cerebral oxygenation in preterm infants

Cerebral Oxygenation in Preterm Infants

WHAT’S KNOWN ON THIS SUBJECT: Prone sleeping is a major riskfactor for sudden infant death syndrome (SIDS). Cerebraloxygenation and blood pressure are reduced in the pronesleeping position in healthy term infants. Preterm infants are atsignificantly increased risk of SIDS.

WHAT THIS STUDY ADDS: Preterm infants display reducedcerebral oxygenation compared with term infants, mostprominently at 2 to 3 months corrected age in the prone positionwhen blood pressure is concurrently reduced. This maycontribute to the increased risk for SIDS among infants bornpreterm.

abstractBACKGROUND AND OBJECTIVE: Prone sleeping is a major risk factorfor sudden infant death syndrome (SIDS) and preterm infants are atsignificantly increased risk. In term infants, prone sleeping is associ-ated with reduced mean arterial pressure (MAP) and cerebral tissueoxygenation index (TOI). However, little is known about the effects ofsleeping position on TOI and MAP in preterm infants. We aimed to ex-amine TOI and MAP in preterm infants after term-equivalent age,during the period of greatest SIDS risk.

METHODS: Thirty-five preterm and 17 term infants underwentdaytime polysomnography, including measurement of TOI (NIRO-200 spectrophotometer, Hamamatsu Photonics KK, Japan) and MAP(Finapress Medical Systems, Amsterdam, Netherlands) at 2 to 4weeks, 2 to 3 months, and 5 to 6 months postterm age. Infantsslept prone and supine in active and quiet sleep. The effects ofsleep state and position were determined by using 2-way repeatedmeasures analysis of variance and of preterm birth by using 2-wayanalysis of variance.

RESULTS: In preterm infants, TOI was significantly lower when pronecompared with supine in both sleep states at all ages (P, .05). Notably,TOI was significantly lower in preterm compared with term infants at 2to 4 weeks, in both positions (P, .05), and at 2 to 3 months when prone(P , .001), in both sleep states. MAP was also lower in preterm infantsin the prone position at 2 to 3 months (P , .01).

CONCLUSIONS: Cerebral oxygenation is reduced in the prone positionin preterm infants and is lower compared with age-matched terminfants, predominantly in the prone position when MAP is alsoreduced. This may contribute to their increased SIDS risk. Pediatrics2014;134:435–445

AUTHORS: Karinna L. Fyfe, BMedSc,a,b Stephanie R.Yiallourou, PhD,a,b Flora Y. Wong, MBBS, PhD,a,b,c

Alexsandria Odoi, BNS (Hons),a Adrian M. Walker, PhD,a

and Rosemary S.C. Horne, PhDa,b

aThe Ritchie Centre, Monash Institute of Medical Research andPrince Henry’s Institute and Monash University, Melbourne,Australia; bDepartment of Paediatrics, Monash University,Melbourne, Australia; and cMonash Newborn, Monash MedicalCentre, Melbourne, Australia

KEY WORDSpreterm birth, sudden infant death syndrome, prone sleepingposition, cerebral oxygenation, blood pressure

ABBREVIATIONSANOVA—analysis of varianceAS—active sleepCA—corrected ageCBF—cerebral blood flowGA—gestational ageHb—hemoglobinHR—heart rateMAP—mean arterial pressureQS—quiet sleepSIDS—sudden infant death syndromeSpO2—pulse oxygen saturationTOI—tissue oxygenation index

Ms Fyfe participated in recruitment for the study, conducted thedata collection, carried out the data analyses, wrote the firstdraft of the manuscript, and critically reviewed and revised themanuscript; Dr Yiallourou contributed to design of the study,participated in data collection, and reviewed and revised themanuscript; Dr Wong contributed to design of the study,obtained funding for the study, assisted in recruitment for thestudy, and reviewed and revised the manuscript; Ms Odoiparticipated in data collection and reviewed and revised themanuscript; Dr Walker contributed to design of the study,obtained funding for the study, and reviewed and revised themanuscript; Dr Horne conceptualized and designed the study,obtained funding for the study, supervised data collection andanalysis, and critically reviewed and revised the manuscript;and all authors approved the final manuscript as submitted.

www.pediatrics.org/cgi/doi/10.1542/peds.2014-0773

doi:10.1542/peds.2014-0773

Accepted for publication May 27, 2014

Address correspondence to Rosemary S. C. Horne, PhD, TheRitchie Centre, Level 5 Monash Medical Centre, 246 Clayton Rd, POBox 5418, Clayton, Victoria, Australia 3168. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2014 by the American Academy of Pediatrics

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Preterm birth is increasing in incidenceand now accounts for over 10% of livebirths annually worldwide.1 Preterminfants are at significantly increased riskof sudden infant death syndrome (SIDS),2,3

with 29% of SIDS victims being bornpreterm.4 SIDS peaks in incidence at 2 to4 months of age5,6 and is believed to in-volve an uncompensated cardiovascularevent presumed to occur during sleep, inconjunction with failure of the life-savingarousal response.7–11 Preterm infants ex-hibit immature cardio-respiratory control,which persists past term-equivalentage,12 is related to gestational age (GA) atbirth,13,14 and may contribute to theirheightened risk for SIDS.15

Prone sleeping is a major risk factor forSIDS, particularly among infants bornpreterm.2,16 Term infants sleeping pronehave alterations in cardiovascular con-trol,17–21 and we have previously dem-onstrated that this is reflected in thecerebral circulation, expressed as re-duced cerebral oxygenation and alteredcerebrovascular control.22,23 It has beensuggested that reduced cerebral oxy-genation may contribute to impairedarousal,22 which is seen in the proneposition in both term18,24 and preterminfants25–27 and is likely to be significantin the pathophysiology of SIDS.10,28

Preterm infants display immature ce-rebrovascular control before term-equivalent age,29–32 the severity ofwhich is related to their GA at birth.30

However, little is known about cerebraloxygenation in preterm infants duringthe period of greatest SIDS risk. Wemeasured cerebral oxygenation andblood pressure during sleep in both theprone and supine positions in preterminfants across the first 6 months post-term. We hypothesized that cerebraloxygenation would be lower in infantsborn at earlier GA, in the prone position,at 2 to 3months postterm corrected age(CA) and in preterm compared withterm infants and that perturbations incerebral oxygenation would be associ-

ated with alterations in systemic car-diovascular parameters.

METHODS

Ethical approval was obtained from theMonash Health and Monash Universityhuman research ethics committees.Written parental consent was obtained,and no monetary incentive was pro-vided for participation.

Subjects

Thirty-five preterm infants born at 26 to 36weeks’ GA and 17 term infants born at 38to 42weeks’ GAwere studiedwith daytimepolysomnography (Table 1). All infantswere appropriately grown for GA, born tononsmoking mothers, had no family his-tory of SIDS and routinely slept supine athome. In the preterm cohort, exclusioncriteria included intrauterine growth re-striction, major congenital abnormalities,hemodynamically significant patent duc-tus arteriosus, significant intraventricularhemorrhage (grade III or IV), and chroniclung disease requiring ongoing re-

spiratory stimulant medication or oxygentherapy at term-equivalent age.

Of the preterm infants, 24 were studiedon 3 occasions at 2 to 4 weeks, 2 to 3months, and 5 to 6months posttermCA;7 were studied at only 2 to 4 weeks CA,and 4were studied only at 2 to 3monthsand 5 to 6months CA. Term infantswereall studied at 3 ages: 2 to 4 weeks, 2 to 3months, and 5 to 6 months chronolog-ical age, and data from this study havepreviously been published.22,23

Study Protocol

Daytime polysomnography was per-formedinasleep laboratorywithconstanttemperature (22–23°C), dim lighting, andquiet conditions. Infants slept both proneand supine, with the initial sleep positionrandomized. Sleep position was changedafter a midday feed.

Electrodes required for determining sleepstate were applied during a morning feed;these included EEG, electrooculogram,submental electromyogram, electrocar-diogram, and abdominal and thoracic

TABLE 1 Neonatal History and Characteristics at the Time of Study of Preterm and Term Infants

Clinical Feature Preterm Infants (n = 35) Term Infants (n = 17)

GA, wk 31.2 (0.4)*** 40.1 (0.3)Birth weight, g 1697 (92)*** 3666 (105)Boy/girl (% boy) 21/14 (60%) 9/8 (53%)Apgar scores1st min 6 (2–9)*** 9 (7–9)5th min 9 (5–9)** 9 (9–10)

Received respiratory stimulant duringhospitalization, n (%)

20 (57%)a 0

Antenatal steroids, n (%) 25 (71%) 0Anemia of prematurity, n (%) 14 (40%) 02–4 weeksAge, wkb 3.2 (0.1) 3.4 (0.1)Weight, g 3742 (103) 3956 (148)Length, cm 51.9 (0.5) 53.3 (0.6)

2–3 monthsAge, wkb 10.6 (0.2) 10.6 (0.2)Weight, g 5323.9 (165) 5214 (179)Length, cm 56.9 (0.7) 57.8 (0.4)

5–6 monthsAge, wkb 22.7 (0.3) 22.3 (0.3)Weight, g 7179 (209) 6964 (200)Length, cm 63.7 (0.5) 64.3 (0.5)

Values are presented as mean (SEM) with the exception of Apgar scores, which are presented as median (range). ***P, .001term versus preterm. **P , .01 term versus preterm.a Nineteen preterm infants received caffeine before discharge, and 1 infant received theophylline and aminophylline; noinfants were receiving respiratory stimulant medication at the time of study.b CA for preterm infants; postnatal age for term infants.

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respiratory belts (Resp-ez bands, EPMSystems, Midlothian, VA). Pulse oxygensaturation (SpO2; Masimo, Frenchs For-est, NSW, Australia) and abdominal skintemperature (ADInstruments, Sydney,NSW, Australia) were also recorded.

Cerebral Oxygenation

Cerebral tissue oxygenation index (TOI %)was measured continuously by usingnear-infrared spectroscopy (NIRO-200spectrophotometer, Hamamatsu Pho-tonics KK, Tokyo, Japan). Near-infraredspectroscopy enables calculation of ce-rebral TOI by using continuous-wave lightemission and detection measured overthe frontal region of the infant’s brain,with the detection probe placed 4 cmaway from the emission probe. TOI wascomputed at 6 Hz by using a spatiallyresolved spectroscopy algorithm33 andrepresents mixed oxygen saturations ofall cerebral vascular compartments.

Mean Arterial Pressure

Mean arterial pressure (MAP) wasmeasured by using a photoplethysmo-graphic cuff (Finapress Medical Sys-tems, Amsterdam, Netherlands) placedaround the infant’s wrist, using a tech-nique previously validated by ourgroup.34 Data were collected in 1- to2-minute epochs with at least 2 minutesbetween inflations to prevent venouspooling in the hand.

All physiologic variableswere recordedwith a sampling rate of 512 Hz by usingan E-series sleep systemwith Profusionsoftware (Compumedics, Abbotsford,VIC, Australia).

Data Analysis

At the completion of each study, datawere transferred to LabChart7 soft-ware (ADInstruments) for analysis.Sleep state was defined as either quietsleep (QS) or active sleep (AS).35 Beat-to-beat values were calculated for ce-rebral TOI, MAP, heart rate (HR), SpO2,and temperature during each 1- to 2-

minute epoch; data were averaged foreach epoch and pooled for each sleepstate and position within each infant.An average of 6 epochs was analyzedin each sleep state and position foreach infant. Data containing move-ment artifact and epochs where MAPdata lay .1.5 times the interquartilerange outside the first and thirdquartiles were excluded from furtheranalysis.36

Statistical Analysis

Statistical analysis was performed byusing SigmaPlot 12.0 software (SystatSoftware Inc, San Jose, CA). Linear re-gression was used to determine therelationships between GA at birth andcerebral TOI and between GA at birth andMAP. The effects of sleep state and posi-tion were determined by using 2-wayrepeated measures analysis of variance(ANOVA) at each CA. The effect of in-creasing CA was determined by using2-way repeated measures ANOVA with CAand sleep state as factors. The effect ofpreterm birth was determined by using2-way ANOVAwith birth and sleep state asfactors.Whenasignificantdifferencewasindicated on ANOVA, the specific sourceof the difference was identified withStudent-Newman-Keuls posthoc analysis.Results are presented as mean 6 SEMwith significance taken at P, .05.

RESULTS

Effects of GA at Birth in PretermInfants

No significant correlation was foundbetween cerebral TOI and GA at birth orbetweenMAPand GA at birth at any agestudied in either sleep state or position(data not shown).

Effects of Sleep Position in PretermInfants

Cerebral TOI

Inpreterm infants, cerebral TOIwas lowerin the prone compared with the supine

position in both sleep states at 2 to 4weeks (P, .05), 2 to 3 months (P, .01),and 5 to 6 months CA (P, .01; Fig 1).

MAP and HR

MAP was not significantly affected bysleep position at any age, althougha trend toward lowerMAPwasevident inthe prone position at 2 to 3months CA, inboth sleep states. Overall, HRwas higherin the prone compared with the supineposition at both 2 to 4 weeks (P , .05)and 5 to 6months CA (P, .01), reachingsignificance in QS (2 to 4 weeks CA P,.05; 5 to 6 months CA P, .01). In AS, HRtended to be higher in the prone posi-tion at 2 to 4 weeks (P = .085) and 5 to 6months CA (P = .069). At 2 to 3 monthsCA, therewas no effect of position on HR.

Temperature and SpO2

Temperature (Fig 1) was higher in theprone compared with the supine posi-tion in both sleep states at 2 to 4 weeks,2 to 3months, and 5 to 6months CA (P,.001 for all). SpO2 (data not shown) washigher in the supine compared with theprone position in AS at 2 to 4 weeks CAand in QS at 5 to 6 months CA (P, .05);however, differences were within 1%and unlikely to be of clinical significance.

Effects of Sleep State in PretermInfants

Cerebral TOI

TOI was higher in QS compared with ASin both the supine and prone positions(P, .01) at 2 to 4 weeks CA (Table 2). At2 to 3 months CA, cerebral TOI was notaffected by sleep state in either posi-tion. At 5 to 6 months CA, cerebral TOIwas lower in QS compared with AS inboth the supine and prone (P , .01)positions.

MAP and HR

MAP was higher in AS compared with QSat 2 to 4 weeks CA (P, .001) and 2 to 3months CA (P, .05) in both sleep posi-tions, and at 5 to 6months CA (P, .05) in

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the supine position. HR tended to behigher in AS compared with QS, reachingsignificance at 2 to 3 months CA in thesupine position (P , .05) and at 5 to 6months CA in both the supine (P, .001)and prone (P, .001) positions.

Skin Temperature and SpO2

Temperature and SpO2 were not af-fected by sleep state at any age in ei-ther position.

Effects of Postterm CA in PretermInfants

Cerebral TOI

In the supine position in QS, TOI washigherat 2 to 4weeks comparedwith 2

to 3 months CA (P , .05) and 5 to 6months CA (P , .05), with no differ-ence between 2 to 3 months and 5 to 6months CA (Table 2). In the supineposition in AS, TOI was lower at 2 to 3months compared with 5 to 6 monthsCA (P , .05). In the prone position, inboth QS and AS, TOI was higher at 2 to4 weeks compared with 2 to 3 monthsCA (P , .05) and higher at 5 to 6months compared with 2 to 3 monthsCA (P , .05). In AS in the supine po-sition and in both sleep states in theprone position, there was no differ-ence in TOI between 2 to 4 weeks and 5to 6 months CA, so that an age-relatednadir in TOI was evident at 2 to 3months CA.

MAP and HR

Age-related differences in MAP wereevident in QS in the supine position,where MAP was higher at 5 to 6 monthsCA compared with 2 to 4 weeks CA (P,.01), and in both QS and AS in the proneposition where MAP was higher at 5 to6 months CA compared with both 2 to 4weeks (P, .001) and 2 to 3 months CA(P , .01). HR declined significantly inboth sleep states and in both sleeppositions with increasing postterm CA(P , .05 for all).

Temperature and SpO2

There was no effect of postterm CA ontemperature. SpO2 was higher (∼1%) at2 to 4 weeks compared with 5 to 6

FIGURE 1Effect of sleeppositionon (A) cerebral TOI, (B)MAP, (C)HR, and (D) abdominal skin temperature (Temp) inpreterm infants. Results aremean6SEM. *P, .05; **P, .01; ***P , .001 prone versus supine.


months CA in QS in the supine position(P, .05), a difference unlikely to be ofclinical significance.

Effects of Preterm Birth

There were no differences betweenterm and preterm infants for age,weight, and lengthatanyof the3studies(Table 1).

Cerebral TOI and MAP

At 2 to 4 weeks CA, cerebral TOI waslower in preterm compared with terminfants in both sleep states in the prone(P, .01 for both) and supine (P, .05for both) sleep positions (Fig 2). At 2 to3months CA, there was no difference incerebral TOI between term and pre-term infants in the supine position.However, in the prone position cerebralTOI was lower in preterm comparedwith term infants in both QS and AS(P, .001 for both). At 5 to 6months, therewas no effect of preterm birth on TOI.

In the supine position at all 3 ages, andin thepronepositionat 5 to6monthsCA,

there was no effect of preterm birth onMAP (Fig 2). In the prone position, therewas an overall effect of preterm birthon MAP at 2 to 4 weeks CA, with MAPbeing lower in the preterm cohort (P,.05), although posthoc analysis did notidentify whether the difference lay inAS or QS. At 2 to 3 months CA, MAP waslower in the preterm cohort in both QS(P , .01) and AS (P , .01).

HR, Temperature, and SpO2

In both sleep positions, there was noeffect of preterm birth on HR at 2 to 4weeks CA and 5 to 6months CA, in eithersleep state (Table 3). At 2 to 3 monthsCA, HR was lower in the preterm cohortin QS in the supine position (P , .05)and in both QS (P , .01) and AS (P ,.01) in the prone position.

Temperature was higher in term com-pared with preterm infants (P, .05) inall sleep states and positions except ASin the supine position at 5 to 6 months.SpO2 was higher in preterm comparedwith term infants in both QS and AS in

the prone and supine position at 2 to 4weeks (P , .001 for all) and 5 to 6months CA (P , .05 for all). At 2 to 3months CA, there was no effect of pre-term birth on SpO2.

DISCUSSION

To our knowledge, this is the first studyto assess the effects of sleeping posi-tion on cerebral TOI in preterm infantsduring the period of greatest SIDS risk.We found cerebral TOI to be consistentlylower in the prone compared with thesupine position, with the maximal dif-ference at 2 to 3 months CA. Further-more, we found cerebral TOI to be lowerin preterm compared with term-borninfants at similar postterm ages, mostprominently at 2 to 3months in the proneposition, coinciding with a reduction inMAP and HR.

Effects of GA at Birth

In contrast to our hypothesis, we foundno association between GA at birth andcerebral TOI among this cohort ofpreterm infants born at 26 to 36 weeks’GA. Any potential effect of GA may havebeen obscured by studying the infantsat similar postconceptional ages, whenbrain maturation may have been simi-lar regardless of GA at birth. Further-more, our strict exclusion of infantswith significant intracranial pathologyensured a low-risk cohort. PreviousMRI studies assessing brain matura-tion in low-risk preterm infants haverevealed only subtle effects of GA.37

Similarly, we found no association be-tween GA at birth and MAP, probablybecause infants had reached normalweight by the time of study, a strongpredictor of MAP,38 with no differencesin weight between term and preterminfants.

Effects of Sleep Position

Cerebral TOI was consistently reducedin the prone compared with the supineposition in preterm infants, a finding

TABLE 2 Effect of Sleep State and Increasing CA on Cerebral TOI, MAP, HR, Abdominal SkinTemperature, and Spo2

TOI, % MAP, mm Hg HR, beats per min Abdominal SkinTemperature, °C

SpO2, %

2–4 weeks CASupineQS 63.2 (0.4)***#‡ 63.1 (1.6)**‡ 136.3 (0.6)###‡‡‡ 35.7 (0.2)‡ 98.8 (0.1)‡‡AS 59.9 (0.5) 70.1 (1.6) 137.1 (0.6)###‡‡‡ 35.8 (0.2) 98.6 (0.1)

ProneQS 58.0 (0.5)*# 61.8 (1.7)***‡‡‡ 139.3 (0.6)###‡‡‡ 36.7 (0.2) 99.0 (0.1)AS 56.2 (0.4)# 70.3 (1.6)‡‡ 139.2 (0.6)###‡‡‡ 36.6 (0.2) 98.8 (0.1)

2–3 months CASupineQS 59.6 (0.5)** 67.6 (1.8)*† 126.8 (0.5)*††† 35.6 (0.1) 98.1 (0.1)AS 57.1 (0.6)† 73.1 (1.9) 128.7 (0.5)†† 35.6 (0.1) 98.2 (0.1)

ProneQS 50.9 (0.5)† 64.7 (1.9)**††† 128.5 (0.5)†† 36.2 (0.1) 98.3 (0.1)AS 51.9 (0.6)† 70.4 (2.0)††† 129.6 (0.5) 36.3 (0.1) 98.4 (0.1)

5–6 months CASupineQS 56.6 (0.5)*** 72.0 (2.5)* 117.2 (0.4)*** 35.0 (0.1) 97.7 (0.10)AS 60.8 (0.5) 76.3 (2.8) 121.2 (0.5) 35.0 (0.1) 98.0 (0.1)

ProneQS 53.3 (0.5)** 75.5 (2.8) 120.4 (0.4)*** 36.1 (0.1) 98.3 (0.1)AS 57.4 (0.6) 78.6 (3.1) 123.5 (0.5) 36.2 (0.1) 98.5 (0.1)

Values are presented as mean (SEM). *P, .05; **P, .01; ***P, .001 QS versus AS. #P, .05; ##P, .01; ###P, .001 2 to 4weeks versus 2 to 3 months. †P , .05; ††P , .01; †††P , .001 2 to 3 months versus 5 to 6 months. ‡P , .05; ‡‡P , .01;‡‡‡P , .001 2 to 4 weeks versus 5 to 6 months.

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similar to our previous study in term-born infants.22 Cerebral TOI reflects theratio of oxygenated to deoxygenatedhemoglobin (Hb) in the cerebral vas-culature and is largely influenced bychanges in the cerebral venous com-partment because of its greater volumerelative to the arterial compartment.Thus impaired cerebral venous drain-age, resulting in venous congestion,may contribute to the reduction in

cerebral TOI seen in the prone position.Additionally, impaired cerebral bloodflow (CBF) may be an important con-tributor. Previous studies have revealedblood flow to be impaired through theinternal jugular vein39 and the vertebraland basilar arteries40,41 of infants in theprone position with their heads turnedto the side. Furthermore, in preterminfants these prone-related deficitsin vertebral artery flow were found

to be maximal at 1 month CA comparedwith the newborn period,42 suggestingposition-dependent changes in CBF maybe aggravated with advancing age.

We found the maximal effect of sleepposition on cerebral TOI to occur at 2 to 3months CA, with cerebral TOI averaging51% inpronesleeping. Although the lowerthreshold for safe cerebral TOI in infancyremains unclear,43 in animal studies ce-rebral TOI falls below 40% during

FIGURE 2Effect of pretermbirth on cerebral TOI (left) andMAP (right) at 2 to 4weeks (upper), 2 to 3months (middle), and 5 to 6months posttermage (lower). Results aremean 6 SEM. *P , .05; **P , .01; ***P , .001 term versus preterm.


imposed hypoxic-ischemic insults.44 Withcerebral TOI values approaching this levelin the prone position, preterm infantsmay be at risk for critically impaired ce-rebral TOI during hypoxic or hypotensiveepisodes occurring during sleep.

The effect of prone sleeping in preterminfantsmaybemaximal at 2 to 3monthsCA because of impaired cardiovascularcontrol during this period. It is wellestablished that prone sleeping is as-sociated with an increase in tempera-ture and peripheral vasodilation ininfancy.20,45,46 This reduction in periph-eral vascular resistance stimulatesa baroreflex-mediated increase in HRto maintain MAP.19,45 This reflex re-sponse is consistent with our obser-vations at 2 to 4 weeks and 5 to 6months CA, where HR and temperaturewere increased in the prone positionand MAP was maintained. In contrast,we found no increase in HR in the proneposition at 2 to 3 months CA, despitethe observed increase in temperature;this coincided with a tendency for MAPto be lower in the prone compared withthe supine position. This suggests that

baroreflex-mediated HR responsesmay be impaired during this period,resulting in a reduced ability to main-tain MAP in the prone position, poten-tially reflecting reduced cardiac output.This is consistent with findings of re-duced cardiac index, a measure ofcardiac output relative to body surfacearea, in adults47,48 and children49 in theprone compared with the supine posi-tion. Reduced cardiac output may ex-plain the large deficit in cerebraloxygenation seen in the prone positionat 2 to 3 months CA.

Althoughstillpresentat5 to6monthsCA,the effect of position on cerebral TOIlessenswithage.This is likely tobeduetomaturation of cardiovascular control,anatomicmaturation allowing improvedblood flow through position-affectedvessels and a reduced head-to-bodyratio with growth of the infant.22

Effects of Sleep State

Consistent with our findings in terminfants, cerebral TOI was also influ-enced by sleep state in the pretermcohort.22 At 2 to 4 weeks CA cerebral TOI

was lower in AS compared with QS, at 2to 3 months no effect of sleep state wasobserved and at 5 to 6 months CA ce-rebral TOI was higher in AS comparedwith QS. We suggest that this age-related progression is due to matura-tion of CBF-metabolism coupling dur-ing this period. AS is a state ofincreased brain activity, similar towakefulness, and CBF normally increa-ses from the level in QS to meet theheightened metabolic demands.50,51 Inthe mature brain, CBF usually over-shoots the metabolic demands of ASresulting in an increase in oxygenatedHb relative to deoxygenated Hb andtherefore increased cerebral TOI.52 At 2to 4 weeks CA, the CBF-metabolismcoupling response appears to be rela-tively immature with inadequateincreases in CBF22 during AS resulting inincreased oxygen extraction, increaseddeoxygenated Hb, and decreased cere-bral TOI. The reversal of this observationat 5 to 6 months CA suggests that mat-uration of CBF-metabolism coupling isoccurring during this period.

Effects of Postterm CA

Consistent with previous findings interm infants,22 increasing age hada considerable influence on cerebral TOIin preterm infants. TOI reached a nadirat 2 to 3months CA, most consistently inAS. We speculate that immature CBF-metabolism coupling at 2 to 3 monthsCA in combination with continuing braingrowth and accompanying increases incerebral oxygen requirements result ina mismatch between cerebral meta-bolic demands and the capacity for ce-rebral oxygen delivery during thisperiod. Furthermore, physiologic ane-mia peaks at ∼10 weeks of age in terminfants with the nadir in Hb being moresevere and earlier in onset in preterminfants.53 Anemia is associated withreduced cerebral TOI because of in-creased oxygen extraction necessitatedby a reduced oxygen carrying capacity.54

Although Hb was not measured in

TABLE 3 Effect of Preterm Birth on SpO2, HR, and Temperature

SpO2, % HR, beats per minute Temperature, °C

Preterm Term Preterm Term Preterm Term

2–4 weeksSupineQS 98.8 (0.2)*** 97.3 (0.3) 135.8 (1.3) 137.8 (1.8) 35.7 (0.2)*** 36.8 (0.2)AS 98.6 (0.2)*** 97.0 (0.4) 136.9 (1.4) 139.5 (1.9) 35.8 (0.2)*** 36.8 (0.2)

ProneQS 98.9 (0.2)*** 96.9 (0.3) 139.2 (1.6) 141.2 (2.0) 36.7 (0.2)* 37.3 (0.2)AS 98.8 (0.2)*** 96.9 (0.3) 139.2 (1.6) 141.4 (2.0) 36.6 (0.1)* 37.2 (0.2)

2–3 monthsSupineQS 98.1 (0.2) 97.8 (0.3) 126.8 (1.9)* 133.2 (2.5) 35.6 (0.1)*** 36.6 (0.1)AS 98.2 (0.2) 97.6 (0.3) 129.3 (1.9) 135.2 (2.6) 35.7 (0.1)*** 36.6 (0.1)

ProneQS 98.3 (0.2) 98.2 (0.2) 128.5 (1.8)* 136.1 (2.3) 36.2 (0.1)*** 37.2 (0.1)AS 98.4 (0.2) 98.3 (0.2) 129.4 (1.8)** 137.4 (2.3) 36.3 (0.1)*** 37.1 (0.1)

5–6 monthsSupineQS 97.8 (0.2)** 96.8 (0.3) 117.9 (1.7) 121.4 (1.9) 35.0 (0.3)* 36.1 (0.3)AS 98.1 (0.2)*** 96.9 (0.3) 122.2 (1.8) 125.1 (1.9) 35.0 (0.3) 35.4 (0.3)

ProneQS 98.3 (0.2)* 97.4 (0.3) 122.2 (1.9) 125.1 (2.1) 36.1 (0.1)*** 36.9 (0.2)AS 98.4 (0.2)** 97.4 (0.3) 124.5 (2.0) 128.8 (2.1) 36.2 (0.1)*** 37.0 (0.2)

Values are mean (SEM). *P , .05; **P , .01; ***P , .001 preterm versus term.

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our study, it is likely that Hb concen-trationswould be relatively low at 2 to 3months CA, contributing to reducedcerebral TOI.

Furthermore, in preterm infants in theprone position we saw a plateau inMAPbetween 2 to 4 weeks and 2 to 3monthsCA, followed by a significant increasebetween2 to3monthsand5 to6monthsCA. Relative depression of MAP at 2 to 3months CA is similar to the nadir inMAPseen in term infants.20 Reduced MAPmay compound impaired oxygen de-livery because of the peak in physio-logic anemia during this period,55

contributing to reduced cerebral oxy-genation during the period of greatestrisk for SIDS.

Our data suggest that cerebral oxygendelivery relative to consumptionimproves by 5 to 6 months CA, withincreased cerebral TOI most notably inAS. This is likely to be due tomaturationof CBF-metabolism coupling in com-bination with improvements in Hbconcentration.

Effects of Preterm Birth

We found cerebral TOI to be lower inpreterm compared with term infantsuntil 2 to 3 months CA. To exclude dif-ferences in arterial SpO2 as a cause forthe difference in cerebral TOI, weassessed arterial SpO2 and foundhigher SpO2 in preterm infants at 2 to 4weeks CA and no difference at 2 to 3months CA. The differences in SpO2were within 2% and therefore unlikelyto be either clinically significant orunderlie the differences in cerebralTOI. Therefore, we can assume that thedifference in cerebral TOI is due toincreased oxygen extraction in thepreterm infant brain, resulting in in-creased deoxygenated Hb and re-duced cerebral TOI. A limited numberof previous studies have assessedcerebral TOI in preterm and terminfants with conflicting findings.56–59

However, these studies failed to match

infants according to postconceptionalor term-equivalent age, so age-relateddifferences were likely to be ob-scured by the range of developmentalstages.56–59

Lower cerebral TOI in preterm infantscomparedwith term infantsmaybedueto inadequate cerebral oxygen deliveryrelative to consumption.22 Impairedoxygen carrying capacity because ofanemia, which is likely to be more se-vere in preterm infants, as mentionedpreviously, may contribute to this mis-match.53 Furthermore, it is well estab-lished that prematurity and a period ofneonatal intensive care can result inaltered brain maturation as evidencedby MRI studies at term-equivalent ageassessing cerebral volumes,60,61 corti-cal folding,62 and neural networks.63

Although few data exist on brain de-velopment in preterm infants afterterm-equivalent age, we suggest thatthe preterm infant brain undergoessignificant “catch-up” growth result-ing in an increased cerebral metabolicrate for oxygen compared with terminfants, a maturational difference thatappears to resolve by 5 to 6 monthsCA.

Interestingly, the effect of pretermbirth was greatest in the prone po-sition at 2 to 3 months CA, with a ce-rebral TOI deficit of ∼10%. Weattribute this to our finding of signif-icantly reduced MAP and HR in pre-term compared with term infants inthe prone position during this period.We suggest preterm infants may havealtered cardiovascular regulatoryresponses to prone sleeping at 2 to 3months CA, as they appear not to in-crease HR to maintain MAP. Previousstudies in the supine position haverevealed alterations in the de-velopment of autonomic cardiovas-cular control in preterm comparedwith term infants during the first 6months of life.64,65 Specifically, highfrequency HR variability reflecting

parasympathetic cardiac modulationhas been found to be lower in pre-term compared with term infants atterm-equivalent age.14 At 2 to 3months CA, altered peripheral vaso-motor tone is seen in preterm com-pared with term infants in the supineposition.64 Moreover, preterm infants,assessed at term-equivalent age, dis-played a diminished HR response toa cardiovascular stress comparedwith term infants.66 Our data provideevidence that impaired autonomiccardiovascular control seen in pre-term infants in the supine positionmay be exacerbated in the prone sleepposition at 2 to 3 months CA, mani-festing as significant differences inMAP and HR between term and pre-term infants.

Implications for SIDS

Our findings of reduced cerebral TOI inpreterm infants, particularly in theprone position, in conjunction with re-duced MAP in preterm compared withterm infants in thepronepositionat 2 to3 months CA, have significant implica-tions for SIDS. We speculate that re-duced cerebral TOI in the prone positionmay reflect impaired oxygen delivery tothe brainstem and contribute to de-ficient autonomic activation and blun-ted arousal responses in the proneposition. Furthermore, lower baselinecerebral TOI in preterm infants mayrepresent an increased vulnerabilityfor critically impaired cerebral TOIduring a hypotensive or hypoxemicevent occurring during sleep. Our datasuggest that deficits in cerebral oxy-genation are exacerbatedby immaturesystemic cardiovascular control asperiods during which cerebral oxy-genation was lowest were associatedwith concomitant reductions in MAPand HR.

It is important to note that epidemio-logic studies have identified that thepeak in SIDS deaths occurs at a slightly


earlier postterm CA (7–9 weeks CAdepending on GA at birth) for pretermcompared with term infants.6 In thisstudy we chose to investigate termand preterm infants at similar post-term CAs to enable comparison atequivalent developmental ages. It maybe that the cerebral oxygenation andcardiovascular differenceswe observedwere in fact underestimated, as ourinfants were studied at a slightly olderage than that of peak SIDS risk in pre-term infants.

CONCLUSIONS

Cerebral oxygenation is depressed inthe prone sleep position in preterminfants until at least 5 to 6months CA. Inaddition, cerebral oxygenation is re-duced in preterm compared with terminfants until ∼2 to 3 months CA, pre-dominantly in the prone position. Thegreatest deficit in cerebral oxygenationbetween term and preterm infants wasseen at 2 to 3 months CA in the proneposition, when MAP and HR were con-

currently reduced in preterm infants. Wesuggest preterm infants may be partic-ularly vulnerable to critically impairedcerebral oxygenation in the prone posi-tion, particularly in the presence of car-diovascular instability, contributing totheir heightened risk of SIDS.

ACKNOWLEDGMENTSWe thank the parents and infants whoparticipated in this study and the staffof the Melbourne Children’s Sleep Centrewhere these studies were carried out.

REFERENCES

1. Blencowe H, Cousens S, Oestergaard MZ,et al. National, regional, and worldwideestimates of preterm birth rates in theyear 2010 with time trends since 1990 forselected countries: a systematic analysisand implications. Lancet. 2012;379(9832):2162–2172

2. Blair PS, Platt MW, Smith IJ, Fleming PJ,Group CSR, Platt MW; CESDI SUDI ResearchGroup. Sudden infant death syndrome andsleeping position in pre-term and low birthweight infants: an opportunity for targetedintervention. Arch Dis Child. 2006;91(2):101–106

3. Blair PS, Sidebotham P, Berry PJ, EvansM, Fleming PJ. Major epidemiologicalchanges in sudden infant death syn-drome: a 20-year population-based studyin the UK. Lancet. 2006;367(9507):314–319

4. Trachtenberg FL, Haas EA, Kinney HC,Stanley C, Krous HF. Risk factor changes forsudden infant death syndrome after initi-ation of Back-to-Sleep campaign. Pediat-rics. 2012;129(4):630–638

5. Halloran DR, Alexander GR. Preterm de-livery and age of SIDS death. Ann Epi-demiol. 2006;16(8):600–606

6. Malloy MH. Prematurity and sudden infantdeath syndrome: United States 2005-2007. JPerinatol. 2013;33(6):470–475

7. Schechtman VL, Harper RM, Kluge KA,Wilson AJ, Hoffman HJ, Southall DP. Heartrate variation in normal infants and vic-tims of the sudden infant death syndrome.Early Hum Dev. 1989;19(3):167–181

8. Kelly DH, Pathak A, Meny R. Sudden severebradycardia in infancy. Pediatr Pulmonol.1991;10(3):199–204

9. Harper RM. Sudden infant death syn-drome: a failure of compensatory cerebellarmechanisms? Pediatr Res. 2000;48(2):140–142

10. Kato I, Franco P, Groswasser J, et al. In-complete arousal processes in infantswho were victims of sudden death. Am JRespir Crit Care Med. 2003;168(11):1298–1303

11. Paterson DS, Trachtenberg FL, ThompsonEG, et al. Multiple serotonergic brainstemabnormalities in sudden infant death syn-drome. JAMA. 2006;296(17):2124–2132

12. Witcombe NB, Yiallourou SR, Walker AM,Horne RSC. Blood pressure and heart ratepatterns during sleep are altered in preterm-born infants: implications for sudden in-fant death syndrome. Pediatrics. 2008;122(6).Available at: www.pediatrics.org/cgi/content/full/122/6/e1242

13. Katona PG, Frasz A, Egbert J. Maturation ofcardiac control in full-term and preterminfants during sleep. Early Hum Dev. 1980;4(2):145–159

14. Eiselt M, Curzi-Dascalova L, ClairambaultJ, Kauffmann F, Médigue C, Peirano P.Heart-rate variability in low-risk pre-maturely born infants reaching normalterm: a comparison with full-term new-borns. Early Hum Dev. 1993;32(2–3):183–195

15. Horne RS. Effects of prematurity on heartrate control: implications for sudden infantdeath syndrome. Expert Rev CardiovascTher. 2006;4(3):335–343

16. Moon RY; Task Force on Sudden InfantDeath Syndrome. SIDS and other sleep-related infant deaths: expansion of recom-mendations for a safe infant sleeping

environment. Pediatrics. 2011;128(5):1030–1039

17. Tuladhar R, Harding R, Cranage SM,Adamson TM, Horne RSC. Effects of sleepposition, sleep state and age on heart rateresponses following provoked arousal interm infants. Early Hum Dev. 2003;71(2):157–169

18. Galland BC, Reeves G, Taylor BJ, Bolton DP.Sleep position, autonomic function, andarousal. Arch Dis Child Fetal Neonatal Ed.1998;78(3):F189–F194

19. Chong A, Murphy N, Matthews T. Effect ofprone sleeping on circulatory control ininfants. Arch Dis Child. 2000;82(3):253–256

20. Yiallourou SR, Walker AM, Horne RS. Effectsof sleeping position on development of in-fant cardiovascular control. Arch Dis Child.2008;93(10):868–872

21. Yiallourou SR, Walker AM, Horne RS.Prone sleeping impairs circulatory con-trol during sleep in healthy term infants:implications for SIDS. Sleep. 2008;31(8):1139–1146

22. Wong FY, Witcombe NB, Yiallourou SR, et al.Cerebral oxygenation is depressed duringsleep in healthy term infants when theysleep prone. Pediatrics. 2011;127(3). Avail-able at: www.pediatrics.org/cgi/content/full/127/3/e558

23. Wong F, Yiallourou SR, Odoi A, Browne P,Walker AM, Horne RSC. Cerebrovascularcontrol is altered in healthy term infantswhen they sleep prone. Sleep. 2013;36(12):1911–1918

24. Horne RS, Ferens D, Watts AM, et al. Theprone sleeping position impairs arous-ability in term infants. J Pediatr. 2001;138(6):811–816

ARTICLE


http://www.pediatrics.org/cgi/content/full/122/6/e1242




25. Ariagno RL, van Liempt S, Mirmiran M.Fewer spontaneous arousals during pronesleep in preterm infants at 1 and 3 monthscorrected age. J Perinatol. 2006;26(5):306–312

26. Bhat RY, Hannam S, Pressler R, Rafferty GF,Peacock JL, Greenough A. Effect of proneand supine position on sleep, apneas, andarousal in preterm infants. Pediatrics.2006;118(1):101–107

27. Horne RS, Bandopadhayay P, Vitkovic J,Cranage SM, Adamson TM. Effects of ageand sleeping position on arousal fromsleep in preterm infants. Sleep. 2002;25(7):746–750

28. Moon RY, Horne RS, Hauck FR. Sudden in-fant death syndrome. Lancet. 2007;370(9598):1578–1587

29. Wong FY, Leung TS, Austin T, et al. Im-paired autoregulation in preterm infantsidentified by using spatially resolvedspectroscopy. Pediatrics. 2008;121(3).Available at: www.pediatrics.org/cgi/con-tent/full/121/3/e604

30. Soul JS, Hammer PE, Tsuji M, et al. Fluctu-ating pressure-passivity is common in thecerebral circulation of sick prematureinfants. Pediatr Res. 2007;61(4):467–473

31. Tsuji M, Saul JP, du Plessis A, et al. Cerebralintravascular oxygenation correlates withmean arterial pressure in critically illpremature infants. Pediatrics. 2000;106(4):625–632

32. Hahn GH, Maroun LL, Larsen N, et al. Ce-rebral autoregulation in the first day afterpreterm birth: no evidence of associationwith systemic inflammation. Pediatr Res.2012;71(3):253–260

33. Suzuki S, Takasaki S, Ozaki T, Kobayashi Y.Tissue oxygenation monitor using NIR spa-tially resolved spectroscopy. Optical To-mography and Spectroscopy of Tissue III.1999;3597:582–592

34. Yiallourou SR, Walker AM, Horne RS. Vali-dation of a new noninvasive method tomeasure blood pressure and assess bar-oreflex sensitivity in preterm infants duringsleep. Sleep. 2006;29(8):1083–1088

35. Anders T, Emde RN, Parmelee AH, Univer-sity of California LABIS. A Manual ofStandardized Terminology, Techniquesand Criteria for Scoring of States of Sleepand Wakefulness in Newborn Infants. LosAngeles, CA: UCLA Brain Information Ser-vice; 1971

36. Brase CH, Brase CP. Understandable Sta-tistics: Concepts and Methods. Stamford,CA: Cengage Learning; 2011

37. Mewes AU, Hüppi PS, Als H, et al. Regionalbrain development in serial magnetic res-

onance imaging of low-risk preterminfants. Pediatrics. 2006;118(1):23–33

38. Georgieff MK, Mills MM, Gómez-Marín O,Sinaiko AR. Rate of change of blood pres-sure in premature and full term infantsfrom birth to 4 months. Pediatr Nephrol.1996;10(2):152–155

39. Watson GH. Effect of head rotation on jug-ular vein blood flow. Arch Dis Child. 1974;49(3):237–239

40. Gabai N, Cohen A, Mahagney A, Bader D,Tirosh E. Arterial blood flow and auto-nomic function in full-term infants. ClinPhysiol Funct Imaging. 2006;26(2):127–131

41. Pamphlett R, Raisanen J, Kum-Jew S. Ver-tebral artery compression resulting fromhead movement: a possible cause of thesudden infant death syndrome. Pediatrics.1999;103(2):460–468

42. Eichler F, Ipsiroglu O, Arif T, et al. Positiondependent changes of cerebral blood flowvelocities in premature infants. Eur JPediatr. 2001;160(10):633–639

43. van Bel F, Lemmers P, Naulaers G. Mon-itoring neonatal regional cerebral oxy-gen saturation in clinical practice: valueand pitfalls. Neonatology. 2008;94(4):237–244

44. Ioroi T, Peeters-Scholte C, Post I, Leusink C,Groenendaal F, van Bel F. Changes in cere-bral haemodynamics, regional oxygen satu-ration and amplitude-integrated continuousEEG during hypoxia-ischaemia and reperfu-sion in newborn piglets. Exp Brain Res. 2002;144(2):172–177

45. Skadberg BT, Markestad T. Behaviour andphysiological responses during prone andsupine sleep in early infancy. Arch Dis Child.1997;76(4):320–324

46. Sahni R, Schulze KF, Ohira-Kist K, KashyapS, Myers MM, Fifer WP. Interactionsamong peripheral perfusion, cardiac ac-tivity, oxygen saturation, thermal profileand body position in growing low birthweight infants. Acta Paediatr. 2010;99(1):135–139

47. Poon K-S, Wu K-C, Chen C-C, et al. Hemody-namic changes during spinal surgery inthe prone position. Acta Anaesthesiol Tai-wan. 2008;46(2):57–60

48. Yokoyama M, Ueda W, Hirakawa M, YamamotoH. Hemodynamic effect of the prone positionduring anesthesia. Acta Anaesthesiol Scand.1991;35(8):741–744

49. Brown ZE, Görges M, Cooke E, MalherbeS, Dumont GA, Ansermino JM. Changes incardiac index and blood pressure onpositioning children prone for scoliosissurgery. Anaesthesia. 2013;68(7):742–746

50. Münger DM, Bucher HU, Duc G. Sleepstate changes associated with cerebralblood volume changes in healthy termnewborn infants. Early Hum Dev. 1998;52(1):27–42

51. Meek JH, Elwell CE, Khan MJ, et al. Regionalchanges in cerebral haemodynamics asa result of a visual stimulus measured bynear infrared spectroscopy. Proc Biol Sci.1995;261(1362):351–356

52. Khadra MA, McConnell K, VanDyke R, et al.Determinants of regional cerebral oxygen-ation in children with sleep-disorderedbreathing. Am J Respir Crit Care Med.2008;178(8):870–875

53. Strauss RG. Anaemia of prematurity: path-ophysiology and treatment. Blood Rev.2010;24(6):221–225

54. van Hoften JC, Verhagen EA, Keating P, terHorst HJ, Bos AF. Cerebral tissue oxygensaturation and extraction in preterminfants before and after blood transfusion.Arch Dis Child Fetal Neonatal Ed. 2010;95(5):F352–F358

55. Widness JA. Pathophysiology of Anemia Dur-ing the Neonatal Period, Including Anemia ofPrematurity. Neoreviews. 2008;9(11):e520

56. Arri SJ, Muehlemann T, Biallas M, BucherHU, Wolf M. Precision of cerebral oxygenationand hemoglobin concentration measure-ments in neonates measured by near-infraredspectroscopy. J Biomed Opt. 2011;16(4):047005

57. Bokiniec R, Zbiec A, Seliga J, et al. Assessmentof brain oxygenation in term and pretermneonates using near infrared spectroscopy.Adv Med Sci. 2012;57(2):348–355

58. Wijbenga RG, Lemmers PM, van Bel F.Cerebral oxygenation during the firstdays of life in preterm and term neo-nates: differences between differentbrain regions. Pediatr Res. 2011;70(4):389–394

59. Tina LG, Frigiola A, Abella R, et al. Near In-frared Spectroscopy in healthy pretermand term newborns: correlation with ges-tational age and standard monitoringparameters. Curr Neurovasc Res. 2009;6(3):148–154

60. Inder TE, Warfield SK, Wang H, Hüppi PS,Volpe JJ. Abnormal cerebral structure ispresent at term in premature infants. Pe-diatrics. 2005;115(2):286–294

61. Inder TE, Huppi PS, Warfield S, et al.Periventricular white matter injury inthe premature infant is followed by re-duced cerebral cortical gray mattervolume at term. Ann Neurol. 1999;46(5):755–760

62. Dubois J, Benders M, Borradori-Tolsa C,et al. Primary cortical folding in the human




newborn: an early marker of later func-tional development. Brain. 2008;131(pt 8):2028–2041

63. Smyser CD, Inder TE, Shimony JS, et al.Longitudinal analysis of neural networkdevelopment in preterm infants. CerebCortex. 2010;20(12):2852–2862

64. Yiallourou SR, Witcombe NB, Sands SA, WalkerAM, Horne RS. The development of autonomiccardiovascular control is altered by pretermbirth. Early Hum Dev. 2013;89(3):145–152

65. Witcombe NB, Yiallourou SR, Sands SA,Walker AM, Horne RS. Preterm birth altersthe maturation of baroreflex sensitivity in

sleeping infants. Pediatrics. 2012;129(1).Available at: www.pediatrics.org/cgi/con-tent/full/129/1/e89

66. Cohen G, Lagercrantz H, Katz-Salamon M.Abnormal circulatory stress responses ofpreterm graduates. Pediatr Res. 2007;61(3):329–334

(Continued from first page)

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: Funded by the National Health and Medical Research Council of Australia and the Victorian Government Infrastructure Program.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

COMPANION PAPER: A companion to this article can be found on page 598, and online at www.pediatrics.org/cgi/doi/10.1542/peds.2014-1875.

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DOI: 10.1542/peds.2014-0773; originally published online August 25, 2014; 2014;134;435Pediatrics

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