Maternal red blood cell folate and periconceptional folic acid supplementation are associated with neonatal brain maturation: a retrospective EEG-MRI study with term-equivalent imaging.

OBJECTIVE

To examine whether maternal red blood cell (RBC) folate concentrations (biomarker of folate status) and documented periconceptional folic acid supplementation (FAS) are associated with neonatal brain maturation at term-equivalent age (TEA), using standardized MRI and EEG scoring.

METHODS

We retrospectively analyzed 144 mother-infant pairs (March 2022-March 2024). Analyses used a two-factor design denoted GA × Folate, combining gestational age group (Preterm < 37 weeks; Term ≥ 37 weeks) and RBC folate status (Deficient < 906 nmol/L; Sufficient ≥ 906 nmol/L). All MRI/EEG was performed at term-equivalent age (TEA) 40 ± 1 weeks postmenstrual age (PMA). MRI was scored using a modified Kidokoro system; EEG used standard neonatal metrics including Burdjalov aEEG background continuity and cycling, and conventional EEG delta-brush frequency. Readers were blinded to group. Analyses used two-way ANOVA (GA × Folate) with Benjamini-Hochberg FDR control, effect sizes, and ANCOVA adjusting for sex and birthweight.

RESULTS

Maternal RBC folate sufficiency was associated with higher MRI myelination scores (Δ = 0.6 points, 95% CI 0.3-0.9, η2p = 0.08, q = 0.012) and greater EEG maturation (delta-brush frequency ↑ and aEEG continuity ↑; η2p = 0.07-0.10, q ≤ 0.02). Term infants outperformed preterm infants (main GA effect, q < 0.01). No GA × Folate interaction survived FDR. Maternal RBC folate correlated with MRI myelination (r = 0.42, 95% CI 0.27-0.55) and delta-brush frequency (r = 0.37, 95% CI 0.21-0.51), both q < 0.01. Inter-rater reliability: MRI ICC = 0.86; EEG ICC = 0.83.

CONCLUSION

Higher maternal RBC folate at delivery is associated with more advanced structural and functional brain maturation at TEA. Documented periconceptional folic acid supplementation was more common among mothers with RBC folate sufficiency, suggesting supplementation may contribute to achieving adequate folate status.