Chronic hypertension is one of the strongest risk factors for cardiovascular disease (CVD) but might not be the primary pathway through which hypertensive disorders of pregnancy (HDPs) can affect a woman’s health and life span.
In a study of more than 88,000 women, published today in the Journal of American College of Cardiology, gestational hypertension and pre-eclampsia were associated with a 42% higher age-adjusted risk of dying before age 70.
The association remained significant even after full adjustment for potential confounders and postpregnancy dietary, lifestyle, and reproductive factors (hazard ratio [HR], 1.31; 95% CI, 1.18 – 1.46).
When the investigators took into account the subsequent development of chronic hypertension, the elevated risk for premature all-cause mortality persisted in women with:
HDPs only: HR, 1.20 (95% CI, 1.02 – 1.40)
Chronic hypertension only: HR, 1.67 (95% CI, 1.50 – 1.84)
Both HDPs and subsequent chronic hypertension: HR, 2.02 (95% CI, 1.75 – 2.33).
A similar pattern was found for premature CVD-related mortality, with corresponding HRs of 1.71, 3.23, and 6.35.
“This really adds to the evidence that hypertensive disorders of pregnancy are an important risk factor for cardiovascular disease and possibly cardiovascular disease mortality. And the important message for a clinical audience is that it doesn’t have to go through chronic hypertension,” senior author Jorge Chavarro, MD, ScD, Brigham and Women’s Hospital, Harvard Medical School, Boston, told theheart.org | Medscape Cardiology.
Shared risk factors, such as insulin resistance and systemic inflammation, might explain part of the association, but pathologic processes implicated in HDPs — such as angiogenic imbalance, complement activation, and hemodynamic changes — might also contribute directly to cardiac stress that exceeds normal pregnancy, leading to overt cardiac damage, the authors note. The relation between HDPs and CVD might also be mediated by epigenomic changes.
Commenting on the study, Leslie Cho, MD, lead author of the recent ACC/American Heart Association updated guideline recommendations for primary prevention of CVD in women, said the findings highlight the need for greater awareness among both physicians and patients of HDPs as risk enhancers.
“Without having cardiologists know and accept these risk factors, which are true risk factors, it’s hard to move the needle,” said Cho, a cardiologist at the Cleveland Clinic. “I think that educational piece is really, really important. Also, convincing women is important, so they become aware of their risk and take ownership of their body.”
HDPs complicate about 10% of all pregnancies, and 10% of women will have chronic hypertension at 12 months. Studies have shown a higher mortality risk in women with a history of HDPs but few have prospectively explored the association, or whether it is fully explained by women subsequently developing chronic hypertension, observed Chavarro.
Using data from the Nurses’ Health Study II, the investigators identified HDPs in 14% of 88,395 parous women prospectively followed with health questionnaires and other assessments from 1989 to 2017.
Women with gestational hypertension and/or pre-eclampsia had a greater baseline body mass index and higher prevalence of gestational diabetes, chronic hypertension, and parental history of diabetes and myocardial infarction/stroke than those without an HDP.
Over 28 years of follow-up, there were 2387 premature deaths before age 70, including 1141 cancer deaths and 212 CVD deaths.
Cause-specific analyses showed that women with a history of HDP had more than a twofold higher risk for premature CVD mortality (HR, 2.26; 95% CI, 1.67 – 3.07).
They also had a greater risk for death due to infectious diseases (HR, 2.77), respiratory diseases (HR, 2.26), nervous system disorders (HR, 2.51), and metabolic/immunity disorders (HR, 4.85), whereas HDPs were unrelated to premature cancer mortality (HR, 0.97).
The investigators expected that the association with premature mortality would be stronger for pre-eclampsia — one of the most important contributors to maternal and neonatal mortality worldwide — than gestational hypertension. But the risk for all-cause and cause-specific mortality was similar when the two complications were examined separately, Chavarro pointed out.
Another twist to the findings is that, historically, hypertension during a first pregnancy has been thought to be more important than its presence in subsequent pregnancies. “But that’s not what we see here,” he said. “We see that women who go from having an initial pregnancy that’s normotensive to having a second pregnancy where she experiences hypertension are still at an elevated risk of premature mortality.”
In the fully adjusted model, women with an HDP after a normotensive pregnancy and those also reporting an HDP in subsequent pregnancies were at the highest risk of dying prematurely, compared with normotensive women (HR, 1.82 [95% CI, 1.22 – 2.69] and HR, 1.23 [95% CI, 0.74 – 2.04], respectively).
The question going forward is “whether women who may be at increased risk of CV mortality can be identified with regular screening tools because we know some of them will be missed with blood pressure,” Chavarro said.
In a related editorial, Garima Sharma, MD, Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, and colleagues point to a lack of data on what type of screening and interventions are needed to alter these risks, despite increased recognition of HDPs by professional societies.
They note that available tools to predict CVD risk lack the accuracy to identify high-risk women younger than 40 years because they were developed and validated in older populations. Three recent population-based cohort studies also showed no added value of HDPs, preterm birth, and small-for-gestational age birth above well-established risk factors for the prediction of CVD risk in women.
“Contemporary treatment of women with HDPs will need better risk assessment tools informed by precision medicine to appropriately identify those women who are at greatest risk of premature CVD and to develop algorithms for early intervention to change the trajectory of these women,” Sharma and colleagues write.
Cho noted that nonattendance at postpartum visits is extremely common for busy young mothers, and cautioned that as the obesity epidemic becomes more and more prevalent, “gestational hypertension is going to be an epidemic.”
“We often talk about personalized medicine and think of it as fancy genetics and all this other stuff, but personalized medicine is knowing your risk,” Cho said. “Having this important risk and really understanding what that means for you long-term is super important.”
Weaknesses of the study are self-reported diagnoses of HDPs and chronic hypertension, which can result in misclassification of disease status and biased risk estimates, and its largely White cohort could limit generalizability.
The study was supported by grants from the National Institutes of Health. The investigators, Cho, and the editorialists reported having no relevant relationships to disclose.
J Am Coll Cardiol. Published online March 8, 2021. Article, Editorial