Pregnancy: Introduction

Last updated: Thursday, February 07, 2019

NB: See learning outcomes for this tutorial mapped to competencies, a PDF of the whole text, and a one-page summary

☞  Why this subject matters…

The number of women needing to take medicines during pregnancy is increasing, in part due to women becoming pregnant at an older age, and requiring treatment for pre-existing medical problems, and/or suffering obstetric complications.  It is essential that women can make informed decisions about whether to use a medicine during their pregnancy. Therefore you need to be familiar with the stages of development of the embryo and the fetus, the potential harm that medicines can pose, and strategies to reduce any risk(s).

Teratogenicity

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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 always 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.

A note on nomenclature
As it is difficult to know exactly what date ovulation and conception happens, the stage of a woman’s pregnancy is counted from the first day of her last menstrual period (LMP). For example, a woman who misses her period, finds out she is pregnant, and the first day of her LMP was four weeks ago, is described as ‘4 weeks pregnant’. This is despite conception only happening about 2 weeks ago.

Another term that is used is the ‘gestational age’ which is also counted from the first day of the last menstrual period. It is essential to use this nomenclature accurately, and seek clarity if necessary.

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 antiepileptic 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.