Facial clefts and congenital heart defects in children of parents with epilepsy: genetic and environmental etiologic factors

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Abstract
Increased prevalence of cleft lip with or without cleft palate (CL(P], isolated cleft palate (CP), and congenital heart defects (CHD) in children of epileptic mothers have been ascribed to early fetal exposure to antiepileptic drugs (AED). However, common genetic factors responsible for both the malformations in question and the epileptic disorder might be of relevance for the increased rate of CL(P), CP, and CHD, rather than the influence of AED. The present review analyzes the literature on genetic and environmental etiologic factors (i.e. AED and epileptic seizures) that have been reported to increase the rate of CL(P), CP, and CHD in children of parents with epilepsy. Our data suggest that genetic factors are of minor importance for the etiology of facial clefts in offspring of epileptic patients. The rate of facial clefts was increased by a factor of 4.7 in children of AED-treated mothers with epilepsy compared with the background population values. Children of fathers with epilepsy and sibs of epileptic patients had no more facial clefts than expected. The rate of CHD in children of mothers and fathers with epilepsy was comparable to population figures. The role of epileptic seizures as a causative factor for CL(P), CP, and CHD is not settled, but seems to be of limited importance. Areas of future research are outlined concerning the teratogenic role of AED and their metabolites, especially on the postnatal intellectual development of the exposed children. Finally, the need for studies on prophylactic measures as well as the necessity of international surveillance systems on new AED teratogenicity are emphasized.