Seminars in Neonatology (2004) 9, 205e211

www.elsevierhealth.com/journals/siny

Clinical correlates, natural history and outcome of neonatal apnoea

Terry M. Baird)
Case Western Reserve University, 11100 Euclid Ave., Cleveland, OH 44106, USA

KEYWORDS
Apnoea; Bradycardia; Sudden infant death syndrome (SIDS)

Summary Apnoea is common in the newborn period and especially in preterm newborns. Bradycardia and desaturation of oxyhaemoglobin typically occur with apnoea. These abnormalities reect an immature cardiorespiratory system and resolution of this immaturity can be expected within a predictable time frame. Infants who have apnoea in the newborn period are thought not to be at higher risk for sudden infant death syndrome (SIDS). Whether apnoea episodes are associated with a higher incidence of long-term handicap for these infants is not yet clear. 2003 Elsevier Ltd. All rights reserved.

Episodes of apnoea resulting from immaturity of respiratory control decrease with advancing age and eventually the breathing abnormalities exhibited by premature infants become indistinguishable from their counterparts born at full term.1,2 There are two areas of concern regarding neonatal apnoea: rst, whether these episodes are precursors to, or predictors of, any other cardiorespiratory problems and second whether apnoea episodes and the resultant hypoxia compromise a newborns long-term outcome. Immature cardiorespiratory control has been traditionally described in terms of the effect on heart rate and breathing pattern. Recently interest had been directed toward oxyhaemoglobin saturation as detected by pulse oximetry. Abnormalities in breathing are therefore seen as apnoea, bradycardia and desaturations and

the development of cardiorespiratory control can be described and followed clinically in all three.

Clinical aspects of apnoea, bradycardia and their resolution

Pauses in breathing are a relatively common phenomenon in newborns and these pauses are increasingly frequent and longer in duration with decreasing gestational age.3,4 These episodes are present beginning on the rst day of life for some premature infants and often include bradycardia and oxyhaemoglobin desaturation as measured by pulse oximetry.3,5,6 Apnoea can be classied according to various physiological mechanisms (central, obstructive and mixed).7 Central apnoea occurs in the absence of respiratory effort. Obstructive apnoea occurs when there is collapse of the airway and no airow takes place despite continued breathing effort. When airway collapse occurs in association with a central pause, mixed apnoea results. Because these subtypes differ in

) Tel.: D1-216-844-5140; fax: D1-216-844-3380. E-mail address: tbaird73@hotmail.com.

1084-2756/$ - see front matter 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2003.11.007

206 certain physiological features, the detection of apnoea is dependent on the methodology employed to observe it. Most neonatal intensive care units (NICUs) and home monitors utilize impedance technology. Impedance pneumography detects respiration by translating changes in electrical properties of the thorax into a waveform that represents breathing. Movement of the chest wall contributes the signal of greatest magnitude, although blood ow through the heart and great vessels also affects this signal. Both false-positive and falsenegative detection of apnoea can occur. Preterm infants typically exhibit mixed apnoea,8 which can go undetected by transthoracic impedance. Therefore the extent of abnormal breathing will not be appreciated. Respiratory inductance plethysmography may give a more accurate picture of an infants cardiorespiratory development, however this technique is not in widespread clinical use.9 Additional features of immature cardiorespiratory control are similarly dependent on technological considerations, such as whether pulse oximetry is monitored and how these data are displayed and recorded. Clinical ndings associated with apnoea may include cyanosis, pallor and hypotonia. While apnoea may occur as an isolated event, it commonly is associated with bradycardia and desaturation of peripheral oxyhaemoglobin. These associations are consistently seen in both hospitalized infants and those on home monitoring. While clinical care has focused on prolonged apnoea, that is, pauses greater than 20 s, alterations of heart rate and oxyhaemoglobin saturation may be seen with shorter episodes. Additionally, apnoea events exceeding 30 s are occasionally seen in both healthy term and preterm infants.1 This suggests that apnoea duration per se may not be the critical feature of altered breathing and its relation to circulatory consequences. Apnoea episodes lasting longer than 30 s were described by Daily (1969) in 25% of hospitalized preterm infants.10 Later reports would focus on apnoea that continued after discharge from the hospital, with the apnoea duration interval of interest shortened to 15e20 s. While no data have been offered to arrive at an optimal denition of apnoea, the conventional denition is absence of breathing for more than 20 s, or a shorter pause associated with clinical signs, such as bradycardia or cyanosis. Numerous conditions in the newborn may have apnoea as a presenting sign. Before concluding that apnoea is due to immature respiratory control, other potential causes should be considered. Central nervous system problems, particularly intra-

T.M. Baird cranial bleed can produce apnoea. Infections (sepsis, meningitis) and anaemia may also present with an abnormal breathing pattern. Other conditions that sometimes precipitate apnoea include metabolic disorders, especially hypoglycaemia, temperature instability and drugs administered to the mother such as opiates and magnesium. The possibility of gastro-oesophageal reux (GOR) as a cause for apnoea should be considered cautiously. Although both apnoea and GOR are often seen in premature infants, investigations into the timing of reux suggest the relationship is often coincidental rather than causal. This may explain the nding that treatment of reux in premature infants has little effect on apnoea episodes.11 Episodes of bradycardia are common in preterm infants and often occur along with apnoea. Bradycardia may be a result of chemoreceptor induced inhibition of heart rate,12 or possibly hypoxia associated with apnoea (Fig. 1). Episodes of bradycardia that include intervals of as long as 3 s without a QRS complex are sometimes seen in preterm infants, typically with no clear evidence of a disturbance in cardiac rhythm. With the increasing availability and accuracy of pulse oximetry, attention has turned to desaturation events.13 Episodes of oxyhaemoglobin desaturation are familiar in preterm infants and can also be demonstrated in healthy term infants. When home monitoring data were sampled for epochs of non-event data in a control (healthy term) cohort of infants, occasional episodes of desaturation were not uncommon. Desaturation to at least 10% below baseline was found in 59% of the infants. These episodes occurred in 0.51% of the sampled time intervals.14 The likelihood of oxyhaemoglobin desaturation and the depth of this desaturation are generally related to the duration of apnoea and to any associated heart rate change. When 21 647 events of

Decreased Respiratory Drive

APNOEA, HYPOVENTILATION inhibitory reflexes decreased oxygen delivery BRADYCARDIA carotid body DESATURATION

Figure 1 Possible mechanisms relating apnoea, bradycardia and oxyhaemoglobin desaturation (reprinted with permission from Ref.13).

Clinical correlates, natural history and outcome of neonatal apnoea

207

Median decrease % SpO2

30 25 20 15 10 5 0

Apnoea duration
< 16 s 1619.9 s 2029.9 s > 30 s

None

Mild

Moderate

Severe

Bradycardia
Figure 2 Decrease in percentage of oxygen saturation (SpO2) in infants experiencing apnoea or bradycardia. The baseline saturation for all events was 98e99% (reproduced with permission from Ref.1).

apnoea were analyzed for decrease in oxyhaemoglobin saturation (SpO2), median desaturation increased (SpO2 was lower) with increasing length of apnoea duration. Furthermore, by categorizing bradycardia according to severity, this desaturation was seen to worsen with increasing severity of bradycardia, except the most extreme events (Fig. 2).1

Treatment of apnoea
The methylxanthines are the pharmacological agents most commonly used for the treatment of apnoea. Theophylline (1,3-dimethylxanthine) was rst reported for use in apnoea of prematurity in the 1970s.15 It has been used extensively since that time. Initial reports emphasized increased respiratory centre output16 and enhanced diaphragmatic contractility17 as a mechanism of action. Caffeine (1,3,7-trimethylxanthine) has also been shown to decrease apnoea in preterm infants and may be the preferable agent for a number of reasons. Its therapeutic index is higher, making toxicity less of a concern. Also, because of its longer halflife, once a day dosing is possible.18 A Cochrane review of the use of methylxanthines concluded that there is evidence that they reduce apnoea episodes and decrease the use of intermittent positive pressure ventilation (IPPV) in preterm infants.19 Although the precise site of action and mechanism(s) whereby apnoea is decreased have not been determined, evidence suggests methylxanthines stimulate central neural output to the respiratory muscles, probably via antagonism of adenosine receptors.

Side effects of theophylline include hyperactivity, tachycardia, cardiac dysrhythmias, feeding intolerance and seizures. Mild diuresis is seen with all methylxanthines. Possible drugedrug interactions include medications that affect liver function and medications where clearance is dependent on cytochrome P-450. Due to the limited therapeutic benet and ongoing questions regarding long-term side effects,20 clinical trials continue in the use of methylxanthines for apnoea of prematurity. Doxapram is a respiratory stimulant that is typically used in addition to a methylxanthine.21,22 In two head-to-head trials (both involving small numbers of infants) it was shown to be effective but no better for the reduction of apnoea in preterm infants and may have some additive effect when used in refractory cases.23,24 Side effects include poor tolerance of the oral preparation and a report of second-degree heart block in a small number of preterm infants.25 Non-pharmacological approaches have been used in the treatment of apnoea. Continuous positive airway pressure (CPAP) is a relatively safe and effective treatment. CPAP is thought to decrease the frequency of apnoea by splinting the upper airway with positive pressure. Because apnoea frequently involves an obstructive component, CPAP is effective in infants whose episodes are precipitated or prolonged by pharyngeal obstruction. High-ow nasal cannula has been suggested as an equivalent treatment modality.26 For refractory cases, endotracheal intubation and articial ventilation may be needed. Minimal ventilator settings should be used to allow for spontaneous ventilatory efforts and to minimize the risk of barotrauma.

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T.M. Baird abnormalities in normal infants, apnoea exceeding 15 s was only found in the rst month of life, although the duration of shorter apnoeas did not change as development proceeded.29 Apnoea of prematurity can be expected to resolve by about 37 weeks post-conceptual age (PCA), with some notable exceptions. CHIME Study data showed that cardiorespiratory events in preterm infants return to the baseline normal level at about 43e44 weeks PCA. In other words, beyond 43e44 weeks post-PCA the incidence of cardiorespiratory events in preterm infants does not significantly exceed that in term babies.1 In an earlier report of term and preterm infants, 249 infants with apnoea were drawn from a pool of O25 000 births. Apnoea episodes were shown to disappear by 37 weeks PCA in 92% of these infants and by 40 weeks PCA 98% were apnoea-free.30 This sample may not have included sufcient numbers of extremely small infants to reect their special problems. More recently, it has been shown that in the most premature infants (24e28 weeks gestation) apnoea frequently persists beyond 36 weeks post-PCA and may persist beyond 40 weeks postPCA.31

Resolution of apnoea
Frequency and severity of events
In the largest study to date of post-discharge cardiorespiratory events, the Collaborative Home Infant Monitoring Evaluation (CHIME study) described 6993 events exceeding conventional monitor thresholds in 445 infants. These subjects were from a total enrollment of 1097 infants that included six epidemiological groups thought to possibly be at risk for SIDS, and normal control infants. There was a total of 718 358 h of monitor use; inductance plethysmography was utilized. Events occurred in 41% of all infants, including the healthy term (control) infants. The majority of events were apnoea without bradycardia: 75% of all events.1 This is in contrast to reports of events when transthoracic impedance is utilized, which have suggested that bradycardia is the predominant event.27 This discrepancy is most likely due to methodology as explained above. Indeed, 70% of all apnoeic events included at least three obstructed breaths in the CHIME study event data. When apnoea of shorter duration is considered, the frequency of events rises dramatically.1,4 Di Fiore et al. described events in a group of infants referred for clinical bedside studies; she found that the incidence of 20 s apnoea episodes was relatively low and did not distinguish clinically abnormal infants from matched controls. There were numerous events of shorter duration and these were often associated with bradycardia and desaturations.28 In a cohort of 35 infants monitored overnight, there were 865 events of either apnoea, bradycardia or desaturation. When considering the question of longterm morbidity associated with apnoea, short events will therefore account for the majority of instances of oxyhaemoglobin desaturation, although the magnitude of desaturation increases as apnoea duration lengthens. If recurrent episodes of hypoxia are found to compromise an infants long-term outcome, measuring and quantifying events will be a central question in describing abnormal breathing.

Discharge from hospital

Most preterm infants no longer have signicant episodes of apnoea by the time they are ready for hospital discharge. This generally occurs at about the same time as maturation of temperature control and feeding pattern. An apnoea-free observation period, usually ranging from 3e7 days is often utilized as a criterion for determining discharge. In the only study that has attempted to address this issue, an apnoea-free interval of 8 days was suggested.32 In a subset of infants, however, discharge may be delayed by persistence of cardiorespiratory events. In these infants, home cardiorespiratory monitoring until 43e44 weeks PCA may offer an alternative to a prolonged hospital stay.

Home monitoring
When home cardiorespiratory monitoring is prescribed, documented (event recording) monitoring can help the clinician follow the ongoing resolution of events. The question of whether or not monitoring otherwise benets these infants is still unresolved. One of the ways in which the home apnoea monitor may function is as a therapeutic device. It has been suggested that the alarm may not only alert the caregivers, but the auditory stimulus may arouse the infant sufciently to terminate

Resolution of apnoea
Both full term and preterm infants show a progressive decrease in apnoea episodes over time. However, a large variation of apnoea frequency is found between infants and in the same infant on repeat apnoea recordings. Both periodic breathing density and apnoea density decrease with advancing age. In a relatively small study describing these

Clinical correlates, natural history and outcome of neonatal apnoea an event. This hypothesis has never been rigorously tested. Alternatively, the monitor may serve as an alarm mechanism. According to this model, the monitor alarm alerts a caregiver to a potentially dangerous condition and intervention can be made in a timely fashion. However, there is no good evidence to suggest that monitors as they are currently congured and used provide a warning that is related to an impending dangerous event. It is similarly not known whether such an event could be terminated while in progress. It has been suggested that infants with frequent events should be rehospitalized and have further studies and that additional diagnoses might come to medical attention in this manner.27 Whether these infants would eventually declare themselves otherwise is uncertain. Epidemiological studies have not shown an effect of home monitors when used in Sudden Infant Death Syndrome (SIDS) prevention.33 Rosen et al. have recently observed that sleep disordered breathing in 8e11 year old children is more prevalent in those with a history of prematurity.34 This raises the questions as to whether a prior history of apnoea of prematurity and accompanying physiological phenomena might predispose to longer lasting disordered respiratory regulation and might be worthy of a prospective study.

209

function, neuropsychological abilities, academic achievement and parent and teacher ratings of child behaviour and school performance. Another series of very low birth weight (VLBW) infants followed to 24 months of age showed a correlation between predischarge apnoea and lower mental and motor neurodevelopmental scores.36 Other series of case comparisons have reported no difference in outcome of infants with apnoea.37,38 It is possible that recurrent hypoxia, not apnoea per se is the detrimental feature of the breathing abnormalities exhibited by some preterm infants. However, even if an association between recurrent hypoxia and poor neurodevelopment can be established, this does not prove a cause and effect relationship.

Relationship to SIDS
Evidence indicates that apnoea is not predictive of, or a precursor to, SIDS. An initial case report from the early 1970s linked apnoea and SIDS in multiple infants in a family.39 This report generated the hypotheses that apnoea might be a precursor to SIDS and also that abnormal breathing might predict which infants might later die of SIDS. When this initial case report was revealed (years later) to be multiple cases of infanticide, reconsideration of the role of apnoea was warranted. Numerous abnormalities in breathing, heart rate and sleep have been identied in selected populations thought to represent infants who might die of SIDS. Suspected abnormalities have included periodic breathing,40 abnormalities in short-term descriptors of heart rate and breathing41,42 and apnoea characteristics.43 Many of the described abnormalities were seen in infants with a so-called near-miss event, or who came to attention as subsequent siblings of SIDS infants. These groups may be a heterogeneous mixture with various problems and ndings have been inconsistent. A prospective approach has been to describe breathing abnormalities in infants who had physiological studies (for various reasons) and who would later die of SIDS. Whereas one of these population-based studies identied subtle breathing and heart rate abnormalities,44 generally this approach has failed to show any conclusive predictors.45 Similarly, epidemiologically based data on the use of home apnoea monitors are limited, but have failed to show any conclusive effect of home monitoring on SIDS rates.32,46 When age at SIDS death is compared to the disappearance of pathological apnoea, it is seen that apnoea of prematurity resolves prior to the peak incidence of SIDS. This nding lends further support to the

Consequences of apnoea of prematurity

Developmental outcome
There are few conclusive reports describing the relationship between apnoea in premature infants and neurodevelopmental outcome. The reports that do exist are all confronted with the problem of separating the consequences of premature birth from the effects of apnoea. Infants born prematurely have a higher rate of central nervous system injury, especially periventricular leukomalacia and intraventricular haemorrhage. These conditions by themselves contribute to poor neurodevelopmental outcome and also cause apnoea. No study has looked at baseline neurological status and retested this nding after the occurrence of events. Finally, studies that assess improvement in long-term outcome as a result of treating apnoea of prematurity are few and are confounded by these same issues. Nevertheless, a few follow-up studies of at-risk infants have attempted to address this problem. In one cohort of preterm infants, factors that predicted poor neurodevelopmental outcomes at early school age included apnoea of prematurity.35 Outcomes measured in this group included cognitive

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T.M. Baird
monitors: comparison of healthy infants with those at increased risk for SIDS. J Am Med Assoc 2001;285:2199e207. 2. Parmelee AH, Stern E, Harris MA. Maturation of respiration in prematures and young infants. Neuropadiatrie 1972; 3:294e304. 3. Henderson-Smart DJ. The effect of gestational age on the incidence and duration of recurrent apnoea in newborn babies. Aust Pediatr J 1981;17:273e6. 4. Hodgeman JE, Gonzalez F, Hoppenbrouwers T, Cabal LA. Apnea, transient episodes of bradycardia, and periodic breathing in preterm infants. Am J Dis Child 1990;144:54e7. 5. Barrington K, Finer N. The natural history of the appearance of apnea of prematurity. Pediatr Res 1991;29:372e5. 6. Carlo WA, Martin RJ, Versteegh FGA, Goldman MD, Robertson SS, Fanaroff AA. The effect of respiratory distress syndrome on chest wall movements and respiratory pauses in preterm infants. Am Rev Respir Dis 1982;26:103e7. 7. Miller MJ, Martin RJ. Pathophysiology of apnea of prematurity. In: Polin RA, Fox WW, editors. Fetal and neonatal physiology. 2nd ed. London: W.B. Saunders Company; 1998. p. 1129e41. 8. Thach BT, Stark AR. Spontaneous neck exion and airway obstruction during apneic spells in preterm infants. J Pediatr 1979;94:275. 9. Brouillette RT, Morrow AS, Weese-Mayer DE, Hunt CE. Comparison of respiratory inductive plethysmography and thoracic impedance for apnea monitoring. J Pediatr 1987; 111:377e83. 10. Daily WJR, Klaus M, Meyer HBP. Apnea in premature infants: monitoring, incidence, heart rate changes, and an effect of environmental temperature. Pediatrics 1969;43: 510e8. 11. Kimball AL, Carlton DP. Gastroesophageal reux medications in the treatment of apnea in premature infants. J Pediatr 2001;138:355e60. 12. Henderson-Smart DJ, Butcher-Puech MC, Edwards DA. Incidence and mechanism of bradycardia during apnoea in preterm infants. Arch Dis Child 1986;61:227e32. 13. Martin RJ, Fanaroff AA. Neonatal apnea, bradycardia or desaturation: does it matter? J Pediatr 1998;132:758e9. 14. Hunt CE, Corwin MJ, Lister G, Weese-Mayer DE, Neuman MR, Tinsley L, et al. Longitudinal assessment of hemoglobin oxygen saturation in healthy infants during the rst 6 months of age. J Pediatr 1999;134:580e6. 15. Aranda JV, Gorman W, Bergsteinsson H, Gunn T. Efcacy of caffeine in treatment of apnea in the low-birthweight infant. J Pediatr 1977;90:467e72. 16. Gerhardt T, McCarthey J, Bancalari E. Effect of aminophylline on respiratory center activity and metabolic rate in premature infants with idiopathic apnea. Pediatrics 1979; 63:537e42. 17. Aubier M, DeTroyer A, Sampson M, Macklem PT, Roussos C. Aminophylline improves diaphragmatic contractility. N Engl J Med 1981;305:249e52. 18. Aranda JV, Cook CE, Gorman W, Collinge JM, Laughnan PM, Outerbridge EW, et al. Pharmacokinetic prole of caffeine in the premature newborn infant with apnea. J Pediatr 1979;94:664e8. 19. Steer PA, Henderson-Smart DJ. Caffeine versus theophylline for apnea in preterm infants. Cochrane Database Syst Rev 2000;2:CD000273. 20. Schmidt B. Methylxanthine therapy in premature infants: sound practice, disaster, or fruitless byway? J Pediatr 1999;135:526e8. 21. Bairam A, Faulon M, Monin P, Vert P. Doxapram for the initial treatment of idiopathic apnea of prematurity. Biol Neonate 1992;61:209e13.

Relative incidence

Apnoea of prematurity 24 weeks GA

}
40 weeks GA Pre-term Term 3 months Age

SIDS (m SD)

6 months

Figure 3 Relationship between the timing of peak incidence of SIDS (sudden infant death syndrome) to the (relative) incidence of apnoea in infants with apnoea of prematurity. GA, gestational age; m, mean; SD, standard deviation (reproduced with permission from Ref.47).

notion that apnoea of prematurity is unrelated to SIDS (Fig. 3).

Practice points
 A thorough consideration of the possible causes is necessary for each infant who presents with apnoea.  The time course for the resolution of apnoea of prematurity is predictable on the basis of post-conceptual age.  The most premature infants can be expected to take longer to resolve their apnoea of prematurity.  Methylxanthines may decrease the need for more invasive respiratory support, however, further investigation regarding their long-term side effects is warranted.

Research directions
Research is needed for the following:  Understanding of the relationship of apnoeic episodes to oxygenation of vital organs, particularly the brain.  Determining the long-term consequences of treating apnoea with methylxanthines.  Dening a method for quantifying apnoea in the newborn.  Determining whether apnoea has any longterm outcome consequences independent of preterm birth.

References
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Clinical correlates, natural history and outcome of neonatal apnoea

22. Poets CF, Darraj S, Bohnhorst B. Effect of doxapram on episodes of apnoea, bradycardia and hypoxaemia in preterm infants. Biol Neonate 1999;76:207e13. 23. Eyal F, Alpan G, Sagi E, Glick B, Peleg O, Dgani Y, et al. Aminophylline versus doxapram in idiopathic apnea of prematurity: a double-blind controlled study. Pediatrics 1985;75:709e19. 24. Peliowski A, Finer N. A blinded, randomized, placebocontrolled trial to compare theophylline and doxapram for the treatment of apnea of prematurity. J Pediatr 1990; 116:648e53. 25. De Villers GS, Walele A, Van Der Merwe P-L, Kalis NN. Second-degree atrioventricular heart block after doxapram administration. J Pediatr 1998;133:149e50. 26. Sreenan C, Lemke RP, Hudson-Mason A, Osiovich H. Highow nasal cannulae in the management of apnea of prematurity: a comparison with conventional nasal continuous positive airway pressure. Pediatrics 2001;107:1081e3. 27. Cote A, Hum C, Brouilette RT, Themens M. Frequency and timing of recurrent events in infants using home cardiorespiratory monitors. J Pediatr 1998;312:783e9. 28. Di Fiore JM, Arko MK, Miller MJ, Krauss A, Betkerur A, Zadell A, et al. Cardiorespiratory events in preterm infants referred for apnea monitoring studies. Pediatrics 2001;108:1304e8. 29. Hoppenbrouwers T, Hodgeman JE, Harper RM, Hofman E, Sterman MB, McGinty DJ. Polygraphic studies of normal infants during the rst six months of life: III. Incidence of apnea and periodic breathing. Pediatrics 1977;60:418e25. 30. Henderson-Smart DJ. The effect of gestational age on the incidence and duration of recurrent apnoea in newborn babies. Aust Paediatr J 1981;17:273e6. 31. Eichenwald EC, Aina A, Stark AR. Apnea frequently persists beyond term gestation in infants delivered at 24 to 28 weeks. Pediatrics 1997;100:354e9. 32. Darnall RA, Kattwinkel J, Nattie C, Robinson M. Margin of safety for discharge after apnea in preterm infants. Pediatrics 1977;100:795e801. 33. Ward SL, Keens TG, Chan LS, Chipps BE, Carson SH, Deming DD, et al. Sudden infant death syndrome in infants evaluated by apnea programs in California. Pediatrics 1986;77:451e5. 34. Rosen CL, Larkin EK, Kirchner L, Emancipator JL, Bivins SF, Surovec SA, et al. Prevalence and risk factors for sleepdisordered breathing in 8- to 11-year-old children: association with race and prematurity. J Pediatr 2003;142:383e9.

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35. Taylor HG, Klein N, Schatschneider C, Hack M. Predictors of early school age outcomes in very low birth weight infants. J Dev Behav Pediatr 1998;19:235e43. 36. Cheung P, Barrington KJ, Finer NN, Robertson CMT. Early childhood neurodevelopment in very low birth weight infants with predischarge apnea. Pediatr Pulmonol 1999;27:14e20. 37. Koons AH, Mojica N, Jadeja N, Ostfeld B, Hiatt M, Hegyi T. Neurodevelopmental outcome of infants with apnea of infancy. Am J Perinatol 1993;10:208e11. 38. Levitt GA, Mushin A, Bellman S, Harvey DR. Outcome of preterm infants who suffered neonatal apnoeic attacks. Early Hum Dev 1998;16:235e43. 39. Steinschneider A. Prolonged apnea and the sudden infant death syndrome: clinical and laboratory observations. Pediatrics 1972;50:646e54. 40. Kelly DH, Shannon DC. Periodic breathing in infants with near-miss sudden infant death syndrome. Pediatrics 1979; 63:355e69. 41. Leistner HL, Haddad GG, Epstein RA, Lai TL, Epstein MA, Mellins RB. Heart rate and heart rate variability during sleep in aborted sudden infant death syndrome. J Pediatr 1980; 97:51e5. 42. Gordon D, Cohen RJ, Kelly D, Akselrod S, Shannon DC. Sudden infant death syndrome: abnormalities in short term uctuations in heart rate and respiratory activity. Pediatr Res 1984;18:921e6. 43. Kahn A, Blum D, Rebuffat E, Sottiaux M, Levitt J, Bochner A, et al. Polysomnographic studies of infants who subsequently died of sudden infant death syndrome. Pediatrics 1988; 82:721e7. 44. Schectman VL, Harper RM, Wilson AJ, Southall DP. Sleep apnea in infants who succumb to the sudden infant death syndrome. Pediatrics 1991;7:841e6. 45. Hoffman HJ, Damus K, Hillman L, Krongrad E. Risk factors for SIDS. Results of the National Institute of Child Health and Human Development SIDS Cooperative Epidemiological Study. Ann N Y Acad Sci 1988;533:13e30. 46. MacKay M, Abreu e Silva FA, MacFadyen UM, Williams A, Simpson H. Home monitoring for central apnea. Arch Dis Child 1984;59:136e42. 47. Miller MT, Fanaroff AA, Martin RJ. Respiratory disorders in preterm and term infants. In: Fanaroff AA, Martin RJ, editors. Neonataleperinatal medicine. 7th ed. Philadelphia: Harcourt; 2002. p. 1025e49.