Pregnancy and risk of melanoma: a matched retrospective cohort study

Pregnancy-associated melanoma has long been debated, with hypotheses that gestational immune tolerance and elevated sex hormones may promote melanocytic transformation; however, large-scale, real-world evidence remains limited and conflicting. Using the TriNetX Global Collaborative Network, we conducted a retrospective cohort study of pregnant patients with documented first and third trimester encounters versus reproductive-age nonpregnant females with an encounter for contraceptive management and equivalent follow-up. Cohorts were 1:1 propensity-score matched on demographics, comorbidities relevant to immune function and cancer risk, and proxies for sun exposure and dermatologic surveillance. Incident invasive melanoma and melanoma in situ (MIS), stratified by anatomic site, were evaluated over a 21-month observation window corresponding to the duration of pregnancy plus 1 year postpartum. A sensitivity analysis restricted the pregnant cohort to patients with prior estrogen-based therapy exposure. In the primary analysis ( n  = 854 193 per cohort), pregnancy was not associated with increased risk of invasive melanoma [hazard ratio: 0.92, 95% confidence interval (CI): 0.78-1.07) or MIS (hazard ratio: 1.01, 95% CI: 0.82-1.24), and no significant differences emerged at head and neck, trunk, or extremity subsites. In the sensitivity analysis ( n  = 128 716 per cohort), findings were consistent, with no observed association with invasive melanoma (hazard ratio: 1.06, 95% CI: 0.76-1.49) or MIS (hazard ratio: 1.05, 95% CI: 0.67-1.65). Our results argue against pregnancy as an independent melanoma risk factor and point toward a baseline risk inherent to reproductive-age females.