99

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 definitions, monitoring practices, and consensus about
clinical significance leads to significant variation in practice. The purpose
of this clinical report is to review the evidence basis for the definition,
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. filed conflict of interest statements with the American Academy
of Pediatrics. Any conflicts 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 benefit 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 reflect 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 guidance in this report does not indicate an exclusive course of
the incidence of apnea is inversely proportional to gestational age.3 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 reaffirmed,
revised, or retired at or before that time.
the lack of consistent definitions, monitoring practices, and consensus
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

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 100 SECTION 3: High-Risk Newborn/Prematurity

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
Most studies examining the time heart rate, respiratory rate, and
episodes in preterm infants are
course to resolution of apnea oxygen saturation. Cardiac alarms
mixed events, in which obstructed
of prematurity have relied on are most commonly set at 100
airflow results in a central apneic
nurses' recording of events in beats per minute, although lower
pause, or vice versa.
the medical record; however, alarm settings are acceptable in
several studies have shown a lack convalescent preterm infants.
of correlation with electronically Apnea alarms are generally set
EPIDEMIOLOGY AND TIME COURSE TO
RESOLUTION recorded events.9,10 Standard at 20 seconds. However, apnea
NICU monitoring techniques are detection by impedance monitoring
In an observational study, is potentially misleading. Impedance
unable to detect events that are
Henderson-Smart3 reported that monitoring is prone to artifact
primarily obstructive in nature. With
the incidence of recurrent apnea attributable to body movement or
continuous electronic recording,
increased with decreasing gestational cardiac activity and is unable to
it is evident that some preterm
age. Essentially, all infants born detect obstructive apnea. Practices
infants continue to have clinically
at ≤28 weeks’ gestation were differ as to when continuous
unapparent apnea, bradycardia, and
diagnosed with apnea; beyond 28 oximetry is discontinued. In a study
oxygen desaturation events even
weeks’ gestation, the proportion of investigating the age at last recorded
after discharge. The Collaborative
infants with apnea decreased, from apnea and age at discharge from the
Home Infant Monitoring Evaluation
85% of infants born at 30 weeks’ hospital in 15 different NICUs, the
Study examined the occurrence of
gestation to 20% of those born at 34 duration of use of pulse oximetry was
apnea/bradycardia events in >1000
weeks’ gestation. This relationship significantly different among hospital
preterm and healthy term infants
has important implications for NICU sites.5 Later discontinuation of pulse
monitored at home.11 “Extreme
policy, because infants born at less oximetry was associated with a later
events” (apnea >30 seconds and/or
than 35 weeks’ gestation generally PMA at recorded last apnea and
heart rate <60 beats per minute for
require cardiorespiratory monitoring longer length of stay, suggesting that
>10 seconds) were observed most
after birth because of their risk oximetry may detect events that
frequently in former preterm infants,
of apnea. As expected with a cardiorespiratory monitoring does
decreasing dramatically until about
developmental process, some infants not.
born at 35 to 36 weeks’ gestation 43 weeks’ PMA. After 43 weeks’ PMA,
may have respiratory control “extreme events” in both preterm There are no data to suggest that a
instability, especially when placed in and term infants were very rare. diagnosis of apnea of prematurity is
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 Reflex 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 chemoreflex
Delayed central nervous system development Excessive bradycardic response
bradycardia events persisting beyond

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 Apnea of Prematurity 101

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
weeks’ PMA.11 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
may be prescribed for some preterm to facilitate extubation.17 Dosing (mean difference: 6 days; P < .001).22
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 No trials have addressed when to
a shorter duration of mechanical
discontinue xanthine treatment in
ventilation, lower incidence of
preterm infants; however, timely
bronchopulmonary dysplasia, and
TREATMENTS discontinuation is advised to avoid
improved neurodevelopmental
unnecessary delays in discharge.
Xanthine Therapy outcome at 18 months.18 Differences
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

PEDIATRICS Volume 137, number 1, January 2016 3

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 102 SECTION 3: High-Risk Newborn/Prematurity

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
to 6 cm H2O, usually in conjunction before.27 These authors also reported Practice and management
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 Reflux 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

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 Apnea of Prematurity 103

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 discharge of 5 to 7 days is
3. Individual NICUs are encouraged
events, which may not always commonly used, although a
to develop policies for
correlate with those events that are longer period may be suitable
cardiorespiratory monitoring
electronically recorded.9,10 Preterm for infants born at less than
for infants considered at risk of
infants with a history of apnea 26 weeks’ gestation. The specific
apnea of prematurity.
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.
documentation and clinical approach LEAD AUTHOR
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
timing.38 apnea/bradycardia events off
COMMITTEE ON FETUS AND NEWBORN,
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
stresses, including general anesthesia William E. Benitz, MD, FAAP
6. Evidence suggests that GER is James J. Cummings, MD, FAAP
and viral illnesses. Additional close not associated with apnea of
monitoring in these situations may Eric C. Eichenwald, MD, FAAP
prematurity, and treatment of Jay Goldsmith, MD, FAAP
be indicated in preterm infants presumed or proven GER solely Brenda B. Poindexter, MD, FAAP
until 44 weeks’ PMA, including for the reduction in apnea events Karen Puopolo, MD, FAAP
former preterm infants readmitted is not supported by currently Dan L. Stewart, MD, FAAP
for elective surgical procedures, available evidence. Kasper S. Wang, MD, FAAP
such as hernia repair. In addition,
the exacerbation of apnea has 7. Brief, isolated bradycardic
episodes that spontaneously LIAISONS
been reported in very preterm
infants after their initial 2-month resolve and feeding-related Wanda D. Barfield, 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
Erin L. Keels, APRN, MS, NNP-BC – National
need not delay discharge.
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

PEDIATRICS Volume 137, number 1, January 2016 5

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 104 SECTION 3: High-Risk Newborn/Prematurity

8. Eichenwald EC, Aina A, Stark AR. Apnea 18. Schmidt B, Roberts RS, Davis P, et al;
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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
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Pantalitschka T, Diebold J, Vagedes
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