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
Depression^4		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	Mefloquine^1 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

Stilboestrol^b Vaginal adenocarcinoma

Malformations of male and 22-58%

female genital tracts.

Psychosexual disturbance, Depression

Systemic Retinoids^c CNS malformations, CHD,

Facial dysmorphism 40%

Folic acid antagonists^c NTDs, Craniofacial abnormalities 30%

eg, Methotrexate Limb defects

Thalidomide^b Phocomelia, CHD, gut and 20%

(and structurally-related renal malformations

Immunomodifiers)

Cytotoxic agents^c,d, Various effects, IUGR »20%

e.g. Cyclophosphamide

Lithium^c CHD, Neonatal effects 2.5%

Phenytoin^c Dysmorphic facies, hypoplasia distal 3 - 9%

ie Dilantin & most phalanges, IUGR, neonatal bleeding,

anticonvulsants mental retardation

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

anticoagulants^c retardation and genital defects

Androgenic hormones Masculinization of female 0.3-18%

incl. eg. Danazol^c genitalia

19 nortestosterone progestins^b,x

Misoprostol Moebius sequence ?>50%

Disulfiram^c Multiple malformations ?50%

Methylene Blue^g Intestinal atresia

Valproic acid, Carbamazepine Spina bifida^z, 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

Tetracyclines^x Dental staining^f, skeletal abnormalities Unknown

Maternal acute fatty liver

Antithyroid drugs^x Congenital goitre Unknown

Iodides^x Congenital goitre Unknown

(including diagnostic agents)

Cocaine^y Renal tract malformations Unknown

Ethanol Fetal alcohol syndrome

Neurobehavioural abnormalities Dose dependent

Infarction of digits

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

Renal failure &

Fetal death in 2^nd & 3^rd trimesters

NSAIDs Premature closure ductus arteriosus Depends on gestation

Flucanazole Craniostenosis, craniofacial & middle-

ear defects, cleft lip/palate, limb defects,

CHD^w

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 24^th April 2018