A Teaching and Learning Resource in Maternal Health

PO Box 20559

Nimbin NSW 2480

Australia

 

Maxwell Brinsmead MB BS PhD

 

Phone +61 409 870 346

Retired Obstetrician & Gynaecologist

 

E-mail max@brinsmead.net.au

 

 

Website www.brinsmead.net.au

 

 

DRUGS IN PREGNANCY - WHAT IS SAFE?

 

It is important to recognise that pregnancy is a symptom-producing event. The first responsibility of the physician is to communicate to the patient, her family and the general public, the risk of unlimited self-administration of over-the-counter drugs and to explain the essentially physiological nature of many of the discomforts which arise during pregnancy. Non-pharmacological methods should be used to overcome problems wherever possible before reaching for the prescription pad. Simple home remedies, herbal medicines etc. may be appropriate. However, take care not to overlook widely accepted and safe drugs in favour of an exotic compound of unknown constituents, potency and teratogenic potential.

 

There is now a body of evidence to suggest that quite a number of drugs can be safely used in pregnancy when the need arises. A list is provided in the Table below. In general, drugs regarded as safe in pregnancy are Category A drugs, i.e., "which have been taken by a large number of pregnant women ... without any proven increase in the frequency of malformations or other ... harmful effects on the fetus being observed".


Listed also within the column "Acceptable Drugs" are those which may be assumed with a high degree of probability to have been taken by a large number of pregnant women without demonstrable effect. Animal studies may have shown evidence of teratogenicity for some of these but their relevance to the human situation is suspect. Also, the therapeutic potential of the drug in the appropriate clinical context outweighs their risk.

 

Listed in the column "Drugs to Avoid" are those which are known to be teratogenic or for which there is insufficient data available to provide unqualified reassurance. Alternatively there are safer drugs that may be used for a particular clinical problem.

 

Personal preferences of the author - no liability accepted. The Australian Drug Evaluation Committee Category is given in brackets

 

Problem

Drugs which are Safe

Drugs which are Acceptable

Drugs to Avoid where Possible

 

Acne

 

Topical Erythromycin,

Clindamycin (A)

 

Topical Vitamin A

 

Systemic Retinoids (X)

Tetracyclines (D)

 

Allergy

 

Doxylamine (A)

Pheniramine (A)

Diphenhydramine (A)

Dexchlorpheniramine (A)

 

Loratadine (B1)

Fexofenadine (B2)

Methdilazine (B2)

Beclomethazone Nasal (B3)

Cetirizine (B2)

 

Livostin Nasal Spray (B3)

Promethazine (C)

Trimeprazine (C)

 

Anaerobic infections

 

Clindamycin (A)

 

Metronidazole (B2)1

 

 

 

Anaesthesia

 

Most local and general anaesthetics when indicated

 

Avoid large doses of local anaesthetic in labour

 

Ketamine (B3)

Methoxyflurane (C)

Propofol (C)

 

Analgesia

 

Paracetamol (A)

Codeine (A)

 

Narcotics (C)

 

Aspirin in large doses (C)

NSAIDs (C)

 

Anticoagulation

 

Low MW Heparins

 

Heparin (C)

 

Warfarin (D)

 

Anxiety

 

Buspirone (Buspar) (B1)

 

Benzodiazepines (C)3

 

 

 

Asthma

 

Betamimetics (A)

Theophylline (A)

Sodium cromoglycate (A)

Inhaled steroids (A)

 

Oral or injected Steroids (A)

 

 

Autoimmune disease

 

 

Oral or injected steroids (A)

 

Prednisone (A)

 

Cyclosporin (C)

 

Azothioprine (D)

 

Cellcept (D)

 

Doxorubicin (D)

 

Leflunomide (X)

 

 

Chest Infection

 

Amoxycillin (A)

Cephalosporins (A)

Erythromycin (A)

 

Trimethoprim (B3)1

Sulphonamides (C)2

Clavulanic acid (B1)

Roxithromycin (B1)

 

Tetracyclines (D)

Chloramphenicol (C)

 

Constipation

 

Bulk forming laxatives

Faecal softening agents

 

 

 

Bowel stimulating agents

eg Danthron, Senna (A), Agarol

 

Depression4

 

 

 

Moclobemide (B3)

MAO Inhibitors (B3)

 

Tricyclics (C)2

Fluoxetine (C)6

 

Sertraline (C)5

Paroxetine (D)5

 

Diabetes

 

Insulin

 

Metformin (C)

Gybenclamide (C)

 

 

 

Diarrhoea

 

Kaolin, Kaomagma, Kaopectate

 

 

Codeine (A)

Sulfasalazine (A) for Crohns

 

Diphenyloxalate ie Lomotil (C)

Loperamide, Hyoscyamine (B3)

 

Epilepsy

 

 

 

Carbamazepine (D)

Clonazepam (C)

Lamotrigine (C)

Phenobarbitone (D)

 

 

Sodium valproate (D)

Ethosuximide (D)

Phenytoin (D)

 

 

 

Fungal infections (incl Candida)

 

Nystatin (A)

Clotrimazole Topical (A)

Miconazole (A)

Econazole (A)

 

Isoconazole (B2)

 

Griseofulvin (B3)

Ketoconazole (B3)

Amphotericin (B3)

Fluconazole (D)

 

Heartburn

 

Most antacids

 

Cimetidine, Ranitidine (B1)

Cisapride, Sucralfate (B1)

 

Bismuth subcitrate (B2)

 

Hyperemesis (Vomiting or Nausea)

 

Pyridoxine

Diphenhydramine ie Benadryl (A)

Dimenhydrinate ie Dramamine (A)

Metoclopramide (A)

 

Ondansetron (B1)

Prochlorperazine (C)2

Promethasine (C)2

Hyoscine (B2) by patch

 

 

 

Hypertension

 

Methyldopa (A)

 

Prazosin (B2)

Labetalol (C)

Oxyprenolol (C)

Most other beta blockers (C)

Clonidine (B3)

 

ACE Inhibitors (D)

Propranolol (C)

Thiazide diuretics (C)

Ca channel blockers (C)

Atenalol

 

 

Hyperlipidaemia

 

 

 

 

 

Lipid lowering agents (D)

 

Insomnia

 

Horlicks in hot milk

 

Benzodiazepines (C)3

Chlormethiazole (A)

Chlorpromazine (C)

Amytriptyline (C)

 

Barbiturates (C)

Paraldehyde (D)

 

Lice

 

Hair condtioners

 

Maldison, Permethrin (B2)

 

 

 

Malaria (incl. prophylaxis)

 

Chloroquine (A - for malaria otherwise D) or

Hydroxychloquine

 

 

Mefloquine1

Daraprim, Maloprim (B3)1

 

Malarone (Proguanil) (B2)

Fansidar (C)2

Doxycycline (D)

 

 

Migraine

 

Paracetamol (A)

Codeine (A)

 

Sandomigran (B1)

Sumatriptan (B3)

Narcotics (A)

 

Ergot alkaloids (C)

Methysergide (C)

 

Pruritis and Dermatoses

 

Topical steroids (A)

Calamine, Pinetarsol

Diphenylhydramine (A)

 

Loratidine (B1)

Promethazine (C)

 

Psychosis

 

 

 

Phenothiazines (C)

Haloperidol etc (C)

 

Lithium salts (D)

 

Scabies

 

Benzyl benzoate (B2)

Permethrine (B2)

 

 

 

 

 

 

Thyroid diseases

 

Thyroxine (A)

 

Propylthiouracil (C)

Carbimazole (C)

 

Radioactive iodine (D)

Iodides

 

Trichomonas

 

 

 

Metronidazole (B2)1

 

 

 

Upper Respiratory Tract Infection (URTI)

 

Paracetamol (A)

Diphenhydramine (A)

Pholcodine (A)

 

Ephedrine (A)

 

Promethazine(C)

Aspirin (C)

Iodide containing expectorants

Decongestant nasal sprays

 

Urinary Tract Infections

 

Cephalexin

Amoxicillin (A)

Clavulinic acid (A)

Nitrofurantoin (A)

 

Trimethoprim (B3)1

Sulphonamides (C)2

 

 

Tetracyclines (D)

Aminoglycosides (D)

 

Vaccination

 

Tetanus

Influenza (B1)

Polio (A)

Quadrivalent HPV

 

BCG

Cholera

Diphtheria

Hepatitis B

Pertussis

Rabies

Rotavirus (B2)

 

 

Rubella

Measles

Mumps

Smallpox

Varicella

 

Vaginosis (Gardnerella)

 

Topical Clindamycin (A)

 

Metronidazole (B2)1

 

 

 

Viral Infections

 

 

 

Famciclor (B1)

Acyclovir (B3), Valaciclovir (B2)

 

Podophyllin

Idoxuridine (B3)

Ganciclovir (D)

Ribavarin (X)

 

Vitamins

 

Vitamins B, C & E

 

Vitamin K

 

Vitamins A & D in large doses

 

Warts

 

 

 

 

Podophyllin (D)

 

Worms

 

Pyrantel embonate (B2)

 

Mebendazole (B3)

 

Albendazole (D)

 

NSAID = Nonsteroidal anti-inflammatory drugs

1These drugs are best avoided in the first trimester

2These drugs are best avoided in the third trimester

3For short term use only

4Considerable controversy still current, but overall Tricyclics are still regarded as having lower risk in pregnancy than SSRIs

5Some rare defects so the absolute risk is small (NEJM 06.2007)

6Fluoexetine is the SSRI with the lowest known risk in pregnancy

 

 

Notes

 

The administration of drugs to women in pregnancy receives closer scrutiny than perhaps any other field of therapeutics. The epidemic of thalidomide-affected children in the early 1960s focussed the attention of both medical and public minds on the potential for a drug that was administered to the mother to have profound and long lasting effects on the fetus and child. This experience illustrates several important principles. First, thalidomide was administered for the improvement of maternal wellbeing but the condition for which it was mostly prescribed is a physiological side effect of pregnancy and drug treatment is required only occasionally. Secondly, its potential for fetal effects is limited to and dependent upon a unique stage of fetal development. Thirdly, the pathogenic effect on the fetus was quite unexpected.

 

From this experience, therefore, arises three important principles that should guide the practitioner in the use of drugs in pregnancy:

 

     Use drugs only when the potential risk to the fetus is outweighed by the proven needs or benefit to the mother.

     It is important to avoid any drug with a teratogenic potential in that period of gestation when organogenesis is occurring, i.e. essentially the first trimester.

     It is best to use drugs which have been tested by time and repeated use in human pregnancy.

 

No Placental Barrier

 

With the exception of a few large molecular weight substances such as heparin it is clear that most drugs and chemical substances administered to the mother cross the placenta to some extent unless destroyed or altered during passage. This placental transport is established at about the fifth week of fetal life. Substances of low molecular weight diffuse freely across the placenta, driven primarily by the concentration gradient. Almost every substance used for therapeutic purposes can, and does, pass from the mother to the fetus and we must discard the concept that there is a placental barrier.

 

Malformations

 

Experiments with animals have provided considerable information concerning the teratogenic effects of drugs. Unfortunately, these experimental findings cannot always be extrapolated from species to species, or even from strain to strain within the same species, much less from animals to humans. While all drugs which have proven teratogenic for women have also been teratogenic in animals at the same dose and with the defects the reverse is not true. This has led in the past to considerable unnecessary anxiety. Two good examples of this are corticosteroids and benzodiazepines which cause oral clefts in animals but have no such effect on the human fetus.

 

The prediction of toxicity to the human fetus are further hampered by a lack of specificity between cause and effect. Traditionally, teratogenic effects of drugs have been noted as anatomic malformations. It is clear that these are dose and time related and that the fetus is at greatest risk during the first three months of gestation. However, it is possible for drugs and chemicals to exert their effects upon the fetus at any time. Evidence exists that intellectual, social and functional development can be affected when drugs are used at times other than the first trimester.

 

Principles of Counselling after Exposure to Potential Teratogenic Drugs

 

From a practical point of view, the physician is usually confronted by two problems with respect to drugs during pregnancy:

 

1. The woman who reports the ingestion of a drug (often before she recognises that she is pregnant) and asks about its teratogenic potential.

 

2. Some coincidental or intrinsic problem of pregnancy for which the physician is responsible for choosing a safe drug to use.

 

For a patient who has already taken a drug the following points are worth noting:

 

     Allow sufficient time to deal with the problem. It may be better to schedule another appointment to talk with both parents at some length. This also gives an opportunity to seek good information on the teratogenic potential of the drug in question. Good sources of information are listed at the conclusion of this chapter.

     Collect a detailed history of the nature, timing, dose and duration of the exposure. At the undifferentiated stage of zygote proliferation and before implantation, exposure to a teratogen usually either kills the fertilised ovum or spares it completely. Carefully explain the importance of timing of the exposure to patients.

     It may be important to collect a detailed family history since this may uncover other risk factors for malformation.

     Explain the usual malformation rate which is at least 2% of all births if only major malformations are considered and 4% if minor malformations are taken into account.

     Discuss the available data on the drugs in question, their reliability and relevance in the particular situation. For this the physician needs a capacity to evaluate available data. The product information which is supplied by the manufacturers of drugs often states that a drug is not recommended for use in pregnancy. This usually means that there is insufficient data to be sure that the drug is safe. A careful analysis of animal studies, case reports and, most importantly, epidemiological studies is important. All this must be put into terms that patients can understand.

     If necessary, seek further advice or information so that the available data is put into perspective.

 

In most instances the advice can be reassuring but occasionally other prenatal tests, for example, ultrasound examination, may be considered. Ultrasound, however, will only be useful if the malformation involved can be detected by this means and the pregnancy has reached a stage where a morphometric analysis is possible. It is inappropriate to blandly promise ultrasound to a woman who is worried about some drug ingestion when the pregnancy has only just been detected. Often with appropriate information, firm reassurance can be given and this is preferable to waiting 16 weeks for a scan!

 

In the final analysis, there are only two options: continuation of the pregnancy or termination. Having obtained the best available estimate of risk, the most important role of the counsellor is to put the risk clearly in perspective, to allow the patient to make her own choice regarding termination or otherwise and to provide the support and follow-up that is required by that family, whichever option is chosen.

 

Risk Factor Categorisation

 

A number of authorities have produced guides to the use of drugs in pregnancy which categorise the agents according to the degree of knowledge concerning their effects. Such categorisation requires constant updating. The Australian Drug Evaluation Committee (ADEC) classifies drugs in five separate categories from A to D (plus X) and the second category B is further divided into 3 subgroups. This is useful because it distinguishes fetal effects which are usually reversible from known and possible teratogenic effects which are irreversible. However, unlike the US Food and Drug Administration, the ADEC system does not specifically address the potential benefit to the mother from certain drugs which may need to be used for a very serious or life threatening disorder.

 

Most manufacturers assign their own classification to their own drugs and, in the case of new agents, they usually err firmly on the side of caution. As a result many a woman has been unnecessarily alarmed by direct or indirect consultation with a manufacturer's recommendations concerning a certain drug.

 

Resources

 

A Counselling Service, called Mothersafe, for mothers and their doctors is available from the Royal Hospital for Women, Randwick

 

Phone 1 800 647 848 See also http://www.mothersafe.org.au

 

References and Further Reading

 

1.   http://www.tga.gov.au/hp/medicines-pregnancy.htm#searchname

2.   Drugs in Pregnancy and Lactation. A reference guide to fetal and neonatal risk. Authors: Briggs GG, Freeman RK and Yaffe SJ. Williams and Wilkins, Baltimore.

 

3. Koren G, Pastuszak A and Ito S: Drugs in Pregnancy. New Eng J Med, 338:1128, 1998.

 

4. Stanley FJ and Bower C: Teratogenic drugs in pregnancy. Med J Aust, 145:596, 1986.

 

5. Rubin PC: Drugs in pregnancy and lactation. Medicine International, 60:2485, May 1989.

 

6. Hawkins DF and Tebutt H: Drugs in pregnancy. Current Therapeutics, May 1989.

 

7. Medicines in Pregnancy. Australian Drug Evaluation Committee. Third Edition. Australian Government Publishing Service. Canberra, 1996.

 

8. NH&MRC Report. Modification of the "Ten-day Rule" on radiological examination of women. Med J Aust, 142:149, 1985.

 

9. Lione A: Ionizing radiation and human reproduction. Reprod Toxicology, 1:3, 1987.

 

10. Ilett KF, Kristensen JH, Wojnar-Horton RE and Begg EJ: Drug Distribution in Human Milk. Australian Prescriber 20(2):35, 1997.

 

11. NICE Guidelines April 2007 http://guidance.nice.org.uk/CG45/Guidance/pdf/English

 

 

 


 

Known Teratogenic Drugs in Humans

 

Drug Defects observed Risk to infant of exposed mothers

 

Stilboestrolb Vaginal adenocarcinoma

Malformations of male and 22-58%

female genital tracts.

Psychosexual disturbance, Depression

 

Systemic Retinoidsc CNS malformations, CHD,

Facial dysmorphism 40%

 

 

Folic acid antagonistsc NTDs, Craniofacial abnormalities 30%

eg, Methotrexate Limb defects

 

 

Thalidomideb Phocomelia, CHD, gut and 20%

(and structurally-related renal malformations

Immunomodifiers)

 

Cytotoxic agentsc,d, Various effects, IUGR 20%

e.g. Cyclophosphamide

 

Lithiumc CHD, Neonatal effects 2.5%

 

Phenytoinc Dysmorphic facies, hypoplasia distal 3 - 9%

ie Dilantin & most phalanges, IUGR, neonatal bleeding,

anticonvulsants mental retardation

 

Warfarin & similar Dysmorphic facies, CHD, mental 4 - 8%

anticoagulantsc retardation and genital defects

 

Androgenic hormones Masculinization of female 0.3-18%

incl. eg. Danazolc genitalia

19 nortestosterone progestinsb,x

 

Misoprostol Moebius sequence ?>50%

 

Disulfiramc Multiple malformations ?50%

 

Methylene Blueg Intestinal atresia

 

Valproic acid, Carbamazepine Spina bifidaz, ASD, Cleft palate 1-5%

Hypospadias, Polydactyly, Craniosyostosis

 

Lamotrigine Isolated oral cleft malformations ~1%

 

Paroxetine Heart defects Unknown

 

Endothelin Receptor

Antagonists Multiple defects in animals Unknown

 

Tetracyclinesx Dental stainingf, skeletal abnormalities Unknown

Maternal acute fatty liver

 

Antithyroid drugsx Congenital goitre Unknown

 

Iodidesx Congenital goitre Unknown

(including diagnostic agents)

 

Cocainey Renal tract malformations Unknown

 

Ethanol Fetal alcohol syndrome

Neurobehavioural abnormalities Dose dependent

Infarction of digits

 

ACE Inhibitors CHD & CNS abnormalities in 1st trimester 3-fold increased risk

Renal failure &

Fetal death in 2nd & 3rd trimesters

 

NSAIDs Premature closure ductus arteriosus Depends on gestation

 

Flucanazole Craniostenosis, craniofacial & middle-

ear defects, cleft lip/palate, limb defects,

CHDw

 

 

 

CHD = Congenital heart disease

CNS = Central Nervous System

NTD = Neural tube defects

IUGR = Intrauterine fetal growth retardation

b Dose and gestation dependant. NB There is no unequivocal evidence that oral contraceptives are teratogenic.

c Liable to be prescribed to women of childbearing age and specific warning should be given together with contraceptive advice.

d May occur after paternal use of the drug ie transmitted by sperm

e Some of the increased rate of malformations ascribed to anticonvulsant medication is inherent to epileptics.

f Does not occur before 20 weeks gestation.

g After intra amniotic use

w Tetralogy of Fallot OR 3.16, CI 1.49-6.71 after doses of 150 300 mg. Other defects only with high dose antifungal therapy

x Since the defects are relatively minor, termination of pregnancy is not appropriate.

y Further data required for confirmation.

z Prenatal diagnosis is appropriate and termination of pregnancy can be offered.


 

 

Revised 24th April 2018