Folic acid dose, valproate, and fetal malformations

Frank J.E. Vajda, Terence J. O'Brien, Janet E. Graham, Alison A. Hitchcock, Piero Perucca, Cecilie M. Lander, Mervyn J. Eadie

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12 Citations (Scopus)


Objective: To determine whether there is a relationship between folic acid dose and the degree of protection against valproate-associated and other antiepileptic drug (AED)-associated fetal structural malformations in women with AED-treated epilepsy. Methods: Statistical analysis of data from the Raoul Wallenberg Australian Register of Antiepileptic Drugs in Pregnancy involving 2104 folic acid-treated pregnancies in women with epilepsy. Results: Multiple variable logistic regression failed to demonstrate any statistically significant effect of folic acid dosage in reducing overall fetal malformation rates in women taking folic acid either before and during pregnancy (P = 0.640) or during early pregnancy only (P = 0.801), and in reducing spina bifida occurrence rates (P = 0.409). Conclusions: In the present state of knowledge, it would seem misguided to hope that a folic acid dose of 5 mg/day taken before and during pregnancy would protect against the occurrence of valproate-associated and other AED-associated fetal structural malformations. Future studies are required to determine whether high-dose periconceptional folate use may decrease the risk of other valproate-associated adverse fetal outcomes, including impaired post-natal neurobehavioral development.

Original languageEnglish
Article number107569
Number of pages3
JournalEpilepsy & Behavior
Issue numberPart A
Publication statusPublished - Jan 2021


  • AED dosage
  • Fetal malformation
  • Folic acid
  • Spina bifida
  • Valproate

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