A greater risk for potential development of incident heart failure (HF), especially HF with preserved ejection fraction (HFpEF), was seen among a cohort of postmenopausal women who self-reported a history of infertility, according to study findings published in Journal of the American College of Cardiology. Their outcomes were compared with those among women not reporting infertility.
“Infertility is a reproductive factor that is consistently underrecognized with respect to cardiovascular [CV] risk, in part because of the paucity of rigorous data examining CV risk in women with a history of infertility,” the study’s authors wrote. “The risk of infertility should not be overlooked because it affects >14% of women in the United States and has been linked to higher risk of overall cardiovascular disease risk in some studies, although the available data are conflicting.”
The women included in this analysis (N = 38,528) were current participants of the Women’s Health Initiative, and their mean (SD) age was 63 (7) years. Fourteen percent overall self-reported infertility issues, and the investigators used multivariable cause-specific Cox models to investigate the probability of an association between infertility and HFpEF, and infertility and HF with reduced ejection fraction (HFrEF). For this study, HFpEF was defined as having a left ventricular ejection fraction (LVEF) of at least 50%, and HFrEF was defined as having an LVEF below 50%.
Six percent of the study population—50% non-Hispanic White, 33% Black, 15% Hispanic—developed incident HF during the study’s follow-up period, which was a median (IQR) 15 (8-20) years. At baseline, their mean systolic blood pressure was 129 (18) mm Hg, 7% had comorbid diabetes, and 3% reported comorbid coronary heart disease.
Infertility was found to have independent associations with greater risks of overall HF and HFpEF. There was a 16% greater risk of developing HF overall when considering the influence of infertility (HR, 1.16; 95% CI, 1.04-1.30; P = .006), and this was even higher for HFpEF, which had a 27% greater risk (HR, 1.27; 95% CI, 1.09-1.48; P = .002).
Conversely, there was a slightly reduced risk of HFrEF (HR, 0.97; 95% CI, 0.80-1.18).
At baseline, the most common infertility-related risk factor reported among all women was premature menopause (30%), and this echoed when comparing risk factors among the infertility (n = 5399) and no infertility groups (n = 33,129), of whom 35% and 30%, respectively, reported premature menopause. Other infertility-related risk factors cited by the women were irregular menses (17% overall; 24%, infertility cohort; 15%, no infertility cohort), thyroid disease (19%, 24%, and 18%, respectively), and waist circumference (in centimeters; 90 , 89 , and 90  cm, respectively). However, the authors noted, waist circumference was not associated with infertility status.
The infertility cohort was also more likely to have a smoking history, with 42% reporting being former smokers compared with 38% (P < .001) in the no infertility group.
A press release discussing the findings highlighted the increasing prevalence of HFpEF over the past decade, such that it is now the “the dominant form of heart failure in both men and women. But it remains more common in women.”
“We don’t understand why we see HFpEF more in women,” said the study’s first author Emily Lau, MD, MPH, a cardiologist and director of the menopause, hormones & cardiovascular clinic at Massachusetts General Hospital, in the press release. “Looking back in a woman’s early reproductive life may give us some clues as to why.”
Pregnancy-related outcomes, such as a live birth or conception, did not influence the investigators’ findings. Patients were excluded from analyses if they were missing infertility data or had prevalent HF.
The authors’ findings were seen even after adjusting for race/ethnicity, and a sensitivity analysis that evaluated a possible association between infertility, HF, and women with coronary heart disease also produced a 16% greater risk of women developing HF if they reported infertility issues (HR, 1.16; 95% CI, 1.04-1.30; P = .009).
No association was found linking infertility and the 10-year risk of developing atherosclerotic cardiovascular disease or its risk factors, including hypertension, obesity, and diabetes.
“Although traditional CV risk factors and infertility-related risk factors were independently associated with incident HF, they did not explain the association between infertility with incident HF and HFpEF,” the authors concluded. “Our findings highlight the need for rigorous studies investigating the mechanisms by which infertility may lead to future HFpEF and overall CV risk.”
Lau ES, Wang D, Roberts M, et al. Infertility and risk of heart failure in the Women’s Health Initiative. J Am Coll Cardiol.2022;79(16):1594-1603. doi:10.1016/j.jacc.2022.02.020