Folic Acid and Autism: A Systematic Review of the Current State of Knowledge

Background: Autism spectrum disorders (ASDs) prevalence has increased over time. Different studies indicate folic acid (FA) importance in improving childhood behavioral outcomes and underline its role as a modifiable risk factor for ASDs. Modulations dependent reduced folate uptake and auto-antibodies against folate receptor alpha (FRAA) were associated with neurodevelopmental disorders.

Objective: A systematic review was conducted in both animal and human clinical studies to determine the association of FA with ASDs.

Methods: Different keywords in PubMed, Scopus, Medline, Embase databases were used to identify and select the eligible studies without language and date limitation. Two authors independently screened potentially eligible articles and extracted relevant data.

Results: 43 studies met the inclusion criteria, of which 8 were conducted in animals. 14 clinical trials investigated the association between maternal vitamin supplementation and the risk of ASDs in offspring; 10 studies investigated the role of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in ASDs risk; 9 studies observed the clinical benefits after folate supplementation in ASDs diagnosed children; 2 studies investigated the frequency of serum FRAA in ASDs children. All of them associated maternal FA use to a significant reduction risk of the ASDs in offspring, particularly when assumed at least from 4 weeks before the start of pregnancy. Serum FRAA were present in 77.5% (31/40) of children with ASDs compared with 54.8% (23/42) of neurotypical development children in a 2018 cohort study. MTHFR 677T-allele frequency was found to be significantly higher in ASDs cases compared with nonautistic children. A recent study concluded that maternal FA supplementation (600µg) during first month of pregnancy may reduce ASDs recurrence in families with ASDs children.

Conclusion: Biological, genetic and epidemiological evidence underline the important role of folate supplementation in reducing the ASDs risk and behavioral improvement in offspring.