Reduction of the Teratogenic Effects of Phenytoin by Folic Acid and a Mixture of Folic Acid, Vitamins, and Amino Acids: A Preliminary Trial

Four groups of pregnant rats were used to study the effects of dietary supplements of folic acid (FA) alone or a mixture of FA, vitamins (Vit), and amino acids (AA) on the teratogenic effects of phenytoin (PHT). Groups A, B, and C received intraperitoneal (i.p.) injections of high-dose (75 mg/kg/day) phenytoin (PHT) between 9 and 11 days of gestation, while the controls, group D, rats received distilled water. The diet was modified in groups A and B. Group A received a mixture of FA, Vit, and AA, while group B received FA supplementation alone. Groups C and D received a regular diet. We found that PHT, when administered without dietary supplementation, resulted in a decrease in weight and length of the fetuses, an increased rate of subcutaneous (s.c.) bleeding, a retardation of ossification centers, and an increased number of malformations. Supplementation of the diet with FA alone or FA with Vit and AA resulted in statistically greater fetal weight and length, decreased subcutaneous bleeding, more ossification centers, and fewer malformations. The mixture of FA and Vit and AA was superior to FA alone in reducing the incidence of internal abnormalities, ossification abnormalities of the distant phalanxes, and s.c. bleeding.