Adverse Pregnancy Outcomes—Risk Enhancers Whose Time Has Finally Arrived

Heart disease is the leading cause of death globally for both sexes, affecting 1 in 5 women in the United States.¹ Although women have a lower prevalence of obstructive epicardial coronary artery disease compared with men of a similar age, they have higher rates of myocardial ischemia and associated cardiovascular morbidity and mortality.² While both sex-based differences due to biological factors such as the timing of menarche and menopause and gender-related differences related to social constructs (eg, delays in time to evaluation of chest pain for women vs men) contribute to these disparities, there is a growing recognition that traditional cardiovascular risk calculators fail to account for sex-specific risk factors such as adverse pregnancy outcomes, which are unique to birthing people who predominantly identify as women. Adverse pregnancy outcomes, including pregnancy-induced hypertensive disorders (preeclampsia and gestational hypertension), preterm birth, and fetal growth restriction, are common manifestations of ischemic placental disease³ and share a vascular pathophysiologic origin. Along with gestational diabetes, adverse pregnancy outcomes comprise a group of sex-specific cardiovascular risk enhancers associated with a 2- to 4-fold increased risk of future heart disease.⁴ Unfortunately, due to a lack of detailed pregnancy history in most existing cohorts and clinical trials of coronary artery disease, to date it has been difficult to examine whether there is a difference in the pathophysiologic development of coronary artery disease in women with a history of adverse pregnancy outcomes compared with those with uncomplicated pregnancies.

Coronary computed tomography (CT) angiography is a highly accurate, noninvasive diagnostic test that can be used to assess for presence of obstructive epicardial coronary arterial disease with high sensitivity and negative predictive value.⁵ While prior strategies of reducing heart disease risk focused on obstructive coronary artery disease burden (defined as stenosis >70%), there is a growing understanding that not only obstructive plaque, but also the presence of any plaque, even noncalcified, is associated with higher risk of cardiovascular morbidity and mortality in a dose-dependent manner (more plaque burden equals greater risk), particularly for women. Similarly, a coronary artery calcium (CAC) score has been shown to be positively correlated with and add incremental value to the assessment of future cardiovascular risk. Compared with a score of 0, even minimal CAC scores are associated with an increased risk of major adverse cardiovascular events.^5,6

In this issue of JAMA, Sederholm Lawesson and colleagues⁷ advance knowledge and provide information about the heightened risk of asymptomatic coronary artery disease following individual adverse pregnancy outcomes. Their protocol in the present work from the Swedish Cardio-pulmonary Bioimage Study used a single low-dose CT scan to quantify the presence, severity, and extent of atherosclerotic coronary arterial stenoses as well as the presence of noncalcified plaque, and a CAC score. This cross-sectional, population-based cohort study examined 10 528 women with a median age at the time of the scan of 57 years, and in whom imaging was conducted a median of 30 years after their first linked pregnancy in the Swedish National Medical Birth Register. Consistent with other studies, 19% of women had a history of an adverse pregnancy outcome and those individuals also had a higher burden of traditional cardiovascular risk factors, including higher systolic blood pressure and higher prevalence of diabetes, at the time of imaging. The study reported several key findings, including a 3.8% absolute increase in the prevalence of any coronary atherosclerosis in women with a history of adverse pregnancy outcomes compared with those without (32.1% vs 28.3%). The highest increases were seen following a pregnancy affected by preeclampsia (8.0% prevalence increase, 3.1% absolute increase in significant stenosis, 4.2% increase in noncalcified plaque, and 4.1% increase in CAC score >100), with similar findings for gestational hypertension. This translates into an accelerated vascular age, the hypothetical adjustment to chronological age that accounts for the observed severity of coronary artery disease, of 4 to 11 years for women with an exposure to pregnancy-induced hypertensive disorders compared with women without this history, but not for those with history of gestational diabetes or preterm delivery. The findings after delivery of a small-for-gestational-age infant were mixed.

The authors took their work a step further and examined the burden of CT-diagnosed coronary artery disease in the 83% of women (n = 8334) who had a low predicted 10-year cardiovascular risk (<5%) and would not qualify for aggressive risk factor reduction based on current guidelines. For this Swedish cohort, from a moderate cardiovascular risk region, the SCORE2⁸ algorithm was used to provide a low, moderate, or high risk estimate of fatal and nonfatal incident cardiovascular disease. The SCORE2 risk factors include sex, age, smoking status, systolic blood pressure, and total and high-density lipoprotein cholesterol, but unlike the Pooled Cohort Equations,⁹ SCORE2 does not consider diabetes, race, or treatment for hypertension, but does incorporate country-specific cardiovascular disease mortality rates by dividing countries in Europe and the Middle East/North Africa into 4 risk regions (low, moderate, high, and very high). For women with a history of preeclampsia who had less than 5% predicted disease risk, their observed burden of significant stenosis (4.5%) was similar to women who had no adverse pregnancy outcome history and intermediate predicted cardiovascular risk (4.8%). Thus, the current risk factor stratification system does an injustice to women with preeclampsia by not accounting for the contribution of preeclampsia as a sex-specific risk factor. This provocative finding confirms what has been shown in 2 prior small studies,^10,11 and effectively suggests that women with a history of preeclampsia could benefit from reclassification to a higher level of risk, although the generalizability of this finding to more racially and ethnically diverse or younger populations is unknown.

Prior attempts at incorporating adverse pregnancy outcomes into cardiovascular disease risk calculators have failed to provide a meaningful shift in disease classification status.^12,13 This may in part be due to the grouping of adverse pregnancy outcomes together as an exposure to enhance power; it is likely that some adverse pregnancy outcomes mediate risk through their association with a heightened burden of traditional risk factors postpregnancy, while other adverse pregnancy outcomes like preeclampsia exert a direct effect on the coronary vessels, among other targets. Clustering vascular and nonvascular adverse pregnancy outcomes together may bias the reclassification schema toward the null, resulting in a smaller effect after accounting for traditional risk factors. Thus, before moving forward to attempt to refine the currently available risk calculators to include all adverse pregnancy outcomes, clinicians must first better understand individual adverse pregnancy outcomes and whether they enhance risk directly or through a shared burden of traditional risk factors. Despite the relatively homogeneous nature of this Scandinavian cohort, one of its great strengths is the population-based study design. Most prior studies examining cardiovascular disease during and after adverse pregnancy outcomes have been retrospective, single-center, cross-sectional analyses examining referred populations of limited size and often lacking adequate control groups. Given the overlap in risk factors for adverse pregnancy outcomes and cardiovascular disease, these studies have not been able to clarify contributing roles of specific adverse pregnancy outcomes in the development of heart disease. The current work is an important step in that direction, demonstrating the independent risk of coronary disease following a hypertensive disorder of pregnancy, while confirming that most of the risk experienced by individuals with a history of other adverse pregnancy outcomes such as gestational diabetes is mediated predominantly by conventional risk factors.

Failure to recognize, prevent, and treat the unique aspects of heart disease in women has resulted in less aggressive lifestyle and medical interventions in women relative to men, leading to potentially avoidable morbidity and mortality.¹⁴ To close the gap between currently delivered and ideal care, and to improve the cardiovascular health of women, clinicians must better understand the unique aspects and mechanistic pathways of heart disease in women. The study by Sederholm Lawesson and colleagues takes us one step closer to parity. While further data accumulate to refine risk calculators and prospectively test whether the addition of adverse pregnancy outcomes to cardiovascular risk stratification is warranted, there are steps that can be taken now to do better by our female patients. Taking a pregnancy history when assessing cardiovascular risk and incorporating adverse pregnancy outcomes, particularly preeclampsia and gestational hypertension, into the risk/benefit discussion around primary preventive strategies and risk factor targets is imperative. Clinicians must also educate birthing people at the time of their pregnancy to understand the impact of an adverse pregnancy outcome on their risk of future heart disease, encourage them to receive timely preventive care focused on risk factor modification, and empower them to share this important medical history with future clinicians if they are not asked about it. There is no time like the present to redouble the efforts to reduce cardiovascular disease in women.