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Association of Folic Acid Supplementation During Pregnancy With the Risk of Autistic Traits in Children Exposed to Antiepileptic Drugs In Utero.
JAMA Neurol. 2018 02 01; 75(2):160-168.JN

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.

Authors+Show Affiliations

Department of Clinical Medicine, University of Bergen, Bergen, Norway. Department of Neurology, Haukeland University Hospital, Bergen, Norway.Department of Clinical Science, University of Bergen, Bergen, Norway. Laboratory of Clinical Biochemistry, Section of Clinical Pharmacology, Haukeland University Hospital, Bergen, Norway.Department of Clinical Pharmacology, St Olav University Hospital, Trondheim, Norway. Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway.Department of Neurology, Haukeland University Hospital, Bergen, Norway.Department of Clinical Medicine, University of Bergen, Bergen, Norway. Department of Neurology, Haukeland University Hospital, Bergen, Norway.Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway. Division of Epidemiology, Norwegian Institute of Public Health, Bergen, Norway.Department of Clinical Medicine, University of Bergen, Bergen, Norway. Department of Neurology, Haukeland University Hospital, Bergen, Norway.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29279889

Citation

Bjørk, Marte, et al. "Association of Folic Acid Supplementation During Pregnancy With the Risk of Autistic Traits in Children Exposed to Antiepileptic Drugs in Utero." JAMA Neurology, vol. 75, no. 2, 2018, pp. 160-168.
Bjørk M, Riedel B, Spigset O, et al. Association of Folic Acid Supplementation During Pregnancy With the Risk of Autistic Traits in Children Exposed to Antiepileptic Drugs In Utero. JAMA Neurol. 2018;75(2):160-168.
Bjørk, M., Riedel, B., Spigset, O., Veiby, G., Kolstad, E., Daltveit, A. K., & Gilhus, N. E. (2018). Association of Folic Acid Supplementation During Pregnancy With the Risk of Autistic Traits in Children Exposed to Antiepileptic Drugs In Utero. JAMA Neurology, 75(2), 160-168. https://doi.org/10.1001/jamaneurol.2017.3897
Bjørk M, et al. Association of Folic Acid Supplementation During Pregnancy With the Risk of Autistic Traits in Children Exposed to Antiepileptic Drugs in Utero. JAMA Neurol. 2018 02 1;75(2):160-168. PubMed PMID: 29279889.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Association of Folic Acid Supplementation During Pregnancy With the Risk of Autistic Traits in Children Exposed to Antiepileptic Drugs In Utero. AU - Bjørk,Marte, AU - Riedel,Bettina, AU - Spigset,Olav, AU - Veiby,Gyri, AU - Kolstad,Eivind, AU - Daltveit,Anne Kjersti, AU - Gilhus,Nils Erik, PY - 2017/12/28/pubmed PY - 2019/9/10/medline PY - 2017/12/28/entrez SP - 160 EP - 168 JF - JAMA neurology JO - JAMA Neurol VL - 75 IS - 2 N2 - 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. SN - 2168-6157 UR - https://www.unboundmedicine.com/medline/citation/29279889/Association_of_Folic_Acid_Supplementation_During_Pregnancy_With_the_Risk_of_Autistic_Traits_in_Children_Exposed_to_Antiepileptic_Drugs_In_Utero_ L2 - https://jamanetwork.com/journals/jamaneurology/fullarticle/10.1001/jamaneurol.2017.3897 DB - PRIME DP - Unbound Medicine ER -