The Effect of Maternal Folic Acid Supplementation on Neurodevelopmental Disorders in Offspring: An Umbrella Review of Systematic Reviews and Meta-Analyses.

Objectives

Maternal folic acid supplementation is recommended to prevent neural tube defects (NTDs), yet its influence on offspring neurodevelopmental disorders (NDDs) remains uncertain. This umbrella review aims to evaluate whether maternal folic acid supplementation before and/or during pregnancy affects the risk of NDDs.

Methods

We conducted a systematic search in MEDLINE, Cochrane Library, EMBASE, PubMed, and Web of Science from inception to 30 June 2025, to identify systematic reviews (SRs) and meta-analyses (MAs) that synthesized evidence from non-randomized studies on maternal folic acid supplementation and NDDs. Methodological quality was assessed using the AMSTAR-2 assessment and evidence certainty using the GRADE framework.

Results

A total of 23 SRs/MAs were included, of which 14 did not perform meta-analysis. Most included SRs/MAs were methodologically limited, with 50.00% rated as very low quality and only 36.37% achieving high or moderate quality. MAs indicated a protective effect of supplementation, with odds ratio (OR) of 0.66 (95% confidence interval (CI): 0.55-0.79) for autism spectrum disorder (ASD), 0.86 (95% CI: 0.78-0.95) for attention-deficit/hyperactivity disorder (ADHD), and 0.75 (95% CI: 0.63-0.91) for behavioral problems. No significant associations were found for motor, intellectual/cognitive, or language development. SRs reported inconsistent conclusions across most outcomes.

Conclusions

In summary, maternal folic acid supplementation may reduce the risk of ASD, ADHD, and behavioral problems in offspring. Although the current evidence is of low quality, supplementation guidelines are justified by the well-established benefits for NTDs. Further research is required to address remaining uncertainties.