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

摘要 母亲阿片类药物使用障碍(OUD)的患病率正在迅速上升，并与严重的发病率有关 在后代中，如新生儿阿片类药物戒断综合征(NOWS)、脑发育不成熟和受损 神经发育(ND)。然而，关于母体OUD引起的机制却知之甚少。 这些结果，所以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，我们建议检验POE导致神经发育异常的中心假设 通过对胎儿大脑的直接作用。此外，我们认为POE会导致神经发育异常 通过胎盘的调节作用，通过缺氧和炎症机制。引人注目的是，我们的 17例POE妊娠的胎盘病理初步结果证实，每个患者都有缺氧性损害。 此外，我们的初步工作使用了胎盘免疫成像(PII)，这是一种先进的扩散磁 磁共振成像(DMRI)技术，证实胎盘炎症增加和氧合减少， 在妊娠36周的POE患者中，两者均位于绒毛膜板附近，与未暴露的对照组相比。胎盘缺氧 和炎症是导致胎儿WM损伤和大脑发育不成熟的两个已知原因，而我们自己 数据显示，大脑氧合受损的胎儿大脑体积和WM的减少幅度最大 改装。重要的是，我们已经证明，胎儿脑体积最一致地预测了2年后的ND (n=78，r=0.32-0.47；均P&lt；0.05)。为了检验我们的假设，我们利用诊所的认可， 康复和赋权，是全国为数不多的综合性产前诊所之一，我们正在进行的 人类胎盘计划(R01HD094381-04)的工作与胎盘炎症的纵向成像 来自未暴露的患者，作为对治愈倡议的回应：阿片类药物的暴露和对胎盘功能的影响， 脑发育和神经发育结果(RFA-HD-23-030)。我们建议使用R01来定义 POE对胎盘炎症和氧合的纵向影响(目标1)，胎儿大脑发育和 氧合作用(目标2)以及胎盘和胎儿脑发育标志物与NOWS的关系 和POE婴儿的早期ND结果(目标3)。完成这些目标将探索和完善一个 POE导致不良结局的创新胎儿途径，并确定免疫反应的标记物 胎盘和胎脑中的氧合状态预示着NOWS和ND。从长远来看，这项工作将 使我们能够确定治疗目标，以减轻母体OUD对后代的不利影响。

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.