Cardiovascular disease risk factors and infertility: multivariable analyses and one-sample mendelian randomisation analyses in the trøndelag health study

Are cardiovascular disease (CVD) risk factors causally associated with higher risk of infertility among women and men? We found evidence to support a causal relationship between smoking initiation and history of infertility in women. Several CVD risk factors are associated with history of infertility. Previous studies using Mendelian randomisation (MR) further support a causal relationship between BMI and infertility in women. 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). Our 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. A total of 4,702 women (18%) and 2,508 men (16%) were classified with 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. 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. Women 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. 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 from 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). None of the funding organisations 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 organisation. D.A.L. reports grants from Medtronic Ltd and Roche Diagnostics outside the submitted work. The other authors have no conflicts of interest. N/A.