InfantFeeding MethodandNeonatalAbstinenceSyndrome. Outcomes:ASystematicReview. CarleighTaylor

Transkript

1 Runninghead: INFANTFEEDING METHODANDNASOUTCOMES InfantFeeding MethodandNeonatalAbstinenceSyndrome Outcomes:ASystematicReview by CarleighTaylor Athesis presentedtolakeheaduniversity infulfilmentofthe thesisrequirementforthedegreeof MasterofSocial Work ThunderBay,Ontario,Canada,2018 CarleighTaylor2018

2 INFANTFEEDING METHODANDNASOUTCOMES 2 Abstract Background:NeonatalAbstinenceSyndrome(NAS)isacomplexdisorder,observedininfants experiencingsymptomsofwithdrawal,asaresultofinuteroexposuretothematernaluseof opioids.breastfeedinghasbeenrecognizedastheoptimalsourceofnutritionforinfants.while theadvantagesasociatedwithbreastfeedingareundisputed,thepromotionofbreastfeedingfor infantsdiagnosedwithneonatalabstinencesyndromeisinconsistent.thereisevidenceto suggestthatbreastfeedinginfantswhohavebeenexposedtoopioidsinuteromayimprovenas outcomes. Aim:Asystematicreviewwasconductedtoasesandcriticalyappraisetheexistingliterature regardingtheefectofinfantfeedingmethodamonginfantswithneonatalabstinencesyndrome (NAS)onneonataloutcomes. Method:AsystematicsearchoftheliteratureoffeedingmethodsamonginfantswithNASwas conductedusingtheelectronicdatabasespubmed,cinahl,nursingandaliedhealth, PyschINFO,EvidenceBased Medicine, WebofScience,and Medline(EMBASE).Studieswere eligibleforinclusioninthereviewiftheyfulfiledthefolowingcriteria:(1)reportedoriginal dataonoutcomesrelatedtoinfantfeedingandnas,(2)thestudymethodincludedanytypeof quantitativedesignthatincludedaninpatientcomparisongroupofbreastfedandformulafed infantswithnas,and(3)thearticleswerepublishedinenglishinapeerreviewedjournal.al articlesselectedforinclusionwereasesedformethodologicalqualitybyfirstandsecondary authorusingthejbistandardizedcriticalappraisalchecklistforcohort/casecontrolstudiesand thejbistandardizedcriticalappraisalchecklistforrandomizedcontroledstudies.theprincipal authorextractedthedatafromthefultextstudiesandentereditintoadataextractiontemplate developedforthesystematicreview.thesecondaryauthorsindependentlyreviewedand

3 INFANTFEEDING METHODANDNASOUTCOMES 3 comparedtheextracteddata.thedatawassynthesizednarativelyduetothediversestudy samplesandoutcomesthatwereevaluated. Results:Thesearchidentified491studies,ofwhich17providedinformationrelatedtoNASand infantfeedingmethod.eightstudiesmettheinclusionandexclusioncriteriaafterfurther examinationoftheful-textstudies.themajorityofstudiesfoundthatbreastfeedingwas asociatedwithareducedneedforpharmacologictreatmentandadecreaseinthedurationof pharmacotherapywhencomparedtoformula-fedorcombination-fedinfants.breastfeeding, whencomparedtoformula-feeding,wasalsoconsistentlyasociatedwithashorter hospitalizationandareducedseverityofnas,includinglowerfinneganscores.studiesalso identifiedalatertimetowithdrawalandadelayedonsetofnasasociatedwithbreastfed infantswhencomparedtoformula-fedinfants. ConclusionsandRelevance:ThestudiesconsistentlyidentifiedatrendtowardsimprovedNAS outcomesforinfantswhowerebreastfedwhencomparedtoformulaorcombination-fed.these findingsprovideevidenceforbreastfeedingasanefectivenon-pharmacologictreatmentfor NAS.BreastfeedingamongstabilizedmothersonOpioidMaintenance Therapy(OMT)should berecommendedasanon-pharmacologicapproachtoimprovingnasoutcomes.

4 INFANTFEEDING METHODANDNASOUTCOMES 4 InfantFeeding MethodandNeonatalAbstinenceSyndrome Outcomes:ASystematicReview Researchhasdemonstratedthesubstantialadvantagesforinfants,mothers,andthe community,frombreastfeeding(americanacademyofpediatrics,2005).duetothe considerablebenefitsasociatedwithhumanmilk,breastfeedinghasbeenrecognizedasthe optimalsourceofnutritionforinfants(worldhealthorganization,2001).theseadvantages includebenefitstoinfanthealth,nutrition,immunity,andneurodevelopment,aswelasmaternal health,andcommunityeconomicbenefits(americanacademyofpediatrics,2005;boland, 2005; WorldHealthOrganization,2001). Whiletheadvantagesasociatedwithbreastfeedingare undisputed,thepromotionofbreastfeedingforinfantsdiagnosedwithneonatalabstinence syndrome(nas)isinconsistent(janson,velez,&harow,2004).understandingtheevidence regardingbreastfeedingforinfantswithnasisanimportantconsiderationforcliniciansto promotethismethodoffeeding.assuch,thepurposeofthissystematicreviewwastoasesand criticalyappraisetheexistingliteratureregardingtheefectofinfantfeedingmethodamong infantswithnasonneonataloutcomes.thisreviewmethodwasselectedtoprovideathorough overviewofthecurentliteratureandtoalowfortheinclusionofavarietyofmethodologies, diferentscoringtoolstomeasuresymptomology,anddiversenasoutcomes. Background NeonatalAbstinenceSyndrome(NAS)isacomplexdisorder,observedininfants experiencingsymptomsofwithdrawal,asaresultofin-uteroexposuretothematernaluseof opioids(stover&davis,2015;sublet,2013).neonatalabstinencesyndromeisamultisystem conditionthatpresentsashyperiritabilityofthecentralnervoussystem,autonomicdysfunction, andgastrointestinaldisturbances(kocherlakota,2014;stover&davis,2015).thesymptomsof

5 INFANTFEEDING METHODANDNASOUTCOMES 5 NASarecharacterized,butnotlimitedtovomiting,loosestools,poorfeeding,tremors,highpitchedcrying,alteredsleep-wakecycles,seizures, respiratorydistres,andtemperature instability(finnegan,connaughton,kron,&emich,1975;kocherlakota,2014;sublet,2013). Themanifestationofsymptomsvariesamonginfants,andtheonset,duration,andseverityof NASdependonanumberoffactors(Kocherlakota,2014).NeonatalAbstinenceSyndromemay beafectedbythesubstanceingestedbythemother,thetimeofthelastdose,in-uteroduration ofexposure,andmaternalandplacentalmetabolism(hudak&tan,2012).thediagnosisof NASisbasedonsymptomsofneonatalwithdrawal,ratherthantheneedforpharmacotherapy (Kraft,Stover,&Davis,2016).TheonsetofNASsymptomsistypicalyobservedwithinthe first24-72hours(hudak&tan,2012). OnemethodtoasestheseverityofNASsymptomsisthroughtheuseofscoringtools. ScoringtoolsareusedtoobjectivelyevaluatetheinfantfortheseverityofNASsymptoms,guide pharmacotherapy,andasistinthestructuredprocesofweaning(mcqueen& Murphy- Oikonen,2016).Curently,theFinneganNeonatalAbstinenceScoringToolisthemost commonlyusedtool,ineitherits1975originalformatorthemodifiedshortformversion (Finneganetal.,1975;Finnegan,1986).Othertoolshavebeenusedtoscoreseverityof symptomsandguidepharmacologic treatmentofnas,butthefinneganneonatalabstinence ScoringToolremainsthemostcomprehensive(Wiles,Isemann, Ward,Vinks,&Akinbi,2014). Regardlesofthetoolused,inter-observerreliabilityisanimportantconsideration,duetothe subjectivityoftheasessment(kocherlakota,2014). StudieshavesuggestedthattheincidenceofNASisontherise.IntheUnitedStates,for every1000hospitalbirthsannualy,thediagnosisofinfantnasgrewfrom1.20to3.39between 2000and2009(Patricketal.,2012).Corespondingly,therewasanincreaseinmaternaluseor

6 INFANTFEEDING METHODANDNASOUTCOMES 6 dependenceonopiatesfrom1.19in2000to5.63in2009forevery1000hospitalbirthsperyear (Patricketal.,2012).WesternAustralia(O Donneletal.,2009)andCanada (Daviesetal., 2016;Dowetal.,2012)haveobservedsimilarincreases.TheetiologyofNAShasalsohad considerablechangesovertime.inthelast40years,theprecursorofnashasshiftedfrom primarilybeingaresultofilicitopiateuse,tonowbeinginclusiveofopioidreplacementtherapy (ORT)suchasmethadoneandbuprenorphine(Hudak&Tan,2012;Kieviet,Dolman,&Honig, 2013).Theriseinopiateuse,coupledwiththecomplicationofsimultaneouslicitandilicit substanceshasledtonasbecomingincreasingly commonandcomplex(kocherlakota,2014). SeveraladverseoutcomeshavebeenasociatedwithNAS.Between2004and2013the numberofinfantsadmitedtonicuintheusafornasincreasedfrom7to27admisionsfor every1000hospitalbirths(toliaetal.,2015).theuseofpharmacotherapyasaformofnas treatmentalsoincreasedfrom74%to87%,withsimultaneous growthinthepharmacological durationoftreatment(toliaetal.,2015).duetothemanagementofwithdrawalsymptoms throughpharmacologictreatment,admisiontothenicuandlengthyhospitalizationsareoften required(hudak&tan,2012; Wachmanetal.,2011).Separationofmotherandherinfantata criticaltimeforbonding(abrahamsetal.,2010),andoveraldecreasedratesofbreastfeding (Wachman,Byun,&Philipp,2010)inthispopulationareaddednegativeoutcomesasociated withnas. Whiletheneedsofeachinfantareunique,thetreatmentofinfantNASsymptomsoften folowsanapproachbasedonpharmacologicaldrugtreatment,withoralmorphineormethadone recommendedasafirst-linemedicationtotreatwithdrawal(mcqueen& Murphy-Oikonen, 2016;Wilesetal., 2014).Althoughpharmacotherapyhasbeenwelresearched,thereisa growingbodyofevidenceregardingtheimpactofinfantfeedingmethodonnasoutcomes.

7 INFANTFEEDING METHODANDNASOUTCOMES 7 Furthermore,breastfeedinghasbeenestablishedascompatibleformothersstabilizedonORT withnocontraindications(mcqueen& Murphy-Oikonen,2016;O Connor,Colet,Alto,& Brien,2013).Researchhassuggestedthatmethadoneconcentrationsfoundinhumanmilkare low,andwomenonstabledosesofmethadoneshouldbeencouragedtobreastfeed,regardlesof maternalmethadonedose(mccarthy&posey,2000).despitethisindication,thepromotionof breastfeedingfornasinfantsisinconsistentandvariesacroshospitals(jansson,2009; ProvincialCouncilfor MaternalandChildHealth,2012).Thissystematicreviewwilasessand criticalyappraisetheexistingliteratureregardingtheefectofinfantfeedingmethodamong infantswithnasonneonataloutcomes. Method SearchStrategy TheelectronicdatabasesPubmed,CINAHL,NursingandAliedHealth,PsychINFO, Evidence-Based Medicine, WebofScience,and Medline(EMBASE)weresearchedfrom1990 tofebruary2018.subjecttermsusedinthesearchstrategyincluded neonatalabstinence syndrome [MeSH]andoneofthefolowingadditionalterms,breastfeeding[MeSH], breastfeed*,orinfantformula[mesh].toensurerelevantarticleshadnotbeenmised,the referencelistsofincludedstudieswerereviewedforadditionalarticlesrelevanttotheinitial search.aforwardcitationsearchofincludedstudieswascompletedjuly1 sț 2018andyielded noadditionalarticles. StudySelection ThereviewfolowedthePreferedReportingItemsforSystematicReviewsand Metaanalysis(PRISMA)statement(Figure1)(Moheretal.,2009).Studieswereeligibleforinclusion inthereviewiftheyfulfiledthefolowingcriteria:1)reportedoriginaldataonoutcomesrelated

8 INFANTFEEDING METHODANDNASOUTCOMES 8 tobreastfedandformulafedinfantswithnas,2)thestudymethodincludedanytypeof quantitativedesignthatincludedaninpatientcomparisongroupofbreastfedandformulafed infantswithnas,and3)thearticleswerepublishedinenglishinapeerreviewedjournal.for thepurposeofthisreview,naswasdefinedasapostnatalwithdrawalsyndromeininfantsthat wereexposedtoopioidsinutero(mcqueen& Murphy-Oikonen,2016).Thus,NASininfants exclusivelyfromsubstancesotherthanopioids(e.g.,selectiveserotoninreuptakeinhibitors) wereexcludedfromthisreview.additionalexclusioncriteriaincluded:1)descriptivestudies withnocomparisonofbreastfedandformulafedinfantswithnas,2)reviewarticlesand3) infantswhowerere-admitedtohospitalwithnasafterdischarge. ThefirstauthorenteredalstudiesfromthesearchintotheZoteroReference Manager andremovedduplicates.theremainingstudieswerescreenedforinclusionbasedonthetitleand abstractbyboththefirst(ct)andsecondauthor(jm).remainingfultextarticleswere independentlyreviewedbyalauthorsandinclusioncriteriawasdiscuseduntilagreementwas achieved.articlesthatdidnotmeettheinclusionandexclusioncriteriawereeliminatedfor furtherreview. DataExtraction Theprincipalauthorextractedthedatafromthefultextstudiesandentereditintoadata extractiontemplatedevelopedforthesystematicreview.thetemplateincludedtheauthors names,yearofpublication,country,purpose,definitionoffeedingmethod,studydesign,sample size,infantfeedingmethod,in-uterodrugexposure,infanttreatment,andnasoutcomes.the secondandthirdauthors(jmandkm)independentlyreviewedandcomparedtheextracteddata. Alldiferenceswerediscused,referingbacktothearticleuntilanagreementwasobtained.

9 INFANTFEEDING METHODANDNASOUTCOMES 9 Asesmentof MethodologicalQuality Alarticlesselectedforinclusionwereasesedformethodologicalqualitybythefirst andsecondaryauthors(ct&jm)usingthejoannabriggsinstitute(jbi)standardizedcritical appraisalchecklistforcohort/casecontrolstudiesandthejbistandardizedcriticalappraisal checklistforrandomizedcontroledstudies(joannabriggsinstitute,2014).studieswere evaluatedashavingalow,moderate,orhighriskofbiasbasedontheselectionofparticipants, measuresofnasoutcomes,confoundingfactors,andfolow-upcare.ctandjmindependently reviewedandcomparedtheasesments,andanydisagreementswereresolvedthrough discusionwiththethirdauthorkmuntilanagreementwasobtained.nostudieswere eliminatedbasedonthecriticalappraisal. DataSynthesis Thedatawassynthesizednarativelyduetothediversestudysamplesandoutcomesthat wereevaluated.outcomesevaluatedincludedrequirementforpharmacologictreatment,duration ofpharmacology,lengthofhospitalstay,andnasseverityscoresandtimetowithdrawal. Results Thesearchidentified491studies,ofwhich17providedinformationrelatedtoNAS outcomesandinfantfeedingmethod.furtherasessmentoftheinclusionandexclusioncriteria eliminated9ofthestudiesdueto:descriptivestudies/nocomparisongroup(n=1);nonas outcomedata(n=3);nasincludedsubstancesotherthanopioids(n=2);noinfantfeeding methoddata(n=2);andconferenceabstract(n=1).atotalof8articlesmetalcriteriaandare includedinthereview.seefigure1fortheprismaflowdiagram.

10 INFANTFEEDING METHODANDNASOUTCOMES 10 StudyCharacteristics ThecharacteristicsoftheeightincludedstudiesareprovidedinAppendixA.Alofthe studieswerepublishedbetween2006and2018,withpopulationsamplesfrom5countries includingaustralia(n=2),canada(n=1),norway(n=1),theunitedstates(n=3),andscotland (n=1).theprimarypurposeforfiveofthestudieswastoevaluatetheefectofinfantfeeding methodonnasoutcomes (Abdel-Latifetal.,2006;Lui,Juarez,Nair,&Nanan,2015; McQueen, Murphy-Oikonen,Gerlach,& Montelpare,2011;O Connoretal.,2013; Wele-Strand etal.,2013).theotherthreestudiesreportednasoutcomesinrelationtoinfantfeeding method,althoughitwasnottheprimarypurposeofthestudy(isemann, Meinzen-Der,& Akinbi,2010;Jansonetal.,2007; MacVicar,Humphrey,&Forbes-McKay,2017).Sixofthe studieswereretrospectivecohortreviews(abdel-latifetal.,2006;isemannetal,2010;luiet al.,2015; McQueenetal.,2011;O Connoretal.,2013)withoneofthesestudiesalsoincludinga prospectivereview(wele-strandetal.,2013).onestudywasamatcheddesign(jansonetal., 2007),andonestudywasmixedmethodsincludingarandomizedcontroltrial(MacVicaretal., 2017). Samplesizesrangedfrom14to194mother-infantdyads.Categorizationofinfant feedingmethodwasbasedonself-selectedsamples.however,thedefinitionofbreastfeeding variedbetweenstudiesandonestudydidnotclearlydefinethefeedingmethod(isemannetal., 2010).Thisisanimportantconsideration,asthefeedingmethodinrelationtoNASoutcomesis evaluated.theprevalenceofbreastfeedingrangedfrom23%to79%.itisimportanttoconsider thevariationinbreastfeedingratesmayberelatedtothedefinitionofbreastfeedinginselect studies,withbreastfeedingdefinedasongoingatemptstolatchontothebreast,infantswho receivedbreastmilkatbirthandpostpartumeveniftheywerealsogivenformula,andself-

11 INFANTFEEDING METHODANDNASOUTCOMES 11 reportedinitiationandcontinuationofbreastfeeding(macvicar,2017;o Connoretal.,2013; Wele-Strand,2013). Alinfantswereexposedtoopioidmaintenancetherapy(OMT)inutero,including methadone(n=5),buprenorphine(n=1)andeithermethadoneorbuprenorphine(n=2).the primarymedicationsusedforpharmacologictreatmentofnaswasmorphine(n=1), phenobarbital(n=1),eithermorphineorphenobarbital(n=1),methadoneorphenobarbital(n=1), anddilutedtinctureofopiumormorphine(n=1).threestudiesdidnotspecifythe pharmacologictreatmentfornas(seeappendixa). TheFinneganoramodifiedversionoftheFinneganScoringToolwasusedinalofthe studiestoasesssymptomsofnasandtoguidepharmacologictreatment.however,thestudies diferedintheirevaluationofrequirementforpharmacologictreatment.threestudiesinitiated pharmacologictreatmentfolowingtwoconsecutivefinneganscoresgreaterthan8(abdel-latif etal.,2006;isemannetal.,2010;jansonetal.,2007).twostudiesinitiatedpharmacologic treatmentfolowingthreeconsecutivefinneganscoresgreaterthan8(mcqueenetal.,2011; O Connoretal.,2013)andthreestudiesdidnotreporttheinitiationofpharmacologictreatment inrelationtonasfinneganscores(luietal.,2015; MacVicaretal.,2017; Wele-Strandetal., 2013).Furthermore,themodificationsofthetooland/orthenumberofitemswerenotspecified inthestudies.alstudiesexploredoneormorenasoutcomesincludingrequirementfor pharmacologictreatment,overaldurationofpharmacotherapy,hospitallengthofstay,andnas severity(seeappendixb). MethodologicalQuality Fivestudieswereidentifiedasalowriskofbias(Abdel-latifetal.,2006;Isemannetal., 2010;Jansonetel.,2007;Luietal.,2015; MacVicaretal.,2017)andthreestudieswere

12 INFANTFEEDING METHODANDNASOUTCOMES 12 identifiedasamoderateriskofbias(mcqueenetal.,2011;o Connoretal.,2013; Wele-Strand etal.,2013).infantfeedingmethodwasself-selectedbymothers.thus,selectionbiaswas presentinsixofthesevenstudiesappraisedwithjbistandardizedcriticalappraisalchecklistfor cohort/casecontrolstudies(abdel-latifetal.,2006;isemannetal.,2010;luietal.,2015; McQueenetal.,2011;O Connoretal.,2013; Welle-Strandetal.,2013).Inonestudy,selection biaswasnotpresentasthegroupswerematchedwithrespecttorace,parity(primiparousversus multiparous),agewithin5years,andmethadonedosewithin10mg(jansonetel.,2007). Selectionbiaswasnotpresentintherandomizedcontroltrialstudy,asacomputer-generated proceswasusedfortruerandomizationofparticipantstogroups(macvicaretal.,2018).the majorityofthestudiesidentifiedcriteriaforcategorizationofinfantfeedingmethod,which includedbreastfeeding,expresedbreastmilk,combinationfeeding,andformulafeeding. However,thedefinitionandcategorizationofinfantfeedingmethodvariedbetweenstudies.Al studiesidentifiedusingthefinneganscoringtoolora ModifiedFinnegantoasessNASand guidepharmacologictreatment.however,thestudiesdiferedinprotocolsforpharmacological initiationandthevalidityandreliabilityofthetoolwasnotindicatedinmoststudies.thus, measurementbiaswasprobable. Moststudiesidentifiedconfoundingfactors,includingmaternalandinfantbaseline characteristics(maternalomt,polydruguse,smoking,parity,birthweight,andgestation)and themajorityofstudiesmadeadjustmentsindataanalysistoaccountfortheconfoundingfactors measured.finaly,duetothemajorityofthestudiesbeingconductedinhospital,theatrition biaswasunlikely,andisanoveralstrength(seeappendixcandd).

13 INFANTFEEDING METHODANDNASOUTCOMES 13 InfantFeeding MethodandNASOutcome:Pharmacology AlstudiesreportedNASoutcomesinrelationtopharmacology,includingtheneedfor pharmacologictreatmentand/orthedurationofpharmacotherapyfornas(seeappendixb). Amongthestudies(n=7)evaluatinginfantswhoreceivedpharmacologictreatment,twostudies reportedbreastfedinfantsweresignificantlyleslikelytorequirepharmacologictreatment comparedtoformula-fedinfants(abdel-latifetal.,2006;wele-strandetal.,2013).four studiesfoundthatbreastfedinfantswereleslikelytorequirepharmacologictreatmentwhen comparedtoformula-fedorcombination-fedinfants;however,theresultswerenotstatisticaly significant(jansonetal.,2007;macvicar,2017; McQueenetal.,2011; O Connoretal.,2013). Onestudyreportednostatisticaldiferenceintheincidenceofpharmacologictreatmentwhen comparingmethodsoffeeding(luietal.,2015),andonestudydidnotevaluatethelikelihodof requiringpharmacologictreatmentfornas(isemannetal.,2010). Threestudiesevaluatedthedurationofpharmacologictreatment.Intwoofthestudies, researchersidentifiedstatisticalysignificantdiferencesinthemeandurationofnastreatment betweengroups(abdel-latifetal.,2006; Wele-Strandetal.,2013).Overal, Wele-Strandetal. (2013)reportedalbreastfedinfantsofwomenonOMThadastatisticalysignificantshorter meanpharmacologictreatmentfornas(28.6days+19.1)incontrasttoformula-fedinfantsof womeninomt(46.7days+27.2;p=<0.05). Wele-Strandetal.(2013)furtheridentifieda statisticalysignificantshortermeanpharmacologictreatmentforbreastfedinfantsofmothersin MMT (31days+21.4)whencomparedtoformula-fedinfantsofwomenin MMT(48.9days+ 27.2;p=<0.05).However,nodiferencesindurationwerefoundinthebuprenorphine-exposed infants.althoughnotstatisticalysignificant,abdel-latifetal.(2006)alsofoundthatbreastfed infantshadashortermeandurationofnastreatment(85days+71.7)whencomparedto

14 INFANTFEEDING METHODANDNASOUTCOMES 14 formula-fedinfants(108.2days+81.8;p=.185).similarly,isemannetal.(2010)reported diferencesinthemediandurationofpharmacologictreatmentfornas,withbreastfedinfants havingashortermediandurationofpharmacotherapy(10.8days)whencomparedtoformula-fed infants(12.4days;p<.35);however,theresultswerenotreportedasstatisticalysignificant. InfantFeeding MethodandNASOutcome:LengthofStay Lengthofhospitalstaywasevaluatedinfouroftheeightstudies(seeAppendixB). AmonginfantswithNAS,twostudiesfoundthatbreastfedinfantshadastatisticalysignificantly reducedlengthofstayinhospitalwhencomparedtoformula-fedinfants(abdel-latifetal., 2006;Isemannetal.,2010).Ashortermedianhospitalstaywasidentifiedforbreastfedinfants (12.5days;rangingfrom3-51days)whencomparedtoformula-fedinfants(18.5days;ranging from9to43days;p=0.01)(isemannetal.,2010).similarly,abdel-latifetal.(2006)found breastfedinfantshadashortermeanhospitalstay(14.7days+14.9)whencomparedtoformulafedinfants(19.1days+15.0;p=.049).macvicaretal.(2017) alsofoundthemeanhospitalstay wasshorterforbreastfedinfants(10.8days+6.7)whencomparedtoformula-fedinfants(30.0 days+11.8),however,thesignificanceoftheresultswasnotreported.although,o Connoret al.(2013)alsoevaluatedthemeanhospitalstayforbreastfed(7.08days+4.4)andformula-fed infants(6.6days+1.7;p=.35),noconclusionsweredrawnduetocomplicationsunrelatedto NASinthegroupofbreastfedinfants. InfantFeeding MethodandNASOutcome:NASSeverity SeverityofNASsymptomswasevaluatedinfouroftheeightstudies(seeAppendixB). OfthefourstudiesthatevaluatedNASseverity,alreportedoutcomesrelatedtomeanFinnegan scoresbetweengroups(abdel-latifetal.,2006;luietal.,2015; McQueenetal.,2011; O Connoretal.,2013).Abdel-Latifetal.(2006)reportedmeanFinneganscoresforthefirst9

15 INFANTFEEDING METHODANDNASOUTCOMES 15 daysoflifewerelowerinbreastfedinfantswhencomparedtoformula-fedinfants(p<.05). Likewise,McQueenetal.(2011)reported meanfinneganscoreswerelowerinbreastfedinfants ( )whencomparedtocombination-fed( )andformula-fedinfants( ;p=.0001).Corespondingly,themeannumberofFinneganscoresrecordedwasalsolowerin breastfedinfants( )whencomparedtocombination-fed( )andformula-fed infants( ;p=.001)(mcqueenetal.,2011).alternatively,luietal.(2015)foundno statisticaldiferenceinmeannasscoresofbreastfedinfants( ),expresedbreastmilk ( )andformula-fed( ;p=0.47).Althoughtheresultswerenotreportedas significant,o Connoretal.(2013)reportedbreastfedinfantswereleslikelytoscore8orabove onthefinneganscoringtool,aswelasleslikelytoscore12orabovewhencomparedto formula-fedinfants.similarly,mcqueenetal.(2011)reportedalower meanareaoffinnegan scoresforbreastfedinfants( )comparedtocombination-fed( )andformulafed( ;p=.04). WhileO Connor(2013)reportedlowermeanFinneganpeakscoresand ashortermeanfinnegantimetopeakforbreastfedinfantswhencomparedtoformula-fed infants,neitheroftheseresultswerereportedasstatisticalysignificant. TimetoNASwithdrawalwasalsoevaluatedintwooftheeightstudies(Abdel-Latifet al.,2006;luietal.,2015)withlongertimetotheonsetofsymptomsamongbreastfedinfants. Breastfeedingduringthefirst2daysoflifewassignificantlyasociatedwithadelayedonsetof NASamonginfantsof MMTmothers(p=.04)(Luietal.,2015).Similarly,themediantimeto withdrawaloccuredlaterinbreastfedinfants(10days)whencomparedtoformula-fedinfants(3 days;p=.001)(abdel-latif,2006).overal,meanfinneganscoreswereconsistentlyreportedas lowerinbreastfedinfantswhencomparedtoformula-fedinfantswithnas,whichsuggests

16 INFANTFEEDING METHODANDNASOUTCOMES 16 breastfedinfantshaveadelayedonsetoralatertimetowithdrawalwhencomparedtoformulafedinfants. Discusion Thepurposeofthissystematicreviewwastoasesandcriticalyappraisetheexisting literatureregardingtheefectofinfantfeedingmethodamonginfantswithneonatalabstinence Syndrome.ThestudiesconsistentlyidentifiedatrendtowardsimprovedNASoutcomesfor infantswhowerebreastfed.themajorityofstudiesfoundthatbreastfeedingwasasociatedwith areducedneedforpharmacologictreatmentandadecreaseinthedurationofpharmacotherapy whencomparedtoformula-fedorcombination-fedinfants.breastfeeding,whencomparedto formula-feeding,wasalsoconsistentlyasociatedwithashorterhospitalizationandareduced severityofnas,includinglowerfinneganscores.studiesalsoidentifiedalatertimeto withdrawalandadelayedonsetofnasasociatedwithbreastfedinfantswhencomparedto formula-fedinfants.thesefindingswereconsistentregardlesoftheinuteroopioidexposureor infanttreatmenttype.itisimportanttonotethatbreastfeedinghasbeenshowntopromote atachment,andappearstosoothagitatedinfants(abdeletal.,2006).breastfeedinghasalso beensuggestedasaninterventionforthemanagementofnasinfantsymptoms(jansonetal., 2004)thus,proposingthatamothers breastmilkmayhaveaweaningefect. WhilebreastfeedinghasbeenasociatedwithpositiveoutcomesforNASinfants, breastfeedingratesamongmothersofinfantswithnasarelowwhencomparedtotheratesof breastfeedingamongnon-substanceusers(pritham,2013).researchershaveidentifiedanumber ofchalengesthatexistfortheopioid-dependentmotherandherinfant.nasisrelatedtofeeding dificulties,includingnasalstufines,uncoordinatedmovements,andcomplicationswith sucking(janson,velez,&butz,2017),whichmayimpactamother sabilitytoinitiateor

17 INFANTFEEDING METHODANDNASOUTCOMES 17 succesfulybreastfeed.outcomesrelatedtonasoftenleadtoaseparationofmotherandher infantatacriticaltimeforbonding,includinganincreasedriskforadmisiontothenicu, prolongedhospitalstay,andtheuseofpharmacotherapy(toliaetal.,2015).theseoutcomesand theincreasedlikelihoodofmotherandinfantseparationmaycreatepotentialbariersto breastfeeding.furtherbarierstobreastfeedinginthispopulationincludealackofinformationor inconsistentpromotionofbreastfeedingbyhealthcareprofesionals(janson,2009; McQueen& Murphy-Oikonen,2016).Thus,suggestingthatdespitethebenefitsofbreastfeeding,structural bariersmaydecreaseratesofbreastfeedinginthispopulation. Understandingtheinfluencessuroundingawoman sdecisiontobreastfeedisanother importantconsideration.feelingsofguiltanddistresmaybeexperiencedbymanyopioiddependentmothersduetotheirinfant sinuteroexposuresandnassymptomology,whichmay createchalengessuroundingamother sdecisiontobreastfeed(pritham,2013;velez& Janson,2008).Someadditionalfactorsthatcontributetothedecisiontobreastfeedinclude knowledgeofbreastfeeding,curentphysicalandmentalhealth,andsocialinfluence(pritham, 2013).Patricketal.(2012)suggestthatthemajorityofopioid-dependentpregnantwomenare socioeconomicalydisadvantaged.lowsocioeconomicstatusalongwithmaritalstatus,ageand educationalsoappeartoplayaroleininfluencingamother sdecisiontobreastfeed(pritham, 2013).Additionaly,thereisacomplexitysuroundingthemother-infantdyad,particularlywhen themotherhasasubstanceusedisorderandasexualabusehistory(janson,velez,&butz, 2017).Survivorsofsexualabusemayexperienceadistortedviewofthedualroleoftheirbreasts asbothsexualandmaternalobjects,thuscontributingtoisuessuroundingthedecisionof breastfeedinginthispopulation(janson,velez,&butz,2017).givenboththestructuraland personalbarierstobreastfeeding,andtheimportanceofthepostnatalperiodformother-infant

18 INFANTFEEDING METHODANDNASOUTCOMES 18 bondingandatachment(shannon,blythe,&peters,2016;toliaetal.,2015),anincreased understandingsuroundingtheevidenceofbreastfeedingfornasiscrucialforconsistent promotionofthismethodoffeeding.theincludedstudiesofthissystematicreviewhave consistentlysupportedpositiveoutcomesasociatedwithbreastfeedingwhencomparedto formulaorcombination-fedinfants. Limitations AlthoughbreastfeedingwasconsistentlyasociatedwithpositiveNASoutcomesamong diversepopulations,variousmethodologicalweakneseswereevident.sixoftheeightincluded studiesreliedontheaccuracyofmedicalrecordsthrougharetrospectivedesign.theothertwo includedstudieswereasmalsamplematcheddesignandamixedmethodspilotstudy,bothof whichdidnotevaluatenasoutcomesinrelationtofeedingmethod,astheprimarypurpose. Furthermore,twooftheincludedstudiesdidnotidentifyacleardefinitionofthecategorization offeedingmethod,whichisanimportantconsideration,asthenasoutcomeswerecompared betweenfeedingmodalities.anumberofstudieshadsmalsamplesizes,andthein-uteroopioid exposureandpostnatalinfanttreatmentvariedbetweenstudies. Whilelimitationswereapparent, thecriticalappraisalidentifiedthatthemajorityoftheincludedstudies(n=5)werealowriskof biasforcohortstudies.despitetheselimitations,consistenttrendswerefoundthatsuggestthat breastfeedingisasociatedwithpositivenasoutcomes,includingareducedneedandduration ofpharmacologictreatment,shorterhospitalization,delayedonsetofnas,andareduced severityofnas,includinglowerfinneganscores. ImplicationsforPractice Thesefindingshaveimportantclinicalimplicationsandsuggestthatbreastfeedingmay beanefectivenon-pharmacologicinterventioninthetreatmentofinfantswithnas.assuch,

19 INFANTFEEDING METHODANDNASOUTCOMES 19 breastfeedingshouldbeencouragedamongmothersonomt,wherenoothercontraindications forbreastfeedingarepresent(mcqueen& Murphy-Oikonen,2016;Pritham,2013).Itis importanttoconsiderthatthepromotionofbreastfeedinginthispopulationisinconsistent (Janson,Velez,Harow,2004).Thus,gapsinknowledgemayexistamong healthcareproviders regardingbreastfeedingcompatibility,contraindications,andthepotentialbenefitsof breastfeedinginthispopulation.educationofhealthcareprovidersmayasistinpromoting breastfeedinginopioid-dependentmotherswhencontraindicationsarenotpresent.earlyand consistentmaternaleducationsuroundingthebenefitsofbreastfeeding,includingthepotential toimprovenasoutcomesisneeded,asthisknowledgemayincreasebreastfeedinginitiation anddurationinthispopulation.inhospitalsupportsandfolow-upservicesmaybebeneficialto bothmotherandinfant,howeverfurtherresearchisnecesarytodetermineefective interventionstosupportmothersonomt. ImplicationsforFutureResearch Thefindingsfromthissystematicreviewhaveimplicationsforfutureresearch.Larger studies,withaprospectivedesign,arenecesarytocontinuetoasestheefectofinfantfeeding methodonnasoutcomes.futureresearchwhichcomparesdiferentomtinrelationtofeeding methodandnasoutcomesisanimportantconsiderationtoexpandtheknowledgesurounding thispopulation.tofurtherunderstandboththestructuralandpersonalbarierstobreastfeeding inthispopulation,qualitativeresearchwhichexplorestheexperiencesandperceptionsofopioiddependentmothersisneeded.inaddition,researchtodetermineefectiveinterventionsto supportmothersonomtwithbreastfeedingiswaranted.

20 INFANTFEEDING METHODANDNASOUTCOMES 20 Conclusion Theresultsfromthissystematicreviewsuggestthatbreastfeedinghasthepotentialto improvenasoutcomes,includingadecreasedincidenceofpharmacologicneedfornas treatment,ashorterdurationofpharmacotherapy,areductioninhospitalstay,andreducednas severityandtimetowithdrawal. WhilethestudiesconsistentlyreportimprovedNASoutcomes, chalengesexistinthispopulation,andconsiderationtoamother spoly-substanceuseandother contraindicationsforbreastfeedingarenecesary,inconjunctionwiththepromotionofthis feedingmethod.

21 INFANTFEEDING METHODANDNASOUTCOMES 21 References Abdel-Latif, M.E.,Pinner,J.,Clews,S.,Cooke,F.,Lui,K.,&Oei,J.(2006).Efectsofbreast milkontheseverityandoutcomeofneonatalabstinencesyndromeamonginfantsof drug-dependentmother.pediatrics,117(6).e1163-e1169. Abrahams,R.R., MacKay-Dunn, M.H.,Nevmerjitskaia,V., MacRae,G.S.,Payne,S.P.,& Hodgson,Z.G.(2010).Anevaluationofrooming-inamongsubstanceexposednewborns inbritishcolumbia.journalofobstetricsandgynaecologycanada,32, AmericanAcademyofPediatrics(2005).Breastfeedingandtheuseofhumanmilk.Pediatrics, 115(2), Boland, M.(2005).Exclusivebreastfeedingshouldcontinuetosixmonths.Pediatrics&Child Health,10(3),148. Davies,H.,Gilbert.R.,Johnson,K.,Peterson.,I.,Nazareth,I.,O Donnel, M.Gutman,A.,& Gonzalez-Izquierdo,A.(2016).Neonatalwithdrawalsyndrome:cros-country comparisonsusinghospitaladministrativedatainengland,theusa, WesternAustralia andontario,canada.archivesofdiseaseinchildhood FetalandNeonatalEdition, 101(1),26-30.doi: /archdischild Dow,K.,Ordean,A., Murphy-Oikonen,J.,Pereira,J.,Koren,G.,Roukema,H.,Selby,P.,& Turner,R.(2012).NeonatalabstinencesyndromeclinicalpracticeguidelinesforOntario. JournalofPopulationTherapeuticsandClinicalPharmacology,19(3),e Finnegan,L.P.(1986).NeonatalAbstinenceSyndrome:AsesmentandPharmacotherapy.In: GranatiB,ed.NeonatalTherapy:AnUpdate.NewYork:ElsevierScience, Finnegan,L.P.,Connaughton,J.F.,Kron,R.E.,&Emich,J.P.(1975).Neonatalabstinence syndrome:asessmentandmanagement.addictivediseases,2(1-2),

22 INFANTFEEDING METHODANDNASOUTCOMES 22 Hudak, M.L.,&Tan,R.C.(2012).Neonataldrugwithdrawal.Pediatrics,129(2),e htps:/doi.org/ /peds Isemann,B., Meinzen-Der,J.,&Akinbi,H.(2011). Maternalandneonatalfactorsimpacting responsetomethadonetherapyininfantstreatedforneonatalabstinencesyndrome. JournalofPerinatology,31,25-29.doi: /jp Janson,L.M.(2009).ABMClinicalProtocol#21:GuidelinesforBreastfeedingandtheDrug- Dependent Woman.BreastfeedingMedicine,4(4), htps:/doi.org/ /bfm Janson,L.,Choo,R.,Velez, M.,Harow,C.,Schroader,J.,Shakleya,D.,&Huestis, M.(2007). Methadonemaintenanceandbreastfeedingintheneonatalperiod. Pediatrics,121, ,Doi: /peds Janson,L. M.,Velez, M.,&Butz(2017).TheEfectofSexualAbuseandPrenatalSubstance UseonSuccesfulBreastfeeding.JOGNN,46, htp:/dx.doi.org/ /j.jogn Janson,L. M.,Velez, M.,&Harow,C.(2004). Methadonemaintenanceandlactation:areview oftheliteratureandcurentmanagementguidelines.journalofhumanlactation,20(1), JoannaBriggsInstitute(2014).Reviewers Manual.Adelaide:Author. Kieviet,N.,Dolman,K.,&Honig,A.(2013).Theuseofpsychotropicmedicationduring pregnancy:howaboutthenewborn?neuropsychiatricdiseaseandtreatment,9, htp:/doi.org/ /ndt.s36394 Kocherlakota,P.(2014).Neonatalabstinencesyndrome.Pediatrics,134(2),e htps:/doi.org/ /peds

23 INFANTFEEDING METHODANDNASOUTCOMES 23 Kraft, W.K.,Stover, M. W.,&Davis,J. M.(2016).Neonatalabstinencesyndrome: Pharmacologicstrategiesforthemotherandinfant.SeminarsinPerinatology. htps:/doi.org/ /j.semperi Lui,A.,Juarez,J.,Nair,A.,&Nanan,R.(2015).Feedingmodalitiesandtheonsetofthe neonatalabstinencesyndrome.frontiersinpediatrics,3,14. doi: /ped MacVicar, S.,Humphrey,T.,Forbes-McKay,K.(2018).Breastfeedingandthesubstance exposedmotherandbaby.birth,1-9.htps:/doi.org/ /birt McCarthy,J.J.,&PoseyB.L.(2000).Methadonelevelsinhumanmilk. JournalofHuman Lactation,16, McQueen,K.A., Murphy-Oikonen,J.,Gerlach,K.,& Montelpare, W.(2011).Theimpactof infantfeedingmethodonneonatalabstinencescoresofmethadone-exposedinfants. AdvancedNeonatalCare,11(4), htp:/dx.doi.org/ /anc.0b013e318225a30c McQueen,K.,& Murphy-Oikonen,J.(2016).NeonatalAbstinenceSyndrome.TheNewEngland JournalofMedicine,375(25), doi: /NWJMra Moher,D.,Liberati,A.,Tetzlaf,J.,&Altman,D.G.,PRISMAGroup(2009).Prefered reportingitemsforsystematicreviewandmeta-analysis:theprismastatement.plos Medicine, 6,e O Connor,A.B.,Colet,A.,Alto, W.A.,&O Brien,L. M.(2013).Breastfeedingratesandthe relationshipbetweenbreastfeedingandneonatalabstinencesyndromeinwomen maintainedonbuprenorphineduringpregnancy.journalofmidwiferywomenshealth, 58(4) htp:/dx.doi.org/ /jmwh.12009

24 INFANTFEEDING METHODANDNASOUTCOMES 24 O Donnel, M.,Nasar,N.,Leonard,H.,Hagan,R., Mathews,R.,Paterson,Y.,&Stanley,F. (2009).Increasingprevalenceofneonatalwithdrawalsyndrome:populationstudyof maternalfactorsandchildprotectioninvolvement.pediatrics,123(4),e htps:/doi.org/ /peds Patrick,S. W.,Schumacher,R.E.,Benneyworth,B.D.,Krans,E.E., McAlister,J. M.,&Davis, M. M.(2012).Neonatalabstinencesyndromeandasociatedhealthcareexpenditures: UnitedStates, JAMA,307(18), doi: /jama Pritham,U.(2013).BreastfeedingPromotionfor ManagementofNeonatalAbstinence Syndrome.JOGNN,42, DOI: / ProvincialCouncilfor MaternalandChildHealth,2012.NeonatalAbstinenceSyndrome(NAS) ClinicalPracticeGuidelines.RetrievedonFebruary4 th,2018from htp:/ March for-website-May-2016.pdf. Shannon,J.,Blythe,S.,&Peters,K.(2016).NeonatalAbstinencesyndromeandtheatachment relationship.australiannursing&midwiferyjournal,24, Stover, M. W.,&Davis,J. M.(2015).Opioidsinpregnancyandneonatalabstinencesyndrome. SeminarsinPerinatology,39(7), htps:/doi.org/ /j.semperi Sublet,J.(2013).Neonatalabstinencesyndrome:therapeuticinterventions.MCN:TheAmerican JournalofMaternal/ChildNursing,38(2), doi: /nmc.0b013e31826e978e Tolia,V.N.,Patrick,S.W.,Bennet, M. M., Murthy,K.,Sousa,J.,Smith,P.B.,Clark,R.H.,& Spitzer,A.(2015).IncreasingincidenceoftheneonatalabstinenceinU.S.neonatalICUs. TheNewEnglandJournalofMedicine,372,

25 INFANTFEEDING METHODANDNASOUTCOMES 25 Velez, M.&Janson,L.M.(2008).Theopioiddependentmotherandnewborndyad:nonpharmacologiccare.JournalofAddictionMedicine,2(3), doi: /ADM.0b013e31817e6105 Wachman,E. M.,Byun,J.,Philipp,B.L.(2010).Breastfeedingratesamongmothersof infants withneonatalabstinencesyndrome.journaloftheacademyofbreastfeedingmedicine, 5, Wachman,E. M.,Newby,P.K.,Vreeland,J.,Byun,J.,Bonganzi,A.,Bauchner,H.,&Philipp, B.L.(2011).Therelationshipbetweenmaternalopioidagonistsandpsychiatric medicationsonlengthofhospitalizationforneonatalabstinencesyndrome.journalof AddictionMedicine,5(4), htps:/doi.org/ /ADM.0b013e a3a Wele-Strand,G.K.,Skurtveit,S.,Janson,L. M.,Bakstad,B.,Bjarko,L.,Ravndal,E.(2013). Breastfeedingreducestheneedforwithdrawaltreatmentinopioid-exposedinfants.ACTA PaediatricaNurturingtheChild,102(11), doi: /apa Wiles,J.R.,Isemann,B., Ward,L.P.,Vinks,A.A.,&Akinbi,H.,(2014).Curent Management ofneonatalabstinencesyndromesecondarytointrauterineopioidexposure.the JournalofPediatrics,165(3), htp:/doi.org/ /j.jpeds WorldHealthOrganization(2001).Theoptimaldurationofexclusivebreastfeeding:reportofan expertconsultation.geneva,switzerland: WorldHealthOrganization.Retrievedfrom htp:/apps.who.int/iris/bitstream/10665/67219/1/who_nhd_01.09.pdf?ua=1

26 INFANTFEEDING METHODANDNASOUTCOMES 26 Fig1.PreferedReportingItemsforSystematicReviews(PRISMA)flowdiagram Recordsidentifiedthrough databasesearchingincluding: PUBMED;NursingandAlied Health;CINAHL,EvidenceBased Medicine; WebofScience, MedlineandPsychinfo (n=491) Screening Included Identification Additionalrecordsidentified throughforwardcitationsearch (n=0) Recordsafterduplicatesremoved (n=363) TitleandAbstract screened (n=17) Eligibility Recordsexcluded (n=346) Primarilyre:nobreastfeeding outcomes;notaprimarystudy; notnas Fultextarticles assessedforeligibility (n=17) Studiesincludedin quantitativesynthesis (n=8) Ful-textarticlesexcluded re: (n=1)descriptive studies/nocomparison group (n=3)nonasoutcome data (n=2)nasincluded substancesotherthan opioids (n=2)noinfantfeeding methoddata (n=1)conference abstract (n=9)

27 INFANTFEEDING METHODANDNASOUTCOMES 27 AppendixI JBICriticalAsesmentofSelectedArticles ComparableCohort/CaseControl Study Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Q11 Total Abdel- N Y Y Y Y Y Y Y Y N/A Y 9/10 Latifet al.(2006) Isemann N N Y Y Y Y Y Y Y N/A Y 8/10 etal. (2011) Janson Y Y Y Y Y Y Y Y Y N/A Y 10/10 etal. (2008) Luietal. (2015) N Y Y Y Y Y U Y Y N/A Y 8/10 McQueen N Y Y Y U Y N Y Y N/A U 6/10 etal. (2011) O Connor N Y Y Y N Y N Y Y N/A Y 7/10 etal. (2013) Wele- Strandet al.(2013) N N Y Y Y Y N Y Y N/A Y 7/10 Total(%) N/A 85.7 AppendixI JBICriticalAsesmentofSelectedArticles RandomizedControledTrials Study Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Q11 Q12 Q13 Total MacVicar etal. (2018) Y Y Y N N N Y N Y Y Y Y Y 9/13 Total(%)

28 INFANTFEEDING METHODANDNASOUTCOMES 28 AppendixA StudyCharacteristicsofIncludedStudies Author/ Year Abdel-Latif etal.(2006) Isemannet al.(2010) Janson,et al.(2007) Luietal. (2015) Study Design/ Country Retrospective Cohort Reviewin Australia Retrospective Cohort Reviewin UnitedStates Matched Designin UnitedStates Retrospective Cohort Reviewin Australia PurposeofStudy Feeding MethodDefined Sample Feeding Method Asestheefectsof breastmilkonthe severityandoutcome ofneonatalabstinence syndrome Identifymaternaland neonatalfactorsthat impactresponseto methadonetherapy forneonatal abstinencesyndrome Toevaluate concentrationsof methadonein breastmilkamong breastfeedingwomen inasampleof methadone maintained breastfeedingwomen andamatchedgroup offormula-feeding women Tocomparethe impactofdiferent feedingmodalitieson theonsetofnas Categorizedbasedon predominantmethodof feedingonthe5 dayof life;>2feedsofformula duringthe5 th daywere clasifiedasformula-fed 190 Breastfed (n=85) Formula-fed (n=105) NotSpecified 128 Breastfed (n=75) Formula-fed (n=53) Categorizedbymothers expresingadesireto breastfeedexclusivelyat obstetriccarevisits. Womenwerethen matchedwithrespectto race,age,andmethadone dosewithin10mgand desiretobotle-feed exclusively. Categorizedbasedon predominantmethodof feedingduringthefirst2 daysoflife.breastfeeding group>50%ofdaily feeds;expresed Breastmilk>15mlof expresedbreastmilkand breastfed<3timesper day;formula-fedgroup >50%ofdailyfeedsand minimalebm (<15ml/day) 16 Breastfed (n=8) Formula-fed (n=8) 194 Breastfed (n=32) Expresed Breastmilk (EBM) (n=12) Formula-fed (n=150) % Sample Breastfeeding InUtero Opioid Exposure Infant Treatment 45% Methadone Morphine, Phenobarbitol 59% Methadone Methadone, Phenobarbitol Quality Appraisal /Riskof Bias Low Low 50% Methadone NotSpecified Low 23% Methadone Morphine Low

29 INFANTFEEDING METHODANDNASOUTCOMES 29 MacVicaret al.(2017) McQueenet al.(2011) O Connoret al.(2013) Wele- Strandetal. (2013) Mixed MethodsPilot Studyin Scotland Randomized Controled Trialand Maternal Questionnaire Retrospective Cohort Reviewin Canada Retrospective Cohort Reviewin UnitedStates Retrospective (n=36) Prospective (n=36)and Retrospective (n=52)cohort Study innorway Toexplorethe feasibilityofinhospital,tailored breastfeedingsupport forthesubstanceexposedmotherand infant.secondary analysisoffeeding methodandnas severity Todeterminewhether neonatalabstinence scoresofinfants exposedtomethadone inuterodiferedby infantfeedingmethod Todescribe breastfeedingrates amongopioiddependentwomenand todeterminewhether breastfeedingis relatedtothe duration,severity,and frequencyof pharmacologic treatmentfornas Toexaminetherate anddurationof breastfeedingina cohortofwomenin opioidmaintenance treatmentandthe efectofbreastfeeding ontheincidenceand durationofnas Breastfeedingdefinedas feedingatbreast,ongoing atemptstolatchonto breast,andexpresed breastmilkfor>50%of oralintakeon5 th day Breastfeedingdefinedas morethen75%ofal feedings;combination feedingdefinedas breastfeeding75%orles, but25%orgreaterofal feedings;formulafeedingdefinedas breastfeedinglesthen 25%ofalfeedings Breastfeedingdefinedas infantswhowere receivingbreastmilkat birthandcontinuedto receivebreastmilk6-8 weekspostpartum,evenif theseinfantswerealso givenformula Self-reportedinitiation, continuation,and terminationof breastfeeding. 14 Breastfed (n=11) Formula-fed (n=3) 28 Breastfed (n=8) Combination- Fed(n=11) Formula-fed (n=9) 85 Breastfed (n=65) Formula-fed (n=20) 124 Breastfed (n=95) Formula-fed (n=29) 79% Methadone, Buprenorphine NotSpecified Low 29% Methadone NotSpecified Moderate 76% Buprenorphine Phenobarbital Moderate 77% Methadone, Buprenorphine Diluted tinctureof opium,oral Morphine Moderate

30 INFANTFEEDING METHODANDNASOUTCOMES 30 AppendixB NASOutcomes Author/ Pharmacology LengthofStay NASSeverity Year Treatment Duration Scores Timeto Withdrawal Abdel- Latifetal. (2006) Isemannet al.(2010) Breastfedinfantswereles likelytorequire pharmacologictreatment (45of85infants;52.9%) comparedtoformula-fed (83of105infants;79.0%), p<.001) NotEvaluated Breastfedinfantshada shortermeandurationof NAStreatment(85days+ 71.7)comparedtoformulafed(108.2days+81.8;p=.185) Breastfedinfantshada shortermediandurationof methadonepharmacotherapy (10.8days)comparedto formula-fed(12.4days;p<.35).resultnotstatisticaly significant. Breastfedinfantshada shortermeanhospitalstay (14.7days+14.9) comparedtoformulafed (19.1days+15.0;p=.049) Breastfedinfantshada shortermedianhospital stay(12.5days;ranging from3-51days)compared toformula-fed(18.5days; rangingfrom9to43days; p=.01) Mean FinneganScores forthefirst9daysoflife werelowerinbreastfed infantscomparedto formula-fed(p<.05) NotEvaluated Median timeto withdrawaloccured laterinbreastfedinfants (10days)comparedto formula-fed(3days;p<.001) NotEvaluated Jansonet al.(2007) Breastfedinfantswereles likelytorequire pharmacologictreatment (1of8infants;12%) comparedtoformula-fed (4of8infants;50%),p=.28) NotEvaluated NotEvaluated NotEvaluated NotEvaluated Luietal. (2015) Nostatisticaldiferencein theincidenceof pharmacologicneedfor NAStreatmentfor breastfed(23of32infants; 72%),expresedbreast milk(12of12infants; 100%)andformula-fed (121of150infants;81%), p=.11) NotEvaluated NotEvaluated Nostatisticaldiference inmeannasscoresof breastfedinfants( ),expresedbreast milk( )and formula-fed( ),p =0.47) Breastfeedingduringthe first2daysoflifewas asociatedwithadelayed onsetofnas(p=0.04). CoxRegresionAnalysis usedtodetermine variablespredictiveof timetoonsetofnas amonginfantsof MMT mothers.

31 INFANTFEEDING METHODANDNASOUTCOMES 31 MacVicar etal. (2017) Breastfedinfantswereles likelytorequire pharmacologictreatment (3of11infants;27%) comparedtoformula-fed (3of3infants;100%). Pvaluenotreported. NotEvaluated Breastfedinfantshada shortermeanhospitalstay ( days) comparedtoformula-fed infants( days). Pvaluenotreported. NotEvaluated NotEvaluated McQueen etal. (2011) Breastfedinfantswereles likelytorequire pharmacologictreatment (17%)comparedto formula-fed(38.8%)and combination-fed(40.2%) NotEvaluated NotEvaluated Breastfedinfantshadalower meannumberfinnegan scoresrecorded( ) comparedtocombination-fed ( )andformula-fed ( ;p=.001) Mean FinneganScoreswere lowerinbreastfedinfants( )comparedto combination-fed( ) andformula-fed( ;p =.0001) Breastfedinfantshadalower meanareafinneganscore ( )comparedto combination-fed( ) andformula-fed( ; p=.04) NotEvaluated O Connor etal. (2013) Breastfedinfantswereles likelytorequire pharmacologictreatment (15of65infants;23%) comparedtoformula-fed (6of20infants;30%),p=.56) NotEvaluated Breastfedinfantshada variablemeanhospitalstay (7.08days+4.4) comparedtoformula-fed ( ;p=.35)dueto complicationsunrelatedto NAS.Noconclusions drawn. MeanFinneganpeakscores waslowerinbreastfedinfants ( )comparedto formula-fed( ;p=.17) MeanFinnegantimetopeak scoreswasshorterin breastfedinfants( )comparedtoformulafed( ;p=.32) NotEvaluated

32 INFANTFEEDING METHODANDNASOUTCOMES 32 Breastfedinfantswereles likelytoscore8oraboveon Finnegantool(65%) comparedtoformula-fed (75%),p=NS) Breastfedinfantswereles likelytoscore12oraboveon Finnegantool(17%) comparedtoformula-fed (30%),p=NS) Wele- Strandet al.(2013) Breastfedinfantsinthe methadone-exposedgroup wereleslikelytorequire pharmacologictreatment (44of95infants;53%) comparedtoformula-fed (23of29infants;80%),p =<0.05) Forbuprenorphineexposedinfants,no diferencewasfoundinthe incidenceof pharmacologicneedfor NAStreatmentfor breastfed(61of95infants; 64%)comparedto formula-fedinfants(13of 29infants;44%),p=NS) Breastfedinfantsofwomen inomthadashortermean durationofnastreatment (28.6days+19.1)compared toformula-fed(46.7days+ 26.3;p=<0.05) Breastfedinfantsofwomen in MMThadashortermean durationofnastreatment (31days+21.4)compared toformula-fed(48.9days+ 27.2;p=<0.05) Forbuprenorphine-exposed infants,nodiferencewas foundindurationofnas treatmentforbreastfed infants(25.7days+16.0) comparedtoformula-fed (38.8days+24.0;p=NS) NotEvaluated NotEvaluated NotEvaluated