Infertility in Women Linked to Subsequent Risk of HFpEF

Infertility is a predictor of increased risk for heart failure with preserved ejection fraction (HFpEF) later in life, according to an analysis of over 38,000 postmenopausal women followed for a median of 15 years.

Those with a history of infertility had a 16% greater risk of developing any heart failure compared with women without infertility (P = 0.006), but among the HF subtypes, only the association with HFpEF was significant (P = 0.002). Examination of established CV risk factors, including 10-year atherosclerotic cardiovascular disease (ASCVD) score and infertility-related risk factors, did not help explain the association.

“We actually don't know very much about the long-term health effects of infertility, despite how common a condition it is,” said Emily S. Lau, MD, MPH (Massachusetts General Hospital, Boston), the study’s lead author. “There's a lot of social stigma associated with infertility. Plus, it's just not an exposure variable that many people have rigorously tried to ascertain when they design studies.”

In the paper, published Monday in the Journal of the American College of Cardiology, Lau and colleagues drew on the wealth of sex-specific data from the Women’s Health Initiative (WHI), which enrolled over 160,000 women in the 1990s. The WHI was a pioneering effort, gathering information related to pregnancy, menstrual cycles, and menopause decades before those factors began to be recognized as important in the long-term health consequences of women, said Lau. This latest research, she added, complements evidence linking other reproductive factors, including preeclampsia, nulliparity, and shorter reproduction duration, to an increased risk of HF in women.

To TCTMD, Lau said the findings are a bit surprising since the hypothesis initially was that heart failure with reduced ejection fraction (HFrEF) would be more common in women with infertility, driven by ischemic heart disease. In the paper, she and her colleagues say it appears that the mechanisms mediating HF risk in infertility are independent of ASCVD risk.

Writing in an accompanying editorial, Ersilia M. DeFilippis, MD (Columbia University Irving Medical Center, New York, NY), adds that the lack of an association with traditional CVD risk provides more justification for sex-specific risk scores that “incorporate reproductive factors, such as history of preeclampsia, gestational hypertension, and infertility, that can incur risk independent of traditional cardiovascular risk factors.”

No Mediators for Infertility/HF Association

In the WHI data set, 38,528 postmenopausal women (mean age 63.7 years; 33% Black; 15% Hispanic) had adjudicated HF outcomes. Among them, 14% had a history of infertility. Women with versus without infertility were more likely to be former or current smokers and to have a history of irregular menses, thyroid disease, and early menopause (≤ 45 years).

Over the 15-year follow-up period, 2,373 women developed incident HF, including 807 cases of HFrEF and 1,133 of HFpEF. The increased risk of HF in the group with infertility remained consistent after adjustment for race/ethnicity and exclusion of women who never became pregnant. Looking at causes of infertility, slightly more women with a history of infertility attributable to hormones or ovulation developed incident HF compared with those who did not, but the differences were not statistically significant.

When the researchers analyzed the association of infertility with traditional CV risk factors, they found body mass index, white race, and smoking status were independently associated with having infertility. Both former and current smoking were associated with a nearly 1.2-fold higher odds of infertility compared with never smoking. No association was seen between systolic blood pressure, hypertension treatment, diabetes, or hyperlipidemia and having infertility.

In exploratory analyses, having irregular menses was not associated with future risk of overall HF or HF subtypes. Thyroid disease was associated with future risk of overall HF (HR 1.11; 95% CI 1.01-1.22) but not incident HFpEF or HFrEF. Early menopause was associated with future risk of overall HF (HR 1.11; 95% CI 1.02-1.21) and HFrEF (HR 1.17; 95% CI 1.01-1.35), but not HFpEF.

“However, further adjustment for these infertility-related risk factors did not attenuate the association between infertility and incident HF, which argues that they do not mediate the association between infertility and HF,” Lau and colleagues write.

Emphasis on Better History-Taking

DeFilippis notes that the WHI data differ from an analysis of women in the Framingham Heart Study, in which infertility was associated with increased odds of obesity and diabetes, higher serum triglycerides, and decreased HDL-cholesterol levels.

According to Lau, while studies such as this help investigators see potential links between a woman's reproductive risk factors and subsequent heart disease risk, in clinical practice physicians are not asking questions about infertility, pregnancy, and menopause.

“It's important for both physicians and for patients to bring these topics to the table,” she said. “As doctors, we would never think twice about asking about high blood pressure, family history of heart disease, hypertension, etc. We need to also be asking about a woman's reproductive history . . . because we're still trying to parse together these links and history-taking is a fundamental tool.”

DeFilippis adds that history-taking in young women of reproductive age should include “an assessment of traditional cardiovascular risk factors but also inquire about age of menarche, difficulty conceiving, number of pregnancies and any adverse pregnancy outcomes, breastfeeding, and timing of menopause.

Furthermore, this risk assessment should be an iterative process as new information about a woman's reproductive health becomes available,” she writes.