Table 6.

An overview of all reviews, systematic reviews, and metanalysis included in the study.

No	Study	Type of Study	Aim of Study	Parameters Assessed in the Study	Outcomes
1	DeVilbiss EA et al., (2015) [14]	Review	Overview and summaries of the folate role in neurodevelopmental disorders; relationship between maternal folate and ASDs	Maternal folate and autism spectrum disorders and related traits. Self-reported maternal folate and autism spectrum disorder traits. Maternal folate biomarker and autism spectrum disorder traits. Folate supplementation and ASDs	Inconclusive evidences underline the need for future studies of maternal folate status during the pre- and peri-conceptional periods. In addition, an incorporation of genetic data could complete better these assessments [14].
2	Wiens D et al., (2017) [72]	Review	Examination of folic acid (FA) effects on neuronal development from tissue culture experiments, understanding ASDs metabolic causes and alternative folinic acid treatment	Unmetabolized FA neural development metabolic abnormalities.Autoantibodies in ASD autism risk	Evidence concludes that optimal levels are important for healthy development, but over-supplementation can lead to negative outcomes [72].
3	Gao Y et al., (2016) [73]	Systematic Review	Evaluation of evidence of FA impact on neurodevelopment	FA supplementation.Maternal red blood cell (RBC) folate levels. Plasma folate	The review suggests a beneficial effect of folic acid supplementation in pregnancy on children’s neurodevelopment [73].
4	Guo B-Q et al., (2019) [74]	Systematic Review and Meta-Analysis	Elucidate the association of maternal FA intake during the prenatal period and ASD risk in offspring	FA intake.Period of FA intake. FA intake and risk of ASDs subtypes. FA supplementation (excluding diet consumption) and risk of ASDs. Geographical area and risk of ASDs	Findings do not support the link between FA supplementation during prenatal period and ASD reduced risk in offspring. In addition, more investigation is needed because of many study limitations [74].
5	Pu D et al., (2013) [75]	Meta-Analysis	Investigation of the MTHFR polymorphisms (C677T and A1298C) and the ASD risk	Meta-Analysis of MTHFR Polymorphisms between ASD children and controls. Distributions of MTHFR C677T/A1298C genotypes. Meta-Analysis of MTHFR C677T/A1298C polymorphisms on risk of ASD patient population based on whether they were from a country with food fortification of FA or not	This meta-analysis found that periconceptional FA supplementation may reduce ASD risk in those with MTHFR 677C>T polymorphisms where an increased risk of ASDs was indicated. The C677T polymorphism was found to be associated with ASDSs only in children from countries without food fortification [75].
6	Cierna AV et al., (2016) [16]	Review	Investigating the methylation of cytosine bases as one of the most stable and crucial forms of epigenetic regulation of the genome	DNA methylation at different regulatory genomic elements across tissues and cell types and during different developmental stages	In genetically susceptible individuals with altered DNA-methylation patterns, a potential protective effect of supplementation taken before conception was suggested [16].
7	Modabbernia A et al., (2017) [8]	Review	Investigating environmental risk factors for ASDs.	Advanced parental age. Pregnancy-related complications and conditions. Environmental risk factors for ASDs, Genetic and epigenetic-related effects	Studies of environmental risk factors were inconclusive as a result of significant methodological limitations [8].
8	Dias CM et al., (2020) [2]	Review	Elucidate how genetic risk affects cellular functioning and clinical phenotypes	Roles of de novo copy number variants and single-nucleotide variants—causing loss-of-function or missense changes. Mosaic single-nucleotide variants. Inherited variants (including common variants). Rare recessive inherited variants. Noncoding variants, both inherited and de novo	Findings underline the need of whole-exome sequencing and further genome studies with increased sample size for better understanding of neuro-developmental disorders [2].
9	Castro K et al., (2016) [76]	Review	Evaluation of serum nutrient levels and nutritional interventions targeting ASDs.	Folate intake.Serum homocysteine and folate levels.Oral folinic acid supplementation.Urine homocysteine level in children	Inconsistent conclusions were found regarding the association of FA supplementation during pregnancy and ASDs [76].
10	Waye MMY et al., (2017) [6]	Review	Summary of genetic and epigenetic ASDs studies	Environmental risk factors. Genetic risk factors	Study evaluation concluded that although Fragile X, SHANK3, CASPR2 has been linked to ASDs risk, also folate based dietary intervention and environmental pollutants reduction might help to suppress epigenetic changes during maternity. Further study of autoantibodies against Caspr2 and folate receptor alpha has been proposed as important therapeutic targets [6].
11	Schaevitz LR et al., (2012) [77]	Review	Focus on DNA methylation	Genetic polymorphisms. Levels of nutrients in parents and children with ASDs	Evidence underlined the important role of both nutrition and genetic components of the C1 metabolic pathway on increasing susceptibility to ASDs. Further studies are needed to better understand the different risk factors and the critical periods most essential for normal development of the brain [77].
12	Paul L et al., (2017) [78]	Review	Summarize interaction between folate and vitamin B12 on health consequences	Folate status and biochemical markers of vitamin B12 insufficiency. Clinical outcomes associated with vitamin B12 deficiency, B vitamin imbalance during pregnancy	Negative health consequences, especially in women during pregnancy and their offspring, have been associated with impaired folate status or intake and vitamin B12 status or intake [78].
13	Neggers Y et al., (2014) [79]	Review	Investigation of FA and autism risk	Frequency of MTHFR alleles 677C→T1298A→C in cases and controls. Plasma levels of folate metabolites. Serum folate, cerebrospinal folate, CSF 5MTHF folate receptor (FR) autoantibodies. Consumption of prenatal multivitamins and nutrients from 3 months before conception during pregnancy. Maternal FAintake. Serum FR blocking. Autoimmune antibody levels	Although results show a positive link of perinatal FA supplementation in reducing ASD incidence, recent studies underline the importance of further studies to understand the modulative role of high maternal FA intake in DNA methylation in ASD and ASD-related traits [79].
14	Chaste P et al., (2012) [7]	Review	Summary of genetic, epigenetic, and environmental risk factors related to autism	Genetic risk factors. Environmental risk factors. Gene-environment interaction	Conclusions are inconsistent as further studies are needed to better characterize the impact of environmental factors, although an additive or multiplicative effect has been indicated [7].
15	Frye RE et al., (2017) [80]	Review	Investigation on biomarkers used to detect folate abnormalities	Polymorphisms in folate genes related to autism environment—genome interaction. Folate metabolism FRAAs in pregnancy. Folate and ASDs	Evidence underlined the need of further studies for specific biomarkers of the folate pathway that might help to detect ASDs early and diagnose ASDs, as the abnormality of FA metabolism has a potential impact in ASD offspring. Thus, specific type and dose of folate and other cofactors could be used for treating or preventing ASD traits [80].