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Maternal use of epilepsy drug may decrease school performance in offspring
Pregnant women who used valproate had children with significantly lower school performance vs. children who were exposed to lamotrigine or not exposed to anti-epileptic drugs at all, according to findings recently published in JAMA Neurology.
“Numerous studies demonstrate increased risk of malformations after prenatal exposure, especially to valproate sodium. In addition, growing evidence indicates reduced IQ in young children after valproate exposure, and increased risk of autism spectrum disorders has been reported. Animal studies of prenatal and postnatal exposure also indicate affected brain development,” Lars Skou Elkjær, MD, of the department of neurology at Aarhus University Hospital in Denmark, and colleagues wrote.
“However, knowledge of the long-term consequences of prenatal exposure to valproate and newer generations of [anti-epileptic drugs] is scarce,” they added.
Of 656,496 potential children born in Denmark between 1997 and 2006 that were eligible for the register-based, cohort study, only 479,027 children took the math and Danish tests that were part of the analysis. These test results were standardized to z scores and adjusted for parental income, maternal education, sex and an adjusted calendar year based on the year the student took the test.
Elkjær and colleagues found that 1,865 children had mothers who used different antiepileptic drugs in utero. Offspring whose mother used valproate did worse on sixth-grade math tests (adjusted difference = 0.33 SD; (95% CI, 0.47 to 0.19 and sixth-grade Danish tests (adjusted difference = 0.27 SD; 95% CI, 0.42 to 0.12) and) vs. offspring whose mothers used lamotrigine (adjusted difference = 0.33 SD; 95% CI, 0.60 to 0.06) or offspring not exposed to any anti-epileptic drugs.
In addition, those offspring whose mothers used clonazepam did worse in the sixth-grade Danish tests (adjusted difference = 0.07 SD; 95% CI, 0.12 to 0.02). Oxcarbazepine, phenobarbital, lamotrigine, and carbamazepine were not associated with poor school performance vs. offspring whose mothers who did not use any anti-epileptic drugs while pregnant.
“Every child was required to participate in the tests regardless of proficiency level, and assistance for participating was allowed if needed,” Elkjaer and colleagues wrote. “Still, tests were missed by a relatively high proportion of students with special education needs. This exclusion might lead to an underestimation of the association between [anti-epileptic drugs] exposure and cognitive deficiency as measured by school performance.”
Researchers added that their findings suggest women of childbearing age should be cautioned against using valproate.
In a related editorial, Page B. Pennell, MD, of the department of neurology at Harvard Medical School called the findings “not just additive but rather synergistic with the current literature.”
She also put Elkjaer and colleagues’ findings and warning about valproate use in women who may become pregnant into a greater context.
“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 into the teenage years,” Pennell wrote. “One could argue that comparisons to an [anti-epileptic drugs]-unexposed group is not clinically useful, because most women with epilepsy and major psychiatric disorders need to continue taking medication owing to the adverse fetal effects of uncontrolled maternal disease... However, this study verified that the consequences of valproate prenatal exposure were worse than exposure to the [anti-epileptic drugs] alternative, lamotrigine, which is effective for bipolar disorder as well as epilepsy.” – by Janel Miller
Disclosure: Neither Elkjaer nor Pennell report any relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.