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Valproic Acid Monotherapy in Pregnancy and Major Congenital Malformations
Jentink J, Loane MA, Dolk H, et.al., for the EUROCAT Antiepileptic Study Working Group
N Engl J Med. 2010;362:2185-2193
Summary
Although the risk for spina bifida appears to be increased with the use of valproic acid in the first trimester of pregnancy, evidence to date is limited regarding the risk for other congenital malformations associated with this exposure.
In 8 published cohort studies, a total of 118 major malformations were identified in 1565 pregnancies during which the mother had used valproic acid. Combined data from these studies identified 14 malformations that were significantly more common among the offspring of women who had received valproic acid during the first trimester.
Using the European Surveillance of Congenital Anomalies (EUROCAT) antiepileptic study database, which is derived from population-based registries of congenital anomalies, the investigators evaluated the association between use of valproic acid during the first trimester and these 14 malformations by performing a case-control study. Registry cases (pregnancy outcomes with any of these 14 malformations included in EUROCAT) were compared with 2 control groups: infants with malformations not previously linked to valproic acid use (control group 1) and infants with chromosomal abnormalities (control group 2). Data for analysis were derived from 98,075 live births, stillbirths, or terminations with malformations among 3.8 million births in 14 European countries from 1995 through 2005.
Of 180 registrations for which exposure to valproic acid monotherapy was recorded, 122 were in the case group, 45 were in control group 1, and 13 were in control group 2. For 6 of the 14 malformations studied, risks were significantly increased with valproic acid monotherapy vs no use of an antiepileptic drug during the first trimester. Adjusted odds ratios were 12.7 for spina bifida (95% confidence interval [CI], 7.7 to 20.7); 6.8 for craniosynostosis (95% CI, 1.8 to 18.8); 5.2 for cleft palate (95% CI, 2.8 to 9.9); 4.8 for hypospadias (95% CI, 2.9 to 8.1); 2.5 for atrial septal defect (95% CI, 1.4 to 4.4); and 2.2 for polydactyly (95% CI, 1.0 to 4.5).
Viewpoint
Limitations of this study include lack of information regarding dosage of valproic acid, which has been previously reported to be a factor predicting risk for congenital malformations, and other potential confounders. For rare malformations, this study was able to rule out very large risks associated with valproic acid exposure but not smaller risks. Nonetheless, the use of valproic acid monotherapy in the first trimester was associated with a significantly increased risk for several congenital malformations in this study compared with no use of antiepileptic drugs or with use of other antiepileptic drugs.
Findings from this study support the American Academy of Neurology recommendation to avoid the use of valproic acid during pregnancy because exposure to valproic acid is associated with an increased risk for major congenital malformations and poor cognitive outcomes, and because the risk is higher than that associated with exposure to other antiepileptic drugs. However, the absolute rates of specific malformations are low, and most children born to mothers who take valproic acid do not have malformations.
In deciding whether to prescribe antiepileptic drugs to a woman who is pregnant, and in choosing a specific antiepileptic drug, the physician must consider various factors, including the goal of optimizing seizure control in the individual patient. Because changing an antiepileptic drug regimen during or just before pregnancy may pose problems, clinicians should routinely consider the risks associated with valproic acid when prescribing treatment for women who could become pregnant.
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