Risk of Mortality in Family Members of Men Seeking Fertility Assessment.

OBJECTIVE To assess mortality in family members of men seeking fertility assessment. Subfertility serves as a biomarker for overall somatic health and poor semen quality is associated with increased risk of hospitalization and mortality from chronic conditions. However, it is unclear if these risks extend to family members of men with low sperm count. DESIGN Retrospective cohort study. SUBJECTS Family members, out to third-degree relatives, of men in the Subfertility, Health and Assisted Reproduction and the Environment cohort who underwent a semen analysis as part of a fertility assessment 1996-2017. Relatives of men with a recorded total sperm count who lived in Utah for ≥1 year 1904-2017 were included in the analysis (N=11,355 families). EXPOSURE Individuals were classified by family membership. Families were classified as relatives of azoospermic (0M), oligozoospermic (<39M), or normozoospermic (≥39M) men. Average total sperm count of the proband (male relative) with fertility assessment was also included as a continuous exposure measure. MAIN OUTCOME MEASURES The main outcomes were all-cause and cause-specific mortality risk by sex, age, and degree of relation: first-, second-, and third-degree. Cox proportional hazard models were used to test the association between fertility classification and mortality controlling for sex and birth year. RESULTS A total of 666,437 relatives of men with fertility assessment (Ndeaths=183,974) were included in the analysis. Relative to normozoospermia families, all-cause mortality risk increased in oligozoospermia families (HRoligozoospermia=1.03 95%CI=1.01-1.05). Close relatives, first- (HRoligozoospermia=1.17 95%CI=1.07-1.28) and second-degree relatives (HRazoospermia=1.11 95%CI=1.04-1.20; HRoligozoospermia=1.05 95%CI=1.01-1.09), of azoospermic and oligozoospermic men had the highest all-cause and cause-specific mortality risk, including death due to cardiovascular disease, congenital birth conditions. CONCLUSION Our results suggest that familial all-cause and cause-specific mortality risk differs by fertility phenotype. Families of azoospermic and oligozoospermic men showed significantly increased risk, particularly for close relatives. This study provides further evidence that shared genetic and/or environmental factors could influence both fertility and somatic health.