Associations of Folic Acid Supplements and Dietary Folate Intake with Gestational Diabetes Mellitus: Complementary Evidence from a Multimethod Investigation

Yanyan HU¹Yifei Wang¹Cheng Xue^1,2Yifang Hu^1,3Dan Wang¹Jizheng Wang¹Yanfei Mo⁴Wen-Song Zhang⁵Ting Ge¹Wenjie Ma¹Ying Lu^6*Yun Liu^1*Shan Lu^6*

• ¹Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China, nanjing, China
• ²Division of Geriatric, Liyang People’s Hospital, Liyang Branch Hospital of Jiangsu Province Hospital, Changzhou, China, changzhou, China
• ³Department of the Clinical medical research , The Friendship Hospital of Ili Kazakh Autonomous Prefecture, Yining, Xinjiang, China, xinjiang, China
• ⁴Nanjing Pukou District Chinese Medicine Hospital, Nanjing, Jiangsu Province, China., nanjing, China
• ⁵Department of the Core Facility, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China, nanjing, China
• ⁶Women and Children Department of the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China, nanjing, China

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 3,681 pregnant women in the National Health and Nutrition Examination Survey (NHANES) evaluated total folate intake and dietary folate equivalents (DFEs) via 24-hour 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 nonusers, 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 nonlinear 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 towards an increased risk. Conclusions: 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 on current recommendations on prenatal folate levels.