The fetal hydantoin syndrome: answers from a mouse model

In spite of a large body of literature suggesting that prenatal exposure to hydantoin anticonvulsant drugs can be teratogenic in humans, resulting in offspring with congenital malformations, the wide phenotypic variability of this syndrome has led many clinicians to question its very existence. Because solutions to major teratologic questions may be impossible to find within the constraints of human clinical or epidemiologic investigations, we have developed an animal model for the fetal hydantoin syndrome. With this model, we have been able to demonstrate the dose-related teratogenic effects of phenytoin on mouse development and the positive correlation between increasing maternal plasma phenytoin concentrations and the risk for congenital anomalies among offspring. Further, we have shown that genetic differences in susceptibility to particular phenytoin-induced malformations exist within different inbred mouse strains. Finally, in homozygous quaking (qk/qk) mice, the fetal malformations were associated not with the presence of a maternal seizure disorder, but with the phenytoin treatment of the disorder. An animal model such as the one described in this paper serves as a valuable adjunct to human clinical studies, and may serve to shorten the distance between our current understanding and our goal of preventing preventable birth defects.