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Relationship Between Bilirubin and Auditory RELATIONSHIP BETWEEN BILIRUBIN AND AUDITORY FUNCTION IN PREMATURE NEONATES BY Gabriel Anne Bargen Submitted to the graduate degree program in Audiology and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy. Committee: _______________________________ Chairperson _______________________________ _______________________________ _______________________________ _______________________________ Date approved:_______________________ ii The Dissertation Committee for Gabriel Anne Bargen certifies that this is the approved version of the following dissertation: RELATIONSHIP BETWEEN BILIRUBIN AND AUDITORY FUNCTION IN PREMATURE NEONATES Committee: _______________________________ Chairperson _______________________________ _______________________________ _______________________________ _______________________________ Date approved:_______________________ iii To the four individuals that love me unconditionally, Jason, Peyton and my parents iv ABSTRACT Research has shown hyperbilirubinemia in preterm infants is more prevalent and its course more protracted than in term neonates. High levels of bilirubin have been documented to be toxic to the central nervous system and may cause neurological impairments in newborns. Impairment of auditory function is the most consistent abnormality, especially in premature infants. Hyperbilirubinemia is a risk factor for sensorineural hearing loss according the Joint Committee on Infant Hearing. If premature infants are at a greater risk for hyperbilirubinemia it can be assumed that they will be at a greater risk of having auditory dysfunction caused, or contributed to, by hyperbilirubinemia. Currently, national guidelines are needed which address when treatment options should be considered and implemented regarding bilirubin levels in premature infants. The need for these guidelines is a necessity, as preterm infants require much closer follow-up and more aggressive therapy than full term infants. The objective for this research project was to determine the relationship between bilirubin levels and auditory function in preterm infants. The auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) tests were prospectively investigated in premature infants while monitoring total serum bilirubin (TSB) levels. Ten subjects with a mean gestational age of 31.5 weeks participated in the study. The mean peak TSB was 7.91 mg/dL. Based on the peak TSB to birth weight ratio all subjects were assigned to the control group. Spearman’s correlation coefficient indicated no significant correlation between peak TSB levels and auditory function. This study provided baseline data for further research evaluating auditory function in preterm hyperbilirubinemic subjects. v TABLE OF CONTENTS ABSTRACT ................................................................................................................................... iv LIST OF TABLES ......................................................................................................................... vi LIST OF FIGURES ...................................................................................................................... vii CHAPTER 1 INTRODUCTION .....................................................................................................1 CHAPTER 2 REVIEW OF THE LITERATURE ...........................................................................6 CHAPTER 3 METHODS ..............................................................................................................37 CHAPTER 4 RESULTS ................................................................................................................46 CHAPTER 5 DISCUSSION ..........................................................................................................54 CHAPTER 6 CONCLUSIONS .....................................................................................................62 APPENDIX A TABLES ................................................................................................................63 APPENDIX B FIGURES ..............................................................................................................73 APPENDIX C HUMAN SUBJECTS COMMITTEE DOCUMENTATION ...............................85 APPENDIX D RAW DATA FIGURES AND TABLES ..............................................................89 REFERENCES ............................................................................................................................118 vi LIST OF TABLES Table Page 1. The Joint Committee on Infant Hearing 2007 position statement list of risk factors for infant hearing loss. ............................................................................................................63 2. Subject demographics and correlations between peak TSB level and birth weight and GA. ..................................................................................................................................64 3. Auditory brainstem response collection parameters. ...............................................................65 4. ABR absolute latencies and interwave interval latencies from the worst ear at the second and third follow-up collections. ...................................................................................66 5. The means and standard deviations (mean ± SD) for the latencies of various waves and interwave intervals for the second and third follow-up collections compared to the normative data from Gorga et al. (1987) for the corresponding average CA. ........................67 6. DPOAE levels and noise floor levels for subjects’ worst ear at the second and third follow-up collections for 2000, 3000, and 4000 Hz. Subjects GA (weeks) and peak TSB (mg/dL) are provided for reference. ...............................................................................68 7. Peak total bilirubin to birth weight ratios. ..............................................................................69 8. Means ± standard deviations, Spearman’s correlations, and p-values for comparison between ABR latencies (msec), both absolute and interwave interval, and peak TSB levels for the second and third follow-up collections. ............................................................70 9. Means ± standard deviations, Spearman’s correlations, and p-values for comparison between peak TSB levels and ABR thresholds (dB nHL) for the second and third follow-up collections. .............................................................................................................71 10. Means ± standard deviations, Spearman’s correlations, and p-values for comparison between peak TSB levels and DPOAE responses (dB) for the second and third follow-up collections. .............................................................................................................72 vii LIST OF FIGURES Figure Page 1. Sample ABR waveforms from subject 1, a normal hearing infant, in response to a click stimulus recorded during the second follow-up collection. ...........................................73 2. Sample ABR waveforms from subject 1, a normal hearing infant, in response to a click stimulus recorded during the third follow-up collection. ...............................................74 3. Sample DP-gram recorded at the baseline collection from the right ear of subject 1. ...........75 4. Sample DP-gram recorded at the second follow-up collection from the right ear of subject 1. .................................................................................................................................76 5. Scatter plot of peak TSB levels to birth weight ratio for all subjects. ....................................77 6. Scatter plots of peak TSB levels and ABR wave III latencies. ...............................................78 7. Scatter plots of peak TSB levels and ABR wave V latencies. ................................................79 8. Scatter plots of peak TSB levels and ABR interwave interval III-V latencies. ......................80 9. Scatter plots of peak TSB levels and ABR interwave interval I-V latencies. .........................81 10. Scatter plots of peak TSB levels and ABR thresholds. ...........................................................82 11. Scatter plots of peak TSB levels and DPOAE responses from the second follow-up collection. ................................................................................................................................83 12. Scatter plots of peak TSB levels and DPOAE responses from the third follow-up collection. ................................................................................................................................84 1 CHAPTER 1 INTRODUCTION The Joint Committee on Infant Hearing (JCIH) (2007) identifies hyperbilirubinemia, at a serum level requiring exchange transfusion, as a risk factor for progressive or delayed-onset sensorineural hearing loss (SNHL). Impairment of auditory function is the most consistent abnormality that is associated with permanent damage from hyperbilirubinemia, especially in premature infants (Volpe, 2001). Over the past five decades, research has shown that hyperbilirubinemia in pre-term infants is more prevalent, more severe, and its course more protracted than in term neonates (Billings, Cole, & Lathe, 1954; Harris, 1961; Watchko, 2000). Unfortunately, a reliable protocol for the consideration and initiation of treatment
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