Premature Menopause Increases Lifetime Heart Disease Risk Regardless of Race

Women who have premature onset of natural menopause are more likely to develop heart disease over their lifetimes, with similarly increased risk seen between Black and white individuals, according to a population-based cohort study.

While natural menopause occurring before the age of 40 was more common in those who were Black, all women in the study who had early menopause had about a 40% higher risk of fatal and nonfatal MI than those whose menopause happened after age 40. The follow-up period encompassed 163,660 person-years.

“These data highlight the importance of a detailed reproductive history when assessing CVD risk in women,” write Priya M. Freaney, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), and colleagues in the study published today in JAMA Cardiology.

The study expands on some prior work, including a 2019 analysis on the risk of incident CVD in women with natural or surgical premature menopause. That study of nearly 145,000 women, using data from the UK Biobank, had a more than 90% white population and 7 years of follow-up.

Freaney and colleagues say their analysis, which includes 3,522 Black women and 6,514 white women fills in some important gaps and raises the issue of whether “the higher frequency of premature menopause observed in Black women may contribute in part to known disparities in coronary heart disease between Black and White women.”

Among the unanswered questions are whether “the menopausal transition truly represents a more disease-permissible vascular environment or whether those who experience premature menopause are the same individuals who already have a disease-permissible vascular environment where risk is unmasked and premature menopause is a marker,” they add.

Michael C. Honigberg, MD (Massachusetts General Hospital, Boston, and the Broad Institute of MIT and Harvard, Cambridge), who led the UK Biobank study, said these new data affirm the earlier findings with nearly identical point estimates for lifetime risk for women with, versus without, premature menopause.

“They have up to 30 years of follow-up and it looks like the curves are continuing to diverge, which I just think is a really fascinating finding,” he said, adding that it bears a striking similarity to observations that have been made of decades-long increased lifetime CV risk in women who had adverse pregnancy outcomes, including preeclampsia.

“We see this persistent divergence of risk over the long term, which is really interesting when we think about this sort of life course of reproductive events in women,” Honigberg said.

For the new study, women self-reported their menopause history, which both the researchers and Honigberg say may have introduced some error. To TCTMD, Honigberg said one indication that that may be the case is that the incidence of premature menopause is a bit higher than typical population estimates, which put the percentage of women with a natural premature menopause at around 2%.

Premature Menopause Three Times Higher in Black Women

Freaney et al conducted a longitudinal individual-level analysis of data from the Cardiovascular Disease Lifetime Risk Pooling Project, specifically from six long-running studies that followed women from as far back as 1964 up to 2018: Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Framingham Heart Study, Framingham Offspring Study, Multi-Ethnic Study of Atherosclerosis, and Women’s Health Initiative.

The incidence of premature menopause was 15.5% in Black women and 4.8% in white women. Black women had a mean age at baseline of 61 and white women had a mean age of 60. Other baseline characteristics were similar, although diabetes was more prevalent in Black women with premature menopause and current smoking was more prevalent in white women with premature menopause.

Over the follow-up period, having premature menopause was associated with a higher event rate for coronary heart disease events (fatal and nonfatal MI) after age 55 in both Black and white women compared with not having premature menopause. Ater adjustment for age, smoking, education, obesity, hypertension, and diabetes, hazard ratios for Black and white women were 1.41 (95% CI 1.04-1.90) and 1.39 (95% CI 1.03-1.87), respectively. The difference in lifetime risk between the premature menopause and normal-age menopause groups increased over time, with widening separation of the event curves around years 7 or 8 of follow-up.

According to the study authors, the findings “support the perimenopausal period as a unique window of opportunity to measure, monitor, and modify CVD risk in women.”

Honigberg added that the data underscore the importance of considering a woman’s reproductive history as part of her cardiovascular risk profile and as part of a comprehensive cardiovascular risk assessment.

“It should trigger clinicians to be more aggressive with prevention,” he said, adding that there is an unfortunate history of overt CV risk factors being ignored in younger women.

“When a woman has a history of early menopause, we should not [ignore] that.  We should make sure that we are really on top of modifiable risk factors,” Honigberg stressed. “We can’t modify her history of early menopause, but we can make sure that things like her blood pressure, cholesterol, and blood sugar are well controlled, that we’re paying attention to body weight and not smoking, eating a healthy diet, exercising, and other aspects of cardiometabolic health.”

Freaney and colleagues point out that while premature menopause is a well-established risk-enhancing factor, “it remains unclear if premature menopause should be included in risk prediction models, such as the new American Heart Association PREVENT equations.”

Their own prior work found that adding premature menopause status to the pooled cohort equations used to predict 10-year risk did not result in any incremental benefit in terms of prediction ability.

However, Honigberg said the age cut-off needs to be considered in this conversation since menopause before age 40 may be too strict an indicator that leaves out some at-risk women with early, but not necessarily premature, menopause. The newly released dyslipidemia guidelines, he noted, endorsed an onset cutoff age of 45 or younger for early menopause, considering it a risk-enhancing factor that qualifies women for preventive therapy.

“The switch from premature to early in the newest guidelines does definitely expand the pool of women who have a risk-enhancing factor based on their menopause history,” he added.