Effects of sodium warfarin administered during pregnancy in mice

Fetal death and congenital malformations have been reported to occur following oral anticoagulant therapy during pregnancy. Therefore, a systematic study of the possibility of teratogenic and fetopathic effects of sodium warfarin was undertaken in mice. Sodium warfarin was administered to pregnant mice in single doses of 1, 2, 3, or 4 mg. per kilogram of body weight on one of Gestation Days 8, 9, 10, or 11. Maternal prothrombin times were prolonged by 2 to 3 times normal 24 hours after a single 4 mg. per kilogram injection and returned to normal after about 48 hours. The frequency of minor fetal malformations was significantly increased. There was a significant increase in fetal death and resorption with a maximum around Gestation Day 10. Administration of vitamin K1 to mice treated with warfarin on Day 10 reduced the incidence of fetal death to that of the control mice, suggesting that the embryotoxicity of warfarin is related to its vitamin K antagonism. Sodium warfarin administered to pregnant mice from Days 3 to 11 in doses of 2 or 4 mg. per kilogram per day resulted in placental hemorrhage and subsequent fetal loss. The results of these experiments support the current clinical practice of avoiding oral anticoagulants during the first trimester of pregnancy.