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      The association between maternal use of folic acid supplements during pregnancy and risk of autism spectrum disorders in children: a meta-analysis

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          Abstract

          Previous reviews have been conducted to evaluate the association between maternal use of folic acid supplements during pregnancy and risk of autism spectrum disorders (ASD) in children, with no definitive conclusion. We therefore conducted a more comprehensive meta-analysis to reassess the relationship between folic acid and the risk of ASD. The electronic databases PubMed, Web of Knowledge, and Wanfang Data were carefully searched to find eligible studies as recent as March 2017. A random effects model was used to combine the relative risk (RR) with 95% confidence intervals (CI). Sensitivity analysis and publication bias were conducted. A total of 12 articles with 16 studies comprising 4514 ASD cases were included in this report. It was found that supplementation with folic acid during pregnancy could reduce the risk of ASD [RR = 0.771, 95% CI = 0.641–0.928, I 2  = 59.7%, P heterogeneity = 0.001] as compared to those women without folic acid supplementation. The associations were significant among Asian, European, and American populations. In summary, this comprehensive meta-analysis suggested that maternal use of folic acid supplements during pregnancy could significantly reduce the risk of ASD in children regardless of ethnicity, as compared to those women who did not supplement with folic acid.

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          The online version of this article (10.1186/s13229-017-0170-8) contains supplementary material, which is available to authorized users.

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          Assessing the influence of a single study in the meta‐analysis estimate

          A. Tobías, Tobias, A Pedroza-Tobías … (1999)
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            Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children.

            Pål Surén, Christine M Roth, Michaeline Bresnahan … (2013)
            Prenatal folic acid supplements reduce the risk of neural tube defects in children, but it has not been determined whether they protect against other neurodevelopmental disorders. To examine the association between maternal use of prenatal folic acid supplements and subsequent risk of autism spectrum disorders (ASDs) (autistic disorder, Asperger syndrome, pervasive developmental disorder-not otherwise specified [PDD-NOS]) in children. The study sample of 85,176 children was derived from the population-based, prospective Norwegian Mother and Child Cohort Study (MoBa). The children were born in 2002-2008; by the end of follow-up on March 31, 2012, the age range was 3.3 through 10.2 years (mean, 6.4 years). The exposure of primary interest was use of folic acid from 4 weeks before to 8 weeks after the start of pregnancy, defined as the first day of the last menstrual period before conception. Relative risks of ASDs were estimated by odds ratios (ORs) with 95% CIs in a logistic regression analysis. Analyses were adjusted for maternal education level, year of birth, and parity. Specialist-confirmed diagnosis of ASDs. At the end of follow-up, 270 children in the study sample had been diagnosed with ASDs: 114 with autistic disorder, 56 with Asperger syndrome, and 100 with PDD-NOS. In children whose mothers took folic acid, 0.10% (64/61,042) had autistic disorder, compared with 0.21% (50/24,134) in those unexposed to folic acid. The adjusted OR for autistic disorder in children of folic acid users was 0.61 (95% CI, 0.41-0.90). No association was found with Asperger syndrome or PDD-NOS, but power was limited. Similar analyses for prenatal fish oil supplements showed no such association with autistic disorder, even though fish oil use was associated with the same maternal characteristics as folic acid use. Use of prenatal folic acid supplements around the time of conception was associated with a lower risk of autistic disorder in the MoBa cohort. Although these findings cannot establish causality, they do support prenatal folic acid supplementation.
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              Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study.

              Flora Tassone, Jaana Hartiala, Hooman Allayee … (2012)
              Periconceptional folate is essential for proper neurodevelopment. Maternal folic acid intake was examined in relation to the risk of autism spectrum disorder (ASD) and developmental delay (DD). Families enrolled in the CHARGE (CHildhood Autism Risks from Genetics and Environment) Study from 2003 to 2009 were included if their child had a diagnosis of ASD (n = 429), DD (n = 130), or typical development (TD; n = 278) confirmed at the University of California Davis Medical Investigation of Neurodevelopmental Disorders Institute by using standardized clinical assessments. Average daily folic acid was quantified for each mother on the basis of dose, brands, and intake frequency of vitamins, supplements, and breakfast cereals reported through structured telephone interviews. Mean (±SEM) folic acid intake was significantly greater for mothers of TD children than for mothers of children with ASD in the first month of pregnancy (P1; 779.0 ± 36.1 and 655.0 ± 28.7 μg, respectively; P T variant genotypes. A trend toward an association between lower maternal folic acid intake during the 3 mo before pregnancy and DD was observed, but not after adjustment for confounders. Periconceptional folic acid may reduce ASD risk in those with inefficient folate metabolism. The replication of these findings and investigations of mechanisms involved are warranted.
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                Author and article information

                Contributors
                Meiyun Wang: wangmeiyunjn@163.com
                Kaiqin Li: li_kaiqin@163.com
                Dongmei Zhao: zhao_dm@yeah.net
                Ling Li: +8618853108861 , ling_li2017@yeah.net
                Journal
                Journal ID (nlm-ta): Mol Autism
                Journal ID (iso-abbrev): Mol Autism
                Title: Molecular Autism
                Publisher: BioMed Central (London )
                ISSN (Electronic): 2040-2392
                Publication date (Electronic): 2 October 2017
                Publication date PMC-release: 2 October 2017
                Publication date Collection: 2017
                Volume: 8
                Electronic Location Identifier: 51
                Affiliations
                [1 ]Department of Pediatric Health Care, Ji’nan Children’s Hospital of Shandong University, No. 23976, Jingshi Road, Ji’nan, Shandong Province 250022 China
                [2 ]Department of Gynecology, The Central Hospital of Linyi City, Linyi, Shandong 276000 China
                Article
                Publisher ID: 170
                DOI: 10.1186/s13229-017-0170-8
                PMC ID: 5625821
                PubMed ID: 29026508
                SO-VID: cc0277bb-9585-4493-9dde-36dd5ae840af
                Copyright © © The Author(s). 2017
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 29 May 2017
                Date accepted : 22 September 2017
                Categories
                Subject: Short Report
                Custom metadata
                issue-copyright-statement © The Author(s) 2017

                ScienceOpen disciplines: Neurosciences
                Keywords: maternal,folic acid supplements,autism spectrum disorders,children,meta-analysis
                Data availability:
                ScienceOpen disciplines: Neurosciences
                Keywords: maternal, folic acid supplements, autism spectrum disorders, children, meta-analysis

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