Antiepileptic Agents and Birth Defects

Abstract

An association exists between maternal use of antiepileptic drugs (AEDs) during pregnancy and birth defects in offspring. The overall malformation rate is 11.1% in offspring of AED-treated epileptic mothers, while it is 5.7% in the offspring of untreated epileptic mothers and 4.8% in those of the general population. Cardiovascular defects, facial cleftings and skeletal anomalies are the most frequently occurring AED-associated malformations. No firm patterns of specific AEDs inducing particular birth defects have been established. Nevertheless, neural tube defects may be specific malformations in infants exposed to both valproic acid (sodium valproate) and/or carbamazepine. Several minor anomalies are influenced by genetic factors. From prospective studies a number of primary risk factors for increased incidences of congenital malformations in the offspring of epileptic mothers receiving AEDs have been identified. These include high drug dosage, high serum drug concentration, the use of AEDs with high teratogenicity potency [primidone > valproic acid > phenytoin > carbamazepine > phenobarbital (phenobarbitone)] and AED polypharmacy (especially combinations of valproic acid and carbamazepine, and phenytoin and/or carbamazepine with or without barbiturates). The mechanism of teratogenicity of AEDs is still being investigated, but it is postulated that epoxide intermediates and other toxic metabolites of AEDs might be involved. In addition, the folate deficiency and impaired folate metabolism caused by AEDs may contribute to the teratogenicity of these drugs. To prevent birth defects, the use of the lowest effective AED dosage and a change from polypharmacy to monotherapy are recommended before conception. A decrease in serum AED concentrations during pregnancy does not in itself justify an increase in drug dosage. The high risk of neural tube defects in offspring exposed to valproic acid (or carbamazepine) warrants prenatal examination in pregnant women receiving this drug, such as ultrasound and amniotic fluid α-fetoprotein investigations. To reduce the risk of this malformation, replacement of conventional formulations of valproic acid with controlled release formulations and the use of folate supplementation are recommended.