Enamel Hypoplasia and Early Childhood Caries in Preterms with Jaundice

描述（由研究者提供）：黄疸（非共轭性高胆红素血症）在新生儿中极为常见，已被证明可导致慢性核后脑病（CPKE），这是一种终身疾病，其特征是牙釉质发育不全、动脉样脑瘫和听力丧失。与足月婴儿相比，早产儿发生CPKE的风险增加。目前的文献表明，与足月婴儿相比，早产儿牙釉质发育不全的患病率更高，然而，患病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。牙釉质发育不全会增加患龋齿及相关疾病的风险，因此预防牙釉质发育不全至关重要。本研究的主要重点是建立新生儿黄疸与早产儿牙釉质发育不全及相关龋齿之间的关系。目前，血清总胆红素（TSB）被用于评估和管理早产儿黄疸，尽管研究表明TSB是CPKE的一个较差指标。最近，非结合胆红素被首席研究员证明是比TSB更好的预测早产儿胆红素引起的听觉毒性的指标。因此，我们的第二个目标是扩大这项研究，以确定非结合胆红素作为胆红素诱导的早产儿牙齿毒性（牙釉质发育不全和严重的幼儿龋齿）比TSB更敏感和特异性的预测因子的有效性。该项目被提议作为R-21，因为关于胆红素引起的早产儿牙齿毒性的数据很少。我们有一个独特的机会来进行这些研究，因为我们有250名早产儿，他们的未结合胆红素水平和相关的临床信息是作为美国国立卫生研究院资助的胆红素研究的一部分前瞻性收集的。具有共同兴趣和互补角色的经验丰富的研究人员将合作评估150名胎龄33周的婴儿在两年内参与胆红素研究的胆红素诱导的牙齿毒性。校准的牙科检查将由经验丰富的儿科牙医进行，而不需要了解危险因素，包括校正年龄3岁时的未结合胆红素水平。未结合胆红素采用过氧化物酶法测定，使用FDA批准的UB分析仪。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。采用受试者工作特征曲线比较未结合胆红素、胆红素：白蛋白比和TSB对胆红素所致牙齿毒性的敏感性和特异性。本研究的发现可能会对发育期间胆红素引起的毒性提供更多的见解，并进一步证明非结合胆红素对预测早产儿CPKE的其他表现（如牙釉质发育不良）的有用性。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，为未来的干预提供依据，3)建立非结合胆红素预测CPKE的有效性。

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.