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

## TL;DR

This study suggests that folic acid supplements and dietary folate may increase the risk of gestational diabetes, based on multiple research methods.

## Contribution

The study combines multiple methods to investigate the link between folate intake and gestational diabetes, providing new evidence for potential causal associations.

## Key findings

- Folic acid supplement users had a 46.2% higher likelihood of gestational diabetes compared to non-users.
- Higher total folate and dietary folate equivalents intake were linked to increased gestational diabetes risk with non-linear dose-response patterns.
- Genetically predicted folic acid supplement use showed a potential causal link to gestational diabetes risk.

## Abstract

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.

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.

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.

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.