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

描述（由申请人提供）：妊娠期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相关，包括高血压、肥胖、胰岛素抵抗、糖尿病和心血管疾病。肾上腺激素分泌失调，暴露于皮质醇和肾上腺雄激素增加，与这些和其他不良后果有关。极度早产的婴儿可能有更高的风险出现类似的不良后果，因为他们在妊娠期有很高的生长失败率，在儿童时期有可变的追赶生长，因为作为新生儿，他们暴露在明显高于同等妊娠期胎儿的皮质醇浓度。我们有一个独特的机会，通过新生儿研究网络（NRN）长期“神经影像学和神经发育结局研究”的辅助研究，研究6 ~ 7岁时肾上腺功能与心血管危险因素的关系，利用：(1)大量早产儿队列，具有广泛的前瞻性围产期数据库；(2) NRN基础设施和良好的后续跟踪记录；(3)已安排体格、神经发育和行为检查。儿童时期心血管风险的临床指标已被证明与成人预后相关。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，而投入远远少于独立研究，最大限度地提高正在进行的研究的价值，识别出不良后果风险最高的人群，并为未来的介入研究指明方向。这项研究可能直接适用于其他有围产期压力和生长改变的人群，如先天性心脏病儿童。假设：(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，易导致代谢综合征的发展，在6 ~ 7岁时表现为血压升高、肥胖和肾上腺素早熟；(2)这些指标与妊娠和妊娠期出生体重呈负相关，与新生儿疾病严重程度和出生后生长轨迹呈正相关；(3)这些措施将与调节皮质类固醇表达位点的DNA甲基化呈正相关。测量：(1)血压和人体测量；(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)唾液细胞特定基因位点DNA甲基化影响皮质类固醇调控。分析：我们将分析皮质醇分泌模式和脱氢表雄酮浓度与(a)血压和肥胖措施的关系；(b)产前和产后生长模式；(c) DNA甲基化模式。时间至关重要，因为第一批儿童已经进入随访窗口。RFA-HL-13-003的加速审查过程将允许大约340名符合条件的儿童参与，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.