Soon after valproic acid was introduced to clinical use for epilepsy, cases emerged
suggesting an increased risk of neural tube defects (NTDs), particularly of spina
bifida, among offspring exposed to the drug in early gestation.1,2
The experimental animal
work by Nau and colleagues was very important in establishing that valproic acid caused
development of NTDs.3
The overall risk for NTDs
has been estimated at 2%. While this looks like a low rate, it virtually doubles the
overall risk for major malformations in the general population from its usual 1% to 3%.
Because NTDs can be detected in utero in most cases by detailed ultrasonography and by
measuring levels of alpha-fetoproteins in maternal serum or amniotic fluid, women
treated with valproic acid in early gestation should be informed of these diagnostic
Over the last 15 years, an increasing number of anecdotal reports and case series have
suggested that valproic acid causes malformations other than NTDs, including limb and
cardiac anomalies. Until recently, a lack of controlled or large-scale studies precluded
corroboration of these impressions. To complicate the situation, increasing numbers of
women are now receiving valproic acid as part of treatment for a variety of psychiatric
Over the last few years, larger cohort studies of pregnancy outcome among women exposed
to valproic acid in pregnancy have been published, now allowing us to evaluate the
overall rates of teratogenic risk of valproic acid.
We searched the MEDLINE, EMBASE, and Cochrane databases from 1978, when reports on
valproic acid use in pregnancy began to emerge, to December 31, 2005. We selected
controlled cohort studies that reported the use of valproic acid during the first
trimester of pregnancy and that had a comparison group of women treated with other
antiepileptic drugs, untreated epileptic women, or healthy women representing the
general population of pregnant women. To be included in our analysis, the studies had to
describe rates of major malformations among the study and comparison groups. Several
studies had comparison groups, but the papers did not allow extraction of these numbers.
Individual and summary relative risks were calculated with the Mantel-Haenszel random
effect test using Cochrane’s Review Manager (version 4.2). We calculated the relative
risk for major malformations among babies exposed to valproic acid alone or in
combination with other anticonvulsant drugs during embryogenesis as compared with babies
exposed to other anticonvulsants, or babies of unexposed healthy control subjects.