Novel non-invasive approach for predicting retinopathy of prematurity in premature neonates

摘要： 早产儿微血管发育不良是其并发症的主要原因。 早产，终生后果，如早产儿视网膜病变(ROP)、坏死性小肠结肠炎 (NEC)和肺动脉高压(PHTN)合并支气管肺发育不良(BPD)，这是主要的 早产儿发病和死亡的原因。不幸的是，没有非侵入性的方法。 建立评估和监测早产儿全身微血管发育以预测 婴儿会出现这些并发症。甲皱毛细支气管镜是一种非侵入性技术，适用于成人和 结缔组织病儿童预测复发，但目前不用于早产儿 评估毛细血管发育。我们的初步数据表明，在极低出生体重(VLBW)婴儿中， 钉床毛细血管网络密度参数(例如单位面积的毛细血管骨架长度和每分支点 面积)在生命的第一个月内显著减少。我们的数据还表明，最终 与未发育的ROP相比，发育的ROP在出生后的头几周有更高的毛细血管密度。 在这项提案中，我们将检验这样一个假设，即甲皱毛细管镜可以非侵入性地检测毛细血管。 早产儿的发育障碍和预测ROP的发展需要医疗干预。 因此，我们将解决以下具体目标：1)识别甲皱的纵向发展变化 早产儿的毛细血管；2)定义毛细甲皱参数，最可靠地预测中到 极低出生体重儿发生严重ROP。我们已经建立了一支多学科的研究团队， 包括西北大学(NU)成像核心、NU工程学院和 芝加哥安和罗伯特·H·鲁里儿童医院的眼科和新生儿。如果成功，则 该项目的科学前提包括：1)非侵入性地鉴定有血管生长的婴儿 可受益于旨在预防微血管的新型治疗干预措施的损害 早产并发症，包括ROP，从而改善患者预后；2)监测全身影响 针对微血管系统的治疗，例如抗血管内皮生长因子抗体。对于这项原则证明研究，我们将 重点预测中到重度ROP，因为其诊断直接基于视网膜毛细血管的范围 发育不良。然而，我们计划在未来将我们的研究扩展到其他较少的微血管床 可用于检查并确定甲皱毛细血管发育异常是否能够预测其他 早产儿并发症，如NEC、BPD相关的PHTN。

ABSTRACT: Maldevelopment of the microvasculature in premature neonates plays a major role in complications of prematurity with life-long consequences such as retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC) and pulmonary hypertension (PHTN) complicating bronchopulmonary dysplasia (BPD), which are major causes of morbidity and mortality in premature infants. Unfortunately, there is no non-invasive method established to assess and monitor systemic microvascular development in premature babies to predict which infant will develop these complications. Nailfold capillaroscopy is a non-invasive technique useful in adults and children with connective tissue diseases to predict relapses, but not currently used in premature neonates to assess capillary development. Our preliminary data suggest that, in very-low-birthweight (VLBW) infants, nailbed capillary network density parameters (e.g. capillary skeletal length per area and branch points per area) significantly decrease during the first month of life. Our data also suggest that babies who ultimately developed ROP had a higher capillary density in the first few weeks after birth compared to those who do not. In this proposal, we will test the hypothesis that nailfold capillaroscopy can non-invasively detect capillary development impairment in premature infants and predict development of ROP requiring medical intervention. Therefore, we will address the following specific aims: 1) Identify the longitudinal developmental changes of nailfold capillaries in premature infants; 2) define capillary nailfold parameters that most reliably predict moderate to severe ROP development in VLBW infants. We have established a multi-disciplinary research team which includes the Northwestern University (NU) Imaging Core, the NU school of engineering and the departments of Ophthalmology and Neonatology at Ann & Robert H. Lurie Children’s Hospital of Chicago. If successful, the scientific premise of this project would include: 1) To non-invasively identify infants with vascular growth impairment which could benefit from novel therapeutic interventions aimed at preventing microvascular complications of prematurity, including ROP, thus improving patient outcomes; 2) To monitor the systemic effect of therapies targeting the microvasculature e.g. anti-VEGF antibodies. For this proof-of-principle study, we will focus on prediction of moderate to severe ROP as its diagnosis is directly based on the extent of retinal capillary maldevelopment. However, we plan in the future to expand our study to other microvascular beds that are less accessible to exam and to determine whether abnormal nailfold capillary development is able to predict other complications of prematurity e.g. NEC, BPD-related PHTN.