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EarlyNutri+onandGrowthinELBWInfants-StrategiestoImproveOutcomes

Neonatology2016Atlanta,GA

BrendaPoindexter,MD,MS

DirectorofClinicalandTransla+onalResearchProfessorofPediatrics

DisclosureInforma+on

•  Norelevantfinancialdisclosure

•  Thispresenta+onwillinvolvediscussionoftheinves+ga+onaluseofhumanmilkanalyzer(notapprovedbyFDAforclinicaluse)

Objec+ves

1.  Evaluatetheevidenceofassocia+onbetweengrowth,nutri+onalsupport,andneurodevelopmentaloutcomesinELBWinfants

2.  Reviewprac+calapproachtoprovisionofearlyparenteralandenteralnutri+on

3.  Describestrategiestoop+mizegrowthininfantsreceivinghumanmilk–bothintheNICUandfollowinghospitaldischarge

GrowthAssessmentofPretermInfantsisImportantBecause…

•  Postnatalgrowthfailureremainsasubstan+alproblem,

•  hasnega+veimpactonhealthoutcomessuchasneurodevelopment,

•  ismodifiable,(nutri+onmakesadifference!)

A B

Fenton,BMCPediatrics2013

BMI-for-ageIntrauterineGrowthCurves

Irene E. Olsen et al. Pediatrics 2015;135:e572-e581

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Ehrenkranz,Pediatrics1999

©1999 by American Academy of Pediatrics

©2001 by American Academy of Pediatrics

PostnatalGrowthvs.ExpectedIntrauterineGrowth Associa+onbetweenGrowth,Nutri+on,andNeurodevelopmentalOutcomes

•  Be^ernutri+onalsupportisassociatedwithimprovedgrowthandlessextrauterine/postnatalgrowthfailure

•  Improvedgrowthcorrelateswithimprovedneurodevelopmentaloutcomes

•  Be^ernutri+onalsupportisassociatedwithimprovedneurodevelopmentaloutcomes

EarlyAminoAcidsImproveGrowthOutcomesat36weeksPMA

•  SecondaryanalysisofELBWinfantsenrolledinNICHDNeonatalResearchNetworkglutaminetrial

•  Stra+fiedbywhethertheyreceivedatleast3g/kg/dofaminoacidsinthefirst5daysoflife

•  Infantswhoreceivedearlyaminoacidshadsignificantlyimprovedgrowthoutcomes(weight,length,andHC)at36weeksPMA- ORforweight<10thpercen+le4.2(2.4-7.5)forinfantsinlateAAgroup

Poindexter,JPediatr2006

EarlyAminoAcidsandHeadCircumferenceat18monthsCA

Poindexter,JPediatr2006

%

<10th%+le <5th%+le

*nosignificantdifferencesbetweengroupsonneurodevelopmentaltes+ng

In-HospitalGrowthisAssociatedwithImprovedNeurodevelopmentalOutcomes

•  Cohortof1616infantswhosurvivedtodischarge(23-26weeksGA)

•  Dividedintoquar+lesbasedonin-hospitalweightgainvelocity

•  86%seenat18-22monthsCAinfollow-up

Poindexter,PAS2013

Rela+onshipbetweenWeightGainQuar+le(1vs4)andOutcomes

AdjustedOR 95%CISevere/ProfoundNDI 7.3 3.9-13.9BSIDIIICogni+ve<70 5.9 2.7-13.0BSIDIIICogni+ve<85 3.1 2.0-4.9Mod/SevereCP 12.3 4.6-32.9

Poindexter,PAS2013

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LengthGrowthVelocityandNeurodevelopment

•  Improvedlineargrowththroughoutthefirstyearoflifeassociatedwithimprovedneurodevelopmentat24months–  Increaseof1z-scoreatdischargeassociatedwith8pointincreaseinlanguagescore

–  Increaseof1z-scoreat4and12monthsassociatedwith4.5pointincreaseincogni+vescore

Ramel,Neonatology2012

MonitoringGrowth-Summary

•  Goalistopreventgrowthfailure–requirespromptrecogni+onofgrowthfalteringandinterven+on

•  Monitornotonlyweight,butalsolengthandheadcircumference;propor+onalgrowth(bodycomposi+on)alsoimportant

•  Reviewgrowthvelocityonweeklybasis– Typicalgoalof15g/kg/dlikelyunderes+matesGVnecessarytoachieveop+malgrowthandoutcomes

– Con+nuetomonitorfollowingNICUdischarge

Prac+calApproachtoEarlyParenteralandEnteralNutri+on

SuggestedTargetIntakesofNutrientsfromPNinFirstWeek

Nutrient Day0* Day1-2 Day3AminoAcids ≥2g/kg/d ≥3.5g/kg/d

3.5-4g/kg/d

Lipid ≥2g/kg/d

3-4g/kg/d 3-4g/kg/d

TotalEnergy 60-80kcal/kg/d 80-100kcal/kg/d ≥100kcal/kg/d

Embleton, Nutritional Care of Preterm Infants, 3rd Ed

*first 24 hrs after birth

THISISNOTAN“AGGRESSIVE”APPROACH!

BeMindfulofDifferencesBetweenPrescribedandActualIntake

Abel,PhDdisserta+on2012

ReasonableStrategytoOp+mizeEnteralFeedingPrac+cesinELBWandVLBWInfants

Senterre, Nutritional Care of Preterm Infants, 3rd Ed

ELBW VLBWMilk HM HMFirstfeeding Between6-48hrs Between6-48hrsIni+alfeeding(MEF) 0.5mL/kg/hr

or1mL/kgq2hr

1mL/kg/hror

2mL/kgq2hrDura+onofMEF 1-4days 1-4daysFeedingadvancement

15-25mL/kg/d 20-30mL/kg/d

HMfor+fica+on Before100mL/kg/d Before100mL/kg/dTargetenteralintakes

EnergyProtein

-110-135kcal/kg/d

4-4.5g/kg/d

110-135kcal/kg/d

3.5-4g/kg/d

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AdvancingEnteralVolume–“Becau+ouslyrelentless”

•  Defaultshouldbetoincreasefeedsdaily•  GastricResiduals- Almostalwaysimmaturegutmo+lity- Li^lemovementinsmallintes+neun+l30weeksinfetallife,whatthereisisweakanduncoordinated- Fullmul+phasicmotorcomplexesmaynotmatureun+l36weeks- OccasionallyasignofileusassociatedwithsepsisorNEC(thisiswhatmakesresidualsscary)

StandardizedFeedingGuidelines

•  ConsensusearlyPNandENevidence-basedstrategies

•  Guidelinesmediateimpactofperceivedseverityofillness

•  Plantomanagefeedingintoleranceand/orconsistentapproachtoresiduals(donotcheck)

•  Strategytomaintainsteadyrateofpostnatalgrowth,withadjustmentofnutri+onalsupportifgrowthparametersnotmet

•  Feedingguidelinestypicallydonotincludeplansforpostdischargenutri+on

ImpactofStandardizedFeedingGuidelinesonNEC

•  Reviewofobserva+onalstudies(n=6)repor+ngincidenceofNECbeforeandaperimplementa+onofstandardizedfeedingregimen

•  Significantheterogeneityinthefeedingregimensthemselves

•  Pooledriskra+oof0.13forNEC•  BWregainedsooner,fullenteralnutri+onachievedsooner,cumula+veproteinanddeficitsreduced,improvedgrowthoutcomes

Patole, Arch Dis Child Fetal Neonatal Ed 2005

FailuresofFeedingProtocol

•  Stafffailures(complianceissues)•  Pa+entfailures(clinicalsymptomsorsitua+ons)

FeedingProtocolCompliance

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HumanMilk

BenefitsofMaternalMilkinVLBWInfants

•  Associatedwithdecreasedin-hospitalmorbidityincludinglowerratesof:– NEC(andcompositeofNECordeath)– Late-onsetsepsis– BPD– SevereROP

•  Shorterhospitalstayandlowerincidenceofrehospitaliza+onthanpretermformula

Heller, Pediatrics 2007 Meinzen-Derr, J Perinatol 2009

Maayan-Metzger, Am J Perinatol 2011

MeanMDIandPDIscoresat18and30monthsaccordingtoANYmaternalmilkfeeding

Copyright ©2007 American Academy of Pediatrics Vohr,Poindexter,Pediatrics2006and2007

MaternalMilkImprovesOutcomes

•  Dose-responserela+onship-foreach10mL/kg/dayofmaternalmilkfedintheNICU:– MDIincreased0.59points(=5pointadvantagewithfullHMdiet)

–  PDIincreased0.56points•  Only30%ofinfantsweredischargedhomeonbreastmilkfeedings-  Allsignificantdifferencesremainedwhentheseinfantswereremovedfromanalysis

Vohr,Poindexter,Pediatrics2006and2007

Will short term exposure to donor milk result in similar improved outcomes?

RCTsofDonorHumanMilkandNeurodevelopmentalOutcomes

•  SingleCenter– CanadianDoMINOtrial(n=363)

(Unger,BMCPediatrics2014)

– USDonorHMandNeurodevelopmentalOutcomesinVLBWinfants(Iowapilot)

•  UKPREMFOODStudy(pilotn=66then4000)•  NICHDNeonatalResearchNetwork–TheMILKtrial(plannedn=670)

ISRCTN35317141NCT01232725NCT01534481

TupsBSIDIIIscoresat2years

Highlightstheimportanceofongoingrandomizedtrialsbeingcompleted

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HumanMilkandGrowth

•  Observa+onalstudieshaveshownthatprematureinfantsfedhumanmilkhavelowergrowthratesthaninfantsfedtermorpreterminfantformula

•  Providesinsufficientquan++esofprotein,sodium,phosphate,andcalciumtomeetthees+matedneedsofthepreterminfant

•  Poorbonemineraliza+on,rickets,andfractureshavebeendescribedinpreterminfantsreceivinginadequateintakeofcalciumandphosphate

Atkinson, J Pediatr 1983 Cooper, J Pediatr Gastroent Nutr 1984

Roberts, Human Nutr 1987

DonorBreastMilkandGrowth

•  Randomizedtrialofdonorbreastmilkorpretermformulafoundlowestweightgainindonormilkgroupanddespitereceivinggreatermilkintakesandmorenutri+onalsupplements,infantsfeddonormilkhadlessergainsinweightandmorewereswitchedtoapretermformuladietbecauseofpoorweightgain(Schanler,Pediatrics2005)

•  InrecentanalysisofexclusiveHMvsbovineformula,lengthgainvelocitysignificantlylowerinHMgroup(0.84±0.21vs.1.12±0.28cm/wk)(Cristofalo,JPediatr2013)

•  Retrospec+vecohortstudyfoundVLBWinfantsreceiving>75%donormilkhadhighratesofSGAatdischarge(Colaizy,BMCPediatrics2012)

Composi+onofPretermHumanMilk

Weeksoflacta+on

MakersofHMFassume1.4-1.6g/dL–anddonotaccountforthedecreaseinproteinover+me

í

_____________________________donormilk

ProteinContentofDonorMilk

•  Pretermmilkhastypically1.5-2g/dlproteincontentforthefirst4-6weeksoflacta+on

•  Donorhumanmilktypicallyhasless:– Studyof273donors,mean1.16g/dl(95%CI1.13-1.2)Wojciketal,JAmDietAssoc2009;109:137.

– Mother’sMilkBankofIowa,196batchesofpooledmilk,mean0.85(sd0.08)

–  IndianaMilkBank,mean0.7•  Poolingleadstoconsistentproteincontent

Shouldourfor+fica+onstrategiesbedifferentforinfantsreceivingmostlydonormilk?

Effectsofhandlingondonormilknutri+onalcontent

StepinProcess Fatg/dl Proteing/dl

Raw*# 2.17±1.47 1.03±0.39

Post-Pasteuriza+on*# 2.05±1.46 0.99±0.42

Thawed*# 2.00±1.45 0.97±0.41

pvalue,ANOVA*(3condi+ons)

<0.001 <0.001

FedbyNGbolus# 1.88±1.22 0.94±0.38

Con+nuousinfusion# 1.00±0.99 0.89±0.41

pvalue,ANOVA#(all5condi+ons)

<0.001 0.046

Adapted from Viera et al, Early Human Development 2011; 87:577

Study of milk donated to Brazilian milk bank, assessed protein and fat by NIRS The more times you handle milk, the more you lose…

UpdatedRecommenda+ons(2014)

perkgperdFluids,mL 135-200Energy,kcal 110-130Protein,g 3.5-4.5Lipid,g 4.8-6.6

DHA,mg 18-60ARA,mg 18-45

Carbohydrate,g 11.6-13.2

Koletzko B et al, eds. World Rev Nutr Diet 2014;110:297-99

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CurrentOp+onsforHumanMilkFor+fica+on

•  BovineHMF•  Humanmilk-basedHMF•  Humanmilk-basedRTF•  Humanmilk-derived“cream”supplement•  LiquidProtein“For+fier”•  HighCalorieFormula(suchas30kcal/ozpreterm)

ComparisonsofFor+fica+onOp+ons(at150mL/kg/d)

Protein(g/kg/d)

Energy(kcal/kg/d)

P:E(g/100kcal)

HumanMilk* 1.6-2.1 100 1.6-2.1

HM:SHMF1:25 3.2-3.8 120 2.7

HM:EHMFAL1:25 4.2 120 3.5

HM:Prolact+480:20 3.2 120 2.7

HM:SHMF1:25+1mLliquidprotein

4.2 120 3.5

*assumeproteincontentof1.1g/100mLofTerm/DonorHMand1.4g/100mLPretermHM

Human-milkBasedFor+fier

•  Comparisonofhuman-milkbasedfor+fierwithbovinefor+fier;unfortunatelysupplementedonegroupwithformula,notdonormilk

•  207randomized(BW900g;GA27wks)- MM+DM+humanHMF(startedat100mL/kg/d)- MM+DM+humanHMF(startedat40mL/kg/d)- MM+formula+bovineHMF

•  Nodifferencein+meonTPN,+mewithCVL,weightgain,lengthofstay,orcombinedoutcomeoflate-onsetsepsisorNEC

Sullivan, J Pediatr 2010 Sullivan, J Pediatr 2010

Exclusively Human Milk-based Diet is Associated with Lower Rate of NEC

Secondary Outcomes: Medical NEC reduced from 16% to 6%; surgical NEC from 10% to 2% - how to separate out the impact of the fortifier vs. the formula?

ApproachestoFor+fica+on

•  Standard,fixeddosagefor+fica+on•  Adjustablefor+fica+onusingasurrogateforproteinstatustomodifydosage

•  Targeted(customized,individualized)for+fica+onusingresultsfromhumanmilkanalysis

Changeinfor+fica+onstrategyshouldnotbetriggeredbypoorgrowth!

AdjustableFor+fica+onofHumanMilk•  Comparedproteinfor+fica+onwithHMFplusbovinewheyproteintostandardfor+fica+oninpreterminfants(BW600-1750g;GA26-34wks)

•  Studygroupreceivedincrementalincreasesinproteinguidedbytwice-weeklyBUNmeasurements

•  Averageintakeof3.2g/kg/dvs.2.9g/kg/d•  Results

–  Weightgain+3g/kg/d;HC+0.4mm/d–  Weightandheadcircumferencegainsignificantlycorrelatedwithproteinintake

–  NosignificantdifferencesbetweengroupsinBUN,crea+nine,calcium,orphosphorus

Arslanoglu, J Perinatology 2006

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HumanMilkAnalysis

•  Pointofcare•  Measures“true”protein,

fat,andlactoseusingnear-infraredspectroscopy

•  Severalbrandsavailable–notyetapprovedbyFDA

•  Usessmallvolumeofmilk

EnergyContentofHM

Weeks of lactation

Kca

l/oz

Radmacher,PAS2012

HumanMilkCreamSupplementUnmasked,NoninferiorityRCT

StudyDesignP–BW750-1250g(n=79)I–HMcreamifenergycontent<20kcal/oz*C–HMassumed20kcal/ozO–weightgain(g/kg/d)T–interven+onun+l36wksPMA

Results•  14.0±2.5vs12.4±3.0g/

kg/dweightgain•  1.03±0.33vs0.83±0.41

cm/wklengthvelocity

Hair, J Pediatr 2014

*Typicalgoalof15g/kg/dlikelyunderes+matesGVnecessarytoachieveop+malgrowthandoutcomes *energycontentmeasureddaily

usingnear-infraredmilkanalyzer

TargetFor+fica+onofBreastMilk

•  Implementa+onoftargetfor+fica+oninNICUbymeasuringandadjus+ngfat,protein,andcarbohydratecontentevery12hrs

•  All650samplesofbreastmilkrequiredatleast1macronutrientadjustedtomeetESPGHANguidelines

•  Infantsontargetfor+fica+onhadgrowthrateswhichwerelinearlycorrelatedtothefeedingvolume

Rochow,JPediatr2013

*Todate,moststudiesevalua+ngtargetfor+fica+onhaveonlyevaluatedaddi+onofprotein

Early Fortification of Human Milk

•  Beawarethatbothmaternalanddonormilkhavelessprotein(andenergy)thanwhatweuseforcalcula+ons

•  Earliestprac+cal+mepoint– 25mlperdayifusingmaternalmilk(limitswastage)

– Typicallydonebetween40-60ml/kg/dforELBWs

EarlyandRapidAdvancementofFor+fica+onandGrowth

•  Singlecenter,prospec+veobserva+onalcohortstudyofpreterminfants≤1250gBW(n=104)

•  Exclusivehumanmilk-baseddietun+l34weeksPMA•  Donorhumanmilkderivedfor+fierstartedat60mL/kgandadvancedtoprovide6-8addi+onalkcalperounce

•  Improvedgrowth(weightandlength)comparedtohistoricalcohort;only43%ofinfantswithEUGR

Hair,BMCResearch2013

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Troubleshoo+ngSubop+malGrowth

•  Knowwhatthebabyisactuallyreceiving•  Carefullymonitorweightgainvelocityandlineargrowth

•  Reviewmom’spumping- Makesuresheisbringinginallofmilk(notjustfirstamcollec+onwhichislowerinfat/calories)

•  Increasecaloricdensityorliberalizevolume•  AddmoreproteinormoreHMF

– Mayneedtoabandonuseofdonormilkifgrowthissubop+mal

Moving beyond Standard Fortification

•  Standard24kcal/ozfor+fica+onrecipedoesnotmeetthegrowthneedsofourbabies,especiallywithdonormilk

•  Toincreaseproteinintake,wemayfor+fyto27-30kcal/ozusingmorefor+fierandliquidprotein

•  Dependingonamountofmaternalmilkavailable,mayalsomixwith30kcalpretermformula

NICUDischargeandBeyond

Rela+onshipbetweenCatch-upGrowthandNeurodevelopmentatPreschoolAge

•  745ELBWinfantsseenatboth18and30months(82%follow-up)

•  Weight<10thpercen+le:– 48%ofinfantsat18months– 32%ofinfantsat30months

•  ELBWinfantswithweight<10th%+leorHC<10th%+leatpreschoolagehave:– LowermeanBayleyMDI– LowerBayleyPDI

Dusick&Poindexter,PediatrRes2005

Post-DischargeFor+fica+onofHumanMilkCochraneReview

•  Onetrial(n=39)iden+fied•  For+fica+onfor12weeksaperdischargeresultedinhigherratesofgrowthduringinfancy- 12monthsCA–weight,length,andHCsignificantlygreaterininterven+ongroup

- Noeffectonneurodevelopmentalassessmentsat18monthsCA

McCormick, The Cochrane Library 2010

Transi+oningtoDischarge

•  Send1-2casesofHMFhomewithfamilyat+meofdischarge

•  For+fyingbreastmilkforinfantsfeddirectlyfromthebreastislogis+callydifficultandhasthepoten+altointerferewithbreas~eeding

•  Onestrategyistofocusfor+fica+oneffortsonthosefeedsnotatthebreast(par+algavageorsupplementalbo^lefeeds)usinghighercaloricdensityfeeds–  Ifbabyhadbeenon22-or24-kcal/ozfeedsinNICU,transi+onwith27-or30kcal/ozsupplementsinaddi+ontobreas~eedinga^empts

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Post-DischargeFollowup–Prac+calAdvice

•  Follow-upwithNICUdie++antoreassessandprovideprimarycarephysicianwithgoalsforgrowthandadviceondura+onofsupplementa+on

•  Callbackfromdiettechtoaskques+onsaskinghowfamilyispreparinghumanmilkand/orformula

•  Vitamins/iron–asktorepeatdoseandwhethertheyaregivingdaily

•  Communica+onwithprimarypediatricianiskeyforimplementa+onofplan

Suppor+ngPrematureInfantNutri+on(SPIN)

ThankYou!

brenda.poindexter@cchmc.org