Premature ovarian insufficiency in patients with systemic lupus erythematosus on cyclophosphamide: a systematic review and meta-analysis

Background: Premature ovarian insufficiency (POI) is a major long-term adverse effect of cyclophosphamide (CYC) therapy in systemic lupus erythematosus (SLE). Reported prevalence varies due to differences in populations, protocols, and diagnostic criteria. Objective: To estimate the prevalence of POI in women with SLE exposed to CYC and explore sources of heterogeneity. Methods: MEDLINE, Embase, Web of Science, Scopus, and LILACS were searched from inception through October 2024. Twenty-one studies were included in the systematic review; 12 CYC-exposed cohorts contributed to the primary meta-analysis. Two reviewers independently extracted data and assessed study quality using the Joanna Briggs Institute checklist. Results: = 0.0353). In contrast, prevalence among unselected SLE populations was markedly lower, confirming the potential gonadotoxic effect of CYC. Temporal analysis showed reduced prevalence in studies published after 2005 (9%) compared with pre-2005 (29%), coinciding with adoption of Euro-Lupus low-dose protocols. Meta-regression identified age at exposure as a significant predictor (β = 0.21, 95% CI: 0.04-0.38, p = 0.017). Cumulative CYC dose was not independently associated with prevalence, likely reflecting the widespread adoption of lower-dose regimens after 2005. Methodological sensitivity analyses using logit transformation (20.0%, 95% CI 12.7-30.1) and GLMM (14.5%, 95% CI 7.1-27.2) were added to assess model robustness. Funnel-plot and the Egger's test indicated no evidence of publication bias (p = 0.91). Conclusions: Women with SLE treated with CYC show a substantial burden of POI, with an estimated prevalence of approximately 15%. These results underscore the need for standardized diagnostic criteria, fertility counseling, and individualized treatment decisions. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/, identifier CRD42025641213.