Insights from a Pseudo-Polygyny Cohort unmasking high sperm concentration and low forward motility as potential risk factors for recurrent failure of sperm donation IVF (RFDI), a subset of unexplained male infertility (UMI)

BACKGROUND: Unexplained male infertility (UMI) accounts for 15%-30% of cases of male infertility, but it is poorly understood. We investigated potential risk factors for UMI leveraging data from a sperm bank with a "one male to multiple females" structure to reduce confounding arising from female factors. METHODS: /mL or FR < 90% was termed high-risk RFDI (HR-RFDI). Logistic regression was used to assess correlations of RFDI. Propensity score matching (PSM) was used to match the RFDI and non-RFDI populations. Miscarriage conditions were also analysed in this study. FINDINGS: We included 4734 qualifying sperm donors and 17,307 IVF DICs, of which 2447 donors had more than 4 DICs per donor, forming a Pseudo-Polygyny Cohort. 8.05% of the 2447 donors with normal semen parameters and more than 4 DICs met RFDI criteria. RFDI donors exhibited higher sperm concentration (96.00 [75.00, 130.00] vs. 90.00 [72.00, 122.22], p = 0.057) and lower Forward Motility Rate (95.12 [89.02, 97.01] vs. 96.59 [93.33, 97.30], p < 0.001) compared to non-RFDI. Forward Motility Rate, rather than Progressive Motility Rate, correlated with cLBR -DI Compared to the normal group, HR-RFDI had an over three-fold higher risk of RFDI before (RR = 3.48, 95% CI [1.94, 6.25], p < 0.0001) and after (OR = 3.04, 95% CI [1.92, 4.81], p < 0.0001) PSM adjustment. Notably, RFDI donors had higher miscarriage rates (10.80 ± 14.20% vs. 3.90 ± 8.50%, p < 0.0001) compared to non-RFDI donors. High-risk RFDI donors also had higher miscarriage rates (5.40 ± 9.20% vs. 4.20 ± 9.40%, p = 0.011) compared to low-risk RFDI donors. INTERPRETATION: The negative impact of high sperm concentration on pseudo-polygyny cohort in vitro fertilization (IVF) outcomes strongly supports the hypothesis of a potential "inverted U-shape" relationship between sperm concentration and fertility. The superior correlation of FR with sperm donation IVF outcomes compared to PR suggests that FR may be a more meaningful measure of sperm motility in this context. The identification of an RFDI population, characterized by recurrent IVF failure and high miscarriage rates despite normal semen parameters, provides substantial evidence that the prevalence and severity of unexplained male infertility (UMI) may be greater than currently recognized. Therefore, a more comprehensive evaluation of male fertility should be considered in couples experiencing these issues.