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History of Infertility in Women Linked to Risk of Future Heart Failure

Key findings

  • This large prospective cohort study, with a median follow-up of 15 years, tracked 38,528 postmenopausal women enrolled in the Women's Health Initiative who did not have heart failure (HF) at enrollment
  • At enrollment, 5,399 women (14%) self-reported a history of infertility
  • Infertility was independently associated with future risk of overall HF (HR, 1.16; P=0.006), driven by greater risk of HF with preserved ejection fraction (HR, 1.27; P=0.002) but not HF with reduced ejection fraction
  • The association between infertility and HF was not explained by conventional cardiovascular risk factors or infertility-related conditions, highlighting the need for further investigation into the underlying mechanisms

Reproductive factors such as early age at menopause and gestational diabetes are emerging as risk factors for future atherosclerotic cardiovascular disease (ASCVD). Previous research demonstrated an association between infertility with ASCVD, but the data have been conflicting.

Now, an analysis of data from the Women's Health Initiative has linked infertility in women to a higher risk of future heart failure, driven primarily by an increased risk of heart failure with preserved ejection fraction (HFpEF).

Emily S. Lau, MD, MPH, director of the Menopause, Hormones and Cardiovascular Disease Clinic at Massachusetts General Hospital, Jennifer E. Ho, MD, formerly a cardiologist in the Heart Failure and Transplant Program at Mass General and now director of Research in the Division of Cardiology at Beth Israel Deaconess Medical Center, and colleagues present the findings in the Journal of the American College of Cardiology.

Methods

The Women's Health Initiative is a nationwide prospective study of 161,808 postmenopausal women recruited across 40 clinical centers between 1993 and 1998. The current analysis included a subset of 38,528 participants who did not have HF at enrollment, of whom 33% were Black, and 15% were Hispanic.

At enrollment, 5,399 women (14%) self-reported a history of infertility. Infertility was defined as the inability to conceive after one or more years of trying to become pregnant, regardless of the eventual pregnancy outcome.

Over a median follow-up of 15 years, 2,373 women developed incident (newly diagnosed) HF, including 807 who had HF with reduced EF (HFrEF; defined as EF <50%) and 1,133 who had HFpEF (EF ≥50%).

Infertility and HF

Infertility was independently associated with future risk of:

  • Overall HF—HR, 1.16 (P=0.006)
  • HFpEF—HR, 1.27 (P=0.002)

The results were consistent after adjustment for race/ethnicity. Infertility was not significantly associated with HFrEF even when it was redefined as EF <40%.

Trying to Explain the Association

BMI and smoking status were independently associated with infertility, but systolic blood pressure, hypertension treatment, diabetes, hyperlipidemia, and 10-year estimated ASCVD risk score were not.

Early menopause and thyroid disease, two risk factors for infertility, were associated with incident HF. However, the association between infertility and incident HF persisted when analyses were adjusted for those factors and other infertility-related conditions like irregular menses. These findings suggested that infertility-related conditions also did not explain the association between infertility and HF.

Further Studies Needed

If the relationship between infertility and HF were driven by ischemic heart disease, infertility should be associated with a greater risk of HFrEF. Instead, the opposite was true. Whether the association of infertility with HFpEF is causal or attributed to shared risk factors warrants further investigation.

16%
increased risk of future heart failure in women who have experienced infertility

27%
increased risk of future heart failure with preserved ejection fraction in women who have experienced infertility

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In a study that may improve the understanding of pathophysiologic mechanisms, women and men who had heart failure with preserved ejection fraction (HFpEF) differed in cardiac and skeletal muscle responses to exercise. Women with HFpEFexhibited worse systolic reserve, diastolic reserve and peripheral oxygen extraction.

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Emily Lau, MD, Jennifer E. Ho, MD, and colleagues observed arterial stiffness and load are closely tied to invasive measures of hemodynamic responses to exercise in heart failure with preserved ejection fraction. The association was particularly pronounced in women.