Preconception One‐Carbon Metabolism Nutrient Levels in Preparing for Pregnancy Couples and Spontaneous Pregnancy Loss: A Prospective Cohort Study

Spontaneous pregnancy loss (SPL) remains an important yet poorly understood pregnancy outcome. One-carbon metabolism (OCM) nutrients play an essential role in embryonic development, but their relationship with SPL remains unclear. In this prospective cohort of 11,033 couples and 2862 unpaired mothers, we assessed associations between preconception parental one-carbon metabolism (OCM) nutrients and SPL risk. We used generalized linear models to estimate risk ratios (RRs) and 95% confidence intervals (CIs) for fathers, mothers, and the combined parental population, respectively. Each 100 ng/mL increase in paternal and maternal red blood cell (RBC) folate was associated with a 19% (aRR = 0.81; 95% CI, 0.73-0.90) and an 8% (aRR = 0.92; 0.85-0.98) lower SPL risk, respectively. The risk was reduced by 64% (aRR = 0.36; 0.16-0.79) when both parents achieved levels ≥ 400 ng/mL, compared to neither. Exploratory case-control analysis suggested associations of parental serum betaine with increased risk of SPL (β [standard error]: 0.09 [0.11] for fathers; 0.02 [0.08] for mothers) and inverse associations for taurine (-0.09 [0.11] and -0.03 [0.08], respectively). These findings highlight paternal and maternal preconception RBC folate, and imbalances in OCM metabolites are associated with an increased SPL risk, offering novel insights into SPL etiology and have public health implications.