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

极早产后 6 岁时的肾上腺功能和不良心血管结局

• 批准号: 9102166
• 负责人: KRISTI L. WATTERBERG
• 金额: $ 38.85万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-17 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9102166
• 关键词: 6 year old; Accelerated Executive Review; Adrenal Cortex Hormones; Adrenal Glands; Adrenal hormone preparation; Adult; Affect; Age; Ancillary Study; Androgens; Behavioral; Birth; Birth Weight; Blood Pressure; Body fat; Cardiovascular system; Cells; Child; Childhood; Circadian Rhythms; Clinic Visits; Clinical; Clinical Markers; DNA Methylation; Data; Databases; Development; Diabetes Mellitus; Disease; Exposure to; Failure; Fetus; Funding; Future; Genes; Gestational Age; Glucocorticoid Receptor; Growth; Heart Diseases; Home environment; Hormones; Hydrocortisone; Hypertension; Individual; Infant; Insulin Resistance; Intervention; Investigation; Investments; Link; Low Birth Weight Infant; Measurement; Measures; Metabolic; Metabolic syndrome; Morbidity - disease rate; Multicenter Neonatal Research Network; National Heart, Lung, and Blood Institute; National Institute of Child Health and Human Development; Neonatal; Network Infrastructure; Newborn Infant; Obesity; Outcome; Outcome Study; Pattern; Perinatal; Physical Examination; Population; Pregnancy; Premature Birth; Process; Randomized; Regulation; Research; Risk; Salivary; Schedule; School-Age Population; Severities; Site; Stress; Structure; Testing; Time; adverse outcome; cardiovascular risk factor; cohort; congenital heart disorder; dehydroepiandrosterone; design; early childhood; experience; follow-up; high risk; hypothalamic-pituitary-adrenal axis; methylation pattern; neuroimaging; obesity risk; postnatal; prenatal; programs; promoter; prospective; public health relevance; respiratory; response; salivary cell; trial comparing

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.

描述（由申请人提供）：足月妊娠时的低出生体重与成人疾病发育规划相关的不良结果风险增加相关，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，随着皮质醇和肾上腺雄激素暴露的增加，与这些和其他不良后果有关。极度早产的婴儿出现类似不良后果的风险可能会增加，这不仅是因为他们在足月妊娠时生长失败率非常高，并且在儿童时期的追赶性生长存在差异，而且因为作为新生儿，他们接触到的皮质醇浓度比同等妊娠的胎儿要高得多。 我们有一个独特的机会，通过对新生儿研究网络 (NRN) 长期“神经影像和神经发育结果研究”的一项辅助研究，研究 6 至 7 岁时肾上腺功能与心血管危险因素的关系，利用 (1) 一大群极早产儿，并拥有广泛的前瞻性围产期数据库； (2) NRN 基础设施和出色的后续跟踪记录； (3) 已安排的身体、神经发育和行为检查。儿童心血管风险的临床标志物已被证明与成人结局相关。在这项辅助研究中，我们可以用比独立研究少得多的投资来研究肾上腺功能与心血管危险因素的关系，从而最大限度地提高正在进行的研究的价值，识别出不良结果风险最高的人群，并为未来的干预研究指明道路。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，例如患有先天性心脏病的儿童。 假设：（1）下丘脑-垂体-肾上腺轴失调导致皮质醇和肾上腺雄激素暴露增加，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) 这些措施与妊娠和妊娠出生体重呈负相关，与新生儿疾病的严重程度和产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）唾液皮质醇对压力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 DHEA 浓度与 (a) 血压和肥胖指标的关系； (b) 产前和产后生长模式； (c) DNA 甲基化模式。时间至关重要，因为第一批孩子已经进入后续窗口。如果该申请在 2013 年 7 月 1 日之前获得资助，RFA-HL-13-003 的加速审查流程将允许纳入约 340 名符合条件的儿童。