Effect modification of prenatal folic acid supplementation on the associations of pre-pregnancy BMI and gestational weight gain with offspring birth weight: a large prospective cohort study.
Hu Y, Hou L, et al. • European journal of nutrition • 2026
Prenatal folic acid supplementation was modestly associated with lower macrosomia risk and may modify the association between pre-pregnancy BMI and birth weight, though effect sizes were small and findings should be interpreted cautiously.
Key Findings
Results
Folic acid supplementation was associated with slightly lower mean birth weight compared to no supplementation, though the absolute difference was of limited clinical significance.
Mean birth weight in the supplementation group was 3,289.64 ± 414.93 g versus 3,304.50 ± 427.78 g in the no-supplementation group (P < 0.001)
The absolute difference was approximately 15 grams
The study included 192,596 mother-infant pairs with complete follow-up and essential variables
Authors explicitly noted the absolute difference was 'of limited clinical significance'
Results
Prenatal folic acid supplementation was associated with a modestly lower risk of macrosomia.
Adjusted odds ratio for macrosomia with folic acid supplementation was 0.927 (95% CI: 0.889–0.967, P < 0.001)
Sensitivity analyses supported the findings for excessive fetal growth using gestational-age- and sex-specific classifications of small, appropriate, and large for gestational age
Multivariable regression models were used to assess this association
Results
Folic acid supplementation interacted with pre-pregnancy BMI on macrosomia risk.
The interaction adjusted odds ratio for folic acid supplementation and pre-pregnancy BMI on macrosomia risk was 0.977 (95% CI: 0.962–0.993, P = 0.005)
Spline analyses showed that supplementation modestly attenuated the non-linear positive association between pre-pregnancy BMI and birth weight (Pinteraction < 0.001)
Interaction terms were incorporated into multivariable regression models to evaluate effect modification
Results
Restricted cubic spline analyses revealed a non-linear positive association between pre-pregnancy BMI and birth weight that was modestly attenuated by folic acid supplementation.
The interaction between supplementation and pre-pregnancy BMI on the BMI–birth weight association was statistically significant (Pinteraction < 0.001)
The attenuation of the BMI–birth weight association by supplementation was described as 'modest'
Non-linear dose-response relationships were examined using restricted cubic splines
Methods
The study was a secondary analysis of a large population-based prospective cohort originally established to evaluate folic acid supplementation for neural tube defect prevention in China.
The cohort included 192,596 mother-infant pairs with complete follow-up and essential variables
Data were prospectively collected from a population-based cohort study in China
The original cohort was established to evaluate prenatal folic acid supplementation for neural tube defect prevention
Sensitivity analyses used gestational-age- and sex-specific classifications of small, appropriate, and large for gestational age
Conclusions
The authors cautioned that findings should be interpreted with caution given small effect sizes, observational design, and historical cohort context.
Effect sizes for both mean birth weight difference and macrosomia risk reduction were described as small or modest
The study was observational in design, precluding causal inference
The cohort was described as a 'historical cohort,' which may limit generalizability to contemporary populations
The absolute mean birth weight difference (~15 g) was explicitly characterized as being 'of limited clinical significance'
What This Means
This research suggests that taking folic acid supplements before and during pregnancy is associated with a small reduction in the risk of having a baby with macrosomia (a birth weight that is unusually high, generally above 4,000 grams). The study analyzed data from nearly 193,000 mother-infant pairs in China and found that babies born to mothers who took folic acid supplements weighed about 15 grams less on average than those born to mothers who did not supplement — a difference so small it is unlikely to matter clinically. However, the reduction in macrosomia risk, while modest, was statistically meaningful, with supplemented mothers having about a 7% lower odds of delivering a macrosomic baby.
The study also found that folic acid supplementation appeared to modify the relationship between a mother's pre-pregnancy body weight (BMI) and her baby's birth weight. Higher pre-pregnancy BMI is generally associated with higher birth weight, but this association was slightly weaker among mothers who took folic acid. This suggests folic acid may partially buffer some of the effects of higher maternal body weight on fetal growth, though the effect was described as modest.
This research matters because macrosomia is associated with complications during delivery and health risks for both mother and baby. However, the study has important limitations: it was observational (meaning it cannot prove that folic acid caused the lower macrosomia risk), was based on historical data, and the effect sizes were small. These findings add to existing reasons to recommend folic acid supplementation in pregnancy (primarily for neural tube defect prevention) but do not on their own establish folic acid as a tool for managing birth weight.
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Hu Y, Hou L, Yu M, Zhang R, Wu X, Wang B, et al.. (2026). Effect modification of prenatal folic acid supplementation on the associations of pre-pregnancy BMI and gestational weight gain with offspring birth weight: a large prospective cohort study.. European journal of nutrition. https://doi.org/10.1007/s00394-026-04065-w