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 Ba dozen 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). It is thus likely that the effects of RBC folate and vitamin B12 on GDM may be confounded, and this may partially explain the disappeared association for GDM when the percentile ratio of RBC folate and vitamin B12 was used.
This study has several limitations. First, selection bias may exist because we only included pregnancies with measurements of RBC folate, serum folate, and vitamin B12 in early pregnancy from the large-scale SPCC, and the generalizability of our findings to other regions needs further validation. Second, residual confounding cannot be ruled out, as we did not have data on covariates, including physical activities, diet, medication use, and lipid levels. Third, the exploratory nature of our study without a prespecified power calculation precludes us from drawing any confirmative conclusions regarding the association among folate, vitamin B12, and GDM.
In conclusion, we report that higher maternal RBC folate and vitamin B12 levels in early pregnancy are significantly associated with GDM risk, while the balance of folate/vitamin B12 is not significantly associated with GDM. Given the exploratory nature of this study, more investigations are needed to figure out the appropriate levels of folate and vitamin B12 in early pregnancy that are essential for maternal and offspring health.
Acknowledgments. The fresh new article authors thank all of the participants within this research. Brand new article writers in addition to thank the new physicians, interviewers, research aspects, and also the entire SPCC class for their focus on this study.
Capital. This research is actually backed by this new Federal Secret Lookup and you will Innovation Program (offer amount 2016YFC1000500), Chinese Academy out of Scientific Sciences Search Product (give matter 2018RU002), while the Around three-Season Action plan to have Building the development of Social Wellness System in the Shanghai (grant number GWIV-24).
Vitamin B12 deficiency has been associated with risk of metabolic abnormalities in pregnant women, such as insulin resistance, fatty acids, and GDM (16). Imbalanced levels of folate and vitamin B12 increase the risk of being born small for gestational age (17). Increasing concerns have risen about supplementing high doses of folic acid to women of reproductive age with low vitamin B12 intake, although this issue has not been well investigated yet (5). Several case-control studies demonstrated that higher serum folate/vitamin B12 ratio was positively associated with GDM risk (18,19). However, to our knowledge, no studies have investigated the relationship between maternal vitamin B12 in early pregnancy and GDM. In this study, we aimed to evaluate the association of maternal folate, vitamin B12, and percentile ratio of folate/vitamin B12 in early pregnancy with GDM using a prospective cohort study. The findings of this study would be useful to provide a theoretical basis for early prevention of GDM.
The mechanisms by which folate and vitamin B12 may confer an increased GDM risk are not well understood. Evidence from an animal model revealed that higher maternal folate concentration was positively associated with insulin resistance in offspring (28). A positive correlation between RBC folate and insulin resistance was observed in the obese population (29). In addition, folate was reported to play a role in the progression of type 1 diabetes via NK cell dysfunction in human subjects (30). Regarding vitamin B12, higher levels of its circulating form in our study may be partially due to liver function impairment. About 50% of absorbed vitamin B12 is stored in the liver, and elevated serum vitamin B12 levels have been found in chronic viral hepatitis and cirrhosis and severe alcoholic liver disease (31,32). In our additional subgroup analysis, we found that higher ?-glutamyl transferase levels, which were an indicator of mild liver dysfunction and were associated with GDM risk (33), were higher in our group with GDM (Supplementary Fig. 3). We thus assumed pregnancies with GDM might have concurrent mild liver dysfunction. Consequently, the observed association of serum vitamin B12 in early pregnancy with GDM might reflect differences in liver function between the pregnancies with or without GDM.