Women’s Cardiovascular Health After Hypertensive Pregnancy: The Long View From Labor and Delivery Becomes Clearer

An ideal screening test reveals disease risk in its preclinical phase; is easily measured; and, when abnormal, leads to interventions that improve future health outcomes. Screening low-density lipoprotein cholesterol (LDL-C) represents a well-established example: elevated LDL-C is causal for atherosclerotic cardiovascular disease (ASCVD) events, and treatment to reduce LDL-C confers proportional reduction in ASCVD risk (1). Mounting evidence suggests that among women, pregnancy may serve as a highly effective screening test, with adverse pregnancy outcomes, including hypertensive disorders of pregnancy (HDP), gestational diabetes, and preterm delivery, signaling heightened risk of future adverse cardiovascular outcomes (2). However, limitations of the literature, gaps in mechanistic understanding of these conditions, and less clear therapeutic implications to date have led to inconsistent use of pregnancy history in later-life preventive care.

Pre-eclampsia and the other related HDP (which also include gestational hypertension; eclampsia; and hemolysis, elevated liver enzymes, and low platelet count [HELLP] syndrome) represent a leading cause of maternal and fetal morbidity and mortality worldwide and in the United States (3,4). A growing body of evidence now clearly demonstrates that elevated maternal risk after HDP persists long-term, further exacerbating societal and individual-level impacts. Specifically, HDP history confers a 2-fold risk of coronary artery disease and stroke (5,6). Furthermore, women with HDP demonstrate accelerated development of cardiovascular disease (CVD) risk factors, including chronic hypertension, hyper-cholesterolemia, and type 2 diabetes (7). Chronic hypertension in particular explains a large portion, albeit not all, of the increased CVD risk observed after HDP in epidemiologic analyses (8,9). Elevated CVD risk among women with HDP emerges within years of delivery and persists for decades following hypertensive pregnancy (9). In 2011, the American Heart Association first recommended that providers incorporate HDP history when assessing women’s ASCVD risk (10). The 2018 update to the American College of Cardiology/American Heart Association cholesterol guideline (11) and the 2019 American College of Cardiology/American Heart Association primary prevention guideline (12) extended this recommendation by codifying HDP history as a “risk-enhancing factor” to guide prescription of statins for primary ASCVD prevention among woman deemed intermediate-risk (i.e., 7.5% to 20% 10-year ASCVD risk) by conventional risk calculation.

More recent literature has demonstrated that HDP-associated risks extend beyond ASCVD to include diverse CVD conditions: increased risks of heart failure (9) and cardiomyopathy (13), atrial fibrillation (14), venous thromboembolism (5), and valvular heart disease (9) have now been reported. Coupled with a signal of persistently increased arterial stiffness after HDP (9), this constellation of findings suggests that women with HDP may experience global acceleration of cardiovascular aging.

In this issue of the Journal, Garovic et al. (15) advance the understanding of the burden of HDP-associated multimorbidity. First, the authors calculated the incidence of HDP per pregnancy using a cohort of 7,544 women who carried a pregnancy beyond 20 weeks’ gestation (gestational hypertension, pre-eclampsia, and eclampsia by definition do not occur before this threshold) in Olmstead County, Minnesota, between 1976 and 1982, and per woman among 1,839 women with complete data available for all pregnancies. HDP history was ascertained using a validated health records–based algorithm with superior test characteristics compared with International Classification of Diseases code-based diagnoses (16), which are more commonly used in contemporary studies. Because most HDP cases occur in first pregnancies and most with HDP do not experience recurrent HDP in subsequent pregnancies (3), HDP incidence per woman was greater than incidence per pregnancy. The per-pregnancy incidence of pre-eclampsia (3.3%) was on par with widely cited estimates of U.S. pre-eclampsia incidence (3% to 5%) (17,18). However, the authors show that the total HDP burden expressed as incidence per woman (also incorporating gestational hypertension and chronic pre-pregnancy hypertension) is considerably higher at 15.3%. A previous United Kingdom-based study reported 16% HDP prevalence (19), but a similar estimate has not previously been derived in a U.S. cohort. Compared with the present cohort of women who were predominantly white and gave birth in the 1970s and 1980s, a more ethnically diverse contemporary cohort with inherently greater prevalence of HDP risk factors (e.g., obesity, pre-pregnancy hypertension) and known ethnic disparities in HDP risk (17) is likely to have even higher HDP incidence.

Second, the authors followed 571 women with HDP and 1,142 age- and parity-matched control subjects over a median 36 years for the development of 16 cardiovascular and noncardiovascular chronic conditions based on billing codes (to date, the most comprehensive set of outcomes studied with respect to HDP history over one of the longest follow-up periods). The authors reinforced prior associations with hypertension, hyperlipidemia, diabetes mellitus, coronary artery disease, heart failure, stroke, and chronic kidney disease and additionally found novel associations with cardiac arrhythmia, dementia, and arthritis. Taken together, these findings provide compelling evidence that HDP heralds a syndrome of accelerated cardiovascular aging.

Accelerated development of CVD and multi-morbidity among women with HDP in this and other contemporary cohorts implies that previous preventive strategies are insufficient, underused among women with HDP, or both. These data support existing guideline recommendations to incorporate HDP history in ASCVD risk assessment for statin allocation. Although prior studies have shown either null (20) or modest (21) effects of HDP history on ASCVD risk reclassification compared with conventional ASCVD risk calculators, such as the Pooled Cohort Equations, albeit in relatively low-risk cohorts, this is likely because conventional risk models incorporate hypertension, which lies on the causal pathway from HDP to ASCVD. HDP history may be most useful for risk discrimination among younger women (20), before development of overt CVD risk factors, serving as an early risk signal to guide primordial prevention to prevent or delay risk factor development.

How might preventive care therefore evolve for this high-risk population? Observational data suggest avoidance of overweight and obesity postpartum may reduce risk of chronic hypertension after HDP (22), implying that weight reduction interventions may be effective. Because women with HDP currently develop CVD at higher rates despite presumably similar preventive care, should HDP history trigger different thresholds for initiating preventive pharmacotherapies (e.g., for blood pressure and LDL-C) and/or different treatment targets? Dedicated lifestyle and pharmacologic interventions for primordial and primary prevention to improve long-term health trajectories warrant prospective study.

The findings of Garovic et al. (15) additionally highlight the need for more precise mechanistic understanding of CVD risk in women with HDP. Although key causal HDP biomarkers (e.g., soluble fms-like tyrosine kinase receptor [sFlt]-1 [23]) have been identified, fundamental knowledge gaps about HDP pathogenesis and links to long-term CVD risk remain, both with respect to hypertension risk and risk mechanisms beyond hypertension. Research is needed to clarify novel pathways, such as derangement in cellular senescence, as the authors hypothesize, and to reveal unique therapeutic targets. Work to elucidate the fundamental maternal and fetal genetic architecture of HDP and metabolomic and proteomic signatures may help elucidate these gaps.

Whether risk mechanisms are uniform across ASCVD and non-ASCVD conditions is also currently unclear. Efforts to improve HDP prediction and prevention before pregnancy may yield long-term maternal health benefits, in addition to important short-term benefits to mother and child. Ultimately, discovery of effective, targeted risk-reducing interventions for women with HDP would make pregnancy an even more actionable and powerful screening test.