Genes May Help Explain Link Between Adverse Pregnancy Outcomes, Later CVD

Preeclampsia, gestational hypertension, and other adverse pregnancy outcomes (APOs) are known predictors of worse cardiovascular health later in life, but a new mendelian randomization study suggests that it’s not the events themselves—but rather, shared genetic underpinnings—that explain the added risk.

The results were published as a research letter in Circulation.

“There is a very strong link between adverse pregnancy outcomes and maternal future risk of cardiovascular diseases, and this is something that clinicians and women also are increasingly aware of,” investigator Tormod Rogne, MD, PhD (University of Oslo, Norway), told TCTMD.

He said the big question is: “Does this only serve for predictive purposes, or is it actually a causal effect? Would the same cardiovascular disease in the future have happened if the adverse pregnancy outcome did not occur?”

The field is approaching the question of APOs and cardiovascular disease from various angles, including what biological changes happen at a vascular level after a female patient experiences one of these pregnancy-related conditions, said Rogne.

It may be that some aspects of the relationship are causative and some are not. He also cautioned that while their new data suggest the link isn’t causal, the analysis also does not definitively rule out that possibility and future studies may provide contradictory results.

“In epidemiology, we have this idea that for anything to be interesting it has to be causal. But that’s not really true,” he specified. “In a clinical setting, it doesn’t really matter that much whether the preterm birth or the preeclampsia are causally linked to future cardiovascular disease risk. It has happened, [so] the question is: what do we do about it now? The point is that it still has a very important predictive function.”

Rachel Bond, MD (Dignity Health, Gilbert, AZ), who didn’t take part in the study, told TCTMD it drives home the idea that when women have an APO, “it could potentially reflect an underlining susceptibility to CAD, but doesn’t necessarily mean that you materially can alter their actual risk.”

The data suggest a shared mechanism, she agreed. “Is that mechanism potentially genetic or metabolic or vascular? The likelihood is it’s probably all of the above, if not more.”

Irrespective of the mechanism, the knowledge that APOs can signal higher CVD risk over a female patient’s lifetime can inspire closer monitoring and attention to other risk factors, Bond and Rogne said.

The study results, too, don’t dramatically shift the approach to these patients, since APOs signal a high-risk phenotype, Bond noted.

“We would still be recommending that we screen aggressively and do appropriate risk stratification. . . . We need to identify and manage these preexisting risk factors, the ones that we could modify,” she said, citing high blood pressure, high cholesterol, and diabetes. “Not only are we doing cardiodiagnostic testing a little bit earlier because they have a history of adverse pregnancy outcomes, but sometimes we’re even more aggressive when it comes to their management.”

 APOs are considered “risk enhancers” in current guidelines, she added, but with this new report, clinicians may be inspired to think about the conditions as independent risk factors that, in and of themselves, merit attention.

In a clinical setting, it doesn’t really matter that much whether the preterm birth or the preeclampsia are causally linked to future cardiovascular disease risk. Tormod Rogne

Rogne and co-author Dipender Gill, BMBCh, PhD (Imperial College London, England), used a unique tactic to get at the mechanisms driving the relationship: a comparison of both female and male individuals. The idea was that while the two sexes could share genetic characteristics predisposing them to CAD, only females could become pregnant and thus develop APOs.

Male, Female Risks in Parallel

Rogne pointed out that even the 2021 American Heart Association scientific statement on the topic has wording that implies causation by specifying that seven specific APOs “increase” both CVD risk factors and incidence—hypertensive disorders of pregnancy, preterm delivery, gestational diabetes, small-for-gestational-age delivery, placental abruption, and pregnancy loss.

The researchers evaluated these same APOs in their study. First, using a genome-wide association study in a population with European ancestry, they identified single nucleotide polymorphisms (SNPs) linked to each APO yet independent from one another. They also, from a different genome-wide association study, extracted sex-specific SNPs linked to coronary artery disease.

Their mendelian randomization analysis confirmed that, for females, genetic propensity to gestational diabetes, gestational hypertension, and preeclampsia was significantly associated with higher risk of CAD, with odds ratios ranging from 1.03 to 1.15. Preterm birth showed a trend, but no links were seen for miscarriage or placental abruption.

Strikingly, though, these associations were similar for women and men regardless of the occurrence of APOs, which suggests the links between the pregnancy- and CV-related risks are driven by shared genetic liabilities, the authors write. “In other words, our study suggests that experiencing an APO may reveal a person’s underlying susceptibility to future risk of CAD, but experiencing an APO may not materially change that risk,” they explain.

As a “stress test” for their methods, Rogne said, the researchers also looked from the opposite perspective: at whether CAD foretold APO risk, a counterintuitive notion since few women would have CAD at such a young age prior to pregnancy. These bidirectional analyses similarly showed that genetic liability to CAD was closely tied to gestational hypertension, preeclampsia, and preterm birth, with a trend toward higher risk of gestational diabetes.

This may change how we approach CVD risk stratification in people who were born from pregnancies complicated with APOs. Josephine Chou

Josephine Chou, MD (Denver, CO), who commented on the study for TCTMD, noted that its concept of shared genetic liability dovetails with earlier evidence showing a link between APOs in women and CVD risk in their offspring. “While not definitively causative, the results are intriguing and hypothesis-generating,” she said.

“Currently, most of the focus on APO and future CVD has focused on the lifelong risk for the mother, and the need for intensive maternal CVD risk screening and treatment,” Chou wrote in an email. “However, if there is a significant genetic etiology that can be passed down to her offspring, this may change how we approach CVD risk stratification in people who were born from pregnancies complicated with APOs.”

What Next?

One thing that limits the generalizability of the study is “we have only evaluated women of European ancestry. . . . It might be that in other contexts in other countries, you would find different things,” Rogne acknowledged. “These sorts of gene-environment interactions are always difficult to tease out.”

Chou, for her part, stressed that it’s critically important to do a similar study in other populations, such as Black women, who are known to be especially at risk during pregnancy. “It would also be interesting to see if strategies to reduce the burden of APOs”—for example, aspirin for preeclampsia prevention—might “reduce the risk of, or attenuate the genetic susceptibility of, offspring CVD,” she said.

A promising path for future research, Rogne suggested, would be to analyze data from existing randomized trials that were designed to prevent APOs. Those trials tend to stop after birth, but 10-year follow-up could reveal new insights about whether the interventions they tested in fact reduced long-term CV risks.

Bond also highlighted the many possible directions for research. In particular, “future studies really do need to continue to explore the shared genetic and maybe even molecular pathways that help us to improve these early risk identifiers,” she suggested, noting that this knowledge might allow for precision medicine in female patients.