A comparison of the teratogenic activity of the antiepileptic drugs carbamazepine,clonazepam, ethosuximide,phenobarbital, phenytoin,and primidone in mice

The teratogenic activity of six commonly used antiepileptic drugs, carbamazepine, clonazepam, ethosuximide, phenobarbital, phenytoin, and primidone, was studied at three dose levels (3, 9, and 18 times the human therapeutic dose) in CD1 mice. The drugs, suspended in 1% carboxymethylcellulose, were administered by gastric intubationon Days 6–16 of pregnancy, which covers the period from implantation to the end of structural development. The dams were killed 1 day before term and the fetuses were examined. Full-length cleft palates were observed in all treated groups with the exception of the clonazepam-treated group. This defect was not observed in any of the control groups. Other defects such as exencephaly, enlarged cerebral ventricles, exomphalos, open eyes, undescended testes, abnormal palatal bones other than cleft palate, and fused ribs were seen less frequently. If these results are assessed by ranking the drugs in order of teratogenicity, assessed on either a pooled fetus or a pooled litter basis, the drugs fall into three categories: Phenytoin produced the highest incidence of teratogenic effects; carbamazepine, phenobarbital, and primidone produced a lower but still significant incidence of defects; and clonazepam and ethosuximide were the least teratogenic. Nevertheless, there was at least a two-fold increase in defects in these latter two treatment groups compared with the controls.