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BloodRev.AuthormanuscriptavailableinPMC2011Nov1.
Publishedinfinaleditedformas:

PMCID:PMC2981681
NIHMSID:NIHMS228754

BloodRev.2010Nov24(6):221225.
doi:10.1016/j.blre.2010.08.001

AnaemiaofPrematurity:Pathophysiology&Treatment
RonaldGStrauss,MD
RonaldGStrauss,ProfessorEmeritusofPathology&Pediatrics,UniversityofIowaCollegeofMedicine,200HawkinsDrive,C250GH,IowaCity,IA
522421009,Phone:(319)3388071,Fax:(319)3560331
RonaldGStrauss:ronaldstrauss@uiowa.edu
CopyrightnoticeandDisclaimer
Publisher'sDisclaimer

Thepublisher'sfinaleditedversionofthisarticleisavailableatBloodRev
SeeotherarticlesinPMCthatcitethepublishedarticle.

Abstract

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Mostinfantswithbirthweight<1.0kgaregivenmultipleredbloodcell(RBC)transfusionswithinthefirstfew
weeksoflife.Theanaemiaofprematurityiscausedbyuntimelybirthoccuringbeforeplacentalirontransportand
fetalerythropoiesisarecomplete,byphlebotomybloodlossestakenforlaboratorytesting,bylowplasmalevelsof
erythropoietinduetobothdiminishedproductionandacceleratedcatabolism,byrapidbodygrowthandneedfor
commensurateincreaseinredcellvolume/mass,andbydisorderscausingRBClossesduetobleedingand/or
hemolysis.RBCtransfusionsarethemainstayoftherapywithrecombinanthumanerythropoietinlargelyunused
becauseitfailstosubstantiallydiminishRBCtransfusionneedsdespiteexertingsubstantialerythropoieticeffects
onneonatalmarrow.
Introduction

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Preterminfantswithbirthweight<1.0kg(commonlydesignatedasextremelylowbirthweight,orELBW,infants)
havecompleted29weeksofgestation,andnearlyallwillneedredbloodcell(RBC)transfusionsduringthefirst
weeksoflife.EveryweekintheUnitedStates,approximately10,000infantsarebornprematurely(ie,<37weeks
ofgestation),with600(6%)ofthesepreterminfantsbeingELBW.(1)Approximately90%ofELBWneonateswill
receiveatleastoneRBCtransfusion.(2,3)Physiologicandnonphysiologicfactorsrelatedtoprematurityare
responsiblefortheanaemiaofprematurityandthishightransfusionrate,withphlebotomybloodlossforlaboratory
testingas,perhaps,thebiggestcontributor.(4)Becauseofeffortstominimizetheamountsofblooddrawnfrom
neonatesforlaboratorytesting(5)andtotransfusemoreconservatively(ie,toacceptlowerpretransfusion
hematocritvalues),thenumberofRBCtransfusionsgiventopreterminfantshasdroppedovertheyears.(2,6)At
theUniversityofIowaHospitals&Clinics,themeanvalueduringyears2000to2005ofRBCtransfusionsgiven
toeachtransfusedELBWinfantwas5.4/infant,comparedto1.1/infantforprematureinfantswithhigherbirth
weightsfrom1001to1500g.
PathophysiologyoftheAnaemiaofPrematurity

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AllneonatesexperienceadeclineincirculatingRBCsduringthefirstweeksoflife.Thisdeclineresultsbothfrom
multiplephysiologicalfactorsand,insickpreterminfants,fromseveraladditionalfactorsthemajoronebeing
phlebotomybloodlossesforlaboratorytesting.Inhealthyterminfants,thenadirhemoglobinvaluerarelyfalls
below10g/dLatanageof10to12weeks.Becausethispostnataldropinhemoglobinlevelinterminfantsiswell
toleratedandrequiresnotherapy,itiscommonlyreferredtoasthephysiologicalanaemiaofinfancy.Incontrast,
thisdeclineismorerapid(ie,nadirat46weeksofage)andthebloodhemoglobinconcentrationfallstolower
levelsininfantsbornprematurelytoapproximately8g/dLininfantswithbirthweightsof1.0to1.5kgandto
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approximately7g/dLininfantswithbirthweights<1kg.Consequently,becausethepronounceddeclinein
hemoglobinconcentrationthatoccursinmanyELBWinfantsisassociatedwithabnormalclinicalsignsandneed
forallogeneicRBCtransfusions,theanaemiaofprematurityisnotacceptedtobeaphysiologicalandbenign
event.(7)
Physiologicalfactorsplayaroleinthepathogenesisoftheanaemiaofprematurity.BecauseELBWinfantsareborn
beforethe3rdtrimesterofgestation,theyaredeprivedofmostoftheirontransportedfromthemotherandagreat
dealofinuterofetalerythropoiesis.Extrauterinebodygrowthisextremelyrapidduringthefirstmonthsoflife,and
RBCproductionbyneonatalmarrowmustincreasecommensurately.Itiswidelyacceptedthatthecirculatinglife
spanofneonatalRBCsinthebloodstreamisshorterthanthatofadultRBCsduetoseveraldevelopmental
differencesinmetabolicandmembranecharacteristicsofneonatalRBCscomparedtoRBCsfromadults.However,
thisisdifficulttomeasureaccuratelybecausestudiesoftransfusedautologous(neonatalorplacental)RBCslabeled
withbiotinorradioactivechromiummayunderestimateRBCsurvivalintheinfantsbloodstreamfortechnical
reasons.(8)InhealthyadultswherebodysizeisstablesothatbloodandRBCvolumesareconstant(ie,not
increasingwithgrowth),whennoRBCtransfusionsaregiven,andwhenlargevolumesofblood(RBCs)arenot
beingtakenforlaboratorystudiesthegradualdisappearanceoftransfusedlabeledRBCs,causedbydilution
withRBCsproducedbythebonemarrow,accuratelyreflectsRBCsurvivalinthebloodstream.Incontrast,oneor
moreoftheseconfoundingfactors(ie,growthandincreasingbloodvolume,RBCtransfusions,phlebotomyRBC
losses)existsininfantsparticularly,sickpretermstointroduceerrorsintothecalculationsperformedwhen
determiningRBCsurvival.
Akeyreasonthatthehemoglobinnadirislowerinpretermthaninterminfantsistheformergroup'sdiminished
plasmaerythropoietin(EPO)levelinresponsetoanaemia.(9)AlthoughanaemiaprovokesEPOproductionin
prematureinfants,theplasmalevelsachievedinanemicinfants,atanygivenhematocritvalue,arelowerthanthose
observedincomparablyanemicolderpersons.(10)Erythroidprogenitorcellsofnewborninfantsarequite
responsivetoEPOinvitroafindingsuggestingthatinadequateproductionEPOis,atleast,onemajorcauseof
neonatalanaemia,notmarrowunresponsiveness.(11)
AllofthemechanismsresponsibleforthelowplasmaEPOlevels,asseeninpretermneonates,areonlypartially
definedand,likely,theyaremultiple.OnemechanismisthattheprimarysiteofEPOproductioninpreterminfants
isintheliver,ratherthankidney.(12)ThisdependencyonhepaticEPOisimportantbecausetheliverisless
sensitivetoanaemiaandtissuehypoxiahence,thereisarelativelysluggishEPOresponse(ie,production)tothe
infantsfallinghematocrit(HCT)level.ThetimingoftheswitchfromlivertokidneyastheprimarysiteforEPO
productionissetatconceptionandisnotacceleratedtocompensateforpretermbirth.Viewedfromateleological
perspective,decreasedhepaticproductionofEPOunderinuteroconditionsofrelativetissuehypoxiamayofferan
advantagetothefetus.Ifthiswerenotthecase,normallevelsoffetalhypoxiainuterocouldtriggerhighlevelsof
EPOproductionandleadtoextremeerythrocytosisandconsequenthyperviscosity.Followingbirth,however,
diminishedEPOresponsivenesstotissuehypoxiaisdisadvantageoustotheinfantandleadstoanaemiabecauseit
impairscompensationforlowHCTlevelscausedbyrapidgrowth,RBClossesduetophlebotomy,clinical
bleeding,hemolysis,etc.
DiminishedEPOproductioncannotentirelyexplainlowplasmaEPOlevelsinanemicinfantsbecause
extraordinarilyhighplasmalevelsofEPOhavebeenreportedinsomefetusesandinfants.(13,14)Moreover,
macrophagesfromhumancordbloodproducenormalquantitiesofEPOmessengerRNAandprotein.(15)Thus,
additionalmechanismsbeyondlowproductionmustcontributetodiminishedEPOplasmalevels.Forexample,
plasmalevelsofEPOareinfluencedbyrapidmetabolism(clearance)aswellasbyproduction.Datainhuman
infants(16)havedemonstratedlowplasmaEPOlevelsduetoincreasedplasmaclearance,increasedvolumeof
distribution,morerapidfractionalelimination,andshortermeanplasmaresidencetimeswhencomparedto
valuesinadults.Thus,acceleratedcatabolismcompoundstheproblemofdiminishedEPOproduction,sothatthe
lowplasmaEPOlevelsareacombinedeffectofdecreasedsynthesisplusincreasedmetabolism.
PhlebotomybloodlossesplayakeyroleintheanaemiaofprematurityandintheneedforRBCtransfusions
particularly,duringthefirstfewweeksoflife.Themodernpracticeofneonatologyrequirescriticallyillneonatesto
bemonitoredcloselywithseriallaboratorystudiessuchasbloodgases,electrolytes,bloodcountsandcultures.
Smallpreterminfantsarethemostcriticallyill,requirethemostfrequentbloodsampling,andsufferthegreatest
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proportionallossofRBCsbecausetheircirculatingRBCvolumesaresmallest.Inthepast,themeanvolumeof
bloodremovedforsamplinghasbeenreportedtorangefrom0.8to3.1mL/kgperdayduringthefirstfewweeks
oflifeforpreterminfantsrequiringintensivecare.(17)Promisinginlinedevicesthatwithdrawblood,measure
multipleanalytesandthenreinfusemostofthesampledbloodhavebeenreported.(18,19)Theyhavedecreasedthe
needforRBCtransfusions.However,untilthesedevicesareprovenmoreextensivelytobefeasible,costeffective,
clinicallyefficaciousandsafe,replacementofbloodlossesduetophlebotomywillremainakeyfactorresponsible
forRBCtransfusionsgiventocriticallyillneonatesparticularly,transfusionsgivenduringthefirstfourweeksof
life.Meanwhile,itiscriticaltolimittestingtoonlythosetestsabsolutelyneededforoptimalcareandtoavoid
overdraw(ie,takingmoreinfantbloodthanactuallyneeded).(5)
RBCTransfusionstoTreattheAnaemiaofPrematurity

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GuidelinesfortransfusingRBCstopretermneonatesarecontroversial,andpracticesvarygreatly.(2024)Thislack
ofauniversalapproachstemsfromlimitedknowledgeofthecellularandmolecularbiologyoferythropoiesis
duringtheperinatalperiod,anincompleteunderstandingofinfantphysiological/adaptiveresponsestoanaemia,and
contrary/controversialtransfusionpracticeguidelinesasbasedonresultsofrandomizedclinicaltrialsandexpert
opinions.Generally,RBCtransfusionsaregiventomaintainalevelofbloodhemoglobinorHCTbelievedtobe
optimalforeachneonate'sclinicalcondition.GuidelinesforRBCtransfusions,judgedtobereasonablebymost
neonatologiststotreattheanaemiaofprematurity,arelistedbyTableI.Theseguidelinesareverygeneral,anditis
importantthattermssuchassevereandsymptomaticbedefinedtofitlocaltransfusionpractices/policies.
Importantly,guidelinesarenotmandatesforRBCtransfusionsthatmustbefollowedtheysimplysuggest
situationswhenanRBCtransfusionwouldbejudgedtobereasonable/acceptable.
TableI
AllogeneicRBCTransfusionsfortheAnaemiaofPrematurity

Animportantcontroversythatisstillunresolvedisthewisdomorlack,thereofofprescribingRBC
transfusionstoneonatesusingrestrictive(RES)guidelines(ie,permittingrelativelylowpretransfusionHCTvalues
beforegivinganRBCtransfusion)versusliberal(LIB)guidelines(ie,relativelyhighpretransfusionHCTvalues).
Tworandomized,controlledtrialshavebeenpublishedand,althoughmanyoftheirresultsagree,theydisagreein
oneextremelyimportantwayspecifically,whetherpreterminfantsareatincreasedriskofbraininjurywhen
givenRBCtransfusionsperRESguidelines.(25,26)Inbothtrials,preterminfantswererandomlyallocatedto
receiveallsmallvolumeRBCtransfusionspereitherRESorLIBguidelineswithguidelinesbasedona
combinationofthepretransfusionHCTorhemoglobinlevel,ageoftheneonate,andclinicalcondition(ie,needfor
ventilation,oxygen,etc)atthetimeeachtransfusionwasgiven.
BothstudiesfoundthatneonatesintheRESgroupreceivedfewerRBCtransfusions,withoutanincreasein
mortalityorinmorbidityasassessedbyseveralclinicaloutcomes.However,onecriticaldiscrepancywaspresent.
Belletal(25)foundincreasesinapnea,severeintraventricularbleedingandbrainleukomalaciaininfantstransfused
perRESguidelines,whereas,Kirpalanietal(26)foundnodifferencesinseriousoutcomesbetweeninfantsinthe
RESversusLIBgroups.However,ratesofseriousoutcomeswerefairlyhighinbothgroupsoftheKirpalanistudy
perhaps,duetotheextremeprematurityoftheinfants.(26)Althoughitistemptingtospeculatethatthehigher
bloodHCTlevels,insomeway,protectedtheLIBgroupinfantsofBelletal,itmustbenotedthatthepoor
neurologicaloutcomereportedbyBelletalwasaposthoccompositeendpoint.(25)Althoughthecombinationof
severeapnea,intraventricularbleedingandbrainleukomalaciawasstatisticallysignificantlymorefrequentinRES
infants,thetrialwasnotdesignedtostudythisendpointapriori.Thus,thefindingcannotbeacceptedasprovenat
thistime,norhasacauseandeffectrelationshipbetweenRBCtransfusionpracticesandneurologicaldamagebeen
established.
ItisimportanttonotethatafollowupstudyofinfantsenrolledinthetrialofKirpalanietal(26)wascompleted
whentheinfantsreachedtheageof1824months.(27)Therewasnostatisticallysignificantdifferencefound
betweenRESandLIBgroupswhenassessedbytheprimaryoutcome,statedapriori,asacompositeofeither
deathorsurvivalwithoneormorefindingsofcognitivedelay(BayleyIIMDI<70),cerebralpalsy,blindnessor
deafness.However,inaposthocanalysisusingahigherBayleyIIMDIscoreof<85,subjectsintheRESgroup
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didsignificantlyworsesuggestingsomeagreementwiththefindingofBelletal(25)thatRBCtransfusions
givenperRESguidelinesmayplacepreterminfantsatriskofneurologicalinjury.Obviously,additionalstudiesare
neededtoestablishoptimaltransfusionpractices,butuntilmoreinformationisavailable,itseemswisetotransfuse
pretermneonatesusingconventional,notgreatlyrestrictiveguidelines(ie,donotplaceinfantsatpossiblerisksof
undertransfusion).
ThevastmajorityofRBCtransfusionsgiventoELBWinfantsaresmallvolumeandconsistof10to20mLper
Kg(infantsweightonthedayoftransfusion)ofallogeneicRBCsstoredinpreservativesolutionatanhematocrit
(HCT)of~60%(42daystoragepermittedinmodernadditiveAS1,AS3,AS5solutions)or~70%(35day
storagepermittedinolderCPDAsolution).Otherthanpersonalbias,therearenodemonstratedadvantagesfor
transfusingCPDARBCsordisadvantagesforAS1,AS3orAS5RBCswhenusedforsmallvolume
transfusions.(2831)Moreover,thequantitiesofadditivestransfusedwithsmallvolumesofAS1,AS3orAS5
RBCsareextremelysmallcomparedtoestimatedtoxicdoses(Table2)and,importantly,multipleclinicaltrials
havedocumentedbothefficacyandsafetyofRBCsstoredinadditivesolutionswhentransfusedintoinfants.
(28,30)Accordingly,theremainderofthisdiscussionwilldealwithRBCsstoredinadditivesolutions.
Table2
Quantityofadditivestransfused(mg/kginfantbodyweight)witha
15/mL/KgRBCtransfusion*
MostRBCtransfusionsgiventoinfantsareprescribedtotreattheanaemiaofprematurityandconsistof155
mL/KgRBCsinfusedover24hours.Becauseofthesmallquantityofextracellularfluid(RBCadditivestorage
media)thatisinfusedveryslowlywithsmallvolumetransfusions,thetypeofanticoagulantandpreservative
solutioninwhichtheRBCsaresuspendedposesnoapparentriskformostprematureinfants.Accordingly,the
historicalpracticetotransfuseonlyfreshRBCs(<7daysofstorage)hasbeenreplacedinmostcentersbythe
practiceoftransfusingaliquotsofRBCsfromadedicatedunitofRBCsstoredupto42days,asameansto
diminishthehighdonorexposureratesamonginfantswhoundergonumeroustransfusions.(30)Neonatologists
whoinsistontransfusingfreshRBCsgenerallyraisethefollowingfourobjectionstoprescribingstoredRBCs:(a)
theprogressiveincreaseintheconcentrationofpotassiumintheplasma(ie,RBCstorage/supernatantfluid)during
storage(b)thedecreaseinthelevelofRBC2,3DPG(c)thepossiblerisksofindividualadditivessuchas
mannitolandadenineandtherelativelylargeamountsofglucose(dextrose)andphosphatepresentinadditive
solutionsand(d)thechangesinRBCshapeanddeformabilitythatdevelopduringstorageand,consequently,may
leadtopoorflowthroughthemicrovasculature.Althoughtheseconcernsarelegitimateforlargevolume(25
mL/Kg)transfusions,particularlywheninfusionisrapid,theydonotapplytosmallvolumetransfusionsforthe
followingfourreasons.
First,after42daysofstorageinadditivesolutions(AS1,AS3,AS5)ataHCTofapproximately60%,
extracellular(plasma)potassiumconcentrationsinRBCunitsapproximate50mEq/L(0.05mEq/mL),alevelthat
atfirstglanceseemsalarminglyhigh.Simplecalculations,however,showthattheactualdoseofionicpotassium
transfusedintheextracellularplasmafluidissmall.Aninfantweighing1Kggivena15mL/Kgtransfusionof
RBCsstored42daysinextendedstoragemediumataHCTof60%receivesonly0.3mEqK+adosequite
smallwhencomparedtotheusualdailyK+requirementof2to3mEq/Kgandonethathasbeenshownin
severalclinicalstudiesnottocauseclinicallysignificanthyperkalemiafollowingRBCtransfusions.(28,30,32)
Second,by21daysofstorage,2,3DPGistotallydepletedfromRBCs,asreflectedbyaP50value[defined
simplyasthepressureofoxygenneededtokeepthehemoglobin50%saturatedwithoxygenthelowertheP50
value,themoretightlyoxygenisheldbyhemoglobinwithlesserquantitiesofoxygenreleasedtothetissues]
thatdecreasesfromapproximately27mmHginfreshbloodto18mmHginstoredRBCsatthetimeofoutdate.
OwingtotheeffectsofhighfetalhemoglobinlevelsinneonatalRBCs,the18mmHgvalueofRBCstransfused
aftermaximumstorageisquitesimilartotheexpectedlylowP50valuepresentinendogenousRBCsproducedby
themarrowofhealthypreterminfantsatbirth.Thus,botholderstoredRBCsandendogenousRBCsfromneonates
haveasimilarlyreducedabilitytooffloadoxygencomparedwithfreshadultRBCs.However,olderadultRBCs
inunitsofbloodbankprovideanadvantageovertheinfant'sownRBCsbecause2,3DPGandtheP50valuesof
transfusedadultRBCs(butnotendogenousinfantRBCs)increaserapidlyaftertransfusion.Wheninfantblood
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sampleswerestudiedseriallyinthesettingofsmallvolume(15mL/Kg)RBCtransfusions,RBC2,3DPGlevels
weremaintainedininfantsgivenstoredRBCs.(33)
Third,thequantityofadditivespresentinRBCsstoredinextendedstoragemediaisunlikelytobedangerousfor
neonatesgivensmallvolumetransfusions(15mL/Kg).Regardlessofthetypeofadditivestoragesolution,the
quantityofadditivesisquitesmallintheclinicalsettinginwhichaneonatewouldreceiveasmallvolume
transfusionofRBCsinfusedover2to4hours(Table2).Moreover,efficacyandsafetyhavebeenprovenin
clinicalstudiesinwhichinfantsreceivedoneormoreRBCtransfusions.(28,30,32,33)
Fourth,duringstorageinallconventionalpreservativesolutions,RBCssustainprogressivedecreasesin2,3DPG
andadenosinetriphosphate,andtheyundergomembraneandcytoskeletalchangesthatleadtotheformationof
echinocytesandmicrovesciclesandtodecreaseddeformability.Thelastchangesmayleadtodiminishedperfusion
ofthemicrovasculatureand,consequently,totissue/organdysfunction.Forthelastfewyears,theargumenthas
ragedoverwhethercriticallyilladultpatientsareharmedbyreceivingoldRBCs(usuallydefinedasstored15
days),andwhethermortality,multiorganfailure,infections,needformechanicalventilation,lengthofstayin
intensivecareunitsandinthehospital,etccouldbediminishedbytransfusingonlyfreshRBCs.Theargumentis
unresolved,witharecentmetaanalysesactuallyfindingpooreroutcomesinsomepatientsgivenfreshRBC
transfusions.(34)
ThesituationissimilarinthesettingofneonatalRBCtransfusions(ie,neonatesareoftencriticallyillandquestions
aboutmorbidityduetotransfusingstoredRBCshavebeenraised).However,welldesignedtrialshaveaddressed
efficacyandsafetyand,withinthelimitsofthenumberofinfantsstudied,freshandstoredRBCshavebeen
documentedtobeequivalent,(28,30,32,33)Moreover,theintravascularrecovery24hoursaftertransfusionand
longtermsurvivalofstoredallogeneicdonorRBCsisnormal,whenmeasuredinhumaninfantsusingbiotinylated
RBCs.(8)BecausetherisksofmultipledonorexposurecanbenearlyeliminatedbytransfusinginfantswithRBCs
takenfromdedicated,storedunitsandthefactthatspeculatedincreasedrisksoftransfusingstoredRBCsversus
freshhavenotbeenconvincinglydemonstrated,itseemsprudentatpresenttocontinuetransfusingRBCsstoredin
additivesolutionsupto42daysforsmallvolumetransfusions.
RecombinantErythropoietintoTreattheAnaemiaofPrematurity

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RecognitionoflowplasmaEPOlevelsandnormallyresponsiveRBCprogenitorcellsinpreterminfantsprovidesa
rationalbasistoconsiderrecombinanthumanerythropoietin(rHuEPO)astreatmentfortheanaemiaof
prematurity.BecausetheinadequatequantityofplasmaEPOisthemajorcauseofanaemianotasubnormal
responseofmarrowerythroidprogenitorstoEPOitislogicaltoassumethatrHuEPOwillcorrectEPO
deficiencyandwilleffectivelytreattheanaemiaofprematurity.Regardlessoftheassumedlogic,rHuEPOhasnot
beenwidelyacceptedinclinicalneonatologypracticebecauseitsefficacyisincomplete.Ononehand,clonogenic
erythroidprogenitorsfromneonatesrespondwelltorHuEPOinvitroandrHuEPOandironeffectivelystimulate
erythropoiesisinvivoasevidencedbyincreasedbloodreticulocyteandRBCcountsinrecipientinfants(ie,efficacy
successfulatthemarrowlevel).Ontheotherhand,whentheprimarygoalofrHuEPOtherapyistoeliminateRBC
transfusions,rHuEPOoftenfailstodoso(ie,efficacyattheclinicallevelhasnotbeenconsistentlysuccessful).
(20,35)
Bytheendof1999,over20controlledclinicaltrialsassessingtheefficacyofrHuEPOtoeliminateRBC
transfusionsintheanaemiaofprematuritywerepublishedwithinconsistentresults.Toinvestigatetheextentand
reasonsfortheinconsistencies,ametaanalysiswasconductedofthecontrolledclinicalstudiespublishedbetween
1990thru1999.Twomajorconclusionsemergedfromthemetaanalysis.(35)First,thecontrolledtrialsofr
HuEPOtotreattheanaemiaofprematuritydifferedfromoneanotherinmultiplewaysand,consequently,
producedmarkedlyvariableresultsthatcouldnotbeadequatelyexplained.Hence,itwasjudgedprematureto
makefirmrecommendationsregardinguseofrHuEPOinclinicalpracticetotreattheanaemiaofprematurity.
Second,whenthefourstudieswithhighlydesiredcharacteristicswereanalyzedseparately,rHuEPOwasfoundto
beefficaciousinsignificantlyreducingRBCtransfusionneeds.However,themagnitudeoftheeffectofrHuEPO
onreducingthetotalRBCtransfusionsgiventoinfantsthroughouttheirinitialhospitalizationwas,infact,relatively
modestandofquestionableclinicalimportance.(35)
Becausemetaanalysisofreportsthrough1999didnotgivefirmguidelinesfortheuseofrHuEPO,neonatologists
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mustdetermineifreportspublishedafter2000haveprovidedusefulinformation.Donatoetal(36)randomized114
neonateswithbirthweight<1.25kgtoreceiveeitherrHuEPOorplaceboduringthefirsttwoweeksoflife,
followedbyasixweektreatmentperiodduringwhichallinfants(ie,bothgroups)weregivenrHuEPO,ironand
folicacid.Duringthefirstthreeweeksoflife,rHuEPOincreasedreticulocytesandhematocritvalues,butthere
wasnodifferenceinRBCtransfusionsbetweengroups.However,attheendofalltreatment(eightweeks),a
subgroupofinfantswithbirthweight<0.8kgandphlebotomylosses>30mL/kg,givenrHuEPOshortlyafter
birth,receivedfewertotalRBCtransfusionsthaninfantsinitiallygivenplacebo(3.41.1vs5.43.7,p<0.05).
Similarly,Yeoetal(37)foundamodestadvantageforasubgroupofverylowbirthweightinfantsgivenrHuEPO.
Infantswithbirthweight0.8to0.99kgweregivenfewerRBCtransfusionswithrHuEPOthancontrolinfantsnot
givenrHuEPO(2.11.9vs3.51.6,p<0.04).
Arandomized,blindedtrialbyMeyeretal(38)foundanadvantageforrHuEPO.Neonateswithbirthweight<1.7
kg,plusfulfillingcriteriathatpredictedalikelyneedforRBCtransfusions,wererandomizedeithertoreceiver
HuEPObeginningshortlyafterbirthortoexperienceashamtreatmentsimulatingplaceboinjections.Ironwas
giventoallinfants,butattwodifferentdoses(unfortunately)amuchlowerdosewasgiventocontrolinfantsnot
givenrHuEPOandahigherdosewasgiventoinfantsgivenrHuEPOthus,creatingtwoexperimental
variables/differencesthatmightaffecterythropoiesisandneedforRBCtransfusions(rHuEPOandirondose,
ratherthanjustrHuEPO)intreatedvscontrolinfants.Overall,therewasnooveralldifferencefoundinRBC
transfusions,butinasubsetofinfantswithbirthweight<1.0kg,RBCtransfusionsgivenlate(ie,after30daysof
age)werereducedbyrHuEPOvscontrols(0.50.7vs1.61.1,p=0.01).
TworeportsdefinedrHuEPOsuccessasmaintainingahematocritof30%withoutneedforanyRBC
transfusions.Maieretal(39)randomized219neonateswithbirthweights0.5to0.99kgtoreceiveeitherearlyr
HuEPO(fromthefirstweekoflifefornineweeks),laterHuEPO(fromthefourthweekoflifeforsixweeks),or
norHuEPO.Successratesweremodest(13%withearlyrHuEPO,11%withlaterHuEPO,and4%withnor
HuEPO).OnlyearlyrHuEPOinfantsweresignificantlysuperiortonorHuEPO(p=0.026).Aventetal(40)
randomized93neonateswithbirthweight0.9to1.5kgtoreceiveeitherlowdoserHuEPO(250units/kg),high
doserHuEPO(400units/kg),ornorHuEPO.Treatmentbeganwithin7daysoflifeandcontinueduntildischarge
(median32daysandmaximum74days).SuccessatmaintainingareasonablehematocritwithoutRBC
transfusionswasmetby75%oflowdoserHuEPOinfants,71%ofhighdoserHuEPOand40%ofnorHuEPO
infants(p<0.001).Interestingly,thetotalnumberofRBCtransfusionsgiventoallinfantstreatedwithrHuEPOvs
thosegivennorHuEPOwasnotsignificantlydifferent!Onfurtheranalysis,theauthorsconcludedthatrHuEPO
didnotsignificantlydecreaseRBCtransfusionsininfants,birthweight0.9to1.5kg,whenphlebotomylosseswere
smallandwhenRBCtransfusionsweregivenperstringenttransfusionguidelines.(40)
TheobservationbyAventetal(40)thatthebenefitsofrHuEPOinreducingthenumberofRBCtransfusions
givencanbeequalledbystringent/conservativetransfusionguidelineshasbeenmadebyothers.Franzand
Pohlandt(41)assessedboththenumberofRBCtransfusionsgiventheandRBCtransfusionguidelinesfollowedin
fourprospective,randomizedtrialsofrHuEPOgiventopretermneonates.Tobeselectedforanalysis,theclinical
trialshadtoincludeventilatedinfants(ie,sickinfantslikelytoreceiveRBCtransfusions).Theauthorsfoundthat,
whenrestrictivetransfusionguidelineswerefollowed,thenumberofRBCtransfusionsandthevolumeofRBCs
transfusedweresimilarlylowininfantseithergivenornotgivenrHuEPO.(41)Similarly,Amin(42)foundno
differenceinthenumberofRBCtransfusionsgivenwhetherornotrHuEPOwasprescribedtopreterminfants
withbirthweight1.0kg,whenRBCtransfusionsweregivenperstricttransfusionguidelines.
PracticePoints

RBCtransfusionsarethekeytreatmentmodalityfortheanaemiaofprematurity.
RBCsstoredupto42dayssincedonationareefficaciousandsafeforsmallvolumetransfusions(155
mL/kg).
Vigorousattemptsmustbemadetolimitvolumesofblooddrawnforlaboratorytesting.
Recombinanthumanerythropoietin,althoughclearlystimulatingerythropoiesisininfantmarrow,has
verylimiteduse,currently,totreattheanaemiaofprematurity.

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ResearchAgenda

Defineoptimal(ie,efficacyandtoxicity)pretransfusionbloodhematocrit/hemoglobinlevelsthattrigger
redbloodcelltransfusionsinpreterminfants.
Explorebiology/pharmacologyofrecombinanthumanerythropoietininneonatal/infanterythropoiesisto
establishthebasisforpossiblefuturetherapyoftheanaemiaofprematurity.
DeterminelongtermoutcomesofRBCtransfusionsgiventoneonates/infantsonthebasisofrestrictive
vsliberaltransfusionguidelinesandofredbloodcellunitsstoredbrieflysincedonationvslongterm
storage(eg,stored<14daysvsstored>14days)todefineoptimalRBCtransfusionpractices.

Acknowledgments

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SupportedbyNHLBIGrantPO1HL46925
Footnotes

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Conflictofintereststatement
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Publisher'sDisclaimer:ThisisaPDFfileofanuneditedmanuscriptthathasbeenacceptedforpublication.Asaserviceto
ourcustomersweareprovidingthisearlyversionofthemanuscript.Themanuscriptwillundergocopyediting,typesetting,and
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