International Journal of Pediatric Otorhinolaryngology 78 (2014) 1852–1856
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Childhood hearing impairment in northern Finland, etiology and additional disabilities Sanna Ha¨kli a,b,c,*, Mirja Luotonen a, Risto Bloigu d, Kari Majamaa b,e,f, Martti Sorri a,c a
Department of Otorhinolaryngology, Oulu University Hospital, Oulu, Finland Medical Research Center, Oulu University Hospital, Oulu, Finland c Institute of Clinical Medicine, Department of Otorhinolaryngology, University of Oulu, Oulu, Finland d Medical Informatics and Statistics Research Group, University of Oulu, Oulu, Finland e Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland f Department of Neurology, Oulu University Hospital, Oulu, Finland b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 May 2014 Received in revised form 6 August 2014 Accepted 9 August 2014 Available online 17 August 2014
Objectives: The purpose of this study was to determine the prevalence and etiology of hearing impairment (HI) in Finnish children and to evaluate the frequency and type of additional disabilities among children with HI. Methods: Subjects consisted of 214 children with mild to profound HI ascertained until the age of 10 years. They belonged to the birth cohort spanning the years 1993–2002 in northern Finland. The clinical data were collected from the electronic patient records of the Oulu University Hospital. Age at ascertainment, degree and type of HI and audiogram configuration were determined. Risk factors and etiology of HI and co-existing disabilities were recorded. Results: The prevalence of childhood HI was 2.3/1000 live births (95% CI; 2.0, 2.7). The etiology of HI was genetic in 47.2%, acquired in 16.4% and unknown in 36.4% children. Among the 214 children with HI, 101 (47.2%) had other minor or major disabilities. The frequency of additional disabilities did not differ between children with mild HI and those with moderate or severe HI (p = 0.78). Additional disabilities were more common (65.7%) in children with acquired HI than in children with genetic or unknown HI (43.6%) (p = 0.035). Conclusion: The prevalence of childhood HI has remained unchanged in northern Finland as compared to previous studies. Genetic causes were the most common (47%) etiology of childhood HI. Among acquired causes of HI, perinatal risk factors were more common than previously. The frequency of additional disabilities was similar among children with different degrees of HI. Because almost 40% of children had one or more additional disabilities affecting development or learning, it is important to take them into consideration in rehabilitation. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Additional disorder Configuration Comorbidity Hearing loss Prevalence
1. Introduction The prevalence of childhood hearing impairment (HI) is about 1 to 2 per 1000 live births and it increases with age [1]. The prevalence varies between countries and between ethnic groups.
Abbreviations: BEHL, better ear hearing level; CI, confidence interval; CMV, cytomegalovirus; GJB2, gap junction beta 2 protein; HI, hearing impairment; OUH, Oulu University Hospital; PTA, pure tone average. * Corresponding author at: Department of Clinical Medicine, Otorhinolaryngology, University of Oulu, PO Box 5000, FIN-90014 Oulu, Finland. Tel.: +358 83153448; fax: +358 83153459. E-mail address: sanna.hakli@oulu.fi (S. Ha¨kli). http://dx.doi.org/10.1016/j.ijporl.2014.08.007 0165-5876/ß 2014 Elsevier Ireland Ltd. All rights reserved.
The epidemiology and etiology of moderate to profound childhood HIs has been studied in northern Finland in two birth cohorts spanning the years 1973–1982 and 1983–1992. The prevalence of at least moderate HI was 1.2/1000 live births [2] and that of at least mild childhood HI was 2.1/1000 live births in eastern Finland [3]. In general, it is assumed that the cause of childhood HI is genetic in 30–50% and acquired in 14–30% [1,4]. During the past decades, etiologies of childhood HIs have changed. Universal immunization programs and improved antibiotic treatments for meningitis have decreased post infectious HIs and improvements in neonatal intensive care have increased the survival of premature newborns. Therefore, in more recent studies, the proportion of asphyxia and prematurity are more common etiologies of HI. Advances in
S. Ha¨kli et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 1852–1856
genetic diagnostics have enabled the discovery of new causes of HI, but the proportion of unknown etiology has remained high, being about 40% [4,5]. The reported proportions of acquired and genetic etiologies of childhood HI vary greatly between studies mainly because of methodological reasons. Children with HI may have additional disabling conditions as a part of a syndrome or as a comorbid condition. About 30–40% of children with HI have been reported to have additional health or developmental problems that may affect their development and learning [6–9]. The presence or absence of additional disabilities is a significant predictor of outcome in children with HI [10–12]. Most studies on additional disabilities in hearing impaired children have focused on children with a cochlear implant or children with severe or profound HI [9,13], whereas little is known about additional disabilities in children with mild or moderate HI. The aim of the present study was to investigate the prevalence and etiology of childhood HI in northern Finland in a 10-year birth cohort spanning the years 1993–2002. Our clinical experience is that possible additional disabilities among hearing impaired children are often ignored although they may be even more significant than HI for the development of the child. Therefore, we evaluated frequency and type of additional disorders among children with HI and investigated the relation between additional disabilities and the degree of HI. 2. Subjects and methods 2.1. Subjects The subjects of this study were 214 children with mild to profound HI ascertained until the age of 10 years belonging to the birth cohort from January 1st 1993 to December 31st 2002. The 10-year birth cohort included 91,022 children. The ascertainment area included the entire northern Finland including the provinces of Northern Ostrobothnia and Lapland. Oulu University Hospital (OUH) is the tertiary care hospital that serves this population and provides the most advanced medical treatment, including diagnostics of early childhood HIs and rehabilitation of children. 2.2. Definition of hearing impairment The data from 214 children were collected retrospectively from the electronic patient records of the OUH. The age at ascertainment, the risk factors and the etiology of HI were recorded. Information on clinical examinations, such as the first and the most recent audiogram as well as co-existing disabilities were recorded. The degree and type of HI and audiogram configuration were determined on the basis of the most recent audiogram. According to definitions recommended by the EU expert group, the degree of HI was based on average thresholds calculated over the frequencies 0.5, 1, 2 and 4 kHz in the better hearing ear. The degree of HI according to better ear hearing level (BEHL) was classified as mild (21–39 dB), moderate (40–69 dB), severe (70–94 dB) and profound (95 dB) [14]. If any hearing could not be measured at a given frequency, the value of 130 dB was used in the calculations as recommended by the British Society of Audiology (1988). The first reliable audiological examination at the Department of Audio-Phoniatrics of the OUH was considered as the time of ascertainment of HI. In 16 children no reliable audiograms were obtained and hearing level was evaluated on the basis of sound field audiometry and auditory brainstem responses. The type or symmetry of HI could not be determined in some children, because exact thresholds could not be measured. Audiogram configurations were calculated based on air conduction thresholds as recommended by the EU expert group [14] with the exception of the less stringent definition for the flat
1853
configuration i.e. G mutation in mitochondrial DNA, while two children had received cisplatin treatment for a malignant disease. The etiology of HI could not be determined in the remaining 11 children. Configurations could be determined for 375 audiograms (Table 2). The most common configuration was high-frequency gently sloping, which accounted for 24% of the audiograms. Ninetyfour audiograms (25%) remained unclassified, but a clinical evaluation suggested that 45 of them were high-frequency gently or steeply sloping configuration, 21 were flat configuration, five were lowfrequency ascending and 23 were mid-frequency U-shaped.
p.([M34T];[V37I]) and one with respect to p.([M34T];[R143W]). In total, pathogenic GJB2 mutations were found in 19 children accounting for 16.7% of nonsyndromic HIs.
3.2. Etiology of HIs
3.3. Additional disabilities
The etiology of HI among the 214 hearing impaired children was defined to be genetic in 101 (47.2%) children, acquired in 35 (16.4%) and unknown in 78 (36.4%). The most common cause of nonsyndromic HI was a mutation in GJB2 (Table 3), while chromosomal aberration was the most common cause in syndromic HI (Supplementary Table 1). Sequencing of GJB2 was carried out in 123 (57.5%) children, including all children with nonsyndromic HI. Homozygous c.35delG was the most prevalent mutation in the GJB2 gene being found in 11 children. In addition, we found the homozygous p.M34T mutation in four children, while three children were compound heterozygotes with respect to
Among the 214 children with HI, 101 (47.2%) children had other minor or major disabilities (Table 4). Seventeen (7.9%) children had minor anomalies, which obviously did not affect their development or learning skills, while 84 children (39.3%) had one or more additional disabilities with potential adverse effect on their development or learning. Intellectual disability could be verified in 36 (16.8%) children. Fifty-three children with additional disabilities had more than one disability. The frequency of additional disabilities was similar in children with mild HI and those with moderate or severe HI (p = 0.78) (Table 5). In addition, 23 (65.7%) out of the 35 children with acquired HI had additional disabilities, whereas among the 179 children with genetic or unknown etiology the frequency of additional disabilities (n = 78; 43.6%) was significantly lower (p = 0.035).
Table 2 Configurations in 375 audiograms obtained from 198 children. Configuration Flat HFGS HFSS LFA MFU Unclassified
Totala
Right ear
Left ear
Total
N (%)
N (%)
N (%)
38 46 33 17 8 45
39 44 33 15 8 49
77 90 66 32 16 94
(19.1) (23.1) (16.6) (8.5) (4.0) (22.6)
187 (100.0)
(20.7) (22.1) (16.6) (7.5) (4.0) (24.6)
188 (100.0)
(20.5) (24.0) (17.6) (8.5) (4.2) (25.0)
375 (100.0)
a Configuration could not be determined for 21 audiograms because of insufficient data. See footnote in Table 1. HFGS, high frequency gently sloping, HFSS, high frequency steeply sloping, LFA, low frequency ascending, MFU, middle frequency U-shaped.
N Genetic Autosomal recessive Autosomal dominant Maternal Nonspecified
Acquired Perinatal Postnatal
Unknown
GJB2 mutation Positive family history pattern Positive family history pattern m.1555A > G mutation Positive family history
3 perinatal risk factors, negative family history Meningitis Chemotherapy
%
57 19 11 13 2 12
50.0
11 8
9.6
1 2
Negative family history, 2 perinatal risk factors
Total
46
40.4
114
100.0
Table 4 The frequency and type of additional disabilities in 101 Finnish children with hearing impairment. The percentages are shown from total group of 214 children.
Intellectual disability Developmental delay/neurocognitive conditions* Motor impairment Visual deficits Craniofacial anomalies Other anomalies
N
%
36 21
16.8 9.8
23 22 24 16
10.8 10.3 11.2 7.5
* Neurocognitive conditions include epilepsy, attention deficit/hyperactivity disorder and autism spectrum disorders.
S. Ha¨kli et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 1852–1856
1855
Table 5 The frequency of additional disabilities in 214 children stratified with respect to degree of HI. Degree of HI
Additional disabilities affecting development/learning
Mild Moderate Severe/profound Not known
34 24 10 16
Total
84 (39.3%)
(35.8%) (33.3%) (32.3%) (100.0%)
4. Discussion We found that the prevalence of childhood HI has remained unchanged in northern Finland throughout three decades. The age at ascertainment was clearly higher than that put forward in consensus guidelines, where it is suggested that moderate or more severe HIs should be ascertained before the age of 6 months [16]. However, it should be noted that newborn hearing screening was implemented only in 2002 at OUH. Almost one third of the children had asymmetric HI and the distribution of audiogram configurations was more variable than that reported in adults [17,18]. Unknown etiology is still common. Additional disabilities were common and they were present in children with any degree of HI. 4.1. Hearing impairment The prevalence of any childhood HI in our study was slightly over 2/1000 and that of moderate or more severe HI was slightly over 1/1000, these figures being in line with those in previous studies in Finland [2,3]. Although the prevalence of congenital and early childhood HI is low, the consequences are widespread, because childhood HI influences speech and language development [19,20]. Early detection and rehabilitation of HI improve outcomes of the hearing impaired children [16]. We found that the mean age at ascertainment of moderate or more severe HI was 3.0 years and that of severe or profound HI was 1.5 years. Unfortunately, results from the three consecutive 10-year periods did not indicate any decrease in the ascertainment age. It has been shown [21] that the only effective means to find congenital HIs is a universal newborn hearing screening, which has been implemented in OUH in 2002. The decrease in the ascertainment age may be evident only in the next 10-year cohort. We found that more than 40% of the audiograms belonged to the high-frequency sloping configuration. Indeed, children have substantially different audiogram configurations compared with those of adults with HI, whose audiograms are more often (50–90%) high-frequency sloping [17,18]. We also found that approximately one third of children had asymmetric HI. Asymmetric HIs have been reported to be more common and the degree of asymmetry more extensive among children than the adults [17]. These special features need to be taken into consideration when fitting hearing aids for children. 4.2. Etiology The causes of childhood HIs are more diverse than those among adults. We found that 47% of childhood HI were genetic, which is a slightly higher than the proportion of 30% reported in recent reviews [4,5]. Advances in molecular genetics have revealed that the molecular etiology of childhood HI is diverse, and with the exception of GJB2, no major HI genes have been identified. Hence, the proportion of unknown etiology of HI has remained high, but the increase in the clinical use of genetic testing will obviously decrease this proportion. It is plausible that recessive mutations are responsible for many of the cases now defined as unknown in
Minor anomalies 9 7 1 0
(9.5%) (9.7%) (3.2%) (0.0%)
17 (7.9%)
No additional disabilities 52 41 20 0
(54.7%) (56.9%) (64.5%) (0.0%)
113 (52.8%)
Total 95 72 31 16
(44.4%) (33.6%) (14.5%) (7.5%)
214 (100.0%)
etiology. In our study, GJB2 gene sequencing was carried out in altogether 123 children, including all children with nonsyndromic HI. A pathogenic mutation in GJB2 was found in 19 of them giving a frequency, which is similar to that reported a decade ago in the same area [22]. The etiology of HI was defined to be acquired in 16% out of the 214 children in our study, which is in line with other reports [4]. Furthermore, we found 13% children with at least three perinatal risk factors and negative family history. In a review of recent studies, asphyxia and prematurity were found to be more common etiologies of childhood HI than previously [5]. The high number of perinatal risk factors among hearing impaired children is probably a manifestation of increased survival of premature and very premature newborns. In our study, the proportion of intrauterine infections was a less frequent cause of HI, as we found only two children with cytomegalovirus (CMV) infection. However, the prevalence of CMV infections may be underestimated because of non-diagnosed cases. In recent studies, CMV infection has been found to be the second most frequent cause of early childhood HI in developed countries after GJB2 mutations [23,24]. The birth prevalence of congenital CMV infection is estimated to be 0.64% [25] and 6–21% of newborns with asymptomatic CMV infection have been estimated to develop HI [26–28]. Application of these frequencies to our cohort would suggest that 16-60 children with HI caused by CMV infection should have been ascertained. So, at least part of unknown cases may be caused by CMV infection. 4.3. Additional disabilities The risk factors for acquired HI, such as prenatal infections and perinatal problems, are also risk factors for developmental disabilities [29–31]. Thus, it is conceivable that in our study, children with acquired HI had more often additional disabilities than those children with genetic or unknown etiology of HI. Our findings are in line with those recently reported [13]. We found that almost 40% of children had at least one or more additional disabilities potentially affecting development or learning. The proportion of hearing impaired children with disabilities in this study was similar to that in earlier published reports [7–9,32]. Interestingly, we found that the frequency of additional disabilities was similar regardless of the degree of HI. The similar frequency of additional disabilities among different degrees of childhood HI have been found also in some earlier studies [7,33]. However, previous studies on children with HI and with additional disabilities have focused mainly on children with severe or profound HI and only a few have dealt with children with mild HI and additional disabilities [7,13]. In addition, it has been reported that children with moderate or profound HI are more likely to be evaluated by developmental pediatrician than children with mild HI [33]. Because additional disabilities seem to be as common among children with mild HI as among those with at least moderate HI, it is important to keep in mind a comprehensive examination and rehabilitation.
1856
S. Ha¨kli et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 1852–1856
5. Conclusions In summary, we found that the prevalence of childhood HI has remained unchanged in northern Finland through three decades. Genetic causes were the most frequent etiology of childhood HI, but unknown causes were also common despite the advances in medicine. Among acquired causes of HI, perinatal risk factors were found more often than previously. Additional disabilities were more common in children with acquired HI. Altogether, almost 40% of children had one or more additional disabilities influencing adversely their development or learning independent of the degree of HI. Thus, it is essential to take them into consideration when planning comprehensive rehabilitation. Acknowledgements The authors are grateful to the families who participated in this study. This work was supported in part by grants from the Academy of Finland (project number 127764), the Ear Research Foundation, the Arvo and Lea Ylppo¨ Foundation, The Alma and K. A. Snellman Foundation and the National Graduate School of Clinical Investigation. Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ijporl.2014.08.007. References [1] C.C. Morton, W.E. Nance, Newborn hearing screening—a silent revolution, N. Engl. J. Med. 354 (2006) 2151–2164. [2] E.M. Maki-Torkko, P.K. Lindholm, M.R. Vayrynen, J.T. Leisti, M.J. Sorri, Epidemiology of moderate to profound childhood hearing impairments in northern Finland. Any changes in ten years? Scand. Audiol. 27 (1998) 95–103. [3] A. Dietz, T. Lopponen, H. Valtonen, A. Hyvarinen, H. Lopponen, Prevalence and etiology of congenital or early acquired hearing impairment in Eastern Finland, Int. J. Pediatr. Otorhinolaryngol. 73 (2009) 1353–1357. [4] A.M. Korver, R.J. Admiraal, S.G. Kant, F.W. Dekker, C.C. Wever, H.P. Kunst, et al., Causes of permanent childhood hearing impairment, Laryngoscope 121 (2011) 409–416. [5] S. Morzaria, B.D. Westerberg, F.K. Kozak, Systematic review of the etiology of bilateral sensorineural hearing loss in children, Int. J. Pediatr. Otorhinolaryngol. 68 (2004) 1193–1198. [6] L. Holden-Pitt, J. Albertorio, Thirty years of the Annual Survey of Deaf and Hard-ofHearing Children & Youth: a glance over the decades, Am. Ann. Deaf 143 (1998) 72–76. [7] K. Van Naarden, P. Decoufle, K. Caldwell, Prevalence and characteristics of children with serious hearing impairment in metropolitan Atlanta, 1991–1993, Pediatrics 103 (1999) 570–575. [8] H.M. Fortnum, D.H. Marshall, A.Q. Summerfield, Epidemiology of the UK population of hearing-impaired children, including characteristics of those with and without cochlear implants—audiology, aetiology, comorbidity and affluence, Int. J. Audiol. 41 (2002) 170–179. [9] C.S. Birman, E.J. Elliott, W.P. Gibson, Pediatric cochlear implants: additional disabilities prevalence, risk factors, and effect on language outcomes, Otol. Neurotol. 33 (2012) 1347–1352.
[10] K. Huttunen, Development of speech intelligibility and narrative abilities and their interrelationship three and five years after paediatric cochlear implantation, Int. J. Audiol. 47 (Suppl. 2) (2008) S38–S46. [11] I. Cruz, I. Vicaria, N.Y. Wang, J. Niparko, A.L. Quittner, CDaCI Investigative Team, Language and behavioral outcomes in children with developmental disabilities using cochlear implants, Otol. Neurotol. 33 (2012) 751–760. [12] T.Y. Ching, H. Dillon, V. Marnane, S. Hou, J. Day, M. Seeto, et al., Outcomes of earlyand late-identified children at 3 years of age: findings from a prospective population-based study, Ear Hear. 34 (2013) 535–552. [13] A.M. Chilosi, A. Comparini, M.F. Scusa, S. Berrettini, F. Forli, R. Battini, et al., Neurodevelopmental disorders in children with severe to profound sensorineural hearing loss: a clinical study, Dev. Med. Child Neurol. 52 (2010) 856–862. [14] D. Stephens, A. Martini, Study group on Terminology, Definitions and Hearing Assessment, European Work Group on Genetics of Hearing Impairment. European Commission Directorate, Biomedical and Health Research Program (HEAR) Info Letter, 2, European Commission Directorate, 1996. [15] M. Sorri, A. Muhli, E. Maki-Torkko, K. Huttunen, Unambiguous systems for describing audiogram configurations, J. Audiol. Med. 9 (2000) 160–169. [16] American Academy of Pediatrics, Joint Committee on Infant Hearing, Year 2007 position statement: Principles and guidelines for early hearing detection and intervention programs, Pediatrics 120 (2007) 898–921. [17] A.L. Pittman, P.G. Stelmachowicz, Hearing loss in children and adults: audiometric configuration, asymmetry, and progression, Ear Hear. 24 (2003) 198–205. [18] S. Hannula, R. Bloigu, K. Majamaa, M. Sorri, E. Maki-Torkko, Audiogram configurations among older adults: prevalence and relation to self-reported hearing problems, Int. J. Audiol. 50 (2011) 793–801. [19] C.R. Kennedy, D.C. McCann, M.J. Campbell, C.M. Law, M. Mullee, S. Petrou, et al., Language ability after early detection of permanent childhood hearing impairment, N. Engl. J. Med. 354 (2006) 2131–2141. [20] H. Pimperton, C.R. Kennedy, The impact of early identification of permanent childhood hearing impairment on speech and language outcomes, Arch. Dis. Child 97 (2012) 648–653. [21] A.L. Mehl, V. Thomson, The Colorado newborn hearing screening project, 1992– 1999: on the threshold of effective population-based universal newborn hearing screening, Pediatrics 109 (2002) E7. [22] T. Lopponen, M.L. Vaisanen, M. Luotonen, M. Allinen, J. Uusimaa, P. Lindholm, et al., Connexin 26 mutations and nonsyndromic hearing impairment in northern Finland, Laryngoscope 113 (2003) 1758–1763. [23] E. Karltorp, S. Hellstrom, I. Lewensohn-Fuchs, E. Carlsson-Hansen, P.I. Carlsson, M.L. Engman, Congenital cytomegalovirus infection—a common cause of hearing loss of unknown aetiology, Acta Paediatr. 101 (2012) e357–e362. [24] V. Avettand-Fenoel, S. Marlin, C. Vauloup-Fellous, N. Loundon, M. Francois, V. Couloigner, et al., Congenital cytomegalovirus is the second most frequent cause of bilateral hearing loss in young French children, J. Pediatr. 162 (2013) 593–599. [25] A. Kenneson, M.J. Cannon, Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection, Rev. Med. Virol. 17 (2007) 253–276. [26] K.B. Fowler, S.B. Boppana, Congenital cytomegalovirus (CMV) infection and hearing deficit, J. Clin. Virol. 35 (2006) 226–231. [27] S.C. Dollard, S.D. Grosse, D.S. Ross, New estimates of the prevalence of neurological and sensory sequelae and mortality associated with congenital cytomegalovirus infection, Rev. Med. Virol. 17 (2007) 355–363. [28] I. Foulon, A. Naessens, W. Foulon, A. Casteels, F. Gordts, A 10-year prospective study of sensorineural hearing loss in children with congenital cytomegalovirus infection, J. Pediatr. 153 (2008) 84–88. [29] D.J. Lee, L. Lustig, M. Sampson, J. Chinnici, J.K. Niparko, Effects of cytomegalovirus (CMV) related deafness on pediatric cochlear implant outcomes, Otolaryngol. Head Neck Surg. 133 (2005) 900–905. [30] S. Johnson, J. Fawke, E. Hennessy, V. Rowell, S. Thomas, D. Wolke, et al., Neurodevelopmental disability through 11 years of age in children born before 26 weeks of gestation, Pediatrics 124 (2009) e249–e257. [31] C.M. Robertson, T.M. Howarth, D.L. Bork, I.A. Dinu, Permanent bilateral sensory and neural hearing loss of children after neonatal intensive care because of extreme prematurity: a thirty-year study, Pediatrics 123 (2009) e797–e807. [32] H. Fortnum, A. Davis, Epidemiology of permanent childhood hearing impairment in Trent Region, 1985–1993, Br. J. Audiol. 31 (1997) 409–446. [33] S. Wiley, E. Arjmand, Jareenmeinzen-Derr, M. Dixon, Findings from multidisciplinary evaluation of children with permanent hearing loss, Int. J. Pediatr. Otorhinolaryngol. 75 (2011) 1040–1044.
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Childhood hearing impairment in northern Finland, etiology and additional disabilities Sanna Ha¨kli a,b,c,*, Mirja Luotonen a, Risto Bloigu d, Kari Majamaa b,e,f, Martti Sorri a,c a
Department of Otorhinolaryngology, Oulu University Hospital, Oulu, Finland Medical Research Center, Oulu University Hospital, Oulu, Finland c Institute of Clinical Medicine, Department of Otorhinolaryngology, University of Oulu, Oulu, Finland d Medical Informatics and Statistics Research Group, University of Oulu, Oulu, Finland e Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland f Department of Neurology, Oulu University Hospital, Oulu, Finland b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 May 2014 Received in revised form 6 August 2014 Accepted 9 August 2014 Available online 17 August 2014
Objectives: The purpose of this study was to determine the prevalence and etiology of hearing impairment (HI) in Finnish children and to evaluate the frequency and type of additional disabilities among children with HI. Methods: Subjects consisted of 214 children with mild to profound HI ascertained until the age of 10 years. They belonged to the birth cohort spanning the years 1993–2002 in northern Finland. The clinical data were collected from the electronic patient records of the Oulu University Hospital. Age at ascertainment, degree and type of HI and audiogram configuration were determined. Risk factors and etiology of HI and co-existing disabilities were recorded. Results: The prevalence of childhood HI was 2.3/1000 live births (95% CI; 2.0, 2.7). The etiology of HI was genetic in 47.2%, acquired in 16.4% and unknown in 36.4% children. Among the 214 children with HI, 101 (47.2%) had other minor or major disabilities. The frequency of additional disabilities did not differ between children with mild HI and those with moderate or severe HI (p = 0.78). Additional disabilities were more common (65.7%) in children with acquired HI than in children with genetic or unknown HI (43.6%) (p = 0.035). Conclusion: The prevalence of childhood HI has remained unchanged in northern Finland as compared to previous studies. Genetic causes were the most common (47%) etiology of childhood HI. Among acquired causes of HI, perinatal risk factors were more common than previously. The frequency of additional disabilities was similar among children with different degrees of HI. Because almost 40% of children had one or more additional disabilities affecting development or learning, it is important to take them into consideration in rehabilitation. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Additional disorder Configuration Comorbidity Hearing loss Prevalence
1. Introduction The prevalence of childhood hearing impairment (HI) is about 1 to 2 per 1000 live births and it increases with age [1]. The prevalence varies between countries and between ethnic groups.
Abbreviations: BEHL, better ear hearing level; CI, confidence interval; CMV, cytomegalovirus; GJB2, gap junction beta 2 protein; HI, hearing impairment; OUH, Oulu University Hospital; PTA, pure tone average. * Corresponding author at: Department of Clinical Medicine, Otorhinolaryngology, University of Oulu, PO Box 5000, FIN-90014 Oulu, Finland. Tel.: +358 83153448; fax: +358 83153459. E-mail address: sanna.hakli@oulu.fi (S. Ha¨kli). http://dx.doi.org/10.1016/j.ijporl.2014.08.007 0165-5876/ß 2014 Elsevier Ireland Ltd. All rights reserved.
The epidemiology and etiology of moderate to profound childhood HIs has been studied in northern Finland in two birth cohorts spanning the years 1973–1982 and 1983–1992. The prevalence of at least moderate HI was 1.2/1000 live births [2] and that of at least mild childhood HI was 2.1/1000 live births in eastern Finland [3]. In general, it is assumed that the cause of childhood HI is genetic in 30–50% and acquired in 14–30% [1,4]. During the past decades, etiologies of childhood HIs have changed. Universal immunization programs and improved antibiotic treatments for meningitis have decreased post infectious HIs and improvements in neonatal intensive care have increased the survival of premature newborns. Therefore, in more recent studies, the proportion of asphyxia and prematurity are more common etiologies of HI. Advances in
S. Ha¨kli et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 1852–1856
genetic diagnostics have enabled the discovery of new causes of HI, but the proportion of unknown etiology has remained high, being about 40% [4,5]. The reported proportions of acquired and genetic etiologies of childhood HI vary greatly between studies mainly because of methodological reasons. Children with HI may have additional disabling conditions as a part of a syndrome or as a comorbid condition. About 30–40% of children with HI have been reported to have additional health or developmental problems that may affect their development and learning [6–9]. The presence or absence of additional disabilities is a significant predictor of outcome in children with HI [10–12]. Most studies on additional disabilities in hearing impaired children have focused on children with a cochlear implant or children with severe or profound HI [9,13], whereas little is known about additional disabilities in children with mild or moderate HI. The aim of the present study was to investigate the prevalence and etiology of childhood HI in northern Finland in a 10-year birth cohort spanning the years 1993–2002. Our clinical experience is that possible additional disabilities among hearing impaired children are often ignored although they may be even more significant than HI for the development of the child. Therefore, we evaluated frequency and type of additional disorders among children with HI and investigated the relation between additional disabilities and the degree of HI. 2. Subjects and methods 2.1. Subjects The subjects of this study were 214 children with mild to profound HI ascertained until the age of 10 years belonging to the birth cohort from January 1st 1993 to December 31st 2002. The 10-year birth cohort included 91,022 children. The ascertainment area included the entire northern Finland including the provinces of Northern Ostrobothnia and Lapland. Oulu University Hospital (OUH) is the tertiary care hospital that serves this population and provides the most advanced medical treatment, including diagnostics of early childhood HIs and rehabilitation of children. 2.2. Definition of hearing impairment The data from 214 children were collected retrospectively from the electronic patient records of the OUH. The age at ascertainment, the risk factors and the etiology of HI were recorded. Information on clinical examinations, such as the first and the most recent audiogram as well as co-existing disabilities were recorded. The degree and type of HI and audiogram configuration were determined on the basis of the most recent audiogram. According to definitions recommended by the EU expert group, the degree of HI was based on average thresholds calculated over the frequencies 0.5, 1, 2 and 4 kHz in the better hearing ear. The degree of HI according to better ear hearing level (BEHL) was classified as mild (21–39 dB), moderate (40–69 dB), severe (70–94 dB) and profound (95 dB) [14]. If any hearing could not be measured at a given frequency, the value of 130 dB was used in the calculations as recommended by the British Society of Audiology (1988). The first reliable audiological examination at the Department of Audio-Phoniatrics of the OUH was considered as the time of ascertainment of HI. In 16 children no reliable audiograms were obtained and hearing level was evaluated on the basis of sound field audiometry and auditory brainstem responses. The type or symmetry of HI could not be determined in some children, because exact thresholds could not be measured. Audiogram configurations were calculated based on air conduction thresholds as recommended by the EU expert group [14] with the exception of the less stringent definition for the flat
1853
configuration i.e. G mutation in mitochondrial DNA, while two children had received cisplatin treatment for a malignant disease. The etiology of HI could not be determined in the remaining 11 children. Configurations could be determined for 375 audiograms (Table 2). The most common configuration was high-frequency gently sloping, which accounted for 24% of the audiograms. Ninetyfour audiograms (25%) remained unclassified, but a clinical evaluation suggested that 45 of them were high-frequency gently or steeply sloping configuration, 21 were flat configuration, five were lowfrequency ascending and 23 were mid-frequency U-shaped.
p.([M34T];[V37I]) and one with respect to p.([M34T];[R143W]). In total, pathogenic GJB2 mutations were found in 19 children accounting for 16.7% of nonsyndromic HIs.
3.2. Etiology of HIs
3.3. Additional disabilities
The etiology of HI among the 214 hearing impaired children was defined to be genetic in 101 (47.2%) children, acquired in 35 (16.4%) and unknown in 78 (36.4%). The most common cause of nonsyndromic HI was a mutation in GJB2 (Table 3), while chromosomal aberration was the most common cause in syndromic HI (Supplementary Table 1). Sequencing of GJB2 was carried out in 123 (57.5%) children, including all children with nonsyndromic HI. Homozygous c.35delG was the most prevalent mutation in the GJB2 gene being found in 11 children. In addition, we found the homozygous p.M34T mutation in four children, while three children were compound heterozygotes with respect to
Among the 214 children with HI, 101 (47.2%) children had other minor or major disabilities (Table 4). Seventeen (7.9%) children had minor anomalies, which obviously did not affect their development or learning skills, while 84 children (39.3%) had one or more additional disabilities with potential adverse effect on their development or learning. Intellectual disability could be verified in 36 (16.8%) children. Fifty-three children with additional disabilities had more than one disability. The frequency of additional disabilities was similar in children with mild HI and those with moderate or severe HI (p = 0.78) (Table 5). In addition, 23 (65.7%) out of the 35 children with acquired HI had additional disabilities, whereas among the 179 children with genetic or unknown etiology the frequency of additional disabilities (n = 78; 43.6%) was significantly lower (p = 0.035).
Table 2 Configurations in 375 audiograms obtained from 198 children. Configuration Flat HFGS HFSS LFA MFU Unclassified
Totala
Right ear
Left ear
Total
N (%)
N (%)
N (%)
38 46 33 17 8 45
39 44 33 15 8 49
77 90 66 32 16 94
(19.1) (23.1) (16.6) (8.5) (4.0) (22.6)
187 (100.0)
(20.7) (22.1) (16.6) (7.5) (4.0) (24.6)
188 (100.0)
(20.5) (24.0) (17.6) (8.5) (4.2) (25.0)
375 (100.0)
a Configuration could not be determined for 21 audiograms because of insufficient data. See footnote in Table 1. HFGS, high frequency gently sloping, HFSS, high frequency steeply sloping, LFA, low frequency ascending, MFU, middle frequency U-shaped.
N Genetic Autosomal recessive Autosomal dominant Maternal Nonspecified
Acquired Perinatal Postnatal
Unknown
GJB2 mutation Positive family history pattern Positive family history pattern m.1555A > G mutation Positive family history
3 perinatal risk factors, negative family history Meningitis Chemotherapy
%
57 19 11 13 2 12
50.0
11 8
9.6
1 2
Negative family history, 2 perinatal risk factors
Total
46
40.4
114
100.0
Table 4 The frequency and type of additional disabilities in 101 Finnish children with hearing impairment. The percentages are shown from total group of 214 children.
Intellectual disability Developmental delay/neurocognitive conditions* Motor impairment Visual deficits Craniofacial anomalies Other anomalies
N
%
36 21
16.8 9.8
23 22 24 16
10.8 10.3 11.2 7.5
* Neurocognitive conditions include epilepsy, attention deficit/hyperactivity disorder and autism spectrum disorders.
S. Ha¨kli et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 1852–1856
1855
Table 5 The frequency of additional disabilities in 214 children stratified with respect to degree of HI. Degree of HI
Additional disabilities affecting development/learning
Mild Moderate Severe/profound Not known
34 24 10 16
Total
84 (39.3%)
(35.8%) (33.3%) (32.3%) (100.0%)
4. Discussion We found that the prevalence of childhood HI has remained unchanged in northern Finland throughout three decades. The age at ascertainment was clearly higher than that put forward in consensus guidelines, where it is suggested that moderate or more severe HIs should be ascertained before the age of 6 months [16]. However, it should be noted that newborn hearing screening was implemented only in 2002 at OUH. Almost one third of the children had asymmetric HI and the distribution of audiogram configurations was more variable than that reported in adults [17,18]. Unknown etiology is still common. Additional disabilities were common and they were present in children with any degree of HI. 4.1. Hearing impairment The prevalence of any childhood HI in our study was slightly over 2/1000 and that of moderate or more severe HI was slightly over 1/1000, these figures being in line with those in previous studies in Finland [2,3]. Although the prevalence of congenital and early childhood HI is low, the consequences are widespread, because childhood HI influences speech and language development [19,20]. Early detection and rehabilitation of HI improve outcomes of the hearing impaired children [16]. We found that the mean age at ascertainment of moderate or more severe HI was 3.0 years and that of severe or profound HI was 1.5 years. Unfortunately, results from the three consecutive 10-year periods did not indicate any decrease in the ascertainment age. It has been shown [21] that the only effective means to find congenital HIs is a universal newborn hearing screening, which has been implemented in OUH in 2002. The decrease in the ascertainment age may be evident only in the next 10-year cohort. We found that more than 40% of the audiograms belonged to the high-frequency sloping configuration. Indeed, children have substantially different audiogram configurations compared with those of adults with HI, whose audiograms are more often (50–90%) high-frequency sloping [17,18]. We also found that approximately one third of children had asymmetric HI. Asymmetric HIs have been reported to be more common and the degree of asymmetry more extensive among children than the adults [17]. These special features need to be taken into consideration when fitting hearing aids for children. 4.2. Etiology The causes of childhood HIs are more diverse than those among adults. We found that 47% of childhood HI were genetic, which is a slightly higher than the proportion of 30% reported in recent reviews [4,5]. Advances in molecular genetics have revealed that the molecular etiology of childhood HI is diverse, and with the exception of GJB2, no major HI genes have been identified. Hence, the proportion of unknown etiology of HI has remained high, but the increase in the clinical use of genetic testing will obviously decrease this proportion. It is plausible that recessive mutations are responsible for many of the cases now defined as unknown in
Minor anomalies 9 7 1 0
(9.5%) (9.7%) (3.2%) (0.0%)
17 (7.9%)
No additional disabilities 52 41 20 0
(54.7%) (56.9%) (64.5%) (0.0%)
113 (52.8%)
Total 95 72 31 16
(44.4%) (33.6%) (14.5%) (7.5%)
214 (100.0%)
etiology. In our study, GJB2 gene sequencing was carried out in altogether 123 children, including all children with nonsyndromic HI. A pathogenic mutation in GJB2 was found in 19 of them giving a frequency, which is similar to that reported a decade ago in the same area [22]. The etiology of HI was defined to be acquired in 16% out of the 214 children in our study, which is in line with other reports [4]. Furthermore, we found 13% children with at least three perinatal risk factors and negative family history. In a review of recent studies, asphyxia and prematurity were found to be more common etiologies of childhood HI than previously [5]. The high number of perinatal risk factors among hearing impaired children is probably a manifestation of increased survival of premature and very premature newborns. In our study, the proportion of intrauterine infections was a less frequent cause of HI, as we found only two children with cytomegalovirus (CMV) infection. However, the prevalence of CMV infections may be underestimated because of non-diagnosed cases. In recent studies, CMV infection has been found to be the second most frequent cause of early childhood HI in developed countries after GJB2 mutations [23,24]. The birth prevalence of congenital CMV infection is estimated to be 0.64% [25] and 6–21% of newborns with asymptomatic CMV infection have been estimated to develop HI [26–28]. Application of these frequencies to our cohort would suggest that 16-60 children with HI caused by CMV infection should have been ascertained. So, at least part of unknown cases may be caused by CMV infection. 4.3. Additional disabilities The risk factors for acquired HI, such as prenatal infections and perinatal problems, are also risk factors for developmental disabilities [29–31]. Thus, it is conceivable that in our study, children with acquired HI had more often additional disabilities than those children with genetic or unknown etiology of HI. Our findings are in line with those recently reported [13]. We found that almost 40% of children had at least one or more additional disabilities potentially affecting development or learning. The proportion of hearing impaired children with disabilities in this study was similar to that in earlier published reports [7–9,32]. Interestingly, we found that the frequency of additional disabilities was similar regardless of the degree of HI. The similar frequency of additional disabilities among different degrees of childhood HI have been found also in some earlier studies [7,33]. However, previous studies on children with HI and with additional disabilities have focused mainly on children with severe or profound HI and only a few have dealt with children with mild HI and additional disabilities [7,13]. In addition, it has been reported that children with moderate or profound HI are more likely to be evaluated by developmental pediatrician than children with mild HI [33]. Because additional disabilities seem to be as common among children with mild HI as among those with at least moderate HI, it is important to keep in mind a comprehensive examination and rehabilitation.
1856
S. Ha¨kli et al. / International Journal of Pediatric Otorhinolaryngology 78 (2014) 1852–1856
5. Conclusions In summary, we found that the prevalence of childhood HI has remained unchanged in northern Finland through three decades. Genetic causes were the most frequent etiology of childhood HI, but unknown causes were also common despite the advances in medicine. Among acquired causes of HI, perinatal risk factors were found more often than previously. Additional disabilities were more common in children with acquired HI. Altogether, almost 40% of children had one or more additional disabilities influencing adversely their development or learning independent of the degree of HI. Thus, it is essential to take them into consideration when planning comprehensive rehabilitation. Acknowledgements The authors are grateful to the families who participated in this study. This work was supported in part by grants from the Academy of Finland (project number 127764), the Ear Research Foundation, the Arvo and Lea Ylppo¨ Foundation, The Alma and K. A. Snellman Foundation and the National Graduate School of Clinical Investigation. Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ijporl.2014.08.007. References [1] C.C. Morton, W.E. Nance, Newborn hearing screening—a silent revolution, N. Engl. J. Med. 354 (2006) 2151–2164. [2] E.M. Maki-Torkko, P.K. Lindholm, M.R. Vayrynen, J.T. Leisti, M.J. Sorri, Epidemiology of moderate to profound childhood hearing impairments in northern Finland. Any changes in ten years? Scand. Audiol. 27 (1998) 95–103. [3] A. Dietz, T. Lopponen, H. Valtonen, A. Hyvarinen, H. Lopponen, Prevalence and etiology of congenital or early acquired hearing impairment in Eastern Finland, Int. J. Pediatr. Otorhinolaryngol. 73 (2009) 1353–1357. [4] A.M. Korver, R.J. Admiraal, S.G. Kant, F.W. Dekker, C.C. Wever, H.P. Kunst, et al., Causes of permanent childhood hearing impairment, Laryngoscope 121 (2011) 409–416. [5] S. Morzaria, B.D. Westerberg, F.K. Kozak, Systematic review of the etiology of bilateral sensorineural hearing loss in children, Int. J. Pediatr. Otorhinolaryngol. 68 (2004) 1193–1198. [6] L. Holden-Pitt, J. Albertorio, Thirty years of the Annual Survey of Deaf and Hard-ofHearing Children & Youth: a glance over the decades, Am. Ann. Deaf 143 (1998) 72–76. [7] K. Van Naarden, P. Decoufle, K. Caldwell, Prevalence and characteristics of children with serious hearing impairment in metropolitan Atlanta, 1991–1993, Pediatrics 103 (1999) 570–575. [8] H.M. Fortnum, D.H. Marshall, A.Q. Summerfield, Epidemiology of the UK population of hearing-impaired children, including characteristics of those with and without cochlear implants—audiology, aetiology, comorbidity and affluence, Int. J. Audiol. 41 (2002) 170–179. [9] C.S. Birman, E.J. Elliott, W.P. Gibson, Pediatric cochlear implants: additional disabilities prevalence, risk factors, and effect on language outcomes, Otol. Neurotol. 33 (2012) 1347–1352.
[10] K. Huttunen, Development of speech intelligibility and narrative abilities and their interrelationship three and five years after paediatric cochlear implantation, Int. J. Audiol. 47 (Suppl. 2) (2008) S38–S46. [11] I. Cruz, I. Vicaria, N.Y. Wang, J. Niparko, A.L. Quittner, CDaCI Investigative Team, Language and behavioral outcomes in children with developmental disabilities using cochlear implants, Otol. Neurotol. 33 (2012) 751–760. [12] T.Y. Ching, H. Dillon, V. Marnane, S. Hou, J. Day, M. Seeto, et al., Outcomes of earlyand late-identified children at 3 years of age: findings from a prospective population-based study, Ear Hear. 34 (2013) 535–552. [13] A.M. Chilosi, A. Comparini, M.F. Scusa, S. Berrettini, F. Forli, R. Battini, et al., Neurodevelopmental disorders in children with severe to profound sensorineural hearing loss: a clinical study, Dev. Med. Child Neurol. 52 (2010) 856–862. [14] D. Stephens, A. Martini, Study group on Terminology, Definitions and Hearing Assessment, European Work Group on Genetics of Hearing Impairment. European Commission Directorate, Biomedical and Health Research Program (HEAR) Info Letter, 2, European Commission Directorate, 1996. [15] M. Sorri, A. Muhli, E. Maki-Torkko, K. Huttunen, Unambiguous systems for describing audiogram configurations, J. Audiol. Med. 9 (2000) 160–169. [16] American Academy of Pediatrics, Joint Committee on Infant Hearing, Year 2007 position statement: Principles and guidelines for early hearing detection and intervention programs, Pediatrics 120 (2007) 898–921. [17] A.L. Pittman, P.G. Stelmachowicz, Hearing loss in children and adults: audiometric configuration, asymmetry, and progression, Ear Hear. 24 (2003) 198–205. [18] S. Hannula, R. Bloigu, K. Majamaa, M. Sorri, E. Maki-Torkko, Audiogram configurations among older adults: prevalence and relation to self-reported hearing problems, Int. J. Audiol. 50 (2011) 793–801. [19] C.R. Kennedy, D.C. McCann, M.J. Campbell, C.M. Law, M. Mullee, S. Petrou, et al., Language ability after early detection of permanent childhood hearing impairment, N. Engl. J. Med. 354 (2006) 2131–2141. [20] H. Pimperton, C.R. Kennedy, The impact of early identification of permanent childhood hearing impairment on speech and language outcomes, Arch. Dis. Child 97 (2012) 648–653. [21] A.L. Mehl, V. Thomson, The Colorado newborn hearing screening project, 1992– 1999: on the threshold of effective population-based universal newborn hearing screening, Pediatrics 109 (2002) E7. [22] T. Lopponen, M.L. Vaisanen, M. Luotonen, M. Allinen, J. Uusimaa, P. Lindholm, et al., Connexin 26 mutations and nonsyndromic hearing impairment in northern Finland, Laryngoscope 113 (2003) 1758–1763. [23] E. Karltorp, S. Hellstrom, I. Lewensohn-Fuchs, E. Carlsson-Hansen, P.I. Carlsson, M.L. Engman, Congenital cytomegalovirus infection—a common cause of hearing loss of unknown aetiology, Acta Paediatr. 101 (2012) e357–e362. [24] V. Avettand-Fenoel, S. Marlin, C. Vauloup-Fellous, N. Loundon, M. Francois, V. Couloigner, et al., Congenital cytomegalovirus is the second most frequent cause of bilateral hearing loss in young French children, J. Pediatr. 162 (2013) 593–599. [25] A. Kenneson, M.J. Cannon, Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection, Rev. Med. Virol. 17 (2007) 253–276. [26] K.B. Fowler, S.B. Boppana, Congenital cytomegalovirus (CMV) infection and hearing deficit, J. Clin. Virol. 35 (2006) 226–231. [27] S.C. Dollard, S.D. Grosse, D.S. Ross, New estimates of the prevalence of neurological and sensory sequelae and mortality associated with congenital cytomegalovirus infection, Rev. Med. Virol. 17 (2007) 355–363. [28] I. Foulon, A. Naessens, W. Foulon, A. Casteels, F. Gordts, A 10-year prospective study of sensorineural hearing loss in children with congenital cytomegalovirus infection, J. Pediatr. 153 (2008) 84–88. [29] D.J. Lee, L. Lustig, M. Sampson, J. Chinnici, J.K. Niparko, Effects of cytomegalovirus (CMV) related deafness on pediatric cochlear implant outcomes, Otolaryngol. Head Neck Surg. 133 (2005) 900–905. [30] S. Johnson, J. Fawke, E. Hennessy, V. Rowell, S. Thomas, D. Wolke, et al., Neurodevelopmental disability through 11 years of age in children born before 26 weeks of gestation, Pediatrics 124 (2009) e249–e257. [31] C.M. Robertson, T.M. Howarth, D.L. Bork, I.A. Dinu, Permanent bilateral sensory and neural hearing loss of children after neonatal intensive care because of extreme prematurity: a thirty-year study, Pediatrics 123 (2009) e797–e807. [32] H. Fortnum, A. Davis, Epidemiology of permanent childhood hearing impairment in Trent Region, 1985–1993, Br. J. Audiol. 31 (1997) 409–446. [33] S. Wiley, E. Arjmand, Jareenmeinzen-Derr, M. Dixon, Findings from multidisciplinary evaluation of children with permanent hearing loss, Int. J. Pediatr. Otorhinolaryngol. 75 (2011) 1040–1044.
