eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Neonatology
Apnea of Prematurity
Updated: Oct 26, 2009
Introduction
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 apnea of prematurity. 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 apnea of prematurity.
- Systematic research has not been conducted to investigate the value of different interventions for apnea of prematurity.
- Available technology is not routinely used to document real-time events associated with apnea.
- The time required to demonstrate an improvement in apnea of prematurity with a specific treatment has not been established.
- The observational period needed after therapy for apnea of prematurity 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 apnea of prematurity are poorly recognized and/or integrated into care.
- The relationship between gastroesophageal reflux (GER) and apnea of prematurity requires additional investigation because current knowledge suggests an infrequent association.
- Improved characterization of the effects of apnea of prematurity on neurodevelopment during infancy and childhood is needed.
- Other confounders associated with brain injury in preterm infants are difficult to separate from apnea of prematurity as meaningful causes of abnormal child development.
The NICHD review group also made recommendations about what issues associated with apnea of prematurity that need urgent attention, what research methods might be best for future studies, what outcomes are essential to our understanding of apnea of prematurity, and what ethical principles should govern future investigations of apnea of prematurity.
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 apnea of prematurity.
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).
Central apnea is defined as the cessation of both airflow and respiratory effort. ECG = electrocardiogram; HR = heart rate; THO = thoracic impedance; FLOW = air flow; ACT = ; SpO2 = peripheral oxygen saturation; STAGE = sleep stage.
- 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.
Polysomnogram. Mixed apnea contains elements of both central and obstructive apnea. ECG = electrocardiogram; HR = heart rate (bpm); THO = thoracic movement; FLOW = flow the from nose and mouth; ACT = gross body movement; SpO2 = peripheral oxygen saturation (%); STAGE = sleep stage, where AT = active sleep.
Apnea of infancy
Apnea of infancy (AOI) occurs when apnea persists in a neonate older than 37 weeks after conception. The physiologic aspects of apnea of prematurity 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).
Polysomnogram. Periodic breathing is defined as periods of regular respiration for as long as 20 seconds followed by apneic periods no longer than 10 seconds that occur at least 3 times in succession. ECG = electrocardiogram; HR = heart rate (bpm); THO = thoracic movement; FLOW = flow the from nose and mouth; ACT = gross body movement.
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 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 apnea of prematurity.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 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 apnea of prematurity 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. 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 various 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 apnea of prematurity.
An extensive literature review was undertaken to justify arguments about the role of GER in apnea of prematurity. 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 Special Concerns.
Frequency
United States
Although not always apparent, apnea of prematurity 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 apnea of prematurity. 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 and Barrington showed that apnea may begin on the first day of life in neonates without respiratory distress syndrome.50,51 However, apnea of prematurity 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 apnea of prematurity in the United States with those of other countries.
Mortality/Morbidity
Butcher-Puech and coworkers 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 apnea of prematurity 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 apnea of prematurity.
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 apnea of prematurity.
Age
A young gestational age at birth is associated with an increased incidence of apnea of prematurity. The age at which apnea of prematurity resolves depends on several factors. The mean time for severe apnea of prematurity 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 apnea of prematurity does not resolve at term in many low birth weight infants and that it may persist for some time after hospital discharge.
Clinical
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 apnea of prematurity.59 This classification for apnea of prematurity 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 apnea of prematurity is made, other causes of apnea in neonates must be excluded (see Differentials).
All forms of apnea may be difficult to detect visually, although obstructive apnea is usually most obvious to a trained observer.
Cardiorespiratory monitoring and pulse oximetry have improved bedside detection of apnea of prematurity.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 apnea of prematurity episodes.
Precise diagnosis of apnea of prematurity 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 apnea of prematurity.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 apnea of prematurity 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 apnea of prematurity. Although the etiology of apnea of prematurity is not fully understood, several mechanisms have been proposed to explain this condition, including those described below.
- Apnea of prematurity 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 apnea of prematurity represents neuronal immaturity of the brain. (For an excellent review of this topic, see the article by Darnall et al.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 apnea of prematurity.
- 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 gastroesophageal reflux (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
- 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 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
More on Apnea of Prematurity |
 Overview: Apnea of Prematurity |
| Differential Diagnoses & Workup: Apnea of Prematurity |
| Treatment & Medication: Apnea of Prematurity |
| Follow-up: Apnea of Prematurity |
| Multimedia: Apnea of Prematurity |
| References |
| Next Page » |
References
Darnall RA, Ariagno RL, Kinney HC. The late preterm infant and the control of breathing, sleep, and brainstem development: a review. Clin Perinatol. Dec 2006;33(4):883-914; abstract x. [Medline].
Gaultier C, Gallego J. Development of respiratory control: evolving concepts and perspectives. Respir Physiol Neurobiol. Nov 15 2005;149(1-3):3-15. [Medline].
Gozal D. New concepts in abnormalities of respiratory control in children. Curr Opin Pediatr. Jun 2004;16(3):305-8. [Medline].
Martin RJ, Abu-Shaweesh JM. Control of breathing and neonatal apnea. Biol Neonate. 2005;87(4):288-95. [Medline].
Chatonnet F, Dominguez del Toro E, Thoby-Brisson M, et al. From hindbrain segmentation to breathing after birth: developmental patterning in rhombomeres 3 and 4. Mol Neurobiol. Dec 2003;28(3):277-94. [Medline].
Kotecha S. Lung growth for beginners. Paediatr Respir Rev. Dec 2000;1(4):308-13. [Medline].
Givan DC. Physiology of breathing and related pathological processes in infants. Semin Pediatr Neurol. Dec 2003;10(4):271-80. [Medline].
Sinha SK, Donn SM. Fetal-to-neonatal maladaptation. Semin Fetal Neonatal Med. Jun 2006;11(3):166-73. [Medline].
[Guideline] Finer NN, Higgins R, Kattwinkel J, Martin RJ. Summary proceedings from the apnea-of-prematurity group. Pediatrics. Mar 2006;117(3 Pt 2):S47-51. [Medline]. [Full Text].
American Academy of Pediatrics, Committee on Fetus and Newborn. Apnea, sudden infant death syndrome, and home monitoring. Pediatrics. Apr 2003;111(4 Pt 1):914-7. [Medline]. [Full Text].
Kelly DH, Shannon DC. Periodic breathing in infants with near-miss sudden infant death syndrome. Pediatrics. Mar 1979;63(3):355-60. [Medline].
Martin RJ, Miller MJ, Carlo WA. Pathogenesis of apnea in preterm infants. J Pediatr. Nov 1986;109(5):733-41. [Medline].
Lagercrantz H. Improved understanding of respiratory control--implications for the treatment of apnoea. Eur J Pediatr. 1995;154(8 Suppl 3):S10-2. [Medline].
Putnam RW, Conrad SC, Gdovin MJ, et al. Neonatal maturation of the hypercapnic ventilatory response and central neural CO2 chemosensitivity. Respir Physiol Neurobiol. Nov 15 2005;149(1-3):165-79. [Medline].
Simakajornboon N, Kuptanon T. Maturational changes in neuromodulation of central pathways underlying hypoxic ventilatory response. Respir Physiol Neurobiol. Nov 15 2005;149(1-3):273-86. [Medline].
Henderson-Smart DJ, Pettigrew AG, Campbell DJ. Clinical apnea and brain-stem neural function in preterm infants. N Engl J Med. Feb 17 1983;308(7):353-7. [Medline].
Amin SB, Charafeddine L, Guillet R. Transient bilirubin encephalopathy and apnea of prematurity in 28 to 32 weeks gestational age infants. J Perinatol. Jun 2005;25(6):386-90. [Medline].
Gauda EB, Miller MJ, Carlo WA, et al. Genioglossus and diaphragm activity during obstructive apnea and airway occlusion in infants. Pediatr Res. Dec 1989;26(6):583-7. [Medline].
Martin RJ, Abu-Shaweesh JM, Baird TM. Apnoea of prematurity. Paediatr Respir Rev. 2004;5 Suppl A:S377-82. [Medline].
Gould JB, Lee AF, James O, et al. The sleep state characteristics of apnea during infancy. Pediatrics. Feb 1977;59(2):182-94. [Medline].
Hoppenbrouwers T, Hodgman JE, Rybine D, et al. Sleep architecture in term and preterm infants beyond the neonatal period: the influence of gestational age, steroids, and ventilatory support. Sleep. Nov 1 2005;28(11):1428-36. [Medline].
Bryan AC, Bryan MH. Control of respiration in the newborn. Clin Perinatol. Sep 1978;5(2):269-81. [Medline].
Martin RJ, Okken A, Rubin D. Arterial oxygen tension during active and quiet sleep in the normal neonate. J Pediatr. Feb 1979;94(2):271-4. [Medline].
Krimsky WR, Leiter JC. Physiology of breathing and respiratory control during sleep. Semin Respir Crit Care Med. Feb 2005;26(1):5-12. [Medline].
Cohen G, Katz-Salamon M. Development of chemoreceptor responses in infants. Respir Physiol Neurobiol. Nov 15 2005;149(1-3):233-42. [Medline].
Hunt CE, Hauck FR. Sudden infant death syndrome. CMAJ. Jun 20 2006;174(13):1861-9. [Medline].
Koons A, Hegyi T, Mehta R, et al. Cerebral vascular responses to changes in carbon dioxide tension in term and preterm infants with apnea. Biol Neonate. 2003;84(2):115-8. [Medline].
Carlo WA, DiFiore JM. Respiratory muscle responses to changes in chemoreceptor drive in infants. J Appl Physiol. Mar 1990;68(3):1041-7. [Medline].
Noble LM, Carlo WA, Miller MJ, et al. Transient changes in expiratory time during hypercapnia in premature infants. J Appl Physiol. Mar 1987;62(3):1010-3. [Medline].
Gerhardt T, Bancalari E. Apnea of prematurity: II. Respiratory reflexes. Pediatrics. Jul 1984;74(1):63-6. [Medline].
Cross KW, Oppe TE. The effect of inhalation of high and low concentrations of oxygen on the respiration of the premature infant. J Physiol. May 1952;117(1):38-55. [Medline].
Gauda EB, McLemore GL, Tolosa J, et al. Maturation of peripheral arterial chemoreceptors in relation to neonatal apnoea. Semin Neonatol. Jun 2004;9(3):181-94. [Medline].
Rigatto H, De La Torre Verduzco R, Gates DB. Effects of O2 on the ventilatory response to CO2 in preterm infants. J Appl Physiol. Dec 1975;39(6):896-9. [Medline].
Simakajornboon N, Beckerman RC, Mack C, et al. Effect of supplemental oxygen on sleep architecture and cardiorespiratory events in preterm infants. Pediatrics. Nov 2002;110(5):884-8. [Medline].
Carlo WA, Miller MJ, Martin RJ. Differential response of respiratory muscles to airway occlusion in infants. J Appl Physiol. Sep 1985;59(3):847-52. [Medline].
Gerhardt T, Bancalari E. Apnea of prematurity: I. Lung function and regulation of breathing. Pediatrics. Jul 1984;74(1):58-62. [Medline].
Miller MJ, Petrie TG, Difiore JM. Changes in resistance and ventilatory timing that accompany apnea in premature infants. J Appl Physiol. Aug 1993;75(2):720-3. [Medline].
Waggener TB, Frantz ID 3rd, Stark AR, Kronauer RE. Oscillatory breathing patterns leading to apneic spells in infants. J Appl Physiol. May 1982;52(5):1288-95. [Medline].
Thach BT. The role of pharyngeal airway obstruction in prolonging infantile apneic spells. In: Tilden JT, Roeder JM, Steinschneide A, eds. Sudden Infant Death Syndrome. New York: Academic Press; 1983:279.
Carlo WA, Martin RJ, Difiore JM. Differences in CO2 threshold of respiratory muscles in preterm infants. J Appl Physiol. Dec 1988;65(6):2434-9. [Medline].
van Lunteren E, Strohl KP, Parker DM, et al. Phasic volume-related feedback on upper airway muscle activity. J Appl Physiol. Mar 1984;56(3):730-6. [Medline].
Harding R. Function of the larynx in the fetus and newborn. Annu Rev Physiol. 1984;46:645-59. [Medline].
Gauda EB, Carroll TP, Schwartz AR, et al. Mechano- and chemoreceptor modulation of respiratory muscles in response to upper airway negative pressure. J Appl Physiol. Jun 1994;76(6):2656-62. [Medline].
Miller MJ, DiFiore JM. A comparison of swallowing during apnea and periodic breathing in premature infants. Pediatr Res. Jun 1995;37(6):796-9. [Medline].
Zaidi SI, Jafri A, Martin RJ, Haxhiu MA. Adenosine A2A receptors are expressed by GABAergic neurons of medulla oblongata in developing rat. Brain Res. Feb 3 2006;1071(1):42-53. [Medline].
Darnall RA Jr. Aminophylline reduces hypoxic ventilatory depression: possible role of adenosine. Pediatr Res. Jul 1985;19(7):706-10. [Medline].
Arad-Cohen N, Cohen A, Tirosh E. The relationship between gastroesophageal reflux and apnea in infants. J Pediatr. Sep 2000;137(3):321-6. [Medline].
Peter CS, Sprodowski N, Bohnhorst B, et al. Gastroesophageal reflux and apnea of prematurity: no temporal relationship. Pediatrics. Jan 2002;109(1):8-11. [Medline].
Kiatchoosakun P, Dreshaj IA, Abu-Shaweesh JM, et al. Effects of hypoxia on respiratory neural output and lower esophageal sphincter pressure in piglets. Pediatr Res. Jul 2002;52(1):50-5. [Medline].
Carlo WA, Martin RJ, Versteegh FG, et al. The effect of respiratory distress syndrome on chest wall movements and respiratory pauses in preterm infants. Am Rev Respir Dis. Jul 1982;126(1):103-7. [Medline].
Barrington KJ, Finer NN. Periodic breathing and apnea in preterm infants. Pediatr Res. Feb 1990;27(2):118-21. [Medline].
Finer NN, Barrington KJ, Hayes BJ, Hugh A. Obstructive, mixed, and central apnea in the neonate: physiologic correlates. J Pediatr. Dec 1992;121(6):943-50. [Medline].
Butcher-Puech MC, Henderson-Smart DJ, Holley D, et al. Relation between apnoea duration and type and neurological status of preterm infants. Arch Dis Child. Oct 1985;60(10):953-8. [Medline].
Perlman JM, Volpe JJ. Episodes of apnea and bradycardia in the preterm newborn: impact on cerebral circulation. Pediatrics. Sep 1985;76(3):333-8. [Medline].
Emancipator JL, Storfer-Isser A, Taylor HG, et al. Variation of cognition and achievement with sleep-disordered breathing in full-term and preterm children. Arch Pediatr Adolesc Med. Feb 2006;160(2):203-10. [Medline].
Janvier A, Khairy M, Kokkotis A, et al. Apnea is associated with neurodevelopmental impairment in very low birth weight infants. J Perinatol. Dec 2004;24(12):763-8. [Medline].
Barrington KJ, Finer N, Li D. Predischarge respiratory recordings in very low birth weight newborn infants. J Pediatr. Dec 1996;129(6):934-40. [Medline].
Sola A, Chow L, Rogido M. Pulse oximetry in neonatal care in 2005. A comprehensive state of the art review [in Spanish]. An Pediatr (Barc). Mar 2005;62(3):266-81. [Medline].
Mayock DE. Apnea. Revised February 24, 2000. University of Washington Division of Neonatology Web site. NICU-WEB. Available at http://depts.washington.edu/nicuweb/NICU-WEB/apnea.stm.
Di Fiore JM. Neonatal cardiorespiratory monitoring techniques. Semin Neonatol. Jun 2004;9(3):195-203. [Medline].
Gamble YD, Lutin WP, Mathew OP. Non-sinus bradyarrhythmias in very low birth weight infants. J Perinatol. Jan 2007;27(1):65-7. [Medline].
Menon AP, Schefft GL, Thach BT. Apnea associated with regurgitation in infants. J Pediatr. Apr 1985;106(4):625-9. [Medline].
Newell SJ, Booth IW, Morgan ME, et al. Gastro-oesophageal reflux in preterm infants. Arch Dis Child. Jun 1989;64(6):780-6. [Medline].
Khalaf MN, Porat R, Brodsky NL, Bhandari V. Clinical correlations in infants in the neonatal intensive care unit with varying severity of gastroesophageal reflux. J Pediatr Gastroenterol Nutr. Jan 2001;32(1):45-9. [Medline].
Andrade EO, Arain A, Malow BA. Partial epilepsy presenting as apneic seizures without posturing. Pediatr Neurol. Nov 2006;35(5):359-62. [Medline].
Robles P, Poblano A, Hernandez G, et al. Cortical, brainstem and autonomic nervous system dysfunction in infants with post-hemorrhagic hydrocephalus. Rev Invest Clin. Mar-Apr 2002;54(2):133-8. [Medline].
Fanaroff AA, Korones SB, Wright LL, et al. Incidence, presenting features, risk factors and significance of late onset septicemia in very low birth weight infants. The National Institute of Child Health and Human Development Neonatal Research Network. Pediatr Infect Dis J. Jul 1998;17(7):593-8. [Medline].
Gonzalez BE, Mercado CK, Johnson L, et al. Early markers of late-onset sepsis in premature neonates: clinical, hematological and cytokine profile. J Perinat Med. 2003;31(1):60-8. [Medline].
Halasa NB, Williams JV, Wilson GJ, et al. Medical and economic impact of a respiratory syncytial virus outbreak in a neonatal intensive care unit. Pediatr Infect Dis J. Dec 2005;24(12):1040-4. [Medline].
Rudd PT, Carrington D. A prospective study of chlamydial, mycoplasmal, and viral infections in a neonatal intensive care unit. Arch Dis Child. Feb 1984;59(2):120-5. [Medline].
Cheromcha DP, Hyman PE. Neonatal necrotizing enterocolitis. Inflammatory bowel disease of the newborn. Dig Dis Sci. Mar 1988;33(3 Suppl):78S-84S. [Medline].
Rasch DK, Huber PA, Richardson CJ, et al. Neurobehavioral effects of neonatal hypermagnesemia. J Pediatr. Feb 1982;100(2):272-6. [Medline].
Ali A, Walentik C, Mantych GJ, et al. Iatrogenic acute hypermagnesemia after total parenteral nutrition infusion mimicking septic shock syndrome: two case reports. Pediatrics. Jul 2003;112(1 Pt 1):e70-2. [Medline].
Westkamp E, Soditt V, Adrian S, et al. Blood transfusion in anemic infants with apnea of prematurity. Biol Neonate. 2002;82(4):228-32. [Medline].
[Best Evidence] Bell EF, Strauss RG, Widness JA, et al. Randomized trial of liberal versus restrictive guidelines for red blood cell transfusion in preterm infants. Pediatrics. Jun 2005;115(6):1685-91. [Medline].
Armony-Sivan R, Eidelman AI, Lanir A, et al. Iron status and neurobehavioral development of premature infants. J Perinatol. Dec 2004;24(12):757-62. [Medline].
Kurth CD, Spitzer AR, Broennle AM, Downes JJ. Postoperative apnea in preterm infants. Anesthesiology. Apr 1987;66(4):483-8. [Medline].
Malviya S, Swartz J, Lerman J. Are all preterm infants younger than 60 weeks postconceptual age at risk for postanesthetic apnea?. Anesthesiology. Jun 1993;78(6):1076-81. [Medline].
Craven PD, Badawi N, Henderson-Smart DJ, O'Brien M. Regional (spinal, epidural, caudal) versus general anaesthesia in preterm infants undergoing inguinal herniorrhaphy in early infancy. Cochrane Database Syst Rev. 2003;(3):CD003669. [Medline].
Henderson-Smart DJ, Steer P. Methylxanthine treatment for apnea in preterm infants. Cochrane Database Syst Rev. 2001;(3):CD000140. [Medline].
Pourcyrous M, Korones SB, Crouse D, Bada HS. Interleukin-6, C-reactive protein, and abnormal cardiorespiratory responses to immunization in premature infants. Pediatrics. Mar 1998;101(3):E3. [Medline].
Ellison VJ, Davis PG, Doyle LW. Adverse reactions to immunization with newer vaccines in the very preterm infant. J Paediatr Child Health. Aug 2005;41(8):441-3. [Medline].
Pfister RE, Aeschbach V, Niksic-Stuber V, et al. Safety of DTaP-based combined immunization in very-low-birth-weight premature infants: frequent but mostly benign cardiorespiratory events. J Pediatr. Jul 2004;145(1):58-66. [Medline].
Faldella G, Galletti S, Corvaglia L, et al. Safety of DTaP-IPV-HIb-HBV hexavalent vaccine in very premature infants. Vaccine. Jan 22 2007;25(6):1036-42. [Medline].
Lee J, Robinson JL, Spady DW. Frequency of apnea, bradycardia, and desaturations following first diphtheria-tetanus-pertussis-inactivated polio-Haemophilus influenzae type B immunization in hospitalized preterm infants. BMC Pediatr. 2006;6:20. [Medline].
Thach BT. Reflux associated apnea in infants: evidence for a laryngeal chemoreflex. Am J Med. Nov 24 1997;103(5A):120S-124S. [Medline].
Vermeylen D, Franco P, Hennequin Y, et al. Laryngeal oedema in neonatal apnoea and bradycardia syndrome (a pilot study). Early Hum Dev. Apr 2005;81(4):361-7. [Medline].
Jolley SG, Halpern CT, Sterling CE, Feldman BH. The relationship of respiratory complications from gastroesophageal reflux to prematurity in infants. J Pediatr Surg. Jul 1990;25(7):755-7. [Medline].
Justo RN, Gray PH. Fundoplication in preterm infants with gastro-oesophageal reflux. J Paediatr Child Health. Aug 1991;27(4):250-4. [Medline].
de Ajuriaguerra M, Radvanyi-Bouvet MF, Huon C, Moriette G. Gastroesophageal reflux and apnea in prematurely born infants during wakefulness and sleep. Am J Dis Child. Oct 1991;145(10):1132-6. [Medline].
Di Fiore JM, Arko M, Whitehouse M, et al. Apnea is not prolonged by acid gastroesophageal reflux in preterm infants. Pediatrics. Nov 2005;116(5):1059-63. [Medline].
Kimball AL, Carlton DP. Gastroesophageal reflux medications in the treatment of apnea in premature infants. J Pediatr. Mar 2001;138(3):355-60. [Medline].
Bohnhorst B, Gill D, Dordelmann M, et al. Bradycardia and desaturation during skin-to-skin care: no relationship to hyperthermia. J Pediatr. Oct 2004;145(4):499-502. [Medline].
Bohnhorst B, Heyne T, Peter CS, Poets CF. Skin-to-skin (kangaroo) care, respiratory control, and thermoregulation. J Pediatr. Feb 2001;138(2):193-7. [Medline].
Berterottiere D, D'Allest AM, Dehan M, Gaultier C. Effects of increase in body temperature on the breathing pattern in premature infants. J Dev Physiol. Jun 1990;13(6):303-8. [Medline].
Tirosh E, Bader D, Hodgins H, et al. Apnoea-associated heart rate changes among preterm and full-term infants exposed to hyperthermia. Clin Physiol. Jul 1998;18(4):331-5. [Medline].
Ludington-Hoe SM, Anderson GC, Swinth JY, et al. Randomized controlled trial of kangaroo care: cardiorespiratory and thermal effects on healthy preterm infants. Neonatal Netw. May-Jun 2004;23(3):39-48. [Medline].
Sontheimer D, Fischer CB, Scheffer F, et al. Pitfalls in respiratory monitoring of premature infants during kangaroo care. Arch Dis Child Fetal Neonatal Ed. Mar 1995;72(2):F115-7. [Medline].
Arnon SS, Midura TF, Clay SA, et al. Infant botulism. Epidemiological, clinical, and laboratory aspects. JAMA. May 2 1977;237(18):1946-51. [Medline].
Jeffery HE, Rahilly P, Read DJ. Multiple causes of asphyxia in infants at high risk for sudden infant death. Arch Dis Child. Feb 1983;58(2):92-100. [Medline].
Cademartiri F, Luccichenti G, Laganà F, et al. Effective clinical outcome of a mandibular distraction device using three-dimensional CT with volume rendering in Pierre-Robin sequence. Acta Biomed. Aug 2004;75(2):122-5. [Medline].
Denny A, Amm C. New technique for airway correction in neonates with severe Pierre Robin sequence. J Pediatr. Jul 2005;147(1):97-101. [Medline].
Wittenborn W, Panchal J, Marsh JL, et al. Neonatal distraction surgery for micrognathia reduces obstructive apnea and the need for tracheotomy. J Craniofac Surg. Jul 2004;15(4):623-30. [Medline].
Young TE, Mangum B. Methylxanthines. In: NeoFax. 19th ed. Raleigh, NC: Acorn; 2006:200-3.
[Best Evidence] Pantalitschka T, Sievers J, Urschitz MS, et al. Randomised crossover trial of four nasal respiratory support systems for apnoea of prematurity in very low birthweight infants. Arch Dis Child Fetal Neonatal Ed. Jul 2009;94(4):F245-8. [Medline].
Millar D, Schmidt B. Controversies surrounding xanthine therapy. Semin Neonatol. Jun 2004;9(3):239-44. [Medline].
Schmidt B. Methylxanthine therapy for apnea of prematurity: evaluation of treatment benefits and risks at age 5 years in the international Caffeine for Apnea of Prematurity (CAP) trial. Biol Neonate. 2005;88(3):208-13. [Medline].
Henderson-Smart DJ, Davis PG. Prophylactic methylxanthines for extubation in preterm infants. Cochrane Database Syst Rev. 2003;(1):CD000139. [Medline].
[Best Evidence] Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity. N Engl J Med. May 18 2006;354(20):2112-21. [Medline].
Eichenwald EC, Howell RG 3rd, Kosch PC, et al. Developmental changes in sequential activation of laryngeal abductor muscle and diaphragm in infants. J Appl Physiol. Oct 1992;73(4):1425-31. [Medline].
Heyman E, Ohlsson A, Heyman Z, Fong K. The effect of aminophylline on the excursions of the diaphragm in preterm neonates. A randomized double-blind controlled study. Acta Paediatr Scand. Mar 1991;80(3):308-15. [Medline].
Chang J, Gray PH. Aminophylline therapy and cerebral blood flow velocity in preterm infants. J Paediatr Child Health. Apr 1994;30(2):123-5. [Medline].
Dani C, Bertini G, Reali MF, et al. Brain hemodynamic changes in preterm infants after maintenance dose caffeine and aminophylline treatment. Biol Neonate. Jul 2000;78(1):27-32. [Medline].
Pryds O, Schneider S. Aminophylline reduces cerebral blood flow in stable, preterm infants without affecting the visual evoked potential. Eur J Pediatr. Mar 1991;150(5):366-9. [Medline].
Robel-Tillig E, Vogtmann C. Aminophylline influences cerebral hyperperfusion after severe birth hypoxia. Acta Paediatr. Aug 2000;89(8):971-4. [Medline].
Rosenkrantz TS, Oh W. Aminophylline reduces cerebral blood flow velocity in low-birth-weight infants. Am J Dis Child. May 1984;138(5):489-91. [Medline].
Cikrit D, Mastandrea J, Grosfeld JL, et al. Significance of portal vein air in necrotizing entercolitis: analysis of 53 cases. J Pediatr Surg. Aug 1985;20(4):425-30. [Medline].
Cikrit D, Mastandrea J, West KW, et al. Necrotizing enterocolitis: factors affecting mortality in 101 surgical cases. Surgery. Oct 1984;96(4):648-55. [Medline].
Hufnal-Miller CA, Blackmon L, Baumgart S, Pereira GR. Enteral theophylline and necrotizing enterocolitis in the low-birthweight infant. Clin Pediatr (Phila). Nov 1993;32(11):647-53. [Medline].
Dani C, Bertini G, Pezzati M, et al. Brain hemodynamic effects of doxapram in preterm infants. Biol Neonate. 2006;89(2):69-74. [Medline].
Roll C, Horsch S. Effect of doxapram on cerebral blood flow velocity in preterm infants. Neuropediatrics. Apr 2004;35(2):126-9. [Medline].
Henderson-Smart D, Steer P. Doxapram treatment for apnea in preterm infants. Cochrane Database Syst Rev. 2004;(4):CD000074. [Medline].
Darnall RA, Kattwinkel J, Nattie C, Robinson M. Margin of safety for discharge after apnea in preterm infants. Pediatrics. Nov 1997;100(5):795-801. [Medline].
American Academy of Pediatrics, Task Force on Sudden Infant Death Syndrome. The changing concept of sudden infant death syndrome: diagnostic coding shifts, controversies regarding the sleeping environment, and new variables to consider in reducing risk. Pediatrics. Nov 2005;116(5):1245-55. [Medline]. [Full Text].
[Guideline] Persing J, James H, Swanson J, Kattwinkel J. Prevention and management of positional skull deformities in infants. American Academy of Pediatrics Committee on Practice and Ambulatory Medicine, Section on Plastic Surgery and Section on Neurological Surgery. Pediatrics. Jul 2003;112(1 Pt 1):199-202. [Medline].
Spitzer AR, Fox WW. Infant apnea. Pediatr Clin North Am. Jun 1986;33(3):561-81. [Medline].
Spitzer AR, Gibson E. Home monitoring. Clin Perinatol. Dec 1992;19(4):907-26. [Medline].
Hymel KP. Distinguishing sudden infant death syndrome from child abuse fatalities. Pediatrics. Jul 2006;118(1):421-7. [Medline].
Bull M, Agran P, Laraque D, et al. American Academy of Pediatrics. Committee on Injury and Poison Prevention. Safe transportation of newborns at hospital discharge. Pediatrics. Oct 1999;104(4 Pt 1):986-7. [Medline].
Ojadi VC, Petrova A, Mehta R, Hegyi T. Risk of cardio-respiratory abnormalities in preterm infants placed in car seats: a cross-sectional study. BMC Pediatr. 2005;5:28. [Medline].
Pilley E, McGuire W. Pre-discharge "car seat challenge" for preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev. 2006;(1):CD005386. [Medline].
Salhab WA, Khattak A, Tyson JE, et al. Car seat or car bed for very low birth weight infants at discharge home. J Pediatr. Mar 2007;150(3):224-8. [Medline].
Mitchell EA, Blair PS, L'Hoir MP. Should pacifiers be recommended to prevent sudden infant death syndrome?. Pediatrics. May 2006;117(5):1755-8. [Medline].
Collins CT, Ryan P, Crowther CA, et al. Effect of bottles, cups, and dummies on breast feeding in preterm infants: a randomised controlled trial. BMJ. Jul 24 2004;329(7459):193-8. [Medline].
Ariagno RL, van Liempt S, Mirmiran M. Fewer spontaneous arousals during prone sleep in preterm infants at 1 and 3 months corrected age. J Perinatol. May 2006;26(5):306-12. [Medline].
Bhat RY, Hannam S, Pressler R, et al. Effect of prone and supine position on sleep, apneas, and arousal in preterm infants. Pediatrics. Jul 2006;118(1):101-7. [Medline].
Oyen N, Markestad T, Skaerven R, et al. Combined effects of sleeping position and prenatal risk factors in sudden infant death syndrome: the Nordic Epidemiological SIDS Study. Pediatrics. Oct 1997;100(4):613-21. [Medline].
Mattia FR, deRegnier RA. Chronic physiologic instability is associated with neurodevelopmental morbidity at one and two years in extremely premature infants. Pediatrics. Sep 1998;102(3):E35. [Medline].
Al-Matary A, Kutbi I, Qurashi M, et al. Increased peripheral chemoreceptor activity may be critical in destabilizing breathing in neonates. Semin Perinatol. Aug 2004;28(4):264-72. [Medline].
Brooks JG. Apparent life-threatening events and apnea of infancy. Clin Perinatol. Dec 1992;19(4):809-38. [Medline].
Chardon K, Bach V, Telliez F, et al. Effect of caffeine on peripheral chemoreceptor activity in premature neonates: interaction with sleep stages. J Appl Physiol. Jun 2004;96(6):2161-6. [Medline].
Chardon K, Telliez F, Bach V, et al. Effects of warm and cool thermal conditions on ventilatory responses to hyperoxic test in neonates. Respir Physiol Neurobiol. May 20 2004;140(2):145-53. [Medline].
Decker MJ, Rye DB. Neonatal intermittent hypoxia impairs dopamine signaling and executive functioning. Sleep Breath. Dec 2002;6(4):205-10. [Medline].
Eichenwald EC, Aina A, Stark AR. Apnea frequently persists beyond term gestation in infants delivered at 24 to 28 weeks. Pediatrics. Sep 1997;100(3 Pt 1):354-9. [Medline].
Gewolb IH, Vice FL. Abnormalities in the coordination of respiration and swallow in preterm infants with bronchopulmonary dysplasia. Dev Med Child Neurol. Jul 2006;48(7):595-9. [Medline].
Gewolb IH, Vice FL. Maturational changes in the rhythms, patterning, and coordination of respiration and swallow during feeding in preterm and term infants. Dev Med Child Neurol. Jul 2006;48(7):589-94. [Medline].
Henderson-Smart DJ, Butcher-Puech MC, Edwards DA. Incidence and mechanism of bradycardia during apnoea in preterm infants. Arch Dis Child. Mar 1986;61(3):227-32. [Medline].
Henderson-Smart DJ, Ponsonby AL, Murphy E. Reducing the risk of sudden infant death syndrome: a review of the scientific literature. J Paediatr Child Health. Jun 1998;34(3):213-9. [Medline].
Henderson-Smart DJ, Steer P. Prophylactic caffeine to prevent postoperative apnea following general anesthesia in preterm infants. Cochrane Database Syst Rev. 2001;(4):CD000048. [Medline].
Herschel M, Mittendorf R. Tocolytic magnesium sulfate toxicity and unexpected neonatal death. J Perinatol. Jun 2001;21(4):261-2. [Medline].
Hunt CE. Ontogeny of autonomic regulation in late preterm infants born at 34-37 weeks postmenstrual age. Semin Perinatol. Apr 2006;30(2):73-6. [Medline].
Khan A, Qurashi M, Kwiatkowski K, et al. Measurement of the CO2 apneic threshold in newborn infants: possible relevance for periodic breathing and apnea. J Appl Physiol. Apr 2005;98(4):1171-6. [Medline].
Kugelman A, Bilker A, Bader D, et al. Sidestream end-tidal capnometry as related to infant's position and maturation. Acta Paediatr. 2002;91(8):869-73. [Medline].
Lipsky CL, Gibson E, Cullen JA, et al. The timing of SIDS deaths in premature infants in an urban population. Clin Pediatr (Phila). Aug 1995;34(8):410-4. [Medline].
Martin RJ, Okken A, Katona PG, Klaus MH. Effect of lung volume on expiratory time in the newborn infant. J Appl Physiol. Jul 1978;45(1):18-23. [Medline].
Molloy EJ, Di Fiore JM, Martin RJ. Does gastroesophageal reflux cause apnea in preterm infants?. Biol Neonate. 2005;87(4):254-61. [Medline].
Perlman JM. Brain injury in the term infant. Semin Perinatol. Dec 2004;28(6):415-24. [Medline].
Pichler G, Urlesberger B, Müller W. Impact of bradycardia on cerebral oxygenation and cerebral blood volume during apnoea in preterm infants. Physiol Meas. Aug 2003;24(3):671-80. [Medline].
Razi NM, DeLauter M, Pandit PB. Periodic breathing and oxygen saturation in preterm infants at discharge. J Perinatol. Sep 2002;22(6):442-4. [Medline].
Rigatto H. Maturation of breathing. Clin Perinatol. Dec 1992;19(4):739-56. [Medline].
Rigatto H, Brady JP. Periodic breathing and apnea in preterm infants. I. Evidence for hypoventilation possibly due to central respiratory depression. Pediatrics. Aug 1972;50(2):202-18. [Medline].
Sanchez PJ, Laptook AR, Fisher L, et al. Apnea after immunization of preterm infants. J Pediatr. May 1997;130(5):746-51. [Medline].
Sawnani H, Jackson T, Murphy T, et al. The effect of maternal smoking on respiratory and arousal patterns in preterm infants during sleep. Am J Respir Crit Care Med. Mar 15 2004;169(6):733-8. [Medline].
Southall DP, Levitt GA, Richards JM, et al. Undetected episodes of prolonged apnea and severe bradycardia in preterm infants. Pediatrics. Oct 1983;72(4):541-51. [Medline].
Stefano JL, Anday EK, Davis JM, et al. Pneumograms in premature infants: a study of longitudinal data. Am J Perinatol. May 1991;8(3):170-3. [Medline].
Tamim H, Khogali M, Beydoun H, et al. Consanguinity and apnea of prematurity. Am J Epidemiol. Nov 15 2003;158(10):942-6. [Medline].
Yamamoto A, Yokoyama N, Yonetani M, et al. Evaluation of change of cerebral circulation by SpO2 in preterm infants with apneic episodes using near infrared spectroscopy. Pediatr Int. Dec 2003;45(6):661-4. [Medline].
Further Reading
Keywords
apnea of prematurity, AOP, fetal breathing, pathologic apnea, central apnea, obstructive apnea, mixed apnea, apnea of infancy, AOI, neonatal apnea, sudden infant death syndrome, SIDS, crib death, cot death
