Abstracts

Rationale:
Adverse neurodevelopmental effects of fetal antiseizure medication (ASM) exposures have been demonstrated in animal and human studies, but the effects for many ASMs are uncertain. Further, teratogens can affect both structure and function, and are known to work in an exposure-dependent manner. However, fetal dose-dependent effects on neuropsychological outcomes in children have been demonstrated previously only for valproate. This report examines these effects in other ASMs.
Method:
The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a prospective, observational, multi-center investigation of pregnancy outcomes for both the mother and child. Women with epilepsy (WWE) and healthy women (HW) were enrolled during pregnancy if they were ages 14-45 years and their pregnancy was <20 weeks gestational age. Exclusion criteria included history of psychogenic spells, IQ < 70, other major medical illness, progressive cerebral disease, and switching ASMs pre-enrollment. Children were assessed at age 2 years old using the Bayley Scales of Infant and Toddler Development-3 (BSID-III) yielding 5 Scale scores (i.e., Language, Motor, Cognitive, Social-Emotional, Adaptive Behavior). To compare ASM blood levels (ABLs) across drugs, they were converted to a percent of their therapeutic range (%ABL), and the primary analysis for ABLs was for the maximum observed level in the 3rd trimester based on similarity to the effects of fetal alcohol exposure. Analyses were conducted using linear regression and ANCOVA models adjusting for significant factors (e.g., maternal IQ). Similar analyses were conducted for maximum % Defined Daily Dose (%DDD), which were defined by the World Health Organization.
Results:
Most pregnant WWE enrolled in the study were on monotherapy (76%), and 78% of monotherapies were lamotrigine (LTG, 41% monotherapy) or levetiracetam (LEV, 37% monotherapy). Also, 41% of the polytherapies were on dual therapy with LTG+LEV. BSID-III assessments were conducted in 292 children of WWE and 90 children of HW. In the primary adjusted analyses, there were no differences in children for WWE vs HW and for Monotherapy vs Polytherapy on the a priori main outcomes of Language domain or any of the other 4 BSID-III Scale score domains. Significant factors in the regression for age 2yo IQ of children of WWE included maternal IQ, education and depression, and child ethnicity. However, in secondary analyses for children of WWE on ASM, lower BSID-III scores for the Motor domain were associated with higher max observed %ABLs in the 3rd trimester, and there was a trend for the General Adaptive domain (Table). These effects were seen for Monotherapy (-8.9; 95% CIs= -15.1, -2.6) but not Polytherapy, and for Levetiracetam monotherapy (-13.3; 95% CIs= -22.3, -4.4) but not Lamotrigine monotherapy or Other monotherapies combined (see Figure). Exposure effects were not seen for max observed %ABLs in second trimester or across all pregnancy. Similar analyses revealed that higher max %DDD in the 3rd trimester was associated with lower scores in the General Adaptive domain with a trend in the Cognitive Domain (Table).
Conclusion:
Neurodevelopmental outcomes for some domains were poorer with higher max observed %ABLs and higher max %DDD during the 3rd trimester. Such an exposure-dependent effect would be expected for teratogens. These secondary analyses need to be confirmed in this and other cohorts at older ages, where neuropsychological testing is more sensitive to cognitive outcomes.
Funding:
:National Institutes of Health, NINDS and NICHD #U01-NS038455.