More Complications in Pregnancy Equals Higher Risk of ASCVD Mortality

A woman’s pregnancy history—specifically, the overlap among number of pregnancies and number of complications—at age 40 predicts her risk of dying from atherosclerotic cardiovascular disease (ASCVD) over the next three decades, an observational study from Norway suggests. With each added complicated pregnancy, risk rises in a dose-response fashion.

The research was published earlier this week in the 2024 Go Red for Women spotlight issue of the Journal of the American Heart Association.

As previously reported by TCTMD, it’s well established that preeclampsia and gestational hypertension translate into higher CV risk many decades later. An open question is how best to quantify that risk.

“There has been increasing focus in the literature on this link between pregnancy complications and later health,” Liv G. Kvalvik, MD, PhD (University of Bergen, Norway), the study’s lead author, told TCTMD. Thanks to the Norwegian national registries, it was possible for Kvalvik and colleagues to know, for this analysis, how many pregnancies each woman experienced and delve into the data in a new way: from the perspective of complete reproductive history.

“It’s already known that women who only have one [complicated] pregnancy in Norway are at increased risk of cardiovascular death,” but their study goes further by looking at various scenarios, she said.

As Kvalvik explained, the researchers set the bar at age 40 because by that point 97% of women are done having children.

Aditi Singh, MD (University of Bergen), a study co-author, pointed out that this also allows a clearer picture of increased risk. “Women may be unaware of their increased cardiovascular disease risk, and this matrix might help to identify high-risk women before clinical indicators of CVD, like high blood pressure and cholesterol, emerge,” she said.

In Norway, as elsewhere, women aren’t routinely questioned about their pregnancy histories as they age, they said. For clinicians counseling patients, the concept that risk accrues alongside an increasing number of complicated pregnancies could be a useful communication tool.

“We think it’s a broad and easy way: a matrix that you can use,” said Kvalvik. She cautioned, though, that there’s variation even within the risk categories. Someone who has had a total of two pregnancies but only experienced a complication in their first, with none in the later pregnancy, might have a different risk of ASCVD mortality than a woman whose complication occurred in her second pregnancy.

We think it’s a broad and easy way: a matrix that you can use. Liv G. Kvalvik

By combining several Norwegian registries, Kvalvik and colleagues were able to identify 854,442 women born after 1944 or had a pregnancy registered from 1967 onwards and lived to at least age 40 years. They added up the number of recorded pregnancies (zero to four) and the number of those pregnancies that involved various complications: preterm delivery < 35 gestational weeks, preeclampsia, placental abruption, perinatal death, and term or near-term birth weight < 2,700 g). The ASCVD mortality endpoint encompassed maternal deaths from ischemic heart disease, acute ischemic stroke, and peripheral artery disease.

In the study cohort, 15% of women had one pregnancy, 43% had two, 22% had three, and 4% had four—the rate of complications across all these categories was 17% overall. Another 16% of women in the dataset were nulliparous, meaning that they had never given birth to a live baby (but may have had a miscarriage or an elective abortion).

A total of 2,038 women (0.24%) died from ASCVD by age 69.

Among women who reached the age of 40, subsequent risk of ASCVD mortality through age 69 rose in a dose-response fashion with each additional complicated pregnancy. The lowest risk was seen for women who had three pregnancies with no complications—which served as the reference group—and the highest was seen for women with four complicated pregnancies.

Risk of ASCVD Death at Age 40-69 Years: HR (95% CI)

For one in five women, pregnancy history explained an increased risk of death from ASCVD in the range of 2.5-fold to fivefold.

It’s not yet clear what biological pathways link these diverse complications to later CV risk, though they could share the same underlying causes, the investigators suggest. “Predisposing conditions for pregnancy complications may include inflammation, dyslipidemia, endothelial dysfunction, metabolic syndrome, and obesity, any of which may contribute to a dysfunctional placenta as well as to CVD.”

Another possibility, they add, is “that certain pregnancy complications might trigger events that themselves increase CVD risk.”

What Next?

Kvalvik said that what the team wants to do next is obtain details on what traditional CV risk factors the women have at age 40, to see if considering the number of pregnancies and complications has additive predictive power.

“Further research might focus on specific underlying clinical or subclinical markers of CVD risk associated with particular pregnancy complications. Prediction of cardiovascular risk might be further improved by identifying specific combinations of pregnancy complications that confer higher (or lower) CVD risk. In principle, interventions to improve these underlying conditions might also improve future pregnancy outcomes,” the researchers note in their paper.

Heather M. Johnson, MD (Baptist Health South Florida, Boca Raton), in an accompanying editorial, makes the case for why clarifying these relationships is “critical to improve individual CVD risk assessment, primary prevention, and global population health.”

Johnson, too, calls for further research to see how total pregnancy history, not just adverse pregnancy outcomes (APOs), affects CVD risk stratification. “However, the primary outcome of ASCVD death in a younger population by Kvalvik et al underlines the need for effective interventions to support primordial prevention and to address prevalent CVD risk factors in younger populations,” she emphasizes. “Suboptimal cardiovascular health before pregnancy contributes to increased risk of APOs, future CVD risk factors, and CVD events.”

Unfortunately, as Johnson highlights, trends are moving in the wrong direction: young women on the whole are ever more likely to develop cardiometabolic disorders like obesity and diabetes.