Effects of therapeutic approach on the neonatal evolution of very low birth weight infants with patent ductus arteriosus

www.jped.com.br

ORIGINAL

ARTICLE

Effects

of

therapeutic

approach

on

the

neonatal

evolution

of

very

low

birth

weight

infants

with

patent

ductus

arteriosus

夽

,

夽夽

Lilian

S.R.

Sadeck

,

Cléa

R.

Leone

,

Renato

S.

Procianoy

,

Ruth

Guinsburg

,

Sergio

T.M.

Marba

_,

_Francisco

_E.

_Martinez

_,

_Ligia

_M.S.S.

_Rugolo

_,

M.

Elisabeth

L.

Moreira

_,

_Renato

_M.

_Fiori

_,

_Ligia

_L.

_Ferrari

_,

Jucille

A.

Menezes

_,

_Paulyne

_S.

_Venzon

_,

_Vânia

_Q.S.

_Abdallah

_,

José

Luiz

M.B.

Duarte

_,

_Marynea

_V.

_Nunes

_,

_Leni

_M.

_Anchieta

_,

Navantino

Alves

Filho

a_{FaculdadedeMedicina,UniversidadedeSãoPaulo(USP),SãoPaulo,SP,Brazil}

b_{DepartmentofPediatrics,FaculdadedeMedicina,UniversidadedeSãoPaulo(USP),SãoPaulo,SP,Brazil}

c_{DepartmentofPediatricsandChildCare,FaculdadedeMedicina,UniversidadeFederaldoRioGrandedoSul(UFRGS),Porto}

Alegre,RS,Brazil

d_{DepartmentofPediatrics,FaculdadeCiênciasMédicas,UniversidadeEstadualdeCampinas(UNICAMP),Campinas,SP,Brazil} e_{DepartmentofPediatrics,FaculdadedeMedicinadeRibeirãoPreto,UniversidadedeSãoPaulo(USP),RibeirãoPreto,SP,Brazil}

f_{DepartmentofPediatrics,FaculdadedeMedicinadeBotucatu,UniversidadeEstadualPaulista(UNESP),Botucatu,SP,Brazil} g_{DepartmentofNeonatology,Fundac¸ãoOswaldoCruz(FIOCRUZ),InstitutoFernandesFigueira,RiodeJaneiro,RJ,Brazil} h_{DepartmentofPediatrics,FaculdadedeMedicina,PontifíciaUniversidadeCatólicadoRioGrandedoSul(PUC-RS),PortoAlegre,}

RS,Brazil

i_{FaculdadedeMedicina,UniversidadeEstadualdeLondrina(UEL),Londrina,PR,Brazil}

j_{InstitutodeMedicinaIntegralProf.FernandoFigueira,Recife,PE,Brazil}

k_{DepartmentofPediatrics,UniversidadeFederaldoParaná(UFPR),Curitiba,PR,Brazil}

夽 _{Pleasecitethisarticleas:SadeckLS,LeoneCR,ProcianoyRS,GuinsburgR,MarbaST,MartinezFE,etal.Effectsoftherapeuticapproach}

ontheneonatalevolutionofverylowbirthweightinfantswithpatentductusarteriosus.JPediatr(RioJ).2014;90:616---23.

夽夽_{Studylinkedto16unitsfromtheBrazilianNeonatalResearchNetwork:UniversidadedeSãoPaulo(USP);FIOCRUZ/InstitutoFernandes}

Figueira(IFF);PontifíciaUniversidadeCatólicadoRioGrandedoSul(PUC-RS)/HospitalSãoLucas(HSL);UniversidadeEstadualPaulista (UNESP)/FaculdadedeMedicinadeBotucatu(FMB);UniversidadeFederaldoRioGrandedoSul(UFRGS)/HospitaldeClínicasdePortoAlegre (HCPA);UniversidadeFederaldeSãoPaulo(UNIFESP)/EscolaPaulistadeMedicina(EPM);UniversidadedeSãoPaulo(USP),RibeirãoPreto; UniversidadeEstadualdeCampinas(UNICAMP)/HospitaldaMulherProf.Dr.JoséAristodemoPinotti(CAISM);UniversidadeEstadualdoRio deJaneiro(UERJ)/HospitalUniversitárioPedroErnesto(HUPE);UniversidadeFederaldeMinasGerais(UFMG)/HospitaldeClínicas(HC); UniversidadeFederaldoParaná(UFPR)/HospitaldeClínicas(HC);FaculdadedeCiênciasMédicasdeMinasGerais(FCMMG)/Maternidade HildaBrandão(MHB);UniversidadeFederaldeUberlândia(UFU)/HospitaldeClínicas(HC);UniversidadeEstadualdeLondrina(UEL)/Hospital Universitário(HU);InstitutodeMedicinaIntegralProfessorFernandoFigueira(IMIP);UniversidadeFederaldoMaranhão(UFMA)/Hospitalde Clínicas(HU).

∗_{Correspondingauthor.}

E-mail:liliansadeck@uol.com.br(L.S.R.Sadeck).

http://dx.doi.org/10.1016/j.jped.2014.04.010

l_{UniversidadeFederaldeUberlândia(UFU),Uberlândia,MG,Brazil} m_{UniversidadeEstadualdoRiodeJaneiro(UERJ),RiodeJaneiro,RJ,Brazil} n_{UniversidadeFederaldoMaranhão(UFMA),SãoLuiz,MA,Brazil}

o_{UniversidadeFederaldeMinasGerais(UFMG),BeloHorizonte,MG,Brazil}

p_{FaculdadedeCiênciasMédicasdeMinasGerais(CMMG),BeloHorizonte,MG,Brazil}

Received28October2013;accepted3April2014

Availableonline19July2014

KEYWORDS Preterm; Verylowbirth weight; Ligation;

PDAmanagement

Abstract

Objective: Toanalyzetheeffectsoftreatmentapproachontheoutcomesofnewborns(birth weight [BW] < 1,000g) with patent ductus arteriosus (PDA), from the Brazilian Neonatal ResearchNetwork(BNRN)on:death,bronchopulmonarydysplasia(BPD),severe intraventricu-larhemorrhage(IVHIII/IV),retinopathyofprematurityrequiringsurgical(ROPsur),necrotizing enterocolitisrequiringsurgery(NECsur),anddeath/BPD.

Methods: Thiswasamulticentric,cohortstudy,retrospectivedatacollection,including new-borns(BW<1000g)withgestationalage(GA)<33weeksandechocardiographicdiagnosisof PDA,from16neonatalunitsoftheBNRNfromJanuary1,2010toDec31,2011.Newbornswho diedorweretransferreduntilthethirddayoflife,andthosewithpresenceofcongenital mal-formationorinfectionwereexcluded.Groups:G1---conservativeapproach(withouttreatment), G2--- pharmacologic(indomethacinoribuprofen),G3---surgicalligation(independentof previ-oustreatment).Factorsanalyzed:antenatalcorticosteroid,cesareansection,BW,GA,5min. Apgarscore<4,malegender,ScoreforNeonatalAcutePhysiologyPerinatalExtension(SNAPPE II),respiratorydistresssyndrome(RDS),latesepsis(LS),mechanicalventilation(MV), surfac-tant(<2hoflife),andtimeofMV.Outcomes:death,O2dependenceat36weeks(BPD36wks),

IVHIII/IV,ROPsur,NECsur,anddeath/BPD36wks.Statistics:Student’st-test,chi-squaredtest,or

Fisher’sexacttest;Oddsratio(95%CI);logisticbinaryregressionandbackwardstepwise mul-tipleregression.Software:MedCalc(MedicalCalculator)software,version12.1.4.0.p-values< 0.05wereconsideredstatisticallysignificant.

Results: 1,097newbornswereselectedand494newbornswereincluded:G1-187(37.8%),G2 -205(41.5%),andG3-102(20.6%).ThehighestmortalitywasobservedinG1(51.3%)andthe lowestinG3(14.7%).ThehighestfrequenciesofBPD36wks(70.6%)andROPsurwereobservedin

G3(23.5%).Thelowestoccurrenceofdeath/BPD36wksoccurredinG2(58.0%).Pharmacological

(OR0.29;95%CI:0.14-0.62)andconservative(OR0.34;95%CI:0.14-0.79)treatmentswere protectivefortheoutcomedeath/BPD36wks.

Conclusion: TheconservativeapproachofPDAwasassociatedtohighmortality,thesurgical approach totheoccurrenceofBPD36wks andROPsur,andthepharmacologicaltreatmentwas

protectivefortheoutcomedeath/BPD36wks.

©2014SociedadeBrasileiradePediatria.PublishedbyElsevierEditoraLtda.Allrightsreserved.

PALAVRAS-CHAVE Prematuridade; Muitobaixopeso; Ligaduracirúrgica; Canalarterial

Efeitosdaabordagemterapêuticadapersistênciadecanalarterialsobreaevoluc¸ão

neonatalderecém-nascidosdeextremobaixopeso

Resumo

Objetivo: Analisar os efeitos daterapêutica adotada para ocanal arterial(CA) em recém-nascidos(RN)<1.000gadmitidosemunidadesneonatais(UN)daRedeBrasileiradePesquisas Neonatais (RBPN), sobre os desfechos: óbito, displasia broncopulmonar (DBP), hemorragia intraventriculargrave(HIVIII/IV),retinopatiadaprematuridadecirúrgica(ROPcir),enterocolite

necrosantecirúrgica(ECNcir)eodesfechocombinadoóbitoeDBP.

(SDR),sepsetardia,ventilac¸ãomecânica(VM), surfactante<2horasdevida, tempodeVM eosdesfechos:óbito,dependênciade oxigêniocom36semanas (DBP36s),HIV III/IV,ROPcir,

ECNcir e óbito/DBP36s.Estatística: Testet-Student, Qui-Quadradoouteste Exato de Fisher.

TestesdeRegressãoBináriaLogísticaeRegressãoMúltiplaStepwiseBackward.MedCalc(Medical Calculator)software,versão12.1.4.0.p<0,05.

Resultados: Foramselecionados1.097RNe494foramincluídos:G1-187(37,8%),G2-205(41,5%) eG3-102(20,6%).Verificou-se:maiormortalidade(51,3%)noG1emenornoG3(14,7%);maior frequência DBP36s (70,6%)e ROPcir (23,5%)no G3; maiorfrequência de óbito/DBP36s no G2

(58,0%).Asabordagensfarmacológica(OR-0,29;95%,IC-0,14-0,62)econservadora(OR-0,34; 95%,IC-0,14-0,79)foramprotetorassomenteparaodesfechoóbito/DBP36sem.

Conclusão: Em RNcomPCA,aabordagemconservadorarelacionou-se àmaiormortalidade, acirúrgicaàocorrênciadeDBP36seROPcir.,enquantootratamentofarmacológicomostrou-se

protetorparaodesfechoóbito/DBP36sem.

©2014SociedadeBrasileiradePediatria.PublicadoporElsevierEditoraLtda.Todososdireitos reservados.

Introduction

Theapproachofpatentductusarteriosus(PDA)inthe neona-talperiodhasbeenwidelydiscussedintheliterature,both regardingthebesttimetodetectit,aswellastheconductto beusedinthepresenceofDA,particularlyinpreterm new-borns(PNBs)oflowbirthweight,consideringitsimplications fortheevolutionofthesenewborns.

While the DA is an essential structure during the intrauterineperiod,responsibleforthedeviationofthe pul-monarycirculation totheaortaand maintainingthe fetal systemicbloodflow,itspersistenceafterbirthmaytrigger aseriesofevents,culminatingwithheartfailure.1

Particu-larlyininfantswithbirthweight(BW)below1,000g,patent ductusarteriosus (PDA)withhemodynamic effectsmaybe associatedwithgreatermorbimortality,2_{resultinginhigher}

risksof heart failure, duration of mechanical ventilation, bronchopulmonarydysplasia (BPD),3 _{intraventricular}

hem-orrhage(IVH),4_{andnecrotizingenterocolitis(NEC).}5

However,a considerable percentage ofPDAs will close spontaneously,6,7 _{or may remain patent without causing}

significant symptoms.7 _{Consequently, early start of the}

treatment mayunnecessarily exposeNBsto prostaglandin inhibitorsorsurgicalductusligation,which areassociated withadverseeffects.8_{Thissituationmightbepreventedif}

preterm infants more likely to undergo spontaneous PDA closureareidentified.

ConductrelatedtothemanagementofPDAinPNBshas beenhighlyvariableintheliterature,resultinginmany stud-ies,especiallyininfantswithbirthweight(BW)<1,000g.8

To date, there is not enough evidence to define the bestapproachtoPDAinPNBs.9---11_{Althoughpharmacological}

treatmentwithindomethacinoribuprofenhasbeenproven effectiveinPDAclosure,noimprovementwasobservedin evolutionwhenthefollowingeventswereanalyzed:death, BPD, and necrotizing enterocolitis (NEC). Most published clinicaltrialsfocusedonPDAclosurewithpharmacological orsurgicalapproach.12

Considering the current knowledge and existing ques-tionsonthe treatment option tobeusedin thepresence of PDA, whether conservative, pharmacological, or surgi-cal,thepresentstudyaimedtoassesstheeffectsofthese approachesin infants weighingless than 1,000gadmitted

to neonatal intensive care units (NICUs) of the Brazilian NeonatalResearchNetwork(BNRN)in2010and2011,onthe occurrenceofthefollowingoutcomes:death,BPD, severe intraventricularhemorrhage(IVHIII/IV),retinopathyof pre-maturityrequiringsurgery(ROPsur),necrotizingenterocolitis

requiring surgery (NECsur), and the combined outcome of

deathandBPD.

Methods

Amulticenter,cohortstudywasperformedwith retrospec-tivedatafromBNRN,whichincludedinfantsadmittedat16 BNRNNICUsfromJanuary1st,2010toDecember31st,2011. Thenewbornswereselectedaccordingtothefollowing inclusioncriteria:BW:400-999g,gestationalage(GA)<33 weeks,andechocardiographicdiagnosisofPDA,regardless ofhemodynamiceffects.Newbornswhodiedorwere trans-ferreduptothethirddayoflifeandthosediagnosedwith congenitalinfectionsormalformationswereexcluded.

The NBsincluded in the study weredivided into study groups according tothe therapeutic managementof PDA: G1-conservativeapproach(withoutmedicationorsurgical intervention),G2-pharmacologicalapproaches(treatment withindomethacinoribuprofen),andG3-surgicalapproach (surgicalligation,regardlessofwhetherornottheNBhad previouslyreceivedprostaglandininhibitor).

Thevariablesanalyzedwereperinatalconditions:useof antenatalsteroidsandCesareandelivery;birthconditions: birthweight,gestationalage,adequatebirthweightfor ges-tationalage,consideringsmallforgestationalage(SGA)as PNBswithweightbelowthe5thpercentileoftheAlexander etal.13 _{curve,Apgar 5min.<4,andmalegender;} neona-taloutcome:ScoreforNeonatalAcutePhysiologyPerinatal Extension (SNAPPE II) risk score, respiratory distress syn-drome (RDS), late-onset neonatal sepsis (LONS) (positive blood culture), need for mechanical ventilation, duration ofmechanicalventilation,andsurfactantadministrationup to 2hours of life; and primary outcomes: death, oxygen dependenceat36weeks(BPD36wks),IVH III/IVaccordingto

the classification of Papille, ROPsur,NECsur, and the

com-binedoutcomedeath/BPD36wks.

oftheClinicalBoardofHospitaldasClínicasandFaculdade deMedicinadaUniversidadedeSãoPaulo)throughresearch protocol 1383/09 and later adopted by the other institu-tions.

StatisticalAnalysis

Categorical data are shown with frequency distribution, andcontinuousdatausingmeanandstandarddeviation,as indicated. The univariate analysisof categorical variables usedthechi-squaredorFisher’sexacttest,whenindicated, whereas Student’s t-test was used for continuous varia-bles.Tocalculatetherisk,afterdeterminingtheoddsratio (95%CI),logisticbinaryregressionandbackwardstepwise multiple regression were performed using MedCalc (Medi-cal Calculator) software,version 12.1.4.0. The statistical significancelevelwassetat5%(p<0.05).

Results

Atotalof 1,097newborns withBW= 400to999gand GA < 33 weeks were admitted in 16 NICUs of the BNRN dur-ingthestudy period.Ofthese,220 wereexcluded dueto deathortransferduringthefirstthreedaysoflife, malfor-mations,andcongenitalinfections;494newborns metthe inclusion criteriawithechocardiographic diagnosis of PDA andnoinformationregardingthepresenceofsymptoms.

Theinfantsweresubdividedaccordingtothetherapeutic approach,into:G1-187(37.8%),G2-205(41.5%),andG3 -102(20.6%)(Fig.1).

The characteristicsofthepopulationaccordingtoeach studygroupisshowninTable1;itcanbeobservedthatthere weredifferencesbetweenthegroupsinrelationtotheGA, mean SNAPPEII score,frequency and timeof mechanical ventilation,andoccurrenceofLONS.

Regardingtheanalyzedoutcomes,itwasobservedthat mortalitywas higherin G1 (51.3%), while it waslowerin G3 (14.7%).The highest incidenceof BPD36wks (70.6%) and

ROPsur (23.5%) was observed in G3, while the combined

outcomedeath/BPD36wks waslessfrequentinG2(58.0%).It

wasnotpossibletoanalyzetheeffectsofthetherapyused ontheoccurrenceofNECsur,duetotheverysmallnumber

ofcases,althoughastatisticallysignificantdifferencewas observedbetweenG1andG2(Table2).

Themultivariateregressionanalysisshowednoinfluence of thetypeof therapeutic approachontheprobabilityof deathortheoccurrenceofBPD36wksalone,ratheronlyforthe

combinedoutcomedeath/BPD36wks.However,thefollowing

were identified asrisk factors for the outcome of death: NECsur (OR 5.64, 95% CI: 1.03 to 30.7) and IVH-III/IV (OR

3.62,95%CI:1.30to10.11).Forthemalegender(OR2.59, 95%CI:1.33to5.02),LONS(OR1.88,95%CI:1.00to3.54), GA(OR1.49,95%CI:1.22to1.81),andtimeofMV(OR1.04, 95%CI:1.02to1.07)werefactorsrelatedtothepresence of BPD36wks. BWalone wasaprotective factor against the

outcomesdeathandBPD36wks(OR0.99,95%CI:0.99to0.99)

(Table3).

Regarding the combined outcome of death/BPD36wks,

thefollowing were identifiedasrisk factors:malegender (OR 3.24, 95% CI: 1.73 to 6.18) and LONS (OR 2.53, 95% CI: 1.42 to 4.52), while the protective factors were:

pharmacologicaltreatment(OR0.29,95%CI:0.14to0.62), conservativeapproach(OR0.34,95%CI:0.14to0.79),and BW(OR0.99,95%CI:0.99to0.99).

Discussion

Thesurvivalofpreterminfantswithoutsequelaehasbeen theobjectiveofperinatalcareoftheseat-riskNBs.Among the factors that may influence their evolution, PDA has beenconsideredariskfactorwithimportantconsequences. Therefore, the need to define a therapeutic approach in the presence of PDA that can ensure greater control of these complications has increased, particularly in infants withlowerBW.

Inthepresent study,conductedwithNBsweighingless than1,000gatbirthandwithPDA,theprotectionof con-servativeandpharmacologicaltreatmentsforthecombined outcome death/BPD36wks was demonstrated, although the conservative treatment was related to higher mortality. Malegender wasalsoidentified,together withLONS,GA, andtime of mechanical ventilation, as factorsassociated withthepresenceofBPD36wks.Thedeathoutcomewas asso-ciatedwiththepresenceofNECsurandIVHIII/IV.

Theinfantsincludedinthisstudy,althoughconstitutinga groupathighriskfortheeventsanalyzedherein,astheyhad onaverage,less than28weeksofgestationalageandBW lowerthan800grams,mighthavehadthisriskattenuated, becausetwo-thirdsofthemreceivedantenatal corticoste-roidsandwerebornwithgoodvitalsigns.Inthepostnatal period,althoughmorethan90%developedRDSandrequired mechanicalventilation,approximately70%received surfac-tantwithin2hoursoflife.However,theoccurrenceofLONS inapproximatelyhalfofthenewbornsmayhavecontributed tothehigherfrequenciesBPD36wks,especiallyinG3,which correspondedto65.7%oftheNBs.

Duetothehighfrequencyofantenatalcorticosteroiduse intheanalyzedgroups,withnodifferencebetweenthem, itwasnotpossibletoassesstheinfluenceofthesedrugson theanalyzedoutcomes.

Consideringthestudygroups,itwasobservedthatthey differedinrelationtoGA,whichwaslowerinthegroupthat required surgical ligation of the PDA, which also showed a higher frequency of late-onset sepsis, characterizing a higherriskof BPD36wks andROPsur,accordingtotheresults obtained. Nevertheless, higher mortality was observed in thegroupreceiving conservativetreatment, which proba-blyexplainsthelowerfrequencyoftheothercomplications in this group, and the option for non-pharmacological or surgical treatment due to clinical conditions of the NBs. Thegroupthatreceivedpharmacologicaltreatmenthadthe lowest SNAPPE II score, which characterizeslower risk of morbimortality and also, possibly, the occurrence of the assessedoutcomes.

NBs with GA < 33 weeks BW 400 to 999 grams in

16 NICUs of BNRN (n = 1,097 NBs)

Period: 2010 to 2011

Group I n = 187 (37.8%)

PDA Treatment: Conservative

Group III

n = 102 (20.6%) PDA Treatment: Surgical

Ligation, regardless of pharmacological

treatment

Maternal data: ANCS, C-section delivery

Characteristics of NB: Apgar 5 min. < 4, BW, GA, male gender, SNAPPE II

Evolution: RDS, surfactant within up to 2 hours of life, MV, time of MV, late sepsis Group II

n = 205 (41.5%)

PDA Treatment: Pharmacological indomethacin or

ibuprofen

Groups I, II, III

Outcomes:

Mortality O2 dependence with 36

weeks (BPD36wks) IVH III/IV

ROP_sur NEC_sur Combined outcome:

death/BPD_36wks PDA diagnosis (ECHO)

n = 494 NBs Excluded: 220 NBs

Death or transfer < 3 days, malformations, and/or

congenital infections

Figure1 Studydesign.

BNRN,BrazilianNeonatalResearchNetwork;PDA(ECHO),patentductusarteriosusdiagnosedbyechocardiogram;ANCS,antenatal corticosteroids;BW,birthweight;GA,gestationalage;SNAPPEII,ScoreforNeonatalAcutePhysiologyPerinatalExtension;RDS, respiratorydistresssyndrome;MV,mechanicalventilation;BPD,bronchopulmonarydysplasia;IVHIII/IV,intraventricularhemorrhage gradeIII/IV;ROPsur,retinopathyofprematuritywithsurgicalprocedure;NECsur,necrotizingenterocolitiswithsurgicalprocedure.

clinicaleffectsandlong-termresults,particularlyregarding BPD.8,14---17 _{However, there are potential complications of}

thepharmacologicaltreatment ofPDA,such asrenal dys-functionandintestinalperforation,aswellasthosearising fromsurgicalligation,suchascardiopulmonarydysfunction. In this study, comparing the three forms of therapeu-tic approach, it can be observed that infants treated withprostaglandin inhibitors (indomethacin or ibuprofen)

demonstratedlessBPD,ROPsur,NECsur,anddeath/BPD36wks,

especiallywhen comparedtothose whounderwent surgi-calligation.When weconsidered theoutcomesdeathand BPD36wksseparately,thetypeofmedicalorsurgicalapproach

didnotinfluence them,while conservativetreatmentwas associatedwithhighermortality.However,intheanalysisof thecombinedoutcome(death/BPD36wks),the

Table1 Birthstatusandin-hospitalevolutionofthepopulation,accordingtothestudygroups,between2010and2011.

Characteristics G1

n=187

G2 n=205

G3 n=102

p G1xG2

p G1xG3

p G2xG3

ANCS 130(69.5) 161(78.5) 70(68.6) 0.054a _0.981a _0.079a

C-section 121(64.7) 136(66.3) 59(57.8) 0.815a _0.306a _0.183a

MeanBW(g)

(SD)

772.0(142.3) 804(121.6) 781.0(118.5) 0.017 0.555 0.117

MeanGAin

weeks(SD)

27.6(2.2) 27.4(1.9) 26.6(1.8) 0.307 <0.001 <0.001

Malegendern

(%)

91(48.7) 90(43.9) 48(47.1) 0.399a _0.890a _0.688a

Apgar5min.<

4n(%)

13(6.9) 3(1.5) 3(2.9) 0.013b _0.247b _0.615b

SGA<5%n(%) 49(26.2) 32(15.6) 13(12.7) 0.013a _0.012a _0.619a

MeanSNAPPEII

(SD)

43(22.1) 34(18.6) 40(19.5) <0.001 0.177 0.026

RDS

n(%)

167(89.3) 182(88.8) 95(93.1) 0.996a _0.391a _0.314a

LONSn(%) 83(44.4) 95(46.3) 67(65.7) 0.7741 _<0.001a _0.002a

Surfactant<2h

n(%)

118(63.1) 140(68.3) 66(64.7) 0.329a _0.886a _0.616a

MVn(%) 171(91.4) 195(95.1) 101(99.0) 0.159a _0.007a _0.107a

Meantimeof

MV(days)

(SD)

16.8(20.1) 20.4(20.7) 44.8(32.4) 0.044 <0.001 <0.001

ANCS,maternaluseofantenatalcorticosteroids;BW,birthweight;GA,gestationalage;SGA<5%,birthweightbelowthe5th_percentile% oftheAlexanderetal.13_{curve;SNAPPEII,ScoreforNeonatalAcutePhysiologyPerinatalExtension;SD,standarddeviation;RDS,}

respira-torydistresssyndrome;LONS,late-onsetneonatalsepsisconfirmedbypositivebloodculture;surfactant<2h,surfactantadministration within2hoursoflife;MV,needformechanicalventilation.

a _{Chi-squaredtest.} b _{Fisher’sexacttest.}

Table2 Univariateanalysisofoutcomesanalyzedaccordingtothestudiedgroups.

Outcomes G1

n=187

G2 n=205

G3 n=102

p G1xG2

p G1xG3

p G2xG3

Deathn(%) 96(51.3) 58(28.3) 15(14.7) <0.001a _<0.001a _0.013a

BPD36wksn(%) 48(25.7) 65(31.7) 72(70.6) 0.227a <0.001a <0.001a

IVHIII/IVn(%) 37(19.8) 35(17.1) 23(22.5) 0.573a _0.688a _0.317a

ROPsurn(%) 10(5.3) 16(7.8) 24(23.5) 0.417b <0.001b <0.001b

NECsurn(%) 14(7.5) 3(1.5) 5(4.9) 0.005b 0.465b 0.120b

Death/BPD36wks

n(%)

134(71.6) 119(58.0) 83(81.4) 0.007a _0.098a _<0.001a

BPD36wks,bronchopulmonarydysplasiawithoxygendependenceat36weekscorrectedbygestationalage;IVHIII/IV,intraventricular hemorrhagegradeIIIandIV;ROPsur,retinopathyofprematurityrequiringsurgicalintervention;NECsur,necrotizingenterocolitisrequiring surgicalintervention;Death/BPD36wks,combinedoutcomeofdeathandBPD36wks.

a _{Chi-squaredtest.} b _{Fisher’sexacttest.}

These findings agree withthose of Mirea etal.16 _who,

usingmultivariateanalyses,toattempttoadjustfor treat-ment selection bias, provided evidence of an association between surgical ligation of PDA and increased neonatal mortality or severe morbidity, but conversely, found no effectoftreatment withindomethacinwhencomparedto conservativetreatment.

Basedontheaboveconsiderations,thepresentfindings suggest greater protection for the outcomes analyzed in the group treated pharmacologically, although there are

Table3 Riskfactorsidentifiedforoutcomesanalyzedbybackwardstepwisemultipleregression.

Outcome Variable OR(95%CI) p

Death BW 0.99(0.99-0.99) 0.0401

NECsur 5.64(1.03-30.7) 0.0455

IVHIII/IV 3.62(1.30-10.11) 0.0139

BPD36wks BW 0.99(0.99-0.99) 0.0207

Malegender 2.59(1.33-5.02) 0.0048

LONS 1.88(1.00-3.54) 0.0484

GA 1.49(1.22-1.81) 0.0001

MVduration 1.04(1.02-1.07) <0.0001

Death/BPD36wks PharmacologicalTreatment 0.29(0.14-0.62) 0.0012

ConservativeTreatment 0.34(0.14-0.79) 0.0123

BW 0.99(0.99-0.99) 0.0001

Malegender 3.24(1.73-6.18) 0.0002

LONS 2.53(1.42-4.52) 0.0017

NECsur,necrotizingenterocolitisrequiringsurgicalintervention;IVHIII/IV,intraventricularhemorrhagegradeIIIandIV;BPD36wks, bron-chopulmonarydysplasiawithoxygendependenceat36weeksofcorrectedgestationalage;BW,birthweight;GA,gestationalageat birth;MVduration,durationofmechanicalventilation;Death/BPD36wks,combinedoutcomeofdeathorbronchopulmonarydysplasia withoxygendependenceat36weeksofcorrectedgestationalage;LONS,late-onsetneonatalsepsis; OR,oddsratio;CI,confidence interval.

Even with the aforementioned limitations, these find-ings indicate the need to conduct more randomized controlled studies to evaluate the possible protective effectof pharmacologicaltreatment inhigh-risk NBswith PDA.

Collaborators

The following researchersfrom theNeonatal Unitsof the BrazilianNeonatal ResearchNetwork wereresponsible for datacollectionforthisresearch:

VeraLúciaJornadaKrebsandWertherBrunowCarvalho, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil. Rita de Cássia Silveira, Department of PediatricsandChildCare,Faculdade deMedicina, Univer-sidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.MariaFernandaBrancodeAlmeida,JuniaSCastro, andSimone NAFigueira, Departmentof Pediatrics, Facul-dadedeMedicina,UniversidadeFederal deSãoPaulo, São Paulo,SP, Brazil.José MariaLopesandOlgaBonfim, Insti-tuto Fernandes Figueira, Rio de Janeiro, RJ, Brazil. Ana Luiza Macedo, Geisy MSLima, andTereza Carvalho, Insti-tuto de Medicina Integral Prof. Fernando Figueira (IMIP), Recife,PE,Brazil. AdrianaSaito andAliceM. Kiy, Depart-ment of Pediatrics, Faculdade de Medicina de Botucatu, UniversidadeEstadualPaulista,Botucatu,SP,Brazil.Walusa Assad Goncalvez Ferri, Department of Pediatrics, Facul-dade deMedicina de Ribeirão Preto,Universidade de São Paulo, Ribeirão Preto, SP, Brazil. Maria Regina Bentlin, DepartmentofPediatrics,Faculdade deMedicinade Botu-catu,Universidade EstadualPaulista,Botucatu,SP, Brazil. Regina Vieira Cavalcante da Silva, Department of Pedi-atrics,UniversidadeFederaldoParaná,Curitiba,PR,Brazil. ÂngelaSaraJamussedeBrito,MariaRafaelaConde Gonza-lez,and Ana Berenice Ribeiro de Carvalho, Faculdade de Medicina,UniversidadeEstadualdeLondrina,Londrina,PR, Brazil.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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