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Pathogenesis, clinical manifestations, and diagnosis of apnea of prematurity

Pathogenesis, clinical manifestations, and diagnosis of apnea of prematurity
Author:
Richard Martin, MD
Section Editors:
Joseph A Garcia-Prats, MD
George B Mallory, MD
Deputy Editor:
Laurie Wilkie, MD, MS
Literature review current through: Jun 2022. | This topic last updated: May 01, 2020.

INTRODUCTION — Apnea of prematurity is a developmental disorder in preterm infants that is a consequence of immature respiratory control. Apnea of prematurity is most widely defined as cessation of breathing for more than 20 seconds, or a shorter respiratory pause associated with oxygen desaturation and/or bradycardia in infants who are younger than 37 weeks gestation [1]. The frequency of symptoms is inversely proportional to gestational age (GA), and almost all infants with a GA less than 28 weeks are affected.

The pathogenesis, diagnosis, and clinical presentation of apnea of prematurity are reviewed here. The management of apnea of prematurity is discussed separately. (See "Management of apnea of prematurity".)

DEFINITION

Apnea — Apnea is defined as the cessation of respiratory airflow. Short breathing pauses (5 to 10 seconds) occur frequently in preterm infants and are normal.

Apnea of prematurity is most widely defined as cessation of breathing for more than 20 seconds or a shorter respiratory pause associated with oxygen desaturation and/or bradycardia in infants who are younger than 37 weeks gestation [1]. Apnea of infancy refers to infants with a gestational age (GA) of 37 weeks or greater at the onset of apnea.

Apnea is classified as central, obstructive, or mixed depending on the presence of continued inspiratory efforts and upper airway obstruction.

Central apnea – Inspiratory efforts are absent

Obstructive apnea – Inspiratory efforts persist, but are ineffective in the presence of upper airway obstruction

Mixed apnea – Upper airway obstruction with inspiratory efforts that precedes or follows central apnea

Most apnea spells in preterm infants are central or mixed. This was illustrated in a study of physiologic recordings of 2082 apneic episodes in 47 infants: 40 percent of episodes were central, 50 percent were mixed, and 11 percent were obstructive [2]. Of note, longer episodes are most likely to be mixed apnea as opposed to short respiratory pauses, which are primarily classified as central apnea.

Periodic breathing — Periodic breathing episodes are characterized by a pattern of alternating breaths and brief respiratory pauses. Although descriptions vary, periodic breathing is usually defined as repetitive cycles of breathing and respiratory pauses that are approximately 5 to 10 seconds in duration. These pauses may be accompanied by modest oxygen desaturation and bradycardia that do not require clinical intervention. Periodic breathing is common in preterm infants. It needs to be differentiated from apnea of prematurity as it typically does not require intervention. In some infants, episodes of severe decreases in the percent of oxygenated hemoglobin measured by pulse oximetry (SpO2) need to be addressed.

INCIDENCE — The incidence of apnea increases with decreasing gestational age (GA).

Term infants – The incidence of apnea in term infants is quite low [3]. As a result, the cause of apnea in term infants should be assumed to be pathologic and can include hypoglycemia, seizure disorder, infection, severe birth asphyxia, intracranial hemorrhage or stroke, drug depression, and micrognathia with obstruction of the airway. (See 'Differential diagnosis' below.)

Moderately preterm infants – In a multicenter study, apnea was diagnosed in 50 percent of infants born between 33 and 34 6/7 weeks gestation based on documentation in the medical record [4]. Persistent apnea was associated with longer hospitalization. However, there was a wide range in the rate of apnea among the neonatal intensive care units (NICUs) as the criteria for diagnosing apnea varied. The authors speculated that the true incidence of apnea was underestimated because of underreporting of events. This underestimation of events by nursing documentation has been confirmed by ongoing cardiorespiratory monitoring [5].

Very preterm infants – Apnea occurs in virtually all infants born at less than 28 weeks gestation based on review of cardiorespiratory recordings from pneumography and cardiac and pulse oximetry monitoring [6,7]. Infants born at 24 to 28 weeks gestation may continue to exhibit apnea beyond 38 weeks postconception, which prolongs their hospitalization [6], although resolution of apnea is typically complete by around 43 to 44 weeks postmenstrual age (PMA) [8].

PATHOGENESIS — Apnea of prematurity is a developmental disorder that reflects physiologic immaturity rather than a pathologic process. In fetal life, gas exchange occurs via the placenta, and respiratory muscle activity is intermittent. At delivery, the change to postnatal life requires continuous respiratory muscle activity to sustain gas exchange. However, the mechanisms underlying the transition from intermittent to continuous breathing are not fully understood. It is thought that apnea of prematurity is due to disruption of these developmental ventilation control processes due to immaturity resulting in impaired respiratory drive and/or failure to maintain airway patency. (See "Control of ventilation".)

Respiratory drive — Central respiratory drive initiates inspiratory effort in response to changes in arterial partial pressure of carbon dioxide (PaCO2), arterial partial pressure of oxygen (PaO2), and pH via input from neural and chemical receptors. The respiratory center in the brain integrates receptor input and transmits neuronal signals via efferent pathways to the respiratory muscles.

In preterm infants, the immaturity of breathing responses affects all levels of respiratory control, including central and peripheral chemosensitivity and inhibitory pulmonary neuronal signal [9]. Based on limited data from physiologic studies in preterm infants and animal studies, the following observations have been made regarding the pathogenesis of central respiratory drive impairment in preterm infants with apnea [9]:

In the fetus, respiratory activity is decreased due to descending inhibition from higher brain mechanisms (ie, above the brainstem) and from the low fetal arterial partial pressure of oxygen (approximately 25 mmHg). After preterm delivery, these mechanisms appear to persist until the infant is able to developmentally adapt to the extrauterine environment.

Histologic analysis demonstrates a decreased number of synaptic connections, dendritic arborizations, impaired astrocyte development, and poor myelination. These findings suggest immaturity of the brain contributes to poor ventilatory control.

Upregulation of inhibitory neurotransmitters regulates respiratory control such as adenosine, gamma aminobutyric acid (GABA), and endorphins.

A (yet to be determined) genetic component appears to be associated with apnea of prematurity, as illustrated by the higher concordance rate of apnea among monozygotic preterm twin pairs compared with same gender dizygotic twins (87 versus 62 percent) [10].

In preterm infants with apnea, these and other yet to be identified factors appear to disrupt central respiratory drive, as manifested by the impaired ventilatory response to hypercapnia and hypoxia.

Hypercapnia – The major chemical driver of central respiratory output is elevated CO2, which is sensed primarily through brainstem receptors with a smaller contribution from peripheral chemoreceptors in the carotid and aortic bodies. Preterm infants have a blunted ventilatory response to inhaled CO2 [11,12]. The response to CO2 is even lower in preterm infants with apnea compared with preterm controls matched by gestational age (GA), birth weight (BW), and postnatal age [13]. This decreased ventilatory response at a given CO2 level is primarily due to changes in central respiratory drive rather than pulmonary mechanics.

Hypoxia – Increase in ventilation in response to hypoxia is almost exclusively dependent on feedback from carotid body peripheral chemoreceptors situated in the thorax. Preterm infants have a biphasic response to hypoxia with an initial increase (hyperventilation) and subsequent decrease in inspiratory efforts (hypoventilation and sometimes apnea) [14]. This biphasic response to hypoxia can persist to 38 weeks postconceptual age and may contribute to the persistence of apnea in some infants [15]. Although adults may also exhibit a biphasic ventilatory response to hypoxia, the degree of respiratory depression (following the initial increase in ventilation) is not as severe.

Decreased peripheral chemosensitivity in response to hypoxia may delay recovery from apnea. As noted above, the normally low fetal PaO2 results in decreased fetal respiratory activity. With the fourfold increase in oxygen levels at birth, the peripheral chemoreceptors, which have adapted to the low fetal oxygen levels, are initially unresponsive until a subsequent increase in their sensitivity to extrauterine oxygen levels. However, the underlying mechanisms leading to this maturation remain unclear.

Increased peripheral chemoreceptor responses to hypoxia have also been shown to destabilize breathing in preterm infants and contribute to periodic breathing [16]. This has been attributed to the fact that the eupneic and apneic PaCO2 thresholds are very close in preterm infants, and frequent oscillations in breathing elicited by increased peripheral chemosensitivity may drive the eupneic PaCO2 below the PaCO2 threshold and induce apnea [17].

Hyperbilirubinemia – Although limited, there are data that suggest that unconjugated hyperbilirubinemia is associated with central apnea [18]. The proposed mechanism is that unbound bilirubin crosses the blood-brain barrier and results in brainstem dysfunction, which would decrease the respiratory drive in response to either hypercapnia or hypoxia.

Upper airway patency — Patency of the upper airway is essential to the flow of respiratory gases between the environment and the alveolar-capillary interface.

Factors associated with upper airway obstruction in preterm infants include:

Collapse of the airway due to poor hypopharyngeal muscle tone - Maintenance of upper airway patency is dependent on the resting tone and active contraction of the hypopharyngeal muscles [17]. The hypopharynx is a frequent site of upper airway obstruction in preterm infants because pharyngeal muscle tone is poor, resulting in airway collapse, especially during rapid eye movement (REM) sleep. The infant's airway is especially susceptible to collapse when the neck is flexed [19].

Inhibitory upper airway reflexes – Activation or stimulation of inhibitory upper airway reflexes (also referred to as the laryngeal chemoreflex) may contribute to the pathogenesis of apnea, although the mechanism is poorly understood. This reflex appears to be mediated through irritant receptors in the larynx. The reflex response evolves from apnea and bradycardia in early postnatal life to protective coughing and swallowing with advancing maturation. In newborn animal models, for example, milk from a different species or water instilled in the airway resulted in decreased ventilation or apnea [20]. In human infants, prolonged hypopharyngeal suctioning or aspiration of small volumes of milk also may induce this apneic response [21]. However, no temporal relationship has been demonstrated between apnea of prematurity and gastroesophageal reflux. (See "Gastroesophageal reflux in premature infants", section on 'Relationship to apnea'.)

Viral infections with respiratory syncytial virus (RSV) may also enhance this apneic response, which is a common manifestation of RSV infection. In addition, upper respiratory infection may cause edema and obstruction of the airway. (See "Respiratory syncytial virus infection: Clinical features and diagnosis", section on 'Apnea'.)

Nasal obstruction – Newborn infants depend upon a patent nasal airway for adequate ventilation because neonates are obligate or preferential nose breathers [22]. Therefore, apnea may be precipitated by intermittent nasal obstruction from swelling that may occur in association with excessive suctioning during prolonged nasal continuous positive airway pressure (nCPAP), or with prolonged use of nasogastric tubes.

Laryngeal and tracheal abnormalities – The larynx and trachea are less common sites of mechanical airway obstruction because these rigid structures are less likely to collapse than the hypopharynx. Nevertheless, mild obstruction caused by laryngeal edema, vocal cord dysfunction, tracheal stenosis, or laryngeal and/or tracheal malacia can precipitate apnea in some cases.

CLINICAL MANIFESTATIONS

Presentation — Apnea may become evident in the first two to three days after birth in preterm infants who are breathing spontaneously without respiratory support or being treated with continuous positive airway pressure (CPAP). Breathing pauses usually are accompanied by bradycardia and hypoxemia [23].

In infants who are intubated and receiving mechanical ventilation, episodic desaturation and bradycardia are also quite common and are manifestations of ineffective ventilation and possibly cardiorespiratory reflex responses to airway stimulation by an endotracheal tube [24,25]. (See 'Upper airway patency' above.)

Regardless of ventilatory mode, episodic desaturation in preterm infants typically increases in frequency after the second or third week of life [26]. These episodes persist for several weeks, especially in infants who have a low baseline oxygen saturation [27].

Late presentation or recurrence — For infants without previous episodes of apnea after the first few weeks of life or who present with recurrent apnea after one to two weeks without apnea spells, the cause of apnea may be due to a serious underlying pathologic condition such as sepsis. These infants require a thorough evaluation to determine if there is a precipitating cause, which may be treatable. (See 'Differential diagnosis' below and 'Evaluation to determine cause of apnea' below.)

Natural history — Apnea of prematurity typically resolves before 37 weeks postmenstrual age (PMA) in infants delivered after 28 weeks gestation. In contrast, in infants born before 28 weeks, apnea frequently persists until term PMA [6,7,28]. However, significant apnea does not typically persist beyond 43 weeks PMA. This was best illustrated in a study that included 443 preterm infants (gestational age [GA] ≤34 weeks) that demonstrated significant cardiorespiratory events were rare beyond 43 weeks PMA and occurred no more frequently in the preterm group than in healthy term infants [8].

DIAGNOSIS — The diagnosis of apnea of prematurity is considered when either a respiratory pause greater than 20 seconds or a shorter respiratory pause accompanied by oxygen desaturation and/or bradycardia is detected in an infant with a gestational age (GA) less than 37 weeks. These events are typically identified by the routine use of cardiorespiratory monitors and/or pulse oximeters for preterm infants in the neonatal intensive care unit (NICU). Because apnea occurs in most infants born below 28 weeks gestation and in over half of more mature preterm infants, all preterm infants should be monitored for apnea. (See 'Incidence' above.)

However, the diagnosis of apnea of prematurity is a diagnosis of exclusion. Other causes of apnea need to be considered and eliminated before the diagnosis of apnea of prematurity can be conclusively made. This is especially true for any preterm infant in whom there is a recent onset of apnea following a time period without apneic events. (See 'Differential diagnosis' below and 'Evaluation to determine cause of apnea' below.)

Respiration — Neonatal cardiorespiratory monitors utilize impedance technology to measure respiration, which only measures chest wall motion. This technology is only effective to diagnose central apnea, and the use of these apnea monitors will miss mixed apnea, which is frequently associated with upper airway closure and continued respiratory muscle activity and obstructive apnea. Monitoring heart rate and oxygen saturation with a pulse oximeter provides additional data to ensure that infants with both mixed and obstructive apnea that result in significant decreases in heart rate or percent of oxygenated hemoglobin measured by pulse oximetry (SpO2) are also identified.

Apnea monitor alarms are typically set to identify cessation of respirations of 15 to 20 seconds' duration.

Heart rate — Heart rate monitoring is important in the detection of apnea of prematurity, since bradycardia usually accompanies apnea of prematurity. The decreased heart rate is thought to be a reflex response to a fall in oxygenation. The most frequent reason for persistent cardiorespiratory alarms in preterm infants is short respiratory pauses (<15 seconds) associated with bradycardia [23]. While many centers have traditionally set bradycardia alarms at <80 beats per minute (bpm), we have lowered alarm settings to 70 bpm in convalescing preterm infants to decrease the frequency of alarms without apparent adverse effects. This approach is supported by the observation that isolated bradycardia is unlikely to adversely affect cerebral oxygenation [29,30]. However, there are no data that determine the optimal threshold alarm setting for bradycardia.

Pulse oximetry — Pulse oximeters are used as a frequent adjunct to cardiorespiratory monitors in the NICU. As with bradycardia alarms, they provide an additional safety measure for respiration monitors. Typically, the alarms are set at <85 or <80 oxygen saturation. The incidence and depth of oxygen desaturation episodes after apnea are dependent on pulmonary oxygen stores and baseline level oxygen saturations levels [27]. As many preterm infants have low lung volumes associated with residual lung disease and a very compliant chest wall, they are vulnerable to frequent and deep falls in oxygen saturation with relatively short respiratory pauses. The time interval for the determination of the average oxygen saturation can be adjusted. A longer averaging time will smooth out the signal and decrease the number of short alarms [26], but may transform repetitive short desaturations into a falsely longer episode [31]. In addition, patients with pulmonary hypertension are predisposed to desaturation during a respiratory pause.

DIFFERENTIAL DIAGNOSIS — Although apnea of prematurity is the most common cause of apnea in preterm infants, it is a diagnosis of exclusion. The following etiologies that may present with apnea in preterm infants need to be considered and eliminated before the diagnosis of apnea of prematurity can be conclusively made.

Anemia. (See "Anemia of prematurity".)

Infection, including sepsis. (See "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation".)

Metabolic disorders including hypoglycemia. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Clinical presentation'.)

Unstable thermal environment (especially warming).

Antepartum administration of magnesium sulfate or opiates to the mother.

Administration of opiates or general anesthesia to the infant.

Neurologic disorders, including intracranial hemorrhage and neonatal encephalopathy [28]. (See "Germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH) in the newborn: Pathogenesis, clinical presentation, and diagnosis", section on 'Clinical presentation'.)

Necrotizing enterocolitis (NEC). (See "Neonatal necrotizing enterocolitis: Clinical features and diagnosis".)

Congenital anomalies of the upper airway. (See "Congenital anomalies of the nose" and "Congenital anomalies of the larynx" and "Congenital anomalies of the jaw, mouth, oral cavity, and pharynx".)

Seizures. (See "Clinical features, evaluation, and diagnosis of neonatal seizures".)

Dysphagia and feeding difficulties. (See "Neonatal oral feeding difficulties due to sucking and swallowing disorders".)

EVALUATION TO DETERMINE CAUSE OF APNEA — The goal of the diagnostic evaluation is to differentiate apnea of prematurity from other causes of neonatal apnea. (See 'Differential diagnosis' above.)

The diagnostic evaluation includes the following:

Maternal and neonatal history:

Maternal administration of magnesium sulfate or opioids

Neonatal administration of opioid therapy

Risk factors for neonatal sepsis

Traumatic delivery and/or perinatal asphyxia (see "Perinatal asphyxia in term and late preterm infants" and "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Markers of acute hypoxia-ischemia')

Infant of a diabetic mother (see "Infants of women with diabetes")

Assessment of the infant for other signs of an underlying etiology:

Signs and symptoms of hypoglycemia (eg, jitteriness, hypotonia, and lethargy) (see "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Who should be screened?' and "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Clinical presentation')

Signs and symptoms of sepsis (eg, temperature instability, lethargy, and poor feeding) (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Clinical manifestations' and "Bacterial meningitis in the neonate: Clinical features and diagnosis", section on 'Clinical features')

Signs and symptoms of neurologic impairment due to intraventricular hemorrhage, posthemorrhagic hydrocephalus, or neonatal encephalopathy (see "Germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH) in the newborn: Pathogenesis, clinical presentation, and diagnosis", section on 'Clinical presentation' and "Germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH) in the newborn: Prevention, management, and complications", section on 'Posthemorrhagic ventricular dilatation (PHVD)' and "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Markers of acute hypoxia-ischemia' and "Perinatal asphyxia in term and late preterm infants")

Signs and symptoms of necrotizing enterocolitis (NEC) (eg, abdominal distension, feeding intolerance, and bloody stools) (see "Neonatal necrotizing enterocolitis: Clinical features and diagnosis", section on 'Clinical presentation')

Although less likely, consider assessment of the airway to detect congenital anomalies of the upper airway (see "Congenital anomalies of the larynx" and "Congenital anomalies of the nose" and "Congenital anomalies of the intrathoracic airways and tracheoesophageal fistula")

Oral feeds – Apnea of prematurity must be distinguished from the hypoxemia, cyanosis, and bradycardia sometimes associated with the introduction of oral feedings in preterm infants. These changes in color and heart rate occur commonly before 34 to 36 weeks postmenstrual age (PMA) as a result of ineffective coordination of sucking, swallowing, and breathing, which may cause impaired ventilation. These events may persist in some neonates to 38 weeks PMA [32]. High rates of milk flow may also contribute to reduced ventilation [33]. (See "Neonatal oral feeding difficulties due to sucking and swallowing disorders", section on 'Development and physiology of oral feeding'.)

Laboratory evaluation includes the following tests that may be helpful in identifying an underlying diagnosis. Testing is typically reserved for patients with significant or abrupt increases in events based on clinical judgement:

Complete blood count: anemia and sepsis

Blood culture: sepsis

Measurements of blood glucose: hypoglycemia

Blood gas: hypoxemia and acidosis, which may be present in patients with inborn errors of metabolism, sepsis, or NEC

Other laboratory studies may be indicated if a metabolic disorder is suspected (see "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Clinical manifestations')

Cranial imaging should be obtained in cases in which intracranial hemorrhage, infarction, or neonatal encephalopathy is suspected. (See "Germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH) in the newborn: Pathogenesis, clinical presentation, and diagnosis", section on 'Diagnosis' and "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Neuroimaging' and "Stroke in the newborn: Classification, manifestations, and diagnosis", section on 'Brain imaging'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Apnea of prematurity".)

SUMMARY AND RECOMMENDATIONS — Apnea of prematurity is a developmental disorder in preterm infants that occurs as a direct consequence of immature respiratory control.

Apnea of prematurity is most widely defined as cessation of breathing for more than 20 seconds or a shorter respiratory pause associated with oxygen desaturation and/or bradycardia in infants who are younger than 37 weeks gestation. Apnea is classified as central, obstructive, or mixed depending upon the presence of continued inspiratory effort and upper airway. In preterm infants, most apnea spells are classified as either being central or mixed. (See 'Apnea' above.)

The incidence of apnea is inversely proportional to gestational age (GA), and almost all extremely preterm infants (GA <28 weeks) are affected. (See 'Incidence' above.)

Although the exact mechanisms underlying apnea of prematurity are unknown, it is thought to be due to disruption of ventilation control processes due to immaturity that results in impaired central respiratory drive and/or inability to maintain upper airway patency. (See 'Pathogenesis' above.)

Apnea of prematurity typically presents within the first few days of life in affected preterm infants who are not mechanically ventilated. It typically resolves before 37 postmenstrual weeks in infants delivered after 28 weeks gestation, but in infants born before 28 weeks, apnea frequently persists until 43 weeks postmenstrual age (PMA). (See 'Clinical manifestations' above.)

The diagnosis of apnea of prematurity is considered when either cessation of breathing greater than 20 seconds or a shorter period of respiratory pause accompanied by oxygen desaturation and/or bradycardia is detected. These events are typically identified by the routine use of cardiorespiratory monitors and/or pulse oximeters for preterm infants in the neonatal intensive care unit (NICU). Although apnea of prematurity is the most common cause of apnea in preterm infants, it is a diagnosis of exclusion. Other causes of apnea need to be considered and eliminated before the diagnosis of apnea of prematurity is made. (See 'Diagnosis' above and 'Differential diagnosis' above.)

The goal of the diagnostic evaluation is to identify any underlying cause (eg, sepsis). The evaluation is based on a comprehensive history and assessment of the infant, and laboratory testing. (See 'Evaluation to determine cause of apnea' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges James M Adams Jr, MD, who contributed to an earlier version of this topic review.

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