Associations of folic acid supplements and dietary folate intake with gestational diabetes mellitus: complementary evidence from a multimethod investigation

Objective The relationships between folic acid supplementation, folate intake, and GDM remain controversial. We conducted a preliminary investigation using a multimethod approach integrating a retrospective cohort study, Mendelian randomization, and dose–response analysis to explore this association. Methods We examined the relationship between folic acid supplement use (including a combination preparation) and the GDM risk in a retrospective cohort of 10,479 pregnant women receiving care at Jiangsu Provincial People’s Hospital using multivariable logistic regression analysis. MR analysis provides genetic support for a potential causal link between genetically predicted folic acid supplement use and GDM. A cross-sectional analysis of 3,680 pregnant women in the National Health and Nutrition Examination Survey (NHANES) evaluated total folate intake and dietary folate equivalents (DFEs) via 24-h dietary recall; multivariable logistic regression and restricted cubic spline models were used to characterize associations and generate dose–response curves. The models were adjusted for age, BMI, race or ethnic origin, education, and smoking history. Subgroup analyses were performed to assess potential effect modifications. Results In this retrospective cohort study, compared with non-users, folic acid supplement users had a 46.2% greater likelihood of having GDM (OR = 1.46, 95% CI: 1.339–1.595; p < 0.001). MR analysis supported a potential causal association between genetically predicted folic acid products and GDM risk (OR = 1.40, 95% CI 1.17–1.67, p < 0.001). In the NHANES cohort, higher total folate (OR = 1.42, 95% CI: 1.05–1.92, p = 0.02) and DFE intake (OR = 1.61, 95% CI: 1.23–2.10, p < 0.001) were linked to an increased GDM risk, with non-linear dose–response inflection points at approximately 445 μg/day and 582 μg/day, respectively. These associations were generally maintained after multivariable adjustment, and subgroup analyses revealed consistent trends toward an increased risk. Conclusion This multimethod study indicates that both supplemental folic acid and dietary folate intake may be associated with an increased GDM risk. These observations support the need for additional research to better understand the potential impact of current recommendations on prenatal folate levels.