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. 2023 Jul;118(1):303-313.
doi: 10.1016/j.ajcnut.2023.05.023. Epub 2023 May 20.

Does maternal genetic liability to folate deficiency influence the risk of antiseizure medication-associated language impairment and autistic traits in children of women with epilepsy?

Elisabeth Synnøve Nilsen Husebye  1 , Julia Romanowska  2 , Anne-Lise Bjørke-Monsen  3 , Nils Erik Gilhus  4 , Kaja Selmer  5 , Kristina Gervin  6 , Bettina Riedel  3 , Marte Helene Bjørk  4
Affiliations

Does maternal genetic liability to folate deficiency influence the risk of antiseizure medication-associated language impairment and autistic traits in children of women with epilepsy?

Elisabeth Synnøve Nilsen Husebye et al. Am J Clin Nutr. 2023 Jul.

Abstract

Background: Prenatal exposure to antiseizure medication (ASM) may lead to low plasma folate concentrations and is associated with impaired neurodevelopment.

Objectives: To examine whether maternal genetic liability to folate deficiency interacts with ASM-associated risk of language impairment and autistic traits in children of women with epilepsy.

Methods: We included children of women with and without epilepsy and with available genetic data enrolled in the Norwegian Mother, Father, and Child Cohort Study. Information on ASM use, folic acid supplement use and dose, dietary folate intake, child autistic traits, and child language impairment was obtained from parent-reported questionnaires. Using logistic regression, we examined the interaction between prenatal ASM exposure and maternal genetic liability to folate deficiency expressed as polygenic risk score of low folate concentrations or maternal rs1801133 genotype (CC or CT/TT) on risk of language impairment or autistic traits.

Results: We included 96 children of women with ASM-treated epilepsy, 131 children of women with ASM-untreated epilepsy, and 37,249 children of women without epilepsy. The polygenic risk score of low folate concentrations did not interact with the ASM-associated risk of language impairment or autistic traits in ASM-exposed children of women with epilepsy compared with ASM-unexposed children aged 1.5-8 y. ASM-exposed children had increased risk of adverse neurodevelopment regardless of maternal rs1801133 genotype {adjusted odds ratio [aOR] for language impairment aged 8 y was 2.88 [95% confidence interval (CI): 1.00, 8.26] if CC and aOR 2.88 [95% CI: 1.10, 7.53] if CT/TT genotypes}. In children of women without epilepsy aged 3 y, those with maternal rs1801133 CT/TT compared with CC genotype had increased risk of language impairment (aOR: 1.18; 95% CI: 1.05, 1.34).

Conclusions: In this cohort of pregnant women reporting widespread use of folic acid supplements, maternal genetic liability to folate deficiency did not significantly influence the ASM-associated risk of impaired neurodevelopment.

Keywords: MBRN; MTHFR; MoBa; autism spectrum disorder; folic acid; language delay; polygenic risk score.

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Figures

FIGURE 1
FIGURE 1
Flowchart of included and excluded cases. ASM, antiseizure medication; MoBa, The Norwegian Mother, Father, and Child Cohort Study; PRS, polygenic risk score.
FIGURE 2
FIGURE 2
Maternal plasma folate concentrations (sum of concentrations of 5-methyltetrahydrofolate and 4-alfa-hydroxy-5-methyltetrahydrofolate) during gestation weeks 17–19 stratified by maternal rs1801133 genotype and folic acid supplement dose in women with antiseizure medication (ASM)-treated epilepsy (n = 80). The data are presented as boxplots with varying width: the middle line is the median, the box extends from the first to the third quartile, and the whiskers reach the largest value in the data, not larger than 1.5 × IQR; any data beyond these bounds are plotted as separate points. The width of the boxplot is proportional to the sample size. Folic acid supplement dose is defined as low dose if ≤0.4 mg/d, medium dose if 0.4 <1 mg/d, and high dose if ≥1 mg/d. NA, not applicable.
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