Open Access Review

Article DOI: 10.7759/cureus.21783

Treating Apnea of Prematurity

Joseph Pergolizzi 1 , Alexander Kraus 2 , Peter Magnusson 3, 4 , Frank Breve 5 , Kailyn Mitchell 6 , Robert Raffa
7 , Jo Ann K. LeQuang 8 , Giustino Varrassi 9

Received 09/16/2021
Review began 09/20/2021 1. Cardiology, Native Cardio Inc., Naples, USA 2. Research and Development, Enalare Therapeutics, Inc., Lorrach, DEU
Review ended 01/21/2022
3. Cardiology, Center of Research and Development Region Gävleborg/Uppsala University, Gävle, SWE 4. Medicine,
Published 01/31/2022
Cardiology Research Unit, Karolinska Institutet, Stockholm, SWE 5. Pharmacy, Temple University, Philadelphia, USA 6.
© Copyright 2022 NEMA Research Inc., Naples, USA 7. School of Pharmacy, Temple University (Emeritus), Philadelphia, USA 8. NEMA
Pergolizzi et al. This is an open access Research, Inc., Naples, USA 9. President, Paolo Procacci Foundation, Rome, ITA
article distributed under the terms of the
Creative Commons Attribution License CC-
BY 4.0., which permits unrestricted use, Corresponding author: Jo Ann K. LeQuang, [email protected]
distribution, and reproduction in any
medium, provided the original author and
source are credited.

Abstract
Premature babies often suffer apnea of prematurity as a physiological consequence of an immature
respiratory system. Hypercapnia may develop, and neonates with apnea of prematurity are at an increased
risk of morbidity and mortality. The long-term effects of apnea of prematurity or their treatments are less
clear. While a number of treatment options exist for apnea of prematurity, there is no clear-cut “first-line”
approach or gold standard of care. Effective treatments, such as caffeine citrate, carbon dioxide inhalation,
nasal continuous positive airway pressure, nasal intermittent positive pressure ventilation, and others, may
be associated with safety concerns. More conservative treatments are available, such as kangaroo care,
postural changes, and sensory stimulation, but they may not be effective. While apnea of prematurity
resolves spontaneously as the respiratory system matures, it can complicate neonatal care and may have
both short-term and long-term consequences. The role, if any, that apnea of prematurity may play in
mortality of preterm neonates is not clear.

Categories: Pediatrics, Pulmonology

Keywords: doxapram, neonatal intensive care, neonatology, caffeine, preterm birth, apnea of prematurity

Introduction And Background

Approximately 11% of births globally are preterm, which s defined as birth before 37 gestational weeks [1].
Premature birth does not accelerate respiratory development, meaning that these neonates must rely on
fetal pulmonary mechanisms, which often leads to a form of respiratory instability known as apnea of
prematurity (AOP). Increasingly, preterm infants of lower gestational age survive, making AOP more
prevalent in the neonatal intensive care unit (NICU). A variety of treatments may help stimulate respiration,
but great care is warranted as the immature respiratory systems of preterm infants can easily be injured by
aggressive approaches. AOP is a potentially life-threatening sign associated with preterm birth, which
resolves spontaneously as the respiratory system matures [1]. AOP may be more complex and more
dangerous than is commonly considered. Complications associated with AOP may involve the physiological
consequences such as altered neonatal ventilatory responses to hypoxia and hypercapnia, and disruptions to
neonatal sleep architecture [2].

AOP has been defined as the abrupt cessation of breathing for at least 20 seconds, accompanied by both
bradycardia and oxygen desaturation in an infant with a gestational age < 37 weeks (Table 1) [3]. It may be
accompanied by a clinically significant cardiopulmonary event (CSCPE), defined as 20 seconds without
respiration or 10 seconds without respiration accompanied by a heart rate under 80 beats per minute or an
oxygen desaturation level <85% [4]. The incidence of AOP and CSCPE increases with lower birth weight,
affecting 25% of neonates weighing less than 2,500 g at birth [5]. Apnea may be central, obstructive (blocked
airways), or mixed; central and mixed apnea are more frequently observed. However, clear distinctions
between these three broad categories may sometimes become blurred [6].

How to cite this article

Pergolizzi J, Kraus A, Magnusson P, et al. (January 31, 2022) Treating Apnea of Prematurity. Cureus 14(1): e21783. DOI 10.7759/cureus.21783
 Gestational age Incidence of apnea of prematurity Birth weight

34-35 weeks 7%

32-33 weeks 15%

30-31 weeks 54%

<29 weeks ~100% <1,000 g

TABLE 1: The incidence of AOP is inversely related to gestational age and birth weight[5].
AOP, apnea of prematurity

The fetus lives in an environment with very low oxygen (PaO2 of 23-27 mmHg) and transitions at birth
abruptly into an oxygen-rich environment, which necessitates a rapid and radical change in ventilation.
Neonatal oxygen therapy must provide adequate oxygen for tissue perfusion without causing oxygen
toxicity and retinopathy of prematurity [7]. Babies in distress administered 100% oxygen at delivery may
experience oxidative stress as well as toxicity involving the eyes, the brain, or the lungs [7,8]. Preterm infants
may lack chemoreceptor sensitivity, respiratory control system, and adequate synaptic connections in order
to make this ventilatory adjustment safely and quickly [2]. Moreover, preterm infants may develop
hypercapnia, which may prolong expiration without increasing the respiratory rate. In fact, poor hypercapnic
response is more common in premature infants with AOP than in those without AOP [2]. AOP appears to be
more complex than a simple breathing dysfunction related to an immature anatomy.

If left untreated, AOP can lead to failure to thrive, developmental delays, and other forms of morbidity and
mortality. It increases the neonate’s likelihood of having other disorders such as respiratory failure,
pulmonary hemorrhage, cardiovascular problems, intracranial hemorrhage, and sudden death [9]. While AOP
typically resolves as the infant matures, in some cases, apneic events may persist beyond infancy; in a cross-
sectional study of 137 children between the ages of 4 and 6 years, obstructive sleep apnea was significantly
more common in preterm than full-term patients [10]. The association between AOP and
neurodevelopmental delays is difficult to establish because preterm infants may have multiple underlying
health problems and developmental challenges separate from AOP. In most cases, AOP resolves by 36 weeks
of postmenstrual age, but this is not a universally observed outcome [11]. Indeed, there is a paucity of data
about the natural course of AOP, although the condition is far from rare. The purpose of this narrative review
is to summarize and contextualize the current treatment options for AOP.

Review
A literature search was conducted using PubMed for the keywords “apnea of prematurity” with results
delimited to randomized clinical trials (n=46 results). The Cochrane Library database was searched for meta-
analyses of data by searching for “apnea of prematurity” in the title, abstract, or keywords (n=37). Google
Scholar was searched for “apnea of prematurity” and “apnea of prematurity guidelines.” The last searches of
these databases were performed in June 2021. Embase was searched on July 22, 2021, for “apnea of
prematurity” from 2000 to 2021, with results limited to controlled clinical trials and randomized controlled
trials (n=56). Results were excluded if they were not in English; if articles did not report randomized trials,
clinical trials, or meta-analyses; or if the authors did not specifically address treatment modalities for AOP.
The emphasis of our search was on treatment options. Bibliographies of articles were also searched. There
was some duplication in results. In total, 96 articles were used. Since AOP increases a neonate’s probability
of morbidity and mortality [9], it is important to find safe and effective ways to treat this condition. The
natural history of AOP is such that it often resolves on its own, but the most beneficial course of action in
this setting is not clear. The main currently available treatments are described in the next sections.

Methylxanthine
The only treatment for AOP approved by the U.S. Food and Drug Administration (FDA) is caffeine citrate.
Caffeine is one of several methylxanthine drugs used in this setting, similar to theophylline and
aminophylline [12]. Among these agents, caffeine has a higher therapeutic ratio, good enteral absorption, a
longer half-life, and fewer adverse effects; its efficacy and tolerability make it the first choice among
methylxanthines [13]. Since 2013, caffeine has been used more often than other drugs to treat AOP [14]. As a
central nervous system stimulant, methylxanthines cross the blood-brain barrier and act as antagonists at
the adenosine receptors [15]. Genetic differences may make some neonates more or less sensitive to these
agents, accounting for an observed variability in response [16]. It has been speculated that methylxanthines
administered to a neonate may have adverse effects on the cardiovascular and central nervous systems [17].
An international study of 13 academic hospitals followed the progress of 870 neonates with AOP who were
administered caffeine citrate for the next 11 years; the study used regression models to ascertain the
potential neurobehavioral effects of neonatal administration of caffeine [18]. Overall, neurobehavioral

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 results were similar in the caffeine and control groups, but the caffeine group had better performance in fine
motor coordination, visual-motor integration, and visual-spatial organization than the controls. Attention,
intelligence, and general behavior were similar between groups [18]. In another study, caffeine therapy did
not significantly affect academic performance, motor skills, or behavioral impairments up to middle-school
age compared to placebo patients in a study of 920 neonates with AOP followed for 11 years [19].

Caffeine is labeled for short-term use for a limited range of gestational ages, but there is limited specific
guidance regarding when to start treatment, dose and duration of treatment, when treatment should be
discontinued, and whether caffeine might have adverse effects [3]. The long-term effects of caffeine
administered to the developing brain are not fully known, and it has been suggested that the positive
respiratory benefits of caffeine in preterm neonates may be outweighed by caffeine’s adverse effects on the
central nervous system [20]. In a retrospective cohort study of 109 infants with a gestational age of <31
weeks and birth weight under 1,500 g, the administration and duration of caffeine citrate therapy were
associated with osteopenia of prematurity, a potentially serious condition [21]. Dosing can be particularly
challenging because the preterm population has limited hepatic, renal, and respiratory function. A meta-
analysis (n=1,515 patients in 13 randomized clinical trials) found that higher doses (10-20 mg/kg daily) were
associated with greater efficacy than lower doses (5-10 mg/kg daily) and that higher doses were more closely
associated with withdrawal from the ventilator, but higher doses were also more associated with tachycardia
than lower doses [22]. In another study of caffeine administered to 120 preterm infants (<32 weeks
gestational age), high-dose caffeine therapy (loading dose of 40 mg/kg and then 20 mg/kg daily) was
associated with a significant decrease in extubation failure, apnea rates, and days of documented apnea
compared to low-dose caffeine (loading dose 20 mg/kg and then 10 mg/kg daily) [23]. A clinical study
compared the same doses of caffeine to treat AOP in 78 preterm infants in the NICU [24]. There was no
significant difference in the frequency or total days of apnea between groups, and adverse events were
similar as well [24]. While high doses were not associated with worse outcomes, this study suggests that
high-dose caffeine therapy may not confer any benefits in this population. By contrast, a study of 111
preterm infants with AOP randomly assigned to high-dose (20 mg/day) or low-dose caffeine therapy (10
mg/day) found that the high-dose group had significantly lower rates with respect to extubating failure
(16.7% vs. 36.8%), age at extubating (8.2±2.1 days vs. 10.7±2.3 days), duration of invasive ventilation,
duration of ventilation prior to extubating, and number of days of apnea (1.8±1.3 vs. 3.2±1.1 days), with a
similar rate of adverse events [25]. In contrast to other studies, this study suggests that a higher
maintenance dose of caffeine is associated with better outcomes.

The largest study of caffeine in preterm infants to date, the Caffeine for Apnea of Prematurity (CAP) Trial,
randomized 2,006 neonates with birth weights ranging from 500 to 1,250 g to the caffeine group or placebo
for the first 10 days of life. Caffeine was administered as a loading dose of 20 mg/kg followed by a
maintenance dose of 5 mg/kg/day, which could be increased to 10 mg/kg/day in cases of persistent apnea
[26]. The caffeine group had a shorter duration of mechanical ventilation, lower rate of bronchopulmonary
dysplasia (BPD), and improved neurodevelopmental outcomes at 18 months; these advantages were less
pronounced at five years, but benefit for the caffeine group was still shown [27].

In a randomized, single-center, controlled study of AOP prophylaxis, 26 preterm infants received either 20
mg/kg caffeine citrate as a loading dose followed by 5 mg/kg daily over 10 days or were in a control group
[28]. AOP occurred significantly less frequently in the caffeine compared to the control group, with only 15%
of the caffeine group (n=4) developing AOP versus 62% (n=16) in the control group [28]. A randomized study
of 90 preterm infants evaluated whether prophylactic caffeine treatment, defined as caffeine administered
in the first 72 hours of life, conferred benefits over therapeutic caffeine administered only to infants with
apnea and/or who required mechanical ventilation. The prophylactic caffeine group had a shorter duration
of oxygen therapy, shorter duration of invasive or noninvasive ventilation, a lower incidence of moderate
BPD, and a shorter length of hospital stay [29].

Moreover, caffeine was associated with a significantly reduced risk of motor impairment versus placebo
(p=0.009) in neonates with AOP [19]. The composite endpoint of death or disability at five years was
statistically similar in 1,640 children randomized to be treated with caffeine or placebo for AOP [27]. The rate
of cognitive impairment was less at five years than 18 months in both groups and not different between
groups [27]. In the children in the CAP study (n=1433), the rate of developmental coordination disorder was
evaluated in children who had received caffeine (n=735) or placebo (n=698) five years later. The rate of
developmental coordination disorder was significantly lower in the caffeine group than the placebo group
(11.3% vs. 15.2%, p=0.032) [30]. In a study of seventy 11-year-old children who had been born preterm
(≤1,250 g weight at birth) and were treated with caffeine or placebo for AOP, imaging evidence showed that
caffeine-treated children had a smaller corpus callosum than placebo patients, although volumetric
development of the brain was similar between groups [31]. The clinical significance of this finding is not
known, nor is it known if this difference persists beyond age 11. In another study, 201 children who had
been treated as preterm neonates with caffeine citrate or placebo were evaluated at ages between 5 and 12
years for abnormalities in sleep architecture or breathing during sleep [32]. It was found that caffeine had no
long-term effects on sleep duration or sleep apnea, although all of the preterm infants in this study had
similar and elevated risks for obstructive sleep apnea and periodic limb movements during sleep at older age
[32].

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 Caffeine has interindividual pharmacodynamic variations in preterm neonates, with the plasma elimination
half-life estimated to be about 100 hours [13]. There is no expert consensus as to when caffeine treatment
should be started in preterm neonates, but it is often initiated in the first few hours or days of life [33]. Early
treatment with caffeine is associated with a significantly decreased need for invasive ventilation or duration
of mechanical ventilation, but early administration may pose risks for the developing brain and central
nervous system [33]. Likewise, there is no clear expert consensus as to when caffeine treatment should be
discontinued. In a study of neonates of 26 to 32 weeks’ gestational age with AOP, 120 infants were
randomized to be treated with caffeine until the seventh apnea-free day or for a fixed time period that
culminated at 34 weeks of postmenstrual age [34]. Results were similar between groups, and the study
suggests that caffeine may be stopped as early as 33 to 34 weeks of postmenstrual age without risking
recurrence of apnea [34]. A survey of caffeine use in neonates with AOP in the United States found that
caffeine was most frequently discontinued at the postmenstrual age of 34 weeks (62%) and that most of
them were not discharged home on caffeine therapy (70%) [35].

The dose of caffeine and the toxicity threshold are not well defined [13]. Issues with caffeine citrate may
involve dose calculation errors, as the product is usually available only in a few commercially available sizes
and neonatal doses are usually extemporaneously compounded. It is also important to recognize that
caffeine citrate is only available in a preservative-free formulation, and therefore left-over compounded
product must be promptly discarded. Elimination of caffeine increases nonlinearly after birth of a preterm
infant up to the age of around six weeks [36]. Peak plasma concentrations occur in within one hour, and
caffeine, being hydrophobic, tends to distribute rapidly in the body and not accumulate in tissue. Preterm
neonates metabolize caffeine mainly by N-demethylation, and females tend to metabolize caffeine more
rapidly than males [13]. At up to 38 weeks’ gestational age, the hepatic enzymes are immature and can reduce
caffeine metabolism, prolonging the plasma half-life of caffeine. Hepatic enzymes do not function at an
adult level until the age of approximately four months [37].

Aminophylline is a bronchodilator that helps relax airway muscles. In a retrospective study of 206 preterm
infants treated with aminophylline for AOP, it was found that 62% received effective therapy and 26% had
adverse events. Higher rates of adverse events could be associated with low birth weight and high serum
concentrations of the drug [38]. The effects of aminophylline on cardiac parameters in neonates appear to be
similar to those of caffeine [39]. In a randomized, double-blind study, 87 preterm neonates with AOP
(gestational age of 27-32 weeks) were treated with either theophylline plus 0.5 L/m room air via nasal prongs
or placebo with 0.5 L/min room air with carbon dioxide (about 1% inhaled) for three days [40].

Blood transfusion
Red blood cell transfusions have been reported as a treatment of AOP, but there is little evidence to support
their effectiveness [41]. In fact, since neonates are already hyperglobulinemic, this treatment seems
inappropriate. An infusion of red blood cells is thought to treat AOP by boosting the oxygen content of the
blood, and, in that way, enhancing oxygenation of the tissues [42]. Unblinded studies have produced
conflicting results [43,44]. Furthermore, blood transfusions delivered to low birth-weight neonates for any
reason are associated with an increased risk of BPD and necrotizing enterocolitis [44].

Carbon dioxide inhalation

Since apnea occurs when the baseline level of carbon dioxide falls below the apnea threshold, inhalation of
carbon dioxide is sometimes used in mammals as a way to physiologically induce breathing. In a study of 42
preterm infants, inhaled carbon dioxide 0.8% was found to be as effective as theophylline in terms of
reducing apneic episodes without altering cerebral blood flow velocity [45]. However, a randomized double-
blind study of 87 preterm infants with AOP found inhaled carbon dioxide therapy ineffective [40]. Neonates
may accommodate themselves to carbon dioxide treatments, making them less effective over time, and the
longer-term consequences of this type of treatment have not been evaluated.

Creatinine supplementation
Preterm infants with AOP were randomized to be treated with creatinine supplementation or placebo (n=38).
Creatinine supplementation was well tolerated but had no significant effect on bradycardia incidence or
oxygen desaturation [46].

Device-based treatment (neuromodulation)

It is known that limb movements can drive respiration; for example, walking stimulates breathing in
humans [47]. Since this effect occurs with passive limb movement as well, gentle vibrations were used to
stimulate the proprioceptors on the palms of the hands and soles of the feet of preterm infants. The concept
was that vibrations would activate a proprioceptive fiber discharge similar to such that might occur with
ambulation, involving a reflexive coupling of respiration and movement. In a study of 19 preterm infants
(≥23-34 weeks’ gestational age), this treatment was shown to reduce AOP, reduce oxygen desaturation, and
result in fewer instances of bradycardia. The neuromodulatory approach is noninvasive and was well
tolerated [47].

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 Doxapram
Doxapram, a respiratory stimulant, is sometimes administered to preterm infants with AOP at doses of about
1.5 mg/kg per hour [48], but doxapram has dose-dependent side effects that must be carefully considered
[49]. A systematic review of doxapram to treat AOP in neonates of <34 weeks’ gestational age (n=28 studies,
1,994 patients) found that doxapram conferred a benefit in terms of apnea rate but with the risk of dose-
related adverse events [50]. These investigators could reach no conclusions on the safety or efficacy of this
drug in this population and therefore did not recommend its routine use [50].

In preterm infants, doxapram is considered an appropriate but third-line treatment for AOP, suitable for use
if the neonate does not respond to caffeine or continuous positive airway pressure (CPAP) [51]. In a
randomized double-blind study of 85 preterm infants with AOP for whom neither caffeine nor CPAP was
effective, neonates were treated with doxapram and followed for four days. The study found that regulating
doxapram dosing by considering infant weight and sex did not significantly increase plasma levels of the
drug in the therapeutic range but did improve efficacy with 76% of these infants responding to doxapram
therapy compared to 56% of controls (p<0.001) with no adverse events observed [51]. In a study of 11
preterm infants randomized to intravenous doxapram or placebo, the doxapram group had fewer treatment
failures within 48 hours, but this study only evaluated short-term responses [52]. In a study of 1,501
neonates of <32 weeks’ gestational age who were treated with doxapram over the course of five years at a
single center in the Netherlands, the majority of those (64.8%) treated with doxapram did not need
intubation. No neonates in this study died [53].

Kangaroo care
Kangaroo care, the skin-to-skin contact between parent and newborn infant, has gained acceptance as a way
to improve the infant’s vital signs and clinical status, particularly for healthy babies. Its role in the
treatment of AOP is not clear, as the results of studies of kangaroo care for reducing AOP have been mixed
[54-56]. In fact, kangaroo care may interfere with adequate respiratory monitoring of preterm infants with
AOP unless special steps are taken [57]. However, kangaroo care may reduce morbidity and mortality in low
birth weight infants [58] and promote weight gain [59].

Less-invasive surfactant administration

Pulmonary surfactants are substances that prevent the pulmonary air sacs from collapsing by reducing
surface tension. Surfactants may be derived from animal products, but synthetic surfactants with comparable
effectiveness and potential cost advantages also exist [60]. Recent advances in surfactant treatments have
focused primarily on ways to administer exogenous surfactants through minimally invasive or even
noninvasive routes [60]. These include aerosolized delivery (nebulizer), laryngeal mask airway delivery, or
delivery through a thin endotracheal catheter.

The 2019 European Consensus Guidelines recommend porcine over bovine surfactants and report that a dose
of 200 mg/kg has greater therapeutic efficacy than 100 mg/kg [61]. The challenge with surfactant use in
neonates is their safe administration, in particular, ways to obviate the need for intubation and bolus
delivery [62]. Aerosolization of the agent appears promising, although the development of the appropriate
equipment to nebulize molecules small enough to pass through the main neonatal airways and reach the
alveoli has been an obstacle [62]. A current method allows sedation of the infant, intubation for surfactant
administration, followed by rapid extubation [63].

The less-invasive surfactant administration (LISA) method inserts a small-size catheter through the vocal
cords and into the infant’s trachea through which the surfactant is administered, whereupon the catheter is
withdrawn [64]. LISA may be used to help spontaneously breathing preterm infants in order to reduce the
need for mechanical ventilation. LISA is typically administered with noninvasive forms of respiratory
support, such as CPAP and noninvasive positive-pressure ventilation (NIPPV) [65].

In an observational study (n=7,533) of very low birth weight neonates (gestational ages 22 0/7 to 28 6/7 weeks),
one group never received surfactants (n=1214), one group was treated with LISA (n=2,624), and another
group was administered surfactants by way of endotracheal tubes (n=3,695) [66]. The use of LISA was
associated with significantly lower rates of mortality, BPD, intracerebral hemorrhage, and retinopathy of
prematurity than the other groups. However, in infants under 26 weeks, there was an increased rate of focal
intestinal perforation with LISA [66]. The advantage of LISA over other surfactant administration protocols
is that it avoids the sedation and intubation of preterm infants. However, there is a risk that surfactant may
be unequally distributed, for example, favoring one lung over the other, because of the difficulty in
estimating the depth of catheter introduction into the trachea [62].

Nasal continuous positive airway pressure and nasal intermittent

positive pressure ventilation
CPAP at 4-6 cmH2O has been demonstrated to be effective for obstructive but not central AOP [67]. NIPPV
may be effective in treating AOP and preventing extubating failure [68]. There are no placebo-controlled

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 studies of NIPPV for AOP infants, but NIPPV may avoid mechanical ventilation in infants with AOP [69]. In a
study of 79 preterm infants randomized to NIPPV or NCPAP, the two groups had similar failure rates at 48
hours (13.5% vs. 15%, respectively) with a trend toward less surfactant use in the NIPPV group (32.4% vs.
53.7%, respectively) [70].

In a study of infants who were mechanically ventilated, 132 were randomized to receive biphasic nasal CPAP
or regular nasal CPAP for 48 hours post-extubation [71]. The biphasic group had significantly fewer AOP
events over 48 hours (p=0.002) and a higher rate of extubation success (p=0.074) with adverse events being
similar between groups [71]. In a study of 19 preterm infants with AOP (mean gestational age of 30 weeks),
neonates received flow-synchronized NIPPV, conventional NIPPV, or NCPAP for four-hour treatment
sessions and then were crossed over [72]. All modes used a conventional nasal ventilator and synchronized
flow with a pneumotachograph. The median event rate per hour was 2.9 (flow-synchronized NIPPV), 6.1
(regular NIPPV), and 5.9 (NCPAP), and central apneas per hour were 2.4, 6.3, and 5.4, respectively. Flow-
synchronized NIPPV was more effective than conventional NIPPV or NCPAP in reducing desaturation,
bradycardia, and central apnea episodes [72]. In another study, nasal CPAP was associated with a higher rate
of failure than NPIVV in a study of 80 preterm infants [73].

Posture and positioning

Placing the neonate in the prone position has been shown to reduce AOP [74] and may also improve sleep in
very premature infants [75]. Since prone sleeping also increases the risk of sudden infant death syndrome,
care is to be taken that preterm infants sleep prone while in hospital but sleep supine after discharge [76]. A
meta-analysis of five studies including 114 preterm infants treated by body positioning for AOP found no
evidence that these body positioning changes decreased apnea or improved oxygen saturation [77].

Sensory stimulation
One of the oldest methods of treating AOP is still in common use: sensory stimulation. Sensory stimulation
relies on tactile, auditory, and olfactory stimuli to help prevent or reduce apnea [78]. It is thought that the
stimulation leads to excitatory neuronal activity in the brainstem, which, in turn, triggers respiratory drive
[78]. The drawback to sensory stimulation is that it can arouse a neonate from sleep or disrupt sleep. In a
study of olfactory stimulation, vanilla scent reduced AOP by 36% in 12/14 preterm infants with no side
effects, but this study was conducted only over 24 hours and longer-term results are not known [79].
Kinesthetic stimulation, such as the use of an oscillating mattress, was not found to be effective in reducing
AOP [80].

Stochastic resonance effects

Stochastic resonance therapy involves using noise to alter a biological system [81]. It had long been
speculated that stochastic vibro-tactile stimulation may help regulate breathing patterns in preterm infants
[82]. In a crossover study, special mattresses were equipped to offer preterm neonates with AOP
mechanosensory stimulation by means of subarousal-level vibrations [83]. A total of 36 infants (mean
gestational age of 30.5 weeks) were evaluated, and stochastic resonance treatment reduced apneic events by
50%, decreased oxygen desaturation, and reduced the intensity of bradycardic events by almost 20%. The
procedure was noninvasive and well tolerated [83].

Head-to-head studies
Head-to-head studies of different treatment modalities or dosing regimens can be helpful in guiding clinical
practice, but such studies are not frequent for AOP. A study comparing theophylline versus an oscillating
waterbed for treating AOP was conducted in 20 preterm infants and found no significant differences
between groups [84]. A meta-analysis of five clinical trials (n=108 total) comparing theophylline to caffeine
for treating AOP in preterm infants found no differences between groups in terms of early treatment failure
(one to three days), or later treatment failure (five to seven days) or the rate of apnea, but the caffeine
groups had fewer adverse events [85]. In one study evaluating theophylline compared to mask CPAP for
treating AOP, results were measured as a 50% reduction in apnea or the need to use an alternative treatment.
The study found that for every 2.4 infants treated with mask CPAP instead of theophylline, there was one
treatment failure. Thus, theophylline was more effective than mask CPAP for treating preterm infants with
AOP [86].

A randomized study of 240 preterm infants (≤34 weeks) with AOP grouped neonates into those who received
caffeine citrate (loading dose of 20 mg/kg followed by a daily maintenance dose of 5 mg/kg) and those who
received aminophylline (loading dose of 5 mg/kg with a maintenance dose of 1.5 mg/kg every 8 hours). The
aminophylline group had significantly fewer apneic spells after four to seven days of treatment (p=0.03), but
the apnea rate and isolated desaturations were similar in days 1-3 of treatment, days 4-7, and days 8-14.
Stays in the NICU were similar in both groups, and the mean heart rate was significantly faster in the
aminophylline group (p<0.001) and aminophylline patients were at a greater risk for tachycardia. Thus, it
appears that aminophylline is as effective as caffeine to prevent apneic spells in preterm infants with AOP,
but aminophylline may have effects on the heart rate [87]. Compared to theophylline (n=100), caffeine was
significantly more effective at reducing apnea events than theophylline over 21 days [88]. Results were

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 similar when caffeine treatment was compared to aminophylline (n=67) [89]. In a meta-analysis of studies
using theophylline (n=3 studies) and caffeine (n=3 studies) for AOP, these substances were effective in
reducing the number of apneic events and reduced the need and time for mechanical ventilation [90]. In a
meta-analysis of four trials (n=91 total) of preterm infants treated with either IV doxapram or
methylxanthine over 48 hours, results were similar between groups and no adverse events were reported
[91].

Preterm births are associated with higher morbidity and mortality rates compared to full-term births, but
earlier gestational ages are seen in clinical practice. Since the heritability of AOP is 87% among same-sex
twins, it is likely that AOP has a strong genetic component, which has not been entirely elucidated [92].
While AOP is often associated with an immature respiratory system, other factors such as infection,
encephalopathy, intracranial hemorrhage, metabolic imbalances, or even body temperature may also be
involved [2,93,94]. For many preterm infants, AOP resolves as the pulmonary system matures, but in other
babies, apnea may persist into childhood [93].

Future directions in the care of AOP likely mean more studies to provide better and more specific guidance,
but pharmacological innovation may be an important aspect. New agnostic respiratory stimulants in
development may stimulate respiratory drive regardless of the etiology of the apnea. Such drugs are being
considered for a variety of applications, including rescue from drug-induced respiratory distress, viral
respiratory distress, and altitude sickness. The preterm population poses special challenges as this is an
immature and highly vulnerable population at a particularly crucial stage of neurodevelopment. The role of
AOP as a contributor to preterm infant morbidity and mortality has yet to be elucidated; however, it is not
appropriate to relegate it to a benign condition simply because it tends to resolve as preterm infants mature.
Interventions such as caffeine citrate may be effective but can have adverse effects and have been implicated
in causing long-term damage to babies, while more conservative interventions such as prone posture,
kangaroo care, and sensory stimulation may not be adequately effective. There is an unmet need for a
treatment that is both effective and safe for this particular special population.

Conclusions
Premature delivery is associated with increased morbidity and mortality. Many preterm infants have AOP,
which tends to resolve as the neonate matures. Nevertheless, AOP may contribute to neonatal morbidity. A
variety of treatment modalities exist with limited expert consensus to guide care. Pharmacological
treatments, such as caffeine citrate and doxapram, are known to be effective but may be associated with side
effects. The long-term effects of drug therapy in preterm infants are only beginning to be studied.
Nonpharmacological treatments are often more conservative, safe, but less effective. Guidelines for
therapeutic interventions in this population are scarce and even caffeine - a frequently used treatment - has
no clear guidance in terms of dosing, when to start therapy, and when to discontinue it. New safe, effective,
and appropriate treatments are needed for this vulnerable population.

Additional Information
Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the
following: Payment/services info: All authors have declared that no financial support was received from
any organization for the submitted work. Financial relationships: All authors have declared that they have
no financial relationships at present or within the previous three years with any organizations that might
have an interest in the submitted work. Other relationships: Joseph Pergolizzi is a consultant/speaker,
owner, and researcher for Spirify, US World Meds, BDSI, Salix, Enalare, Scilex, Pfizer, Lilly, Teva, Regeneron,
Redhill, Grunenthal, and Neumentum.

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