NHLBI Workshop
Bridging Preeclampsia and Future Cardiovascular Disease

Executive Summary

A two-day Workshop was convened on September 16th and 17th, 2010 in Rockville, MD to provide recommendations to the National Heart, Lung and Blood Institute (NHLBI) regarding pregnancy complications, specifically preeclampsia, and future maternal cardiovascular risk. The purpose of the Workshop was to bring together experts in the field to examine the associations between preeclampsia and future cardiovascular disease across different domains, including basic science and clinical practice, with a goal of identifying knowledge gaps and research opportunities that could facilitate the prevention of cardiovascular disease outcomes long-term. The Workshop consisted of experts in preventive cardiology, maternal-fetal medicine, nephrology, epidemiology, and biostatistics.

Background

Preeclampsia affects between approximately six and eight percent of pregnancies in the United States and is associated with significant maternal and fetal morbidity. The relationship of preeclampsia to future cardiovascular disease has been well-established. Women who develop preeclampsia during pregnancy are four times more likely to develop hypertension later in life, and are twice as likely to develop heart disease, stroke, and blood clots in the future. The development of preeclampsia is one of the earliest clinically-identifiable markers of a woman’s heightened risk of cardiovascular disease. However, it is unknown whether the increased risk of future cardiovascular disease can be attributed to factors that develop during pregnancy or to pre-pregnancy factors that are also associated with the risk of developing preeclampsia and cardiovascular disease.

Recommendations

The following recommendations were made to NHLBI by the members of the Workshop. The recommendations are included below in their order of prioritization based on a balance between feasibility/burden and clinical impact/return.

• Utilize already established cohort studies
  It was suggested that studies/trials with a well-defined diagnosis of preeclampsia be utilized to follow patients prospectively for cardiovascular outcomes and to determine when disease progression occurs. It was noted that the Combined Antioxidant and Preeclampsia Prediction Studies (CAPPS) would meet this criterion. Another recommendation is to utilize studies with cardiovascular disease endpoints, such as the Coronary Artery Risk Development in Young Adults (CARDIA) study, and retrospectively seek a diagnosis of preeclampsia. It was also suggested that studies/trials with stored biological samples should be utilized to determine the “natural history” of cardiovascular disease risk following complicated pregnancies. It was felt that rigorous confirmation of the diagnosis of preeclampsia, and its sub-classifications, is essential in any clinical study, and that this may not be possible in retrospective studies that rely on non-validated databases, diagnostic codes, or patient report.
  
  
• Utilize pregnancy cohorts from study start-up 
  Pregnancy cohorts provide a unique opportunity for NHLBI to follow women prospectively for cardiovascular outcomes and to determine the optimal age to intervene. The Eunice Kennedy Shriver National Institute of Child Health and Human Development’s Nulliparous Pregnancy Outcomes Study:  Monitoring Mothers-to-Be (nuMoM2b) is a prospective cohort study of a racially, ethnically, and geographically diverse population of 10,000 nulliparous women with singleton gestations. The women will undergo intensive research assessments during the course of their pregnancies to study the mechanisms for and prediction of adverse pregnancy outcomes (APOs) in their first pregnancy. The following APOs are the focus of this investigation:  preterm birth, preeclampsia and fetal growth restriction. It was recommended that NHLBI utilize the nuMoM2b cohort to obtain maternal cardiovascular outcomes, beginning from study start-up through the length of the parent study and beyond.
  
  
• Preclinical Studies
  Utilize animal models with overlapping dysfunctions to determine the extent to which preeclampsia is merely a ‘stress test’ that uncovers predisposing risk factors for cardiovascular disease or actually causes direct cardiovascular injury. This may be accomplished by inducing a preeclampsia-like condition in animals with and without pre-pregnancy risk factors, such as hyperlipidemia, obesity, or nitric oxide deficiency. Vascular function can then be followed in the dams after delivery, in order to determine the time-course of the dysfunction and investigate potential mechanisms.
  
  
• Preeclampsia “clinometric”
  Develop a pregnancy history “clinometric” that could be added to currently available cardiovascular disease risk scoring systems to identify women at high-risk for cardiovascular disease and who subsequently need to be followed more aggressively. Low birth weight, pre-term birth, delivery of a small for gestational age infant, recurrent miscarriage, and preeclampsia are all associated with future cardiovascular disease. Including a brief pregnancy history “clinometric” and obtaining birth weight in all future NHLBI-supported studies, as applicable, would help determine whether the “clinometric” does or does not make a difference in identifying individuals at higher risk of cardiovascular disease. 
  
  
• Longitudinal studies with intensive cardiovascular disease risk  
  Launch longitudinal studies with intensive cardiovascular disease risk assessment at various intervals following complicated pregnancies, including pre-term births, intrauterine growth restriction, and gestational diabetes. Longer follow-up (i.e., 8, 10, 15 years postpartum) will be needed to determine the timeline when cardiovascular risk emerges. These studies can also identify mechanisms that may be responsible for the increased risk of cardiovascular disease in order to guide future preventive strategies.
  
  
• Independent contribution of pregnancy history to cardiovascular disease risk
  Determine the independent contribution of pregnancy history to risk prediction, above and beyond already measured ‘traditional’ cardiovascular disease risk factors such as hypertension and lipids. Ideally, this would be achieved by assessing cardiovascular risk factors before, during and after pregnancy and following women long-term to definitely resolve this issue. 
  
  
• Effect of preeclampsia management on long-term cardiovascular function
  It was noted that delaying delivery in preeclampsia, or certain complications that may occur in preeclamptic patients, such as renal failure and cardiomyopathy, may lead to long-term cardiovascular dysfunction. Clinical studies evaluating various management strategies should take into consideration the long-term effects of such strategies.
  
  
• Targeted Campaigns
  Cardiovascular disease campaigns and education awareness programs must emphasize that women who developed preeclampsia are at a higher risk for high blood pressure, cardiovascular disease, and stroke later in life and consequently need to be more closely monitored for cardiovascular disease than women with normotensive pregnancies.  These campaigns may need to await development of evidence-based strategies for follow-up and management.

Publication Plans

A summary of the workshop proceedings and recommendations will be published in a peer-reviewed scientific journal.

Sponsors

• National Heart, Lung and Blood Institute
• Eunice Kennedy Shriver National Institute of Child Health and Human Development
• American College of Obstetricians and Gynecologists
• Society for Maternal-Fetal Medicine

NHLBI Contacts

Megan Mitchell, MPH
Division of Cardiovascular Sciences
mitchellm3@nhlbi.nih.gov

Eser Tolunay, PhD
Division of Cardiovascular Sciences
tolunaye@nhlbi.nih.gov

Workshop Members

Chair

• George Saade, MD

Members

• Sean Blackwell, MD, University of Texas Health Science Center at Houston
• Irina Buhimschi, MD, Yale University School of Medicine
• S. Ananth Karumanchi, MD, Beth Israel Deaconess Medical Center and Harvard Medical School
• Judette Louis, MD, MPH, Case Western Reserve University School of Medicine
• Tanya E. Melnik, MD, University of Minnesota Twin Cities
• C. Noel Bairey Merz, MD, FACC, FAHA, Cedars-Sinai Medical Center
• Michael J. Paidas, MD, Yale University School of Medicine
• Janet Rich-Edwards, ScD, MPH, Harvard Medical School and Brigham and Women's Hospital
• James M. Roberts, MD, Magee-Women’s Research Institute
• Baha Sibai, MD, University of Cincinnati College of Medicine
• Gordon C. S. Smith, MD, PhD, Cambridge University
• Graeme N. Smith, MD, PhD, Queen’s University
• Elizabeth Thom, MSc, MA, PhD, George Washington University Biostatistics Center
• Melissa Wilson, PhD, MPH , USC Keck School of Medicine

NICHD Representatives

• John Ilekis, PhD
• Uma Reddy, MD, MPH
• Caroline Signore, MD, MPH
• Catherine Spong, MD

Society for Maternal-Fetal Medicine Representative

• George Saade, MD

American College of Obstetricians and Gynecologists Representatives

• Sean Blackwell, MD
• Baha Sibai, MD

Last Updated: November 2010