OBJECTIVE:

To assess the association between gentamicin exposure in the neonatal period and hearing in school age.

METHODS:

This study included children exposed to a high-dose (6 mg/kg) gentamicin regimen as neonates (2004–2012), invited for follow-up at school age, and a healthy age-matched control group. We assessed hearing with pure tone audiometry including the extended high-frequency (EHF) range. Outcomes were average hearing thresholds in the midfrequencies (0.5–4 kHz) and the EHFs (9–16 kHz). The measures of gentamicin exposure were cumulative dose and highest trough plasma concentration. We used linear regression models to assess the impact of gentamicin exposure, and other peri- and postnatal morbidities, on hearing thresholds.

RESULTS:

A total of 219 gentamicin-exposed and 33 healthy-control children were included in the audiological analysis. In the gentamicin cohort, 39 (17%) had a birth weight <1500 g. Median cumulative doses and trough plasma concentrations were 30 (interquartile range 24–42) mg/kg and 1.0 (interquartile range 0.7–1.2) mg/L, respectively. Median hearing thresholds for the midfrequencies and the EHFs were 2.5 (0 to 6.3) dB hearing level and −1.7 (−5.0 to 5.0) dB hearing level, both of which were within the normal range. In an adjusted analysis, increasing hearing thresholds were associated with lower birth weight and postnatal middle-ear disease but not level of gentamicin exposure. After adjusting for birth weight, there was no difference in hearing threshold between the gentamicin-exposed cohort and healthy controls.

CONCLUSIONS:

Exposure to a high-dose gentamicin regimen in the neonatal period was not associated with an increase in hearing thresholds in schoolchildren being able to complete audiometry.

What’s Known on This Subject:

Evidence for ototoxic hearing loss after gentamicin exposure is mainly from studies in adults and older children. Neonatal studies report low rates of ototoxicity but have commonly used only moderately sensitive hearing tests.

What This Study Adds:

We performed pure tone audiometry, including the extended high-frequency range, in 219 schoolchildren (median age 9 years) exposed to a high-dose gentamicin regimen in the neonatal period. We found no association between exposure to gentamicin and hearing levels.

Gentamicin is widely used for the treatment of neonatal sepsis.1,2  Extended-interval dosing regimens are currently recommended.3  To ensure effective therapy, it is necessary to attain a high circulating dose, and some experts suggest that each dose should be as high as 7.5 mg/kg because of the large distribution volume in neonates.4  There is still uncertainty about the optimal dosing regimen and safety, in particular regarding potential ototoxicity.

Ototoxic hearing loss typically first affects the high frequencies (>8 kHz), may then progress to involve lower frequencies, and is usually bilateral and irreversible.5,6  Neonates admitted to NICUs have up to a 10-fold increase in prevalence of hearing loss.7,8  Prolonged gentamicin treatment and high trough plasma concentrations (TPCs) have been suggested to increase the risk of ototoxicity.3,9,10  Prematurity and low birth weight, severe perinatal morbidities, other ototoxic drugs, and environmental noise are also risk factors for hearing loss.8,1113  These factors will often coexist with gentamicin treatment, making it difficult to delineate which risk factor is of greatest clinical importance.

Current evidence indicates a low risk of hearing loss after gentamicin treatment in neonates.5,14,15  However, data are limited by several factors. The objective testing methods used in newborn hearing screening (otoacoustic emissions or automated brainstem audiometry) evaluate hearing at frequencies between 2 and 6 kHz and do not detect mild hearing loss or early signs of ototoxicity. Moreover, most studies have evaluated hearing shortly after exposure to gentamicin and could not identify late-onset or progressive hearing loss.

Pure tone audiometry in the extended high-frequency (EHF) range is the most sensitive subjective testing method to detect ototoxic hearing loss even before it becomes evident in the conventional hearing range.16,17  For this method, children must be able to cooperate.18,19  In this study, we performed a hearing assessment of schoolchildren exposed to a high-dose gentamicin regimen in the neonatal period to assess long-term safety.

Children included in this study had been admitted to the NICU at the University Hospital of North Norway and received gentamicin therapy between 2004 and 2012. This NICU is the only unit offering care for infants born before 32 weeks’ gestation and all other newborn infants (≥32 weeks’ gestation) in need of mechanical ventilation or intensive care in the 2 northern-most counties in Norway. We previously validated our extended-interval, high-dose (6 mg/kg) gentamicin dosing regimen in 440 neonates who were exposed to at least 3 doses of gentamicin between 2004 and 2012.20  The vast majority of TPCs (94%) were within the normal range, there was a low rate of prescription error, and we found no evidence of early-onset ototoxicity using a transient evoked otoacoustic emissions screening test before hospital discharge.20 

For the current study (Fig 1), 357 children from the original cohort were invited for a detailed hearing assessment at age 6 to 14 years. We also, from public primary schools, recruited a control group of 33 healthy children with no history of previous use of aminoglycosides and no previous hearing problems or tympanostomy tubes. Parents of all children filled out a questionnaire including any history of middle-ear infections, treatment with tympanostomy tubes, or use of intravenous antibiotics after the neonatal period.

FIGURE 1

Participant flow diagram. The final study populations, from the original cohort through exclusions, are displayed.

FIGURE 1

Participant flow diagram. The final study populations, from the original cohort through exclusions, are displayed.

Close modal

For the gentamicin-exposed cohort, we collected data on birth weight, gestational age (GA), Apgar scores, neurologic abnormalities, mechanical ventilation, and any phototherapy for jaundice. Preterm neonates are more susceptible to bilirubin-induced neurologic damage, suffer adverse effects at lower total serum bilirubin (TSB) levels, and receive more phototherapy than term infants.21,22  We recorded the peak TSB level within the first 2 weeks of life and divided this value by GA in weeks, creating an age-adjusted variable of possible bilirubin toxicity instead of using crude peak TSB levels. To assess level of gentamicin exposure during hospitalization, we recorded 2 variables: the highest measured gentamicin TPC (mg/L) and the cumulative gentamicin dose (mg/kg). For the healthy-control group, we collected data on birth weight, admission to a NICU for reasons other than infection, and any phototherapy for jaundice.

Participants attended 1 study visit between September 2017 and September 2018. We did otoscopy and tympanometry at 226 Hz (Zodiac; Otometrics, Taastrup, Denmark) before pure tone audiometry. Tympanogram results were classified as type A (normal), B (flat), and C (negative pressure). We collected a urine sample for analysis of the mitochondrial 1555A>G gene mutation in all gentamicin-exposed children. DNA was extracted by using the Quick-DNA Urine Kit (Zymo Research, Irvine, CA). The m.1555A>G gene mutation was analyzed by using polymerase chain reaction amplification and melting curve analysis (LightCycler 480; Roche, Basel, Switzerland).

Pure tone audiometry thresholds were measured with the Equinox 2.0 clinical audiometer by using Equinox Suite 2.9.0 software (Interacoustics A/S, Middelfart, Denmark). The audiometer was calibrated according to the manufacturer’s specifications and in accordance with International Organization for Standardization references.23,24  We used the DD45 supra-aural earphones (RadioEar, Middelfart, Denmark) for the conventional frequencies (0.125–8 kHz) and Sennheiser HDA200 closed circumaural earphones (Sennheiser, Wedemark, Germany) for the EHFs (9–16 kHz). Testing was done first in the conventional frequency range before the EHF range. We used the ascending method to acquire thresholds.25  Special care was taken for each child to avoid fatigue and loss of concentration. The first ear tested (left or right) was randomly assigned by the survey management software (Research Electronic Data Capture). Audiometry testing was done by a trained audiologist or an audiology-trained ear-nose-throat physician. The hearing thresholds are expressed as dB hearing levels (HLs).

The main audiological outcomes were average hearing thresholds in the conventional frequencies and the EHF range. We calculated the established pure tone average (PTA), representing the mean of the conventional midfrequencies (0.5, 1, 2, and 4 kHz), according to an established reference method.26  There is no established equivalent to PTA in the EHF range. We chose to use the average of all 6 EHFs (9, 10, 11.2, 12.5, 14, and 16 kHz), hereafter termed the extended high-frequency average (EHFA). Middle-ear problems can be unilateral, but ototoxic hearing losses are most often bilateral. Thus, we used the PTA and EHFA for the best ear in the final analysis. A relevant clinical hearing loss was defined as PTA and/or EHFA threshold >20 dB in the best ear. We report tympanogram results corresponding to the best-ear result.

The study was approved by the Committee for Human Medical Research Ethics for Northern Norway. All parents signed a written informed consent form, and all participating children received age-appropriate written information about the study. The study was registered with www.clinicaltrials.gov (number NCT03253614) in August 2017.

On the basis of previous studies,27,28  we estimated that the mean EHFA threshold would be ∼5 to 10 dB in the healthy-control group. We realistically hoped to include 60% to 70% of the 357 invited gentamicin-exposed children. We considered that a 10 dB difference in the EHFA hearing threshold would represent a clinically relevant difference between healthy controls and the gentamicin-exposed group. By including ∼30 healthy controls and ∼250 gentamicin-exposed children, we would have 80% power with a 2-sided 5% level of significance to detect a difference of 4 to 5 dB between the groups. Moreover, within the group of gentamicin-exposed children, we knew that approximately half of them had a gentamicin TPC ≥1.0 mg/L, and the rest had a TPC <1.0 mg/L. With 125 children in each group, we would have 80% power with a 2-sided 5% level of significance to detect a difference of 3 to 4 dB between the groups.

All clinical data were first entered into Research Electronic Data Capture, a secure, Web-based software platform designed to support data capture for research studies (Vanderbilt University, Nashville, TN). Clinical and audiometry data were analyzed by using IBM SPSS Statistics version 23 (IBM SPSS Statistics, IBM Corporation). Descriptive results are expressed as medians and interquartile ranges (IQRs). We used a univariable linear regression model to analyze level of gentamicin exposure and other predictors that may affect hearing thresholds.29  We then plotted all predictors in a directed acyclic graph, and on the basis of clinical and biological knowledge, we identified birth weight as the central confounder of both the outcome and other predictor variables. Finally, we adjusted each predictor separately for birth weight. Results from univariable and adjusted analyses are presented as regression coefficients with 95% confidence intervals (CIs). We defined P <.05 as significant.

After parental consent, 226 of 357 (63%) gentamicin-exposed children were included. Eight children had relevant hearing loss (Table 1). Five of these had known etiology (3 with ongoing middle-ear disease and 2 with developmental delay and genetic hearing loss) and were therefore not included in the main audiological analysis. The 3 remaining children had hearing loss of uncertain etiology and were included in the main audiological analysis. Two more children were excluded from the main audiological analysis because of obvious lack of concentration during testing with uncertain validity of audiometry results.

TABLE 1

Children With Hearing Loss, Defined as PTA Threshold >20 dB HL (n = 3) and/or EHFA Threshold >20 dB HL (n = 5)

Age, yPTA (Best Ear), dB HLEHFA (Best Ear), dB HLClinical CharacteristicsGentamicin TPC, mg/LGentamicin Cumulative Dose, mg/kgIncluded Main Audiological Analysis
12 14 22 GA 41 wk; middle-ear effusion 3.5 66 No 
14 14 38 GA 32 wk; middle-ear effusion 1.2 30 No 
21 NA GA 39 wk; middle-ear effusion 1.8 24 No 
18 41 Twin, GA 28 wk; mild psychomotor delay of unknown cause; genetic hearing loss diagnosed at school age 0.3 72 No 
58 55 Twin, GA 28 wk; mild psychomotor delay of unknown cause; genetic hearing loss diagnosed at school age 0.3 54 No 
12 46 49 Twin, GA 24 wk; long respiratory support; hearing loss diagnosed at age 8 y 0.6 72 Yes 
28 GA 26 wk; normal middle ear; no mechanical ventilation 0.7 108 Yes 
15 21 GA 41 wk; admitted to NICU for observation, no perinatal complications; normal middle ear but previous tympanostomy tubes 0.9 18 Yes 
Age, yPTA (Best Ear), dB HLEHFA (Best Ear), dB HLClinical CharacteristicsGentamicin TPC, mg/LGentamicin Cumulative Dose, mg/kgIncluded Main Audiological Analysis
12 14 22 GA 41 wk; middle-ear effusion 3.5 66 No 
14 14 38 GA 32 wk; middle-ear effusion 1.2 30 No 
21 NA GA 39 wk; middle-ear effusion 1.8 24 No 
18 41 Twin, GA 28 wk; mild psychomotor delay of unknown cause; genetic hearing loss diagnosed at school age 0.3 72 No 
58 55 Twin, GA 28 wk; mild psychomotor delay of unknown cause; genetic hearing loss diagnosed at school age 0.3 54 No 
12 46 49 Twin, GA 24 wk; long respiratory support; hearing loss diagnosed at age 8 y 0.6 72 Yes 
28 GA 26 wk; normal middle ear; no mechanical ventilation 0.7 108 Yes 
15 21 GA 41 wk; admitted to NICU for observation, no perinatal complications; normal middle ear but previous tympanostomy tubes 0.9 18 Yes 

NA, not available.

High-quality audiometry results were obtained for 219 children exposed to gentamicin in the neonatal period and for 33 healthy controls (Table 2). In the gentamicin cohort, 39 (17%) had very low birth weight (VLBW) (<1500 g birth weight), and 46 (20%) had been treated with mechanical ventilation. One child was diagnosed with a m.1555A>G gene mutation. This child had culture-confirmed group B streptococcal early-onset sepsis and received gentamicin for 12 days but had normal audiometry results (best-ear thresholds: PTA 6 dB and EHFA 8 dB). Three term children who underwent therapeutic hypothermia because of severe perinatal asphyxia also received gentamicin; all 3 later had normal psychomotor development and no hearing loss.

TABLE 2

Background Characteristics, Gentamicin Exposure Data, and Audiometry Results

Variables and ResultsGentamicin Cohort (n = 219)Control Cohort (n = 33)
Age, y, at study visit, median (IQR) 9 (7–11) 10 (9–12) 
Female sex, n (%) 84 (38.4) 17 (51.5) 
Birth wt, g, median (IQR) 3360 (2154–3896) 3500 (3239–3816) 
 <1500, n (%) 39 (17.8)  
 1500–2499, n (%) 25 (11.4)  
 ≥2500, n (%) 155 (70.8)  
GA, wk, median (IQR) 39 (33–41) No information 
 ≤31, n (%) 47 (21.5)  
 32–36, n (%) 28 (12.8)  
 ≥37, n (%) 144 (65.8)  
Small for GA, <10th centile, n (%) 19 (8.7) 0 (0%) 
Mechanical ventilation, n (%) 46 (21) 0 (0%) 
Apgar score 5 min, median (IQR) 9 (7–10) No information 
Phototherapy, n (%) 71 (32.4) 3 (10) 
Neurologic abnormalities as neonates, n (%) 13 (5.9) 0 (0%) 
 Intracranial hemorrhage 8 (3.7)  
 Cystic periventricular leukomalacia 3 (1.4)  
 Meningitis 3 (1.4)  
Gentamicin TPC, mg/L, median (IQR) 1.0 (0.7–1.2) NR 
 TPC <1 mg/L, n (%) 128 (58.4)  
 TPC ≥1 mg/L, n (%) 91 (41.6)  
Gentamicin cumulative dose, mg/kg, median (IQR) 30 (24–42) NR 
 ≤30 mg/kg (3–5 doses), n (%) 111 (50.7)  
 ≥36 mg/kg (6 doses or more), n (%) 108 (49.3)  
m.1555 G>A mutation, n (%) 1 (0.5) Not tested 
Tympanostomy tubes, any, n (%) 19 (8.7) 0 (0%) 
PTA threshold (best ear), dB HL,a* median (IQR) 2.5 (0–6.25) 2.5 (−0.6 to 3.8) 
EHFA threshold (best ear), dB HL,b** median (IQR) −1.7 (−5.0 to 5.0) −4.2 (−5.9 to 0) 
Variables and ResultsGentamicin Cohort (n = 219)Control Cohort (n = 33)
Age, y, at study visit, median (IQR) 9 (7–11) 10 (9–12) 
Female sex, n (%) 84 (38.4) 17 (51.5) 
Birth wt, g, median (IQR) 3360 (2154–3896) 3500 (3239–3816) 
 <1500, n (%) 39 (17.8)  
 1500–2499, n (%) 25 (11.4)  
 ≥2500, n (%) 155 (70.8)  
GA, wk, median (IQR) 39 (33–41) No information 
 ≤31, n (%) 47 (21.5)  
 32–36, n (%) 28 (12.8)  
 ≥37, n (%) 144 (65.8)  
Small for GA, <10th centile, n (%) 19 (8.7) 0 (0%) 
Mechanical ventilation, n (%) 46 (21) 0 (0%) 
Apgar score 5 min, median (IQR) 9 (7–10) No information 
Phototherapy, n (%) 71 (32.4) 3 (10) 
Neurologic abnormalities as neonates, n (%) 13 (5.9) 0 (0%) 
 Intracranial hemorrhage 8 (3.7)  
 Cystic periventricular leukomalacia 3 (1.4)  
 Meningitis 3 (1.4)  
Gentamicin TPC, mg/L, median (IQR) 1.0 (0.7–1.2) NR 
 TPC <1 mg/L, n (%) 128 (58.4)  
 TPC ≥1 mg/L, n (%) 91 (41.6)  
Gentamicin cumulative dose, mg/kg, median (IQR) 30 (24–42) NR 
 ≤30 mg/kg (3–5 doses), n (%) 111 (50.7)  
 ≥36 mg/kg (6 doses or more), n (%) 108 (49.3)  
m.1555 G>A mutation, n (%) 1 (0.5) Not tested 
Tympanostomy tubes, any, n (%) 19 (8.7) 0 (0%) 
PTA threshold (best ear), dB HL,a* median (IQR) 2.5 (0–6.25) 2.5 (−0.6 to 3.8) 
EHFA threshold (best ear), dB HL,b** median (IQR) −1.7 (−5.0 to 5.0) −4.2 (−5.9 to 0) 

NR, not relevant.

a

P = .33 (adjusted analysis for birth weight; gentamicin-exposed cohort versus healthy-control cohort).

b

P = .10 (adjusted analysis for birth weight; gentamicin-exposed cohort versus healthy-control cohort).

*

P = .10 (unadjusted analysis; gentamicin-exposed cohort versus healthy-control cohort).

**

P < .02 (unadjusted analysis; gentamicin-exposed cohort versus healthy-control cohort).

Overall, the gentamicin-exposed cohort and the control group had normal hearing thresholds for the whole frequency range (Table 2, Fig 2). Unadjusted statistical analysis showed a 2.5 dB absolute difference in median EHF hearing thresholds between the gentamicin-exposed children and healthy controls, which is not of clinical significance. After adjusting for birth weight, the statistical difference was lost (Table 2). No International Organization for Standardization references exist for the EHF range in children. We compared our results with data from the hitherto largest published reference study, which included 90 healthy children and adolescents aged 5 to 19 years.30  EHF hearing thresholds between groups from the current study and the reference study were comparable (Fig 2).

FIGURE 2

Hearing thresholds in dB HL (mean and SD) in the conventional and EHF range in the gentamicin-exposed cohort, healthy controls, and a reference population.30 

FIGURE 2

Hearing thresholds in dB HL (mean and SD) in the conventional and EHF range in the gentamicin-exposed cohort, healthy controls, and a reference population.30 

Close modal

Tables 3 and 4 display the linear regression analysis of predictors for hearing thresholds in the conventional midfrequencies and EHFs. In the conventional midfrequencies, we found that birth weight, mechanical ventilation, and tympanometry results were all significant predictors in the unadjusted analysis. After adjusting each predictor for birth weight, only birth weight and tympanometry result remained significant predictors. In the EHFs, we found that cumulative gentamicin dose, birth weight, phototherapy, being small for GA, mechanical ventilation, and tympanostomy tubes were significant predictors in the unadjusted analysis. After adjusting each predictor for birth weight, only birth weight and tympanostomy tubes remained significant predictors.

TABLE 3

Regression Analysis of Gentamicin Exposure and Other Predictors for Hearing Thresholds in the Conventional Midfrequencies in the Gentamicin-Exposed Cohort (n = 219)

PTA Threshold (Best Ear), dB HLUnivariableAdjusted for Birth Wt
β (95% CI)Pβ (95% CI)P
Gentamicin, cumulative dose .01 (−0.01 to 0.03) .35 −.002 (−0.03 to 0.02) .83 
Gentamicin, highest TPC −.17 (−1.4 to 1.1) .78 −.03 (−1.2 to 1.1) .96 
Birth wt per 500 g −.4 (−0.7 to −0.1) .004 — <.02a 
Mechanical ventilation 2.3 (0.7 to 3.9) .004 1.5 (−0.4 to 3.4) .13 
Phototherapy 1.2 (−0.2 to 2.6) .10 .02 (−1.6 to 1.7) .98 
Peak bilirubin (n = 161)b .08 (−0.3 to 0.5) .68 −.07 (−0.5 to 0.3) .72 
Apgar 5 min <6 .7 (−1.1 to 2.5) .43 −1.1 (−2.9 to 0.7) .22 
Small for GA 1.2 (−1.2 to 3.5) .33 .4 (−2.0 to 2.7) .76 
Age at study visit −.2 (−0.5 to 0.1) .17 −.3 (−0.6 to 0.02) .07 
Tympanostomy tubes 1.6 (−0.7 to 3.9) .18 1.4 (−0.9 to 3.7) .22 
Tympanometry, best ear −4.4 (−7.1 to −1.6) .002 −4.1 (−6.8 to −1.4) .003 
PTA Threshold (Best Ear), dB HLUnivariableAdjusted for Birth Wt
β (95% CI)Pβ (95% CI)P
Gentamicin, cumulative dose .01 (−0.01 to 0.03) .35 −.002 (−0.03 to 0.02) .83 
Gentamicin, highest TPC −.17 (−1.4 to 1.1) .78 −.03 (−1.2 to 1.1) .96 
Birth wt per 500 g −.4 (−0.7 to −0.1) .004 — <.02a 
Mechanical ventilation 2.3 (0.7 to 3.9) .004 1.5 (−0.4 to 3.4) .13 
Phototherapy 1.2 (−0.2 to 2.6) .10 .02 (−1.6 to 1.7) .98 
Peak bilirubin (n = 161)b .08 (−0.3 to 0.5) .68 −.07 (−0.5 to 0.3) .72 
Apgar 5 min <6 .7 (−1.1 to 2.5) .43 −1.1 (−2.9 to 0.7) .22 
Small for GA 1.2 (−1.2 to 3.5) .33 .4 (−2.0 to 2.7) .76 
Age at study visit −.2 (−0.5 to 0.1) .17 −.3 (−0.6 to 0.02) .07 
Tympanostomy tubes 1.6 (−0.7 to 3.9) .18 1.4 (−0.9 to 3.7) .22 
Tympanometry, best ear −4.4 (−7.1 to −1.6) .002 −4.1 (−6.8 to −1.4) .003 

—, not applicable.

a

The P value for birth weight remained <.02 when adjusting for all predictors except for a strong correlation between birth weight and mechanical ventilation; thus, P = .13 for this adjusted analysis.

b

Peak bilirubin adjusted for gestational age.

TABLE 4

Regression Analysis of Gentamicin Exposure and Other Predictors for Hearing Thresholds in the EHFs in the Gentamicin-Exposed Cohort (n = 219)

EHFA Threshold (Best Ear), dB HLUnivariableAdjusted for Birth Wt
β (95% CI)Pβ (95% CI)P
Gentamicin, cumulative dose .05 (0.01 to 0.08) .007 .02 (−0.01 to 0.06) .21 
Gentamicin, highest TPC −.6 (−2.5 to 1.3) .54 −.29 (−2.2 to 1.6) .76 
Birth wt per 500 g −.9 (−1.3 to −0.5) <.001 — <.02a 
Mechanical ventilation 4.6 (2.1 to 7.2) <.001 .41 (−0.6 to 5.5) .12 
Phototherapy 3.6 (1.3 to 5.8) .002 1.5 (−1.2 to 4.1) .28 
Peak bilirubin (n = 161)b .3 (−0.3 to 0.9) .38 −.02 (−1.5 to 0.6) .96 
Apgar 5 min <6 1.7 (−1.2 to 4.6) .25 −2.5 (−5.4 to 0.3) .08 
Small for GA 3.8 (0.01 to 7.5) .049 2.1 (−1.7 to 5.9) .28 
Age at study visit .4 (−0.06 to 0.9) .08 .3 (−0.2 to 0.8) .22 
Tympanostomy tubes 9.1 (5.5 to 12.7) <.001 8.8 (5.3 to 12.2) <.001 
Tympanometry, best ear −3.0 (−7.9 to 1.8) .22 −2.1 (−6.8 to 2.7) .39 
EHFA Threshold (Best Ear), dB HLUnivariableAdjusted for Birth Wt
β (95% CI)Pβ (95% CI)P
Gentamicin, cumulative dose .05 (0.01 to 0.08) .007 .02 (−0.01 to 0.06) .21 
Gentamicin, highest TPC −.6 (−2.5 to 1.3) .54 −.29 (−2.2 to 1.6) .76 
Birth wt per 500 g −.9 (−1.3 to −0.5) <.001 — <.02a 
Mechanical ventilation 4.6 (2.1 to 7.2) <.001 .41 (−0.6 to 5.5) .12 
Phototherapy 3.6 (1.3 to 5.8) .002 1.5 (−1.2 to 4.1) .28 
Peak bilirubin (n = 161)b .3 (−0.3 to 0.9) .38 −.02 (−1.5 to 0.6) .96 
Apgar 5 min <6 1.7 (−1.2 to 4.6) .25 −2.5 (−5.4 to 0.3) .08 
Small for GA 3.8 (0.01 to 7.5) .049 2.1 (−1.7 to 5.9) .28 
Age at study visit .4 (−0.06 to 0.9) .08 .3 (−0.2 to 0.8) .22 
Tympanostomy tubes 9.1 (5.5 to 12.7) <.001 8.8 (5.3 to 12.2) <.001 
Tympanometry, best ear −3.0 (−7.9 to 1.8) .22 −2.1 (−6.8 to 2.7) .39 

—, not applicable.

a

The P value for birth weight remained <.02 when adjusting for all predictors except for a strong correlation between birth weight and mechanical ventilation; thus, P = .12 for this adjusted analysis.

b

Peak bilirubin adjusted for gestational age.

We compared data from the population-based original study cohort, including all gentamicin-exposed neonates during the 8-year study period (n = 440), with data from the follow-up cohort (n = 226) to assess the representativeness of the follow-up cohort. There were no differences in birth weight, the proportion of VLBW infants, cumulative gentamicin doses, the highest median gentamicin TPCs, and the proportion of children with gentamicin TPC >2.0 mg/L between the 2 cohorts (Supplemental Table 5).

Our main objective in this study was to perform a detailed hearing assessment of schoolchildren exposed to a high-dose gentamicin regimen in the neonatal period to assess potential clinical or subclinical signs of ototoxic hearing loss as markers of long-term harm or safety. We tested hearing in both the conventional frequencies and the EHFs, adjusted findings for other potential peri- and postnatal risk factors for hearing loss, and compared audiological data with those of a healthy-control cohort. We found no association between level of gentamicin exposure in the neonatal period and hearing thresholds after 9 years median follow-up time.

Previous studies and reviews indicate a low risk of gentamicin-induced ototoxicity in the newborn period regardless of dosing regimen. However, there is a paucity of long-term, detailed follow-up studies. One recent case-control study compared level of gentamicin exposure in 25 VLBW infants who presented with hearing loss during the first 5 years of life and a matched control group without hearing loss and found no differences in gentamicin exposure between groups.31  One study from the 1970s reported 4-year follow-up hearing results after newborn aminoglycoside therapy using play audiometry (0.5–4 kHz). Only 25% of their original cohort were assessed at 4 years, but the authors did not identify any substantial aminoglycoside-attributable hearing loss.32  Our study is the first long-term follow-up study performing high-quality pure tone audiometry, including the EHFs, of children exposed to gentamicin in the newborn period. A delay between exposure and hearing loss is well known from platinum-induced hearing loss in children.33,34  This has also been suggested in sporadic cases after neonatal treatment with gentamicin.35,36  We found no indication of late-onset gentamicin-induced ototoxicity in our study.

The mechanisms behind gentamicin-induced ototoxicity are not fully understood.37  Currently, there is stronger evidence for aminoglycoside ototoxicity in older children than in neonates.6,18,19  A possible explanation is that older children (eg, with cystic fibrosis or cancer) receive larger cumulative doses than those commonly administered in neonates.6,18,19  Alternatively, the newborn inner ear is less vulnerable to ototoxicity or gentamicin-induced ototoxicity, so these effects may be partly reversible. Indeed, reversible ototoxic effects from aminoglycosides have been demonstrated in animal models.38  Moreover, transient hearing loss in neonates is reported and could be explained by a transient cochlear dysfunction due to inflammation39  or a delayed maturation of the auditory system.40  However, in our study cohort, there were no signs of ototoxicity either at NICU discharge or at follow-up in children exposed to gentamicin.

Hearing loss in infants admitted to NICUs has a prevalence of ∼2% to 4% compared with 0.1% to 0.3% in the general newborn population.7,29,41,42  Low GA, VLBW, mechanical ventilation, perinatal infections, hyperbilirubinemia, and severe asphyxia are all identified as risk factors for hearing loss.8,11,13  In line with other studies, we found a strong association between decreasing birth weight and increasing hearing thresholds.14  Some authors argue that low birth weight itself does not cause hearing loss43  but is rather associated with other perinatal factors that more directly affect hearing. We evaluated other possible predictors for hearing, such as Apgar scores, hyperbilirubinemia and/or phototherapy, and mechanical ventilation, but none of these were associated with increasing hearing thresholds after adjusting for birth weight.

The m.1555A>G mutation is associated with hearing loss, in particular after exposure to aminoglycoside antibiotics.44  In our cohort, only 1 patient (0.44%) had this mitochondrial mutation, and this patient had normal hearing despite a cumulative gentamicin dose of 72 mg/kg. In another cohort of infants treated with gentamicin, 4 of 436 (0.9%) had a mitochondrial 12sRNA mutation, but only 1 showed evidence of possible hearing loss.45  Some authors suggest testing for mitochondrial mutations before neonatal aminoglycoside treatment.46  A clinical study is planning to assess rapid pharmacogenetic testing of the m.1555A>G mutation to avoid aminoglycoside therapy in at-risk neonates.47  However, given the low and variable prevalence of this mutation in different ethnic populations combined with a variable penetrance, this approach may not be justified or cost-effective in all settings.44,48,49 

Middle-ear disease in childhood may cause mechanical hearing loss because of permanent inflammatory damage and/or sensorineural hearing loss secondary to toxic effects on the inner ear.50,51  Isolated sensorineural hearing loss in the EHFs after otitis media is also reported in children.52  We found a significant association between previous tympanostomy tubes, which is a marker for more severe middle-ear disease, and EHF hearing thresholds. We also found increased hearing thresholds in the conventional midfrequencies in children with negative middle-ear pressure. The latter may reflect a subtle mechanical hearing loss caused by ongoing middle-ear pathology.

The strength of our study is the unique long-term audiological data that are sensitive enough to detect subtle and subclinical hearing loss. We also present data on different levels of gentamicin exposure, with cumulative dose being the most important proxy for exposure, but found only a weak correlation between cumulative dose and EHF-thresholds, which was not significant after adjusting for birth weight (Table 3, Supplemental Fig 3). It is a paradox that most neonatal gentamicin dosing regimens recommend lower gentamicin doses (4–5 mg/kg) than those of older children (7 mg/kg) despite a proportionally higher distribution volume in neonates.4  Since 2004, we have used a dosing regimen with a fixed gentamicin dose (6 mg/kg) for all neonates and a variable dosing interval (24–48 h) depending on GA and postnatal age.20  This dosing regimen has a low risk of prescription errors.20  Our study also has limitations. Children from the original cohort with the most severe comorbidities were not included in our follow-up because of clinical conditions that made them unable to complete audiometric testing. Some of these children may have hearing problems in addition to other disabilities. However, we are only aware of 1 child from the original cohort, who was diagnosed with a congenital cytomegalovirus infection, who has a cochlea implant. Since 2009, our unit has avoided routine use of gentamicin in children with severe asphyxia who undergo therapeutic hypothermia. Therefore, only 3 children with this condition were included in the follow-up cohort, all 3 of whom had normal hearing. There are conflicting results on a possible association between gentamicin exposure and hearing loss in children with severe perinatal asphyxia who have undergone therapeutic hypothermia.53,54  Only 10% of the children in our study received >10 doses (>60 mg/kg) of gentamicin, and we cannot exclude that long courses of gentamicin have a greater ototoxic potential, also in the neonatal period. Finally, a response rate of 63% adds potential selection bias. Still, the gentamicin exposure data and the proportion of VLBW infants were similar in the original and follow-up cohorts.

In schoolchildren with no severe disabilities and who were therefore able to complete a detailed hearing assessment, we found no association between neonatal exposure to a high-dose, extended-interval gentamicin regimen and increased risk of hearing loss in the conventional midfrequencies and EHFs. Increasing hearing thresholds were associated with lower birth weight and middle-ear disease in childhood, but the vast majority of children had normal hearing. Potential damage to hearing early in life is of great concern because childhood hearing loss, and prelingual hearing loss in particular, may affect both language and general development.55  It is therefore important to provide high-quality, long-term follow-up data on hearing after gentamicin exposure in neonates because this drug is widely used in neonates, and safety is therefore paramount.

We greatly appreciate the professional work of the staff at the Clinical Research Department at the University Hospital of North Norway in Tromsø. We are also grateful to Marthe Larsen (Clinical Research Department, University Hospital of North Norway, Tromsø, Norway) for statistical advice and Bo Engdahl (Norwegian Institute of Public Health, Oslo, Norway) for advice on audiological methods and analyses. Finally, we thank all the children and parents for participating in this study; without their voluntarily contribution, this study would not have been possible.

The raw data supporting the conclusion of this article will be made available by the authors, without undue reservation, to any qualified researcher.

Dr Hemmingsen conceptualized and designed the study, conducted the initial analysis, wrote the first draft of the manuscript, had full access to all of the data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis; Ms Mikalsen collected data and reviewed and revised the manuscript; Mr Hansen collected data, conducted the initial analysis, and reviewed and revised the manuscript; Dr Fjalstad reviewed all gentamicin data, established the cohort from the neonatal period, contributed to statistical analyses, and revised the manuscript; Dr Stenklev provided substantial contribution to the study design and interpretation of the data and reviewed and revised the manuscript; Dr Klingenberg conceptualized and designed the study, coordinated and supervised data collection, directed all phases of the study, revised the final manuscript, had full access to all of the data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

This trial has been registered at www.clinicaltrials.gov (identifier NCT03253614).

FUNDING: Supported by Northern Norway Regional Health Authority and the Clinical Research Department at the University Hospital of North Norway. A grant from Eckbos Legater supported the presentation of preliminary data.

     
  • CI

    confidence interval

  •  
  • EHF

    extended high frequency

  •  
  • EHFA

    extended high-frequency average

  •  
  • GA

    gestational age

  •  
  • HL

    hearing level

  •  
  • IQR

    interquartile range

  •  
  • PTA

    pure tone average

  •  
  • TPC

    trough plasma concentration

  •  
  • TSB

    total serum bilirubin

  •  
  • VLBW

    very low birth weight

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

Supplementary data