Using Metabolomics to Understand CVD Risk in Women with a History of Preterm Delivery

Project Summary/Abstract Background: Cardiovascular disease (CVD) is the leading cause of mortality in both women and men. Preterm delivery (PTD) occurs in 10% of US pregnancies and is associated with twice the risk of long-term CVD morbidity and mortality in mothers. Only 13-17% of the association between PTD and CVD is explained

by subsequent development of established cardiovascular risk factors such as hypertension, diabetes, hyperlipidemia and obesity. Our poor understanding of the physiologic pathways from PTD to CVD limits our ability to use PTD as an `early warning system' to better prevent and treat CVD in women. The goal of this

project is to expand our understanding of PTD and CVD through discovery and validation of metabolomic signatures and scores among women with a history of PTD, confirming their association with CVD events and performing mediation analysis. We will also examine the association of PTD clinical phenotypes with CVD.

Setting: We have assembled an exceptional team with deep expertise in CVD, pregnancy exposures, metabolomics, and biostatistics/ bioinformatics. Investigators on this project have decades of experience studying CVD, pregnancy complications, and metabolomic epidemiological studies. This application will

leverage U01-funded infrastructure and biosamples of the Nurses' Health Study (NHS) 2 and 3 cohorts, as well as CVD outcomes and previously measured metabolomic profiles in NHS1 and the Women's Health Initiative. Research Plan: We will measure metabolomic profiles in 1500 women, including 400 women with a history of

PTD, and 400 parous women with no preterm deliveries. Metabolomics will be performed at the Broad Institute. Using a robust methodology of discovery and validation, we will: 1) Discover and validate metabolomic profiles and PTD metabolite (M-PTD) scores for midlife women with a history of PTD (NHS2/3). PTD

phenotypes to be examined: a) Total PTD; b) Clinical PTD: Preterm prelabor rupture of membranes, spontaneous preterm labor with intact membranes, medically-indicated PTD; c) Timing of PTD: