Repeated Neural Tube Defects and Valproate Monotherapy Suggest a Pharmacogenetic Abnormality

Abstract

Summary: Valproate (VPA) is an effective, widely used antiepileptic drug. Unfortunately its use in pregnant women is associated with neural tube defects in the offspring. Although the etiology of neural tube defects is multifactorial, there is evidence that underlying genetic susceptibility plays a part. We describe two women taking moderate doses of VPA who repeatedly bore children with neural tube defects, despite folate supplementation. This suggests a pharmacogenetic susceptibility to the teratogenic effects of VPA.

Improving adherence to NICE guidance for bipolar illness: valproate use in women of childbearing potential

“…It is unclear, however, whether prophylactic use of high-dose folate in women prescribed valproate confers the same benefits. 24 There is also a suggestion that preconceptual high-dose folate supplementation can lead to twin births. [24][25][26] It is possible that either or both of these factors contributed to the low rates of folate prescription in the women in our survey.…”

Antiepileptic drugs as human teratogens

“…Subsequently, Lindhout and Schmidt [53] reported a 1 -2% rate of spina bifida associated with intrauterine valproate exposure. Genetic factors may also play a part in the genesis of valproate-associated neural tube defects, Duncan et al [54] described a valproatetreated mother who gave birth to infants with spina bifida in several pregnancies. Considerable evidence has now accumulated that intrauterine valproate exposure is associated with various malformations other than neural tube defects.…”

Currently Available Antiepileptic Drugs

“…Sodium valproate is teratogenic, 12 and has been associated with neural tube defects. 33 Sodium valproate inhibits hepatic metabolism, reducing the clearance of PHT, PB, CBZ-epoxide, and LTG.…”