1. Extremely low gestation infants are at high risk for auditory neuropathy Lynn M. Iwamoto, MD; Konstantine Xoinis, MD; Yusnita Weirather, MA, CCC-A; Hareesh Mavoori, PhD; Steven Shaha, PhD Kapiolani Medical Center for Women & Children, Hawaii Pacific Health Center for Health Outcomes Honolulu, Hawaii

2. Faculty Disclosure Information In the past 12 months, I have not had a significant financial interest or other relationship with the manufacturer(s) of the product(s) or provider(s) of the service(s) that will be discussed in my presentation. In the past 12 months, I have not had a significant financial interest or other relationship with the manufacturer(s) of the product(s) or provider(s) of the service(s) that will be discussed in my presentation. This presentation will not include discussion of pharmaceuticals or devices that have not been approved by the FDA. This presentation will not include discussion of pharmaceuticals or devices that have not been approved by the FDA.

3. Auditory Neuropathy Auditory dys-synchrony (AD) Auditory dys-synchrony (AD) Transmission of sound to the brain is abnormal Transmission of sound to the brain is abnormal Abnormal brainstem evoked responses (ABR) Abnormal brainstem evoked responses (ABR) Normal acoustic emissions (OAE) Normal acoustic emissions (OAE) Preserved cochlear microphonics Preserved cochlear microphonics Acoustic reflex absent Acoustic reflex absent May be missed with OAE screening May be missed with OAE screening

4. Auditory Neuropathy Pathophysiology Pathophysiology Cochlear inner hair cells Cochlear inner hair cells Neural pathways: CN VIII Neural pathways: CN VIII Brainstem Brainstem Speech perception is impaired Speech perception is impaired Fluctuating losses Fluctuating losses Difficulty in background noise Difficulty in background noise Prognosis is unpredictable Prognosis is unpredictable Optimum management is unclear Optimum management is unclear

5. High risk neonates Sensorineural hearing loss is 10 times more prevalent Sensorineural hearing loss is 10 times more prevalent Auditory neuropathy (AN) Auditory neuropathy (AN) Rance, et al 1999 Rance, et al 1999 1991-1996 1991-1996 5199 infants screened (at risk population) 5199 infants screened (at risk population) 2.3/1000 AN 2.3/1000 AN 11% of 109 SNHL 11% of 109 SNHL Berg, et al 2005 Berg, et al 2005 Mar 2002-Dec 2003 Mar 2002-Dec 2003 24.1% of 432 NICU (regional perinatal center) 24.1% of 432 NICU (regional perinatal center)

6. Risk Factors Family history Family history Prematurity Prematurity Hyperbilirubinemia Hyperbilirubinemia Ototoxic medications Ototoxic medications Hypoxia Hypoxia Hydrocephalus Hydrocephalus Meningitis Meningitis

7. Objectives Establish prevalence rate for auditory neuropathy in the high risk nursery Establish prevalence rate for auditory neuropathy in the high risk nursery Differentiate infants with auditory neuropathy from those with cochlear hearing loss Differentiate infants with auditory neuropathy from those with cochlear hearing loss

8. Patient Population Retrospective review Retrospective review 1999-2003 1999-2003 Kapiolani Medical Center for Women and Children Newborn Special Care Unit Kapiolani Medical Center for Women and Children Newborn Special Care Unit Sensorineural hearing loss Sensorineural hearing loss Auditory neuropathy Auditory neuropathy Gestational age-matched controls Gestational age-matched controls

9. Data Collected Demographics Gestational age Gestational age Birthweight Birthweight Gender Gender Ethnicity Ethnicity Apgar scores Apgar scores Severity of illness Severity of illness Length of hospitalization Length of hospitalization Chronic lung disease Chronic lung disease Intraventricular hemorrhage Intraventricular hemorrhage Necrotizing enterocolitis Necrotizing enterocolitis

10. Data Collected Risk Factors Medications Medications Furosemide Furosemide Aminoglycosides Aminoglycosides Vancomycin Vancomycin Dexamethasone Dexamethasone Infections Infections CMV CMV Toxoplasmosis Toxoplasmosis Meningitis Meningitis

11. Mechanical ventilation Mechanical ventilation Conventional ventilation Conventional ventilation High frequency ventilation High frequency ventilation Hyperbilirubinemia Hyperbilirubinemia Pulmonary hypertension Pulmonary hypertension Nitric oxide Nitric oxide Data Collected Risk Factors

12. AN vs SNHL vs Control AN/AD(24)SNHL(71)Control(92) Gestational age (wks) 28±5 28±5 33±532±5 Birthweight (g) 1318±894 1318±894 1968±10061872±996 Male gender (%) 586153 1 min apgar 4.8±2.56.1±2.25.6±2.3 5 min apgar 6.7±1.67.7±1.77.3±1.7 Length of hospitalization (d) 117±76* 117±76* 73±89* 40±62 *p<0.05 vs. Control p<0.05 vs. SNHL

13. Gestational Age Distribution High Risk Nursery 1999-2003

14. PREVALENCE By Gestational Age Group

15. Exposure to Medications AN/AD(%)SNHL(%)Control(%) Aminoglycoside s 95.8* 80.370.7 Furosemide 50.7* 32.6 Vancomycin 79.2 * 41.427.2 Dexamethasone 54.2* 32.4* 14.1 *p<0.05 vs control p p< 0.05 vs SNHL

16. Neonatal Morbidities AN/ADSNHLControl Peak Bilirubin (mg/dl) 12.7±4.2 13.1±6.3* 10.0±3.5 Ventilation (d) 45±42* 28±3119±29 HFOV (%) 16.7 28.2* 8.7 CMV Infection (%) 0 7.0* 0 *p<0.05 vs Control

17. Neonatal Morbidities AN/AD(%)SNHL(%)Control(%) BPD 66.7 * 30.0* 23.9 IVH16.79.93.3 Hydrocephalus4.28.53.3 NEC8.38.53.3 * p<0.05 vs. control p < 0.05 vs. SNHL

18. Summary SNHL = 21/1000 in the NICU SNHL = 21/1000 in the NICU AN/AD = 5.3/1000 AN/AD = 5.3/1000 26% of hearing loss 26% of hearing loss 2/3 were 28 wks gestation 2/3 were 28 wks gestation 44% of hearing loss for those 28 wks 44% of hearing loss for those 28 wks

19. Summary AN/AD vs. SNHL AN/AD vs. SNHL Younger gestation Younger gestation Lower birthweight Lower birthweight Greater exposure to potential ototoxic medications Greater exposure to potential ototoxic medications Furosemide Furosemide Vancomycin Vancomycin Higher incidence of BPD Higher incidence of BPD Longer hospitalization Longer hospitalization

20. Conclusions Auditory neuropathy is a significant problem in the high risk nursery population. Auditory neuropathy is a significant problem in the high risk nursery population. Extremely premature infants are at highest risk. Extremely premature infants are at highest risk.

21. Perspective Infants in the high risk nursery should be routinely screened by both ABR and OAE before hospital discharge. Infants in the high risk nursery should be routinely screened by both ABR and OAE before hospital discharge. Early identification of AN/AD will lead to a better understanding of the pathophysiology and the development of appropriate intervention strategies. Early identification of AN/AD will lead to a better understanding of the pathophysiology and the development of appropriate intervention strategies.