Baseline erythrocyte folate and outcomes of low grade cervical intraepithelial neoplasia in a prospective cohort

Objective To examine the association between baseline erythrocyte folate and reversal, persistence, and progression of cervical intraepithelial neoplasia grade 1 (CIN1). Methods This community-based prospective cohort included 564 Chinese women with CIN1, with follow-up assessments at 6, 12, and 24 months. Baseline erythrocyte folate was measured by chemiluminescence immunoassay. Histological outcomes were classified as reversal, persistence, or progression to CIN2 or worse (CIN2+); persistence and progression formed a composite adverse outcome. Analyses included Cox regression, restricted cubic splines, and receiver operating characteristic (ROC) curves. Exploratory experiments assessed proliferation and apoptosis in C33A and CaSki cervical cancer cells. Results Among the 453 women assessed at 24 months, 342 (75.5%) had reversal, 58 (12.8%) had persistence, and 53 (11.7%) had progression to CIN2+. Lower baseline erythrocyte folate was associated with the composite adverse outcome in the reported adjusted model (adjusted hazard ratio [aHR] = 2.42, 95% confidence interval [CI]: 1.62–3.61). No statistically significant nonlinearity was detected for this outcome at 6 or 12 months ( p = 0.655 and p = 0.127), whereas an L-shaped association was observed at 24 months (P for nonlinearity = 0.005). At 24 months, the area under the ROC curve (AUC) for folate was 0.703 (95% CI: 0.647–0.760) overall and 0.742 (95% CI: 0.646–0.837) within the high-risk human papillomavirus (HR-HPV)-positive subgroup. Higher nominal folate concentrations reduced proliferation and increased apoptosis in the two cell lines. Conclusion Lower baseline erythrocyte folate was associated with adverse CIN1 outcomes after adjustment for the covariates included in the reported model. Event-time assumptions and residual confounding limit interpretation. These findings do not establish causality, an interaction with HR-HPV, or a therapeutic benefit of folate supplementation. Prognostic use requires further validation.