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Among a subgroup of the study sample, we also observed associations of higher serum folate levels at the time of the OGTT with a higher risk of GDM (Supplementary Table 2), which confirmed the findings of previous studies (19). Furthermore, greater decrease of serum folate from early to midgestation was associated with a lower risk of GDM, supporting our hypothesis that high folate levels in early pregnancy could be a risk factor for GDM. Our novel findings raise an important question regarding the potential mechanism or causality for the development of GDM in subjects with vitamin insufficiency. Future studies longitudinally assessing the relationship of early pregnancy vitamin status in women with low folate and B_twelve levels late in gestation with GDM may be helpful to explore the mechanism behind the positive associations of folate and vitamin B₁₂ with GDM.

Considering that both folate and vitamin B₁₂ are essential for nucleic acid synthesis, methyl group generation, and conversion of homocysteine to methionine, their balance may have important implications for maternal and neonatal health (5–7). A recent case-control study of 406 pregnant women reported that a higher serum folate/vitamin B₁₂ ratio midgestation (24–28 weeks) calculated based on raw values was associated with a higher risk of GDM (19). We extended their work to using RBC folate/vitamin B₁₂ ratio at early gestation by using a percentile ratio that is robust to differences in measurement scales. Intriguingly, we did not find any significant association between this ratio at early pregnancy and GDM. Unlike the work by Li et al. (19), in which directionally opposite associations were found for folate and vitamin B₁₂, these two markers showed directionally similar associations with GDM in our study. Besides, >95% of the pregnant women took multivitamins in which proportions of the two nutrients were fixed, and the levels of these two biomarkers correlated significantly in our population (r = 0.12; P < 0.001; data not shown).