Cognition After Early Tonsillectomy forMild OSAKaren A. Waters, MBBS, FRACP, PhD, GCCM,a,b Jasneek Chawla, MBBS, BSC(Hons), FRACP,c,d Margaret-Anne Harris, MBBS, FRACP,c

Helen Heussler, MBBS, FRACP, DM,e Robert J. Black, MBBS, FRACS, FRCS(Ed), FACS,f Alan T. Cheng, MBChB, BHB, FRACS,a,b

Kurt Lushington, PhD, MPsychg

abstractOBJECTIVES: It remains uncertain whether treatment with adenotonsillectomy for obstructivesleep apnea in children improves cognitive function. The Preschool Obstructive Sleep ApneaTonsillectomy and Adenoidectomy study was a prospective randomized controlled study inwhich researchers evaluated outcomes 12 months after adenotonsillectomy compared with nosurgery in preschool children symptomatic for obstructive sleep apnea.

METHODS: A total of 190 children (age 3–5 years) were randomly assigned to earlyadenotonsillectomy (within 2 months) or to routine wait lists (12-month wait, noadenotonsillectomy [NoAT]). Baseline and 12-month assessments included cognitive andbehavioral testing, medical assessment, polysomnography, and audiology. The primaryoutcome was global IQ at 12-month follow-up, measured by the Woodcock Johnson III BriefIntellectual Ability (BIA). Questionnaires included the Pediatric Sleep Questionnaire, ParentRating Scale of the Behavioral Assessment System for Children–II, and Behavior RatingInventory of Executive Function, Preschool Version.

RESULTS: A total of 141 children (75.8%) attended baseline and 12-month assessments, and BIAwas obtained at baseline and 12-month follow-up for 61 and 60 participants in theadenotonsillectomy versus NoAT groups, respectively. No cognitive gain was found afteradenotonsillectomy compared with NoAT, adjusted for baseline; BIA scores at 12-monthfollow-up were as follows: adenotonsillectomy, 465.46 (17.9) versus NoAT, 463.12 (16.6)(mean [SD]). Improvements were seen for polysomnogram arousals and apnea indices and forparent reports of symptoms (Pediatric Sleep Questionnaire), behavior (Behavior AssessmentSystem for Children behavioral symptoms, P = .04), overall health, and daytime napping.

CONCLUSIONS: Structured testing showed no treatment-attributable improvement in cognitivefunctioning of preschool children 12 months after adenotonsillectomy compared with NoAT.Improvements were seen after adenotonsillectomy in sleep and behavior by usingpolysomnogram monitoring and parental questionnaires.

WHAT’S KNOWN ON THIS SUBJECT: Studies to evaluate changes inneurocognition after adenotonsillectomy for obstructive sleep apneasuggest that younger children may have potential for greaterimprovement. The previous study with a randomized design was inschool-aged children.

WHAT THIS STUDY ADDS: This randomized study of preschool childrenshowed reduced frequency of day naps and confirmedpolysomnographic and behavioral improvements afteradenotonsillectomy compared with those still awaiting surgery, butour primary analysis showed no improvement in global IQ.

To cite: Waters KA, Chawla J, Harris M, et al. CognitionAfter Early Tonsillectomy for Mild OSA. Pediatrics. 2020;145(2):e20191450

aDepartment of Sleep Medicine, The Children’s Hospital at Westmead, Westmead, Australia; bDiscipline of Childand Adolescent Health, Faculty of Medicine, The University of Sydney, Sydney, Australia; cDepartment of PaediatricRespiratory and Sleep Medicine, Queensland Children’s Hospital, Brisbane, Australia; dMater Medical ResearchInstitute, Faculty of Medicine and eCentre for Children’s Health Research, The University of Queensland, Brisbane,Australia; fDepartment of Paediatric Otolaryngology Head and Neck Surgery, Children’s Health Queensland, SouthBrisbane, Australia; and gSchool of Psychology, Social Work and Social Policy, University of South Australia,Adelaide, Australia

Dr Waters was the lead investigator and contributed to conception, design, overseeing studyprogress, collation and interpretation of data, and drafting and revising the article; Dr Chawlacontributed to collation and interpretation of data and drafting and revising the article; Dr Harriscontributed to conception and design, oversight of study progress, and drafting and revising thearticle; (Continued)

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Most pediatric studies evaluatingcorrelations between intellectualfunction and obstructive sleep apnea(OSA) have studied school-agedchildren. Deleterious impacts ofsnoring and OSA are reported onbehavior and aspects of cognitivefunction in children, with emphasis onexecutive function regardless of OSAseverity.1 The first line of treatment ofchildhood OSA is adenotonsillectomy.There is general agreement thatchildren’s behavior improves aftertreatment with adenotonsillectomy,2

but impacts of treatment onintellectual function are less clear.

In a meta-analysis of cross-sectionalstudies, researchers concluded thatattention-executive function andverbal ability improve afteradenotonsillectomy compared withchildren’s own baseline and thatattention-executive function andmemory are restored.3,4 In 2 studiesin preschool children, researchersfound IQ values initially below thenormal mean of 100 and reportedincreases at follow-up (90.2 6 9.4increased to 102.2 6 7.2 [P , .001]and 82.5 6 14.0 increased to 87.2 614.7 [P = .02]), respectively).5,6 Songet al3 conclude that preschoolchildren may show more recoverythan school-aged children, requiringmore studies in this age group.7

One previous randomized study ofadenotonsillectomy, undertaken inschool-aged (age 5–9 years) children,was the Childhood AdenotonsillectomyTrial (CHAT) study. In the primaryanalysis, investigators found no changein measures of attention or executivefunction at 7-month follow-up afteradenotonsillectomy, compared withcontrols who had not undergonesurgery.8 Further analysis, modifiedfrom the original protocol, suggestedsmall but positive effects oftonsillectomy on tests of nonverbalreasoning, attention, and fine motorskills that correlated to bothrespiratory disturbances and sleepquality.9 Effects on younger childrenremain uncertain because this, the

most comprehensive study to date,targeted school-aged children.9,10

Given that children of younger age arein critical periods for braindevelopment, and neural pathways forexecutive function are established bymiddle childhood, it was important toevaluate this question in youngerchildren.11

The current randomized study (thePreschool Obstructive Sleep ApneaTonsillectomy and Adenoidectomy[POSTA] study) was undertaken inpreschool children (3–5 years old) withthe goal of evaluating whetheradenotonsillectomy improvedintellectual function after (early)adenotonsillectomy in this younger agegroup. We compared outcomes tochildren still waiting for surgery at thetime of their 12-month follow-up (noadenotonsillectomy [NoAT]). Ourhypothesis was that a cohort ofchildren, younger than in previousstudies and with a longer recovery timeof 12 months, would show improvedcognition after adenotonsillectomycompared with controls who were stillawaiting surgery (NoAT).

METHODS

Design and Setting

This multicenter, randomizedcontrolled study was undertakenat 3 Australian tertiary children’shospitals. The protocol has beenpreviously published.12 The trial wasregistered with the Australian andNew Zealand Clinical Trials Registry(registration numberACTRN12611000021976).

Centralized ethical approval wasobtained from the human researchethics committee at The Children’sHospital at Westmead (CHW) and ateach site (ethics approval numberHREC/14/SCHN/332). Writteninformed consent was obtained fromthe parent or caregiver of theparticipating children. Regularteleconferences and/or face-to-facemeetings were held among theinvestigators to discuss problems and

ensure adherence to the protocol. Thestudy was funded by government andphilanthropic agencies with nocommercial support. All authors areresponsible for the completeness andaccuracy of the data.

Eligibility and Randomization

Children were eligible if they were 3 to5 years of age, without major medicalcomorbidities, and referred withsymptoms of OSA to either the ear, nose,and throat (ENT) or sleep medicineservices at participating hospitals.

The Pediatric Sleep Questionnaire(PSQ)13 was used to screen forsymptoms of OSA, and a positive PSQscore (.30% of positive answers) ledto further evaluation. The secondaryinclusion criterion was an obstructiveapnea hypopnea index (OAHI) value of#10 per hour, so children withprimary snoring and with mild ormoderate OSA were included.Eligibility required ENT evaluation assuitable for adenotonsillectomy,normal audiometry, and ability toundertake neurocognitive testing inEnglish. Baseline evaluations includedreview by a pediatric sleep physicianand an ENT surgeon, overnightpolysomnography, neurocognitivetesting by a psychologist, andquestionnaires completed by theparents to assess the child’s executivefunction and behavior. Aftercompleting baseline evaluations,children were randomly assigned toadenotonsillectomy or NoAT groups.Because fewer children were likely tohave higher apnea hypopnea index(AHI) values, we used blockrandomization for AHI values ,5 or$5 obstructive respiratory events perhour to ensure that those with higherOAHI values were evenly distributedbetween the adenotonsillectomy andNoAT groups. Randomization wascentralized. As children wererecruited, investigators telephoned anadministrative assistant at CHW (whowas otherwise uninvolved in theproject) to receive randomlygenerated assignments using

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a randomization sequence provided bya statistician.

When the study began, nonurgentsurgical wait lists for children with mildto moderate OSA averaged 12 monthsor more at all participating hospitals sothat surgery after a 12-month follow-up visit was considered routine care.For those randomly assigned toadenotonsillectomy in this study,surgery was within 2 months. Childrenwith an AHI score of .10 events perhour were excluded and managed viaclinical pathways for severe OSA,including adenotonsillectomy. Otherexclusions included inability to performthe neurocognitive testing in Englishand an abnormal hearing test result(bilateral hearing loss .35 dB).Children in the routine waiting groupdid not receive any medical treatmentduring the period while they werewaiting for surgery.

Assessments

Children underwent standardizedpolysomnography, medical review,audiology, and cognitive andbehavioral assessments at baselineand at 12-month follow-up. Cognitiveand behavioral testing wasadministered and scored by qualifiedand experienced psychologists understandard test conditions. Testing wascompleted in 1 session at a time ofconvenience to the parents orcaregiver. The psychologistperforming the testing was blinded tothe random assignment of the subject,and parents were coached to avoiddisclosure. Scoring was undertakenelectronically. Additional details arein the Supplemental Information.

Outcome Measures

Neuropsychological Testing

The Woodcock Johnson III (WJ-III)Test of Cognitive abilities was used.It is used to measure cognitivefunction in individuals from age2 years to adulthood.

The Brief Intellectual Ability (BIA)score combines comprehensionknowledge (verbal ability), fluid

reasoning (thinking ability), andprocessing speed (efficiency inperforming cognitive tasks) in a shortbut reliable measure of intelligence.The BIA score correlates well with theGeneral Intellectual Ability (GIA) andother measures of intellectual ability.Many younger children could notcomplete all the tests required togenerate a GIA score, so the BIA score,obtained in a greater proportion ofthe participants, was used as theprimary outcome measure.

The GIA reflects the best weightedcombination of tests that account forthe largest portion of the variance ina collection of tests and does not varymuch with age. The GIA is a compositeof oral vocabulary, number series,verbal attention, letter patternmatching, phonological processing,story recall, and visualization.

The Australian Adaptation NormativeWJ-III software program was used togenerate test and functional values(WJ-III Normative UpdateCompuScore and Profiles Program;Riverside; Houghton, Mifflin andHarcourt). The mean (SD) percentiles,z scores, and W scores (taskproficiency) are reported.

Questionnaires of Behavior andExecutive Function (BehaviorAssessment System for Children ParentRating Scale, Behavior Rating Inventoryof Executive Function, and BehaviorRating Inventory of Executive Function,Preschool Version)

Age-appropriate questionnaires ofexecutive function, parental stress,and behavior were undertaken atbaseline and 12-month assessments.

The Behavior Assessment System forChildren–II (BASC 2) Parent RatingScale (PRS) was used to assesschildren’s behavior.14 Thequestionnaire for the preschool (ages2–5) age group includes 139 items ina 4-choice response format to provideclinical and adaptive measures ofbehavior, and all items were evaluated.

The Behavior Rating Inventory ofExecutive Function, Preschool Version

(BRIEF-P) was used. This has 63 itemsin 5 nonoverlapping scales to providea window into everyday behaviorsassociated with specific domains ofexecutive functioning in children, andall items were evaluated.15

For the Behavior Assessment Systemfor Children (BASC) and BehaviorRating Inventory of ExecutiveFunction (BRIEF) questionnaires, Tscores (mean: 50; SD: 10) were usedfor the analysis, after excluding testswith high inconsistency scores.

Polysomnography

Full overnight sleep studies(polysomnography) were performedin clinical pediatric sleep laboratories.Sleep staging used 4 EEG leads (bothleft and right central and occipitalleads), bilateral electro-oculographicleads (which also provide EEGsignals), and submentalelectromyogram. To evaluaterespiratory events, we used chestwall and abdominal movementmeasured with inductanceplethysmography, surface measuresof diaphragmatic and abdominalelectromyogram activity, and airflowby using a pressure transducer signalfrom the nose via nasal prongs andfrom the mouth via thermistor.Oxyhemoglobin saturation wasmeasured by pulse oximetry, andcarbon dioxide levels were measuredby using transcutaneous CO2. Cardiacrhythm was monitored with standardelectrocardiogram leads.

Studies were analyzed using theAmerican Academy of Sleep Medicine2007 guidelines with the AustralasianSleep Association amendmentbecause those rules were currentwhen the study protocol wasestablished.16,17 Obstructive apneawas defined as a cessation of airflowfor at least 2 respiratory cycles.Hypopnea was defined as a reductionin airflow, resulting in either anarousal or desaturation of at least 3%.Central apnea was defined ascessation of airflow and respiratoryeffort for at least 20 seconds or ,20-

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second duration but associated withan arousal or oxyhemoglobindesaturation of at least 3%. Totalsleep time was determined, andapnea indices were calculated as theaverage number of apneic episodesper hour of sleep. The AHI is theaverage number of apneic andhypopneic episodes per hour of sleep,regardless of type. The OAHI is thenumber of obstructive and mixedapneas and hypopneas per hourof sleep. At each center,polysomnography analysis waslimited to a maximum of 2 analystswith suitable concordance, blinded tothe randomization of the subjects.

Other Outcomes

Caregivers were contacted at 2-monthintervals after randomization. A set of7 standard questions were provided toresearch assistants to ask during thosephone calls (Supplemental Table 4).

Intervention: Adenotonsillectomy

Complete extracapsular tonsillectomyand adenoidectomy was undertaken.Adenoidectomy was undertakenregardless of the size of the adenoids,with diathermy an acceptabletechnique. The adenoidal bed wasvisualized at the end of the procedureto ensure that removal was satisfactory.

Adverse events are listed in theSupplemental Information.

Statistical Analysis

Every attempt was made to collectoutcome data on all participants.Primary analysis was by intention totreat and used linear regression(analysis of covariance) in which WJ-III outcomes of BIA W score at 12-month follow-up were the dependentvariables, with treatment groupallocation (adenotonsillectomy orNoAT) the main effect variable andbaseline scores the covariate. Theeffect of adenotonsillectomy on otheroutcomes from sleep studies andbehavioral measures was tested in ananalogous manner. Where residualsfrom the regression were not normally

distributed, the dependent variablewas transformed to fit a more-appropriate model. The use ofregression allowed us to assesswhether regression to the meanoccurred and thus whether somechildren might benefit most, inaddition to measuring the group effect.(See the Supplemental Information.)

RESULTS

Sample Characteristics

Study flow is shown in Fig 1. Includinga feasibility study at CHW (Sydney)from January 2010 to December 2012,all study centers participated fromJanuary 2014 to 2017. We enrolledand randomly assigned 190 childrenand compared children who completedthe study against those who showedno demographic differences.

After 12 months, 141 (75.8%)children attended follow-up visits, 136(70.4%) completed the WJ-III testing,and BIA results were analyzed for 121(64.4%). Results excluded fromanalysis included IQ subscales thatchildren could not complete and BASCor BRIEF results with (in)consistencyscores indicating unreliable responses.

Baseline demographic and clinicalcharacteristics were generally wellbalanced between the study groupsas shown in Tables 1 and 2 andSupplemental Table 5.

Primary Outcome

At the 12-month follow-up, WJIIresults were available for 67 and 69children in the adenotonsillectomy andNoAT surgical groups, respectively,with BIA scores available for 60(adenotonsillectomy) versus 61(NoAT) at both baseline and 12months. Intellectual ability scoresimproved in both groups over timewith no effect attributable to theintervention (adenotonsillectomy):baseline W scores for BIA = 448.36(17.9) vs 451.3 (15.6) and 12months = 465.46 (17.9) vs 463.12(16.6) (adenotonsillectomy versusNoAT, respectively; not significant)(Fig 2). Valid GIA scores wereavailable for 38 and 31 children in theadenotonsillectomy and NoAT groups,respectively, again with no effectattributable to the intervention. Mean(SD) W scores for these 2 measuresare shown in Table 2. Among thesubscales, significant improvement

FIGURE 1Consort diagram showing the flow of patients and numbers assessed at various points in the study.OAHI is per hour of sleep time. a Two children were randomly assigned to the early surgery arm butwere unable to complete full baseline assessments. Analysis (baseline 1 12 months) included num-bers for each test with valid results for both baseline and follow-up assessments of the listed test.

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was seen in long-term retrieval (meandifference: 4.06, P = .008) whereas themean difference for visual-spatialthinking was 4.44 (P = .09).

Secondary Outcomes

The BRIEF questionnaire, used toassess executive function in everydayactivities, was valid in 52 and 47 of

the adenotonsillectomy and NoATgroups, respectively. T scores (mean:50) showed variable shifts frombaseline, but no effect wasattributable to the intervention(adenotonsillectomy). Selectedsubscales are presented in Table 2,with full results presented in theSupplemental Information.

Questionnaire assessment of behaviorshowed improvement in thecomposite “behavioral symptomsindex” and subscales of somatization(being overly sensitive andcomplaining about physical ailments).Nonsignificant trends forimprovement were seen foratypicality and attention.

Sleep studies confirmed reducedarousal indices and decreased apneaindices (total and obstructive) for theadenotonsillectomy group.

Routine parent questions alsorevealed that children in theadenotonsillectomy group hadimmediate and sustainedimprovements in sleep and “eatingwell,” with fewer reports of troublebreathing during sleep, snoring, anddaytime sleeping. See Fig 3 andTable 3.

TABLE 1 Baseline Demographics and Assessments

Adenotonsillectomy NoAT

Age, mo 46.5 6 8.8 47.8 6 8.8Sex, male:female 52:47 57:34Social risk score 2.47 6 2.3 1.97 6 1.9PSQ score 0.62 6 0.15 0.60 6 0.16W score (n)a

BIA 448.4 6 17.9 (89) 451.3 6 15.6 (84)GIA 452.8 6 14.3 (66) 455.0 6 13.7 (63)

Tonsil size, range 1–4 2.96 6 0.53 2.98 6 0.61OAHI 1.9 6 1.9 1.9 6 2.0MinSaO2 88.5 6 6.7 90.2 6 3.9

Details of the social risk score are provided in the Supplemental Information. MinSaO2, minimum oxygen saturation value.a For GIA and BIA, numbers in parentheses are numbers of children with valid scores.

TABLE 2 Results of Primary and Secondary Outcome Parameters

Outcome Adenotonsillectomy NoAT Adjusted Mean Difference P

Baseline 12 mo Baseline 12 mo

PrimaryWJ-III (W score)BIA 448.6 (17.0) 465.4 (17.8) 451.4 (15.5) 463.1 (16.5) 2.25 .29

SecondaryWJ-III (W score)GIA 453.2 (14.5) 472.4 (13.9) 455.1 (13.6) 472.0 (15.6) 2.35 .40

BRIEF (T score)Executive 56.1 (11.0) 52.9 (11.1) 57.7 (11.1) 53.6 (11.0) 23.54 .78

CompositeInhibition 56.1 (10.6) 53.8 (10.0) 56.1 (9.7) 54.1 (7.8) 21.86 .33Working memory 56.8 (10.5) 53.8 (10.3) 58.4 (11.1) 56.3 (9.6) 21.14 .28Shifting 50.6 (10.3) 52.0 (9.2) 51.4 (11.1) 51.3 (9.2) 22.20 .34

BASC (T score)Behavioral 56.6 (10.3) 51.0 (11.6) 54.4 (10.3) 52.6 (10.3) 23.56 .03a

Adaptability 48.7 (10.2) 51.8 (11.1) 50.3 (10.3) 49.7 (10.3) 3.69 .06a

Somatization 60.4 (9.4) 51.0 (9.9) 60.3 (9.9) 57.5 (10.3) 21.37 .0003a

Attention 55.2 (10.1) 49.9 (10.6) 53.4 (9.3) 51.8 (9.7) 3.69 .05a

PSQ proportion “yes” 0.62 (0.15) 0.24 (0.18) 0.61 (0.16) 0.53 (0.21) 2.89 .07Parent rating, out of 10 — 8.7 (1.2) — 5.7 (1.6) 20.21 ,.001a

PolysomnogramTST, min 469.2 (73.8) 481.8 (66.7) 463.8 (76.1) 475.3 (74.6) 22.12 ,.001a

Efficiency, % 84.9 (9.7) 87.1 (9.0) 86.0 (10.1) 84.9 (9.8) 2.57 .08AHI, events per h 3.0 (2.1) 1.0 (0.9) 3.0 (2.5) 2.1 (2.4) 21.11 .0001a

OAHI, events per h 1.9 (1.9) 0.3 (0.5) 1.9 (2.0) 1.3 (2.0) 20.98 ,.0001a

Arousal, per h 11.0 (5.4) 9.1 (3.9) 12.1 (6.7) 11.4 (4.5) 24.15 .001a

MinSaO2, % 88.5 (6.7) 90.7 (4.0) 90.2 (3.9) 90.3 (3.6) 0.53 .27MaxCO2, mmHg 49.1 (5.3) 48.6 (5.5) 48.2 (5.3) 48.5 (0.7) 20.40 .75

Measures are reported for baseline and the 12-mo follow-up. Measures included the following: WJ-III (W score); BIA; GIA; BRIEF T score (note, preschool and school-aged scores werecombined); T score for the BASC; PSQ; parent rating, answer to the question, “On a scale of 1 to 10, how would you rate your child at the moment?”; total sleep time (TST) in minutes; sleepefficiency; total number of apneas and hypopneas per hour of sleep time; total number of obstructive and mixed apneas and hypopneas per hour of sleep time; minimum oxygensaturation value (MinSaO2); and maximum transcutaneous carbon dioxide (MaxCO2). —, not applicable.a P values of significance.

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DISCUSSION

In the primary analysis of thisrandomized study ofadenotonsillectomy in preschoolchildren symptomatic for OSA, itwas found that although global IQscores improved over time forboth groups, no change in globalIQ was attributable to theintervention (adenotonsillectomy).Questionnaire results demonstratedparent-perceived improvements inbehavior and well-being; sleepchanges were indicated by fewerday sleeps and improvedpolysomnography parameters.The study adds significantly toliterature regarding this youngerage group.

The expectation that IQ wouldimprove after surgery was based onsignificant preceding literature: ina meta-analysis of 1697 childrenaged 5 to 17 years (mean = 9.81years; SD = 0.34) from observationalcohort studies, researcherscompared children with OSA tocontrols and concluded that OSAis associated with reduced

performance on neuropsychologicalmeasures. Severity of OSA(measured by OAHI) had no impacton the results of formal testing(generativity) or questionnaire-based evaluations (equivalent to ouruse of the BRIEF) for inhibition,working memory, and shifting.1 Ina meta-analysis of 250 to 375children aged 6.6 6 2.3 years(range: 2.5–14 years) in prospectivestudies of adenotonsillectomy,researchers found 3 studiessuggesting improvement in thepreschool age group.3 The negativeoutcome of the CHAT study inschool-aged children left open thepossibility of an age thresholdeffect.3,7,8

Our randomized design is helpful inanswering the question, especiallywith a 12-month delay to follow-up.Although the trajectory of overallIQ change appeared improved inthe adenotonsillectomy group, it wasnot clinically significant (Fig 2).Among subscales, long-term retrieval(memory) improved in theadenotonsillectomy group, and this is

1 area of neurocognitionidentified both as impaired andshowing improvement after therapyin adult OSA.18 Possible explanationsfor improved neurocognition overtime include improvements withage and/or effects of developmentand a learning effect, although the12-month recommended retestinginterval, included in our design,minimizes any learning effect. Itmay also be important that weexcluded children with hearing lossfrom the baseline assessments,a factor not routinely considered instudies of OSA and IQ, despite itsdemonstrable association withexecutive function in OSA.19

Nonetheless, our primary analysisrejects the hypothesis that younger(preschool) children have improvedglobal IQ after earlier interventionwith adenotonsillectomy, nor werethere improvements in BRIEFscores (parent-reported executivefunction).

Notwithstanding the bias in parentreports of symptoms, ourquestionnaire assessments ofbehavior and symptoms indicatedlarge parent-perceivedimprovements afteradenotonsillectomy and that thoseimprovements were sustained overthe 12-month follow-up. Importantly,we were able to compare againstour control group in which changeswere minimal. Broad questionshighlighted the differences in overallsymptoms of OSA, such as snoringand breathing difficulties (Table 3,Fig 2).

An interesting, and perhapsimportant, finding was that fewerpreschool children continued daysleeps after adenotonsillectomy(Fig 2B). This is the first confirmatoryreport that preschool children stopday sleeps after adenotonsillectomycompared with a randomized(control) group. Although sleepinessis commonly reported inassociation with OSA, previousdocumentation of improvement after

FIGURE 2BIA W score at baseline and 12-month assessments for children who had adenotonsillectomycompared with those still awaiting surgery (NoAT).

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adenotonsillectomy is limited,undertaken in older children, andused the modified EpworthSleepiness Scale, including the CHATstudy and a study of children with

narcolepsy and OSA.20,21 The onlyparameter on our polysomnographs,other than apnea indices, to showimprovement in the group whounderwent adenotonsillectomy was

the arousal index, in whichdifferences were statistically, but notclinically, significant and remained inthe normal range for our laboratory.This suggests that polysomnographyparameters are relatively insensitiveto the changes that occur or that thebrain is sensitive to arousal(Table 2).

An important difference between thecurrent and previous studies is ouruse of the PSQ reports of symptoms.The majority of children in this studyhad mild OSA (Supplemental Fig 4A),but this also meant we includedchronically snoring children withnegative polysomnography results(primary snorers). Although not allsequelae of OSA are apparent inchildren with an AHI value of,1.0 per hour, there is increasingevidence that measurement ofsnoring in children can identifydifferent physiologic phenomena tothe AHI and that this potentiallyassociates more closely withsequelae than polysomnographymeasures.22–25

Our analysis was for primary andsecondary endpoints in a clinical trialin which treatment was randomized.Baseline value of the outcomevariable was the only predictor usedin the analysis, intended to givea more precise estimate of thetreatment effect rather than becausewe believed there may be imbalance.More detailed analyses, such as thoseundertaken by Taylor et al9 with theCHAT data, would not be appropriatein this report.

Limitations of the study are commonto randomized trials and our selectedmethod of analysis. The mostimportant are difficulties withrecruitment and retention of subjectsin a study that can be demanding offamilies with young children, creatingan inherent loss of data across time.Although reliance on intention totreat gives more “real world” results,it can cause loss of power because ofsubject attrition. Together, these

FIGURE 3Proportion of parents answering “yes” to symptoms of (1) snoring and (2) sleeping during the day.“No answer” or “don’t know” are counted as missing. The time points are at baseline (from PSQdata) then the follow-up phone calls at 2-month intervals until 12 months. A, Proportion answering“yes” to the question, “Does your child snore?” Baseline data regarding snoring were derived fromthe PSQ with an answer of “yes” to any of the 3 questions regarding snoring (.1/2 the time, alwayssnore, or snore loudly). B, Proportion answering “yes” to the question, “Is your child sleeping duringthe day?” As the PSQ did not include a baseline question about day sleeps, baseline data for daysleep were derived from the PSQ with an answer of “yes” to any of the following: "Does your childwake up feeling unrefreshed in the morning?"; "Does your child have a problem with sleepinessduring the day?"; "Has a teacher or other supervisor commented that your child appears sleepyduring the day?"

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factors combine to increase the riskfor a type II error. The time fromprotocol development to completionof the study has been significant, andother literature has been publishedwhile the study was in progress, somore specific testing has potential todetect changes attributable to OSA.9

Long-term memory was a single IQsubscale showing statisticallysignificant change (see SupplementalTable 6). Given the overall negativeresult and the number of analysesundertaken, it may be a chancefinding, but larger studies includingmore children with moderate orsevere disease and/or more detailedanalysis, such as that undertaken byTaylor et al,9 may clarify this. Whenpreparing the protocol, we used thestandard IQ testing scores witha mean of 100 and SD of 15 pointsfor our power calculations and aimedto detect a 0.5-SD change. Whenanalyzing our results, it became clearthat for children aged 3 to 5 years,the BIA score from the WJ-III was themost appropriate measure of IQ.Mean values for the W score varywith age (from 432.84, 445.86, and458.32 at ages 3, 4, and 5,respectively), with SD values rangingfrom 8.99 to 12.28 (WJ-III technicalmanual), and this increase withage accounts, at least partly, forthe increase seen in bothadenotonsillectomy and NoATgroups. Study recruitment endedwhen we were close to our target(190 of 210) and could reasonablyexpect to complete the testing of allrecruited children with availablefunding.12 The numbers in ourfollow-up of 64 per group give 80%

power to detect a 0.5 SD, and ourachieved sample size of 60 out of 61for the BIA has 78% power to detect0.5-SD difference in the BIA scores,which is further strengthened by ouranalysis method accounting forbaseline values.26 Evidence suggeststhat IQ measures in preschool arestable, despite this still beinga critical period of braindevelopment, and for comparison ofthe effect size, differences of 0.5 SDor even smaller are consideredsignificant across studies examiningthe effects of lead exposure oncognitive performance.27,28 It may bethat the inclusion of mildly affectedchildren diluted our results, althoughanalysis by OAHI severity did notreveal such an effect. Problemscontributing to all studies evaluatingthe influence of insults orinterventions on IQ, especially inyounger children and evident inliterature pertaining to brain injury,include difficulties determininginfluences of ongoing developmentrelative to those of the injury andthen the impact of any interventionand interactions between thoseprocesses.29 Although surgery oranesthesia itself may have a detrimentaleffect on children’s cognition andcontribute to our negative finding,more recent studies in this field havebeen reassuringly negative.30

CONCLUSIONS

In this study, we demonstratedimprovements in polysomnographyparameters, sleep quality, parent-reported symptoms, and aspects ofbehavior in preschool children withmild to moderate OSA undergoing

early adenotonsillectomy comparedwith those awaiting surgery onroutine waitlists. No difference in theglobal cognitive measures wasattributable to study intervention ata 12-month follow-up.

ACKNOWLEDGMENTS

We thank the families of theparticipants in this study and TheAustralian Sleep Research Networkfor their support toward the protocoldevelopment. We also thank researchstaff Melissa Neylan, Sarbjeet Kaur,Anna Kontos, Sylvia Pignata, ChendaCastro, and Marie-Josee Leclerc;clinicians Drs Carolyn Dakin, DeclanKennedy, Daniel Novakovic, JoannaWalton, and Hannah Burns; andstatisticians Drs Liz Barnes and AnneBernard.

ABBREVIATIONS

AHI: apnea hypopnea indexBASC: Behavior Assessment

System for ChildrenBASC 2: Behavior Assessment

System for Children–IIBIA: Brief Intellectual AbilityBRIEF: Behavior Rating Inventory

of Executive FunctionBRIEF-P: Behavior Rating

Inventory of ExecutiveFunction, PreschoolVersion

CHAT: ChildhoodAdenotonsillectomy Trial

CHW: The Children’s Hospital atWestmead

ENT: ear, nose, and throatGIA: General Intellectual AbilityNoAT: no adenotonsillectomyOAHI: obstructive apnea hypopnea

indexOSA: obstructive sleep apneaPOSTA: Preschool Obstructive

Sleep ApneaTonsillectomy andAdenoidectomy

PRS: Parent Rating ScalePSQ: Pediatric Sleep QuestionnaireWJ-III: Woodcock Johnson III

TABLE 3 Proportion of Parents Answering "Yes" to the Routine Follow-up Questions.

Parameter Adenotonsillectomy NoAT P

Snoring, % yes 17.5 93.2 ,.001Trouble sleeping at night, % yes 8.4 74.1 ,.001a

Day sleeps, % yes 6.8 43.8 ,.001Trouble breathing when asleep, % yes 11.5 44.2 ,.001Eating well, % yes 88.9 59.4 ,.001Overall rating, out of 10 8.7 5.7 ,.001

Further details of the questions are provided in the Supplemental Information.a Also changed with time.

8 WATERS et al at Medical Library on March 5, 2020www.aappublications.org/newsDownloaded from

Dr Heussler contributed to interpretation of data and revising the article; Drs Black and Lushington contributed to conception, design, and interpretation of data

and revising the article; Dr Cheng contributed to conception, design, and drafting and revising the article; and all authors contributed to the acquisition of data,

participated in revisions of the article, provided important intellectual content, approved the final manuscript as submitted, and agree to be accountable for all

aspects of the work.

This trial has been registered with the Australian and New Zealand Clinical Trials Registry (https://www.anzctr.org.au; registration number ACTRN12611000021976).

For data sharing, the database will be maintained, permitting sharing of deidentified data for 4 years after publication. Exported data will therefore be available to

applicants whose submitted proposals are approved by a data-sharing committee.

DOI: https://doi.org/10.1542/peds.2019-1450

Accepted for publication Oct 31, 2019

Address correspondence to Karen A. Waters, MBBS, FRACP, PhD, GCCM, Sleep Medicine, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145,

Australia. E-mail: karen.waters@health.nsw.gov.au

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2020 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: Funded by the National Health and Medical Research Council (APP1049788), Sydney University, The Garnett Passe and Rodney Williams Memorial

Foundation, and The Golden Casket, Brisbane. All funding was provided after review of the study, and there was no commercial involvement in the study.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2019-2479.

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Black, Alan T. Cheng and Kurt LushingtonKaren A. Waters, Jasneek Chawla, Margaret-Anne Harris, Helen Heussler, Robert J.

Cognition After Early Tonsillectomy for Mild OSA

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