613
3.4 Milk plasma ratio 614
3.5 Amount of medication in the milk and relative dose 615
3.6 Toxicity of medications in the mother’s milk 617
3.7 Medications that affect lactation 619
3.8 Breastfeeding support 620
4 Specific drug therapies during lactation
Christof Schaefer and Ruth Lawrence
4.1 Analgesics, antiphlogistics and anesthetics 623

4.2.10 Antitussives 644
4.3 Gastrointestinal drugs 648
Christof Schaefer
4.3.1 Antacids 648
4.3.2 H
2
-receptor blockers and other ulcer therapeutics 649
4.3.3 Peristaltic stimulators 650
4.3.4 Cholinergics 651
4.3.5 Anticholinergic spasmolytics 652
4.3.6 Laxatives 652
4.3.7 Agents used for chronic inflammatory bowel diseases 653
4.3.8 Antidiarrheals for acute diarrhea 654
4.3.9 Carminatives 654
4.3.10 Lipid reducers 655
4.3.11 Chenodeoxycholic acid and ursodeoxycholic acid 655
4.3.12 Appetite suppressants 656
4.3.13 Antiemetics 656
4.4 Anti-infectives 659
Christof Schaefer
4.4.1 Antibiotics in general 660
4.4.2 Penicillins, cephalosporins, and other β-lactam antibiotics 660
4.4.3 Erythromycin and other macrolides 661
4.4.4 Tetracyclines 662
4.4.5 Dapsone, nitrofurantoin, and other drugs for urinary
tract infections 662
4.4.6 Quinolones 663
4.4.7 Other antibiotics and urinary tract antiseptics 664
4.4.8 Nitroimidazole antibiotics 665
4.4.9 Aminoglycoside antibiotics 665

4.6.8 Dihydroergotamine and other antihypotensives 686
4.6.9 Digitalis 686
4.6.10 Antiarrhythmics 687
4.6.11 Diuretics 690
4.6.12 Circulatory drugs and vasodilators 691
4.7 Anticoagulants and fibrinolytics 695
Christof Schaefer
4.7.1 Heparin 695
4.7.2 Vitamin K antagonists (coumarin derivatives and 696
indanediones)
4.7.3 Other anticoagulants 696
4.7.4 Fibrinolytics 697
4.8 Antiepileptics 699
Christof Schaefer
4.8.1 Carbamazepine 700
4.8.2 Clobazam and clonazepam 700
xviii Contents
Prelims-N52072.qxd 5/24/07 7:46 PM Page xviii
4.8.3 Ethosuximide and mesuximide 701
4.8.4 Phenobarbitone (phenobarbital), primidone, and 701
barbexaclone
4.8.5 Phenytoin 702
4.8.6 Valproic acid 702
4.8.7 Recommendations: classical anticonvulsants 703
4.8.8 Gabapentin 703
4.8.9 Lamotrigine 704
4.8.10 Levetiracetam 704
4.8.11 Oxcarbazepine 704
4.8.12 Topiramat 705
4.8.13 Vigabatrin 705

Prelims-N52072.qxd 5/24/07 7:46 PM Page xix
4.11.7 Corticosteroids 752
4.11.8 Adrenaline 753
4.11.9 Insulin and oral antidiabetics 754
4.11.10 Estrogens, gestagens, and hormonal contraceptives 755
4.11.11 Androgens and anabolics 757
4.11.12 Cyproterone acetate and other sex-hormone inhibitors 757
4.11.13 Prostaglandins 758
4.12 Dermatological drugs and local therapeutics 762
Ruth Lawrence and Christof Schaefer
4.12.1 General aspects of external applications: cosmetics, hair
products, sunscreens 762
4.12.2 Medications for lice and scabies 763
4.12.3 Treatments for acne and psoriasis 765
4.12.4 Other dermatological medications 766
4.12.5 Eye, ear, and nose drops 766
4.12.6 Vaginal therapeutics 767
4.12.7 Vein therapeutics and other local therapeutics 768
4.13 Alternative remedies, vitamins, and minerals 771
Ruth Lawrence and Christof Schaefer
4.13.1 Alternative remedies and phytotherapeutics 771
4.13.2 Herbal galactogogues and anti-galactogogues 773
4.13.3 Topical treatment for breast problems 775
4.13.4 Vitamins, minerals, and trace elements 775
4.13.5 Bisphosphonates 776
4.13.6 Exercise 777
4.13.7 Glucose 6-phosphate-dehydrogenase deficiency 777
4.14 Diagnostics 779
Ruth Lawrence and Christof Schaefer
4.14.1 X-ray studies, ultrasound, and magnetic resonance 779

4.17 Plant toxins 808
Ruth Lawrence and Christof Schaefer
4.18 Industrial chemicals and environmental contaminants 810
Christof Schaefer
4.18.1 Persistent organochlorine compounds (pesticides,
polychlorinated biphenyls and dioxins) 811
4.18.2 Mercury 816
4.18.3 Lead 818
4.18.4 Cadmium 819
4.18.5 Other contaminants 820
4.18.6 Breastfeeding despite environmental contaminants? 821
4.18.7 Breastfeeding and the workplace 822
Appendix A:Teratology information services and centers 827
Appendix B: Addresses for breastfeeding support 839
Subject index 853
Contents xxi
Prelims-N52072.qxd 5/24/07 7:46 PM Page xxi
List of contributors
MATITIAHU BERKOVITCH
Drug Information Center, Assaf Harofeh Medical Center, 70300
Zerifin, Israel
HANNEKE GARBIS
Teratology Information Service, National Institute of Public
Health and Environment, PO Box 1, 3720 BA Bilthoven,
The Netherlands
LEE H. GOLDSTEIN
Internal Medicine Department C, Haemek Medical Center, Afula
18101, Israel
HENRY M. HESS
Department of Obstetrics and Gynecology, University of Rochester,

Servicio de Informacion sobre Teratogenos (SITTE), Sección de
Teratología Clínica,
Centro de Investigacion sobre, Anomalias Congenitas (CIAC),
Instituto de Salud Carlos III, c/ Sinesio Delgado 6 (Pabellon 6),
28029 Madrid, Spain
MARGREET ROST VAN TONNINGEN
Teratology Information Service, National Institute of Public Health
and Environment, PO Box 1, 3720 BA Bilthoven, The Netherlands
CHRISTOF SCHAEFER
Pharmakovigilanz- und Beratungszentrum für Embryonaltoxikologie,
Berlin Institute for Clinical Teratology and Drug Risk Assessment
in Pregnancy, Spandauer Damm 130, Haus 10, 14050 Berlin,
Germany
HERMAN VAN GEIJN
Department of Obstetrics and Gynaecology, VU University
Medical Center, PO Box 7057, 1007 MB Amsterdam,
The Netherlands
CORINNA WEBER-SCHÖNDORFER
Pharmakovigilanz- und Beratungszentrum für Embryonaltoxikologie,
Berlin Institute for Clinical Teratology and Drug Risk Assessment
in Pregnancy, Spandauer Damm 130, Haus 10, 14050 Berlin,
Germany
List of contributors xxiii
Prelims-N52072.qxd 5/24/07 7:46 PM Page xxiii
Preface
Physicians and all health care providers who care for women in
their reproductive years are frequently asked by concerned women
who are planning a pregnancy, are pregnant or breastfeeding about
the risk of medicinal products for themselves, their unborn or
breastfed infant. These Dermatologists, Family Medicine physicians,

and environmental contaminants, herbs, supplements and breastfeed-
ing during infectious diseases are discussed in detail.
The second edition has had major revisions throughout, most
sections were completely rewritten. The content has been adapted
for an international readership. Two additional editors were enlisted;
Prelims-N52072.qxd 5/24/07 7:46 PM Page xxiv