Preventing Inter-generational Transmission of Obesity and Cardiometabolic Risk

描述（由申请人提供）：有效的一级预防需要了解疾病风险的可改变的前因。肥胖、自主神经失调和HPA轴失调是心血管和代谢（心脏代谢）疾病的危险因素。其在所有年龄人口中的流行率都在上升，包括在幼儿中。汇聚的证据将心脏代谢风险的起源追溯到生命的宫内和出生后早期，支持健康和疾病的发育规划概念。母亲超重和过度的压力暴露正在成为影响后代发育的重要妊娠环境因素，并可能导致后来的疾病。以前的研究主要是横断面或回顾性和/或评估产前影响的有限系统。拟议的研究通过利用现有的产前干预控制试验来扩大这项研究，以减少孕产妇死亡率。 压力和体重过度增加，以检查宫内暴露对随后儿童心脏代谢风险的影响。我们建议随访168名女性的后代，从出生到4岁，对心脏代谢危险因素（肥胖、自主神经和HPA轴失调）及其发育轨迹进行纵向评估。我们将评估干预措施（目标1）以及产前压力和体重增加（目标2）的个体水平变化对新生儿和儿童结局的影响，这些结局可能是心血管疾病风险的早期驱动因素。评估的跨度使我们能够将产前影响与产后影响分开，并检查重要的发育轨迹;对其他暴露的评估将减少混淆，并提供有关途径和进一步干预目标的线索。产前干预的初步数据表明，它减少了母亲的压力和体重增加，我们的后代试点研究的数据为我们的假设提供了初步支持，显示母亲的压力和体重增加的改善预测后代肥胖和神经行为调节的改善指数。具体目标是：1）测试干预中母亲所生的后代在出生时和生命的前4年是否具有更有利的心脏代谢结果（较低水平：肥胖，自主神经失调和HPA轴失调），相对于对照组的后代。2)在168个母婴配对的完整样本中检查（对照治疗组）是否：a）出生时和出生后前4年的心脏代谢风险结果，在妊娠期间肥胖和/或压力较大的母亲的后代中更为不利。 B）体重和压力水平均较高的母亲所生后代的不良心脏代谢结果更高（协同效应）。动物模型为这种关联提供了支持，但这种对后代心脏代谢风险结果的相互作用尚未在人类研究中得到验证。

DESCRIPTION (provided by applicant): Effective primary prevention requires knowledge of modifiable antecedents of disease risk. Obesity, autonomic dysregulation, and HPA axis dysregulation are risk factors for cardiovascular and metabolic (cardiometabolic) disorders. Their prevalence in populations of all ages is increasing, including among young children. Converging evidence traces the origins of cardiometabolic risk back to the intrauterine and early postnatal period of life, supporting the concept of developmental programming of health and disease. Maternal excess weight and excess stress exposure are emerging as important gestational environment factors that affect offspring development and are plausible contributors to later disease. Previous research has been primarily cross-sectional or retrospective and/or has assessed limited systems for prenatal effects. The proposed research expands this research by capitalizing on an existing control trial of a prenatal intervention to reduce maternal stress and excessive weight gain during gestation to examine the effects of intrauterine exposures on subsequent child cardiometabolic risk. We propose to follow 168 offspring of women in the trial from birth until 4 years age, with longitudinal assessments of cardiometabolic risk factors (adiposity, autonomic and HPA axis dysregulation) and their developmental trajectories. We will evaluate the effects of the intervention (Aim 1), as well as the effects of individual-level variation in prenatal stress and weight gain (Aim 2), on newborn and child outcomes that are likely early drivers of cardiovascular disease risk. The span of assessments allows us to separate the effects of prenatal from postnatal influences and examine important developmental trajectories; and assessment of other exposures will reduce confounding and provide clues about pathways and further targets of intervention. Preliminary data from the prenatal intervention suggest it reduces stress and weight gain in mothers and data from our offspring pilot study provide initial support for our hypotheses, showing maternal improvements in stress and weight gain predicted improved indices of offspring adiposity and neurobehavioral regulation. The SPECIFIC AIMS are to: 1) Test whether offspring born to mothers in the intervention have more favorable cardiometabolic outcomes (lower levels of: adiposity, autonomic dysregulation, and HPA-axis dysregulation) at birth and over the first 4 years of life, relative to offspring in the control group. 2) Examine across the full sample of 168 mother-infant dyads (controlling for treatment group) whether: a) Cardiometabolic risk outcomes, at birth and over the first 4 years of life, are more adverse in offspring from mothers with greater adiposity and/or stress during pregnancy. b) Adverse cardiometabolic outcomes are heightened in offspring from mothers with higher levels of both weight and stress (synergistic effects). Animal models provide support for such associations, but this interactive effect on offspring cardiometabolic risk outcomes has not yet been tested in human studies.