Fertility Treatment and Risk of Melanoma: A Certainty‐Rated Systematic Review and Meta‐Analysis of 3,733,499 Women
Dimitrios Stylianakis, Cinzia Solinas, Fausto Petrelli, Gianluca Nazzaro, Emanuela Passoni, Serafina Martella, Ioannis Stylianakis, Laura Atzori, Mario Scartozzi, Matteo Lambertini, Ornella Garrone, Nerina DenaroABSTRACT
Background
Cancer safety after fertility treatment is well studied for breast and gynaecological tumours, but melanoma risk remains poorly characterized. We synthesized internally controlled evidence on this association.
Methods
PubMed/MEDLINE, Scopus, Cochrane Library, and ClinicalTrials.gov (2000–2025) were searched for comparative observational studies of melanoma incidence. The primary outcome was incident melanoma; treatment‐pathway/SIR analyses were secondary. Hazard ratios and case–cohort relative risks (rare‐disease approximation) were pooled using random‐effects meta‐analysis (REML, Hartung–Knapp) in R; SIRs were synthesized separately. Risk of bias was assessed with ROBINS‐E and certainty graded using GRADE.
Results
Twelve observational studies (3,733,499 women; 219,357 exposed) were included. ROBINS‐E rated no study overall low risk of bias (83% some concerns, 17% high risk), reflecting incomplete ultraviolet‐exposure adjustment. Melanoma risk was modestly elevated (HR 1.24, 95% CI 1.02–1.50; I 2 = 0%; prediction interval 0.97–1.58); drug‐only ovulation induction showed a stronger association (HR 1.39, 95% CI 1.01–1.92), while ART/IVF was near‐null (HR 1.09, 95% CI 0.81–1.48). Corresponding absolute increases were approximately 3–8, 5–13, and 1–3 per 10,000 women over 10 years (baseline 13.3–33.1/100,000/year). Certainty was very low for any fertility treatment and drug‐only treatment, and low for ART/IVF. SIR‐based analyses were non‐significant and highly heterogeneous (SIR 1.25, 95% CI 0.66–2.38; I 2 = 80%).
Conclusions
Observed associations are small and of very low to low certainty, reflecting incomplete ultraviolet‐exposure and risk‐factor adjustment; causality cannot be established. Current evidence does not justify changes in fertility‐treatment practice. Future studies require cycle‐level exposure data and rigorous ultraviolet‐exposure control.