Comparative teratogenicity of chlordiazepoxide, amitriptyline, and a combination of the two compounds in the fetal hamster

Abstract

A combination of chlordiazepoxide and amitriptyline maternally administered as a single intraperitoneal injection on day 8 of gestation in the fetal hamster produced predominantly central nervous system anomalies including exencephaly and encephalocoele. In addition, omphalocoele, spinal flexion, and microcephaly were noted. A dose response relationship was found in which a maternal dose range of 13/33 mg/kg--33/83 mg/kg chlordiazepoxide/amitriptyline produced 7-92 percent fetal anomalies. Combination drug dose levels up to 23/58 mg/kg produced no maternal mortality. However, higher levels did result in a marked dose dependent mortality rate. The teratogenic potential of the combined drugs is much more pronounced than that of either drug administered alone since chlordiazepoxide at a maternal dose range of 280/3100 mg/kg produced 3-55 percent fetal anomalies, and amitriptyline at a maternal dose range of 60-100 mg/kg produced 6-45 percent fetal anomalies. The majority of these aberrant fetal developmental entities also were classifiable as exencephaly and encephalocoeles. Dose-dependent maternal mortality was observed at all dose levels for each drug administered separately.