Hydantoin-induced teratogenesis: are arene oxide intermediates really responsible?

A large body of literature indicates that prenatal exposure to hydantoin anticonvulsant drugs can be teratogenic and therefore result in offspring with congenital malformations [6, 10-12, 18, 27, 30]. Literature discussing the actual etiologic agent responsible for the malformation and the types of anomalies typical of hydantoin-induced teratogenicity is contradictory [3, 10, 11, 35]. The majority of published cases of the fetal hydantoin syndrome have been associated with maternal ingestion of the most widely prescribed of all the hydantoin anticonvulsants, phenytoin (Dilantin; Parke, Davis) [11]. Occasional reports of mephenytoin (Mesantoin; Sandoz) teratogenicity have been noted [10-11, 27], but our review of the literature yielded only one case report of birth defects in a child exposed to ethotoin (Peganone; Abbott Laboratories in utero [38]. We wish herein to describe three siblings prenatally exposed to ethotoin, all of whom had clinical features compatible with in utero exposure to hydantoin anticonvulsants. Unlike phenytoin and mephenytoin, ethotoin is not metabolized through an arene oxide intermediate. The presence of these clinical findings suggests, therefore, that epoxide metabolites are not the causative agents in hydantoin-induced teratogenicity.