Abstracts

Rationale: Antiseizure medications (ASMs) are potential teratogens, and teratogens act in an exposure-dependent manner. Teratogenic effects include malformations and neurodevelopmental effects. We investigate exposure-dependent neuropsychological effects of fetal ASMs in children at age 6 years-old (yo) of women with epilepsy (WWE) in the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study.

Methods: The MONEAD study is a prospective, observational, multi-center, NIH-fuded investigation of pregnancy outcomes which enrolled WWE during pregnancy. Our a priori main neurodevelopmental outcome was blindly-assessed 6 yo Verbal Index score which is an average of several standardized language measures. Adjusted linear regression models were run to assess the associations between maximum 3rd-trimester ratio ASM concentrations and VIS.

Results: There were 268 children of WWE on ASM with 3^rd-trimester concentrations. Enrolled WWE were primarily on monotherapy (73%) with 79% of monotherapies on lamotrigine or levetiracetam, and 42% of polytherapies were on dual therapy of these two ASMs. Our study is limited in sample size for other ASMs. Parameter Estimates (95% CIs) for significant covariates in the adjusted model included mother’s IQ (0.3 (0.2, 0.4), p< .001), age (0.3 (0.0, 0.6)), p=0.023), education level (p=0.043 across 3 categories), and child’s small for gestational age -11.0 (-19.0, -3.0), p=0.007) and sex (-2.9 (-5.0, -0.7), p=0.009). Exposure-dependent effects, measured as 3^rd trimester ASM blood concentrations, differed across ASMs. Higher levetiracetam concentrations were associated with lower Verbal Index scores (-8.8 (-16.1, -1.5), p=0.018) while lamotrigine exhibited opposite effects (13.0 (2.4, 23.6), p=0.017). However, it should be noted that the mean (95% CI) Verbal Index score at 6 yo did not differ between children exposed to levetiracetam monotherapy (107.4 (104.4, 110.4)) compared to lamotrigine monotherapy (109.2 (106.9, 111.5)) or compared to children of healthy women (108.4 (106.0, 110.9)).

Conclusions: Our findings at age 6 yo demonstrate exposure-dependent effects on fetal brain development, as measured by verbal abilities in children of WWE for levetiracetam. Our findings suggest that even for safer ASMs, dosing need to be adjusted to levels that prevent convulsions but balance risks to the fetus that high levels may pose. Additional studies are needed to understand neurodevelopmental effects of fetal exposure for the majority ASMs.


Funding: NIH, NINDS and NICHD #U01-NS038455.