Evaluating the Duration of Folic Acid Supplementation in Pregnancy: Clinical Insights from a Chinese Cohort Study

In a large Chinese multicenter cohort of 15,694 singleton pregnancies, extending folic acid supplementation into mid‑pregnancy was associated with lower risks of gestational hypertensive disorders (aRR 0.84, 95% CI 0.74–0.96) and pre‑eclampsia (aRR 0.81, 95% CI 0.67–0.97), shifting the clinical focus from neural‑tube prevention alone to broader pregnancy outcome trade‑offs.

In this prospective multicenter cohort (N=15,694) enrolled March 2017–June 2021 across mainland China, exposure was categorized as no‑FAS, peri‑FAS (peri‑conception), mid‑FAS (through mid‑pregnancy), and late‑FAS (through late pregnancy). Primary endpoints included gestational hypertensive disorders (GHDs), pre‑eclampsia, gestational diabetes mellitus (GDM), preterm birth, small‑for‑gestational‑age (SGA), and large‑for‑gestational‑age (LGA). Analyses used mixed‑effects log‑binomial models adjusted for maternal age, pre‑pregnancy BMI, parity, ethnicity, conception mode, education, pre‑pregnancy smoking and alcohol; offspring sex was assessed in sensitivity testing. Multivariable models and subgroup tests focused on maternal age and BMI.

Extended folic acid supplementation through mid‑pregnancy was linked with lower GHDs and pre‑eclampsia (mid‑FAS aRR for GHDs 0.84, 95% CI 0.74–0.96; pre‑eclampsia aRR 0.81, 95% CI 0.67–0.97). Late‑FAS was associated with reduced 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). However, subgroup analyses identified metabolic risk signals: prolonged supplementation was associated with higher GDM incidence in women aged ≥35 years (mid‑FAS aRR 1.10, 95% CI 1.01–1.21) and in those with pre‑pregnancy overweight/obesity (mid‑FAS aRR 1.34, 95% CI 1.10–1.63). Thus, hypertensive and fetal‑growth benefits coexist with subgroup‑specific metabolic risks.

Taken together, the data support a nuanced counseling conversation: extending folic acid into mid‑pregnancy may reduce hypertensive disorders and some adverse growth outcomes, but clinicians should weigh these potential benefits against observed increases in GDM risk among older and overweight/obese pregnant people. Duration of supplementation, patient age, and pre‑pregnancy BMI should inform individualized monitoring plans rather than a universal policy change.