Can coronavirus disease 2019 affect male fertility or cause spontaneous abortion? A two-sample Mendelian randomization analysis.

To investigate the causal relationship between two adverse reproductive outcomes (male infertility and spontaneous abortion) and COVID-19 infection using Mendelian randomization (MR) analysis. A two-sample MR study was conducted to examine potential causal links between COVID-19 infection severity and reproductive outcomes, using large-scale genome-wide association study (GWAS) summary statistics from European-ancestry populations. GWAS summary statistics were analyzed for COVID-19 phenotypes (infection: n = 1,683,769; hospitalized: n = 1,557,411; very severe respiratory-confirmed: n = 1,388,342; critical illness: n = 10,056) and reproductive outcomes (spontaneous abortion: n = 98,453; male infertility: n = 73,479). Causal estimates were calculated using inverse variance weighted (IVW), weighted median, MR-Egger regression, and weighted mode methods. IVW analysis revealed no significant association between genetic susceptibility to COVID-19 infection and male infertility (odds ratio [OR] = 0.7668; 95% confidence interval [CI]: 0.3798-1.5484; p = 0.4590) or spontaneous abortion (OR = 0.9936; 95% CI: 0.8066-1.2241; p = 0.8518). Similar null associations between COVID-19 severity phenotypes (hospitalized, very severe respiratory-confirmed, and critical illness) and male infertility or spontaneous abortion were observed. Sensitivity analyses using alternative methods confirmed the absence of pleiotropy and heterogeneity. This two-sample MR analysis provides robust evidence against a causal relationship between COVID-19 and increased risks of male infertility or spontaneous abortion.