Association of Folic Acid Supplementation During Pregnancy With the Risk of Autistic Traits in Children Exposed to Antiepileptic Drugs In Utero

Abstract

IMPORTANCE Strategies to prevent autism in children exposed to antiepileptic drugs (AEDs) during pregnancy are important. OBJECTIVE To explore whether folic acid supplementation and folate status in pregnancy are associated with reduced risk of autistic traits owing to in utero AED exposure. DESIGN, SETTING, AND PARTICIPANTS The population-based, prospective Norwegian Mother and Child Cohort Study approached Norwegian-speaking women attending routine ultrasonographic examinations from June 1999 through December 31, 2008 (163 844 of 277 702 women refused). No exclusion criteria were applied beyond language. Questionnaires during and after pregnancy, analysis of blood samples, and linkage to the Medical Birth Registry of Norway were performed. Children aged 18 to 36 months of women with available information on use of AEDs and of folic acid supplementation (n = 104 946) were included in the analysis from March 1, 2016, through June 13, 2017. EXPOSURES Maternal folic acid supplementation 4 weeks before to 12 weeks after conception. Plasma folate concentration was analyzed at gestational weeks 17 to 19. MAIN OUTCOMES AND MEASURES Autistic traits were evaluated using the Modified Checklist for Autism in Toddlers and Social Communication Questionnaire. Odds ratios (ORs) for autistic traits in children by maternal use vs nonuse of folic acid supplements were adjusted for maternal health and socioeconomic factors. Folate concentrations and folic acid doses were associated with the degree of autistic traits. RESULTS The overall mean (SD) age of the 104 946 mothers of participating children was 29.8 (4.6) years, with complete information available for analysis in 103 868. Mean (SD) age of women with epilepsy who received AED treatment was 29.4 (4.9); women with epilepsy who did not receive AED treatment, 29.1 (4.9); and without epilepsy, 29.8 (4.6) years. In the 335 children exposed to AEDs, the risk for autistic traits was significantly higher at 18 months of age (adjusted OR [AOR], 5.9; 95% CI, 2.2-15.8) and 36 months of age (AOR, 7.9; 95% CI, 2.5-24.9) when their mothers had not used folic acid supplements compared with children of mothers who had used supplements. Among women without epilepsy, the corresponding risks were lower at 18 months of age (AOR, 1.3; 95% CI, 1.2-1.4) and 36 months of age (AOR, 1.7; 95% CI, 1.5-1.9); among the 389 children of women with untreated epilepsy, the corresponding risks were not significant at 18 months of age (AOR, 1.0; 95% CI, 0.4-3.0) and 36 months of age (AOR, 2.5; 95% CI, 0.4-16.6). Degree of autistic traits was inversely associated with maternal plasma folate concentrations (β = −0.3; P = .03) and folic acid doses (β = −0.5; P < .001). Concentrations of AEDs were not associated with the degree of autistic traits. CONCLUSIONS AND RELEVANCE Risk of autistic traits in children exposed to AEDs in utero may be mitigated by periconceptional folic acid supplementation and folate status. Fertile women using AEDs should take folic acid supplements continuously.

Language impairment in children aged 5 and 8 years after antiepileptic drug exposure in utero – the Norwegian Mother and Child Cohort Study

“…This strongly suggests a role of folate in the mechanism of AED-associated language impairment. Furthermore, these findings emphasize the importance of folic acid supplement use in the periconceptional period in all women with epilepsy who use AEDs [5,10,12,22]. Language impairment in children requires intervention, as it may have severe consequences for language skills in adulthood, academic achievements, mental health, behaviour and social life [21,27].…”

Lamotrigine clearance increases by 5 weeks gestational age: Relationship to estradiol concentrations and gestational age

“…Lamotrigine (LTG) is approved for use as chronic therapy in patients with epilepsy and bipolar disorder. It is now the most commonly used antiepileptic drug (AED) across several pregnancy registries and studies . Major physiological changes during pregnancy can lead to significant changes in AED pharmacokinetics, causing possible interruptions in seizure stability.…”

Maternal blood folate status during early pregnancy and occurrence of autism spectrum disorder in offspring: a study of 62 serum biomarkers

“…This case-control study with pre-diagnostic, first trimester maternal blood samples is the first of its kind to investigate a comprehensive panel of biomarkers reflecting vitamin status (including folate, and vitamin D), lifestyle (smoking and coffee consumption), and inflammation and immune activation (CRP, kynurenine, kynurenic acid, and quinolinic acid, KTR and neopterin) in relation to the occurrence of ASD in the offspring. The other characteristics of the present study is that biomarkers were analyzed in individual, pre-diagnostic maternal blood samples and not estimated based on register data or food frequency questionnaires [21][22][23][24][25][26][27][28][29][30][31][32][35][36][37][38][39][40][41][42][43][44][45][46]. The majority of blood samples were taken at week 14, but ranged between week 7 and week 18 in the total cohort.…”

“…Previous studies were usually limited to one or two metabolic factors such as body-mass index and result of maternal diet and fatty acid metabolism [21][22][23], smoking [24] vitamin D [25][26][27][28][29][30][31][32][33][34] and folate supplementation [35][36][37][38][39][40][41][42][43], paracetamol [44,45], valproic acid, thalidomide, and antidepressants [13,46,47], and phthalates [48]. Maternal defects in one-carbon metabolism have also been proposed to influence ASD risk [49][50][51][52].…”

“…Maternal folate levels during pregnancy may even cause onset of ASD in children through immune system modulation. More than a decade ago, it was suggested that folic acid use by the mothers could been one of the factors that increase the risk of ASD in children [97], an observation confirmed by some [42,43,96,98] but rejected by other [35][36][37][38][39]98] studies. It is important, therefore, to explore the question further.…”