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

2025-10-31
Nutrients 17(21)
- Miao Yu
- Yiming Hu
- Lei Hou
- Xiaomin Wu
- Xiangxin Chen
- Ruohan Yan
- Jie Dong
- Jing Wu

PubMed: 41228512
DOI: 10.3390/nu17213443

Study Design

Type: Systematic Review
Sample size: n = 23
Methods: systematic search in MEDLINE, Cochrane Library, EMBASE, PubMed, and Web of Science from inception to 30 June 2025, to identify systematic reviews and meta-analyses that synthesized evidence from non-randomized studies on maternal folic acid supplementation and NDDs

Rigorous Journal

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.

Research Insights

Vitamin B9→Improved Attention Span
MAs indicated a protective effect of supplementation, with odds ratio (OR) of 0.86 (95% CI: 0.78-0.95) for attention-deficit/hyperactivity disorder (ADHD)
Effect
Beneficial
Effect size
Small
Dose
not specified
Vitamin B9→Improved Cognitive Development
No significant associations were found for motor, intellectual/cognitive, or language development.
Effect
Neutral
Effect size
Small
Dose
not specified
Vitamin B9→Improved Iron Levels
No significant associations were found for motor, intellectual/cognitive, or language development
Effect
Neutral
Effect size
Small
Dose
not specified
Vitamin B9→Improved Language Development
No significant associations were found for motor, intellectual/cognitive, or language development
Effect
Neutral
Effect size
Small
Dose
not specified
Vitamin B9→Improved Motor Development
No significant associations were found for motor, intellectual/cognitive, or language development
Effect
Neutral
Effect size
Small
Dose
not specified
Vitamin B9→Reduced Autism Spectrum Disorder Risk
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)
Effect
Beneficial
Effect size
Moderate
Dose
not specified
Vitamin B9→Reduced Behavioral Problem
MAs indicated a protective effect of supplementation, with odds ratio (OR) of 0.66 (95% 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.
Effect
Beneficial
Effect size
Moderate
Dose
not specified
Vitamin B9→Reduced Behavioral Problems
MAs indicated a protective effect of supplementation, with odds ratio (OR) of 0.75 (95% CI: 0.63-0.91) for behavioral problems
Effect
Beneficial
Effect size
Moderate
Dose
not specified
Vitamin B9→Reduced Risk of Autism Spectrum Disorder
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)
Effect
Beneficial
Effect size
Moderate
Dose
not specified