pediatrics 2011 sleep disordered breathing

8/6/2019 Pediatrics 2011 Sleep Disordered Breathing

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Sleep Disordered Breathing in a Population-Based Cohort: Behavioral Effects at 4 and 7 Years

Karen Bonuck, PhD (corresponding author)Professor, Department of Family Medicine

Albert Einstein College of Medicine1300 Morris Park AvenueBronx, NY [email protected] phone 718 430 4085

Katherine Freeman, Dr.P.H.Professor, Department of Epidemiology and Population HealthMontefiore Medical Center/Albert Einstein College of Medicine111East 210 th StreetBronx, NY 10467

[email protected] phone: 718 920 5223

Ronald D. Chervin, MD, MSProfessor, Department of Neurology and Director, Sleep Disorders CenterUniversity of MichiganC728 Med Inn Bldg1500 E. Medical Center Dr.Ann Arbor, MI [email protected] phone 734-647-9064

Linzhi Xu, PhDResearch Associate, Department of Family and Social MedicineAlbert Einstein College of Medicine1300 Morris Park AvenueBronx, NY [email protected]

KeyWords: sleep-disordered breathing, behavior, longitudinal

This study was supported by grants from the National Heart Lung & Blood Institute- R21HL091241 and

R21HL091241-01A1.

Conflict of Interest: The authors have no conflicts of interest relevant to this article to disclose

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The American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007

Confidential - Not for Circulation

mailto:[email protected]










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Contributor’s Statement Page

All authors meet the criteria for authorship. Dr. Bonuck conceptualized and designed the study, drafted theinitial manuscript, reviewed and modified the analyses in collaboration with Drs. Freeman and Xu, andincorporated co-author feedback into the final manuscript. Dr. Freeman worked to develop the methods, carriedout initial analyses, supervised final analyses of Dr. Xu, and reviewed and revised the final manuscript. Dr.Chervin advised on study design and analyses, and carefully reviewed and revised multiple versions of themanuscript. Dr. Xu collaborated on statistical design issues, completed final analyses, and reviewed and revised

the final version of the paper.

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Objectives: Examine statistical effects of sleep-disordered breathing (SDB) symptom trajectories from 6months to 7 years on subsequent behavior.

Patients and Methods: Parents in the Avon Longitudinal Study of Parents and Children (ALSPAC) reported onchildren’s snoring, mouth breathing, and witnessed apnea at >2 surveys at 6, 18, 30, 42, 57, and 69 months, andcompleted the Strengths and Difficulties Questionnaire (SDQ) at 4 (n=9,206) and 7 (n=8,342) years. Clusteranalysis produced 5 “Early” (6-42 months) and “Late” (6-69 months) symptom trajectories (“clusters”).Adverse behavioral outcomes were defined by top 10 th percentiles on SDQ total and subscales, at 4 and 7 years,

in multivariable logistic regression models.

Results: The SDB clusters predicted ≈ 20%-90% increased odds of subsequent problematic behavior,controlling for 16 potential confounders. Early clusters predicted problematic behavior at 7 years equally wellas at 4 years. The “Worst Case” cluster, with peak symptoms at 2.5 years that subsequently resolved,nonetheless at 7 years predicted hyperactivity (OR=1.96, 95% CI [1.52 to 2.53]), conduct (1.61, [1.39 to 2.19]),and peer difficulties (1.69, [1.39 to 2.06]), whereas a “Later Symptom” cluster predicted emotional difficulties(1.69, [1.39 to 2.06]). In two clusters, all SDB symptoms peaked before 1.5 years and abated by 2.5 years, butstill predicted 40%-50% increased odds of behavior problems at 7 years.

Conclusions: In this large, population-based, longitudinal study, early-life SDB symptoms had strong,

persistent statistical effects on subsequent behavior in childhood. Findings suggest that SDB symptoms mayrequire attention as early as the first year of life.

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What is Known on This Subject● Sleep disordered breathing (SDB) is associated with neurobehavioral morbidity in children.● Prior related research has generally been cross-sectional or short (i.e. 1-2 years) follow-up studies of a singlesymptom (i.e. snoring, obstructive sleep apnea, mouth-breathing), with limited control for confounders.

What This Study Adds● SDB was assessed as a trajectory of combined symptoms from 6 months to 6.75 years, in over 11,000

children.● SDB was associated with 40% and 60% more behavioral difficulties at 4 and 7 years, respectively.

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Introduction

Neurobehavioral morbidity is common in childhood sleep disordered breathing (SDB) that can range

from snoring to obstructive sleep apnea (OSA). Mouth-breathing is another frequent clinical finding. 1 2 SDB

causes abnormal gas exchange, interferes with normal restoration during sleep, and disrupts cellular and

chemical homeostasis. 3 The supposed resultant dysfunction of the prefrontal cortex impairs attention,

executive functioning, behavioral inhibition, self-regulation of affect and arousal, and other socio-emotional

behaviors. 4 Behavioral manifestations include both externalizing (e.g., hyperactivity, aggression, impulsivity)

and internalizing (e.g., somatic complaints, social withdrawal) behaviors. 5 SDB reportedly peaks from 2-6

years of age, 6 but also occurs in younger children. 7 It is unclear which of the core biological processes

associated with SDB best predict neurobehavioral morbidity; genetic, individual, and environmental variables

likely play a role in how this morbidity is expressed. 4 Regardless of etiology, SDB’s neurological effects may

be irreversible, 8 highlighting the saliency of under-detection.

Despite the breadth of studies on SDB’s neurobehavioral effects in children, methodological limitations

persist. Meta-analyses found existing work rife with poor sampling, insufficient consideration of confounders,

and imprecise use of statistical tools. 9 10 Nearly all studies have been cross-sectional, and most longitudinal

studies have focused on pre/post-adenotonsillectomy (T&A) assessments or have included no more than 2 years

of follow-up. A meta-analysis of SDB differences associated with attention-deficit/hyperactivity disorder

(ADHD) 11 relied upon just 2 small studies 12, 13 and excluded children with anxiety or depressive disorders.

This study describes the combined trajectory of 3 hallmark SDB symptoms—snoring, mouth-breathing,

and witnessed apnea—and their longitudinal statistical effects on behavior. Our research questions were: 1)

“What effect do early SDB patterns (i.e., “clusters”) from 6 through 42 months of life have upon social-

emotional behavior at 4 and 7 years?”; and 2) “What effect do SDB patterns from 6 months through nearly 6

years have on behavior at 7 years of age?” Data were collected over 7 time points during the critical period in

SDB development, from 6 months through nearly 7 years of age in a prospective, population-based cohort.

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Patients and Methods

Population

The Avon Longitudinal Study of Parents and Children (ALSPAC), a geographically based cohort study

of children, enrolled pregnant women residing in a defined part of the former county of Avon in southwest

England with an expected date of delivery between April 1991 and December 1992. A total of 14,541 pregnant

women were enrolled. The cohort , described in detail elsewhere, 14 is broadly representative of the UK

population in terms of socioeconomic status (SES), although with a slight under-representation of ethnic

minority families, and overrepresentation of wealthier families. Our analyses excluded: triplet and quadruplet

births, children who did not survive to 1 year and children with conditions such as major congenital disorders

that are likely to affect SDB or behavioral assessment. The resulting base sample, used to derive SDB clusters

and behavioral outcomes, was 13,810 infants.

ALSPAC’s internal law and ethics committee reviews all proposals for secondary analyses and approves

policies for data handling and analysis. Ethical approval for this study was obtained from the ALSPAC Law and

Ethics Committee and the Local Research Ethics Committee. All participants provided informed consent.

SDB Assessment

In ALSPAC’s mailed questionnaires, parents reported on their child’s snoring, apnea and mouth-

breathing when s/he was 6, 18, 30, 42, 57, 69 or 81 months of age. These items were: 1) Mouth-breathing:

“Does she breathe through her mouth rather than her nose?”. At 57 months and older, parents were asked to

report separately for mouth-breathing when awake vs. asleep, though only the latter was used in analyses; 2)

Snoring: “Does she snore for more than a few minutes at a time?”; and 3) Apnea: “When asleep, does she seem

to stop breathing or hold breath for several seconds at a time?”.

Responses were categorized along ordinal scales of 3, 4, or 5 levels. Given this inconsistency in

response categories, we extrapolated the values to a common scale (0-100) with the ‘Always’ responses

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anchored at one end and the ‘Never’ or ‘Rarely/Never’ responses anchored at the other, and proportionate

spacing in-between (i.e. 4 category scale was recoded as 0, 33, 66, 100). Variables were then transformed to z-

scores, with higher scores indicating greater symptom burden.

The ALSPAC parent-reported SDB measures are similar or identical to question-items previously

validated against polysomnographic (PSG) data from sleep laboratories. Some validated questionnaires have

included parent report of all three SDB symptoms, 15-19 -- whereas others have included only snoring and

apnea. 20, 21

Behavior Assessment

The Strengths & Difficulties Questionnaire (SDQ), 22 a widely used behavioral screen, was completed

by mothers when children were ≈ 4 and 7 years old. The 25 item SDQ has 5 scales: inattention/hyperactivity;

emotional symptoms (anxiety and depression); peer problems; conduct problems (aggressiveness and rule-

breaking); and a prosocial scale (sharing, helpfulness, etc.). A total difficulties (range= 0-40) score is generated

by summing all but the latter scale because the absence of prosocial behavior is conceptually different from the

presence of psychological difficulties. Higher scores denote more problems. Missing data were prorated

according to SDQ instructions.23

The SDQ scores were dichotomized at the upper 10% based on psychometric

testing, 24 ALSPAC, 25, 26 and other UK cohort studies. 27

Covariate Assessment

Initial covariate selection was guided by prior ALSPAC studies of SDQ outcomes 26, 28-34 , and non-

ALSPAC studies of sleep problem effects upon SDQ outcomes. 35, 36 Based upon this literature review, and

exploratory analyses, 16 potential confounders were incorporated into analyses.

Socioeconomic status was measured by paternal employment (manual vs. professional), maternal

education (higher vs. lower), and housing inadequacy (if either > 1 person/room or homeless). Family adversity

was measured by an 18 item index of stressors (e.g., maternal psychopathology, crime, financial insecurity)

used in other ALSPAC analyses; 37 higher values signify more adversity. Intrauterine exposures of maternal

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smoking or alcohol use in the first trimester (yes/no), and fish intake at 32 weeks gestation (servings/week)

were assessed, as was whether the child was ever breast-fed, and mother’s age at delivery. Household variables

included family size (0, 1, or >2 children in household at 6 months interview) and the HOME Inventory 38 to

assess the quality of parenting and home environment. Child demographics included race (white vs. other) and

gender, low birth weight (<2500 grams) and prematurity (< 37 weeks). BMI contributes to increased levels of

SDB, which, given causal mechanisms, 39 is more likely to affect neuro-behavioral outcomes than BMI.

Therefore, to decrease risk of over-adjustment in multivariate models, BMI was not included as a covariate.

Derivation of SDB Clusters

To predict behavior at 4 years, “Early” clusters were derived from n=11,309 participants in the base

sample with >2 of the first 4 SDB measures. To predict 7 year behavioral outcomes, we derived “Later” clusters

from n=11,510 participants in the base sample with >2 of the first 6 SDB measures. SDB Z scores (see above)

were partitioned into clusters using SAS FASTCLUS version 9.1 (Cary, NC) with k-means cluster solutions for

5, 6, 7 and 8 unique sets of clusters; within each solution, differences across time points were compared among

clusters to demonstrate their uniqueness. We validated the clusters’ clinical significance and uniqueness against

measures of a) wheezing and b) tonsils and/or adenoid removal. Wheezing history in ALSPAC is predictive of

physician-diagnosed asthma, 40 a known risk factor for SDB, 41, 42 while adenotonsillectomy is the first line

treatment for SDB. 7 Our methodology for selecting final cluster solutions was informed by prior analytic

work, 43-45 , This process produced e xposure variables that included n=5 conceptually and statistically distinct

“Early” clusters (6-42 months), and n=5 comparable “Later” clusters (6-69 months) that were extensions of

Early clusters. Briefly, these are: 1)symptoms “Peak @ 6” and then return to normal, 2) symptoms “Peak @ 18”

months and then return to normal, 3) symptoms peak at 30 months and then persist (“Worst case”), 4)

symptoms emerge at 42 months and then persist (“Late Symptom”) and 5) “Normals” who are asymptomatic

throughout.

Statistical Analysis

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For SDQ scores at 4 and 7 years, we calculated the mean (sd), and proportions above and below the 10%

cut-off for the base sample, and their associations with putative covariates. We describe the association between

SDQ mean (sd) total scores at 4 and 7 years and the Early and Later clusters, by analysis of variance

(ANOVA), Only participants with non-missing SDQ data are included in analyses of behavioral outcomes.

Multivariate logistic regression analyses examined adjusted and unadjusted relationships between

clusters and SDQ total and subscales at 4 and 7 years. Initial models included all putative covariates. Only

those variables that were significant (p<=0.05) variables were retained in multivariate models. Odds ratios (OR)

and 95% confidence intervals (95%CIs) represent the odds of being in the top 10% vs. the remaining 90% of

SDQ scores. To address multi-collinearity, variance inflation factors (VIF) were derived to assess the effects of

individual independent variables upon variance. A conservative VIF threshold of 10 was employed in model

testing. 46 Analyses were conducted using SAS v9.1. 47

Results:

Data completion and attrition.

SDB longitudinal data were relatively complete (not shown): Early cluster analyses (4 year SDQ

outcomes), based upon 9,206 participants, included n=7,701 (84%), n=1,107 (12%) and=398 (4%) with SDB

data for 4/4, 3/4, and 2/4 timepoints, respectively. Early cluster analyses of the n=8,167 participants with 81

month SDQ outcomes included n=7,875 (96%) with SDB data for >3/4 timepoints. Later cluster analyses (81

month SDQ data) for n=8,243 participants, included n=7,528 (91%) with SDB data for >5/6 timepoints.

Missing SDQ or SDB data were significantly associated with: non-white race, pre-maturity, low birth weight,

manual (vs. professional) paternal employment, lower (vs. higher) maternal educational status, housing

inadequacy, not being breastfed, and higher levels of wheezing (not shown).

Sample Characteristics and Association with Top 10% of SDQ Total Scores

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Characteristics of the base sample and associations with behavioral outcomes are shown in Table

1.Children in the upper 10% of SDQ scores had significantly more adverse characteristics (e.g.,higher maternal

smoking, lower maternal education, higher Family Adversity Index scores, and lower HOME scores) than the

remaining 90%, at 4 and 7 years, but no differences by race, maternal alcohol intake during pregnancy, or

adenoid removal.

Cluster Description and Association with Sample Characteristics

Five early clusters representing n=11,309 children are illustrated in Figures 1a-1e; their descriptive

characteristics are shown in Table 2. Four are symptomatic ( ≈ 55% of sample) and one (“Normals,” 45% of

sample) is asymptomatic. “Worst Case” has the greatest symptom burden, and most adverse risk profile,

followed by “Late Symptom”. The three symptoms’ patterns are essentially parallel in the other clusters, but in

these two, snoring levels are nearly double those of apnea or mouth-breathing. “Peak@ 18” and “Peak @ 6”

have moderate symptom levels which abate prior to 30 months. Whether assessed as a continuous or

dichotomous (10% v. 90%) variable, SDQ total scores differed significantly across the four symptomatic

clusters, and in combined symptomatic clusters vs. “Normals.”

Five comparable later clusters representing n=8,243 children are illustrated in Figures 2a-e (descriptive

characteristics not shown). Patterns are similar to the Early clusters, except that in this “Late Symptom” cluster

snoring and mouth-breathing peak together at lower levels at 57 months with no marked apnea, and; the “Peak

@ 6” apnea levels are nearly double those of the Early clusters.

SDQ Total Score

The SDB clusters significantly predict SDQ total scores at 4 and 7 years (Table 3). Unadjusted Early

cluster effects of ≈ 40%-140% attenuate to 20%-90% in multivariate analyses. The strongest and most persistent

Early cluster effects are for “Worst Case,” with outcomes essentially unchanged between 4 (OR=1.66, 95%

CI=1.29-2.13) and 7 years (OR=1.67, 95% CI= 1.27-2.18). Later clusters’ unadjusted effect sizes of ≈ 65%-

140% attenuate to 40%-90% in multivariate analyses. In these Later cluster models there is a ≈ 40% effect for

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“Peak@6” and ≈ 50% effect for “Peak@18.”Membership in any symptomatic cluster is associated with being in

the upper 10% of total SDQ scores (v. “Normals”), an effect that increases slightly from 4 (OR=1.40, 95%

CI=1.21 to 1.61) to 7 years (OR=1.57, 95% CI=1.34 to 1.84: Later clusters).

SDB effects were stronger than those of maternal smoking, alcohol use in pregnancy, maternal education

and paternal employment in multivariate analyses (Table 3). Neither race, pre-maturity, low- birthweight,

maternal fish intake, nor maternal age, were significant in any multivariate analyses—total or subscale (not

shown). Only male gender and not being the second or later-born child had greater adverse effects. Greater

family adversity was associated with poorer behavioral outcomes, while higher home environment scores were

associated with improved outcomes. Gender-cluster interactions were not significant for any total or sub-score

analyses.

SDQ Subscores

Unadjusted effects of Early and Later cluster models are shown in Table 4. For the Hyperactivity,

Emotional, Conduct, and Peer subscales, all but one cluster-subscale association was significant, with effects of

≈ 30%-130%. For the Pro-Social subscale, “Peak@6” was the only cluster to have consistent significant adverse

effects. In adjusted analyses, nearly every cluster-subscale association remained significant (Table 5), with

effects of 20%-100%.

Prosocial - “Peak@6” was associated with approximately 30% greater odds of being in the lowest decile across

outcomes at 4 and 7 years. All but one of the remaining associations was not significant.

Hyperactivity -with two exceptions, all effects were significant, and increased from 4 to 7 years. Furthermore,

Early cluster effects at 4 years for “Worst Case” (OR=1.55, 95% CI=1.23 to 1.96) and “Late Symptom”

(OR=1.51, 95% CI=1.21 to 1.88) clusters equaled or increased, respectively, at 7 years [(OR=1.95, 95%

CI=1.51 to 2.52) and (OR=1.59, 95% CI=1.23 to 2.04)].

Emotional - with one exception at 4 years, all effects were significant (range ≈ 20%-70%), and most increased

from 4 to 7 years. “Late Symptom” had the strongest effect at 4 (OR=1.49, 95% CI=1.18 to 1.89) and 7 years

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(OR=1.63, 95% CI=1.29 to 2.06) based upon Early cluster models, with effects persisting to 7 years (OR=1.69,

95% CI= 1.39 to 2.06) in Later cluster models.

Conduct - with two exceptions, all effects were significant (range ≈ 20%-70%). Both “Worst Case” and

“Peak@18” effects increased from 4 to 7 years, while “Late Symptom” and “Peak @6” effects attenuated over

that time.

Peer - While 8 of 12 cluster-subscale associations were significant, SDB effects were more modest (range ≈ 20%-

40%) and stable over time, compared to the other subscales. Effects were strongest for “Worst Case” in the

Later cluster models (OR=1.40, 95% CI=1.09 to 1.78).

Discussion

We examined the effects of snoring, apnea, and mouth-breathing patterns (clusters) upon behavior, from

infancy through 7 years in over 11,000 children. By 4 years, children in any symptomatic cluster were 40%

more likely to exhibit behavioral difficulties consistent with a clinical diagnosis; by 7 years, they were nearly

60% more likely. These effects, in a population-based cohort that controlled for 16 putative confounders,

exceeded those of any measured pre-natal (i.e., maternal age, smoking or alcohol use), gestational age, birth-

weight, breast-feeding, SES, family adversity, or home environment exposure. Furthermore, symptom clusters

observed through 3.5 years were as predictive of behavioral difficulties at 7 years, as they were at 4 years, for

nearly every SDQ total and subscale outcome. Regarding specific clusters, “Worst Case” had the greatest

overall effects-- 90% increased likelihood of behavioral problems based upon symptoms observed through 3.5

years—followed by the “Late Symptoms” cluster. In two clusters, all SDB symptoms peaked before 1.5 years

and abated by 2.5 years, but still predicted 40%-50% increased odds of behavior problems at 7 years. Regarding

specific behaviors, Hyperactivity, Emotional, Conduct, and Peer difficulties were significantly higher for

symptomatic children, with nearly every cluster-subscale association significant. As expected from prior

literature, effects were strongest for Hyperactivity, especially for “Worst Case-- nearly 60% at 4 years, and

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nearly 100% at 7 years. Peer relations, though generally linked to earlier SDB symptoms, appear to have

suffered the least among the behavior subscales.

Compared to prior parent-reported effects of SDB upon later behavior, our findings are conservative. In

a study of ≈ 1,000 third graders, snoring at baseline was associated with 2-10 fold increases in SDQ-assessed

hyperactivity, emotional, conduct and peer difficulties at one year follow-up in age- and gender-adjusted

analyses. 48 A pediatric clinic sample of 229 2-13 year olds found that baseline SDB symptoms predicted 4-fold

increases in hyperactive behaviors at 4 year follow-up, after adjustment for age, gender, and baseline

hyperactivity. 49 These studies differed from ours, with smaller, less representative samples, lack of data from

the earliest years, use of other (non-SDQ) behavioral measures, and limited control for confounders.

Alternatively, several cross-sectional studies that employed different operational definitions of SDB and SDQ

outcomes found no effects. One, a large nationally representative cross-sectional sample of ≈ 5000 Australian 4-

5 year olds, found that neither SDQ total, nor the Hyperactivity, Peer, or Emotional scale (actual) scores were

greater among children with ‘snoring and/or breathing difficulties’ during sleep > 4 times per week. 35 Likewise,

among n=635 6-8 year olds, snoring >1 time week in the past 6 months was not associated with high (upper

10 th%ile) SDQ scores. 36

This is the first study to assess SDB as a trajectory of combined symptoms, across a key period of

development from 6 months to 6.75 years, in a large sample. Previous studies had smaller samples that were

often cross-sectional, or longitudinal 2 years or less of follow-up. Many were not population-based, involved

school-age children only, or did not adjust for as wide a range of counfounders. 8, 50 The potential impact of

confounders is evidenced by the fact that aside from the SDB clusters, 10 of 16 putative covariates were not

significant in any multivariate analyses, and most unadjusted effects of SDB attenuated in controlled analyses.

The current study has several limitations. First, SDB data were derived from parent report, rather than objective

testing. However, the symptom-items used reflect widely accepted and well-validated SDB risk factors.

Further, use of objective measures such as polysomnography in large epidemiological studies is infeasible, and

may be less effective given their limited ability to predict SDB morbidity or response to treatment. 16 Second,

missing SDB and SDQ data were associated with identified SDB risk factors, e.g., maternal smoking, lower

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SES. Although biases that involve selective drop-out may alter prevalence estimates, other ALSPAC analyses

found only marginal effects on regression models predicting behavioral outcomes. 51 This is likely the case in

our study, in which such biases would render our findings more conservative.

These robust findings, from the largest ever cohort study of SDB exposure and future neurobehavioral

morbidity, provide importance evidence that early childhood SDB affects the developing brain to produce

phenotypes that may only become apparent years later. The most significant long-term effects occurred in

children who experienced the worst symptoms by 2.5 years of age. Furthermore, children whose symptoms

peaked by 1.5 years but then abated by 30 months continued to experience significant adverse behavioral

outcomes at 7 years. SDB is relatively common in childhood. In prior analyses of this cohort the prevalence of

habitual snoring ranged from 10%- 21% from 6 months to 6.75 years. 52 The potential clinical implications are

significant: in a large national survey of children’s health, those with ADHD in comparison to their peers had

increased adjusted risks of co-morbid learning disability (8-fold), anxiety (8-fold), and low social competence

(3-fold). 53

Conclusion

If ultimately confirmed by randomized controlled treatment trials, findings presented here could have

substantial implications for public health approaches to screening and treatment. A 2009 consensus statement

by U.K. pediatricians and pediatric specialists noted that “the natural history of SDB, where a child changes

from normality to abnormality, and where the risks of developing complications of the condition outweigh the

risks of the surgical intervention, has not been established.” 54 Although data from multicenter, randomized

controlled trials, such as the current NIH-funded Childhood Adenotonsillectomy (CHAT) study, will ultimately

be required to prove cause-and-effect relationships, the new data presented here provide important

epidemiologic evidence to support attention to SDB symptoms beginning as early as the first year of life.

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Acknowledgements:

We are extremely grateful to all the families who took part in this study, the midwives for their help in

recruiting them, and the whole ALSPAC team, which includes interviewers, computer and

laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and

nurses. In addition, the authors wish to thank the following members of the study’s advisory group:

Dr. Raanan Arens (Montefiore Medical Center/Albert Einstein College of Medicine), Dr. John Bent

(Montefiore Medical Center/Albert Einstein College of Medicine), Dr. Peter Blair (University of Bristol), Dr.

Pauline Emmett (University of Bristol), Dr. Peter Fleming (University of Bristol), Dr. Jon Heron (University of

Bristol), Dr. Carole Marcus (Children’s Hospital of Philadelphia), Dr. Kenneth Ong (Cambridge University), Dr.

Sanjay Parikh (Montefiore Medical Center/Albert Einstein College of Medicine), and Dr. Susan Redline (Case

Western Reserve University).

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24. Goodman R. Psychometric properties of the strengths and difficulties questionnaire. J. Am. Acad. Child Adolesc. Psychiatr. Nov 2001;40(11):1337-1345.

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27. Kelly Y, Sacker A, Gray R, Kelly J, Wolke D, Quigley MA. Light drinking in pregnancy, a risk forbehavioural problems and cognitive deficits at 3 years of age? Int. J. Epidemiol. Feb 2009;38(1):129-140.

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33. Wiles NJ, Peters TJ, Heron J, et al. Fetal growth and childhood behavioral problems: Results from theALSPAC cohort. American Journal of Epidemiology. May 2006;163(9):829-837.

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45. Lambert M, Schimmelmann BG, Schacht A, et al. Long-term patterns of subjective wellbeing inschizophrenia: Cluster, predictors of cluster affiliation, and their relation to recovery criteria in 2842patients followed over 3 years. Schizophrenia Research. Feb 2009;107(2-3):165-172.

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Table 1: Sample: Demographics for total sample and by SDQ Scores at 4 and 7 YearsSDQ total Score, 4 years SDQ Total Score, 7 Years

Total Sample * N=13,810

Top 10%N=1,250

Lower 90%N=8,102

Top10%N=908

Lower 90%N=7,208

Maternal

Smoked during pregnancy, any 25.1% 30.6%† 20.0% 30.9%† 18.7%

Alcohol during pregnancy, any 54.5% 55.7% 55.4% 58.4% 55.6%

Fish intake during pregnancy, mean(sd)

1.88(1.75) 1.94 (1.80) 1.87 (1.73) 1.80 (1.53) 1.89 (1.75)

Age at delivery, mean years (sd) 27.99(4.96) 27.52 (4.78)† 28.87 (4.64) 28.12 (4.74)† 29.03 (4.56)

Breastfed this child, ever 75.3% 72.6%† 78.51% 76.8% 79.2%

Child

Gender, male 51.6% 55.2%† 51.2% 60.0%† 50.6%

Race, white 97.4% 98.2% 98.3% 98.2% 98.3%

Premature, <37 weeks 5.9% 6.2% 5.2% 6.5%‡ 4.9%

Low birthweight, <2500 grams 5.2% 5.7% 4.5% 5.6%‡ 4.2%

Adenoids removed, ever 7.6% ----- ----- 4.9% 3.9%

Tonsils removed, ever 4.6% ----- ----- 9.2%† 6.3%

Socioeconomic and Family

Maternal Education, § Lower (%) 64.6% 70.9%† 59.0% 60.7%† 57.8%

Paternal Employment, Manual (%) 44.0% 51.9%† 2,328 (39.3%) 363 (47.5%)† 39.1%

Housing, Inadequate, (%) 12.4% 18.7%† 11.8% 18.4%† 11.1%Family Adversity Index, Mean (range,

0-18) 1.78(1.98) 2.63 (2.26) † 1.74 (1.88) 2.85 (2.38) † 1.71 (1.85)

HOME Score, mean (range: 0-8) 5.75(1.66) 5.61 (1.76) † 5.81 (1.62) 5.48 (1.75) † 5.84 (1.61)

Parity, >=1 55.4% 52.0% 54.5% 50.7%‡ 54.5%

*These n=13,810 constitute the base sample used to derive the clusters and SDQ outcomes.†p<.01 for difference between top 10% vs. lower 90%‡p<.05 for difference between top 10% vs. lower 90%§“Lower” defined as “O” level education or less (equivalent to school leaving certificate at 16 in the UK), from 5 original groupings.

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Table 2: Association Between Early Clusters (n= 11,309) and Potential Confounders and SDQ outcomePeak @ 6

n=2270(21.1%)

(1)

Peak @ 18n=2009(17.8%)

(2)

Worst Casen=862(7.6%)

(3)

Late Symptomn=1063(9.4%)

(4)

Normalsn=5105(45.1%)

(5)

P *

Maternal Characteristics

Smoked during pregnancy,any 24.9% 25.4% 29.2% 28.3% 18.3% <0..001Alcohol during pregnancy,any 53.8% 53.8% 55.0% 53.9% 56.5% 0.119Fish intake duringpregnancy, mean 1.85 1.86 1.95 1.93 1.87 0.673Age at delivery, mean(years) 28.32 28.01 27.78 27.90 28.93 <0.001Breastfed this child, Ever 74.9% 75.2% 69.3% 74.5% 78.5% <0.001Child Characteristics

Gender, male 54.1% 52.8% 55.7% 52.0% 49.3% <0.001Race, white 98.1% 96.8% 97.9% 97.6% 98.2% 0.008Premature, <37 weeks 5.4% 5.5% 7.7% 7.1% 5.0% 0.005Low birth weight, <2500grams 4.3% 5.7% 5.8% 5.8% 4.3% 0.013Socioeconomic andFamily CharacteristicsMaternal Education,Lower (%) 65.5% 66.4% 67.7% 67.1% 58.4% <0.001Paternal Employment,Manual (%) 43.1% 46.5% 47.4% 43.7% 39.5% <0.001Housing, Inadequate (%) 15.1% 15.0% 17.3% 12.9% 10.1% <0.001Family Adversity Indexmean (range, 0-18) 2.14 2.14 2.48 2.12 1.62 <0.001

HOME Score, mean(range: 0-8) 5.72 5.73 5.72 5.71 5.81 0.081Parity, >=1 55.1% 53.3% 55.1% 53.8% 55.7% 0.437Outcome SDQSDQ top10% @ 4 year 13.5% 15.1% 18.6% 20.1% 10.1% <0.001SDQ top10% @ 7 year 11.8% 12.9% 16.7% 14.6% 8.6% <0.001SDQ continuous @4 year 14.58 14.65 15.32 15.36 13.90 <0.001SDQ continuous @7 year 8.12 7.90 8.74 8.27 6.77 <0.001

Combined Symptomatic (1,2,3,&4)SDQ top10% @4 year 15.77% 10.14% <0.001SDQ top10% @7 year 13.28% 8.61% <0.001SDQ continuous @4 year 14.83 13.90 <0.001

SDQ continuous @7 year 8.16 6.78 <0.001*P values are calculated from chi-square test or analysis of variance.

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Table 3: Cluster Effects Upon SDQ Total Scores at 4 and 7 Years

Early Cluster Models Later Cluster Models

Top 10% v. Lower 90% OR (95% CI) 4 Years 1 p 7 years 1.2 p 7 years 1,2 p

Unadjusted, SDB

“Peak @ 6”(1) 1.38(1.17,1.63) <0.001 1.43(1.18,1.72) <0.001 1.65(1.34,2.04) <0.001

“Peak @ 18 Mos.”(2) 1.57(1.33,1.86) <0.001 1.57(1.29,1.91) <0.001 1.69(1.39,2.05) <0.001

“Worst Case” (3) 2.02(1.62,2.51) <0.001 2.12(1.66,2.72) <0.001 2.42(1.90,3.09) <0.001

“Late Symptom”(4) 2.23(1.83,2.72) <0.001 1.82(1.43,2.31) <0.001 2.03(1.66,2.48) <0.001

Symptomatic(1,2,3,4) v.“Normals” (5) 1.66(1.46,1.88) <0.001 1.63(1.41,1.88) <0.001 1.86(1.61,2.16) <0.001

Adjusted , SDB

“Peak @ 6”(1) 1.20(1.00,1.45) 0.051 1.20(0.98,1.47) 0.082 1.39 (1.11,1.74) 0.004“Peak @ 18 Mos.”(2) 1.36(1.13,1.65) <0.001 1.29(1.05,1.60) 0.017 1.49 (1.29,1.84) <0.001

“Worst Case” (3) 1.66(1.29,2.13) <0.001 1.67(1.27,2.18) <0.001 1.89(1.45,2.47) <0.001

“Late Symptom”(4) 1.84(1.46,2.30) <0.001 1.50(1.16,1.94) 0.002 1.69 (1.35,2.10) <0.001

Clusters1,2,3 & 4 v.“Normals” (5)

1.40(1.21,1.61) <0.001 1.34(1.15,1.36) <0.001 1.57(1.34,1.84) <0.001

Covariates 3

Smoking duringpregnancy

---------- N.S. 1.24 (1.04,1.49) <0.017 1.24 (1.04,1.48) 0.019

Gender, male 1.22 (1.07,1.40) 0.004 1.54 (1.32,1.80) <0.001 1.55 (1.33,1.81) <0.001Maternal education,

lower1.38 (1.18,1.61) <0.001 1.29 (1.10,1.52) 0.002 1.29 (1.10,1.52) 0.002

Paternal employment,manual 1.33 (1.15,1.54) 0.001 ----------- N.S. ---------- N.S.

Family Adversity Index 1.21 (1.17,1.25) <.001 1.24 (1.20,1.29) <0.001 1.24 (1.20,1.28) <0.001Home Score ---------- N.S. 0.91 (0.87,0.95) <0.001 0.91 (0.87,0.95) <0.001

Parity 1 v. 02 v. 0

0.91 (0.78,1.05)0.63 (0.52,0.78)

0.088<0.001

0.73 (0.61,0.86)0.58 (0.46,0.72)

0.6180.001

0.73 (0.62,0.87)0.59 (0.47,0.73)

0.600<0.001

1Adjusted for fish intake, FAI, Mother and home score, smoke during pregnancy, alcohol during pregnancy, race, breast feeding ever,housing inadequency, parity, gestation age, paternal social, maternal education, birth weight, maternal age, gender.2 Additional adjusted for Tonsils or adenoids removed.3 Covariates shown are only those that were significant (p<.05) in reduced models with each of the four symptomatic modelsincorporated as a separate variable (vs. combined clusters 1,2,3, & 4).

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Table 4 Unadjusted Cluster Effects Upon SDQ Subscales at 4 and 7 Years


Top 10% v. Lower 90%

OR (95% CI)

4 Years p 7 years p 7 years p

Pro-Social “Peak @ 6” 1.35(1.13,1.63) 0.001 1.41(1.16,1.70) <0.001 1.37(1.11,1.68) 0.003

“Peak @ 18 Mos.” 1.17(0.96,1.43) 0.121 1.33(1.08,1.63) 0.006 1.22(0.99,1.49) 0.055

“Worst Case” 1.29(0.98,1.69) 0.068 1.37(1.03,1.82) 0.030 1.11(0.83,1.48) 0.481

“Late Symptom” 1.01(0.77,1.33) 0.928 0.95(0.71,1.27) 0.731 0.88(0.69,1.11) 0.275

Hyperactivity “Peak @ 6” 1.34(1.15,1.57) <0.001 1.56(1.30,1.88) <0.001 1.69(1.37,2.08) <0.001

“Peak @ 18 Mos.” 1.31(1.11,1.55) 0.001 1.53(1.26,1.87) <0.001 1.58(1.29,1.92) <0.001

“Worst Case” 1.89(1.53,2.33) <0.001 2.23(1.74,2.85) <0.001 2.25(1.76,2.88) <0.001

“Late Symptom” 1.72(1.41,2.10) <0.001 1.74(1.36,2.22) <0.001 1.94(1.58,2.37) <0.001

Emotional “Peak @ 6” 1.27(1.06,1.52) 0.011 1.47(1.23,1.75) <0.001 1.65(1.36,2.00) <0.001

“Peak @ 18 Mos.” 1.32(1.10,1.60) 0.003 1.43(1.19,1.71) <0.001 1.53(1.28,1.84) <0.001

“Worst Case” 1.58(1.23,2.02) <0.001 1.63(1.27,2.09) <0.001 1.76(1.38,2.24) <0.001

“Late Symptom” 1.54(1.23,1.95) <0.001 1.66(1.32,2.08) <0.001 1.90(1.58,2.29) <0.001

Conduct “Peak @ 6” 1.60(1.36,1.88) <0.001 1.51(1.25,1.82) <0.001 1.43(1.16,1.77) 0.001

“Peak @ 18 Mos.” 1.45(1.22,1.72) <0.001 1.55(1.27,1.88) <0.001 1.61(1.33,1.96) <0.001

“Worst Case” 1.71(1.37,2.15) <0.001 1.95(1.51,2.52) <0.001 1.98(1.54,2.55) <0.001

“Late Symptom” 1.95(1.59,2.39) <0.001 1.46(1.13,1.89) 0.004 1.55(1.26,1.91) <0.001

Peer “Peak @ 6” 1.29(1.07,1.54) 0.006 1.31(1.11,1.56) 0.002 1.37(1.14,1.66) 0.001

“Peak @ 18 Mos.” 1.29(1.07,1.56) 0.008 1.41(1.18,1.68) <0.001 1.42(1.19,1.70) <0.001

“Worst Case” 1.43(1.11,1.83) 0.006 1.65(1.30,2.09) <0.001 1.64(1.30,2.08) <0.001

“Late Symptom” 1.25(0.98,1.59) 0.077 1.38(1.10,1.74) 0.006 1.40(1.16,1.69) <0.001

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Table 5 Adjusted Clusters Effects Upon SDQ Subscales at 4 and 7 Years


Top 10% v. Lower 90% OR (95% CI)

4 Years 1

p 7 years 2

p 7 years 2

p Pro,Social

“Peak @ 6” 1.25(1.03,1.51) 0.025 1.32(1.09,1.60) 0.005 1.27(1.03,1.56) 0.029

“Peak @ 18 Mos.” 1.16(0.94,1.43) 0.164 1.27(1.03,1.56) 0.024 1.16(0.95,1.42) 0.150“Worst Case” 1.16(0.87,1.54) 0.317 1.23(092,1.64) 0.162 0.99(0.74,1.33) 0.942

“Late Symptom” 0.99(0.74,1.31) 0.936 0.91(0.68,1.23) 0.538 0.87(0.68,1.10) 0.243Hyperactivity

“Peak @ 6” 1.13 (0.95,1.34) 0.166 1.42 (1.17,1.72) <0.001 1.50 (1.21,1.86) <0.001“Peak @ 18 Mos.” 1.07 (0.89,1.28) 0.500 1.36 (1.11,1.67) 0.004 1.42(1.16,1.75) <0.001

“Worst Case” 1.55 (1.23,1.96) <0.001 1.95 (1.51,2.52) <0.001 1.96(1.52,2.53) <0.001“Late Symptom” 1.51 (1.21,1.88) <0.001 1.59 (1.23,2.04) <0.001 1.78(1.44,2.20) <0.001

Emotional “Peak @ 6” 1.17(0.97,1.41) 0.105 1.39(1.16,1.67) <0.001 1.48(1.21,1.81) <0.001

“Peak @ 18 Mos.” 1.23(1.01,1.49) 0.037 1.33(1.09,1.61) 0.004 1.47(1.21,1.77) <0.001

“Worst Case” 1.44(1.12,1.86) 0.005 1.37(1.05,1.80) 0.022 1.51(1.15,1.97) 0.003“Late Symptom” 1.49(1.18,1.89) <0.001 1.63(1.29,2.06) <0.001 1.69(1.39,2.06) <0.001

Conduct “Peak @ 6” 1.41(1.20,1.66) <0.001 1.30(1.07,1.58) 0.009 1.21(0.97,1.51) 0.085

“Peak @ 18 Mos.” 1.26(1.05,1.50) 0.011 1.34(1.09,1.64) 0.005 1.41(1.15,1.72) 0.009“Worst Case” 1.40(1.11,1.77) 0.005 1.64(1.26,2.13) <0.001 1.61(1.39,2.19) <0.001

“Late Symptom” 1.68(1.36,2.08) <0.001 1.26(0.97,1.64) 0.088 1.36(1.09,1.68) 0.006Peer

“Peak @ 6” 1.22(1.02,1.47) 0.033 1.16(0.98,1.39) 0.093 1.19(0.98,1.45) 0.083“Peak @ 18 Mos.” 1.25(1.03,1.52) 0.022 1.27 (1.06,1.53) 0.010 1.28(1.07,1.54) 0.008

“Worst Case” 1.31(1.02,1.70) 0.038 1.36(1.06,1.75) 0.014 1.40(1.09,1.78) 0.008“Late Symptom” 1.15(0.90,1.48) 0.267 1.22(0.96,1.55) 0.099 1.25(1.03,1.52) 0.027

1Adjusted for fish intake, FAI, Mother and home score, smoke during pregnancy, alcohol during pregnancy, race, breastfeeding ever, housing inadequacy, parity, gestation age, paternal social, maternal education, birth weight, maternal age,gender.2Additional adjusted for Tonsils or adenoids removed ever.

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1a. Early Cluster

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pediatrics 2011 sleep disordered breathing

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