Spironolactone to Improve Pregnancy-Associated Hypertension Trajectories

Spironolactone to Improve Pregnancy-Associated Hypertension Trajectories

The hypertensive disorders of pregnancy (preeclampsia and gestational hypertension) are associated with increased long-term maternal risk of developing cardiovascular disease. Recent evidence suggests that activation of the mineralocorticoid receptor promotes ongoing susceptibility to hypertension in women following hypertensive disorders of pregnancy. In addition, women with overweight/obesity are at increased risk for progression to chronic hypertension after experiencing hypertensive disorders of pregnancy. Among women with hypertensive disorders of pregnancy and pre-pregnancy overweight/obesity, the investigators will conduct a randomized trial to test the effect of pharmacologically blocking the mineralocorticoid receptor for three months after delivery on blood pressure and cardiac remodeling at nine months postpartum.

The hypertensive disorders of pregnancy (HDP, e.g., gestational hypertension and preeclampsia) are a leading cause of maternal and infant morbidity and mortality and are associated with increased long-term risk of maternal atherosclerotic cardiovascular disease (CVD) and heart failure. The American College of Cardiology and American Heart Association now recognize the HDP as a sex-specific CVD risk factor to guide prescription of preventive statin therapy. Beyond this focused recommendation, however, targeted strategies for CVD risk reduction in women with HDP are not yet established. Maternal overweight/obesity is a risk factor for accelerated progression from HDP to chronic hypertension, a key mediator of heightened long-term CVD risk in women with a history of HDP, and for adverse cardiac remodeling in pregnancy. Recent preclinical evidence suggests that the HDP induce heightened vascular smooth muscle cell mineralocorticoid receptor (MR) sensitivity that persists postpartum, promoting chronic hypertension and CVD. In addition, the recent POP-HT trial suggested that blood pressure control in the very early postpartum period has long-lasting effects on the risk of chronic hypertension and cardiac remodeling in women after HDP. Integrating these lines of evidence, the investigators hypothesize that short-term pharmacologic blockade of the MR in the early postpartum period after HDP will yield long-term maternal cardiovascular benefits in women with overweight/obesity. To test this hypothesis, the investigators will compare a strategy of adding low-dose spironolactone, a breastfeeding-compatible MR antagonist, or placebo to usual care for 3 months following delivery with HDP. This multi-site trial will randomize 204 women with HDP and pre-pregnancy overweight/obesity delivering at Massachusetts General Hospital, Brigham and Women's Hospital, and the University of Pittsburgh-Magee Womens Hospital. The investigators will test the effect of short-term adjunctive postpartum spironolactone on 24-hour ambulatory blood pressure (Aim 1) and postpartum cardiac remodeling by echocardiography (Aim 2) at 9 months postpartum (i.e., 6 months after completion of study treatment).

Inclusion Criteria:

• Females aged ≥18 years
• HDP (gestational hypertension or preeclampsia) without pre-pregnancy chronic hypertension
• BMI ≥25 kg/m2 prior to pregnancy or in the first trimester
• Requirement for antihypertensive medication within one week of delivery
• Ability to provide informed consent

Exclusion Criteria:

• LV ejection fraction <50% or history of clinical heart failure with reduced or preserved ejection fraction
• Hypertrophic or other genetic cardiomyopathy
• Hyperkalemia: potassium >5.3 mEq/L
• BMI at screening ≥50 kg/m2
• Pre-pregnancy diabetes
• Estimated glomerular filtration rate (eGFR) <60mL/min/1.73 m2
• Cirrhosis
• Primary aldosteronism
• Intention to become pregnant within 9 months
• Active substance abuse
• Other serious medical illnesses or concerns about protocol adherence/ mortality within 9 months
• Participation in another interventional clinical study
• Hypersensitivity to spironolactone
• Addison's disease
• Concomitant use of eplerenone or finerenone