There have long been concerns regarding the use of the anticonvulsant valproate (Depakote) during pregnancy.  First trimester use of valproate has been associated with a 3-5% risk of neural tube defects, as well as an increased risk of other malformations affecting the heart, limbs, and genitals. Prenatal exposure to valproate may also result in lower IQ and increased risk of autism spectrum disorders in the offspring.  

Most studies have observed cognitive functioning in young children; however, a recent study has focused on outcomes in older children.   In a prospective, population-based cohort study, researchers analyzed data collected between August 1, 2015 and May 31, 2017 from children who were born in Denmark between 1997 and 2006 (n?=?656,496). A large number of children were not included in the final analysis because they either did not participate in the national standardized testing or were missing information on their mother’s educational level or household income (n?=?177,469).

The final analysis included 479,027 children. The primary outcome was performance on national academic tests administered to students in Danish primary and lower secondary schools. Among the 1576 children exposed to antiepileptic drug monotherapy, 253 were exposed to valproate, 86 to phenobarbital, 236 to oxcarbazepine, 396 to lamotrigine, 188 to clonazepam, 294 to carbamazepine, and 123 to other AEDs.

Performance in Danish language and mathematics  in children with prenatal exposure to valproic acid was compared to test performance of unexposed children and children exposed to another antiepileptic drug, lamotrigine.

The Good News First:  Children exposed to carbamazepine, lamotrigine, phenobarbital, and oxcarbazepine did not differ in school performance compared to unexposed children.

Now the Bad News:  Valproate-exposed children scored worse on the sixth-grade Danish language tests (adjusted difference, ?0.27 SD; 95% CI, ?0.42 to ?0.12) and mathematics tests (adjusted difference, ?0.33 SD; 95% CI, ?0.47 to ?0.19) compared to unexposed children and children exposed to lamotrigine.  Similar results were observed in testing carried out during third grade and eighth grade.

Given previous research on the use of valproic acid during pregnancy and the impact of this exposure on neurodevelopmental outcomes, these finding are not surprising.  What this study adds is evidence that the negative effects of valproic acid exposure persist and are evident in older children up to the age of 14.

Back in 2009, the American Academy of Neurology and American Epilepsy Society recommended against the use of valproic acid in women of childbearing age because of the various risks associated with prenatal exposure.  Raising similar concerns, in 2014 the European Medicine Agency (EMA)’s Pharmacovigilance and Risk Assessment Committee recommended restricting the use of valproic acid in women of reproductive age.  The EMA made the following specific recommendations regarding the use of valproic acid in this population:

Ruta Nonacs, MD PhD


Elkjær LS, Bech BH, Sun Y, Laursen TM, Christensen J.  Association Between Prenatal Valproate Exposure and Performance on Standardized Language and Mathematics Tests in School-aged Children.  JAMA Neurol. 2018 Feb 19.


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