Cardiovascular disease risk factors and infertility: multivariable analyses and one-sample Mendelian randomization analyses in the Trøndelag Health Study.

study questionAre cardiovascular disease (CVD) risk factors causally associated with higher risk of infertility among women and men? SUMMARY ANSWER: We found evidence to support a causal relationship between smoking initiation and history of infertility in women. WHAT IS KNOWN ALREADY: Several CVD risk factors are associated with history of infertility. Previous studies using Mendelian randomization (MR) further support a causal relationship between BMI and infertility in women. STUDY DESIGN SIZE DURATION: We used data from the Trøndelag Health Study (HUNT) in Norway, a prospective population-based cohort study, including 26 811 women and 15 598 men participating in three survey collections in 1995-1997 (HUNT2), 2006-2008 (HUNT3), and 2017-2019 (HUNT4). PARTICIPANTS/MATERIALS SETTING

methodsOur outcome was women's self-reported history of infertility, defined as ever having tried to conceive for 12 months or more or having used ART. We assigned the history of infertility reported by women to their male partners; therefore, the measure of infertility was on the couple level. We used both conventional multivariable analyses and one-sample MR analyses to evaluate the association between female and male CVD risk factors (including BMI, blood pressure, lipid profile measurements, and smoking behaviours) and history of infertility in women and men, separately. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 4702 women (18%) and 2508 men (16%) were classified with a history of infertility. We found a higher risk of infertility among female smokers compared to non-smokers in both multivariable and MR analyses (odds ratio (OR) in multivariable analysis, 1.20; 95% CI, 1.12-1.28; OR in MR analysis, 1.13; CI, 1.02-1.26), and potentially for higher BMI (OR in multivariable analysis, 1.13; CI, 1.09-1.18; OR in MR analysis, 1.11, CI, 0.92-1.34). In multivariable analysis in women, we also found evidence of associations between triglyceride levels, high-density lipoprotein cholesterol, lifetime smoking index, and smoking intensity with higher risk of infertility. However, these results were not consistent in MR analyses. We found no robust or consistent associations between male CVD risk factors and infertility. LIMITATIONS REASONS FOR CAUTION: Our main limitation was that the CVD risk factors measured might not adequately capture the relevant time periods for when couples were trying to conceive. Additionally, we did not have information on causes of infertility in either women or men. WIDER IMPLICATIONS OF THE

findingsWomen with infertility could have a worse CVD risk factor profile and thus public health interventions aimed at reducing the impact of some CVD risk factors, such as smoking and BMI, could reduce the burden of infertility. However, additional MR studies of the relationship between CVD risk factors and infertility with a larger sample size would be of value. STUDY FUNDING/COMPETING INTERESTS: The study was supported by a grant from the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreements no. 947684). This research was also supported by the Research Council of Norway through its Centres of Excellence funding scheme (project no. 262700) and partly funded by the Research Council of Norway, project: Women's fertility-an essential component of health and well-being (project no. 320656). D.A.L. and A.F. work in a unit that is supported by the University of Bristol and the UK Medical Research Council (MC_UU_00011/6). D.A.L.'s contribution to the article is supported by the European Research Council (101021566), the British Heart Foundation (CH/F/20/90003 and AA/18/7/34219). S.B.'s contribution to the article is supported by the Wellcome Trust (225790/Z/22/Z). B.M.B. is funded by The Liaison Committee for education, research and innovation in Central Norway; and the Joint Research Committee between St. Olavs Hospital and the Faculty of Medicine and Health Sciences, NTNU. The genotyping in HUNT was financed by the National Institute of Health (NIH); University of Michigan; The Research Council of Norway; The Liaison Committee for education, research and innovation in Central Norway; and the Joint Research Committee between St. Olavs Hospital and the Faculty of Medicine and Health Sciences, NTNU. None of the funding organizations influenced the study design, reporting, or interpretation of results. The views expressed in the present article are those of the authors and not necessarily any acknowledged funding organization. D.A.L. reports grants from Medtronic Ltd and Roche Diagnostics outside the submitted work. The other authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.