Adrenal function and adverse CV outcomes at age 6 after extremely preterm birth

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DESCRIPTION (provided by applicant): Low birth weight at term gestation is associated with increased risk for adverse outcomes related to developmental programming of adult disease including hypertension, adiposity, insulin resistance, diabetes, and cardiovascular morbidities. Dysregulation of adrenal hormone secretion, with increased exposure to cortisol and adrenal androgens, has been linked to these and other adverse outcomes. Infants born extremely preterm may be at increased risk for similar adverse outcomes both because they have a very high rate of growth failure by term gestation, with variable catch-up growth during childhood, and because as newborns they are exposed to remarkably higher cortisol concentrations than are fetuses at an equivalent gestation. We have a unique opportunity to study the relationship of adrenal function to cardiovascular risk factors at age 6 ¿ 7 years with an ancillary study to the Neonatal Research Network (NRN) long-term ¿Neuroimaging and Neurodevelopmental Outcomes Study¿, taking advantage of (1) a large cohort of children born extremely preterm, with an extensive prospective perinatal database; (2) the NRN infrastructure and superb follow-up track record; (3) already scheduled physical, neurodevelopmental and behavioral examinations. Clinical markers of cardiovascular risk in childhood have been shown to correlate with adult outcomes. We can study the relationship of adrenal function to cardiovascular risk factors in this ancillary study with far less investment than for an independent study, maximizing the value of on-going research, identifying those at highest risk for adverse outcomes, and pointing the way for future interventional studies. This study may be directly applicable to other populations with perinatal stress and altered growth, such as children with congenital heart disease. Hypotheses: (1) dysregulation of the hypothalamic-pituitary-adrenal axis results in increased exposure to cortisol and adrenal androgens, predisposing to development of the metabolic syndrome, manifested at age 6 ¿ 7 as increased blood pressure, adiposity, and precocious adrenarche; (2) these measures will correlate inversely with gestation and birth weight for gestation, and positively with severity of neonatal illness and postnatal growth trajectory; (3) these measures will correlate positively with DNA methylation at sites regulating corticosteroid expression. Measurements: (1) blood pressure and anthropometrics, (2) salivary cortisol response to stress and diurnal secretion patterns; (3) salivary dehydroepiandrosterone (DHEA); (4) salivary cell DNA methylation at specific gene sites affecting corticosteroid regulation. Analyses: We will analyze the relationship of cortisol secretion patterns and DHEA concentrations to (a) blood pressure and adiposity measures; (b) prenatal and postnatal growth patterns; (c) DNA methylation patterns. Time is critical, as the first children have already entere their follow-up window. The accelerated review process of RFA-HL-13-003 will allow inclusion of approximately 340 eligible children if this application is funded by July1, 2013.