SYSTEMIC CONDITIONS AND DEVELOPMENTAL DEFECTS OF ENAMEL IN A COHORT OF VLBW AND NBW INFANTS by HUN SHIM Submitted in partial fulfillment of the requirements for the degree of Master of Science Clinical Research Scholars Program School of Medicine CASE WESTERN RESERVE UNIVERSITY August, 2016 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of Hun Shim, DMD Candidate for the Master of Science degree *. (signed) Suchitra Nelson, PhD . (Chair of committee) James Spilsbury, PhD MPH . Kristin Victoroff, DDS, PhD . __________________________________________ __________________________________________ (Date) May 12, 2016 *We also certify that written approval has been obtained for any proprietary material contained therein. 1 Dedicated to my family and my many mentors who have helped shape my paradigm in education, career, and life. 2 Table of Contents LIST OF TABLES ............................................................................................................. 4 LIST OF FIGURES ........................................................................................................... 5 ACKNOWLEDGEMENTS ............................................................................................... 6 LIST OF ABBREVIATIONS ............................................................................................ 7 ABSTRACT ....................................................................................................................... 8 BACKGROUND AND SIGNIFICANCE ......................................................................... 9 METHODS ...................................................................................................................... 16 RESULTS ........................................................................................................................ 21 DISCUSSION .................................................................................................................. 28 APPENDIX ...................................................................................................................... 35 BIBLIOGRAPHY ............................................................................................................ 39 3 List of Tables Table 1: Characteristics of participants and non-participants .......................................... 21 Table 2: Infant Clinical Risk Grouping (CRG) classification distribution ....................... 22 Table 3: Association of CRG with hypoplasia and demarcated opacity .......................... 22 Table 4: Correlation of maternal sociodemographic and medical risk factors with DDE 23 Table 5: Correlation among CRG and maternal sociodemographic and medical risk factors ................................................................................................................................ 24 Table 6. Hierarchical model of 8-month CRG and maternal sociodemographic and medical risk factors predicting 36-month hypoplasia and demarcated opacities ............. 25 Table 7. Hierarchical model of 8-month CRG and maternal sociodemographic and medical risk factors predicting 36-month enamel hypoplasia stratified by birth group .. 26 4 List of Figures Figure 1: Conceptual Model ............................................................................................. 34 Figure 2: Infant medical abstraction and follow-up medical history form ....................... 35 5 Acknowledgements I would like to thank the following individuals for their guidance and mentorship with this project and my program: Dr. Suchitra Nelson for mentoring me throughout my Mastership, specifically providing valuable feedback to my project’s progress and being a source of inspiration for my career in dentistry as a clinician and researcher. Shelley Curtan for all assistance with administrative needs. Yiying Liu for assistance in data analysis and interpretation My family and church for caring and being the spiritual and social support during challenging times to help me focus on my Mastership 6 List of Abbreviations VLBW Very Low Birth Weight NBW Normal Birth Weight CWRU Case Western Reserve University CDC Centers for Disease Control DDE Developmental Defects of Enamel NICU Neonatal Intensive Care Unit CRG Clinical Risk Grouping BPD Bronchopulmonary Dysplasia RDS Respiratory Distress Syndrome 7 Systemic Conditions and Developmental Defects of Enamel in a Cohort of VLBW and NBW Infants Abstract by HUN SHIM This retrospective cohort study investigated the effects of VLBW and NBW infants’ systemic health on DDE. The sample consisted of 293 infant-caregiver dyads that attended all three visits based on an original cohort study. Infants’ systemic conditions were classified by a modified CRG index for 8 and 18-month visits. Developmental defects of enamel (DDE: hypoplasia and demarcated opacities) were obtained from 36- month dental examination records. A hierarchical negative binomial model was utilized. The model controlling for maternal sociodemographic and prenatal factors indicated that severe 8-month CRG level compared to healthy significantly increased 36-month hypoplasia (p<0.05), but not for demarcated opacities. Caregiver’s low socioeconomic status and prenatal smoking also significantly influenced 36-month hypoplasia also. The model stratified by birth group indicated that severe CRG affected hypoplasia significantly in VBLW infants, but not in NBW infants. In conclusion, severe systemic conditions were significantly associated with enamel hypoplasia. 8 Background and Significance Facts about VLBW Infants Preterm births (< 37weeks gestation) and very low birth weight (VLBW: < 1500 grams) lead to chronic conditions and physical and mental developmental anomalies in infants (Hack et al., 1993); Recent national survey (Center for Disease Control: CDC) in 2014 estimated that 1 in 10 births are VLBW in the United States. Studies have found that caregiver risk factors such as education attainment below high school, younger maternal age at birth, history of substance abuse including smoking (Hack et al., 1993; Kleinment et al., 1985; Diaz et al., 2001; Najati and Gojazadeh, 2010), and being in non-Hispanic African American race (Kempe et al., 1992) increased the risk of infants born preterm and VLBW. VLBW infants are susceptible to numerous systemic problems that include the following: Necrotizing entercolitis a disease that impairs the function of the enteral system in absorption of sugars, proteins, vitamins, and other key nutrients (Patel et al., 2012); bronchopulmonary dysplasia (BPD) and respiratory distress syndrome (RDS), which affect 68% VLBW infants and are the most common causes of pulmonary mortalities in this population (Kair et al., 2012; Beam et al., 2014); Anemia of prematurity and jaundice as a result of hyperbilirubinemia following excessive red blood cell breakdown (Watchko and Maisels, 2003) with as much as 76.6% in VLBW susceptible to jaundice and 37.3% with more severe levels of anemia and jaundice to require transfusion in order to recover appropriate blood cell levels (Narang et al., 2001); Patent ductus arteriosus, a pathologic communication in the circulation bypassing the respiratory system, 9 contributing to low blood cell levels predisposing VLBW infants to sepsis that can be life threatening (Hornik et al., 2012); neurological conditions such as intraventricular hemorrhage and periventricular leukomalacia that have been implicated in cognitive disabilities and neurodevelopmental delays (McCrea and Ment, 2008; Pellicer et al., 2009; Linsell et al., 2015). Due to the complex, multi-system nature of VLBW infant’s systemic conditions, barriers still remain in consolidating evidence for the most effective interventions to reduce the morbidity and mortality burdens of the VLBW cohort and restore them to comparable health of NBW infants (Patel et al., 2012; Eber et al., 2001; Ballot et al., 2015; Kusuda et al., 2008). VLBW infants are also susceptible to oral conditions. Being born VLBW predisposes infants to delayed eruption patterns. Studies have shown that birth weight is inversely related to eruption of the first deciduous teeth (Ramos et al., 2006; Khalifa et al., 2014; Nelson et al., 2013). VLBW infants are also subject to malocclusion; Seow et al., 1987 suggested that VLBW infants with more severe cases of medical compromise may experience space loss leading to malocclusion in deciduous and thereby succadaneous teeth. Most importantly, VLBW infants are subject to developmental defects of enamel (DDE) in deciduous teeth. DDE or enamel defects can be divided into enamel hypoplasia and opacities: enamel hypoplasia is defined as a break in continuity of enamel leading to reduced thickness and enamel pits and grooves; opacities are defined as alterations in translucency of the enamel in demarcated or diffused form of which demarcated is more prevalent in VLBW infants (Commision on Oral Health 1992). A recent literature review investigated preterm birth as etiology for oral morbidities and found DDE as the most 10 prevalent overall compared to other conditions including delayed eruption and malocclusion (Zaidi et al., 2015). The prevalence of DDE ranges from 62.3% to 96%, depending on the birth weight of the infant (Lai et al., 1997; Aine et al., 2000; Cruvinel et al., 2012). The consequences of DDE are substantial and multifaceted. On a social psychological level, DDE has been shown to be a source of embarrassment and dissatisfaction to adolescents and caregivers due to