Clinical and Biochemical Features of Metabolic Dysregulation in Formerly Preterm Children

In the US, ~100,000 babies are born premature at <34 weeks gestational age (GA) each year, or ~2.7% of all live births. While infant preterm respiratory, pulmonary vascular, and systemic vascular diseases are common among those born preterm, many become asymptomatic in early childhood. Yet, emerging data point to subclinical abnormalities among adult survivors of preterm birth that may ultimately drive their increased rates of long-term cardiopulmonary complications including obstructive lung disease, pulmonary and systemic hypertension, and metabolic disease including diabetes, obesity and metabolic syndrome. Preterm-born young adults have systemic evidence of energy metabolism dysregulation, insulin insensitivity and oxidative stress. This application has four objectives: 1) Understand the cardiopulmonary phenotypic burden of disease among formerly preterm children (FPC) ages 5-12 years; 2) Evaluate for systemic evidence of metabolic dysregulation characterized by inflammation, oxidative stress, and insulin resistance in FPC; 3) Explore mechanisms by determining whether FPC have systemic molecular signatures of abnormal energy metabolism and inflammation; and, 4) Incorporate metrics of social determinants of health (SDOH), to understand how exposures interact with and modify the clinical condition as well as systemic and cellular features. There is a critical need to determine the burden of disease and mechanistic features during mid-childhood, when early interventions may change an otherwise predetermined lifespan trajectory toward chronic illness. We propose a strategy of dense clinical phenotyping paired with molecular studies and information about SDOH. We will leverage the clinical and research infrastructures built at our three centers over the past twenty or more years in the care and study of children born preterm. We hypothesize that school age FPC display systemic metabolic energy dysregulation, characterized by inflammation, oxidative stress, and insulin resistance, with associated cardiopulmonary abnormalities and suboptimal reactivity to stress challenge, and that these outcomes may be modified by social determinants of health (SDOH). Establishing a new human cohort of 100 FPC ages 5-12 years, matched by 50 formerly term healthy controls, we will pursue the following Aims: Aim 1: identify the clinical cardiopulmonary vascular features that characterize FPC; Aim 2: identify the biochemical markers in circulation that suggest metabolic dysregulation characterized by inflammation, oxidative stress, and insulin resistance; Aim 3: deeply explore mechanistic drivers by generating expression data from RNA Sequencing to determine the molecular variations that drive alterations in energy metabolism. In each Aim, we will integrate the phenotypic, biochemical, and molecular variations with socio-ecologic exposures. These studies will confirm the presence of cardiopulmonary irregularities among FPC in mid-childhood and connect these phenotypes with alterations in biochemical and expression markers, as well as SDOH, offering the foundation for future studies and a step toward personalizing care and surveillance guided by biologic data.