History of hypertensive disorders of pregnancy and cardiovascular-kidney-metabolic syndrome in 220,000 women
D Ezzat, M A Pabon, Linke Li, A Chang, N De Moor, Z Yu, S M J Cho, P Natarajan, D C Soria Contreras, R A Hoshi, S Mora, O Demler, C E Powe, M C HonigbergAbstract
Background
In 2023, the American Heart Association (AHA) proposed a novel framework defining cardiovascular-kidney-metabolic (CKM) syndrome, recognizing the interconnected and progressive pathophysiology of obesity, diabetes, chronic kidney disease, and cardiovascular disease (CVD). Hypertensive disorders of pregnancy (HDP), including gestational hypertension and preeclampsia, affect over 10% of childbearing women worldwide and are associated with accelerated development of cardiometabolic risk factors.
Purpose
To test the association of a history of HDP with CKM stage and progression to late-stage CKM syndrome among midlife women.
Methods
We included participants from the UK Biobank (aged 40-70 years at enrollment) with at least one prior pregnancy. The primary exposure was a history of HDP. In accordance with AHA definitions, CKM syndrome was classified into stage 0 (no CKM risk factors), 1 (excess or dysfunctional adiposity), 2 (metabolic risk factors and chronic kidney disease), 3 (subclinical CVD), or 4 (established CVD). Logistic regression was used to assess the association of HDP history with CKM syndrome stages 1-4 vs. stage 0 at baseline, with adjustment for age, age2, race, Townsend Deprivation Index, and smoking status. Next, among women with stages 0-3 at baseline, Cox models tested the association between HDP history and progression to stage 4, adjusting for the same covariates plus baseline CKM stage.
Results
Among 219,639 women in the UK Biobank (mean age 56.9±7.9 years), 2,836 (1.3%) had a history of HDP. Baseline CKM stage distribution was: stage 0, 26,111 (11.9%); stage 1, 20,791 (9.5%); stage 2, 160,565 (73.1%); stage 3, 4,199 (1.9%); and stage 4, 7,973 (3.6%). When analyzed using ordinal logistic regression, a history of HDP was significantly associated with higher CKM syndrome stages (adjusted odds ratio [aOR] 2.30 [95% confidence interval [CI] 2.12-2.51]; P < 0.001). Compared with stage 0, HDP history was associated with CKM syndrome stage 1 (aOR 1.50 [95% CI 1.23-1.83]; P < 0.001), stage 2 (aOR 3.26 [95% CI 2.82-3.79]; P < 0.001), stage 3 (aOR 6.00 [95% CI 3.58-9.94]; P < 0.001), and stage 4 (aOR 3.81 [95% CI 2.80-5.16]; P < 0.001; Figure 1). Over a median (interquartile range) follow-up of 13.6 (12.7-14.3) years, women with prior HDP had a higher risk of progression to CKM stage 4 compared with those without HDP history, both overall among women in stage 0-3 at baseline (adjusted hazard ratio [aHR] 1.29 [95% CI 1.15-1.46]; P < 0.001; Figure 2) and specifically among the large proportion of women with CKM stage 2 at baseline (aHR 1.30 [95% CI 1.15-1.48]; P < 0.001).
Conclusion
A history of HDP was independently associated with more advanced CKM syndrome stage and higher risk of progression to stage 4. These findings suggest that HDP history represents an early-life clinical marker of adverse CKM trajectory and support its use in cardiometabolic risk stratification and targeted prevention.