Does intracytoplasmic sperm injection outperform conventional in vitro fertilization in couples without severe male factor infertility? A systematic review and meta-analysis of randomized controlled trials

Abstract STUDY QUESTION Does ICSI improve the live birth rate in couples without severe male factor infertility compared to conventional IVF (cIVF)? SUMMARY ANSWER High-quality evidence showed no benefit of ICSI over cIVF in improving live birth or cumulative live birth rates among couples without severe male factor infertility. WHAT IS KNOWN ALREADY Although ICSI is an effective method within ART for severe male factor infertility, it is frequently used for other infertility etiologies despite insufficient evidence. The effectiveness of ICSI compared with cIVF in couples with mild male or without severe male factor infertility remains uncertain. STUDY DESIGN, SIZE, DURATION Systematic review and meta-analysis. PubMed, EMBASE, MEDLINE, Web of Science, Cochrane Library, ProQuest Dissertations & Theses Global, Scopus, CINAHL Plus, Chinese Wan Fang, and CNKI databases were searched from inception to 31 May 2025 without language restrictions. The search strategy encompassed three key domains: ICSI, cIVF, and ART treatment outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS We included randomized controlled trials (RCTs) comparing outcomes of ICSI versus cIVF per couple. Exclusion criteria were duplicate studies, conference abstracts or proceedings, trial registry records, editorials, letters, non-randomized designs, RCTs that did not randomize participants to ICSI or cIVF, studies comparing effects per oocyte rather than per couple, studies lacking complete outcome data, and those not meeting predefined criteria for trustworthiness. Study characteristics and ART outcomes were extracted. The risk of bias and study trustworthiness were independently evaluated by two investigators using the Cochrane Collaboration’s Risk of Bias 2 Tool and TRACT checklist, respectively. GRADE decision-making was used to evaluate the quality of evidence. MAIN RESULTS AND THE ROLE OF CHANCE Six RCTs reporting on couples without severe male factor infertility were included. The meta-analysis showed no benefit from ICSI over cIVF in live birth rate (four studies, N = 1438, 32.8% vs 34.5%, pooled risk ratio (RR) = 0.96, 95% CI: 0.85–1.09, I2 = 37%, high-quality evidence) or cumulative live birth rate (three studies, N = 1911, 43.2% vs 47.4%, pooled RR = 0.92, 95% CI: 0.84–1.01, I2 = 41%, high-quality evidence). ICSI was associated with a lower preterm birth rate (three studies, N = 222, 4.6% vs 6.0%, pooled RR = 0.77, 95% CI: 0.59–1.00, P = 0.0447, I2 = 0, high-quality evidence). No significant differences were observed for other fertility or pregnancy outcomes. LIMITATIONS, REASONS FOR CAUTION The findings should be interpreted with caution due to the limited number of high-quality studies reporting live birth data, limited subgroup-specific evidence, and some heterogeneity in outcome measures. WIDER IMPLICATIONS OF THE FINDINGS Evidence from this meta-analysis shows no advantage of ICSI over cIVF in improving live birth or cumulative live birth rates among couples without severe male factor infertility. Based on current evidence, ICSI should not be routinely recommended for indications other than severe male infertility. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by the National Natural Science Foundation of China (No. 82204052), the National Key Research and Development Program of China (No. 2022YFC2703102), and Peking University Third Hospital (No. BYSYDL2022001, BYSYDL2024003) with salaries for J.Q., Y.W., K.K., Y.F., Y.Y., T.T., F.L., and J.G. The funders of the study played no role in study design, data collection, data analysis, data interpretation, or writing of the report. S.B. has received scientific grants from Gedeon Richter and Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis’ Fond. K.V. has received speakers’ fees from Gedeon Richter, Merck, and IBSA. L.N.V. has received grants, speakers’ fees, and conference fees (including travel support) from Merck Sharp & Dohme, and Ferring, and scientific board fees from Ferring. T.M.H. has received speakers’ fees from Merck, Merck Sharp & Dohme, and Ferring. A.P. has received speakers’ fees (including those classified as honoraria) from Ferring Pharmaceuticals, Merck, Gedeon Richter, IBSA, Abbott and Consulting fees from Gedeon Richter and Ferring and travel support from Gedeon Richter. H.S.N. received speakers’ fees from Ferring Pharmaceuticals, Merck, Astra Zeneca, Cook Medical, Gedeon Richter, Ibsa Nordic, Novo Nordisk, and Bessins. B.W.M. reports consulting fees, travel support, and research funding from Merck and consulting fees from Ferring, Organon, Repronovo, UNILAB, Vitra, and Norgine. N.l.C.F. has received speakers’ fees from Merck and Ferring Pharmaceuticals, consulting fees from Merck, and meeting support/registration fees from Merck, Ferring Pharmaceuticals, IBSA, and Gedeon Richter (paid to institution). She is also an unpaid chair in the steering committee for the guideline groups of The Danish Fertility Society. All other authors declare no competing interests REGISTRATION NUMBER CRD42023479967.