Highlights
Pregnancy functions as a natural cardiovascular stress test, offering a unique clinical window to identify women at elevated risk for future cardiovascular disease (CVD).
Maternal age, hypertensive disorders of pregnancy (HDPs), and third-trimester concentrations of soluble fms-like tyrosine kinase-1 (sFlt-1) and high-sensitivity cardiac troponin I (hs-cTnI) are independent predictors of long-term CVD risk.
A prognostic model combining maternal age and sFlt-1 levels at 29 weeks gestation significantly improved discrimination for future CVD compared to age alone, outperforming traditional clinical models using blood pressure and cholesterol.
The predictive value of these biomarkers remains consistent across various subgroups, including women without a history of hypertension or pregnancy complications, highlighting their potential for universal screening.
Introduction: The Pregnancy Stress Test
Cardiovascular disease (CVD) remains the leading cause of mortality among women globally. Despite this, traditional risk assessment tools often fail to capture the unique physiological trajectories of women, particularly during their reproductive years. Pregnancy represents a period of profound hemodynamic and metabolic adaptation, effectively acting as a natural cardiovascular stress test. During this time, the maternal heart and vasculature are subjected to increased cardiac output, blood volume expansion, and hormonal shifts. Failure to adapt to these stresses often manifests as obstetric complications, such as preeclampsia or gestational diabetes, which are well-documented precursors to later-life CVD.
However, recent evidence suggests that even in seemingly uncomplicated pregnancies, subclinical markers of cardiovascular strain may be present. Identifying these markers early could allow for a lifetime of targeted preventive care. A landmark study published in JAMA Cardiology by Bacmeister and colleagues explores whether clinical measures and specific biomarkers obtained during pregnancy can serve as early warning signs for long-term maternal cardiovascular health.
Study Design and Methodology
The researchers conducted a registry-linked, population-based cohort study in Southern Denmark, involving pregnancies reaching at least 22 weeks between June 2010 and October 2013. The primary focus was a nested prospective subcohort from the Odense Child Cohort, which provided detailed pregnancy biomarker data. Women with preexisting CVD were excluded to ensure that the findings reflected incident disease.
The study analyzed 38,455 eligible women, with a specific focus on 2,056 women who had biomarker data available at week 12 (first trimester) or week 29 (third trimester). The investigators evaluated several key biomarkers: soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), high-sensitivity cardiac troponin I (hs-cTnI), and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Follow-up was remarkably comprehensive, extending through December 31, 2023, with a median follow-up duration of 11.9 years.
Key Findings: Identifying the High-Risk Signature
Over the decade-long follow-up period, 1.4% of the biomarker cohort developed incident CVD. While this percentage may seem low, it reflects the relatively young and healthy status of the cohort at baseline (median age 30.4 years) and underscores the importance of identifying risk before clinical disease manifests. The study revealed several critical insights into how pregnancy data can be leveraged for risk stratification.
The Power of Third-Trimester Biomarkers
The research found that maternal age and a history of hypertensive disorders of pregnancy (HDPs) were significant clinical predictors of future CVD. However, the addition of biomarkers measured at 29 weeks gestation provided a substantial boost in predictive accuracy. Specifically, third-trimester concentrations of hs-cTnI and sFlt-1 were independently associated with a higher risk of long-term CVD. sFlt-1, an anti-angiogenic protein often elevated in preeclampsia, and hs-cTnI, a marker of myocardial injury, appear to capture different facets of cardiovascular strain.
Model Performance: Biomarkers vs. Traditional Metrics
One of the most striking findings was the performance of the prognostic models. A base model consisting solely of maternal age had limited predictive power. However, adding sFlt-1 levels measured at week 29 significantly improved the area under the curve (AUC), with a delta AUC of 0.16 (95% CI, 0.02-0.30). Interestingly, a traditional clinical model—incorporating age, systolic blood pressure, and non-high-density lipoprotein cholesterol—did not show the same level of improvement. This suggests that the physiological stress revealed by pregnancy biomarkers may be a more sensitive indicator of underlying cardiovascular vulnerability in young women than traditional risk factors measured during that same period.
Consistency Across Subgroups
Crucially, the predictive value of these biomarkers was not limited to women who experienced pregnancy complications. The results were consistent in women without prior hypertension or HDPs and in nulliparous women. This indicates that biomarkers like sFlt-1 and hs-cTnI might identify a “subclinical” risk profile that traditional obstetric diagnoses miss.
Expert Commentary and Mechanistic Insights
The biological plausibility of these findings is robust. sFlt-1 is known to antagonize vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), leading to endothelial dysfunction—a hallmark of both preeclampsia and long-term atherosclerosis. The elevation of sFlt-1 in the third trimester may signal an underlying predisposition to endothelial instability that persists or worsens over time. Similarly, elevated hs-cTnI suggests that the heart is experiencing subtle myocardial stress or injury during the volume-overload state of pregnancy. In women with limited cardiac reserve, this transient injury may be the first sign of a pathway toward heart failure or ischemic disease.
Clinicians should view these results as a call to action. Currently, many women lose contact with specialized healthcare providers after the postpartum period. Integrating pregnancy-derived data into a woman’s long-term health record could bridge this “gap in care.” However, as experts note, several limitations must be considered. The event rate in this study was low, and the cohort was primarily of Northern European descent, which may affect generalizability to more diverse populations. Furthermore, while the statistical association is strong, the optimal clinical thresholds for these biomarkers in a non-preeclamptic population remain to be defined.
Conclusion: A New Paradigm for Women’s Heart Health
The findings by Bacmeister et al. support a paradigm shift in how we view the gestational period. Rather than seeing pregnancy as an isolated event, it should be viewed as an opportunistic window for sex-specific cardiovascular risk assessment. By utilizing biomarkers like sFlt-1 and hs-cTnI during the third trimester, healthcare providers can identify high-risk individuals decades before a major cardiovascular event occurs. This allows for earlier lifestyle interventions, more rigorous monitoring, and potentially, the use of preventive pharmacotherapy. Future research should focus on validating these findings in larger, more diverse cohorts and determining whether intervening based on these pregnancy biomarkers can truly alter the trajectory of cardiovascular health in women.
References
Bacmeister L, Glintborg D, Kjer-Møller JJ, et al. Clinical Factors and Biomarkers During Pregnancy and Risk of Cardiovascular Disease. JAMA Cardiol. 2026 Feb 18:e255595. doi: 10.1001/jamacardio.2025.5595.
Brown HL, Smith GN. Pregnancy as a Window to Future Cardiovascular Health: Design and Implementation of the Postpartum Cardiovascular Risk Clinic. American Journal of Obstetrics and Gynecology. 2020.
Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia: Pathophysiology, Challenges, and Perspectives. Circ Res. 2019;124(7):1094-1112.
