The aim of the study was to investigate risk factors of hearing impairments in preterm infants and analyze factors associated with discrepancies between neonatal hearing screening (NHS) and confirmatory test results.
We analyzed the medical records of 352 preterm infants born at 23 to 32 weeks’ gestational age (GA) who underwent both automated auditory brainstem response (aABR) and confirmatory ABR (cABR).
Mean GA, mean birth weight, the incidence of small for GA and cesarean section birth were significantly different between the pass and refer groups on aABR and the normal and abnormal groups of cABR. On univariate analysis, bronchopulmonary dysplasia (odds ratio [OR], 2.74; 95% confidence interval [CI], 1.00 to 7.48), intraventricular hemorrhage (OR, 7.02; 95% CI, 1.59 to 31.05), and use of furosemide (OR, 3.84; 95% CI, 1.38 to 10.73) were the factors related to refer results on aABR. Periventricular leukomalacia (PVL; OR, 4.00; 95% CI, 1.39 to 11.52) and use of vancomycin (OR, 2.86; 95% CI, 1.22 to 6.73) were associated with abnormal cABR. Twenty-five (7.9%) infants had discrepant aABR and cABR results, particularly males and those in whom vancomycin was used.
PVL and use of vancomycin were confirmed as independent risk factors for hearing loss in infants born at less than 32 weeks’ GA. Also, discrepancies between the screening and confirmatory test may occur, especially among male infants and those in whom vancomycin was used. The hearing of infants must be assessed more carefully in such groups regardless of NHS results.
Hearing impairment (or hearing loss [HL]) is among the major neurodevelopmental deficits associated with preterm birth [
Without appropriate stimuli reaching the auditory center of the brain, infants cannot achieve normal linguistic and socialemotional development and later tend to experience psychological and mental disorders [
In clinical practice, infants with congenital HL may receive a pass result on the neonatal screening test, meaning that the early detection of hearing impairment fails and timely treatment is not provided [
The Joint Committee on Infant Hearing reported several risk factors associated with PHL in 2000 and updated the list in 2007 [
In this study we investigated the risk factors of hearing impairment in preterm infants born at less than 32 weeks’ GA and analyzed the factors that cause discrepancies between neonatal hearing screening (NHS) and confirmatory test results.
The study was a retrospective single-center cohort study conducted at the neonatal intensive care unit (NICU) of Severance Children’s Hospital, Yonsei University College of Medicine, Seoul, Korea. Of the 352 preterm infants born at 23 to 32 weeks’ GA between August 2008 and December 2017, five infants with genetic or major structural anomalies such as skeletal dysplasia, coarctation of the aorta, severe congenital ventriculomegaly, cleft palate, and Down syndrome were excluded. We reviewed the electronic medical records of the remaining 347 infants who underwent both aABR and cABR testing.
As soon as the general condition of infants allowed, NHS testing using the aABR method was performed in the NICU prior to discharge. A reliable response from the infant at a threshold level of 35 dB on the test leads to a pass result; otherwise, a refer result is given. Regardless of the aABR results, all infants also underwent cABR testing performed by a specialized technician from the Department of Otolaryngology. HL was diagnosed when the cABR test result was ≥40 dB.
For analyses of risk factors for hearing impairment in general, information on a variety of factors along with those already known to be associated with hearing impairments like GA at birth, small for gestational age (SGA), and a low Apgar score were collected. SGA was defined as having a birth weight <10th percentile for the given GA. Some complications of prematurity reported by some studies as risk factors of HL in premature babies were chosen for the analysis, including bronchopulmonary dysplasia (BPD), periventricular leukomalacia (PVL), intraventricular hemorrhage (IVH), culture-proven sepsis, retinopathy of prematurity, and patent ductus arteriosus. Prolonged duration of mechanical ventilation and some ototoxic drugs known to make hearing problems were also included.
Discrepancies between the aABR and cABR tests were categorized into two groups: those with a refer result on the aABR test and a normal result on the cABR test (group of nonconcern [GN]); and those with a pass result on the aABR test and abnormal result on the cABR test (group of concern [GC]). With a refer aABR test result in routine clinical settings, the infants are bound to undergo the cABR test within 3 months to ascertain whether there are actual hearing impairments; thus, this type of discrepancy would raise little safety concern in the clinical setting as with GN group. However, for the other group GC in clinical settings, where a pass result on the aABR test means no cABR test required, there is a high probability that the infants might miss the opportunity of detecting HL in time for proper treatments. We focused our analysis only on this latter group.
Data are given as mean±standard deviation. For continuous variables with a normal distribution and homogeneous variance, t-tests were performed to compare two groups. For nominal variables, the chi-square test or Fisher’s exact test was performed. Binary and multiple logistic regression models were used to identify factors significantly associated with abnormal results on the aABR and cABR tests. Odds ratio (OR) and 95% confidence interval (CI) were also calculated. Statistical significance was considered at values of
Of the 347 preterm infants, the mean GA at birth was 29.2±2.0 weeks and mean birth weight was 1,232±367 g. A total of 267 (76.9%) neonates were born by cesarean section, 52 (15.0%) were SGA, and 189 (54.5%) were male.
On the aABR method, 317 (91.4%) neonates showed a pass result and other 30 (8.6%) neonates had a refer result (
Risk factors affecting hearing impairments ware shown in
Factors related to an abnormal cABR result among patients with a normal aABR result are listed below (
Hearing impairment is among the most important consequences of preterm birth. The NHS test is considered an effective method for the early detection of hearing impairments in infants; therefore, it should be of priority in neonatal care [
Routine NHS testing of all neonates in Korea began in 2007. Since then, the implementation of NHS programs for newborns has continued to grow. However, the sensitivity and accuracy of such NHS tests remain issues. The interpersonal and interinstitutional variance of the test are also concerning, especially among preterm infants. To our knowledge, this is the first study to analyze risk factors for the discrepant results between aABR and cABR testing. Here we show the results of abnormal hearing screening tests in preterm infants in a single center in Korea over a 10-year period.
The pathophysiology of HL in preterm infants is complex. Along with prematurity, SGA, and a low Apgar score, HL is commonly associated with multiple risk factors that can influence hearing in an additive fashion. A family history of hearing deficits and genetic diseases that can affect the auditory system reportedly influence the degree of impairment. Thus, we excluded infants with any genetic diseases from the analysis of the discrepancies.
Other causes particularly important to HL in premature infants include ototoxic drugs such as aminoglycosides, vancomycin, and loop diuretics [
Another risk factor for HL is exposure to the constant background noise generated by contemporary life-support equipment in the NICU [
Infants with BPD invariably require prolonged periods of mechanical ventilation with an endotracheal tube, resulting in edema of the soft tissues around the Eustachian tube. As suggested previously [
PVL, a white-matter injury affecting the brains of premature infants, is commonly associated with spastic diplegia, seizures, developmental delay, and visual and hearing impairments [
The results of the aABR and cABR tests were analyzed by GA and birth weight. Both are widely known factors associated with HL in preterm infants [
We may fail to identify some patients with HL because of the imperfect nature of the NHS test. Since the risk of HL in preterm infants is greater than that in the normal group, despite the normal result of the screening test, we must carefully check for the presence of HL. In this study, male infants and those in whom vancomycin was used were significant risk factors for a discrepancy between the NHS and confirmatory test results. There can be some sex-based differences in several aspects of the brain; with regard to the auditory system, men show longer delays on ABR tests than women, mainly because of the slightly longer length of the male cochlea [
Although debate persists, vancomycin is sometimes said to be an ototoxic drug [
This study has several limitations. First, it was not a prospective cohort study; thus, some confounding factors could have affected the results. Second, the aABR and cABR tests were conducted at different times. Third, the sensitivities and specificities differ between the aABR and cABR; thus, some bias in risk factors may be unavoidable. Finally, the relatively small number of infants with abnormal hearing could have caused some errors in the statistical analysis. Further studies with a greater sample of preterm infants should be conducted.
In conclusion, this study confirmed that PVL and use of vancomycin for more than 5 days as independent risk factors for HL despite the adjustment for GA in infants born at less than 32 weeks’ GA. Careful consideration of the use of vancomycin and a timely examination for HL are needed. We also found that, especially in male infants and those in whom vancomycin was used, a discrepancy existed between the screening and confirmatory test results. It is important to carefully assess highrisk babies for false-negative results on the NHS test. Further studies on the risk factors of hearing impairments in premature babies are needed to ensure their normal future development.
This study was reviewed and approved by the Institutional Review Board of Severance Children’s Hospital (4-2020-0364), and was conducted in accordance with the Declaration of Helsinki. The informed consents were waived since the study design was retrospective chart review in nature.
No potential conflict of interest relevant to this article was reported.
Conception or design: J.H.H., J.E.S., H.S.E.
Acquisition, analysis,or interpretation of data: J.H.H., M.S.P.
Drafting the work or revising: S.M.L., K.I.P.
Final approval of the manuscript: S.M.L., M.S.P.
None
Baseline Characteristics Associated with Hearing Impairments
Characteristic | Automated ABR |
Confirmatory ABR |
||||
---|---|---|---|---|---|---|
Pass (n=317) | Refer (n=30) | Normal (n=306) | Hearing loss (n=41) | |||
Gestational age (wk) | 29.3±2.0 | 28.1±2.0 | 0.002 | 29.3±1.9 | 28.4±2.3 | 0.011 |
Birth weight (g) | 1,261±358 | 933±328 | <0.001 | 1,259±364 | 1,039±335 | <0.001 |
SGA | 38 (12) | 14 (47) | <0.001 | 37 (12) | 15 (37) | <0.001 |
Csec | 239 (76) | 28 (93) | 0.037 | 231 (76) | 36 (90) | 0.045 |
Male sex | 175 (55) | 14 (47) | 0.444 | 164 (54) | 25 (61) | 0.407 |
Apgar score1 min | 3.9±1.5 | 2.9±1.2 | 0.001 | 3.9±1.5 | 3.5±1.2 | 0.151 |
Apgar score5 min | 5.9±1.5 | 5.6±1.5 | 0.209 | 5.9±1.5 | 5.8±1.5 | 0.535 |
Values are expressed as mean±standard deviation or number (%).
Abbreviations: ABR, auditory brainstem response; SGA, small for gestational age; C-sec, cesarean section.
Risk Factors Affecting Hearing Impairments
Variable | aABR |
OR (95% CI) | Confirmatory ABR |
OR (95% CI) | ||||
---|---|---|---|---|---|---|---|---|
Pass (n=317) | Refer (n=30) | Normal (n=306) | Hearing loss (n=41) | |||||
Mechanical ventilation ≥14 d | 127 (40) | 12 (40) | 1.00 (0.46–2.14) | 0.18 | 120 (39) | 19 (46) | 0.66 (0.25–1.77) | 0.41 |
BPD (≥moderate) | 140 (44) | 20 (67) | 2.74 (1.00–7.48) | 0.05 | 137 (45) | 23 (56) | 1.26 (0.52–3.05) | 0.61 |
PVL | 14 (4) | 5 (17) | 3.54 (0.92–13.61) | 0.07 | 13 (4) | 6 (15) | 4.00 (1.39–11.52) | 0.04 |
IVH (≥grade 3) | 6 (2) | 4 (13) | 7.02 (1.59–31.05) | 0.01 | 6 (2) | 4 (10) | 3.16 (0.69–14.52) | 0.14 |
Sepsis | 9 (3) | 1 (3) | 0.19 (0.02–2.14) | 0.18 | 9 (3) | 1 (2) | 0.30 (0.03–3.35) | 0.33 |
ROP | 47 (15) | 8 (27) | 1.60 (0.51–5.04) | 0.42 | 47 (2) | 8 (20) | 0.86 (0.31–2.42) | 0.77 |
PDA | ||||||||
Medical treatment | 86 (27) | 15 (50) | 2.23 (0.90–5.47) | 0.18 | 86 (28) | 15 (37) | 1.04 (0.46–2.37) | 0.92 |
Surgical treatment | 49 (16) | 10 (33) | 2.13 (0.73–6.24) | 0.17 | 48 (16) | 11 (27) | 1.75 (0.69–4.42) | 0.24 |
Furosemide ≥14 d | 45 (14) | 13 (43) | 3.84 (1.38–10.73) | 0.01 | 47 (15) | 11 (27) | 1.34 (0.51–3.52) | 0.56 |
Vancomycin ≥5 d | 40 (13) | 3 (10) | 0.65 (0.16–2.69) | 0.57 | 34 (11) | 9 (22) | 2.86 (1.22–6.73) | 0.02 |
Aminoglycoside ≥5 d | 20 (6) | 2 (7) | 2.51 (0.49–12.94) | 0.27 | 22 (7) | 0 | - |
Values are expressed as number (%).
Abbreviations: aABR, automated auditory brainstem response; OR, odds ratio; CI, confidence interval; ABR, auditory brainstem response; BPD, bronchopulmonary dysplasia; PVL, periventricular leukomalacia; IVH, intraventricular hemorrhage; ROP, retinopathy of prematurity; PDA, patent ductus arteriosus.
Factors Correlated with Abnormal cABR Results Despite Normal aABR Results
Variable | Comparison of test results (n=317) |
OR (95% CI) | ||
---|---|---|---|---|
Concordant (n=292) | Discrepant (n=25) | |||
Gestational age (wk) | 29.3±1.9 | 28.6±2.4 | 0.83 (0.53–1.31) | 0.42 |
Birth weight (g) | 1,271±363 | 1,148±285 | 1.00 (1.00–1.00) | 0.65 |
SGA | 33 (11) | 5 (20) | 1.68 (0.32–8.76) | 0.54 |
Mode of delivery, Csec | 218 (75) | 22 (88) | 2.81 (0.80–9.95) | 0.11 |
Male sex | 156 (53) | 19 (76) | 3.05 (1.16–8.07) | 0.02 |
Apgar score1 min | 3.9±1.5 | 3.9±1.1 | 1.27 (0.70–2.30) | 0.43 |
Apgar score5 min | 5.8±1.5 | 5.9±1.3 | 1.03 (0.58–1.83) | 0.92 |
Mechanical ventilation ≥14 d | 115 (39) | 12 (48) | 0.66 (0.16–2.65) | 0.55 |
BPD (≥moderate) | 127 (44) | 13 (52) | 0.77 (0.22–2.64) | 0.67 |
PVL | 12 (4) | 2 (8) | 3.25 (0.47–22.29) | 0.23 |
IVH (≥grade 3) | 5 (2) | 1 (4) | 1.21 (0.08–17.71) | 0.89 |
Proven sepsis | 9 (3) | 0 | – | |
ROP | 44 (15) | 3 (12) | 0.47 (0.10–2.27) | 0.35 |
PDA | ||||
Medical treatment | 78 (27) | 8 (32) | 0.99 (0.33–3.01) | 0.99 |
Surgical treatment | 43 (15) | 6 (24) | 1.81 (0.47–6.92) | 0.39 |
Furosemide ≥14 d | 40 (14) | 5 (20) | 1.51 (0.36–6.31) | 0.57 |
Vancomycin ≥5 d | 33 (11) | 7 (28) | 3.92 (1.45–10.55) | 0.01 |
Aminoglycoside ≥5 d | 20 (7) | 0 | |
Values are expressed as mean±standard deviation or number (%).
Abbreviations: cABR, confirmatory auditory brainstem response; aABR, automated auditory brainstem response; OR, odds ratio; CI, confidence interval; SGA, small for gestational age; C-sec, cesarean section; BPD, bronchopulmonary dysplasia; PVL, periventricular leukomalacia; IVH, intraventricular hemorrhage; ROP, retinopathy of prematurity; PDA, patent ductus arteriosus.