International Journal of Audiology 2015; 54: 89–95
Original Article
Auditory neuropathy in late preterm infants treated with phototherapy for hyperbilirubinemia Emrah Can*, Ayşegül Verim†, Engin Başer‡ & Nurkan İnan‡ *Edirne State Hospital, Neonatal Intensive Care Unit, Edirne, Turkey, †Otolaryngology, Haydarpaşa Numune Education and Research Hospital, Istanbul, Turkey, and ‡Otolaryngology, Edirne State Hospital, Edirne, Turkey
Abstract Objective: To evaluate the prevalence of auditory neuropathy (AN) in late preterms treated with phototherapy for hyperbilirubinemia. Design: Prospective observational study comprising late preterms treated with phototherapy for hyperbilirubinemia. Newborns were screened with combined transient-evoked otoacoustic emissions (TEOAEs) / automated auditory brainstem responses (AABR). Infants who failed screening underwent diagnostic (ABR). Infants were all re-evaluated with AABR at one year. Study sample: Eighty-five infants with a mean serum total bilirubin concentration of 22.3 ⫾ 1.76 mg/dl; severe-hyperbilirubinemia (SH), and 102 infants with a mean serum total bilirubin concentration of 18.6 ⫾ 1.26 mg/dl; non-severe hyperbilirubinemia (NSH) were included. Results: From 85 late preterms with SH, six (7.1%) failed screening and underwent diagnostic ABR for six weeks. AN was diagnosed in two (2%) infants with SH. Four (3.9%) of the 102 controls with NSH demonstrated failure at TEOAE/AABR. No AN was diagnosed in the control group at the diagnostic ABR. No statistically significant difference was found between infants treated with phototherapy for SH and NSH with regard to AN/AD either in the postnatal period or at one year. No correlation was found between serum bilirubin levels and ABR latencies or thresholds. Conclusions: AN (2%) in late preterms treated with phototherapy for severe-hyperbilirubinemia was not higher than in those with non-severe hyperbilirubinemia.
Key Words: Hyperbilirubinemia; auditory brainstem-evoked response; transient-evoked otoacoustic emissions; auditory neuropathy; late preterms; neonates
Sensorineural hearing loss has been widely described as a characteristic feature of chronic post-kernicteric encephalopathy. More recently, auditory neuropathy (AN), an auditory disorder presenting with normal otoacoustic missions (OAE) test and cochlear microphonic (CM) but abnormal or absent auditory brainstem evoked response (ABR), has been reported in a series by Saluja, in association with a prior history of neonatal jaundice (Saluja et al, 2010). Basically ANSD is defined as a condition that affects the inner hair cells, their synapses and/or the cochlear nerve. As evidenced by the presence of evoked otoacoustic emissions (EOAEs) and/or CM outer hair cell function is normal. However, there is abnormal neural function at the level of the inner hair cells, cochlear nerve, or an impaired neural conduction in the auditory pathways characterized by an absent or significantly altered auditory brainstem response (ABR) (Luo et al, 2008; Hood et al, 2003; Madden et al, 2002). This condition accounts for 7% of permanent childhood hearing losses and a significant percentage of adulthood hearing impairments
(Sheykholeslami & Kaga, 2000). The most frequent infantile problems accompanying AN include anoxia, hyperbilirubinemia, some syndromic peripheral neuropathies, and genetic disorders. Although most infantile hyperbilirubinemia (60%) is physiological and harmless, even short-term increases in the bilirubin level can induce temporary or permanent changes in evoked potentials, such as an increase in threshold and wave latency (I–V) in ABR, which indicates the sensitivity of both peripheral and central auditory systems to high bilirubin levels (Rance, 2005). However, the rate of diagnosis of AN has increased with the routine use of OAEs and AABR testing in newborn hearing screening programs; there is still a paucity of information on the prevalence and factors associated with AN and this condition still remains an important area to investigate. Regarding the limited number of scientific studies in the literature due to the rarity of this condition, the present study aimed to evaluate AN in late preterm infants with sub-exchange transfusion bilirubin levels.
Correspondence: Emrah Can, Edirne State Hospital, Neonatal Intensive Care Unit, Atatürk Caddesi 22000 Edirne, Turkey. E-mail: [email protected] (Received 10 October 2012; accepted 22 June 2014 ) ISSN 1499-2027 print/ISSN 1708-8186 online © 2015 British Society of Audiology, International Society of Audiology, and Nordic Audiological Society DOI: 10.3109/14992027.2014.938779
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formations, history of exposure to aminoglycosides, family history of hearing loss, perinatal asphyxia, congenital infections, and sepsis were defined as exclusion criteria. After a full work-up for neonatal jaundice (total, conjugated, and unconjugated serum bilirubin, liver function tests, congenital infection screening, direct Coombs’ test, hemoglobin and hematocrit values, erythrocyte morphology), total serum bilirubin levels were monitored according to hour-specific norms using the Bhutani Nomogram (Bhutani et al, 1999). Infants were treated in line with the guidelines from the American Academy of Pediatrics Subcommittee on Hyperbilirubinemia (AAP). Newborns with hyperbilirubinemia who did not respond to phototherapy and who were undergoing exchange transfusion were excluded from the study (American Academy of Pediatrics Subcommittee on Hyperbilirubinemia, 2004).
Abbreviations AABR ABR AD AN ANSD CM EOAE NICU OAE SNHL TEOAE
Automated auditory brainstem response Auditory brainstem response Auditory dyssynchrony Auditory neuropathy Auditory neuropathy spectrum disorder Cochlear microphonics Evoked otoacoustic emission Neonatal intensive care unit Otoacoustic emission Sensorineural hearing loss Transient evoked otoacoustic emission
Evaluation and diagnostic tests
Methods Study design This was a prospective observational study carried out in a Level II neonatal intensive care unit (NICU) to evaluate the prevalence of AN in late preterm infants who were treated with phototherapy for severe and non-severe hyperbilirubinemia. Late preterm infants, gestational age between 34 weeks and 36 weeks, 6 days and with a birth weight greater than or equal to 2500 g admitted to the NICU for hyperbilirubinemia (total serum bilirubin level below, equal or greater than 20 mg/dl) and treated with phototherapy, were enrolled in the study (Wang et al, 2004; American Academy of Pediatrics Subcommittee on Hyperbilirubinemia, 2004). Approval was obtained from the institutional local ethics committee, and written informed consent was taken from one of the parents before study enrollment.
Subjects A total of 187 late preterms with sub-exchange transfusion bilirubin levels who underwent phototherapy for the treatment of hyperbilirubinemia, were included in the study. The study group (severe hyperbilirubinemia group) comprised 85 infants with total serum bilirubin ⱖ 20 mg/dl. The control group (non-severe hyperbilirubinemia group) was constituted of 102 late preterms with total serum bilirubin ⬍ 20 mg/dl. Sensitivity and specificity analyses of bilirubin levels were done for determining the optimal cut-offs for predicting AN/AD in newborns and the levels of hyperbilirubinemia were decided based on these results; Table1. All infants were assessed for risk factors that may affect hearing. Craniofacial mal-
Table 1. ROC curve analysis for severe hyperbiluribinemia. Criterion Sensitivity ⬍ 20 ⱕ 20.5* ⱕ 21.2 ⱕ 22 ⱕ 22.8 ⱕ 23 ⱕ 24.6
0.00 50.00 50.00 66.67 66.67 100.00 100.00
95%CI
Specificity
95%CI
0.0–45.9 12.4–87.6 12.4–87.6 22.7–94.7 22.7–94.7 54.1–100.0 54.1–100.0
100.00 100.00 79.45 56.16 42.47 23.29 0.00
95.0–100.0 95.0–100.0 68.4–88.0 44.1–67.8 31.0–54.6 14.2–34.6 0.0–5.0
⫹ LR
2.43 1.52 1.16 1.30 1.00
⫺ LR 1.00 0.50 0.63 0.59 0.78 0.00
⫹ LR: Positive likelihood ratio. ⫺ LR: Negative likelihood ratio. Area under the ROC curve: 0.723. Standard error: 0.093. 95% Confidence interval: 0.610 to 0.817. Significance level P (Area ⫽ 0.5): 0.0162.
Otoscopic examinations were performed with Mini-Heine otoscopes to confirm that the external and middle ears of the newborns were free of any disease before the screening tests. Screening tests for hearing loss using combined transient-evoked otoacoustic emissions (TEOAEs) and automated auditory brainstem response (AABR) were carried out on infants immediately after treatment of hyperbilirubinemia, as was indicated by a serial decrease in total serum bilirubin levels to ⬍ 13 mg/dl within 48 hours before discharge from hospital. After the completion of phototherapy, TEOAE and AABR tests were performed in a quiet room with a portable AccuScreen OAE/ ABR screener (Otometrics Madsen Electronics, Copenhagen, Denmark). For TEOAEs the device emitted significant signal peaks obtained with non-linear click levels of about 70–84 dB SPL (45–60 dB nHL), with a click rate of approximately 60 Hz and frequency range of 1500–4500 Hz . The presence or absence of TEOAEs was based on the evaluation of amplitude and signal to noise ratio. For AABR, the device applied 35, 40, or 45 dB nHL clicks with a click rate of approximately 80 Hz and an impedance of ⬍ 12 kΩ. When each test was completed, the results were presented on the screen as ‘PASS’ or ‘REFER’ with regard to the presence or absence of the response to stimuli. When the device displayed ‘REFER’ after TEOAE screening, the test was repeated twice after a second otoscopy to remove vernix or debris that may plug the ear canals and temporarily prevent the signal from reaching the cochlea. AABR screening was carried out after TEOAE screening using the same device. Results were recorded from the ipsilateral mastoids of the infant using silver / silver chloride EEG scalp electrodes. The auditory stimuli were in the form of alternating clicks of 80 ms pulses, with an intensity of 35 dB nHL delivered via bilateral ear probes. On completion of the AABR tests, the results were presented as either ‘PASS’, when there was a response to the stimulus at ⱕ 35 dB nHL, or ‘REFER’ when there was no response to the clicking stimuli at these settings, suggesting possible sensorineural hearing loss or auditory neuropathy. A different protocol was used in the audiology laboratory of a tertiary referral center for detailed ABR testing on infants whose results were ‘REFER’ after portable TEOAE/AABR screening in NICU, within six weeks after discharge from hospital, by one of the audiology technicians who was not aware of the screening results and the peak total serum bilirubin levels of the infants. Detailed ABR test parameters were as follows: time window 0–15 ms, average response 2000 times, a rate of 11.2 stimuli/s, a stimulus intensity of 90 dB nHL. Alternating polarity
Auditory neuropathy in late preterms with hyperbilirubinemia was used in the first ABR recordings. Absolute latencies of waves I, III, and V, and inter-wave latencies of I–III, III–V, and IV waves were measured. In order to identify the hearing threshold for wave V, the stimulus intensity was lowered through decreasing levels in 20 dB steps. The criterion for normal hearing was the presence of wave V at a stimulus intensity of 20 dB nHL. Infants with no detection of waves at the maximal stimulus level or with abnormal waves on diagnostic ABR were suspected of having AN, and CM were considered to confirm the diagnosis. Click stimuli of 0.1 ms duration, intensity of 90 dB nHL, repetition rate of 87.1/s, and a bandpass filter from 300 Hz to 5000 Hz were used via tubal insert earphones in a 10-ms time window. Later recordings were obtained with condensation and rarefaction polarities, and were compared to observe CM in ABR recordings. Multiple runs were performed with the insert tube clamped to confirm that the potential was a real CM and not an artefact. AN was confirmed in infants after observing CM on detailed ABR. One year later, AABR tests were repeated in all infants for screening late effect of hyperbilirubinemia on children’s auditory system at one year.
Statistical analysis The power and sample size were calculated based on the differences in prevalence of AN in late preterms with severe and nonsevere hyperbilirubinemia, using a comparison of postnatal AABR, detailed ABR, and long-term AABR results. The sensitivity analysis and power calculation demonstrated that a sample size with a total of 78 neonates in the study group would give us the ability to detect statistically significant differences in the prevalence of AN between groups (δ ⫽ 0.45; SD: 0.8; power 80%; α ⫽ 0.05). The association between serum bilirubin levels and TEOAE/ AABR test results was evaluated with non-parametric Spearman correlation tests, while differences between groups of discrete variables were compared with the chi-square and Mann-Whitney U-test. Initial and one-year AABR tests were compared with Wilcoxon tests. P-values ⬍ 0.05 were considered to be statistically significant.
Results A total of 187 neonates, of these 85 infants with severe hyperbilirubinemia (22.3 ⫾ 1.76 mg/dl, mean ⫾ SD), and 102 controls with non-severe hyperbilirubinemia (18.6 ⫾ 1.26, mean ⫾ SD) were enrolled in the study. Details of the group characteristics are shown in Table 2. There was no statistically significant difference between the groups with regard to weeks of gestation, birth weight, Cesarean section, gender, and admission time to the NICU. However, there was a statistically significant difference between mean serum total bilirubin levels of the groups (p ⬍ 0.001).
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Twenty (23.5%) late preterms in the study group failed the initial TEOAE tests. These infants were retested after a detailed otoscopic evaluation by the Ear Nose and Throat (ENT) department. Of these, four infants passed the repeat TEOAE tests while 16 (19%) failed. As for the initial combined AABR tests, 79 (93%) late preterms with severe hyperbilirubinemia passed, whereas six (7%) failed AABR screening. These infants who had failed AABR screening underwent detailed ABR testing. Sixteen (15.6%) infants in the control group failed the initial TEOAE tests and underwent a detailed ENT evaluation before the repeat tests. Four infants passed whereas 12 (12%) infants failed the repeat TEOAE tests. However, 98 infants (96.0%) in the control group, passed AABR screening while four (4%) failed. Except for children with AN/AD, neonates with abnormal or absent AABR all failed at TEOAE tests. Details of the combined TEOAE/AABR screenings are shown in Table 3. Diagnostic ABR responses of all infants who failed AABR screening tests were measured within six weeks postnatally. Based on the ABR threshold, hearing loss was categorized into the following classes: mild (36–50 dB nHL), moderate (51–70 dB nHL), severe (71–90 dB nHL), and profound (⬎ 90 dB nHL). Neonates with abnormal or absent ABR at 90 dB were suspected of having AN, and CM recordings were considered for a definitive diagnosis. Four (5%) preterms with severe hyperbilirubinemia (study group) displayed moderate hearing loss (60 dB nHL) in both ears, while two (2%) showed abnormal waves on ABR testing. These infants were diagnosed as having AN when sinusoidal waveforms in the rarefaction and condensation polarities were observed, beginning within 1 ms of stimulus and lasting up to 5 or 6 ms with a polarity reversal with click polarity. Four (5%) preterms with severe hyperbilirubinemia were diagnosed as having moderate sensorineural hearing loss (SNHL) on detailed ABR recordings. The prevalence of SNHL and AN was 5% and 2%, respectively, in late preterms with no additional risk factors treated with phototherapy and with mean total serum bilirubin levels of 22.3 ⫾ 1.76 mg/dl. In the control group, although increased latencies were found in 4 (4%) infants, on detailed ABR, the presence of wave V was demonstrated at 50 dB nHL in all four. The prevalence of SNHL was 4% and no AN was detected in late preterms with no additional risk factors treated with phototherapy and with mean total serum bilirubin levels of 18.6 ⫾ 1.26 mg/ dl. However, with regard to the prevalence of AN/AD and SNHL, the difference between the groups was not statistically significant (p ⬎ 0.53) (Table 4). One year later, all of the infants were re-tested with AABR screening. Only two (2%) infants with an abnormal diagnostic ABR test and presence of CM in the severe hyperbilirubinemia group failed the AABR screening test at one year; infants who were thought to have SNHL all passed the AABR test at one year.
Table 2. Baseline characteristics of groups.
Weeks of gestation Birth weight (g), mean ⫾ SD Cesarean section, n (%) Serum total bilirubin (mg/dl), (mean ⫾ SD) Male sex, n (%) Time to admission to NICU (days), mean ⫾ SD (range)
Severe hyperbilirubinemia (n ⫽ 85)
Non-severe hyperbilirubinemia (n ⫽ 102)
P-value
35.2 ⫾ 1.1 (34–36) 2876.16 ⫾ 229.26 33 (38.9) 22.3 ⫾ 1.76 59 (69.4) 5.7 ⫾ 1.4 (2.1–9.4)
35.5 ⫾ 1.2 (34–36) 2916.16 ⫾ 235.13 42 (38.9) 18.6 ⫾ 1.26 (71.4) 6.0 ⫾ 1.6 (3.2–10.6)
0.07 0.24 0.85 0.001 0.06 0.17
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Table 3. Initial screening tests: Combined TEOAE/AABR results in late preterms. Non-severe hyperbilirubinemia (n ⫽ 102)
Severe hyperbilirubinemia (n ⫽ 85) Right ear
Left ear
In the literature, there is not a threshold level for hyperbilirubinemia that may cause AN in infants treated with exchange transfusion. Bilirubin values varying from 7 to 25 mg/dl were reported to cause AN/AD (Raveh et al, 2007). Nevertheless, in this study, prematurity is suggested to be an additional factor contributing to the etiology of AN developed at low bilirubin levels which is in line with earlier reports that listed prematurity and low birth-weight as additional risk factors for kernicterus, permanent sequelae, and AN/AD development at serum bilirubin levels below those thought to be safe for term infants (Stein et al, 1996). In addition to the level of bilirubin, the duration of exposure to high levels of bilirubin was also found to be related to AN (De Vries et al, 1987). In line with the abovementioned suggestions, in a retrospective study carried out on infants with hearing problems, although therapeutic intervention was performed as appropriate to the level of bilirubin, ranging from no intervention to phototherapy or exchange transfusion when needed, AN/AD was present with mean total bilirubin levels of about 19.4 mg/dl, that increased in the early postpartum period (day 2 or 3) and lasted for 4 to 10 days with a mean of 6.8 days duration (Madden et al, 2002). In a recent study on 13 late preterm and term infants who underwent exchange transfusion for the treatment of severe jaundice, the authors found no AN/AD with mean peak total serum bilirubin concentrations of about 23 ⫾ 7.3 mg/dl (Saluja et al, 2010). The high levels of hyperbilirubinemia that were thought to cause neuropathy did not play a role in the development of the disease in that study as infants were free from other co-morbid conditions. Our study differed from the above in several respects including study population, treatment and follow-up of hearing disorders. Apart from the late preterm nature of the infants, a factor which is known to predispose them to develop hyperbilirubinemia, all other predisposing factors were accepted as exclusion criteria. We primarily aimed to investigate prospectively the effect of sub-exchange bilirubin levels on the prevalence of AN/AD and to determine cutoffs for predicting bilirubin-induced AN/AD. In fact with regard to the absence of AN in our late preterms with mean total serum bilirubin levels of about 18.6 ⫾ 1.26 mg/dl, we may suggest that total serum bilirubin levels ⬍ 20 mg/dl may be accepted as a safe cut-off value for AN/AD in late preterms with sub-exchange bilirubin levels and with no additional risk factors. Moreover, based on the results derived from our study, we may assert that total serum bilirubin levels ⬎ 20 mg/dl (mean 22.3 ⫾ 1.76 mg/dl) may cause AN/ AD in 2% of late preterms treated with phototherapy, Table 1. The low prevalence of AN/AD in the present study was a consequence of our stricter inclusion criteria, and was not in accordance with the high rates of AN/AD seen in the studies of Saluja et al (46.15%), Xu
Right ear
Left ear
Pass Refer Pass Refer Pass Refer Pass Refer P-value* TEOAE 69 AABR 79
16 6
69 79
16 6
90 98
12 4
90 98
12 4
0.25 0.53
*p ⬍ 0.05
Auditory neuropathy was detected in 2% of the infants treated with phototherapy for severe hyperbilirubinemia, whereas all of the infants with non-severe hyperbilirubinemia passed the AABR test at one year (Table 5). However, no statistically significant difference was found between groups either in the postnatal period or one year later with regard to the presence of auditory neuropathy (P ⬎ 0.05). Moreover, no correlation was found between serum bilirubin levels and latencies or thresholds at detailed ABR tests [r2: 0.15 (CI 0.12–0.35)]. SNHL detected on detailed ABR in the postnatal period was not confirmed at AABR screening after one year.
Discussion Auditory neuropathy, also known as auditory dyssynchrony (AN/ AD) or auditory neuropathy spectrum disorder (ANSD), comprises a spectrum of problems that may affect any part of the auditory pathway, from the inner hair cells to the auditory brainstem. Patients with this disorder have difficulty with language decoding and speech perception out of proportion to their hearing loss. Several risk factors such as neonatal history of anoxia, mechanical ventilation, hypoxia, congenital brain abnormalities, low birthweight, premature birth (⬍ 28 week), genetic disorders, or family history have been speculated in the etiology of AN/AD. However, because of the high sensitivity of the central auditory system to bilirubin toxicity, neonatal history of hyperbilirubinemia was observed to be a significant factor among terms and preterms in recent studies (Starr et al, 2000; Akman et al, 2004; Berlin et al, 2010; Shapiro & Popelka, 2011; Kirkim et al, 2008; Rhee et al, 1999). In early reports, one-third to one-half of infants with AN/AD were defined to be associated with significant hyperbilirubinemia (Funato et al, 1994; Deltenre et al, 1997).
Table 4. Diagnostic ABR test results in postnatal period. Severe hyperbilirubinemia (n ⫽ 85) Right ear ABR thresholds Mild SNHL (36–50 dB nHL) Moderate SNHL 51–70 dB nHL Severe SNHL 71–90 dB nHL Absent/abnormal *p ⬍ 0.05
Left ear
Non-severe hyperbilirubinemia (n ⫽ 102) Right ear
Left ear
P-value* 0.53
4 4 2
4 4 2
2
4
4
4
Auditory neuropathy in late preterms with hyperbilirubinemia
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Table 5. Initial and one-year AABR test results in infants with severe and non-severe hyperbilirubinemia. Initial AABR Right ear
Severe hyperbilirubinemia Non-severe hyperbilirubinemia
AABR after 1 year
Left ear
Right ear
Left ear
Pass
Refer
Pass
Refer
Pass
Refer
Pass
Refer
79 98
6 4
79 98
6 4
83 102
2 0
83 102
2 0
P-value* 0.27
*Wilcoxon test, p ⬍ 0.05
et al (24%), Akman et al (36.8%), and Baradaranfar et al (14.3%) (Saluja et al, 2010; Akman et al, 2004; Baradaranfar et al, 2011; Xu et al, 2011). Our finding of a very significant difference (p ⬍ 0.001) between total serum bilirubin levels of late preterms with and without AN is not in line with the findings of other authors who observed no significant difference between mean peak total serum bilirubin concentrations of neonates with and without acute AN (Saluja et al, 2010). However, mean peak total serum bilirubin concentrations were obviously higher in the group with AN (27.9 ⫾ 2.4 mg/dl versus 23 ⫾ 7.3 mg/dl) in the aforementioned study, and no AN was observed with mean peak total serum bilirubin concentrations of about 23 ⫾ 7.3 mg/dl. In our opinion, given the neurotoxic effect of hyperbilirubinemia on the auditory pathway, there should have been a significant difference between bilirubin levels of infants with and without AN. The non-significant difference seen between bilirubin levels in the study by Saluja et al would probably be statistically significant in a well powered study. Considering the well-known degenerative effect of neonatal hyperbilirubinemia on the auditory system, the second objective that prompted the present study was to investigate the prevalence and course of SNHL associated with sub-exchange bilirubin levels in late preterms (Haustein et al, 2010). Early detection of hearing impairment around six months of age has been found to be of crucial importance in regard to higher expressive and receptive language development, higher general development, and lifelong improvement in social status (Yoshinaga-Itano et al, 1998). Although it still remains a challenge to define the actual effect of hyperbilirubinemia in hearing loss, a comprehensive review of the literature revealed various rates of SNHL associated with hyperbilirubinemia ranging from 2.09% to 28% (Clarós et al, 2003; Rance, 2005; Xu et al, 2011; Oğün et al, 2003). Moreover, apart from some studies that have shown transient and permanent ABR abnormalities such as elevated ABR thresholds and prolonged ABR wave I–V latencies resulting from short episodes of hyperbilirubinemia, there are still only a limited number of reports on the outcome of SNHL related to neonatal hyperbilirubinemia on long-term development (Hung, 1989; Starr et al, 2000). However, SNHL resulting from neonatal hyperbilirubinemia is thought to be more likely to be reversible than other types of hearing loss during the first year of life (Madden et al, 2002). SNHL detected in the present study was not significantly different between groups with regard to bilirubin levels ⬍ 20 mg/dl and ⬎ 20 mg/dl; 3.92% of the late preterms with hyperbilirubinemia ⬍ 20 mg/dl demonstrated 50 dB nHL on detailed ABR performed within two months. Meanwhile, 4.7% of preterms with hyperbilirubinemia ⬎ 20 mg/dl were diagnosed as having moderate SNHL on detailed ABR recordings in the postnatal period. However, as implicated
before in other studies, SNHL seen on diagnostic ABR was not observed in one year AABR screening, suggesting improvement in early SNHL initiated by bilirubin toxicity in the newborn period. This improvement may be attributable to the transient neurotoxic effect of sub-exchange bilirubin levels in neonates free from other co-morbid conditions. AN/AD is characterized by abnormal ABRs, absent middle-ear reflexes, normal OAEs, and cochlear microphonic responses that invert with stimulus polarity. In an effort to detect and define earlier hearing disorders and types, various medical devices (OAE and ABR alone or combined in the same screener) have been developed. Use of combined OAE and ABR testing has been shown to ensure high sensitivity and acceptable specificity in predicting the auditory neuropathy profile as well as sensorineural hearing losses in NICU infants (Xu et al, 2011). In our study, screening tests were performed with a combined TEOAE and AABR screening device. The failure rate observed in TEOAE screening was 16/85 (19%) and 12/102 (12%) in the severe and non-severe hyperbilirubinemia groups, respectively. However, the numbers of infants diagnosed with hearing problems after ABR testing were 6/85 (7%) and 4/102 (4%) in the severe and non-severe hyperbilirubinemia groups, respectively. Although OAE is a useful first-line diagnostic test in detecting outer hair cell damage, some authors, relying on the absence of OAE observed in preterm babies, hypothesized that this condition may be the result of smaller middle-ear cavities that may impede the transmission of OAE energy from the cochlea to the external ear that may persist to at least the sixth postnatal month (Mason & Herrmann, 1998; Abdala, 2004; Bonfils et al, 1992; Kok et al, 1993; Suppiej et al, 2007). This theory may help to explain the high percentage of OAE failures seen in groups with or without severe hyperbilirubinemia in the present study, even after the second otoscopic control and elimination of all conditions in the external ear that may hinder emissions. TEOAE screening is recommended in the diagnosis of ANSD. However, since several studies have reported the disappearance of otoacoustic emissions or their absence in a large number of AN patients due to underlying conductive loss, the absence of a recordable OAE cannot be taken as evidence for the absence of ANSD (Rance et al, 1999; Starr et al, 2001; Deltenre et al, 1999). As TEOAE screening is not a highly reliable method in the diagnosis of AN/AD, we referred ultimately to cochlear microphonics recording which is a sine qua non for surveying the integrity of cochlear hair cells to identify AN/AD in preterms with abnormal waves on diagnostic ABR. The absence or severe abnormality of the ABR at maximum levels in ears with sensorineural hearing loss is an indicator of cochlear damage. In such cases, the cochlear microphonics would also be expected to be absent. The presence of CM
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with complete phase reversal between rarefaction and condensation stimuli on our ABR recordings demonstrated that the outer hair cells were intact. Therefore, the normal function of the outer hair cells indicated the neural transmission abnormality in preterms with absent or abnormal ABR potentials (Chisin et al, 1979; Berlin et al, 2003; Rapin & Gravel, 2003). The limitations of this study were its small sample size due to the exclusion of children with risk factors that may contribute to SNHL, and its restriction to a moderate level of hyperbilirubinemia which did not require exchange transfusion. However, the study was designed to investigate the impact of moderate levels of hyperbilirubinemia on the auditory nerve. In this regard, our study is, to our knowledge, the only prospective study to determine AN/AD in late preterms with repeat AABRs at one year. The association of hyperbilirubinemia with auditory neuropathy spectrum disorder is still an important area to investigate. With future innovations in laboratory testing, we hope that we would be able to prevent this incapacitating condition.
Conclusion The results of this study demonstrated that 19% of late preterms with mean total serum bilirubin levels of 22.3 ⫾ 1.76 mg/dl, and 12% with mean total bilirubin levels of 18.6 ⫾ 1.26 mg/dl failed TEOAE screening; 7% of late preterms with mean total serum bilirubin levels of 22.3 ⫾ 1.76 mg/dl and 4% with mean total bilirubin levels of 18.6 ⫾ 1.26 mg/dl failed AABR screening. Five percent of late preterms with mean total serum bilirubin levels of 22.3 ⫾ 1.76 mg/dl displayed SNHL (60 dB nHL) in both ears, and 2% AN/AD at detailed ABR within six weeks; 4% of late preterms with mean total bilirubin levels of 18.6 ⫾ 1.26 mg/dl demonstrated SNHL in both ears (50 dB nHL) and none with AN/AD at detailed ABR within six weeks. Two percent of late preterms with mean total serum bilirubin levels of 22.3 ⫾ 1.76 mg/dl were diagnosed as having permanent AN/AD at AABR screening after one year. SNHL detected in the postnatal period was not verified in one year AABR screening in either group.
Acknowledgements The authors would like to thank Mrs Başak Fırat from the audiology laboratory for her contribution in ABR testing of the infants.
Declaration of interest: The authors state that there is no conflict of interest.
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Original Article
Auditory neuropathy in late preterm infants treated with phototherapy for hyperbilirubinemia Emrah Can*, Ayşegül Verim†, Engin Başer‡ & Nurkan İnan‡ *Edirne State Hospital, Neonatal Intensive Care Unit, Edirne, Turkey, †Otolaryngology, Haydarpaşa Numune Education and Research Hospital, Istanbul, Turkey, and ‡Otolaryngology, Edirne State Hospital, Edirne, Turkey
Abstract Objective: To evaluate the prevalence of auditory neuropathy (AN) in late preterms treated with phototherapy for hyperbilirubinemia. Design: Prospective observational study comprising late preterms treated with phototherapy for hyperbilirubinemia. Newborns were screened with combined transient-evoked otoacoustic emissions (TEOAEs) / automated auditory brainstem responses (AABR). Infants who failed screening underwent diagnostic (ABR). Infants were all re-evaluated with AABR at one year. Study sample: Eighty-five infants with a mean serum total bilirubin concentration of 22.3 ⫾ 1.76 mg/dl; severe-hyperbilirubinemia (SH), and 102 infants with a mean serum total bilirubin concentration of 18.6 ⫾ 1.26 mg/dl; non-severe hyperbilirubinemia (NSH) were included. Results: From 85 late preterms with SH, six (7.1%) failed screening and underwent diagnostic ABR for six weeks. AN was diagnosed in two (2%) infants with SH. Four (3.9%) of the 102 controls with NSH demonstrated failure at TEOAE/AABR. No AN was diagnosed in the control group at the diagnostic ABR. No statistically significant difference was found between infants treated with phototherapy for SH and NSH with regard to AN/AD either in the postnatal period or at one year. No correlation was found between serum bilirubin levels and ABR latencies or thresholds. Conclusions: AN (2%) in late preterms treated with phototherapy for severe-hyperbilirubinemia was not higher than in those with non-severe hyperbilirubinemia.
Key Words: Hyperbilirubinemia; auditory brainstem-evoked response; transient-evoked otoacoustic emissions; auditory neuropathy; late preterms; neonates
Sensorineural hearing loss has been widely described as a characteristic feature of chronic post-kernicteric encephalopathy. More recently, auditory neuropathy (AN), an auditory disorder presenting with normal otoacoustic missions (OAE) test and cochlear microphonic (CM) but abnormal or absent auditory brainstem evoked response (ABR), has been reported in a series by Saluja, in association with a prior history of neonatal jaundice (Saluja et al, 2010). Basically ANSD is defined as a condition that affects the inner hair cells, their synapses and/or the cochlear nerve. As evidenced by the presence of evoked otoacoustic emissions (EOAEs) and/or CM outer hair cell function is normal. However, there is abnormal neural function at the level of the inner hair cells, cochlear nerve, or an impaired neural conduction in the auditory pathways characterized by an absent or significantly altered auditory brainstem response (ABR) (Luo et al, 2008; Hood et al, 2003; Madden et al, 2002). This condition accounts for 7% of permanent childhood hearing losses and a significant percentage of adulthood hearing impairments
(Sheykholeslami & Kaga, 2000). The most frequent infantile problems accompanying AN include anoxia, hyperbilirubinemia, some syndromic peripheral neuropathies, and genetic disorders. Although most infantile hyperbilirubinemia (60%) is physiological and harmless, even short-term increases in the bilirubin level can induce temporary or permanent changes in evoked potentials, such as an increase in threshold and wave latency (I–V) in ABR, which indicates the sensitivity of both peripheral and central auditory systems to high bilirubin levels (Rance, 2005). However, the rate of diagnosis of AN has increased with the routine use of OAEs and AABR testing in newborn hearing screening programs; there is still a paucity of information on the prevalence and factors associated with AN and this condition still remains an important area to investigate. Regarding the limited number of scientific studies in the literature due to the rarity of this condition, the present study aimed to evaluate AN in late preterm infants with sub-exchange transfusion bilirubin levels.
Correspondence: Emrah Can, Edirne State Hospital, Neonatal Intensive Care Unit, Atatürk Caddesi 22000 Edirne, Turkey. E-mail: [email protected] (Received 10 October 2012; accepted 22 June 2014 ) ISSN 1499-2027 print/ISSN 1708-8186 online © 2015 British Society of Audiology, International Society of Audiology, and Nordic Audiological Society DOI: 10.3109/14992027.2014.938779
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formations, history of exposure to aminoglycosides, family history of hearing loss, perinatal asphyxia, congenital infections, and sepsis were defined as exclusion criteria. After a full work-up for neonatal jaundice (total, conjugated, and unconjugated serum bilirubin, liver function tests, congenital infection screening, direct Coombs’ test, hemoglobin and hematocrit values, erythrocyte morphology), total serum bilirubin levels were monitored according to hour-specific norms using the Bhutani Nomogram (Bhutani et al, 1999). Infants were treated in line with the guidelines from the American Academy of Pediatrics Subcommittee on Hyperbilirubinemia (AAP). Newborns with hyperbilirubinemia who did not respond to phototherapy and who were undergoing exchange transfusion were excluded from the study (American Academy of Pediatrics Subcommittee on Hyperbilirubinemia, 2004).
Abbreviations AABR ABR AD AN ANSD CM EOAE NICU OAE SNHL TEOAE
Automated auditory brainstem response Auditory brainstem response Auditory dyssynchrony Auditory neuropathy Auditory neuropathy spectrum disorder Cochlear microphonics Evoked otoacoustic emission Neonatal intensive care unit Otoacoustic emission Sensorineural hearing loss Transient evoked otoacoustic emission
Evaluation and diagnostic tests
Methods Study design This was a prospective observational study carried out in a Level II neonatal intensive care unit (NICU) to evaluate the prevalence of AN in late preterm infants who were treated with phototherapy for severe and non-severe hyperbilirubinemia. Late preterm infants, gestational age between 34 weeks and 36 weeks, 6 days and with a birth weight greater than or equal to 2500 g admitted to the NICU for hyperbilirubinemia (total serum bilirubin level below, equal or greater than 20 mg/dl) and treated with phototherapy, were enrolled in the study (Wang et al, 2004; American Academy of Pediatrics Subcommittee on Hyperbilirubinemia, 2004). Approval was obtained from the institutional local ethics committee, and written informed consent was taken from one of the parents before study enrollment.
Subjects A total of 187 late preterms with sub-exchange transfusion bilirubin levels who underwent phototherapy for the treatment of hyperbilirubinemia, were included in the study. The study group (severe hyperbilirubinemia group) comprised 85 infants with total serum bilirubin ⱖ 20 mg/dl. The control group (non-severe hyperbilirubinemia group) was constituted of 102 late preterms with total serum bilirubin ⬍ 20 mg/dl. Sensitivity and specificity analyses of bilirubin levels were done for determining the optimal cut-offs for predicting AN/AD in newborns and the levels of hyperbilirubinemia were decided based on these results; Table1. All infants were assessed for risk factors that may affect hearing. Craniofacial mal-
Table 1. ROC curve analysis for severe hyperbiluribinemia. Criterion Sensitivity ⬍ 20 ⱕ 20.5* ⱕ 21.2 ⱕ 22 ⱕ 22.8 ⱕ 23 ⱕ 24.6
0.00 50.00 50.00 66.67 66.67 100.00 100.00
95%CI
Specificity
95%CI
0.0–45.9 12.4–87.6 12.4–87.6 22.7–94.7 22.7–94.7 54.1–100.0 54.1–100.0
100.00 100.00 79.45 56.16 42.47 23.29 0.00
95.0–100.0 95.0–100.0 68.4–88.0 44.1–67.8 31.0–54.6 14.2–34.6 0.0–5.0
⫹ LR
2.43 1.52 1.16 1.30 1.00
⫺ LR 1.00 0.50 0.63 0.59 0.78 0.00
⫹ LR: Positive likelihood ratio. ⫺ LR: Negative likelihood ratio. Area under the ROC curve: 0.723. Standard error: 0.093. 95% Confidence interval: 0.610 to 0.817. Significance level P (Area ⫽ 0.5): 0.0162.
Otoscopic examinations were performed with Mini-Heine otoscopes to confirm that the external and middle ears of the newborns were free of any disease before the screening tests. Screening tests for hearing loss using combined transient-evoked otoacoustic emissions (TEOAEs) and automated auditory brainstem response (AABR) were carried out on infants immediately after treatment of hyperbilirubinemia, as was indicated by a serial decrease in total serum bilirubin levels to ⬍ 13 mg/dl within 48 hours before discharge from hospital. After the completion of phototherapy, TEOAE and AABR tests were performed in a quiet room with a portable AccuScreen OAE/ ABR screener (Otometrics Madsen Electronics, Copenhagen, Denmark). For TEOAEs the device emitted significant signal peaks obtained with non-linear click levels of about 70–84 dB SPL (45–60 dB nHL), with a click rate of approximately 60 Hz and frequency range of 1500–4500 Hz . The presence or absence of TEOAEs was based on the evaluation of amplitude and signal to noise ratio. For AABR, the device applied 35, 40, or 45 dB nHL clicks with a click rate of approximately 80 Hz and an impedance of ⬍ 12 kΩ. When each test was completed, the results were presented on the screen as ‘PASS’ or ‘REFER’ with regard to the presence or absence of the response to stimuli. When the device displayed ‘REFER’ after TEOAE screening, the test was repeated twice after a second otoscopy to remove vernix or debris that may plug the ear canals and temporarily prevent the signal from reaching the cochlea. AABR screening was carried out after TEOAE screening using the same device. Results were recorded from the ipsilateral mastoids of the infant using silver / silver chloride EEG scalp electrodes. The auditory stimuli were in the form of alternating clicks of 80 ms pulses, with an intensity of 35 dB nHL delivered via bilateral ear probes. On completion of the AABR tests, the results were presented as either ‘PASS’, when there was a response to the stimulus at ⱕ 35 dB nHL, or ‘REFER’ when there was no response to the clicking stimuli at these settings, suggesting possible sensorineural hearing loss or auditory neuropathy. A different protocol was used in the audiology laboratory of a tertiary referral center for detailed ABR testing on infants whose results were ‘REFER’ after portable TEOAE/AABR screening in NICU, within six weeks after discharge from hospital, by one of the audiology technicians who was not aware of the screening results and the peak total serum bilirubin levels of the infants. Detailed ABR test parameters were as follows: time window 0–15 ms, average response 2000 times, a rate of 11.2 stimuli/s, a stimulus intensity of 90 dB nHL. Alternating polarity
Auditory neuropathy in late preterms with hyperbilirubinemia was used in the first ABR recordings. Absolute latencies of waves I, III, and V, and inter-wave latencies of I–III, III–V, and IV waves were measured. In order to identify the hearing threshold for wave V, the stimulus intensity was lowered through decreasing levels in 20 dB steps. The criterion for normal hearing was the presence of wave V at a stimulus intensity of 20 dB nHL. Infants with no detection of waves at the maximal stimulus level or with abnormal waves on diagnostic ABR were suspected of having AN, and CM were considered to confirm the diagnosis. Click stimuli of 0.1 ms duration, intensity of 90 dB nHL, repetition rate of 87.1/s, and a bandpass filter from 300 Hz to 5000 Hz were used via tubal insert earphones in a 10-ms time window. Later recordings were obtained with condensation and rarefaction polarities, and were compared to observe CM in ABR recordings. Multiple runs were performed with the insert tube clamped to confirm that the potential was a real CM and not an artefact. AN was confirmed in infants after observing CM on detailed ABR. One year later, AABR tests were repeated in all infants for screening late effect of hyperbilirubinemia on children’s auditory system at one year.
Statistical analysis The power and sample size were calculated based on the differences in prevalence of AN in late preterms with severe and nonsevere hyperbilirubinemia, using a comparison of postnatal AABR, detailed ABR, and long-term AABR results. The sensitivity analysis and power calculation demonstrated that a sample size with a total of 78 neonates in the study group would give us the ability to detect statistically significant differences in the prevalence of AN between groups (δ ⫽ 0.45; SD: 0.8; power 80%; α ⫽ 0.05). The association between serum bilirubin levels and TEOAE/ AABR test results was evaluated with non-parametric Spearman correlation tests, while differences between groups of discrete variables were compared with the chi-square and Mann-Whitney U-test. Initial and one-year AABR tests were compared with Wilcoxon tests. P-values ⬍ 0.05 were considered to be statistically significant.
Results A total of 187 neonates, of these 85 infants with severe hyperbilirubinemia (22.3 ⫾ 1.76 mg/dl, mean ⫾ SD), and 102 controls with non-severe hyperbilirubinemia (18.6 ⫾ 1.26, mean ⫾ SD) were enrolled in the study. Details of the group characteristics are shown in Table 2. There was no statistically significant difference between the groups with regard to weeks of gestation, birth weight, Cesarean section, gender, and admission time to the NICU. However, there was a statistically significant difference between mean serum total bilirubin levels of the groups (p ⬍ 0.001).
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Twenty (23.5%) late preterms in the study group failed the initial TEOAE tests. These infants were retested after a detailed otoscopic evaluation by the Ear Nose and Throat (ENT) department. Of these, four infants passed the repeat TEOAE tests while 16 (19%) failed. As for the initial combined AABR tests, 79 (93%) late preterms with severe hyperbilirubinemia passed, whereas six (7%) failed AABR screening. These infants who had failed AABR screening underwent detailed ABR testing. Sixteen (15.6%) infants in the control group failed the initial TEOAE tests and underwent a detailed ENT evaluation before the repeat tests. Four infants passed whereas 12 (12%) infants failed the repeat TEOAE tests. However, 98 infants (96.0%) in the control group, passed AABR screening while four (4%) failed. Except for children with AN/AD, neonates with abnormal or absent AABR all failed at TEOAE tests. Details of the combined TEOAE/AABR screenings are shown in Table 3. Diagnostic ABR responses of all infants who failed AABR screening tests were measured within six weeks postnatally. Based on the ABR threshold, hearing loss was categorized into the following classes: mild (36–50 dB nHL), moderate (51–70 dB nHL), severe (71–90 dB nHL), and profound (⬎ 90 dB nHL). Neonates with abnormal or absent ABR at 90 dB were suspected of having AN, and CM recordings were considered for a definitive diagnosis. Four (5%) preterms with severe hyperbilirubinemia (study group) displayed moderate hearing loss (60 dB nHL) in both ears, while two (2%) showed abnormal waves on ABR testing. These infants were diagnosed as having AN when sinusoidal waveforms in the rarefaction and condensation polarities were observed, beginning within 1 ms of stimulus and lasting up to 5 or 6 ms with a polarity reversal with click polarity. Four (5%) preterms with severe hyperbilirubinemia were diagnosed as having moderate sensorineural hearing loss (SNHL) on detailed ABR recordings. The prevalence of SNHL and AN was 5% and 2%, respectively, in late preterms with no additional risk factors treated with phototherapy and with mean total serum bilirubin levels of 22.3 ⫾ 1.76 mg/dl. In the control group, although increased latencies were found in 4 (4%) infants, on detailed ABR, the presence of wave V was demonstrated at 50 dB nHL in all four. The prevalence of SNHL was 4% and no AN was detected in late preterms with no additional risk factors treated with phototherapy and with mean total serum bilirubin levels of 18.6 ⫾ 1.26 mg/ dl. However, with regard to the prevalence of AN/AD and SNHL, the difference between the groups was not statistically significant (p ⬎ 0.53) (Table 4). One year later, all of the infants were re-tested with AABR screening. Only two (2%) infants with an abnormal diagnostic ABR test and presence of CM in the severe hyperbilirubinemia group failed the AABR screening test at one year; infants who were thought to have SNHL all passed the AABR test at one year.
Table 2. Baseline characteristics of groups.
Weeks of gestation Birth weight (g), mean ⫾ SD Cesarean section, n (%) Serum total bilirubin (mg/dl), (mean ⫾ SD) Male sex, n (%) Time to admission to NICU (days), mean ⫾ SD (range)
Severe hyperbilirubinemia (n ⫽ 85)
Non-severe hyperbilirubinemia (n ⫽ 102)
P-value
35.2 ⫾ 1.1 (34–36) 2876.16 ⫾ 229.26 33 (38.9) 22.3 ⫾ 1.76 59 (69.4) 5.7 ⫾ 1.4 (2.1–9.4)
35.5 ⫾ 1.2 (34–36) 2916.16 ⫾ 235.13 42 (38.9) 18.6 ⫾ 1.26 (71.4) 6.0 ⫾ 1.6 (3.2–10.6)
0.07 0.24 0.85 0.001 0.06 0.17
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Table 3. Initial screening tests: Combined TEOAE/AABR results in late preterms. Non-severe hyperbilirubinemia (n ⫽ 102)
Severe hyperbilirubinemia (n ⫽ 85) Right ear
Left ear
In the literature, there is not a threshold level for hyperbilirubinemia that may cause AN in infants treated with exchange transfusion. Bilirubin values varying from 7 to 25 mg/dl were reported to cause AN/AD (Raveh et al, 2007). Nevertheless, in this study, prematurity is suggested to be an additional factor contributing to the etiology of AN developed at low bilirubin levels which is in line with earlier reports that listed prematurity and low birth-weight as additional risk factors for kernicterus, permanent sequelae, and AN/AD development at serum bilirubin levels below those thought to be safe for term infants (Stein et al, 1996). In addition to the level of bilirubin, the duration of exposure to high levels of bilirubin was also found to be related to AN (De Vries et al, 1987). In line with the abovementioned suggestions, in a retrospective study carried out on infants with hearing problems, although therapeutic intervention was performed as appropriate to the level of bilirubin, ranging from no intervention to phototherapy or exchange transfusion when needed, AN/AD was present with mean total bilirubin levels of about 19.4 mg/dl, that increased in the early postpartum period (day 2 or 3) and lasted for 4 to 10 days with a mean of 6.8 days duration (Madden et al, 2002). In a recent study on 13 late preterm and term infants who underwent exchange transfusion for the treatment of severe jaundice, the authors found no AN/AD with mean peak total serum bilirubin concentrations of about 23 ⫾ 7.3 mg/dl (Saluja et al, 2010). The high levels of hyperbilirubinemia that were thought to cause neuropathy did not play a role in the development of the disease in that study as infants were free from other co-morbid conditions. Our study differed from the above in several respects including study population, treatment and follow-up of hearing disorders. Apart from the late preterm nature of the infants, a factor which is known to predispose them to develop hyperbilirubinemia, all other predisposing factors were accepted as exclusion criteria. We primarily aimed to investigate prospectively the effect of sub-exchange bilirubin levels on the prevalence of AN/AD and to determine cutoffs for predicting bilirubin-induced AN/AD. In fact with regard to the absence of AN in our late preterms with mean total serum bilirubin levels of about 18.6 ⫾ 1.26 mg/dl, we may suggest that total serum bilirubin levels ⬍ 20 mg/dl may be accepted as a safe cut-off value for AN/AD in late preterms with sub-exchange bilirubin levels and with no additional risk factors. Moreover, based on the results derived from our study, we may assert that total serum bilirubin levels ⬎ 20 mg/dl (mean 22.3 ⫾ 1.76 mg/dl) may cause AN/ AD in 2% of late preterms treated with phototherapy, Table 1. The low prevalence of AN/AD in the present study was a consequence of our stricter inclusion criteria, and was not in accordance with the high rates of AN/AD seen in the studies of Saluja et al (46.15%), Xu
Right ear
Left ear
Pass Refer Pass Refer Pass Refer Pass Refer P-value* TEOAE 69 AABR 79
16 6
69 79
16 6
90 98
12 4
90 98
12 4
0.25 0.53
*p ⬍ 0.05
Auditory neuropathy was detected in 2% of the infants treated with phototherapy for severe hyperbilirubinemia, whereas all of the infants with non-severe hyperbilirubinemia passed the AABR test at one year (Table 5). However, no statistically significant difference was found between groups either in the postnatal period or one year later with regard to the presence of auditory neuropathy (P ⬎ 0.05). Moreover, no correlation was found between serum bilirubin levels and latencies or thresholds at detailed ABR tests [r2: 0.15 (CI 0.12–0.35)]. SNHL detected on detailed ABR in the postnatal period was not confirmed at AABR screening after one year.
Discussion Auditory neuropathy, also known as auditory dyssynchrony (AN/ AD) or auditory neuropathy spectrum disorder (ANSD), comprises a spectrum of problems that may affect any part of the auditory pathway, from the inner hair cells to the auditory brainstem. Patients with this disorder have difficulty with language decoding and speech perception out of proportion to their hearing loss. Several risk factors such as neonatal history of anoxia, mechanical ventilation, hypoxia, congenital brain abnormalities, low birthweight, premature birth (⬍ 28 week), genetic disorders, or family history have been speculated in the etiology of AN/AD. However, because of the high sensitivity of the central auditory system to bilirubin toxicity, neonatal history of hyperbilirubinemia was observed to be a significant factor among terms and preterms in recent studies (Starr et al, 2000; Akman et al, 2004; Berlin et al, 2010; Shapiro & Popelka, 2011; Kirkim et al, 2008; Rhee et al, 1999). In early reports, one-third to one-half of infants with AN/AD were defined to be associated with significant hyperbilirubinemia (Funato et al, 1994; Deltenre et al, 1997).
Table 4. Diagnostic ABR test results in postnatal period. Severe hyperbilirubinemia (n ⫽ 85) Right ear ABR thresholds Mild SNHL (36–50 dB nHL) Moderate SNHL 51–70 dB nHL Severe SNHL 71–90 dB nHL Absent/abnormal *p ⬍ 0.05
Left ear
Non-severe hyperbilirubinemia (n ⫽ 102) Right ear
Left ear
P-value* 0.53
4 4 2
4 4 2
2
4
4
4
Auditory neuropathy in late preterms with hyperbilirubinemia
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Table 5. Initial and one-year AABR test results in infants with severe and non-severe hyperbilirubinemia. Initial AABR Right ear
Severe hyperbilirubinemia Non-severe hyperbilirubinemia
AABR after 1 year
Left ear
Right ear
Left ear
Pass
Refer
Pass
Refer
Pass
Refer
Pass
Refer
79 98
6 4
79 98
6 4
83 102
2 0
83 102
2 0
P-value* 0.27
*Wilcoxon test, p ⬍ 0.05
et al (24%), Akman et al (36.8%), and Baradaranfar et al (14.3%) (Saluja et al, 2010; Akman et al, 2004; Baradaranfar et al, 2011; Xu et al, 2011). Our finding of a very significant difference (p ⬍ 0.001) between total serum bilirubin levels of late preterms with and without AN is not in line with the findings of other authors who observed no significant difference between mean peak total serum bilirubin concentrations of neonates with and without acute AN (Saluja et al, 2010). However, mean peak total serum bilirubin concentrations were obviously higher in the group with AN (27.9 ⫾ 2.4 mg/dl versus 23 ⫾ 7.3 mg/dl) in the aforementioned study, and no AN was observed with mean peak total serum bilirubin concentrations of about 23 ⫾ 7.3 mg/dl. In our opinion, given the neurotoxic effect of hyperbilirubinemia on the auditory pathway, there should have been a significant difference between bilirubin levels of infants with and without AN. The non-significant difference seen between bilirubin levels in the study by Saluja et al would probably be statistically significant in a well powered study. Considering the well-known degenerative effect of neonatal hyperbilirubinemia on the auditory system, the second objective that prompted the present study was to investigate the prevalence and course of SNHL associated with sub-exchange bilirubin levels in late preterms (Haustein et al, 2010). Early detection of hearing impairment around six months of age has been found to be of crucial importance in regard to higher expressive and receptive language development, higher general development, and lifelong improvement in social status (Yoshinaga-Itano et al, 1998). Although it still remains a challenge to define the actual effect of hyperbilirubinemia in hearing loss, a comprehensive review of the literature revealed various rates of SNHL associated with hyperbilirubinemia ranging from 2.09% to 28% (Clarós et al, 2003; Rance, 2005; Xu et al, 2011; Oğün et al, 2003). Moreover, apart from some studies that have shown transient and permanent ABR abnormalities such as elevated ABR thresholds and prolonged ABR wave I–V latencies resulting from short episodes of hyperbilirubinemia, there are still only a limited number of reports on the outcome of SNHL related to neonatal hyperbilirubinemia on long-term development (Hung, 1989; Starr et al, 2000). However, SNHL resulting from neonatal hyperbilirubinemia is thought to be more likely to be reversible than other types of hearing loss during the first year of life (Madden et al, 2002). SNHL detected in the present study was not significantly different between groups with regard to bilirubin levels ⬍ 20 mg/dl and ⬎ 20 mg/dl; 3.92% of the late preterms with hyperbilirubinemia ⬍ 20 mg/dl demonstrated 50 dB nHL on detailed ABR performed within two months. Meanwhile, 4.7% of preterms with hyperbilirubinemia ⬎ 20 mg/dl were diagnosed as having moderate SNHL on detailed ABR recordings in the postnatal period. However, as implicated
before in other studies, SNHL seen on diagnostic ABR was not observed in one year AABR screening, suggesting improvement in early SNHL initiated by bilirubin toxicity in the newborn period. This improvement may be attributable to the transient neurotoxic effect of sub-exchange bilirubin levels in neonates free from other co-morbid conditions. AN/AD is characterized by abnormal ABRs, absent middle-ear reflexes, normal OAEs, and cochlear microphonic responses that invert with stimulus polarity. In an effort to detect and define earlier hearing disorders and types, various medical devices (OAE and ABR alone or combined in the same screener) have been developed. Use of combined OAE and ABR testing has been shown to ensure high sensitivity and acceptable specificity in predicting the auditory neuropathy profile as well as sensorineural hearing losses in NICU infants (Xu et al, 2011). In our study, screening tests were performed with a combined TEOAE and AABR screening device. The failure rate observed in TEOAE screening was 16/85 (19%) and 12/102 (12%) in the severe and non-severe hyperbilirubinemia groups, respectively. However, the numbers of infants diagnosed with hearing problems after ABR testing were 6/85 (7%) and 4/102 (4%) in the severe and non-severe hyperbilirubinemia groups, respectively. Although OAE is a useful first-line diagnostic test in detecting outer hair cell damage, some authors, relying on the absence of OAE observed in preterm babies, hypothesized that this condition may be the result of smaller middle-ear cavities that may impede the transmission of OAE energy from the cochlea to the external ear that may persist to at least the sixth postnatal month (Mason & Herrmann, 1998; Abdala, 2004; Bonfils et al, 1992; Kok et al, 1993; Suppiej et al, 2007). This theory may help to explain the high percentage of OAE failures seen in groups with or without severe hyperbilirubinemia in the present study, even after the second otoscopic control and elimination of all conditions in the external ear that may hinder emissions. TEOAE screening is recommended in the diagnosis of ANSD. However, since several studies have reported the disappearance of otoacoustic emissions or their absence in a large number of AN patients due to underlying conductive loss, the absence of a recordable OAE cannot be taken as evidence for the absence of ANSD (Rance et al, 1999; Starr et al, 2001; Deltenre et al, 1999). As TEOAE screening is not a highly reliable method in the diagnosis of AN/AD, we referred ultimately to cochlear microphonics recording which is a sine qua non for surveying the integrity of cochlear hair cells to identify AN/AD in preterms with abnormal waves on diagnostic ABR. The absence or severe abnormality of the ABR at maximum levels in ears with sensorineural hearing loss is an indicator of cochlear damage. In such cases, the cochlear microphonics would also be expected to be absent. The presence of CM
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with complete phase reversal between rarefaction and condensation stimuli on our ABR recordings demonstrated that the outer hair cells were intact. Therefore, the normal function of the outer hair cells indicated the neural transmission abnormality in preterms with absent or abnormal ABR potentials (Chisin et al, 1979; Berlin et al, 2003; Rapin & Gravel, 2003). The limitations of this study were its small sample size due to the exclusion of children with risk factors that may contribute to SNHL, and its restriction to a moderate level of hyperbilirubinemia which did not require exchange transfusion. However, the study was designed to investigate the impact of moderate levels of hyperbilirubinemia on the auditory nerve. In this regard, our study is, to our knowledge, the only prospective study to determine AN/AD in late preterms with repeat AABRs at one year. The association of hyperbilirubinemia with auditory neuropathy spectrum disorder is still an important area to investigate. With future innovations in laboratory testing, we hope that we would be able to prevent this incapacitating condition.
Conclusion The results of this study demonstrated that 19% of late preterms with mean total serum bilirubin levels of 22.3 ⫾ 1.76 mg/dl, and 12% with mean total bilirubin levels of 18.6 ⫾ 1.26 mg/dl failed TEOAE screening; 7% of late preterms with mean total serum bilirubin levels of 22.3 ⫾ 1.76 mg/dl and 4% with mean total bilirubin levels of 18.6 ⫾ 1.26 mg/dl failed AABR screening. Five percent of late preterms with mean total serum bilirubin levels of 22.3 ⫾ 1.76 mg/dl displayed SNHL (60 dB nHL) in both ears, and 2% AN/AD at detailed ABR within six weeks; 4% of late preterms with mean total bilirubin levels of 18.6 ⫾ 1.26 mg/dl demonstrated SNHL in both ears (50 dB nHL) and none with AN/AD at detailed ABR within six weeks. Two percent of late preterms with mean total serum bilirubin levels of 22.3 ⫾ 1.76 mg/dl were diagnosed as having permanent AN/AD at AABR screening after one year. SNHL detected in the postnatal period was not verified in one year AABR screening in either group.
Acknowledgements The authors would like to thank Mrs Başak Fırat from the audiology laboratory for her contribution in ABR testing of the infants.
Declaration of interest: The authors state that there is no conflict of interest.
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