Pregnancy: Introduction

Last updated: Sunday, July 12, 2015

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Agents or factors that cross the placenta to cause congenital malformations are termed teratogens. This strict definition is often relaxed to include any agent that, directly or indirectly, causes structural or functional abnormalities in the fetus or child after birth when administered to a pregnant woman. Teratogens do not cause abnormalities in all fetuses exposed at the critical period. For example thalidomide, which is a highly teratogenic drug, caused abnormalities in less than half of all fetuses exposed during the critical period.

The incidence of major congenital malformations in the UK general population is estimated to be between 2-3%. A high proportion of these malformations are of unknown aetiology; only 1-2% are thought to be due to drugs.

There are diagrams illustrating when teratogens might be more likely to adversely affect specific aspects of fetal development, including this example.

The embryo is most vulnerable to teratogens during the embryonic phase, from days 18 to 55, when the cells differentiate and the major organs are formed. If differentiated cells are damaged they are unlikely to be replaced resulting in permanent malformations. During the fetal period, from day 56 until birth, organs such as the cerebral cortex and the renal glomeruli continue to develop and remain particularly susceptible to damage. Functional abnormalities such as deafness may also occur.

Teratogenicity is usually dose-dependent and there is normally a threshold dose below which a drug does not exert any teratogenic effects. For example the incidence of neural tube defects with sodium valproate may be dose-related. The risk of teratogenicity may also be increased if the number of concomitant drugs is increased. This has been studied especially in women with epilepsy: the incidence of malformations increases with the number of anti-epileptic drugs taken.

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Teratogenicity is not the only risk posed by medicines. They can, for example, trigger spontaneous miscarriage (also known as spontaneous abortion). The background incidence of spontaneous miscarriage is about 10-20% of all pregnancies.

Animal studies

Although rodents are normally used to evaluate the safety of drugs in pregnancy during pre-clinical studies, their physiology, metabolism and development are very different to humans. It cannot be assumed that a drug that does not cause embryotoxicity, fetotoxicity or teratogenicity in animal studies can be used ‘safely’ in human pregnancies. However, if a drug does cause fetal toxicity in several animal species, this is an indicator that the same effects may occur in humans.