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Background Developmental impairments in children have been attributed to persistent middle-ear effusion in their early years of life. Previously, we reported that among children younger than 3 years of age with persistent middle-ear effusion, prompt as compared with delayed insertion of tympanostomy tubes did not result in improved cognitive, language, speech, or psychosocial development at 3, 4, or 6 years of age. However, other important components of development could not be assessed until the children were older.
Methods We enrolled 6350 infants soon after birth and evaluated them regularly for middle-ear effusion. Before 3 years of age, 429 children with persistent effusion were randomly assigned to undergo the insertion of tympanostomy tubes either promptly or up to 9 months later if effusion persisted. We assessed literacy, attention, social skills, and academic achievement in 391 of these children at 9 to 11 years of age.
Results Mean (±SD) scores on 48 developmental measures in the group of children who were assigned to undergo early insertion of tympanostomy tubes did not differ significantly from the scores in the group that was assigned to undergo delayed insertion. These measures included the Passage Comprehension subtest of the Woodcock Reading Mastery Tests (mean score, 98±12 in the early-treatment group and 99±12 in the delayed-treatment group); the Spelling, Writing Samples, and Calculation subtests of the Woodcock–Johnson III Tests of Achievement (96±13 and 97±16; 104±14 and 105±15; and 99±13 and 99±13, respectively); and inattention ratings on visual and auditory continuous performance tests.
Conclusions In otherwise healthy young children who have persistent middle-ear effusion, as defined in our study, prompt insertion of tympanostomy tubes does not improve developmental outcomes up to 9 to 11 years of age. (ClinicalTrials.gov number, NCT00365092
[ClinicalTrials.gov]
.)
In 1991, because evidence regarding the developmental effects of otitis media early in life was inconclusive,2 and because of the lack of evidence that insertion of tympanostomy tubes in children with persistent middle-ear effusion affects their development favorably, we began a study to address those issues. Previously, we reported that prompt as compared with delayed insertion of tympanostomy tubes before 3 years of age in study participants who had persistent effusion did not have a favorable effect on their cognitive, language, speech, or psychosocial development at 3, 4, or 6 years of age5,6,7; on their phonological memory at 4 or 6 years of age6,7; or on their auditory processing skills at 6 years of age.7 However, it remained uncertain whether developmental effects that were not present or could not be measured reliably by 6 years of age might emerge or become discernible as the children grew older. Of particular interest were domains of development previously reported by others to be unfavorably affected by persistent otitis media early in life — literacy,8,9,10,11 attention,11,12,13,14,15,16 and academic achievement.14,17
On what basis might adverse outcomes in those domains be expected? To develop literacy, children must learn to isolate phonemes within words and match them to letter sounds to form representations of written words, tasks that may require finer discrimination among speech sounds than does the development of oral language. Accordingly, it seems possible that children who had prolonged periods of hearing loss early in life but whose oral language development remained unaffected would nonetheless encounter difficulty later with reading or spelling. That difficulty might contribute to other learning difficulties, and those in turn, to problems in behavior. Similarly, if children had been receiving decreased, distorted, or inconsistent auditory signals when they were younger, they might have tuned out sound and become inattentive and distractible, and these effects might first come into play in the classroom and first be measurable objectively as the children grew older. Finally, both learning difficulties and impaired attention would be likely to limit children's academic achievement. We describe here our findings concerning literacy, auditory processing, attention, behavior, social skills, and academic achievement in the children in our study at 9 to 11 years of age.
Methods
General Procedures
Our study included two main components. In one component, children with persistent middle-ear effusion were randomly assigned to undergo either prompt insertion of tympanostomy tubes or delayed insertion if the effusion persisted. In the other component, we examined the relationship between the cumulative duration of effusion and later developmental outcomes in a subgroup of children who did not meet the randomization criteria regarding the persistence of effusion. We have described the study procedures in detail previously.2,5,6,7 From June 1991 through December 1995, we enrolled 6350 healthy infants who were 2 to 61 days of age at Children's Hospital of Pittsburgh, Mercy Hospital of Pittsburgh, and six pediatric group practices in the Pittsburgh area. The study was limited to children whose only household language was English. The study was approved by the review boards of the two hospitals, and we obtained written informed consent from one or both parents or guardians of each enrolled infant.
We monitored the children's middle-ear status until they were 3 years of age. We used the term "middle-ear effusion" to encompass all types of otitis media, including acute otitis media and tube otorrhea. We estimated the duration of episodes of effusion on the basis of diagnoses made at hospital or office visits and interpolations for intervals between visits, and we conducted audiometric testing frequently. Hearing was abnormal in approximately half the children with unilateral effusion and in approximately three quarters of those with bilateral effusion.5
Eligibility Criteria for Randomization
Children were eligible to participate in the clinical trial if, between the ages of 2 months and 3 years, they had middle-ear effusion that persisted for 90 days in the case of bilateral effusion or 135 days in the case of unilateral effusion. Children with intermittent effusion for a specified proportion of a longer period were also eligible, as described previously.5 For example, children were eligible if they had had bilateral effusion for at least 67% of the preceding 180-day period or unilateral effusion for at least 67% of the preceding 270-day period. A total of 429 children who met one of these criteria and whose parents or guardians gave written informed consent were stratified according to practice site, age (in 6-month categories), and whether the children met the eligibility criteria on the basis of bilateral or unilateral effusion. They were then assigned randomly, within those strata and in balanced blocks of four children, to undergo insertion of tympanostomy tubes either promptly (the early-treatment group) or 6 months later if bilateral effusion persisted or 9 months later if unilateral effusion persisted (the delayed-treatment group). Children for whom consent for randomization was not obtained were treated according to parental choice and followed for the duration of the study. During the first 12 months after randomization, 45% of the children in the delayed-treatment group had middle-ear effusion for more than 50% of the days, as compared with 14% of the children in the early-treatment group.5
Subgroup of Children Who Were Not Eligible for Randomization
We randomly selected a subgroup of 241 children to represent the demographic characteristics of the study population as a whole and to represent the spectrum of children ranging from those with no middle-ear effusion to those with a duration of effusion that fell just short of meeting the criteria for randomization. Our objective was to assess the correlations between the duration of effusion in these children and their outcomes and to compare their outcomes with those of the children who underwent randomization. In this subgroup of children, the estimated cumulative duration of middle-ear effusion (unilateral and bilateral combined) ranged from no effusion to 66% of the first year of life and to 45% of the first 3 years of life.2
Developmental Tests and Procedures
We assessed development in the children at the earliest mutually convenient date between their 9th and 12th birthdays and, if possible, when their hearing-level thresholds were 15 dB or less in each ear at 1000, 2000, and 4000 Hz. Assessments were conducted in a specified order.
We used the following measures to assess literacy: the Woodcock Reading Mastery Tests — Revised, normative updated version,18 for reading progress; the number of words in a grade-level passage read correctly in 1 minute for oral-reading fluency19,20; and the Spelling and Writing Samples subtests of the Woodcock–Johnson III Tests of Achievement, Standard Battery,21 for writing skills. To assess phonological awareness, we used the Elision and Rapid Letter Naming subtests of the Comprehensive Test of Phonological Processing,22 and to assess auditory processing ability, the children's version of the Hearing in Noise Test.23,24 To assess attention, impulsivity, and psychosocial function, we used the Disruptive Behavior Disorders Rating Scale,25 the Child Behavior Checklist,26 the Impairment Rating Scales,27 and the Social Skills Scale of the Social Skills Rating System,28 each completed separately by parents and teachers, and computer-based visual and auditory continuous performance tests.29,30 To assess intelligence and academic achievement, we used the Wechsler Abbreviated Scale of Intelligence31 and the Calculation subtest of the Woodcock–Johnson III Tests of Achievement, Standard Battery.21 The individual assessments are described briefly in Table 1. The examiners and analysts were unaware of the children's medical histories and treatment-group assignments.
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We calculated the duration of middle-ear effusion in children beginning from the age of 2 months. In the randomized clinical trial, to detect differences of 0.33 SD or greater on any outcome measure with a statistical power of 80%, we calculated that we would need to enroll 182 children in each group. Analyses were performed according to the intention-to-treat principle. In the subgroup of children who were not eligible for randomization, the sample of 241 children was sufficient to detect correlations of 0.25, at a power of 91%, between scores on developmental tests and the estimated cumulative proportion of days with middle-ear effusion. Because correlations involving days with bilateral effusion differed little from correlations involving total days with effusion (i.e., bilateral plus unilateral), the reported results are for total days with any effusion.
All scoring of tests and data entries were double-checked. All analyses were performed by the authors with the use of two-tailed tests, with a P value of 0.05 or less considered to indicate statistical significance. We used chi-square tests to evaluate between-group differences in proportions of children. We used analysis of variance to test for differences between mean results, Pearson pairwise correlation analysis to test for correlations, and linear regression analysis to adjust for potentially confounding variables and to test for interactions. We did not adjust for the multiple comparisons performed.
Results
Study Sample and Treatment Groups
A total of 391 of the 429 children who underwent randomization (91%), 127 of the 159 children whose parents or guardians declined randomization (80%), and 223 of the 241 children in the subgroup not eligible for randomization (93%) underwent developmental assessment at 9 to 11 years of age. At the time of testing, 84% of the children in the early-treatment group and 45% of the children in the delayed-treatment group had undergone tube insertion (Figure 1).
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No significant differences in the results favored the early-treatment group over the delayed-treatment group, either before or after adjustment for the children's sex and age on measures for which normative standard scores were not available. We tested for interactions to determine whether scores on any of the 48 outcome measures differed in relation to whether the children met the randomization criteria of the study during their first, second, or third year of life; whether they met the criteria on the basis of bilateral continuous middle-ear effusion, unilateral continuous effusion, bilateral discontinuous effusion, or unilateral discontinuous effusion; and, in the 355 children who received hearing tests during one or more episodes of effusion before undergoing randomization, whether one or more of those tests had abnormal results (as defined in Table 3) or showed a pure-tone average threshold of 30 dB or more or 40 dB or more. In 10 of the 240 instances, there were significant interactions; after adjustment for these interactions, no results significantly favored the early-treatment group.
Among the children who underwent randomization, there were no significant differences in mean scores between those who received tympanostomy tubes before 3 years of age (irrespective of the treatment assignment) and those who did not. There were also no significant differences between the mean scores of children who underwent randomization and those of children for whom randomization was declined.
Observational Cohort
In the subgroup of children who were not eligible for randomization, unadjusted correlations between the scores on each outcome measure (for oral reading fluency, the two children in grade 3 were excluded) and the cumulative duration of middle-ear effusion in the children during their first, second, and third years of life and their first 2 and first 3 years of life were all less than 0.27. For most children (142 of 235), these correlations were less than 0.10, and for most children (183 of 235), the correlations were nonsignificant. After adjustment for demographic variables, there were significant correlations between the duration of effusion during one or more of the periods considered and scores on 4 of the 19 formal test measures and 16 of the 28 measures based on reports by parents and teachers (data not shown). In each case, a longer duration of effusion was associated with a less favorable score. However, the percentage of variance in scores that was explained by the duration of middle-ear effusion, apart from that explained by the demographic variables, was low, ranging from 1.8% to 6.4% (mean, 3.0%). Also, after adjustment for demographic variables, the scores on 39 of the 47 comparable outcome measures did not differ significantly between the children in the subgroup not eligible for randomization and the children who underwent randomization. Six of the eight exceptions are shown in Table 4; the remaining two exceptions involved scores on individual Child Behavior Checklist scales.
Discussion
We describe follow-up developmental findings in a cohort of children in relation to the cumulative duration of middle-ear effusion before the age of 3 years and receipt or nonreceipt of tympanostomy tubes. In a clinical trial in which the children who had persistent effusion during that age period were assigned randomly to undergo prompt insertion of tympanostomy tubes or delayed insertion if the effusion persisted, there were no significant differences at 9 to 11 years of age in scores favoring early treatment over delayed treatment on any of the 48 developmental measures we used. For 46 of the measures, the associated 95% confidence intervals afforded assurance that the presence of any difference that was 0.33 SD or larger favoring the early-treatment group would probably have been detected. These findings affirm our observation made when the children were younger. That is, early tympanostomy tube placement as compared with delayed tube placement in the children in whom effusion continued unremittingly did not result in a significant effect on the children's cognitive or psychosocial development or on their phonological and auditory processing skills.2,5,6,7,32 Our findings also extend that observation to include measures of the children's literacy, attention, social skills, and academic achievement.
Among the children in whom the duration of middle-ear effusion did not meet the eligibility criteria for enrollment in the clinical trial, correlations between the duration of effusion during various periods in the first 3 years of life and developmental outcomes were generally weak and not significant — results that are consistent with our findings when the children were younger.2,6,7,32 For the significant correlations, the percentage of variance in the results that was explained by the duration of effusion was negligible. Nevertheless, these significant correlations, along with certain outcomes that were better for these children than for the children who underwent randomization, raise the possibility that prolonged effusion had some adverse developmental effects. A more likely explanation for these findings, however, is residual confounding, given the more favorable socioeconomic status of the children in the subgroup that was not eligible for randomization and the fact that low socioeconomic status was a major risk factor both for early-life otitis media in these children33 and for less than optimal developmental outcomes in children in this and other studies.2,6,7,32,34
Our study included close monitoring of children's middle-ear status throughout their first 3 years of life, a broad array of developmental assessments, and a high rate of follow-up. The consistency of the results in different age periods not only affirms the validity of our findings but also suggests that developmental differences between the treatment groups will not emerge at later ages.
As we have noted previously,2,6,7 our findings cannot be generalized to children who are not otherwise healthy or have disabling conditions such as sensorineural hearing loss or Down's syndrome; to children with longer periods of effusion than those we studied; or to children in whom effusion is consistently accompanied by extreme degrees of hearing loss. However, such children are seen infrequently in general clinical practice.
Given the consistency of our current findings with those reported when the children were younger, we conclude that for otherwise healthy children who are younger than 3 years of age and have asymptomatic middle-ear effusion that is persistent, as defined in our study, prompt insertion of tympanostomy tubes does not improve the developmental outcomes as compared with delayed insertion in children in whom effusion continues unremittingly. Accordingly, in children such as those we studied, watchful waiting for at least 6 additional months when effusion is bilateral and for at least 9 additional months when effusion is unilateral is the preferred management option. Such conservative management was recommended in a recent practice guideline that cited our findings in children at 3 years of age, but this guideline was formulated before our findings in the children at later ages were reported.35
Supported by grants from the National Institute of Child Health and Human Development and the Agency for Healthcare Research and Quality (HD26026 and HD42080), from the University of Pittsburgh Competitive Medical Research Fund, and from the Children's Hospital of Pittsburgh Research Advisory Committee and by gifts from GlaxoSmithKline and Pfizer.
No potential conflict of interest relevant to this article was reported.
We thank the following physicians for integrating this study into their office practices: D.J. Cahill, J. Scibilia, and J.A. Vogel, Jr., in Beaver; M. Diamond and T.D. Skelly in Brentwood; A.V. Agustin and E.A. Vogeley in Gibsonia; H.A. Altman, J.K. Greenbaum, K.R. Keppel, and D.J. Vigliotti in Kittanning; S.L. Tyson and C.J. Welkon in Mt. Lebanon; K.G. Pai and H.M. Rubin in Pleasant Hills; and B.J. Bradford at Mercy Hospital of Pittsburgh — all in Pennsylvania. We also thank Andrew R. Greiner for assistance with the continuous performance tests and the many other persons who served as clinicians for the study subjects or assisted in other clinical, administrative, or analytic capacities.
Source Information
From the University of Pittsburgh (J.L.P., H.M.F., T.F.C., C.A.D., H.E.R., M.K.-L., J.E.J., D.L.S., R.E.O.) and Children's Hospital of Pittsburgh (J.L.P., H.M.F., T.F.C., D.L.P., C.G.S., D.K.C., B.S.B., D.L.S.) — both in Pittsburgh; Stanford University School of Medicine, Stanford, CA (H.M.F.); the University of Texas, Dallas (T.F.C., C.A.D.); the University of California, Riverside (R.E.O.); and the State University of New York at Buffalo, Buffalo (W.E.P.).
Address reprint requests to Dr. Paradise at Children's Hospital of Pittsburgh, 3705 Fifth Ave., Pittsburgh, PA 15213, or at jpar{at}pitt.edu.
References
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