Congenital malformations due to antiepileptic drugs

To identify the major risk factors for the increased incidence of congenita l malformations in offspring of mothers being treated for epilepsy with ant iepileptic drugs (AEDs) during pregnancy and, to determine the relative ter atogenic risk of AEDs, we prospectively analyzed 983 offspring born in Japa n, Italy, and Canada. The incidence of congenital malformations in offsprin g without drug exposure was 3.1%, versus an incidence with drug exposure of 9.0%. The highest incidence in offspring exposed to a single AED occurred with primidone (PRM; 14.3%), which was followed by valproate (VPA; 11.1%), phenytoin (PHT; 9.1%), carbamazepine (CBZ; 5.7%), and phenobarbital(PBI 5.1 %). The VPA dose and level positively correlated with the incidence of malf ormations. This study first determined a cut-off value of VPA dose and leve l at 1000 mg/day and 70 mu g/ml, respectively, to avoid the occurrence of m alformations. The incidence of malformations increases as the number of dru gs increases, and as the total daily dose increases. Specific combinations of AEDs such as VPA+ CBZ and PHT+PRM +PB produced a higher incidence of con genital malformations. The incidence of malformations was not associated wi th any background factors studied except for the presence of malformations in siblings. These results indicate that the increased incidence of congeni tal malformations was caused primarily by AEDs, suggesting that malformatio ns can be prevented by improvements in drug regimen, and by avoiding polyph armacy and high levels of VPA (more than 70 mu g/ml) in the treatment of ep ileptic women of childbearimg age. (C) 1999 Elsevier Science B.V. All right s reserved.