Vitamin D deficiency and long-term risk of female genital cancer: a multicenter real-world cohort study.

BACKGROUND: A growing body of evidence implicates vitamin D deficiency (VDD) in carcinogenesis, yet evidence linking VDD to female genital cancers remains inconsistent, with most studies evaluating individual cancer subtypes in isolation using heterogeneous designs. METHODS: We conducted a retrospective propensity score-matched cohort study using the TriNetX Global Collaborative Network. Female adults aged ≥30 years with serum 25-hydroxyvitamin D <20 ng/mL (VDD group) were matched 1:1 with those with levels ≥30 ng/mL (control group). A 2-year landmark design was used to reduce reverse causation. The primary outcome was incident overall female genital cancer within 10 years. Secondary outcomes included ovarian, cervical, and corpus uteri cancers, and all-cause mortality. RESULTS: After matching, 675,079 patients were included in each group. VDD was associated with a higher risk of overall female genital cancer compared with normal vitamin D status [hazard ratio (HR), 1.47; 95% confidence interval (CI), 1.38-1.55, p < 0.001]. Associations were also observed for ovarian cancer (HR, 1.30; 95% CI, 1.17-1.44, p < 0.001), cervical cancer (HR, 1.31; 95% CI, 1.13-1.51, p < 0.001), and corpus uteri cancer (HR, 1.55; 95% CI, 1.43-1.68; p < 0.001). These associations persisted across sensitivity analyses and were consistent in both patients aged 30-65 years and those aged >65 years. The exposure-gradient analysis demonstrated a modestly attenuated association for vitamin D insufficiency compared with VDD. CONCLUSION: This multicenter real-world cohort study demonstrated that VDD was associated with a higher long-term risk of overall female genital cancer and its major subtypes. Given the observational design and the absence of a clear exposure-gradient pattern, these findings should be interpreted as associative rather than causal and warrant further prospective investigation.