Highlights
- Systolic blood pressure (SBP) polygenic risk scores (PGS) are independently associated with new-onset hypertension 2 to 7 years post-delivery.
- The predictive value of genetic risk is most pronounced in women without a history of hypertensive disorders of pregnancy (HDP).
- Despite the significance of genetics, clinical factors—specifically elevated body mass index (BMI) and a history of HDP—account for a substantially higher proportion of population attributable risk.
- Persistence of specific proteomic signatures in complement and coagulation pathways provides a potential mechanistic bridge between pregnancy complications and long-term vascular disease.
Background
Hypertensive disorders of pregnancy (HDP), including preeclampsia, eclampsia, and gestational hypertension, affect approximately 10% of pregnancies worldwide and are well-established precursors to chronic hypertension and premature cardiovascular disease (CVD). Pregnancy serves as a unique physiological “stress test,” where the inability to adapt to the hemodynamic demands of gestation often unmasks underlying cardiovascular vulnerabilities.
While the epidemiological link between HDP and later-life hypertension is clear, clinicians face challenges in stratifying risk among the much larger population of women who have normotensive pregnancies. Furthermore, the interplay between an individual’s baseline genetic predisposition and their obstetric history remains poorly defined. The advent of polygenic risk scores (PRS)—which aggregate the effects of thousands of genetic variants across the genome—offers a potential tool for precision medicine in maternal health. This review synthesizes recent evidence on the utility of genetic, clinical, and proteomic markers in predicting the transition from pregnancy to chronic hypertension.
Key Content
The Impact of SBP Polygenic Scores on Incident Hypertension
A pivotal cohort study, the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b) Heart Health Study (Hemeryck et al., 2026), followed 2,852 participants without pregestational hypertension for 2 to 7 years post-delivery. Using a genome-wide SBP polygenic score, researchers found that women in the highest quintile of genetic risk had a significantly higher likelihood of developing stage 1+ hypertension (≥130/80 mm Hg or medication use) compared to those in the lowest quintile (adjusted odds ratio [aOR], 1.50; 95% CI, 1.09-2.07).
Notably, the association between genetic risk and incident hypertension was found to be independent of sociodemographic factors, first-trimester blood pressure, and postpartum BMI. However, a significant interaction was observed regarding obstetric history: the SBP genetic risk was strongly associated with incident hypertension in women who had normotensive pregnancies (aOR, 1.25 per SD), but this association was attenuated and not statistically significant in those with a history of HDP (aOR, 1.01 per SD). This suggests that the physiological insult of HDP may be a sufficiently potent risk factor to overshadow baseline genetic predisposition in the early postpartum years.
Comparison of Genetic and Modifiable Risk Factors
While genetic scores provide a statistically significant window into future risk, their clinical weight must be balanced against traditional risk factors. Analysis of Population Attributable Risk (PAR) in the nuMoM2b cohort revealed a striking hierarchy:
- Postpartum BMI (≥25): Accounted for 41.5% of the population attributable risk for hypertension.
- HDP History: Accounted for 10.8% of the PAR.
- High SBP Genetic Risk: Accounted for only 4.7% of the PAR.
These findings emphasize that while genetics contribute to individual vulnerability, public health and clinical efforts should remain aggressively focused on weight management and lifestyle interventions, which address a much larger share of the preventable disease burden.
Evidence from Asian Populations and Cardiovascular Outcomes
The utility of genetic risk scores extends beyond immediate blood pressure monitoring to long-term cardiovascular health. A large-scale population-based cohort study of over 35,000 Korean women (BJOG, 2026) utilized a polygenic risk score for pre-eclampsia (PE-PRS). This study found that women in the high PE-PRS group had a 25% higher risk of incident hypertension (aHR 1.25) and a 28% higher risk of ischemic heart disease (aHR 1.28) later in life. Interestingly, the highest risk was observed in women who had *both* a history of pre-eclampsia and a high genetic risk, suggesting that in certain populations and over longer time horizons, genetics and obstetric history may act synergistically rather than as independent contributors.
Proteomic Signatures as Mechanistic Bridges
To understand *why* HDP leads to long-term hypertension, researchers have turned to high-throughput proteomics. Evidence published in Hypertension (2025) identified a persistent proteomic signature in women with a history of HDP that remained detectable for years after delivery.
Using machine learning to analyze over 7,000 plasma proteins, the study identified 28 specific proteins—primarily involving the complement and coagulation cascades (e.g., complement factors 3, B, H, and coagulation factor IX)—that were consistently dysregulated in both the immediate postpartum period and mid-life. This suggests that HDP triggers a chronic state of low-grade inflammation and vascular activation that does not fully resolve, potentially explaining the accelerated progression to chronic hypertension regardless of genetic background.
Parallel Models: Gestational Diabetes and Genetic Risk
The paradigm of using genetic scores to refine postpartum risk is also evident in metabolic health. Research involving women with a history of gestational diabetes mellitus (GDM) (Diabetologia, 2013) demonstrated that a weighted genetic risk score (wGRS) composed of 48 variants significantly improved the prediction of future type 2 diabetes. The addition of genetic information to clinical models provided modest but statistically significant improvements in risk reclassification (NRI 0.430), mirroring the potential for SBP genetic scores to refine hypertension risk assessments in women with “borderline” clinical profiles.
Expert Commentary
The integration of polygenic risk scores into obstetric and primary care represents a significant frontier in maternal-fetal medicine. The data from Hemeryck et al. suggest a nuance that clinicians must appreciate: the genetic “signal” for hypertension is clearest in those who *passed* the pregnancy stress test (normotensive pregnancies). In these women, the absence of an acute clinical event (HDP) makes the slow, cumulative influence of polygenic predisposition more apparent.
However, from a practical standpoint, the PAR data is a call to action for lifestyle intervention. If 41.5% of incident hypertension in the years following birth is attributable to elevated BMI, then weight management in the “fourth trimester” and beyond should be a cornerstone of postpartum care.
One current controversy is the timing of genetic testing. Should PRS be assessed during the first trimester to tailor prenatal monitoring, or post-delivery to guide long-term follow-up? Current guidelines from the NCCN and AHA focus on clinical history. While the PE-PRS and SBP-PGS show promise, they are currently best viewed as complementary tools for risk reclassification rather than standalone diagnostic tests. Furthermore, the persistent proteomic changes observed in complement pathways suggest that future therapies might target subclinical inflammation post-HDP to break the link between pregnancy and cardiovascular decline.
Conclusion
In summary, genetic predisposition to high systolic blood pressure is a significant and independent predictor of hypertension within a decade of delivery. However, its influence is secondary to the profound impacts of maternal BMI and history of hypertensive disorders of pregnancy. The most effective strategy for preventing postpartum hypertension remains a robust clinical focus on metabolic health and blood pressure monitoring, with genetic scores serving as a potential refinement tool for women categorized as low-risk by traditional obstetric standards. Future research must determine if providing patients with their genetic risk scores improves adherence to lifestyle modifications and whether early intervention in inflammatory pathways can mitigate the long-term vascular consequences of high-risk pregnancies.
References
- Hemeryck J, et al. Blood Pressure Genetic Risk and Incident Hypertension at 2 to 7 Years Post Partum. JAMA Cardiol. 2026; PMID: 41920533.
- BJOG. Polygenic Risk for Pre-Eclampsia and the Long-Term Risk of Incident Hypertension and Cardiovascular Disease. 2026; PMID: 41236086.
- Hypertension. Persistence of a Proteomic Signature After a Hypertensive Disorder of Pregnancy. 2025; PMID: 39981573.
- Diabetologia. Prediction of type 2 diabetes in women with a history of gestational diabetes using a genetic risk score. 2013; PMID: 24057154.
