Association between Early Pregnancy Maternal Folate and Glycemic Indices at Oral Glucose Tolerance Test: A Systematic Review and Meta-analysis

Background: Folate plays a crucial role in fetal development, but its relationship with maternal glucose metabolism remains inconclusive. Recent meta-analyses have suggested a correlation between high folate and risk of gestational diabetes mellitus in pregnancy; however, its association with different glycemic parameters has not yet been explored.

Objectives: This study aims to comprehensively synthesize evidence and test the association between early pregnancy circulating folate (<16 wk of gestation) and glycemic indices measured during oral glucose tolerance testing (OGTT) at 24–28 wk.

Methods: We conducted a systematic search of databases up to 25 June, 2025, examining the relationship between early pregnancy folate and maternal glycemic indices. Study quality was assessed by Newcastle-Ottawa Scale. Standardized effect sizes (std. β coefficients) for serum/plasma folate were pooled using a random-effects model. Subgroup and sensitivity analyses were performed to account for between-study heterogeneity.

Results: Ten studies were included in this meta-analysis. Early pregnancy maternal folate levels were positively associated with glycemic indices measured at the time of OGTT. One standard deviation (nmol/L) increase in early pregnancy serum folate was associated with 0.01 [95% confidence interval (CI): −0.001, 0.01] mmol/L higher fasting, 0.17 (95% CI: 0.15, 0.18) mmol/L higher 1-h glucose, and 0.10 (95% CI: 0.05, 0.15) mmol/L higher 2-h glucose levels during OGTT Subgroup analyses revealed similar positive association between mid-pregnancy circulating folate and glucose levels measured at the time of OGTT despite substantial between-study heterogeneity (I²>70%).

Conclusions: Our analysis suggests a possible association between higher early pregnancy folate levels and higher glucose levels at the time of OGTT. However, these findings should be interpreted cautiously, given the methodological limitations and the limited number of studies included in this review.

This trial was registered at PROSPERO as CRD42021255022.