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Auris Nasus Larynx 31 (2004) 361368

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The effects of hypoxia, premature birth, infection, ototoxic drugs,


circulatory system and congenital disease on neonatal hearing loss
Satoko Yoshikawa1,*, Katsuhisa Ikeda, Takayuki Kudo, Toshimitsu Kobayashi
Department of Otorhinolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine,
Seiryou-machi 1-1, Aoba-ku, Sendai 980-8575, Japan
Received 4 September 2003; accepted 16 July 2004
Available online 6 November 2004

Abstract
Objectives: To investigate the incidence of neonatal hearing loss in well-baby populations and in a neonatal intensive care unit and to identify
potential risk factors for hearing loss in a neonatal intensive care unit which the Joint Committee on Infant Hearing (JCIH) had not
recommended.
Methods: Auditory screening was conducted in 226 infants (452 ears) born in Tohoku University from 2000 to 2001. The cases included 124
healthy newborn infants (248 ears), and 102 newborn infants (204 ears) treated in the neonatal intensive care unit (NICU). Hearing impairment was
confirmed through a primary screening of the automated auditory brainstem response (AABR) and a secondary test of the auditory brainstem
response (ABR) with otolaryngologic evaluation. Based on these examinations, we divided infants into two groups, Pass and Refer.
Results: Nine patients (15 ears) in Refer group were identified through our protocol. The incidence of the Refer group was 0.8% (1 out of 124) in
the well-baby nursery, 7.8% (8 out of 102) in the NICU populations. The infants in Refer group were shown to have a higher incidence of
congenital infection (P < 0.01), high C-reactive protein (CRP) (10 mg/dl), chromosomal aberration, and central nervous system abnormality
(P < 0.05). On the other hand, there were no statistical differences between the Pass and Refer groups in NICU, birth weight (<2200 g), gestational
age, the values of total serum bilirubin, the values of arterial blood gases (pH, PaCO2 , PaO2 ), percutaneous oxygen saturation (SpO2 ), hemodynamics
(blood pressure and heart rate) (P > 0.1). Respiratory status such as the Apgar score (the abbreviation for appearance, pulse, grimace, activity,
respiration) (1 min; 4), (5 min; 6), Silverman retraction score, ototoxic drug use, respiratory distress syndrome (RDS), Meconium aspiration
syndrome (MAS), and persistent pulmonary hypertension of newborn (PPHN) were also not statistically related to hearing loss (>0.999).
Conclusion: Even in a small number of infants, there are positive relationships between hearing loss and congenital infection, high CRP
(10 mg/dl), chromosomal aberration and central nervous system abnormality. The CRP (10 mg/dl) variable are not listed in the high-risk
register published by the JCIH, but we can say that the variable may predict hearing impairment in our patient population. The possibility of
autosomal recessive inheritance of genes for deafness is supposed when newborns have no other risk factors for hearing loss. This leads us to
conclude that hearing screening is an effective way to find out hearing loss population.
# 2004 Elsevier Ireland Ltd. All rights reserved.
Keywords: Neonatal hearing loss; C-reactive protein; Arterial blood gases; Percutaneous oxygen saturation; Hemodynamics

1. Introduction
It has been reported that 12 out of 1000 newborns suffer
from congenital or perinatally acquired hearing disorders
* Corresponding author. Present address: Department of Speech-Language-Hearing Therapy, Sendai Medical and Welfare College, 1-23 Kitamemachi, Aoba-ku, Sendai 980-3222, Japan. Tel.: +81 22 716 0777;
fax: +81 22 716 0778.
E-mail address: yoshikaway@aol.com (S. Yoshikawa).
1
Tel: +81 22 717 7304; fax: +81 22 717 7307.

[1,2]. It has been reported that 24% of neonates in a neonatal


intensive care unit (NICU) have significant bilateral hearing
loss [3]. Moderate to severe bilateral hearing loss (i.e., >40 dB)
distorts the development of an infants speech production. The
newborn high risk factors for hearing loss consist of diseases
and disorders known to cause hearing impairment through
the destruction of hearing-related structures and interference
with their development. In order to identify hearing impaired
infants within an appropriate period, identification of the risk
factors for neonatal hearing loss is important.

0385-8146/$ see front matter # 2004 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.anl.2004.07.007

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S. Yoshikawa et al. / Auris Nasus Larynx 31 (2004) 361368

Since 1972, the Joint Committee on Infant Hearing


(JCIH) has been searching for specific risk indicators that are
closely associated with hearing impairment [4,5], and
several studies have re-evaluated the validity of these risk
factors [68]. The risk factors described previously include:
in utero infections, family history of hereditary childhood
sensorineural hearing loss, low birth weight, craniofacial
anomalies, bacterial meningitis, hyperbilirubinemia, ototoxic
medications, low Apgar scores (the abbreviation for appearance, pulse, grimace, activity, respiration), mechanical
ventilation lasting 5 days or longer, and a possible syndrome
known to be associated with hearing loss [4]. In NICU,
medical treatments and technologies continue to emerge,
including high frequency ventilation and the use of
surfactant. The number of extremely low birth weight
infants surviving at the limits of viability has been increasing.
Some type of morbidity which previously had high prevalence rates, such as congenital rubella, has essentially been
decreased. Changes in the types of therapeutic interventions
and the characteristics of an NICU population have resulted
in limitations in using the previous risk factors to predict
hearing loss.
The objective of the current study, therefore, was to
investigate the incidence of neonatal hearing loss in wellbaby populations and in NICU populations and was to
identify the risk factors which the JCIH had not recommended. These factors included that Silverman retraction
score, arterial blood gases (pH, PaCO2 , PaO2 ), percutaneous
oxygen saturation (SpO2 ), various indicators related to the
circulatory status such as the blood pressure, heart rate, and
C-reactive protein (CRP).

2. Methods
2.1. Subjects
Auditory screening was conducted in 226 infants (452
ears) born in Tohoku University. The cases included 124
healthy newborn infants (248 ears) who were hospitalized in
the Department of Obstetrics and Gynecology, and 102
newborn infants (204 ears) treated in the neonatal intensive
care unit (NICU) for various causes. The basic clinical
backgrounds of each infant are shown in Table 1.

Fig. 1. Blockdiagram illustrating the methods of neonatal auditory screening. AABR: automated auditory brainstem response; ABR: auditory brainstem response.

2.2. Auditory screening


The auditory screening was carried out in three stages.
The automated auditory brainstem response (AABR) was
assessed in the first two stages, and conventional auditory
brainstem response (ABR) with otolaryngologic examination was assessed in the third stage (Fig. 1). Informed
consent was obtained from the parents.
2.3. Measurements of AABR
AABR screening was performed using a Natus-ALGO2e
automated screener (Natus Medical, USA). The screening
was carried out under a natural sleeping condition in the
newborn ward and was performed corrected ages 40.2 weeks
(S.D. 1.6 weeks) in the well-baby nursery and 38.4 weeks
(S.D. 6.1 weeks) in the NICU. Three disposable electrodes
were attached to the infant. The non-inverting electrode was
placed on the forehead, the inverting electrode on the nape
of the neck, and a ground electrode on the shoulder. The
applied stimuli of the test devices were clicks of 100 ms
duration, at a rate of 37 clicks per second (right ear) or 34
clicks per second (left ear), with an intensity of 35 dB nHL.
This protocol allows simultaneous measurement in both
ears. The measurement was automatically stopped when
excessive movement, extreme background noise, or high
resistance in the electrode potential was detected. The
apparatus also interrupted the measurement at once when the
noise level was over 50 dB or showed an S/N ratio below

Table 1
Clinical data of evaluated population

All values are expressed in mean  standard deviation. NICU: neonatal intensive care unit; NSD: normal spontaneous delivery; C/S: caesarean operation.

S. Yoshikawa et al. / Auris Nasus Larynx 31 (2004) 361368

6 dB. The impedance of the electrode was over 12 kV [9].


The algorism of detection of an abnormality in AABR does
not involve the detection of V waves as does ABR. The
responses of 25 ms following the click onset were band-pass
filtered from 50 to 1500 Hz and averaged. For every 500
stimuli, the ALGO statistically compared the obtained
waveform to a template. The pass criterion of ALGO
screening was based on the likelihood ratio of 160 which
indicates how much the response plus the background noise
differs from only the noise. After at least 500 clicks, a
likelihood ratio of 160 is judged to imply a 99.8%
confidence rate that a response is present. If a likelihood
ratio of 160 is not achieved after the presentation of a
maximum of 15,000 stimuli, the result is a Refer or Fail.
2.4. Measurements of ABR
ABR was recorded using NEC SYNAX 1100. The
measurement was performed under a sleeping condition
with a sedative, 0.6 ml/kg (Tricloryl, triclofos sodium) in a
sound proof room. Active electrodes were attached to the
ipsilateral mastoid region and was referenced to a vertex
electrode. Ground electrode was put on the forehead. Interelectrode impedance was maintained below 5 kV. Stimuli
were clicks and were presented alternatively 1000 times with
a rate of 9.5 Hz through a headphone set. The analyzing time
was 10 ms. To determine the hearing threshold, the
amplitude of the stimuli started from 105 dB nHL and
was decreased to 55 dB nHL at steps of 10 dB. The pass
criteria for the diagnostic ABR was as follows; a subject was
considered to have sufficient hearing sensitivity for the
development of speech and language if ABR threshold
searching showed a Wave V was present at 35 dB nHL.
2.5. Criteria for risk factors
2.5.1. Premature birth
1. Birth weight (2200 g) (81011).
2. Gestational age.
2.5.2. Disease
1. Chromosomal aberration.
2. Central nervous system disease: central nervous system
disease included hydrocephalus, microcephalus, and
seizures as defined according to a previous study [10].
We further added these criteria: both ventricular
expansion and lack of corpus callosum.
3. Respiratory disease: we investigated for respiratory distress
syndrome (RDS), Meconium aspiration syndrome (MAS),
and persistent pulmonary hypertension of newborn
(PPHN) as defined according to some reports [11,12].
4. Hyperbilirubinemia: total serum bilirubin (TSB) was
analyzed for 50 ml of venous blood sampling from
heeling cut using BL 200 Toitu and was analyzed for
maximum values obtained during the entire course before
the auditory screening.

363

2.5.3. Respiratory status


1. Apgar score: we divided them into these categories for
analysis as defined according to JCIH [4]: 4 at 1 min;
6 at 5 min.
2. Silverman retraction score: the Silverman retraction
score is a scoring system for respiratory failure in
neonates. A high score of more than 5 reflects a poor
respiratory status.
3. Arterial blood gas sampling (pH, PaCO2 , PaO2 ): blood gas
samplings were analyzed from artery using Chiba
Corning-170 (Chiba-Corning), and was analyzed for
mean and standard deviation in the acute period during
the entire course before the auditory screening.
4. SpO2 : SpO2 was measured every 2030 min using
Supermon 7210 (KONTRON). Pulse oximeter was
attached to hand and foot using Biox 3700 (Ohmeda).
SpO2 was analyzed for mean and standard deviation in the
acute period during the entire course before the auditory
screening. The values of SpO2 were excluded if the
measurement was done during accidental disengagement
of the tube, feeding or crying.
2.5.4. Circulatory abnormality
1. Blood pressure: blood pressure was analyzed for mean
and standard deviation in the acute period during the
entire course before the auditory screening.
2. Heart rate (times per minute): heart rate was analyzed
for mean and standard deviation in the acute period
during the entire course before the auditory screening.
2.5.5. Infection
1. CRP (10 mg/dl): blood sampling was analyzed using
Quick Turbo II (A&T). CRP was analyzed for maximum
values obtained during the entire course before the
auditory screening.
2. Congenital infections: congenital infections including
prenatal infections were defined by TORCH agents
(toxoplasmosis, rubella, cytomegalovirus, syphilis, and
herpes).
2.5.6. Ototoxic medications
We investigated for aminoglicosides and loop diuretics as
defined according to JCIH [4].

2.6. Statistical analysis


Statistical analysis was performed as follows. The two
sample Students t-test was applied to compare means
among Refer group and Pass group using two independent
samples with unequal variances. For variables reported as
frequencies in both Refer group and Pass group, the Fishers
exact test was used to compute the probability that the actual
and expected frequencies are similar by chance. Statistical
significance was achieved if P was less than 0.05.

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S. Yoshikawa et al. / Auris Nasus Larynx 31 (2004) 361368

Table 2
The background of infants with hearing loss

CNS: central nervous system; SOM: secretory otitis media; n.e.: not examined; *: AABR thresholds only.

nursery, 7.8% (8 out of 102) in the NICU populations. These


data are shown in Table 2.

3. Results
3.1. Otological examination

3.2. Risk factors for hearing impairment


From a total of 226 infants (452 ears), our screening using
AABR revealed nine infants (15 ears) with a possibility of
hearing loss, whereas 217 infants (437 ears) showed normal
responses. Of the nine infants (15 ears), seven infants (12
ears) underwent conventional ABR examination and showed
an increased threshold. Otological examination of this Refer
group revealed secretory otitis media (SOM) in two infants
(four ears), whereas the middle ear was normal in five
infants (eight ears). We did not perform conventional ABR
in two infants (three ears) due to their physical condition.
Based on the failed result of AABR using 70 dB nHL
stimuli, they were also classified into the Refer group. The
middle ears of these two patients were normal. The seven
infants (12 ears) who showed Refer in AABR and were
examined with conventional ABR had the following
findings: eight ears showed thresholds above 75 dB and
four ears were between 50 and 65 dB. The incidence of the
Refer group was 0.8% (1 out of 124) in the well-baby

The characteristics of nine infants in the Refer group, one


in the well-baby populations and eight in the neonatal
intensive care unit populations, are summarized in Table 2.
To evaluate possible risk factors for hearing impairment,
Refer group was compared with Pass group in the NICU
populations. The results are summarized in Figs. 2 and 3.
Statistically, infants in Refer group had a higher incidence of
congenital infection (P < 0.01), high CRP (10 mg/dl),
central nervous system abnormality, and chromosomal
aberration (P < 0.05). Chromosomal aberrations found in
our study include a case of balanced translocation between
chromosome no. 5 and no. 7, and a case of 4p-syndrome
(Wolf syndrome) whose translocation chromosome no. 4
and no. 10 resulted in the deletion of 4p. Central nervous
system abnormalities were found in two cases. Ventricular
expansion was observed in one case, and lack of corpus
callosum and epilepsy were found in the other. Congenital

Fig. 2. The risk indicators of CRP (10 mg/dl) and congenital infection.

S. Yoshikawa et al. / Auris Nasus Larynx 31 (2004) 361368

365

Fig. 3. The risk indicators of central nervous system abnormality and chromosomal aberration.

infections were observed in three cases, two cases with


cytomegalovirus, and one case with toxoplasma.
On the other hand, there were no statistical differences
between the Pass and Refer groups in the NICU populations
in birth weight (2200 g), gestational age and in various

indicators related to the respiratory and circulatory status


such as the Apgar score (1 min, 4), (5 min, 6), Silverman
retraction score, hemodynamics (blood pressure, heart rate)
and the values of arterial blood gases (pH, PaCO2 , PaO2 ),
SpO2 , and total serum bilirubin (TSB). Ototoxic drug use,

Table 3
The variables of negative data in the NICU population (I)

RDS: respiratory distress syndrome; MAS: Meconium aspiration syndrome; PPHN: persistent pulmonary hypertension of newborn.

Table 4
The variables of negative data in the NICU population (II)

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S. Yoshikawa et al. / Auris Nasus Larynx 31 (2004) 361368

respiratory distress syndrome (RDS), Meconium aspiration


syndrome (MAS), and persistent pulmonary hypertension of
newborn (PPHN) were also not statistically related to
hearing loss. These were not seen in the Refer group. The
statistical values of these factors are summarized in Tables 3
and 4.

4. Discussion
In order to identify hearing impaired infants within an
appropriate period, identification of the risk factors for
neonatal hearing loss is important. The Joint Committee on
Infant Hearing has been searching for specific risk indicators
that are closely associated with hearing impairment. A lot of
viruses have long been known to invade the structures of the
ear, causing hearing loss, for example, mumps virus,
varicella-zoster virus, measles virus, rubella virus, cytomegalovirus, herpes simplex virus, and adenovirus. There is
considerable interest in understanding the mechanisms
underlying viral hearing loss. A number of mechanisms have
been implicated in viral hearing loss. (1) The infection leads
to damage to the upper respiratory tract, occurring acute
otitis media, acute myringitis, causing conduction hearing
loss. (2) Viral infections are known to invade the structures
of the inner ear, causing cochlear hearing loss. (3) The
infection leads to damage to retrocochlear and central
nervous system. Viral infections and bacterial infections
are the leading infectious causes of hearing loss, sudden
bilateral deafness. In previous study, it was reported to show
a correlation between rising of the sequential CRP values
and sudden bilateral deafness, bacterial meningitis [1315].
Our result is in agreement with these findings. The CRP
variable is not listed in the high-risk register published by the
JCIH, but we can say that the variable may predict hearing
impairment in our patient population.
The incidence of birth weight (2200 g) did not show a
statistical difference between the normal and hearing loss
groups (P = 0.25). The relationship between birth weight and
hearing loss is controversial. Some reports found no correlation between them [610], while others reported significant relationships [16]. In general, infants with low birth
weight often have several factors that may result in brain
damage or hearing loss. These factors include immaturity,
administration of ototoxic drugs, ambient incubator noise,
and perinatal complications such as hypoxia, acidosis, and
so forth [17]. Therefore, it is reasonable to assume that there
is risk of an unfavorable condition for the cochlea and the
auditory pathway. However, our result was not in agreement
with such reports.
The effects of hypoxia, and in some instances asphyxia,
may play a role in cochlear damage. The Apgar score and
Silverman retraction score are associated with the neurological and respiratory status just after delivery. PaO2 , PaCO2 ,
pH, SpO2 , variables are not listed in the high-risk register
published by the JCIH, however, are also associated with a

diagnosis of hypoxia. Several investigations have examined


the effects of varying degrees of hypoxia on the recovery or
auditory sensitivity. These early investigations showed that
the threshold shifts produced by short-term cochlear hypoxia
are reversible if normal oxygenation is resumed in a
relatively short time [1820]. However, if systemic hypoxia
persists, cochlear damage as well as damage to the central
nervous system can occur [21]. However, there was little
difference between the two groups for those factors. Our
data also did not support any serious relationship between
respiratory parameters and hearing loss.
Our data indicated a statistically significant difference
between the groups in the incidence of central nervous
system disease. This was unsurprising, since one of the biproducts of hypoxia is a redistribution of the blood from the
periphery and the non-vital organs to the brain and central
nervous system [21]. It stands to reason, therefore, that
blood and oxygen shortages would affect the brain last, so
that peripheral organ damage almost always precedes the
type of brain or central nervous system damage that would
result in an auditory dysfunction. The ear should be one of
the last organs to suffer from neonatal hypoxia because of its
proximity to the brain and central nervous system. Infants
who have continuing depressed cerebral function are also
at greatest risk for major neurological handicaps and
derangements in other organs [22]. Our results are in
agreement with these findings. In the current study,
chromosomal aberrations included 4p syndrome (Wolf
syndrome) in addition to translocation chromosome. This
was reported to mainly present conductive deafness with the
remains of the mesenchymal tissue in the middle ear,
abnormalities of the auditory ossicles, and aplasia of the
oval window [23]. The majority of infants included in the
craniofacial group had significant abnormalities such as
microtia, atresia, and cleft palate, which are known to be
associated with conductive hearing loss [8]. Unsurprisingly,
therefore, our data indicated a statistically significant
difference between the groups in the incidence of
chromosomal aberrations. This result suggests that chromosomal aberrations are one of the better predictors of the
possibility of hearing loss.
Hypotension has been considered by several authors as
a possible causative factor of either sudden or slowly
progressive sensorineural hearing loss [24,25]. Several
reports have supported the hypothesis that a condition of
hemodynamic imbalance linked to hypotension plays a role
in the genesis of cochlear damage in subjects. A blood
pressure-dependent sympathetic effect on the labyrinthine
circulation has been shown by several studies. Previous
studies also, based on animal studies, noted reduced inner
ear blood flow after a hemorrhagic hypotension, predicting a
similar behavior in humans. On the other hand, it is well
known that blood flow in the brain usually remains constant
even during physiological systemic blood pressure changes.
In the cochlea, a similar regulatory mechanism of blood flow
is presumed to exist. Our data did not indicate a statistically

S. Yoshikawa et al. / Auris Nasus Larynx 31 (2004) 361368

significant difference between the groups in the blood


pressure. These results are in agreement with the latter
findings. This requires further investigation.
One of the infants with Refer group showed none of the
conventional risk factors. The percentage of hearing
impaired infants without risk factors has been reported
to be as high as 50% [26]. The possibility of autosomal
recessive inheritance of genes for deafness is often raised
when newborns have no other risk factors for hearing loss,
and one hypothesis is that a defect of the connexin-26
gene may account for up to 70% of autosomal recessive
inheritance hearing loss [27]. Finally, it should be noted that
a drawback of the current study is the limited number of
enrolled infants, resulting in a small number of those with
impaired hearing. Infants in a severe condition may have
multiple risk factors that do not relate to the hearing problem
directly. In addition, the possibility of a positive relationship
between hearing loss and some of the risk factors cannot be
excluded.

5. Conclusions
Nine patients (15 ears) in Refer group were identified
through our protocol. The incidence of the Refer group was
0.8% (1 out of 124) in the well-baby nursery, 7.8% (8 out of
102) in the neonatal intensive care unit populations. The
infants in Refer group had a higher prevalence of congenital
infection (P < 0.01), chromosomal aberration, C-reactive
protein, and central nervous system abnormality (P < 0.05).
Even in a small number of infants, there are positive
relationships between hearing loss and congenital infection,
high CRP (10 mg/dl), chromosomal aberration and central
nervous system abnormality. The CRP (10 mg/dl) variable
is not listed in the high-risk register published by the
JCIH, but we can say that the variable may predict hearing
impairment in our patient population. The possibility of
autosomal recessive inheritance of genes for deafness is
supposed when newborns have no other risk factors for
hearing loss. This leads us to conclude that hearing
screening is an effective way to find out hearing loss
population.

Acknowledgements
The authors express their appreciation to Dr. K. Iinuma,
Dr. K. Okamura, Dr. T. Sakai, Dr. T. Kamohara, Dr. H.
Chiba, Dr. T. Watanabe, Dr. M. Aonuma, Dr. M. Sanjyo, Dr.
T. Hanita, Dr. H. Umebayashi and nursing staff of the
Maternity and Neonatalogy Departments and Dr. J.
Murotsuki, Obstetrics and Gynecology Departments of
Tohoku University Hospital for their great cooperation and
support. We also thank Dr. S. Matsutani, Department of
Otorhinolaryngology, Sendai Red Cross Hospital, for
helpful comments on the manuscript, A. Houzawa in the

367

Department of Public Health in Tohoku University Hospital


for his kind advice on the statistics.

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