This study investigated the association of hearing loss and tinnitus with overall health‐related quality of life (HRQoL) among long‐term oropharyngeal cancer (OPC) survivors.This study included OPC survivors treated between 2000 and 2013 and surveyed from September 2015 to July 2016. Hearing loss and tinnitus were measured by asking survivors to rate their “difficulty with hearing loss and/or ringing in the ears” from 0 (not present) to 10 (as bad as you can imagine). Hearing loss and tinnitus scores were categorized as follows: 0 for none, 1–4 for mild, and 5–10 for moderate to severe. The primary outcome was the mean score of MD nderson Symptom Inventory Head & Neck module interference component as a HRQoL surrogate dichotomized as follows: 0 to 4 for none to mild and 5 to 10 for moderate to severe interference.p = 0.012) and moderate  hearing loss and tinnitus were associated with higher odds of reporting moderate to severe symptom interference scores in comparison to no hearing loss and tinnitus. This association of hearing dysfunction was consistent with all domains of HRQoL.Among 880 OPC survivors, 35.6% (314), reported none, 39.3% (347) reported mild, and 25.1% (221) reported moderate to severe hearing loss and tinnitus. On multivariable analysis, mild . In the current study, the authors identified an association between hearing loss and tinnitus with worse symptom distress and HRQoL among oropharyngeal cancer (OPC) survivors and this association was consistent across all domains of HRQoL. Findings suggest that preservation of audiological function to enhance HRQoL is vital among growing numbers of OPC survivors. These survivors are expected to resume normal daily life activities after treatment completion but are at risk of developing toxicities which can have an adverse impact on quality of life (QoL).Irradiation fields for head and neck tumors often include the auditory system with the cochlea and the temporal bone, and contribute to the radiotherapy‐associated external, middle, and internal ear injury.OPC Treatment can also contribute to tinnitus or ringing in the ears.Impairment and interference in daily life activities due to hearing loss and tinnitus can contribute to severe decline in HRQoL, which encompasses functional, physical, psychological, and social domains of health and well‐being. To understand the disease burden due to hearing loss and tinnitus, it is critical to evaluate the association of hearing loss and tinnitus with HRQoL. However, to our knowledge, the association of hearing loss and tinnitus with impairment in daily life activities and HRQoL has not been comprehensively investigated in OPC survivorship. Therefore, the primary objective of this study was to investigate the association of hearing loss and tinnitus symptoms with the severity of cancer treatment–related symptom distress, impairment of daily function, and overall HRQoL among long‐term OPC survivors. Secondary objectives were to investigate the association of hearing loss and tinnitus symptoms with individual domains of HRQoL. We hypothesized that hearing loss and tinnitus would be associated with impairment of daily function, diminished overall HRQoL, and interference in individual domains of HRQoL.22.1A cross‐sectional cancer survivorship survey was administered to 1740 OPC survivors from September 9, 2015, to July 7, 2016. All eligible study participants were adults (age at diagnosis ≥18 years); received curative OPC treatment at The University of Texas MD Anderson Cancer Center during January 1, 2000, to December 31, 2013; and had completed at least 1 year of post‐treatment follow‐up. This study protocol (PA11‐0936) was approved by the MD Anderson Cancer Center institutional review board and included a consent statement on the survey cover letter as informed consent from study participants.A total of 972 OPC survivors responded (56% response rate), of which 65 survivors with recurrent disease, distant metastasis, and second primary tumors of the head and neck, central nervous system, and thorax were excluded. In addition, 25 patients were excluded for not responding to the hearing loss and tinnitus question on the survey, and two more patients were excluded due to missing the primary outcome (MDASI‐HN symptom interference). In total, 880 OPC survivors were included in the analyses. Additional details of survey administration are available.2.2α = 0.72–0.92).The survivorship survey included the MD Anderson Symptom Inventory Head and Neck Cancer Module (MDASI‐HN), a validated multi‐symptom patient‐reported outcomes assessment instrument that evaluates the severity of symptoms and subsequent symptom distress.2.3The primary outcome variable for this study was the mean of the interference component of the MDASI‐HN. Mean interference scores were dichotomized per previously defined thresholds: 0 to 4, defined as none to mild interference, and 5 to 10, defined as moderate to severe interference.Six secondary outcomes were the individual interference items: General activity, walking, work, mood, relationships with other people, and enjoyment of life. Individual interference scores were also categorized as 0 to 4 for none to mild interference and 5 to 10 for moderate to severe interference.2.4The hearing loss and tinnitus variable was the primary exposure of interest for our study. Hearing loss and tinnitus was assessed by asking: “How severe are your symptoms? People with cancer frequently have symptoms that are caused by their disease or their treatment. We ask you to rate how severe the symptoms have been in the last 24 hours.” The respondents were then asked to rate their “difficulty with hearing loss and/or ringing of the ears at its worst” on a scale of 0 (not present) to 10 (as bad as you can imagine). As per previous symptom literature regarding symptom thresholds, hearing loss and tinnitus scores were categorized as follows; 0 for none, 1–4 for mild, and 5–10 for moderate to severe hearing loss and tinnitus.2.5Our analyses adjusted for potential clinical and sociodemographic covariates. Information on these covariates were extracted from the electronic medical records of study participants as listed in Table 2.6p ≤ 0.05 was considered statistically significant. Analysis was performed using STATA 14.0 (StataCorp).Descriptive analysis was conducted to summarize the mean interference categories across demographic and clinical variables. Univariate logistic regression and multivariable logistic regression were conducted to investigate unadjusted and adjusted associations, respectively, between hearing loss and tinnitus and interference scores. Similar analyses were conducted to investigate associations between hearing loss and tinnitus and secondary outcomes. All multivariable logistic regression models controlled for age at diagnosis, radiotherapy dose, survival time, sex, race, education, tumor subsite, T‐classification, N‐classification, HPV status, cigarette smoking, treatment modality, surgery, neck dissection, radiotherapy schedule, radiotherapy type, chemotherapy, and concurrent cisplatin therapy. Univariate and multivariable odds ratios and their corresponding 95% CIs were computed. A variance inflation factor greater than 10 was the criterion used to establish any multicollinearity. Two‐sided 33.1Among 880 OPC survivors the median age at diagnosis was 56 years , the median survival duration at the time of survey was 7 years range, 1–16 years), and the median total RT dose was 70 Gy . Of these 84.7% (745/880) were males, 92.4% (813/880) were non‐Hispanic white, and 72.3% (636/880) had greater than high school education. The study population's clinical and sociodemographic characteristics, stratified by mean interference scores, are summarized in Table –16 years3.2p = 0.012) and moderate to severe hearing loss and tinnitus  were significantly associated with higher odds of reporting moderate to severe mean interference scores compared with no hearing loss and tinnitus.Table 3.3p < 0.001) in comparison to no hearing loss and tinnitus. Also, moderate to severe hearing loss and tinnitus was associated with higher odds of reporting moderate to severe interference with work  in comparison to no hearing loss and tinnitus. Further, moderate to severe hearing loss and tinnitus were associated with higher odds of reporting moderate to severe interference with walking  in comparison to no hearing loss and tinnitus.Table p = 0.028) and moderate to severe hearing loss and tinnitus  were significantly associated with higher odds of reporting moderate to severe interference in mood in comparison to no hearing loss and tinnitus. Also, mild hearing loss and tinnitus  and moderate to severe hearing loss and tinnitus  were significantly associated with higher odds of reporting moderate to severe interference in relations with other people in comparison to no hearing loss and tinnitus. Lastly, moderate to severe hearing loss and tinnitus was associated with higher odds of reporting moderate to severe interference with the enjoyment of life  in comparison to no hearing loss and tinnitus.For psychosocial domains, on multivariable analysis mild hearing loss and tinnitus  reporting moderate to severe impairment in overall HRQoL. Importantly, 64.4% of the OPC survivors reported mild to severe hearing symptoms, including 25.1% who reported moderate to severe hearing dysfunction, indicating the need for supportive treatment to optimize audiological function in this population. Hearing dysfunction as measured by hearing loss and/or tinnitus symptom severity was associated with worse overall HRQoL and symptom distress in our study. Furthermore, hearing loss and tinnitus symptoms were also associated with all the individual domains of multidimensional HRQoL, including general activity, walking, work, mood, relationships with other people, and enjoyment of life. Effect estimates for the association of hearing dysfunction with overall HRQoL and individual components of HRQoL were significantly large; however, confidence intervals were wider because of the small sample sizes. Our study results raise great concern given the importance of hearing function in all aspects of life.Our results suggest that OPC survivors who experienced mild hearing loss and tinnitus had 5.8 times and those who experienced moderate to severe hearing loss and tinnitus had 30.0 times greater odds of reporting moderate to severe mean interference scores adjusting for clinical, and demographic covariates compared to survivors with no hearing loss and tinnitus. As mean interference score reflects impairment in multiple domains including functional and psychosocial components, our study findings suggest substantial downstream negative sequelae of loss of hearing function on overall HRQoL.In addition to hearing loss and tinnitus, total radiotherapy dose to the primary tumor site, female sex, and current smoking at the time of survey were associated with increased odds of reporting moderate to severe interference scores in multivariable models in our study. Only IMRT ipsilateral regimens were associated with lower odds of reporting moderate to severe interference scores. It has been hypothesized that higher total radiotherapy dose to the primary tumor site can contribute to increased irradiation of adjacent nerves, blood vessels, and structures in the head and neck region and subsequent injury that can lead to increased morbidity, impairment of function, and diminished QoL.However, our study did not identify other reported associations between age,Given the importance of hearing function in daily life activities, communication, and function, the results of our secondary analysis revealing the association of hearing loss and tinnitus with all domains of HRQoL including functional components such as general activity, walking, and work and psychosocial components such as mood, relations with other people, and enjoyment of life is illuminating. Hearing loss and tinnitus may also add additional morbidity with vestibular dysfunction causing imbalance, dizziness, and vertigo, although definitive studies on cisplatin‐induced vestibular symptoms are lacking.Hearing loss and associated deficits with communication, physical function, cognitive function, and psychosocial impairment can also contribute to impairment of work‐life and contribute to problems with employment.Hearing loss with inability to comprehend conversation and associated communication problems can have a debilitating impact of psychosocial domains of life, with decline in interpersonal relationships, low self‐esteem, frustration, embarrassment, social isolation/withdrawal, depression, inability to enjoy life, and overall poor HRQoL.Our study has some limitations that need to be acknowledged. First, the hearing loss and tinnitus assessment were patient‐reported with a single question without the ability to study the symptoms independent of one another. Another critical limitation is that the hearing outcomes here are exclusively by patient‐report without any objective audiological testing of hearing function. However, patient‐reported assessment in our study allows evaluation of ototoxicity and associated impairment in daily life and function from a patient perspective, leaving the opportunity to build upon these patient‐centered data in future studies incorporating more conventional clinical audiologic and vestibular measurements. Small sample sizes across sub‐groups contributed to wide confidence intervals for effect estimates in our study; however, effect estimates across HRQoL domains showed a consistent detrimental impact of hearing loss. Also, we could not assess the association of hearing loss and tinnitus separately on interference scores because our question combined hearing loss and tinnitus together, and future studies might consider using domain‐specific PROs such as the Tinnitus Handicap InventoryN‐acetylcysteine, and other agents may also be further investigated and considered to protect patients from hearing problems.Our study results can inform future studies and potential development of surveillance strategies and supportive care interventions that can be implemented early to prevent irreversible hearing loss and alleviate the impact of hearing dysfunction in OPC survivors. Management of hearing loss may include the use of hearing aids or assistive hearing devices, middle ear or cochlear implants for sound amplification, and individual psychological counseling regarding other communication strategies.Given the substantial burden of diseases due to hearing loss and tinnitus reported in our study, it is of utmost importance that ototoxicity be further investigated in the OPC patient population. Future prospective longitudinal studies investigating ototoxicity need to incorporate objective as well as patient‐reported measures, uniformly define clinically significant hearing loss criteria, and include audiology hearing assessments at baseline, during treatment, and long‐term post‐treatment. Different types of hearing loss, laterality of hearing loss, tinnitus, and balance problems and cognitive impairment, depression, and social isolation due to hearing loss also need to be investigated. Identification of predictors of ototoxicity can also help stratify patient populations at high‐risk of hearing dysfunction for targeted rehabilitation therapy. Furthermore, there is a need for the development of an effective evidence‐based ototoxicity surveillance and management program with uniform definitions of ototoxicity and standard criteria and grading for audiological and associated HRQoL assessments to mitigate some of the downstream impacts of hearing dysfunction on QoL in OPC survivors.5Hearing dysfunction is a serious treatment‐related toxicity, and prolonged life with hearing impairment has been shown to be profoundly concerning.substantial contributions to, critical revision of the manuscript for important intellectual content, and contributions to the final version of the manuscript. Katherine A. Hutcheson: Responsible for data collection, substantial contributions to the study conception or design or the acquisition; interpretation of data; critical revision of the manuscript for important intellectual content, and contributions to the final version of the manuscript. Sanjay Shete: Concept and design, interpretation of data, initial draft of the manuscript, study supervision, critical revision of the manuscript for important intellectual content, and contributions to the final version of the manuscript. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved.Puja Aggarwal: Substantial contributions to the study conception or design; data management, supervised analysis, and interpretation; drafting manuscript, manuscript revisions; and contributions to the final version of the manuscript. Marc‐Elie Nader, Paul W. Gidley, Raj Pratihar, Shirin Jivani, Adam S. Garden, Frank E. Mott, Ryan P. Goepfert, Christopher Wallace Ogboe, Camille Charles, Clifton D. Fuller, Stephen Y. Lai, G. Brandon Gunn, Erich M. Sturgis, Ehab Y. Hanna: Clinical data interpretation and analytic support; This study was supported by the NIH/NCI under award number 5P30CA016672 (SS), a Cancer Prevention Fellowship supported by the Cancer Prevention and Research Institute of Texas (CPRIT) grant award, RP170259 , and the Betty B. Marcus Chair in Cancer Prevention (SS). The OPC Survivorship Survey data collection was supported by the Charles and Daneen Stiefel Oropharynx Fund. This study was also supported by the Alvin R. Tarlov and John E. Ware Jr. Post‐Doctoral Award in Patient‐Reported Outcomes for 2020‐2021 . Mark‐Ellie Nader reports stock ownership in 3M, Amgen, Cardinal Health, Johnson & Johnson, Medtronic, and Pfizer.The funding sources had no role in the design and conduct of the study; data collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.This study (PA11‐0936) was approved by the MD Anderson Cancer Center institutional review board prior to commencing the study.


Background: Speech discrimination assessments are used to validate amplification fittings of older children who are hard of hearing (CHH). Unfortunately, speech discrimination is not assessed clinically  Following the National Institute of Health Consensus Development Conference on Early Identification of Hearing Impairment in Infants and Young Children  in 1993 Despite these significant advances in early identification and intervention, procedures to assess speech discrimination in very young infants and children before the acquisition of spoken language remain limited. Recent findings among CHH between 6 and 17 months of age who benefited from UNHS/EHDI suggest that vowel sounds  are more likely to be discriminated than consonant sounds  ,11,12,13Research among children with normal hearing (CNH) suggests that speech discrimination skills at six months of age assessed through Conditioned Head Turn (CHT) techniques  predict Since the inception of UNHS/EHDI, research has revealed a wide array of demographic characteristics, such as a lesser degree of hearing loss ,19,20 anHearing aids are programmed using a computer, an individual’s hearing thresholds, and proprietary software from the hearing aid manufacturer. The resulting gain of the hearing aids is verified by measuring the output in the individual’s ear canal using specialized equipment . The gain/output of the hearing aid is compared to the prescription for each listener based on age, amount of hearing loss, and the prescription being used  . How welIs there a difference in speech discrimination abilities between CHH and CNH on /a-i/ and /ba-da/ discrimination?How do early speech discrimination abilities relate to later spoken receptive and expressive language abilities in CHH?At 30 months of age, will scores from a parent questionnaire of their child’s spoken language inventory significantly correlate with their assessed early receptive and expressive spoken language ability?Among CHH, what effect does audibility and hearing aid use have on early speech discrimination and spoken language abilities?We propose that the earlier infants/toddlers are fit well with amplification, the more likely that they will be able to discriminate speech sounds early in life and then achieve higher language outcomes. Therefore, the ability to assess speech discrimination in the first year of life and its relationship with language abilities assessed later in childhood is needed. This experiment aimed to assess the relationship between audibility and speech discrimination in infancy and later language abilities. In this manuscript, we report on the effects of audibility and speech discrimination on receptive and expressive spoken language for infants with hearing loss, who met the EHDI benchmarks, and a comparison group of peers with normal hearing. Specifically, this study seeks to demonstrate that well-fit hearing aids  and behavioral speech discrimination scores utilizing a conditioned head turn technique  in the first year of life predict spoken language outcomes measured at 30 months of age. Additionally, we assess the relationship between a commonly used parent questionnaire, the MacArthur-Bates Communicative Development Inventories, , and anData from 90 infants participating in an ongoing longitudinal study were analyzed. All participants’ hearing was screened via universal newborn screening, and results per parent report were recorded. Participants included 41 CHH (21(M), 20(F)) and 49 CNH (23(M), 26(F)). All were born full-term and healthy see . CHH infCriteria for inclusion into the study (between 1 and 5 months of age) were (a) no evidence of significant developmental delays or secondary disabilities per parent report, or as indicated in the electronic medical record, (b) absence of fluid in the middle ear day of testing, (c) English as the primary language is spoken in the home, and (d) demonstrated conditioned head turn in visual reinforcement audiometry after 6 months of age.All CHH participants used their personal hearing aids or cochlear implants (two children transitioned to cochlear implants during this study) during the CHT and MSEL testing. Children were fit following diagnosis of hearing loss with bilateral, behind-the-ear hearing aids coupled to custom earmolds, filtered ear hooks, and programmed using DSL v5.0 . Childrep = 0.079).Hearing aid use was collected by reading the average daily data logging values from the child’s hearing aid at the time of CHT and MSEL. The mean data logging recorded was 6.39 hours per day (SD = 4.16) for CHT and increased at MSEL to 8.26 averaged hours per day (SD = 4.70), see The local institutional Review Board approved this project. Consent was obtained from parents/guardians before beginning the research project. Parents were provided with compensation for their child’s participation. Participant compensation was paid in cash or gift cards at a rate of USD15 per hour for in-person or telepractice visits and USD20 for MBCDI completion.The four stimuli used for the experiment were /ba/, /da/, /a/, and /i/. The stimuli were natural speech tokens produced by a female speaker, and adult listeners in the laboratory verified that the stimuli sounded natural. See Two sessions were required to complete the speech discrimination protocol. The first session consisted of the case history , screening for middle ear fluid , hearing screening, and, if time allowed, a threshold search for /a/ using CHT. The second visit consisted of the threshold search for /a/, if not completed at the first visit, and the CHT assessment protocol. Two speech contrasts were assessed (/ba-da/ and /a-i/) during CHT testing. Presentation order was randomized and within each stimulus pair either contrast could serve as the background stimulus. The other speech sound served as the target. The member of the pair serving as the target stimulus was counterbalanced across participants. The infant learned to respond by turning his/her head when the target stimulus was presented. Testing was completed in a sound booth. Caretakers accompanied infants into the sound booth for the CHT assessment. The background stimulus was on and being repeated with a 1200 ms interstimulus interval when they entered the room. Infants were either seated on the caretaker’s lap or in a highchair in the center of the room to minimize distractions or task fatigue. Regardless of positioning, the distance between the infant’s head and the speaker was the same. The speaker and visual reinforcement video screen were 90º to the right of the infant’s midline. An assistant who centered the infant’s gaze was positioned in front of the infant, slightly to their left. During testing, the caretaker and the assistant listened to music through supra-aural headphones to prevent them from hearing the sounds presented and inadvertently reinforcing the child or alerting the child to a contrast stimulus. The evaluator observed the infant through a window in a separate room outside the sound booth. The discrimination task consisted of two phases: conditioning and testing. In the conditioning phase, only change trials were conducted so infants could learn the association between a change in the sound and the reinforcer. During conditioning, the target sound was presented at a louder level than the background sound (+6 dB SPL-A) to alert infants to the sound change. Initially, the reinforcer was automatically activated after two target sounds were presented. After the infant made two consecutive head turns before the end of the first two presentations of the target sounds , the intensity cue was removed. Once testing began, the evaluator could no longer hear the stimuli. Trials were initiated by a button press once the evaluator determined the child’s attention was directed toward the midline.Computer software determined trial-type presentation, with either 7 or 8 of the 15 trials being a change or no-change trial as randomly determined by the computer; the evaluator was blind to trial type. If the trial was a no-change trial, the background sound was presented three times. If the trial was a change trial, the target sound was presented three times. At the end of each trial, the background sound continued. The evaluator indicated when the child executed a head turn toward the speaker by button press. The CHT software determined if the child’s head turn was a correct response to a change trial or a false positive to a no-change trial. Correct responses were rewarded by the automatic presentation of a visual reinforcer, an animated video. Performance on the task was quantified using d-prime . d’ is cThe advantage of d’ is that it eliminates the effect of response bias, as the calculation considers the number of false positives/alarms and hit rate. A “false alarm” occurs when a child turned their head, but no change occurs in the stimuli (/a-a-a/). In this case, the button indicating that a head turn occurred would be pressed, but no reinforcement would occur. In contrast, a “hit” occurs when a child turns their head in response to a change in stimuli, which would lead to the behavior being rewarded. If the child achieved a d’ of at least 1.2 at 50 dB SPL-A, then testing was complete . The ratIf the child did not reach criterion at 50 dB SPL-A, the level was increased to 70 dB SPL-A, and testing resumed. Once 15 trials at 70 dB SPL-A were completed, the presentation level was reduced to 60 dB SPL-A, and 15 trials were completed at that presentation level, regardless of whether or not a child reached criterion, at 70 dB SPL-A. Therefore, for children who did not reach criterion at 50 dB SPL-A, a total of three conditions  were completed. In each session, testing continued until all conditions were completed, or the child was too fussy or tired to continue. On average, a single condition  was completed in an average of 5 minutes and 32 seconds (SD = 5.35 min). Because some infants who reached criterion were only tested at 50 dB SPL-A, the score for which criterion was reached was used in the analysis, regardless of intensity. For infants who did not reach criterion, their best score was used in the analysis, regardless of intensity. To determine the expected range of d’ values if children were performing at chance, a Monte Carlo study of 200,000 simulations indicated that d’ values equal to or above 1.28 could be considered significantly above chance .n = 4). During this visit, the MSEL [When the children turned 30 months of age, their caretakers brought them to the laboratory, or during the COVID-19 pandemic, testing was completed via telepractice , and percent, as appropriate. Effect sizes were calculated using Cohen’s partial f2. Multivariate linear regression or ANOVA was used to model each outcome of interest (MSEL receptive and expressive language at 30 months) as a function of CHT score. During analysis, CHH were separated into two groups according to hearing status (mild (16–40 dBHL) or moderate ≥ 41 dBHL). Mixed-effects regression and analysis of variance (ANOVA) were implemented via version 1.1–29 of the lme4 [lmerTest [2 was calculated using version 0.7.0 of the effectsize package in R. Post-hoc t-tests with Tukey corrections for multiple comparisons were completed using version 1.7.5 of the emmeans package in R.The CHT score used for the analysis was the best d’ score regardless of intensity, summarized in lmerTest  packageslmerTest . Cohen’sResults from the CHT as an effect of intensity level are shown in Question 1: Is there a difference in speech discrimination abilities between CHH and CNH on /a-i/ and /ba-da/ discrimination? Does maternal level of education impact speech discrimination?A mixed-effects MANOVA with fixed-effects of presentation level  and hearing status (CNH (0–15 dB HL), Mild (16–40 dB HL), or ≥Moderate (≥41 dB HL)), as well as a random effect of child, was completed. Only children who completed the CHT task at all levels were included in the analysis. This included 22 CNH, 13 children with mild hearing loss, and 9 children with ≥moderate hearing loss. Maternal level of education and possible interactions with hearing status and presentation level were excluded from the model because a model comparison test revealed that including them did not significantly improve model fit. Results are shown in Question 2: How do early speech discrimination abilities relate to later receptive and expressive spoken language abilities?th percentile of the age-referenced score, allowing readers to have a reference to the standard scores (dotted line). Note that for each 1 unit increase in CHT score , there is an estimated 1.06 point increase in MSEL receptive spoken language score (95% CI = 0.0 to 2.1). When hearing status was included in the model, it was not significant, which can be confirmed by the substantial overlap between CNH and CHH in 2 for the CNH and CHH groups were 0.14 and −0.01, respectively, suggesting that goodness-of-fit was poorer for the CHH compared to CNH group. The relationship between the speech discrimination as measured by CHT for the /a-i/ contrast and language outcomes is shown in 2 for the CNH and CHH groups were 0.24 and 0.08, respectively, suggesting that the goodness-of-fit was poorer for the CHH compared to CNH group. In contrast to /a-i/, regressions including /ba-da/ contrasts used to predict spoken language outcomes revealed no significant relationship between receptive or expressive spoken language.The mean expressive language raw scores were 28.8 (SD = 4.6) for CHH and 29.4 (SD = 4.3) for CNH. Among all children, the CHT score was positively associated with MSEL expressive language at 30 months see . Figure Question 3. At 30 months of age, will scores from a parent questionnaire of their child’s spoken language inventory significantly correlate with their assessed early receptive and expressive spoken language ability?Results from the MBCDI words produced (reported in percentile) are shown in Results with expressive language were similar. Results revealed that the percentage of words produced increased over time see . Post-hoThe relationship between MBCDI words produced at 30 months and CHT was assessed via regression. Upon initial analysis with multiple linear regression using the same predictors as Question 4: How do receptive and expressive language abilities in CHH compare to CNH?p = 0.681.Language outcomes are shown in Question 5: Among CHH, what effect does audibility and hearing aid use have on early speech discrimination and language abilities?We examined the relationship between aided SII at two time points, at the CHT visit and at the MSEL visit, which are reported in Next, we examined the relationship between data logging and speech discrimination and language abilities see . DatalogThe current study’s primary aim was to examine whether an individual infant’s speech discrimination score at nine months predicted receptive and expressive spoken language abilities at 30 months of age among CHH and CNH. Speech discrimination measured at 9 months of age using the /a-i/ contrast predicted both receptive and expressive spoken language at 30 months. These results demonstrated, for the first time, that a clinically recommended tool, CHT, for assessing each infant’s speech discrimination performance at nine months of age  significTo address our first questions: (1) is there a difference in speech discrimination abilities between CHH and CNH on /a-i/ and /ba-da/ discrimination, and (2) if maternal level of education impacts speech discrimination? We found that most infants (CHH and CNH) discriminated /a-i/ at one of three intensity levels . There was no significant difference in speech discrimination abilities between CHH and CNH. Discrimination of the /ba-da/ contrast was observed in fewer infants across both groups. Of note, all CHH were identified through newborn hearing screenings, fit with hearing aids, and enrolled in early intervention by six months. Among CHH, there was no difference in speech discrimination abilities as a function of the degree of hearing loss . Though non-significant findings are typically not discussed, our findings showed no significant differences between CHH and CNH groups for discrimination of either /a-i/ or /ba-da/. Moreover, these findings within the CHH group, that no significant differences were found as a function of the degree of hearing loss, are theoretically important. These findings highlight the effectiveness of the early identification/intervention as a result of UNHS/EHDI for these CHH on speech discrimination abilities in infancy. Before UNHS/EHDI systems, it would not have been possible to assess infant speech discrimination among CHH  because While all children demonstrated conditioning to the task before testing began, bringing children back may have resulted in more children being able to discriminate the /ba-da/ contrast. Because we aimed to examine the clinical utility of this CHT procedure, we did not design the study for return visits. The logistics of having parents return within a short timeframe would likely increase subject attrition and be challenging to accommodate in future clinical settings. Additionally, assessing speech discrimination for one contrast took an average of 5 min which is feasible to complete in a clinical audiology setting among young infants. Next, we address our second question, is there a relationship between early speech discrimination abilities and later receptive and expressive spoken language abilities? Yes, during the first year, discrimination of the /a-i/ contrast is related to expressive and receptive language abilities as measured by the MSEL at 30 months of age, but not as measured by the MBCDI among CHH and CNH. Infants who were unable to demonstrate a discrimination response at nine months of age had poorer language on average than those who could discriminate these speech sounds. Our present findings are consistent with other studies demonstrating a relationship between discrimination skills, measured both behaviorally and using evoked potentials, during the first year of life, e.g., ,46,48,49While our approach was similar to the study design implemented by Tsao et al. , there wIn contrast, the Tsao et al.  study emFurthermore, we examined receptive and expressive spoken language using the MBCDI and the MSEL. In contrast to the relationship between speech discrimination and the MSEL, we did not observe a significant relationship between speech discrimination and the MBCDI expressive language abilities. However, we did observe an association between speech discrimination and the MSEL, thus suggesting that these different measures may be tapping into different cognitive-linguistic skills. Similar to Tsao et al. , we examThirdly, we examined if at 30 months of age, scores from a parent questionnaire of their child’s spoken language inventory significantly correlate with their assessed early receptive and expressive spoken language ability. Assessing MBCDI and MSEL at the same timepoint allowed examination of how a parent’s report of language abilities relates to a clinically administered assessment of receptive and expressive language abilities. The MBCDI was predictive of both receptive and expressive language outcomes measured by the MSEL at 30 months. We employed the MSEL as it allowed direct observation of a child’s ability to follow complex directions and assess their abilities to repeat back complex sentences. However, it does require additional resources to complete, compared to a parent survey. Furthermore, due to the difference in the relationship between infant speech discrimination abilities and each language measure, perhaps differences in these relationships with the MSEL are because it measures beyond lexical or vocabulary skills. Finally, due to the small effect sizes, these results may reflect the need to examine these relationships in a larger population of CHH and CNH and necessitate further examination. Fourthly, we examined “How receptive and expressive language abilities in CHH compare to CNH?” We were surprised that including receptive and expressive language raw scores as dependent variables and hearing status as the predictor showed no significant effect of hearing status on language outcomes. Our own clinical interests lie in predicting the risks of language difficulties in CHH. Two to three per 1000 children are born yearly with mild to severe hearing loss or deafness . These cOur final question was the following: among CHH, what effect does audibility and hearing aid use have on early speech discrimination and language abilities?Aided SII  was positively related to CHT performance for /a-i/ and /ba-da/ contrasts when measured at the same timepoint. However, aided SII, neither measured at 9 months (time of CHT) nor measured at 30 months (time of MSEL) significantly correlated with MSEL receptive vocabulary raw scores. These results were unexpected based on recent research findings from the Outcomes in Children with Hearing Loss (OCHL) group, which have reported relationships between aided SII and later language outcomes ,21,56. PWe have produced a conceptual replication of Tsao et al.’s previous work , and ourFor a tool of speech discrimination to be clinically useful, speech discrimination must predict not only successful language outcomes, but also outcomes for children at risk for language learning difficulties . Speech discrimination ability predicted expressive and receptive language. Early identification of children at risk for developing abnormal language is important. Children identified with expressive language delays  and hearThe results of this study should be viewed in light of certain limitations. First, due to the motivation of clinical utility, participants were not brought back to repeat the assessment of speech discrimination if they could not reach criterion. Additionally, there was little variability among CHH regarding how well their hearing aids were fit; all children benefited from early identification of hearing loss and intervention services. Therefore, these results may not generalize to a different population of CHH. The limitations of this work have helped formulate new lines of inquiry. Future studies will examine the cognitive-linguistic relationship with infant speech discrimination due to the complex nature of language learning and its dynamic processes. These findings are the first to document a relationship between infant speech discrimination measured during the first year of life, using a clinically feasible pre-linguistic speech discrimination assessment and later receptive and expressive language abilities among both CHH and CNH. It is important to note that not all children reached criterion for speech discrimination but including these children in our model still resulted in performance on CHT being a significant predictor of later receptive and expressive language abilities. Establishing the relationship between infant speech discrimination and later language outcomes using a clinically viable protocol is an essential step towards validating the utility of infant speech discrimination as a validation of amplification fitting, and a predictor of later spoken language development.


The use of hearing aids by individuals with hearing loss brings a better quality of life. Access to and benefit from these devices may be compromised in patients who present difficulties or limitations in traditional behavioral audiological evaluation, such as newborns and small children, individuals with auditory neuropathy spectrum, autism, and intellectual deficits, and in adults and the elderly with dementia. These populations  are unable to undergo a behavioral assessment, and generate a growing demand for objective methods to assess hearing. Cortical auditory evoked potentials have been used for decades to estimate hearing thresholds. Current technological advances have lead to the development of equipment that allows their clinical use, with features that enable greater accuracy, sensitivity, and specificity, and the possibility of automated detection, analysis, and recording of cortical responses.To determine and correlate behavioral auditory thresholds with cortical auditory thresholds obtained from an automated response analysis technique.®) was used to record the behavioral and cortical thresholds. The subjects remained awake in an acoustically treated environment. Altogether, 150 tone bursts at 500, 1000, 2000, and 4000 Hz were presented through insert earphones in descending-ascending intensity. The lowest level at which the subject detected the sound stimulus was defined as the behavioral (hearing) threshold (BT). The lowest level at which a cortical response was observed was defined as the cortical electrophysiological threshold. These two responses were correlated using linear regression.The study included 52 adults, divided into two groups: 21 adults with moderate to severe hearing loss (study group); and 31 adults with normal hearing (control group). An automated system of detection, analysis, and recording of cortical responses (HEARLabThe cortical electrophysiological threshold was, on average, 7.8 dB higher than the behavioral for the group with hearing loss and, on average, 14.5 dB higher for the group without hearing loss for all studied frequencies.The cortical electrophysiological thresholds obtained with the use of an automated response detection system were highly correlated with behavioral thresholds in the group of individuals with hearing loss. The use of hearing aids by individuals with hearing loss brings a better quality of life. Access to and benefit from these devices may be compromised in patients with difficulties or limitations in traditional behavioral audiological evaluation, such as newborns and small children, individuals with auditory neuropathy spectrum, autism, intellectual deficits, and in adults and the elderly with dementia. These populations  are unable to undergo a behavioral assessment, and generate a growing demand for objective methods to assess hearing.Cortical auditory evoked potentials (CAEP) have been the focus of interest and study since the 1960s and 1970s. In the past, the principal application of this potential was an objective estimation of hearing threshold in difficult-to-test adults, but it was also extensively investigated in children.The assessment of hearing thresholds using CAEP has numerous advantages as it assesses the entire auditory system from brainstem to cortex. It can be recorded in conscious subjects using a variety of acoustic stimuli presented either through earphones or in open field.6® . The difference of this system to its currently available counterparts is that it is more affordable and has the potential for clinical use. Among other features, it contains advanced and differentiated technologies that can reduce the registration of noise and interference by providing residual noise measurements, and has electrodes that are more sensitive in capturing responses. However, the principal difference is that it relies on a unique method of automatic detection and analysis of responses that takes into account statistical methods and tests, similar to the t-test, that determines the presence or absence of cortical response through confidence level calculations. This software exempts the examiner from the difficult task of subjectively interpreting the presence or absence of cortical response based solely on a visual analysis.14In order to overcome these barriers and promote its clinical use, the National Acoustic Laboratory (NAL), an Australian government institution, over the past few years has developed a device for the investigation of cortical auditory evoked potentials named HEARLabThe hypothesis of this study is that it is possible to estimate the behavioral hearing thresholds based on the cortical electrophysiological thresholds obtained from automatic analysis equipment.In Brazil, there no studies of auditory thresholds have been performed with an automated analysis equipment of cortical response. The present study aimed to analyze the use of CAEP to estimate hearing thresholds through an automated CAEP response analysis equipment.This study was approved by the Research Ethics Committee of the institution under No. 361/11. All participants were informed about the objectives of the study and signed an informed consent form.•Group C (control): adults (age ≤ 65 years), of both sexes, with normal hearing , without hearing complaints or history of otologic problems.•Group S (study): adults (age ≤ 65 years), of both sexes, with bilateral symmetrical sensorineural hearing loss that was moderate to severe .The following inclusion criteria were established:The exclusion criteria were the presence of neurological, psychiatric impairment, and/or declared or proven syndromes.All sample subjects underwent the same evaluation protocol specified below.To rule out problems in the middle ear that would prevent the inclusion in the study, visual inspection and tympanometry were performed using a middle ear analyzer (Interacoustics Model AZ-7R).For the investigation of behavioral pure tone thresholds, the audiometer GN Otometrics Itera was used with supra-aural TDH-39 earphones in acoustic booths. Full behavioral audiometric evaluation was performed by pure tones at frequencies 250–8000 Hz for air and 500–4000 Hz for bone conduction using the descending–ascending classical technique of tonal threshold assessment. These thresholds were herein termed audiometric thresholds (AT).® system was used. The equipment provides auditory stimuli at 500, 1000, 2000, 3000, and 4000 Hz, at intensities ranging from 0 to 110 dB HL, presented through insert earphones in an acoustically treated room. The descending–ascending threshold measurement technique was used, and the lowest intensity at which the subject was able to detect the tone burst presented was termed behavioral threshold (BT).For the assessment of behavioral hearing thresholds for tone burst stimulus, the HEARLabIn preparation for the CAEP assessment, the patient's skin was properly cleaned and prepared. The electrodes were placed according to the following position: active electrode in the vertex (Cz), reference electrode in the right or left mastoid (M1 and M2), ground electrode in the forehead (Fz); the minimum acceptable conditions of maximum impedance and between electrodes (≤5 kΩ) were ensured. Participants were assessed while awake, distracted by images aired on a TV without sound, in an acclimatized and acoustically treated room.Assessment of BT and cortical electrophysiological threshold (CET) at 500, 1000, 2000, and 4000 Hz was performed in only one ear of each subject, chosen according to the subject's perception of his/her “better ear” or at random, in the absence of reference.® system was used, which has a module that enables the assessment of cortical electrophysiological threshold .To detect and record the CAEP, the HEARLabThe assessment of cortical thresholds for tone burst followed the following protocol, depending on the assessment group: 1) For Group C, adults with normal hearing, the initial intensity of 70 dB HL was used; the response was recorded and then decreased to 20 dB HL. When there was also cortical response at that intensity, descending intensities were used in steps of 10 dB and ascending intensities of 5 dB up to the minimum threshold of automatic response detection (minimum intensity). 2) For Group S, adults with hearing impairment, the initial intensity of 70 dB HL was also used. When there was also a cortical response at that intensity, descending intensities in steps of 10 dB and ascending intensities of 5 dB were used up to the minimum threshold of automatic response detection, as in Group C. However, if no response was detected in the initial intensity of 70 dB HL, the assessment survey was performed in increments of intensity in steps of 10 dB and descending of 5 dB up to the minimum threshold of cortical response detection. The detected thresholds were termed CET.p-value in an exclusive software provided with the equipment. The lower the p-value, the greater the probability that the recorded wave is related to the sound stimulus. A p-value of 0.05 is the threshold considered by the equipment and examiner for decision-making regarding the presence or absence of cortical response; that is, this threshold means that there would be only a 5% chance for this equipment to record a response as false-positive.The automatic detection of the presence and respective cortical response threshold to acoustic stimulation takes into account the statistical For statistical analysis, central tendency measurements, Pearson's correlation, and linear regression were used.In all tests, a 0.05 significance level (or 5%) was used to reject the null hypothesis.The final sample of this study included the participation of 52 adult subjects , divided into two groups, Group C and Group S, composed of individuals with normal hearing and hearing loss, respectively. In Group C, 31 adults were evaluated: 23 (74.2%) females and eight (25.8%) males; mean age of 23.7 years (SD = 5.2 years), with mean tritonal audiometric thresholds of 2.1 dB HL (SD = 2.9 dB HL). In Group S, 21 adults participated: 15 (71.4%) females and six (28.6%) males, mean age of 48.9 years (SD = 7.2 years), with mean tritonal valuesat 500, 1000, and 2000 Hz of 58 dB HL  in both groups. Thus, it was decided to correlate the behavioral and electrophysiological thresholds.The linear regression analyzes performed between AT for pure tone (“gold standard”) and BT for specific-frequency stimuli (tone bursts) showed that these thresholds are strongly correlated to all frequencies ; regardless of the group, we chose in this study to correlate CET with BT.This study assessed and compared the behavioral hearing thresholds obtained through pure tones (“gold standard” – AT) and through specific frequencies (tone burst – BT) of all individuals in the sample, for both groups with loss hearing and with normal hearing. Due to the strong correlation between the two thresholds for all frequencies . The impedance of electrodes remained balanced and did not exceed 5 kΩ. The sound stimuli presented through insert earphones were tone bursts with 150 μs duration, although LightfootThe technical protocol used was that suggested by the manufacturer of the HEARLab SystemIn the present study, subject alertness during the evaluation was controlled and maintained. NäätänenThe automatic CAEP responses detection equipment aims to facilitate the examiner's task of subjectively interpreting the electrophysiological waves based solely on a visual analysis for the presence or absence of cortical response to acoustic stimuli. The statistical method used in the equipment was shown in previous studies to be able to detect cortical responses with combined sensitivity and specificity equal to or greater than that achieved by experienced examiners,In Group S, the mean differences between CET and BT were 7.8 dB. The values found in this study are slightly higher than those reported in a preliminary study by Van Dun et al.,In Group C, the differences between thresholds were higher (mean of 14.5 dB) for the same frequencies studied. The mean difference between the present study thresholds was similar to that found in the study by Lightfoot and Kennedy.When comparing the mean detection and response thresholds of CAEP between the groups of subjects with normal hearing and subjects with hearing loss, the difference between BT and CET was higher in the Group C. This difference between groups was also reported in the study by Golding et al.10Given the findings of this study, the CAEP obtained through automatic response analysis equipment was shown to be a viable test to estimate the auditory threshold in adults with hearing loss.Complementary studies using the automatic cortical response threshold analysis equipment would be of great clinical relevance to establish correction factors for the assessment of hearing thresholds, as well as the evaluation of different populations.The results of this study indicated a strong correlation between behavioral thresholds and cortical electrophysiological thresholds for frequencies of 500, 1000, 2000, and 4000 Hz in adults with hearing loss.The authors declare no conflicts of interest.


Iodine, through the thyroid hormones, is required for the development of the auditory cortex and cochlea (the sensory organ for hearing). Deafness is a well-documented feature of endemic cretinism resulting from severe iodine deficiency. However, the range of effects of suboptimal iodine intake during auditory development on the hearing ability of children is less clear. We therefore aimed to systematically review the evidence for the association between iodine exposure (i.e. intake/status/supplementation) during development (i.e. pregnancy and/or childhood) and hearing outcomes in children. We searched PubMed and Embase and identified 330 studies, of which thirteen were included in this review. Only three of the thirteen studies were of low risk of bias or of good quality, this therefore limited our ability to draw firm conclusions. Nine of the studies (69 %) were in children  and four (31 %) were in pregnant women . The RCT of iodine supplementation in mildly iodine-deficient pregnant women found no effect on offspring hearing thresholds. However, hearing was a secondary outcome of the trial and not all women were from an iodine-deficient area. Iodine supplementation of severely iodine-deficient children (in both non-RCT interventions) resulted in improved hearing thresholds. Five of six cross-sectional studies (83 %) found that higher iodine status in children was associated with better hearing. The current evidence base for the association between iodine status and hearing outcomes is limited and further good-quality research on this topic is needed. A number of observational studies have shown that even milder forms of iodine deficiency in pregnancy are associated with suboptimal neurodevelopmental outcomes in the offspring, such as reading, intelligence quotient (IQ) scores, language skills and school performance,7; though others have not found such associations–10.Iodine, as part of the thyroid hormones, is crucial for brain development. Sufficient iodine intake is required for optimal thyroid function; thyroid hormones are involved in auditory development and studies in rodents have demonstrated the role of triiodothyronine (T3) at several levels in the auditory system . T3 plays a crucial role particularly in the development of the cochlea (the sensory organ for hearing) in the inner ear–14. The development of the human auditory system begins in utero with the formation and maturation of the cochlea, but it also continues during early and late childhood when the maturation of the auditory cortex occurs. It has been suggested that the period of auditory development that is most sensitive to T3 occurs predominantly in utero, but developmental events in early postnatal life might also be T3-sensitive.Alongside mental deficiency, congenital deafness is another well-documented clinical feature of endemic neurological cretinism observed in areas of severe iodine deficiency and endemic goitre. It has been almost a decade since that narrative review was published and the current evidence is unclear and warrants further investigation.Although the association between iodine deficiency and cognition has been widely explored in the context of milder forms of iodine deficiency (i.e. mild-to-moderate), the association between less severe forms of iodine deficiency and hearing in individuals without clinical features of endemic cretinism is relatively underexplored and therefore the more subtle effects of iodine deficiency on hearing ability are unclear. A previous narrative review in 2013 brought attention to this topic and concluded that there were limited number of studies that had investigated the link between iodine deficiency and auditory performance; however, most studies included in the review were suggestive of an association and therefore the association between iodine nutrition and auditory development should also be explored across the full range of iodine status/intake.Suboptimal iodine intake is not confined only to iodine deficiency, and it can manifest as iodine excess; both scenarios may be harmful for brain development. Hearing problems can have a negative effect on language development and communication and may adversely affect school performance, cognitive and social skills, and it may also lead to unemployment or underemployment. Even mild hearing impairment, which could remain unnoticed, may adversely impact speech and language development in children–21. Data from the WHO show that the global yearly cost of unaddressed hearing impairment is 980 billion USA dollars.Although most research in mild-to-moderate iodine deficiency is focussed on cognitive outcomes, hearing is also an important outcome, both as a stand-alone effect and as a potential mediator of the association between iodine status and other cognitive outcomes investigated in previous studies. Hearing impairment, especially if unaddressed, can be very damaging for individuals, particularly for children and young people, as well as for the society and the economyConsidering the role of iodine in auditory development and the great individual and societal impact of hearing impairment, the aim of this study was to systematically review and summarise the evidence for the association between: (i) iodine exposure (intake/status/supplementation) during pregnancy and hearing ability in the offspring and (ii) child iodine exposure and hearing ability in childhood or later in life. Based on the findings, we also aimed to review the knowledge gaps and provide future research directions in this area. in the reporting of this systematic review. The review is registered with the International prospective register of systematic reviews (PROSPERO: CRD42021226223); the study protocol is available online (www.crd.york.ac.UK/prospero).We followed the updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelineshttps://pubmed.ncbi.nlm.nih.gov/) and Embase (https://www.embase.com/) databases from inception through to 1 March 2021, using a combination of search terms (online Supplementary Methods). The search was restricted to studies in humans and in the English language. We also identified studies from the reference lists of relevant publications retrieved from the searches and by consulting experts on the topic.To identify relevant articles, we searched the PubMed (Our inclusion criteria were based on the following: (i) the target exposure – iodine status/intake  and/or iodine-to-creatinine ratio measured in urine samples, or estimated iodine intake from dietary assessment), iodine supplementation  or use of iodised salt; (ii) the target population – iodine exposure in pregnant women and children < 18 years and (iii) the target outcome – any measures of hearing ability/function  in the offspring of pregnant women or in children/non-pregnant adults ≤ 65 years (in studies where the exposure was measured in childhood); we included this upper age limit for the outcome to capture whether any effects of iodine exposure during development persist into adulthood. To provide a full account of the available evidence, which, to our knowledge, has not been systematically assessed previously, we included all types of study design , non-randomised studies of interventions and randomised controlled trials (RCTs)).in vitro studies, unpublished or non-peer reviewed articles , as well as narrative reviews/comment articles/editorials and other systematic reviews and/or meta-analysis were also excluded.Studies that measured the outcome in older adults (> 65 years) were excluded as the focus of this review was not on age-related hearing impairment. Studies that measured iodine exposure in adults (aged 18 years and over) were also excluded, except when a study included data from both children and adults combined. We also excluded studies in Pendred syndrome patients and/or in individuals with Pendred syndrome symptoms or with any genetic mutations, as the hearing defects in these conditions are not as a result of the target exposure  but as a result of genetic defects (e.g. iodide organification deficits). We also excluded studies in individuals with known thyroid disease or thyroid cancer, as well as studies where only thyroid function parameters were measured and data on iodine status/intake or iodine supplementation were not available. Studies in languages other than English, animal studies, After retrieving the records from the database searches, duplicates were removed. The abstracts of the remaining search records and the additional records identified from other sources were screened independently by at least two reviewers  using an abstract checklist with the inclusion and exclusion criteria. Following the abstract screening, the full texts of the eligible records were retrieved and reviewed independently by at least two reviewers . Records with no abstract were examined at the full-text stage. The reasons for the exclusion of the full-text articles were documented, and the remaining eligible full texts were included in the data-extraction stage. Disagreements between reviewers at any screening stage were resolved through discussion.Data were extracted independently by two reviewers (M. D. and M. T.) using a piloted data-extraction form; extracted data were checked for discrepancies. The data extracted included: (i) general study details – author, publication year, country and study design; (ii) participant details – overall population group, age range for studies in children, sample size, baseline iodine status/intake; (iii) exposure details for observational studies – iodine status/intake based on the measures of urinary iodine excretion or dietary intake mentioned earlier, iodine supplement use  or iodised salt use in the study groups, indicators of iodine intake/status other than urinary iodine concentration or its derivatives (e.g. thyroid volume/goitre rate and thyroglobulin (Tg)); (iv) intervention details for intervention studies – type, dose, start and duration of iodine supplement, placebo/control treatment and (v) hearing outcome details – method of hearing assessment, age at testing, assessor and all results on any measures of hearing at any time point. We presented all available effect measures as reported by the authors of each study because the effect measures for the hearing outcome varied across studies. In instances where data were presented on graphs, we estimated the values (where possible) and reported these. For each study, we specified if there was any unclear or missing information. Where necessary, units for the exposure measures were converted, so that UIC and iodine-to-creatinine ratio were expressed in µg/l and µg/g, respectively.v. childhood) and then based on study design (in order of the hierarchy of the included evidence i.e. from RCTs to case reports); within each group, studies were presented in chronological order. We were not able to perform any quantitative synthesis of the evidence  because of the scarcity of comparable studies; the included studies had differences in the study design and reported outcomes that meant it was not possible to combine into a meta-analysis.Extracted data were tabulated, and studies were grouped based on the timing of the iodine exposure  as ‘low’, ‘some concerns’ or ‘high’; based on this, an overall risk-of-bias judgement was also assigned to each study . The risk of bias in the non-randomised studies of interventions was assessed using the Risk Of Bias In Non-randomised Studies – of Interventions (ROBINS-I) tool; bias was judged in seven domains and as an overall bias across all domains  with a similar methodology to that for RoB 2. The quality of the observational studies was judged as good, fair or poor using the Newcastle-Ottawa scale (NOS). The risk-of-bias and the quality assessments were performed by at least one reviewer (M. D. and/or M. T.).The risk of bias of the included RCTs was assessed using Version 2 of the Cochrane Risk-of-Bias tool (RoB 2)n 85), the abstracts of 245 records were screened. In total, 207 records were excluded after the abstract screening and four reports could not be retrieved, leaving thirty-four full-text reports. A total of twenty-one reports were excluded at full-text screening  were observational  and only four (31 %) were intervention studies , while the remaining two included studies (15 %) were case reports,37.The thirteen studies included were published between 1975 and 2018. The majority , total sample size ranged from forty-five to 1252 for the observational studies and from 197 to 234 for the intervention studies.Studies were from eleven countries: three in the USAn 9, 69 %) and child hearing–32,34,35, and only four studies (31 %) investigated maternal iodine exposure during pregnancy in relation to child hearing,33,36,37.Most studies investigated the association between iodine exposure during childhood/adolescence , and the two case reports in the USA had no measure of iodine intake or status (just use of an iodine supplement that provided excess iodine),37.In the studies of pregnant women, iodine status was reported as median UIC in two studies,30–32,34 (range: 19 to 181 µg/l) and as mean/median iodine-to-creatinine ratio in six studies,29–31,35 (range: 16 to 130 µg/g); two studies reported both measures,31. Based on the reported UIC or iodine-to-creatinine ratio, there were four studies in severely iodine-deficient children,29,34,35, one in severe-to-moderate deficiency, one in mild deficiency and three in iodine-sufficient children,30,31. None of the studies had a measure of dietary iodine intake (µg/d), and thus the iodine exposure in our review is solely based on measures of urinary iodine excretion .In the studies of children and adolescents, iodine status was reported as mean/median UIC in five studies (that in pregnant women); this was judged as having a low risk of bias in all domains (online Supplementary Table S1). The other RCT, in childhood, was judged as having a high risk of bias overall; this RCT had some concerns of bias in the randomisation process and the deviations from intended interventions domains, as well as a high risk of bias in the selection of reported results domain. Based on the ROBINS-I assessment, both non-randomised studies of interventions had a serious risk of bias in at least one domain and were thus judged as being at a serious risk of bias overall,35 (online Supplementary Table S2). The only cohort study included was of good quality, according to the NOS assessment. The majority of cross-sectional studies were of poor quality–28,30, one was of fair quality and only one was of good quality (online Supplementary Table S3).Based on the RoB 2 assessment, the overall risk of bias was low in one of the two RCTs, one was a cohort study and two were case reports,37  in the two groups were identical for the right ear (13·3 dB), there was a small difference for the left ear, with a slightly higher hearing threshold in the iodine group , indicating worse auditory performance.In the RCT in mildly iodine-deficient pregnant women (median UIC: 131 µg/l) in India and Thailand, women received either 200 µg iodine/d or placebo from the first trimester until delivery and auditory performance of children  was measured at age 5–6 years. This study also found no difference between the two groups of women in the auditory memory and the auditory processing of their children at 13–14 years; neither group of children reached a speech reception threshold indicative of a clinical diagnosis of central auditory processing disorder. There was, however, a statistically significant difference in binaural integration, which reflects a child’s ability to process information presented to both ears simultaneously when each ear is presented with different information, with a lower percentage of correctly repeated digits in children of women with UIC < 150 µg/l v. those of women with UIC ≥ 150 µg/l; though this difference was observed for the right ear only .A cohort study in mildly-to-moderately iodine-deficient pregnant women in Australia (median UIC: 99 µg/l) found that all children had normal hearing (hearing threshold ≤ 20 dB) at 13–14 years regardless of whether their mothers were broadly classified as iodine deficient (UIC < 150 µg/l) or iodine sufficient (UIC ≥ 150 µg/l) during pregnancy) from dietary supplements,37. In both cases, the iodine excess resulted in fetal goitre and hypothyroidism; however, the effect on child hearing was different. In one of the reports, the iodine supplements were discontinued at 29 gestational weeks, but an auditory brainstem response test of the infant indicated sensorineural hearing loss and the infant was fitted with bilateral hearing aids at five weeks. By contrast, in the other case report, the iodine supplementation was discontinued around 21 weeks, and the fetus was treated with serial intra-amniotic levothyroxine injections between 22 and 26 weeks; this resulted in fetal euthyroidism and the infant had normal response bilaterally to the neonatal hearing screening.We identified two case reports of pregnant women in the USA who took over fifty times the recommended daily allowance for iodine in pregnancy . Overall, eight of the nine studies (89 %) found an association between indicators of iodine status and child hearing, where better iodine status was associated with better hearing–32,34,35.A total of nine studies investigated the association between child iodine exposure and child hearing; one RCTudies–31 . The age. Despite being set up as an RCT, this study did not compare hearing thresholds between the study groups because the whole population began to have access to iodised salt three to four months after the start of the intervention . Iodine status of the total sample improved from baseline, and children were mildly deficient at the end of the study (median UIC: 85 µg/l). The authors of this study performed an alternative analysis of the data from the total sample; this showed that thyroglobulin (Tg) (a marker positively correlated with the severity of iodine deficiency) was positively correlated with the mean hearing threshold of the seven frequencies tested (between 250 and 6000 Hz); although statistically significant, this correlation was only weak . Children with Tg in the highest tertile had a higher mean hearing threshold at each of the seven frequencies than children with Tg in the lowest tertile, but these differences were statistically significant only at the higher frequencies (≥ 2000 Hz)  and measured their hearing thresholds by pure-tone audiometry eleven months later2000 Hz) . By cont and China showed that the administration of iodised oil or iodised salt resulted in a significant reduction in the hearing thresholds (i.e. better hearing). The study in Iranian school-age children (7–13 years) showed that the mean hearing threshold at the speech frequencies  was statistically significantly lower in children recruited three years after the administration of iodised oil  and seven years after the introduction of iodised salt in Iran  than in the children recruited prior to any iodine prophylaxis . Moreover, a significantly lower proportion of children with hearing thresholds > 15 dB was observed in 1992  and in 1999  than in 1989 (prior to iodine prophylaxis); 10 % in both 1992 and 1999 v. 46 % in 1989. The study in China found that the mean hearing threshold at the speech frequencies of school children (7–11 years) who lived in two endemic areas of severe iodine deficiency was higher than that of children in a non-endemic control area . Children in one of the iodine-deficient areas were followed up for three years after the introduction of iodised salt; the mean hearing threshold of these children decreased significantly two and three years after introducing iodised salt  to a value similar to that of children living in the control non-endemic area. The improvement in hearing thresholds after supplementation with iodised salt was also accompanied by a reduction in goitre rate , an increase in the mean iodine-to-creatinine ratio  and a normalisation of thyroid function tests. To account for the effect of advancing age in this study, in one of the endemic areas, two groups of children were recruited – one before iodine prophylaxis and one three years after the introduction of iodised salt but of the same age. Children recruited before iodised-salt supplementation had a significantly higher hearing threshold than the group of children of the same age and from the same area recruited three years after supplementation .Both studies of iodine interventions in children in Irann 121) either with or without goitre and found that all children had normal hearing as measured by pure-tone audiometry. Although the study groups differed based on the presence of goitre , the median iodine-to-creatinine ratio was similar (83 v. 88 µg/g).Only one of the six cross-sectional studies did not find any association between measures of child iodine status and hearing; that study examined 9–16-year-old children  was associated with worse hearing in children (indicated by higher hearing thresholds).Of the five cross-sectional studies that found an association, three found an association between UIC and hearing thresholds in children or adolescentsr = 0·10; P < 0·02) and not at the speech frequencies . Overall, higher hearing threshold was observed in the children with UIC < 100 µg/l than in those with UIC > 100 µg/l, but the exact results for each of these groups were not reported.A study in France found a correlation between UIC and hearing threshold in 4-year-old children (median UIC: 116 µg/l), where higher UIC indicated better hearing; however, it was weak and was statistically significant only when the hearing threshold was measured at 4000 Hz  were in the range of 17·2–30·0 dB in children with UIC < 50 µg/l and between 9·3–19·7 dB in children with UIC 101–150 µg/l. In children without palpable goitre, a higher hearing threshold was seen in children with lower UIC but the differences were smaller and not statistically significant. The results for the bone-conduction auditory thresholds were mixed in children with goitre, whereas, similarly to the air-conduction results, there was no statistically significant association with UIC in children without goitre. Children with Tg > 10 ng/ml had higher auditory thresholds for both ears at almost all frequencies than those with Tg < 10 ng/ml; results were similar for both air-conduction  and bone-conduction testing . In multiple regression analysis, Tg was positively associated with hearing thresholds only in children with goitre and only in those with UIC ≤ 100 µg/l. UIC was negatively associated with air-conduction hearing threshold at 2000 Hz only in children with UIC ≤ 100 µg/l. In children with goitre and UIC ≤ 100 µg/l, Tg, UIC and age accounted for 75 % of the variance in the air-conduction hearing threshold at 2000 Hz. In adjusted model, children with thyroid volume > 95th percentile were nearly four times (OR: 3·86) more likely to have a hearing threshold > 20 dB. Higher odds of hearing threshold > 20 dB were also seen when goitre was defined by palpation (OR: 1·97) or when thyroid volume > 75th percentile (OR: 3·06).A cross-sectional study in Spanish school-age children (6–16 years) reported a statistically significant negative association between spot-UIC and air-conduction auditory thresholds at all tested frequencies (except at 8000 Hz) in the children with palpable goitre. The association was even more pronounced in those with UIC < 50 µg/l compared with the same reference group (i.e. UIC 100–199 µg/l) (OR: 5·52). In this study, UIC was not associated with high-frequency hearing impairment.A study of USA adolescents (12–19 years) found that in adjusted analyses, those with UIC < 100 µg/l had an increased risk of speech-frequency hearing impairment  compared with those with UIC 100–199 µg/l (OR: 2·10),29. A study in Indonesia included both children and adults (4–50 years) in the following groups: those from a community affected by endemic goitre (mean iodine-to-creatinine ratio: 16 µg/g) with cretinism (Group A) and without cretinism (Group B), as well as individuals from a nearby non-endemic goitre control area (mean iodine-to-creatinine ratio: 42 µg/g) (Group C). We included this study because although it contained data on iodine exposure in adults, most participants in groups B and C were children (age range: 5–20 years). Group A included participants up to 50 years, but these individuals had cretinism, which would have likely indicated exposure to iodine deficiency during pregnancy. They found that the proportion with bilateral hearing impairment (defined as a hearing threshold measured by pure-tone audiometry ≥ 20 dB) was significantly higher in Group A than in Group B or C . There was no statistically significant difference between Groups B and C. By contrast, a study in Iranian school-age children (6–16 years) without visible signs of endemic cretinism (i.e. similar to Group B in the previous study) found a higher proportion of children with abnormal hearing function in two endemic-goitre areas with mean iodine-to-creatinine ratio 18–20 µg/g (Groups A and B) than in another area with mean iodine-to-creatinine ratio 66 µg/g (Group C) . The mean hearing threshold at the speech frequencies  was also statistically significantly higher in the severely iodine-deficient children (Group A) than in those who were mildly-moderately deficient (Group C) . Notably, over 90 % of children in Group A also had a visible goitre.Two of the six cross-sectional studies investigated hearing thresholds in areas of severe iodine deficiency and endemic goitre in comparison with non-endemic/control areasin utero and/or in childhood) and hearing outcomes in children. Overall, limited and poor-quality data were available, thus affecting our ability to draw firm conclusions. The fact that there is a lack of good-quality evidence is an important finding that highlights the need for further research in this area. We therefore discuss the current knowledge gaps and provide directions for future research.This systematic review provides an overview of the available evidence on the association between iodine exposure during development . Although iodine supplementation significantly increased maternal UIC, it did not result in major differences in thyroid function tests between the iodine and placebo groups. The iodine status of the placebo group also improved during the study (second and third trimester median UIC were above the WHO cut-off of 150 µg/l indicating iodine sufficiency in pregnancy); this might have contributed to the null findings. Furthermore, the setting of this RCT limits interpretation of the results as the women in India were iodine sufficient at baseline and therefore improvements in auditory performance would not be expected with the intervention in this iodine-sufficient group. Although the authors have subsequently re-analysed just the data of the iodine-deficient pregnant women from Thailand, this did not include analysis of the auditory outcomes.Studies investigating associations between maternal iodine status during pregnancy and child hearing are lacking; only four such studies were identified in this review and only one of these was an RCT. This study was in a setting of mild-to-moderate iodine deficiency and was of good quality; however, it only included 45 mother–child pairs. Evidence in settings of mild-to-moderate iodine deficiency in pregnancy is therefore lacking.The only cohort study in pregnant women found mostly no associations between maternal iodine status (UIC) and child hearing outcomes at 13–14 years, though children of iodine-deficient women had lower scores for binaural integration (processing information presented to both ears simultaneously). In the two case reports included in this review,37, both pregnant women were taking an extremely high dose of iodine from dietary supplements ; however, this resulted in hearing problems in the newborn only in one of these cases. The timing of discontinuation of the supplement (at 21v. 29 weeks) and the administration of intra-amniotic levothyroxine injections in one of the cases might account for the different outcomes. In one of the reports (where the newborn had hearing problems), the mother was also hypothyroid during pregnancy, while the mother in the other case report was euthyroid. More evidence on the safe dose of iodine supplements in pregnancy is needed.Excessive iodine intake in the diet can also have negative consequences for the fetus and neonate, who might be at risk of iodine-induced thyroid dysfunction. It is unclear which developmental periods are most sensitive to the effects of iodine deficiency and whether child hearing impairment resulting from iodine deficiency in pregnancy could be reversed by the correction of iodine deficiency in childhood. Some studies included in this review showed an improvement in hearing thresholds after iodine supplementation in childhood,35, suggesting that hearing impairment might be reversible in later childhood. The RCT and cohort study in pregnant women who were mildly-to-moderately iodine deficient did not find an association between maternal iodine exposure and child hearing threshold, but notably the children in these studies were iodine sufficient. By contrast, it has been suggested that the processes of auditory development most susceptible to changes in T3 availability occur mostly during pregnancy and to a lesser extent postnatally. The limited existing evidence in pregnancy, however, does not provide information about the critical timing of maternal iodine deficiency in relation to auditory development.The development of the auditory system is prolonged and continues after pregnancy into childhood; it is possible that the effects of iodine depend on the period of exposure during auditory development. This concept could be explored in future cohort studies with measures of iodine status at different time points in pregnancy.Studies in pregnant women with child hearing outcomes are needed to expand the body of evidence in this area. Ideally, these would be RCTs, but this study type is becoming increasingly challenging to conduct as more countries introduce iodine-supplementation recommendations for pregnant women and therefore there are ethical concerns over having a placebo group. In the absence of further RCTs, cohort studies could provide more data on the association between iodine status in pregnancy and offspring hearing function. We identified only one such study where iodine status was assessed throughout pregnancy and results were not reported according to trimester,32,34,35, just one study was in a population with mild deficiency and three were in areas of iodine sufficiency,30,31. The negative effects of severe iodine deficiency, including mental retardation, goitre and deafness, are well documented,3, whereas the consequences of exposure to milder forms of deficiency are less clear. Nowadays, severe iodine deficiency is rare, whereas mild-to-moderate deficiency is more prevalent; this highlights the need for more studies on hearing in mild-to-moderate deficiency.Most studies in this review were focussed on iodine exposure during childhood; the majority (five of nine) were conducted in areas of endemic goitre and severe or severe-to-moderate iodine deficiency–31. In three of the studies, the associations were based on UIC,30,31, though in one of the studies, the associations were weak and not present at all hearing frequencies, and in another study – only seen in children with goitre. As these studies were cross-sectional, it is important to note that the low iodine status in childhood might also be a marker of inadequate iodine exposure in utero; the hearing impairment observed in children might be as a result of suboptimal iodine status of their mothers who also resided in these severely iodine-deficient areas during pregnancy.The studies in children were predominantly cross-sectional and five of six found that lower iodine status indicated by various measures was associated with higher hearing thresholds in children (i.e. worse hearing),29. The study in Indonesia found that the proportion with bilateral hearing impairment was significantly higher in children with cretinism in the endemic goitre area, compared with children either without cretinism from the same area, or from the control area, while there was no difference between children without cretinism and the control area. This might suggest that hearing impairment is only likely when children have cretinism; however, children in the control area were still moderately iodine-deficient and their iodine status was not much higher than that of children in the endemic-goitre area. By contrast, the study in Iran found a higher mean hearing threshold and a higher proportion with abnormal hearing in children without cretinism from endemic-goitre areas v. in children from a control area; notably, the difference in iodine status between the goitre and control areas was greater than between the groups of children in Indonesia. The study in Iran suggests that severe iodine deficiency in children might affect hearing thresholds, even without the presence of clinical cretinism.Two cross-sectional studies (Indonesia and Iran) compared hearing thresholds of individuals in areas of severe iodine deficiency and endemic goitre with those in control areas,45). Moreover, different levels of otitis media between study groups could explain some of the differences in hearing in observational studies. Better-quality studies in children are needed to strengthen the evidence observed in previous studies.The majority of these cross-sectional studies were of poor quality and most did not adjust for confounders, so it is unclear whether the observed associations are independent of socio-demographic characteristics (e.g. age) and other potential confounders  had higher hearing thresholds (i.e. worse hearing) than those in the lowest tertile, though differences were small (around 1–2 dB). By contrast, UIC was not associated with hearing thresholds, which could be because Tg is a longer-term marker of iodine intake (preceding weeks to months) than UIC, which reflects recent iodine intake (last 24–48 h). A cross-sectional study also found that children with Tg > 10 ng/ml had higher hearing thresholds than children with Tg ≤ 10 ng/ml (around 2–5 dB different at most frequencies), whereas UIC was negatively associated with hearing thresholds only in children with goitre.The RCT in children did not report the difference in hearing thresholds between the iodine (as iodised oil) and placebo groups because iodised salt was introduced in the population during the study. In some studies, most hearing thresholds were below 20 dB,32. Both intervention studies in severely iodine-deficient children showed that the administration of iodised oil or iodised salt resulted in a significant reduction in the hearing thresholds. However, the mean hearing threshold at the speech frequencies  was below 20 dB (i.e. 15·8 dB and 17·4 dB) even in the non-supplemented groups. In a cross-sectional study, children from an endemic-goitre area had a mean hearing threshold at the speech frequencies of 15·4 dB, and in another, most hearing thresholds were above 20 dB only in children with goitre and with UIC < 50 µg/l. Taken together, these results suggest that in individuals without clinical features of endemic cretinism, the effect of iodine deficiency on hearing might be relatively subtle; however, this does not mean that the effects are unimportant. It is possible that even small differences in hearing thresholds or mild hearing impairment may have consequences for cognitive outcomes. This is supported by data from a study in children with average hearing thresholds within the normal range that showed that poorer hearing threshold was associated with lower IQ (7–13 years), poorer scores for reading (11–15 years) and language comprehension and expression (3–9 years).The hearing results in the included studies should be considered in the context of the WHO grades of hearing impairment, hearing thresholds of 20 dB or lower in both ears is defined as ‘normal’ hearing, IQ scores, language skills and school performance,7. As previously noted by Hay et al., mild-to-moderate maternal iodine deficiency tends to be associated with difficulties in processing information quickly, and these effects are usually captured by measures of verbal processing and language. However, the role of child hearing in these reported associations is unclear; for instance, whether these are separate negative effects of iodine deficiency, or whether the association between maternal iodine status and child cognition reported in previous studies might be partly explained by suboptimal child hearing ability. Alternatively, poorer cognitive ability could explain poorer performance on audiometry, a subjective, psychophysical test which requires a child to sustain attention and process sound to measure their hearing threshold accurately.Previous studies have shown a link between maternal mild-to-moderate iodine deficiency and offspring reading. For instance, a study in the UK ALSPAC cohort showed that a significantly lower proportion of children with hearing impairment achieved the top grades of A*–C on five or more General Certificate of Secondary Education exams at 16 years (including English and Maths) compared with children with normal hearing and vision (64 v. 73 %), though the association was attenuated after adjustment for IQ. The relationship between IQ and hearing has been documented previously, even slight-to-moderate sensorineural hearing loss was strongly negatively associated with IQ of 7-year-old children. In one of the studies in our review, hearing thresholds were also negatively associated with mental performance; children in the highest tertile of hearing thresholds performed significantly worse on the total mental test battery than children in the lowest tertile. The interrelationship between hearing impairment and cognitive outcomes in relation to iodine status should be investigated in future studies.Hearing problems in children can have an effect on cognitive, academic and social skills (e.g. communication and spoken language) because they do not provide information on whether hearing differences are conductive (indicating problems with the outer and/or middle ear and mainly temporary) or sensorineural (indicating problems with the cochlea or beyond and permanent). They also do not assess auditory processing and individuals with hearing thresholds in the normal range might have difficulties in processing auditory information. Therefore, the effect of iodine on these other aspects of hearing remains unknown.Most studies in our review are limited by the fact that the hearing outcomes were based on hearing thresholds measured by air-conduction pure-tone audiometry. These should not be used as the sole measure of auditory development,31; however, since the majority of participants in these studies were children and it was not possible to separate the data by age, we did not exclude these studies as we considered that they contribute to the overall evidence in children. The use of inconsistent measures of iodine intake/status  across the included studies limited comparability between studies. The lack of a meta-analysis is a limitation; however, this could not be performed due to the scarcity of comparable and good-quality studies.We included articles in the English language only; thus, we might have omitted relevant studies in other languages. The inclusion of all types of study design, including case-reports, is not optimal; however, considering the relatively unexplored nature of the topic, we believe this review provides a comprehensive account of the available evidence. It is important to note that two of the studies in our review also included adults (≥ 18 years)in utero and therefore more maternal studies are needed. More observational evidence could be gathered from good-quality cohort studies that assess the association between maternal iodine status and child hearing. This would add to the evidence base and inform the design of future RCTs of iodine supplementation in pregnancy that might consider including an assessment of child hearing as one of the outcomes.In conclusion, the evidence on the association between suboptimal iodine status and child hearing is based on few and mostly poor-quality studies; there is a lack of RCTs and interventions, with mostly observational evidence from cross-sectional studies. Most studies are in children, with limited evidence in pregnancy. The critical thyroid-hormone-dependent auditory development occurs predominantly