Association of the Maternal Folic Acid Supplementation with the Autism Spectrum Disorder: A Systematic Review

Sampaio, Adalberto Cruz; Matos Neto, Francisco Facundo de; Lopes, Lucas de Lucena; Marques, Ítalo Marcelo Maia; Tavares, Ravel Moreira; Fernandes, Marcus Vinicius de Macedo; Teixeira, Maria Raquel Vieira da Silva; Brito, Alessandra Bezerra de; Feitosa, Andrea Couto; Guedes, Tarciana Oliveira; Mota, Magaly Lima

doi:10.1055/s-0041-1736298

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Review Article • Rev. Bras. Ginecol. Obstet. 43 (10) • Oct 2021 • https://doi.org/10.1055/s-0041-1736298 copy

Association of the Maternal Folic Acid Supplementation with the Autism Spectrum Disorder: A Systematic Review

Associação da suplementação de ácido fólico materno com o transtorno do espectro do autismo: uma revisão sistemática

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Objective

To analyze the scientific production regarding maternal folic acid (FA) supplementation and its relationship with autistic spectrum disorder (ASD).

Data Sources

We performed unrestricted electronic searches in the BIREME virtual bank, Virtual Health Library (VHL) and Medical Literature Analysis and Retrieval System Online (MEDLINE/PubMed) databases.

Selection of Studies

For sample selection, articles that met the proposed objectives were included, published in English, Spanish and Portuguese, the use of Health Sciences Descriptors (DeCS): autistic OR autism AND autism spectrum disorder AND folic acid, AND, with the use of the Medical Subject Headings (MeSH): autistic OR autism AND autistic spectrum disorder AND folic acid.

Data Collection

Data extraction was performed by the reviewers with a preestablished data collection formulary.

Data Synthesis

The Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) was used based on a checklist with 27 items and a 4-step flowchart.

Results

A total of 384 articles was found by the search strategies, of which 17 were eligible following the pre-established criteria. The main findings of the present review point to maternal FA supplementation in the pre-conception period and beginning of pregnancy as a protective effect in relation to ASD, which should be indicated in this period as prevention to the problem.

Conclusion

According to the research analyzed, more studies are necessary to know its effects on pregnancy, since the consumption of excessive FA may not be innocuous.

Keywords:
autistic spectrum disorder; folic acid; pregnancy; supplementation

Authors	Year	Place	Main results
Steenweg-de-Graaff et al.⁶6 Steenweg-de Graaff J, Ghassabian A, Jaddoe VW, Tiemeier H, Roza SJ. Folate concentrations during pregnancy and autistic traits in the offspring. The Generation R Study. Eur J Public Health. 2015; 25(03):431-433. Doi: 10.1093/eurpub/cku126 https://doi.org/10.1093/eurpub/cku126...	2015	Rotterdam, Netherlands.	The concentration of folic acid at the beginning of pregnancy does not show a direct relationship with autism in the offspring. However, it shows a decrease in traces of childhood autism, related to early folic acid supplementation.
Neggers¹⁴14 Neggers Y. The relationship between folic acid and risk of autism spectrum disorders. Healthcare (Basel). 2014;2(04):429-444. Doi: 10.3390/healthcare2040429 https://doi.org/10.3390/healthcare204042...	2014	Alabama, USA.	Autism may be related to the potential association between DNA methylation by high folic acid intake, food fortification with folic acid, and it may also be pointed out as a protective factor for autism. Therefore, the cause of autism could not be affirmed, only possible relations with the problem, being necessary further studies in this respect.
Braun et al.⁷7 Braun JM, Froehlich T, Kalkbrenner A, Pfeiffer CM, Fazili Z, Yolton K, et al. Brief report: are autistic-behaviors in children related to prenatal vitamin use and maternal whole blood folate concentrations? J Autism Dev Disord. 2014;44(10):2602-2607. Doi: 10.1007/s10803-014-2114-x https://doi.org/10.1007/s10803-014-2114-...	2014	Cincinnati, Ohio, USA	Among the mother-son pairs who used multivitamins with folic acid in the 2^nd trimester of pregnancy, it was shown to have a beneficial effect in reducing autistic characteristics. When the concentrations of folate in maternal whole blood alone were seen, a protective relationship against the disorder was not observed.
Berry et al.¹⁵15 Berry RJ, Crider KS, Yeargin-Allsopp M. Can we change the risk of autism? JAMA. 2013;309(06):611-613. Doi: 10.1001/jama.2013.198 https://doi.org/10.1001/jama.2013.198...	2013	Atlanta, Georgia, USA.	The increasing number of ASD cases, together with the fortification of food folic acid, leads to some aspects of ASD. It may be protective in relation to folic acid supplementation and ASD or it may have an adverse effect of this excessive supplementation, increasing the risk for the problem. As its role is not yet clear regarding its relationship with ASD, future studies are needed.
Schmidt⁸8 Schmidt RJ. Maternal folic acid supplements associated with reduced autism risk in the child. Evid Based Med. 2013;18(06): e53. Doi: 10.1136/eb-2013-101311 https://doi.org/10.1136/eb-2013-101311...	2013	California, USA.	The prevalence of ASD decreases as preconception folic acid is used and in early pregnancy. A 40% decrease in the risk of developing the disorder is observed.
Gao et al.²¹	2016	Columbia, USA.	Although studies have been observed that indicate a relationship between folic acid supplementation and autism, most of the articles studied in this review suggest that folic acid supplementation in the pregnancy has a protective effect against ASD.
Raghavan et al.¹⁸18 Raghavan R, Riley AW, Volk H, Caruso D, Hironaka L, Sices L, et al. Maternal multivitamin intake, plasma folate and vitamin B12 levels and autism spectrum disorder risk in offspring. Paediatr Perinat Epidemiol. 2018;32(01):100-111. Doi: 10.1111/ppe.12414 https://doi.org/10.1111/ppe.12414...	2018	Boston, USA.	Based on folate measured in the maternal blood plasma, there is a relationship between increased and decreased folic acid consumption with an increased risk of ASD. However, moderate intake of multivitamins indicates a decreased risk for ASD.
Strøm et al.²²	2018	Denmark	The supplementary consumption of preconception folic acid and at the beginning of pregnancy did not present ASD as an outcome. A detailed examination of genetic factors and biomarkers of exposure is necessary.
Wang et al.⁹9 Wang M, Li K, Zhao D, Li L. The association between maternal use of folic acid supplements during pregnancy and risk of autism spectrum disorders in children: a meta-analysis. Mol Autism. 2017;8:51. Doi: 10.1186/s13229-017-0170-8 https://doi.org/10.1186/s13229-017-0170-...	2017	China	Maternal folic acid supplementation demonstrates protective action against ASD. The consumption of folic acid could allow a significant reduction in the risk of the disorder when compared with those who did not perform the supplementation.
Rangel-Rivera et al.¹⁶16 Rangel-Rivera DA, Osma-Zambrano SE. Consumo de ácido fólico en el embarazo y reducción del riesgo de transtornos del espectro autista. Med UIS. 2015;28(03):327-336. Accessed on March 1, 2020 at: https://pesquisa.bvsalud.org/portal/resource/pt/lil 776289 https://pesquisa.bvsalud.org/portal/reso...	2015	Colombia	Folic acid remains a major ally against structural defects of the central nervous system. There are aspects that affirm its protective effect in relation to ASD, but this study is inconclusive to affirm its protection.
Wiens et al.¹³13 Wiens D, DeSoto MC. Is high folic acid intake a risk factor for autism? A review. Brain Sci. 2017;7(11):149. Doi: 10.3390/brainsci7110149 https://doi.org/10.3390/brainsci7110149...	2017	Iowa, USA.	Excessive consumption of folic acid proves not to be innocuous, high levels of nonmetabolized folic acid denote a negative effect on neurological development, being consequently related to disorders such as ASD.
Moussa et al.¹⁰10 Moussa HN, Hosseini Nasab S, Haidar ZA, Blackwell SC, Sibai BM. Folic acid supplementation: what is new? Fetal, obstetric, longterm benefits and risks. Future Sci OA. 2016;2(02):FSO116. Doi: 10.4155/fsoa-2015-0015 https://doi.org/10.4155/fsoa-2015-0015...	2016	Houston, Texas, USA.	Preconception and early pregnancy folic acid consumption show a positive effect in reducing the risk of ASD, but its effects are not known if used during the entire pregnancy.
Neggers¹⁷17 Neggers YH. Increasing prevalence, changes in diagnostic criteria, and nutritional risk factors for autism spectrum disorders. ISRN Nutr. 2014;2014:514026. Doi: 10.1155/2014/514026 https://doi.org/10.1155/2014/514026...	2014	Alabama, USA.	Fortification of folic acid associated with preconception folic acid supplementation has shown a close relationship with the increase in the number of ASD cases. Further studies in this area are needed to reach a conclusion.
DeVilbiss et al.¹⁹19 DeVilbiss EA, Gardner RM, Newschaffer CJ, Lee BK. Maternal folate status as a risk factor for autism spectrum disorders: a review of existing evidence. Br J Nutr. 2015;114(05):663-672. Doi: 10.1017/S0007114515002470 https://doi.org/10.1017/S000711451500247...	2015	Philadephia, USA.	Folic acid consumption has shown a relationship with ASD, and this relationship is both with risk, related to high consumption, and with insufficient intake, given its necessity in neurodevelopment. The dosage of folic acid, vitamin B12 and homocysteine is necessary for a more complete and conclusive evaluation of this relationship.
Surén et al.¹¹11 Surén P, Roth C, Bresnahan M, Haugen M, Hornig M, Hirtz D, et al. Association between maternal use of folic acid supplements and risk of autism in children. JAMA. 2013;309(06):570-577. Doi: 10.1001/jama.2012.155925 https://doi.org/10.1001/jama.2012.155925...	2013	Norway	Maternal folic acid supplementation between the 4^th week and before the 8^th week after the beginning of pregnancy is associated with a lower risk of ASD. However, the inverse association observed represents a causal relationship, indicating that folate deficiency around conception and early pregnancy, or reduced capacity to use available folate, are important causes of ASD.
Tan et al.¹²12 Tan M, Yang T, Zhu J, Li Q, Lai X, Li Y, et al. Maternal folic acid and micronutrient supplementation is associated with vitamin levels and symptoms in children with autism spectrum disorders. Reprod Toxicol. 2020;91:109-115. Doi: 10.1016/j.reprotox.2019.11.009 https://doi.org/10.1016/j.reprotox.2019....	2019	China	The study demonstrates that maternal use of folic acid and/or micronutrients during pregnancy offer reduced the risk of autistic characteristics in the offspring. Observing characteristic signs regarding social cognition, media, autism behavioral mannerisms, adaptive behavior, coarse motor behavior and problems in gastrointestinal tract of children with ASD. There is also a relationship with the consumption of the micronutrient in pregnancy and vitamin status in children with ASD.
Altamimi²⁰20 Altamimi M. Could autism be associated with nutritional status in the Palestinian population? The outcomes of the Palestinian micronutrient survey. Nutr Metab Insights. 2018; 11:1178638818773078. Doi: 10.1177/1178638818773078 https://doi.org/10.1177/1178638818773078...	2018	Palestine	Through a systematic review, the relationship of ASD with maternal use of micronutrients was evaluated, and it was observed that folic acid can be related to ASD due to its relationship with glutathione, a product of the methionine cycle that depends on folic acid and B12. This element is involved in neuroprotection against oxidative stress and neuroinflammation in the brain. According to studies, glutathione is deficient in children with autism compared with typically developed children.

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[1] Address for correspondence Magaly Lima Mota, PhD, Avenue Leão Sampaio, 400, 63040-000, Campus Health, Lagoa Seca, Juazeiro do Norte, CE, Brazil (e-mail: magaly@leaosampaio.edu.br).