Reproductive History May Inform CV Prevention Strategies in Women

Detailed reproductive histories are an important part of a woman’s overall CVD risk factor assessment and may help pinpoint those who could benefit from early prevention strategies, new data suggest.

An analysis of the VIRGO and NHANES databases that included a wide range of reproductive factors showed greater odds of early-onset acute MI in women who had early menarche (OR 2.07; 95% CI 1.56-2.73), had reached menopause (OR 1.82; 95% CI 1.50-2.22), had gestational diabetes (OR 1.65; 95% CI 1.23-2.19), had used birth control pills for 1-5 years (OR 1.67; 95% CI 1.36-2.05), and had used female hormones, excluding birth control methods or hormonal treatment for infertility, at any point (OR 1.99; 95% CI 1.62-2.46).

Breastfeeding for a month or longer, having a first live birth at age 30 years or older, and current contraceptive use were associated with lower odds of early-onset acute MI.

Senior author Yuan Lu, ScD (Yale School of Medicine, New Haven, CT), said while the study examined associations, not causation, the findings raise important questions about types of reproductive history information that could be relevant to future CV health trajectories.

“When women are meeting with their clinicians, it would be very helpful for the clinician to ask questions about their pregnancy complications, their menopause status, their breastfeeding history, and about any hormone use in the past,” she told TCTMD. “It can complement the traditional risk factor assessment tools [and] provide additional information to evaluate their risk of cardiovascular disease.”

Commenting for TCTMD, Erica P. Gunderson, PhD, MPH (Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA), a reproductive life-course epidemiologist, said although the case-control design included more younger women than prior studies that focused on older women who develop CVD decades after their childbearing years, “it is limited by lack of data on history of hypertensive disorders of pregnancy and unknown age at onset of traditional risk factors relative to the pregnancies.”

Conditions such as diabetes, hypertension, and obesity may develop before pregnancy or many years later and thus may not necessarily act as mediators of the association between reproductive factors and acute MI. When present before pregnancy, they may potentially lead to reverse causation, Gunderson said. For example, prepregnancy risk factors can increase the risk of adverse pregnancy outcomes and shorter breastfeeding, which then increases the risk of future MI.

“In the current study, the associations for younger age at menarche and birth control hormones remained statistically significant after addition of traditional risk factors to the model—they develop or are predominantly used before the start of childbearing years and prior to the onset of chronic disease,” Gunderson noted.

She said what is needed are prospective cohort studies of women during their childbearing years that evaluate development of cardiometabolic risk factors relative to reproductive patterns, preserve the temporality of pregnancy relative to the onset of traditional CVD risk factors, and better characterize phenotypes for the severity and type of adverse pregnancy outcomes and other reproductive factors.

Timing and Influence Questions

For the study, published recently in the American Journal of Preventive Cardiology, Lu and colleagues, with lead author Weilai Dong, PhD (Yale School of Medicine), examined data on 1,561 women in the VIRGO study ages 18-55 years (mean age 47 years) who had acute MI and 1,561 participants from NHANES (mean age 47 years) who formed the control group. Compared with cases, the control participants were more likely to be Hispanic (29.5% vs 4.5%) and to be married or living with a partner (63.4% vs 53.7%). Case participants had a higher prevalence of hypertension than controls (62.7% vs 30.0%), as well as more hyperlipidemia, diabetes, and current smoking.

There was a lower likelihood of early-onset acute MI in women who had a first live birth at 30 years of age or older (OR 0.50; 95% CI 0.36-0.69), breastfed their infants for at least a month (OR 0.46; 95% CI 0.38-0.56), and currently used contraceptives (OR 0.49; 95% CI 0.32-0.76).

Of note, Dong and colleagues point out that information on the types and doses of contraceptives and female hormones, as well as on initiation timing and indication, was lacking in the databases.

In analyses adjusted for traditional risk factors (ie, hypertension, hyperlipidemia, diabetes, current smoking, and body mass index), use of birth control pills for 1-5 years and female hormone use were still significantly associated with increased risk of early-onset acute MI.

In exploratory analyses that stratified women by menopausal status and adjusted for race and ethnicity, the factors most strongly correlated with early acute MI in premenopausal women were early menarche (< 11 years), diabetes during pregnancy, and ever taking female hormones. In women who had reached menopause at the time of acute MI, being 30 years of age or older at first live birth and use of birth control pills for 1-5 years showed the strongest associations.

Dong and colleagues say reproductive factors that occur early in life such as menarche and pregnancy-related complications “may exert effects over shorter time horizons, whereas later-life exposures, such as delayed childbearing, may require longer latency to influence cardiovascular risk.”

How these reproductive factors exert their influence is unclear, but metabolic pathways may offer one explanation.

“For instance, early menarche is associated with higher lifetime adiposity and metabolic risk, and pregnancy complications are linked with later development of hypertension and diabetes,” Dong and colleagues write. “Breastfeeding for at least 1 month is nominally associated with reduced acute MI risk, which may be due to lactation’s capacity to modulate more favorable cardiometabolic profiles through mechanisms such as increasing insulin sensitivity, increasing HDL cholesterol, and reducing the risk of diabetes.”

In a recent study, Gunderson’s group looked at the impact of early-pregnancy blood pressure patterns on the risk of developing hypertension 14 years after pregnancy, concluding that blood pressure trajectory phenotype combined with hypertensive diseases of pregnancy may help identify individual hypertension risk levels. To TCTMD, Gunderson said it is one of the first studies to provide the granular phenotypes needed to identify risk for future CVD.

Lu said she views the information from VIRGO and NHANES as highlighting the need for further study in this area to better understand and capture the reproductive data that are most important for women and their clinicians to discuss in conversations about CVD risk.