Peer-reviewed article

Maternal folic acid supplement timing and learning difficulties in children assessed at ages 4 to 7 years.

Hanbin Wu, Zhuoyuan Xu, Yingren Luo, Chengchen Zhang · 25 Sept 2026

Abstract

BACKGROUND: Periconceptional folic acid supplementation prevents neural tube defects and may influence offspring neurodevelopment, but evidence for domain-specific learning difficulties remains unclear. We examined whether maternal-reported first-trimester initiation of folic acid supplementation was associated with parent-reported learning difficulties in offspring assessed at ages 4-7 years. MATERIALS AND METHODS: This retrospective cohort study used data from the Dutch Perined-Lifelines birth cohort. We excluded preterm birth (<37 weeks), high-dose folic acid exposure (4.0 mg), and supplementation initiated after the first trimester. Exposure was retrospective maternal-reported folic acid supplementation timing and categorized as before conception/prepregnancy through the first trimester and first trimester only. Outcomes were parent-reported binary indicators of poor concentration, reading disability, difficulty with calculating, and difficulty keeping up at school without clinical diagnoses or standardized neuropsychological assessments. Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for child age, sex, body rate, stress rate, and preschool sleeping problems. RESULTS: Of 3,216 children, 2,314 (71.9%) were in the preconception group and 902 (28.1%) in the first-trimester-only group. In adjusted models, first-trimester-only supplementation was not associated with poor concentration, reading disability, or difficulty keeping up at school but was nominally associated with higher odds of parent-reported difficulty with calculating (OR = 1.60; 95% CI: 1.02-2.50). CONCLUSION: Maternal-reported first-trimester initiation of folic acid supplementation was nominally associated with parent-reported difficulty with calculating assessed at ages 4-7, but the retrospective observational design, potential misclassification, and residual confounding preclude causal interpretation. Prospective studies with biomarkers and standardized developmental assessments are warranted.