Effects of maternal folate and vitamin B12 on gestational diabetes mellitus: a dose-response meta-analysis of observational studies

To comprehensively estimate the association of gestational diabetes mellitus (GDM) risk with maternal red blood cell (RBC) folate, plasma/serum folate, dose and duration of folic acid supplement (FAS) intake and vitamin B12 separately. PubMed, Web of science, CNKI, and Wanfang Databases were searched through March 26, 2021. We synthesized data using random-effects model meta-analysis in Stata 12.0. Sensitivity, subgroup and dose-response analyses were also performed. The certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE). Twenty six datasets from thirteen eligible observational studies were included in the study. We found a significant increase of GDM risk with the highest versus lowest category of RBC folate (OR = 1.96, 95% CI: 1.48–2.61, I2 = 0.0%, moderate-certainty evidence) and plasma/serum folate (OR = 1.23, 1.02–1.48, I2 = 57.8%, low-certainty evidence). The dose-response analysis revealed that each 200 ng/ml increase in RBC folate was significantly associated with 8% higher GDM risk. No significant association between dose of FAS intake and GDM risk was found with very low cetainty. Meanwhile, longer duration (≥3 months) of FAS conferred 56% significant higher GDM risk (OR = 1.56, 1.02–2.39, very low certainty evidence). No significant association of GDM risk with highest plasma/serum B12 was observed compared to lowest B12 (OR = 0.77, 0.58–1.02, very low-certainty evidence). Moderate-certainty evidence suggests that higher RBC folate appears to significantly increase GDM risk. Higher plasma/serum folate may increase GDM risk but with low certainty. Further well-designed trials or prospective studies are needed.