obstructive sleep apnea syndrome ( osa ) is a common problem among children and especially boys , with estimated prevalence of 2 - 3% , with most children being diagnosed at the age of 26 years . at night
osa is characterized by interrupted sleep , snoring , and disrupted breathing . at daytime , children present hyperactive behavior , cognitive deficits , and attention problems .
adenotonsillar hypertrophy is considered the leading cause of pediatric osa and tonsillectomy and adenoidectomy ( t&a ) is still considered and clinically used as a first line treatment for children with osa .
there is growing evidence on osa 's associated neurobehavioral , cognitive , cardiovascular , and metabolic morbidities .
furthermore , new studies found an improvement in cognitive   and cardiovascular   functions after t&a . in the last 30 years
there were several studies , as well as case studies , suggesting osa as a major risk factor for growth failure [ 9 , 10 ] .
these studies were conducted mostly among kindergarten and school children and showed an improvement of somatic growth accompanied with an increased level of igf-1 and the ratio growth hormone ( gh)/igf-1 after t&a [ 11 , 12 ] .
the very few studies that followed somatic growth in toddlers have also shown an improvement of somatic growth , but none of them have ever tried to estimate the role of growth hormone in the process [ 11 , 12 ] .
there are several possible mechanisms for growth retardation among children with osa , including increased energy expenditure during sleep due to labored breathing , decreased appetite , and enlarged tonsils that serve as a mechanical barrier limiting the amount of food swallowed .
another possible explanation is interruption in the axis of growth hormone ( gh ) secretion .
gh is secreted from the pituitary gland mainly during slow - wave sleep in a pulsatile fashion .
gh secretion positively correlates with igf-1 and igfbp-3 levels which triggers bone growth . notwithstanding the direct effects of gh on growth plate chondrocytes
, it is now accepted that the indirect local and systemic effects of gh function in a highly coordinated manner regulate growth plate activities and linear bone growth . in children with osa
there is a decrease in the slow - wave sleep component , and an increase in its percentage of the total sleep time is noted following t&a .
this phenomenon was revealed by others and serves as a reasonable explanation to growth retardation before t&a and the improvement in growth after surgery .
linear bone growth is adversely affected in children with chronic kidney disease ( ckd ) and other chronic inflammatory disorders .
ckd patients have been reported to have elevated circulating levels of il-6 and tnf , similar to patients with osa [ 16 , 17 ] .
the ( gh)/(igf-1 ) pathway is anabolic to the skeleton and inflammatory cytokines compromise bone growth through several mechanisms , which include interference with the systemic as well as the tissue - level gh / igf-1 axis .
recent studies have shown that , in children , osa is accompanied by systemic inflammation , reflected by increased levels of markers like circulating c - reactive protein ( crp ) , that decrease after t&a .
interestingly , the role of systemic inflammation , in regard to growth , in such children was not studied so far .
therefore , we assessed growth in osa young children before and after t&a and evaluated potential mechanisms that may influence growth in these children .
the study was approved by soroka university medical center human irb committee , and informed consent was obtained from the legal caretaker of each participant .
young children with psg proven osa were enrolled and followed prospectively before t&a surgery and 46 months afterwards .
inclusion criteria were children older than 6 and younger than 36 months of age who were diagnosed with an obstructive apnea - hypopnea index ( ahi ) > 5 events / hour of sleep in an overnight polysomnographic evaluation and informed consent from the legal caregiver who agreed was obtained .
exclusion criteria were craniofacial , neuromuscular , syndromatic , or defined genetic abnormalities , any known previous allergies , no upper respiratory infection use of any corticosteroids or antibiotics within 4 weeks preceding the initial sleep study , and any children that had had t&a or adenoidectomy in the past .  

children were studied in a dedicated quiet , darkened room with an ambient temperature of 24c in the company of one of their parents .
polysomnography was performed with a computerized , commercially available , sleep monitoring system ( sensormedics inc .
sleep staging was performed with the standard criteria published by the aasm in 2007   and not by the latest revision of 2012 since we recruited our last child in february 2012 .
the ahi was defined as the airflow with continued chest wall and abdominal movement over at least two breaths .
hypopneas were defined as a 50% decrease in nasal flow with a corresponding 3% decrease in spo2 and/or arousal or awakening .
arousals were defined as recommended by the revised aasm rules . in each visit the child
anthropometric data was analyzed by the endocrinologist ( n.l . ) for z score using the software 
z score represents standard deviations gap from the mean to child 's age . a short food frequency questionnaire ( sffq ) for energy assessment was completed for each child on both encounters .
this sffq is based on a list of items reported by 160 mothers of infants at the age of 6 to 24 months describing the previous day 's food items offered or consumed .
all sffqs were assessed for caloric intake and for the differential percent of protein , fat , and carbohydrates in diet .
circulating hscrp was measured by means of particle - enhanced immunonephelometry using the bn prospec system ( newark , de ) .
blood draws were performed at the morning of t&a and 46 months following surgery also at the morning hours at the pediatric sleep clinic .
igf-1 levels were measured using an immunoradiometric assay after extraction ( dsl , webster , tx , usa ) .
interassay coefficient of variation ( cv ) was < 14% ; data are presented in nmol / l .
the markers were measured at the endocrinology and immunology laboratories at the soroka university medical center .
all parents filled a validated questionnaire given on the day of surgery and at the postsurgical follow - up visit in our pediatric sleep clinic . in brief , it includes eight items scored by the parent in a 04 scale ( 0 = never ; 4 = most of the time ) .
questions included are being hard to awake , witnessed apnea , breathing difficulties , snoring , sweating , mouth breathing , awakening , and restless sleep .
all numeric data were subjected to statistical analyses with either t tests or 2-way analysis of variance procedures for repeated measures , as described by neuman - keuls .
four children were lost to followup and were not different than the remaining participants . all 16 children ( 10 boys and 6 girls )
their mean age at the first encounter was 23  6 months ( range 733 months ) , and the mean time of follow - up was 5  2 months ( range 3.86.2 months ) .
most children showed significant improvements in their height ( 4.81  cm ) and weight ( 1.88  kg ) following adenotonsillectomy ( average : p < 0.001 for both ) .
thus bmi also increased by 0.85  0.42  kg / m ( p = 0.037 ) . at diagnosis ,
mean z scores for height , weight , and bmi were 1.18  0.32 , 1.29  0.35 , and 0.51  0.15 , respectively .
after treatment , there were significant improvements in weight z scores ( p = 0.002 ) and in bmi z scores ( p = 0.007 ) as shown in figure 1 .
the decrease in systemic inflammation was reflected by decrements of 0.51  0.28  mg% in crp levels after t&a ( p = 0.131 ) , while small increases in igf-1 levels also emerged ( 2.37  1.41  nmol / l ; p = 0.104 ) .
sffq were filled by the parents and compared the caloric intake ( table 1 ) . on average , the children added 377.6  292.4 calories to their daily diet after surgery ( p < 0.001 ) .
there were a significant increase in protein intake ( 2.0  1.4% ; p = 0.045 ; figure 2 ) and decrease in fat intake ( 4.49  2.36% ; p = 0.016 ) .
there was also an increase in consumption of carbohydrates of 2% that failed to reach statistical significance ( p = 0.44 ) .
a multivariate analysis identified a significant negative correlation between systemic inflammation and weight in boys , such that , with more prominent decreases in circulating crp levels , weight gain following surgery was magnified ( r = 0.775 ; p = 0.041 ; figure 3 ) .
this study found a major improvement in anthropometric parameters accompanied by a decrease in systemic inflammation and an increase in caloric intake and endocrinologic markers following t&a .
furthermore , for the first time it has been proved that even young children with osa show improvement in somatic growth that is associated in boys with a reduction in systemic inflammation .
this study also identified , for the first time , a significant change in diet composition in children with osa after surgery .
interestingly , the improvement in somatic growth correlated with an improvement in systemic inflammation but did not correlate with the changes in caloric intake .
we demonstrated that children aged 636 months who suffer from sleep disordered breathing are indeed smaller , for height and weight , than their peers before surgery .
this gap was minimized following t&a , as shown in the rise in the z scores .
this gap narrowing can be referred to as the  catch - up  growth .
it has been long known that children with osa improve their somatic growth after surgery , but so far a comprehensive assessment of children 636 months was not done .
previous studies that were held in this age group evaluated children for anthropometric parameters before and after t&a and found an improvement of somatic growth [ 11 , 12 ] . none of them tried to measure circulating levels of endocrine factors or the presence of systemic inflammation and their effect on growth .
furthermore , no dietary assessment has ever been performed in this age group and no one tried to estimate how surgical intervention affects the diet composition .
several mechanisms have been proposed during the years to try and explain growth retardation in children with osa . among them
are the presence of systemic inflammation that is well documented in children with osa [ 8 , 14 , 25 ] and dysphagia from hypertrophied tonsils that serve as a mechanical barrier and obstruct food entry , thus reducing caloric intake .
one of the day symptoms of osa is hyperactive behavior which results in increased motor activity that increases energy expenditure , thus contributing to growth failure .
this study tried to find the factor that imposes the biggest influence on  catch - up  growth in these children . circulating crp and igf-1 levels
were measured to estimate level of systemic inflammation and growth hormone - insulin - like growth factor 1 ( gh - igf-1 ) axis , respectively . in order to assess caloric intake
, parents completed a short food frequency questionnaire ( sffq ) for energy assessment for each child on both encounters .
this sffq is based on a list of items reported by 160 mothers of infants at the age of 6 to 24 months describing the previous day 's food items offered or consumed and was validated in previous studies [ 22 , 23 ] . other studies that assessed the relationship between nutrition and t&a surgery
did show a rise in carbohydrates consumption after t&a , but these studies used 24-hour dietary - recalls and were performed in preschool children .
this is the first study that performed dietary assessment in toddlers with osa before and after t&a using a validated questionnaire .
furthermore , this sffq evaluates meal compound during the month prior to each encounter and is less prone to recall bias .
analyzing the sffqs showed that all children but one increased their caloric intake after surgical intervention .
moreover , looking at their dietary compound , a rise of 2% in protein and a decline of 4.49% in fat consumption were significantly shown . a nonsignificant rise of 2% percent in carbohydrates was also noticed .
although these changes were found to be significant , their actual effect on growth pattern is not clear , and there is certainly a need to repeat the sffq in a larger group in order to draw conclusions . in parallel to the rise in caloric intake , the children narrowed the weight gap between them and their peers .
these two findings can be linked because t&a surgery removes the hypertrophied tissue of tonsils and adenoids , thus removing a mechanical barrier that limits food swallow .
removing this barrier enables the child to eat and swallow more easily and increases his caloric intake according to physiologic requirements and gaining weight accordingly .
in addition , the change in diet compound not only might indicate hormonal changes that influence appetite but also may represent a rise in anabolic process in the body that is manifested by weight gain .
though being statistically significant , these changes in dietary compound are not marked enough to explain the rise in somatic growth .
previous studies in children with osa reported high circulating levels of inflammatory factors such as crp .
those studies showed a decline of up to 50% in crp levels after t&a [ 14 , 25 ] .
we hypothesized that an improvement in systemic inflammation will be followed by an improvement in somatic growth .
there was an average decrease of 0.535  mg% in crp level after surgery ; however , the change was not significant probably due to small sample and this should be studied on a larger cohort .
igf-1 mediates the effects of growth hormone in tissues , especially the bone , and promotes its growth .
previous studies reported on shortening of the relative part of slow - wave sleep and improvement in its relative part after t&a . a meta - analysis that tried to determine
the role of t&a on gh - igf-1 axis did find an increase in igf-1 and igfbp-3 serum levels , but all the studies were conducted on older children .
this may explain the improvement in their weight but it was not significant probably due to a small sample . in order to find the factor that imposes the biggest influence on  catch - up  growth in osa children , a multivariate analysis was performed .
the more prominent the decrease in circulating crp levels was , the more weight was gained by the child .
. this might support the assumption that the major factor influencing somatic growth in children with osa is systemic inflammation and not the increase in caloric intake per se .
one hypothesis is that local mediators effect bone growth , similar to children with chronic kidney disease .
the growth hormone ( gh)/insulin - like growth factor 1 ( igf-1 ) pathway is anabolic to the skeleton and inflammatory cytokines compromise bone growth through a number of different mechanisms , which include interference with the systemic as well as the tissue - level gh / igf-1 axis .
it is known that suppressor of cytokine signaling 2 ( socs2 ) expression is increased in inflammatory conditions including ckd and is a recognized inhibitor of gh signaling .
therefore , socs2 signaling represents a critical pathway in growth plate chondrocytes through which osa 's activated proinflammatory cytokines alter both gh / igf-1 signaling and cellular function .
our report is the first to note the correlation between enhanced somatic growth and decreased systemic inflammation following surgery .
it corroborates previous observations regarding other osa 's related morbidities ( cardiovascular and neurocognitive ) that improved following surgery and correlated with decreased systemic inflammation [ 8 , 30 ] .
finally , although our findings may be of interest , there is a need to address the limitations of our study .
although they were well studied , there may be bias in the outcomes due to the small sample size .
the questionnaire we used shows that the overall symptom improvement was very good ( all 8 questions with a scale of 15 : preop 3.7  1.3 ; postop 1.3  0.4 ; p = 0.002 ) , but questionnaires can be limited .
the sleep disordered breathing scale predicts polysomnographic results to an extent useful for research but it is not always reliable enough for individual patients .
however , the sleep disordered breathing scale may predict osa - related neurobehavioral morbidity and its response to adenotonsillectomy as well as or better than polysomnography . we also need to point out the fact that the children studied represent very accurately the average child in our lab in terms of bmi but not in other countries .
although we also see obese children in our sleep lab , most of the young children are normal or underweight for their age .
therefore , the population recruited in our study may not be representative of current trends in the united states , for example , but still reflects what pediatric sleep specialists encounter in many other countries . in summary , this study assessed the effect of potential mechanisms on growth in young children treated for osa .
we found that young children improve their anthropometric measures substantially following surgical removal of their lymphadenoid tissues .
we have learned that the increase in caloric intake is accompanied by a change in the dietary composition , that is , an increase in protein and a decrease in fat consumption .
the most prominent result is the degree to which t&a changes in systemic inflammation as reported by hscrp to correlate at least in boys with the degree of catch - up weight gain .
this may point to the important role systemic inflammation plays in the growth processes of children with osa .
 
 background . obstructive sleep apnea ( osa ) is associated with growth impairment that usually improves following effective treatment . in this study we investigated the mechanisms underlying the growth processes in young children diagnosed with osa , before and after adenotonsillectomy ( t&a ) . 
 methods . young children ( 636 months old ) were enrolled and evaluated before and several months after t&a surgery for height , weight , circulating high sensitive c - reactive protein ( crp ) , and insulin - like growth factor 1 ( igf-1 ) levels . 
 caloric intake was assessed by a validated short food frequency questionnaire ( sffq ) . 
 results . following t&a 
 , children added 4.81  cm and 1.88  kg to their height and weight , respectively ( p < 0.001 for both ) and had a significant increase in bmi z score ( p = 0.002 ) . 
 increased caloric intake of 377  kcal / day was noted ( p < 0.001 ) , with increased protein and decreased fat intake . the decrease in crp levels correlated with the increase in body weight in boys ( p < 0.05 , adjusted for caloric intake ) . conclusions . 
 adenotonsillectomy results in enhanced somatic growth in young children that correlates with a decrease in systemic inflammation and caloric intake increment . 
 our findings imply that systemic inflammation may have an important role in this osa - related morbidity . 
1. Background
2. Methods
3. Results
4. Discussion