Fetal Behavior, Brain & Stress Response: Ultrasound Markers of Maternal Smoking

描述(由申请人提供)：孕妇在怀孕期间吸烟与婴儿的发病率和死亡率以及婴儿和较大儿童的行为缺陷有关。尽管普遍禁止怀孕期间吸烟，但13%-30%的婴儿出生时就暴露在空气中。鉴于持续的高接触率以及与代价高昂的后代后果的联系，需要新的方法来识别和保护高风险后代，并帮助怀孕的吸烟者戒烟。这项拟议的研究在使用二维和三维胎儿超声识别母亲吸烟风险的实时、产前神经行为和神经标记物方面提供了一种范式转变。具体地说，我们测试了以下建议：a)母亲吸烟将影响怀孕期间胎儿神经行为、应激反应以及神经和神经内分泌结构的轨迹，以及b)胎儿神经行为、应激反应和神经结构的丰富特征轨迹将预测婴儿神经行为缺陷。使用我们小组首创的方法(2D超声结合胎儿心动图)，我们的初步工作揭示了母亲吸烟对胎儿神经行为缺陷的影响，并在妊娠晚期改变了应激反应。然而，导致晚期妊娠缺陷的胎儿发育轨迹尚不清楚。此外，尽管结构性大脑缺陷被认为是母亲吸烟和子女神经行为缺陷之间潜在联系的关键候选机制，但还没有研究整合母亲吸烟风险的神经和行为标记物。三维超声的出现提供了更高分辨率的胎儿图像，允许对特定的胎儿大脑和神经内分泌结构进行体积表征。我们小组的开创性初步工作证明了3D评估的可行性，并揭示了暴露于母亲吸烟的胎儿额小脑结构的体积减少。这项拟议的研究是对母亲吸烟风险的超声标志物的深入调查。我们的研究包括对吸烟者的前瞻性调查和怀孕期间的控制。将使用最高安全标准完成三项胎儿超声评估，以观察胎儿行为、对轻度应激的反应(振声刺激)和胎儿神经(额小脑区域)和神经内分泌(肾上腺)结构的3D体积评估，随后将完成两项婴儿神经行为和皮质醇反应性评估。我们的目标是确定母亲吸烟对以下方面的影响：1)胎儿神经行为缺陷的轨迹，2)胎儿应激反应的改变，以及3)怀孕期间神经和神经内分泌结构的体积减少。然后，我们将测试胎儿神经行为和神经风险标记物的轨迹预测婴儿神经行为缺陷和应激反应的提议。结果提供了潜在的：a)促进在怀孕期间实时发现母亲吸烟的机制，b)确定新的产前风险标记，可以改善对怀孕吸烟者和其他高危妊娠的临床护理，c)确定新的治疗目标以保护暴露的胎儿，以及d)开发新的针对怀孕吸烟者的干预努力的焦点。

DESCRIPTION (provided by applicant): Maternal smoking during pregnancy is associated with morbidity and mortality in infants and behavioral deficits in infants and older children. Despite pervasive sanctions against smoking during pregnancy, 13-30% of infants are born exposed. Given continued high exposure rates and links to costly offspring outcomes, novel approaches are needed to identify and protect high risk offspring and help pregnant smokers quit. The proposed study offers a paradigm shift in identifying real-time, pre-birth neurobehavioral and neural markers of risk from maternal smoking using 2 and 3-dimensional fetal ultrasound. Specifically, we test the proposal that: a) maternal smoking will influence trajectories of fetal neurobehavior, stress response, and neural and neuroendocrine structures over pregnancy, and b) richly characterized trajectories of fetal neurobehavior, stress response, and neural structures will predict infant neurobehavioral deficits. Using an approach pioneered by our group (2D ultrasound combined with fetal actocardiography), our preliminary work revealed effects of maternal smoking on fetal neurobehavioral deficits and altered stress response during third trimester. However, fetal developmental trajectories leading to third trimester deficits are not known. Further, although structural brain deficits have been proposed as a key candidate mechanism underlying links between maternal smoking and offspring neurobehavioral deficits, no studies have integrated neural and behavioral markers of risk from maternal smoking. The advent of 3D ultrasonography offers higher resolution fetal images, allowing volumetric characterization of specific fetal brain and neuroendocrine structures. Seminal preliminary work from our group demonstrated feasibility of 3D assessment and revealed volume decrements in fronto-cerebellar brain structures in fetuses exposed to maternal smoking. The proposed study is an intensive investigation of ultrasound markers of risk from maternal smoking. Our study involves prospective investigation of smokers and controls over pregnancy. Three fetal ultrasound assessments will be completed using highest safety standards to observe fetal behavior, response to mild stress (vibro-acoustic stimulus), and 3D volumetric assessment of fetal neural (fronto-cerebellar regions) and neuroendocrine (adrenal gland) structures, followed by two infant neurobehavior and cortisol reactivity assessments. Our goals are to determine effects of maternal smoking on: 1) trajectories of fetal neurobehavioral deficits, 2) alterations in fetal stress response, and 3) volume decrements in neural and neuroendocrine structures over pregnancy. We will then test the proposal that trajectories of fetal neuro-behavioral and neural markers of risk predict infant neurobehavioral deficits and stress response. Results offer potential for: a) promoting discovery of mechanisms of maternal smoking in real- time during pregnancy, b) identifying new pre-birth markers of risk that could improve clinical care for pregnant smokers and other high-risk pregnancies, c) identifying novel therapeutic targets to protect exposed fetuses, and d) developing new foci for intervention efforts with pregnant smokers.