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

基本信息

批准号：
8703176
负责人：
KRISTI L. WATTERBERG
金额：
$ 37.47万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-17 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8703176
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 National Heart, Lung, and Blood Institute National Institute of Child Health and Human Development Neonatal Newborn Infant Obesity Outcome Outcome Study Pattern Perinatal Physical Examination Population Pregnancy Premature Birth Process Randomized Regulation Research Research Infrastructure 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 neuroimaging obesity risk postnatal prenatal programs promoter prospective public health relevance respiratory response salivary cell trial comparing

项目摘要

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后果风险增加相关，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。暴露于皮质醇和肾上腺雄激素，与这些和其他不良后果有关，极端早产的婴儿可能面临类似不良后果的风险增加，因为他们足月生长失败的比率非常高。妊娠期的追赶性生长存在差异，而且新生儿时期的皮质醇浓度比同等妊娠期的胎儿高得多，因此我们有一个独特的机会来研究 6 岁时肾上腺功能与心血管危险因素的关系。 ¿ 7 年新生儿研究网络 (NRN) 长期辅助研究 ¿神经影像和神经发育结果研究¿ ，利用 (1) 大量早产儿，拥有广泛的前瞻性围产期数据库；(2) NRN 基础设施和出色的随访记录；(3) 已安排的身体、神经发育和行为临床检查。儿童心血管风险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风险因素的关系，其投资远少于独立研究，从而最大限度地提高正在进行的研究的价值。识别那些在不良结果的风险最高，并为未来的干预研究指明了道路，该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-垂体失调。 -肾上腺轴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生，在 6 岁时表现出来 ¿ 7 血压升高、肥胖和性早熟；(2) 这些指标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出生后生长轨迹呈正相关；(3) 这些指标与 DNA 呈正相关；调节皮质类固醇表达的位点的甲基化：（1）血压和人体测量学，（2）唾液皮质醇对压力和昼夜分泌模式的反应；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：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； (c) DNA 甲基化模式。时间至关重要，因为第一批儿童已经进入了加速审查过程。如果该申请在 2013 年 7 月 1 日之前获得资助，RFA-HL-13-003 将允许纳入大约 340 名符合条件的儿童。