Smoking May Reduce the Fertility Benefit of Folic Acid Supplementation

Background: Folic acid supplementation is recommended to prevent neural tube defects and has been associated with improved fertility, while cigarette smoking is linked to reduced circulating folate even after accounting for intake. We examined whether cigarette smoking modifies the association between folic acid supplementation and fecundability among females attempting to conceive. Methods: We conducted a prospective preconception cohort study of 15,350 females aged 21–45 years attempting to conceive without fertility treatment, enrolled between 2013 and 2025 during the first six cycles of their pregnancy attempt. At baseline, participants self-reported folic acid-containing supplement use and current regular smoking. Discrete-time proportional probabilities regression estimated fecundability ratios (FRs) and 95% confidence intervals (CIs), adjusting for age, race/ethnicity, BMI, parity, income, education, and partner smoking, with stratification by smoking status and a model containing the product of folic acid and smoking. Results: Across 67,169 cycles and 10,234 pregnancies, folic acid supplementation was associated with higher fecundability overall (adjusted FR = 1.23, 95% CI 1.16–1.30). Stratified estimates were similar among never/former smokers (FR = 1.24, 95% CI 1.17–1.31) and lower but imprecisely estimated among regular smokers (FR = 1.10, 95% CI 0.87–1.40; ratio of FRs = 0.90, 95% CI 0.71–1.15). A sensitivity analysis restricting the reference to never-smokers gave similar results (ratio of FRs = 0.91,95% CI 0.71–1.16). Conclusions: Folic acid supplementation was associated with higher fecundability overall. The point estimate was lower among regular smokers, but the between-stratum difference was small and imprecisely estimated. Together, these findings are consistent with a slight attenuation of the folic acid–fecundability association by smoking, but also consistent with no difference between smokers and never/former smokers.