Enamel Hypoplasia and Early Childhood Caries in Preterms with Jaundice

描述(由研究人员提供)：黄疸(非结合性高胆红素血症)在新生儿中非常常见，已被证明会导致慢性核黄体后脑病(CPKE)，这是一种终生疾病，特征是牙釉质发育不良、手足徐动型脑瘫和听力丧失。与足月儿相比，早产儿患CPKE的风险更高。目前的文献表明，早产儿牙釉质发育不良的发生率高于足月儿，然而，其发生率较高的原因及其与高胆红素血症的关系尚未得到很好的研究。已知牙釉质发育不良会增加患龋齿的风险和相关的发病率，因此，预防釉质发育不良至关重要。这项研究的主要焦点是建立早产儿中新生儿黄疸与牙釉质发育不良及相关龋齿之间的关系。目前，血清总胆红素(TSB)被用来评估和管理早产儿的黄疸，尽管研究表明TSB是CPKE的一个很差的指标。最近，首席调查员已经证明，游离胆红素比TSB更能预测早产儿胆红素所致的听觉毒性。因此，我们的次要目标是扩大这项研究，以确定游离胆红素作为一种比TSB更敏感和更特异的指标来预测早产儿胆红素引起的牙齿毒性(牙釉质发育不良和严重的儿童早期龋齿)。该项目被提议作为R-21，因为关于胆红素对早产儿的牙齿毒性的数据非常少。我们有一个独特的机会来进行这些研究，因为我们有250名未结合胆红素水平和相关临床信息的早产儿队列，这些信息是NIH资助的胆红素研究的一部分。具有共同兴趣和互补作用的经验丰富的研究人员将合作评估参与胆红素研究的150名胎龄33周的婴儿在两年内的胆红素引起的牙齿毒性。校准的牙科检查将由经验丰富的儿科牙医进行，但不了解风险因素，包括校正年龄3岁时的未结合胆红素水平。采用美国食品和药物管理局批准的UB分析仪，采用过氧化物酶测定法测定游离胆红素。将进行回归分析，以评估新生儿黄疸和牙齿毒性之间的关联强度。受试者操作特征曲线将用于比较未结合胆红素、胆红素/白蛋白比率和TSB对胆红素所致牙科毒性的敏感度和特异度。这项研究的结果可能会提供更多关于胆红素在发育期的毒性的见解，并扩大无结合胆红素在预测CPKE的其他表现(如早产儿牙釉质发育不良)中的有效性的证据。最终目标将是减少：1)黄疸相关的牙齿毒性，2)识别牙釉质发育不良和龋齿的高危早产儿，以便将来进行干预，以及3)建立无结合胆红素对预测CPKE的有用性。 公共卫生意义儿童早期龋病是最常见的儿童疾病，通常与影响儿童、其家庭和社区的健康和生活质量的有害影响有关。这项由经验丰富的美国研究人员开展的临床项目将前瞻性地评估未结合的高胆红素血症(黄疸)与牙釉质发育不良和相关的龋齿(胆红素毒性)之间的关系，并研究在不同种族的早产儿中，无结合胆红素作为胆红素引起的牙齿毒性的预测指标的有效性。如果黄疸与早产儿牙釉质发育不良和相关龋病相关，并且结合胆红素是比总胆红素更好的预测胆红素毒性的指标，这将大大提高对有胆红素牙毒性风险和需要治疗干预的婴儿的识别能力。这项研究的总体结果将对全球公共卫生产生影响，因为它将有助于减少黄疸相关的牙釉质发育不良和儿童早期龋齿，还将有助于降低与儿童早期龋齿及其相关共病的治疗相关的成本。

DESCRIPTION (provided by investigator): Jaundice (unconjugated hyperbilirubinemia), which is extremely common in neonates, has been shown to cause chronic post-kernicteric encephalopathy (CPKE), a life-long disorder, characterized by dental enamel hypoplasia, athetoid cerebral palsy, and hearing loss. Premature infants are at increased risk of CPKE compared to term infants. Current literature suggests that premature infants have a higher prevalence of dental enamel hypoplasia compared to term infants, however, the reasons for higher prevalence and its associations with hyperbilirubinemia have not been well studied. Dental enamel hypoplasia is known to increase the risk of dental caries and related morbidity, therefore, prevention of enamel hypoplasia is of paramount importance. The primary focus of this research is to establish the association between neonatal jaundice and dental enamel hypoplasia and related dental caries in premature infants. Currently, total serum bilirubin (TSB) is used to evaluate and manage jaundice in premature infants, although studies have shown that TSB is a poor indicator of CPKE. Recently, unbound bilirubin has been shown by the Principal Investigator to be a better predictor than TSB of bilirubin-induced auditory toxicity in premature infants. Therefore, our secondary objective is to expand this research to establish the usefulness of unbound bilirubin as a more sensitive and specific predictor than TSB of bilirubin-induced dental toxicity (dental enamel hypoplasia and severe early childhood caries) in premature infants. The project is being proposed as an R-21 since very little data exist regarding bilirubin- induced dental toxicity in premature infants. We are in a unique opportunity to conduct these studies as we have a cohort of 250 premature infants with unbound bilirubin levels and relevant clinical information prospectively collected as part of NIH-funded bilirubin study. Experienced investigators with common interest and complimentary roles will collaborate to evaluate bilirubin-induced dental toxicity in 150 infants d 33 weeks gestational age over two year period who participated in bilirubin study. Calibrated dental examinations will be performed by an experienced pediatric dentist without knowledge of risk factors, including unbound bilirubin levels at 3 years corrected age. The unbound bilirubin was measured by the peroxidase method using FDA approved UB analyzer. Regression analyses will be performed to evaluate the strength of association between neonatal jaundice and dental toxicity. Receiver operating characteristic curves will be performed to compare sensitivity and specificity of unbound bilirubin, bilirubin:albumin ratio, and TSB for bilirubin-induced dental toxicity. The findings of this study may provide additional insight regarding bilirubin-induced toxicity during a developmental period and extend the evidence for usefulness of unbound bilirubin for predicting other manifestation of CPKE such as dental enamel hypoplasia in premature infants. The ultimate goal will be to reduce: 1) jaundice related dental toxicity, 2) identify at-risk premature infants for dental enamel hypoplasia and caries for future interventions, and 3) establish usefulness of unbound bilirubin for predicting CPKE. PUBLIC HEALTH RELEVANCE: Public Health Significance Early childhood caries is the most common childhood disease and is often associated with detrimental effects on health and quality of life affecting children, their families, and the community. This clinical project to be performed by experienced US investigators will prospectively evaluate the association of unconjugated hyperbilirubinemia (jaundice) with dental enamel hypoplasia and related caries (bilirubin toxicity) and also examine the usefulness of unbound bilirubin as a predictor of bilirubin-induced dental toxicity in a diverse racial population of premature infants with jaundice. If jaundice is associated with dental enamel hypoplasia and related caries in premature infants and unbound bilirubin is a better predictor than total serum bilirubin of bilirubin-induced toxicity, it will greatly improve identification of infants who are at risk for bilirubin-induced dental toxicity and in need of therapeutic intervention. The overall findings of this study have ramifications for public health globally as it will help decrease jaundice associated dental enamel hypoplasia and early childhood caries, and will also help reduce costs associated with the treatment of early childhood caries and its associated co-morbidities.