The Effects of Valproic Acid on the Skeletal Development and the Ameliorative Effects of Combined Use of Folic Acid and Vitamin E in Pregnant Albino Rats

Abstract

Objectives: To evaluate skeletal developmental defects secondary to chronic valproic acid (VPA) use during pregnancy and the extent of ameliorative effect of combined use of vitamin E and folic acid (FA) during VPA therapy. Materials and Methods: Thirty virgin female albino rats were allowed to get pregnant and were divided into three equal groups: Control group received no medications; VPA group received oral VPA 400 mg/kg body weight (BW) starting on gestational day (GD) 1 till GD20 and Prophylaxis group received oral VPA (400 mg/kg BW) and vitamin E 250 mg/kg BW and folic acid 100 µg/kg BW using gastric tube starting on GD1 till GD20. At GD20, uterine horns were examined for resorption sites, alive or dead fetuses. Extracted living fetuses were examined for BW, crown-rump length (CRL), and antero-posterior (AP) and biparietal diameters and for congenital malformations. Results: VPA significantly reduced all body measurements of living dams compared to control dams. Prophylaxis therapy significantly increased BW, CRL and AP skull diameter compared to VPA dams. The GD20 fetus of VPA group showed delayed ossification of skull bones with wide anterior fontanel (AF) and widely separated parietal bones, very small ossification center (OC) for hyoid bone. Caudal vertebrae were unossified or showed very small OC with no evident OC for calcaneous, metatarsal bones or distal phalanges. Fetuses of prophylaxis group showed slightly wide AF than that of control animals and parietal bones are separated to lesser extent than VPA group. Mandible is developed, with an OC for hyoid bone and sternebrae are seen. Six caudal vertebrae and few OC in phalanges are seen, but no OC in calcaneous. Conclusion: VPA chronic administration during pregnancy showed deleterious effects on fetal body measurements and skeletal system development. Concomitant administration of vitamin E and FA significantly ameliorated these changes.