早产儿生长曲线图

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Asystematicreviewandmeta-analysistorevisetheFentongrowthchartforpreterminfants

TanisRFenton1,2*andJaeHKim3

Background

Theexpectedgrowthofthefetusdescribesthefastesthumangrowth,increasingweightoversix-foldbetween22and40weeks.Preterminfants,whoarebornduringthisrapidgrowthphase,relyonhealthprofessionalstoassesstheirgrowthandprovideappropriatenutritionandmedicalcare.

*Correspondence:tfenton@ucalgary.ca1

AlbertaChildren’sHospitalResearchInstitute,TheUniversityofCalgary,Calgary,AB,Canada2

DepartmentofCommunityHealthSciences,TheUniversityofCalgary,3280HospitalDriveNW,Calgary,AB,Canada

Fulllistofauthorinformationisavailableattheendofthe

article

In2006,theWorldHealthOrganization(WHO)publishedtheirmulticentregrowthreferencestudy,whichisconsideredsuperior[1]topreviousgrowthsurveyssincethemeasuredinfantswereselectedfromcommunitiesinwhicheconomicswerenotlikelytolimitgrowth,amongculturallydiversenon-smokingmotherswhoplannedtobreastfeed[2].Weeklylongitudinalmeasuresoftheinfantsweremadebytraineddatacollectionteamsduringthefirst2yearsofthisstudy[3].TheseWHOgrowthcharts,althoughrecommendedforpreterminfantsaftertermage[4],beginattermandsodonotinformpreterminfantgrowthassessmentsyoungerthanthisage.

©2013FentonandKim;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(/licenses/by/2.0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.

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Optimumgrowthofpreterminfantsisconsideredtobeequivalenttointrauterinerates[5-7]sinceasuperiorgrowthstandardhasnotbeendefined.Perhapsthebestestimateoffetalgrowthmaybeobtainedfromlargepopulation-basedstudies,conductedindevelopedcoun-tries[8],whereconstraintsonfetalgrowthmaybelessfrequent.

Arecentmulticentrestudybyourgroup(thePretermMulticentreGrowth(PreMGrowth)Study)revealedthatalthoughthepatternofpreterminfantgrowthwasgener-allyconsistentwithintrauterinegrowth,thebiggestdevi-ationinweightgainvelocitybetweenthepreterminfantsandthefetusandinfantwasjustbeforeterm,between37and40weeks(FentonTR,NasserR,EliasziwM,KimJH,BilanD,SauveR:Validatingtheweightgainofpretermin-fantsbetweenthereferencegrowthcurveofthefetusandtheterminfant,ThePretermInfantMulticentreGrowthStudy.SubmittedBMCPed2012).Ratherthandemon-stratingtheslowinggrowthvelocityoftheterminfantduringtheweeksjustbeforeterm,thepreterminfantshadsuperior,closetolinear,growthatthisage.Thisfindinghasbeenobservedbyothersaswell[9-11].Therefore,thereisevidencetosupportasmoothtransitionongrowthchartsbetweenlatefetalandearlyinfantages.

Severalpreviousgrowthchartsbasedonsizeatbirthpresentedtheirdataascompletedage,whichaffectstheinterpretationanduseofagrowthchart[12].Theuseofcompletedweekswhenplottingagrowthchartrequiresallthemeasurementstobeplottedonthewholeweekverticalaxes.However,theuseofcompletedweeksinaneonatalunitmaynotbeintuitive,asnurserystaffandparentsthinkofinfantsastheirexactage,andnotagetruncatedtopreviouswholeweeks.Theadventofcomputersinhealthcare,forclinicalcareandhealthrecording,allowtheuseofthecomputertoplotgrowthcharts,dailyandwithaccuracy.Itwouldmakesensetosupportplottingdailymeasurementscontinuouslybyshiftingthedatacollectedascompletedweekstothemidpointofthenextweektoremovethetruncationofthedatacollectionascompletedweeks.

Theobjectivesofthisstudyweretorevisethe2003FentonPretermGrowthChart,specificallyto:a)usemorerecentdataonsizeatbirthbasedonaninclusioncriteria,b)harmonizethepretermgrowthchartwiththenewWHOGrowthStandard,c)tosmooththedatabetweenthepretermandWHOestimateswhilemaintainingintegritywiththedatafrom22to36andat50weeks,d)toderivesexspecificgrowthcurves,andtoe)re-scalethechartx-axistoactualageratherthancompletedweeks,tosupportgrowthmonitoring.

Methods

Torevisethegrowthchart,thoroughliteraturesearcheswereperformedtofindpublishedandunpublished

population-basedpretermsizeatbirth(weight,length,and/orheadcircumference)references.Theinclusioncriteria,definedapriori,designedtominimizebiasbyrestriction[13],weretolocatepopulation-basedstudiesofpretermfetalgrowth,fromdevelopedcountrieswith:a)Correctedgestationalagesthroughfetalultrasoundand/orinfantassessmentand/orstatisticalcorrection;

b)Datapercentilesat24weeksgestationalageorlower;

c)Sampleofatleast25,000babies,withmorethan500infantsagedlessthan30weeks;d)Separatedataonfemalesandmales;

e)Dataavailablenumericallyinpublishedformorfromauthors,

f)Datacollectedwithinthepast25years(1987to2012)toaccountforanyseculartrends.

A.Dataselectionandcombination

Majorbibliographicdatabasesweresearched:MEDLINE(usingPubMed)andCINHAL,bybothauthorsbacktoyear1987(givenour25yearlimit),withnolanguagerestrictions,andforeignarticlesweretranslated.Thefollowingsearchtermsasmedicalsubjectheadingsandtextwordswereused:(“Preterminfant”OR“PrematureBirth”[Mesh])OR(“Infant,Premature/classification”[Mesh]OR“Infant,Premature/growthanddevelopment”[Mesh]OR“Infant,Premature/statisticsandnumericaldata”[Mesh]OR“Infant,verylowbirthweight”[Mesh])AND(percentileOR*centile*ORweeks)AND(weightORheadcircumferenceORlength).GreyliteraturesitesincludingclinicaltrialwebsitesandGoogleweresearchedinFebruary2012.Referencelistswerereviewedforrelevantstudies.AllofthefounddatawasreportedascompletedweeksexceptfortheGermanPerinatalStatistics,whichwerereportedasactualdailyweights[14].Tocombinethedatasets,theGermandatawastemporarilyconvertedtocompletedweeks.Afinalstepconvertedthemeta-analysestoactualage.

binethedatatoproduceweightedintrauterinegrowthcurvesforeachsex

Thelocateddata(3rd,10th,50th,90th,and97thpercentilesforweight,headcircumference,andlength)thatmettheinclusioncriteriawereextractedbycopyingandpastingintospreadsheets.Themaleandfemalepercentilecurvesfromeachincludeddatasetforweight,headcircumferenceandlengthwereplottedtogethersotheycouldbeexaminedvisuallyforheterogeneity(Figures1,2,and3).Thedataforeachgenderwerecombinedbyusingtheweeklydataforthepercentiles:3rd,10th,50th,90th,and97th,weightedbythesamplesizes.Thecombineddatawasrepresentedbyrelativelysmoothcurves.

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C.Developgrowthmonitoringcurves

Todevelopthegrowthmonitoringcurvesthatjoinedtheintrauterinemeta-analysisdatawiththeWHOGrowthStandard(WHOGS)smoothly,thefollowingcubicsplineprocedurewasusedtomeettwoobjectives:

a)Tomaintainintegritywiththemeta-analysiscurvesfrom22to36weeks.Integrityofthefitwas

assumedtobeagreementwithin3%ateachweek.b)ToensurefitofthedatatotheWHOvaluesat50weeks,within0.5%.Procedure:

1)Cubicsplineswereusedtointerpolatesmooth

valuesbetweenselectedpoints(22,25,28,32,34,36and50weeks).Extrapointsweremanuallyselectedat40,43and46weeksinordertoproduceacceptablefitthroughtheunderlyingdata.ThePreMGrowthstudy(FentonTR,NasserR,EliasziwM,KimJH,BilanD,SauveR:Validatingtheweightgainofpreterminfantsbetweenthereference

growthcurveofthefetusandtheterminfant,ThePretermInfantMulticentreGrowthStudy.

SubmittedBMCPed2012)conductedtoinformthetransitionbetweenthepretermandWHOdata,wasusedtoinformthisstep.ThePremGrowthStudyfoundthatpreterminfantsgrowthinweight

followedapproximatelyastraightlinebetween37and45weeks,asothershavealsonoted[9-11].2)LMSvalues(measuresofskew,themedian,andthestandarddeviation)[15]werecomputedfromtheinterpolatedcubicsplinesatweeklyintervals.Cole’sprocedures[15]andaniterativeleastsquaresmethodwereusedtoderivetheLMSparameters(L=Box-Coxpower,M=median,S=coefficientofvariation)

from

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Table 1 Details of the data sourcesVoight, 2010 Data source Sample size n< 30 weeks Lowest gestational age Dates Data Exclusion criteria German Perinatal Survey 2,300,000 14146 22 1995 to 2000 Weight None stated, included both live and stillborn Olsen, 2010 Pediatrix Medical Group hospitals 130,111 11377 23 1998 to

2006 Weight, head, length Multiple births, congenital anomalies, death before discharge, outlier measures (> 2 x interquartile range below the first and 3rd quartile). Kramer, 2001 Canadian national file 676,605 3247 22 1994 to 1996 Weight Ontario province was excluded due to problems with data quality. Roberts, 1999 Bonellie, 2008 Bertino, 2010 WHO, 2006 WHO multicentre growth reference study 882 N/A term 1997-2003 Weight, head, length Maternal smoking, not breastfeeding, solids before 4 months. Screened for environmental or economic constraints. Australian National Scottish maternity data Italian Neonatal Perinatal Statistics Unit collection Study 734,145 3193 20 1991 to 1994 Weight Omitted multiple and still births (births< 400 grams did not need to be recorded) 100,133 2053 24 1998 to 2003 Weight Multiple births, lethal anomalies, weights< 250 grams, and outlier measures (> 2 x interquartile range outside the first and 3rd quartile). Clinician assessment based on ultrasound, maternal dates, and clinical estimates Cubic spline fitting 45,462 623 23 2005 to 2007 Weight, head, length Multiple births, stillbirths, major congenital anomalies, and fetal hydrops

Method to assess gestational age

Ultrasound Neonatologist assessment assessment 8–14 weeks and Naegle’s rule.

“early ultrasound has increasingly been the basis for gestational age assessments in recent years” Assumed a log normal distribution of birthweight at each gestational age and compared the probabilities of accurate versus misclassification of infant’s gestational age

Dates, prenatal, or postnatal assessment

Ultrasound assessment first trimester

Not stated

Outliers/smoothing Cubic regression, LMS methods, with the method LOESS smoothing, skew set to one and LMS parameter further manual smoothing smoothing

Omitted outlier measures (> 2 x interquartile range below the first and 3rd quartile).

Generalized logistic functions

Omitted outliers> 3 SD, LMS parameter smoothing, skew set to one for weight, cubic spline fitting.

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Table2Numberofinfantseachweekfromeachstudy

Gestationalage

22232425262728293031323334353637383940

*Notreported.

Voight,2010Females18843157571381210731276151618532283*********

Males32156070484696812031536183822122956*********

Olsen,2010Females-1334386037739661187125416062044300741865936508246904372575559785529

Males-15345172288110301281150519922460367750147291695270116692878683247235

Bertino,2010Females-32040355279701071261652112633665621291352452955672

Males-82438586163721141401832403494186651492397654525653

Kramer,2001Females801061481841911882872993904617951055201833918203173084751675068110738

Males821141562022342543303924675849971368255343149648199655194777623112737

Roberts,1999Females71791151361882312873254405488771200208634187320161054780968846137570

Males749513518023528436139757174311171471265740928788186605140472871141553

Bonellie,2008Females--120115179174246245317136193239374644104820064630869912644

Males--1261181721772392653131482052564226531265249963871070614230

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themulticentremeta-analysesforweight,headcircumferenceandlength.TheLMSsplinesweresmoothedslightlywhilemaintainingdataintegrityasnotedabove.

3)ThefinalpercentilecurveswereproducedfromthesmoothedLMSvalues.

4)Agridsimilartothe2003growthchartwasused,butthegrowthcurveswerere-scaledalongthex-axisfromcompletedweekstoallowclinicianstoplotinfantgrowthbyactualageinweeks,andaslightmodification(scaledto60centimetersinsteadof65)wasmadetothey-axis.

paredtherevisedchartswiththe2003version

Therevisedgrowthchartswerecomparedgraphicallywiththeoriginal2003Fentonpretermgrowthchart.Tomakethedifferencesinchartvaluesmoreapparent,the2003chartdatawasalsoshiftedtoactualweeksforthesecom-parisonfigures.

Results

Sixlargepopulationbasedsurveys[14,16-20]ofsizeatpretermbirthfromcountriesGermany,UnitedStates,Italy,Australia,Scotland,andCanadawerelocatedthatmettheinclusioncriteria(Table1).Theliteraturesearchidentified2436papers,ofwhich2373werediscardedasbeingnotrelevantorduplicatesbasedonthetitles(Figure4).Reviewingreferencelistsidentifiedanother12studies.Seventy-fivestudieswereexaminedindetail,however27ofthesedidnotmeetthedatecriteria.Amongthe48studiesthatmetthedateofbirthcriteria,somedidnotmeettheotherinclusioncriteriaforthefollowingreasons:Didnotmeetthecriterionformorethan25,000babies[21-35],nolowgestationalageinfantslessthan25weeks[31,36-41],insufficientnumberlessthan30weeks[34,42-45],nostatisticalcorrectionforinaccurategestationalages[46-48],numericaldatanotavailable[49-51],numberofinfantseachweekwerenotavailable

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[52],numberofinfantsinthesubgroupseachweekwerenotavailable[53],wasnotpopulationbased[54-56],nodirectmeasurements[27],someofthedata[57]wasalsoinoneofthelargerincludedstudies[17].

Includedinthemeta-analyseswerealmostfourmillion(3,986,456)infantsatbirth(34,639lessthan30weeks)fromsixstudiesforweight(Table2),and173,612infantsforheadcircumference,and151,527forlength[16,18].TheWorldHealthOrganizationdatameasurementsweremadelongitudinallyon882infants.

Theindividualdatasetsfromtheliteratureshowedgoodagreementwitheachother,especiallyalongthe50thandlowercentiles(Figures1,2,and3)andthemeta-analysiscurveshadaclosefitwiththeindividualdatasetsupto36weeksandat50weeks(Figures5,6,7).Thefinalsplinedweightcurveswerewithin3%ofthemeta-analysiscurvesfor24through36weeksforbothgen-ders,exceptfora3.8%differenceforgirlsat32weeksalongthe90thcentile.Noneofthelengthmeasurementsdifferedbymorethan1.8%percentbetweenthemeta-analysisandthesplinedcurves;allweeksoftheheadcircumferencecurveswerewithin1.5%.Themeta-analysesfor

head

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circumferenceandlengthforgirlsandboyswerecloseenoughtonormaldistributionsthatnormaldistributionswereusedtosummarizethedata.Themeasuresat50weekswerewithin0.5%oftheWHOGSvalues.

Girlandboychartswereprepared(Figure8and9),byshiftingtheageby0.5weekstoallowplottingbyexactageinsteadofcompletedweeks.TheLMSParameters[15]wereusedtodeveloptheexactz-scoreandpercentilecalculatorsforthenewgrowthchart.

Inthetwographicalcomparisonsbetweentherevisedgrowthcharts,oneforeachsex,withthe2003Fentonpretermgrowthchartrevealedthatthecurveswerequitesimilar(Figures10and11).Generallythenewgirls’curveswereslightlylower(Figure10)andthenewboys’slightlyhigher(Figure11)forall3parameters(weight,headcir-cumference,andlength)thanthe2003curves.Themostdramaticvisualandnumericaldifferencebetweenthenewchartsandthe2003chartwasthehighershiftoftheboys’weightcurvesafter40weekscomparedtothe2003chart,reachingamaximumdifferenceat50weeksof650,580,and740gramsatthe3rd,50th,and97thpercentiles,re-spectively.Thesecondbiggestvisualdifferencewas

the

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lowerpatternofthegirls’lengthcurvesbelow37weeks;thedifferenceinlengthreachedamaximumnumericalvalueof1.7centimetersat24weeksalongthe97thpercentile.

Discussion

Weusedastrictsetofinclusioncriteriatoincludeonlythebestdataavailabletoconvertfetalandinfantsizedataintofetal-infantgrowthchartsforpreterminfants.There-visedsex-specificactual-age(versuscompletedweeks)growthcharts(Figure9and10),arebasedonbirthsizein-formationofalmostfourmillionbirthswithconfirmedor

correctedgestationalages,bornindevelopedcountries(SeeFeaturesofthenewgrowthchart).Therevisedchartsarebasedontherecommendedgrowthgoalforpreterminfants,thefetusandtheterminfant,withsmoothingofthedisjunctionbetweenthesedatasets,basedonthefind-ingsofourinternationalmulticentrevalidationstudy(FentonTR,NasserR,EliasziwM,KimJH,BilanD,SauveR:Validatingtheweightgainofpreterminfantsbetweenthereferencegrowthcurveofthefetusandthetermin-fant,ThePretermInfantMulticentreGrowthStudy.SubmittedBMCPed2012).Thesechartsareconsist-entwiththemeta-analysisdatauptoand

including

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36weeks,thustheycanbeusedfortheassessmentofsizeforgestationalageforpreterminfantsunder37weeksofgestationalage.Thisgrowthchartislikelyap-plicabletopreterminfantsinbothdevelopedandde-velopingcountriessincethedatawasselectedfromdevelopedcountriestominimizetheinfluencefromcir-cumstancesthatmaynothavebeenidealtosupportgrowth.

Featuresofthenewgrowthchart

Basedontherecommendedgrowthgoalforpreterm

Datafromdevelopedcountriesincluding

infants:ThefetusandtheterminfantGirlandboyspecificcharts

EquivalenttotheWHOgrowthchartsat50weeksgestationalage(10weeksposttermage).

Largepretermbirthsamplesizeof4millioninfants;Recentpopulationbasedsurveyscollectedbetween1991to2007

Germany,Italy,UnitedStates,Australia,Scotland,andCanada

Curvesareconsistentwiththedatato36weeks,thuscanbeusedtoassignsizeforgestationalageuptoandincluding36weeks.

Chartisdesignedtoenableplottingasinfantsaremeasured,notascompletedweeks.Thexaxiswasadjustedforthischartsothatinfantsizedatacanbeplottedwithoutageadjustment,i.e.Babiesshouldbeplottedasexactages,thatisababyat253/7weeksshouldbeplottedalongthexaxisbetween25and26weeks.

Exactz-scoreandpercentilecalculatoravailablefordownloadfromhttp://ucalgary.ca/fenton.Dataisavailableforresearchuponrequest.Itmaybemoreintuitivetoplotongrowthchartsusingexactagesratherthanonthebasisof

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weeks.Severalyearsago,theWHOusedcompletedageforgrowthchartdevelopment[12].Thisrecommenda-tionwaslikelyduetothewaydatahadbeencollectedinthepast,thatisall260/7through266/7weekinfantswereincludedinthe26weekcompletedweekcategory.However,withtheuseofcomputerstoplotongrowthchartscomesthepotentialtomoreaccuratelyplotmea-surementstotheexactdayofdatacollection.Thusthetimescaleofthehorizontalaxesofthesenewgrowthchartswerere-scaledtoactualage,foreaseofuseandun-derstanding.Forexample,ababyat253/7canbeintui-tivelyplottedbetween25and26weeks.

Exactz-scoreandcentilecalculatorsfortherevisedchartsareavailablefordownload:http://ucalgary.ca/fenton.Dataisavailableforresearchuponrequest.

Thedatarevealedthatbetween22weeksto50weekspostmenstrualage,thefetus/infantmultipliesitsweighttenfold,forexample,thegirls’ingafetal-infantgrowthchartallowsclinicianstocomparepreterminfants’growthtoanestimatedreferenceofthefetusandtheterminfant.

Therewasaremarkablyclosefitoftheincludedpretermsurveysforweight,headcircumferenceandlengthfromthe6countries,especiallyatthe50thpercentile,eventhoughthedatacamefromdifferentcountries.

Thespliningproceduresweusedhaveproducedachartthathasintegrityandgoodagreementwiththeoriginaldata.SmoothingoftheLMSparametersisrecommendedsinceminorfluctuationsaremorelikelyduetosamplingerrorsratherthanphysiologicalevents[15].ExpertsrecommendthatgrowthchartsbedevelopedbasedonsmoothedL,MandS,toconstraintheadjacentcurvessothattheyrelatetoeachothersmoothly[15].TheWorldHealthOrganizationsettheirLparameterto1forheadcircumferenceandlength,whiletheymaintainedtheexactLvaluesforinfants’weights[58].ThedataunderstudyhererevealedthesameeffectastheWHOdata;

we

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foundthatbothheadcircumferenceandlengthwerecloseenoughtonormaldistributionsthatnormaldistributionscouldsummarizethedata,whiletheexactL’swereneededtoretainthenuancesoftheweightcurves.

Thedifferencesbetweentherevisedgrowthchartsandthe2003Fentonpretermgrowthchartmayreflectimprovementssincetheselectedpretermgrowthreferencesforthenewversionsaremorelikelygloballyrepresentativeoffetalandinfantgrowth.Someofthedifferencesbetweenthecurrentchartsandthe2003versionarelikelyduetotheseparationintogirlandboycharts,sincetheshiftsofthegirls’curvestendtobedownwardandtheboys’curvesupward.Theweightshiftsafter40weekswereupwardforbothsexes,duetothehighervaluesfortheWHOGScomparedtotheCDCgrowthreference[59]at10weekspostterm.

Theidealgrowthpatternofpreterminfantsremainsundefined.Theserevisedgrowthchartsweredevelopedbasedonthegrowthpatternsofthefetus(ashasbeendeterminedbysizeatbirthinthelargepopulationstud-ies)andtheterminfant(basedontheWHOGrowthStandard)[2].Ultrasoundstudiesandcomparisonofsubgroupsofprematurelyborninfantssuggestthatthefetalstudies,suchasthoseusedinthisdevelopment,maybebiasedbytheprematurebirthsincefetuseswhoremaininuterolikelydifferinimportantwaysfrombabieswhoarebornearly[60,61].However,fetalsizefromtheseimperfectstudiesmaybethebestdataavailableatthispointintimeforcomparingthegrowthofpreterminfantssincethealternative,tocomparetoinuteroinfantsrequiresextrapolationfromultrasoundmeasurements.Touseotherprematureinfantsasthegrowthreferenceforpreterminfantsmaynotbeidealsincetheidealgrowthofpreterminfantshasnotbeendefined,hasbeenchangingovertime[62],andisinfluencedbythenutritionandmedicalcarereceivedafterbirth[63,64].

AlthoughtheWHOGSisconsideredtobeagrowthstandard,theinfantsinthepopulation-basedsurveysofsizeatbirtharemorelikelyrepresentativeofthereferencepopulationsandwerenotselectedtobehealthy.Thusthesegrowthchartsaregrowthreferencesandarenotagrowthstandard.TheINTERGROWTHstudy,currentlyunderway,willrectifythisproblem,sincetheirpurposeistodevelopprescriptivestandardsforfetalandpretermgrowth[65].

Conclusion

Theinclusionofdatafromanumberofdevelopedcountriesincreasesthegeneralizabilityofthegrowthchart.Therevisedpretermgrowthchart,harmonizedwiththeWorldHealthOrganizationGrowthStandardat50weeks,maysupportanimprovedtransitionofpreterminfantgrowthmonitoringtotheWHOcharts.

Competinginterests

Theauthorsdeclarethattheyhavenocompetinginterests.

Authors’contributions

Theauthor’sresponsibilitieswereasfollows:JHKsuggestedthestudy,TRF&JHKdesignedthestudyandconductedindependentliteraturesearches,TRFextractedthedata,performedthestatisticalanalysis,andwrotethe

manuscript.Bothoftheauthorscontributedtointerpretthefindingsandwritingthemanuscript,andbothauthorsreadandapprovedthefinalmanuscript.

Acknowledgements

ManythankstoPatrickFentonandMishaEliasziwforstatisticalassistance,RoseannNasser,RegSauve,DebbieO’Connor,andSharonUngerforencouragementandadvice,andJayneThirskforeditingadvice.

Author1

detailsAlbertaChildren’sHospital2ResearchInstitute,TheUniversityofCalgary,Calgary,AB,Canada.DepartmentofCommunityHealthSciences,The

UniversityofCalgary,3280HospitalDriveNW,Calgary,AB,Canada.3DivisionofNeonatology,UCSanDiegoMedicalCenter,200WestArborDriveMPF1140,SanDiego,CA,USA.

Received:12October2012Accepted:10April2013Published:20April2013

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