Association between homocysteine level and unexplained recurrent pregnancy loss: a meta-analysis

Unexplained recurrent pregnancy loss (uRPL) remains a major clinical challenge, with increasing evidence suggesting a potential role of hyperhomocysteinemia (HHcy) in its pathogenesis. However, findings from individual studies are inconsistent. A meta-analysis was therefore performed to summarize the findings.

A systematic search of PubMed, Embase, and Web of Science was conducted to identify observational studies evaluating the association between elevated homocysteine (Hcy) levels and uRPL. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were synthesized using a random-effects model accounting for the potential influence of heterogeneity.

Thirteen case-control studies comprising 1,473 women with uRPL and 1,605 controls were included. Overall, HHcy was significantly associated with uRPL (OR 3.46, 95% CI 2.33-5.14; I² = 57%). Subgroup analyses showed consistent associations across geographic regions, with pooled ORs of 4.41 in Asia, 2.96 in Europe, and 2.59 in Africa/Middle East (p for subgroup difference = 0.58). The association was stronger in studies with Hcy cutoff > 12 μmol/L compared to ≤ 12 μmol/L (OR 4.02 vs. 2.00; p = 0.02), and in studies using HPLC or immunoassay compared with enzymatic methods (OR 3.59 and 4.53 vs. 1.84; p = 0.02). Meta-regression identified Hcy cutoff as a significant contributor to heterogeneity (coefficient = 0.044, p = 0.04; adjusted R² = 65.2%).

Elevated Hcy levels are associated with increased odds of uRPL. Variations in Hcy cutoff definitions may partly explain between-study heterogeneity. These findings support HHcy as a potential risk indicator in uRPL, although further prospective studies are warranted.

https://www.crd.york.ac.uk/PROSPERO/view/, identifier CRD420261368753.