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Journal of Perinatology (2013) 33, 3–8

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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, 3–8; doi:10.1038/jp.2012.105; published online 9 August 2012
Keywords: aminoglycosides; mitochondrial DNA mutations; auditory; noise; ototoxicity; preterm infants

NEONATAL HEARING Neonatal Intensive Care Unit (NICU). First, the hearing experience
Early auditory development in the NICU, where sounds are transmitted through air, is very
Development of the auditory system begins as early as 3–6 weeks different from the transmission of sounds through the amniotic
of gestation age (GA).1,2 By B25 weeks GA, the structural aspects fluid in the womb. In addition, the type of sounds and levels of
necessary for audition are intact, and the fetus can already per- noise typically present in the NICU are very different from those
ceive and respond to low-frequency sounds passing through present in utero, putting preterm infants at risk for exposure to
amniotic fluid.3 The neurosensory pathways of the auditory system sound frequencies that they are not yet ready to process. Noises in
are known to develop later in gestation, eliciting brainstem and the NICU come from fans, ventilators, telephones, pagers, doors,
cortical auditory evoked responses at around 28 weeks GA.4,5 loud conversations and intermittent alarms. Previous studies
Many of the sounds that are audible in the womb are generated have shown that the median noise levels in the NICU range from
internally by the mother’s respiration, digestion, heart rhythms 55 to 67 dBA with intermittent peaks ranging from 75 to 120
and physical movements.6,7 Fetuses, however, can also respond to dBA,11–14 which exceeds the recommended noise level from
sounds outside of the womb. Animal and human studies have the American Academy of Pediatrics (45–55 dBA).15 Studies
used ultrasound technology to observe fetuses’ behavioral res- have shown that loud noise can lead to unwarranted transient
ponses to sound stimuli.8,9 For example, Hepper and Shahidullah8 changes in the physiologic, motor and state-related systems of
examined the development of fetal responsiveness to pure tones extremely preterm neonates.16 This vulnerable population of
at various frequencies. They found that at 19 weeks GA, the newborns is especially sensitive to noise, because their ability
fetuses could only respond to the 500-Hz tone; whereas, at to self-regulate and filter noxious stimuli is extremely limited.
27 weeks GA, almost all fetuses responded to both the 250 and It has therefore been suggested that excessive exposure to
500-Hz tones. Responsiveness to higher frequencies (1000 and loud noise during the neonatal period can heighten the risk for
3000 Hz) was not observed until 33 weeks GA. Although sensory deficits and developmental disabilities (for a review, see
this study was based on indirect measurements of hearing, it ref. 17).
revealed that fetal responsiveness to sounds begins at the lower
frequencies first and is followed by the higher frequencies later in
development. Thus, frequencies heard within the womb parallel Hearing loss in preterm neonates
the course of frequency development within the cochlea,10 Hearing loss is one of the most common health problems affecting
making the womb an optimal and protective environment for one in 700–1000 newborns.18 The rate of hearing loss in preterm
auditory maturation. infants is between 2% and 15%, with the majority of the cases
having no known etiology.19,20 Classifications for hearing loss include:
genetic or nongenetic, pre-lingual or post-lingual, and syndromic
The transition from the womb to the NICU environment or non-syndromic. Overall, 50% of congenital/pre-lingual sensorin-
The well-structured course of auditory development is severely eural hearing impairments are attributed to genetic factors, and
interrupted when a preterm infant enters the noisy world of the 20–25% of cases are due to identifiable environmental causes
1
Department of Newborn Medicine, Brigham and Women’s 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 Women’s 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, of anatomical development and differentiation within the
acoustic or cerebral trauma affecting the cochlea, or ototoxic cochlea.
drugs such as aminoglycosides.21 Additionally, non-syndromic There is a growing concern that the administration of
hearing impairment (NSHI) accounts for B80% of cases of aminoglycoside treatment in a noisy NICU environment can result
heredity deafness. However, a majority of hearing-loss cases in adverse auditory outcomes. This combination may be
remain unknown. 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
AMINOGLYCOSIDES AND LOUD NOISE among this population. The majority of research in this area,
Preterm infants have underdeveloped immune systems that are however, is derived from animal studies.
inefficient at preventing infection. A common infection seen in Darrouzet and Limasobrinhoe30 found that animals who
NICU infants is sepsis, a condition where the bloodstream is received aminoglycosides appeared to be more susceptible
overwhelmed by bacteria. Depending on whether the sepsis onset to noise-induced hearing loss. This study was soon followed
is early or late, often a combination of aminoglycosides, b-lactam by Gannon and Tso et al.31 who described the potentiation
and other various pharmaceuticals are used for treatment. of aminoglycoside-induced toxicity by simultaneous expo-
Aminoglycosides are a class of antibiotics utilized against certain sure to noise. These early discoveries have laid the ground-
types of bacteria, specifically Gram-negative infections.22 The most work for many follow-up studies examining the combination
common aminoglycoside used in the NICU is gentamicin23, and it of noise and aminoglycosides under various conditions (see
has often been the aminoglycoside of choice because of its low Figure 1).32–48
cost and effectiveness against most aerobic Gram-negative The commonly cited animal studies in this field are presented in
bacilli.24 Figure 1. With the exception of one study by Fernandez et al.,43 all
Although aminoglycosides are vital for reducing bacterial sixteen studies shown in Figure 1 found a potentiating effect
infections, they are also known to have adverse side-effects. In between noise and aminoglycosides, with the majority of studies
general, aminoglycosides are toxic to the eighth cranial nerve reporting hair-cell damage. The noise exposure in the study by
(auditory nerve)25 and the kidneys.26 Studies have shown that Fernandez et al.43 was likely too brief (30 s) to cause a potentiating
aminoglycosides progressively accumulate in the endolymph and effect when compared with the much-longer noise exposure
perilymph of the inner ear,27,28 which may result in temporary (4 1 h) used in other studies. Interestingly, the noise level used
and/or permanent hearing loss. in these studies was 475 dBA, which is comparable to the loud
There are points throughout development where amino- intermittent peaks often experienced by preterm infants in the
glycosides may be more ototoxic than others. For example, NICU (Figure 1, yellow shading).11–14
Bernard29 found that exposure to aminoglycosides during the Although the combination of noise and aminoglycosides has
neonatal period can alter auditory responses in the kitten model. been well studied, there are still several inconsistencies across
A striking finding in this study was that the immature ear was study designs that limit our ability to draw definite conclusions.
more susceptible to cochlear damage than the adult’s ear, Much of the variability across studies is because of the various
revealing a sensitive period for aminoglycoside-induced toxicity. types of aminoglycosides, dosage amounts, level and duration of
Interestingly, this sensitive period coincides with the final stages 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)11–14 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.

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Ototoxicity in preterm infants
E Zimmerman and A Lahav
5
controlled and age-restricted studies need to be completed in an COCHLEAR SUSCEPTIBILITY
effort to make the results more generalizable to the newborn Often, damage to hair cells progresses from the base of the
population in the NICU. 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
NOISE POTENTIATES AMINOGLYCOSIDE TOXICITY: A POSSIBLE stages has the highest open probability of the MET channels.55
MECHANISM In utero, the fetus hears predominately low-frequency sounds that
The complete mechanism by which noise potentiates aminoglyco- stimulate the apex of the cochlea; however, while in the NICU, the
side ototoxicity is still unfolding. However, for the purpose of this infant is unwillingly exposed to high-frequency sounds coming
paper, we propose a possible mechanism for how noise and from phones and alarms that stimulate one of the most vulnerable
aminoglycosides combine together to potentiate ototoxicity. The areas of the cochlea – the base. This unwarranted stimulation in
proposed mechanism is supported by the literature and is an extremely sensitive area at the base of the cochlea, where the
illustrated in Figure 2. When the animal/infant is exposed to open probability of MET channels is most heightened, is especially
excessive noise, the basilar membrane in the cochlea vibrates dangerous because it allows for significantly more aminoglycoside
more vigorously resulting in an immense amount of hair-cell uptake into the hair cells of this region. Taken together, it is likely
movement that can cause hair-cell and structural damage within that the administration of aminoglycosides in a loud NICU
the cochlea. As noise increases, it creates more vibration on the environment during a sensitive period of auditory development
basilar membrane—this increases both the number of hair cells is an undesirable recipe for hearing loss.
that are stimulated and the rate at which they generate nerve
impulses.
Loud noises cause more hair cells to be stimulated, thereby AMINOGLYCOSIDES AND GENETICS
allowing for more mechanoelectrical transduction (MET) to occur Mitochondrial DNA mutations
at the apical surface of the hair cells. Normally, when MET Hearing loss can occur from mutation(s) in a single gene or from a
channels open, an array of ion-channel kinetics take place combination of mutations in various genes. Mitochondrial DNA
resulting in depolarization. However, once aminoglycosides have (mtDNA) contains 37 genes, all essential for proper mitochondrial
entered the endolymph of the scala media, they can permeate function. However, the mitochondrial 12S rRNA is a prime target
through the MET channels,49 thereby blocking the rapid depolariz- for mutations associated with aminoglycoside-induced NSHI. The
ing transduction current.50 Figure 2 illustrates how exposure to identified NSHI mutations in the 12S rRNA gene include the following:
loud noise increases the open probability and current through A1555G,56 T1095C,57 C1494T58 and 961 mutations.56 Previous studies
MET channels which, in turn, results in a greater aminoglycosides have shown a genetic link between aminoglycoside-induced
uptake within the hair cells.51 Aminoglycoside entry into the hair ototoxicity and mutations in the human 12S rRNA gene.59
cells can cause cellular death, which consequently leads to Therefore, with the above mitochondrial mutations, it is believed
hearing loss.52 Other mechanisms that potentiate ototoxicity at that aminoglycoside is the predominating modifying factor for
cellular levels are likely. 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
E Zimmerman and A Lahav
6

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 need to be completed that examine the prevalence of mtDNA
mutations is not fully understood, several studies have shown that mutations in preterm infants receiving aminoglycosides. In
human mitochondrial 12S rRNA alter the binding properties of addition, premature infants are exposed to NICU noise, which
aminoglycosides.60,61 Variants within the mitochondrial mutations may further increase the ototoxicity experienced by individuals
make the mitochondrial ribosome more similar to bacterial with mtDNA mutations while taking aminoglycosides.
ribosomal RNA, resulting in the cells being more susceptible to It is likely that when preterm infants who carry the mitochon-
aminoglycoside-induced damage. As discussed earlier, aminogly- drial mutation are exposed to not only aminoglycosides but also
cosides are highly concentrated in the perilymph and endolymph to loud NICU noise, the following occurs: (1) more hair cells are
of the inner ear. Because the cells in the inner ear are rich recruited because of the loud noise level; (2) more aminoglyco-
with mitochondria (owing to their high metabolic activity and sides enter the hair cells and alter the binding properties; (3)
role in sensory transduction,62 they may be more predisposed mitochondrial translation defects occur resulting in a reduction in
to aminoglycoside-induced damage. Consequently, exposure to ATP production and an increase in reactive oxygen species; (4) cell
aminoglycosides in subjects with mtDNA mutations leads to death occurs and eventually leads to hearing loss and/or deafness.
impaired mitochondrial translation in the cochlea. In fact, Guan Although this theory has not been formally tested, it is likely that
et al. and Zhao et al.63,64 found that the addition of amino- the addition of NICU noise can further potentiate ototoxicity in
glycosides caused a 30% decrease in the rate of mitochondrial subjects with mtDNA mutations exposed to aminoglycosides
protein synthesis in cells carrying the 1555 A4G or 1494 C4T during the neonatal period. More research in this area needs to be
mutation, thereby reducing the overall mitochondrial translation completed in an effort to prevent drug-induced hearing loss
rate below the level required for normal cell function, and inducing among the preterm infant population.
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 IMPLICATIONS FOR CLINICAL CARE
mutations. In his hypothesis, mitochondrial translation defects Preventing the combination between noise levels and aminogly-
result in a reduction in ATP production of cochlear cells, which cosides in the NICU is an arduous task. However, there are several
increases the reactive oxygen species, inducing/potentiating steps that can be taken to improve clinical care and reduce
hearing loss in individuals carrying these mutations (for review ototoxicity, including reducing NICU noise, performing genetic
see ref. 65). testing, attaining family history of mtDNA mutations and
increasing the safety of aminoglycosides through better pharma-
Mitochondrial DNA mutations and NICU infants cological innovations.
The exact prevalence of mtDNA mutations among infants born
prematurely is unknown. Ealy et al.66 examined the prevalence of NICU noise
mitochondrial mutations in a population of 703 former NICU An immense amount of the loud noise present in the NICU can be
graduates from Iowa Children’s Hospital and found the frequency easily reduced, or eliminated, with some design modifications to
of these variants was B1.8%. In addition, they did not find hearing the NICU environment. For example, implementing (1) a silent
loss in patients at risk.66 Although this study showed a relatively alarm system; (2) a noise-level meter at the bedside; and (3) a
small prevalence with no hearing loss associated, more studies private bed suite (for reviews on ways to improve the NICU

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Ototoxicity in preterm infants
E Zimmerman and A Lahav
7
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