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ntroduction Polysomnography [PSG] is the current gold standard test for diagnosis of sleep disordered breathing in adults and children, including neonates and infants. There is a reported increased prevalence of sleep disordered breathing in former preterm children. However, there is limited data on the clinical utility of PSG in neonates and infants, as well as a lack of epidemiologic data on the anatomic causes of obstructive sleep apnea in neonates and infants.

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Volume 8 • Issue 1 • 1000448 J Pulm Respir Med an open access journal ISSN: 2161-105X Journal of Pulmonary Respiratory Medicine ISSN: 2161-105X Journal of Pulmonary Respiratory Medicine Bandyopadhyay et al. J Pulm Respir Med 2018 8:1 DOI: 10.4172/2161-105X.1000448 Research Article Open Access Endoscopic Airway Findings in Infants with Obstructive Sleep Apnea Anuja Bandyopadhyay 1 Heather Muston 1 James E Slaven 2 Hasnaa E Jalou 1 William A Engle 3 and Ameet S DaftaryMS 1 1 Department of Pediatrics Section of Pediatric Pulmonology Allergy and Sleep Medicine Indiana University School of Medicine Indianapolis Indiana USA 2 Department of Biostatistics Indiana University School of Medicine Indianapolis Indiana USA 3 Department of Pediatrics Section of Neonatology Indiana University School of Medicine Indianapolis Indiana USA Abstract Objectives: This study describes the un-sedated endoscopic airway fndings in infants with obstructive sleep apnea confrmed by polysomnography PSG. Methods: A retrospective chart review was performed on infants who had undergone both a documented airway endoscopy and PSG from 2006 to 2015 at our center. Demographics comorbidities fndings of airway endoscopy and fndings on PSG were extracted from the electronic medical record. Regression analyses were performed to determine the relationship between AHI endoscopic airway fndings and gestational age. Results: We identifed 39 patients with PSG in room air and confrmed obstructive sleep apnea Apnea Hypopnea Index AHI 1/hour who had undergone unsedated airway endoscopy. The median gestational age at time of PSG was 40 weeks and for endoscopy was 40 weeks. Median AHI on PSG was 17.2/hour. Laryngomalacia 87.2 pharyngomalacia 33.3 and tracheomalacia 10.3 were the three most prevalent fndings on endoscopy. Surgically correctable fxed airway obstruction was uncommon. Prevalence of pharyngomalacia decreased with increased gestational maturity p0.05. As the postmenstrual age at PSG completion increased there was a trend towards a decline of the AHI p0.087. Twenty-two 56.4 patients had a follow up PSG performed. Using paired t test there was a signifcant decrease in AHI Δ13.41: -40.9 15.8 15.8 from 23.4/hour 1.3-62 to 10.0/hour 0-32 despite no interim surgical intervention. Conclusions: Dynamic airway collapse including laryngomalacia and pharyngomalacia were the most common fndings in obstructive sleep apnea during infancy. The decreased prevalence of pharyngomalcia and trend towards improvement of AHI with time suggests airway immaturity contributes to obstructive sleep apnea observed during infancy and improves with age. Corresponding author: Anuja Bandyopadhyay Department of Pediatrics Section of Pediatric Pulmonology Allergy and Sleep Medicine Riley Hospital for Children at Indiana University Health 705 Riley Hospital Dr. ROC 4270 Indianapolis IN 46202-5225 Indiana USA Tel: 3179448602 Fax: 317 944-5791 E-mail: anubandyiupui.edu Received March 01 2018 Accepted March 07 2018 Published March 14 2018 Citation: Bandyopadhyay A Muston H Slaven JE Jalou HE Engle WA et al. 2018 Endoscopic Airway Findings in Infants with Obstructive Sleep Apnea. J Pulm Respir Med 8: 448. doi: 10.4172/2161-105X.1000448 Copyright: © 2018 Bandyopadhyay A et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License which permits unrestricted use distribution and reproduction in any medium provided the original author and source are credited. Keywords: Pharynx Laryngomalacia Tracheomalacia Leukomalacia- periventricular Sleep apnea-obstructive Polysomnography Infant-newborn Bronchoscopy Airway obstruction Abbreviations: PSGPolysomnogram AHIApnea Hypopnea Index CO 2 Carbon-dioxide ETCO 2 End Tidal Carbon-dioxide BPD Bronchopulmonary Dysplasia Introduction Polysomnography PSG is the current gold standard test for diagnosis of sleep disordered breathing in adults and children including neonates and infants 1. Tere is a reported increased prevalence of sleep disordered breathing in former preterm children 2. However there is limited data on the clinical utility of PSG in neonates and infants 1 as well as a lack of epidemiologic data on the anatomic causes of obstructive sleep apnea in neonates and infants 3. Tis patient population has anatomic and physiologic characteristics that place them at increased risk for scored respiratory events during polysomnography using the current scoring criteria from the American Academy of Sleep Medicine 4. Neonates and infants are physiologically prone to sleep apnea due to immaturity of the respiratory control system 56 increased airway collapsibility due to high airway compliance 7-9 craniofacial factors that narrow the airway lumen 10 and low functional residual capacity 11. Endoscopic evaluation of infants with sleep associated upper airway obstruction under light anesthesia was frst described more than 27 years ago 12. Since this initial report only a limited number of studies have been published involving neonates and infants with PSG proven obstructive sleep apnea and subsequent management 1314. Recently children 1.3 years to 1.8 years of age with obstructive sleep apnea were shown to have obstruction at the adenoid and tonsillar level in 89 and 82 of children respectively 14. However there is no such available data in the neonatal and infant age group. Tere is a critical need to identify endoscopic fndings in PSG proven neonatal obstructive sleep apnea to formulate subsequent therapeutic options. Te aim of this study was to describe the airway anatomic fndings from unsedated airway endoscopies and associated comorbidities in neonates and infants with PSG confrmed obstructive sleep apnea. We hypothesize that neonates and infants with PSG confrmed obstructive sleep apnea have a high prevalence of dynamic airway abnormality that improves with age. Methods Patient selection A retrospective chart review was performed to identify neonates and infants who had undergone a fexible airway endoscopy and also had documented obstructive sleep apnea on PSG between 2006 and 2015 at Riley Hospital for Children in Indianapolis Indiana. Our institutional PSG database was searched for an obstructive apnea hypopnea index AHI of greater than 1 per hour to identify potential

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Citation: Bandyopadhyay A Muston H Slaven JE Jalou HE Engle WA et al. 2018 Endoscopic Airway Findings in Infants with Obstructive Sleep Apnea. J Pulm Respir Med 8: 448. doi: 10.4172/2161-105X.1000448 Page 2 of 5 Volume 8 • Issue 1 • 1000448 J Pulm Respir Med an open access journal ISSN: 2161-105X subjects and endoscopic fndings were extracted from the medical record. Obstructive sleep apnea was defned as an AHI of greater than 1 per hour. Only PSGs performed in room air were included in our study as oxygen use may afect the number of scored events. Patients were excluded if they did not have both a documented PSG and airway endoscopy in the electronic medical record. Patients who had any central apnea were excluded from the study since the focus of our chart review were infants with obstructive sleep apnea. Patients with cyanotic heart disease were excluded from this investigation. Te study was performed with permission of the Institutional Review Board. Patient demographics comorbidities birth gestational age PSG fndings and endoscopy fndings were extracted from the electronic medical record. Postmenstrual age was defned as the sum of birth gestational age and chronological age. Prematurity was defned as birth gestational age less than or equal to 37 weeks. Comorbidities including diagnoses of bronchopulmonary dysplasia BPD based on clinical assessment oromotor incoordination based on speech pathologist assessment genetic abnormality determined based on chromosomal microarray craniofacial anomaly based on clinical examination intraventricular hemorrhage/periventricular leukomalacia/hydrocephalus based on head ultrasound examination and pulmonary hypertension based on echocardiographic assessment were obtained from neonatal discharge summaries. Polysomnography Te PSGs were attended studies performed in the sleep laboratory and included the following monitoring parameters: electroencephalogram electrooculogram chin electromyogram electrocardiogram thermistor and pressure transducer airfow signals respiratory inductance plethysmography or thoracic impedance measurement prior to 2007 continuous oximetry and end tidal CO 2 monitoring. Te collection sofware was Sandman v 9.0 Embla systems LLC Tonawanda NY. Oxyhemoglobin saturation was measured via pulse oximetry Masimo Irvine CA. End tidal CO 2 was measured at the nose using BCI Capnocheck Smiths Medical PM Inc Waukesha WI with side stream sampling. Nasal airfow was acquired with a nasal cannula Salter Labs Arvin CA. PSGs were staged per scoring guidelines from Anders Parmalee and Emdee 15. Before 2007 the institutional criteria followed for scoring respiratory events were: apnea for airfow limitation of 80 or greater from baseline for at least 2 breaths and hypopneas for airfow limitation of 30 or greater for at least 2 breaths duration associated with either ≥ 4 desaturation or an arousal. Afer 2007 AASM respiratory rules for children were followed for scoring respiratory events 16. Before 2007 institutional criteria were followed for scoring arousals and awakenings. During NREM quiet indeterminate sleep arousals were scored as change in EEG frequency from theta to alpha or beta or from delta to theta alpha or beta for 3 seconds to 15 seconds. Afer 15 seconds the EEG change was scored as an awakening. All gross body movements were scored as either arousals or awakenings consistent with the duration of the event. In REM active sleep in addition to an EEG frequency change an additional elevation of EMG amplitude during the event was also required. Afer 2007 arousal indices were scored as per AASM scoring criteria 16. Apneas were obstructive if activity was detected in the respiratory inductance plethysmography channels during airfow limitation. PSGs were reviewed and reported by board certifed pediatric sleep medicine physicians. Bronchoscopy Flexible airway endoscopy was performed by a board certifed pediatric pulmonologist at bedside following standard guidelines 17. Te procedures were performed without sedation using a Pentax FB- 8V bronchoscope with video processor and topical lidocaine. Statistical Analysis Results were analyzed for distributional ft with outcomes having skewed distributions. Hence results were reported as median range for continuous variables and frequency percentage for categorical variables. Regression analysis was performed to fnd a relationship between prevalence of various bronchoscopic fndings and birth gestational age. Logistic regression analyses were performed to fnd a relationship between various endoscopic fndings and comorbidities. Regression analyses were also performed to determine the presence of a relationship between AHI and birth gestational age comorbidities postmenstrual age at the time of sleep study and airway endoscopic fndings. A p-value of 0.05 or below was considered statistically signifcant. We collected data on follow up polysomnogram performed on patients who did not have any interim surgical intervention. We performed a paired t test in order to determine if the change in AHI was signifcantly lower than zero. Analyses were performed with SAS v9.4 SAS Institute Cary NC. Results Tirty-nine patients met our inclusion criteria. Te demographics of the patient sample are described in Table 1. Te indication for the PSG was clinical suspicion of upper airway obstruction. Te median postmenstrual age at the time of PSG and endoscopy was close to 40 weeks. Oromotor incoordination and prematurity were the most common comorbidities. Of note 15.4 of patients had neurologic sequelae such as Grade III or IV intraventricular hemorrhage IVH periventricular leukomalacia PVL and post hemorrhagic hydrocephalus PHH. Twenty-nine 74.4 had a PSG and endoscopy performed within 7 days of one another. Te most common fndings on airway endoscopy involved dynamic airway collapse including laryngomalacia 87.2 pharyngomalacia 33.3 and tracheomalacia 10.3 Table 2. Surgically treatable fxed obstructions were rare. Tere was a positive association between periventricular leukomalacia and pharyngomalacia Odds Ratio 15.63 1.58-154.28 p0.02. Tere was no statistically signifcant relationship identifed Demographics n39 Sex Male 18 46.2 Birth Gestational age weeks 36 26-41 + Chronological age at the time of bronchoscopy weeks 3.57 0.57-45.29 + Post menstrual age at the time of bronchoscopy weeks 40 36-71 + Post menstrual age at the time of sleep study weeks 40 36-52 + Time interval between bronchoscopy and sleep study days 4 0-142 + Comorbidities Oromotor incoordination 27 69.2 Prematurity 21 53.9 Bronchopulmonary dysplasia 5 12.8 Genetic abnormality 4 10.3 Periventricular leukomalacia 6 15.4 Craniofacial anomaly 1 2.6 Pulmonary Hypertension 0 0 Neuromuscular disorder 0 0 Frequency percentage + Median min-max Table 1: Baseline characteristics.

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Citation: Bandyopadhyay A Muston H Slaven JE Jalou HE Engle WA et al. 2018 Endoscopic Airway Findings in Infants with Obstructive Sleep Apnea. J Pulm Respir Med 8: 448. doi: 10.4172/2161-105X.1000448 Page 3 of 5 Volume 8 • Issue 1 • 1000448 J Pulm Respir Med an open access journal ISSN: 2161-105X between laryngomalacia tracheomalacia or bronchomalacia and any of the comorbidities. Te median AHI for our patients was 17.2/hour 1.3-62 the median mean-end-tidal CO 2 was 40 mm of Hg 30-52 and median arousal index was 15.7/hour 2.2-33.9. Other sleep parameters have been reported in Table 3. Tere was a trend towards a negative association between the AHI and postmenstrual age at the time of PSG correlation coefcient-0.23 p0.087. Figure 1 shows the relationship between postmenstrual age at time of PSG and AHI Figure 2. Twenty-two 57 patients had a follow up PSG performed without interim surgical intervention. Using paired t-test there was a signifcant decrease in AHI Δ13.41: -40.9 15.8 15.8 from 23.4/hour 1.3-62 to 10.0/hour 0-32 despite no interim surgical intervention as shown in Figure 3. Discussion We have described the unsedated airway endoscopy fndings in neonates and infants with PSG-confrmed obstructive sleep apnea. Te fndings suggest that dynamic airway collapse is more prevalent in obstructive sleep apnea during infancy than surgically correctable fxed airway obstruction. We also found that the prevalence of pharyngomalacia decreased with gestational maturation. Furthermore there was improvement in the severity of sleep apnea over time without surgical intervention. Tese observations suggest that respiratory immaturity may be an important contributory factor to obstructive sleep apnea in neonates and infants. 53.9 of our patients were premature which validates existing literature showing a higher prevalence of sleep disordered breathing in the preterm population. However only fve 12.8 patients had signifcant underlying lung pathology such as bronchopulmonary dysplasia BPD. Presence of underlying lung disease such as BPD results in decreased lung reserve and may afect the scoring of respiratory events during PSG. In the absence of signifcant lung pathology the etiology of obstructive sleep apnea may be attributed Bronchoscopy Findings n39 Frequency Percentage Laryngomalacia 34 87.2 Pharyngomalacia 13 33.3 Tracheomalacia 4 10.3 Bronchomalacia 0 0 Abnormal Vocal Cord Motility 0 0 Subglottic Stenosis 0 0 Extrinsic Compression of Trachea 1 2.6 Choanal Atresia 0 0 Adenoidal Hypertrophy 1 2.6 Subglottic Cyst 0 0 Table 2: Bronchoscopic fndings. Figure 1: Relationship between post menstrual age and AHI p0.087. Figure 3: Change in AHI over time in 22 patients without interim surgical intervention. PSG fndings Median min-max AHI per hour 17.2 1.3-62 Arousal Index per hour 15.7 2.2-33.9 Mean ETCO21 mmHg 3 40 30-52 Max ETCO21 mmHg 3 54 40-80 Nadir SpO22 85 47-98 Mean SpO22 98.55 77-100 Percentage of sleep time with ETCO21 45 mmHg 3 1.9 0.1-20.1 Percentage of sleep time with SpO2 90 0.95 0-14.2 ETCO 2 End-Tidal Carbon Dioxide Level SpO 2 Oxygen Saturation mmHgMillimeters of Mercury Table 3: PSG fndings. Figure 2: Prevalence of pharyngomalacia at various birth gestational ages p0.04.

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Citation: Bandyopadhyay A Muston H Slaven JE Jalou HE Engle WA et al. 2018 Endoscopic Airway Findings in Infants with Obstructive Sleep Apnea. J Pulm Respir Med 8: 448. doi: 10.4172/2161-105X.1000448 Page 4 of 5 Volume 8 • Issue 1 • 1000448 J Pulm Respir Med an open access journal ISSN: 2161-105X to upper airway obstruction. Our study suggests that PSG confrmed obstructive sleep apnea in a neonates and infants is ofen associated with dynamic airway collapse. Progressive resolution of airway obstruction caused by airway collapsibility has previously been reported in 2 moths to 12 month old infants 18. Isono et al. 19 demonstrated that velopharyngeal closing pressure progressively decreased with increasing age. Te proposed mechanisms include increased stifness of sof tissue surrounding the upper airway 19 increased longitudinal tension of pharyngeal wall due to downward displacement of the larynx and hyoid bone as well as increased tracheal traction due to expansion in lung volume with age 2021. Tis explanation may justify at least in part the decreasing prevalence of pharyngomalacia and obstructive sleep apnea with advancing gestational maturation demonstrated in our study. Our study is the frst to report endoscopic fndings in association with PSGs in this age group. Drug-induced sleep endoscopy DISE which is now standard of care was not being routinely performed at our institution during the years from which our patient sample was obtained. Future studies using drug-induced sleep endoscopy are needed to support the results demonstrated in this study in infants during their frst year of life. Tere was a trend towards a decrease in obstructive AHI with an increase in postmenstrual age at the time of PSG. Tis failed to achieve statistical signifcance possibly due to the small sample size. We analyzed longitudinal data in a smaller subset of patients with follow up PSG without any interim surgical intervention and found a statistically signifcant decrease in AHI for the paired samples. Tis observation from our data suggests that neonatal obstructive sleep apnea improves with time. Tis trend can be explained by physiologic airway maturation of neonates and infants. Given the unique physiologic characteristics of neonates and infant and their predisposition to scored respiratory events under current pediatric PSG scoring guidelines an AHI threshold for signifcant sleep apnea of one or more events per hour may be too liberal and result in over-diagnosis of neonatal obstructive sleep apnea. According to current consensus pediatric sleep apnea is defned as severe for an AHI greater than 10 events per hour 22. It may be worth reconsidering an alternative severity classifcation for sleep apnea in neonates and infants. Tere is an urgent need for normative PSG data in neonates to appropriately use this increasingly accessible diagnostic tool in clinical decision making 15.4 of our patients had periventricular leukomalacia. Tere was a signifcant association between periventricular leukomalacia and pharyngomalacia Odds Ratio 15.63 1.58-154.28 p0.02. Due to the retrospective nature of the study further data on the severity of periventricular leukomalacia were not consistently available. Periventricular leukomalacia is a form of white matter brain injury characterized by necrosis of white matter near lateral ventricles with difuse gliosis in the surrounding white matter 23. It is a strong predictor of motor disability such as cerebral palsy 24 and can also impact cognitive outcomes 25. Our study is the frst to report an association between pharyngeal dynamic collapsibility and periventricular leukomalacia. Tis association may be due to accompanying injury to centers in the brain responsible for muscle tone with secondary impact on pharyngeal muscles. Further studies reviewing detailed brain imaging of patients with periventricular leukomalacia and pharyngomalacia may better elucidate this association. Te primary weaknesses of our study are its retrospective and predominantly cross-sectional nature as well as use of unsedated fexible endoscopy for airway evaluation. Discharge diagnoses were obtained from discharge summary notes. Criteria establishing the diagnosis of bronchopulmonary dysplasia were not consistently documented. Tere was also a selection bias in this study as patients were primarily in the NICU at the time of evaluation. Another signifcant limitation of this study is how the airway endoscopies were performed. Te clinical practice of the institution at the young age of the patients was the primary reason for unsedated airway endoscopy. Obtaining airway evaluations in this manner can lead to increased dynamic airway abnormalities observed given the varying degrees of agitation and coughing at the time of procedure. However this trade of needs to considered against the risk that deep sedation can mask airway dynamic abnormalities and there is increasing literature regarding neurocognitive efects from anesthesia in children 26. Furthermore an additional limitation of our study was that the fndings on endoscopy including the presence of airway malacia was based on the subjective assessment of the endoscopist. Tere may have been inter-observer variability based on the experience and biases of the endoscopist. Unfortunately due to unavailability of endoscopy videos a review of those could not be performed by the authors. We therefore did not include severity assessment of the endoscopic fndings due to this subjectivity. A prospective study with consistent grading of degree of airway obstruction will be useful in confrming our fndings. Future studies utilizing drug-induced sleep endoscopy are recommended to validate the observations in our study. Finally this is the experience of a single center and practices may vary between institutions. We acknowledge a practice bias at our center given access to a large pediatric sleep laboratory and capability to perform inpatient neonatal PSG. Conclusions Airway dynamic abnormalities are more common than surgically treatable fxed airway obstruction in obstructive sleep apnea in neonates and infants. Tis may be more a refection of airway immaturity rather than true pathology in a signifcant number of neonates and infants. Prevalence of airway immaturity particularly pharyngomalacia increased with prematurity. AHI the most common parameter to determine severity of obstructive sleep apnea improved with time without any surgical intervention. Future multicenter prospective longitudinal studies are needed to describe the epidemiology of airway anatomical fndings in neonatal obstructive sleep apnea using standard bronchoscopy and sedation protocols. References 1. DeHaan KL Seton C Fitzgerald DA Waters KA MacLean JE 2015 Polysomnography for the diagnosis of sleep disordered breathing in children under 2 years of age. Pediatr Pulmonol. 50: 1346–1353. 2. Rosen CL Larkin EK Kirchner HL Emancipator JL Bivins SF et al. 2003 Prevalence and risk factors for sleep-disordered breathing in 8- to 11-year-old children: association with race and prematurity. J Pediatr 142: 383-389. 3. Katz ES Mitchell RB D’Ambrosio CM 2012 Obstructive sleep apnea in infants. Am J Respir Crit Care Med 185: 805-816. 4. Sanchez I Vega-Briceno L Munoz C Mobarec S Brockman P et al. 2006 Polysomnographic fndings in 320 infants evaluated for apneic events. Pediatr Pulmonol 41: 215-221. 5. Abu-Shaweesh JM Martin RJ 2008 Neonatal apnea: What’s new Pediatr Pulmonol 43: 937-944. 6. Horemuzova E Katz-Salamon M Milerad J 2000 Breathing patterns oxygen and carbon dioxide levels in sleeping healthy infants during the frst nine months after birth. Acta paediatr 89: 1284-1289. 7. Gaultier C Praud JP Canet E Delaperche MF D’Allest AM 1987 Paradoxical

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Citation: Bandyopadhyay A Muston H Slaven JE Jalou HE Engle WA et al. 2018 Endoscopic Airway Findings in Infants with Obstructive Sleep Apnea. J Pulm Respir Med 8: 448. doi: 10.4172/2161-105X.1000448 Page 5 of 5 Volume 8 • Issue 1 • 1000448 J Pulm Respir Med an open access journal ISSN: 2161-105X inward rib cage motion during rapid eye movement sleep in infants and young children. J Dev Physiol 9: 391-397. 8. Heldt GP. 1988 Development of stability of the respiratory system in preterm infants. J Appl Physiol 65: 441-444. 9. Papastamelos C Panitch HB England SE Allen JL 1985 Developmental changes in chest wall compliance in infancy and early childhood. J Appl Physiol 78: 179-184. 10. Arens R Marcus CL 2004 Pathophysiology of upper airway obstruction: A developmental perspective. Sleep 27: 997-1019. 11. Kendig EL Wilmott RW Boat TF Bush A Chernick V 2012 Kendig and Chernick’s disorders of the respiratory tract in children: Elsevier Health Sciences USA. 12. Croft CB Thomson HG Samuels MP Southall DP 1990 Endoscopic evaluation and treatment of sleep-associated upper airway obstruction in infants and young children. Clin Otolaryngol Allied Sci 15: 209-216. 13. Robison JG Wilson C Otteson TD Chakravorty SS Mehta DK 2013 Analysis of outcomes in treatment of obstructive sleep apnea in infants. Laryngoscope 123: 2306-2314. 14. Boudewyns A Van de Heyning P Verhulst S 2017 Drug-induced sedation endoscopy in children 2 years with obstructive sleep apnea syndrome: Upper airway fndings and treatment outcomes. Eur Arch Otorhinolaryngol 274: 2319- 2325. 15. Anders TF Emde RN Parmelee AH 1971 A manual of standardized terminology techniques and criteria for scoring of states of sleep and wakefulness in newborn infants: UCLA Brain Information Service/BRI Publications Offce NINDS Neurological Information Network. 16. Medicine AAOS 2017 The AASM manual for the scoring of sleep and associated events: Rules. Terminology and Technical Specifcations Westchester: AASM. 17. Green CG Eisenberg J Leong A Nathanson I Schnapf BM et al. 1992 Flexible endoscopy of the pediatric airway. American Rev Respir Dis 145: 233- 235. 18. Isono S Tanaka A Ishikawa T Nishino T 2000 Developmental changes in collapsibility of the passive pharynx during infancy. Am J Respir Crit Care Med 162: 832-836. 19. Bosma JF 1988 Functional anatomy of the upper airway during development. Respiratory function of the upper airway. pp: 47-86. 20. Van de Graaff WB. 1988 Thoracic infuence on upper airway patency. J Appl Physiol 65: 2124-2131. 21. Thut DC Schwartz AR Roach D Wise RA Permutt S et al. 1993 Tracheal and neck position infuence upper airway airfow dynamics by altering airway length. J Appl Physiol 75: 2084-2090. 22. Mindell JA Owens JA 2015 A clinical guide to pediatric sleep: Diagnosis and management of sleep problems: Lippincott Williams Wilkins USA. 23. Kinney HC 2009 The encephalopathy of prematurity: One pediatric neuropathologist’s perspective. Semin Pediatr Neurol 16: 179-190. 24. Skiöld B Vollmer B Böhm B Hallberg B Horsch S et al. 2012 Neonatal magnetic resonance imaging and outcome at age 30 months in extremely preterm infants. J Pediatr 160: 559-66. 25. Woodward LJ Clark CA Bora S Inder TE 2012 Neonatal white matter abnormalities an important predictor of neurocognitive outcome for very preterm children. PloS one 7: e51879. 26. Glatz P Sandin RH Pedersen NL Bonamy AK Eriksson LI et al. 2017 Association of anesthesia and surgery during childhood with long-term academic performance. JAMA Pediatr 171: e163470.

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