CLINICAL REPORT Guidance for the Clinician in Rendering Pediatric Care

Apnea of Prematurity Eric C. Eichenwald, MD, FAAP, COMMITTEE ON FETUS AND NEWBORN

Apnea of prematurity is one of the most common diagnoses in the NICU. abstract Despite the frequency of apnea of prematurity, it is unknown whether recurrent apnea, bradycardia, and hypoxemia in preterm infants are harmful. Research into the development of respiratory control in immature animals and preterm infants has facilitated our understanding of the pathogenesis and treatment of apnea of prematurity. However, the lack of consistent defi nitions, monitoring practices, and consensus about clinical signifi cance leads to signifi cant variation in practice. The purpose of this clinical report is to review the evidence basis for the defi nition, epidemiology, and treatment of apnea of prematurity as well as discharge recommendations for preterm infants diagnosed with recurrent apneic events.

BACKGROUND This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have Apnea of prematurity is one of the most common diagnoses in the NICU. fi led confl ict of interest statements with the American Academy of Pediatrics. Any confl icts have been resolved through a process Despite the frequency of apnea of prematurity, it is unknown whether approved by the Board of Directors. The American Academy of recurrent apnea, bradycardia, and hypoxemia in preterm infants are Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication. harmful. Limited data suggest that the total number of days with apnea and resolution of episodes at more than 36 weeks’ postmenstrual age Clinical reports from the American Academy of Pediatrics benefi t from expertise and resources of liaisons and internal (AAP) and external (PMA) are associated with worse neurodevelopmental outcome in reviewers. However, clinical reports from the American Academy of preterm infants.1,2 However, it is difficult to separate any potential Pediatrics may not refl ect the views of the liaisons or the organizations or government agencies that they represent. adverse effects of apnea from the degree of immaturity at birth, because the incidence of apnea is inversely proportional to gestational age.3 The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking Research into the development of respiratory control in immature into account individual circumstances, may be appropriate. animals and preterm infants has facilitated our understanding of the All clinical reports from the American Academy of Pediatrics pathogenesis and treatment of apnea of prematurity (Table 1). However, automatically expire 5 years after publication unless reaffi rmed, the lack of consistent definitions, monitoring practices, and consensus revised, or retired at or before that time. about clinical significance leads to significant variation in practice.4–6 DOI: 10.1542/peds.2015-3757 The purpose of this clinical report is to review the evidence basis for PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). the definition, epidemiology, and treatment of apnea of prematurity as Copyright © 2016 by the American Academy of Pediatrics well as discharge recommendations for preterm infants diagnosed with recurrent apneic events. To cite: Eichenwald EC and AAP COMMITTEE ON FETUS AND NEWBORN. Apnea of Prematurity. Pediatrics. 2016;137(1):e20153757

Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 137 , number 1 , January 2016 :e 20153757 FROM THE AMERICAN ACADEMY OF PEDIATRICS DEFINITION AND CLASSIFICATION 38 weeks’ PMA is higher in infants Preterm infants with resolved apnea who were 24 to 26 weeks’ gestational also may have clinically unapparent An apneic spell is usually defined age at birth compared with those intermittent hypoxia events. In a as a cessation of breathing for 20 born at ≥28 weeks’ gestation.8 recent study in former preterm seconds or longer or a shorter pause Infants with bronchopulmonary infants after discontinuation of accompanied by bradycardia (<100 dysplasia may have delayed medical therapy for apnea, the mean beats per minute), cyanosis, or pallor. maturation of respiratory control, number of seconds/hour of oxygen In practice, many apneic events in which can prolong apnea for as long saturation less than 80% was 20.3 preterm infants are shorter than 20 as 2 to 4 weeks beyond term PMA.8 at 35 weeks’ PMA, decreasing to 6.8 seconds, because briefer pauses in In most infants, apnea of prematurity seconds/hour at 40 weeks’ PMA.12 airflow may result in bradycardia follows a common natural history, or hypoxemia. On the basis of with more severe events that require respiratory effort and airflow, intervention resolving first. Last to MONITORING FOR APNEA/ apnea may be classified as central resolve are isolated, spontaneously BRADYCARDIA (cessation of breathing effort), resolving bradycardic events of obstructive (airflow obstruction uncertain clinical significance.8 Most infants in NICUs are usually at the pharyngeal level), continuously monitored for or mixed. The majority of apneic heart rate, respiratory rate, and episodes in preterm infants are Most studies examining the time oxygen saturation. Cardiac alarms mixed events, in which obstructed course to resolution of apnea are most commonly set at 100 airflow results in a central apneic of prematurity have relied on beats per minute, although lower pause, or vice versa. nurses' recording of events in the medical record; however, alarm settings are acceptable in several studies have shown a lack convalescent preterm infants. EPIDEMIOLOGY AND TIME COURSE TO of correlation with electronically Apnea alarms are generally set RESOLUTION recorded events.9,10 Standard at 20 seconds. However, apnea NICU monitoring techniques are detection by impedance monitoring In an observational study, unable to detect events that are is potentially misleading. Impedance Henderson-Smart3 reported that primarily obstructive in nature. With monitoring is prone to artifact the incidence of recurrent apnea continuous electronic recording, attributable to body movement or increased with decreasing gestational it is evident that some preterm cardiac activity and is unable to age. Essentially, all infants born infants continue to have clinically detect obstructive apnea. Practices at ≤28 weeks’ gestation were unapparent apnea, bradycardia, and differ as to when continuous diagnosed with apnea; beyond 28 oxygen desaturation events even oximetry is discontinued. In a study weeks’ gestation, the proportion of after discharge. The Collaborative investigating the age at last recorded infants with apnea decreased, from Home Infant Monitoring Evaluation apnea and age at discharge from the 85% of infants born at 30 weeks’ Study examined the occurrence of hospital in 15 different NICUs, the gestation to 20% of those born at 34 apnea/bradycardia events in >1000 duration of use of pulse oximetry was weeks’ gestation. This relationship preterm and healthy term infants significantly different among hospital has important implications for NICU 5 monitored at home.11 “Extreme sites. Later discontinuation of pulse policy, because infants born at less events” (apnea >30 seconds and/or oximetry was associated with a later than 35 weeks’ gestation generally heart rate <60 beats per minute for PMA at recorded last apnea and require cardiorespiratory monitoring >10 seconds) were observed most longer length of stay, suggesting that after birth because of their risk frequently in former preterm infants, oximetry may detect events that of apnea. As expected with a decreasing dramatically until about cardiorespiratory monitoring does developmental process, some infants 43 weeks’ PMA. After 43 weeks’ PMA, not. born at 35 to 36 weeks’ gestation “extreme events” in both preterm There are no data to suggest that a may have respiratory control and term infants were very rare. diagnosis of apnea of prematurity is instability, especially when placed in a semiupright position.7 In Henderson-Smart’s study, apneic TABLE 1 Factors Implicated in the Pathogenesis of Apnea of Prematurity spells stopped by 37 weeks’ PMA in Central Mechanisms Peripheral Refl ex Pathways 92% of infants and by 40 weeks’ PMA Decreased central chemosensitivity Decreased carotid body activity in more than 98% of infants.3 The Hypoxic ventilatory depression Increased carotid body activity proportion of infants with apnea/ Upregulated inhibitory neurotransmitters Laryngeal chemorefl ex bradycardia events persisting beyond Delayed central nervous system development Excessive bradycardic response

Downloaded from www.aappublications.org/news by guest on September 25, 2021 2 FROM THE AMERICAN ACADEMY OF PEDIATRICS associated with an increased risk of with resultant excitation of gestation who do not require sudden infant death syndrome (SIDS) respiratory neural output, as well as positive pressure support, one or that home monitoring can prevent blockade of excitatory adenosine A2A reasonable approach would be SIDS in former preterm infants. receptors located on γ-aminobutyric to await the occurrence of apnea Although infants born preterm have acidergic neurons. Specific before initiating therapy.20 In the a higher risk of SIDS, epidemiologic polymorphisms in the A1 and A2A Caffeine for Apnea of Prematurity and physiologic data do not support a adenosine receptor genes have been Trial, earlier treatment with caffeine causal link with apnea of prematurity. associated with a higher risk of apnea (<3 days) compared with later (≥3 The mean PMA for SIDS occurrence of prematurity as well as variability days) was associated with a shorter for infants born between 24 and in response to xanthine therapy.15 duration of mechanical ventilation, 28 weeks’ gestation is estimated These observations may help explain although it is not clear whether to be 47.1 weeks, compared with apparent genetic susceptibility infants started earlier on caffeine 53.5 weeks for term infants.13 to apnea of prematurity, high were assessed to be more likely to be Apnea of prematurity resolves at concordance of its diagnosis in extubated soon.21 In a retrospective a PMA before which most SIDS twins, and variability in response to cohort study in 62 056 infants with deaths occur; in the Collaborative xanthine therapy.16 very low birth weight discharged Home Infant Monitoring Evaluation between 1997 and 2010, early Study, extreme events in former The largest trial of caffeine citrate caffeine therapy compared with later preterm infants resolved by 43 (Caffeine for Apnea of Prematurity therapy was associated with a lower 11 weeks’ PMA. As such, routine home Trial) randomly assigned 2006 incidence of bronchopulmonary monitoring for preterm infants with infants with birth weights between dysplasia (23.1% vs 30.7%; odds resolved apnea of prematurity is not 500 and 1250 g to caffeine or ratio: 0.68; 95% confidence interval: recommended. Cardiorespiratory placebo in the first 10 postnatal 0.69–0.80) as well as a shorter monitoring after hospital discharge days to prevent or treat apnea or duration of mechanical ventilation P 22 may be prescribed for some preterm to facilitate extubation.17 Dosing (mean difference: 6 days; < .001). infants with an unusually prolonged of caffeine citrate in this study Further trials are needed to assess course of recurrent, extreme apnea. included a loading dose of 20 mg/kg the safety and the potential benefits Current evidence suggests that if followed by maintenance of 5 mg/ of early prophylactic caffeine in such monitoring is elected, it can be infants who require mechanical kg per day, which could be increased discontinued in most infants after 43 ventilation. to 10 mg/kg per day for persistent weeks’ PMA unless indicated by other apnea. Caffeine-treated infants had significant medical conditions.14 a shorter duration of mechanical No trials have addressed when to discontinue xanthine treatment in ventilation, lower incidence of preterm infants; however, timely bronchopulmonary dysplasia, and discontinuation is advised to avoid TREATMENTS improved neurodevelopmental unnecessary delays in discharge. outcome at 18 months.18 Differences Xanthine Therapy Because of variability in when in neurodevelopmental outcome Methylxanthines have been the apnea resolves, the use of any were less evident at 5 years but mainstay of pharmacologic treatment specific gestational age may result in favored the caffeine-treated of apnea for decades. Adverse unnecessarily continuing therapy.4,5,8 subjects.19 The study did not collect effects include tachycardia, emesis, One approach might be a trial off data on the frequency of apnea and and jitteriness. Both theophylline therapy after a clinically significant therefore did not directly address and caffeine are used, but caffeine apnea-free period (off positive the effect of caffeine on apnea; citrate is preferred because of its pressure) of 5 to 7 days or 33 to 34 however, the data indicated that longer half-life, higher therapeutic weeks’ PMA, whichever comes first. caffeine therapy, as used clinically index, and lack of need for drug-level However, there may be significant in this trial, is safe and may have monitoring. Xanthines have multiple effects of caffeine on respiratory additional benefits by yet unknown effects on respiration, including control in preterm infants with mechanisms. However, the use increased minute ventilation, clinically resolved apnea. A recent of prophylactic caffeine solely for improved carbon dioxide sensitivity, study in preterm infants who had decreased periodic breathing, and potential neurodevelopmental been treated with caffeine for apnea decreased hypoxic depression of benefits requires additional study. showed a decrease in the frequency breathing. Their primary mechanism The optimal time to start caffeine of intermittent hypoxia episodes of action is thought to be blockade of therapy in infants at risk of apnea in those who received a prolonged inhibitory adenosine A1 receptors, is not known. In infants >28 weeks’ course of therapy compared with a

Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 137 , number 1 , January 2016 3 usual-care group.12 Further study of caregivers.25,26 A recent study that incidence of necrotizing enterocolitis, is necessary to determine the used a novel computer algorithm late-onset sepsis, and death) of implications of this finding. to detect apnea, bradycardia, and medications to reduce gastric acidity oxygen desaturation in continuously in preterm infants.33 Nasal Continuous Positive Airway recorded physiologic data from 67 Pressure preterm infants showed decreased Nasal continuous positive airway apnea for the 3 days after blood DISCHARGE CONSIDERATIONS pressure (NCPAP) at pressures of 4 transfusions compared with 3 days before.27 These authors also reported Practice and management to 6 cm H2O, usually in conjunction with treatment with a xanthine, is that the probability of an apnea surrounding discharge decisions for effective in reducing the frequency event in a 12-hour epoch was higher infants with apnea of prematurity and severity of apnea in preterm with a lower hematocrit, adjusted vary widely, but most physicians infants.23 It appears to work by for PMA. These results suggest that require infants to be apnea/ splinting open the upper airway and anemia may increase the likelihood bradycardia free for a period of decreasing the risk of obstructive of apnea of prematurity and that time before discharge. In 1 survey, apnea.23 NCPAP may also decrease blood transfusions may result in the majority of neonatologists the depth and duration of oxygen a short-term reduction in apnea. (approximately 75%) required a desaturation during central apneas However, there are no data to 5- to 7-day observation period.4 by helping maintain a higher end- indicate that blood transfusion Common practice is to initiate this expiratory lung volume. Limited results in any long-term reduction countdown period a few days after evidence suggests that variable-flow in apnea. discontinuation of caffeine therapy continuous positive airway pressure (caffeine half-life, approximately (CPAP) devices may be more Gastroesophageal Refl ux Treatment 50–100 hours)34 and to include effective in the reduction in apnea only spontaneously occurring events than conventional delivery Preterm infants have a hyperreactive (ie, not feeding-related) events. systems for CPAP (ventilator or laryngeal chemoreflex response Limited information exists about the bubble CPAP).24 that precipitates apnea when recurrence of apnea or bradycardia stimulated. In addition, almost all after a specific event-free period. Humidified high-flow nasal preterm infants show some degree In a retrospective cohort of 1400 cannula or nasal intermittent of gastroesophageal reflux (GER). infants born at ≤34 weeks’ gestation, positive-pressure ventilation These 2 physiologic observations Lorch et al35 reported that a 5- to may be acceptable substitutes for have led to speculation that GER can 7-day apnea-free period successfully NCPAP. However, larger studies precipitate apnea in preterm infants predicted resolution of apnea in that specifically examine the and that pharmacologic treatment 94% to 96% of cases. However, advantages and disadvantages of of GER might decrease the incidence the success rate was significantly nasal intermittent positive-pressure or severity of apnea. Despite the lower for infants born at younger ventilation and high-flow nasal frequent coexistence of apnea and gestational ages. A 95% success cannula versus conventional NCPAP GER in preterm infants, several rate threshold was 1 to 3 apnea-free on the incidence and severity of studies examining the timing of days for infants born at ≥30 weeks’ recurrent apnea are needed. reflux episodes in relation to apneic gestation, 9 days for those born at events indicate that they are rarely 27 to 28 weeks’ gestation, and 13 Blood Transfusion temporally related.28,29 Additional days for infants born at <26 weeks’ An increase in respiratory drive data indicate that GER does not gestation. Similar gestational age resulting from increased oxygen- prolong or worsen concurrent effects were observed in another carrying capacity, total content of apnea.30 There is no evidence that smaller retrospective study by oxygen in the blood, and increased pharmacologic treatment of GER with Zupancic et al.36 These results tissue oxygenation is the proposed agents that decrease gastric acidity or suggested that the specified event- mechanism for red blood cell that promote gastrointestinal motility free period need not be uniform for transfusions to reduce apnea of decreases the risk of recurrent apnea all infants, and shorter durations prematurity. Retrospective and in preterm infants.31,32 Indeed, some may be considered for older prospective studies of the effects of studies have shown a coincident gestational ages. However, such blood transfusions on the incidence increase in recorded events with recommendations are based on and severity of recurrent apnea pharmacologic treatment of GER.32 In observed events, which may not in preterm infants are conflicting, addition, recent data suggest harmful be accurate, and the prescribed perhaps because of a lack of blinding effects (including an increased event-free periods do not

Downloaded from www.aappublications.org/news by guest on September 25, 2021 4 FROM THE AMERICAN ACADEMY OF PEDIATRICS preclude the possibility that a new 36 to 37 weeks’ PMA in infants bradycardia/desaturation events circumstance (eg, intercurrent born at ≥28 weeks’ gestation. as well as the duration of the illness) may result in the period of observation before 2. Infants born at <28 weeks’ re-emergence of apnea. discharge. gestation may have apnea that Discharge considerations are usually persists to or beyond term 9. A clinically significant apnea based on nursing observation and gestation. event–free period before recording of apnea or bradycardia 3. Individual NICUs are encouraged discharge of 5 to 7 days is events, which may not always to develop policies for commonly used, although a correlate with those events that are cardiorespiratory monitoring longer period may be suitable electronically recorded.9,10 Preterm for infants considered at risk of for infants born at less than infants with a history of apnea apnea of prematurity. 26 weeks’ gestation. The specific who are otherwise deemed ready event-free period may need for discharge may have clinically 4. Initial low heart rate alarms are to be individualized for some unsuspected apnea, bradycardia, most commonly set at 100 beats infants depending on the and/or hypoxemia events if archived per minute. Lower settings for gestational age at birth and continuous electronic recording is convalescent preterm infants the nature and severity of interrogated.37 There is no evidence, older than 33 to 34 weeks’ PMA recorded events. however, that such events predict the may be reasonable. 10. Interrogation of electronically recurrence of clinically significant 5. Caffeine citrate is a safe and archived monitoring data may events on discharge, SIDS, or the effective treatment of apnea of reveal clinically unsuspected need for readmission to the hospital. prematurity when administered events of uncertain significance. As such, more intensive monitoring at a 20-mg/kg loading dose Such events do not predict or pneumogram recordings in and 5 to 10 mg/kg per day subsequent outcomes, including convalescent preterm infants maintenance. Monitoring routine recurrent clinical apnea or SIDS. approaching discharge may not be serum caffeine levels usually is useful. However, standardizing the not contributory to management. LEAD AUTHOR documentation and clinical approach A trial off caffeine may be to apnea within individual NICUs considered when an infant has Eric C. Eichenwald, MD, FAAP may reduce the variation in discharge been free of clinically significant 38 COMMITTEE ON FETUS AND NEWBORN, timing. apnea/bradycardia events off 2014–2015 Infants born preterm may develop positive pressure for 5 to 7 apnea and other signs of respiratory days or at 33 to 34 weeks’ PMA, Kristi L. Watterberg, MD, FAAP, Chairperson control instability with certain whichever comes first. Susan Aucott, MD, FAAP William E. Benitz, MD, FAAP stresses, including general anesthesia 6. Evidence suggests that GER is and viral illnesses. Additional close James J. Cummings, MD, FAAP not associated with apnea of Eric C. Eichenwald, MD, FAAP monitoring in these situations may prematurity, and treatment of be indicated in preterm infants Jay Goldsmith, MD, FAAP presumed or proven GER solely Brenda B. Poindexter, MD, FAAP until 44 weeks’ PMA, including for the reduction in apnea events former preterm infants readmitted Karen Puopolo, MD, FAAP is not supported by currently Dan L. Stewart, MD, FAAP for elective surgical procedures, available evidence. such as hernia repair. In addition, Kasper S. Wang, MD, FAAP the exacerbation of apnea has 7. Brief, isolated bradycardic LIAISONS been reported in very preterm episodes that spontaneously infants after their initial 2-month resolve and feeding-related Wanda D. Barfi eld, MD, MPH, FAAP – Centers for immunizations or ophthalmologic events that resolve with Disease Control and Prevention examinations, and rarely after the interruption of feeding are James Goldberg, MD – American College of Obstetricians and Gynecologists 4-month immunizations, while still in common in convalescent Thierry Lacaze, MD – Canadian Pediatric Society the NICU.39 preterm infants and generally need not delay discharge. Erin L. Keels, APRN, MS, NNP-BC – National Association of Neonatal Nurses 8. Individual units are encouraged Tonse N.K. Raju, MD, DCH, FAAP – National CLINICAL IMPLICATIONS to develop policies and Institutes of Health 1. Apnea of prematurity reflects procedures for caregiver immaturity of respiratory assessment, intervention, STAFF control. It generally resolves by and documentation of apnea/ Jim Couto, MA

Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 137 , number 1 , January 2016 5 8. Eichenwald EC, Aina A, Stark AR. Apnea 18. Schmidt B, Roberts RS, Davis P, et al; ABBREVIATIONS frequently persists beyond term Caffeine for Apnea of Prematurity Trial CPAP: continuous positive airway gestation in infants delivered at 24 to Group. Long-term effects of caffeine pressure 28 weeks. Pediatrics. 1997;100(3 pt therapy for apnea of prematurity. N GER: gastroesophageal reflux 1):354–359 Engl J Med. 2007;357(19):1893–1902 NCPAP: nasal continuous positive 9. Razi NM, Humphreys J, Pandit PB, 19. Schmidt B, Anderson PJ, Doyle LW, et airway pressure Stahl GE. Predischarge monitoring of al; Caffeine for Apnea of Prematurity PMA: postmenstrual age preterm infants. Pediatr Pulmonol. (CAP) Trial Investigators. Survival SIDS: sudden infant death 1999;27(2):113–116 without disability to age 5 years after neonatal caffeine therapy syndrome 10. Brockmann PE, Wiechers C, for apnea of prematurity. JAMA. Pantalitschka T, Diebold J, Vagedes 2012;307(3):275–282 J, Poets CF. Under-recognition of alarms in a neonatal intensive care 20. Schmidt B, Davis PG, Roberts RS. unit. Arch Dis Child Fetal Neonatal Ed. Timing of caffeine therapy in very REFERENCES 2013;98(6):F524–F527 low birth weight infants. J Pediatr. 2014;164(5):957–958 1. Janvier A, Khairy M, Kokkotis A, 11. Ramanathan R, Corwin MJ, Hunt Cormier C, Messmer D, Barrington CE, et al; Collaborative Home Infant 21. Davis PG, Schmidt B, Roberts RS, et KJ. Apnea is associated with Monitoring Evaluation (CHIME) al; Caffeine for Apnea of Prematurity neurodevelopmental impairment Study Group. Cardiorespiratory Trial Group. Caffeine for Apnea of in very low birth weight infants. J events recorded on home monitors: Prematurity Trial: benefi ts may Perinatol. 2004;24(12):763–768 comparison of healthy infants with vary in subgroups. J Pediatr. those at increased risk for SIDS. JAMA. 2010;156(3):382–387 2. Pillekamp F, Hermann C, Keller T, von 2001;285(17):2199–2207 Gontard A, Kribs A, Roth B. Factors 22. Dobson NR, Patel RM, Smith PB, et al. infl uencing apnea and bradycardia 12. Rhein LM, Dobson NR, Darnall RA, Trends in caffeine use and association of prematurity—implications for et al; Caffeine Pilot Study Group. between clinical outcomes and timing neurodevelopment. Neonatology. Effects of caffeine on intermittent of therapy in very low birth weight 2007;91(3):155–161 hypoxia in infants born prematurely: a infants. J Pediatr. 2014;164(5):992–998 randomized clinical trial. JAMA Pediatr. 23. Miller MJ, Carlo WA, Martin RJ. 3. Henderson-Smart DJ. The effect of 2014;168(3):250–257 Continuous positive airway pressure gestational age on the incidence selectively reduces obstructive and duration of recurrent apnoea 13. Malloy MH. Prematurity and sudden apnea in preterm infants. J Pediatr. in newborn babies. Aust Paediatr J. infant death syndrome: United 1985;106(1):91–94 1981;17(4):273–276 States 2005-2007. J Perinatol. 2013;33(6):470–475 24. Pantalitschka T, Sievers J, Urschitz 4. Darnall RA, Kattwinkel J, Nattie 14. Committee on Fetus and Newborn, MS, Herberts T, Reher C, Poets CF. C, Robinson M. Margin of safety American Academy of Pediatrics. Randomised crossover trial of for discharge after apnea in Apnea, sudden infant death syndrome, four nasal respiratory support preterm infants. Pediatrics. and home monitoring. Pediatrics. systems for apnoea of prematurity 1997;100(5):795–801 2003;111(4 pt 1):914–917 in very low birthweight infants. 5. Eichenwald EC, Blackwell M, Lloyd JS, Arch Dis Child Fetal Neonatal Ed. 15. Kumral A, Tuzun F, Yesilirmak DC, 2009;94(4):F245–F248 Tran T, Wilker RE, Richardson DK. Inter- Duman N, Ozkan H. Genetic basis of neonatal intensive care unit variation apnoea of prematurity and caffeine 25. Valieva OA, Strandjord TP, Mayock in discharge timing: infl uence of apnea treatment response: role of adenosine DE, Juul SE. Effects of transfusions in and feeding management. Pediatrics. receptor polymorphisms. Acta extremely low birth weight infants: 2001;108(4):928–933 Paediatr. 2012;101(7):e299–e303 a retrospective study. J Pediatr. 2009;155(3):331–337 6. Eichenwald EC, Zupancic JA, Mao 16. Bloch-Salisbury E, Hall MH, Sharma WY, Richardson DK, McCormick MC, P, Boyd T, Bednarek F, Paydarfar D. 26. Westkamp E, Soditt V, Adrian S, Escobar GJ. Variation in diagnosis of Heritability of apnea of prematurity: a Bohnhorst B, Groneck P, Poets CF. Blood apnea in moderately preterm infants retrospective twin study. Pediatrics. transfusion in anemic infants with predicts length of stay. Pediatrics. 2010;126(4). Available at: www. apnea of prematurity. Biol Neonate. 2011;127(1). Available at: www. pediatrics. org/ cgi/ content/ full/ 126/ 4/ 2002;82(4):228–232 pediatrics. org/ cgi/ content/ full/ 127/ 1/ e779 27. Zagol K, Lake DE, Vergales B, et e53 17. Schmidt B, Roberts RS, Davis P, et al; al. Anemia, apnea of prematurity, 7. Davis NL, Condon F, Rhein LM. Caffeine for Apnea of Prematurity and blood transfusions. J Pediatr. Epidemiology and predictors of failure Trial Group. Caffeine therapy for 2012;161(3):417–421 of the infant car seat challenge. apnea of prematurity. N Engl J Med. 28. Peter CS, Sprodowski N, Bohnhorst Pediatrics. 2013;131(5):951–957 2006;354(20):2112–2121 B, Silny J, Poets CF. Gastroesophageal

Downloaded from www.aappublications.org/news by guest on September 25, 2021 6 FROM THE AMERICAN ACADEMY OF PEDIATRICS refl ux and apnea of prematurity: no in the treatment of apnea in premature Available at: www.pediatrics. org/ cgi/ temporal relationship. Pediatrics. infants. J Pediatr. 2001;138(3):355–360 content/ full/ 128/ 2/ e366 2002;109(1):8–11 36. Zupancic JA, Richardson DK, O’Brien 33. Terrin G, Passariello A, De Curtis M, 29. Poets CF. Gastroesophageal refl ux and BJ, Eichenwald EC, Weinstein MC. Cost- et al. Ranitidine is associated with apnea of prematurity—coincidence, effectiveness analysis of predischarge infections, necrotizing enterocolitis, not causation [commentary on monitoring for apnea of prematurity. and fatal outcome in newborns. Corvaglia L et al. A thickened formula Pediatrics. 2003;111(1):146–152 Pediatrics. 2012;129(1). Available at: does not reduce apneas related to www.pediatrics. org/ cgi/ content/ full/ 37. Barrington KJ, Finer N, Li D. gastroesophageal refl ux in preterm 129/ 1/ e40 Predischarge respiratory recordings infants. Neonatology. 2013;103(2):98– in very low birth weight newborn 102]. Neonatology. 2013;103(2):103–104 34. Charles BG, Townsend SR, Steer infants. J Pediatr. 1996;129(6):934–940 PA, Flenady VJ, Gray PH, Shearman 30. Di Fiore JM, Arko M, Whitehouse M, 38. Butler TJ, Firestone KS, Grow A. Caffeine citrate treatment for Kimball A, Martin RJ. Apnea is not JL, Kantak AD. Standardizing extremely premature infants with prolonged by acid gastroesophageal documentation and the clinical apnea: population pharmacokinetics, refl ux in preterm infants. Pediatrics. approach to apnea of prematurity absolute bioavailability, and 2005;116(5):1059–1063 reduces length of stay, improves staff implications for therapeutic drug 31. Wheatley E, Kennedy KA. Cross-over satisfaction, and decreases hospital monitoring. Ther Drug Monit. trial of treatment for bradycardia cost. Jt Comm J Qual Patient Saf. 2008;30(6):709–716 attributed to gastroesophageal 2014;40(6):263–269 refl ux in preterm infants. J Pediatr. 35. Lorch SA, Srinivasan L, Escobar 39. Sánchez PJ, Laptook AR, Fisher L, 2009;155(4):516–521 GJ. Epidemiology of apnea and Sumner J, Risser RC, Perlman JM. 32. Kimball AL, Carlton DP. bradycardia resolution in premature Apnea after immunization of preterm Gastroesophageal refl ux medications infants. Pediatrics. 2011;128(2). infants. J Pediatr. 1997;130(5):746–751

Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 137 , number 1 , January 2016 7 Apnea of Prematurity Eric C. Eichenwald and COMMITTEE ON FETUS AND NEWBORN Pediatrics 2016;137; DOI: 10.1542/peds.2015-3757 originally published online December 1, 2015;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/137/1/e20153757 References This article cites 37 articles, 12 of which you can access for free at: http://pediatrics.aappublications.org/content/137/1/e20153757#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Current Policy http://www.aappublications.org/cgi/collection/current_policy Committee on Fetus & Newborn http://www.aappublications.org/cgi/collection/committee_on_fetus__ newborn Fetus/Newborn Infant http://www.aappublications.org/cgi/collection/fetus:newborn_infant_ sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 25, 2021 Apnea of Prematurity Eric C. Eichenwald and COMMITTEE ON FETUS AND NEWBORN Pediatrics 2016;137; DOI: 10.1542/peds.2015-3757 originally published online December 1, 2015;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/137/1/e20153757

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2016 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Downloaded from www.aappublications.org/news by guest on September 25, 2021