A scientific review: mechanisms of valproate-mediated teratogenesis

Abstract

Living with epilepsy, for the majority of patients, is a continuous cycle of careful monitoring and attention to health. When coupled with pregnancy, safety becomes the primary focus. Epileptic women with reproductive intentions are confronted with a dilemma to either continue or discontinue current medication. Remaining on medication incurs the possibility of foetal abnormalities. However, discontinuation of medication could result in an uncontrolled condition that is potentially life threatening for both mother and child. Valproic acid (VPA) is a monocarboxylic acid with unclear mechanism of action and this is widely prescribed for epilepsy, bipolar disorder, migraine, Alzheimer’s disease and recently, cancer and HIV polytherapies. Originally, low incidences of toxicity were reported; however, emerging teratogenic properties warranted further investigation. This paper examines the major contraindications that VPA facilitates during pregnancy and proposes the degree of teratogenic influence each may inflict upon the developing foetus. The relevant aspects addressed are drug accumulation within the foetus, oxidative stress, folate antagonism and histone deacetylase (HDAC) inhibition. Review of the literature has shown vast numbers of investigations proving and disproving various proposed mechanisms of VPA-induced teratogenicity; these are still largely undefined. Based on the evidence presented, HDAC inhibition provided the strongest association with terato genicity, followed closely by the formation of reactive oxygen species. Both were particularly influential in the first trimester of pregnancy when DNA dysregulation has the largest impact on foetal organ development. In comparison, drug accumulation posed a lower risk as VPA is not the primary substrate for the majority of drug transporters across the placenta and lastly, folate inhibition was considered the lowest risk as new evidence has highlighted that the natural progression of gestation increases folate deficiency irrespective of VPA. All the suggested mechanisms (and possibly many more) may be contributing factors, together with inter-patient variability, environmental and lifestyle factors, each of which is also undefined, and lead to an increased risk of the teratogenic effects of VPA.