Examination of the Incidence of Malformations for Evidence of Drug Teratogenesis

The discovery that thalidomide can cause human malformations has been followed in recent years by a large number of reports of malformations in the offspring of women who have taken other drugs in pregnancy. But it has remained uncertain whether any of these drugs are teratogenic, since those reporting on them have not been in a position to relate their findings to the distribution of malformations in the general population. There are two reasons why population data are needed for the interpretation of associations between drugs and malformations. Firstly, the relative frequencies of the different types of defects in the general population need to be compared with those in affected children born after exposure to the drug in question; if teratogenic, it is likely to cause only a few specific types of defects, which will therefore be present in an abnormally high proportion of the exposed group. Secondly, comparisons between the population incidence of malformations at different times are needed to detect or exclude the changes that are likely to occur if any drug which is being used increasingly has teratogenic properties. These changes may be either prolonged trends or shortterm fluctuations. If a drug is used to treat endemic conditions such as anxiety or morning sickness, its output is likely to rise gradually as it becomes more widely known, and consequently any related increase in the malformation rate is also likely to be prolonged. Short-term fluctuations in incidence may occur if a teratogen is being used in the treatment of epidemic diseases (of which the commonest in pregnancy is influenza). In three previous reports (Leek and Millar, 1962, 1963; Leek, 1963) we examined the incidence of certain malformations in Birmingham for shortterm fluctuations between 1957 and 1961, and found