PRegnancy OuTcomEs and subclinical Cardiovascular disease sTudy: (PROTECT)

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ABSTRACT The goal of this proposal, PRegnancy OuTcomEs and subclinical Cardiovascular disease sTudy (PROTECT), is to understand the trajectory of risk factors and mechanisms linking interrelated adverse pregnancy outcomes (APOs) and subclinical cardiovascular disease (CVD). Hypertensive disorders of pregnancy, preterm delivery, and small for gestational age are common APOs, increasing in incidence, and currently complicate nearly 1 in 5 pregnancies in the United States. These APOs are associated with increased short- and long-term risk of CVD, which was the focus of a recent NHLBI Working Group. Despite phenotypic heterogeneity in the clinical manifestations of APO subtypes (hypertensive disorders of pregnancy, preterm delivery, and small for gestational age), these APOs are thought to be interrelated vascular disorders with shared underlying pathophysiology related to defective placental development. The processes leading to abnormal placentation begin long before APOs are clinically apparent, and women who later experience any of the APO subtypes (including and in addition to hypertensive disorders of pregnancy) are more likely (but not universally) to enter pregnancy with higher BP levels. Therefore, it is unclear whether APOs reflect latent CVD risk or are themselves independent risk factors for future CVD. Moreover, women who experience any of these APO subtypes have a higher risk of incident hypertension within 5 years post-pregnancy. However, development of hypertension and other traditional CVD risk factors following an APO may only partially explain the increased risk for later CVD. Preliminary data from small-scale biomarker studies suggest underlying mechanisms linking APOs and CVD may be related to inflammation and anti-angiogenesis. Therefore, in order to elucidate the pathways between APOs, and CVD, it is critical to begin with a woman’s first pregnancy and incorporate both intra-pregnancy risk factor levels (upstream of APOs) and longitudinal follow-up post-pregnancy (downstream of APOs). We propose to leverage the ongoing NHLBI-funded Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-To-Be Heart Health Study (nuMoM2b-HHS): a racially/ethnically and geographically diverse cohort recruited during the first pregnancy with rigorously adjudicated pregnancy outcomes, extensive exposure data, and longitudinal follow-up. We will perform carotid artery ultrasound to assess standard and novel imaging parameters to examine differences in women who have and have not experienced APOs. In Aim 1, we will quantify the strength and directionality of associations between APOs and subclinical CVD, independent of BP in early pregnancy. In Aim 2, we will determine the extent to which the relationship between APOs and subclinical CVD is mediated by post-pregnancy BP. In Aim 3, we will identify early pregnancy proteomic pathways that are associated with APOs and subclinical CVD. Completion of these aims will yield novel and significant insights into the trajectory and mechanisms of development of subclinical CVD, inform tailored CVD prevention strategies, and advance discovery of new therapeutic targets for women following APOs.