Maternal folate levels during pregnancy and offspring brain development in late childhood

Background: Cumulative evidence shows that low maternal folate levels during pregnancy are associated with offspring neuropsychiatric disorders even in the absence of neural tube defects. However, the relationship between prenatal exposure to folate and brain development in late childhood has been rarely investigated. Methods: In 2095 children from a prospective population-based cohort in Rotterdam, the Netherlands, we examined the association of maternal folate levels during pregnancy with downstream brain development in offspring. Maternal folate concentrations were measured from venous blood in early gestation. Child structural neuroimaging data were measured at age 9–11 years. In addition, measures of child head circumference using fetal ultrasound in the third trimester and total brain volume using magnetic resonance imaging at age 6–8 years were used for analyses with repeated assessments of brain development. Results: Maternal folate deficiency (i.e., <7 nmol/L) during pregnancy was associated with smaller total brain volume (B = −18.7 cm³, 95% CI −37.2 to −0.2) and smaller cerebral white matter (B = −7.2 cm³, 95% CI −11.8 to −2.6) in children aged 9–11 years. No differences in cortical thickness or surface area were observed. Analysis of the repeated brain assessments showed that children exposed to deficient folate concentrations in utero had persistently smaller brains compared to controls from the third trimester to childhood (β = −0.4, 95% CI −0.6 to −0.1). Conclusions: Low maternal folate levels during pregnancy are associated with altered offspring brain development in childhood, suggesting the importance of essential folate concentrations in early pregnancy.