Journal of Perinatology (2007) 27, 718–723

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ORIGINAL ARTICLE
Extremely low birth weight infants are at high risk for
auditory neuropathy
K Xoinis1, Y Weirather2, H Mavoori3, SH Shaha4 and LM Iwamoto5
1
Department of Pediatrics, University of California at San Francisco, San Francisco, CA, USA; 2Rehabilitation Services, Kapi’olani
Medical Center for Women and Children, Honolulu, HI, USA; 3Center for Health Outcomes, Hawaii Pacific Health, Honolulu, HI, USA;
4
Center for Public Policy and Administration, University of Utah, Salt Lake City, UT, USA and 5Department of Pediatrics, University
of Hawaii, John A. Burns School of Medicine, Honolulu, HI, USA

Infants admitted to the NICU should be routinely screened by automated

Auditory neuropathy (AN) is a condition in which transmission of sound to the
ABR and if abnormal, further evaluation should be started before hospital
brain is abnormal. This is reflected as an electrophysiologic profile of normal
discharge. Early identification of AN will result in better understanding of
otoacoustic emissions (OAE), with abnormal auditory brainstem evoked responses
this disorder and lead to the development of appropriate intervention
(ABR). Functionally speech perception is impaired and management strategies
strategies.
remain controversial. AN can be missed if high-risk newborns are screened for
Journal of Perinatology (2007) 27, 718–723; doi:10.1038/sj.jp.7211803;
hearing loss with only OAE testing. The rate of sensorineural hearing loss (SNHL)
published online 16 August 2007
in high-risk nursery infants is 10 times greater compared with normal term
newborns. Therefore, we hypothesize that infants from the neonatal intensive care Keywords: sensorineural hearing loss; prematurity; auditory brainstem
unit (NICU) are at significantly higher risk for AN than normal term infants. response; otoacoustic emissions

Objective: The objective of this study is to establish a prevalence rate

and characterize risk factors for NICU graduates who demonstrate the
AN electrophysiologic profile.
Study Design: This retrospective study examined infants admitted to the
NICU at Kapi’olani Medical Center for Women and Children in Honolulu,
HI from 1999 through 2003. Infants were screened with automated ABR.
Diagnostic testing and OAE were performed before discharge if the ABR
was abnormal. Hospital courses of 24 AN, 71 SNHL and 95 gestational age
(GA)-matched control infants with normal hearing were reviewed.
Result: With a SNHL prevalence of 16.7/1000, the rate for AN was
5.6/1000 NICU infants. Compared to infants with SNHL, infants with AN
were significantly younger (GA 28.3±4.8 AN vs 32.9±5.2 weeks SNHL,
P<0.0001) and smaller (BW 1318±894 AN vs 1968±1006 g SNHL).
Nearly two-thirds of the AN infants were ELBW and had significantly
longer hospital stays compared to SNHL infants of the same birth weight
group. Exposure to furosemide, aminoglycosides, vancomycin or
dexamethasone was associated with increased AN but not SNHL. Peak
bilirubin level correlated with SNHL but not AN.
Conclusion: Low birth weight NICU infants are at significant risk for
AN. ELBW infants are at significantly higher risk for both AN and SNHL.
Correspondence: Dr LM Iwamoto, Department of Pediatrics, Kapiolani Medical Center for
Women and Children, 1319 Punahou Street, Honolulu, HI 96826, USA.
E-mail: lynni@kapiolani.org
Received 6 February 2007; revised 19 June 2007; accepted 26 June 2007; published online
16 August 2007
Introduction
Auditory neuropathy (AN) or auditory dys-synchrony is a pattern of
hearing loss, considered to be within the spectrum of sensorineural
hearing loss (SNHL) and defined by a profile of absent or severely
distorted auditory brainstem responses (ABR) with preserved
otoacoustic emissions (OAE) and cochlear microphonics (CM).
Acoustic reflexes are also absent.1 This electrophysiologic profile
suggests an abnormality of the hearing apparatus proximal to the
outer hair cell that may include the synapses between the cochlear
inner hair cells, neurons of the spiral ganglion and the entire
auditory nerve. Clinically, the hearing loss is variable with an
unsynchronized auditory signal, and often fluctuating with
particular difficulty in speech perception in the presence of
background noise.
Many of the risk factors associated with AN are the same as
for SNHL. These risk factors include positive family history,
hyperbilirubinemia, exposure to ototoxic medications, hypoxia,
birth asphyxia and intracranial hemorrhages, including
intraventricular hemorrhage.2–7 The exact anatomical location
of abnormality or injury and the pathophysiology of AN are poorly
understood. As such, there are no specific risk factors to distinguish
AN from cochlear hearing loss.
The overall rate for SNHL in newborns is approximately 3 per
1000. There is a range of prevalence rates reported in neonates,
varying from 1 per 1000 for SNHL in normal newborns to 10 per

1000 in neonates from the high-risk nursery. Among children with
diagnosed hearing loss, the prevalence rate of AN is high, ranging
between 5.1 and 14.6 per 100.3,8–10
There have been case reports since the 1970s of patients
presenting with symptoms consistent with AN; however, it was
not until 1996 that AN was first defined by Starr et al.11 Thus, there
is a paucity of information regarding prevalence rates of AN
among neonates. Berg et al.12 recently showed that infants in
the intensive care nursery are at significantly higher risk for the
development of AN. Many of the infants in their nursery had
been transported back to the birth hospital and were not included
in the study, possibly skewing their data toward an increased AN
incidence.
Infants with AN are at high risk for impaired speech and
language development. Management protocols are not well defined
and require a multidisciplinary approach. Early institution of
visual modes of communication is extremely important.
Amplification may or may not be of benefit, likely due to the
lack of temporal synchrony of signal or to the fluctuating nature
of the hearing loss. In selected individuals, cochlear implantation
may improve auditory, speech and language outcomes. Unless
diagnosed early, infants from the intensive care nursery with
AN are at particularly high risk for adverse language and
cognitive outcomes.
Given the scarcity of information regarding AN incidence in
high-risk neonatal populations, we conducted a comprehensive
retrospective cross-sectional case-controlled study to determine the
prevalence rate of the AN profile in high-risk infants in Hawaii and
to identify those risk factors that may distinguish AN from cochlear
hearing loss. We identified infants as high risk if they were
admitted to the neonatal intensive care unit (NICU) and we
hypothesize that the rate of AN among these infants is
significantly higher than that of normal term infants.
Methods
Patient population
AN cases were identified from infants admitted to the NICU at
Kapi’olani Medical Center for Women and Children (KMCWC)
from 1999 through 2003. KMCWC has approximately one-third of
all births in the state of Hawaii and houses the largest tertiary care
nursery in the state, caring for the majority of the high-risk infants
born in the state (excluding the military and Kaiser Permanente).
During this time period from 1999 through 2003, there were
4511 admissions to the NICU at KMCWC. Of those 4511 admissions,
338 infants did not receive a hearing screen during the
hospitalization (102 infants transported out, 120 mortalities
and 39 missed screens).
All infants from the NICU with SNHL and those who
demonstrated the AN electrophysiologic profile were studied.
The AN profile consisted of (1) failed automatic ABR screening,
ELBW infants at risk for auditory neuropathy
K Xoinis et al
719
(2) abnormal diagnostic ABR and (3) normal OAE or preserved
CM. Acoustic reflex testing indicated absence of the stapedial
muscle reflex. Infants with a cochlear pattern of SNHL
demonstrated an abnormal ABR and an abnormal OAE with loss of
CM. Subsequently, functional hearing loss was confirmed by
behavioral testing at 6 to 7 months corrected gestational
age (GA).
Infants from the high-risk nursery are screened using the
automatic ABR (ALGO 2E; (Natus Medical, San Carlos, CA, USA)).
Parameters for the ALGO 2E include a 100 ms click stimulus,
alternating polarity, 35 dBnHL, a frequency spectrum of 700 to
1500 Hz, notch filter
12 dB at 60 Hz and
12 dB at 50 Hz,
bandpass filter 0.05 to 1.5 kHz (6 dB/octave high pass and
24 dB/octave low pass).
Infants who failed the screening underwent diagnostic ABR
(Navigator Pro; Bio-Logic Systems Corp., Mundelein, IL, USA)
using the following parameters: 100 ms click stimulus, 33.3 clicks/s
repetition tone burst at 27.1/s repetition with Blackman ramp
filtering. Responses above 20 dBnHL were considered abnormal.
The CM is defined as occurring earlier than wave I with reverse
waveform morphology when stimulus polarity is changed from
rarefaction to condensation.
Transient evoked OAE or distortion product OAE were used
to determine the presence of OAEs. Transient evoked OAE
(Otodynamics; Herts, UK) was set using plain click stimuli of
78 to 83 peak equivalent dB sound pressure level (SPL) intensity,
duration of 80 ms repeating at 50/s and a response window of
20 ms. Distortion product OAE (Navigator Pro; Bio-Logic Systems
Corp., Mundelein, IL, USA) was set at 6 dB emissions above noise
floor for 1000 to 6000 Hz. Intensity level was set at 65 dB SPL for
band 1 and 55 dB SPL for band 2.
Controls
Control cases were matched for GA and birth weight within the
same year of birth in order to minimize changes in care practices
over the study period. Demographic data included GA, birth weight
and gender. Severity of illness was examined in terms of Apgar
scores, length of hospitalization, duration of conventional and
high-frequency ventilation, and use of dexamethasone. Common
neonatal morbidities including intraventricular hemorrhage,
necrotizing enterocolitis, chronic lung disease (CLD) and
hydrocephalus were also examined. Specific risk factors for hearing
loss were also collected, including congenital cytomegalovirus or
congenital toxoplasmosis infection, bacterial meningitis, and
exposures to potential ototoxic medications such as vancomycin,
aminoglycosides, and furosemide.
Statistics
Associated risk factors for SNHL, AN, and age-matched controls
were compared using a one-way ANOVA test performed for
continuous variables with Bonferroni post hoc testing for multiple
Journal of Perinatology
 ELBW infants at risk for auditory neuropathy
K Xoinis et al
720

comparisons. Chi Square testing was done for categorical variables
with Pearson correlations post hoc. Multivariate analysis was
performed to determine interdependence of variables. Values are
expressed as means±standard error of the mean. For this analysis,
a P-value <0.05 was considered significant. The SPSS 11.5
(SPSS Inc., Chicago, IL, USA) statistical package was used for the
analyses.
Results
There were 4250 infants screened for hearing loss from the NICU
from 1999 through 2003. We identified 95 cases of hearing loss:
71 with cochlear SNHL and 24 with the AN electrophysiologic
profile. From this same cohort, 95 GA-matched controls were
identified. In comparison to infants with SNHL, those with AN were
significantly smaller, and of younger gestation (Table 1). The
ELBW infants (<1000 g birth weight) were at significantly higher
risk compared with the other birth weight groups for both AN and
SNHL (Figure 1). There were no significant differences in gender
distribution between the three groups.
Due to significantly lower birth weight, the infants with AN had
longer hospitalizations and greater duration of mechanical
ventilation compared to those with SNHL and controls. However,
in a sub-analysis of ELBW infants, there was no difference in
length of hospitalization between AN, SNHL and control infants.
In addition, a significantly greater proportion of AN and SNHL
infants were diagnosed with CLD compared with controls.
There were no differences between groups with regard to
other neonatal morbidities including intraventricular hemorrhage,
necrotizing enterocolitis, hydrocephalus and persistent pulmonary
hypertension. Although peak bilirubin levels for infants with SNHL
were higher than for controls, there was not a significant difference
compared to those with AN (Table 2). Infants with AN differed from
those with SNHL with regard to congenital infections. There were
no cases of AN among infants with congenital cytomegalovirus or
toxoplasmosis infections. Interestingly, none of the identified three
cases of bacterial meningitis developed any hearing loss.

Table 1 Demographics Table 2 Diagnoses and interventions before discharge

AN SNHL Control AN SNHL Control
(n ¼ 24) (n ¼ 71) (n ¼ 92) (n ¼ 24) (n ¼ 71) (n ¼ 92)
Gestational age (weeks) 28±5*,** 33±5 32±5 Chronic lung disease (%) 66.7*,** 30.0* 23.9
Birth weight (g) 1318±894*,** 1968±1006 1872±996 Intraventricular hemorrhage (%) 16.7 9.9 3.3
Male gender (%) 58 61 53 Hydrocephalus (%) 4.2 8.5 3.3
Apgar 1 min 4.8±2.5 6.1±2.2 5.6±2.3 Necrotizing enterocolitis (%) 8.3 8.5 3.3
Apgar 5 min 6.7±1.6 7.7±1.7 7.3±1.7 Mechanical ventilation (d) 45±42* 28±31 19±29
Length of hospitalization (d) 117.0±75.9*,** 72.8±88.7* 40.1±61.7 High-frequency ventilation (%) 16.7 28.2* 8.7
Abbreviations: AN, auditory neuropathy; SNHL, sensorineural hearing loss. Persistent pulmonary hypertension 4 6 1
*P<0.05 vs Control; **P<0.05 vs SNHL. (%)
Cytomegalovirus infection (%) 0 7* 0
Toxoplasmosis (%) 0 2.8 0
Bacterial meningitis (%) 0 0 3.3
Peak bilirubin (mg/dl) 12.7±4.2 13.1±6.3* 10.0±3.5
Abbreviations: AN, auditory neuropathy; SNHL, sensorineural hearing loss.
*P<0.05 vs Control; **P<0.05 vs SNHL.

Table 3 Medication exposures

AN (n ¼ 24) SNHL (n ¼ 71) Control (n ¼ 92)

Aminoglycosides
% 95.8* 80.3 70.7
Days 19.3±13.8*,** 9.9±13.3 6.1±8.4

Vancomycin (%) 79.2*,** 41.4 27.2

Furosemide (%) 95.8*,** 50.7* 32.6
Figure 1 Prevalence of sensorineural hearing loss (SNHL) and Auditory
Dexamethasone (%) 54.2* 32.4* 14.1
neuropathy (AN) among infants admitted to the NICU according to birth weight
groups. ELBW infants are at 10 times the risk for AN and 3 to 6 times the risk for Abbreviations: AN, auditory neuropathy; SNHL, sensorineural hearing loss.
SNHL than infants in the other birth weight groups. *P<0.05 vs Control; **P<0.05 vs SNHL.

Journal of Perinatology

Medication exposures are summarized in Table 3. Infants with
AN were more likely to have received aminoglycosides, furosemide
or vancomycin compared to infants in the GA-matched control
group. Duration of aminoglycoside treatment was longer in infants
who developed AN vs SNHL or controls. More infants with AN and
SNHL were exposed to dexamethasone compared to controls, but
dexamethasone exposure did not correlate with an increase in
AN compared with SNHL.
Discussion
In the present study, 95 (2.1%) of all infants admitted to the
KMCWC NICU over a 5-year period developed hearing loss. Of these
infants, 24 (25.3%) demonstrated the AN electrophysiologic profile.
Two-thirds (62.5%) of the infants with the AN profile were ELBW,
compared with 28.2% of infants with SNHL, suggesting that there is
a much greater risk for AN in the smallest, most premature infants.
Among the population of ELBW infants, the prevalence rates of AN
and SNHL were nearly equivalent (4.9 and 5.6 per 100 ELBW
infants, respectively). This is in contrast to the larger infants who
have a 4 to 8 times greater occurrence of SNHL than AN.
The first historical report of AN was in 1979,13 but it was not
defined as a clinical disorder until 1996. Since that time, there
have been few reports on prevalence rates of AN within the pediatric
population. One study of a large population of Australian infants
and children at risk for hearing loss3 reported 12 children with AN
out of 109 with confirmed SNHL, an 11% prevalence. A subsequent
study from the US reported a prevalence rate of 5.1% in a
population of children with hearing loss.8
Although the rate of SNHL in the NICU infant population is 10
times more common than for normal term infants, the prevalence
of AN in this same population is not established. Stein14 reported
an occurrence of AN of 4 per 100 in a consecutive series of
admissions to an infant special care nursery. More recently Berg
et al.12 reported a 24.1% prevalence of AN from a selected group of
NICU infants.
Reported risk factors for AN are the same as for SNHL, including
hyperbilirubinemia, hypoxia, exposure to ototoxic medications and
a positive family history. At present, there are no distinguishing risk
factors specific to one condition vs the other.
Past case reports suggest an association between neonatal
hyperbilirubinemia and the development of AN.8,3,15 Bilirubin is a
known neuronal toxin, and it may play a role in the etiology of
AN.16–19 In a recent study, Berg et al.12 reported an association
between AN and elevated peak total bilirubin levels. However, total
bilirubin levels are difficult to interpret in the absence of additional
metabolic and nutritional information, especially since bilirubin
bound to albumin does not cross the blood–brain barrier. Free
bilirubin more accurately reflects the potential toxicity, but it
cannot be measured in the clinical setting. In this study, there was
ELBW infants at risk for auditory neuropathy
K Xoinis et al
721
an association between peak bilirubin and SNHL, but no significant
association with AN.
According to the Joint Committee on Infant Hearing year 2000
position statement, admission to an NICU for at least 48 h is a
significant risk factor for hearing loss.20 These infants are exposed
to several modalities of treatment and experience specific
morbidities that place them at high risk for hearing loss. As a
group, infants with SNHL and AN had significantly longer hospital
stays than their age matched controls. However, the occurrence of
specific neonatal morbidities like intraventricular hemorrhage,
hydrocephalus and necrotizing enterocolitis were no different. In
addition, length of stay was longer for those with AN compared to
those with SNHL. Although this may be due to the lower mean
birth weight of AN infants, sub-group analysis of ELBW infants did
not show any differences between the three groups.
CLD, or BPD, is the one morbidity that was significantly
correlated with AN and SNHL, with a greater percentage in infants
with AN. Duration of mechanical ventilation was also greater in
these infants. Taken together this may reflect a greater degree of
morbidity. However, the use of high-frequency ventilation, often
used in infants with severe respiratory illness, correlated with the
development of SNHL but not with AN.
Another marker of severe respiratory illness in the NICU
population has been the use of dexamethasone. More recently,
postnatal dexamethasone exposure has been correlated with the
development of cerebral palsy.21–25 In this study, infants with AN
and SNHL were more likely to be exposed to dexamethasone than
controls; however, this was not independent of the diagnosis of CLD.
Exposure to potentially ototoxic medications is another risk
factor for many NICU infants. For this population,
aminoglycosides, vancomycin and furosemide are among the most
commonly administered medications. While the use of
aminoglycosides has long been associated with cochlear hearing
loss, it has also been reported to be a risk factor for AN; however,
the mechanism for this effect is not known.8,12,14 In the present
study, exposure to aminoglycosides was positively correlated with
both SNHL and AN. In addition, those infants with AN had a
significantly longer exposure to aminoglycosides compared to those
with SNHL or controls.
The loop diuretic furosemide, an inhibitor of the Na-K-2Cl
cotransporter, is known to cause hearing loss due to changes in
endolymph composition.26 Alteration in endolymph electrolyte
composition combined with the inhibition of cell proliferation27
may contribute to permanent structural changes within the inner
ear of the developing neonate after loop diuretic exposure. Over the
past two decades, there have been conflicting reports regarding the
association between furosemide and SNHL in high-risk
neonates.7,28,29 Results from the current study associate exposure to
furosemide with both SNHL and AN. Multivariate analysis suggests
that this association is independent of exposure to aminoglycosides,
vancomycin and dexamethasone.
Journal of Perinatology
 ELBW infants at risk for auditory neuropathy
K Xoinis et al
722
In summary, the present study supports the notion that ELBW
infants are at high risk for developing AN. Compared to those
diagnosed with SNHL, infants with the AN profile were more
premature and had lower birth weights. Although many of the risk
factors are the same, infants with the AN profile experienced longer
hospitalizations, more mechanical ventilation and were more likely
to be diagnosed with CLD compared to those with SNHL. In
addition, these infants with the AN profile had more exposure to
furosemide, vancomycin, aminoglycosides and dexamethasone.
These exposures may be primarily involved with the development
of AN or indicators of the degree of illness in this fragile
population. Long-term follow-up, beyond the scope of this study,
is needed to determine if the electrophysiologic findings and
hearing outcomes change with maturity in these preterm
infants.
At present, little is known about the pathophysiology of AN.
Earlier diagnosis during infancy will help to advance our
understanding of etiology and natural history of the condition.
This can then lead to better therapeutic approaches, as treatment
strategies for AN are presently no different than those for SNHL,30
yet the lack of temporal synchrony and the fluctuating losses
experienced by these individuals may lessen the effectiveness of
amplification devices and potentially place them at risk for
noise-induced trauma.11 The diagnosis will be missed if these
high-risk infants are screened by OAE alone. In addition, an
initially normal OAE may become abnormal over time,31 which
will interfere with accurate and early identification. Thus, all
infants from the NICU should be screened by automated ABR, and
an abnormal result should prompt evaluation for AN before
discharge. Long-term follow-up is necessary to determine the
natural history of AN in these immature infants.
Acknowledgments
We thank Ms Patty Iwamoto from the University of Hawaii Clinical Research
Center for help with data collection and Drs Randal Wada, Kenneth Nakamura
and Charles Neal for their advice and review of the manuscript. This investigation
was supported by Hawaii Pacific Health Center for Health Outcomes and
by a Research Centers in Minority Institutions award, P20 RR011091, from
the National Center for Research Resources, National Institutes of Health.
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