Teratogenic effects of vigabatrinin TO mouse fetuses

Vigabatrin (VGB) is a relatively recently introduced antiepileptic drug that enhances the brain levels of gamma aminobutyric acid (GABA). Few data on its teratogenic effects appear to have been reported. Our objective was to determine if VGB was teratogenic in the TO mouse. Single doses of 300-600 mg/kg of VGB dissolved in saline were administered intraperitoneally (IP) to groups of TO mice on one of gestation days (GD) 7-12. The controls were saline treated or untreated. No maternal toxic effects were observed in the 300 or 450 mg/kg groups, and the 600 mg/kg dose was totally lethal to the mothers. Fetuses were collected on GD 18. Both 300 and 450 mg/kgdosesinducedaconsistentlysignificantintrauter- ine growth retardation irrespective of the developmen- tal stage at administration. VGB did not augment the spontaneousincidenceofneuraltubedefectscharacter- istic of this strain, but accelerated destruction of the brain in spontaneous exencephalic embryos. Mandibu- lar and maxillary hypoplasia, arched palate, cleft palate (two cases), limb defects (one case), and exomphalos were observed in the malformed fetuses. The high incidence of exomphalos appears to be a unique result of VGB treatment. Alizarin red-S/alcian blue-stained skeletons revealed hypoplasia of mid facial bones, stage-dependent increase in the frequency of cervical and lumbar ribs, rib fusion, and sternal and vertebral malformations in the drug-treated fetuses. Middle and distal phalanges of the forepaw and mid phalanges and tarsals of the hindpaw failed to ossify in a significant number of experimental fetuses. Homeotic shift in terms of presacral vertebral number and a high inci- dence of lumbar and cervical ribs in the treated group are suggestive of treatment-related alterations in gene expression. In view of the paucity of human and animal data on the reproductive toxicologic effects of VGB, the results of the present study assume particular impor- tance and suggest that VGB should be used in preg- nancy with extreme caution. Teratology 55:165-176, 1997. r1997 Wiley-Liss, Inc. Epilepsy affects millions of people worldwide. It has been estimated that approximately 0.5% of all pregnan- cies occur in women with epilepsy (Svigos, '84; Yerby, '91). Epileptic women demonstrate a higher liability to obstetric complications than non-epileptic females (Mon- touris et al., '79). Epilepsy in either parent is reported to be associated with an increased risk of having a malformed infant (Shapiro et al., '76; Robert and Guibaud, '82; Janz, '82; Lindhout et al., '92; Nakane and Kaneko, '92). Congenital malformations are esti- mated to be more common in infants of epileptic women treated with antiepileptic drugs (AEDs) than those of normal controls or non-treated epileptic mothers (Meadow, '68; Speidel and Meadow, '72;Annegers et al., '78; Kalter and Warkany, '83; Nakane et al., '80; Speidel andMeadow,'72;Kanekoetal.,'88). Bothmajorandminor malformations have been attributed to AED therapy (Gailey et al., '88; Koch et al., '92). Almost allAEDs have been found to induce some form of fetal malformations, often described to constitute a syndrome named after the drug in question. The calculated risk of malforma- tions in fetuses exposed toAED is 7-10% (Lindhout and Omtzigt, '94). Specific risk factors include high mater- nal dosage of AED, low folate levels, drug polytherapy, and possible seizure occurrence during pregnancy. Epi- demiological and experimental studies have corrobo- rated the teratological effects ofAEDs (Miyagawa et al., '71; Hanson et al., '84; Dalessio, '85; Kelly, '84; Robert and Rosa, '83; Lammer et al., '87; Meadow, '91; Martinez- Frias, '90; Yerby, '91; Lindhout et al., '92; Nakane and Kaneko, '92; Finnel, '91; Padmanabhan and Hameed, '94; Padmanabhan and Ahmed, '96). One of the ques- tions that remains yet unanswered is why only a small percentage of the AED-exposed fetuses is affected, whereas the majority are not malformed. It is possible that within the population there are subpopulations with a genetic predisposition who, when exposed to AEDs at critical stages of development, become mal- formed (Khoury et al., '92). One way of testing this hypothesis of ''drug-susceptibility interaction'' is to use experimental animals with a known susceptibility to a