Characterizing the effects of in utero valproic acid exposure on murine fetoplacental development

Abstract

IntroductionValproic acid (VPA) is an effective anti-epileptic drug clinically used to treat seizures, bipolar disorders and neuropathic pain in women of reproductive age. Current approval of VPA for psychiatric conditions and migraine has increased the number of VPA exposed pregnancies. VPA crosses the placental barrier and induces birth defects in about 10% of exposed pregnancies. In addition, VPA exposure results in neurodevelopmental disorders in children without any overt birth defects. The current study was designed to investigate the effects of in utero VPA exposure on fetoplacental growth in a mouse model. MethodsPregnant CD-1 dams were exposed to a single teratogenic dose of 400 mg/kg VPA or saline via subcutaneous injection on gestational day (GD) 9 and fetuses were harvested on GD 13, 15, 17 and 19, respectively. Resorptions, gross malformations, fetal weight, fetal head weight, fetal crown-rump length, fetal head transverse and anteroposterior diameters, placental weight and placental diameter were noted. ResultsVPA exposure led to multiple external deformities including exencephaly, open eye defect, subcutaneous hemorrhage and underdevelopment of tail. All fetoplacental growth parameters fetal weight, fetal head weight, fetal crown-rump length, placental weight and placental diameter were significantly reduced in VPA-exposed fetuses with and without congenital malformations such as exencephaly, compared to control fetuses. DiscussionIn conclusion, the effects of in utero VPA exposure on fetal and placental growth persisted throughout pregnancy and our results suggest that the effects of VPA on placental growth may play a role in VPA-induced toxicity.