Clinical Pharmacology and Therapeutics. Группа авторов
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The greatest risk of teratogenesis occurs at a stage when a women might not know that she is pregnant
Only a few drugs are known definitely to be teratogenic, but many more could be under certain circumstances
When prescribing for a woman of childbearing age, remember that she might be pregnant and ask yourself if the benefits of drug use outweigh the risks of teratogenesis
Introduction
Nearly 40% of women in the UK take at least one drug during pregnancy, excluding iron, vitamins and drugs used during delivery. Once in the maternal circulation, drugs are separated from the foetus by a lipid placental membrane, which any given drug crosses to a greater or lesser extent depending on the physicochemical properties of the molecule.
Drugs in pregnancy can be viewed from two perspectives:
1 Effect of drugs on the foetus
2 Effect of pregnancy on the drug
Effect of drugs on the foetus
Drugs can influence foetal development at three separate stages:
1 Fertilisation and implantation period: conception to about 17 days' gestation
2 Organogenesis: 18–55 days
3 Growth and development: 56th day onwards
The possible consequences of drug exposure are different at each stage. In addition, drugs given at the end of pregnancy can influence structure or function in the neonate.
Fertilisation and implantation period
Interference by a drug with either of these processes leads to failure of the pregnancy at a very early and probably subclinical stage. Therefore, very little is known about drugs that influence this process in humans.
Organogenesis
It is during this period that the developing embryo shows great sensitivity to the teratogenic effects of drugs. A teratogen is any substance (virus, environmental toxin or drug) that produces deformity. Before discussing the teratogenic properties of certain drugs, the following points must be appreciated:
1 Teratogenesis in humans is very difficult to predict from animal studies because of considerable species variation. Thalidomide, the most notorious drug teratogen of recent times, showed no teratogenicity in mice and rats
2 Serious congenital deformities are present in 1–2% of all babies; therefore, a drug is only readily identified as teratogenic if its effects are frequent, unusual and/or serious. A low‐grade teratogen that infrequently causes minor deformities is likely to pass unnoticed
Table 1.8 Drugs that are known to be teratogenic.
| Drug | Deformity |
|---|---|
| Danazol | Virilisation of female foetus |
| Lithium | Cardiac (Ebstein's complex) |
| Phenytoin | Craniofacial; limb |
| Carbamazepine | Craniofacial; limb |
| Retinoids | Central nervous system |
| Valproate | Neural tube; neurodevelopment |
| Diethylstilbestrol (stilboestrol) | Adenocarcinoma of vagina in teenage years |
| Warfarin | Multiple defects; chondrodysplasia punctata |
Table 1.8 lists some drugs that are known to be teratogenic. It is important to emphasise that, even for known teratogens, first trimester use often results in a normal baby, e.g. phenytoin is teratogenic in about 4% of exposures and warfarin in up to 5%. Also, there will be occasions, such as the use of warfarin in women with prosthetic heart valves, where the risks to the mother of not using the drug outweigh the risks of exposure in the foetus. The greatest risk of teratogenesis occurs at a time when a woman might not even be aware that she is pregnant.
Growth and development
During this stage major body structures have been formed, and it is their subsequent development and function that can be affected:
1 Antithyroid drugs cross the placenta and can cause foetal and neonatal hypothyroidism
2 Tetracyclines inhibit bone growth and discolour teeth
3 Angiotensin‐converting enzyme inhibitors can seriously damage foetal kidney function
4 Warfarin can cause bleeding into the foetal brain
5 Drugs with dependence potential, e.g. benzodiazepines and opiates, which are taken regularly during pregnancy, can result in withdrawal symptoms in the neonate
Drugs given at the end of pregnancy
1 Aspirin in analgesic doses can cause haemorrhage in the neonate
2 Indomethacin (and possibly other NSAIDs) causes premature closure of the ductus arteriosus with resulting pulmonary hypertension
3 Central nervous system depressant drugs (e.g. opiates, benzodiazepines) can cause hypotension, respiratory depression and hypothermia in the neonate
Effect of pregnancy on drug absorption, distribution and elimination
The substantial physiological changes that occur in pregnancy can influence drug disposition, while pathological conditions in pregnancy can accentuate these changes.
Drug distribution
Maternal plasma volume and extracellular fluid volume increase by about 50% by the last trimester, and this may decrease the steady‐state concentration of drugs with a small volume of distribution. Considerable changes in protein concentration occur during the last trimester, with serum albumin falling by about 20% while α1‐acid glycoprotein increases in concentration by about 40% in normal pregnancies. These changes are accentuated in pre‐eclampsia, with albumin concentration falling by about 35% and glycoprotein rising by as much as 100%. This means that the free fraction of acidic drugs can increase substantially, while that of basic drugs can be decreased greatly, in the last trimester. Diazepam, phenytoin and sodium valproate have been shown to have significantly elevated free fractions in the last trimester.
Drug elimination
Effective renal plasma flow doubles by the end of pregnancy but this has been shown to be important in only a few cases; for example, the clearance of ampicillin doubles and the dose must also be doubled for systemic (but of course not for renal tract) infections. The hepatic microsomal mixed function oxidase system undergoes induction in pregnancy, probably as the result of high circulating levels of progesterone. This leads to an increased clearance of drugs that undergo metabolism by this pathway, and there is evidence that the steady‐state concentrations of the anticonvulsants sodium valproate, phenytoin and carbamazepine may be decreased to a clinically