Valproic Acid in Pregnancy Revisited: Neurobehavioral, Biochemical and Molecular Changes Affecting the Embryo and Fetus in Humans and in Animals: A Narrative Review

Abstract

Valproic acid (VPA) is a very effective anticonvulsant and mood stabilizer with relatively few side effects. Being an epigenetic modulator, it undergoes clinical trials for the treatment of advanced prostatic and breast cancer. However, in pregnancy, it seems to be the most teratogenic antiepileptic drug. Among the proven effects are congenital malformations in about 10%. The more common congenital malformations are neural tube defects, cardiac anomalies, urogenital malformations including hypospadias, skeletal malformations and orofacial clefts. These effects are dose related; daily doses below 600 mg have a limited teratogenic potential. VPA, when added to other anti-seizure medications, increases the malformations rate. It induces malformations even when taken for indications other than epilepsy, adding to the data that epilepsy is not responsible for the teratogenic effects. VPA increases the rate of neurodevelopmental problems causing reduced cognitive abilities and language impairment. It also increases the prevalence of specific neurodevelopmental syndromes like autism (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). High doses of folic acid administered prior to and during pregnancy might alleviate some of the teratogenic effect of VPA and other AEDs. Several teratogenic mechanisms are proposed for VPA, but the most important mechanisms seem to be its effects on the metabolism of folate, SAMe and histones, thus affecting DNA methylation. VPA crosses the human placenta and was found at higher concentrations in fetal blood. Its concentrations in milk are low, therefore nursing is permitted. Animal studies generally recapitulate human data.

Keywords: autism; neural tube defects; teratogenic antiepileptic drug; valproic acid.

Figure 1

Typical facial changes in VPA syndrome.

Figure 2

Suggested mechanism of the teratogenic action of VPA-inducing epigenetic changes. Several biological pathways by which VPA causes congenital malformations and neurodevelopmental abnormalities have been proposed. Among them, one-carbon metabolism (OCM) and inhibition of HDAC enzymes seem to be the main contributors to VPA teratogenicity. VPA blocks the dihydrofolate reductase and methyltransferases (MTases) enzymes that are involved in folate and SAMe cycles in one-carbon metabolism (OCM). Thus, VPA interferences in OCM resulted in depleted endogenous folate levels, SAM: SAH ratio imbalance and higher plasma concentrations of SAH with lower concentrations of plasma SAMe that were indeed observed in women with NTD-affected pregnancies. The decline in SAMe production, a critical methyl donor, contributes to a decrease in DNA methylation levels, subsequently increasing gene expression. VPA’s disruption of folate-dependent pathways and the subsequent impact on SAMe levels, in turn, influences DNA methylation, and gene expression, and potentially contributes to the observed developmental abnormalities and congenital malformations associated with VPA exposure during pregnancy. Similarly, inhibition of HDAC enzymes leads to enhanced histone acetylation and formation of loose chromatin, and therefore an increase in gene expression.