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Otitis media and associations with overweight status in toddlers
Physiology & Behavior 102 (2011) 511–517
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Physiology & Behavior j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p h b
Otitis media and associations with overweight status in toddlers H.M. Nelson a,⁎, K.A. Daly b, C.S. Davey c, J.H. Himes d, D.J. Synder e, L.M. Bartoshuk e a
University of Minnesota, Department of Otolaryngology, MMC 396, 420 Delaware St. SE, Minneapolis, MN, 55455, United States University of Minnesota, Department of Otolaryngology and Otitis Media Research Center, MMC 396, 420 Delaware St. SE, Minneapolis, MN, 55455, United States c University of Minnesota, Biostatistics Design and Analysis Center, Clinical and Translational Science Institute, Room 223-21, 717 Delaware St. SE, Minneapolis, MN, 55414, United States d University of Minnesota, School of Public Health, Division of Epidemiology and Community Health, 1300 South Second Street, Suite 300, Minneapolis, MN, 55454, United States e University of Florida, College of Dentistry, JHM Health Science Center, PO BOX 100127, Gainesville, FL, 32610, United States b
a r t i c l e
i n f o
Article history: Received 15 September 2010 Received in revised form 23 December 2010 Accepted 4 January 2011 Keywords: Otitis media Overweight Taste
a b s t r a c t Introduction: Otitis media (OM) is a significant disease that affects nearly all children early in life. Recently, childhood overweight has become an epidemic. Past research has demonstrated that a history of OM is related to food preferences and overweight through proposed physiological mechanisms. The purpose of this study was to explore the relationship between recurrent OM (ROM)/tympanostomy tube treatment and overweight status. Methods: Data were analyzed from a prospective cohort of mothers and children recruited from 1991–1996 from a local health maintenance organization. ROM and tympanostomy tube status were obtained through a combination of physical exam and medical record abstraction. ROM and tympanostomy tube status were analyzed as categorical variables with weight-for-length (WFL) data from well child checks. Chi-square and logistic regression for univariate and multivariate analyses were performed. Results: 11.4% of children had a WFL measure at two years of age ≥95th percentile. Those children with a history of tympanostomy tube treatment had a significantly increased risk of having a WFL ≥95th percentile after controlling for birth weight, maternal prenatal smoking, maternal education, and family income (OR 3.32, 95% CI 1.43–7.72). The alternative hypothesis that children with larger WFL at two month of age would have a greater number of OM episodes by two years of age was not significant. Conclusion: The findings of this study are consistent with the hypothesis and prior research that OM treated with tympanostomy tubes is associated with overweight status. © 2011 Elsevier Inc. All rights reserved.
1. Introduction Otitis media (OM), or ear infection, is an inflammatory condition of the middle ear with or without involvement of the mastoid space. Acute OM (AOM) is defined as the presence of purulent fluid within the middle ear space with duration of less than three weeks. Otitis media with effusion (OME) is defined as the presence of fluid (serous or mucoid) that can occur as a post-inflammatory response to AOM from a viral infection or because of eustachian tube dysfunction. OM causes pain, fever, and temporarily reduces hearing. Children diagnosed with chronic/recurrent OM (COM/ROM) experience the greatest morbidity. Antibiotics are used in the treatment for AOM; however, surgical intervention such as myringotomy with or without tympanostomy tube placement is considered when children experience ROM (defined as greater than or equal to four episodes per year or greater than or equal to three episodes in six months) or develop a persistent effusion greater than three months [1]. ⁎ Corresponding author. Tel.: +1 612 625 3200; fax: +1 612 625 2101. E-mail addresses: [email protected] (H.M. Nelson), [email protected] (K.A. Daly), [email protected] (C.S. Davey), [email protected] (J.H. Himes), [email protected]fl.edu (D.J. Synder), [email protected]fl.edu (L.M. Bartoshuk). 0031-9384/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.physbeh.2011.01.002
OM prevention is a priority because it affects quality of life for both the child and the family [2–4], and may have long-term consequences, including impaired hearing [5,6]. Strategies to reduce OM incidence (e.g. xylitol, vaccine and risk factor reduction) have been somewhat successful [7–10], and since the routine use of 7-valent pneumococcal conjugate vaccine (PCV-7) in infancy, OM rates have declined. However, this disease remains one of the most common in early life, especially among those in childcare [11]. Childhood overweight has become epidemic, with the prevalence of this condition doubling over two decades among preschool children [12–14]. Between 1983 and 1995, the period during which data for this study were collected, weight-for-length (WFL) ≥85th percentile increased 18.3% (from 14.2% to 16.8%) and WFL ≥95th percentile increased 25% (5.6% to 7.0%) among 24–35 month-olds [14]. More recently (2003–2004), 26.2% of two to five year-olds were ≥85th percentile, and 13.9% were ≥95th percentile [15]. NHANES data show a steady increase in rates ≥95th percentile in children 2–5 years of age: 5% in 1976–80, 7.2% in 1988–94, 10.3% in 1999–2002, and 12.4% in 2003–06 [16]. A similar trend was seen for OM office visit rates, which more than doubled between 1975 and 1990 [17]. Overweight and obesity during childhood increase the risk of adult obesity and have both pediatric and adult health consequences (e.g.
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type 2 diabetes, hypertension, obstructive sleep apnea, and cardiovascular disease), and these conditions contribute to increased mortality in adulthood [18,19]. Reported predictors of childhood overweight and obesity have been suggested. Dubois and Girard examined factors related to preschoolers' weight status using a population-based cohort of children followed from birth to four and half years of age [20]. Overweight/obese status at age four and half years was associated with male gender during this period, maternal prenatal smoking history, being born into a lower socio-economic class (SEC) status as well as living in a lower SEC family at four and half years of age, height/weight gain in first five months of life, and parental overweight status [20]. Research has shown that OM history is related to both food preference and overweight and obesity [21–23]. The chorda tympani nerve (cranial nerve [CN] VII) passes through the middle ear, innervates the anterior tongue and carries taste information [24]. CN V and IX, the trigeminal and glossopharyngeal nerves, transmit temperature, touch and pain information, and CN IX also innervates the taste buds at the base of the tongue [25]. Central inhibitory connections exist among the cranial nerves, and damage to one nerve releases inhibition on the others, leading to changes in sensory perception [24]. Damage to the chorda tympani (CT) by inflammatory middle ear disease can lessen the taste function on the anterior tongue ipsilateral to the inflammation [26]. Exact mechanisms that account for the observed findings are unknown. One possible explanation is that inflammatory mediators and cytokines in middle ear effusion during ROM and COM damage the CT, which affects taste. Inflammatory cytokines can then upregulate MUC19 gene transcription. MUC19 is a gel-forming mucin that increases middle ear fluid viscosity and decreases mucociliary clearance, predisposing a child to persistent middle ear fluid [27,28]. Food preference data show that perception of sweet and fat vary with body mass index. Higher body mass index (BMI) is associated with decreased perception of sweetness as well as the palatability of fat in obese individuals more than in normal weight individuals [29]. In one preliminary unpublished study, young children with a history of ROM were more likely to have a higher intake of sugar and a lower intake of vegetables than children without a history of frequent OM episodes [21]. These studies led to the theory that OM alters taste perceptions by creating an inflammatory environment that leads to damage to the CT, and results in increased palatability of sweet and fat foods. This theory may then increase the risk of being overweight by altering food intake habits. Using data from the Early Otitis Media Study (EOM) and ROM and tympanostomy tube status as surrogates for middle ear disease, two hypotheses were tested to explore the theory of inflammatory ear disease being associated with weight [30]. The first hypothesis was that the number of OM episodes, ROM, and tympanostomy tube treatment would be associated with overweight status at two years of age. The alternative hypothesis was that overweight children were more likely to have middle ear disease. Here, we tested the theory that children with elevated WFL at two months of age would have more OM episodes, be more likely to have ROM, or to be treated with tympanostomy tubes than infants with lower WFL by two years of age. 2. Materials and methods Data from the EOM Study, a cohort followed for OM from birth to two years of age, were collected between 1991 and 1996 in the Minneapolis-St. Paul metropolitan area [30]. This study was designed to investigate predictors for early OM onset. Pregnant women were recruited from HealthPartners, an integrated health care-system in the metropolitan area, and from the Diana Project [31], a study designed to investigate effects of preconceptual and prenatal influences on infant birth weight. Eligible women were recruited for
the EOM Study during the third trimester, and their infants were enrolled at birth if they would receive care in the HealthPartners system. Infants with a craniofacial anomaly or other conditions predisposing to OM were excluded. Of the 596 eligible infants enrolled, 430 had complete prenatal, postnatal, and outcome data for investigation of the relationship between OM and overweight at two years of age; 538 were available to evaluate the alternative hypothesis that early overweight increased the risk for OM in later years. 2.1. Independent variable Physicians and nurse practitioners performed ear examinations and tympanometry at illness-related and well-child visits, and recorded data on study forms. At each clinic visit, the physician or pediatric nurse practitioner examined the child with pneumatic otoscopy using a standard protocol, and recorded tympanic membrane findings, symptoms, and diagnoses on a standard one-page data form. Additionally, tympanometry was performed at 2, 4, and 6 months, and utilized to determine the presence of middle ear fluid if visual exam was equivocal. If an ear form was not completed for a clinic or urgent care visit, study staff abstracted data from the medical record for that visit. Based on medical practitioners' experiences and exams utilizing components such as history (e.g. fever, ear pulling, and irritability) combined with physical exam which assessed tympanic membrane color, position (full, bulging, and retracted), or mobility (decreased or absent), a diagnosis of AOM (red bulging tympanic membrane associated with or without fever and decreased/absent tympanic mobility) or OME (dull tympanic membrane with decreased/absent mobility) was made. A new episode was defined as AOM or OME in either ear after a normal middle ear examination, or an episode of AOM ≥21 days after a diagnosis of AOM or OME. To assess reliability of the middle ear diagnosis as described above, validated otoscopists performed interobserver testing with a sample of 20 clinicians (κ = 0.54, 0.65). Clinicians' diagnoses were also compared to an algorithm in which OM was confirmed if two or more abnormal exam findings (tympanic membrane color, position, appearance, and mobility) were present. Kappa coefficient of agreement was 0.92 for examiner diagnosis compared with the algorithm described above [27]. The number of OM episodes was calculated and a dichotomous ROM variable was created. Greater than or equal to four OM episodes in twelve months was recorded as presence of ROM. We also speculated that children with persistent disease or more episodes of OM would be more likely to undergo tympanostomy tube placement. Thus status of tympanostomy tube placement would be a surrogate for severe middle ear disease. Tympanostomy tube status obtained from medical records was defined as a minimum of one set of tubes obtained in the first two years of life. 2.2. Dependent variable Length and weight data collected at two month and two year well child checks by clinic personnel were abstracted from medical records. 2.3. Demographics/risk factor/confounders Mailed questionnaires were used to collect maternal information during the third trimester and infant OM risk factors at two weeks and six months of age. Maternal subjects' self-reported breast feeding information was collected monthly. Risk factors data obtained from questionnaires included: prenatal smoking history, maternal OM history, daycare attendance, maternal education, and household income. Maternal prenatal smoking history was obtained by indicating if present, current amount smoked, and pack year history. Breast feeding history was collected by indicating if child was still being breastfed and duration of breast feeding. Daycare attendance information was
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collected as the type of daycare, hours spent per week, number and age range of children at the facility. Maternal education and household income were collected as categorical. Birth weight, weight and length at two months of age, and adenoidectomy history were obtained from medical records.
Infants ≥1.0 month and b3.0 months were considered two months of age, while those classified as two years of age included children ≥21.0 months and b27.0 months. OM was analyzed as a continuous variable (number of OM episodes per child) as well as categorical (0, 1–2, 3–5, and ≥6 episodes). ROM and tympanostomy tube status were analyzed as dichotomous variables. For the dependent variable, our analysis followed the approach of Mei et al. [14]. using two levels of overweight based on WFL percentiles to examine relative degree of overweight. WFL percentiles were calculated based on the 2000 Centers for Disease Control (CDC) Growth Charts [32]. Children were classified as ≥95th percent or b95th percentile. Based upon CDC classification, those children ≥95th percentile were classified as “obese”. For the two year of age WFL variable, children whose WFL was ≥85th percentile but b95th percentile were classified as “overweight”. Given the small number of children classified as “obese”, we also examined WFL ≥85th percentile. Thus a second dichotomous variable was created—children ≥85th percentile vs. those b85th percentile to assess the risk of being at risk for overweight/obese. To analyze our second hypothesis and to control for potential confounding of WFL status at two years of age, a third dichotomous variable was created utilizing WFL data at two months of age (WFL ≥85th vs. b85th percentile). The following risk factors were analyzed as dichotomous: prenatal smoking history (yes vs. no), breast feeding at 6 months of age (breast fed to at least 6 months vs. stopped before 6 months), daycare attendance at 6 months (yes vs. no), maternal education (Nhigh school vs. ≤high school), and household income (N$50,000 vs. ≤$50,000). Birth weight was analyzed as continuous. Analyses were performed with SAS version 9.1 statistical software (SAS Institute, Cary NC). Descriptive statistics were calculated including percentages and means with standard deviations. ROM or tympanostomy tube status relationship with WFL outcomes was investigated. Chi-square test for independence without continuity correction was used to examine the relationship between dichotomous variables to provide univariate analysis. All tests were two-tailed. Logistic regression was utilized to assess multivariate analysis and control for potential confounders. A p valueb 0.05 was considered statistical significant. 3. Results
35 30
% with tubes
2.4. Analysis
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25 20 15 10 5 0
0-1 OM
2- 5 OM
6- 8 OM
9+ OM
Number of OM episodes Fig. 1. Percentage of children treated with tubes by number of OM episodes by age two years.
24 months) and risk factors did not reveal any important differences among those with and without two-year WFL data, although girls were less likely to have 24 month height and weight data.
3.2. Hypothesis 1—univariate analysis With chi-square analyses, the number of OM episodes as analyzed by category was not significantly related to ≥95th percentile or ≥85th percentile at two years of age (p = 0.53, 0.62 respectively). However, ROM history was significantly associated with ≥ 95th percentile (14.8% vs. 8.4%, p = 0.037), but not with ≥85th percentile (26.1% vs. 19.4%, p = 0.10) at two years of age (Tables 1a and 1b). Tympanostomy tube treatment by age two, a proxy for inflammatory middle ear disease, was significantly associated with both ≥95th percentile and ≥85th percentile at two years (Tables 2a and 2b; p b 0.0001, 0.002 respectively).
3.3. Hypothesis 1—multivariate analysis Logistic regression models to predict ≥95th percentile or ≥85th percentile at two years of age included tube treatment, ROM, ≥85th percentile status at two months of age, family income, breast feeding, and daycare (Table 3). Since only 4% of the cohort was ≥95th percentile at two months of age, we used ≥85th percentile at two months of age in the logistic model to increase the sample size when adjusting for two month WFL.
3.1. Descriptive statistics Ninety-six percent of the cohort was white (based on parental race), and 53% was male. Mean age at final weight and length measurement was 24.1 months (standard deviation 0.60) and mean WFL percentile was 54.2% (standard deviation 32.1%). Mean number of ear examinations was 23.5 (standard deviation 10.0). Forty-seven percent had ROM in the first and/or second year of life, and 14% were treated with tympanostomy tubes during this period. The total number of OM episodes by age two was significantly associated with tube treatment (Fig. 1, p b 0.0001). Thirty-seven percent of those with ≥9 OM episodes compared with 8.6% of those with 2 to 5 episodes were treated with tubes. By two years of age, 22.6% were classified ≥ 85th percentile and 11.4% were considered ≥ 95th percentile for WFL. The cohort had 538 infants with two month WFL data, 396 of these also had two year WFL data, and 34 had only two year WFL data. Comparing outcomes (ROM, tubes, and number of OM episodes in
Table 1a Recurrent OM vs. overweight status at 95th percentile. Recurrent OM
≥ 95th percent
b95th percentile
Yes (n = 203) No (n = 227) Total (n = 430)
14.8% (n = 30) 8.4% (n = 19) 11.4% (n = 49)
85.2% (n = 173) 91.6% (n = 208) 88.6% (n = 381)
p = 0.037, Chi-square analysis.
Table 1b Recurrent OM vs. overweight status at 85th percentile. Recurrent OM
≥ 85th percent
b85th percentile
Yes (n = 203) No (n = 227) Total (n = 430)
26.1% (n = 53) 19.4% (n = 44) 22.6% (n = 97)
73.9% (n = 150) 80.6% (n = 333) 77.4% (n = 381)
p = 0.10, Chi-square analysis.
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Table 2a Tympanostomy tubes vs. overweight status at 95th percentile.
Table 4a ≥95th percentile at two months of age and number of OM episodes by two years of age.
Tympanostomy Tubes
≥95th percent
b95th percentile
Yes (n = 60) No (n = 370) Total (n = 430)
26.7% (n = 16) 8.9% (n = 33) 11.4% (n = 49)
73.3% (n = 44) 91.1% (n = 337) 88.6% (n = 381)
p b 0.0001, Chi-square analysis.
Overweight at 2 months of age
Number of OM episodes None
1–2
3–5
≥6
≥95th percentile 0% (n = 0) 28.6% (n=6) 52.4% (n=11) 19.1% (n=4) (n=21) b 95th percentile 7.0% (n=36) 21.5% (n=111) 36.2% (n=187) 35.4% (n=183) (n=517) Total (n=538) 6.7% (n=36) 21.7% (n=117) 36.8% (n=198) 37.4% (n=187) p = 0.18, Chi-square analysis.
Table 2b Tympanostomy tubes vs. overweight status at 85th percentile. Tympanostomy Tubes
≥ 85th percent
b85th percentile
Yes (n = 60) No (n = 370) Total (n = 430)
38.3% (n = 23) 20.0% (n = 74) 22.6% (n = 97)
61.7% (n = 37) 80.0% (n = 296) 77.4% (n = 381)
p = 0.002, Chi-square analysis.
Factors significantly related to ≥95th percentile at two years were tube treatment (crude OR 3.72, adjusted OR 3.32, 95% confidence interval 1.43, 7.72, p = 0.005) and ≥85th percentile at two months of age (crude OR 5.36, 95% confidence interval 2.60, 11.05, p b 0.0001, adjusted OR 6.31, 95% confidence interval 2.90, 13.73, p b 0.0001). Substituting ≥85th percentile as the outcome at two years resulted in lower odds ratio estimates for tube treatment (crude OR 2.49, adjusted OR 2.27, 95% confidence interval 1.13, 4.54, p = 0.02), and ≥85th percentile at two months of age (crude OR 4.30, 95% confidence interval 2.28, 8.14, p b 0.0001; adjusted OR 4.75, 95% confidence interval 2.42, 9.33, p b 0.0001). As expected, ≥85th percentile at two months of age was significantly related to being ≥95th percentile and ≥85th percentile (crude OR 3.72, adjusted OR = 6.31, 95% CI 2.90, 13.73; crude OR 2.49, adjusted OR= 4.75, 95% CI 2.42, 9.33, respectively).
3.4. Hypothesis 2 The hypothesis that infant size at two months of age was related to later OM was tested with Chi-square tests and logistic regression models. Status of ≥95th or ≥85th percentile at two months was not significantly associated with 1) number of OM episodes (p = 0.18, 0.37 respectively, Tables 4a and 4b), 2) ROM by two years of age (Tables 5a and 5b; crude OR 0.73 and 1.19) or 3) tube treatment by two years of age (Tables 6a and 6b; crude OR 0.76, and 0.90). The adjusted odds ratio of having a history of ROM at two years of age was 1.12 (p = 0.50) for those ≥95th percentile at two months of age (vs. b95th percentile) and 1.31 (p = 0.51) for those ≥85th percentile at two months of age (vs. b85th percentile). The odds of having a history tympanostomy tube treatment by two years of age were 1.04 (p = 0.71) for those children ≥95th percentile at two months of age (vs. b95th percentile) and 0.95 (p = 0.80) for those children ≥85th percentile at two months of age (vs. 85th percentile).
Table 4b ≥85th percentile at two months of age and number of OM episodes by two years of age. Overweight at 2 months of age
Number of OM episodes None
1–2
3–5
≥6
≥85th percentile 1.6% (n=1) 22.2% (n=14) 41.3% (n=26) 34.9% (n=22) (n=63) b 85th percentile 7.4% (n=35) 21.7% (n=103) 36.2% (n=172) 34.7% (n=165) (n=475) Total (n=538) 6.7% (n=36) 21.7% (n=117) 36.8% (n=198) 37.4% (n=187) p = 0.37, Chi square analysis.
In multivariate logistic regression, two month size (≥ 95th percentile or ≥85th percentile) was not significantly associated with ROM at two years of age (p = 0.80, p = 0.34 respectively). Similarly, ≥95th percentile and ≥85th percentile at two months did not predict tubes by age two (p = 0.96, 0.91 respectively).
4. Discussion Our findings demonstrate a significant relationship between preceding tympanostomy tube treatment and ≥ 95th percentile and ≥85th percentile for WFL in two year-olds after controlling for risk factors and confounders. This finding supports current published studies. A Korean case–control study examined the relationship between COM and BMI in 2–7 year-olds [33]. One hundred fifty-five cases had tympanostomy tube surgery, and 118 controls had surgery for another indication. All cases that underwent tube treatment were diagnosed with OME based upon otoscopic examination or tympanograms. BMI was significantly higher in cases than in controls (mean 22.0 vs. 16.3, p=0.01). The same group recently repeated the study by further dividing the group into four weight categories (underweight b5th percentile, Table 5a ≥95th percentile at two months of age and history of ROM by two years or age. Percentile at 2 months of age
≥ 95th percentile (n = 21) b 95th percentile (n = 517) Total (n = 538)
Recurrent OM Yes
No
38.1% (n = 8) 45.7% (n = 236) 45.4% (n = 244)
61.9% (n = 13) 54.4% (n = 281) 54.6% (n = 294)
p = 0.50, Chi-square analysis. Table 3 Predictors for ≥95th percentile/≥85th percentile at 2 years of age with logistic regression. Risk factors
≥ 95th percentile odds ratio (95% CI)
≥ 85th percentile odds ratio (95% CI)
Tympanostomy tubes Recurrent OM ≥ 85th at 2 months Family income N $50 K Breast feeding at 6 months Daycare at 6 months
3.32 1.13 6.31 1.55 0.68 1.13
2.27 1.10 4.75 0.92 0.71 1.01
(1.43, (0.54, (2.90, (0.75, (0.32, (0.54,
7.72) 2.38) 13.73) 3.19) 1.44) 2.37)
(1.13, (0.64, (2.42, (0.55, (0.41, (0.59,
4.54) 1.89) 9.33) 1.56) 1.24) 1.75)
Table 5b ≥85th percentile at two months of age and history of ROM by two years or age. Percentile at 2 months of age
≥ 85th percentile (n = 63) b 85th percentile (n = 475) Total (n = 538) p = 0.51, Chi-square analysis.
Recurrent OM Yes
No
49.2% (n = 31) 44.8% (n = 213) 45.4% (n = 244)
50.8% (n = 32) 55.2% (n = 262) 54.6% (n = 294)
H.M. Nelson et al. / Physiology & Behavior 102 (2011) 511–517 Table 6a ≥95th percentile at two months of age and tympanostomy tube status at two years of age. Percentile at 2 months of age
≥ 95th percentile (n = 21) b 95th percentile (n = 517) Total (n = 538)
Tympanostomy tubes Yes
No
9.5% (n = 2) 12.2% (n = 63) 12.1% (n = 65)
90.5% (n = 19) 87.8% (n = 454) 87.9% (n = 473)
p = 0.71, Chi-square analysis.
Table 6b ≥ 85 percentile at two months of age and tympanostomy tube status at two years of age. Percentile at 2 months of age
≥85th percentile (n = 63) b85th percentile (n = 475) Total (n = 538)
Tympanostomy tubes Yes
No
11.1% (n = 7) 12.2% (n = 58) 12.1% (n = 65)
88.9% (n = 56) 87.8% (n = 417) 87.9% (n = 473)
p = 0.80, Chi-square analysis.
normal 5–84th percentile, overweight 85–94th percentile and obese ≥95th percentile) and specifically examining the risk of overweight status [34]. The authors conclude that the frequency of OME treated with tubes was significantly higher among those classified as obese but OME was not related to other weight classifications. Additionally, they assessed the relationship of OME severity resulting in tube placement with body weight. They found no correlation with mean frequency of tube insertion and weight status in the experimental group, and concluded that weight status does not correlate with OME severity. These data are cross sectional and cannot be used to determine a causal relationship. In this study, ROM history was not associated with weight status which would agree with the argument that severity of the disease may not indicate potential for CT damage. It is possible that our association with tube treatment is a better indicator for severity of disease. Based on clinical guidelines, tube treatment is warranted for ROM with poor response to antibiotics or persistent OME. Additionally, it may be that tube treatment is a proxy for the number of OM episodes and it is the actual number of OM episodes that increases the likelihood of creating an environment that would lead to CT damage. It is possible that there is direct damage to CT during the actual tympanostomy tube insertion. Middle ear surgery has been implicated in injury to the CT with resulting perceived changes in taste [25,35,36]. Compared to myringoplasty/tympanoplasty and mastoidectomy patients, tympanotomy patients had the highest rates of taste disturbance. Fifty-eight percent of those with stretched CT, 10% with sectioned CT, and 3% without CT injury reported changes in taste. Moreover, the authors conclude that individuals who did not have history of cholesteatoma disease had a greater perception of taste changes than those with a history. The authors speculate that the inflammatory diseases had a longer period to cause a gradual change in taste vs. those with a traumatic injury. In the context of this study, damage from surgery is less likely given the location of the nerve and the potential for injury by placing a tube. The other surgeries studied above put the operator in close proximity to the nerve with a greater potential to stretch the nerve (e.g. entering the middle ear space through a transcanal approach) or drilling on the CT. A potential confounder in this relationship between tympanostomy tubes status and WFL is the presence of adenoid hypertrophy. Literature has established the relationship with adenoid hypertrophy and development of OM either through mechanical obstruction of the eustachian tube orifice or as a biofilm source. Konstantinidis et al. explored the ability to smell and taste pre and post adenoidectomy in
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children 5–9 years of age as compared to a control group. Three months after surgical removal of adenoids, children had significant improvement in olfaction as compared to controls. Additionally, these children were noted to have an increase in BMI in the follow up period [37]. In our study, no children underwent adenoidectomy based upon medical records obtained up to two years of age. Additionally, nasopharyngeal exams were not performed to assess for adenoid hypertrophy. It can possibly be assumed that no child required an adenoidectomy and thus no confounding occurred. However this is a limitation of the study given we do not know the adenoid status of the children. Compared to prior studies, we did not see an association with ROM and WFL. Several studies have assessed the relationship of CT damage and changes to taste in the presence of inflammatory ear disease. Goyal et al. performed a prospective study of 85 patients with unilateral chronic inflammatory middle ear disease and then evaluated gustatory function on both sides of the tongue. Mean taste scores were significantly lower on the affected side as compared to the healthy ear (mean 9.16 vs. 13.24, p b 0.0001). Interestingly, this difference was not necessarily perceived by the subject. Additionally, duration of disease did not significantly affect the taste score [38]. It is possible that we did not accurately diagnose ROM; although we feel that the combination of the validated ear exams with medical history provided true assessment of the subjects' ear status. It is also possible as described above that it is not necessarily the duration of the disease (e.g. COM) but more number of episodes of inflammatory disease overall that are more likely to cause injury. Another consideration is that the subject needs bilateral disease to truly affect subjective and objective taste perception. This may have been why tympanostomy tubes would be a better predictor as it may indicate bilateral disease as well as potential for bilateral trauma to CT. However, this goes against literature as discussed above. First, the presence of inflammatory disease can provide changes to taste that are gradual in process and are not perceived by the subject [38]. Second, Bartoshuk et al. discuss several studies whereby anesthesia to CT on one side results in intensification of glossopharyngeal on the contralateral side [29]. Thus bilateral disease would not provide the same effect on taste intensification. It is also possible that tympanostomy tubes were the confounders in prior published literature regarding ROM and WFL. As demonstrated in Fig. 1, with more episodes of OM, the subject is more likely to have tympanostomy tubes placed. The more episodes a subject has, the more likely they would be classified as having a ROM history. We do see an association in ≥95th percentile group and ROM in univariate analysis (Table 1a). This association goes away in multivariate analysis after controlling for tube status. 4.1. Reverse hypothesis not supported What is unique to our study compared to prior published literature is examination of the reverse hypothesis. It has been assumed that children with a greater WFL were more likely to develop ROM or have a greater risk of undergoing tympanostomy tubes. The assumption behind this is that children with greater WFL have a larger fat pad around the eustachian tube leading to dysfunction that can result in a greater likelihood to develop inflammatory ear disease. In this study, there was no evidence to support the hypothesis that overweight status at two months was associated with the number of OM episodes, ROM or tube treatment in the first two years of life. In other words, having a larger WFL earlier in life did not predict developing inflammatory ear disease later in life. 4.2. Mechanisms are not clear This study does not provide information on mechanism and works within the theory that CT damage is a step in this process. It has been shown that inflammatory conditions of the middle ear can result in
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objective gustatory changes. Sano reported that patients with unilateral COM or cholesteatoma were significantly more likely than those without these conditions to have an increase in taste threshold on the side of the tongue ipsilateral to the affected ear [36]. However, this study nor published literature, has shown that this taste change is the cause for increased weight gain. More recently, Seaberg et al. directly measured CT function in children (ages 5–18 years) with and without a previous history of AOM to determine relationship to BMI [39]. Using electrogustometric thresholds as a measure of CT function, they found no relationship with nerve function and OM history as well as no association with BMI. The status of AOM was determined by asking subjects/parents to quantify the number of OM episodes by memory which could result in a significant recall bias. Additionally, BMI was calculated without controlling for subjects' gender and age. This study does bring into question the mechanism of CT. There is a possibility that this relationship is confounded and no true statistical relationship exists. We controlled for known confounders related to weight and OM such as breast feeding, early weight gain, prenatal smoking history, SEC, and adenoid status. An unknown variable could also confound the relationship between middle ear disease and increased weight-for-length. Forty-seven percent had ROM in the first and/or second year of life, and 14% were treated with tympanostomy tubes during this period. Office visit rates for OM more than doubled between 1975 and 1990 among children younger than two years of age [17]. Data from Healthy People 2010 show that among children ≤3 years, OM visit rates initially declined from 1160/1000 in 1997 to 695/1000 in 2004, but then increased to 840/1000 in 2006 [40]. The percentage of children undergoing tympanostomy tube treatment in this study is lower than other published studies. Myer and Frances found 30.11% of children under age two who underwent tympanostomy tubes when examining a large HMO cohort during same time period [41]. In this cohort, by two years of age, 22.6% of the children were classified as ≥85th percentile and 11.4% were considered ≥95th percentile. Overweight in early childhood has also been increasing in the last two decades. The proportion of overweight two- to five-year-olds (≥95th percentile) increased 44% from 5.0% to 7.2% between 1976–80 and 1988–94 [15]. More recently, overweight increased 20% in this age group (10.3% to 12.4%) between 1999–2002 and 2003–06 [15]. Among 24–35 month olds, ≥95th percentile increased 25% from 1983 to 1995, the period of the cohort study [14]. The proportion of ≥85th percentile children in this cohort (22.6%) is consistent with the CDC defined standard of ≥85th percentile WFL. 4.3. Study benefits Data in the original cohort study were collected prospectively, so determination of OM history and risk factors preceded assessment of overweight at two years. Tube treatment was documented in the medical record and on study visit forms. Criteria for OM diagnosis were specified in the original study which compared ear exam findings of clinic pediatricians and nurse practitioners against experienced and validated examiners [30]. The relationship between ROM/tubes, taste, and overweight is consistent with clinical studies in adults [22,23,29] and population-based studies of children [42]. 4.4. Study limitations The original cohort study was not designed to examine relationships between OM/tube treatment and infant weight status. Confounders obtained were not specifically related to WFL such as exercise, television time or food intake. Ear examination data were used to determine whether a child had chronic OME (middle ear effusion persisting for three or more months, verified monthly) rather than separate OM episodes. However, very few children met the criteria for chronic OME, so it was not included as an independent variable. Additionally, the
study was not designed to explore the mechanism for this relationship. Ideally, it would be beneficial to include taste information from the children; however, the relationships in this study were post-hoc analysis. Future direction would be to assess a population where taste could be assessed in conjunction with middle ear inflammatory disease, tympanostomy tube treatment, and WFL. 5. Conclusion Tympanostomy tube treatment was associated with overweight in two year-olds in this study. The reverse hypothesis that early weight status was related to later OM, ROM or tube treatment was not supported. Our study suggests that tympanostomy tube status may be a better surrogate for middle ear disease. Tube treatment for COM and ROM may be contributing to the current epidemic of overweight in children through possible mechanisms such as damage to the CT during surgery, or from inflammatory mediators and cytokines present in middle ear effusion, resulting in changes in taste and increased intake of sweet and fat foods. However, this relationship needs to be further explored with prospective studies and evaluation of confounders. References [1] Bailey BJ, Johnson JT, Newlands SD. Head and neck surgery – otolaryngology, 4th edition, Volume 1. Philadelphia, PA: Lippincott Williams & Wilkins; 2006. p. 1265–75. Chapter 91. [2] Boruk M, Lee P, Faynzilbert Y, Rosenfeld RM. Caregiver well-being and child quality of life. Otolaryngol Head Neck Surg 2007;136:159–68. [3] Brouwer CN, Rovers MM, Maille AR, Veenhoven RH, Grobbee DE, Sanders EA, et al. The impact of recurrent acute otitis media on the quality of life of children and their caregivers. Clin Otolaryngol 2005;30:258–65. [4] Lee J, Witsell DL, Dolor RJ, Stinnett S, Hannley M. Quality of life of patients with otitis media and caregivers: a multicenter study. Laryngoscope 2006;116: 1798–804. [5] American Academy of Pediatrics, American Academy of Family Physicians. Clinical practice guideline: diagnosis and management of acute otitis media. Pediatrics 2004;113:1451–65. [6] Rosenfeld RM, Culpepper L, Doyle KJ, Grundfast KM, Hoberman A, Kenna MA, et al. Clinical practice guideline: otitis media with effusion. Otolaryngol Head Neck Surg 2004;130(5 Suppl):S95–S118. [7] Eskola J, Kilpi T, Palmu A, Jokinen J, Haapakoski J, Herva E, et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med 2001;344:403–9. [8] Kilpi T, Ahman H, Jokinen J, Lankinen KS, Palmu A, Savolainen H, et al. Protective efficacy of a second pneumococcal conjugate vaccine against pneumococcal acute otitis media in infants and children: randomized, controlled trial of a 7-valent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine in 1666 children. Clin Infect Dis 2003;37:1155–64. [9] Uhari M, Kontiokari T, Koskela M, Niemela M. Xylitol chewing gum in prevention of acute otitis media: double blind randomised trial. Br Med J 1996;313:1180–3. [10] Bonuck KA, Freeman K, Trombley M. Randomized controlled trial of a prenatal and postnatal lactation consultant intervention on infant health care use. Arch Pediatr Adolesc Med 2006;160:953–60. [11] Bradley RH, The National Institute of Child Health and Human Development Early Child Care Research Network. Child care and common communicable diseases. Arch Pediatr Adolesc Med 2001;155:481–8. [12] Krebs NF, Jacobson MS, Baker RD, Green FR, Hegeman MB, Jaksic T, et al. American academy of pediatrics committee on nutrition. prevention of pediatric overweight and obesity. Pediatrics 2003;112:424–30. [13] Ogden CL, Flegal KM, Carroll MD, Johnson CL. Prevalence and trends in overweight among US children and adolescents, 1999–2000. JAMA 2002;288:1728–32. [14] Mei Z, Scanlon KS, Grummer-Strawn LM, Freedman DS, Yip R, Trowbridge FL. Increasing prevalence of overweight among US low-income preschool children: Centers for Disease Control and Prevention Pediatric Nutrition Surveillance, 1983 to 1995. Pediatrics 1998;101:12, doi:10.1542/peds.101.1.e12. [15] Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999–2004. JAMA 2006;295: 1549–55. [16] Centers for Disease Control and Prevention. NHANES surveys (1976–1980 and 2003–2006). http://www.cdc.gov/obesity/childhood/prevalence.html. [17] Schappert SM. Office visits for otitis media: United States 1975–90. Hyattsville MD, National Center for Health Statistics. Vital Health Stat 1992;214:1–20. [18] Nieto FJ, Szklo M, Comstock GW. Childhood weight and growth rate as predictors of adult mortality. Am J Epidemiol 1992;136:201–13. [19] DiPietro L, Mossberg HO, Stunkard AJ. A 40-year history of overweight children in Stockholm: life-time overweight, morbidity, and mortality. Int J Obes Relat Metab Disord 1994;18:585–90. [20] Dubois L, Girard M. Early determinants of overweight at 4.5 years in a populationbased longitudinal study. Int J Obes 2006;30:610–7.
H.M. Nelson et al. / Physiology & Behavior 102 (2011) 511–517 [21] Arsenault MA, MacLeod E, Weinstein JL, Phillips V, Ferris AM, Duffy VB. Reported history of otitis media (OM) in children associates with intake of vegetables and sweets. Paper presented at the International Congress of Dietetics, Chicago IL; 2004. [22] Snyder DJ, Duffy VB, Chapo AK, Cobbett LE, Bartoshuk LM. Food preferences mediate relationships between otitis media and body mass index. Appetite 2003;40:360. [23] Snyder DJ, Duffy VB, Chapo AK, Hoffman H, Bartoshuk LM. Otitis media influences body mass index by interacting with sex, age and taste perception. Poster presented at the Association for Chemoreception Sciences (AChemS). Chem Senses 2003;28:12. [24] Lehman CD, Bartoshuk LM, Catalanotto FC, Kveton JF, Lowlicht RA. The effect of anesthesia of the chorda tympani nerve on taste perception in humans. Physiol Behav 1995;57:943–51. [25] Yanagisawa K, Bartoshuk LM, Catalanotto FA, Karrer TA, Kveton JF. Anesthesia of the chorda tympani nerve and taste phantoms. Physiol Behav 1998;63:329–35. [26] Landis BN, Beutner D, Frasnelli J, Huttenbrink KB. Gustatory function in chronic inflammatory middle ear diseases. Laryngoscope 2005;115:1124–7. [27] Skotnicka B, Hassmann E. Proinflammatory and immunoregulatory cytokines in middle ear effusions. Int J Pediatr Otorhinolaryngol 2008;72:13–7. [28] Kerschner JE, Khamphang P, Erbe CB, Kolker A, Cioffi JA. Mucin 19 gene (MUC19) expression and response to inflammatory mediators in middle ear epithelium. Glycoconj J 2009;26:1275–84 Epub. [29] Bartoshuk LM, Duffy VB, Hayes JA, Moskowitz HR, Snyder DJ. Psychophysics of sweet and fat perception in obesity: problems solutions and new perspectives. Philos Trans R Soc Lond B Biol Sci 2006;361:1137–48. [30] Daly KA, Brown JE, Lindgren BR, Meland MH, Le CT, Giebink GS. Epidemiology of otitis media onset by six months of age. Pediatrics 1999;103:1158–66. [31] Brown JE, Jacobs DR, Barosso GM, Potter JD, Hannan PJ, Kopher RA, et al. Recruitment, retention and characteristics of women in a prospective study of preconceptional risks to reproductive outcomes: experience of the Diana Project. Paediatr Perinat Epidemiol 1997;11:345–58.
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Physiology & Behavior j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p h b
Otitis media and associations with overweight status in toddlers H.M. Nelson a,⁎, K.A. Daly b, C.S. Davey c, J.H. Himes d, D.J. Synder e, L.M. Bartoshuk e a
University of Minnesota, Department of Otolaryngology, MMC 396, 420 Delaware St. SE, Minneapolis, MN, 55455, United States University of Minnesota, Department of Otolaryngology and Otitis Media Research Center, MMC 396, 420 Delaware St. SE, Minneapolis, MN, 55455, United States c University of Minnesota, Biostatistics Design and Analysis Center, Clinical and Translational Science Institute, Room 223-21, 717 Delaware St. SE, Minneapolis, MN, 55414, United States d University of Minnesota, School of Public Health, Division of Epidemiology and Community Health, 1300 South Second Street, Suite 300, Minneapolis, MN, 55454, United States e University of Florida, College of Dentistry, JHM Health Science Center, PO BOX 100127, Gainesville, FL, 32610, United States b
a r t i c l e
i n f o
Article history: Received 15 September 2010 Received in revised form 23 December 2010 Accepted 4 January 2011 Keywords: Otitis media Overweight Taste
a b s t r a c t Introduction: Otitis media (OM) is a significant disease that affects nearly all children early in life. Recently, childhood overweight has become an epidemic. Past research has demonstrated that a history of OM is related to food preferences and overweight through proposed physiological mechanisms. The purpose of this study was to explore the relationship between recurrent OM (ROM)/tympanostomy tube treatment and overweight status. Methods: Data were analyzed from a prospective cohort of mothers and children recruited from 1991–1996 from a local health maintenance organization. ROM and tympanostomy tube status were obtained through a combination of physical exam and medical record abstraction. ROM and tympanostomy tube status were analyzed as categorical variables with weight-for-length (WFL) data from well child checks. Chi-square and logistic regression for univariate and multivariate analyses were performed. Results: 11.4% of children had a WFL measure at two years of age ≥95th percentile. Those children with a history of tympanostomy tube treatment had a significantly increased risk of having a WFL ≥95th percentile after controlling for birth weight, maternal prenatal smoking, maternal education, and family income (OR 3.32, 95% CI 1.43–7.72). The alternative hypothesis that children with larger WFL at two month of age would have a greater number of OM episodes by two years of age was not significant. Conclusion: The findings of this study are consistent with the hypothesis and prior research that OM treated with tympanostomy tubes is associated with overweight status. © 2011 Elsevier Inc. All rights reserved.
1. Introduction Otitis media (OM), or ear infection, is an inflammatory condition of the middle ear with or without involvement of the mastoid space. Acute OM (AOM) is defined as the presence of purulent fluid within the middle ear space with duration of less than three weeks. Otitis media with effusion (OME) is defined as the presence of fluid (serous or mucoid) that can occur as a post-inflammatory response to AOM from a viral infection or because of eustachian tube dysfunction. OM causes pain, fever, and temporarily reduces hearing. Children diagnosed with chronic/recurrent OM (COM/ROM) experience the greatest morbidity. Antibiotics are used in the treatment for AOM; however, surgical intervention such as myringotomy with or without tympanostomy tube placement is considered when children experience ROM (defined as greater than or equal to four episodes per year or greater than or equal to three episodes in six months) or develop a persistent effusion greater than three months [1]. ⁎ Corresponding author. Tel.: +1 612 625 3200; fax: +1 612 625 2101. E-mail addresses: [email protected] (H.M. Nelson), [email protected] (K.A. Daly), [email protected] (C.S. Davey), [email protected] (J.H. Himes), [email protected]fl.edu (D.J. Synder), [email protected]fl.edu (L.M. Bartoshuk). 0031-9384/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.physbeh.2011.01.002
OM prevention is a priority because it affects quality of life for both the child and the family [2–4], and may have long-term consequences, including impaired hearing [5,6]. Strategies to reduce OM incidence (e.g. xylitol, vaccine and risk factor reduction) have been somewhat successful [7–10], and since the routine use of 7-valent pneumococcal conjugate vaccine (PCV-7) in infancy, OM rates have declined. However, this disease remains one of the most common in early life, especially among those in childcare [11]. Childhood overweight has become epidemic, with the prevalence of this condition doubling over two decades among preschool children [12–14]. Between 1983 and 1995, the period during which data for this study were collected, weight-for-length (WFL) ≥85th percentile increased 18.3% (from 14.2% to 16.8%) and WFL ≥95th percentile increased 25% (5.6% to 7.0%) among 24–35 month-olds [14]. More recently (2003–2004), 26.2% of two to five year-olds were ≥85th percentile, and 13.9% were ≥95th percentile [15]. NHANES data show a steady increase in rates ≥95th percentile in children 2–5 years of age: 5% in 1976–80, 7.2% in 1988–94, 10.3% in 1999–2002, and 12.4% in 2003–06 [16]. A similar trend was seen for OM office visit rates, which more than doubled between 1975 and 1990 [17]. Overweight and obesity during childhood increase the risk of adult obesity and have both pediatric and adult health consequences (e.g.
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type 2 diabetes, hypertension, obstructive sleep apnea, and cardiovascular disease), and these conditions contribute to increased mortality in adulthood [18,19]. Reported predictors of childhood overweight and obesity have been suggested. Dubois and Girard examined factors related to preschoolers' weight status using a population-based cohort of children followed from birth to four and half years of age [20]. Overweight/obese status at age four and half years was associated with male gender during this period, maternal prenatal smoking history, being born into a lower socio-economic class (SEC) status as well as living in a lower SEC family at four and half years of age, height/weight gain in first five months of life, and parental overweight status [20]. Research has shown that OM history is related to both food preference and overweight and obesity [21–23]. The chorda tympani nerve (cranial nerve [CN] VII) passes through the middle ear, innervates the anterior tongue and carries taste information [24]. CN V and IX, the trigeminal and glossopharyngeal nerves, transmit temperature, touch and pain information, and CN IX also innervates the taste buds at the base of the tongue [25]. Central inhibitory connections exist among the cranial nerves, and damage to one nerve releases inhibition on the others, leading to changes in sensory perception [24]. Damage to the chorda tympani (CT) by inflammatory middle ear disease can lessen the taste function on the anterior tongue ipsilateral to the inflammation [26]. Exact mechanisms that account for the observed findings are unknown. One possible explanation is that inflammatory mediators and cytokines in middle ear effusion during ROM and COM damage the CT, which affects taste. Inflammatory cytokines can then upregulate MUC19 gene transcription. MUC19 is a gel-forming mucin that increases middle ear fluid viscosity and decreases mucociliary clearance, predisposing a child to persistent middle ear fluid [27,28]. Food preference data show that perception of sweet and fat vary with body mass index. Higher body mass index (BMI) is associated with decreased perception of sweetness as well as the palatability of fat in obese individuals more than in normal weight individuals [29]. In one preliminary unpublished study, young children with a history of ROM were more likely to have a higher intake of sugar and a lower intake of vegetables than children without a history of frequent OM episodes [21]. These studies led to the theory that OM alters taste perceptions by creating an inflammatory environment that leads to damage to the CT, and results in increased palatability of sweet and fat foods. This theory may then increase the risk of being overweight by altering food intake habits. Using data from the Early Otitis Media Study (EOM) and ROM and tympanostomy tube status as surrogates for middle ear disease, two hypotheses were tested to explore the theory of inflammatory ear disease being associated with weight [30]. The first hypothesis was that the number of OM episodes, ROM, and tympanostomy tube treatment would be associated with overweight status at two years of age. The alternative hypothesis was that overweight children were more likely to have middle ear disease. Here, we tested the theory that children with elevated WFL at two months of age would have more OM episodes, be more likely to have ROM, or to be treated with tympanostomy tubes than infants with lower WFL by two years of age. 2. Materials and methods Data from the EOM Study, a cohort followed for OM from birth to two years of age, were collected between 1991 and 1996 in the Minneapolis-St. Paul metropolitan area [30]. This study was designed to investigate predictors for early OM onset. Pregnant women were recruited from HealthPartners, an integrated health care-system in the metropolitan area, and from the Diana Project [31], a study designed to investigate effects of preconceptual and prenatal influences on infant birth weight. Eligible women were recruited for
the EOM Study during the third trimester, and their infants were enrolled at birth if they would receive care in the HealthPartners system. Infants with a craniofacial anomaly or other conditions predisposing to OM were excluded. Of the 596 eligible infants enrolled, 430 had complete prenatal, postnatal, and outcome data for investigation of the relationship between OM and overweight at two years of age; 538 were available to evaluate the alternative hypothesis that early overweight increased the risk for OM in later years. 2.1. Independent variable Physicians and nurse practitioners performed ear examinations and tympanometry at illness-related and well-child visits, and recorded data on study forms. At each clinic visit, the physician or pediatric nurse practitioner examined the child with pneumatic otoscopy using a standard protocol, and recorded tympanic membrane findings, symptoms, and diagnoses on a standard one-page data form. Additionally, tympanometry was performed at 2, 4, and 6 months, and utilized to determine the presence of middle ear fluid if visual exam was equivocal. If an ear form was not completed for a clinic or urgent care visit, study staff abstracted data from the medical record for that visit. Based on medical practitioners' experiences and exams utilizing components such as history (e.g. fever, ear pulling, and irritability) combined with physical exam which assessed tympanic membrane color, position (full, bulging, and retracted), or mobility (decreased or absent), a diagnosis of AOM (red bulging tympanic membrane associated with or without fever and decreased/absent tympanic mobility) or OME (dull tympanic membrane with decreased/absent mobility) was made. A new episode was defined as AOM or OME in either ear after a normal middle ear examination, or an episode of AOM ≥21 days after a diagnosis of AOM or OME. To assess reliability of the middle ear diagnosis as described above, validated otoscopists performed interobserver testing with a sample of 20 clinicians (κ = 0.54, 0.65). Clinicians' diagnoses were also compared to an algorithm in which OM was confirmed if two or more abnormal exam findings (tympanic membrane color, position, appearance, and mobility) were present. Kappa coefficient of agreement was 0.92 for examiner diagnosis compared with the algorithm described above [27]. The number of OM episodes was calculated and a dichotomous ROM variable was created. Greater than or equal to four OM episodes in twelve months was recorded as presence of ROM. We also speculated that children with persistent disease or more episodes of OM would be more likely to undergo tympanostomy tube placement. Thus status of tympanostomy tube placement would be a surrogate for severe middle ear disease. Tympanostomy tube status obtained from medical records was defined as a minimum of one set of tubes obtained in the first two years of life. 2.2. Dependent variable Length and weight data collected at two month and two year well child checks by clinic personnel were abstracted from medical records. 2.3. Demographics/risk factor/confounders Mailed questionnaires were used to collect maternal information during the third trimester and infant OM risk factors at two weeks and six months of age. Maternal subjects' self-reported breast feeding information was collected monthly. Risk factors data obtained from questionnaires included: prenatal smoking history, maternal OM history, daycare attendance, maternal education, and household income. Maternal prenatal smoking history was obtained by indicating if present, current amount smoked, and pack year history. Breast feeding history was collected by indicating if child was still being breastfed and duration of breast feeding. Daycare attendance information was
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collected as the type of daycare, hours spent per week, number and age range of children at the facility. Maternal education and household income were collected as categorical. Birth weight, weight and length at two months of age, and adenoidectomy history were obtained from medical records.
Infants ≥1.0 month and b3.0 months were considered two months of age, while those classified as two years of age included children ≥21.0 months and b27.0 months. OM was analyzed as a continuous variable (number of OM episodes per child) as well as categorical (0, 1–2, 3–5, and ≥6 episodes). ROM and tympanostomy tube status were analyzed as dichotomous variables. For the dependent variable, our analysis followed the approach of Mei et al. [14]. using two levels of overweight based on WFL percentiles to examine relative degree of overweight. WFL percentiles were calculated based on the 2000 Centers for Disease Control (CDC) Growth Charts [32]. Children were classified as ≥95th percent or b95th percentile. Based upon CDC classification, those children ≥95th percentile were classified as “obese”. For the two year of age WFL variable, children whose WFL was ≥85th percentile but b95th percentile were classified as “overweight”. Given the small number of children classified as “obese”, we also examined WFL ≥85th percentile. Thus a second dichotomous variable was created—children ≥85th percentile vs. those b85th percentile to assess the risk of being at risk for overweight/obese. To analyze our second hypothesis and to control for potential confounding of WFL status at two years of age, a third dichotomous variable was created utilizing WFL data at two months of age (WFL ≥85th vs. b85th percentile). The following risk factors were analyzed as dichotomous: prenatal smoking history (yes vs. no), breast feeding at 6 months of age (breast fed to at least 6 months vs. stopped before 6 months), daycare attendance at 6 months (yes vs. no), maternal education (Nhigh school vs. ≤high school), and household income (N$50,000 vs. ≤$50,000). Birth weight was analyzed as continuous. Analyses were performed with SAS version 9.1 statistical software (SAS Institute, Cary NC). Descriptive statistics were calculated including percentages and means with standard deviations. ROM or tympanostomy tube status relationship with WFL outcomes was investigated. Chi-square test for independence without continuity correction was used to examine the relationship between dichotomous variables to provide univariate analysis. All tests were two-tailed. Logistic regression was utilized to assess multivariate analysis and control for potential confounders. A p valueb 0.05 was considered statistical significant. 3. Results
35 30
% with tubes
2.4. Analysis
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25 20 15 10 5 0
0-1 OM
2- 5 OM
6- 8 OM
9+ OM
Number of OM episodes Fig. 1. Percentage of children treated with tubes by number of OM episodes by age two years.
24 months) and risk factors did not reveal any important differences among those with and without two-year WFL data, although girls were less likely to have 24 month height and weight data.
3.2. Hypothesis 1—univariate analysis With chi-square analyses, the number of OM episodes as analyzed by category was not significantly related to ≥95th percentile or ≥85th percentile at two years of age (p = 0.53, 0.62 respectively). However, ROM history was significantly associated with ≥ 95th percentile (14.8% vs. 8.4%, p = 0.037), but not with ≥85th percentile (26.1% vs. 19.4%, p = 0.10) at two years of age (Tables 1a and 1b). Tympanostomy tube treatment by age two, a proxy for inflammatory middle ear disease, was significantly associated with both ≥95th percentile and ≥85th percentile at two years (Tables 2a and 2b; p b 0.0001, 0.002 respectively).
3.3. Hypothesis 1—multivariate analysis Logistic regression models to predict ≥95th percentile or ≥85th percentile at two years of age included tube treatment, ROM, ≥85th percentile status at two months of age, family income, breast feeding, and daycare (Table 3). Since only 4% of the cohort was ≥95th percentile at two months of age, we used ≥85th percentile at two months of age in the logistic model to increase the sample size when adjusting for two month WFL.
3.1. Descriptive statistics Ninety-six percent of the cohort was white (based on parental race), and 53% was male. Mean age at final weight and length measurement was 24.1 months (standard deviation 0.60) and mean WFL percentile was 54.2% (standard deviation 32.1%). Mean number of ear examinations was 23.5 (standard deviation 10.0). Forty-seven percent had ROM in the first and/or second year of life, and 14% were treated with tympanostomy tubes during this period. The total number of OM episodes by age two was significantly associated with tube treatment (Fig. 1, p b 0.0001). Thirty-seven percent of those with ≥9 OM episodes compared with 8.6% of those with 2 to 5 episodes were treated with tubes. By two years of age, 22.6% were classified ≥ 85th percentile and 11.4% were considered ≥ 95th percentile for WFL. The cohort had 538 infants with two month WFL data, 396 of these also had two year WFL data, and 34 had only two year WFL data. Comparing outcomes (ROM, tubes, and number of OM episodes in
Table 1a Recurrent OM vs. overweight status at 95th percentile. Recurrent OM
≥ 95th percent
b95th percentile
Yes (n = 203) No (n = 227) Total (n = 430)
14.8% (n = 30) 8.4% (n = 19) 11.4% (n = 49)
85.2% (n = 173) 91.6% (n = 208) 88.6% (n = 381)
p = 0.037, Chi-square analysis.
Table 1b Recurrent OM vs. overweight status at 85th percentile. Recurrent OM
≥ 85th percent
b85th percentile
Yes (n = 203) No (n = 227) Total (n = 430)
26.1% (n = 53) 19.4% (n = 44) 22.6% (n = 97)
73.9% (n = 150) 80.6% (n = 333) 77.4% (n = 381)
p = 0.10, Chi-square analysis.
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Table 2a Tympanostomy tubes vs. overweight status at 95th percentile.
Table 4a ≥95th percentile at two months of age and number of OM episodes by two years of age.
Tympanostomy Tubes
≥95th percent
b95th percentile
Yes (n = 60) No (n = 370) Total (n = 430)
26.7% (n = 16) 8.9% (n = 33) 11.4% (n = 49)
73.3% (n = 44) 91.1% (n = 337) 88.6% (n = 381)
p b 0.0001, Chi-square analysis.
Overweight at 2 months of age
Number of OM episodes None
1–2
3–5
≥6
≥95th percentile 0% (n = 0) 28.6% (n=6) 52.4% (n=11) 19.1% (n=4) (n=21) b 95th percentile 7.0% (n=36) 21.5% (n=111) 36.2% (n=187) 35.4% (n=183) (n=517) Total (n=538) 6.7% (n=36) 21.7% (n=117) 36.8% (n=198) 37.4% (n=187) p = 0.18, Chi-square analysis.
Table 2b Tympanostomy tubes vs. overweight status at 85th percentile. Tympanostomy Tubes
≥ 85th percent
b85th percentile
Yes (n = 60) No (n = 370) Total (n = 430)
38.3% (n = 23) 20.0% (n = 74) 22.6% (n = 97)
61.7% (n = 37) 80.0% (n = 296) 77.4% (n = 381)
p = 0.002, Chi-square analysis.
Factors significantly related to ≥95th percentile at two years were tube treatment (crude OR 3.72, adjusted OR 3.32, 95% confidence interval 1.43, 7.72, p = 0.005) and ≥85th percentile at two months of age (crude OR 5.36, 95% confidence interval 2.60, 11.05, p b 0.0001, adjusted OR 6.31, 95% confidence interval 2.90, 13.73, p b 0.0001). Substituting ≥85th percentile as the outcome at two years resulted in lower odds ratio estimates for tube treatment (crude OR 2.49, adjusted OR 2.27, 95% confidence interval 1.13, 4.54, p = 0.02), and ≥85th percentile at two months of age (crude OR 4.30, 95% confidence interval 2.28, 8.14, p b 0.0001; adjusted OR 4.75, 95% confidence interval 2.42, 9.33, p b 0.0001). As expected, ≥85th percentile at two months of age was significantly related to being ≥95th percentile and ≥85th percentile (crude OR 3.72, adjusted OR = 6.31, 95% CI 2.90, 13.73; crude OR 2.49, adjusted OR= 4.75, 95% CI 2.42, 9.33, respectively).
3.4. Hypothesis 2 The hypothesis that infant size at two months of age was related to later OM was tested with Chi-square tests and logistic regression models. Status of ≥95th or ≥85th percentile at two months was not significantly associated with 1) number of OM episodes (p = 0.18, 0.37 respectively, Tables 4a and 4b), 2) ROM by two years of age (Tables 5a and 5b; crude OR 0.73 and 1.19) or 3) tube treatment by two years of age (Tables 6a and 6b; crude OR 0.76, and 0.90). The adjusted odds ratio of having a history of ROM at two years of age was 1.12 (p = 0.50) for those ≥95th percentile at two months of age (vs. b95th percentile) and 1.31 (p = 0.51) for those ≥85th percentile at two months of age (vs. b85th percentile). The odds of having a history tympanostomy tube treatment by two years of age were 1.04 (p = 0.71) for those children ≥95th percentile at two months of age (vs. b95th percentile) and 0.95 (p = 0.80) for those children ≥85th percentile at two months of age (vs. 85th percentile).
Table 4b ≥85th percentile at two months of age and number of OM episodes by two years of age. Overweight at 2 months of age
Number of OM episodes None
1–2
3–5
≥6
≥85th percentile 1.6% (n=1) 22.2% (n=14) 41.3% (n=26) 34.9% (n=22) (n=63) b 85th percentile 7.4% (n=35) 21.7% (n=103) 36.2% (n=172) 34.7% (n=165) (n=475) Total (n=538) 6.7% (n=36) 21.7% (n=117) 36.8% (n=198) 37.4% (n=187) p = 0.37, Chi square analysis.
In multivariate logistic regression, two month size (≥ 95th percentile or ≥85th percentile) was not significantly associated with ROM at two years of age (p = 0.80, p = 0.34 respectively). Similarly, ≥95th percentile and ≥85th percentile at two months did not predict tubes by age two (p = 0.96, 0.91 respectively).
4. Discussion Our findings demonstrate a significant relationship between preceding tympanostomy tube treatment and ≥ 95th percentile and ≥85th percentile for WFL in two year-olds after controlling for risk factors and confounders. This finding supports current published studies. A Korean case–control study examined the relationship between COM and BMI in 2–7 year-olds [33]. One hundred fifty-five cases had tympanostomy tube surgery, and 118 controls had surgery for another indication. All cases that underwent tube treatment were diagnosed with OME based upon otoscopic examination or tympanograms. BMI was significantly higher in cases than in controls (mean 22.0 vs. 16.3, p=0.01). The same group recently repeated the study by further dividing the group into four weight categories (underweight b5th percentile, Table 5a ≥95th percentile at two months of age and history of ROM by two years or age. Percentile at 2 months of age
≥ 95th percentile (n = 21) b 95th percentile (n = 517) Total (n = 538)
Recurrent OM Yes
No
38.1% (n = 8) 45.7% (n = 236) 45.4% (n = 244)
61.9% (n = 13) 54.4% (n = 281) 54.6% (n = 294)
p = 0.50, Chi-square analysis. Table 3 Predictors for ≥95th percentile/≥85th percentile at 2 years of age with logistic regression. Risk factors
≥ 95th percentile odds ratio (95% CI)
≥ 85th percentile odds ratio (95% CI)
Tympanostomy tubes Recurrent OM ≥ 85th at 2 months Family income N $50 K Breast feeding at 6 months Daycare at 6 months
3.32 1.13 6.31 1.55 0.68 1.13
2.27 1.10 4.75 0.92 0.71 1.01
(1.43, (0.54, (2.90, (0.75, (0.32, (0.54,
7.72) 2.38) 13.73) 3.19) 1.44) 2.37)
(1.13, (0.64, (2.42, (0.55, (0.41, (0.59,
4.54) 1.89) 9.33) 1.56) 1.24) 1.75)
Table 5b ≥85th percentile at two months of age and history of ROM by two years or age. Percentile at 2 months of age
≥ 85th percentile (n = 63) b 85th percentile (n = 475) Total (n = 538) p = 0.51, Chi-square analysis.
Recurrent OM Yes
No
49.2% (n = 31) 44.8% (n = 213) 45.4% (n = 244)
50.8% (n = 32) 55.2% (n = 262) 54.6% (n = 294)
H.M. Nelson et al. / Physiology & Behavior 102 (2011) 511–517 Table 6a ≥95th percentile at two months of age and tympanostomy tube status at two years of age. Percentile at 2 months of age
≥ 95th percentile (n = 21) b 95th percentile (n = 517) Total (n = 538)
Tympanostomy tubes Yes
No
9.5% (n = 2) 12.2% (n = 63) 12.1% (n = 65)
90.5% (n = 19) 87.8% (n = 454) 87.9% (n = 473)
p = 0.71, Chi-square analysis.
Table 6b ≥ 85 percentile at two months of age and tympanostomy tube status at two years of age. Percentile at 2 months of age
≥85th percentile (n = 63) b85th percentile (n = 475) Total (n = 538)
Tympanostomy tubes Yes
No
11.1% (n = 7) 12.2% (n = 58) 12.1% (n = 65)
88.9% (n = 56) 87.8% (n = 417) 87.9% (n = 473)
p = 0.80, Chi-square analysis.
normal 5–84th percentile, overweight 85–94th percentile and obese ≥95th percentile) and specifically examining the risk of overweight status [34]. The authors conclude that the frequency of OME treated with tubes was significantly higher among those classified as obese but OME was not related to other weight classifications. Additionally, they assessed the relationship of OME severity resulting in tube placement with body weight. They found no correlation with mean frequency of tube insertion and weight status in the experimental group, and concluded that weight status does not correlate with OME severity. These data are cross sectional and cannot be used to determine a causal relationship. In this study, ROM history was not associated with weight status which would agree with the argument that severity of the disease may not indicate potential for CT damage. It is possible that our association with tube treatment is a better indicator for severity of disease. Based on clinical guidelines, tube treatment is warranted for ROM with poor response to antibiotics or persistent OME. Additionally, it may be that tube treatment is a proxy for the number of OM episodes and it is the actual number of OM episodes that increases the likelihood of creating an environment that would lead to CT damage. It is possible that there is direct damage to CT during the actual tympanostomy tube insertion. Middle ear surgery has been implicated in injury to the CT with resulting perceived changes in taste [25,35,36]. Compared to myringoplasty/tympanoplasty and mastoidectomy patients, tympanotomy patients had the highest rates of taste disturbance. Fifty-eight percent of those with stretched CT, 10% with sectioned CT, and 3% without CT injury reported changes in taste. Moreover, the authors conclude that individuals who did not have history of cholesteatoma disease had a greater perception of taste changes than those with a history. The authors speculate that the inflammatory diseases had a longer period to cause a gradual change in taste vs. those with a traumatic injury. In the context of this study, damage from surgery is less likely given the location of the nerve and the potential for injury by placing a tube. The other surgeries studied above put the operator in close proximity to the nerve with a greater potential to stretch the nerve (e.g. entering the middle ear space through a transcanal approach) or drilling on the CT. A potential confounder in this relationship between tympanostomy tubes status and WFL is the presence of adenoid hypertrophy. Literature has established the relationship with adenoid hypertrophy and development of OM either through mechanical obstruction of the eustachian tube orifice or as a biofilm source. Konstantinidis et al. explored the ability to smell and taste pre and post adenoidectomy in
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children 5–9 years of age as compared to a control group. Three months after surgical removal of adenoids, children had significant improvement in olfaction as compared to controls. Additionally, these children were noted to have an increase in BMI in the follow up period [37]. In our study, no children underwent adenoidectomy based upon medical records obtained up to two years of age. Additionally, nasopharyngeal exams were not performed to assess for adenoid hypertrophy. It can possibly be assumed that no child required an adenoidectomy and thus no confounding occurred. However this is a limitation of the study given we do not know the adenoid status of the children. Compared to prior studies, we did not see an association with ROM and WFL. Several studies have assessed the relationship of CT damage and changes to taste in the presence of inflammatory ear disease. Goyal et al. performed a prospective study of 85 patients with unilateral chronic inflammatory middle ear disease and then evaluated gustatory function on both sides of the tongue. Mean taste scores were significantly lower on the affected side as compared to the healthy ear (mean 9.16 vs. 13.24, p b 0.0001). Interestingly, this difference was not necessarily perceived by the subject. Additionally, duration of disease did not significantly affect the taste score [38]. It is possible that we did not accurately diagnose ROM; although we feel that the combination of the validated ear exams with medical history provided true assessment of the subjects' ear status. It is also possible as described above that it is not necessarily the duration of the disease (e.g. COM) but more number of episodes of inflammatory disease overall that are more likely to cause injury. Another consideration is that the subject needs bilateral disease to truly affect subjective and objective taste perception. This may have been why tympanostomy tubes would be a better predictor as it may indicate bilateral disease as well as potential for bilateral trauma to CT. However, this goes against literature as discussed above. First, the presence of inflammatory disease can provide changes to taste that are gradual in process and are not perceived by the subject [38]. Second, Bartoshuk et al. discuss several studies whereby anesthesia to CT on one side results in intensification of glossopharyngeal on the contralateral side [29]. Thus bilateral disease would not provide the same effect on taste intensification. It is also possible that tympanostomy tubes were the confounders in prior published literature regarding ROM and WFL. As demonstrated in Fig. 1, with more episodes of OM, the subject is more likely to have tympanostomy tubes placed. The more episodes a subject has, the more likely they would be classified as having a ROM history. We do see an association in ≥95th percentile group and ROM in univariate analysis (Table 1a). This association goes away in multivariate analysis after controlling for tube status. 4.1. Reverse hypothesis not supported What is unique to our study compared to prior published literature is examination of the reverse hypothesis. It has been assumed that children with a greater WFL were more likely to develop ROM or have a greater risk of undergoing tympanostomy tubes. The assumption behind this is that children with greater WFL have a larger fat pad around the eustachian tube leading to dysfunction that can result in a greater likelihood to develop inflammatory ear disease. In this study, there was no evidence to support the hypothesis that overweight status at two months was associated with the number of OM episodes, ROM or tube treatment in the first two years of life. In other words, having a larger WFL earlier in life did not predict developing inflammatory ear disease later in life. 4.2. Mechanisms are not clear This study does not provide information on mechanism and works within the theory that CT damage is a step in this process. It has been shown that inflammatory conditions of the middle ear can result in
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objective gustatory changes. Sano reported that patients with unilateral COM or cholesteatoma were significantly more likely than those without these conditions to have an increase in taste threshold on the side of the tongue ipsilateral to the affected ear [36]. However, this study nor published literature, has shown that this taste change is the cause for increased weight gain. More recently, Seaberg et al. directly measured CT function in children (ages 5–18 years) with and without a previous history of AOM to determine relationship to BMI [39]. Using electrogustometric thresholds as a measure of CT function, they found no relationship with nerve function and OM history as well as no association with BMI. The status of AOM was determined by asking subjects/parents to quantify the number of OM episodes by memory which could result in a significant recall bias. Additionally, BMI was calculated without controlling for subjects' gender and age. This study does bring into question the mechanism of CT. There is a possibility that this relationship is confounded and no true statistical relationship exists. We controlled for known confounders related to weight and OM such as breast feeding, early weight gain, prenatal smoking history, SEC, and adenoid status. An unknown variable could also confound the relationship between middle ear disease and increased weight-for-length. Forty-seven percent had ROM in the first and/or second year of life, and 14% were treated with tympanostomy tubes during this period. Office visit rates for OM more than doubled between 1975 and 1990 among children younger than two years of age [17]. Data from Healthy People 2010 show that among children ≤3 years, OM visit rates initially declined from 1160/1000 in 1997 to 695/1000 in 2004, but then increased to 840/1000 in 2006 [40]. The percentage of children undergoing tympanostomy tube treatment in this study is lower than other published studies. Myer and Frances found 30.11% of children under age two who underwent tympanostomy tubes when examining a large HMO cohort during same time period [41]. In this cohort, by two years of age, 22.6% of the children were classified as ≥85th percentile and 11.4% were considered ≥95th percentile. Overweight in early childhood has also been increasing in the last two decades. The proportion of overweight two- to five-year-olds (≥95th percentile) increased 44% from 5.0% to 7.2% between 1976–80 and 1988–94 [15]. More recently, overweight increased 20% in this age group (10.3% to 12.4%) between 1999–2002 and 2003–06 [15]. Among 24–35 month olds, ≥95th percentile increased 25% from 1983 to 1995, the period of the cohort study [14]. The proportion of ≥85th percentile children in this cohort (22.6%) is consistent with the CDC defined standard of ≥85th percentile WFL. 4.3. Study benefits Data in the original cohort study were collected prospectively, so determination of OM history and risk factors preceded assessment of overweight at two years. Tube treatment was documented in the medical record and on study visit forms. Criteria for OM diagnosis were specified in the original study which compared ear exam findings of clinic pediatricians and nurse practitioners against experienced and validated examiners [30]. The relationship between ROM/tubes, taste, and overweight is consistent with clinical studies in adults [22,23,29] and population-based studies of children [42]. 4.4. Study limitations The original cohort study was not designed to examine relationships between OM/tube treatment and infant weight status. Confounders obtained were not specifically related to WFL such as exercise, television time or food intake. Ear examination data were used to determine whether a child had chronic OME (middle ear effusion persisting for three or more months, verified monthly) rather than separate OM episodes. However, very few children met the criteria for chronic OME, so it was not included as an independent variable. Additionally, the
study was not designed to explore the mechanism for this relationship. Ideally, it would be beneficial to include taste information from the children; however, the relationships in this study were post-hoc analysis. Future direction would be to assess a population where taste could be assessed in conjunction with middle ear inflammatory disease, tympanostomy tube treatment, and WFL. 5. Conclusion Tympanostomy tube treatment was associated with overweight in two year-olds in this study. The reverse hypothesis that early weight status was related to later OM, ROM or tube treatment was not supported. Our study suggests that tympanostomy tube status may be a better surrogate for middle ear disease. Tube treatment for COM and ROM may be contributing to the current epidemic of overweight in children through possible mechanisms such as damage to the CT during surgery, or from inflammatory mediators and cytokines present in middle ear effusion, resulting in changes in taste and increased intake of sweet and fat foods. However, this relationship needs to be further explored with prospective studies and evaluation of confounders. References [1] Bailey BJ, Johnson JT, Newlands SD. Head and neck surgery – otolaryngology, 4th edition, Volume 1. Philadelphia, PA: Lippincott Williams & Wilkins; 2006. p. 1265–75. Chapter 91. [2] Boruk M, Lee P, Faynzilbert Y, Rosenfeld RM. Caregiver well-being and child quality of life. Otolaryngol Head Neck Surg 2007;136:159–68. [3] Brouwer CN, Rovers MM, Maille AR, Veenhoven RH, Grobbee DE, Sanders EA, et al. The impact of recurrent acute otitis media on the quality of life of children and their caregivers. Clin Otolaryngol 2005;30:258–65. [4] Lee J, Witsell DL, Dolor RJ, Stinnett S, Hannley M. Quality of life of patients with otitis media and caregivers: a multicenter study. Laryngoscope 2006;116: 1798–804. [5] American Academy of Pediatrics, American Academy of Family Physicians. Clinical practice guideline: diagnosis and management of acute otitis media. Pediatrics 2004;113:1451–65. [6] Rosenfeld RM, Culpepper L, Doyle KJ, Grundfast KM, Hoberman A, Kenna MA, et al. Clinical practice guideline: otitis media with effusion. Otolaryngol Head Neck Surg 2004;130(5 Suppl):S95–S118. [7] Eskola J, Kilpi T, Palmu A, Jokinen J, Haapakoski J, Herva E, et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med 2001;344:403–9. [8] Kilpi T, Ahman H, Jokinen J, Lankinen KS, Palmu A, Savolainen H, et al. Protective efficacy of a second pneumococcal conjugate vaccine against pneumococcal acute otitis media in infants and children: randomized, controlled trial of a 7-valent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine in 1666 children. Clin Infect Dis 2003;37:1155–64. [9] Uhari M, Kontiokari T, Koskela M, Niemela M. Xylitol chewing gum in prevention of acute otitis media: double blind randomised trial. Br Med J 1996;313:1180–3. [10] Bonuck KA, Freeman K, Trombley M. Randomized controlled trial of a prenatal and postnatal lactation consultant intervention on infant health care use. Arch Pediatr Adolesc Med 2006;160:953–60. [11] Bradley RH, The National Institute of Child Health and Human Development Early Child Care Research Network. Child care and common communicable diseases. Arch Pediatr Adolesc Med 2001;155:481–8. [12] Krebs NF, Jacobson MS, Baker RD, Green FR, Hegeman MB, Jaksic T, et al. American academy of pediatrics committee on nutrition. prevention of pediatric overweight and obesity. Pediatrics 2003;112:424–30. [13] Ogden CL, Flegal KM, Carroll MD, Johnson CL. Prevalence and trends in overweight among US children and adolescents, 1999–2000. JAMA 2002;288:1728–32. [14] Mei Z, Scanlon KS, Grummer-Strawn LM, Freedman DS, Yip R, Trowbridge FL. Increasing prevalence of overweight among US low-income preschool children: Centers for Disease Control and Prevention Pediatric Nutrition Surveillance, 1983 to 1995. Pediatrics 1998;101:12, doi:10.1542/peds.101.1.e12. [15] Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999–2004. JAMA 2006;295: 1549–55. [16] Centers for Disease Control and Prevention. NHANES surveys (1976–1980 and 2003–2006). http://www.cdc.gov/obesity/childhood/prevalence.html. [17] Schappert SM. Office visits for otitis media: United States 1975–90. Hyattsville MD, National Center for Health Statistics. Vital Health Stat 1992;214:1–20. [18] Nieto FJ, Szklo M, Comstock GW. Childhood weight and growth rate as predictors of adult mortality. Am J Epidemiol 1992;136:201–13. [19] DiPietro L, Mossberg HO, Stunkard AJ. A 40-year history of overweight children in Stockholm: life-time overweight, morbidity, and mortality. Int J Obes Relat Metab Disord 1994;18:585–90. [20] Dubois L, Girard M. Early determinants of overweight at 4.5 years in a populationbased longitudinal study. Int J Obes 2006;30:610–7.
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