Research
Original Investigation
Sudden Sensorineural Hearing Loss Associated With Iron-Deficiency Anemia A Population-Based Study Shiu-Dong Chung, MD, PhD; Po-Yueh Chen, MD; Herng-Ching Lin, PhD; Shih-Han Hung, MD
IMPORTANCE Vascular events play a big part in the development of sudden sensorineural
hearing loss (SSNHL), but only those associated with sickle-cell anemia have been previously associated with SSNHL. This study demonstrates an association between SSNHL and prior iron-deficiency anemia (IDA). OBJECTIVE To evaluate the association between IDA and SSNHL using a nationwide population-based database. DESIGN, SETTING, AND PARTICIPANTS In this case-control study in Taiwan, participants with SSNHL (n = 4004) were identified, and controls (n = 12 012) were randomly selected. MAIN OUTCOMES AND MEASURES Conditional logistic regression was used to calculate the ORs (95% CIs) for IDA in participants with SSNHL vs controls. RESULTS Of the 16 016 sampled participants, 533 (3.3%) had previously been diagnosed with IDA, including 172 (4.3%) participants with SSNHL and 361 (3.0%) controls. The χ2 test revealed a significant difference (P < .001) in the prevalence of prior IDA between participants with SSNHL and controls. By conditional logistic regression, we found that the OR for previous IDA among the participants with SSNHL was 1.34 (95% CI, 1.11-1.61) (P < .01) after adjusting for monthly income, geographic region, urbanization level, and comorbidities (ie, hypertension, diabetes, hyperlipidemia, renal disease, and coronary heart disease). The significant relationship between SSNHL and prior IDA was most pronounced among those 44 years or younger (adjusted OR, 1.91; 95% CI, 1.35-2.72) (P < .001) for the participants with SSNHL compared with controls, and the strength of this relationship decreased with age. CONCLUSIONS AND RELEVANCE There is an association between SSNHL and prior IDA. Patients with IDA, especially those younger than 60 years, should be more aggressively surveyed and managed to reduce hearing-related morbidities. JAMA Otolaryngol Head Neck Surg. 2014;140(5):417-422. doi:10.1001/jamaoto.2014.75 Published online March 13, 2014.
S
udden sensorineural hearing loss (SSNHL) is a type of hearing loss in which the vestibular cochlear nerve, inner ear, or central processing centers of the brain are suddenly affected, leading to a deterioration of hearing function. The disease is reported to have an annual incidence of 5 to 300 cases per 100 000 population.1,2 Despite many theories regarding its causes, most cases are idiopathic.3 Proposed causes of idiopathic SSNHL include viral infection, autoimmune disease, vascular insults, and labyrinthine membrane rupture.4-10 Among these, vascular events are believed to contribute to a certain degree of SSNHL development. Thrombosis, embolus, reduced blood flow, or vasospasms may lead to vascular compromise of the cochlea. This jamaotolaryngology.com
Author Affiliations: Division of Urology, Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan (Chung); Sleep Research Center, Taipei Medical University, Taipei, Taiwan (Chung, Lin); Department of Otolaryngology, Taipei Medical University–Shuang Ho Hospital, Taipei, Taiwan (Chen); School of Medical Laboratory Sciences and Biotechnology, Taipei Medical University, Taipei, Taiwan (Lin); Department of Otolaryngology, Taipei Medical University Hospital, Taipei, Taiwan (Hung). Corresponding Author: Shih-Han Hung, MD, Division of Urology, Department of Otolaryngology, Taipei Medical University Hospital, Wu-Hsin St, 250, Taipei, Taiwan (seedturtle @gmail.com)
pathogenesis is supported by findings that increased risks of cardiovascular and cerebrovascular events are associated with SSNHL.11,12 Anemia is the most common blood disorder and is highly associated with cardiovascular diseases and cerebrovascular events.13-17 Results of the large-scale Framingham study, for instance, clearly imply that hematocrit is an important risk factor for some cardiovascular diseases.18 However, only sicklecell anemia has been associated with SSNHL. The relationship between anemia and SSNHL remains unclear.19-23 The present study evaluates the association of iron-deficiency anemia (IDA) and the development of SSNHL using a nationwide, population-based database. JAMA Otolaryngology–Head & Neck Surgery May 2014 Volume 140, Number 5
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archotol.jamanetwork.com/ by a University Of Connecticut Health Center User on 05/12/2015
417
Research Original Investigation
Sudden Sensorineural Hearing Loss and Anemia
Statistical Analysis
Methods This study used Longitudinal Health Insurance Database (LHID2000) data, which are deidentified, secondary data released to the public for research purposes. Therefore, Taipei Medical University waived full review and approval by the institutional review board.
Database Data on the sampled subjects were retrieved from the LHID2000, which contains data for 1 million enrollees derived from medical claims records of the Taiwan National Health Insurance (NHI) program. The 1 million enrollees were randomly selected from all enrollees listed in the 2000 Registry of Beneficiaries (n = 23.72 million) under the NHI program. The Taiwan National Health Research Institute has collected data from the NHI program and sorted them into the LHID2000 every year since the inception of the NHI program in 1995. Previous researchers have demonstrated the high validity of data from the NHI program,24,25 and hundreds of studies using the LHID2000 have been published in internationally peer-reviewed journals.26
Selection of Cases and Controls This case-control study identified 4004 participants 18 years or older who received a first-time diagnosis of SSNHL (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 388.2) in an ambulatory care visit (including the outpatient departments of hospitals and clinics) or during hospitalization from January 1, 2001, to December 31, 2011. There was no universal consensus on a definition of SSNHL, so only participants with at least 2 consecutive SSNHL diagnoses in the ambulatory care settings or 1 SSNHL diagnosis during hospitalization were included in this study, to increase the diagnostic validity of SSNHL. The first ambulatory care visit or hospitalization for treatment of SSNHL was assigned as the index date for a case of SSNHL. Controls were selected from the remaining enrollees of the LHID2000. Those with a history of SSNHL since the beginning of the NHI program in 1995 were excluded. Thereafter, the Proc Surveyselect program of SAS, version 8.2 (SAS Institute) was used to randomly select 12 012 controls matched to the participants with SSNHL (3 controls per participant with SSNHL) in terms of sex, age group (18-39, 40-44, 45-49, 50-54, 55-59, 60-64, 65-69, and >69 years), and index year. While the index year of the SSNHL cases was the year of the first diagnosis of SSNHL, the index year for the controls was simply a matched year when the control first utilized the health care system.
Exposure Assessment This study identified IDA participants with SSNHL based on ICD-9-CM codes 280, 280.0, 280.1, 280.8, and 280.9. To increase the validity of the IDA diagnoses, only participants with SSNHL with at least 2 diagnoses of IDA prior to the index date were considered to represent SSNHL cases with IDA. 418
The SAS software system, version 8.2, was used for all statistical analyses, and χ2 tests were first conducted to compare statistical differences between participants with SSNHL and controls in geographic location (northern, central, eastern, and southern Taiwan), residence urbanization level (1, most urbanized; 5 least urbanized), and monthly income measured in New Taiwan dollars (NT$) (0-15 840, 15 841-25 000, and ≥25 001). (At the time of this study, the average exchange rate for US dollars was approximately NT$30 for $1.) A conditional logistic regression analysis (conditioned on sex, age group, and index year) was used to calculate the odds ratios (ORs) (95% CIs) for having a previous diagnosis of IDA between participants with and without SSNHL. Medical comorbidities, including diabetes, hypertension, coronary heart disease (CHD), hyperlipidemia, renal disease, and alcohol abuse/ alcohol dependence syndrome, were taken into consideration in the regression model. Statistical significance was set at P ≤ .05.
Results Data from 16 016 participants were evaluated, including 4004 with SSNHL and 12 012 controls; mean (SD) age, 51.6 (17.5) years. The distribution of demographic characteristics between participants with SSNHL and controls after matching for sex and age group (Table 1) revealed significant differences in geographic region and urbanization level. In terms of medical comorbidities, the participants with SSNHL had a higher prevalence of diabetes (P < .001), hypertension (P < .001), CHD (P < .001), hyperlipidemia (P < .001), and renal disease (P < .001) than controls. There was no significant difference in the prevalence of alcohol abuse. Evaluation of prior IDA prevalence among participants with SSNHL and controls (Table 2) demonstrated that 533 (3.3%) of the 16 016 sampled participants were diagnosed as having IDA prior to the index date, including 172 with SSNHL (4.3%) and 361 controls (3.0%). Correspondingly, the χ2test revealed a significant difference in the prevalence of prior IDA between participants with SSNHL and controls (P < .001). The conditional logistic regression (conditioned on sex, age group, and index year) further suggested that the OR of prior IDA for participants with SSNHL was 1.45 (95% CI, 1.20-1.74) (P < .001) compared with controls. In detailed analysis of the adjusted OR for SSNHL (Table 3) we found that the OR of having a previous IDA diagnosis among participants with SSNHL was 1.34 (95% CI, 1.11-1.61) (P < .01), after adjusting for monthly income, geographic region, urbanization level, and comorbidities (ie, hypertension, diabetes, hyperlipidemia, renal disease, and CHD). Further analysis of the OR for prior IDA by age group (Table 4) indicated that the significant relationship between SSNHL and prior IDA decreased with age. This relationship was strong in patients younger than 60 years and was most pronounced among those 44 years or younger (adjusted OR, 1.91; 95% CI, 1.35-2.72) (P < .001) for participants with SSNHL compared with controls. However, for those 66 years or older, there was no significant increase in the OR of prior IDA among par-
JAMA Otolaryngology–Head & Neck Surgery May 2014 Volume 140, Number 5
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archotol.jamanetwork.com/ by a University Of Connecticut Health Center User on 05/12/2015
jamaotolaryngology.com
Sudden Sensorineural Hearing Loss and Anemia
Original Investigation Research
Table 1. Demographic Characteristics of Participants With SSNHL and Controls Participants, No. (%) (N = 16 016) SSNHL (n = 4004)
Controls (n = 12 012)
Male
2101 (52.5)
6303 (52.5)
Female
1903 (47.5)
5709 (47.5)
Characteristic
P Value
Sex >.99
Age, y
Original Investigation
Sudden Sensorineural Hearing Loss Associated With Iron-Deficiency Anemia A Population-Based Study Shiu-Dong Chung, MD, PhD; Po-Yueh Chen, MD; Herng-Ching Lin, PhD; Shih-Han Hung, MD
IMPORTANCE Vascular events play a big part in the development of sudden sensorineural
hearing loss (SSNHL), but only those associated with sickle-cell anemia have been previously associated with SSNHL. This study demonstrates an association between SSNHL and prior iron-deficiency anemia (IDA). OBJECTIVE To evaluate the association between IDA and SSNHL using a nationwide population-based database. DESIGN, SETTING, AND PARTICIPANTS In this case-control study in Taiwan, participants with SSNHL (n = 4004) were identified, and controls (n = 12 012) were randomly selected. MAIN OUTCOMES AND MEASURES Conditional logistic regression was used to calculate the ORs (95% CIs) for IDA in participants with SSNHL vs controls. RESULTS Of the 16 016 sampled participants, 533 (3.3%) had previously been diagnosed with IDA, including 172 (4.3%) participants with SSNHL and 361 (3.0%) controls. The χ2 test revealed a significant difference (P < .001) in the prevalence of prior IDA between participants with SSNHL and controls. By conditional logistic regression, we found that the OR for previous IDA among the participants with SSNHL was 1.34 (95% CI, 1.11-1.61) (P < .01) after adjusting for monthly income, geographic region, urbanization level, and comorbidities (ie, hypertension, diabetes, hyperlipidemia, renal disease, and coronary heart disease). The significant relationship between SSNHL and prior IDA was most pronounced among those 44 years or younger (adjusted OR, 1.91; 95% CI, 1.35-2.72) (P < .001) for the participants with SSNHL compared with controls, and the strength of this relationship decreased with age. CONCLUSIONS AND RELEVANCE There is an association between SSNHL and prior IDA. Patients with IDA, especially those younger than 60 years, should be more aggressively surveyed and managed to reduce hearing-related morbidities. JAMA Otolaryngol Head Neck Surg. 2014;140(5):417-422. doi:10.1001/jamaoto.2014.75 Published online March 13, 2014.
S
udden sensorineural hearing loss (SSNHL) is a type of hearing loss in which the vestibular cochlear nerve, inner ear, or central processing centers of the brain are suddenly affected, leading to a deterioration of hearing function. The disease is reported to have an annual incidence of 5 to 300 cases per 100 000 population.1,2 Despite many theories regarding its causes, most cases are idiopathic.3 Proposed causes of idiopathic SSNHL include viral infection, autoimmune disease, vascular insults, and labyrinthine membrane rupture.4-10 Among these, vascular events are believed to contribute to a certain degree of SSNHL development. Thrombosis, embolus, reduced blood flow, or vasospasms may lead to vascular compromise of the cochlea. This jamaotolaryngology.com
Author Affiliations: Division of Urology, Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, Taiwan (Chung); Sleep Research Center, Taipei Medical University, Taipei, Taiwan (Chung, Lin); Department of Otolaryngology, Taipei Medical University–Shuang Ho Hospital, Taipei, Taiwan (Chen); School of Medical Laboratory Sciences and Biotechnology, Taipei Medical University, Taipei, Taiwan (Lin); Department of Otolaryngology, Taipei Medical University Hospital, Taipei, Taiwan (Hung). Corresponding Author: Shih-Han Hung, MD, Division of Urology, Department of Otolaryngology, Taipei Medical University Hospital, Wu-Hsin St, 250, Taipei, Taiwan (seedturtle @gmail.com)
pathogenesis is supported by findings that increased risks of cardiovascular and cerebrovascular events are associated with SSNHL.11,12 Anemia is the most common blood disorder and is highly associated with cardiovascular diseases and cerebrovascular events.13-17 Results of the large-scale Framingham study, for instance, clearly imply that hematocrit is an important risk factor for some cardiovascular diseases.18 However, only sicklecell anemia has been associated with SSNHL. The relationship between anemia and SSNHL remains unclear.19-23 The present study evaluates the association of iron-deficiency anemia (IDA) and the development of SSNHL using a nationwide, population-based database. JAMA Otolaryngology–Head & Neck Surgery May 2014 Volume 140, Number 5
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archotol.jamanetwork.com/ by a University Of Connecticut Health Center User on 05/12/2015
417
Research Original Investigation
Sudden Sensorineural Hearing Loss and Anemia
Statistical Analysis
Methods This study used Longitudinal Health Insurance Database (LHID2000) data, which are deidentified, secondary data released to the public for research purposes. Therefore, Taipei Medical University waived full review and approval by the institutional review board.
Database Data on the sampled subjects were retrieved from the LHID2000, which contains data for 1 million enrollees derived from medical claims records of the Taiwan National Health Insurance (NHI) program. The 1 million enrollees were randomly selected from all enrollees listed in the 2000 Registry of Beneficiaries (n = 23.72 million) under the NHI program. The Taiwan National Health Research Institute has collected data from the NHI program and sorted them into the LHID2000 every year since the inception of the NHI program in 1995. Previous researchers have demonstrated the high validity of data from the NHI program,24,25 and hundreds of studies using the LHID2000 have been published in internationally peer-reviewed journals.26
Selection of Cases and Controls This case-control study identified 4004 participants 18 years or older who received a first-time diagnosis of SSNHL (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 388.2) in an ambulatory care visit (including the outpatient departments of hospitals and clinics) or during hospitalization from January 1, 2001, to December 31, 2011. There was no universal consensus on a definition of SSNHL, so only participants with at least 2 consecutive SSNHL diagnoses in the ambulatory care settings or 1 SSNHL diagnosis during hospitalization were included in this study, to increase the diagnostic validity of SSNHL. The first ambulatory care visit or hospitalization for treatment of SSNHL was assigned as the index date for a case of SSNHL. Controls were selected from the remaining enrollees of the LHID2000. Those with a history of SSNHL since the beginning of the NHI program in 1995 were excluded. Thereafter, the Proc Surveyselect program of SAS, version 8.2 (SAS Institute) was used to randomly select 12 012 controls matched to the participants with SSNHL (3 controls per participant with SSNHL) in terms of sex, age group (18-39, 40-44, 45-49, 50-54, 55-59, 60-64, 65-69, and >69 years), and index year. While the index year of the SSNHL cases was the year of the first diagnosis of SSNHL, the index year for the controls was simply a matched year when the control first utilized the health care system.
Exposure Assessment This study identified IDA participants with SSNHL based on ICD-9-CM codes 280, 280.0, 280.1, 280.8, and 280.9. To increase the validity of the IDA diagnoses, only participants with SSNHL with at least 2 diagnoses of IDA prior to the index date were considered to represent SSNHL cases with IDA. 418
The SAS software system, version 8.2, was used for all statistical analyses, and χ2 tests were first conducted to compare statistical differences between participants with SSNHL and controls in geographic location (northern, central, eastern, and southern Taiwan), residence urbanization level (1, most urbanized; 5 least urbanized), and monthly income measured in New Taiwan dollars (NT$) (0-15 840, 15 841-25 000, and ≥25 001). (At the time of this study, the average exchange rate for US dollars was approximately NT$30 for $1.) A conditional logistic regression analysis (conditioned on sex, age group, and index year) was used to calculate the odds ratios (ORs) (95% CIs) for having a previous diagnosis of IDA between participants with and without SSNHL. Medical comorbidities, including diabetes, hypertension, coronary heart disease (CHD), hyperlipidemia, renal disease, and alcohol abuse/ alcohol dependence syndrome, were taken into consideration in the regression model. Statistical significance was set at P ≤ .05.
Results Data from 16 016 participants were evaluated, including 4004 with SSNHL and 12 012 controls; mean (SD) age, 51.6 (17.5) years. The distribution of demographic characteristics between participants with SSNHL and controls after matching for sex and age group (Table 1) revealed significant differences in geographic region and urbanization level. In terms of medical comorbidities, the participants with SSNHL had a higher prevalence of diabetes (P < .001), hypertension (P < .001), CHD (P < .001), hyperlipidemia (P < .001), and renal disease (P < .001) than controls. There was no significant difference in the prevalence of alcohol abuse. Evaluation of prior IDA prevalence among participants with SSNHL and controls (Table 2) demonstrated that 533 (3.3%) of the 16 016 sampled participants were diagnosed as having IDA prior to the index date, including 172 with SSNHL (4.3%) and 361 controls (3.0%). Correspondingly, the χ2test revealed a significant difference in the prevalence of prior IDA between participants with SSNHL and controls (P < .001). The conditional logistic regression (conditioned on sex, age group, and index year) further suggested that the OR of prior IDA for participants with SSNHL was 1.45 (95% CI, 1.20-1.74) (P < .001) compared with controls. In detailed analysis of the adjusted OR for SSNHL (Table 3) we found that the OR of having a previous IDA diagnosis among participants with SSNHL was 1.34 (95% CI, 1.11-1.61) (P < .01), after adjusting for monthly income, geographic region, urbanization level, and comorbidities (ie, hypertension, diabetes, hyperlipidemia, renal disease, and CHD). Further analysis of the OR for prior IDA by age group (Table 4) indicated that the significant relationship between SSNHL and prior IDA decreased with age. This relationship was strong in patients younger than 60 years and was most pronounced among those 44 years or younger (adjusted OR, 1.91; 95% CI, 1.35-2.72) (P < .001) for participants with SSNHL compared with controls. However, for those 66 years or older, there was no significant increase in the OR of prior IDA among par-
JAMA Otolaryngology–Head & Neck Surgery May 2014 Volume 140, Number 5
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archotol.jamanetwork.com/ by a University Of Connecticut Health Center User on 05/12/2015
jamaotolaryngology.com
Sudden Sensorineural Hearing Loss and Anemia
Original Investigation Research
Table 1. Demographic Characteristics of Participants With SSNHL and Controls Participants, No. (%) (N = 16 016) SSNHL (n = 4004)
Controls (n = 12 012)
Male
2101 (52.5)
6303 (52.5)
Female
1903 (47.5)
5709 (47.5)
Characteristic
P Value
Sex >.99
Age, y
