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Observational Study
. 2024 Jun 25;102(12):e209448.
doi: 10.1212/WNL.0000000000209448. Epub 2024 May 29.

Association of Prenatal Exposure to Antiseizure Medications With Creative and Executive Function at Age 4.5 Years

Kimford J Meador  1 , Morris J Cohen  1 , David W Loring  1 , Abigail G Matthews  1 , Carrie A Brown  1 , Chelsea Robalino  1 , Andrea Carmack  1 , Sarah Sumners  1 , Angela K Birnbaum  1 , Laura A Kalayjian  1 , Evan Gedzelman  1 , Paula E Voinescu  1 , Elizabeth E Gerard  1 , Julie Hanna  1 , Jennifer Cavitt  1 , Maria Sam  1 , Sean T Hwang  1 , Alison M Pack  1 , Jeffrey J Tsai  1 , Page B Pennell  1 ; Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Investigator Group  1
Collaborators, Affiliations
Observational Study

Association of Prenatal Exposure to Antiseizure Medications With Creative and Executive Function at Age 4.5 Years

Kimford J Meador et al. Neurology. .

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.

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Conflict of interest statement

K.J. Meador has received research support from the NIH, Eisai, and Medtronic Inc. The Epilepsy Study Consortium pays his university for his research consultant time related to Eisai, GW Pharmaceuticals, NeuroPace, Novartis, Supernus, Upsher-Smith Laboratories, UCB Pharma, and Vivus Pharmaceuticals. In addition, K.J. Meador is Co-I and Director of Cognitive Core of the Human Epilepsy Project for the Epilepsy Study Consortium, and is on the editorial boards for Neurology, Cognitive & Behavioral Neurology, Epilepsy & Behavior, and Epilepsy & Behavior Case Reports. M.J. Cohen receives royalties from Multi Health Systems, Inc. as author of the Children's Memory Scale. D.W. Loring receives research support from the NIH, is a consultant for Medtronic, serves on the editorial boards for Neuropsychology Review and Epilepsia for which he receives editorial stipends, and is on the editorial board for Archives of Clinical Neuropsychology. A.K. Birnbaum reports receiving grant support, paid to her institution, from Supernus Pharmaceuticals and Veloxis Pharmaceuticals, holding patent US9770407B2 on parenteral carbamazepine formulation, licensed to Lundbeck, and patent EP12150783A on novel parenteral carbamazepine formulations, licensed to Lundbeck. P.E. Voinescu received speaking honoraria from Physicians' Education Resource and from Philippines League Against Epilepsy. E.E. Gerard has served as site-PI for clinical trials sponsored by Xenon and Sunovion pharmaceuticals as well as a trial sponsored by Eisai and Stanford University, and has been reimbursed for lectures given to GW Pharmaceuticals Staff and Neurology Week. J. Cavitt received research support from National Institute of Neurological Disorders and Stroke (MONEAD) and from GW Pharmaceuticals, and advisory board fees from Jazz Pharmaceuticals. M. Sam has received advisory board consulting fees for Aquestive. S. Hwang reports no disclosures. A.M. Pack reports funding from NIH, royalties from Up to Date, and travel reimbursement for AAN and ABPN activities. J.J. Tsai reports grant from Institute of Translational Health Sciences (funded by the National Center for Advancing Translational Sciences of the NIH), and has served as site-PI for clinical trials sponsored by Xenon. P.B. Pennell reports grants from NIH, personal fees from NIH for Grant reviews, personal fees from AES and the AAN as speaking honoraria, personal fees from Medical Schools for speaking honoraria and travel, and personal fees from UpToDate, Inc. for royalties outside the submitted work. The other authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.

Figures

Figure 1
Figure 1. Age 4.5 Years TTCT-F Creativity Index by Mother's Study Group—Children of WWE vs HW (N = 324)
Adjusted least squares mean scores (95% CI) 90.5 (87.8–93.2) for children of WWE vs 93.7 (88.6–98.8) for children of HW (nonsignificant). HW = healthy women; TTCT-F = Torrance Test of Creative Thinking—Figural; WWE = women with epilepsy.
Figure 2
Figure 2. Age 4.5 Years TTCT-F Creativity Index Score vs Third-Trimester Maximum Observed Ratio ASM Concentration in Children of WWE With Third-Trimester Blood Concentrations (N = 228)
Adjusted parameter estimate (95% CI) −2.6 (−11.0 to 5.7) (nonsignificant). ASM = antiseizure medication; TTCT-F = Torrance Test of Creative Thinking—Figural.
See this image and copyright information in PMC

References

    1. Sternberg R, Sternberg K. Creativity. In: Cognitive Psychology. 6th ed. Cengage Learning; 2011.
    1. Beaty RE, Benedek M, Silvia PJ, Schacter DL. Creative cognition and brain network dynamics. Trends Cogn Sci. 2016;20(2):87-95. doi: 10.1016/j.tics.2015.10.004 - DOI - PMC - PubMed
    1. Guilford JP, Christensen PR. The one-way relation between creative potential and IQ. J Creat Behav. 1973;7(4):247-252. doi: 10.1002/j.2162-6057.1973.tb01096.x - DOI
    1. Rogers CJ, Tolmie A, Massonnié J, Thomas MS. Complex cognition and individual variability: a mixed methods study of the relationship between creativity and executive control. Front Psychol. 2023;14:1191893. doi: 10.3389/fpsyg.2023.1191893 - DOI - PMC - PubMed
    1. Li Y, Meador KJ. Epilepsy and pregnancy. Continuum (Minneap Minn). 2022;28(1):34-54. doi: 10.1212/con.0000000000001056 - DOI - PMC - PubMed

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