Neurodevelopment After Prenatal Exposure to Newer Epilepsy Drugs Tracked for 3 Years

Children with fetal exposure to newer antiseizure medications showed no difference in neurodevelopmental outcomes at age 3 compared with unexposed children, data from the ongoing MONEAD study showed.

In the prospective observational study, mean verbal index scores at age 3 did not differ for children of women with epilepsy (102.7) versus those born to mothers who did not have epilepsy (102.3), reported Kimford Meador, MD, of Stanford University in Palo Alto, California.

Antiseizure medication exposure effects were not seen for maximum third trimester blood concentrations (adjusted parameter estimate -2.9, 95% CI -6.7 to 1.0), the researchers reported in Lancet Neurology. However, some exposure-dependent antiseizure medication effects were seen in secondary analyses.

The study identified other significant risk factors for reduced verbal index scores including maternal IQ, maternal education, post-birth maternal anxiety, gestational age at enrollment, child’s sex, and child’s ethnicity.

All teratogenicity studies are observational, but the authors identified several factors that set their study apart. “None of the previous studies included a detailed collection of potential confounding factors during pregnancy and after birth,” Meador and co-authors noted. “For example, no previous study has monitored antiseizure medication levels during pregnancy, which is potentially important given that many antiseizure medications have marked clearance changes during pregnancy which might alter fetal exposure.”

Slightly more than 40% of maternal participants with epilepsy took lamotrigine (Lamictal, 43%), while one third took levetiracetam (Keppra, 35%) as monotherapies. Among participants who took a multidrug antiseizure regimen, 41% took both lamotrigine and levetiracetam. Additional monotherapies in the study included oxcarbazepine (Trileptal, 7%), carbamazepine (Tegretol, 6%), zonisamide (Zonegran, 5%), and topiramate (Topamax, 1%).

Investigators enrolled 456 pregnant women during a 4-year period, including 351 with epilepsy and 105 without epilepsy. Women with epilepsy delivered 345 children, while those without epilepsy had 106 children. Assessors blinded to the mothers’ antiseizure medication status conducted neuropsychological assessments with the children.

The investigators created the verbal index score by averaging scores on the naming vocabulary and verbal comprehension subtests of the Differential Ability Scales-II, expressive communication and auditory comprehension subscales of Preschool Language Scale-5, and the Peabody Picture Vocabulary Test-4. They chose to combine standardized verbal tests because previous studies suggested that verbal abilities might be more susceptible to fetal antiseizure medication exposure than other domains, they wrote.

Secondary analyses revealed an association between verbal index scores and the specific antiseizure medication the mother took during the third trimester of pregnancy. This association was strongest with levetiracetam. They did not see any exposure-dependent effects for lamotrigine.

Meador and co-authors noted that higher doses in the third trimester were associated with worse cognitive performance across all antiseizure medications for five of 14 cognitive measures they studied, including the verbal index score. Levetiracetam use was associated with worse cognitive performance on four of the 14 cognitive measures.

Overall, this study showed that, in keeping with contemporary guidelines, prescribing habits have trended away from older antiseizure drugs like valproate (Depakote), which have been shown to be more harmful to developing fetuses, Max Wiznitzer, MD, of Case Western Reserve University in Cleveland, Ohio, wrote in an accompanying editorial.

“The findings of the MONEAD study in children at age 3 years provide reassurance that, with the newer antiseizure medications (particularly levetiracetam and lamotrigine, which were the most common medications used in the study), physicians and patients do not need to be concerned about a significant negative effect on cognitive outcome,” he wrote.

These findings are important, Wiznitzer noted, because Meador and co-authors identified an adverse effect on the verbal index score for children whose mothers experienced post-birth anxiety. This effect was more pronounced in women with epilepsy than in those without epilepsy.

According to Wiznitzer, strengths of the MONEAD study included the geographic diversity of the 20 participating U.S. epilepsy centers, as well as the number of maternal factors that were considered. In addition to maternal age, education level, employment status at enrollment, the co-authors also examined household income, pregnancy type (planned vs unplanned), major depressive episode during pregnancy, smoking, alcohol use, and illicit substance use.

He also cited the evaluation of blood concentrations and dosing of antiseizure medications, and the pediatric neuropsychological tests that were conducted as study strengths. The possible inverse associations between dose and concentration of levetiracetam in the third trimester and some of the test measures used in MONEAD require confirmation during the follow-up of the study, he noted.

Study limitations include the potential for residual confounding that exists in all observational studies, Meador and co-authors acknowledged. The increased use of antiseizure medications for non-epilepsy indications like pain and psychiatric conditions means that further research is needed. In addition, future neuropsychological assessments may detect associations not seen at age 3.

“The findings provide valuable information for women with epilepsy, but there is still much to do as we don’t know the risks for most antiseizure medications,” Meador said in a statement.

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