NHLBI Workshop Predicting, Preventing and Treating Preeclampsia - Executive Summary

Background:

Preeclampsia is a pregnancy-specific, multisystemic disorder that occurs in roughly 5% of pregnancies in the United States. The rates of preeclampsia in the United States have been steadily rising over the past 30 years. But even more importantly, women with preeclampsia, as well as their offspring, are at greater risk for chronic disease, including heart disease later in life. Despite being the leading cause of maternal death and major contributor to maternal and perinatal morbidity, there is no effective drug treatment to prevent preeclampsia, and current management therapies have significant limitations. In fact, at present, delivery is considered the only effective intervention toward treating preeclampsia. The lack of progress in identifying new therapeutic targets for the treatment of preeclampsia is due in part to a paucity of animal models that address the heterogeneity of human preeclampsia as well as lack of understanding of basic mechanisms. Developing novel animal models to mimic human preeclampsia, developing biomarkers to predict preeclampsia, conducting basic studies to better understand disease mechanisms, and ultimately, developing novel therapeutic strategies are clearly needed.

Workshop Discussion:     

The workshop brought together 16 invited experts in the field who discussed the gaps and barriers related to the prediction, prevention, and treatment of preeclampsia. Specific topics discussed on the first day of the workshop were: i) pathophysiology of preeclampsia; ii) immunological origins of preeclampsia; iii) how to define subsets of preeclampsia; iv) biomarkers; v) genetics and epigenetics; vi) animal models; vii) collaboration, harmonization, sharing large data and sample sets in the study of preeclampsia; viii) periconceptional contributors to pathophysiology; ix) clinical risk factors for preeclampsia; x) novel therapies for the prevention and treatment of preeclampsia; xi) long-term cardiovascular consequences of preeclampsia and xii) patient perspectives.

The second day of the workshop all attendees participated in one of four breakout sessions:

1. Pathophysiology of preeclampsia
2. Impact of preeclampsia on long-term health outcomes
3. Biomarkers and diagnostic tools
4. Translational research and novel treatment strategies.

Working Group Recommendations:

The following are the main recommendations that arose from group discussions during the breakout sessions:

Pathophysiology of preeclampsia

1. Elucidate heterogeneity of mechanisms/pathobiology resulting in preeclampsia and related maternal and neonatal outcomes.
2. Understand normal pregnancy physiology and early pathobiology predisposing to preeclampsia, including preconception and very early pregnancy.
3. Determine biological and environmental mechanisms of resilience, e.g., presence of pathobiology that does not result in preeclampsia outcome.
4. Use dyad research to identify past and future risk coupled to preeclampsia.
5. Identify exposures contributing to the preeclampsia pathobiology.

Impact of preeclampsia on long-term health outcomes

1. Characterize the short-term trajectory with surrogate/intermediate endpoints through observational study.
2. Leverage existing cohorts to calculate a risk score for younger women that incorporates preeclampsia and other granular data as risk factors. In addition, utilize these cohorts to assess consequences in offspring including risk for cardiovascular disease (CVD).
3. Investigate mechanisms (in both animals and humans) that underlie the progression to CVD following preeclampsia, especially mechanisms in short and long-term outcomes including -omics.
4. Test whether new models of care that incorporate patient/provider awareness, education, and coordination lead to better outcomes.
5. Examine whether aggressive management of CVD risk factors in post-partum women leads to better CVD outcomes. Outcomes could be surrogate and intermediate.

Biomarkers and diagnostic tools

1. Collect adequate data to capture the spectrum of heterogeneity, since a strict case definition of preeclampsia is currently problematic.
2. Balance discovery science vs. clinical trial.
3. Define minimal/optimal data sets for phenotype/genotype correlation.
4. Standardize data/sample collection and harmonization prospectively from preconception, through pregnancy, postpartum, and interpregnancy.
5. Use bioinformatic tools/innovative statistical methods to combine and utilize existing data sets.
6. Leverage existing data/biospecimens/biomarkers from NIH-funded studies.
7. Apply new technologies to address basic questions.
8. Establish a hierarchical discovery approach: genome (Whole Genome Sequence), transcriptome, proteome, metabolome longitudinally in combination with clinical data.
9. Explore -omics and all relevant cell types.
10. Utilize innovative methods for data collection and analysis (crowdsourcing).

Translational research and novel treatment strategies

1. Establish a Framingham-like cohort for pre-pregnancy and pregnancy, following women and offspring, and families with gestational age-specific biosamples
   • Create an inventory of these cohorts to first understand what exists.
   • Then expand towards having standard biosample and clinical data protocols.
2. Increase access to data and biosamples, particularly longitudinal data. 
3. Invest in research to improve animal models for preeclampsia that mimic human preeclampsia.
4. Include pregnancy in NIH initiatives such as the Accelerating Medicines Partnership and All of Us.
5. Increase access to infrastructure for novel therapeutic development to market. Therapeutic development during pregnancy is often avoided by pharma, so this area will need government support or measures to entice pharma to this area.  
6. Support a workshop that includes FDA, with the goal of accelerating testing of therapeutics for preeclampsia.
7. Test post-partum interventions to prevent future cardiovascular outcomes in women with prior preeclampsia. 

Publication Plans:

A white paper outlining the recommendations that arose from the deliberations of the workshop is in preparation.

NHLBI and NICHD Workshop Organizers:

NHLBI

• Christine Maric-Bilkan, PhD, Division of Cardiovascular Sciences (DCVS)/Vascular Biology and Hypertension Branch
• Victoria Pemberton, RNC, MS, CCRC, DCVS/Heart Development and Structural Diseases Branch
• S. Sonia Arteaga, PhD, DCVS/ Clinical Applications and Prevention Branch
• Aaron Laposky, PhD, Division of Lung Diseases/National Center for Sleep Disorders Research
• Megan Mitchell, MPH, Division of Extramural Research Activities/Office of Extramural Policy and Training

NICHD

• John Ilekis, PhD, Pregnancy and Perinatology Branch
• Menachem Miodovnik, MD, Pregnancy and Perinatology Branch
• Uma Reddy, MD, MPH, Pregnancy and Perinatology Branch

Workshop Members:

Chairs:

• James Roberts, MD, Magee-Women’s Research Institute
• Leslie Myatt, PhD, Oregon Health and Science University

Members:

• Vikki Abrahams, PhD, Yale Univ. School of Medicine
• Ghada Bourjeily, MD, Brown University
• Kirk Conrad, MD, University of Florida College of Medicine
• Janet Catov, PhD, University of Pittsburgh
• Maged Costantine, MD, Univ. of Texas Medical Branch at Galveston
• Brian Cox, PhD, University of Toronto
• Vesna Garovic, MD, PhD, Mayo Clinic
• Eric George, PhD, University of Mississippi Medical Center
• Alison Gernand, PhD, MPH, RN, Pennsylvania State University
• Arun Jeyabalan, MD, MSCR, University of Pittsburgh
• S. Ananth Karumanchi, MD, Cedars-Sinai Medical Center
• Mark Santillan, MD, University of Iowa
• Kent Thornburg, PhD, Oregon Health and Science University
• Kenneth Ward, PhD, Tauret Laboratories