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.

摘要 母体阿片类药物使用障碍（OUD）的患病率迅速增加，并与严重的发病率相关 在后代中，如新生儿阿片类戒断综合征（NOWS），脑发育不良， 神经发育（ND）。然而，关于母体OUD引起的机制知之甚少， 因此，我们减轻产前阿片类药物暴露（POE）对结果影响的能力很差。 在这里，我们建议测试的核心假设，即POE导致异常的神经发育 通过对胎儿大脑的直接作用此外，我们提出，POE导致异常的神经发育 通过胎盘通过缺氧和炎症机制的调节作用。引人注目的是，我们的 17例POE妊娠胎盘病理学的初步结果证实了每位患者的缺氧病变。 此外，我们的初步工作使用胎盘免疫成像（PII），一个先进的扩散磁 核磁共振成像（dMRI）技术，证实胎盘炎症升高和氧合减少， 与未暴露的对照组相比，在POE 36周妊娠中均靠近绒毛膜板。胎盘缺氧 和炎症是导致胎儿WM损伤和脑发育不良的两种已知病因， 数据显示，脑氧合受损的胎儿脑体积和WM的减少最大， 改变。重要的是，我们已经证明胎儿脑体积最能一致地预测2年ND （n=78，r=0.32-0.47;所有p<0.05）。为了验证我们的假设，我们利用诊所接受， 恢复和赋权，全国为数不多的环绕OUD产前诊所之一，我们正在进行的 从事人类胎盘项目（R 01 HD 094381 -04），对胎盘炎症进行纵向成像 来自未暴露患者，作为对HEAL倡议的回应：阿片类药物暴露和对胎盘功能的影响， 脑发育和神经发育结局（RFA-HD-23-030）。我们建议使用R 01来定义 POE对胎盘炎症和氧合（目的1）、胎儿脑发育和 氧合（目的2），以及胎盘和胎儿脑发育标志物与NOWS之间的关系 和POE婴儿的早期ND结局（目标3）。完成这些目标将探索和完善一个 创新的胎儿途径，通过该途径，POE导致不良结局，并确定免疫反应的标志物 胎盘和胎儿脑组织氧合状态可预测NOWS和ND。从长远来看，这项工作将 使我们能够确定治疗靶点，以减轻母体OUD对后代的不良影响。