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Anemiaofprematurity

Author: JosephAGarciaPrats,MD
SectionEditors: StevenAAbrams,MD,DonaldHMahoney,Jr,MD
DeputyEditor: MelanieSKim,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Jan2017.|Thistopiclastupdated:Oct27,2015.

INTRODUCTIONErythropoiesisdecreasesafterbirthasaresultofincreasedtissueoxygenationduetothe
onsetofbreathingandclosureoftheductusarteriosus,andareducedproductionoferythropoietin(EPO)[1].In
terminfants,thehemoglobinleveltypicallyreachesanaveragenadirof11g/dLatapproximately8to12weeks
afterbirth.

Inpreterminfantswhoarealreadybornwithalowerhematocrit,thisdecline,referredtoasanemiaofprematurity
(AOP),occursearlierandismorepronouncedinitsseveritythantheanemiaseeninterminfants.TheAOPwill
bereviewedhere.

PATHOGENESISTheprimarycauseofanemiaofprematurity(AOP)istheimpairedabilitytoincreaseserum
erythropoietin(EPO)appropriatelyinthesettingofanemiaanddecreasedtissueavailabilityofoxygen[2,3].
CirculatingandbonemarrowredcellprogenitorsrespondtoEPO,ifpresent,indicatingthattheimpaired
erythropoiesisisduetolackofEPO,notafailuretorespondtothehormone[46].Otherhematopoieticgrowth
factors(eg,granulocytemacrophagecolonystimulatingfactor)arenotaffected.

ImpairederythropoietinproductionEPOisproducedbythefetalliverandthecorticalinterstitialcellsofthe
kidneyinresponsetohypoxia.Itsproductionisregulatedbythetranscriptionfactorhypoxiainduciblefactor1
(HIF1).Itsprimaryfunctionistoregulateerythrocyteproduction.EPOdoesnotcrosstheplacentainhumans,
andfetalproductionincreaseswithgestationalage[710].

ProductionofEPOinadultsdependsontheoxygensaturationofhemoglobinandtissueoxygendelivery,andis
inverselyproportionaltocentralvenousoxygenation.AlthoughEPOlevelsinpreterminfantswithAOPincrease
slightlywithhypoxia,theyarelowerthanthoseseeninolderchildrenandadultswiththesamelevelofanemia
[2,11].(See"Regulationoferythropoiesis".)

InAOP,thespecificmechanismsleadingtothediscrepancybetweenserumEPOconcentrationandtheseverity
oftheanemiaareuncertain.ProposedpathogeneticpathwaysinvolvethesiteofEPOproductionandthe
developmentalregulationoftranscriptionfactorsintheliverversusthekidney.

TheliveristheprincipalsiteofEPOproductioninthefetus[12,13].ThefeedbackincreaseinhepaticEPO
mRNAinresponsetoanemiaorhypoxiamaybelessthanthatofthekidney[14].EPOmRNAexpressionin
thekidneyispresentinthefetus,andincreasessignificantlyafter30weeksgestation,suggestingthatthe
switchtothekidneyasthemainsiteofEPOproductionisdevelopmentallyregulated.

Thefetalorneonatalenvironmentmayaltertheresponsetohypoxicsignalsbytheliver.Supportforthis
hypothesiscomesfromtheobservationthathepatictransplantationfromfetalandneonatallambsintoadult
sheepincreasedEPOproductionbythetransplantedliver[15].

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Transcriptionalregulatoryfactors,suchasHIF1,maycontributetolowlevelsofEPOinprematureinfants.
Thesefactorsactivatetargetgenes,includingthoseencodingEPO,inresponsetodecreasedcellular
oxygenconcentration[16,17].Theyappeartobedevelopmentallyregulatedinsomefetaltissues,which
mightaccountforthedecreasedexpressionofEPOinresponsetoanemiainpreterminfants[1,18].

OtherfactorsAlthoughAOPisdirectlyduetoimpairedEPOproduction,severalotherfactorscancontribute
toanemiainpreterminfants,includingbloodlossfromphlebotomy,reducedredbloodcelllifespan,andiron
depletion.

BloodlossfromphlebotomyPrematureinfantsfrequentlydevelopanearlyanemiathatisprimarilydue
toiatrogenicbloodlossduetophlebotomyforbloodtests.Thevolumeofbloodlossincreaseswithillnessseverity
anddecreasinggestationalage.Inonereport,withdrawalofbloodinexcessofthatrequiredforlaboratory
studiescontributedtoiatrogenicbloodlossby2to4mL/kgperweek[19].However,effortstoreducebloodloss
fromphlebotomyhaveresultedinchangesinclinicalpracticetolimitbloodsamplingforessentialtestingandthe
useofmicrotechniques,whichhavereducediatrogenicbloodloss.

Theimpactofclinicalpracticeonphlebotomyandbloodtestingwasillustratedinastudyofverylowbirthweight
(VLBW)infants(birthweight<1500g)caredforintwoneonatalintensivecareunits(NICUs)[20].Phlebotomy
lossesincreasedwithdecreasinggestationalageandincreasingillnessseverity,asmeasuredbytheScorefor
NeonatalAcutePhysiology(SNAP).TheaveragelossesduetophlebotomydifferedbetweenthetwoNICUsand
resultedinincreasedaveragebloodtransfusionrequirementsintheNICUwiththegreatervolumeofbloodloss.
However,thisdifferencewasnotassociatedwithdifferencesinthedaysofoxygentherapyormechanical
ventilation,riskofbronchopulmonarydysplasia,orgrowthratebyday28oflife.Thesefindingssuggestthatthe
additionaluseofbloodinoneoftheNICUswasdiscretionaryratherthannecessary,asclinicaloutcomesdidnot
differ.

Thesestudiesindicatethatbloodlossduetophlebotomyinpreterminfantsmaybegreaterthanisnecessaryfor
thecareoftheneonate.Theyemphasizetheneedfornurserypoliciestoensurethatonlytheminimalvolume
requiredfortestingisdrawn,andunnecessarytestsareavoided.

ReducedredbloodcelllifespanRedbloodcellsurvivalinnewbornterminfantsisapproximately60to
80days,butdecreaseswithdecreasinggestationalagetoarangeof45to50daysinextremelylowbirthweight
infants(ELBW)(birthweightbelow1000g)[21].Thereducedredcelllifespancontributestotheseverityof
anemia.Increasedsusceptibilitytooxidantinjurymaycontributetoshortenedredcellsurvivalintheneonate
[22,23].(See"Redbloodcellsurvival:Normalvaluesandmeasurement".)

IrondepletionAlthoughitisnotinvolvedinitspathogenesis,irondepletionmayimpairrecoveryfromAOP.
Becauseoftheirrapidgrowthrate,prematureinfantshaveincreasedutilizationanddepletionofironstoresand,
asnotedabove,bloodlossfromphlebotomy.Theadministrationofirondoesnotinhibitthefallinhemoglobin
concentrationduetoAOP.However,interminfants,itreducestheincidenceofirondeficiencyanemiainthefirst
yearoflife[2].(See"Irondeficiencyininfantsandyoungchildren:Screening,prevention,clinicalmanifestations,
anddiagnosis".)

Lowlevelsofothernutrients,suchasvitaminB12orfolate,donotappeartocontributetoneonatalanemia[1].In
onerandomizedtrial,thecombinationoffolate,vitaminB12,iron,andEPOcomparedwithcontroltherapy
improvedtheELBWinfant'schanceofremainingtransfusionfree(38versus5percent)[24].

OXYGENDELIVERYOxygendeliveryistherateatwhichoxygenistransportedfromthelungstothe
microcirculation.Itisdeterminedbytheproductofcardiacoutputandarterialoxygencontent.Thearterialoxygen
contentistheamountofoxygenboundtohemoglobinplustheamountofoxygendissolvedinarterialblood.(See
"Oxygendeliveryandconsumption".)

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Oxygendeliveryisdependentupon:

Cardiacoutput
Hemoglobinconcentration
Oxygencarryingcapacity(affinity)ofhemoglobin
Arterialoxygensaturationandoxygentension

Inpreterminfantswithanemia,physiologicchanges,whichaimatmaintainingadequateoxygendelivery,
compensateforasignificantdecreaseinhemoglobin,andaresimilartothoseseeninolderchildrenandadults.
Theseincludeincreasesinheartrateandstrokevolume,whichimprovecardiacoutput[25].

However,anemicpreterminfantsmaybelessabletomaintainoxygendeliverybecauseofthefollowing:

Concomitantrespiratorydisease,suchasrespiratorydistresssyndromeandbronchopulmonarydysplasia,
resultinginhypoxia.

Limitationsonmaximumarterialoxygensaturationandoxygentensionforinfantsrequiringrespiratory
support,becausehyperoxiaincreasestheriskofbronchopulmonarydysplasiaandretinopathyof
prematurity.(See"Pathogenesisandclinicalfeaturesofbronchopulmonarydysplasia",sectionon'Oxygen
toxicity'and"Neonatalresuscitationinthedeliveryroom",sectionon'Supplementaloxygen'.)

HemoglobinF(HbF)containingredcellsintheprematureinfanthaveaconsiderablyhigheroxygenaffinity
thanadultredbloodcells,resultinginreduceddeliveryofoxygentotissues(figure1).

HbFbindspoorlyto2,3diphosphoglycerate(2,3DPG),apotentmodulatorthatdiminishestheaffinityof
hemoglobinforoxygen.Decreasedbindingincreasesoxygenaffinityandshiftstheoxyhemoglobindissociation
curvetotheleft,resultingindecreasedperipheraloxygendelivery(figure1).(See"Structureandfunctionof
normalhemoglobins".)

TheproportionofHbFincreaseswithdecreasinggestationalage,andisregulateddevelopmentallysothatHbF
levelsaresimilaratthesamepostmenstrualage[2628].TheconcentrationofHbFinaninfantbornat28weeks
gestationisapproximately90percent,anddecreasestoapproximately60percentat10weeksafterbirth,avalue
thatissimilartothatofaninfantnewlybornat38weeksgestation[26].

CLINICALANDLABORATORYFEATURESAnemiaofprematurity(AOP)typicallyoccursat3to12weeks
afterbirthininfantslessthan32weeksgestation.TheonsetofAOPisinverselyproportionaltothegestational
ageatbirth[1,29,30].Theanemiatypicallyresolvesbythreetosixmonthsofage.

Inastudyof40verylowbirthweight(VLBW)infants,averagehemoglobinconcentrationsfellfrom18.2g/dLat
birthtoameannadirof9.5g/dLatsixweeksofage[31].Valuesof7to8g/dLwerecommoneveninthe
absenceofsignificantphlebotomylosses.Hematocritvalueswerelowestinthesmallestinfantwithaverage
nadirsof21percentininfantswithbirthweights(BW)lessthan1000g,and24percentininfantswithBW
between1000and1500g.

Manyinfantsareasymptomaticdespitehavinghemoglobinvalueslessthan7g/dL[32,33].However,other
infantswithAOParesymptomaticatsimilarorevenhigherhemoglobinlevelsbecauseofareducedcapacityto
maintainadequateoxygenbyothermeansincompensationforAOP.(See'Oxygendelivery'above.)

SymptomsassociatedwithAOPincludetachycardia,poorweightgain,increasedrequirementofsupplemental
oxygen,orincreasedepisodesofapneaorbradycardia.Inaprospectivestudyofpreterminfantswithbirth
weightslessthan1500g,theriskofapneathatlastedformorethan10secondsrosewithdecreasinghematocrit
valuesforbothinfantsgreaterandlessthan32weeksgestation[34].Inaddition,thefrequencyofapneicevents

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detectedbycontinuousmonitoringofchestimpedanceandoxygensaturationdecreasedafterredbloodcell
transfusion.

ThefollowinglaboratoryfindingsinadditiontoanemiaarecharacteristicofAOP:

Peripheralbloodsmeardemonstratesnormocyticandnormochromicredbloodcells.

Thereticulocytecountislow,andredbloodcellprecursorsinthebonemarrowaredecreased[2].

Serumconcentrationsoferythropoietin(EPO)arelowinprematureinfantsduringthefirstpostnatalmonth
comparedwithadults(9.7versus15.2mU/mL)andremaininappropriatelylowfortheextentofanemia
throughthesecondpostnatalmonth[3].

MANAGEMENTClinicianswhocareforprematureinfantsshouldanticipatethedevelopmentofanemiaof
prematurity(AOP).Optimalnutrition(eg,ironsupplementation)shouldbeprovidedandpatientsmonitoredfor
signsofanemia.Bloodsamplingshouldbelimitedtoessentialtesting,andmicrotechniquesshouldbeusedto
minimizebloodlossduetophlebotomy[19,35].(See'Bloodlossfromphlebotomy'above.)

RedbloodcelltransfusionsareprimarilyusedtotreatinfantswithAOP.Humanerythropoietin(EPO)appearsto
havelimitedbenefitindecreasingexposuretodifferentblooddonorsandisNOTrecommendedforroutineuse.

IronsupplementationTheironcontentatbirthislowerinpreterminfantsthaninterminfants,andtheiron
storesofpreterminfantsoftenaredepletedbytwotothreemonthsofage.Asaresult,allpreterminfantswho
arebreastfedshouldreceiveironsupplementationof2to4mg/kgperdaythroughthefirstyearoflife[36].
Infantswhoreceiveironfortifiedformulaneedlessadditionalsupplementationthanthosewhoareexclusively
breastfed,becauseforagivenvolume,ironcontainingformulacontainsahigherconcentrationofironthan
breastmilk.Lowironcontainingpretermformulasshouldnotbeusedastheydonotadequatelyprovidethe
necessaryironrequiredforthesepatients.(See"Irondeficiencyininfantsandyoungchildren:Screening,
prevention,clinicalmanifestations,anddiagnosis".)

AlthoughironsupplementationdoesnotpreventAOP,theuseofironfortifiedformulacomparedwithnonfortified
formulaallowsforgreaterironsubstratewhenerythropoiesisisstimulated[37].Ironsupplementationdoes
reduceirondeficiencyanemia,whichbothprematureandterminfantsareathighriskfordevelopinginthefirst
yearoflife.(See"Nutritionalcompositionofhumanmilkandpretermformulafortheprematureinfant"and"Iron
deficiencyininfantsandyoungchildren:Screening,prevention,clinicalmanifestations,anddiagnosis".)

LaboratorymonitoringThehematocrit(HCT)orhemoglobin(Hb)concentrationshouldbemonitoredona
weeklybasisinextremelylowbirthweight(ELBW)infants(birthweightlessthan1000g)inthefirstweeksoflife.
Thereafter,inhealthy,growingprematureinfants,itisnotnecessarytoroutinelymonitorHCT/Hb.Infantswith
persistentillness(eg,bronchopulmonarydysplasia)orsurgicalissuesmayrequiremonitoring.

Inasymptomaticinfants,measuringareticulocytecountatapproximatelyfourtosixweeksafterbirthisusedto
evaluatewhetheraredbloodcell(RBC)transfusionmaybeneeded.Althoughnoclearlydefinedbiological
markershavebeenidentifiedtoindicatewhenaRBCtransfusionshouldbegiveninaprematureinfant,an
absolutereticulocyte<100,000/microL(<2percent)isoftenusedasacriterionforRBCtransfusionin
asymptomaticinfantswithalowHCT(lessthan20percent)orHb(lessthan7g/dL).Theindicationsforneonatal
RBCtransfusionarediscussedingreaterdetailseparately.(See"Redbloodcelltransfusionsinthenewborn".)

TransfusionRBCtransfusionisthemostrapidlyeffectivetreatmentforAOP.However,transfusionisa
temporarymeasureandhasthedisadvantagesoffurtherinhibitingerythropoiesisandbeingassociatedwithrisks
oftransmittedinfection,graftversushostdisease,andtoxiceffectsofanticoagulantsorpreservatives.(See
"Transfusionassociatedgraftversushostdisease"and"Immunologicbloodtransfusionreactions".)

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RBCtransfusionisperformedwhenthelevelofanemiabecomessymptomaticoristhoughttocompromise
adequateoxygendelivery.GuidelinesforRBCtransfusionarebaseduponthepatient'shematocrit(hemoglobin),
his/herrequirementforrespiratorysupport,andthepresenceofsymptomsconsistentwithanemia(eg,
tachycardia,poorweightgain,increasedrequirementofsupplementaloxygen,orincreasedepisodesofapneaor
bradycardia).Theindicationsfortransfusions,specificbloodproductsavailablefortransfusion,andthe
administrationoftransfusionintheneonatearediscussedindetailseparately.(See"Redbloodcelltransfusions
inthenewborn"and'Oxygendelivery'above.)

ErythropoiesisstimulatingagentsThepathogeneticimportanceofimpairedEPOproductioninAOP
providestherationaleforthetherapywitherythropoiesisstimulatingagents(ESAs)includingrecombinantEPO.
ESAshavealsobeenproposedasneuroprotectiveagentsthatreducepoorlongtermneurodevelopment
outcome,howeveritisuncertainwhetherprophylacticadministrationisneuroprotective(see"Longterm
neurodevelopmentaloutcomeofpreterminfants:Epidemiologyandriskfactors",sectionon'Potential
neuroprotectiveagents').

However,theadministrationofEPOhasnotbeenacceptedwidelybecauseitappearstohavelimitedefficacyin
decreasingthenumberofblooddonorstowhichtheinfantisexposedviatransfusion,whetherEPOis
administeredearly(withinthefirstweekoflife)orlate(atoraftereightdaysoflife).Dataontheoutcomeofearly
andlateEPOadministrationarepresentedinthefollowingtwosections.

Amoreeffectiveapproachtoreducethenumberofdonorexposuresforthepreterminfantthanroutine
administrationofEPOistolimittheamountofblooddrawn,followrestrictiveguidelinesforredbloodcell
transfusion,andtousesatellitepacks[38].Satellitepacksinvolvedividingoneunitofdonorbloodintomultiple
smalleraliquots,whichallowsrepeatedtransfusionsfromthesamedonortotheindividualinfant.(See"Red
bloodcelltransfusionsinthenewborn",sectionon'Targethemoglobinorhematocrit'and"Redbloodcell
transfusionsinthenewborn",sectionon'Administration'.)

Inretrospectivestudies,earlyadministrationofEPOhasbeenassociatedwithanincreasedriskofretinopathyof
prematurity(ROP).Inaddition,EPOisacostlyintervention.Asaresult,theroutineuseofEPOinneonatesis
NOTrecommendedbecausethepotentiallimitedbenefitsareoutweighedbythecostsandpossiblerisksofthe
intervention.

EarlyEPOuseAlthoughearlyadministration(withinthefirsteightdaysoflife)ofEPOappearstoreduce
thenumberoftransfusionsrequiredinpreterminfants,thesmallreductionmaybeoflimitedclinicalimportance,
becauseEPOdoesnotdecreasethenumberofdonorexposuresduetotheuseofsatellitepacks.Inaddition,
sometrialssuggestthatearlyEPOadministrationincreasedtheriskofretinopathyofprematurity(ROP).

Thesefindingswerebestillustratedinametaanalysisof23trials(2074preterminfants)thatevaluatedtheeffect
ofearlyadministrationofEPO(givenbeforeeightdaysofage)comparedwithplaceboornointervention[39].
Manyoftheseinfantshadreceivedbloodtransfusionspriortoenrollmentinthetrials.Thefollowingfindingswere
noted:

In18trialsof1825infants,EPOreducedtheriskofreceivingoneormoreredbloodcelltransfusions(RR
0.80,95%CI0.750.86).

In13trialsof1115infants,EPOslightlyreducedthenumberofredbloodcelltransfusions(weightedmean
differenceof0.27,95%CI0.42to0.12).

In10trialsof1425infants,EPOincreasedtheriskofROP(RR1.18,95%0.991.40).Inasubanalysisofsix
trialsof930infantsinwhichinformationwasavailable,EPOappearedtoincreasetheriskofsevereROP,
definedasstage3orgreater(RR1.71,95%CI1.152.54).

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TherewerenodifferencesbetweentheEPOandplacebogroupsintheratesofmortality,sepsis,
intraventricularhemorrhage(IVH),periventricularleukomalacia(PVL),necrotizingenterocolitis(NEC),
bronchopulmonarydysplasia(BPD),hypertension,lengthofhospitalstay,orlongtermneurodevelopmental
outcome.

Inafollowupstudyfromoneofthetrialsincludedinthemetaanalysis,EPOandplacebotreatedinfantsat18to
22monthscorrectedagewithbirthweights<1000ghadsimilarweightandlength,numberofrehospitalizations,
transfusionsafterdischarge,anddevelopmentaloutcomes[40].

Asubsequentstudyof102preterminfants(birthweight<1250g)demonstratedEPOanddarbepoetinalfa,a
biologicallymodifiedlongactingESA,reducedthemeannumberoftransfusionsperpatientcomparedwith
controlinfants(1.2,1.2,and2.4,respectively),andthemeannumberofdonorexposuresperpatient(0.8,0.7,
and1.2,respectively)[41].Inthisstudy,thenumberofinjectionswaslowerwiththeuseofdarbepoetinalfa,
whichwasadministeredweekly.

Insummary,earlyEPOisassociatedwithonlyasmallreductioninthenumberoftransfusions,butnoclinically
significantreductioninexposuretothenumberofdonors,andhasnoimpactonclinicaloutcomes.

AlthoughthemetaanalysisalsodemonstratedatrendforanincreasedriskofROP,thiscouldbeachance
findingbecausedevelopmentofROPwasoneofmanysecondaryoutcomesevaluated[39].Inaddition,the
subanalysisthatreportedearlyadministrationresultedinanincreasedriskofsevereROPmustbeinterpreted
withcaution,giventhattheoveralleffectonallgradesofROPwassubstantiallylower.Amongthestudies
includedintheanalysis,therewerenodataregardingthegestationalageofthepatientsandillnessseverity,
whichbothdirectlyhaveanimpactontheriskofROP.Furtherstudiesarerequiredtodemonstratewhetheror
notthereisaclinicallysignificantassociationbetweenearlyEPOuseandROP.

AlthoughitisdifficulttodeterminetheroleofEPOinthemultifactorialpathogenesisofROP,thecurrentevidence
issufficienttoraiseconcernsabouttheearlyuseofEPOgiventhelimitedbenefitofreducingexposuretoblood
donors,itscost,andpotentialassociationwithROP.Asaresult,werecommendNOTtoroutinelyadministerEPO
withinthefirsteightdaysoflife.

LateEPOuseLateadministrationofEPOreducesthenumberoftransfusions,butthelimitedbenefitdoes
notjustifyitsuse.Thiswasillustratedina2014metaanalysisthatevaluatedtheeffectsoflateEPO
administration(atorlaterthaneightdaysofage)comparedwithplaceboornointervention[42].Mostofthese
infantshadreceivedbloodtransfusionspriortoenrollmentinthetrials.Thefollowingfindingswerenoted:

EPOreducedtheriskofreceivingoneormoreredbloodcelltransfusions(RR0.71,95%CI0.640.79).

EPOreducedthenumberofredbloodcelltransfusions(weightedmeandifferenceof0.22,95%CI0.38to
0.06).

Therewasnodifferenceinthevolumeofbloodtransfused(meandifference1.6mL/kg,95%CI5.8to2.6).

EPOhadnoeffectontheratesforROP,mortality,sepsis,intraventricularhemorrhage(IVH),periventricular
leukomalacia(PVL),necrotizingenterocolitis(NEC),bronchopulmonarydysplasia(BPD),hypertension,
lengthofhospitalstay,orlongtermneurodevelopmentaloutcome.However,therewasatrendtowardsan
increasedriskofROPassociatedwithEPOadministration(RR1.27,95%CI0.991.64).

LateadministrationofEPOreducedthemeannumberoftransfusionsbyalittlelessthanonetransfusionper
infant.ThissmallbenefitofEPOwasdiminishedduetotheexposureofpreviousbloodtransfusionsbeforeeight
daysoflife,andtheuseofsatellitepacksthatwouldmitigateagainstadditionaldonorexposureinthecontrol

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group.Asaresult,werecommendNOTtoroutinelyadministerEPOaftereightdaysbecauseitslimitedbenefitof
limitingexposuretoblooddonorsdoesnotjustifyitscost.

ComparisonearlyversuslateuseThereappearstobenobenefitofearlyEPOadministrationcompared
withlateadministrationinreducingthenumberoftransfusions,theamountofredcellstransfused,ornumberof
donorexposuresperinfant.Thiswasillustratedinametaanalysisoftwotrials(262patients),whichwasupdated
in2012,thatfoundnostatisticalbenefitofearlyEPOadministration[43,44].However,thereappearedtobean
increasedriskofROPassociatedwithearlyadministration.Thesedatasupporttherecommendationofnot
administratingEPOinthefirsteightdaysoflife.

ComplicationsUseofEPOinprematureinfantsappearstobesafe.Hypertension,rash,bonepain,
seizures,orlaterdevelopmentofantiEPOantibodieshavenotbeenreportedinprematureinfants.
Complicationsincludethefollowing:

Atransientneutropeniathatresolveswithcessationoftherapyisoccasionallyobserved[45,46].Inonetrial,
meanabsoluteneutrophilcountsafter20dayswerelowerinprematureinfantswhoreceivedEPOcompared
withredbloodcelltransfusion(1.8x10(3)versus3.9x10(3))[45].

Irondeficiencyoccursifsupplementationisinadequate[4648].

Asdiscussedabove,earlyadministrationofEPOhasbeenassociatedwithincreasedriskofROP.(See
'EarlyEPOuse'above.)

DoseIfEPOisgiven,itcanbeadministeredintravenouslythreetimesaweekasaoncedailyinfusionof
200units/kgperdoseorasacontinuousinfusionover24hoursof300units/kgorsubcutaneously(400units/kg
perdose,threetimesperweek)[49,50].Whengivenintravenously,EPOshouldbemixedinaproteincontaining
solution(5percentalbumin)andgivenoveratleastfourhours,orcontinuouslyover24hours,oftenasan
additiontototalparenteralnutrition[51].Theundiluteddrug(2000units/mL)canbegivensubcutaneouslyina
volumeof0.2mL/kgforinfantslessthan1000g.EPOpreparationwithhigherconcentrations(upto10,000
units/mL)canbeusedastheinfantgrows.Darbepoetinalfa,alongeractingESA,hasbeenusedinpreterm
infantsusingaweeklydoseof10mcg/kg[41].

Inasmallclinicaltrial,preterminfantswhoreceived1200units/kgonceaweekandcontrolinfantswhoreceived
thestandardthreetimesaweekdosing(400units/kg)hadsimilarincreasesinabsolutereticulocytecountsand
hematocritsattheendofthefourweektrialperiod[52].However,furtherstudiesareneededtoconfirmthat
weeklydosingprovidesthesamebenefitasmorefrequentadministration.

InfantstreatedwithEPOrequireironsupplementation.Aproposedregimenisadailyelementalirondoseof6
mg/kgforinfantsonfullenteralfeedings,and3mg/kgforthosetakingatleast60mL/kgperday[49].Forinfants
receivingtotalparenteralnutrition,irondextrancanbeaddedtothesolution(3to5mg/kgweekly)[49].

Thereticulocytecount,centralhematocritorhemoglobinconcentration,andabsoluteneutrophilcountare
measuredbeforeaswellasonetotwoweeksafterstartingEPOtreatment.EPOiswithheldiftheabsolute
neutrophilcountislessthan1000/microL.Serumferritinlevelsmaybeusefulinevaluatingthoseinfantswhoare
notrespondingtotherapytodetectirondeficiency[49].

SUMMARYANDRECOMMENDATIONS

Newborninfantshaveafallinhematocritsoonafterbirthdueprimarilytoimpairedproductionof
erythropoietin.Inpreterminfants,thedeclineoccursearlier,ismorepronounced,andiscalledanemiaof
prematurity(AOP).AOPtypicallyoccursat3to12weeksafterbirthininfantslessthan32weeksgestation.
(See'Pathogenesis'above.)

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Othercontributorstoanemiainthepreterminfantincludeirondepletion,bloodlossduetophlebotomy,anda
reducedredbloodcelllifespaninpreterminfantscomparedwiththatoffullterminfantsandadults.(See
'Pathogenesis'aboveand'Otherfactors'above.)

Preterminfantsareatparticularriskforimpairedoxygendeliverywithanemiabecauseoftheincreased
likelihoodofconcomitantrespiratorydisease,highlevelsofhemoglobinF,andtheneedtoavoidhyperoxia,
whichincreasestheriskofbronchopulmonarydysplasia(BPD)andretinopathyofprematurity(ROP).(See
'Oxygendelivery'above.)

Manyinfantsremainasymptomaticdespitehavinghemoglobinlevelsbelow7g/dL.However,otherinfants
maybesymptomaticatsimilarorevenhigherhemoglobinlevels.Symptomsincludetachycardia,poorweight
gain,increasedrequirementofsupplementaloxygen,orincreasedfrequencyofapneaorbradycardia.(See
'Clinicalandlaboratoryfeatures'above.)

ThelaboratoryfindingscharacteristicofAOPincludenormocyticandnormochromicredbloodcells,low
reticulocytecount,andlowerythropoietinlevels.(See'Clinicalandlaboratoryfeatures'above.)

AOPmayrequiretreatmentwithredbloodcell(RBC)transfusion.However,transfusionisatemporary
measureandhaspotentialadverseeffects,suchasinfectionandgraftversushostdisease.Guidelinesfor
RBCtransfusionbaseduponarestrictivepolicyintheneonatearepresentedseparately.(See"Redblood
celltransfusionsinthenewborn",sectionon'Indications'.)

Administrationofrecombinanthumanerythropoietin(EPO)appearstohavelimitedefficacyindecreasing
thenumberofblooddonorstowhichtheinfantisexposed.Itisacostlyintervention,andearlyEPOusemay
increasetheriskandseverityofROP.Asaresult,werecommendNOTtoroutinelyadministerEPOto
preterminfants(Grade1B).(See'Erythropoiesisstimulatingagents'above.)

Amoreeffectiveapproachtoreducethenumberofdonorexposuresforthepreterminfantthanroutine
administrationofEPOiscombinationoflimitingtheamountofblooddrawn,arestrictivepolicyforredcell
transfusions,andtheuseofsatellitepacks,whichallowforrepeatedtransfusionsfromthesamedonortothe
individualinfant.(See"Redbloodcelltransfusionsinthenewborn",sectionon'Targethemoglobinor
hematocrit'and"Redbloodcelltransfusionsinthenewborn",sectionon'Administration'and'Management'
above.)

ACKNOWLEDGMENTTheeditorialstaffatUpToDatewouldliketoacknowledgeJoyceMKoenig,MD,who
contributedtoanearlierversionofthistopicreview.

UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

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Topic4962Version17.0

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GRAPHICS

Oxyhemoglobindissociationcurve

Depictedhereistheoxyhemoglobindissociationcurvefornormaladulthemoglobin
(hemoglobinA,solidline).Notethatatapartialpressureofoxygenof27mmHgon
theXaxis,hemoglobinis50%saturatedwithoxygen(theP50is27mmHg),andatan
arterialpartialpressureofoxygenof100mmHg,hemoglobinis100%saturated.Atthe
typicalmixedvenousoxygentensionofapproximately40mmHg,theoxygen
saturationofhemoglobinisapproximately75%.Shiftingthecurvetotheright(redline)
canreduceoxygensaturationto50to60%forthepartialoxygenpressureof40mm
Hg,meaningthatlessoxygenisboundtohemoglobinandmoreoxygenisdeliveredto
thetissues.Theoppositeoccurswithleftshifts(blueline).Ahighproportionoffetal
hemoglobin,whichhashighoxygenaffinity,shiftsthiscurvetotheleftinnewborns.The
effectofrightorleftshiftingofthecurveismostpronouncedatlowpartialpressures
ofoxygen.

Graphic81216Version7.0

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2/2/2017 AnemiaofprematurityUpToDate

ContributorDisclosures
JosephAGarciaPrats,MD Nothingtodisclose StevenAAbrams,MD Grant/Research/ClinicalTrialSupport:
MeadJohnson[PediatricNutrition(Preterminfantformulas)].Consultant/AdvisoryBoards:MilkPrep[Childhood
nutrition(Diary)]NestleNutrition[Infantnutrition(Preterminfantformulas)]. DonaldHMahoney,Jr,MD Nothing
todisclose MelanieSKim,MD Nothingtodisclose

Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseare
addressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobe
providedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofallauthorsandmustconformto
UpToDatestandardsofevidence.

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