Association of Prenatal Exposure to Antiseizure Medications With Creative and Executive Function at Age 4.5 Years
06/2024
Journal Article
Authors:
Meador, K. J.;
Cohen, M. J.;
Loring, D. W.;
Matthews, A. G.;
Brown, C. A.;
Robalino, C.;
Carmack, A.;
Sumners, S.;
Birnbaum, A. K.;
Kalayjian, L. A.;
Gedzelman, E.;
Voinescu, P. E.;
Gerard, E. E.;
Hanna, J.;
Cavitt, J.;
Sam, M.;
Hwang, S. T.;
Pack, A. M.;
Tsai, J. J.;
Pennell, P. B.
Volume:
102
Pagination:
e209448
Issue:
12
Journal:
Neurology
PMID:
38810172
URL:
https://www.ncbi.nlm.nih.gov/pubmed/38810172
DOI:
10.1212/WNL.0000000000209448
Keywords:
Humans Female *Anticonvulsants/adverse effects/therapeutic use *Prenatal Exposure Delayed Effects/chemically induced Child, Preschool Pregnancy *Executive Function/drug effects Male *Epilepsy/drug therapy *Creativity Prospective Studies Adult
Abstract:
BACKGROUND AND OBJECTIVES: Neurodevelopmental effects of fetal antiseizure medication (ASM) exposure on creativity and executive functions are poorly understood. We previously found fetal valproate exposure to adversely affect measures of creativity and executive functions. In this study, we examine fetal exposure of newer ASMs on these functions in children of women with epilepsy (WWE) compared with children of healthy women (HW). METHODS: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study is a multicenter NIH-funded prospective observational cohort study of WWE and HW enrolled in pregnancy and their offsprings. This report examines blindly assessed creativity and executive functions in 4.5-year-old children of WWE vs HW. In addition, exposure-dependent ASM effects during the third trimester were examined in children of WWE, using a ratio of maximum observed ASM concentrations and ratio of defined daily dose (ratio DDD). For polytherapy, ratios were summed across ASMs. Linear regression models adjusted for multiple potential confounding factors were conducted for all analyses. The primary outcome for 4.5-year-old children was the Torrance Test of Creative Thinking-Figural Creativity Index. Secondary outcomes included the Global Executive Composite Score from the Behavior Rating Inventory of Executive Function-Preschool Version and subscales and other indexes of both measures. RESULTS: The primary analysis included 251 children of WWE and 73 of HW. No differences in creativity or executive function were found between children of WWE vs HW. No ASM exposure-dependent effects were found for the creativity measures, but exposure-dependent effects for executive function were present for ratio ASM concentration and ratio DDD. DISCUSSION: Our findings at 4.5 years show no differences in creative thinking between children of WWE vs HW (-3.2 [-9.0 to 2.7], p = 0.286) or associations with fetal exposure to ASMs (-2.6 [-11.0 to 5.7], p = 0.530). Secondary analyses revealed fetal exposure-dependent effects for executive function in children of WWE (7.0 [2.9-11.2], p = 0.001), which are most marked for levetiracetam (12.9 [4.2-21.6], p = 0.004). Our findings suggest that even for relatively safe ASMs, dosing needs to be adjusted to concentrations that prevent seizures, but balance risks to the fetus that high concentrations may pose. TRIAL REGISTRATION INFORMATION: The study is registered at ClinicalTrials.gov as NCT01730170.
