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

描述（由申请人提供）：足月妊娠低出生体重与成人疾病（包括高血压、肥胖症、胰岛素抵抗、糖尿病和心血管疾病）发育规划相关的不良结果风险增加有关。肾上腺激素分泌失调，皮质醇和肾上腺雄激素暴露增加，与这些和其他不良后果有关。极早产儿可能会增加类似不良后果的风险，因为他们在足月妊娠时有很高的生长失败率，在儿童期有可变的追赶生长，因为新生儿暴露于显着更高的皮质醇浓度比同等妊娠的胎儿。 我们有一个独特的机会来研究肾上腺功能与6进行辅助研究，利用（1）大量极早产儿队列，具有广泛的前瞻性围产期数据库;（2）NRN的基础设施和出色的随访记录;（3）已经安排的身体、神经发育和行为检查。儿童期心血管风险的临床标志物已被证明与成人结局相关。我们可以在这项辅助研究中研究肾上腺功能与心血管危险因素的关系，其投资远低于独立研究，最大限度地发挥正在进行的研究的价值，确定不良结局风险最高的患者，并为未来的干预性研究指明方向。这项研究可能直接适用于其他围产期应激和生长改变的人群，如先天性心脏病儿童。 假设条件：（1）下丘脑-垂体-肾上腺轴的失调导致皮质醇和肾上腺雄激素的暴露增加，易患代谢综合征，在6 - 7岁时表现为血压升高、肥胖和肾上腺素早熟;（2）这些测量将与妊娠和妊娠的出生体重负相关，与新生儿疾病严重程度和出生后生长轨迹呈正相关;（3）这些指标与调节皮质类固醇表达位点的DNA甲基化呈正相关。测量值：（1）血压和人体测量学，（2）唾液皮质醇对应激的反应和昼夜分泌模式;（3）唾液脱氢表雄酮（DHEA）;（4）影响皮质类固醇调节的特定基因位点的唾液细胞DNA甲基化。分析：我们将分析皮质醇分泌模式和脱氢表雄酮浓度与（a）血压和肥胖指标;（B）产前和产后生长模式;（c）DNA甲基化模式的关系。时间很关键，因为第一批孩子已经进入了后续窗口期。RFA-HL-13-003的加速审查过程将允许纳入约340名合格儿童，如果该申请在2013年7月1日之前获得资助。

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.