Is Jaundice in Premature Infants a Risk Factor for Autism?

描述(由申请人提供)：自闭症谱系障碍(ASD)的报告患病率一直在上升，至少部分原因是检测的增加和诊断标准的拓宽，目前估计为每88人中有1人。ASD似乎在早产儿中更为普遍，据报道患病率约为8%。增加早产儿风险的新生儿临床因素还没有得到很好的研究。新生儿未结合型高胆红素血症(黄疸)可能是其中一个因素。黄疸在早产儿中普遍存在，可能与小脑、海马体、脑干和基底节损伤有关，而后者最近又与自闭症有关。最近，用血清总胆红素水平评估的新生儿黄疸被发现与晚期早产儿和足月儿的ASD有关，但它与早产儿ASD的关系尚不清楚。此外，最近的研究表明，未结合胆红素(未与蛋白质结合的胆红素，UB)可能比总胆红素更能预测神经发育障碍，但还没有研究评估UB是否与ASD有关。这项建议是一项为期两年的早产儿和33周胎龄的研究，以评估UB在早产儿中新生儿黄疸和ASD之间的相关性，UB是一种更好的神经毒性胆红素生化标记物。罗切斯特大学医学中心有一个独特的机会来进行这项拟议的前瞻性观察研究，原因如下：1)出生后不久参加NIH资助的胆红素研究的胎龄33周的大量婴儿同意在较晚的年龄接受前瞻性跟踪观察神经发育结果；2)新生儿发展计划积极跟踪这些早产儿的神经发育结果，直到10岁，90%的保留率；3)已经创建了一个数据库，其中包含预期收集的所有登记的早产儿的必要的母亲、怀孕和新生儿的临床数据；4)所有登记的早产儿都通过测量出生后2周内的UB水平、血清总胆红素水平和白蛋白水平来进行黄疸的前瞻性评估；5)已经前瞻性地评估了黄疸相关神经毒性的临床危险因素，并前瞻性地收集了关于所有这些早产儿的危险因素的必要数据；以及6)该网站在新生儿黄疸和ASD诊断方面都有专业知识。该项目将涉及470名早产儿，他们参加了胆红素诱导的神经毒性研究，并同意进行后续的神经发育评估。这些婴儿将通过SCQ进行ASD筛查，筛查呈阳性的婴儿将完成孤独症诊断观察计划。在高危早产儿中建立黄疸和ASD之间的联系将提出一种ASD的可预防的病因，并将为在更大范围内证实黄疸和ASD之间的因果联系的预防性试验奠定基础。最终，这类试验的结果将有助于改善黄疸的治疗，继而减少ASD。如果不对这一已建立的群体进行研究，并掌握有关UB的独特信息，就会错失机会。

DESCRIPTION (provided by applicant): The reported prevalence of autism spectrum disorder (ASD) has been rising, at least partly due to increased detection and broadened diagnostic criteria, and is now estimated at 1 in 88. ASD appears to be even more prevalent among premature infants with a reported prevalence of ~8%. Neonatal clinical factors that increase the risk among premature infants are not well studied. Neonatal unconjugated hyperbilirubinemia (jaundice) may be one such factor. Jaundice is ubiquitous among premature infants and may be associated with cerebellar, hippocampal, brainstem, and basal ganglia injury, which in turn has recently been linked to autism. Recently, neonatal jaundice, assessed using total serum bilirubin levels, was found to be associated with ASD in late preterm and term infants, but its association with ASD in premature infants remains unknown. Moreover, recent studies suggest that unbound bilirubin (bilirubin not bound to protein, UB) may be a better predictor of neurodevelopmental disorder than total serum bilirubin, but no studies have evaluated whether UB is linked to ASD. This proposal is for a two year study of premature infants d 33 weeks gestational age to evaluate association between neonatal jaundice and ASD among premature infants using UB, a better bilirubin biochemical marker of neurotoxicity. The University of Rochester Medical Center has a unique opportunity to conduct the proposed prospective observational study for the following reasons: 1) A large cohort of infants d 33 weeks gestational age and enrolled in NIH-funded bilirubin study soon after birth has consented to be prospectively followed for neurodevelopmental outcomes at a later age; 2) These premature infants are actively followed for neurodevelopmental outcomes by the Neonatal Developmental Program up to 10 years of age with 90% retention; 3) A database has been created with requisite maternal, pregnancy, and neonatal clinical data prospectively collected on all enrolled premature infants; 4) All enrolled premature infants had prospective evaluation for jaundice using measurement of UB levels, total serum bilirubin levels, and albumin levels during the first 2 weeks after birth; 5) Clinical risk factors for jaundice associated neurotoxicity has been prospectively evaluated and requisite data on risk factors has been prospectively collected on all these premature infants; and 6) The site has expertise in both neonatal jaundice and ASD diagnosis. The project will involve 470 premature infants enrolled in the bilirubin-induced neurotoxicity study and who have consented for follow-up neurodevelopmental evaluation. These infants will be screened for ASD with the SCQ and those with positive screens will complete the Autism Diagnostic Observation Schedule. Establishing the association between jaundice and ASD in high-risk premature infants will suggest one preventable etiology of ASD and will lay the foundation for preventive trials to confirm the causal association between jaundice and ASD in a larger population. Ultimately, the findings of such trial will help to improv management of jaundice with secondary reduction in ASD. Not studying this established cohort with unique information on UB will be a lost opportunity.