Trimethadione and human teratogenesis

A family is described in which four malformed children were born to a mother while she was taking trimethadione, an antiepileptic drug infrequently prescribed for adults. Following discontinuation of the drug, she had two normal children. This family led to a survey of all 278 epileptic women admitted to one hospital during the 23 years following the introduction of trimethadione for treatment of petit mal. Only eight women had ever taken it or its close congener paramethadione, and only three had taken it early in a pregnancy. Thus the outcomes of 14 pregnancies, during which the mothers took trimethadione or paramethadione early, have become known to the authors, those in the index family and those in three additional families ascertained through the survey. These pregnancies showed a high frequency of abnormality: eight children with developmental defects of various types, only three of whom have survived early infancy; one child with multiple hernias and juvenile, nonfamilial diabetes; and three spontaneous abortions. The survey suggests that neither epileptic women as a group nor those taking antiepileptic drugs usually prescribed for adults have an obviously increased frequency of malformed children but that epileptic women taking trimethadione or paramethadione may constitute a special subgroup whose children do have an increased frequency of birth defects. The small number of observations possible at a single institution, although suggestive, precludes a firm opinion as to the possible role as human teratogens of the oxazolidine-2,4-diones.