Associations of homocysteine levels and implantation failure in the first embryo transfer: a retrospective study

Background Homocysteine (Hcy) has been associated with adverse pregnancy outcomes, but its association with implantation failure in the first embryo transfer and with endometrial characteristics remains unclear. Whether nutritional supplementation is linked to these outcomes also remains unclear Methods Among 1770 participants without established implantation failure risk factors undergoing first embryo transfer (Jan 2015–May 2025), 589 had Hcy measured before transfer and were analyzed. The primary outcome was implantation failure. Results In the overall cohort and in patients with Hcy measured within one year before transfer (≤ 1-year subgroup), implantation failure rates did not differ between patients with Hcy ≥ 8 and < 8 μmol/L. In patients with Hcy measured more than 1 year before transfer (> 1-year subgroup), patients with Hcy ≥ 8 μmol/L exhibited a higher implantation failure rate (53.4% vs. 36.5%, P = 0.026), a lower prevalence of type A endometrium on hCG trigger day (76.3% vs. 93.8%, P = 0.046), and lower implantation (32.8% vs. 49.0%, P = 0.010) and clinical pregnancy rates (46.6% vs. 63.5%, P = 0.026). The association with implantation failure remained significant after multivariable adjustment [adjusted OR (aOR) 1.3, 95% CI 1.1–1.6, P = 0.0033]. Hcy ≥ 8 μmol/L was also associated with a lower prevalence of type A endometrium on hCG trigger day (aOR 0.5, 95% CI 0.2–0.9, P = 0.0288) in the overall cohort. Methylcobalamin supplementation was more common in patients with Hcy ≥ 8 μmol/L in the overall cohort (after Hcy measurement: 9.9% vs. 1.5%; pre-transfer: 9.4% vs. 0.3%) and the ≤ 1-year subgroup (after Hcy measurement: 11.0% vs. 1.4%; pre-transfer: 12.7% vs. 0.3%) (all P < 0.001), but not in the > 1-year subgroup. Among patients with Hcy ≥ 8 μmol/L, nutritional supplementation was positively linked to type A pattern (aOR 2.9, 95% CI 1.2–6.7, P = 0.0153). Conclusions In patients with Hcy measured more than one year before transfer, elevated Hcy was associated with implantation failure and a lower likelihood of type A endometrium. Nutritional supplementation was associated with a higher prevalence of type A endometrial pattern, even among patients with elevated Hcy. These findings are hypothesis-generating and require confirmation before clinical application. Trial registration Not applicable.