Prenatal Exposure to Antiepileptic Valproate Linked to Lower Test Scores Years Later

Children who were exposed to valproate sodium during pregnancy experience a significant decrease in school performance compared with children who were not exposed, according to a new study in JAMA Neurology.

The Study

Study findings further caution against the use of valproate in women with child-bearing potential, who are frequently given the antiepileptic medication as treatment for epilepsy, bipolar disorder, and migraine headaches, according to the study’s authors, led by Lars Skou Elkjær, BSc, of the Department of Neurology at Aarhus University Hospital in Denmark.To arrive at their results, Elkjær and colleagues analyzed the test scores of nearly half a million sixth-grade children with a mean (SD) age of 12.9 years who participated in standardized Danish language and mathematics tests. Of that group, 1,865 were exposed to antiepileptic drugs in monotherapy: valproate, 253; phenobarbital, 86; oxcarbazepine, 236, lamotrigine, 396; clonazepam, 188; and carbamazepine, 294.

Authors found that children who were exposed to valproate scored worse on the sixth-grade Danish tests (adjusted difference, -0.27 SD, 95% CI) and sixth-grade mathematics tests (adjusted difference, -0.33 SD; 95% CI) compared with unexposed children and children exposed to lamotrigine (adjusted difference, -0.33 SD, 95% CI).

The Implications

Page B Pennell MD

Page B Pennell, MD

Additionally, children exposed to clonazepam scored worse in sixth-grade Danish tests (adjusted difference, -0.07 SD 95% CI). Conversely, children exposed to carbamazepine lamotrigine, phenobarbital and oxcarbazepine were not linked to poor school performance compared with unexposed children.In an editorial response to the study, Page B Pennell, MD, of Brigham and Women’s Hospital in Boston, cited previous studies suggesting that prenatal valproate exposure was linked to autism spectrum disorder, in addition to neurocognitive effects. The Danish population-based study included 388 children with prenatal valproate monotherapy exposure who were born between 1996 and 2006. The adjusted hazard ratio was 3.0 (95% cI) for autism spectrum disorder and 4.9 (95% CI) for autism in the valproate-exposed children compared with unexposed children.

“One can presume that this [autism spectrum] study population overlaps substantially with [Elkjær’s] report, although this was not explicitly stated in the text.” Pennell wrote. “Another prospective cohort study found that children who were exposed prenatally to valproate were at a significantly greater risk for a diagnosis of attention-deficit/hyperactivity disorder [ADHD too].”

Previous studies have also shown that prenatal exposure to valproate can increase the risk of malformations and reduced IQ. Animal studies of both prenatal and postnatal exposure also suggest that valproate affects brain development. However these studies did not monitor the long-term consequences of prenatal exposure to valproate.

“In contrast to most other studies, our study was able to compare the school performance of valproate-exposed children with that of children unexposed to AEDs [antiepileptic drugs],” the authors wrote. “However, in the comparison with children prenatally exposed to lamotrigine as the reference group, children prenatally exposed to valproate still showed significant impairment.”

Results supported previous studies, which identified no signs of cognitive impairment after prenatal exposure to lamotrigine, and no identifiable decrease in school performance in children exposed to phenobarbital during pregnancy, although researchers noted that the sample size was small.

Researchers identified several shortcomings of the study. First, it only included students in public schools, which left out 19.2% of the student population. Second, even though children were required to participate in the tests regardless of proficiency level, tests were still missed by a relatively high proportion of students with special education needs, which the authors said could lead to an underestimation of the association between AED exposure and cognitive deficiency as measured by school performance.

Additionally, there was missing information about folic acid use during pregnancy, and a lack of information on covariates (maternal seizure frequency, smoking, etc) could constitute a limitation to the study.

On the other hand, a major strength of the study was that no teacher or evaluator assessment was required, which makes the study unlikely to be affected by information bias.

What's Next?

“A notable advantage of this study by Elkjær et al is the ability of the design to analyze data on all children who had prenatal AED exposure, rather than just the children of women with epilepsy,” Pennell wrote. “Most prospective studies have recruited participants at epilepsy centers. The expansion of this evaluation to women receiving AEDs for other indications is important, because it reflects real prescription practices in the general population.”Elkjær and colleauges noted that further research needs to be conducted to confirm their findings. Additionally, according to Pennell, the study implies that prescribers should carefully consider their prescriptions and dosing strategies throughout pregnancy to balance fetal risk with maternal disease control.

“By choosing to prescribe valproate to women of childbearing age, regardless of indication, the clinician is putting her children at an elevated risk not only for early developmental delay, autism, and autism spectrum disorders, but also lower results on standardized language and mathematics testing in the teenage years,” she wrote.

The study, "Association Between Prenatal Valproate Exposure and Performance on Standardized Language and Mathematics Tests in School-aged Children was published February 19, 2018 in JAMA Neurology.

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