Cognitive Outcomes in Children of Pregnant Women with Epilepsy

Antiseizure medications as a group are known to be teratogenic, although the risks are not equivalent across all medications. In fact, the teratogenic risks for many antiseizure medications are unknown. In addition to malformations, antiseizure medications may cause cognitive or behavioral effects in children with fetal exposure, but studies have not clarified these effects for many of the medications. Except for valproate, dose-dependent effects of antiseizure medications on neurobehavioral outcomes in children have not been reported.

In this study, Meador and investigators asked whether an association can be found between fetal exposure to antiseizure medications and cognition in children at age 2 years. Pregnant women with epilepsy and healthy pregnant controls were enrolled at gestational age ≤20 weeks.

The primary outcomes were the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) language domain score for these children at age 2 years and the association between the score and the maximum ratio of antiseizure medication blood levels during the third trimester. Secondary outcomes were scores on other BSID-III domains and the association between scores and the maximum ratio of the defined daily dose of antiseizure medication in the third trimester.

The investigators analyzed 282 children born to mothers with epilepsy and 90 born to healthy controls who completed the BSID-III assessment at age 2 years. Of the subset who had maternal antiseizure medication blood level measurements in the third trimester, 59% had mothers with focal epilepsy. Lamotrigine and levetiracetam were the most common monotherapies used.

For the primary outcome, the investigators found no significant difference between children of mothers with epilepsy and children of healthy controls in the BSID-III language domain scores at age 2 years. In addition, no association was found between language domain scores and third-trimester maximum ratio of antiseizure medication blood levels.

Analyses for secondary outcomes, however, found statistically significant associations with higher antiseizure exposure and lower cognitive outcomes for the 4 BSID-III domains, but most of these were lost after investigators adjusted for maternal IQ, educational level, postpartum anxiety, child’s sex, ethnicity, and birth weight. After adjustment, the maximum ratio of third-trimester antiseizure medication blood levels was associated with lower scores for the motor domain (P = .03), and the maximum ratio of the defined daily dose in the third trimester was associated with lower scores for the general adaptive domain (P = .049). Thus, the investigators found some evidence that high levels of antiseizure medications in the third trimester affected neurodevelopment.

When BSID-III scores for children of mothers who received monotherapy versus polytherapy antiseizure medications were analyzed, the investigators found no significant differences for any domain. Language domain scores were not significantly different between individual antiseizure medications, but sample sizes for many were too small to evaluate.

Although the investigators noted that the comparable cognitive outcome in children of mothers who were taking antiseizure medications and children of healthy women was an “encouraging finding,” they noted that scores at age 2 years are not strongly predictive of later outcomes. Therefore, “assessments at older ages and in other cohorts are critical.” In the future, the study investigators will analyze outcomes in children at 6 years of age.

Source

Meador KJ, Cohen MJ, Loring DW, et al. Two-year-old cognitive outcomes in children of pregnant women with epilepsy in the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Study. JAMA Neurol. 2021;78(8):927-936.