Apnea of prematurity is defined as respiratory pauses > 20 seconds or pauses < 20 seconds that are associated with bradycardia (< 100 beats/minute) (1), central cyanosis, and/or oxygen saturation < 85% in neonates born at < 37 weeks gestation and with no underlying disorders causing apnea. Cause may be central nervous system immaturity (central apnea); if the episode of apnea is prolonged, there may be a component of airway obstruction as well. Diagnosis is clinical and by cardiorespiratory monitoring. Airway evaluation may be indicated when there is concern for obstructive apnea. Treatment is with respiratory stimulants (caffeine) for central apnea and head positioning for obstructive apnea. Prognosis is excellent; apnea of prematurity resolves in almost all preterm infants by 40 weeks postmenstrual age.37 weeks gestation and with no underlying disorders causing apnea. Cause may be central nervous system immaturity (central apnea); if the episode of apnea is prolonged, there may be a component of airway obstruction as well. Diagnosis is clinical and by cardiorespiratory monitoring. Airway evaluation may be indicated when there is concern for obstructive apnea. Treatment is with respiratory stimulants (caffeine) for central apnea and head positioning for obstructive apnea. Prognosis is excellent; apnea of prematurity resolves in almost all preterm infants by 40 weeks postmenstrual age.
(See also Overview of Perinatal Respiratory Disorders.)
Risk of apnea of prematurity increases with earlier gestational age. Almost all preterm infants born before 28 weeks gestation have some degree of apnea of prematurity, and about 20% of those born at 34 weeks gestation develop it (1).
Apnea of prematurity usually begins 2 to 3 days after birth; apnea on the first day of life may indicate a central nervous system (CNS) malformation or injury. Apnea that develops > 14 days after birth in an otherwise healthy infant may signify a serious illness other than apnea of prematurity (eg, sepsis).
General references
1. Eichenwald EC, Committee on Fetus and Newborn, American Academy of Pediatrics. Apnea of prematurity. Pediatrics. 2016;137(1). doi:10.1542/peds.2015-3757
2. Pergolizzi JV Jr, Fort P, Miller TL, LeQuang JA, Raffa RB. The epidemiology of apnoea of prematurity. J Clin Pharm Ther. 2022;47(5):685-693. doi:10.1111/jcpt.13587
Pathophysiology of Apnea of Prematurity
Apnea of prematurity is a developmental disorder caused by immaturity of neurologic and/or mechanical function of the respiratory system. Apnea may be characterized as:
Central (most common)
Obstructive
A mixed pattern
Central apnea is caused by immature medullary respiratory control centers. The specific pathophysiology is not understood completely but appears to involve a number of factors, including abnormal responses to hypoxia and hypercapnia. This is the most common type of apnea of prematurity.
Obstructive apnea is caused by obstructed airflow, neck flexion causing opposition of hypopharyngeal soft tissues, nasal occlusion, or reflex laryngospasm.
Mixed apnea is a combination of central and obstructive apnea.
All types of apnea can cause hypoxemia, cyanosis, and bradycardia if the apnea is prolonged. Because bradycardia can also occur simultaneously with apnea, a central mechanism may be responsible for both.
Approximately 23% of infants who had a sudden unexpected infant death (SUID), which includes sudden infant death syndrome (SIDS), had a history of prematurity, but there does not seem to be a direct causative link between apnea of prematurity itself and SUID or SIDS (1).
Periodic breathing is repeated cycles of 5 to 20 seconds of normal breathing alternating with brief (< 20 seconds) periods of apnea. Although both periodic breathing and apnea of prematurity share an underlying immaturity of respiratory control by the central nervous system, periodic breathing is common among term and preterm infants, is considered of minimal clinical significance, and does not appear to lead to apnea of prematurity (2).
Pearls & Pitfalls
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Pathophysiology references
1. Horne RS, Harrewijn I, Hunt CE. Physiology during sleep in preterm infants: Implications for increased risk for the sudden infant death syndrome. Sleep Med Rev. 2024;78:101990. doi:10.1016/j.smrv.2024.101990
2. Erickson G, Dobson NR, Hunt CE. Immature control of breathing and apnea of prematurity: the known and unknown. J Perinatol. 2021;41(9):2111-2123. doi:10.1038/s41372-021-01010-z
Diagnosis of Apnea of Prematurity
History and physical examination
Cardiorespiratory monitoring
Other causes (eg, hypoglycemia, sepsis, intracranial hemorrhage) excluded
Although frequently attributable to immature respiratory control mechanisms, apnea in preterm infants can be a sign of infectious, metabolic, thermoregulatory, respiratory, cardiac, or central nervous system dysfunction. Thorough history, physical assessment, and, when necessary, testing should be performed before accepting prematurity as the cause of apnea. Gastroesophageal reflux disease (GERD) has not been found to cause apnea in preterm infants, so the presence of GERD should not be considered an explanation for apneic episodes nor should treatment for GERD be started because of apnea of prematurity (1, 2).
Diagnosis of apnea usually is made by visual observation or with cardiorespiratory monitors used continuously during assessment and ongoing care of preterm infants.
Diagnosis references
1. Smits MJ, van Wijk MP, Langendam MW, Benninga MA, Tabbers MM. Association between gastroesophageal reflux and pathologic apneas in infants: a systematic review. Neurogastroenterol Motil. 2014;26(11):1527-1538. doi:10.1111/nmo.12405
2. Quitadamo P, Giorgio V, Zenzeri L, et al. Apnea in preterm neonates: what's the role of gastroesophageal reflux? A systematic review. Dig Liver Dis. 2020;52(7):723-729. doi:10.1016/j.dld.2020.03.032
Treatment of Apnea of Prematurity
Stimulation
Treatment of underlying disorder
Respiratory stimulants (eg, caffeine)
Continuous positive airway pressure (CPAP)
Patients are admitted to a monitored setting. When apnea is noted, either by observation or monitor alarm, infants are stimulated, which may be all that is required; if breathing does not resume, bag-valve-mask ventilation is provided (see Respiratory Support in Neonates and Infants).
Frequent or severe episodes should be quickly and thoroughly evaluated, and identifiable causes should be treated. If no infectious or other treatable underlying disorder is found, respiratory stimulants are indicated for treatment of frequent or severe episodes, characterized by hypoxemia, cyanosis, bradycardia, or a combination. Oral caffeine is the safest and most commonly used respiratory stimulant. Frequent or severe episodes should be quickly and thoroughly evaluated, and identifiable causes should be treated. If no infectious or other treatable underlying disorder is found, respiratory stimulants are indicated for treatment of frequent or severe episodes, characterized by hypoxemia, cyanosis, bradycardia, or a combination. Oral caffeine is the safest and most commonly used respiratory stimulant.Caffeine is preferred over other methylxanthines because of ease of administration, fewer adverse effects, larger therapeutic window, and less need to monitor drug levels (1, 2). Treatment continues until the infant is 34 to 35 weeks gestation and free from apnea requiring physical intervention for at least 5 to 7 days. Monitoring continues after the last episode of apnea or after caffeine has been stopped until the infant has gone 5 to 10 more days without having apnea requiring intervention.). Treatment continues until the infant is 34 to 35 weeks gestation and free from apnea requiring physical intervention for at least 5 to 7 days. Monitoring continues after the last episode of apnea or after caffeine has been stopped until the infant has gone 5 to 10 more days without having apnea requiring intervention.
If apnea continues despite respiratory stimulants, the infant may be given CPAP (3). Intractable apneic spells require ventilator support.
Discharge practices vary. Some clinicians observe infants for 7 days after treatment has ended to ensure that apnea or bradycardia does not recur, whereas others discharge with caffeine if treatment seems effective, but this practice is less common.
Discharge and home care
Discharge criteria
Hospitalized high-risk infants who have not had clinically significant cardiopulmonary events (eg, apnea > 20 seconds, apnea accompanied by central cyanosis, apnea associated with heart rate < 70 beats/minute) during 3 to 10 days of continuous cardiorespiratory monitoring can be discharged home safely without a monitor, usually with the additional requirement that they have reached 35 weeks postmenstrual age. Sometimes a home cardiorespiratory monitor and/or oral caffeine may be prescribed to shorten the hospital stay for infants who are otherwise ready for discharge but are still having cardiopulmonary events that reverse without intervention. 70 beats/minute) during 3 to 10 days of continuous cardiorespiratory monitoring can be discharged home safely without a monitor, usually with the additional requirement that they have reached 35 weeks postmenstrual age. Sometimes a home cardiorespiratory monitor and/or oral caffeine may be prescribed to shorten the hospital stay for infants who are otherwise ready for discharge but are still having cardiopulmonary events that reverse without intervention.
All preterm infants, especially those with apnea of prematurity, should undergo a car seat challenge test before discharge to evaluate for apnea, bradycardia, and oxygen desaturation related to their size and for positional airway obstruction.
Home monitoring
Few infants are discharged home with an apnea monitor, and only those whose episodes resolve spontaneously and without intervention, including stimulation, should be considered for discharge from the hospital with a monitor. Parents should be taught how to properly use equipment, assess alarm situations, intervene (eg, perform cardiopulmonary resuscitation [CPR]), and keep a log of events. Round-the-clock telephone support and triage as well as outpatient follow-up regarding the decision to stop using the monitor should be provided. Monitors that store event information are preferred. Parents should be informed that home cardiorespiratory monitors have not been shown to reduce the incidence of sleep-related deaths, including SIDS, or of brief, resolved, unexplained events (BRUEs) (4–6).
Pearls & Pitfalls
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Sleep positioning
Infants should always be placed on their back to sleep on a firm, flat, non-inclined sleep surface for every sleep unless other medical conditions prevent this (4). Side sleeping or propping is too unstable. The infant’s head should be kept in the midline, and the neck should be kept in the neutral position or slightly extended to prevent upper airway obstruction.
Investigators often find that infants found dead in a sleep space died of suffocation (accidental suffocation and strangulation in bed, or ASSB, a type of SUID). For additional measures that decrease the risk of SUID and SIDS, see Prevention of SUID and SIDS.
Treatment references
1. Miao Y, Zhou Y, Zhao S, et al. Comparative efficacy and safety of caffeine citrate and aminophylline in treating apnea of prematurity: A systematic review and meta-analysis. PLoS One. 2022;17(9):e0274882. Published 2022 Sep 19. doi:10.1371/journal.pone.0274882
2. Alhersh E, Abushanab D, Al-Shaibi S, Al-Badriyeh D. Caffeine for the Treatment of Apnea in the Neonatal Intensive Care Unit: A Systematic Overview of Meta-Analyses. Paediatr Drugs. 2020;22(4):399-408. doi:10.1007/s40272-020-00404-4
3. Ho JJ, Zakarija-Grkovic I, Lok JW, Lim E, Subramaniam P, Leong JJ. Continuous positive airway pressure (CPAP) for apnoea of prematurity. Cochrane Database Syst Rev. 2023;7(7):CD013660. Published 2023 Jul 18. doi:10.1002/14651858.CD013660.pub2
4. Moon RY, Carlin RF, Hand I; TASK FORCE ON SUDDEN INFANT DEATH SYNDROME and THE COMMITTEE ON FETUS AND NEWBORN. Evidence Base for 2022 Updated Recommendations for a Safe Infant Sleeping Environment to Reduce the Risk of Sleep-Related Infant Deaths. Pediatrics. 2022;150(1):e2022057991. doi:10.1542/peds.2022-057991
5. Tieder JS, Bonkowsky JL, Etzel RA, et al. Brief Resolved Unexplained Events (Formerly Apparent Life-Threatening Events) and Evaluation of Lower-Risk Infants [published correction appears in Pediatrics. 2016 Aug;138(2):e20161487. doi: 10.1542/peds.2016-1487.]. Pediatrics. 2016;137(5):e20160590. doi:10.1542/peds.2016-0590
6. Goodstein MH, Stewart DL, Keels EL, Moon RY; COMMITTEE ON FETUS AND NEWBORN, TASK FORCE ON SUDDEN INFANT DEATH SYNDROME. Transition to a Safe Home Sleep Environment for the NICU Patient. Pediatrics. 2021;148(1):e2021052045. doi:10.1542/peds.2021-052045
Prognosis for Apnea of Prematurity
Apneic spells decrease with increasing corrected gestational age, and apnea of prematurity resolves in 98% of preterm infants by 40 weeks postmenstrual age (1).
Apnea may continue for weeks in infants born at extremely early gestational ages (eg, 23 to 27 weeks).
Death is rare because the vast majority of infants outgrow apnea of prematurity before the age at which SIDS-related deaths occur (2).
Prognosis references
1. Goodstein MH, Stewart DL, Keels EL, Moon RY; COMMITTEE ON FETUS AND NEWBORN, TASK FORCE ON SUDDEN INFANT DEATH SYNDROME. Transition to a Safe Home Sleep Environment for the NICU Patient. Pediatrics. 2021;148(1):e2021052045. doi:10.1542/peds.2021-052045
2. Eichenwald EC; Committee on Fetus and Newborn, American Academy of Pediatrics. Apnea of Prematurity. Pediatrics. 2016;137(1):10.1542/peds.2015-3757. doi:10.1542/peds.2015-3757
Key Points
Apnea of prematurity is caused by immaturity of neurologic and/or mechanical function of the respiratory system.
Until mature, preterm infants may have respiratory pauses > 20 seconds or pauses < 20 seconds combined with bradycardia (< 100 beats/minute) and/or oxygen saturation < 85%.
Diagnose by observation and exclude other, more serious causes of apnea (eg, infectious, metabolic, thermoregulatory, respiratory, cardiac, or central nervous system disorders).
Monitor respiration and give physical stimulation for apnea; if breathing does not resume, give bag-valve-mask ventilation.
Give oral caffeine to neonates who have recurrent episodes.Give oral caffeine to neonates who have recurrent episodes.
Treatment for gastroesophageal reflux disease should not be started as an intervention for apnea of prematurity.
Home monitoring has not been shown to improve outcomes; only infants whose episodes resolve spontaneously and without stimulation should even be considered for discharge with a monitor to shorten hospital stay.
Drugs Mentioned In This Article
