The Opioid in Pregnancy: Imaging of Oxygenation, Inflammation, and Development in Brain & Placenta Project (OPIOID BPP)

怀孕期间的阿片类药物：氧合、炎症和大脑发育的成像

• 批准号: 10750770
• 负责人: Jeannie Chen Kelly
• 金额: $ 233.77万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750770
• 关键词: Adverse effects; Affect; Anatomy; Basal Ganglia; Birth; Birth Weight; Blood; Brain; Brain region; Chronic; Clinic; Country; Data; Development; Diffusion; Diffusion Magnetic Resonance Imaging; Etiology; Fetus; Gestational Age; Helping to End Addiction Long-term; Human; Hypoxia; Image; Imaging Techniques; Imaging technology; Immune response; Impairment; Infant; Inflammation; Inflammatory Response; Injury; Lesion; MRI Scans; Magnetic Resonance Imaging; Magnetism; Maternal Age; Modeling; Morbidity - disease rate; Motor; Mus; Neonatal Abstinence Syndrome; Opioid; Outcome; Pathologic; Pathology; Pathway interactions; Patient Recruitments; Patients; Placenta; Pregnancy; Pregnancy Tests; Prevalence; Publishing; Race; Rattus; Recovery; Resolution; Socioeconomic Status; Structure; Subgroup; T2 weighted imaging; Testing; Text; Umbilical Cord Blood; Villous; Work; adverse outcome; anatomic imaging; biomarker identification; brain magnetic resonance imaging; brain volume; cerebral oxygenation; chorionic plate; cohort; congenital heart disorder; early pregnancy; empowerment; fetal; fetal opioid exposure; immune imaging; innovation; maternal opioid use; neonatal outcome; nerve injury; neurodevelopment; offspring; opioid exposure; opioid use disorder; opioid use in pregnancy; prenatal disorder; recruit; serial imaging; sex; therapeutic target; white matter

Abstract Maternal opioid use disorder (OUD) is rapidly increasing in prevalence, and is associated with severe morbidities in offspring, such as neonatal opioid withdrawal syndrome (NOWS), brain dysmaturation, and impaired neurodevelopment (ND). However, little is known regarding the mechanisms by which maternal OUD causes these outcomes, so our ability to mitigate the impact of prenatal opioid exposure (POE) on outcomes is poor. Here, we propose to test the central hypothesis that POE causes abnormal neurodevelopment through direct actions on the fetal brain. Additionally, we propose that POE causes abnormal neurodevelopment via moderation effects from the placenta through mechanisms of hypoxia and inflammation. Strikingly, our preliminary results from the placental pathology of 17 POE pregnancies confirm hypoxic lesions in every patient. Furthermore, our preliminary work using placental immune imaging (PII), an advanced diffusion magnetic resonance imaging (dMRI) technology, confirmed elevated placental inflammation and decreased oxygenation, both near the chorionic plate in a POE 36-week pregnancy compared to unexposed controls. Placental hypoxia and inflammation are two known etiologies that cause fetal WM injury and brain dysmaturation, and our own data show that fetuses with impaired cerebral oxygenation have the greatest reductions in brain volume and WM alterations. Importantly, we have demonstrated that fetal brain volume most consistently predicted 2-year ND (n=78, r=0.32-0.47; all p<0.05) across all domains. To test our hypothesis, we leverage the Clinic for Acceptance, Recovery, and Empowerment, one of the few wrap-around OUD prenatal clinics in the country, and our ongoing work on the Human Placenta Project (R01HD094381-04) with longitudinal imaging of placental inflammation from unexposed patients, as a respose to the HEAL Initiative: Opioid Exposure and Effects on Placenta Function, Brain Development, and Neurodevelopmental Outcomes (RFA-HD-23-030). We propose this R01 to define the longitudinal effects of POE on placental inflammation and oxygenation (Aim 1), fetal brain development and oxygenation (Aim 2), and the relationship between placental and fetal brain development markers with NOWS and early ND outcomes in infants with POE (Aim 3). Completion of these aims will explore and refine an innovative fetal pathway by which POE leads to adverse outcomes, and identify markers of immune response and oxygenation status in placenta and fetal brain that predict NOWS and ND. In the long term, this work will allow us to identify therapeutic targets to mitigate the adverse effects of maternal OUD on offspring.

抽象的 母体阿片类药物使用障碍（OUD）的患病率正在迅速增加，并且与严重的病态有关 在后代，例如新生儿阿片类药物戒断综合征（Nows），大脑不饱和和受损 神经发育（ND）。但是，关于母体造成的机制知之甚少 这些结果，因此我们减轻产前阿片类药物暴露（POE）对结果的影响的能力很差。 在这里，我们建议测试POE引起异常神经发育的中心假设 通过对胎儿大脑的直接作用。此外，我们建议POE引起异常神经发育 通过胎盘的适度作用，通过缺氧和炎症机制。令人惊讶的是，我们的 17个POE妊娠的胎盘病理学的初步结果证实了每位患者的缺氧病变。 此外，我们使用胎盘免疫成像（PII）的初步工作，高级扩散磁 共振成像（DMRI）技术证实胎盘炎症升高和氧合减少， 与未暴露的对照相比，在POE 36周怀孕的绒毛膜板附近。胎盘缺氧 炎症是两种已知的病因，引起胎儿WM损伤和脑部不饱和的疾病，我们自己 数据表明，脑充氧受损的胎儿的大脑体积和WM的减少最大 改变。重要的是，我们已经证明，胎儿脑量最一致地预测了2年ND （n = 78，r = 0.32-0.47;所有p <0.05）在所有域中。为了检验我们的假设，我们利用诊所接受接受， 恢复和授权，这是该国为数不多的环绕产前诊所之一，以及我们正在进行的 在人体胎盘项目（R01HD094381-04）上使用胎盘炎症的纵向成像 来自未暴露的患者，作为对康复倡议的求助：阿片类药物的暴露和对胎盘功能的影响， 大脑发育和神经发育结果（RFA-HD-23-030）。我们建议此R01定义 POE对胎盘炎症和氧合的纵向影响（AIM 1），胎儿脑发育和 氧合（AIM 2），以及胎盘和胎儿脑发育标记与NOW之间的关系 和POE婴儿的早期结局（AIM 3）。这些目标的完成将探索和完善 POE导致不良结果并识别免疫反应的创新胎儿途径 预测和ND的胎盘和胎儿大脑中的氧合状态。从长远来看，这项工作将 允许我们识别治疗靶标，以减轻母体Oud对后代的不利影响。