MTHFR C677T and one-carbon metabolism in adverse maternal–fetal outcomes: links to hypertension and renal/endothelial burden

Background Adverse pregnancy outcomes (APOs) encompass heterogeneous maternal, fetal/placental, and pregnancy-loss phenotypes. The clinical relevance of methylenetetrahydrofolate reductase (MTHFR) C677T may therefore depend less on genotype alone than on the surrounding one-carbon metabolic environment. We investigated genotype-metabolism relationships across rigorously adjudicated maternal-fetal phenotypes. Methods In this hospital-based retrospective cohort, 474 of 484 pregnancy records met prespecified criteria for primary analysis. Pregnancies were classified as reference, maternal-predominant, fetal/placental-predominant, maternal–fetal dual-hit, or pregnancy loss. MTHFR C677T was modeled primarily as CT/TT versus CC. An a priori one-carbon metabolism index (OCMI) integrated standardized homocysteine, folate, and vitamin B12. Associations were evaluated using age-adjusted regression, interaction modeling, natural cubic splines, and sensitivity analyses including inverse-probability weighting. Results MTHFR C677T showed little evidence of association with overall or phenotype-specific APO after age adjustment. Higher homocysteine was strongly associated with hypertensive disorders of pregnancy (HDP; OR 2.32 per SD, 95% CI 1.61–3.34) and mapped preferentially to a renal/endothelial-related biochemical burden, which was itself strongly associated with HDP (OR 3.99 per SD, 95% CI 2.79–5.70). The MTHFR-homocysteine interaction was null. By contrast, among 177 OCM-complete pregnancies, the MTHFR-OCMI interaction with HDP was suggestive (OR 2.46, 95% CI 1.10–5.52; BH-FDR q = 0.085) and showed evidence of genotype-dependent non-linearity. Renal/endothelial-related burden showed a nonlinear association with maternal–fetal dual-hit involvement, with the strongest association observed in the highest quartile. Conclusion MTHFR C677T appears more consistent with a context-dependent susceptibility factor than with an isolated correlate of APO. Integrating one-carbon metabolism with maternal-fetal phenotyping identified a coherent pattern of associations between metabolic disturbance, hypertensive morbidity, and renal/endothelial-related biochemical burden, while the genotype-OCMI signal warrants prospective validation.