Male infertility and risk of cardiometabolic conditions: a population-based cohort study.

study questionIs male infertility independently associated with an increased risk of incident hypertension, ischemic and non-ischemic heart disease, diabetes, and/or cerebrovascular disease? SUMMARY ANSWER: Fathers diagnosed with male infertility have a modestly increased risk of heart disease, diabetes, and hypertension compared with fertile fathers, after controlling for measured confounders; however, some important confounders remain inadequately measured. WHAT IS KNOWN ALREADY: Cohort studies suggest that infertile men have an increased risk of incident cardiometabolic diseases, including diabetes, hypertension, heart disease, and cerebrovascular disease, although findings are mixed. The reasons for this association are unclear, but cardiometabolic conditions and male infertility share a wide range of shared etiological factors including age, chronic conditions such as obesity and obstructive sleep apnea, cancers and their treatments, environmental exposures such as pollution and pesticides, lifestyle factors such as smoking and cardiorespiratory fitness, autoimmune conditions such as lupus and Hashimoto's thyroiditis, as well as congenital conditions such as cystic fibrosis and muscular dystrophy. STUDY DESIGN, SIZE, DURATION: Our population-based cohort study included 445 909 men whose partner conceived a child between January 2009 and September 2016 in New South Wales (NSW), Australia. We excluded men with a diagnosis of infertility prior to 2009, men who were under the age of 14 at the time of the child's conception, and men diagnosed with cardiometabolic conditions in the 6.5 years prior to their index date. The index date was the later of the date of the child's conception or the date of the vasectomy for fertile men or the date of diagnosis of infertility for infertile men, i.e. the time when the exposure status was determined. From the index date, we followed participants for 5 years up until the latest available date of September 2021. PARTICIPANTS/MATERIALS, SETTINGS,

methodsThe study was conducted in NSW, Australia. We determined infertility status by a diagnosis of male infertility in the Australian and New Zealand Assisted Reproduction Database, hospital records, or a record of fertility-related procedures. We assessed the following outcomes: incident hypertension, ischemic and non-ischemic heart disease, all heart disease, diabetes, and cerebrovascular disease. We calculated age-standardized prevalence rates at baseline. We mapped potential confounding pathways using directed acyclic graphs and controlled for measured confounders using inverse probability of treatment weighting and g-computation. We estimated adjusted marginal risk ratios (aRR) and adjusted marginal risk differences (aRD) using robust Poisson regression. MAIN RESULTS AND THE ROLE OF CHANCE: The number of events and 5-year crude incidence rate for the outcomes were: hypertension (events: 17 433, fertile: 41.09 per 1000 population, infertile: 70.03 per 1000 population), all heart disease (events: 15 549, fertile: 36.44 per 1000 population, infertile: 59.88 per 1000 population), ischemic heart disease (events: 12 628 fertile: 29.24 per 1000 population, infertile: 47.1 per 1000 population), non-ischemic heart disease (events: 5183, fertile: 11.69 per 1000 population, infertile: 20.24 per 1000 population), cerebrovascular disease (events: 512, fertile: 1.14 per 1000 population, infertile: 1.78 per 1000 population) and diabetes (events: 7064, fertile: 16.05 per 1000 population, infertile: 27.59 per 1000 population). Compared with fertile men, men diagnosed with infertility demonstrated increased risk of incident disease for: hypertension aRR = 1.20 (95% CI 1.11-1.31, P < 0.001), aRD = 1.1% (95% CI: 0.6%-1.6%, P < 0.001); all heart disease aRR = 1.20 (95% CI 1.09-1.31, P < 0.001), aRD =0.9% (95% CI: 0.4%-1.4%, P < 0.001); non-ischemic heart disease aRR = 1.26 (95% CI 1.08-1.48, P = 0.004), aRD = 0.4% (95% CI: 0.1%-0.7%, P = 0.009); ischemic heart disease aRR = 1.13 (95% CI 1.02-1.25, P = 0.020), aRD = 0.4% (95% CI: 0.1%-0.7%, P = 0.028); and diabetes aRR = 1.28 (95% CI 1.12-1.46, P < 0.001), aRD 0.6% (0.2%-0.9%, P = 0.001). There was no significant difference in the incidence of cerebrovascular disease, aRR = 1.0 (95% CI 0.56-1.80, P = 0.996), aRD = 0.0% (95% CI: -0.1% to 0.1%, P = 0.996). These results remained consistent in sensitivity analyses, including an expanded exposure definition of infertility, a 10-year follow-up period, changing the outcomes of people who died in follow-up, and using an alternative index date. LIMITATIONS, REASONS FOR CAUTION: The cohort includes men who fathered a child, so men who did not seek to, or were unable to, have a child, and men with poor access to the reproductive healthcare may not be included. This may generate selection effects, biasing the estimates toward the null. We were unable to adequately control for several confounders, including important lifestyle factors like smoking, diet, cardiorespiratory fitness, and alcohol intake, due to data limitations, which may bias estimates away from the null. It appears plausible that a combination of unmeasured and inadequately measured confounders may attenuate the observed estimates. WIDER IMPLICATIONS OF THE

findingsThese findings suggest that male infertility may serve as an early indicator for a slightly heightened cardiometabolic risk, specifically relating to hypertension, diabetes, and various forms of heart disease. Our study is the largest on this topic, with extensive control for confounders. Our findings align with published research, indicating that men diagnosed with infertility have a slightly higher risk of incident diabetes, hypertension, and heart disease. From a public health perspective, fertility treatment may be an opportunity for earlier detection and intervention to help prevent the onset of cardiometabolic conditions in men diagnosed with infertility, particularly given that men generally have low rates of contact with the health system. STUDY FUNDING/COMPETING INTEREST(S): The PhD candidacy of J.M. is supported by Medical Research Future Fund (MRFF) Emerging Priorities and Consumer Driven Research initiative: EPCD000007, 2020. M.K.O'B. and G.M.C. declare receiving payment to their institution by the same MRFF grant. G.M.C. reports receiving funding from an Australian MRFF grant paid to UNSW to support this work, and J.M. reports receiving PhD funding from the same MRFF grant. C.V. declares an unpaid role on Human Reproduction's Editorial Board, and paid employment at the University of New South Wales (UNSW) until January 2023. The National Perinatal Epidemiology and Statistics Unit (NPESU), which belongs to UNSW, is custodian of the Australian and New Zealand Assisted Reproduction Database (ANZARD). Data from ANZARD were used in this study. G.M.C. also declares paid employment from UNSW. The remaining authors have nothing to declare. TRIAL REGISTRATION NUMBER: N/A.