Abstract
STUDY QUESTION: In couples with non-severe male infertility, can sperm DNA fragmentation index (DFI) testing serve as a biomarker to identify couples who would benefit from ICSI over conventional IVF, based on cumulative live birth rate? SUMMARY ANSWER: Our secondary analysis of a randomized clinical trial (RCT) indicated that sperm DFI testing has limited value in identifying couples who would benefit from use of ICSI over IVF, based on cumulative live birth rate. WHAT IS KNOWN ALREADY: We recently demonstrated that in couples with non-severe male factor infertility, ICSI decreases cumulative live birth rates following the first transfer compared to IVF. However, it remains unclear whether sperm DFI testing can effectively guide treatment selection between ICSI and IVF. STUDY DESIGN SIZE DURATION: We used data of participants included in a randomized controlled trial comparing ICSI versus IVF in couples with non-severe male factor infertility. Participants had been recruited between April 2018 and November 2021 from seven centres in China, with follow-up outcomes collected as of 31 August 2023. PARTICIPANTS/MATERIALS SETTING METHODS: We included 953 of 2329 couples in whom the male partner had a baseline sperm DFI test from seven centres within the original RCT. The primary outcome was cumulative live birth, defined as a live birth following embryo transfers that occurred within 12 months after randomization within one oocyte retrieval cycle. The statistical analysis was performed based on an as-treated population, including 480 in the ICSI group and 473 in the IVF group. Multivariable fractional polynomial interaction analysis was performed to investigate non-linear interaction between DFI test and treatment effects of ICSI over IVF. MAIN RESULTS AND THE ROLE OF CHANCE: The median values of sperm DFI were 18.8% (interquartile range [IQR]: 12.2%∼26.3%) in the ICSI group, and 18.4% (IQR: 12.6%∼25.1%) in the IVF group. In each quantile of sperm DFI (Q1: DFI < 12.3%; Q2: 12.3≤DFI < 18.6%; Q3: 18.6≤DFI < 25.9%; Q4: DFI ≥ 25.9%), there were no significant differences of ICSI vs IVF on cumulative live birth (Q1: 36.7% vs 49.6%, adjusted odds ratio (aOR) = 0.61, 95% CI: 0.36 to 1.04; Q2: 51.8% vs 50.4%, aOR = 1.06, 95% CI: 0.60 to 1.84; Q3: 48.4% vs 56.3%, aOR = 0.78, 95% CI: 0.46 to 1.33; Q4: 45.2% vs 49.1%, aOR = 0.80, 95% CI: 0.47 to 1.37). Multivariable fractional polynomial interaction analysis showed no evidence of interaction between sperm DFI and the treatment effect of ICSI over IVF on cumulative live birth (P = 0.298). LIMITATIONS AND REASONS FOR CAUTION: First, sperm DFI testing was not routinely performed across all trial sites. Second, this study may be underpowered to detect differences in some outcomes, especially total fertilization failure, due to the very small number of events. WIDER IMPLICATIONS OF THE FINDINGS: Sperm DFI testing during the basal semen analysis has limited value in guiding the choice of fertilization methods for patients with non-severe male infertility. Based on the current evidence, sperm DFI testing should not be routinely recommended for this population. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the National Key Research and Development Program (2022YFC2703102 to Y.W.), and the Peking University Third Hospital (BYSYDL2022001 to J.Q., BYSYDL2024003 to Y.W., and BYSYZD2019007 to Y.L.). B.W.M. reports consultancy, travel support, and research funding from Merck KGaA and consultancy for Organon and Norgine. TRIAL REGISTRATION NUMBER: The original trial was registered at Clinicaltrials.gov: NCT03298633.