Sperm DNA fragmentation and assisted reproduction: an umbrella meta-analysis

BACKGROUND: Male infertility accounts for nearly half of infertility cases worldwide. Conventional semen parameters provide limited information about sperm function. Sperm DNA fragmentation (SDF) has emerged as a potential biomarker of sperm nuclear quality, but its prognostic role in assisted reproductive technology (ART) outcomes remains controversial. OBJECTIVES: To conduct an umbrella meta-analysis of published meta-analyses assessing the association between SDF and major ART outcomes, including clinical pregnancy (CP), pregnancy loss (PL), and live birth rate (LBR). METHODS: We systematically searched PubMed, Embase, Web of Science, Scopus, and the Cochrane Library through July 2025. Eligible studies were systematic reviews with meta-analyses evaluating SDF in in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), and intrauterine insemination (IUI). Pooled risk ratios (RRs) were extracted or converted to logRRs. Evidence quality was assessed using A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR-2) and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) frameworks. RESULTS: Eight meta-analyses comprising more than 25,000 ART cycles were included. Elevated SDF was significantly associated with reduced CP in IVF (RR = 0.662, 95% CI: 0.547-0.801) and IUI (RR = 0.467, 95% CI: 0.242-0.900), while only a weak, borderline association was observed in ICSI (RR = 0.886, 95% CI: 0.764-0.985). High SDF was strongly associated with increased PL in ICSI (RR = 2.286, 95% CI: 1.383-3.779). Evidence for LBR was limited and inconclusive. Across outcomes, certainty of evidence was graded as low due to heterogeneity, imprecision, and methodological limitations. CONCLUSIONS: Elevated SDF adversely affects ART outcomes, with consistent negative associations in IVF and IUI, a weak effect in ICSI, and a strong link to miscarriage in ICSI. These findings clarify the prognostic role of SDF and emphasize the need for standardized assays and large-scale prospective studies before routine clinical implementation.