One-carbon metabolism, insulin resistance, and fecundability in a Singapore prospective preconception cohort study

One-carbon metabolism, which consists of the folate cycle, methionine cycle, and trans-sulphuration pathway, is associated with nucleotide synthesis. However, the association between one-carbon metabolites, metabolic status, and reproductive health remains poorly understood.

We examined the association between the one-carbon cycle plasma metabolites and fecundability and determined whether it is modified by metabolic health status, as assessed by insulin resistance (IR).

This prospective cohort study utilized data from the Singapore PREconception Study of long-Term maternal and child Outcomes. Fasting blood samples were collected, and one-carbon cycle metabolites were measured. Fecundability was measured by time to pregnancy in menstrual cycles within a year of enrollment. We identified patterns in plasma one-carbon cycle metabolites using principal component (PC) analysis. We estimated fecundability ratios (FRs) and confidence intervals (CIs), with confounder adjustment using discrete-time proportional hazards models. IR was determined using the Homeostatic Model Assessment 2 Insulin Resistance score, classified into lower IR (<0.65) and higher IR (≥0.65). The role of IR was examined through interaction tests and stratification.

We identified 3 one-carbon cycle PCs. PC1, characterized by higher folate and lower homocysteine concentrations; PC2, characterized by higher concentrations of dimethylglycine, choline, methionine, and betaine; and PC3, characterized by higher concentrations of vitamins B2, B12, and B6. Each z-score increase in PC1 was associated with a 17% increase in fecundability (FR: 1.17; 95% CI: 1.03, 1.33). The association between PC1 and fecundability was more evident in women with lower IR (FR: 1.30; 95% CI: 1.08, 1.57) but was attenuated in those with higher IR (FR: 1.09; 95% CI: 0.92, 1.30), with a P-for-interaction of 0.127. PC2 and PC3 were not associated with fecundability.

Our findings suggest that higher folate and lower homocysteine concentrations, which reflected the interlinked folate and methionine cycles, were associated with higher fecundability in preconception women with lower IR but less so in those with higher IR.

This trial was registered at ClinicalTrials.gov as NCT03531658 (https://www.

gov/study/NCT03531658).