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Understanding the causal nature of the relationship between infertility and cardiovascular disease

Periodic Reporting for period 2 - INFERTILITY (Understanding the causal nature of the relationship between infertility and cardiovascular disease)

Periodo di rendicontazione: 2022-07-01 al 2023-12-31

It has been postulated the fertility problems/infertility can be a marker for an underlying poorer health status and increased risk of future chronic diseases. Some studies have reported an increased risk of cardiovascular disease among infertile women. The INFERTILITY project aims to better understand the nature of the relationship between infertility and cardiovascular disease. This includes investigating this relationship from multiple angles. First, we will establish whether there is an association between infertility and cardiovascular disease among men and women. Second, we will investigate whether this association can be explained by a pre-existing poorer cardiometabolic health by investigating the relationship between known risk factors for cardiovascular disease risk factors and infertility. Third, we will identify genetic determinants of infertility, and further explore whether there is any overlap in the genetic determinants of infertility and cardiovascular disease. Fourth, we will evaluate whether women who have used assisted reproductive technologies have an increased risk of cardiovascular disease. Finally, we will also investigate whether cardiometabolic health might contribute to the familiar clustering of fertility problems within families by comparing the cardiometabolic health among offspring according to parental infertility.

The findings from this project will clarify whether couples with infertility should be followed-up with regard to their cardiometabolic health, in order to initiate interventions early and prevent future cardiovascular disease. Furthermore, we will be able to provide evidence to support whether or not intervening on specific cardiovascular risk factors, such as for example smoking or body-mass index, can increase infertile couples’ chance of conceiving.
The INFERTILITY project has published five scientific papers so far during the project period and several additional papers are underway. The published papers include two papers which compared the risk of cardiovascular disease according to underlying infertility (defined as prolonged time-to pregnancy) among men and women in the Norwegian Mother, Father and Child Cohort Study and the Trøndelag Health Study, respectively. The findings from these two papers support an increased risk of cardiovascular disease among infertile women, with some heterogeneity observed across subgroups of cardiovascular disease, while there was only modest evidence of an increased risk among infertile men. Two other published papers use genetic variants associated with body-mass index and smoking in the Norwegian Mother, Father and Child Cohort Study to study their effect on infertility. We observed robust evidence of a non-linear relationship between body-mass index and infertility in both sexes, with a substantial increased risk of infertility among overweight and obese individuals, while there was no evidence to support a relationship between smoking and infertility. Results from these and ongoing papers have been presented at both international and national conferences. This includes invited presentations. Finally, we have published one study indicating no difference in the risk of cardiovascular disease between women who delivered with and without the use of assisted reproductive technologies.

In addition, the project has contributed with results from the Norwegian Mother, Father and Child Cohort Study and the Trøndelag Health Study to two large meta-analyses of cardiometabolic health (body-mass index, blood pressure, cholesterol etc.) trajectories of offspring conceived by assisted reproductive technologies, indicating no great differences in these measures according to mode of conception, which is reassuring to parents who require assistance to conceive.
The INFERTILITY project has provided novel evidence of the relationship between infertility and cardiovascular disease among men. The fact that we did not observe a similar association between infertility and cardiovascular disease among both sexes support a role of sex-specific explanatory mechanisms among women. The findings from the Mendelian randomization analyses supported an association between body-mass index, but not smoking, with infertility in both sexes. As this methodological approach is more robust to unmeasured confounding, these results supports a causal relationship between body-mass index and infertility, although the underlying explanatory mechanisms remain to be fully understood.

Going forward, we will further evaluate the relationship between cardiovascular risk factors and infertility in a different study population (the Trøndelag Health Study). We will also evaluate the risk of cardiovascular disease according to the number and outcome of cycles of assisted reproductive technologies using a Norwegian registry linkage, following up on the Nordic study we have conducted comparing the risk among women who delivered with and without the use of assisted reproductive technologies. Furthermore, the project will identify genetic determinants of infertility, in addition to clarifying whether there is any genetic overlap between infertility and cardiovascular disease with might explain an association between infertility and cardiovascular disease. Finally, we will evaluate whether cardiometabolic health explains a clustering of fertility problems within families, by also investigating whether there are any differences in offspring cardiometabolic health trajectories according to parental infertility.
From left Maria Magnus, Karoline Hansen Skåra and Alvaro Hernaez