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Original Investigation |

Patterns and Predictors of Sensorineural Hearing Loss in Children With Congenital Diaphragmatic Hernia FREE

Misha Amoils, MD1; Mary Crisham Janik, MD2; Lawrence R. Lustig, MD3
[+] Author Affiliations
1Department of Otolaryngology, Stanford University, Stanford, California
2Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois
3Department of Otolaryngology–Head and Neck Surgery, Columbia University Medical Center, New York, New York
JAMA Otolaryngol Head Neck Surg. 2015;141(10):923-926. doi:10.1001/jamaoto.2015.1670.
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Published online

Importance  Although congenital diaphragmatic hernia (CDH) may be associated with sensorineural hearing loss (SNHL), to our knowledge, no studies have yet identified the pattern of this hearing loss or definitive independent risk factors that may place this population at higher risk.

Objective  To characterize the type and degree or SNHL in CDH survivors and better characterize perinatal risk factors.

Design, Setting, and Participants  This was a retrospective cohort study of CDH survivors who had a pure-tone audiogram available for review followed at a multidisciplinary clinic.

Interventions  Treatment for CDH at birth.

Main Outcomes and Measures  Audiograms were used to calculate pure-tone average (PTA) for the most severely affected side and classify SNHL as normal (<20 dB), mild (20-39 dB), moderate (>40-59 dB), severe (≥60 dB), or profound (≥80 dB). Clinically significant SNHL was defined as a PTA of at least 40 dB. Perinatal data evaluated included demographics, characteristics of CDH and neonatal respiratory course, peak total and direct bilirubin levels, exposure to ototoxic drugs, need for supplemental oxygen at discharge, and results of newborn hearing screen. Univariate analysis was conducted to examine the relationship between these variables and (1) any SNHL or (2) significant SNHL.

Results  Fifty patients were included. Audiograms were performed at age 2.7 ± 2.3 years (range, 0.5-10.7 years). Of the 50 patients, 28 (56%) had any SNHL and 9 of the 28 (32%) had significant SNHL (PTA ≥ 40 dB). Any SNHL was not significantly different (P = .42) by newborn hearing screen results: 5 of 7 children (71%) who failed the screening were classified as having any SNHL, and 20 of 40 children (50%) who passed were classified as having any SNHL. While no variables were significantly associated with any SNHL, multiple significant associations were found with significant SNHL: extracorporeal membrane oxygenation support (P = .02), nonprimary CDH repair (P = .01), prolonged ventilation (≥14 days) (P = .001), and high neonatal furosemide exposure (P = .03).

Conclusions and Relevance  Sensorineural hearing loss is prevalent among children with CDH. As would be expected, significant SNHL (PTA ≥ 40 dB) in this cohort was associated with markers of more severe CDH with a more complicated neonatal hospital course. Overall close follow-up for hearing and speech development, including routine audiology testing, is indicated in children with CDH.

Congenital diaphragmatic hernia (CDH) results from a defect in the formation of the muscular tendinous formation of the diaphragm, allowing abdominal viscera to protrude into the thoracic cavity.1 Greater than 80% of defects occur on the left side.2 The diagnosis is made in approximately 1 in 2500 to 3000 live births.1,35 Although survival rates have increased in the past decade with advancement in perinatal management, survivors are severely affected by a number of potential comorbidities.1,2,69 These include pulmonary hypoplasia, abnormalities of pulmonary vasculature, gastroesophageal reflux disorder, growth failure, chest wall and spinal deformities, cognitive delay, and sensorineural hearing loss (SNHL).18,10

Sensorineural hearing loss has been reported in 2.5% to 62% of patients with CDH,1,2,812 a substantially higher rate than that reported in either newborns without complications (0.0015%-0.006%) or patients who require neonatal intensive care (1%-3%). Factors known to be associated with hearing loss and thought to possibly contribute to SNHL in the CDH population include ototoxic drugs, hyperbilirubinemia, prolonged ventilation, high-frequency oscillation (HFO), neuromuscular blockade, extracorporeal membrane oxygenation (ECMO), and low birth weight.1,2,58,10 While causes of SNHL are traditionally classified as congenital vs acquired,13 the mechanism in this population remains to be elucidated. For example, some authors8 have suggested that severe tissue hypoxia may interfere with cochlear oxygenation and function. Others8,14 have theorized that CDH may be due to abnormal neuronal migration and because the cochlea develops at approximately the same gestational age as the diaphragm, the developmental abnormalities of both organs may be related. Conversely, many studies2,10,11 have focused on postnatal factors as the cause for acquired SNHL.

While a number of authors have examined hearing outcomes in this patient population to better elucidate independent predictors of the SNHL seen, to date, to our knowledge none has definitively identified any single causative factor. Thus, to gain a better understanding of the relationship between factors associated with hearing loss in children born with CDH, we retrospectively reviewed a large cohort of patients with this condition at our institution.

This study was approved by the institutional review board of the University of California, San Francisco. The design was a retrospective medical record review of 50 pediatric patients with CDH born from 1999 to 2008 and subsequently followed at a multidisciplinary clinic through the UCSF Benioff Children’s Hospital. Included patients had at least 1 pure-tone audiogram available for review. If more than 1 audiogram had been obtained, the most recent was used. Follow-up audiograms, performed from 2003 to 2010, were used to calculate pure-tone averages (PTAs) (500-4000 Hz) and characterize hearing status as normal (<20 dB), or with SNHL of mild (20-39 dB), moderate (>40-59 dB), severe (≥60 dB), or profound (≥80 dB) degree. Additional data collected included sex, gestational age, birth weight, need for oxygen at discharge, results of newborn hearing screen, type of CDH repair (primary vs patch), presence of liver in the thorax, need for ECMO support, age at extubation, total days intubated, total and direct bilirubin levels, and the doses received of vancomycin, gentamicin, furosemide, and ampicillin. Univariate analysis was then conducted to examine the relationship between these variables and (1) any SNHL or (2) significant SNHL (PTA ≥ 40 dB). Significance from this analysis was defined as P < .05.

A total of 50 patients were included in this study: 26 boys and 24 girls. Demographics are shown in Table 1. A prenatal diagnosis of CDH had been made in 33 patients. Forty patients had a left-sided hernia, and in 27 cases the liver had herniated into the thorax. Overall, 18 patients underwent a primary surgical repair, whereas 32 required a more extensive patch repair. The mean gestational age was 37.4 weeks (range, 28-41 weeks). The mean birth weight was 3046 g (range, 900-4869 g).

Table Graphic Jump LocationTable 1.  Characteristics of the 50 Children in the Cohort

Treatment factors analyzed included age at extubation, total days intubated, need for ECMO support, bilirubin exposure, and exposure to ototoxic drugs (vancomycin, gentamicin, furosemide, and ampicillin) (Table 2). The mean (SD) age at extubation was 17.25 (12.5) days. Only 4 of the 50 patients received ECMO.

Table Graphic Jump LocationTable 2.  Perinatal Factors Associated With Clinically Significant SNHL (PTA ≥ 40 dB)

Results of newborn hearing screen were available for 47 of the patients (Table 3): 40 passed the screen and 7 failed. Of those who failed, 5 went on to develop SNHL of any degree. Of those that passed, 20 went on to develop SNHL of any degree. Follow-up audiograms were performed at age 2.7 ± 2.3 years (range, 0.5-10.7 years). A total of 28 patients (56%) had any degree of SNHL. Of these 28, 9 had significant SNHL defined as a PTA greater than 40 dB: 3 had moderate SNHL, 2 had severe SNHL, and 4 had profound SNHL. On statistical univariate analysis, no factors known to be associated with hearing loss were found to be significantly associated with later SNHL of all degrees combined. However, several factors were associated with significant hearing loss. These included ECMO support (P = .02), nonprimary CDH repair (P = .01), prolonged ventilation (≥14 days) (P = .001), and high neonatal furosemide exposure (top quartile) (P = .03).

Table Graphic Jump LocationTable 3.  Characterization of SNHL by PTA of Most Severely Affected Side in 50 Children

In this study, a retrospective analysis was performed in a large cohort of patients with CDH at our institution to determine factors associated with SNHL. While over one-half of patients (56%) developed SNHL of any degree, no factors known to be associated with hearing loss were significantly associated with this overall loss. However, several perinatal factors were significantly associated with higher degrees of SNHL (PTA ≥ 40 dB): ECMO support, whether the child underwent a nonprimary CDH repair, the use of prolonged ventilation, and a high neonatal furosemide exposure. The 75th to 95th percentile received 6 to 11 mg/kg of furosemide based on birth weight.

Interestingly, although we identified no association between ECMO and any degree of SNHL, a potential relationship was found by Fligor et al,15 who studied hearing outcomes in 111 patients treated with ECMO at Children’s Hospital of Boston. In that study,15 SNHL was diagnosed in 29 of 111 children (26%). Of these 29 children, 13 had been diagnosed as having CDH. In contrast, Robertson et al2 studied the prevalence of SNHL in 2- to 5-year-old survivors with neonatal respiratory failure due to CDH and found similar rates regardless of whether the neonates were treated with ECMO (60% vs 59%). Cheung et al11 also found comparable rates of SNHL in survivors of CDH treated with ECMO vs those who were not (65% vs 59%). However, these authors11 did find SNHL to be significantly associated with the cumulative dose and duration of use. Masumoto et al10 also found usage of pancuronium bromide to be significantly associated with SNHL; all patients with SNHL in their study had been treated with this agent. Other significant associations they noted included duration and treatment by loop diuretics, mechanical ventilation, and high-frequency oscillation.

In a larger study by Morini et al,8 nearly one-half of survivors of CDH (40 of 82) were found to have SNHL. At univariate analysis, these patients had significantly lower gestational age, higher prevalence of sepsis, older age at audiologic examination, more episodes of hypocapnia, higher prevalence of inhaled nitric oxide use, longer mechanical ventilation, and longer aminoglycoside, furosemide, and pancuronium bromide treatments. But on logistic regression analysis, the only independently associated variable was the patient’s age at audiologic follow-up. None of the patients included in this study had been treated with ECMO.8

The rates of SNHL reported by these authors ranged from 25% to 62%.2,8,10,11 This is comparable with the 56% rate of hearing loss found in our study. Interestingly, more recent studies by Morando et al1 and Wilson et al9 show that the incidence of SNHL in survivors of CDH may be lower than previously suggested. Morando et al1 studied 26 patients in Italy, and only 1 (3.8%) was diagnosed as having SNHL. Similarly, Wilson et al9 found only 1 of their 42 patients (2.5%) treated at Montreal Children’s Hospital to have SNHL. One possible explanation for these markedly varied rates of reported hearing loss in this population may be due to the time at which the hearing was measured. For example, 85% of the patients in our study passed their initial newborn hearing screen. This echoes findings by other authors2,10 who have found later development of hearing loss in patients who passed initial hearing screens. In our cohort, audiograms demonstrating SNHL were performed at an average age of 2.7 years. We believe this later development of hearing loss lends more evidence to the SNHL associated with CDH as acquired, rather than congenital, in nature.

Unfortunately, there has been a lack of a uniform predictor reported for the development of SNHL in survivors of CDH. However, given that studies differ in location and population characteristics, use of ECMO or neuromuscular blockade, age at audiologic evaluation, and even in the definition of what constitutes SNHL, this is not too surprising. To date, research has been reported only from treatment centers in Canada, Japan, and Italy.1,2,811 As is true of our series, prior studies1,2,812 have been similarly small with a population size ranging from 17 to 82. Other studies have defined SNHL as a hearing threshold greater than 20 dB for at least 2 octave frequencies,1 or used a cutoff of greater than 20 dB, greater than 30 dB, or greater than 40 dB at any frequency.2,812 The most specific data available regarding the audiological profile of CDH survivors come from Robertson et al.2 Of the 22 children with SNHL, 16 had mild to moderate low-frequency sloping to moderate-to-severe high-frequency loss. Of the remaining patients, 6 had severe to profound loss at 500 Hz or higher. Seventeen presented with delayed-onset SNHL. Five were not tested. Documented progression was found in 9 children. Twenty children were using amplification, and 2 had had cochlear implantation by study completion.2

To our knowledge, no other studies have found an association between SNHL in this population and nonprimary CDH repair. However, we feel that this may be a marker of more severe disease and thus prolonged hospitalization and exposure to other potential defects. Smaller diaphragm defects can be closed primarily, but in more severe cases the opening in the diaphragm is too large or a portion is absent. Thus, additional tissue or material is necessary to close the defect in a more extensive surgery called patch repair.

This study has several limitations, including the retrospective nature and a small cohort size that precludes multivariate analysis. However, in an attempt to perform a more comprehensive evaluation of SNHL in this population, sorting by PTA and further categorizing by mild (20-39 dB), moderate (>40-59 dB), severe (≥60 dB), or profound (≥80 dB) degree, we have begun to identify some factors that may be the cause of SNHL in babies born with CDH. However, it is clear that larger patient numbers and more consistent reporting guidelines among all centers would be helpful to better understand those factors that lead to hearing loss in patients with CDH.

This study documents a higher rate of SNHL in patients with CDH compared with the general pediatric population. This seems especially pertinent given that survivors of CDH may be at higher risk for developing neurocognitive delay, independent of hearing status.4 Our results also suggest that SNHL in CDH is associated with more severe CDH, as indicated by need for ECMO support, nonprimary repair, and prolonged ventilation. Higher neonatal furosemide exposure was associated with SNHL, but also with more severe CDH.

As this and other studies document, SNHL in patients with CDH is common, even though the causative factors remain to be completely elucidated. Until those factors are better understood and hearing loss can be more effectively prevented in these patients, there remains ongoing need for hearing screening in this population, particularly because the loss may not be evident at the time of newborn hearing testing. Prospective studies are still needed to better characterize the natural history of SNHL in CDH survivors, tease out unique risk factors, and provide more conclusive evidence to guide management strategies.

Corresponding Author: Misha Amoils, MD, Department of Otolaryngology, Stanford University, 801 Welch Rd, Stanford, CA 94305 (mamoils@ohns.stanford.edu).

Submitted for Publication: April 14, 2015; final revision received June 24, 2015; accepted July 18, 2015.

Published Online: September 10, 2015. doi:10.1001/jamaoto.2015.1670.

Author Contributions: Dr Amoils 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.

Study concept and design: Lustig.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Amoils, Crisham Janik.

Critical revision of the manuscript for important intellectual content: Amoils, Lustig.

Statistical analysis: Amoils.

Administrative, technical, or material support: Crisham Janik, Lustig.

Study supervision: Lustig.

Conflict of Interest Disclosures: None reported.

Previous Presentation: The data from this study were presented as a poster at Combined Otolaryngology Spring Meetings; May 16-17, 2014; Las Vegas, Nevada (through the American Society of Pediatric Otolaryngology; ASPO Abstract: ASPo20140021).

Additional Information: Drs Amoils and Crisham Janik attended medical school at University of California, San Francisco, and worked with Dr Lustig on this research during that time.

Morando  C, Midrio  P, Gamba  P, Filippone  M, Sgrò  A, Orzan  E.  Hearing assessment in high-risk congenital diaphragmatic hernia survivors. Int J Pediatr Otorhinolaryngol. 2010;74(10):1176-1179.
PubMed   |  Link to Article
Robertson  CMT, Cheung  PY, Haluschak  MM, Elliott  CA, Leonard  NJ; Western Canadian ECMO Follow-up Group.  High prevalence of sensorineural hearing loss among survivors of neonatal congenital diaphragmatic hernia. Am J Otol. 1998;19(6):730-736.
PubMed
Peetsold  MG, Heij  HA, Kneepkens  CM, Nagelkerke  AF, Huisman  J, Gemke  RJ.  The long-term follow-up of patients with a congenital diaphragmatic hernia: a broad spectrum of morbidity. Pediatr Surg Int. 2009;25(1):1-17.
PubMed   |  Link to Article
Benjamin  JR, Gustafson  KE, Smith  PB,  et al.  Perinatal factors associated with poor neurocognitive outcome in early school age congenital diaphragmatic hernia survivors. J Pediatr Surg. 2013;48(4):730-737.
PubMed   |  Link to Article
Bagolan  P, Casaccia  G, Crescenzi  F, Nahom  A, Trucchi  A, Giorlandino  C.  Impact of a current treatment protocol on outcome of high-risk congenital diaphragmatic hernia. J Pediatr Surg. 2004;39(3):313-318.
PubMed   |  Link to Article
Lally  KP, Engle  W; American Academy of Pediatrics Section on Surgery; American Academy of Pediatrics Committee on Fetus and Newborn.  Postdischarge follow-up of infants with congenital diaphragmatic hernia. Pediatrics. 2008;121(3):627-632.
PubMed   |  Link to Article
Nobuhara  KK, Lund  DP, Mitchell  J, Kharasch  V, Wilson  JM.  Long-term outlook for survivors of congenital diaphragmatic hernia. Clin Perinatol. 1996;23(4):873-887.
PubMed
Morini  F, Capolupo  I, Masi  R,  et al.  Hearing impairment in congenital diaphragmatic hernia. J Pediatr Surg. 2008;43(2):380-384.
PubMed   |  Link to Article
Wilson  MG, Riley  P, Hurteau  AM, Baird  R, Puligandla  PS.  Hearing loss in congenital diaphragmatic hernia (CDH) survivors. J Pediatr Surg. 2013;48(5):942-945.
PubMed   |  Link to Article
Masumoto  K, Nagata  K, Uesugi  T, Yamada  T, Taguchi  T.  Risk factors for sensorineural hearing loss in survivors with severe congenital diaphragmatic hernia. Eur J Pediatr. 2007;166(6):607-612.
PubMed   |  Link to Article
Cheung  PY, Tyebkhan  JM, Peliowski  A, Ainsworth  W, Robertson  CMT.  Prolonged use of pancuronium bromide and sensorineural hearing loss in childhood survivors of congenital diaphragmatic hernia. J Pediatr. 1999;135(2, pt 1):233-239.
PubMed   |  Link to Article
Javidnia  H, Vaccani  JP.  Progressive sensorineural hearing loss in children with congenital diaphragmatic hernias. J Otolaryngol Head Neck Surg. 2009;38(1):29-31.
PubMed
Gifford  KA, Holmes  MG, Bernstein  HH.  Hearing loss in children. Pediatr Rev. 2009;30(6):207-215.
PubMed   |  Link to Article
Iritani  I.  Experimental study on embryogenesis of congenital diaphragmatic hernia. Anat Embryol (Berl). 1984;169(2):133-139.
PubMed   |  Link to Article
Fligor  BJ, Neault  MW, Mullen  CH, Feldman  HA, Jones  DT.  Factors associated with sensorineural hearing loss among survivors of extracorporeal membrane oxygenation therapy. Pediatrics. 2005;115(6):1519-1528.
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1.  Characteristics of the 50 Children in the Cohort
Table Graphic Jump LocationTable 2.  Perinatal Factors Associated With Clinically Significant SNHL (PTA ≥ 40 dB)
Table Graphic Jump LocationTable 3.  Characterization of SNHL by PTA of Most Severely Affected Side in 50 Children

References

Morando  C, Midrio  P, Gamba  P, Filippone  M, Sgrò  A, Orzan  E.  Hearing assessment in high-risk congenital diaphragmatic hernia survivors. Int J Pediatr Otorhinolaryngol. 2010;74(10):1176-1179.
PubMed   |  Link to Article
Robertson  CMT, Cheung  PY, Haluschak  MM, Elliott  CA, Leonard  NJ; Western Canadian ECMO Follow-up Group.  High prevalence of sensorineural hearing loss among survivors of neonatal congenital diaphragmatic hernia. Am J Otol. 1998;19(6):730-736.
PubMed
Peetsold  MG, Heij  HA, Kneepkens  CM, Nagelkerke  AF, Huisman  J, Gemke  RJ.  The long-term follow-up of patients with a congenital diaphragmatic hernia: a broad spectrum of morbidity. Pediatr Surg Int. 2009;25(1):1-17.
PubMed   |  Link to Article
Benjamin  JR, Gustafson  KE, Smith  PB,  et al.  Perinatal factors associated with poor neurocognitive outcome in early school age congenital diaphragmatic hernia survivors. J Pediatr Surg. 2013;48(4):730-737.
PubMed   |  Link to Article
Bagolan  P, Casaccia  G, Crescenzi  F, Nahom  A, Trucchi  A, Giorlandino  C.  Impact of a current treatment protocol on outcome of high-risk congenital diaphragmatic hernia. J Pediatr Surg. 2004;39(3):313-318.
PubMed   |  Link to Article
Lally  KP, Engle  W; American Academy of Pediatrics Section on Surgery; American Academy of Pediatrics Committee on Fetus and Newborn.  Postdischarge follow-up of infants with congenital diaphragmatic hernia. Pediatrics. 2008;121(3):627-632.
PubMed   |  Link to Article
Nobuhara  KK, Lund  DP, Mitchell  J, Kharasch  V, Wilson  JM.  Long-term outlook for survivors of congenital diaphragmatic hernia. Clin Perinatol. 1996;23(4):873-887.
PubMed
Morini  F, Capolupo  I, Masi  R,  et al.  Hearing impairment in congenital diaphragmatic hernia. J Pediatr Surg. 2008;43(2):380-384.
PubMed   |  Link to Article
Wilson  MG, Riley  P, Hurteau  AM, Baird  R, Puligandla  PS.  Hearing loss in congenital diaphragmatic hernia (CDH) survivors. J Pediatr Surg. 2013;48(5):942-945.
PubMed   |  Link to Article
Masumoto  K, Nagata  K, Uesugi  T, Yamada  T, Taguchi  T.  Risk factors for sensorineural hearing loss in survivors with severe congenital diaphragmatic hernia. Eur J Pediatr. 2007;166(6):607-612.
PubMed   |  Link to Article
Cheung  PY, Tyebkhan  JM, Peliowski  A, Ainsworth  W, Robertson  CMT.  Prolonged use of pancuronium bromide and sensorineural hearing loss in childhood survivors of congenital diaphragmatic hernia. J Pediatr. 1999;135(2, pt 1):233-239.
PubMed   |  Link to Article
Javidnia  H, Vaccani  JP.  Progressive sensorineural hearing loss in children with congenital diaphragmatic hernias. J Otolaryngol Head Neck Surg. 2009;38(1):29-31.
PubMed
Gifford  KA, Holmes  MG, Bernstein  HH.  Hearing loss in children. Pediatr Rev. 2009;30(6):207-215.
PubMed   |  Link to Article
Iritani  I.  Experimental study on embryogenesis of congenital diaphragmatic hernia. Anat Embryol (Berl). 1984;169(2):133-139.
PubMed   |  Link to Article
Fligor  BJ, Neault  MW, Mullen  CH, Feldman  HA, Jones  DT.  Factors associated with sensorineural hearing loss among survivors of extracorporeal membrane oxygenation therapy. Pediatrics. 2005;115(6):1519-1528.
PubMed   |  Link to Article

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