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Apnea of Prematurity
Dharmendra J Nimavat, MD, FAAP, Assistant Professor of Clinical Pediatrics, Department of Pediatrics, Division of Neonatology, Southern Illinois University School of Medicine
Michael P Sherman, MD, Professor, Department of Child Health, University of Missouri-Columbia School of Medicine; Director, Fellowship Training Program in Neonatal-Perinatal Medicine, NICU, Columbia Regional Hospital; Professor Emeritus, Department of Pediatrics, University of California, Davis, School of Medicine; Rene L Santin, MD, Consulting Staff, Department of Pediatrics, Division of Neonatology, Primary Care Centers of Eastern Kentucky; Rachel Porat, MD, Director, Neonatal Apnea Monitoring Program, Assistant Director, Division of Neonatology, Albert Einstein Medical Center; Associate Professor, Department of Pediatrics, Thomas Jefferson University
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, and 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).
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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.
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Polysomnogram. Mixed apnea contains elements of both central and obstructive apnea. ECG = electrocardiogram; HR = heart rate (bpm); THO = thoracic movement; FLOW = flow from the 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).
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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 from the 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 40-50 mcg/mL is toxic
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 (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
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 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.123 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 apnea of prematurity 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 gastroesophageal reflux (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:124,26
• 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.125 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.126,127 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 apnea of prematurity 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
Medicolegal Pitfalls
An Internet search of the terms preterm infant, sudden infant death syndrome (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).128
Special Concerns
Controversies Related to Apnea of Prematurity
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.129 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.130 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.131
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 reported that apnea and other adverse events were as likely to occur in car beds as in car seats.132 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.133 Moreover, pacifiers do not affect breastfeeding in preterm infants.134 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 apnea of prematurity should or should not have home monitoring have been evaluated in clinical trials.
Gastroesophageal reflux
Despite the overwhelming body of evidence that gastroesophageal reflux (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 apnea of prematurity has been discussed throughout this article.
Sudden Infant Death Syndrome–Related Concerns
Possible risk factors for SIDS or near-miss SIDS
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 apnea of prematurity 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 apnea of prematurity 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 apnea of prematurity 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 apparent life-threatening event [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.
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.135,136 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.124 The mechanism by which sleeping in the prone position can lead to SIDS is unclear.
In the Nordic Epidemiological SIDS study, Oyen et al concluded that sleeping in both the prone and side positions increased the risk of SIDS. In addition, side-lying sleep could result in prone sleep.137 The risk is further increased among low-birth-weight infants, infants born before term, and infants aged 13-24 weeks.
Soft bedding and shared sleeping are other factors related to SIDS. Posturing and cyanosis are often present, as is an increased incidence of prematurity, low birth weight, and evidence of poor prenatal care. Findings from epidemiologic studies suggest that as many as 18% of SIDS cases occur in infants who were born prematurely.
Polygraphic monitoring for SIDS
The aforementioned findings prompted the development of polygraphic monitoring to measure variables such as heart rate, nasal airflow, chest and abdominal movement, and transcutaneous O2 tension or O2 saturation to predict the risk for SIDS in vulnerable infants. A number of studies involving large cohorts of infants have not demonstrated that monitoring of cardiorespiratory variables can be used to prospectively identify infants at risk for SIDS.
At present, no simple and accurate method is available to predict whether a premature infant is likely to die from SIDS.
Home monitoring for SIDS
At present, home monitoring is conducted in more infants born prematurely than in any other pediatric population. Each year, perhaps as many as 15-20% of the 400,000 premature babies are treated with home cardiorespiratory monitoring, primarily to manage apnea but also to prevent SIDS.
Despite the number of premature infants receiving home monitoring, this therapy has not been embraced universally, and it remains controversial. Advocates believe that monitoring can alert caretakers to potentially serious episodes of apnea and/or bradycardia before they cause harm, helping parents to cope with the anxiety of caring for an infant born prematurely. Opponents cite the lack of evidence to indicate that monitoring alters the outcomes in any definable way. To the authors' knowledge, no prospective study has demonstrated that monitoring prevents SIDS. Furthermore, many physicians believe that the decision to use home monitoring places an emotional burden on parents.
Many programs have been developed to enable home cardiorespiratory monitoring of prematurely born neonates to reduce the rate of SIDS. However, to the authors' knowledge, no prospective randomized control study has been conducted to show that home cardiorespiratory monitoring prevents SIDS.
Anecdotal data from some programs suggest that the incidence of SIDS is lowered among premature neonates who are monitored extensively. However, the authors are aware of no data proving that home monitoring has caused this reduction in the incidence of SIDS.
Also unclear is whether this approach is a cost-effective adjunct to neonatal care. Even programs that have reduced the incidence of SIDS have reported deaths among the babies who were monitored. Moreover, the cost of hospitalization has increased to such an extent that the expense of a single inpatient day may be as costly as several months of home cardiorespiratory monitoring.
Ages of death
In term neonates, the acknowledged peak age of death from SIDS is 2-4 months, with a mean age of 52 weeks after conception. The peak age of death for the premature infant is approximately 4-6 months, but the mean age of 52 weeks after conception is the same. Therefore, a premature neonate may be at risk for SIDS for a long period after hospital discharge.
Little data are available regarding the comparative risks of SIDS among preterm neonates born at different postconceptional ages. The similarities in postconceptional ages of death for both term and preterm neonates suggests that a neurodevelopmental phenomenon may be among the etiologies of this as-yet unexplained problem.
SIDS prevention
Accumulating evidence from many countries indicates the importance of 2 factors for SIDS prevention in term infants:
1. Placing infants supine for sleeping
2. Preventing infants' exposure to cigarette smoke both during and after pregnancy
Unless clear contraindications are present, treat premature neonates in a similar manner. These interventions appear to reduce the incidence of SIDS far more than home monitoring does. However, in some clinical situations, monitoring may be valuable to treat apnea of prematurity and to help families cope with the discharge of a low-birth-weight infant.
Non–Sudden Infant Death Syndrome Monitoring Issues
Since the introduction of NICUs, preterm neonates have received an extraordinarily high level of medical support to compensate for various degrees of organ immaturity at birth. Unfortunately, the effectiveness of current NICU technology cannot begin to approach the combined effectiveness of placental circulation and maternal metabolism. As a result, some premature babies survive, with different degrees of injury to certain organ systems.
Bronchopulmonary dysplasia, cardiac disease, periventricular leukomalacia and other neurologic problems, and feeding difficulties are among the many problems that may require home monitoring for ongoing medical care. In these settings, monitoring appears valuable for alerting caretakers to any physiologic changes (eg, bradycardia, tachycardia, hypoxemia, seizures) that may require intervention.
Without home monitoring, many infants might be hospitalized unnecessarily. The emotional and financial costs associated with such hospitalization may be far greater than those borne if they child and family were at home. In such instances, home monitoring may be an effective and safe approach to medical care.
Home monitoring also may be an effective diagnostic tool for children whose events are so sporadic that they cannot be detected easily in the hospital. For example, newly developed monitoring devices can record abnormal events and can be used to detect and quantify infrequent episodes of apnea or ALTE, while helping to maintain a normal living situation for the child. If frequent events are detected, additional evaluation may be needed to identify a specific cause. Studies such as ECG, electroencephalography, cerebral imaging, and metabolic testing may be valuable in such instances.
Whether the use of monitoring devices and/or pharmacologic agents (eg, methylxanthines) reduces apnea and improves neurodevelopmental outcomes in infants born prematurely is unknown. Because of the complex nature of the infant's medical problems, the contribution of apnea to any developmental disability is difficult to estimate but was suggested in recent publications.56 Frequent apnea may adversely affect neurodevelopmental outcomes, especially when it is accompanied by bradycardia and O2 desaturation, and it should be reduced or prevented if possible.138
Neonatologists are aware of the parents' anxiety when they take their low-birth-weight infant home. With recent changes in inpatient care, many premature babies now leave the hospital with discharge weights of 1800-2000 g. Home monitoring may help such infants make the transition to their home setting. Again, carefully train all caretakers who will care for the infant at home. Include instruction in the use of the monitor and in how to perform cardiopulmonary resuscitation (CPR). Of course, inform parents that monitoring might not prevent SIDS.
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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
Contributor Information and Disclosures
Author
Dharmendra J Nimavat, MD, FAAP, Assistant Professor of Clinical Pediatrics, Department of Pediatrics, Division of Neonatology, Southern Illinois University School of Medicine
Dharmendra J Nimavat, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics and American Association of Physicians of Indian Origin
Disclosure: Nothing to disclose.
Coauthor(s)
Michael P Sherman, MD, Professor, Department of Child Health, University of Missouri-Columbia School of Medicine; Director, Fellowship Training Program in Neonatal-Perinatal Medicine, NICU, Columbia Regional Hospital; Professor Emeritus, Department of Pediatrics, University of California, Davis, School of Medicine
Michael P Sherman, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, European Society for Paediatric Research, Perinatal Research Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.
Rene L Santin, MD, Consulting Staff, Department of Pediatrics, Division of Neonatology, Primary Care Centers of Eastern Kentucky
Disclosure: Nothing to disclose.
Rachel Porat, MD, Director, Neonatal Apnea Monitoring Program, Assistant Director, Division of Neonatology, Albert Einstein Medical Center; Associate Professor, Department of Pediatrics, Thomas Jefferson University
Rachel Porat, MD is a member of the following medical societies: American Academy of Pediatrics
Disclosure: Nothing to disclose.
Medical Editor
Steven M Donn, MD, Professor of Pediatrics, University of Michigan Medical School; Director, Division of Neonatal-Perinatal Medicine, Department of Pediatrics, CS Mott Children's Hospital, University of Michigan Health System
Steven M Donn, MD is a member of the following medical societies: American Pediatric Society
Disclosure: Nothing to disclose.
Pharmacy Editor
Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner
Managing Editor
Arun K Pramanik, MD, MBBS, Professor of Pediatrics, Director of Neonatal Fellowship, Louisiana State University Health Sciences Center
Arun K Pramanik, MD, MBBS is a member of the following medical societies: American Academy of Pediatrics, American Thoracic Society, National Perinatal Association, and Southern Society for Pediatric Research
Disclosure: Nothing to disclose.
CME Editor
Carol L Wagner, MD, Professor of Pediatrics, Medical University of South Carolina
Carol L Wagner, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American Medical Women's Association, American Public Health Association, American Society for Bone and Mineral Research, American Society for Clinical Nutrition, Massachusetts Medical Society, National Perinatal Association, and Society for Pediatric Research
Disclosure: Nothing to disclose.
Chief Editor
Ted Rosenkrantz, MD, Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine
Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Pediatric Society, Connecticut State Medical Society, Eastern Society for Pediatric Research, and Society for Pediatric Research
Disclosure: Nothing to disclose.
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