Abstract Study question What is the true incidence and impact of male factor-related poor fertilization in ICSI cycles when analyzed using matched pairs of high quality donor oocytes? Summary answer In ICSI cycles with donor oocytes, male factor-related poor fertilization occurs in 3.3% of cases and contributes to 86.7% of all poor (<30%) fertilization outcomes. What is known already Opting for oocyte donation is a complex decision for couples, involving significant financial and long-term implications. This decision is typically prompted by presumed female infertility as male fertility diagnostics remain limited. Although ICSI is a highly effective treatment, cases of poor or complete fertilization failure can still occur, even when sperm parameters appear normal. This suggests the presence of unidentified male-related factors. However, the precise incidence of such factors remains poorly understood. This study aims to address this gap, offering a unique perspective, by employing a matched oocyte donation model to investigate the influence of sperm-related factors on fertilization outcomes. Study design, size, duration This retrospective cohort study analyzed 14,928 oocyte donation ICSI cycles, derived from 7,519 ovarian stimulations (OS) of 2,963 unique oocyte donors. The data were from a single center from January 2015 to December 2022. Sibling oocytes from the same OS were utilized for at least two different recipients (n = 13,859), facilitating comparisons under varying paternal conditions. Participants/materials, setting, methods Cases from the same oocyte lot with poor (<30%) and good (>65%) fertilization rates were matched to isolate sperm-related factors influencing fertilization success. Paired t-tests were used to compare outcomes. Ordinary least squares regression was used to isolate variables associated with poor fertilization, such as oocyte status (fresh versus vitrified), sperm origin (partner versus donor) and the presence of severe male factor (defined as a concentration of < 1 million/mL and/or <1% progressive motility). Main results and the role of chance The mean fertilization rate was 73.0% across all cycles analyzed. The incidence of poor fertilization (≤30%) was found to be 3.8% across the entire cohort (532 out of 13,859 cycles). Of these, 86.7% (461/532) cases using the same oocyte lot could be matched to cases with high fertilization rates (>65%) in other recipient cycles (n = 1,441), indicating that poor fertilization was male-related. We observed comparable numbers of inseminated oocytes between matched cases with high and low fertilization (7.23 ± 1.32 and 7.42 ± 1.42, respectively, p = 0.011), while the mean number of fertilized oocytes (1.44 ± 0.77 versus 6.12 ± 1.36, p = <0.001) and mean fertilization rates (20% versus 83%, p < 0.001) differed significantly. Notably, oocyte vitrification and the presence of a severe male factor negatively affected fertilization outcomes (coeff. -0.0898, p < 0.001 and coeff. -0.1500, p < 0.001, respectively). Nevertheless, the majority of poor fertilization cases (92.7%) occurred in the absence of these factors, underscoring the limitations of conventional semen diagnosis tests as predictors of poor fertilization. Across the entire cohort male factor alone accounted for 3.3% (461/13,859) of cycles with <30% fertilization rates. Furthermore, sperm-related factors were the primary cause of poor fertilization outcomes in oocyte donation cycles, accounting for 86.7% of cases. Limitations, reasons for caution Certain variables were not analyzed due to the retrospective nature and extended timeframe of the study. The matched oocyte model may overlook certain non-male factor-related instances of poor fertilization, such as procedural or technical issues. Wider implications of the findings This extensive analysis emphasizes the clinical relevance of male factor in fertilization outcomes, highlighting the need for improved semen diagnosis. It also indicates the importance of considering male-related factors in treatment decisions and shifting the focus from female-centric to more balanced fertility evaluations. Trial registration number Not applicable
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