title: Risk of childhood mortality in family members of men with poor semen quality.
abstract: What is the familial childhood mortality in first-degree (FDR) and second-degree relatives (SDR) of patients undergoing semen analysis (SA)?
  
  
  
  The relationship between infertility and congenital malformations (CM) in offspring is complex, with an increased risk of death due to CM in FDR, but not SDR, of men with lower semen parameters.
  
  
  
  Semen quality is an established predictor of men's somatic health. We can gain a better understanding of possible genetic or environmental determinants of the infertility phenotype by exploring familial aggregation of childhood mortality in relatives of men with poor semen quality.
  
  
  
  Retrospective cohort study from the Subfertility, Health and Assisted Reproduction study (cohort compiled 1996-2011) linked with patient/familial information from the Utah Population Database (UPDB). Index cases included a clinic-referred sample of 12 889 men who underwent SA and had adequate familial and follow-up data in the UPDB. Parameters of semen quality included: semen concentration, sperm count, motility, total motile count, sperm head morphology, sperm tail morphology and vitality.
  
  
  
  SA data were collected from two tertiary medical center andrology laboratories that have captured ~90% of all SA performed in Utah since 2004. Age- and sex-matched fertile controls were selected to create the comparison group for determining risk of childhood death (to age 20 years) in family members. A total of 79 750 siblings and 160 016 aunts/uncles were used to investigate the familial aggregation of childhood mortality. The main outcome was childhood mortality in FDR and SDR of men with SA and their matched controls. All-cause and cause-specific Cox proportional hazard models were used to test the association between semen quality and childhood mortality in family members. Cause-specific models were considered for cancer and CM.
  
  
  
  In the cohort of men with SA, there were 406 (1.0%) deaths in FDR and 772 (1.1%) deaths in SDR due to any cause. There was no significant difference in the risk of all-cause childhood mortality between the relatives of men with SA and the fertile control group [hazard ratio (HR)Female= 1.08, 95% CI = 0.88, 1.32; HRMale= 0.88, 95% CI = 0.75, 1.04]. We found no association between semen quality and risk for childhood cancer mortality in FDR or SDR (HRFDR= 0.98, 95% CI = 0.62, 1.54; HRSDR= 1.12, 95% CI = 0.83, 1.50). The FDR of men with SA and fertile controls were followed on average for 19.71 and 19.73 years, respectively. During this period of follow-up, FDR of men with SA had an unadjusted 40% relative risk of increased CM-related death. After stratifying by semen parameters and adjusting for birth year, we found FDR of men with worse semen quality, and notably azoospermic men (HR = 2.69, 95% CI = 1.24,5.84), were at higher risk of CM-related death.
  
  
  
  A large proportion of men with SA in the study had normal semen parameters. It is important to note that these men themselves may not be subfertile, but they were subfertile at the couple level (i.e. the female partner may be infertile). In addition, care is needed when interpreting our results, as we do not have semen measures on our sample of fertile men. Second, we were unable to include potential confounders such as medical comorbidities, smoking status, or environmental exposures. Third, men with SA were seen at the University of Utah or Intermountain Health Care clinics for a fertility evaluation thereby suggesting a more select population. Fourth, we chose to categorize morphology into equally distributed quartiles as a response to the fact that the World Health Organization threshold for normal motility changed multiple times during our study period. Lastly, we do not know the proportion of female partners with diagnosed infertility. We chose not to subcategorize each infertile male by infertile diagnosis because our goal was to understand how semen parameters influenced familial childhood mortality.
  
  
  
  We are not the first study to show a relationship between fertility and CMs. Children conceived through ART may be at higher risk of birth defects, however it is not known if the relationship is causal or if there is some underlying factor linking infertility and birth outcomes. This study provides further evidence that the increased risk of congenital birth defects may not be due to the ART, but rather genetic or environmental factors that link the two outcomes. We encourage further research in order to confirm a relationship between semen quality and increased risk for CM.
  
  
  
  This work was supported by the National Institutes of Health - National Institute of Aging [Grant numbers 1R21AG036938-01, 2R01 AG022095 and 1K12HD085852-01]. Authors have no competing interests to disclose.
  
  
  
  Not applicable.
authors.affiliation: Department of Family and Preventive Medicine, University of Utah, Salt Lake City, UT , USA heidi.hanson@hci.utah.edu.|Population Sciences, Huntsman Cancer Institute, University of Utah, 675 Arapeen Drive, 204, Salt Lake City, UT 84112 , USA.
authors.forename: Heidi A
authors.initials: HA
authors.lastname: Hanson
authors.affiliation: Division of Urology, Department of Surgery, University of Utah, Salt Lake City, UT, USA.
authors.forename: Erik N
authors.initials: EN
authors.lastname: Mayer
authors.affiliation: Division of Urology, Department of Surgery, University of Utah, Salt Lake City, UT, USA.
authors.forename: Ross E
authors.initials: RE
authors.lastname: Anderson
authors.affiliation: Division of Urology, Department of Surgery, University of Utah, Salt Lake City, UT, USA.|Center for Men's Health and Reconstructive Surgery, Salt Lake City, UT , USA.|Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT , USA.
authors.forename: Kenneth I
authors.initials: KI
authors.lastname: Aston
authors.affiliation: Division of Urology, Department of Surgery, University of Utah, Salt Lake City, UT, USA.|Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT , USA.
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Carrell
authors.affiliation: Population Sciences, Huntsman Cancer Institute, University of Utah, 675 Arapeen Drive, 204, Salt Lake City, UT 84112 , USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Berger
authors.affiliation: Division of Urology, Department of Surgery, University of Utah, Salt Lake City, UT, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Lowrance
authors.affiliation: Population Sciences, Huntsman Cancer Institute, University of Utah, 675 Arapeen Drive, 204, Salt Lake City, UT 84112 , USA.|Department of Family and Consumer Studies, University of Utah, Salt Lake City, UT, USA.
authors.forename: Ken R
authors.initials: KR
authors.lastname: Smith
authors.affiliation: Division of Urology, Department of Surgery, University of Utah, Salt Lake City, UT, USA.|Center for Men's Health and Reconstructive Surgery, Salt Lake City, UT , USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Hotaling
mesh_terms: D002648:Child; D046688:Child Mortality; D016208:Databases, Factual; D005190:Family; D005260:Female; D006801:Humans; D007248:Infertility, Male / Q000175:diagnosis*; D008297:Male; D012189:Retrospective Studies; D012306:Risk; D055101:Semen Analysis; D013076:Sperm Count; D013081:Sperm Motility / Q000502:physiology*; D013094:Spermatozoa / Q000502:physiology*
keywords: Utah Population Database; childhood mortality; congenital malformations; familial aggregation; familial risk; infertility; semen; testicular dysgenesis syndrome