The Mediating Effect of Insulin on the Influence of 25(OH)D in Recurrent Pregnancy Loss: A Case–Control Study

Background: Vitamin D deficiency (VDD) and insulin resistance (IR) are well-known risk factors for recurrent pregnancy loss (RPL). Since VDD may contribute to the development of IR, this study aimed to investigate the role of fasting insulin (FINS) levels and the homeostasis model assessment of insulin resistance (HOMA-IR) in the association between vitamin D and RPL. Methods: A total of 934 women were retrospectively analyzed between 2019 and 2022, including patients with RPL and age-matched controls. Clinical and biochemical data were collected, including serum 25(OH)D, FINS, fasting blood glucose (FBG), HOMA-IR, and sex hormone levels. Correlation, multivariate logistic regression, restricted cubic spline (RCS), and mediation analyses were conducted. Results: Compared to controls, the RPL group exhibited lower levels of 25(OH)D and higher levels of FINS and HOMA-IR. In the RPL group, 25(OH)D was negatively correlated with FINS and HOMA-IR. Higher levels of 25(OH)D were associated with reduced RPL, whereas elevated FINS and HOMA-IR levels were linked to an increased risk. A mediation analysis confirmed that FINS and HOMA-IR partially mediated the relationship between vitamin D and RPL, accounting for 10.9% and 10.7% of the total effects, respectively. Conclusions: VDD is closely associated with increased RPL risk, potentially through impaired glucose metabolism. Therefore, improving vitamin D status and insulin sensitivity may help in reducing pregnancy loss and enhancing reproductive outcomes.