Abstract
BACKGROUND: Gestational diabetes mellitus (GDM), a prevalent metabolic complication during pregnancy, has a global prevalence of approximately 14%. Its onset is closely associated with insulin resistance, insufficient compensatory function of β - cells, and abnormal placental function. Epidemiological studies have indicated that type 2 diabetes is an independent risk factor for breast cancer. However, the association between GDM and the risk of breast cancer remains controversial. OBJECTIVE: This systematic review and meta-analysis aim to comprehensively evaluate the association between GDM and the risk of breast cancer and explore its underlying mechanisms. METHODS: This study systematically searched PubMed, Web of Science, Scopus, EMBASE, and the Cochrane Library databases, covering the period from establishing each database until April 14, 2025. Two researchers extracted relevant data and assessed the quality of included studies using the Newcastle-Ottawa Scale. The study evaluated inter-study heterogeneity using the I² statistic. Based on the magnitude of heterogeneity, fixed-effect or random-effect models were employed to calculate the pooled hazard ratio (HR) and its corresponding 95% confidence interval (CI). Additionally, subgroup analyses, sensitivity analyses, funnel plot analyses, and publication bias assessments were performed. All data analyses were conducted using STATA 17 software. RESULTS: The overall analysis revealed no significant association between GDM and breast cancer risk (HR=1.03, 95%CI: 0.92-1.15). However, subgroup analysis revealed significant regional heterogeneity: within the regional subgroups, North American results showed an association between GDM and a reduced breast cancer risk (HR=0.89, 95%CI: 0.84-0.95), whereas Asian findings suggested an association with an increased risk (HR=1.23, 95%CI: 1.15-1.31). No significant associations were observed in subgroups based on study design (cohort/case-control) or follow-up duration (short-term/long-term). Sensitivity analysis demonstrated robust results, and there was no publication bias in this study. CONCLUSION: In summary, there is no significant association between GDM and breast cancer risk overall. However, notable regional heterogeneity exists: in the North American subgroup, GDM is associated with a reduced risk of breast cancer, while in the Asian subgroup, GDM is significantly associated with an increased risk of breast cancer. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251032589.