Adverse pregnancy outcomes increase cardiovascular risk, even in unaffected sisters

A study found that women with adverse pregnancy outcomes face a higher risk of cardiovascular disease, with their APO-free sisters also showing an elevated risk, suggesting shared genetic and environmental influences.

Study: Adverse pregnancy outcomes, familial predisposition, and cardiovascular risk: a Swedish nationwide study. Image Credit: Prostock-studio/Shutterstock.com

Women who experience adverse pregnancy outcomes (APOs) face a significantly higher risk of cardiovascular disease (CVD). However, the extent to which shared familial susceptibility contributes to the frequent co-occurrence of APOs and CVD within families remains unclear. A recent study published in the European Heart Journal explored this connection.

Introduction

APOs, including pregnancy-induced hypertension, fetal growth restriction, placental abruption, and stillbirth, have consistently been linked to an increased risk of both short- and long-term CVD.

While the underlying mechanisms are still debated, they may involve pre-existing lifestyle risk factors as well as genetic links between APOs and CVD. Supporting this hypothesis is the presence of endothelial dysfunction and inflammation in high-risk pregnancies.

To investigate this further, researchers examined the risk of major adverse cardiac events (MACE) among sister pairs—comparing those with and without APOs—alongside unrelated APO-free women.

Since sisters share half their genes and a common family background, this study design helps assess the interplay of genetic and environmental factors.

Study overview

The study analyzed data from a nationwide Swedish cohort of women who had delivered singleton pregnancies for the first time and had no prior history of CVD.

Participants were categorized into three groups: women with one or more APOs, their APO-free sisters, and unrelated APO-free women. The researchers tracked the risk of CVD across these groups from their first childbirth until 2023.

MACE events—including ischemic heart disease (IHD), heart failure, and cerebrovascular events (CVEs)—were identified. The median follow-up period was 14 years.

Key findings

At the start of their first pregnancy, the prevalence of CVD was similar across all groups: 0.26% in women with APOs, 0.20% in their APO-free sisters, and 0.17% in unrelated APO-free controls.

Among those with APOs, 44% experienced preterm delivery, 43% had pregnancy-induced hypertension (PIH), and 27% had small-for-gestational-age (SGA) babies. Placental abruption and stillbirth were less common, occurring in 3% and 0.4% of cases, respectively.

Educational levels varied, with 50% of full sisters and 40% of half-sisters completing 12 years of schooling. APO-exposed women had higher obesity rates (12%) than their APO-free full-sisters (8.5%) and half-sisters (10.4%).

Smoking during early pregnancy was consistent among APO-exposed women, their full-sisters, and unrelated controls (~10%), but twice as common among half-sisters.

MACE risk

Women with APOs had a MACE incidence rate (IR) of 2.8 per 10,000 person-years (PYs), more than double the rate of 1.2/10,000 PYs seen in APO-free controls.

Those with two APOs faced a fourfold higher MACE risk. The most critical period was the first six months postpartum, during which MACE risk was five times higher than in controls before tapering to about twice the baseline risk.

Individually, APOs were linked to a 2.2-fold increase in IHD risk, a 3.5-fold increase in heart failure risk, and a 1.5-fold increase in CVE risk compared to APO-free women.

Risk among sisters

APO-free sisters of women with APOs also had an elevated risk of future CVD, though not for CVEs. Their MACE risk was 40% higher than that of unrelated APO-free women, with an IR of 1.5/10,000 PYs.

This risk was particularly elevated (60%) in the first six months postpartum before stabilizing at 40% over time.

Heart failure and CVE risks were notably higher among APO-free sisters—by 65% and 37%, respectively. Interestingly, half-sisters had a 2.5-fold higher heart failure risk compared to controls, whereas full-sisters showed no increased risk, suggesting additional environmental or socioeconomic influences.

No direct association was found between APO-free sisters and IHD risk. Given that women typically develop IHD later in life, longer follow-ups may reveal increasing acute coronary events in this group, aligning with trends seen in other CVD components.

Comparison between sisters

APO-free sisters had a lower CVD risk than their APO-exposed siblings. They were 33% less likely to experience MACE, 63% less likely to develop IHD, and 44% less likely to have heart failure.

However, CVE rates showed no significant difference. Full sisters had lower MACE and heart failure risk compared to half-sisters, possibly reflecting socioeconomic disparities, as seen in their education levels.

Conclusions

This large-scale sibling-comparison study provides robust evidence that both genetic and environmental factors contribute to the link between APOs and CVD. The findings suggest that women with APOs—and even their unexposed sisters—represent a high-risk population that could benefit from targeted cardiovascular prevention strategies.

Further supporting these results, genome-wide association studies (GWAS) have identified common genetic risk factors for both pre-eclampsia and CVD.

While multiple genes contribute to CVD risk independently of APO family history, this study highlights the need for continued research into shared genetic and environmental influences.