No differences in creativity emerged between children whose mothers had epilepsy and other children, new MONEAD cohort data showed.
Scores on the Torrance Test of Creative Thinking-Figural (TTCT-F) creativity index (difference of -3.2 points, 95% -9.0 to 2.7, P=0.286) and associations with fetal exposure to anti-seizure medications (difference of -2.6 points, 95% -11.0 to 5.7, P=0.530) showed no difference between children of women with epilepsy at age 4.5 years and children of healthy women, reported Kimford Meador, MD, of Stanford University in Palo Alto, California, and co-authors in Neurology.
On the parent-completed Behavior Rating Inventory of Executive Function -- Preschool Version (BRIEF-P) rating scale, however, children of women with epilepsy showed exposure-dependent effects in executive function (P=0.001), which were most pronounced in children of women taking levetiracetam (P=0.004).
"The main finding of no difference in creativity between children of healthy mothers and children of women with epilepsy is consistent with the finding that the large majority of women on the newer antiseizure medications -- lamotrigine and levetiracetam -- have normal pregnancies and children," Meador told MedPage Today. "Unfortunately, there are still many antiseizure medications for which we don't know the risk to the fetus."
Prior research showed that prenatal exposure to valproate -- which carries a boxed warning about fetal malformations and decreased IQ -- impaired creative fluency and originality when children were age 4.5 years. In 2011, the FDA issued a safety communication stating that women of childbearing age treated with valproate should use effective birth control.
Growing evidence points to topiramate exposure as also having an increased risk of adverse neurodevelopmental outcomes, observed Eliza Honybun, MPsych, and Piero Perucca, MD, PhD, both of the University of Melbourne in Australia, in an accompanying editorial. "For valproate and topiramate, these adverse effects seem to be dose-dependent, with higher doses being associated with poorer outcomes," they said.
"Of note, previous analyses of the MONEAD cohort had found higher third-trimester blood concentrations of levetiracetam to be associated with poorer cognitive outcomes at age 3 years and worse adaptive functioning at 4.5 years," Honybun and Perucca wrote.
"A recent population-based study across five Nordic countries also suggested an association between prenatal exposure to levetiracetam and increased risks of anxiety and ADHD [attention deficit-hyperactivity disorder] in children and adolescents," the editorialists added. "Thus, it seems that even levetiracetam, an antiseizure medication widely regarded as one of the safest when used in pregnancy, can affect postnatal neurodevelopment, at least at higher doses."
Meador and colleagues studied 251 children of women with epilepsy and 73 children of healthy women. Among women with epilepsy, the most prevalent third-trimester antiseizure drug regimen was monotherapy (72.5%), followed by polytherapy (21.9%). About 5% were not on antiseizure treatment.
Lamotrigine and levetiracetam were the most common monotherapies (44.5% and 37.4% of all monotherapies, respectively). Lamotrigine combined with levetiracetam was the most common polytherapy (41.8% of all polytherapies).
The primary outcome for children age 4.5 years was the TTCT-F creativity index. TTCT-F scores are normalized; a score of 100 is the mean for the norms and the standard deviation is 20, Meador noted. Secondary outcomes included scores on the BRIEF-P, an assessment completed by the child's parent.
On the TTCT-F creativity index, adjusted mean scores were 90.5 points (95% CI 87.8–93.2) for children of women with epilepsy and 93.7 points (95% CI 88.6–98.8) for children of healthy women. A second primary analysis found no significant relationship between TTCT-F creativity scores and in utero third-trimester blood concentrations of antiseizure drugs.
On the BRIEF-P, worse scores emerged with increasing third-trimester antiseizure medication exposure. Higher blood concentrations of levetiracetam were associated with worse performance on the BRIEF-P global executive composite score, inhibitory self-control index, and emergent metacognition index.
Lamotrigine monotherapy showed no exposure-dependent effects on the BRIEF-P, but higher concentrations of lamotrigine combined with levetiracetam were associated with poorer performance on the flexibility index and the emergent metacognition index. Samples sizes for other drugs were too small to assess individually.
"Our findings highlight that even for epilepsy medications that are generally considered to be safe in pregnancy, dose adjustments should be made with a goal of reaching an optimal balance between controlling seizures and minimizing negative effects on the developing child," Meador said.
MONEAD participants were recruited from tertiary centers and results may not apply to all epilepsy patients, the researchers acknowledged. Selection bias may have been present, and unmeasured confounding may have influenced outcomes.
Disclosures
The study was supported by the NIH's National Institute of Neurological Disorders and Stroke.
Meador reported relationships with NIH, Eisai, Medtronic, the Epilepsy Study Consortium, GW Pharmaceuticals, NeuroPace, Novartis, Supernus, Upsher-Smith Laboratories, UCB Pharma, and Vivus Pharmaceuticals.
Co-authors reported relationships with nonprofit organizations and pharmaceutical companies.
Honybun reported support from the Australian Government Research Training Program. Perucca reported relationships with Chiesi, Eisai, LivaNova, Novartis, Sun Pharma, Supernus, and UCB Pharma.
Primary Source
Neurology
Source Reference: Meador KJ, et al "Association of prenatal exposure to antiseizure medications with creative and executive function at age 4.5 years" Neurology 2024; DOI: 10.1212/WNL.0000000000209448.
Secondary Source
Neurology
Source Reference: Honybun E, Perucca P "Adverse neurodevelopmental outcomes after in utero exposure to antiseizure medications: an ever-expanding story" Neurology 2024; DOI: 10.1212/WNL.0000000000209553.
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