Folate intake and risk of gestational diabetes: dose-response relationship and causal relationship exploration

Objective : The relationship between folate and GDM remains controversial. We conducted a preliminary investigation using a multimethod approach—integrating a retrospective cohort, Mendelian randomization, and dose-response analysis—to explore this association. Methods : In a retrospective cohort of 10,479 pregnant women at Jiangsu Provincial People’s Hospital, we examined the relationship between folate use (including a combination preparation) and GDM risk using multivariable logistic regression. MR analysis leveraged folate-associated single nucleotide polymorphisms from large-scale genome-wide association studies to assess potential causal effects on GDM. A cross-sectional analysis of 3,681 pregnant women in the National Health and Nutrition Examination Survey (NHANES) evaluated total folate intake and dietary folate equivalent (DFE) via 24-hour dietary recall; multivariable logistic regression and restricted cubic spline models characterized associations and dose–response curves. Models adjusted for age, BMI, race, education and smoking history. Subgroup analyses assessed potential effect modification. Results : In the retrospective cohort study, folate users exhibited a 46.2% higher odds of GDM compared to non-users (OR = 1.462, 95% CI: 1.339–1.595, p < 0.001). MR analysis supported a potential causal association between genetically predicted folate levels and GDM risk (β = 33.81, SE = 9.074, p < 0.001). In NHANES, 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 increased GDM risk, with nonlinear dose–response inflection points at approximately 445 µg/day and 582 µg/day.These associations were generally maintained after multivariable adjustment, and subgroup analyses showed consistent trends toward increased risk. Conclusion : This multi-method study indicate that higher folate intake may be associated with an elevated risk of GDM. These observations support the need for additional research to better understand the potential impact on current prenatal folate.