In this prospective cohort, we discovered significant interactions between FA supplements and ppBMI in the risk of GDM. More specifically, we discovered that the risk effect was most pronounced in pregnant women with insufficient FA intake and obese women. Our findings further support the hypothesis that FA levels during pregnancy may play an important role in maternal metabolic disease, particularly in women with higher ppBMI.
FA is an important pregnancy nutrient for its protective effects against birth defects. Previous studies evaluating the association of FA supplementation before or during pregnancy with GDM risk have conflicting results. A large prospective cohort (n = 20,199) showed that preconception habitual intake of FA supplements was inversely associated with GDM risk in the United States. Conversely, a prospective Chinese study of 326 pregnant women showed that high-dose FA supplementation in early pregnancy was associated with an increased risk of GDM. The discrepancy of findings might be due to a smaller sample size in the latter study. Consistent with this, a prospective cohort showed that daily FA supplementation in the first trimester was positively associated with GDM risk. However, it is difficult to interpret this finding as details of the research methods and results are not reported. Heidi T Cueto and colleagues35 reported that there was no clear association between preconception FA use and diabetes diagnosis, and our result are consistent with them. Considering the inconsistent results mentioned above, the relationship between maternal FA status and GDM need further larger cohort studies to examine.
Previous studies have suggested that different BMI levels may influence the effect of FA supplementation on disease. According to a case–control study, the association between FA supplements and the NTDs risk was weaker in overweight/obese mothers than in underweight/normal weight mothers, indicating that maternal BMI could affect the association between FA supplement and the NTDs risk in offspring. Meanwhile, a retrospective cohort study report that the protective effect of FA supplements for PTD is reduced in women whose BMI was equal or greater than 24 kg/m2. We are not aware of direct evidence regarding biological mechanisms for the effect of FA supplement on the association between ppBMI and GDM. However, an intervention study comparing the relationship between BMI and the short-term pharmacokinetic response to oral doses of FA showed that distribution of folate in the body is significantly affected by BMI. A retrospective case-control study found that higher BMI recorded in the first trimester was negatively correlated with serum folate levels measured in the third trimester. Another possible explanation is that obesity can increase estrogen, which has been reported to be associated with decreased serum folate availability. Thus, it is plausible that pathways related to metabolic regulation may underlie associations between BMI and serum folate.
One of the most interesting observations of this study is that the risk for GDM is increased in obese women regardless of adequate folate intake, but the risk of GDM is higher when folate intake is deficiency. Two prospective cohort studies in China have assessed the association of the impact of FA supplement use on GDM with consideration of both doses and durations. One of them shows a U-shape relation between duration of FA supplements and risk of GDM, and another suggested that long-term use of high-dose FA increases GDM risk. Thus, we also compared the interaction between the FA supplements and ppBMI, in the case of FA ≥ 3 months and FA < 3 months. Risk of GDM in obese women with FA-D and FA-S were still higher than women with BMI < 24kg/m2 and FA-S. Although the biological mechanisms that underlie the modified association were complicated and remained unclear, our findings could be partly explained by the theory that FA could inhibit Hcy production[39, 40]. And Hcy concentrations declined as FA concentrations increased, as did the prevalence of hyperhomocysteinemia, while high concentrations of Hcy are associated with insulin resistance[42, 43]. These findings suggest that FA might have a protective effect GDM by reducing Hcy concentration and improving insulin resistance. However, the higher ppBMI decreased the levels of serum folic acid or dietary folate intake[44–46]. The combinative effect of high ppBMI and low dose FA intake leads to the accumulation of Hcy concentrations and reduce insulin resistance, ending up with GDM. Therefore, we suggest that a diverse plan of FA supplementation should be carried out according to women’s BMI category.
Our study has several advantages. Firstly, this study is a prospective cohort, which reduces the effects of selection or recall bias. We excluded women with hypertension or established diabetes to avoid information bias. Furthermore, some studies have shown that vitamin B12 in multivitamin supplements has an impact on the risk of GDM[47, 48]. We collected sufficient data to include various confounders in adjusted analyses and matched for vitamin B12 as a confounder. The effects of the interaction of FA supplements alone with ppBMI on GDM were obtained. Several limitations are present in this study. First, dietary FA was also not estimated, and we were unable to calculate exact FA levels, and the results of this study need further research to verify. Second, we mainly analyzed daily intake of FA by pregnant women during pre-pregnancy to first trimester. Although the FA intake during the whole pregnancy was not analyzed, our study is consistent with the recommended folic acid intake time in the Nationwide Folic Acid Supplementation Program of China. Third, the relatively small sample size in our study also limited our ability to investigate the relationship between FA supplements and ppBMI at different levels. Our findings provide a new perspective on the development of prevention strategies, and further studies should consider larger sample sizes, total time from pre-conception to post-conception, and sophisticated statistical methods to examine the relationship between FA supplements, ppBMI, and pregnancy disorders.