From menarche to menopause, reproductive history may reveal heart disease risk

Key takeaways:

• Reproductive history represents many possible sex-specific risk-enhancing factors for CVD.
• A thorough reproductive history offers an opportunity for early prevention of risk factors and primary prevention.

PHILADELPHIA — A woman’s reproductive history, including the timing of menarche, menopause and any pregnancy complications, may reveal short- and long-term cardiometabolic and cardiovascular risk trajectories, according to a speaker.

Beyond conventional risk factors for CVD, women face an added burden of sex-specific risk factors spanning from early life to midlife and late-life, Michael Honigberg, MD, MPP, a cardiologist and researcher at Massachusetts General Hospital and instructor of medicine at Harvard Medical School, said during a plenary presentation at the Annual Meeting of The Menopause Society.

Early and late menarche, polycystic ovary syndrome, menstrual irregularity, infertility, adverse pregnancy outcomes, such as hypertensive disorders of pregnancy, and absence of breastfeeding are all associated with increased CVD risk, Honigberg said.

The menopause transition in particular represents a period of accelerated CVD risk, with timing, mechanism (natural vs. surgical) and symptoms of menopause, as well as treatment of menopause symptoms, each contributing to this risk.

“Both hypertensive disorders of pregnancy and premature age of menopause onset are risk-enhancing factors for CVD, linked not just to atherosclerosis, but more diverse adverse CV outcomes than we have historically appreciated,” Honigberg said. “For hypertensive disorders of pregnancy specifically, early prevention of chronic hypertension and potentially microvascular aging seem to be key mediators of this excess risk. For premature age of menopause, particularly primary ovarian insufficiency, we increasingly suspect a role of underlying genomics linked to accelerated aging. I treat this as an opportunity in the clinic for early and aggressive primordial and primary prevention.”

Adverse pregnancy outcomes and CVD

Hypertensive disorders of pregnancy are not rare conditions; 15% of U.S. childbearing individuals experience these during at least one pregnancy, Honigberg said. Data show preeclampsia nearly doubles risks for both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction.

“Cardiometabolic risk trajectories are diverging earlier than we have historically appreciated in women with high-risk pregnancy outcomes,” Honigberg said. “It is then perhaps not entirely unsurprising that this translates into long-term risk for CVD through midlife and beyond.”

Heightened CVD risk associated with premature menopause extends to a diverse set of CV conditions, including coronary artery disease, ischemic stroke, heart failure and atrial fibrillation, and does not appear to be fully explained by postmenopausal sex hormone deficiency. Honigberg said data show that some of the most “striking” HRs with premature menopause were for aortic stenosis.

“The HR associated with surgical menopause before age 30 [years] was 17. We still don’t fully understand that association,” Honigberg said. “There is a lot more work to do specifically with valvular aging and the effects of sex hormones on that.”

Role for coronary artery calcium score

Honigberg said a history of adverse pregnancy outcomes and premature menopause are now incorporated in multi-society guidelines as risk-enhancing factors to refine risk assessment for coronary heart disease and stroke and guide allocation of primary prevention statin therapy. The pooled cohort equation risk calculator, which estimates 10-year risk for CVD, can guide prevention efforts for midlife women with these risk-enhancing factors, Honigberg said.

If the risk is uncertain, consider measuring coronary artery calcium (CAC) in selected adults, Honigberg said. A CAC score of zero is considered lower risk for CVD; a CAC score between 1 and 99 favors initiating statin therapy, especially after age 55 years. A CAC score of 100 or greater and/or in the 75^th percentile or greater for age, sex or race favors initiating statin therapy with the goal of preventing a first myocardial infarction or stroke.

“[CAC] is not perfect, but a good proxy for the presence of underlying atherosclerosis,” Honigberg said.

Honigberg said a history of reproductive risk factors represents an opportunity for comprehensive risk factor screening, refinement of CVD risk assessment, and implementation of primordial and primary prevention to optimize long-term cardiometabolic health in women.

A smarter risk assessment: Include reproductive history

Honigberg also highlighted a “prevention paradox”: Most CVD events occur in individuals who do not have high predicted CV risk.

“This seems counterintuitive — the high-risk group has the highest relative risk, but the issue is the denominator of the other groups is much, much larger,” Honigberg said. “We miss people if we only think about the high-risk [group]. The implication of this insight is we should apply certain low-tech, cheap and effective interventions more broadly across populations, but also that we should get smarter about refining our risk assessment tools. Simply asking reproductive history of our female patients is one very good way to do that.”