AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Overview of the current state of knowledge

Our understanding of the anatomy, physiology, biochemistry, and molecular biology of neonatal breathing has increased in recent years.^{1, 2, 3, 4} For instance, emerging data are elucidating the genes involved in the embryonic development of central respiratory centers and their neural networks.⁵ The central respiratory generator is essential for fetal breathing movements. It appears early in pregnancy and importantly contributes to pulmonary development.⁶

In the fetus, breathing is intermittent and occurs during the low-voltage electrocortical state (analogous to rapid eye movement [REM] sleep) and becomes continuous immediately after birth. The regulatory neurologic mechanisms that cause the transition from intermittent fetal breathing to continuous neonatal breathing are incompletely appreciated.^{7, 8}

After birth, apnea of prematurity (AOP) is a major concern for caregivers in intensive care nurseries. The magnitude of this problem resulted in the National Institutes of Child Health and Human Development (NICHD) convening a workshop on AOP. Summary Proceedings from the Apnea-of-Prematurity Group have been published.⁹

The NICHD review group emphasized the following conclusions:

• No consensus has been reached regarding the definition, diagnosis, or treatment of AOP.
• Systematic research has not been conducted to investigate the value of different interventions for AOP.
• Available technology is not routinely used to document real-time events associated with apnea.
• The time required to demonstrate an improvement in AOP with a specific treatment has not been established.
• The observational period needed after therapy for AOP is unknown, and an appropriate duration of surveillance off therapy is needed to reasonably prevent acute life-threatening events.
• Important confounding conditions that influence the occurrence of AOP are poorly recognized and/or integrated into care.
• The relationship between gastroesophageal reflux (GER) and AOP requires additional investigation because current knowledge suggests an infrequent association.
• Improved characterization of the effects of AOP on neurodevelopment during infancy and childhood is needed.
• Other confounders associated with brain injury in preterm infants are difficult to separate from AOP as meaningful causes of abnormal child development.

The NICHD review group also made recommendations about what issues associated with AOP that need urgent attention, what research methods might be best for future studies, what outcomes are essential to our understanding of AOP, and what ethical principles should govern future investigations of AOP.

Given this discussion from the NICHD review group, the present article provides state-of-the-art information regarding what is and what is not known about AOP.

Definitions

Apnea and its classification

Apnea is defined as the cessation of breathing for more than 20 seconds or apnea or the cessation of breathing for less than 20 seconds if it is accompanied by bradycardia or oxygen (O₂) desaturation.^{10, 9}

• Bradycardia in a premature neonate is considered clinically significant when the heart rate slows by least 30 bpm from the resting heart rate.
• An O₂ saturation level of more than 85% is considered pathologic in this age group, as is a decrease in O₂ saturation should it persist for 5 seconds or longer.

These definitions represent clinically significant changes in apnea, bradycardia, and O₂ saturation changes and rarely occur in healthy preterm neonates older than 36 weeks after conception.

Apnea is classified as central, obstructive, or mixed.

• Central apnea is defined as the cessation of both airflow and respiratory effort (see Media file 1).
• Obstructive apnea is the cessation of airflow in the presence of continued respiratory effort.
• Mixed apnea contains elements of both central and obstructive apnea (see Media file 2)—either within the same apneic pause or at different times during a period of respiratory recording.

Apnea of infancy

Apnea of infancy (AOI) occurs when apnea persists in a neonate older than 37 weeks after conception. The physiologic aspects of AOP and AOI coincide, though further studies are needed to determine their exact relationship.

Periodic breathing

Periodic breathing is defined as periods of regular respiration for as long as 20 seconds followed by apneic periods of 10 seconds or less that occur at least 3 times in succession (see Media file 3). Periodic breathing may be observed for 2-6% of the breathing time in healthy term neonates and as much as 25% of the breathing time in preterm neonates. The occurrence of periodic breathing is directly proportional to the degree of prematurity.

Kelly and coworkers (1979) observed periodic breathing in 78% of neonates examined at 0-2 weeks of age.¹¹ The incidence substantially declined to 29% at the postconceptual ages of 39-52 weeks.

Periodic breathing typically does not occur in neonates during their first 2 days of life.

Periodic breathing most frequently occurs during active sleep, but it can also happen when neonates are awake or quietly sleeping. This pattern, commonly observed in patients at high altitudes, is eliminated with supplemental oxygenation and/or with the use of continuous positive airway pressure (CPAP). Because the prognosis is excellent and because the infant is not compromised, no treatment is usually required.

Pathophysiology

Central respiratory regulation

Immaturity and/or depression of the central respiratory drive to the muscles of respiration have been accepted as key factors in the pathogenesis of AOP.¹ Vulnerability of the ventral surface of the medulla and adjacent areas in the brainstem to inhibitory mechanisms is the likely explanation for why apneic episodes occur in prematurely born infants. This vulnerability involves diverse clinicopathologic events.^{12, 4} Inhibitory events that affect the central respiratory generator and initiate apnea include hypoxia, hyperthermia and adenosine secretion.¹³ Studies of preterm infants and in animals (especially genetically altered mice) have enhanced our understanding of the molecular and biochemical events leading to maturation of the central respiratory generator in preterm infants.^{2, 3, 14, 15}

Using noninvasive techniques, Henderson-Smart and coworkers (1983) documented that brainstem conduction times of auditory-evoked responses were longer in infants with apnea than in matched premature infants without apnea.¹⁶ This study elucidated apnea in preterm infants by indirectly showing that infants with apnea had greater-than-expected immaturity of brainstem function, which was based on postconceptional age. This finding supports the concept than an immature brainstem eventually develops control of breathing as dendritic spines and synaptic connections mature. An observation that emphasizes the importance of the central respiratory generator is the finding of increased apnea among preterm infants with bilirubin-encephalopathy diagnosed by using abnormal auditory brainstem-evoked responses.¹⁷

The absence of respiratory muscle activity during central apnea unequivocally implicates depression of respiratory center output. In support of this concept, Gauda and associates (1989) documented reduced electromyographic activity in the diaphragm during spontaneous obstructed inspiratory efforts.¹⁸ Such efforts characterize combined central and obstructive apnea.¹⁹ Therefore, episodes of both central and mixed apneic share an element of decreased respiratory center output to the respiratory muscles.

Sleep state and apnea

Apnea during infancy occurs most frequently during active or REM sleep.^{20, 21} Apnea occurs relatively infrequently during quiet sleep, when respiration is characteristically regular, with little breath-to-breath variation in tidal volume and respiratory rate. However, periodic breathing may predominantly occur during non-REM sleep. During active sleep, respiration is mostly paradoxical due to spinal motoneural inhibition of the activity of intercostal muscles.²²

In extremely preterm infants, the paucity of quiet sleep, together with an extremely compliant rib cage, makes paradoxical chest-wall movements almost a constant phenomenon. Paradoxical chest movement may predispose the baby to apnea by decreasing functional residual capacity (FRC) and limiting oxygenation.²³

Chemoreceptors and mechanoreceptors

Complex relationships exist between respiratory control; several sites of central chemosensitivity to carbon dioxide (CO₂) during sleep; and various neuromechanical factors originating in the lungs, chest wall, and upper airway that modify respiratory function during sleep.²⁴

Responses of chemoreceptors in preterm and term neonates were recently reviewed.^{25, 26, 27} The response to elevated CO₂ concentrations was blunted in prematurely born infants. This diminished response may partly be due to decreased central chemosensitivity or mechanical factors that prevent an adequate ventilatory response.^{28, 29}

The slope of the response curve for CO₂ is decreased for preterm infants who have apnea.³⁰ However, a cause-and-effect relationship between decreased CO₂ responsiveness and AOP has not been clearly established. Administration of CO₂ ameliorates periodic breathing, but inhalation of CO₂ is not a therapeutic option for human infants.

For many years, scientists have known that preterm infants respond to a decrease in inspired O₂ concentration with a transient increase in ventilatory response, followed by return to baseline or even depression of ventilation.³¹ This response to low O₂ in infants appears to result from initial stimulation of peripheral chemoreceptors then overriding depression of the respiratory center as a result of hypoxemia.³² Consistent with these findings is the observation that a progressive decrease in inspired O₂ concentrations causes a significant flattening of CO₂ responsiveness in preterm infants.³³

This unstable response to low inspired O₂ levels may play an important role in the origin of neonatal apnea. It offers a physiologic rationale for the decrease in incidence of apnea observed when a slightly increased concentration of inspired O₂ is administered to infants with apnea.³⁴

The Hering-Breuer reflex also plays an important role in modulating respiratory timing in human neonates. Pulmonary stretch receptors send an afferent neural input to brain and mediate the Hering-Breuer reflex by means of the vagus nerve. Thereafter, they inhibit inspiration, prolong expiration, or both, while increasing lung volume.²³ Active shortening of expiratory duration with decreased lung volume may provide a breathing strategy for preserving FRC in a neonate with a highly compliant chest wall.

Upper airway obstruction substantially contributes to apneic episodes in preterm infants, and upper airway muscles show preferential reflex activation in response to airway obstruction in infants.³⁵

Gerhardt and Bancalari compared the ability of preterm infants with and those without apnea to respond to end-expiratory airway occlusion.^{36, 30} Prolongation of the occluded inspiratory effort was significantly prolonged in the group without apnea. This finding suggested that this group had a relatively mature respiratory reflex response that improved their ability to respond to airway obstruction.

In premature infants, complex changes in pulmonary mechanics and ventilatory timing accompany apnea.³⁷ Before apnea occurs, total pulmonary resistance may increase in association with a decrease in tidal volume and prolongation of the expiratory time. Such changes have been noted before episodes of mixed, obstructive, and central apnea.

In 1982, Waggener and coworkers showed that a diminution in respiratory drive precedes apnea, a finding reminiscent of the cyclic alterations in respiratory drive.³⁸ After apnea resolves and respiration resumes, the respiratory drive in premature infants initially increases, possibly because of a cumulative effect of hypoxia and hypercapnia. Total pulmonary and supraglottic resistance also increases, perhaps in response to a decrease in lung volume and collapse of the upper airway when respiratory drive declines during the apnea.

Of note, within 2 or 3 breaths after apnea, pulmonary resistance and respiratory drive is restored to normal pre-apnea values in premature infants. Therefore, the neural systems that restore respiratory homeostasis appear to be capable of mounting an adequate response, even in premature infants with apnea.

Upper airway instability and muscles of the chest wall

Premature infants have pharyngeal or laryngeal obstruction during spontaneous apnea.

Thach (1983) proposed a model in which the negative luminal pressures generated during inspiration in the upper airway predispose a compliant pharynx to collapse.³⁹

Many muscles of the upper airway, especially the genioglossus muscles, have been widely implicated in mixed and obstructive apnea affecting both infants and adults. In 1988, Carlo, Martin, and Difiore compared the activity of the genioglossus muscles with that of the diaphragm in response to hypercapnic stimulation.⁴⁰ In preterm infants, genioglossus activation was delayed for about one minute after CO₂ rebreathing was begun, and it occurred only after a CO₂ threshold of approximately 45 mm Hg was reached.

In neonates inspiratory time is often modestly prolonged when end-expiratory airway occlusion prevents lung inflation. As indicated earlier, this effect is a manifestation of the Hering-Breuer reflex.

Studies in animals demonstrated that this vagally mediated inhibition of normal lung inflation has more influence on the upper airway muscles than on the diaphragm.⁴¹

Upper airway reflexes

The upper airway contains many sensory nerve endings that may respond to variety of chemical and mechanical stimuli. Sensory input from these upper airway receptors travels to the CNS by means of cranial nerves V, VI, IX, X, XI, and XII. They may strongly affect respiratory rate and rhythm, heart rate, and vascular resistance.⁴²

The chemoreceptor drive may augment the ability of the upper airway muscles to respond to increasing negative pressure, whereas input from pulmonary stretch receptors inhibits it.⁴³

Swallowing during the respiratory pause is unique to apnea and does not occur during periodic breathing.⁴⁴

Effects of adenosine

Adenosine and its analogs cause respiratory depression.⁴⁵ Adenosine antagonism is proposed as a mechanism to explain the therapeutic effect of aminophylline.⁴⁶

Gastroesophageal reflux

GER and apnea are common in preterm infants. Because they often coexist, a lively and ongoing debate persists among healthcare professionals about the role of GER in AOP.

An extensive literature review was undertaken to justify arguments about the role of GER in AOP. Monitoring studies demonstrated that, when a relationship between reflux and apnea is observed, apnea may precede rather than follow reflux.^{47, 48} During an apneic episode, loss of respiratory neural output may be accompanied by a decrease in lower esophageal tone, and GER occurs.

This phenomenon is supported by data from a newborn piglet model, which showed that hypoxia and apnea were accompanied by a reduction in lower esophageal sphincter pressure, which was a predisposing factor for GER.⁴⁹

GER and apnea are also discussed in Differentials and in Controversies related to AOP under Special Concerns.

Frequency

United States

Although not always apparent, AOP is the most common problem in premature neonates.⁹ Approximately 70% of babies born before 34 weeks of gestation have clinically significant apnea, bradycardia, or O₂ desaturation during their hospital stay. The more immature the infant, the higher his or her risk of AOP. Apnea may occur during the postnatal period in 25% of neonates who weighed less than 2500 g at birth and in 84% of neonates who weigh less than 1000 g.

Carlo (1982) and Barrington (1990) showed that apnea may begin on the first day of life in neonates without respiratory distress syndrome.^{50, 51} However, AOP is always a diagnosis of exclusion. Many diseases manifest with apnea on the day of birth; examples are intrapartum magnesium exposure, systemic infections or the fetal inflammatory response syndrome, pneumonia, intracranial pathology, seizures, hypoglycemia, and other metabolic disturbances.

Approximately 50% or more of surviving infants who weighed less than 1500 g at birth have episodes of apnea that must be managed with pharmacologic intervention or ventilatory support. Mixed apnea accounts for about 50% of all cases of apnea in premature neonates; about 40% are central apneas, and 10% are obstructive apneas.⁵² These percentages vary in different reports. In 50% of all apneic episodes, an obstructive component precedes or follows central apnea, which leads to mixed apnea.

International

To the authors' knowledge, no investigators have compared the incidence of AOP in the United States with those of other countries.

Mortality/Morbidity

Butcher-Puech and coworkers (1985) found that infants in whom obstructive apnea exceeded 20 seconds had an increased incidence of intraventricular hemorrhage, hydrocephalus, prolonged mechanical ventilation, and abnormal neurologic development after their first year of life.⁵³

In 1985, Perlman and Volpe described a decrease in the cerebral blood flow velocity that accompanies severe bradycardia (heart rate <80 bpm).⁵⁴ Infants with clinically significant AOP do not perform as well as prematurely born infants without recurrent apneas during neurodevelopmental follow-up testing.^{55, 56}

Race

The authors know of no systematic, prospective clinical study that has been conducted to evaluate the role of a person's race or ethnic background on the incidence of AOP.

Sex

To the authors' awareness, no systematic, prospective clinical study has been performed to evaluate the role of a person's sex on the incidence of AOP.

Age

A young gestational age at birth is associated with an increased incidence of AOP. The age at which AOP resolves depends on several factors. The mean time for severe AOP to resolve is approximately 43 weeks after conception, but a prolonged duration of risk is not uncommon. ¹⁰

In one report, about 6-22% of babies with a very low birth weight had apnea at term.⁵⁷ Approximately 91% of premature neonates had apnea of longer than 12 seconds at the time of hospital discharge. Of these babies, 31% also had bradycardia, and 6.5% required prolonged hospitalization because of the severity of their apnea and bradycardia.

These findings show that AOP does not resolve at term in many low-birth-weight infants and that it may persist for some time after hospital discharge.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Initial identification and assessment of apnea

The bedside caregivers—namely, the nurse in the neonatal intensive care unit (NICU) the respiratory care practitioner—identify the problem for the physician. Apnea should be distinguished from periodic breathing and documented. Use of a cardiorespiratory monitor is essential for identifying apnea of prematurity (AOP) and for monitoring the patient's blood pressure. Events associated with apnea, such as bradycardia and cyanosis, must be quantified. For bradycardia, the magnitude of reduction in heart rate from baseline and the duration of the event should be recorded. The presence and duration of central cyanosis should also be noted.

Pulse oximetry may be helpful for measuring the severity and duration of central O₂ desaturation. Caregivers should be aware of the problems associated with the use of pulse oximetry to evaluate O₂ saturation.⁵⁸

When apnea is observed, its duration must be established. Cardiorespiratory monitors can be used to quantify the duration. Caregivers should attempt to define the type and severity of the patient's apnea. The type of apnea is identified as central, obstructive, or mixed. A nasal thermistor may be needed in conjunction with pneumography to differentiate the type of apnea.

Classification of the severity of apnea

Criteria to classify the severity of apnea have not been well developed in clinical studies.

The University of Washington published indications for different treatments based on the severity of AOP.⁵⁹ This classification for AOP uses the terms spontaneous, mild, moderate, or severe.

• A spontaneous event might be defined by apnea with minimal physiologic changes, an event of brief duration, one associated with self-recovery, or an event only occurring once or twice in 24 hours.
• Mild or moderate events involve apnea, bradycardia, and/or O₂ desaturation of intermediate magnitude. These events require therapeutic interventions less rigorous than those needed for severe episodes.
• A severe event entails prolonged apnea associated with clinically significant and persistent bradycardia, as well as O₂ desaturation (ie, central cyanosis). A severe event requires vigorous stimulation, administration of an increased concentration of inspired O₂, and/or assisted ventilation (eg, bag-mask ventilation).

Clinical centers must develop the classification system they wish to use to measure the severity of apnea. Factors often used to judge the need for future interventions include these:

• Severity of the apnea
• Number of events per day
• Magnitude of the intervention required to alleviate the event

The therapeutic approach used in most NICUs involves a progression from tactile stimulation to methylxanthine therapy and then some form of assisted breathing (eg, nasal continuous airway pressure or assisted ventilation).

Exclusion of other causes of apnea

Before a diagnosis of AOP is made, other causes of apnea in neonates must be excluded (see Differentials).

All forms of apnea may be difficult to detect visually, though obstructive apnea is usually most obvious to a trained observer.

Cardiorespiratory monitoring and pulse oximetry have improved bedside detection of AOP.⁶⁰ Caregivers should familiarize themselves with the advantages and disadvantages of cardiorespiratory monitoring and pulse oximetry in neonates.

Published findings show that even highly trained observers miss more than 50% of AOP episodes.

Precise diagnosis of AOP requires multichannel recordings, which are most commonly measurements of nasal airflow, thoracic impedance, heart rate, and O₂ saturation. Expanded testing may include electroencephalography and/or use of an esophageal pH probe with a high thoracic Clark electrode.

Hydrochloric acid may be added to the feedings to increase the gastric concentration of hydrogen ions.

Physical

Physical examination should include observation of the infant's breathing patterns while he or she is asleep and awake. The prone or supine sleeping positions and other lying postures may be important during this clinical observation.

Important to the assessment of neonatal apnea is the identification of airway abnormalities (eg, choanal obstruction, anomalies of the palate, jaw deformities, neck masses) and conditions in distant organs that influence breathing (eg, brain hemorrhages, seizures, pulmonary disorders, congenital heart disease).

Findings in the head and neck and other obvious major and minor anomalies identified may suggest chromosomal abnormalities or a malformation syndrome. Appropriate work-up must then follow.

Physical examination includes the elements described below:

• Monitor the baby's cardiac, neurologic, and respiratory status.
• Observe the infant for any signs of breathing difficulty, desaturation, or bradycardia during feeding.
• Reflex effects of apnea include characteristic changes in heart rate, blood pressure, and pulse pressure.
• • Bradycardia may begin within 1.5-2 seconds of the onset of apnea.
  • Apneic episodes associated with bradycardia are characterized by decreases in heart rate of more than 30% below baseline rates.
  • This reflex bradycardia is secondary to hypoxic stimulation of the carotid body chemoreceptor or a direct effect of hypoxia on the heart.
  • Transient bradycardias also occur relatively often in very low birth weight infants who also have AOP.⁶¹ These events are not associated with apnea, but they are presumed to be mediated by an increase in vagal tone.
• Pulse oximetry may reveal clinically significant desaturation. However, pulse oximeters typically have a delay in recording the event.

Causes

The physiology related to AOP is reviewed in Pathophysiology. Aspects of causation are briefly reemphasized here.

A premature neonate in whom all other causes of apnea have been excluded may be considered to have AOP. Although the etiology of AOP is not fully understood, several mechanisms have been proposed to explain this condition, including those described below.

• AOP is the clinical phenomenon associated with incompletely organized and interconnected respiratory neurons in the brainstem and their response to a multitude of afferent stimuli. Therefore, the abnormal control of breathing seen in AOP represents neuronal immaturity of the brain. (For an excellent review of this topic, see the article by Darnall et al from 2006.¹)
• In a premature neonate, protective respiratory reflex activity is decreased, and Hering-Breuer reflex activity is increased.
• Dopaminergic receptors may have a role in inhibiting the responses of peripheral chemoreceptor and hypoxia-elicited central neural mechanisms. Evidence from studies of neonatal animals indicates that endogenous endorphin production may depress the central respiratory drive. Although endogenous opiates may modulate the ventilatory response to hypoxia in newborn animals, a competitive opiate receptor antagonist (naloxone) has no therapeutic role in AOP.
• Negative luminal pressures are generated during inspiration, and the compliant pharynx of the premature neonate is predisposed to collapse. Failure of genioglossus activation is most widely implicated in mixed and obstructive apnea among infants and adults.
• The ability of medullary chemoreceptors to sense elevated CO₂ levels is impaired. Therefore, an absent, small, or delayed response of the upper airway muscles to hypercapnia might cause upper airway instability when a linear increase in chest-wall activity also occurs. This impairment may predispose the infant to obstructed inspiration after a period of central apnea.
• Another important factor to consider is the excitation of chemoreceptors in the larynx due to acid reflux. Laryngeal receptors send afferent fibers to the medulla and can elicit apnea when stimulated.
• Swallowing during a respiratory pause is unique to apnea and does not occur during periodic breathing. Accumulation of saliva in the pharynx could hypothetically prolong apnea by means of a chemoreflex mechanism.
• Some practicing neonatologists believe that GER is associated with recurrent apnea and have, therefore, treated preterm neonates with antacid and/or antireflux drugs. However, this assumption has been vigorously challenged.⁹
• • In 1992, Booth suggested that apneic episodes were reduced when esophagitis resolved because apnea clinically improved 1 or 2 days after the start of antireflux therapy. Therefore, neonatologists have treated xanthine-resistant apnea with H2 blockers, metoclopramide, thickened formula, and/or upright positioning during feeding.
  • No controlled trials have demonstrated that antireflux drugs are effective in preventing apnea.
  • Findings from several studies have not demonstrated a relationship between episodes of apnea and episodes of acid reflux into the esophagus (see Pathophysiology and Differentials).
• Menon, Schefft, and Thach (1985) observed that regurgitation of formula into the pharynx after feeding was associated with an increased incidence of apnea in premature infants.⁶² As stated above, gastric fluids can possibly activate laryngeal chemoreflexes, leading to apnea.
• Although well-designed, controlled clinical trials are few, scientists often say that aminophylline exacerbates reflux in infants with apnea. The relationship of GER to methylxanthines is based on the literature about asthma, and limited studies in neonatal only suggest its occurrence.⁶³ Some authors have not related the use of methylxanthine to severe GER disease.⁶⁴

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Apnea of prematurity (AOP) is a diagnosis of exclusion. For many diseases in preterm infants, apnea is a presenting symptom. The causes of these diseases are different when the differential diagnosis occurs shortly after birth compared with later in the patient's hospital stay. Other etiologies must be sought before drug and/or ventilatory therapies for AOP are started.

Conditions associated with apnea

Shortly after birth, apnea can be a manifestation of several types of conditions:

• Respiratory distress syndrome and other pulmonary conditions
• Infections (eg, congenital pneumonia, bacteremia, meningitis, fetal or neonatal inflammatory response syndrome
• Hypoglycemia and other metabolic diseases
• CNS pathology (eg, trauma, intracranial hemorrhage, anoxia and/or ischemia, stroke)

The aforementioned brain insults may be noticed because patients may have seizures and/or associated apnea.^{65, 54} Some of the diseases cited above also occur relatively late during the hospitalization of prematurely born infants, but the signs and symptoms may or may not include apnea.

Intraventricular hemorrhage and posthemorrhagic hydrocephalus without seizures increases the frequency of apnea in preterm infants.^{53, 66}

Other conditions associated with apnea in preterm infants during hospitalization

Other conditions associated with apnea in preterm infants during their hospitalization are summarized below.

Nosocomial bacterial or fungal infection

Apnea, bradycardia, and desaturations are presenting symptoms of nosocomial infections caused by bacteria and fungi or viral agents.^{67, 68}

In a study of 9 infants in an NICU who had respiratory syncytial viral infection, 8 had apnea as a manifestation of disease.⁶⁹

Apnea is also common in preterm infants with Ureaplasma urealyticum infection.⁷⁰

Necrotizing enterocolitis

In addition, apnea is one of several signs and symptoms associated with the onset of necrotizing enterocolitis.⁷¹

Exposure to magnesium

The administration of magnesium to prevent seizures in preeclampsia and tocolysis of preterm labor has been associated with hypoventilation, apnea, and other adverse effects in preterm infants.⁷² Hypermagnesemia during parenteral nutrition has also been a cause of apnea.⁷³

Anemia

Disagreement exists regarding the role of clinically significant anemia in the development of apnea among convalescing preterm infants. Westkamp and colleagues (2002) reported that blood transfusions lowered heart and respiratory rates but had little effect on AOP.⁷⁴ Bell and associates (2005) conversely found that liberal versus restrictive blood transfusion significantly reduced apnea.⁷⁵ The recent interest in the adverse neurodevelopmental outcomes observed in preterm infants with anemia and low iron status emphasizes neonatology-related awareness of the problem.⁷⁶

Surgery

Postoperative apnea occurs in preterm infants, particularly those whose intraoperative pain relief involved general anesthesia.^{77, 78}

Additional research is required to determine whether spinal anesthesia, different analgesic agents, or caffeine can mitigate morbidity associated with apnea after surgery in prematurely born infants.^{79, 80}

Immunization

Apnea transiently increases or recurs in hospitalized preterm infants after immunization. The increase in apnea has been attributed to the whole-cell pertussis component.⁸¹ Investigators have observed reduced morbidity with newer vaccines that contain acellular pertussis.^{82, 83} Some recent reports still identified clinically significant apnea and other adverse events.^{84, 85}

Gastroesophageal reflux

As stated earlier, controversy exists regarding the role of GER as a causative factor in AOP.⁹ One perspective is that the 2 conditions are related.^{63, 86} Laryngeal edema identified during fiberoptic laryngeal endoscopy has been associated with GER, and antireflux surgery has dramatically reduced apnea in preterm infants at highest risk.^{87, 88, 89}

Past and recent research failed to reveal a temporal relationship between GER and AOP.^{47, 90, 91, 92, 48}

Therefore, the NICHD Review Group on Apnea of Prematurity has called for additional investigations with rigorous research designs.⁹

Skin-to-skin contact, or kangaroo care

Skin-to-skin contact, or kangaroo care, for preterm infants has been associated with an increased occurrence of apnea, bradycardia, and desaturation; this appears to be unrelated to hyperthermia.^{93, 94} The observation suggests that obstructive events may occur during skin-to-skin contact. These findings call attention to the importance of environmental hyperthermia as a cause of apnea in preterm infants.^{95, 96}

Recent investigators found no adverse events during kangaroo care.⁹⁷

The disparity among the reported studies may be related to the specific practice of skin-to-skin care in a particular NICU or the validity of monitoring during skin-to-skin contact.⁹⁸

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• A CBC and cultures of blood, urine, and spinal fluid are necessary if a serious bacterial or fungal infection is suspected.
• • Appropriate viral cultures or collection of body fluid for polymerase chain reaction (PCR) analyses are performed if a viral pathogen was suspected.
  • A C-reactive protein level measured at 36-48 hours after birth may be useful for excluding infection (see Maternal Chorioamnionitis).
• Tests for ammonia, amino acid profiles in blood or urine, and organic acid levels in blood and urine are essential if a metabolic disorder is suspected.
• • Testing of pyruvate and lactate concentrations in the blood and CSF may be diagnostically helpful when inborn errors of metabolism are among the differential diagnosis.
  • Ketones in the urine may indicate organic acidemia.
• Serum electrolyte, calcium, magnesium, and glucose levels can be useful for diagnosing a recent stressful condition, a metabolic process, or chronic hypoventilation.
• Analysis of the stool for different toxins related to botulism may reveal a cause in an infant with apnea, constipation, clinically significant hypotonia, difficulty swallowing or crying, or absent eye movements.⁹⁹

Imaging Studies

• Chest radiography and/or a nuclear medicine milk scanning can be helpful if the child has persistent but unexplained lower airway symptoms (eg, wheezing and/or repetitive regurgitation after feeding, rumination).¹⁰⁰
• In cases of airway obstruction, stridor, or unexplained pathologic obstructive apnea, helpful upper airway evaluations include lateral neck radiography, head and neck 3-dimensional tomography, and otolaryngologic evaluation (eg, fiberoptic assessment of the larynx through the nose during spontaneous breathing).¹⁰¹
• Imaging studies of intracranial pathology are necessary when hemorrhage is suspected or when findings include dysmorphic facial and somatic features, abnormal neurologic results, disordered hair whorls, and/or mental status changes.
• A barium swallow study is useful if the infant has signs of swallowing dysfunction or anatomic anomalies (eg, an esophageal web, tracheoesophageal fistula).
• A gastric-emptying study and abdominal sonography are useful in patients whose clinical picture includes a generalized GI motility disorder or pyloric stenosis.

Other Tests

• Obtain a polysomnographic, or continuous multichannel, recording to measure the chest-wall movement, nasal and/or oral airflow (or change in air temperature), O₂ saturation, and heart rate trend. A 2-channel pneumogram that is used to measure only chest-wall excursion and trends in heart rate provides insufficient information. The following results are diagnostic:
• • Central apnea - Absence of nasal airflow and wall movement
  • Obstructive apnea - Lack of airflow despite chest-wall movement
  • Mixed apnea - Combined results of central and obstructive apnea
• If GER is suspected, note the intraesophageal pH as part of the multichannel recording.
• Consider obtaining an electroencephalogram (EEG) in infants who have suspected apneic seizures or who have persistent pathologic central apnea without an identifiable cause.
• Obtain an echocardiogram and consult a cardiologist if the patient's history or physical findings (eg, feeding difficulties, heart murmur, cyanosis) suggest cardiac disease.
• ECG results are useful in patients with severe unexplained tachycardia or bradycardia. Abnormalities in cardiac conduction (eg, prolonged-QT syndrome) are infrequent but important causes of apnea during infancy.
• Evaluate patients for unilateral choanal stenosis and choanal atresia by passing a small-diameter feeding tube through both nares. Three-dimensional tomography is probably the method of choice for definitively diagnosing upper airway malformations.

Procedures

• Several studies may reveal diagnostic findings in selected infants. These include fiberoptic examination of the larynx through the nose during spontaneous breathing, direct laryngoscopy, and bronchoscopy (which is usually performed with the patient under anesthesia).
• Emergency or scheduled tracheostomy may be used to manage severe airway obstruction caused by a number of conditions.
• • Tracheostomy might occur after the airway is stabilized by using endotracheal intubation.
  • Jaw-distraction surgery was recently used to avoid tracheostomy in neonatal conditions (eg, Robin sequence) that involve severe micrognathia as a component of malformation.^{102, 103}

TREATMENT

Section 6 of 11  

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Medical Care

Goal of medical therapy

The principal goals of treating neonatal apnea are to address its cause and to provide appropriate medical management. For example, bacterial sepsis that causes apnea is treated with antibiotics and other supportive therapies, whereas seizures require anticonvulsants. The use of assisted ventilation to manage severe apnea, bradycardia, and O₂ desaturation can be life saving, and assisted ventilation and O₂ may be required to prevent injury to the CNS. The primary disease process must be identified and treated.

When all causes of apnea other than prematurity are excluded during the diagnostic work-up, AOP is the presumptive etiology. Caregivers must decide which intervention is appropriate given the severity of the patient's apnea, bradycardia, and O₂ desaturation. For example, an infant who has an inadequate response to tactile stimulation and O₂ administration and who requires airway suctioning and bag-mask ventilation to recover suggests a serious problem.

A useful strategy is to have a protocol that defines escalating treatments for apnea of prematurity (AOP). Depending on the frequency and the severity of apnea, bradycardia, and O₂ desaturation, common treatments include stimulation (usually tactile), methylxanthine, or assisted ventilation (eg, nasal CPAP, mechanical ventilation).¹⁰⁴

Stimulation

Tactile stimulation is usually sufficient to terminate an isolated apneic event caused by central apnea. Stimulation akin to that used during neonatal resuscitation (eg, a gentle tap to the sole of the foot or rubbing the back) is often enough to terminate a central apnea. However, other measures may be required to treat an obstructive event or an episode of airway obstruction followed by central apnea.

If the upper airway is obstructed, repositioning the patient's head and neck or gently elevating the infant's jaw may alleviate the occlusion.

Use of a high-flow nasal cannula may open the airway enough to reduce obstructive apnea. As an alternative, high-flow oxygenation through a nasal cannula may be an agonist for receptors in the airway. Nasal irritation due to the cannula may prevent central apnea by causing arousal. Additional research is needed to ascertain the usefulness of high-flow nasal cannulas for treating AOP.

Administration of O₂

Supplemental oxygenation or bag-mask ventilation is indicated in infants with signs of bradycardia or desaturation.

Medical treatment is indicated when apneic episodes number 6-10 or more per day; when the infant does not respond to tactile stimulation; or when an event requires O₂ and/or bag-mask ventilation to terminate apnea, bradycardia, and/or desaturation.

Avoid hyperoxia, which may increase the risk of retinopathy of prematurity (ROP).

Use of CPAP

CPAP has been used to treat apnea in preterm neonates, and it is indicated when the infant continues to have apneic episodes despite achieving a therapeutic serum level of methylxanthine.

CPAP is delivered with nasal prongs, a nasal mask, or a face mask with 3-6 cm of water pressure.

CPAP effectively treats mixed and obstructive apnea, but it has little or no effect on central apnea. This limitation suggests that CPAP may reduce the frequency of apnea by means of several mechanisms, including stabilization of the partial pressure of O₂ (PaO₂) by increasing the FRC, by altering the influence of stretch receptors on respiratory timing, or by splinting the upper airway in an open position.

MEDICATION

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Methylxanthines

Methylxanthines may help reduce the incidence of events in a neonate with central apnea, though apnea in 15-20% of infants does not respond to methylxanthines.

Questions have been raised regarding short- and long-term adverse effects in preterm infants.¹⁰⁵ The relationship of methylxanthine therapy to neurodevelopmental outcomes over time is especially of concern. For this reason, a clinical trial related to the safety of caffeine in preterm infants with apnea of prematurity (AOP) is in progress.¹⁰⁶

For the purpose of this review, pharmacotherapy is based on the 2006 NeoFax.¹⁰⁴ This is the source for information regarding the administration, adverse effects, and interactions of methylxanthines (eg, drug and solution compatibility).

Caffeine

Caffeine is the preferred drug for treating AOP.⁸⁰ Caffeine is also the most acceptable prophylactic agent to facilitate successful extubation in preterm infants.¹⁰⁷ Caffeine therapy may reduce the rate of bronchopulmonary dysplasia in very low-birth-weight infants.¹⁰⁸

In addition, caffeine has a therapeutic margin wider than that of other methylxanthines, such as theophylline. Therefore, an overdose is less likely to occur with caffeine than with other drugs in its class.

Aminophylline

Aminophylline is the alternative methylxanthine. Aminophylline may be preferred when the physician wants to enhance contractility in the thoracic musculature or if the infant might benefit from the bronchodilator properties of aminophylline.^{109, 110} This latter effect may be desired in infants with bronchopulmonary dysplasia.

One concern is that aminophylline may decrease cerebral blood flow.^{111, 112, 113, 114, 115}

Early reports in the literature also indicate a concern about the role that aminophylline may play in the occurrence or severity of necrotizing enterocolitis.^{116, 117, 118}

Doxapram

Doxapram is excluded as a therapy for AOP because it is associated with reduced cerebral blood flow.^{119, 120} Use of doxapram was not strongly recommended in a Cochrane Review.¹²¹ Doxapram should be reserved for infants in whom appropriate methylxanthine therapy and CPAP fail to control severe apneic events. If the caregiver wishes to use this agent, they should consult other resources regarding its administration.

Home monitoring

Home monitoring after discharge is always necessary for infants whose apneic episodes continue despite the administration of methylxanthine. Infants undergoing methylxanthine therapy should rarely be sent home without a monitor because apnea may recur when they outgrow their therapeutic level.

Some families cannot manage monitoring in the home. In these cases, caffeine may be the only possible therapy.

For more information about follow-up care, see Follow-up.

Drug Category: Methylxanthines

Aminophylline appears to stimulate skeletal and diaphragmatic muscle contraction, increase the sensitivity of the ventilatory center to CO₂, and stimulate the central respiratory drive.

Aminophylline, theophylline, and caffeine act as nonspecific inhibitors of adenosine A1 and adenosine A2a receptors.¹⁰⁵ It is this last effect that raises concerns about the safety of methylxanthine therapy in preterm infants.

Drug Name	Caffeine citrate (Cafcit)
Description	Indications include AOP (eg, apnea after extubation from assisted ventilation, apnea after general anesthesia). Therapeutic index more favorable than that of aminophylline. Increases output of respiratory center, sensitivity of chemoreceptor to CO2, smooth muscle relaxation, and cardiac output. Serum half-life 40-230 h, which declines until 60-wk postmenstrual age.
Pediatric Dose	Loading dose: 20-40 mg/kg PO or IV over 30 min (equivalent to 10-20 mg/kg caffeine base) Maintenance dose: 5-8 mg/kg PO qd or slow IV bolus starting 24 h after loading dose (equivalent to 2.5-4 mg/kg caffeine base) Therapeutic trough serum concentrations 5-25 mcg/mL; measure trough levels 5 d after start of therapy; serum concentration >40-50 mcg/mL is toxic
Contraindications	Documented hypersensitivity; products containing sodium benzoate
Interactions	Antagonizes actions of adenosine; may reduce clearance of theophylline by 25% and cause additive pharmacologic effects (decrease dose); additive positive inotropic and chronotropic effects may occur with beta-adrenergic agonists; cimetidine and fluconazole decrease clearance, increasing serum levels; phenytoin induces hepatic metabolism, decreasing half-life and increasing clearance; increases metabolism of phenobarbital and increases own metabolism Incompatible with acyclovir, furosemide, lorazepam, oxacillin, and nitroglycerin Solution compatible with 5% or 10% dextrose in water and normal saline Terminal injection site compatible with dextrose and amino acid solutions, lipid emulsions, calcium gluconate, cefotaxime, cimetidine, clindamycin, dexamethasone, dobutamine, dopamine, epinephrine, fentanyl, gentamicin, heparin (<1 U/mL), isoproterenol, lidocaine, morphine, nitroprusside, pancuronium, penicillin G, phenobarbital, sodium bicarbonate, and vancomycin
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	May increase O2 consumption and decrease weight gain; do not administer dose if heart rate persistently >180 bpm; functional cardiac symptoms (eg, extrasystoles) possible; restlessness and vomiting can be signs of toxicity; cholestatic hepatitis may prolong serum half-life

FOLLOW-UP

Section 8 of 11  

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Further Inpatient Care

Apnea-free interval before discharge

Most neonatologists agree that babies should be apnea-free for 2-10 days before discharge. However, the interval between the last apneic event and a safe time for discharge is not clearly established. The minimum apnea-free period is debated among clinicians. Darnall et al (1997) concluded that otherwise healthy preterm neonates continue to have periods of apnea separated by as many as 8 days before the last episode of apnea before discharge.¹²² Infants with long intervals between apneic event often have risk factors other than apnea of prematurity (AOP).

Home monitoring

Home monitoring after discharge is necessary for infants whose apneic episodes continue despite the administration of methylxanthine. Infants undergoing methylxanthine therapy rarely are sent home without a monitor because apnea may recur after they outgrow their therapeutic level. Without a monitor, caregivers may not know when apnea reappears.

Some families cannot manage monitoring in the home. In these cases, the administration of caffeine may be the only possible therapy. Infants in this situation need frequent follow-up visits, and they should be readmitted for further evaluation when their blood levels approach the subtherapeutic range.

Further Outpatient Care

Home monitoring

Various agencies and organizations have stated that home monitoring cannot prevent sudden infant death syndrome (SIDS), also called crib death or cot death, in preterm infants who have AOP during their hospitalization.^{10, 9}

Indications for home monitoring

Home monitoring may be indicated in the situations described below.

• Historical evidence suggests the occurrence of clinically significant apnea or an apparent life-threatening event (ALTE).
• Recording monitoring or multichannel evaluation documents apnea.
• The patient has GER with apnea.
• A sibling or twin of the patient died from SIDS or another postneonatal cause of death (see Special Concerns).

The National Institutes of Health (NIH) consensus conference recommends monitoring for the siblings of infants with SIDS, but only after 2 SIDS-related deaths occur in a family. Physicians often begin monitoring after one sibling dies from SIDS; this practice may be related to a fear of litigation should another child in the family die from SIDS. Siblings of patients who died from SIDS are routinely monitored until one month past the patient's age at death.

Monitoring is not indicated to prevent SIDS in infants older than one year, though proponents believe that such monitoring reduces anxiety in the parents of high-risk infants. Opponents of monitoring cite a lack of evidence to show that monitoring reduces the rate of SIDS. They argue that monitors intrude on the family's life and that they are poorly tolerated by the family.¹⁰

Types of monitors

Several types of cardiorespiratory monitors are available for home use in the United States. The most common type combines impedance pneumography with an assessment of the patient's mean heart rate. The most notable drawback of impedance monitors is their inability to detect obstructive apnea. Newer monitors can minimize false alarms caused by motion artifact.

Standard home monitors detect respiratory signals and heart rates. Electrodes are placed directly on the infant's chest or inside an adjustable belt secured around his or her chest.

Monitoring units should be capable of recording cardiac and respiratory data because this information can help the physician in evaluating the need to stop medication or monitoring. These devices also record compliance with monitor use. The event recorder contains a computer chip that continuously records respiratory and cardiac signals. Normal signals are erased, but any event that deviates from preset parameters activates the monitor to save records of that event, as well as data 15-75 before and 15-75 seconds it. Additional channels are available to record pulse oximetry readings, nasal airflow, and body position (eg, prone vs supine). The records are downloaded within 24 hours after a parent reports an event or after excessive alarms occur.

Many units now have computer modems that instantly transmit data to the physician's office for evaluation. These easily installed devices are especially useful for families who have had problems with events or alarms.

Some devices, such as pulse oximeters, piezo belts, and pressure capsules, have been impractical to use or have had limited applications. Newer technologies and software programs may soon make such oximeters and similar devices more practical than they once were.

All monitoring devices are associated with false alarms, which are alerts without in the absent of a true cardiorespiratory event. False alarms worry parents. If they happen often, they may discourage use of the monitor. Excessive false alarms can usually be minimized by adjusting the placement of the electrodes and by educating the parents.

Details of monitoring depend on the frequency of events observed during neonatal hospitalization, the size and stability of the infant at the time of discharge, and the degree of parental anxiety.

Follow-up of home monitoring and patient education

Careful follow-up is needed with all cases of home monitoring in prematurely born neonates. Physicians who have limited experience with home monitoring or who cannot interpret the downloaded recordings should seek assistance from a center or program with expertise in these areas.

The most important issue with monitoring is that Neonatal Resuscitation Program (NRP) instructors should educate parents, guardians, and other caregivers about neonatal resuscitation by using a mannequin before their child is discharged from the NICU.

Parents should also be educated about prenatal and postnatal factors associated with an increased risk of SIDS, namely, the following:^{123, 26}

• Prenatal and postnatal tobacco use
• Opiate abuse during pregnancy
• Baby's prone sleeping position
• Pacifier use
• Use of soft bedding
• Shared sleeping with children and adults
• Illnesses in infants with bronchopulmonary dysplasia
• Genetic factors

Parents must also be aware that postural skull deformities have occurred after the AAP offered positioning recommendations in its Back to Sleep campaign.¹²⁴ Prematurely born infants are probably at increased risk. Ways to avoid or minimize skull deformities should be discussed with parents.

Parents of infants with home monitors must have a clearly designated person who they can contact on a regular basis and during emergencies. Many programs or centers provide 24-hour assistance for families of children with home monitors.

The mean duration of home monitoring for prematurely born neonates is often more than 6 weeks. Extended monitoring is reserved for infants whose recordings show notable cardiorespiratory abnormalities. Monitoring beyond age 1 year is uncommon. Most often, children who require such monitoring have other conditions that require the use of additional technology. An example is an infant with bronchopulmonary dysplasia who requires mechanical ventilation at home.

For infants who require therapy with a methylxanthine, drug therapy is typically stopped after 8 weeks without true events, but monitoring is continued for an additional 4 weeks.^{125, 126} If no events are noted in this period, monitoring can be discontinued. These recommendations regarding discontinuing methylxanthines or home monitoring are not based on data from controlled studies; these investigations are badly needed.

Complications

Infants born prematurely are at increased risk for apnea and bradycardia after undergoing general anesthesia or sedation with ketamine, regardless of their history of apnea. Because of this increased risk, defer elective surgery, if possible, until approximately 52-60 weeks after conception to allow the infant's respiratory control mechanism to mature.

Prognosis

Regarding the natural history of apnea in infants born prematurely, the frequencies of all types of apnea gradually decreases during the first months of postnatal life. However, in some infants, apnea may persist until the age of 44 weeks after conception.

Patient Education

• Family members and others involved in the care of an infant with AOP should be well trained in cardiopulmonary resuscitation (CPR).
• Many of the pitfalls of home monitoring can be avoided by providing 24-hour telephone access (the ideal level of service) to a designated physician or nurse who is involved in the infant's care. In addition to this access, families should receive frequent, regularly scheduled telephone calls from healthcare providers, as well as home visits by a nurse or respiratory technician or follow-up appointments in a clinic familiar with this field of care.
• For excellent patient education resources, visit eMedicine's Children's Health Center. Also, see eMedicine's patient education article Sudden Infant Death Syndrome (SIDS).

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

An Internet search of the terms preterm infant, SIDS, and malpractice yields results linked to several law practices. Some of these sites tell parents that they should sue over the SIDS-related death of their preterm infant.

The medical literature is relatively silent about medical malpractice suits related to SIDS. The present authors know of malpractice cases involving infants who had apnea just days before discharge, who were discharged home without monitoring, and who then died at home or had an acute life-threatening event with brain injury. Even statements by national agencies that home monitoring cannot prevent SIDS have little impact when such malpractice cases go to a jury.

When an unanticipated death does occur at home, it must be properly investigated. The investigation should address the possibility of death from child abuse, as well as late deaths from unrecognized malformations or inborn errors of metabolism (eg, fatty acid oxidation disorders).¹²⁷

Special Concerns

Controversies related to AOP

Use of car seats or car beds

The AAP has indicated that a car-seat challenge should be performed before preterm infants are discharged from the hospital.¹²⁸ The importance of this testing is emphasized in an AAP pamphlet called Car Safety Seats: A Guide for Families 2007, which is given to parents. It addressed issues related to car-seat safety during infancy.

Adverse events do happen when preterm infants are placed in car seats.¹²⁹ However, authors of a Cochrane Review could not conclude whether car-seat testing with preterm infants was beneficial or detrimental. They did conclude that additional research was needed to evaluate its effectiveness in preventing the complications of apnea.¹³⁰

If problems are found, treatment is another matter. Some have thought that if a preterm infant does not pass a car-seat challenge, they can be safely transported in a car bed. However, Salhab et al (2007) reported that apnea and other adverse events were as likely to occur in car beds as in car seats.¹³¹ A preterm infant riding in a car seat should be carefully observed by a caregiver.

Retinal examinations

In NICUs, preterm infants have had apneic events after retinal examinations. Although the drugs used to dilate the iris are implicated in these apneic events, the incidence and mechanisms associated with apnea have been poorly studied.

Use of a pacifier

Another belief is that a preterm infant is at increased risk for SIDS if they suckle a pacifier. Researchers have concluded that the opposite is true.¹³² Moreover, pacifiers do not affect breastfeeding in preterm infants.¹³³ Pacifiers should obviously be removed from the mouth of a sleeping supine infant.

Hypermagnesemia

Studies reported decades ago demonstrated that hypermagnesemia secondary to maternal magnesium sulfate administration can cause apnea immediately after birth.⁷² Some neonatologists do not agree with this finding.

Methylxanthine therapy

Prophylactic versus intent-to-treat use of methylxanthines is another controversial subject. Some suggest prophylactic use of methylxanthines is indicated when very preterm infants are extubated to discontinue assisted ventilation. Older infants with a history of apnea of prematurity (AOP) may also benefit from prophylactic methylxanthines if they must undergo anesthesia for a surgical procedure.

Likewise, prophylactic therapy with methylxanthines might seem reasonable in preterm infants with birth weights less than 1000 g. Nevertheless, use of methylxanthines in preterm infants are being viewed with caution because of their effects on brain development.

Substantial disagreement exists among neonatologists regarding the criteria for stopping methylxanthine therapy, such as the numbers of days without apnea, bradycardia, or desaturation that are required. The discontinuation of methylxanthines may also depends on the patient's postconceptual age and other factors in an individual infant. Neonatologists are conflicted about what is considered safe in terms of the number of event-free days after a methylxanthine is stopped and the number of days without apnea before hospital discharge. Additional clinical research is urgently needed to resolve these issues.

Use of caffeine versus aminophylline

Despite the relatively broad therapeutic index, the use of caffeine versus aminophylline to treat AOP is still an unsettled issue with some neonatologists.

Home monitoring

To the authors' knowledge, no protocols to determine when a preterm infant with AOP should or should not have home monitoring have been evaluated in clinical trials.

Gastroesophageal reflux

Despite the overwhelming body of evidence that GER is not associated with apnea, many neonatologists still use agents to inhibit gastric acidity and thereby prevent apnea. This controversial issue in preterm infants with AOP has been discussed throughout this article.

SIDS-related concerns

Possible risk factors for SIDS or near-miss SIDS

SIDS and AOP

Infants born prematurely account for approximately 10% of the birth population, yet they experience slightly more than 20% of SIDS-related deaths. The immature respiratory control so commonly observed in premature neonates has led to suggestions of a relationship between AOP and SIDS.

Premature infants in NICUs often cease breathing unexpectedly. These events are frequently accompanied by bradycardia and O₂ desaturation. In many instances, the infant might not have resumed breathing without direct intervention.

The hypothesis that apnea is a cause of SIDS is attractive because the premature neonate does not struggle to resume breathing. This situation appears to be similar to that noted in many cases of SIDS. However, this theory of SIDS causation has not been proven. Furthermore, according to parental reports, most infants who died from SIDS were full-term neonates who had no apparent apneic events before death. However, visual detection of apnea and periodic breathing typically is difficult, even for medical personnel, and parents may miss such episodes.

No evidence identifies AOP as an independent risk factor for SIDS, despite the ongoing controversy surrounding the relationship between apnea and SIDS. Despite all of their common factors, large-scale trials conducted to verify the relationship between AOP and SIDS have failed to delineate an abnormality of ventilatory control that underlies SIDS.

Prolonged apnea has been reported in infants with near-miss SIDS (ie, infants who have had an ALTE). Short episodes of apnea, periodic breathing, and mixed and obstructive apnea have been identified in infants with near-miss SIDS. These observations suggest that an abnormality in ventilatory control may contribute to SIDS. The risk of SIDS risk is highest among infants aged 2-4 months, similar to the risk for an ALTE. Positive family histories for these events are found for infants who die from SIDS and patients with apnea. Incidences of both conditions peak during cold weather months, and both typically occur while the infant is asleep.

Sleeping position

A reduction in postneonatal mortality and SIDS rates have been associated with sleeping in a supine position rather than a prone position. Several research groups have documented physiologic benefits with prone positioning versus supine positioning in preterm infants; advantages included a modest improvement in transcutaneously measured PO₂, prolonged time in quiet sleep, decreased energy expenditure, and increased ventilatory responses to inspired CO₂. However, recent studies indicated that prone sleeping may increase the risk of SIDS after hospital discharge.^{134, 135} The increased risk of SIDS appears related to fewer arousals and more central apnea with prone versus supine sleeping.

To decrease the incidence of SIDS, the AAP has recommended placing healthy neonates on their backs, instead of prone, for sleeping.¹²³ The mechanism by which sleeping in the prone position can lead to SIDS is unclear.

In the Nordic Epidemiological SIDS study, Oyen et al (1997) con