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. 2018 Aug 28;91(9):e811-e821.
doi: 10.1212/WNL.0000000000006073. Epub 2018 Aug 1.

Verbal abilities in children of mothers with epilepsy: Association to maternal folate status

Elisabeth Synnøve Nilsen Husebye  1 , Nils Erik Gilhus  2 , Bettina Riedel  2 , Olav Spigset  2 , Anne Kjersti Daltveit  2 , Marte Helene Bjørk  2
Affiliations

Verbal abilities in children of mothers with epilepsy: Association to maternal folate status

Elisabeth Synnøve Nilsen Husebye et al. Neurology. .

Abstract

Objective: To examine the effect of maternal folic acid supplementation and maternal plasma folate and antiepileptic drug (AED) concentrations on language delay in AED-exposed children of mothers with epilepsy.

Methods: Children of mothers with and without epilepsy enrolled from 1999 to 2008 in the Norwegian Mother and Child Cohort study were included. Information on medical history, AED use, and folic acid supplementation during pregnancy was collected from parent-completed questionnaires. Maternal plasma folate and maternal plasma and umbilical cord AED concentrations were measured in blood samples from gestational weeks 17 to 19 and immediately after birth, respectively. Language development at 18 and 36 months was evaluated by the Ages and Stages Questionnaires.

Results: A total of 335 AED-exposed children of mothers with epilepsy and 104,222 children of mothers without epilepsy were surveyed. For those with no maternal periconceptional folic acid supplementation, the fully adjusted odds ratio (OR) for language delay in AED-exposed children compared to the controls at 18 months was 3.9 (95% confidence interval [CI] 1.9-7.8, p < 0.001) and at 36 months was 4.7 (95% CI 2.0-10.6, p < 0.001). When folic supplementation was used, the corresponding ORs for language delay were 1.7 (95% CI 1.2-2.6, p = 0.01) and 1.7 (95% CI 0.9-3.2, p = 0.13), respectively. The positive effect of folic acid supplement use on language delay in AED-exposed children was significant only when supplement was used in the period from 4 weeks before the pregnancy and until the end of the first trimester.

Conclusion: Folic acid use early in pregnancy may have a preventive effect on language delay associated with in utero AED exposure.

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Figures

Figure 1
Figure 1. Flowchart of excluded and included cases
AED+ = antiepileptic drug use/exposure; AED− = no antiepileptic drug use/exposure.
Figure 2
Figure 2. Relationship between language delay and timing of maternal folic acid intake
Graphs illustrate the proportion of children (percent) exposed to maternal folic acid supplementation at different time intervals during pregnancy and the relationship to language delay (orange lines) and no language delay (green lines) at 18 and 36 months. Language delay at 36 months includes global language delay and expressive language delay. Arrows illustrate median start and median stop of maternal folic acid supplementation during pregnancy. Significant differences in folic acid supplementation (χ2 test for independence) and median start/stop of folic acid supplementation (Mann-Whitney U test) are marked with asterisks. (A) Antiepileptic drug (AED)–exposed children of mothers with epilepsy at 18 months (n = 216) and 36 months (n = 179). (B) AED–unexposed children of mothers with epilepsy at 18 months (n = 260) and 36 months (n = 204). (C) Children of mothers without epilepsy at 18 months (n = 73,606) and 36 months (n = 57,715). Statistically significant differences were seen even with minor or no differences in percentages (p values between 0.02 and 0.05) or medians because of a high number of observations.
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