Developmental toxicity of antiepileptic drugs: relationship to postnatal dysfunction

Abstract

The increased frequency of congenital malformations in children of epileptic mothers, estimated as 2-3 times that in the general population, has been largely attributed to intrauterine anticonvulsant drug exposure . Despite numerous clinical and epidemiological studies supporting an association, however, a pathogenetic relationship between antiepileptic drugs (AED) and malformations has not been conclusively established [1-4] . This owes in part to the presence of the maternal disease, a confounder which necessarily accompanies drug exposure . Thus, questions about the effect of maternal epilepsy on pregnancy outcome, and about the role of genetic factors associated with epilepsy in the aetiology of congenital defects have complicated efforts to examine the potential teratogenicity of AEDs in humans. In addition, the considerable variability and overlap of abnormalities associated with individual agents, as well as the common use of multiple AEDs, limit the extent to which a particular malformation can be ascribed to a specific drug. Therefore, while all clinically used AEDs have been implicated as potential teratogenic agents, most have not been associated with any one type of malformation. The exception is valproic acid (VPA), which has been associated with a 1 % rate of spina bifida [5] . Recently compiled evidence indicates that carbamazepine (CBZ) use may present a similar risk for this defect [6] . Variable patterns of drug use, different indications for individual AEDs, limited information about compliance and drug levels, as well as the practice of polytherapy, make the relative teratogenic potential of AEDs difficult to ascertain . Trimethadione (TRI), which has since been superseded by other AEDs, was reported to be responsible for a high rate of birth defects in prenatally exposed infants [7] . Abnormalities associated with diphenylhydantoin (DPH) are the most frequently described fetal anticonvulsant effects, but this may only be a reflection of the widespread use of this drug in the treatment of seizure disorders . Several studies suggest that there is an increased risk of abnormalities if higher daily doses of AEDs are taken [8,9] and if more than one AED is used, with certain combinations of AEDs being particularly hazardous [10-12] . Dose and number of AEDs may be related to seizure severity and incidence, factors which could also influence the malformation rate, although this has not been confirmed [12,13] .