Valproic Acid Monotherapy in Pregnancy and Major Congenital Malformations

Abstract

Valproic acid has a long history of use for the treatment of seizures but is a recognized teratogen. During the first trimester of pregnancy, maternal exposure to valproic acid monotherapy is associated with increased risk of spina bifida, and several studies have suggested an increased risk of other major congenital malformations. However, individual studies generally have limited power to detect an excess risk of specific major malformations. These authors first conducted a case–control study using combined data from 8 individual cohort studies in the medical literature, including a total of 1565 pregnancy outcomes in which the fetus was exposed to valproic acid; this large study sample had increased power to identify other major malformations associated with valproic acid monotherapy during the first trimester. A total of 118 (7.5%) major congenital malformations were observed; of these, 14 appeared to be significantly increased in association with first trimester exposure to valproic acid monotherapy. The investigators then performed a population-based, case–control study using the EUROCAT (European Surveillance of Congenital Anomalies) antiepileptic study database, which included 98,075 births, stillbirths, and terminations with major congenital malformations among 3.8 million births in 14 European countries from 1995 to 2005, to evaluate the incidence of these 14 malformations in exposed and unexposed fetuses. The association between valproic acid exposure and congenital malformations was evaluated in cases which had the 14 congenital anomalies shown to be associated with valproic acid (n = 37,154) and in 2 control groups. Control group 1 (n = 39,472) was comprised of infants with anomalies that have not been linked to valproic acid exposure and control group 2 (n = 11,763) was comprised of infants with chromosome abnormalities. The frequency of exposure to valproic acid was 3 times higher among cases (3.3 per 1000) than among control groups 1 and 2 (1.1 per 1000 for each). Multiple logistic regression analysis showed that, compared with no exposure to any antiepileptic drug, exposure to valproic acid monotherapy during the first trimester was associated with a significantly increased risk of 6 of the 14 malformations; the adjusted odds ratios were increased for spina bifida (adjusted odds ratios, 12.7; 95% confidence interval [CI], 7.7–20.7); atrial septal defect (2.5; 95% CI, 1.4–4.4); cleft palate (5.2; 95% CI, 2.8–9.9); hypospadias (4.8; 95% CI, 2.9–8.1); polydactyly (2.2; 95% CI, 1.0–4.5); and craniosynostosis (6.8; 95% CI, 1.8–18.8). The odds ratios were similar when valproic acid exposure was compared to exposure to other antiepileptic drugs. These findings show that exposure of the fetus to valproic acid during the first trimester is associated with an increased risk of 6 specific malformations, as compared with no exposure to antiepileptic drugs or exposure to other antiepileptic drugs.