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

描述(申请人提供)：足月妊娠低出生体重与成人疾病发展规划相关的不良结局风险增加，包括高血压、肥胖症、胰岛素抵抗、糖尿病和心血管疾病。肾上腺激素分泌失调，与皮质醇和肾上腺雄激素暴露增加有关，与这些和其他不良后果有关。极早产的婴儿出现类似不良结局的风险可能会增加，这既是因为他们在足月妊娠时的生长失败率非常高，在童年时期有可变的追赶生长，也因为作为新生儿，他们接触到的皮质醇浓度明显高于同等妊娠的胎儿。我们有独一无二的机会在6岁和7岁时研究肾上腺功能与心血管风险因素的关系，这项研究是由新生儿研究网络长期神经成像和神经发育结果研究中心(NNN)的一项辅助研究提供的，该研究利用了(1)大量极早产的儿童，具有广泛的围产期数据库；(2)NRN的基础设施和出色的跟踪记录；(3)已安排的身体、神经发育和行为检查。儿童时期心血管风险的临床标记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，比独立研究投资少得多，最大限度地发挥正在进行的研究的价值，确定不良后果的最高风险人群，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异常的人群，例如患有先天性心脏病的儿童。假设：(1)下丘脑-垂体-肾上腺轴调节失调导致皮质醇和肾上腺雄激素暴露增加，容易发生代谢综合征，在6�7岁时表现为血压升高、肥胖和肾上腺早熟；(2)这些指标将与妊娠和妊娠出生体重负相关，而与新生儿疾病严重程度和出生后生长轨迹正相关；(3)这些指标将与调节皮质类固醇表达的部位的DNA甲基化正相关。测量：(1)血压和人体测量学；(2)唾液皮质醇对压力的反应和每日分泌模式；(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DHEA浓度与(A)血压和肥胖指标的关系；(B)产前和出生后的生长模式；(C)DNA甲基化模式。时间很关键，因为第一批儿童已经进入了他们的后续窗口。RFA-HL-13-003的加速审查程序将允许纳入大约340名符合条件的儿童，如果这项申请在2013年7月1日之前获得资金的话。

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.