Duration of Folic Acid Supplementation and Adverse Pregnancy Outcomes: A Prospective Multicenter Cohort Study in China

<b>Background:</b> Folic acid supplementation (FAS) before and in early pregnancy prevents neural tube defects, but the benefits of extending FAS to late pregnancy on pregnancy outcomes remain unclear. We aimed to investigate the associations between duration of FAS and a spectrum of pregnancy outcomes, and to determine whether the associations were modified by maternal age or pre-pregnancy body mass index (BMI). <b>Methods:</b> This prospective multicenter study included 15,694 singleton pregnancies. We used mixed-effects log-binomial regression models to estimate the adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) for gestational diabetes mellitus (GDM), gestational hypertensive disorders (GHDs), pre-eclampsia, preterm birth, macrosomia, small (SGA) and large for gestational age (LGA), and the interaction effects of advanced maternal age and pre-pregnancy BMI. <b>Results</b>: Of 15,694 women, 4523 (28.8%) did not take FAS before or during pregnancy, 2854 (18.2%) took FAS only during peri-pregnancy, 921 (5.9%) took FAS from peri- to mid-pregnancy, and 7396 (47.1%) took it through late pregnancy. Compared with women without FAS, those supplemented until mid-pregnancy were associated with lower risks of GHDs (aRR 0.84, 95% CI 0.74, 0.96) and pre-eclampsia (aRR 0.81, 95% CI 0.67, 0.97). Supplementation until late pregnancy was associated with lower risks of preterm birth (aRR 0.67, 95% CI 0.59, 0.76), SGA (aRR 0.74, 95% CI 0.63, 0.87), and LGA (aRR 0.88, 95% CI 0.79, 0.97). Among women of advanced maternal age or with overweight/obesity, supplementation until mid-pregnancy was associated with higher risk of GDM. <b>Conclusions:</b> Extending FAS until mid-pregnancy is associated with lower risks of GHDs and preeclampsia, and extending it until late pregnancy is associated with lower risks of preterm birth, SGA, and LGA. However, women of advanced maternal age or with overweight/obesity should be cautious about prolonging FAS.