Folic acid supplementation, dietary folate intake during pregnancy and risk for spontaneous preterm delivery: a prospective observational cohort study

Population-based prospective cohort (Norwegian Mother and Child Cohort Study, MoBa). 66,014 pregnancies with singleton live births (2002-2009) included; pregnant women in Norway were enrolled; data collected via questionnaires and FFQ; observational design.

Folic acid supplementation started 26 weeks before conception and continued through gestational week 24; taken orally; typical dose 400 μg/day from folic acid supplements (often provided via multivitamins containing 200 μg).

No significant association between total dietary folate intake or folic acid supplementation and risk of spontaneous PTD. Dietary folate HR 1.00 (95% CI 0.61-1.65); folic acid supplementation HR 1.00 (95% CI 1.00-1.00). Initiation of folic acid supplementation more than 8 weeks before conception associated with increased risk of spontaneous PTD overall (HR 1.19; 95% CI 1.05-1.34) and with early spontaneous PTD (HR 1.60; 95% CI 1.24-2.10). Among women with low dietary folate intake, early initiation increased risk (adjusted HR 1.18; 95% CI 1.05-1.32). In first pregnancies, early initiation associated with higher risk (adjusted HR 1.30; 95% CI 1.10-1.53). No protective effect; findings warrant further investigation before changing guidelines.

Observational design with potential residual confounding; participation rate 38.5% with underrepresentation of single women and those <25 years; exclusion of prepregnancy diabetes, chronic hypertension, chronic kidney disease, epilepsy, rheumatoid arthritis and multiples; folate intake estimated by FFQ with measurement error; limited generalizability to high-risk pregnancies or fortified settings; few participants with very high folic acid doses; cannot establish causality.