Journal of Perinatology (2013) 33, 38

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www.nature.com/jp

STATE-OF-THE-ART

Ototoxicity in preterm infants: effects of genetics,

aminoglycosides, and loud environmental noise
E Zimmerman1 and A Lahav1,2
Majority of hearing-loss cases with extremely preterm infants have no known etiology. There is a growing concern that the
administration of aminoglycoside treatment in the noisy environment of the Neonatal Intensive Care Unit (NICU) may lead to
hair-cell damage and subsequent auditory impairments. In addition, several mitochondrial DNA mutations are known to have been
associated with aminoglycoside-induced hearing loss. This review provides a systematic analysis of the research in this area and
elucidates the multifactorial mechanisms behind how mitochondrial DNA mutations, aminoglycosides and loud noise can
potentiate ototoxicity in extremely preterm neonates. Recommended steps to minimize the risk of ototoxicity and improve clinical
care for NICU infants are discussed.
Journal of Perinatology (2013) 33, 38; doi:10.1038/jp.2012.105; published online 9 August 2012
Keywords: aminoglycosides; mitochondrial DNA mutations; auditory; noise; ototoxicity; preterm infants

NEONATAL HEARING
Early auditory development
Development of the auditory system begins as early as 36 weeks
of gestation age (GA).1,2 By B25 weeks GA, the structural aspects
necessary for audition are intact, and the fetus can already perceive and respond to low-frequency sounds passing through
amniotic uid.3 The neurosensory pathways of the auditory system
are known to develop later in gestation, eliciting brainstem and
cortical auditory evoked responses at around 28 weeks GA.4,5
Many of the sounds that are audible in the womb are generated
internally by the mothers respiration, digestion, heart rhythms
and physical movements.6,7 Fetuses, however, can also respond to
sounds outside of the womb. Animal and human studies have
used ultrasound technology to observe fetuses behavioral responses to sound stimuli.8,9 For example, Hepper and Shahidullah8
examined the development of fetal responsiveness to pure tones
at various frequencies. They found that at 19 weeks GA, the
fetuses could only respond to the 500-Hz tone; whereas, at
27 weeks GA, almost all fetuses responded to both the 250 and
500-Hz tones. Responsiveness to higher frequencies (1000 and
3000 Hz) was not observed until 33 weeks GA. Although
this study was based on indirect measurements of hearing, it
revealed that fetal responsiveness to sounds begins at the lower
frequencies rst and is followed by the higher frequencies later in
development. Thus, frequencies heard within the womb parallel
the course of frequency development within the cochlea,10
making the womb an optimal and protective environment for
auditory maturation.
The transition from the womb to the NICU environment
The well-structured course of auditory development is severely
interrupted when a preterm infant enters the noisy world of the

Neonatal Intensive Care Unit (NICU). First, the hearing experience

in the NICU, where sounds are transmitted through air, is very
different from the transmission of sounds through the amniotic
uid in the womb. In addition, the type of sounds and levels of
noise typically present in the NICU are very different from those
present in utero, putting preterm infants at risk for exposure to
sound frequencies that they are not yet ready to process. Noises in
the NICU come from fans, ventilators, telephones, pagers, doors,
loud conversations and intermittent alarms. Previous studies
have shown that the median noise levels in the NICU range from
55 to 67 dBA with intermittent peaks ranging from 75 to 120
dBA,1114 which exceeds the recommended noise level from
the American Academy of Pediatrics (4555 dBA).15 Studies
have shown that loud noise can lead to unwarranted transient
changes in the physiologic, motor and state-related systems of
extremely preterm neonates.16 This vulnerable population of
newborns is especially sensitive to noise, because their ability
to self-regulate and lter noxious stimuli is extremely limited.
It has therefore been suggested that excessive exposure to
loud noise during the neonatal period can heighten the risk for
sensory decits and developmental disabilities (for a review, see
ref. 17).

Hearing loss in preterm neonates

Hearing loss is one of the most common health problems affecting
one in 7001000 newborns.18 The rate of hearing loss in preterm
infants is between 2% and 15%, with the majority of the cases
having no known etiology.19,20 Classications for hearing loss include:
genetic or nongenetic, pre-lingual or post-lingual, and syndromic
or non-syndromic. Overall, 50% of congenital/pre-lingual sensorineural hearing impairments are attributed to genetic factors, and
2025% of cases are due to identiable environmental causes

1
Department of Newborn Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston MA, USA and 2Department of Pediatrics, Mass General Hospital for Children,
Boston, MA, USA. Correspondence: Dr A Lahav, Department of Newborn Medicine, Brigham and Womens Hospital, Harvard Medical School, 75 Francis St, CWN 418, Boston, MA,
02115, USA.
E-mail: amir_lahav@hms.harvard.edu
Received 19 December 2011; revised 21 June 2012; accepted 12 July 2012; published online 9 August 2012

Ototoxicity in preterm infants

E Zimmerman and A Lahav

4
such as perinatal and/or postnatal infections due to viruses,
acoustic or cerebral trauma affecting the cochlea, or ototoxic
drugs such as aminoglycosides.21 Additionally, non-syndromic
hearing impairment (NSHI) accounts for B80% of cases of
heredity deafness. However, a majority of hearing-loss cases
remain unknown.

AMINOGLYCOSIDES AND LOUD NOISE

Preterm infants have underdeveloped immune systems that are
inefcient at preventing infection. A common infection seen in
NICU infants is sepsis, a condition where the bloodstream is
overwhelmed by bacteria. Depending on whether the sepsis onset
is early or late, often a combination of aminoglycosides, b-lactam
and other various pharmaceuticals are used for treatment.
Aminoglycosides are a class of antibiotics utilized against certain
types of bacteria, specically Gram-negative infections.22 The most
common aminoglycoside used in the NICU is gentamicin23, and it
has often been the aminoglycoside of choice because of its low
cost and effectiveness against most aerobic Gram-negative
bacilli.24
Although aminoglycosides are vital for reducing bacterial
infections, they are also known to have adverse side-effects. In
general, aminoglycosides are toxic to the eighth cranial nerve
(auditory nerve)25 and the kidneys.26 Studies have shown that
aminoglycosides progressively accumulate in the endolymph and
perilymph of the inner ear,27,28 which may result in temporary
and/or permanent hearing loss.
There are points throughout development where aminoglycosides may be more ototoxic than others. For example,
Bernard29 found that exposure to aminoglycosides during the
neonatal period can alter auditory responses in the kitten model.
A striking nding in this study was that the immature ear was
more susceptible to cochlear damage than the adults ear,
revealing a sensitive period for aminoglycoside-induced toxicity.
Interestingly, this sensitive period coincides with the nal stages

of anatomical development and differentiation within the

cochlea.
There is a growing concern that the administration of
aminoglycoside treatment in a noisy NICU environment can result
in adverse auditory outcomes. This combination may be
particularly harmful considering its occurrence during a critical
period for auditory brain development. Thus, the potentiating
effect of noise and aminoglycosides could possibly account for
some of the unknown etiology reported with hearing-loss cases
among this population. The majority of research in this area,
however, is derived from animal studies.
Darrouzet and Limasobrinhoe30 found that animals who
received aminoglycosides appeared to be more susceptible
to noise-induced hearing loss. This study was soon followed
by Gannon and Tso et al.31 who described the potentiation
of aminoglycoside-induced toxicity by simultaneous exposure to noise. These early discoveries have laid the groundwork for many follow-up studies examining the combination
of noise and aminoglycosides under various conditions (see
Figure 1).3248
The commonly cited animal studies in this eld are presented in
Figure 1. With the exception of one study by Fernandez et al.,43 all
sixteen studies shown in Figure 1 found a potentiating effect
between noise and aminoglycosides, with the majority of studies
reporting hair-cell damage. The noise exposure in the study by
Fernandez et al.43 was likely too brief (30 s) to cause a potentiating
effect when compared with the much-longer noise exposure
(4 1 h) used in other studies. Interestingly, the noise level used
in these studies was 475 dBA, which is comparable to the loud
intermittent peaks often experienced by preterm infants in the
NICU (Figure 1, yellow shading).1114
Although the combination of noise and aminoglycosides has
been well studied, there are still several inconsistencies across
study designs that limit our ability to draw denite conclusions.
Much of the variability across studies is because of the various
types of aminoglycosides, dosage amounts, level and duration of
noise exposure, animal model utilized and age at testing. More

Figure 1. Shown are animal studies (shapes) examining the combination of aminoglycosides and noise superimposed on human studies
(yellow shade) reporting the range of noise peaks in the Neonatal Intensive Care Unit (NICU)1114 in reference to the recommendations for
noise levels (red dashed lines) set by the American Academy of Pediatrics (AAP).15 Our analysis reveals a complete overlap between the noise
levels in the animal studies and the noise levels experienced by NICU infants; therefore, the adverse auditory outcomes evident in the animal
model are highly generalizable to humans.
Journal of Perinatology (2013), 3 8

& 2013 Nature America, Inc.

Ototoxicity in preterm infants

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5
controlled and age-restricted studies need to be completed in an
effort to make the results more generalizable to the newborn
population in the NICU.

NOISE POTENTIATES AMINOGLYCOSIDE TOXICITY: A POSSIBLE

MECHANISM
The complete mechanism by which noise potentiates aminoglycoside ototoxicity is still unfolding. However, for the purpose of this
paper, we propose a possible mechanism for how noise and
aminoglycosides combine together to potentiate ototoxicity. The
proposed mechanism is supported by the literature and is
illustrated in Figure 2. When the animal/infant is exposed to
excessive noise, the basilar membrane in the cochlea vibrates
more vigorously resulting in an immense amount of hair-cell
movement that can cause hair-cell and structural damage within
the cochlea. As noise increases, it creates more vibration on the
basilar membranethis increases both the number of hair cells
that are stimulated and the rate at which they generate nerve
impulses.
Loud noises cause more hair cells to be stimulated, thereby
allowing for more mechanoelectrical transduction (MET) to occur
at the apical surface of the hair cells. Normally, when MET
channels open, an array of ion-channel kinetics take place
resulting in depolarization. However, once aminoglycosides have
entered the endolymph of the scala media, they can permeate
through the MET channels,49 thereby blocking the rapid depolarizing transduction current.50 Figure 2 illustrates how exposure to
loud noise increases the open probability and current through
MET channels which, in turn, results in a greater aminoglycosides
uptake within the hair cells.51 Aminoglycoside entry into the hair
cells can cause cellular death, which consequently leads to
hearing loss.52 Other mechanisms that potentiate ototoxicity at
cellular levels are likely.

COCHLEAR SUSCEPTIBILITY
Often, damage to hair cells progresses from the base of the
cochlea to the apex.53 In vitro and in vivo studies have shown the
basal outer hair cells to be more susceptible to damage from
gentamicin.52,54 It appears that aminoglycosides preferentially
target the base of the cochlea, an area that in early postnatal
stages has the highest open probability of the MET channels.55
In utero, the fetus hears predominately low-frequency sounds that
stimulate the apex of the cochlea; however, while in the NICU, the
infant is unwillingly exposed to high-frequency sounds coming
from phones and alarms that stimulate one of the most vulnerable
areas of the cochlea the base. This unwarranted stimulation in
an extremely sensitive area at the base of the cochlea, where the
open probability of MET channels is most heightened, is especially
dangerous because it allows for signicantly more aminoglycoside
uptake into the hair cells of this region. Taken together, it is likely
that the administration of aminoglycosides in a loud NICU
environment during a sensitive period of auditory development
is an undesirable recipe for hearing loss.
AMINOGLYCOSIDES AND GENETICS
Mitochondrial DNA mutations
Hearing loss can occur from mutation(s) in a single gene or from a
combination of mutations in various genes. Mitochondrial DNA
(mtDNA) contains 37 genes, all essential for proper mitochondrial
function. However, the mitochondrial 12S rRNA is a prime target
for mutations associated with aminoglycoside-induced NSHI. The
identied NSHI mutations in the 12S rRNA gene include the following:
A1555G,56 T1095C,57 C1494T58 and 961 mutations.56 Previous studies
have shown a genetic link between aminoglycoside-induced
ototoxicity and mutations in the human 12S rRNA gene.59
Therefore, with the above mitochondrial mutations, it is believed
that aminoglycoside is the predominating modifying factor for
hearing loss.

Figure 2. A schematic view of the inner ear (a) and a flow chart (b) describing a possible mechanism for the interactions between noise and
aminoglycosides based on previous literature. This illustration demonstrates a potential bio-environmental mechanism through which the
combination of loud noise and aminoglycosides can lead to hearing loss.
& 2013 Nature America, Inc.

Journal of Perinatology (2013), 3 8

Ototoxicity in preterm infants

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Figure 3. A schematic representation based on the hypothesis suggested by Guan,65 depicting how aminoglycosides can potentiate hearing
loss in patients with mitochondrial 12S rRNA mutations.65

Although the exact mechanism of ototoxicity and mtDNA

mutations is not fully understood, several studies have shown that
human mitochondrial 12S rRNA alter the binding properties of
aminoglycosides.60,61 Variants within the mitochondrial mutations
make the mitochondrial ribosome more similar to bacterial
ribosomal RNA, resulting in the cells being more susceptible to
aminoglycoside-induced damage. As discussed earlier, aminoglycosides are highly concentrated in the perilymph and endolymph
of the inner ear. Because the cells in the inner ear are rich
with mitochondria (owing to their high metabolic activity and
role in sensory transduction,62 they may be more predisposed
to aminoglycoside-induced damage. Consequently, exposure to
aminoglycosides in subjects with mtDNA mutations leads to
impaired mitochondrial translation in the cochlea. In fact, Guan
et al. and Zhao et al.63,64 found that the addition of aminoglycosides caused a 30% decrease in the rate of mitochondrial
protein synthesis in cells carrying the 1555 A4G or 1494 C4T
mutation, thereby reducing the overall mitochondrial translation
rate below the level required for normal cell function, and inducing
the deafness phenotype.63,64 Figure 3 is a schematic representation
of the hypothesis by Guan,65 depicting how aminoglycosides can
potentiate hearing loss associated with mitochondrial 12S rRNA
mutations. In his hypothesis, mitochondrial translation defects
result in a reduction in ATP production of cochlear cells, which
increases the reactive oxygen species, inducing/potentiating
hearing loss in individuals carrying these mutations (for review
see ref. 65).
Mitochondrial DNA mutations and NICU infants
The exact prevalence of mtDNA mutations among infants born
prematurely is unknown. Ealy et al.66 examined the prevalence of
mitochondrial mutations in a population of 703 former NICU
graduates from Iowa Childrens Hospital and found the frequency
of these variants was B1.8%. In addition, they did not nd hearing
loss in patients at risk.66 Although this study showed a relatively
small prevalence with no hearing loss associated, more studies
Journal of Perinatology (2013), 3 8

need to be completed that examine the prevalence of mtDNA

mutations in preterm infants receiving aminoglycosides. In
addition, premature infants are exposed to NICU noise, which
may further increase the ototoxicity experienced by individuals
with mtDNA mutations while taking aminoglycosides.
It is likely that when preterm infants who carry the mitochondrial mutation are exposed to not only aminoglycosides but also
to loud NICU noise, the following occurs: (1) more hair cells are
recruited because of the loud noise level; (2) more aminoglycosides enter the hair cells and alter the binding properties; (3)
mitochondrial translation defects occur resulting in a reduction in
ATP production and an increase in reactive oxygen species; (4) cell
death occurs and eventually leads to hearing loss and/or deafness.
Although this theory has not been formally tested, it is likely that
the addition of NICU noise can further potentiate ototoxicity in
subjects with mtDNA mutations exposed to aminoglycosides
during the neonatal period. More research in this area needs to be
completed in an effort to prevent drug-induced hearing loss
among the preterm infant population.
IMPLICATIONS FOR CLINICAL CARE
Preventing the combination between noise levels and aminoglycosides in the NICU is an arduous task. However, there are several
steps that can be taken to improve clinical care and reduce
ototoxicity, including reducing NICU noise, performing genetic
testing, attaining family history of mtDNA mutations and
increasing the safety of aminoglycosides through better pharmacological innovations.
NICU noise
An immense amount of the loud noise present in the NICU can be
easily reduced, or eliminated, with some design modications to
the NICU environment. For example, implementing (1) a silent
alarm system; (2) a noise-level meter at the bedside; and (3) a
private bed suite (for reviews on ways to improve the NICU
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Ototoxicity in preterm infants

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7
environment, see ref. 67, 68). These rather small adaptations to
the hospital environment can make a huge impact on patient care
and can increase the awareness among doctors, nurses, parents
and caregivers about the acoustic environment surrounding
infants taking aminoglycosides.
Genetic testing
NSHI is caused by mutations in mtDNA and is transmitted by
maternal inheritance. It is therefore advisable that pregnant
women at-risk for preterm birth should be given a genetic test for
12S rRNA mutations. In the very least, a thorough family history
inquiring about mtDNA mutations should be completed. This
knowledge will help to guide the physician toward choosing an
alternative drug rather than aminoglycosides, or to closely
monitor the dosage-level owing to the increased risk of hearing
impairment. Those who are positive for 12S rRNA mutations
should be warned about the risk for aminoglycoside-induced
ototoxicity and told to avoid the use of these drugs if possible.
Aminoglycoside dosage and safety
It is also important to optimize the dosage of aminoglycoside
given to NICU infants (for review on this topic see69,70). There are
likely many pharmacological improvements that should be made
to reduce aminoglycoside uptake in the hair cells. Alharazneh
et al.52 suggest that limiting permeation of aminoglycosides
through MET channels or preventing their entry into endolymph
are potential therapeutic targets for preventing hair-cell death and
hearing loss. More pharmacological research needs to be done
in this area in an effort to reduce the potentiating effect of
aminoglycosides on NICU noise and mtDNA mutations.
CONCLUSIONS
This review proposes an integrative model by which loud noise,
mtDNA mutations and aminoglycosides result in repeated toxic
reactions to structures of the inner ear, accounting for some of the
NSHI reported in infants born prematurely. Although it is often
difcult to determine the exact reason for hearing loss among this
population, there is growing evidence to suggest that the unique
combination of environmental, genetic and pharmacological
factors during NICU hospitalization can be very detrimental to
developing auditory system. Steps need to be taken to minimize
the impact of this adverse combination.
CONFLICT OF INTEREST
The authors declare no conict of interest.

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