Highlights
– Genetic liability to preeclampsia and gestational hypertension is causally linked to higher risk of multiple cardiovascular outcomes, including ischemic heart disease, myocardial infarction, stroke, atrial fibrillation and heart failure.
– Polygenic risk scores (PRSs) for blood pressure, coronary disease, stroke and preeclampsia amplify CVD risk in women with a history of hypertensive disorders of pregnancy (HDP); obstetric history provides incremental prognostic value beyond PRSs alone.
– Evidence derives from complementary approaches: two‑sample and one‑sample Mendelian randomization (MR) and large-scale PRS analyses in primarily European-ancestry populations (UK Biobank and FinnGen).
Background: clinical context and unmet need
Hypertensive disorders of pregnancy (HDP)—notably preeclampsia and gestational hypertension—affect roughly 5–10% of pregnancies worldwide and are a leading cause of maternal and perinatal morbidity. Decades of observational epidemiology have established that women who experience HDPs have higher rates of later-life hypertension, ischemic heart disease, stroke and heart failure compared with women with normotensive pregnancies. Whether these associations reflect durable causal mechanisms (shared biology) or confounding by preexisting risk (for example, undiagnosed cardiometabolic disease before pregnancy) has important implications for screening, prevention and mechanistic research.
Study designs and methods summarized
This report synthesizes evidence from three complementary genetic-epidemiological studies that address causality and the interplay between genetic predisposition and obstetric history.
1) Mendelian randomization (MR) — Taageby Nielsen et al., Eur Heart J (2025)
Two-sample MR analyses used summary-level associations from large consortia and FinnGen, with genetic instruments for preeclampsia and gestational hypertension derived from an updated GWAS (20,064 preeclampsia cases, 703,117 controls; 11,027 gestational hypertension cases, 412,788 controls). One-sample MR analyses used individual-level data from 202,876 White British women in UK Biobank. Outcomes included ischemic heart disease, myocardial infarction, stroke and other major CVD endpoints. Sensitivity analyses (MR‑Egger) evaluated horizontal pleiotropy.
2) Polygenic risk score (PRS) analysis — Kivioja et al., Acta Obstet Gynecol Scand (2025)
FinnGen cohort of 213,942 Finnish women (8,858 with preeclampsia, 17,916 with any HDP) classified participants by PRSs for preeclampsia (PE‑PRS), systolic blood pressure (SBP‑PRS), coronary artery disease (CAD‑PRS) and stroke (stroke‑PRS). Participants were grouped into low (80%) genetic risk; normative comparator was women with normotensive pregnancies and moderate PRSs. Time‑to‑event analyses examined long-term CVD risk up to age 80.
3) Complementary MR — Tschiderer et al. (2023)
Individual-participant MR in UK Biobank evaluated genetic liability to HDPs and associations with CVD events and risk factors in ever‑pregnant women; sensitivity analyses included men and nulligravidae to probe whether genetic liability acts through pregnancy‑specific pathways or systemic mechanisms.
Key findings and effect sizes
The three studies provide convergent evidence that genetic liability to HDPs is associated with increased long-term cardiovascular risk. Below are the principal quantitative results and their interpretation.
Mendelian randomization (Taageby Nielsen et al., 2025)
Two‑sample MR results showed that higher genetic predisposition to preeclampsia was associated with elevated odds of major CVD endpoints. Reported odds ratios (ORs) per unit increase in genetic liability were:
- Ischaemic heart disease: OR 1.20 (95% CI 1.06–1.35)
- Myocardial infarction: OR 1.29 (1.13–1.47)
- Any stroke: OR 1.23 (1.12–1.35)
- Ischaemic stroke: OR 1.21 (1.10–1.33)
- Atrial fibrillation: OR 1.13 (1.01–1.25)
- Heart failure: OR 1.11 (1.04–1.20)
For gestational hypertension, effect estimates were similar in magnitude: e.g., myocardial infarction OR 1.26 (1.16–1.36), stroke OR 1.30 (1.23–1.37). MR‑Egger analyses did not indicate substantial directional pleiotropy, and one‑sample MR in UK Biobank broadly replicated these findings.
Polygenic risk score analysis (Kivioja et al., 2025)
PRS analyses in FinnGen demonstrate additive and multiplicative effects of genetic risk and obstetric history. Women with preeclampsia and a high PE‑PRS, high SBP‑PRS, CAD‑PRS or stroke‑PRS had markedly higher CVD risk compared with parous women with normotensive pregnancies and moderate PRSs:
- PE‑PRS (high): HR 1.87 (p = 2 × 10−16)
- SBP‑PRS (high): HR 2.31 (p = 2 × 10−16)
- CAD‑PRS (high): HR 1.94 (p = 2 × 10−16)
- Stroke‑PRS (high): HR 2.07 (p = 2 × 10−16)
By contrast, among women with normotensive pregnancies, a high PRS conferred only modest increases in CVD risk (e.g., SBP‑PRS HR 1.32; CAD‑PRS HR 1.19), indicating that a history of HDP amplifies the penetrance of polygenic cardiovascular risk. The elevated risk persisted into older age (up to ~80 years).
Complementary MR and subgroup analyses (Tschiderer et al., 2023)
MR in ever‑pregnant women found ORs for composite CVD of ~1.20 for genetic liability to preeclampsia/eclampsia and 1.24 for gestational hypertension. Genetic liability was also associated with higher systolic and diastolic BP and younger age at hypertension diagnosis. Sensitivity analyses in nulligravidae and men showed broadly similar associations, suggesting that the genetic liability reflects systemic mechanisms relevant to CVD risk rather than only pregnancy‑specific pathology.
Interpretation and biological plausibility
Taken together, MR and PRS analyses support a partial causal model in which shared heritable determinants and biological pathways underlie both HDPs and later-life cardiovascular disease. Plausible mechanisms include genetic predisposition to endothelial dysfunction, dysregulated angiogenic signalling, pro‑hypertensive loci influencing long‑term blood pressure trajectories, and shared inflammatory or metabolic pathways. The observation that genetic liability predicts higher blood pressure and earlier hypertension diagnosis provides a plausible mediator linking HDP liability to downstream CVD events.
Expert commentary: clinical and research implications
Clinical implications
- Obstetric history should be systematically incorporated into cardiovascular risk assessment for women. A history of preeclampsia or gestational hypertension identifies a woman at higher baseline and lifetime risk.
- Genetic risk (PRS) can stratify risk further but currently does not replace clinical history; the FinnGen data showed obstetric history added important prognostic information beyond PRSs.
- Women with prior HDPs should receive early and sustained cardiovascular risk surveillance: periodic BP monitoring, lipid assessment, lifestyle counselling, and timely management of hypertension and other modifiable risk factors.
Research implications
- Prospective trials are needed to determine whether early, targeted prevention (e.g., aggressive blood pressure control, statin therapy when indicated, structured lifestyle interventions) reduces long‑term CVD incidence among women with prior HDPs.
- Further GWAS in diverse ancestries is critical; the current evidence is dominated by European-ancestry populations (FinnGen, UK Biobank), limiting generalizability.
- Functional studies should prioritize loci shared between HDP and CVD to elucidate mechanisms (angiogenic factors, vascular reactivity, renal function).
- Integration of obstetric history into sex‑specific risk calculators should be tested and validated in different healthcare settings.
Limitations and caveats
Key limitations to keep in mind when interpreting genetic-epidemiologic studies include:
- Population ancestry: FinnGen and UK Biobank participant ancestries are predominantly Northern European; effect sizes and allele frequencies may differ in other groups.
- Genetic instruments indicate liability rather than manifest disease; MR estimates the effect of lifelong propensity to HDP on CVD and may not fully capture pregnancy‑specific exposures or environmental modifiers.
- Pleiotropy: while MR‑Egger and sensitivity analyses did not detect strong directional pleiotropy in the primary study, undetected horizontal pleiotropy could bias estimates.
- PRS performance: currently, PRSs have modest discrimination at the individual level and are sensitive to GWAS size and ancestry; clinical implementation requires careful validation and ethical considerations.
Conclusions and practical takeaways
Genetic evidence from MR and PRS analyses supports a causal link between liability to hypertensive disorders of pregnancy and increased long‑term cardiovascular disease risk. These data strengthen the rationale for routine documentation of pregnancy complications in medical records and for incorporating obstetric history into cardiovascular prevention strategies for women. While PRSs may provide incremental stratification, obstetric history remains a robust, low‑cost predictor that clinicians can act upon today.
Funding and clinicaltrials.gov
Funding sources and trial registrations are reported in the original publications. The MR and FinnGen studies cited here are observational genetic analyses rather than interventional trials and therefore do not have clinicaltrials.gov registrations. Consult the individual papers for detailed funding disclosures and acknowledgements.
References
1. Taageby Nielsen S, Luo J, Tybjærg‑Hansen A, et al. Preeclampsia, gestational hypertension, and cardiovascular disease risk: a genetic epidemiological study. Eur Heart J. 2025 Nov 3;46(41):4316-4325. doi: 10.1093/eurheartj/ehaf565 IF: 35.6 Q1 . PMID: 40900121 IF: 35.6 Q1 ; PMCID: PMC12579974 IF: 35.6 Q1 .
2. Kivioja A, Tyrmi J, Toivonen E, Huhtala H; FinnGen; Jääskeläinen T, Kettunen J, Saarela T, Laivuori H. Long-term cardiovascular risk in women with hypertensive disorders of pregnancy: Insights from polygenic risk scores. Acta Obstet Gynecol Scand. 2025 Oct;104(10):1907-1917. doi: 10.1111/aogs.70021 IF: 3.1 Q1 . Epub 2025 Jul 31. PMID: 40746022 IF: 3.1 Q1 ; PMCID: PMC12451206 IF: 3.1 Q1 .
3. Tschiderer L, van der Schouw YT, Burgess S, et al. Hypertensive disorders of pregnancy and cardiovascular disease risk: A Mendelian Randomisation study. Eur Heart J. 2023 Nov 9;44(Suppl 2):655.2726. doi: 10.1093/eurheartj/ehad655.2726 IF: 35.6 Q1 . PMID: 38304335 IF: 35.6 Q1 .
4. Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre‑eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta‑analysis. Lancet. 2007 Nov 3;370(9599):1096‑1103. doi:10.1016/S0140-6736(07)61304-5 . PMID: 17500581 .
