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Snoring and cognitive development in infancy
Sleep Medicine 12 (2011) 981–987
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Original Article
Snoring and cognitive development in infancy A.M. Piteo a, J.D. Kennedy b,⇑, R.M. Roberts a, A.J. Martin b, T. Nettelbeck a, M.J. Kohler c, K. Lushington c a
School of Psychology, University of Adelaide, South Australia, Australia Discipline of Paediatrics, School of Reproductive Health and Paediatrics, University of Adelaide, South Australia, Australia c School of Psychology, Social Work and Social Policy, University of South Australia, South Australia, Australia b
a r t i c l e
i n f o
Article history: Received 25 November 2010 Received in revised form 27 February 2011 Accepted 2 March 2011 Available online 21 November 2011 Keywords: Snoring Infants Neurocognitive Development Sleep Pediatric
a b s t r a c t Objective: This study aimed to assess the influence of snoring and sleep duration on developmental outcomes in 6 month old infants. Methods: As part of a longitudinal study of snoring in infancy, we identified 16 children (13 males) who commenced snoring shortly after birth and continued to snore frequently (P3 nights/week) at 6 months of age and 88 healthy infant controls who were reported never to snore in the absence of a cold (36 males). Infants were assessed at 6 months of age with the Bayley Scales of Infant and Toddler Development Edition III, and parents completed demographic, sleep, and developmental surveys. Results: Cognitive development was reduced in infants who snored frequently (mean = 95.3; SD = 4.3) from the first month of life compared to control infants (mean = 100.6; SD = 3.9) (F [1, 99] = 23.8, p < .01; gp2 = .21). Conclusion: Snoring during the first 6 months of life was associated with lower cognitive development scores. It is unknown whether these infants will continue to snore through childhood and, if so, whether the associated neurocognitive deficits will become worse with time. Crown Copyright Ó 2011 Published by Elsevier B.V. All rights reserved.
1. Introduction Sleep Disordered Breathing (SDB) is common in childhood and ranges in severity from primary snoring to obstructive sleep apnoea syndrome (OSAS). The cardinal symptom of SDB is frequent or habitual snoring, affecting an estimated 5–26% of infants [1–4] and 5–10% of older children [5]. SDB is associated with neurocognitive and behavioural deficits that are reported even in children with relatively mild snoring [6–10]. To date, most studies have focussed on school-aged children and little is known about the impact of SDB on daytime functioning in much younger children. There is now convincing evidence that OSAS in both children and adults is associated with demonstrable changes in brain structure and function. The precise mechanisms underpinning these changes are currently under intense investigation, but rodent models of OSAS confirm that intermittent hypoxia secondary to upper airway obstruction induces apoptosis in both hippocampal and cortical regions by initiating oxidative stress and upregulating inflammatory pathways [11]. In addition, animal studies have confirmed that sleep fragmentation alone can induce structural ⇑ Corresponding author. Address: University of Adelaide, School of Psychology, Hughes Building North Terrace, Adelaide, SA 5000, Australia. Tel.: +61 8 8303 5693; fax: +61 8 8303 3770. E-mail addresses: [email protected] (A.M. Piteo), declan.kennedy@ adelaide.edu.au (J.D. Kennedy).
changes, with reduction in neurogenesis within the CA1 area of the hippocampus and subsequent impairment of spatial leaning [12–15]. In healthy human infants, Scher et al. [16] has recently reported that increased sleep fragmentation at 10 months of age (as measured by actigraphy) was associated with reduced mental development scores while Hogan, Hill, Harrison, and Kirkham [17] found changes in cerebral vascular flow parameters in children with only mild primary snoring. The literature examining snoring in infancy is limited by the lack of studies validating parental reports of snoring while the assessment of cognitive function in infants with SDB is limited to a single study by Montgomery-Downs and Gozal [18]. These authors investigated 35 healthy 8 month old infants with polysomography (PSG) and reported that snoring-related arousals across the entire group were associated with lower mental development scores. Notably, no infant in that study had episodes of either obstructive hypopnoea or apnoea and only about half of the 35 infants in the study were reported to snore. Indirect evidence that SDB in early life may be associated with impaired development is provided by Hunt and colleagues [19], who examined 256 infants, including healthy infants, infants and siblings of infants who went through apparent life threatening events, and pre-term infants. Hunt’s group reported that >5 extreme cardio-respiratory events (apnoea with bradycardia) by 4 months of age were associated with lower mental development scores at 92 weeks of age. However, this study did not include the evaluation of infants who
1389-9457/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2011.03.023
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snored versus non-snorers. A further issue not addressed by either of these studies is whether particular subgroups of infants are at greater risk for cognitive deficits, for example: habitual snorers who start snoring soon after birth. Given this background, the aim of the present study was to examine cognitive development in infants who developed frequent snoring in the first month of life, and who continued to snore frequently when assessed at 6 months of age, and compare them to healthy non-snoring infants.
2. Methods This research forms part of an ongoing longitudinal study examining snoring in the first year of life (for details see Piteo et al., accepted January 2011 [20]). Infants aged between 0 and 3 months were recruited by Child and Family Health nurses during their mother’s first ‘‘well child’’ visit, which is conducted routinely in South Australia. At that visit, the nurses distributed a parent and child sleep and health questionnaire. A subset of these parents volunteered to participate in a follow-up study examining sleep and cognition at 6 months. Parents of children identified as habitual snorers were recommended to consult their general medical practitioner.
2.1. Participants Participant selection and exclusion details are given in Fig. 1. The final sample at 6 months consisted of 88 full term non-snoring infants and 16 infants who snored frequently from shortly after birth and continued to snore at 6 months. (Note that children classified as infrequent snorers over this time period were excluded from analyses [n = 10]). The study was approved by the Children’s Youth and Women’s Health Services, University of South Australia and the University of Adelaide Human Research Ethics Committees.
2.2. Measures 2.2.1. Demographic information The following demographic information for those infants studied was collected at the initial recruitment stage, when they were 0–3 months old, and included gender, age, and ethnicity. Demographic data collected for the infants’ parents included parental education history (high school, technical education, and university), socio-economic status, and maternal age. Socioeconomic Status (SES) was determined from the Australian Bureau of Statistics (ABS) SES Index of relative advantage and disadvantage (SEIFA) (national mean = 1000; SD = 100). This provided an indication of the social and economic conditions of a neighbourhood area based on the information collected at the 2006 census [21]. (SES was collected at both time points, when infants were 0–3 months old, and again at 6 months old.) 2.2.2. Snoring At 0–3 months old and 6 months old, parents were asked ‘‘How many nights in the past week did your child snore?’’ and children were then classified as controls (never reported to snore in the absence of a cold) (n = 88), infrequent snorers (<1–2 nights/week) (n = 10) or frequent snorers (P3 nights/week) (n = 19). The infants who snored were further classified at both 0–3 months old and 6 months old based on parental response to the question, ‘‘When did the snoring begin?’’ They were classified according to whether they did or did not begin snoring shortly after birth, i.e.: (i) snored frequently before 1 month of age and continued to snore frequently when assessed at 6 months of age (n = 16); or (ii) snored after the first month of life (n = 14) and infrequently (n = 11) or frequently (n = 3) at 6 months of age. 2.2.3. Family and infant health The following infant health variables were collected at 6 months of age: ‘‘In the past 6 months has your child had: (1) episodes of wheezing,’’ ‘‘(2) eczema,’’ and ‘‘(3) reflux’’ (yes/no/don’t
Snoring and sleep survey 0-3 months old (Parent asked if the child was snoring and if so, at what age this began) (n = 515) Exclusion Contact details not provided or declined to participate further (n = 245) Prematurity (n = 35) Infants aged > 3 months at time of survey (n = 23) Assessed for eligibility (n = 212) Exclusion Congenital disorder (n = 2) Non-metropolitan residence (n = 29) Declined to participate at follow-up (n = 64) Neurocognitive, snoring and sleep assessment 6-months-old (Parent asked if the child was snoring and if so, at what age this began) (n = 117) Fig. 1. Participant flow chart and timeline of events.
A.M. Piteo et al. / Sleep Medicine 12 (2011) 981–987
know). Parents were also asked when infants were 0–3 months old, and again when 6 months old, about breast/formula feeding (breast milk only, formula only, or breast milk and formula) and the number of days the infant was breast fed. The following family health information was collected at 0– 3 months old and 6 months old: (1) ‘‘Did the mother smoke during pregnancy?’’ (2) ‘‘Did the mother smoke post-delivery?’’ and (3) ‘‘Were there other smokers in the household post-delivery?’’ (yes/no/don’t know). The following family health information was collected at 6 months only: (1) ‘‘Does the child’s mother snore?’’ (2) ‘‘Does the child’s father snore?.’’ 2.2.4. Sleep To maintain consistency with previous studies we used previously validated questionnaire items [4,22–24] for sleep duration, sleep quality, respiratory, and sleep disordered breathing items which were assessed at 0–3 months old and again at 6 months old. Parents were asked how many nights in the past week their child was reported to snore as well as the age onset of the snoring. SDB items included two items regarding parental concern about their child’s breathing. 2.2.5. Developmental assessment The Bayley Scales of Infant and Toddler Development Edition III was used to assess neuropsychological development [25] at 6 months old. The Bayley is a well validated and reliable instrument with high internal consistency which provides estimates for four developmental domains: Cognitive (sensory-perceptual acuity, discrimination and response abilities, object constancy, learning, memory and problem solving abilities), Language (Receptive Communication and Expressive Communication), Motor (Fine and Gross Motor), and Social-Emotional and Adaptive Behaviour (self-regulation, interest in the world, communicating needs, engaging others, and establishing relationships while using emotions in interactions). The Bayley developmental scores have been reported to correlate moderately to highly with IQ estimates collected later in childhood [26–29]. The test takes 50 min to administer in children <12 months. The Cognitive, Language, and Motor components were administered by a trained psychologist while parents completed the Social–Emotional scale. The results are reported as standard scores with a mean = 100 and SD = 15. Infants were free of colds and other relevant health problems that may affect snoring and daytime functioning at the time of testing. 2.2.6. Statistical analysis Descriptive statistics were calculated for demographic variables, developmental outcomes, and sleep variables. Where appropriate, F-tests and Chi-squared tests were used to test for group differences in demographic and neurocognitive scores. Effect sizes were determined using partial eta squared values ([gp2]; 0.01 = small, 0.06 = medium and 0.14 = large effect size [30]). Pearson-r correlations were used to explore the association between sleep and developmental variables. Hierarchical regression analysis was used to assess the influence of snoring frequency at 6 months on development scores at 6 months of age. In step 1 we entered SES, gender, parental smoking (0 = no, 1 = yes), infant wheezing, infant reflux, infant eczema, and number of days of breast feeding. In step 2 we entered nocturnal sleep duration and number of nocturnal awakenings per night. In step 3 we entered snoring frequency. 3. Results The demographic data for infants and parents are presented in Table 1. Ninety-eight percent of caregivers were mothers and the
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group mean (SD) age for infants was 26.2 (1.9) weeks (range = 17.3–32.9), while for mother’s age it was 32.9 (5.2) years (range = 18.3–43.5). The frequent snorers contained a significantly higher percentage of males. They also had fewer days of breast feeding and more formula feeding. To explore whether gender and breast feeding should be included as covariates in the tests between group differences we undertook preliminary analyses examining the relationship between gender and breast feeding with developmental scores. Neither variable was significantly correlated with any developmental score and therefore gender and breastfeeding were not included as covariates in subsequent analyses (all r < .10, p > .05). The frequent snorers had significantly lower cognitive development scores, more restless sleep, and shorter total sleep duration and nocturnal sleep (Table 2). Correlational analyses revealed that frequent snoring was associated with lower Cognitive development scores and children who slept longer at night or had fewer nocturnal awakenings had higher Social–Emotional development scores (Table 3). No significant association was observed between either sleep duration or restlessness and any developmental outcome (all r < .15; p > .05). Regression analyses revealed a significant relationship between demographic, sleep and cognitive developmental scores. Demographic variables (SES, gender, parental smoking, infant wheezing, infant reflux, infant eczema, and number of days of breast feeding) accounted for 5% of variance (R2) of Cognitive development scores. Nocturnal sleep duration and restlessness accounted for .2% of the variance in cognitive development. Snoring frequency at 6 months shared an extra 12% of the variance in cognitive development (R2 change = .12; F (7, 104) = 2.2, p < .01).
4. Discussion The main finding of the present study was that cognitive ability was lower in a carefully screened group of children who began snoring frequently within the first month of life and who were still snoring frequently at 6 months of age. This is the first study to accurately assess snoring longitudinally in the first 6 months of life and, thereby, establish the duration of snoring and its relationship to developmental ability. Children who snored were also reported to have shorter and more restless sleep while, in contradistinction to the gender prevalence in later childhood, there was an obvious predominance of males in infants who snored. The implications of these findings are far reaching. There is a dearth of data examining the association between snoring and development in the first months of life. Montgomery-Downs and Gozal [18], using PSG, reported in a sample of 35 healthy infants with a mean age of eight months that snoring without demonstrable obstructive hypopnea or apnoea was associated with decrements in cognitive but not motor development. They further reported that snore-associated arousals accounted for 18% of the variance in mental development. In the current study, we examined parental-reported snoring from the first month of life and its relationship to development at 6 months of age. In this cohort of younger infants, we also found that frequent snoring over the first 6 months of life was associated with decrements in cognitive but not motor, language, or social–emotional development. In addition, and similar to the estimate given by Montgomery-Downs and Gozal [18] in older infants, a history of frequent snoring from the first month of life accounted for 12% of the variance in cognitive development. Hunt and colleagues [19] have provided further evidence that hypoxic events during the first 4 months of life are associated with lower cognitive development at 2 years of age. Taken together, these findings suggest that sleep disordered breathing in very early life-characterised by snoring and/or
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Table 1 Infant and parental demographic variables for controls (n = 88) and who snored within the first month of life and continued until six months of age (n = 16) together with Chi-Squared and F-test results. Controls % Gender (male) Ethnicity Caucasian Asian Mother’s education completed High school Technical qualification University Father’s education completed High school Technical qualification University Infant wheezing (yes)a Infant eczema (yes)b Reflux (yes) Oral feeding Breast only Formula only Breast and formula Maternal snoring (yes) Paternal snoring (yes))c Maternal smoking during pregnancy (yes) Maternal smoking post-delivery (yes) Other smokers in the household post-delivery (yes)
* **
%
Chi-square
n
43
(36)
81
(13)
9.6**
99 1
(87) (1)
100 0
(16) (0)
1.1
17 31 52
(15) (27) (46)
19 31 50
(3) (5) (8)
0.1
20 29 51 12 16 7
(18) (26) (43) (10) (14) (6)
12 50 38 33 33 19
(2) (8) (6) (5) (5) (3)
1.9
51 13 36 35 73 7 4 10 Mean 33.0 1007.6 26.2 155.1
Maternal age (y)d SES (SEIFA score) Infant age (weeks) Number of days breast feeding
Snorers 0–6 months n
(45) (11) (32) (29) (59) (6) (4) (9) SD (5.1) (69.8) (1.9) (52.8)
44 50 6 44 75 6 6 19 Mean 34.4 971.9 26.6 119.5
4.6* 2.6 2.4
(7) (8) (1) (7) (14) (1) (1) (3) SD (5.0) (78.1) (2.3) (70.7)
14.4**
0.6 2.9 0.4 2.4 1.0 F-value (effect size (gp2)) 0.7 (0.0) 3.4 (0.1) 0.4 (0.0) 5.5 (0.05)⁄
Denotes p < .05. p < .01. a In addition, three controls and one snorer responded ‘‘don’t know.’’. b One control and one snorer responded ‘‘don’t know’’. c Six controls and one snorer responded ‘‘don’t know’’. d For this analysis, controls = 74 and snorers = 12.
Table 2 Mean (SD) sleep and neurocognitive values for controls (n = 88) and children who snored within the first month of life and continued until six months of age (n = 16). Dependent variable Sleep (previous week) Night sleep (h) Day sleep (h) Total Sleep (h) Time to fall asleep (min) # Nocturnal awakenings per night # Nights of restless sleep per weeka Bayley Developmental Scales Cognitive Language Motor Social–emotional
Controls 10.3 (1.1) 3.12 (1.4) 13.4 (1.8) 19.8 (18.4) 1.92 (1.6) 1.83 (0.8) 100.6 91.4 100.2 99.2
(3.9) (3.6) (7.7) (12.7)
Snorers 0–6 months
F-value
Effect size (gp2)
9.3 (1.6) 2.69 (1.3) 12.2 (2.0) 18.3 (18.4) 2.00 (1.9) 2.38 (0.8)
9.6** 1.3 6.2* 0.1 0.0 6.4*
.09 .00 .06 .00 .00 .06
95.3 (4.3) 91.25 (3.9) 97.25 (7.4) 103.5 (15.2)
23.8** 0.0 2.0 1.3
.21 .00 .02 .01
a * **
How many nights in the past week has your child had restless sleep? Denotes p < .05. Denotes p < .01.
hypoxia – is associated with measurable neurocognitive decrements. It remains to be established whether these decrements persist into later childhood. A substantial percentage of infants in the present study were frequent snorers at 6 months of age (16.2% [19/117]). This estimate is higher than the 5.0–7.0% prevalence range typically reported by several groups [2,4,31]. It is also noteworthy that the majority of children in our study who snored frequently at 6 months of age did so from the first month of life (16/19; 84%). Whether these children will continue to snore is an important question. Zucconi and
colleagues [32], in their sample of 60 children with habitual snoring at 4 years of age, reported that 16.6% snored from the first month of life, supporting the hypothesis of an important subgroup of children in which early frequent snoring persists at least through the first years of life. A further distinguishing characteristic of the infants who snored from the first month of life in the current study was the predominance of males (81%). The major caveat here, however, is that this was not an epidemiological study and the relatively low numbers of infants studied precludes definitive interpretation. In adult life
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A.M. Piteo et al. / Sleep Medicine 12 (2011) 981–987 Table 3 Correlation between sleep and development variables (n = 104). Key sleep variable
Bayley Developmental Scale Cognitive
Night sleep Total Sleep # Nocturnal awakenings per night # Nights of restless sleep Frequency of snoring at 6 months± * ** ±
.02 .04 .07 .08 .41**
Language .03 .04 .02 .04 .03
Motor .03 .08 .09 .07 .02
Social–emotional .24* .12 .22* .17 .11
Denotes p < .05. Denotes p < .01. Snoring frequency is a continuous variable.
the majority of snorers are male [33], but in childhood a slight male predominance has been reported by some groups [3,34–38], but not all [4,35,39]. Less is known about gender differences in snoring in children younger than 6 months of age. Male infants with SDB may also be at greater risk for developmental deficits. Evidence from rat studies indicates that intermittent hypoxia during development may predispose male, but not female, rat pups to alterations in frontal cortical dopaminergic pathways and subsequent deficits in working memory [40]. It is intriguing to speculate whether there is a subset of infants who snore shortly after birth and who go on to become snorers in later childhood. Thus early snorers may be a specific and vulnerable group, within the spectrum of SDB in childhood, who are at potentially greater risk of neurocognitive deficits and therefore diminished academic progress in later childhood. A further interesting finding in the present study was that increased frequency of snoring was associated with formula feeding, in support of the findings by Montgomery-Downs, et al. (2007). It has been suggested that breast milk may provide infants with immunoglobulin protection against early exposure to viruses that may contribute to enhanced proliferation of the upper airway tissues (Goldbart, et al., 2007; Kuehni, et al., 2008; MontgomeryDowns et al., 2007). It is concerning that developmental deficits are discernable in snoring infants within the first 6 months of life because this is a time of rapid brain development. There has been intense research interest over the past decade in the evaluation of pathophysiological mechanisms underlying the neurocognitive deficits associated with OSAS in both children and adults. Brain imaging studies in adults with OSAS have demonstrated injury in multiple brain regions, and particularly in those thought important for memory and executive functions, including hippocampal, frontal, and anterior cingulate areas [41–43]. In children, Halbower et al. [44], utilizing proton magnetic resonance spectroscopy, demonstrated reduction in mean neuronal metabolite ratio N-acetyl aspartate/ choline in the left hippocampus in six children age 6–16 years with severe OSAS, indicating possible neuronal injury. Similarly, Hogan et al. [17] demonstrated increased cerebral blood flow in 21 children of mean age 6 years with mild OSAS. Interestingly, when differences in neurocognitive scores between snorers and non snoring controls were adjusted for cerebral blood flow values, differences between the two groups were reduced. The latter implies that altered cerebral hemodynamics may contribute to decrements in cognition in children with only mild upper airway obstruction. Studies evaluating the mechanisms underlying the neurocognitive and behavioural deficits seen in children and adults with OSAS have focussed on the effects of two main factors, intermittent hypoxia and sleep fragmentation. Intermittent hypoxia results in oxidative stress and up-regulation of inflammatory pathways. Seminal studies in rodent models of OSAS by Gozal and colleagues (for review see 11) have demonstrated that intermittent hypoxia results in apoptosis of neuronal cells, particularly in the CA1 region
of the hippocampus. Inflammatory pathways have also been implicated in the genesis of neuronal injury secondary to intermittent hypoxia, while Zhan et al. [45] recently reported that, in rodents, pharmacological inhibition of one such pathway prevented neuronal apoptosis and decrements in hippocampal dependent learning tasks. Other factors may modulate the susceptibility of individuals to the effects of intermittent hypoxia, including chronological age, lipid cellular processing pathways such as apolipoprotein E [46], and variations in neuronal cell repair or neurogenesis [47]. There is also emerging evidence that sleep fragmentation without hypoxia also affects brain structure and function. In an adult rodent model, Guzman-Marin and colleagues [14] demonstrated that 4–7 days of sleep fragmentation resulted in a marked reduction in neurogenesis in the hippocampal dentate gyrus. Sportiche et al. [12], in a similar adult rodent model, showed that sleep fragmentation reduced not only neurogenesis in this area, but was also associated with changes in spatial learning two weeks after cessation of the sleep fragmentation. In 10 month old infants, Scher et al. [48] found that a more fragmented sleep pattern was moderately associated with lower Bayley mental developmental index scores, supporting the findings of Montgomery-Downs and Gozal [18] discussed earlier. The extent to which SDB in infancy, with or without hypoxia, impacts on sleep quality and subsequent brain function and associated neurocognition and behaviour is yet to be characterised. But it is an important question given the potential for cumulative and long term deficits [49]. The importance of snoring in children is often overlooked by both parents and doctors. A previous study by our group [50] found that the issue was raised by either parents or the primary care doctor in fewer than 20% of children who had a significant history of snoring. The likelihood that snoring is overlooked in infants is potentially greater. The infants who snored from the first month of life had shorter and more restless sleep as assessed by questionnaire. However, neither sleep duration nor restlessness was associated with any significant decrements in development. In infants, longer sleep duration has been associated with higher cognitive functioning in some studies [51–53], but the reverse in others [54–55]. The infants who snored from the first month of life also had more wheezing and were less likely to be breastfed. By contrast, snoring was not associated with smoking, eczema, reflux, and maternal/paternal snoring. These findings are reported in more detail in a companion paper by our group examining the prevalence and factors associated with snoring [20]. As PSG was not undertaken in the current study, we are unable to quantify the degree of sleep disturbance in these infants. However, this is unlikely to be a significant limitation given the report of Montgomery-Downs and Gozal showing that snore-related arousals using PSG were associated with lower mental development [18]. Future studies using PSG are required to help determine the relative contribution of hypoxia vs. sleep fragmentation to neurocognitive deficits in infants.
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A further limitation of the present study is the small number of children who began frequent snoring between 2 and 6 months of life (n = 3), thereby precluding an examination of habitual snoring commenced after the first month of life. Similar to the cohort of children who commenced frequent snoring soon after birth, it is possible that these children may also be at risk for developmental decrements. In conclusion, we identified a cohort of predominantly male children who snored frequently soon after birth and whose cognitive development was impaired when assessed at 6 months of age. It remains to be determined whether these deficits change with snoring status or persist through childhood and if these same snoring male infants become the adult OSAS patients of the future. Conflicts of Interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: doi:10.1016/j.sleep.2011.03.023.
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[32] Zucconi M, Strambi LF, Pestalozza G, Tessitore E, Smirne S. Habitual snoring and obstructive sleep apnea syndrome in children: effects of early tonsil surgery. Int J Pediatr Otorhinolaryngol 1993 Apr;26(3):235–43. [33] Punjabi NM. The epidemiology of adult obstructive sleep apnea. Proc Am Thorac Soc 2008;5(2):136–43. [34] Brunetti L, Rana S, Lospalluti ML, Pietrafesa A, Francavilla R, Fanelli M, et al. Prevalence of obstructive sleep apnea syndrome in a cohort of 1, 207 children of Southern Italy. Chest 2001;120(6):1930–5. [35] Castronovo V, Zucconi M, Nosetti L, Marazzini C, Hensley M, Veglia F, et al. Prevalence of habitual snoring and sleep-disordered breathing in preschoolaged children in an Italian community. J Pediatr 2003;142(4):377–82. [36] Corbo GM, Forastiere F, Agabiti N, Pistelli R, Dell’Orco V, Perucci CA, et al. Snoring in 9 to 15-year-old children: risk factors and clinical relevance. Pediatrics 2001;108(5):1149–54. 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Original Article
Snoring and cognitive development in infancy A.M. Piteo a, J.D. Kennedy b,⇑, R.M. Roberts a, A.J. Martin b, T. Nettelbeck a, M.J. Kohler c, K. Lushington c a
School of Psychology, University of Adelaide, South Australia, Australia Discipline of Paediatrics, School of Reproductive Health and Paediatrics, University of Adelaide, South Australia, Australia c School of Psychology, Social Work and Social Policy, University of South Australia, South Australia, Australia b
a r t i c l e
i n f o
Article history: Received 25 November 2010 Received in revised form 27 February 2011 Accepted 2 March 2011 Available online 21 November 2011 Keywords: Snoring Infants Neurocognitive Development Sleep Pediatric
a b s t r a c t Objective: This study aimed to assess the influence of snoring and sleep duration on developmental outcomes in 6 month old infants. Methods: As part of a longitudinal study of snoring in infancy, we identified 16 children (13 males) who commenced snoring shortly after birth and continued to snore frequently (P3 nights/week) at 6 months of age and 88 healthy infant controls who were reported never to snore in the absence of a cold (36 males). Infants were assessed at 6 months of age with the Bayley Scales of Infant and Toddler Development Edition III, and parents completed demographic, sleep, and developmental surveys. Results: Cognitive development was reduced in infants who snored frequently (mean = 95.3; SD = 4.3) from the first month of life compared to control infants (mean = 100.6; SD = 3.9) (F [1, 99] = 23.8, p < .01; gp2 = .21). Conclusion: Snoring during the first 6 months of life was associated with lower cognitive development scores. It is unknown whether these infants will continue to snore through childhood and, if so, whether the associated neurocognitive deficits will become worse with time. Crown Copyright Ó 2011 Published by Elsevier B.V. All rights reserved.
1. Introduction Sleep Disordered Breathing (SDB) is common in childhood and ranges in severity from primary snoring to obstructive sleep apnoea syndrome (OSAS). The cardinal symptom of SDB is frequent or habitual snoring, affecting an estimated 5–26% of infants [1–4] and 5–10% of older children [5]. SDB is associated with neurocognitive and behavioural deficits that are reported even in children with relatively mild snoring [6–10]. To date, most studies have focussed on school-aged children and little is known about the impact of SDB on daytime functioning in much younger children. There is now convincing evidence that OSAS in both children and adults is associated with demonstrable changes in brain structure and function. The precise mechanisms underpinning these changes are currently under intense investigation, but rodent models of OSAS confirm that intermittent hypoxia secondary to upper airway obstruction induces apoptosis in both hippocampal and cortical regions by initiating oxidative stress and upregulating inflammatory pathways [11]. In addition, animal studies have confirmed that sleep fragmentation alone can induce structural ⇑ Corresponding author. Address: University of Adelaide, School of Psychology, Hughes Building North Terrace, Adelaide, SA 5000, Australia. Tel.: +61 8 8303 5693; fax: +61 8 8303 3770. E-mail addresses: [email protected] (A.M. Piteo), declan.kennedy@ adelaide.edu.au (J.D. Kennedy).
changes, with reduction in neurogenesis within the CA1 area of the hippocampus and subsequent impairment of spatial leaning [12–15]. In healthy human infants, Scher et al. [16] has recently reported that increased sleep fragmentation at 10 months of age (as measured by actigraphy) was associated with reduced mental development scores while Hogan, Hill, Harrison, and Kirkham [17] found changes in cerebral vascular flow parameters in children with only mild primary snoring. The literature examining snoring in infancy is limited by the lack of studies validating parental reports of snoring while the assessment of cognitive function in infants with SDB is limited to a single study by Montgomery-Downs and Gozal [18]. These authors investigated 35 healthy 8 month old infants with polysomography (PSG) and reported that snoring-related arousals across the entire group were associated with lower mental development scores. Notably, no infant in that study had episodes of either obstructive hypopnoea or apnoea and only about half of the 35 infants in the study were reported to snore. Indirect evidence that SDB in early life may be associated with impaired development is provided by Hunt and colleagues [19], who examined 256 infants, including healthy infants, infants and siblings of infants who went through apparent life threatening events, and pre-term infants. Hunt’s group reported that >5 extreme cardio-respiratory events (apnoea with bradycardia) by 4 months of age were associated with lower mental development scores at 92 weeks of age. However, this study did not include the evaluation of infants who
1389-9457/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2011.03.023
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snored versus non-snorers. A further issue not addressed by either of these studies is whether particular subgroups of infants are at greater risk for cognitive deficits, for example: habitual snorers who start snoring soon after birth. Given this background, the aim of the present study was to examine cognitive development in infants who developed frequent snoring in the first month of life, and who continued to snore frequently when assessed at 6 months of age, and compare them to healthy non-snoring infants.
2. Methods This research forms part of an ongoing longitudinal study examining snoring in the first year of life (for details see Piteo et al., accepted January 2011 [20]). Infants aged between 0 and 3 months were recruited by Child and Family Health nurses during their mother’s first ‘‘well child’’ visit, which is conducted routinely in South Australia. At that visit, the nurses distributed a parent and child sleep and health questionnaire. A subset of these parents volunteered to participate in a follow-up study examining sleep and cognition at 6 months. Parents of children identified as habitual snorers were recommended to consult their general medical practitioner.
2.1. Participants Participant selection and exclusion details are given in Fig. 1. The final sample at 6 months consisted of 88 full term non-snoring infants and 16 infants who snored frequently from shortly after birth and continued to snore at 6 months. (Note that children classified as infrequent snorers over this time period were excluded from analyses [n = 10]). The study was approved by the Children’s Youth and Women’s Health Services, University of South Australia and the University of Adelaide Human Research Ethics Committees.
2.2. Measures 2.2.1. Demographic information The following demographic information for those infants studied was collected at the initial recruitment stage, when they were 0–3 months old, and included gender, age, and ethnicity. Demographic data collected for the infants’ parents included parental education history (high school, technical education, and university), socio-economic status, and maternal age. Socioeconomic Status (SES) was determined from the Australian Bureau of Statistics (ABS) SES Index of relative advantage and disadvantage (SEIFA) (national mean = 1000; SD = 100). This provided an indication of the social and economic conditions of a neighbourhood area based on the information collected at the 2006 census [21]. (SES was collected at both time points, when infants were 0–3 months old, and again at 6 months old.) 2.2.2. Snoring At 0–3 months old and 6 months old, parents were asked ‘‘How many nights in the past week did your child snore?’’ and children were then classified as controls (never reported to snore in the absence of a cold) (n = 88), infrequent snorers (<1–2 nights/week) (n = 10) or frequent snorers (P3 nights/week) (n = 19). The infants who snored were further classified at both 0–3 months old and 6 months old based on parental response to the question, ‘‘When did the snoring begin?’’ They were classified according to whether they did or did not begin snoring shortly after birth, i.e.: (i) snored frequently before 1 month of age and continued to snore frequently when assessed at 6 months of age (n = 16); or (ii) snored after the first month of life (n = 14) and infrequently (n = 11) or frequently (n = 3) at 6 months of age. 2.2.3. Family and infant health The following infant health variables were collected at 6 months of age: ‘‘In the past 6 months has your child had: (1) episodes of wheezing,’’ ‘‘(2) eczema,’’ and ‘‘(3) reflux’’ (yes/no/don’t
Snoring and sleep survey 0-3 months old (Parent asked if the child was snoring and if so, at what age this began) (n = 515) Exclusion Contact details not provided or declined to participate further (n = 245) Prematurity (n = 35) Infants aged > 3 months at time of survey (n = 23) Assessed for eligibility (n = 212) Exclusion Congenital disorder (n = 2) Non-metropolitan residence (n = 29) Declined to participate at follow-up (n = 64) Neurocognitive, snoring and sleep assessment 6-months-old (Parent asked if the child was snoring and if so, at what age this began) (n = 117) Fig. 1. Participant flow chart and timeline of events.
A.M. Piteo et al. / Sleep Medicine 12 (2011) 981–987
know). Parents were also asked when infants were 0–3 months old, and again when 6 months old, about breast/formula feeding (breast milk only, formula only, or breast milk and formula) and the number of days the infant was breast fed. The following family health information was collected at 0– 3 months old and 6 months old: (1) ‘‘Did the mother smoke during pregnancy?’’ (2) ‘‘Did the mother smoke post-delivery?’’ and (3) ‘‘Were there other smokers in the household post-delivery?’’ (yes/no/don’t know). The following family health information was collected at 6 months only: (1) ‘‘Does the child’s mother snore?’’ (2) ‘‘Does the child’s father snore?.’’ 2.2.4. Sleep To maintain consistency with previous studies we used previously validated questionnaire items [4,22–24] for sleep duration, sleep quality, respiratory, and sleep disordered breathing items which were assessed at 0–3 months old and again at 6 months old. Parents were asked how many nights in the past week their child was reported to snore as well as the age onset of the snoring. SDB items included two items regarding parental concern about their child’s breathing. 2.2.5. Developmental assessment The Bayley Scales of Infant and Toddler Development Edition III was used to assess neuropsychological development [25] at 6 months old. The Bayley is a well validated and reliable instrument with high internal consistency which provides estimates for four developmental domains: Cognitive (sensory-perceptual acuity, discrimination and response abilities, object constancy, learning, memory and problem solving abilities), Language (Receptive Communication and Expressive Communication), Motor (Fine and Gross Motor), and Social-Emotional and Adaptive Behaviour (self-regulation, interest in the world, communicating needs, engaging others, and establishing relationships while using emotions in interactions). The Bayley developmental scores have been reported to correlate moderately to highly with IQ estimates collected later in childhood [26–29]. The test takes 50 min to administer in children <12 months. The Cognitive, Language, and Motor components were administered by a trained psychologist while parents completed the Social–Emotional scale. The results are reported as standard scores with a mean = 100 and SD = 15. Infants were free of colds and other relevant health problems that may affect snoring and daytime functioning at the time of testing. 2.2.6. Statistical analysis Descriptive statistics were calculated for demographic variables, developmental outcomes, and sleep variables. Where appropriate, F-tests and Chi-squared tests were used to test for group differences in demographic and neurocognitive scores. Effect sizes were determined using partial eta squared values ([gp2]; 0.01 = small, 0.06 = medium and 0.14 = large effect size [30]). Pearson-r correlations were used to explore the association between sleep and developmental variables. Hierarchical regression analysis was used to assess the influence of snoring frequency at 6 months on development scores at 6 months of age. In step 1 we entered SES, gender, parental smoking (0 = no, 1 = yes), infant wheezing, infant reflux, infant eczema, and number of days of breast feeding. In step 2 we entered nocturnal sleep duration and number of nocturnal awakenings per night. In step 3 we entered snoring frequency. 3. Results The demographic data for infants and parents are presented in Table 1. Ninety-eight percent of caregivers were mothers and the
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group mean (SD) age for infants was 26.2 (1.9) weeks (range = 17.3–32.9), while for mother’s age it was 32.9 (5.2) years (range = 18.3–43.5). The frequent snorers contained a significantly higher percentage of males. They also had fewer days of breast feeding and more formula feeding. To explore whether gender and breast feeding should be included as covariates in the tests between group differences we undertook preliminary analyses examining the relationship between gender and breast feeding with developmental scores. Neither variable was significantly correlated with any developmental score and therefore gender and breastfeeding were not included as covariates in subsequent analyses (all r < .10, p > .05). The frequent snorers had significantly lower cognitive development scores, more restless sleep, and shorter total sleep duration and nocturnal sleep (Table 2). Correlational analyses revealed that frequent snoring was associated with lower Cognitive development scores and children who slept longer at night or had fewer nocturnal awakenings had higher Social–Emotional development scores (Table 3). No significant association was observed between either sleep duration or restlessness and any developmental outcome (all r < .15; p > .05). Regression analyses revealed a significant relationship between demographic, sleep and cognitive developmental scores. Demographic variables (SES, gender, parental smoking, infant wheezing, infant reflux, infant eczema, and number of days of breast feeding) accounted for 5% of variance (R2) of Cognitive development scores. Nocturnal sleep duration and restlessness accounted for .2% of the variance in cognitive development. Snoring frequency at 6 months shared an extra 12% of the variance in cognitive development (R2 change = .12; F (7, 104) = 2.2, p < .01).
4. Discussion The main finding of the present study was that cognitive ability was lower in a carefully screened group of children who began snoring frequently within the first month of life and who were still snoring frequently at 6 months of age. This is the first study to accurately assess snoring longitudinally in the first 6 months of life and, thereby, establish the duration of snoring and its relationship to developmental ability. Children who snored were also reported to have shorter and more restless sleep while, in contradistinction to the gender prevalence in later childhood, there was an obvious predominance of males in infants who snored. The implications of these findings are far reaching. There is a dearth of data examining the association between snoring and development in the first months of life. Montgomery-Downs and Gozal [18], using PSG, reported in a sample of 35 healthy infants with a mean age of eight months that snoring without demonstrable obstructive hypopnea or apnoea was associated with decrements in cognitive but not motor development. They further reported that snore-associated arousals accounted for 18% of the variance in mental development. In the current study, we examined parental-reported snoring from the first month of life and its relationship to development at 6 months of age. In this cohort of younger infants, we also found that frequent snoring over the first 6 months of life was associated with decrements in cognitive but not motor, language, or social–emotional development. In addition, and similar to the estimate given by Montgomery-Downs and Gozal [18] in older infants, a history of frequent snoring from the first month of life accounted for 12% of the variance in cognitive development. Hunt and colleagues [19] have provided further evidence that hypoxic events during the first 4 months of life are associated with lower cognitive development at 2 years of age. Taken together, these findings suggest that sleep disordered breathing in very early life-characterised by snoring and/or
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Table 1 Infant and parental demographic variables for controls (n = 88) and who snored within the first month of life and continued until six months of age (n = 16) together with Chi-Squared and F-test results. Controls % Gender (male) Ethnicity Caucasian Asian Mother’s education completed High school Technical qualification University Father’s education completed High school Technical qualification University Infant wheezing (yes)a Infant eczema (yes)b Reflux (yes) Oral feeding Breast only Formula only Breast and formula Maternal snoring (yes) Paternal snoring (yes))c Maternal smoking during pregnancy (yes) Maternal smoking post-delivery (yes) Other smokers in the household post-delivery (yes)
* **
%
Chi-square
n
43
(36)
81
(13)
9.6**
99 1
(87) (1)
100 0
(16) (0)
1.1
17 31 52
(15) (27) (46)
19 31 50
(3) (5) (8)
0.1
20 29 51 12 16 7
(18) (26) (43) (10) (14) (6)
12 50 38 33 33 19
(2) (8) (6) (5) (5) (3)
1.9
51 13 36 35 73 7 4 10 Mean 33.0 1007.6 26.2 155.1
Maternal age (y)d SES (SEIFA score) Infant age (weeks) Number of days breast feeding
Snorers 0–6 months n
(45) (11) (32) (29) (59) (6) (4) (9) SD (5.1) (69.8) (1.9) (52.8)
44 50 6 44 75 6 6 19 Mean 34.4 971.9 26.6 119.5
4.6* 2.6 2.4
(7) (8) (1) (7) (14) (1) (1) (3) SD (5.0) (78.1) (2.3) (70.7)
14.4**
0.6 2.9 0.4 2.4 1.0 F-value (effect size (gp2)) 0.7 (0.0) 3.4 (0.1) 0.4 (0.0) 5.5 (0.05)⁄
Denotes p < .05. p < .01. a In addition, three controls and one snorer responded ‘‘don’t know.’’. b One control and one snorer responded ‘‘don’t know’’. c Six controls and one snorer responded ‘‘don’t know’’. d For this analysis, controls = 74 and snorers = 12.
Table 2 Mean (SD) sleep and neurocognitive values for controls (n = 88) and children who snored within the first month of life and continued until six months of age (n = 16). Dependent variable Sleep (previous week) Night sleep (h) Day sleep (h) Total Sleep (h) Time to fall asleep (min) # Nocturnal awakenings per night # Nights of restless sleep per weeka Bayley Developmental Scales Cognitive Language Motor Social–emotional
Controls 10.3 (1.1) 3.12 (1.4) 13.4 (1.8) 19.8 (18.4) 1.92 (1.6) 1.83 (0.8) 100.6 91.4 100.2 99.2
(3.9) (3.6) (7.7) (12.7)
Snorers 0–6 months
F-value
Effect size (gp2)
9.3 (1.6) 2.69 (1.3) 12.2 (2.0) 18.3 (18.4) 2.00 (1.9) 2.38 (0.8)
9.6** 1.3 6.2* 0.1 0.0 6.4*
.09 .00 .06 .00 .00 .06
95.3 (4.3) 91.25 (3.9) 97.25 (7.4) 103.5 (15.2)
23.8** 0.0 2.0 1.3
.21 .00 .02 .01
a * **
How many nights in the past week has your child had restless sleep? Denotes p < .05. Denotes p < .01.
hypoxia – is associated with measurable neurocognitive decrements. It remains to be established whether these decrements persist into later childhood. A substantial percentage of infants in the present study were frequent snorers at 6 months of age (16.2% [19/117]). This estimate is higher than the 5.0–7.0% prevalence range typically reported by several groups [2,4,31]. It is also noteworthy that the majority of children in our study who snored frequently at 6 months of age did so from the first month of life (16/19; 84%). Whether these children will continue to snore is an important question. Zucconi and
colleagues [32], in their sample of 60 children with habitual snoring at 4 years of age, reported that 16.6% snored from the first month of life, supporting the hypothesis of an important subgroup of children in which early frequent snoring persists at least through the first years of life. A further distinguishing characteristic of the infants who snored from the first month of life in the current study was the predominance of males (81%). The major caveat here, however, is that this was not an epidemiological study and the relatively low numbers of infants studied precludes definitive interpretation. In adult life
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A.M. Piteo et al. / Sleep Medicine 12 (2011) 981–987 Table 3 Correlation between sleep and development variables (n = 104). Key sleep variable
Bayley Developmental Scale Cognitive
Night sleep Total Sleep # Nocturnal awakenings per night # Nights of restless sleep Frequency of snoring at 6 months± * ** ±
.02 .04 .07 .08 .41**
Language .03 .04 .02 .04 .03
Motor .03 .08 .09 .07 .02
Social–emotional .24* .12 .22* .17 .11
Denotes p < .05. Denotes p < .01. Snoring frequency is a continuous variable.
the majority of snorers are male [33], but in childhood a slight male predominance has been reported by some groups [3,34–38], but not all [4,35,39]. Less is known about gender differences in snoring in children younger than 6 months of age. Male infants with SDB may also be at greater risk for developmental deficits. Evidence from rat studies indicates that intermittent hypoxia during development may predispose male, but not female, rat pups to alterations in frontal cortical dopaminergic pathways and subsequent deficits in working memory [40]. It is intriguing to speculate whether there is a subset of infants who snore shortly after birth and who go on to become snorers in later childhood. Thus early snorers may be a specific and vulnerable group, within the spectrum of SDB in childhood, who are at potentially greater risk of neurocognitive deficits and therefore diminished academic progress in later childhood. A further interesting finding in the present study was that increased frequency of snoring was associated with formula feeding, in support of the findings by Montgomery-Downs, et al. (2007). It has been suggested that breast milk may provide infants with immunoglobulin protection against early exposure to viruses that may contribute to enhanced proliferation of the upper airway tissues (Goldbart, et al., 2007; Kuehni, et al., 2008; MontgomeryDowns et al., 2007). It is concerning that developmental deficits are discernable in snoring infants within the first 6 months of life because this is a time of rapid brain development. There has been intense research interest over the past decade in the evaluation of pathophysiological mechanisms underlying the neurocognitive deficits associated with OSAS in both children and adults. Brain imaging studies in adults with OSAS have demonstrated injury in multiple brain regions, and particularly in those thought important for memory and executive functions, including hippocampal, frontal, and anterior cingulate areas [41–43]. In children, Halbower et al. [44], utilizing proton magnetic resonance spectroscopy, demonstrated reduction in mean neuronal metabolite ratio N-acetyl aspartate/ choline in the left hippocampus in six children age 6–16 years with severe OSAS, indicating possible neuronal injury. Similarly, Hogan et al. [17] demonstrated increased cerebral blood flow in 21 children of mean age 6 years with mild OSAS. Interestingly, when differences in neurocognitive scores between snorers and non snoring controls were adjusted for cerebral blood flow values, differences between the two groups were reduced. The latter implies that altered cerebral hemodynamics may contribute to decrements in cognition in children with only mild upper airway obstruction. Studies evaluating the mechanisms underlying the neurocognitive and behavioural deficits seen in children and adults with OSAS have focussed on the effects of two main factors, intermittent hypoxia and sleep fragmentation. Intermittent hypoxia results in oxidative stress and up-regulation of inflammatory pathways. Seminal studies in rodent models of OSAS by Gozal and colleagues (for review see 11) have demonstrated that intermittent hypoxia results in apoptosis of neuronal cells, particularly in the CA1 region
of the hippocampus. Inflammatory pathways have also been implicated in the genesis of neuronal injury secondary to intermittent hypoxia, while Zhan et al. [45] recently reported that, in rodents, pharmacological inhibition of one such pathway prevented neuronal apoptosis and decrements in hippocampal dependent learning tasks. Other factors may modulate the susceptibility of individuals to the effects of intermittent hypoxia, including chronological age, lipid cellular processing pathways such as apolipoprotein E [46], and variations in neuronal cell repair or neurogenesis [47]. There is also emerging evidence that sleep fragmentation without hypoxia also affects brain structure and function. In an adult rodent model, Guzman-Marin and colleagues [14] demonstrated that 4–7 days of sleep fragmentation resulted in a marked reduction in neurogenesis in the hippocampal dentate gyrus. Sportiche et al. [12], in a similar adult rodent model, showed that sleep fragmentation reduced not only neurogenesis in this area, but was also associated with changes in spatial learning two weeks after cessation of the sleep fragmentation. In 10 month old infants, Scher et al. [48] found that a more fragmented sleep pattern was moderately associated with lower Bayley mental developmental index scores, supporting the findings of Montgomery-Downs and Gozal [18] discussed earlier. The extent to which SDB in infancy, with or without hypoxia, impacts on sleep quality and subsequent brain function and associated neurocognition and behaviour is yet to be characterised. But it is an important question given the potential for cumulative and long term deficits [49]. The importance of snoring in children is often overlooked by both parents and doctors. A previous study by our group [50] found that the issue was raised by either parents or the primary care doctor in fewer than 20% of children who had a significant history of snoring. The likelihood that snoring is overlooked in infants is potentially greater. The infants who snored from the first month of life had shorter and more restless sleep as assessed by questionnaire. However, neither sleep duration nor restlessness was associated with any significant decrements in development. In infants, longer sleep duration has been associated with higher cognitive functioning in some studies [51–53], but the reverse in others [54–55]. The infants who snored from the first month of life also had more wheezing and were less likely to be breastfed. By contrast, snoring was not associated with smoking, eczema, reflux, and maternal/paternal snoring. These findings are reported in more detail in a companion paper by our group examining the prevalence and factors associated with snoring [20]. As PSG was not undertaken in the current study, we are unable to quantify the degree of sleep disturbance in these infants. However, this is unlikely to be a significant limitation given the report of Montgomery-Downs and Gozal showing that snore-related arousals using PSG were associated with lower mental development [18]. Future studies using PSG are required to help determine the relative contribution of hypoxia vs. sleep fragmentation to neurocognitive deficits in infants.
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A further limitation of the present study is the small number of children who began frequent snoring between 2 and 6 months of life (n = 3), thereby precluding an examination of habitual snoring commenced after the first month of life. Similar to the cohort of children who commenced frequent snoring soon after birth, it is possible that these children may also be at risk for developmental decrements. In conclusion, we identified a cohort of predominantly male children who snored frequently soon after birth and whose cognitive development was impaired when assessed at 6 months of age. It remains to be determined whether these deficits change with snoring status or persist through childhood and if these same snoring male infants become the adult OSAS patients of the future. Conflicts of Interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: doi:10.1016/j.sleep.2011.03.023.
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