Physiological-based cord clamping in very preterm infants — Randomised controlled trial on effectiveness of stabilisation

Physiological-based

cord

clamping

in

very

preterm

infants

—

Randomised

controlled

trial

on

effectiveness

of

stabilisation

Ronny

Knol

*

,

Emma

Brouwer

,

Thomas

van

den

Akker

,

Philip

DeKoninck

,

Nan

van

Geloven

,

Graeme

R.

Polglase

,

Enrico

Lopriore

,

Ellen

Herkert

,

Irwin

K.M.

Reiss

,

Stuart

B.

Hooper

,

Arjan

B.

Te

Pas

a_{DivisionofNeonatology,DepartmentofPaediatrics,ErasmusUniversityMedicalCentre,Rotterdam,TheNetherlands}

b

DivisionofNeonatology,DepartmentofPaediatrics,LeidenUniversityMedicalCentre,Leiden,TheNetherlands

c

DepartmentofObstetrics,LeidenUniversityMedicalCentre,Leiden,TheNetherlands

d_{DepartmentofObstetricsandGynaecology,ErasmusUniversityMedicalCentre,Rotterdam,TheNetherlands}

e_{TheRitchieCentre,HudsonInstituteofMedicalResearch,MonashUniversity,Clayton,Victoria,Australia}

f_{DepartmentofBiomedicalDataSciences,LeidenUniversityMedicalCentre,Leiden,TheNetherlands}

Abstract

Aim:Totestwhetherstabilisingverypreterminfantswhileperformingphysiological-basedcordclamping(PBCC)isatleastaseffectiveasthestandard

approachoftime-baseddelayedcordclamping(DCC).

Methods:Arandomisedcontrollednon-inferioritystudywasperformedintwocentresfromMayuntilNovember2018,includingpreterminfantsborn

below32weeksofgestationalage.InfantswereallocatedtoPBCCorstandardDCC.InfantsreceivingPBCCwerestabilisedonapurpose-built

resuscitationtablewithanintactumbilicalcord.Thecordwasclampedwhentheinfanthadregularspontaneousbreathing,heartrate100bpmand

SpO2>90%whileusingFiO2<0.40.IninfantsreceivingDCC,thecordwasclampedat30 60secondsafterbirthbeforetheyweretransferredtothe

standardresuscitationtableforfurthertreatmentandstabilisation.Primaryoutcomewastimetoreachrespiratorystability.

Results:Thirty-seveninfants(meangestationalage29+0weeks)wereincluded.Meancordclampingtimewas5:492:37mininthePBCC(n=20)

and1:020:30minintheDCCgroup(n=17).InfantsreceivingPBCCneededlesstimetoreachrespiratorystability(PBCC5:542:27min;DCC

7:072:54min;meandifferencecorrectedforgestationalage 1:19min,95%CI[ 3:04 0:27]),showingnon-inferioritywiththepre-definedlimitof

1:15min.Nosignificantdifferencesbetweenthegroupswerefoundformaternalbloodloss,postpartumhaemorrhage,infanttemperatureatadmission

orshort-termneonataloutcomes.

Conclusion:Stabilisationofverypreterminfantswithphysiological-basedcordclampingisatleastaseffectiveaswithstandardDCC.

ClinicalTrialRegistration:NetherlandsTrialRegister(NTR7194/NL7004).

Introduction

Managementofverypreterminfantsinthefirstminutesoflifecanhave

amajorimpacton neonatalmorbidityandmortality.1,2 Duringthe

transitiontoextra-uterinelife,lungaerationispivotaltoinitiatethe

major physiological changes in respiratory and cardiovascular

functionthat are required forsurvivalafter birth.3,4 _Mostpreterm

infantsrequirerespiratorysupportatbirth,astheyoftenfailtoaerate

theirimmaturelungs.5_{Respiratorysupportiscommonlystartedonly}

afterumbilicalcordclamping,whichinexperimentalstudieshasbeen

showntocompromisecardiovascularfunction.6

Preterminfantscouldbenefitfromplacentaltransfusion (blood

transfer from the placenta to the infant) whencord clamping is

delayed.Arecentmeta-analysiscomparingdelayedcordclamping

(DCC)withimmediatecordclamping(ICC)inpreterminfants,showed

* Correspondingauthorat:DepartmentofPaediatrics,DivisionofNeonatology,ErasmusUniversityMedicalCentre,P.O.Box2060,Rotterdam,3000

CB,TheNetherlands.

E-mailaddress:r.knol@erasmusmc.nl(R.Knol).

1

Theseauthorscontributedequallytothiswork.

https://doi.org/10.1016/j.resuscitation.2019.12.007

Received9September2019;Receivedinrevisedform22November2019;Accepted15December2019

Availableonlinexxx

Available

online

at

www.sciencedirect.com

Resuscitation

increased haematocrits, less blood transfusions, a decrease in

neonatalmortalityandatrendtowardslessintraventricular

haemor-rhages(IVH).7_{However,inmoststudiesDCCwasperformedusinga}

fixedtime-pointof30 60swhereasplacentaltransfusionmaytakeup

to3mintocomplete.8Inaddition,preterminfantsneedingimmediate

interventionsforstabilisationorresuscitationweregenerallyclamped

immediately and excluded from these series. These infants are

howeveratthehighestriskofcomplicationsandmayreceivethe

greatestbenefitfromDCC.

WhiletherationaleofmostDCCstudieswasbasedonincreased

placentaltransfusion,experimentsinpretermlambshaveshownthat

delaying cord clamping until after ventilation onset prevents a

significantreductionincardiacoutput.6_{Thisapproachof}

physiologi-cal-based cord clamping (PBCC) in lambs also prevented large

fluctuationsinsystemicandcerebralbloodpressuresandflows.9In

preterminfantsthesedetrimentaleffectsmaybeavoidedwheninfants

arefirststabilisedwhilstconnectedtothecordandonlyclampedwhen

the infant has a stable breathing pattern, possibly resulting in

decreasedriskofmortalityand(cerebral)morbidity.10

TheaimofthePBCCapproachinpreterminfantsistoestablish

lungaeration,adequatepulmonarybloodflowandpulmonarygas

exchangepriortocordclamping.Tofacilitatethisapproach,anew

purpose-builtresuscitationtable(theConcord)hasbeendevelopedat

LeidenUniversityMedicalCentre(LUMC).Thismobileresuscitation

table isdesigned to provide full standard care in stabilisation of

preterminfantsatbirthwhilethecordremainsintact.Allequipment

thatisneededforstabilisationandresuscitationisincorporatedinthe

tableallowingpreterminfantsneedingimmediaterespiratorysupport

toalsoreceivethepossiblebenefitsofPBCC.Thisstudyisthesecond

in our Aeration, Breathing, Clamping (ABC) research project

determining thebenefitof PBCCusingtheConcord.We recently

demonstratedfeasibilityofthisapproachwithamediancordclamping

timeofalmostfourandhalfminutes(ABC1study).11

Aimofthestudy

Theaimofthepresentstudy(ABC2study)wastoassesswhether

usingtheConcordtostabilisepreterminfantswithPBCCisatleastas

effectiveasusingthestandardapproachofstabilisinginfantsaftera

periodofDCC(30 60s)usingastandardresuscitationtable.12_Our

hypothesis was that stabilisation with PBCC was non-inferior to

stabilisationafterDCC.

Methods

Thestudywasarandomisedcontrollednon-inferioritytrialintwotertiary

centres(Leiden UniversityMedicalCentreandErasmusUniversity

MedicalCentre)andperformedinthelabourroomoroperatingtheatre

incaseofcaesareansection.Infantswererandomised1:1toeither

stabilisationaccordingtothePBCCapproachusingtheConcord,or

stabilisation according to the standard DCC approach using the

standardresuscitationtable.ThestudywasapprovedbytheLUMC

Institutional Review Board (IRB, P18.025) and registered in the

NetherlandsTrialRegister(NTR7194/NL7004).Infantswereincluded

inthestudyfromMay9thuntilNovember18th2018.Detailsonstudy

procedures,randomisation,investigationalproductsandsamplesize

areaspreviouslydescribed.12

Participants

Infantsbornvaginallyorbycaesareansectionpriorto32weeksand

0daysofgestationalage(GA)wereeligible.Exclusioncriteriawere

significant congenital malformations influencing cardiopulmonary

transition,placentalabruption,placentapraeviaandsignsofsevere

fetaldistressnecessitatingemergencycaesareansection.Parental

writteninformedconsentwasobtainedpriortobirth.

Investigationalprocedures

Priortothestartofthestudy,allhealthcareprovidersinvolvedin

labour roomcareweretrainedin usingtheConcordforPBCC.A

standard operating procedure was developed to optimise close

collaborationbetweenneonatologistsandobstetricians.Allneonatal

caregivers involved were trained and accredited for neonatal

resuscitation. Centresadheredtolocalresuscitationguidelinesfor

stabilisationofpreterminfants.

Preterm infants randomised to the intervention group were

stabilisedaccordingtothePBCCapproach(Fig.1).Thisinvolved

providingstandardpostnatalrespiratorymanagementandheatloss

preventionwhiletheinfantwasontheConcordclosetoitsmother,with

thecordstillintact.Importantly,stabilisationstartedassoonasthe

infantwasplacedontheplatform,withthecordstillintact,whichwas

clampedonlyaftertheinfantwasjudgedtobestable,asdefinedbythe

presence of regular spontaneous breathing, a heart rate (HR)

>100bpmand oxygensaturation (SpO2)above90% whileusing

supplementaloxygen(FiO2)<0.40.Uterotonicdrugswere

adminis-teredimmediatelyaftercordclamping.

Incaseoftwinsandvaginalbirth,asimilarstabilisationprotocoland

definitionof themoment of cord clampingwasused. Clampingin thefirst

infantwasperformedsoonerifthesecondinfantwasabouttobeborn.

Thefirstinfantwasthentransferredtothestandardresuscitationtable,

sothatthesecondtwincouldbestabilisedontheConcord.

PBCC couldbeabandonedatany timeduringtheprocedure,

whichinvolvedclampingthecordandtransferringtheinfanttothe

standard resuscitation table. This could result (i) from a clinical

emergency in thewomanor thesecondtwin requiringadditional

working spacefortheobstetrician, (ii)whenfull resuscitationwas

needed,and(iii)whenmaternalbloodlosswasexcessiveandthe

obstetriciandecidedtoclampthecordandadministeruterotonicdrugs

withoutdelay.

Preterminfants randomised to thestandardDCC groupwere

transferredtothestandardresuscitationtablefollowingcordclamping

toadministeranytreatmentsorinterventionsrequiredtostabilisethe

infant,accordingtolocalresuscitationguidelines.Clampingwas

time-basedandoccurred30 60safterbirth,dependingon theclinical

conditionoftheinfant;earlycordclampingwasdeemednecessaryif

theinfantneededassistance.Uterotonicdrugswereadministered

immediatelyaftercordclamping.

Randomisation,blindingandtreatmentallocation

Randomisationwasstratifiedbygestationalage(24 27+6and28

31+6weeks)andbytreatmentcentreusingvariableblock(4 8)

sizes.Concealmentofallocationwasensuredbyusingthe

random-isationprocessofCastorEDC,anelectronicdatacapturesystem.

Blindingofthestudywasnotpossible.

Incaseoftwinsbornvaginally,bothinfantswererandomisedtothe

technically not possible to perform PBCC for both infants. After

consent,bothinfantswereincluded;thefirstinfantalwaysreceived

DCCandthesecondinfantwasrandomisedtoeitherPBCCorDCC.

Primaryoutcome

Primaryoutcomewasthetimetostabilisationoftheinfant,starting

frombirth.Astableinfantwasdefinedbythepresenceofregular

spontaneousbreathing,aHR100bpmandSpO2above90%while

usingFiO2<0.40.

Secondaryoutcomes

Inadditiontopatientandmaternaldemographics,multiplesecondary

outcomeswerecollectedasdescribedinthestudyprotocol.12_These

outcomeswererelatedtotheprocedureitselfandtothetransitionof

theinfant.Furthermore,short-termneonatalandmaternaloutcomes

werecollected.Importantsafetyoutcomeswereinfanttemperatureat

admissionattheNeonatalIntensiveCareUnit(NICU)andmaternal

peripartumblood loss,postpartumhaemorrhageandsurgical site

woundinfectionaftercaesareansection.

Statisticalanalysis

Whendesigningthisstudy,nodatawereavailableonthe

effective-nessofstabilisinginfantsduringPBCCandcomparingPBCCwith

DCCtoconductapoweranalysis.Fewstudieshaveperformedinitial

respiratory supportbeforecord clamping,butall usedpredefined

timingofcord clamping, varyingfrom 30to 120s.Data fromour

feasibilitystudyshowedthatthemediantimetoobtainrespiratory

stabilitywas4:23min[IQR3:00 5:11]duringPBCC.

Inourunit,themeantime(frombirth)neededtostabiliseaninfant

usingDCCis5_2min.13_{Ifthetimetostabilisationwasnotdifferent}

betweenDCCandPBCC,wecalculatedthat64infants(32ineach

treatmentarm)wererequired.Thiswouldgive80%powertoassess

whethertheupperlimitof aone-sided 97.5%confidenceinterval

(equivalent to a 95% two-sided confidence interval) around the

difference in mean timeto stabilisation wouldbe below the

non-inferioritylimitof75s.Anon-inferioritymarginof75swaschosenas

currentclinicalguidelinesfortargetingofoxygensaturationindicate

thatthistimedifferenceisacceptableduringstabilisation.14

Normally distributed data is presented as means_standard

deviations, whereas data that is not normally distributed is

presented asmediansandinterquartile ranges. Categorical data

were analysed using the Chi-square test or Fisher’s exact test.

ContinuousdatawereanalysedusingtheStudent’sttestorMann

Whitney test as appropriate. Intention-to-treat analysis was

performed. For the primary outcome an additional as-treated

analysiswasperformed,analysingresultsbasedon thereceived

ratherthanallocatedtreatment.TheeffectofPBCContheprimary

outcomewasassessedbymultivariablelinearregressionanalysis

including GA as additional covariate. An additional sensitivity

analysis correcting for other possible confounders that were

unbalancedbetweenthegroupswasperformed.Theprimarytest

ofnon-inferiorityisreportedwithaone-sidedp-valueandcompared

toanalphaof2.5%;allother(superiority)p-valuesarereportedtwo

sidedandcomparedtoanalphaof5%.

Results

Followingadiscussionbetweentheinvestigatorsandthree

indepen-dentexperts(anethicist,astatisticianandanepidemiologist),itwas

decidedtostopthistrialbeforereachingthetargetsamplesizedueto

aslowerthananticipatedrecruitment.Therecruitmentperiodforthis

trialwaspredeterminedandlimitedbythefundingconditionsofthe

next-stage,andlarger,ABC3trial.Ceasingthetrialatthistimeallowed

ananalysisoftrialoutcomesinrecruitedinfantsandreviewbythe

researchethicscommitteesothatABC3trialcouldbeapprovedbythe

requireddate,aslongastheresultsofABC2trialweresatisfactory.

The analysis occurred at 50% recruitment and found that the

predefinednon-inferioritylimitwasalreadymet.

Fig.1–Illustrationofthephysiological-basedcordclampingapproachusingtheConcord.Stabilisationoftheinfantis

Atotalof191womenwereassessedforeligibility(Fig.2).Ofthese

women158weredeemed eligibleand 120approached forstudy

participation. A total of 74 parent couples consented for study

participation and 39 infants (35 pregnancies) were randomised,

allocating22infantstoPBCCand17infantstoDCC.Twoinfantswere

excludedeitherbecauseoflunghypoplasiaorduetoanemergency

caesareansection.AnothertwoinfantsinthePBCCgroupreceived

standardtreatment,duetotechnicalfailureoftheradiantheaterofthe

ConcordandbirthpriortotimelypreparationoftheConcord.Baseline

characteristicsofthestudypatientsarepresentedaccordingtotheir

allocation(Table1).

Primaryoutcome

Primary outcome was recorded for 36 infants, as pulse-oximeter

measurementswerenotobtainedforoneinfantandprimaryoutcome

couldthereforenotbedetermined.Intention-to-treatanalysisshowedthat

themeantimetostabilisationwas5:542:27minforinfantsinthePBCC

groupand7:072:54minforinfantsintheDCCgroup.Meandifference,

correctedforGA,was 1:19minwitha95%confidenceintervalof 3:04

to0:27min.Thepre-definednon-inferioritylimitof75sfelloutsideofthe

confidenceinterval(p<0.01;onesidednon-inferioritytest,Fig.3).Atotal

ofthreeinfantsdidnotachievetheprimaryoutcomewithin10min.Twoof

theseinfantswereallocatedtoDCCandonetoPBCC.

The baseline characteristics revealed a higher proportion of

females in the PBCC group. Additionally, correcting for gender

showed amean difference of 0:45min with a 95% confidence

intervalof 2:32to1:02min(p=0.01;one-sidednon-inferioritytest).

As-treatedanalysisshowedthemeantimetostabilisationwas

5:251:35minforinfantsinthePBCCgroupand7:253:10minfor

infantsintheDCCgroup.Meandifference,correctedforGA,was

2:02min with a95%confidence intervalof 3:42 to 0:22min

(p<0.01,onesidednon-inferioritytest;p=0.019,two-sided

superi-oritytest,Fig.3).

Fig.2–CONSORTdiagram.CONSORT,ConsolidatedStandardsofReportingTrials;GA,gestationalage;CS,caesarean

Secondaryoutcomes

Infantsin the PBCCgroupweremorelikely toreceiverespiratory

supportearlier,andcordclampingwasperformedlateratameantime

of5:492:37min(Table2).Nostatisticallysignificantdifferenceswere

shownbetweenthetwogroupsforlabourroomorshorttermneonatal

secondaryoutcomes,exceptforumbilicalcordpH(Tables2&3).

No postoperative infections were reported after caesarean

sections.Medianmaternalbloodloss was300[200 700]mland

450 [263 538] ml for the PBCC and DCC group, respectively

(p=0.53,Table2).

Discussion

Thisisthefirst reportedtrial comparingphysiological-basedcord

clampingtodelayedcordclampingtreatmentinverypreterminfants.

ThetimingofcordclampinginthePBCCgroupwasbasedonthe

infant’s transitional status, which in contrastwith thetime-based

approaches used previously, lead to a considerably longer cord

clampingtimeof5:49min.Ourresultsdemonstratethatstabilisationof

preterminfantswhenperformingPBCCusingtheConcord,isatleast

as effective as stabilising infants using the current routine DCC

approachandastandardresuscitationtable.

Fewstudieshaveinvestigatedtheprovisionofrespiratorysupport

toverypreterminfantsbeforecordclamping.Allpreviousstudieshave

usedatime-basedapproach,withcordclampingvaryingbetween60s

and3minafterbirth.15 19_{Thesestudieseitherusedabedsidetrolley}

orperformedresuscitationwhiletheneonatewaspositionedonthe

mother’s leg or abdomen, reporting feasibility of the approach

between59%and100%.Inthepresentstudy,inallbuttwoinfants

allocatedtothePBCCapproachthiswasfeasibleresultingina90%

success rateofthePBCCapproachusingtheConcord,whichis

comparabletoourfirstcohort.11

The two most important predefined safety parameters were

maternalbloodlossandadmissiontemperatureoftheinfantatthe

NICU.Althoughcordclampingisperformedconsiderablylaterinthe

PBCCgroupthaninallpreviousreportedstudiesperformingDCCin

verypreterminfants,maternalbloodlosswasnotincreased.This

observation is in concordance withearlier studies showing that

maternal bloodloss isnotincreasedafter DCC.20,21Meaninfant

temperature atNICU admissionwas not different, although four

Table1_–Baselinecharacteristics.Datapresentedasmedian[IQR]orn(%).PBCC,physiological-basedcord

clamping;DCC,delayedcordclamping;PE,preeclampsia;HELLP,HaemolysisElevatedLiver-enzymesLow

Plateletssyndrome.

PBCCgroup(n=20) DCCgroup(n=17)

Gestationalage,weeks 28+4[27+6 30+3] 30+2[27+5 31+0]

Birthweight,grams 1155[1043 1349] 1200[895 1620] Female 16(80.0) 8(47.1) Twins 5(25.0) 3(17.6) Antenatalsteroids - Yes 20(100) 17(100) - Complete(48h) 16(80.0) 9(52.9) CaesareanSection 9(45.0) 9(52.9) PE/HELLP 3(15.0) 2(11.8) Prematurecontractions 15(75.0) 12(70.6) Chorioamnionitis 7(35.0) 6(35.3)

Fig.3–Forestplotfortimetostabilisation;shownaremeandifferencesand95%confidenceintervalsfor

intention-to-treat(ITT)analysisandas-treated(AT)analysis,andthepredefinednon-inferiority(NI)marginof75s.DCC,delayed

infantshadmoderatehypothermiainthePBCCgroupascompared

to one infant in the DCC group. Temperature management

frombirthtoNICUadmissionduringPBCCwasperformedconform

standardcare,butremainsanimportantfocusduringtrainingforthe

PBCCapproach,whichisalsoemphasisedbyothersusingslightly

different approaches.17,18 _{No important safety concerns were}

observed for the PBCC approach using the Concord, as all

othershort term neonatal outcomes were not different between

groups. Three infants in the PBCC group were treated for

hypotension in the first 72h after birth by the administrationof

onebolusoffluid.Thisoccurredtwiceaftertheadministrationof

Propofolpriortointubation.Noinfantneededinotropesduringthe

first72hafterbirth.

ThisstudyshowedstabilisationusingPBCCisatleastaseffective

as stabilising infants according to the current DCC approach.

Interestingly, the as-treated analysis, based on actual received

treatment, showed infantswere stabilisedfaster whenthePBCC

approach was performed with a statisticallysignificant difference

betweenthetwogroups(p=0.019).Thismayreflectthepositiveeffect

PBCChasoncardiorespiratorystabilityandultimatelystabilisationof

preterminfants.UmbilicalcordpHwaslowerforthePBCCgroup,

whereas Apgarscores andfirst neonatalpH valuesduring NICU

admission did not differ between the two groups. The delay in

obtainingumbilicalcordbloodafterthePBCCapproachcouldhave

resulted in lower umbilical cord blood pH values, as described

previouslyafterdelayedcordclamping.22,23_{SincefirstneonatalpH}

Table3_–Secondaryoutcomes,shorttermneonatal.Datareportedasanalysedperintention-to-treat.Data

presentedasmean_SDandn(%).PBCC,physiological-basedcordclamping;DCC,delayedcordclamping;NICU,

neonatalintensivecareunit;IVH,intraventricularhaemorrhage;RBC,redbloodcells;NEC,necrotizing

enterocolitis;ROP,retinopathyofprematurity;BPD,bronchopulmonarydysplasia.

PBCCgroup(n=20) DCCgroup(n=17) Pvalue

Haemoglobinfirst24h,g/dL 16.32.9 16.83.4 0.76

Haematocritfirst24h,l/l 0.490.07 0.500.09 0.80

FirstinfantpHafteradmission 7.270.09 7.310.10 0.27

IntubatedduringNICUstay 5(25.0) 5(29.4) 0.76

Needforsurfactant 8(40.0) 6(35.3) 0.77

Treatmentforhypotension<72h 3(15.0) 0 0.23

Patentductusarteriosus 6(30.0) 4(23.5) 0.66

IVH(allgrades) 3(15.0) 2(11.8) 0.77

IVHgrade3 0 1(5.9) 0.46

Maximumbilirubin 169.243.2 163.743.5 0.70

Needforphototherapy 20(100) 15(88.2) 0.12

NeedforRBCtransfusion 4(20.0) 6(35.3) 0.30

Earlyonsetinfection<72h 1(5.0) 2(11.8) 0.45

Lateonsetinfection>72h 7(35.0) 6(35.3) 0.99

NECgrade2A 2(10.0) 1(5.9) 0.65

Death 0 2(11.8) 0.20

ROP(allgrades) 7(35.0) 2(14.3)(n=14) 0.18

BPD(allgrades) 4(20.0) 4(26.7)(n=15) 0.64

Table2_–Secondaryoutcomes,labourroom.Datareportedasanalysedperintention-to-treat.Datapresentedas

meanSD,n(%)andmedian[IQR].PBCC,physiological-basedcordclamping;DCC,delayedcordclamping;min,

minutes;CPAP,continuouspositiveairwaypressure;PPV,positivepressureventilation;FiO2,fractionofinspired

oxygen.

PBCCgroup(n=20) DCCgroup(n=17) Pvalue

Timeuntilcordclamping,min 5:492:37 1:020:30 0.00

Timeuntilstartsupport,min 1:111:18 2:000:47 0.04

Respiratorysupport

- None 1(5.0) 0(0.0) 1.00

- CPAP 18(90.0) 17(100) 0.18

- PPV 14(70.0) 10(58.8) 0.48

- Intubation 1(5.0) 0(0.0) 1.00

MaximumFiO2used,% 70[50 90] 50[30 88] 0.24

Apgar1min 6[5 8] 7[6 8] 0.58 Apgar5min 8[7 9] 9[8 9] 0.39 Apgar10min 9[8 10] 9[9 10] 0.49 UmbilicalcordpH 7.210.09 7.290.09 0.01 Temperatureatadmission,C 36.50.8 36.70.6 0.61 Temperature<36.0C 4(20.0) 1(5.9) 0.21

Maternalbloodloss,ml 300[200 700] 450[263 538] 0.53

Postpartumhaemorrhage (>1000ml)

valuesandApgarscoreswerenotdifferent,clinicalrelevanceofthe

differenceincordbloodpHismostlikelyminimal.

Thisstudyhassomeimportantlimitations.Infantswereonlyincluded

after having received antenatal consent from both parents. Women giving

birthsoonafteradmission,werenotapproachedsincethiswasdeemed

inappropriate. Usingdeferredconsent forthis typeofinterventional

labourroomstudiesmayovercomethisproblemandincrease

general-isability.24_{Likewise,infantsbornbyemergencycaesareansectionwere}

alsonoteligible,astherewouldbeinsufficienttimeforequipmentset-up.

Incontrast,theseinfantsprobablymaybenefitmostfromPBCCand

includingtheseinfantsinfuturestudiesmayfurtherincrease

general-isability.Lastly,respiratorysupportininfantsinthePBCCgroupwas

initiatedearliercomparedtothecontrolgroup,whichissimplyahallmark

andconsequenceoftheoverallPBCCapproach.Thus,evaluationofthe

PBCCapproachinthisstudyincludesearlierstartofrespiratorysupport,

laterumbilicalcordclampingandtheutilizationoftheConcord.

Previousanimalmodelsalreadyshowedincreasedrespiratoryand

haemodynamic stability when using the physiological-based cord

clampingapproach.6_{IncreasedstabilityduringPBCCcouldexplainfor}

infantsinthisgrouptobestabilisedfaster.TheaimofthePBCCapproach

inpreterminfantsistoestablishlungaeration,adequatepulmonaryblood

flowandpulmonarygasexchangepriortocordclamping.Noclearcriteria

areavailabletodefinewhenaninfantisrespiratorystable.Inthisstudy,

stabilised was defined as the infant having established regular

spontaneousbreathing withSpO2above90%,HR>100bpmwhile

usingFiO2<0.40.Othersuseddifferentcriteriaforcordclampingina

physiologicalapproach,forexampleincludingexhaledcarbondioxideas

amarkerforpulmonarygasexchange.25_{Ourdefinitionofbeingstable}

wasusefulinourstudyasSpO2andHRaremonitoredforeverypreterm

infant.However,thetargetof90%maybesetrelativelyhigh,ascurrent

internationalguidelinesaimforSpO2of85%at5min.

Wepreviouslydemonstratedthefeasibilityandnowtestedthe

effectivenessofthePBCCapproachusingtheConcord.11_Thenext

stepistodeterminewhetherthisapproachresultsinbeneficialeffects

onimportantclinicaloutcomesinverypreterminfants.In2019,alarge

multicentrerandomisedclinicaltrial(ABC3trial)hasbeenstartedin

theNetherlands.

Conclusions

Inconclusion, stabilisationof verypreterm infantsperforming the

PBCCapproachresultsinconsiderablylongercordclampingtimes

andisatleastaseffectiveasstabilisationaccordingtothecurrent

routineDCCapproach.Largerrandomisedclinicaltrialsareneededto

showpotentialbeneficialclinicaleffectsforpreterminfants.

Funding

sources

AtPisrecipientofanNWOinnovationalresearchincentivesscheme

(VIDI91716428).RKreceivedagrantfromtheSophiaChildren’s

HospitalFoundation(Rotterdam,S17-14).Thisprojectissponsored

bytheGiselaThierFund(Leiden).

Author

contributions

RK,EB,andAtPwrotethestudyprotocolandallauthorsparticipated

inreviewingtheprotocol.RK,EB,TvdA,PD,GP,EL,IR,SHandAtP

participatedinconceptualizationanddesigningthestudy.RK,EB,

TvdA, PD, NvG, EH and AtP coordinated the study, trained the

cliniciansandcollectedandanalysedthedata.RKandEBwrotethe

firstdraftofthemanuscript.Allauthorsparticipatedinreviewingand

editingandallapprovedthefinalmanuscript.

Conflicts

of

interests

None declared. The Concord tables used in this study were

manufactured by the Department of Medical Engineering of the

LeidenUniversityMedicalCentre.ThecompanyofConcordNeonatal

wasnotinvolvedinthisstudyandtheauthorsdonothaveafinancial

relationshipwithConcordNeonatal.

Acknowledgements

WeacknowledgeourresearchnursesRomyBerkhoutandNandavan

Vlietfortheirgreatassistanceinthisproject.WethankSophieCramer

fordrawingtheillustration.

Appendix

A.

Supplementary

data

Supplementary materialrelatedtothisarticlecanbefound,in the

onlineversion,atdoi:https://doi.org/10.1016/j.resuscitation.2019.12.

007.

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