Ku Chee Wai, Chan Hiu Gwan, Sia Alexandrea Lishan, Huang Christine, Quek Jessica, Cheung Yin Bun, Tan Karen Mei Ling, Lai Jun Shi, Godfrey Keith M, Chan Jerry Kok Yen, Yap Fabian, Loy See Ling
Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore, Singapore; Duke-NUS Medical School, Singapore, Singapore.
Endocrinology Service, Department of Pediatrics, KK Women's and Children's Hospital, Singapore, Singapore.
Am J Clin Nutr. 2025 Jul;122(1):335-343. doi: 10.1016/j.ajcnut.2025.04.035. Epub 2025 May 5.
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).
一碳代谢由叶酸循环、蛋氨酸循环和转硫途径组成，与核苷酸合成相关。然而，一碳代谢产物、代谢状态与生殖健康之间的关联仍知之甚少。
我们研究了一碳循环血浆代谢产物与受孕能力之间的关联，并确定其是否会因胰岛素抵抗（IR）评估的代谢健康状况而改变。
这项前瞻性队列研究利用了新加坡母婴长期结局孕前研究的数据。采集空腹血样并测量一碳循环代谢产物。受孕能力通过入组后一年内月经周期的受孕时间来衡量。我们使用主成分（PC）分析确定血浆一碳循环代谢产物的模式。我们估计受孕能力比（FRs）和置信区间（CIs），并使用离散时间比例风险模型进行混杂因素调整。使用稳态模型评估2胰岛素抵抗评分确定IR，分为低IR（<0.65）和高IR（≥0.65）。通过交互检验和分层研究IR的作用。
我们确定了3个一碳循环主成分。PC1的特征是叶酸浓度较高而同型半胱氨酸浓度较低；PC2的特征是二甲基甘氨酸、胆碱、蛋氨酸和甜菜碱浓度较高；PC3的特征是维生素B2、B12和B6浓度较高。PC1每增加一个z分数，受孕能力增加17%（FR：1.17；95%CI：1.03，1.33）。PC1与受孕能力之间的关联在低IR女性中更明显（FR：1.30；95%CI：1.08，1.57），但在高IR女性中减弱（FR：1.09；95%CI：0.92，1.30），交互作用P值为0.127。PC2和PC3与受孕能力无关。
我们的研究结果表明，反映叶酸和蛋氨酸循环相互关联的较高叶酸浓度和较低同型半胱氨酸浓度与低IR的孕前女性较高的受孕能力相关，但在高IR女性中相关性较弱。
本试验在ClinicalTrials.gov注册为NCT03531658（https://www.
gov/study/NCT03531658）。
