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，但仍有13-30%的婴儿出生时暴露在吸烟环境中。鉴于持续的高暴露率和与昂贵的后代结局的联系，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。这项研究提供了一种模式转变，通过二维和三维胎儿超声来识别母亲吸烟的实时、产前神经行为和神经标志物。具体来说，我们验证了以下建议：a)母亲吸烟会影响胎儿在怀孕期间的神经行为、应激反应、神经和神经内分泌结构的轨迹；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的神经行为缺陷。利用我们小组首创的方法（二维超声结合胎儿心电图），我们的初步工作揭示了母亲吸烟对妊娠晚期胎儿神经行为缺陷和应激反应改变的影响。然而，导致妊娠晚期缺陷的胎儿发育轨迹尚不清楚。此外，尽管结构性脑缺陷被认为是母亲吸烟和后代神经行为缺陷之间联系的关键候选机制，但没有研究整合了母亲吸烟风险的神经和行为标记。3D超声的出现提供了更高分辨率的胎儿图像，允许特定胎儿大脑和神经内分泌结构的体积表征。我们小组开创性的初步工作证明了3D评估的可行性，并揭示了暴露于母亲吸烟的胎儿的额小脑结构体积减少。这项提议的研究是对孕妇吸烟风险的超声标记进行深入调查。我们的研究包括对吸烟者和怀孕控制者的前瞻性调查。将使用最高安全标准完成三项胎儿超声评估，观察胎儿行为、对轻度应激（振动声刺激）的反应，以及胎儿神经（额小脑区）和神经内分泌（肾上腺）结构的3D体积评估，随后进行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；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轨迹和风险神经标记预测婴儿神经行为缺陷和应激反应的建议。研究结果提供了以下方面的潜力：a)促进发现怀孕期间母亲吸烟的实时机制；b)发现新的产前风险标记，可以改善对怀孕吸烟者和其他高危妊娠的临床护理；c)确定新的治疗靶点，以保护暴露的胎儿；d)为怀孕吸烟者的干预工作提供新的重点。

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.