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American Journal of Audiology logoLink to American Journal of Audiology
. 2023 Aug 2;32(3):657–664. doi: 10.1044/2023_AJA-22-00157

Is Methotrexate Ototoxic? Investigating the Ototoxic Late Effects of Pediatric Cancer Treatment

Brittney Moore a, Gabrielle Sheets b, Jordan Doss c, Ayesha Umrigar d, Michael Norman e, Zhide Fang f, Pinki Prasad c, Amanda Musso g, Sloane Clay b, Fern Tsien b,✉
PMCID: PMC10558153  PMID: 37532243

Abstract

Purpose:

Pediatric cancer survivors often experience long-term adverse health conditions or late effects, including hearing loss, that are attributable to cancer therapy. Ototoxic late effects have been documented in patients with cancer treated with cisplatin-based chemotherapy and/or radiation. This study evaluated the late effects of methotrexate as compared to cisplatin and other cancer therapy agents on pediatric cancer survivors at the Children's Hospital of New Orleans in Louisiana (CHNOLA) and patients currently undergoing cancer treatment at Our Lady of the Lake (OLOL) Hospital in Baton Rouge, Louisiana.

Method:

A retrospective chart review was conducted of medical records from the CHNOLA Audiology Clinic and the Treatment After Cancer Late Effects clinic, which followed patients 2–19 years after cancer treatment completion and current patients with pediatric cancer at OLOL. This study identified pediatric cancer survivors between 2 and 24 years of age with treatment protocol information and audiological evaluations. Association studies were performed to calculate p values using an exact chi-square test.

Results:

More than 44% of late-effects patients had significant hearing loss; mild-to-profound hearing loss was observed in 37.5% of patients who received methotrexate treatment without cisplatin or irradiation. Eighty-three percent of the patients who received cisplatin had late-effect hearing loss. In patients currently receiving cancer treatment, 12% had significant hearing loss.

Conclusions:

The results from this study suggest that children who receive therapies not clinically established as ototoxic (i.e., methotrexate) may still be at a high risk of developing long-term hearing loss as a late effect. Due to the high incidence rate of hearing loss among patients with pediatric cancer, we recommend that audiologists be part of the late-effects care team. This study also demonstrates that patients with pediatric cancer treated with methotrexate should receive routine long-term auditory monitoring as part of their standard of care to detect and manage hearing loss early, minimizing adverse outcomes.

Decades of research, clinical trials, and oncology drug development have led to significant improvements in pediatric cancer survival. Today, it is estimated that over 80% of children diagnosed with cancer in the United States will survive (Howlader et al., 2016; World Health Organization, 2021). While remarkable advances in cancer treatment have decreased mortality rates, many highly effective chemotherapy agents are being investigated for their possible involvement in the development of long-term irreversible neurological and psychosocial sequelae ranging in severity, termed late effects (Carpenter et al., 2022; Gibson et al., 2019; Sheth et al., 2017). As survival rates for certain pediatric leukemias approach 95%, the focus of treatment innovation has shifted from increasing survival rates to improving survival quality with reductions of toxicities and deleterious late effects (Carpenter et al., 2022; Gibson et al., 2019; Howlader et al., 2016). Cancer treatment-induced hearing loss can develop immediately after the first treatment or several years later (Dillard et al., 2022). The risk of treatment-induced hearing disorders increases when ototoxic drugs are paired with radiation and other first-line cancer treatments (Bhandare et al., 2010; Shi et al., 2021; Shorter et al., 2017).

Patients acquire common late effects, such as mild-to-profound hearing loss and tinnitus, across various age groups, cancer types, and clinical protocols. Reports have linked chemotherapy with sensorineural hearing loss (SNHL) as well as irradiation with both SNHL and conductive hearing loss (Shi et al., 2021; Shorter et al., 2017). Radiation therapy patients develop hearing loss when the inner ear is included within the radiation field, causing direct radiation damage to DNA, oxidative stress, and inflammation of cochlear cells, stria vascularis endothelial cells, vascular endothelial cells, and spiral ganglion neurons (Mujica-Mota et al., 2014; Shi et al., 2021).

Cisplatin is a well-established and effective chemotherapy for solid tumors (e.g., osteosarcoma, ovarian, testicular, lung, head and neck, and glioblastomas; Dillard et al., 2022; Gómez-Ruiz et al., 2012; Sheth et al., 2017; Steyger, 2021). Ototoxicity has been documented in patients treated with cisplatin-based chemotherapy; it is usually irreversible, bilateral, and characterized by high-frequency SNHL (Coradini et al., 2007; Dillard et al., 2022). Pediatric patients show a greater risk of developing hearing loss following cisplatin treatment than adult patients. In patients with pediatric cancer, the incidence of cisplatin-induced hearing loss ranges from 22% to 77%, reflecting different doses and durations of cisplatin treatment and different age groups (Coradini et al., 2007; Knight et al., 2005; Sheth et al., 2017). Other platinum-based ototoxic chemotherapy drugs include carboplatin and oxaliplatin (Dillard et al., 2022).

Methotrexate (MTX) is a very effective chemotherapy for acute lymphocytic leukemia (Hawkins et al., 2008; Koźmiński et al., 2020; Mandal et al., 2020). It is a synthetic organic compound that belongs to the antifolate therapeutic group and Class III of the Biopharmaceutical Classification System. It was created in the late 1940s as a less-toxic derivative of aminopterin for the treatment of leukemia, rheumatoid arthritis, and psoriasis (Koźmiński et al., 2020). MTX is sometimes combined with cisplatin to treat osteosarcoma (Asselin et al., 2011; Hegyi et al., 2017). However, MTX can cause acute, subacute, and long-term neurotoxicity and leukoencephalopathy with vanishing white matter, a progressive disorder that mainly affects the central nervous system (CNS; Forster et al., 2016; Hawkins et al., 2008; Koźmiński et al., 2020). This neurotoxicity is likely to occur through disruption of CNS folate homeostasis and/or direct neuronal damage (Koźmiński et al., 2020). Subacute MTX neurotoxicity typically occurs 2–14 days after prolonged low-dose oral, intrathecal, or high-dose MTX and manifests with transient stroke-like symptoms, encephalopathy, seizures, and/or aphasia. Late effects may include seizures, memory loss, and problems related to academic achievement and attention (Bhojwani et al., 2014; Daetwyler et al., 2022). Although the late effects of MTX treatment have been recognized for years, the mechanism of its pediatric neurotoxicity is not well understood (Daetwyler et al., 2022). Animal model studies using mice have revealed a decrease in myelin sheath thickness in the white matter of MTX-treated mice and depletion of oligodendrocyte lineage cells compared to controls (Gibson et al., 2019; Mateos et al., 2022; Umugire et al., 2022). The ototoxicity of MTX has not been well described in humans; however, it has been demonstrated to cause hearing loss in mice by crossing the blood–labyrinth barrier and damaging cochlear neurons and outer hair cells (OHCs; Mateos et al., 2022; Umugire et al., 2022).

Method

The study was approved by the institutional review boards of the Louisiana State University Health Sciences Center in New Orleans, Louisiana; Children's Hospital of New Orleans in Louisiana (CHNOLA); and Our Lady of the Lake (OLOL) Hospital in Baton Rouge, Louisiana.

Electronic health records were obtained from 292 children and adolescents ages 2–22 years enrolled in the Treatment After Cancer Late Effects (TACLE) clinic at CHNOLA from 2012 to 2021. TACLE patients were at least 2–19 years after completion of cancer treatment. Sixty-six patients fit our eligibility criteria (i.e., those who had received audiological evaluations after cancer treatment, had no hearing loss before treatment, and had no underlying genetic/health conditions that could be associated with their hearing loss). None of the patients received monoclonal antibody treatment as part of their cancer therapy. Any patients who received aminoglycosides were excluded from our study. To the best of our knowledge, none of the patients in this study have received ototoxic medications aside from the cancer treatments. Patients' race and ethnicity, date of birth, age at the time of audiogram, audiological evaluations and results, cancer type, treatment protocol, and lifetime dosage were recorded.

Two hundred patient charts were analyzed from OLOL Hospital electronic health records of patients undergoing cancer therapy. Of these, 48 had hearing evaluations that fit the above inclusion criteria.

The hearing evaluations included the following for patients younger than 3 years of age: tympanometry of 1k Hz for 0–12 months of age and 226 Hz for 1 year and older; high-frequency distortion product otoacoustic emissions (DPOAEs) of 2k–10k Hz; auditory brainstem response testing; Infant Click and Chirp of 500, 1k, 2k, 4k, and 8k Hz; and Chirp auditory steady-state response testing. Patients aged ≥ 3 years were evaluated via tympanometry (226 Hz), high-frequency DPOAEs of 2k–10k Hz, air-conduction testing at 250, 500, 1k, 2k, 3k, 4k, 6k, and 8k Hz; bone-conduction testing at 250, 500, 1k, 2k, and 4k Hz; speech recognition and word recognition thresholds; and high-frequency air-conduction testing at 10, 12.5, and 16 kHz. The hearing outcomes using the International Society of Pediatric Oncology (SIOP) ototoxicity grading scale are listed in Table 1 (Bass et al., 2014). Table 2 demonstrates the hearing classifications of “mild,” “moderate,” “severe,” or “profound” based on threshold at any frequency within the 250- to 8k-Hz range (Clark, 1981).

Table 1.

Number of pediatric cancer survivors with sensorineural hearing loss (SNHL) and their International Society of Pediatric Oncology ototoxicity scale hearing outcomes.

Grade and parameters Number of patients
0
≤ 20 dB HL at all frequencies		 0
1
> 20 dB HL (i.e., 25 dB HL or greater) SNHL above 4k Hz		 6 a
2
> 20 dB HL SNHL at 4k Hz and above		 3
3
> 20 dB HL SNHL at 2k Hz or 3k Hz and above		 9
4
> 40 dB HL (i.e., 45 dB HL or more) SNHL at 2k Hz and above		 12
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Note. Results from the most recent hearing evaluations from cancer survivors 2–19 years after treatment completion from the Treatment After Cancer Late Effects clinic at Children's Hospital of New Orleans in Louisiana. HL = hearing loss.

a

Due to the International Society of Pediatric Oncology scale omitting any hearing loss in the 250- to 1k-Hz range, one patient with a bilateral sensorineural low-frequency hearing loss did not fit within the scale's parameters and was classified as Grade 1.

Table 2.

Number of pediatric cancer survivors with sensorineural hearing loss and hearing loss thresholds at 2k Hz and above.

Degree of hearing loss Number of patients
Normal for adults; slight for children
16–25 dB HL		 0
Mild
26–40 dB HL		 6
Moderate
41–55 dB HL		 1
Moderately severe
56–70 dB HL		 3
Severe
71–90 dB HL		 16
Profound
91+ dB HL		 4
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Note. Results from the most recent hearing evaluations from cancer survivors 2–19 years after treatment completion from the Treatment After Cancer Late Effects clinic at Children's Hospital of New Orleans in Louisiana.

Statistical methods were applied to analyze contingency frequency tables. For association studies, exact chi-square test was used to obtain p values. All computations were carried out using SAS 9.4.

Results

Patients From the Late Effects Clinic

The ages of the 66 patients from the TACLE clinic when they completed their cancer treatment ranged from 9.5 months to 19 years. All 66 patients had their most recent hearing evaluations at least 2 years (and up to 19 years) after cancer completion, with the oldest cancer survivor being followed at 22 years of age. Of the 66 TACLE patients, 30 (45%) had SNHL. Once ototoxic drugs enter the inner ear, cell degeneration begins to occur at the basal end of the cochlea, the place in which high frequencies are amplified. This makes the presence of a high-frequency hearing loss an indicator that the loss is due to damage caused by treatment. For this study, patients were categorized using the SIOP Boston Ototoxicity Grading Scale, a criterion scale used to presume the severity of damage done to the cochlea posttreatment that is based on the patient's hearing loss thresholds at high frequencies. If hearing levels were asymmetrical, the level in the worst ear was used for the analysis. The SIOP grades and the degree of hearing loss of the 30 affected patients are described on Tables 1 and 2, respectively.

Figure 1a summarizes the audiological results and cancer treatment of the TACLE patients. As expected, hearing loss was observed in 10 of 12 patients (83%) who received cisplatin. Fifty-seven percent of the patients who received radiation therapy and 53.85% of those who received radiation therapy in combination with cisplatin or MTX had hearing loss. Cisplatin dosages ranged from 120 to 600 mg/m2, and MTX dosages ranged from cumulative dosages ranging from 60 to 144,000 mg/m2. All patients who were included in the radiation treatment groups had cranial radiation.

Figure 1.

2 bar graphs. a. The title of the first graph is Sensorineural hearing loss, S N H L, in cancer survivors 2 to 19 years after treatment completion, n = 66. The first graph depicts the percentage of patients for each treatment type with respect to the treatment type and S N H L. White and Black bars represent persons with no S N H L and persons with mild to profound S N H L, respectively. The data in the bar graph is as follows. Cisplatin, n = 12. White bar: 16.67 percent. Black bar: 83.33. Methotrexate, n = 8. White bar: 62.50. Black bar: 37.50. Cisplatin and Methotrexate, n = 6. White bar:16.67. Black bar: 83.33. Radiation, n = 7. White bar: 42.86. Black bar: 57.14. Radiation and Cisplatin or Radiation and Methotrexate, n = 13. White bar: 46.15. Black bar: 53.85. Other, superscript asterisk, n = 20. White bar: 100.00. The captions below the first graph are as follows. Treatment Type, number of patients per treatment. Treatment After Cancer Late Effects Clinic at Children\u2019s Hospital of New Orleans, New Orleans, L A. b. The title of the second graph is Mixed or sensorineural hearing loss, S N H L, in current pediatric cancer patients, n = 48. The second graph depicts the percentage of patients for each treatment type with respect to the treatment type and S N H L. White and Black bars represent No Mixed or S N H L and Mild to Profound Mixed S N H L, respectively. The data is as follows. Cisplatin, n = 12. White bar: 66.67. Black bar: 33.33. Methotrexate, n = 23. White bar: 91.30. Black bar: 8.70. Cistplatin and Methotrexate, n = 0. White bar: 0.00. Black bar: 0.00. Radiation, n = 0. White bar: 0.00. Black bar: 0.00. Radiation and Cisplatin or Radiation and Methotrexate, n = 0. White bar: 0.00. Black bar: 0.00. Other, superscript asterisk, n = 13. White bar: 100.00. Black bar: 0.00. The captions below the second graph are as follows. Treatment Type, number of patients per treatment. Pediatric Cancer Patients from Our Lady of the Lake Hospital, Baton Rouge, L A. In both the graphs, all the values are in percentages.

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(a) Sensorineural hearing loss (SNHL) in cancer survivors 2 years after treatment completion. The most recent audiological evaluation results of 66 pediatric cancer survivors from the Treatment After Cancer Late Effects clinic at Children's Hospital of New Orleans in Louisiana are shown. Numbers of patients with corresponding treatments are in parentheses. Patients completed cancer treatment between 9 months and 19 years of age. The most recent audiological evaluations were conducted from 2 to 19 years after the cancer therapy completion (up to the age of 24 years). (b) Mixed/SNHL in current pediatric cancer patients. Audiological evaluation results of 48 current patients with pediatric cancer from the Our Lady of the Lake Hospital in Baton Rouge, Louisiana. Numbers of patients with corresponding treatments are in parentheses. *Other therapeutic agents include carboplatin, ifosfamide, bleomycin, cyclophosphamide, doxorubicin, vincristine, and cytarabine.

Of particular interest, three of the eight (37.5%) patients who received MTX without cisplatin or cranial irradiation developed hearing loss, which is significantly higher than the incidence rate of 0.1% in the general population (Centers for Disease Control and Prevention [CDC], 2021; two-sided p = 5.579e-8, 95% CI [0.0852, 0.7551]). Among these three patients who received MTX and no other ototoxic therapy, one patient had a mild hearing loss unilaterally, one had a mild hearing loss bilaterally, and one had a severe hearing loss bilaterally. For asymmetrical losses, the degree of hearing loss was determined by thresholds recorded in the patient's worst ear. In addition, six of the seven patients (85.7%) who received MTX in combination with cisplatin experienced hearing loss. Severe and profound hearing loss was most common among patients treated with cisplatin.

Of statistical significance, 100% of the 20 pediatric patients who received cancer therapy that did not include cisplatin, MTX, or radiation (referred to as “Other” category in Figures 1a and 1b) had normal hearing at the time of their most recent audiological evaluation. Surprisingly, none of the patients in the “other” group had hearing loss, although it included carboplatin, a known ototoxic medication. Carboplatin dosages ranged from 108 to 8,225 mg/m2 in all patients, dosages ranged from 108 to 1,700 mg/m2 in those patients with hearing loss (all also received cisplatin or radiation), and dosages ranged from 1,200 to 8,225 mg/m2 in patients without hearing loss (and did not receive cisplatin/radiation/MTX).

The odds of hearing loss for patients not treated with cisplatin, MTX, or radiation were significantly lower than those for patients treated with each of these therapies, as described in Figures 1a and 1b (p < .0001 for cisplatin treatment, p = .0153 for MTX treatment, p < .0001 for cisplatin and MTX treatment, p = .0017 for radiation treatment, and p = .0003 for radiation and cisplatin or radiation and MTX). Statistical significance remained when combining the administration of cisplatin, MTX, and/or radiation into one group and comparing it to the group receiving therapies without any of these agents (p < .0001). There were no statistically significant findings suggesting that posttreatment hearing loss was dose dependent, with a p value of .2685.

Patients Undergoing Cancer Treatment

Six of the 48 (12.5%) patients currently undergoing cancer therapy at OLOL Hospital had hearing loss compared to their past hearing evaluations. The OLOL Hospital results are described in Figure 1b. The data from the two hospitals were not combined, since they represented two distinct populations: The pediatric patients at the TACLE clinic at CHNOLA were patients who have been cancer free for at least 2 years, whereas the pediatric patients at OLOL Hospital were those currently undergoing cancer treatment. Data from patients currently undergoing cancer therapy at OLOL indicate that 8.7% (two of 23 patients treated with MTX) had hearing loss, which is also significantly higher than the incidence rate of 0.1% in the general population (CDC, 2021; p = .0002, 95% CI [0.0107, 0.2804]). This finding reinforces our hypothesis of the possible MTX ototoxicity.

Cancer Types

The number of patients with long-term hearing loss at CHNOLA according to cancer type was investigated. Patients with leukemia and osteosarcoma received MTX as their standard of care, with 30% and 71% of these patients exhibiting significant hearing loss, respectively. All patients with osteosarcoma received cisplatin and MTX; thus, the increased frequency of hearing loss in these patients may be attributed to both MTX and cisplatin. Survivors of medulloblastoma, a brain tumor commonly treated with a combination of surgery, chemotherapy, and radiation therapy, had the highest prevalence of hearing loss, with all eight (100%) of the patients exhibiting SNHL (six with severe-to-profound hearing loss and two in the mild–moderate range). All three patients with hepatoblastoma (100%) had mild–moderate hearing loss. Other cancer types observed in the TACLE clinic included germ cell tumors and Ewing's sarcoma, of which five of 29 (17%) had hearing loss. There was no association between hearing loss and patients' race, ethnicity, or gender.

Discussion

Most patients who were treated with known ototoxic cancer therapy received baseline hearing evaluations (i.e., cisplatin, carboplatin). Although MTX ototoxicity has been documented in mice, it is not a recognized ototoxic agent in humans (Mateos et al., 2022; Umugire et al., 2022). Therefore, many of the patients with leukemia and osteosarcoma who were treated with MTX did not have baseline audiology exams. Part of the goal of this study is to create awareness of the possible MTX ototoxicity in patients with pediatric cancer and to refer these patients to audiologists upon cancer diagnosis for baseline evaluation and long-term follow-up.

The results from this study suggest that children who receive therapies not classically identified as ototoxic (i.e., MTX) may still be at a high risk of developing long-term hearing loss as a late effect. The long-term audiological effects of cancer therapy are evident when comparing Figure 1a (cancer survivors being followed 2–19 years after cancer therapy completion) and Figure 1b (patients currently undergoing cancer treatment).

MTX is a mainstay chemotherapy agent administered intravenously, intrathecally, and orally for the treatment of acute lymphoblastic leukemia (Hawkins et al., 2008; Koźmiński et al., 2020; Mandal et al., 2020). Currently, there are an estimated 119,040 childhood cancer survivors in the United States, and leukemia survivors account for approximately one third of survivors younger than 20 years of age (Hawkins et al., 2008; Howlader et al., 2016; Winter et al., 2018). MTX-related neurotoxicity (MTX neurotoxicity) is characterized by seizures, stroke-like episodes, and encephalopathy (Forster et al., 2016; Hawkins et al., 2008; Koźmiński et al., 2020; Mateos et al., 2022). Although MTX is commonly utilized as a therapy for pediatric and adult cancers and autoimmune issues, such as rheumatoid arthritis, questions remain related to risk factors and long-term neurological outcomes (Koźmiński et al., 2020; Mateos et al., 2022).

When cisplatin was first used as a chemotherapeutic agent, evidence of significant hearing loss stimulated research into the causes and treatment of this side effect (Gómez-Ruiz et al., 2012; Seth et al., 2017; Steyger, 2021). The discovery that hearing loss caused by cisplatin occurs due to an excessive accumulation of reactive oxygen species (ROS) in cochlear cells led researchers to develop antioxidants as otoprotective agents (Seth et al., 2017; Yu et al., 2020). Later discoveries demonstrated that ROS could stimulate cochlear inflammation, which increased the utilization of anti-inflammatory agents, and nanoparticle delivery for the treatment of cisplatin-induced hearing loss (Ramaswamy et al., 2017; Seth et al., 2017; Yu et al., 2020). The entry of cisplatin into cochlear hair cells was recently shown to be mediated by various transporters, leading to the discovery of inhibitors that are effective in treating hearing loss caused by cisplatin (Anderson et al., 2019). Conversely, information on the ototoxic effects of MTX is limited.

Recently, Umugire et al. (2022) demonstrated that MTX can cause severe hearing loss in mice by crossing the blood–labyrinth barrier and damaging neurons and OHCs of the cochlea. Furthermore, this group showed that the antioxidant Avenanthramide C created a strong protective effect against high-dose MTX-induced ototoxicity in mice and conserved the inner ear structures (synapses, neurons, and OHCs) from MTX-induced damage (Umugire et al., 2022). Thus, further clinical, gene expression, molecular, and biochemical studies are warranted to determine its ototoxic and neurotoxic effects in humans and to develop appropriate therapies.

The development of irreversible treatment-induced hearing loss in children increases the emotional trauma, financial burden, and responsibilities that survivors and their families manage after a cancer diagnosis (Dillard et al., 2022; Gibson et al., 2019). Furthermore, hearing loss significantly impacts a child's academic achievement, psychological well-being, and social functioning (Holzinger et al., 2022; Lieu et al., 2020; Runnion & Gray, 2019). Therefore, it is imperative to identify risk factors and monitor patients with regular audiological evaluations so that they may receive the appropriate intervention and support services needed to develop neurologically and improve their quality of life. Care team coordination in educational environments may facilitate the need for appropriate interventions and support services. As cancer survivorship increases, so does the need for research, routine surveillance, and the prevention of toxic late effects caused by cancer treatment, particularly MTX. This study also demonstrates that in addition to the patients treated with cisplatin and/or radiation, patients with pediatric cancer treated with MTX should also receive routine long-term auditory monitoring as part of their standard of care to detect and manage hearing loss early, minimizing adverse outcomes. Future directions include a long-term prospective study of pediatric oncology patients, in which patients with newly diagnosed cancer receive audiometric testing before the start of chemotherapy, throughout their treatment and beyond, to determine baseline levels and detect critical time points when the ototoxic effects of MTX appear.

Ethics Statement

The study was approved by the Louisiana State University Health Sciences Center in New Orleans, Louisiana; Our Lady of the Lake Hospital; and Children's Hospital of New Orleans in Louisiana Institutional Review Boards.

Data Availability Statement

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Acknowledgments

This project was funded by the National Institutes of Health (NIH)-National Cancer Institute Award 5P20CA202922-04 and the NIH-Blueprint for Neuroscience Research, National Institute of Neurological Diseases & Stoke, and the National Eye Institute, Award R25NS114309. Z. F. was supported in part by NIH-National Institute of General Medical Sciences with Grant U54 GM104940.

Funding Statement

This project was funded by the National Institutes of Health (NIH)-National Cancer Institute Award 5P20CA202922-04 and the NIH-Blueprint for Neuroscience Research, National Institute of Neurological Diseases & Stoke, and the National Eye Institute, Award R25NS114309. Z. F. was supported in part by NIH-National Institute of General Medical Sciences with Grant U54 GM104940.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Articles from American Journal of Audiology are provided here courtesy of American Speech-Language-Hearing Association

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