Clinical Factors and Biomarkers During Pregnancy and Risk of Cardiovascular Disease: Leveraging the ‘Natural Stress Test’

Highlights

• Pregnancy acts as a natural cardiovascular ‘stress test’ that can reveal latent vulnerabilities decades before clinical cardiovascular disease (CVD) manifests.
• 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 maternal CVD risk.
• Incorporating week-29 sFlt-1 levels into risk models significantly improves discrimination (ΔAUC 0.16) compared to traditional age-based or clinical models (blood pressure and lipids).
• These findings underscore the importance of the ‘fourth trimester’ and beyond as a critical period for lifelong cardiovascular risk stratification and preventive intervention in women.

Background

Cardiovascular disease (CVD) remains the leading cause of mortality among women globally, yet traditional risk assessment tools often fail to capture sex-specific nuances or identify risk early enough in the life course. For many women, pregnancy represents the first significant challenge to the cardiovascular system, requiring profound physiological adaptations including a 50% increase in blood volume and significant changes in cardiac output and systemic vascular resistance.

When these adaptations fail, obstetric complications such as hypertensive disorders of pregnancy (HDPs)—including preeclampsia and gestational hypertension—arise. While HDPs are established markers for future CVD, they are clinical endpoints of underlying pathological processes. Recent research, exemplified by the Bacmeister et al. (2026) study in JAMA Cardiology, has pivoted toward identifying the molecular precursors of these events. By analyzing specific biomarkers during the ‘stress test’ of pregnancy, clinicians may be able to identify at-risk women even in the absence of overt clinical complications.

Key Content

The Pathophysiological Basis of Pregnancy Biomarkers

The study of pregnancy-related biomarkers focuses on two main axes: placental health (angiogenic factors) and direct cardiac strain. The primary biomarkers investigated include:

• sFlt-1 (Soluble fms-like tyrosine kinase-1): An anti-angiogenic protein that antagonizes vascular endothelial growth factor (VEGF). High levels are associated with endothelial dysfunction and are a hallmark of preeclampsia.
• PlGF (Placental Growth Factor): A pro-angiogenic factor. A low PlGF or a high sFlt-1/PlGF ratio indicates placental insufficiency.
• hs-cTnI (High-sensitivity Cardiac Troponin I): A highly specific marker of myocardial injury. Even minor elevations during pregnancy may signal subclinical cardiac stress.
• NT-proBNP: A marker of hemodynamic wall stress and ventricular stretch.

Evidence from the Odense Child Cohort (OCC)

In a large-scale registry-linked study in Southern Denmark, researchers followed 38,455 women for over a decade. A nested subcohort of 2,056 women provided blood samples at week 12 and week 29 of gestation. This longitudinal design allowed for a direct comparison between early-pregnancy (baseline) and late-pregnancy (peak stress) biomarkers.

Chronological Progression and Risk Discrimination

Analysis revealed that biomarkers measured at week 12 had limited prognostic value for long-term CVD. However, by week 29, the predictive power increased significantly. This suggests that the cumulative physiological burden of pregnancy must reach a certain threshold before individual differences in cardiovascular resilience become apparent.

The study found that maternal age, the presence of HDPs, and third-trimester hs-cTnI and sFlt-1 were independently associated with future CVD events. Most notably, a model combining age and week-29 sFlt-1 provided vastly superior discrimination (Area Under the Curve [AUC] improvement of 0.16) compared to age alone. Conversely, traditional clinical markers measured during pregnancy—such as systolic blood pressure and non-HDL cholesterol—did not significantly improve prediction in this young, generally healthy population.

Comparison of Biomarker Performance

Biomarker (Week 29)	Association with Long-term CVD	Clinical Implication
sFlt-1	Strongly Associated	Reflects systemic endothelial vulnerability and placental stress.
hs-cTnI	Associated	Indicates subclinical myocardial injury during volume expansion.
NT-proBNP	Weakly Associated	Less predictive than sFlt-1 in this specific cohort for long-term risk.

Expert Commentary

The ‘Stressed Heart’ Hypothesis

The finding that sFlt-1 is a better predictor than traditional lipids or blood pressure during pregnancy is revolutionary. It suggests that pregnancy does not just ’cause’ CVD later in life, but rather unmasks a woman’s inherent predisposition to vascular and endothelial dysfunction. If a woman’s vasculature cannot handle the anti-angiogenic surge of late pregnancy (manifested as high sFlt-1), she likely possesses a phenotype that is susceptible to atherosclerosis and hypertensive heart disease in the decades to follow.

Translational Implications for Primary Care

Currently, once a woman delivers, her obstetric history is often ‘lost’ in the transition to primary care. These results argue for a systematic integration of pregnancy data into lifelong electronic health records. A woman with high sFlt-1 or hs-cTnI at week 29—even if she does not develop clinical preeclampsia—should arguably be monitored more closely for hypertension and dyslipidemia in her 30s and 40s.

Methodological Considerations and Limitations

While the study is robust, the total number of CVD events in the biomarker subcohort was relatively small (1.4%). This is expected in a young cohort (median age 30), but it necessitates longer follow-up (20–30 years) to see the full impact on hard endpoints like myocardial infarction or stroke. Furthermore, the population was primarily Northern European; further research is required to validate these biomarkers in more diverse racial and ethnic groups who may have different baseline risks for HDPs and CVD.

Conclusion

The study by Bacmeister et al. provides compelling evidence that pregnancy biomarkers offer a unique, sex-specific window into a woman’s future cardiovascular health. Specifically, sFlt-1 and hs-cTnI measured in the third trimester serve as early warning signs of vascular and cardiac vulnerability. Moving forward, the clinical community must move beyond viewing pregnancy complications as transient obstetric issues and recognize them as critical opportunities for early cardiovascular intervention. Future research should focus on whether early intervention (e.g., statins or intensive BP control) in women with ‘high-risk’ pregnancy biomarker profiles can successfully shift their long-term cardiovascular trajectory.

References

• Bacmeister L, Glintborg D, Kjer-Møller JJ, et al. Clinical Factors and Biomarkers During Pregnancy and Risk of Cardiovascular Disease. JAMA Cardiol. 2026. PMID: 41706460.
• Sattar N, Greer IA. Pregnancy complications and maternal cardiovascular risk: opportunities for intervention and screening? BMJ. 2002;325(7356):157-160. PMID: 12130616.
• Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia: Pathophysiology, Challenges, and Perspectives. Circ Res. 2019;124(7):1094-1112. PMID: 30920918.