1

Title

Managementofpostpartumhaemorrhage:fromresearchintopractice,anarrativereviewofthe

literatureandtheCardiffexperience

PWCollinsa,SFBellb,LdeLloydbandRECollisb

a. InstituteofInfectionandImmunity,SchoolofMedicine,CardiffUniveristy,Cardiff,UK

b. DepartmentofAnaesthetics,IntensiveCareandPainMedicine,CardiffandValeUniversity

HealthBoard,Cardiff,UK

Correspondingauthor

RachelCollis:DepartmentofAnaesthetics,IntensiveCareandPainMedicine,CardiffandVale

UniversityHealthBoard,Cardiff,UK

Email:Rachel.collis@wales.nhs.uk

rachel.collis@wales.nhs.uk

Keywords

Postpartumhaemorrhage;viscoelastometry;fibrinogen;coagulopathy;qualityimprovement

Highlights

• Fibrinogenfallsbeforeothercoagulationfactorsduringpostpartumhaemorrhage(PPH)

• LaboratoryClaussfibrinogenandpointofcareFibtemA5®predictprogressionofPPH

• HaemostaticimpairmentisuncommonduringPPHandcanbeassessedbyFibtem

• Afibrinogenof2g/LorFibtemA512mmandaboveisadequateforhaemostasisduringPPH

• Anationalqualityimprovementprogrammehasbeeninitiatedintegratingtheseresults

Summary

Postpartumhaemorrhage(PPH)iscausedbyobstetriccomplicationsbutmaybeexacerbatedby

haemostaticimpairment.Inatenyearprogrammeofresearchwehaveestablishedthathaemostatic

impairmentisuncommoninmoderatePPHandthatfibrinogenfallsearlierthanothercoagulation

factors.LaboratoryClaussfibrinogenandthepointofcaresurrogatemeasureoffibrinogen(Fibtem®

A5measuredontheRotem®machine)arepredictivebiomarkersforprogressionfromearlytosevere

PPH,theneedforbloodtransfusionandinvasiveprocedurestocontrolhaemorrhage.Fibrinogen

replacementisnotrequiredinPPHunlesstheplasmalevelfallsbelow2g/LortheFibtemA5is

2

below12mm.Deficienciesofcoagulationfactorsotherthanfibrinogenareuncommonevenduring

severePPH,andRotemmonitoringcaninformwithholdingFFPsafelyinmostwomen.Inthe

absenceofplacentalabruption,clinicallysignificantthrombocytopeniaisuncommonunlessthe

plateletcountislowbeforethebleedstarted,orverylargebleeds(>5000mL)occur.Measuring

bloodlossisfeasibleinroutinepracticeduringPPHandismoreaccuratethanestimation.These

researchfindingshavebeencollatedtodesignanongoingqualityimprovementprogrammeforall

maternityunitsinWalescalledOBSCymru(Wales)(TheObstetricBleedingStrategyforWales).

Aims

Theaimsofthisreviewareto:Summarisetheliteraturerelatingtothecoagulationprofileofwomen

withPPH,describehowpointofcare(POC)basedalgorithmscanprovidetimelyinformationfor

clinicianswiththepotentialtoreducebloodproductuseanddescribehowprotocolsusedduring

researchcanhaveapositiveimpactonallpatientswithfewermajorcomplicationsandmassive

bloodtransfusions.

Background

Theincidenceofpostpartumhaemorrhage(PPH)isincreasinginmanycountriesandisthemost

commoncauseofdeathforwomenofchildbearingageworldwide.1-6Blee

dingiscausedbyobstetriccomplicationsbutmaybeexacerbatedbyhaemostaticimpairment.7Itis

widelyassumedthathaemostaticimpairmentoftencomplicatesPPHandconsequently,when

coagulationtestresultsareunavailable,guidelinesendorsetheuseofformulaicinfusionoffresh

frozenplasma(FFP)orcryoprecipitateinfixedratioswithredbloodcells(RBC),8-10basedon

evidenceextrapolatedfromnon-pregnantadultmajortrauma.Itisquestionablewhetherthese

datashouldbeappliedtothemanagementofPPHgiventheverydifferentbaselinecoagulation

statusofthegroups.

HighqualitystudiesdescribingcoagulopathiesassociatedwithPPHarelimited,howeveritis

probablythattheyresultfromcomplexinteractionsbetweendilution,localconsumption,

disseminatedconsumptionandincreasedfibrinolysis.7Thenatureofhaemostaticimpairmentvaries

accordingtothecauseofthebleedandisaffectedbycomplicationsofpregnancysuchaspre-

eclampsia,sepsisandimpairedliverfunction.Thephysiologicaladaptionsofpregnancyresultina

pro-thromboticstateattermwithincreasedlevelsofpro-coagulantsanddecreasedanti-coagulants.

3

Inparticular,attermthefibrinogenlevelis4-6g/Lattermgestation,comparedto2-4g/Linhealthy

non-pregnantwomen.11;12Untilrecentlyitwasnotknownwhetherfibrinogenreplacementduring

severePPHshouldtarget‘normalforterm’(>4g/L),‘normalforthenon-pregnancy’(>2g/L),or

somewhereinbetween.ThisisimportantwhenconsideringtheroleofFFPintreatingcoagulopathy

inPPH.13

FFPcontainsabout2g/Loffibrinogen,whereastheaveragefibrinogenlevelinawomanwith1000-

2000mlbloodlossduetoatonyortraumaisabout4g/L.14Thismeansthatinmostcases,infusion

ofFFPduringPPHwouldreducefibrinogenbydilution.15Thisimpliesthatunmonitoredfixed-ratio

infusionsofFFPwouldexposemanywomentoFFPwithoutanyprospectofimprovinghaemostasis.

Studiesexploringtheuseoffixed-ratioinfusionsofFFP:RBCduringPPHreportfewerwomen

developinglaboratoryevidenceofcoagulopathy,however,someofthesestudiesdescribemultiple

interventionsincludingearlyinvolvementofseniorstaff.16-20Whenguidedbyviscoelastometricpoint

ofcaretesting(VE-POCT),wehaveshownthatFFPcanbewithheldsafelyinwomenexperiencing

moderatetoseverePPH,withoutdevelopmentofclinicalsignificanthaemostaticimpairment.21A

recentreviewsuggestedthatFFPwasnottheoptimalwaytoreplacefibrinogenduringPPH.13

PPHObservationsandResearchAdvancementsinCardiff,Wales

UsingFibrinogenConcentratetoTreatPPHwithHypofibrinogenemia

WeobservedthatsomewomenexperiencingseverePPHhadlaboratoryfibrinogenlevels<1g/L

associatedwithclinicalhaemostaticimpairment.AtthistimetheRoyalCollegeofObstetricsand

Gynaecology(RCOG)guidancewastomaintainfibrinogen>1g/Lusingcryoprecipitate.22Thawing

andinfusingcryoprecipitatetakestime,delayingcorrectionofthecoagulopathy.Atourcentreand

others,weaddressedthisissuebyinfusingfibrinogenconcentratewhichrapidlyincreasedthe

fibrinogenlevelandwasassociatedwiththeclinicalimpressionofimprovementinhaemostasis.23-26

Weinfusedfibrinogenconcentratebetween2and4Gtosixwomenovera2-yearperiod

(approximately12,000deliveries)withclinicalimprovement,althoughthedataonallwomenwith

lowfibrinogenwasnotcollectedatthistime24Theseearlyreportsreflectedareactiveratherthan

preventativestrategytohaemostaticimpairment.Morerecentstudiesfromothergroupshave

reportedimprovementsinhaemostasiswiththeuseoffibrinogenconcentratetotreat

hypofibrinogenaemia.27;28Thesecasereportsareselectiveandpronetoreportingbias,butwere

sufficientlyencouragingtopromotefurtherinvestigation.

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TheroleofStandardCoagulationTestsandClaussFibrinogenforDetectionofCoagulopathyinPPH

Toinvestigatetheeffectofseverityofbleedingonstandardcoagulationtests,weevaluateda

consecutivecohortof18,501womenwhodeliveredatourunitover3years.WomenwithPPH

>1500mL(n=456,2.5%)hadtheirbloodtestresultsreviewed.PTandaPTTusuallyremainedwithin

thenormalrangeuntilbloodlossreached4000-5000mL.29Thisreflectedsufficientcoagulation

factorsforhaemostasisuntilthebleedvolumereached4000-5000ml,andinfusionofFFPuptothat

timewasunlikelytohaveimprovedhaemostasis.Incontrast,fibrinogenfellrapidlyasbloodvolume

lossincreased,suchthatby2000mLthemajorityofcaseshadafibrinogenbelowthenormalrange

forterm(4g/L),andat4000mLmostwomenhadafibrinogen<2g/L.29AUKObstetricSurveillance

System(UKOSS)surveyofwomentransfused≥8unitsofRBC(averagebloodloss6000mL)also

foundthatmanymorewomenhadafibrinogen<2g/LthananabnormalPToraPTTbothatfirst

presentationandwhencoagulationwasatitsworst.30Thelikelihoodofhypofibrinogenaemia

dependedonthecauseofbleedingandwasmostoftenassociatedwithplacentalabruption.14;30

Takentogether,thesestudiesindicatethatthestandardcoagulationtestsPTandaPTTshowthat

earlydepletionofcoagulationfactorsisuncommoninobstetrichaemorrhage,andthatplasma

fibrinogenlevelmaybeamoreimportanttherapeutictarget.

FibrinogenandFibtemasbiomarkerstopredictseverityofprogressionofpostpartumhaemorrhage

Inaninfluentialpaper,Charbitetalmeasuredmultiplecoagulationfactorsinwomenexperiencing

PPH.FibrinogenlevelwastheonlyindependentpredictorofprogressiontoseverePPHanda

fibrinogen<2g/Lhadhada100%positivepredictivevalueforprogressionfrommoderatetosevere

PPH.31Thisfindinghasbeenconfirmedbyusinretrospectiveandprospectivestudiesandbyother

groupsinvestigatingPPHinmultiplecohortsusingdiversemethodologies(Table1).14;31-35These

studiesnowshowconvincinglythatplasmaClaussfibrinogen,measuredearlyduringPPH,isa

biomarkerforpredictingprogressiontoseverePPH.

AlthoughplasmaClaussfibrinogenlevelsyieldsusefulinformation,ittakesatleastanhourfora

resulttobeavailable,limitingitsutilitytodirectpracticeduringPPH.VE-POCTsgenerateasurrogate

measureoffibrinogenwithresultsavailablewithin10minutesofvenipuncture.36-38Weinitiatedthe

ObstetricBleedingStudy1(OBS-1)toinvestigatewhetheraFibtem®assay,performedontheRotem®

machine(Werfen,Barcelona,Spain),couldpredictprogressionfromearlytoseverePPH.A

consecutivecohortof346womenwithPPH>1000mLwasenrolled.AtrecruitmentbaselineFibtem

wasperformedconcurrentlywithaplasmaClaussfibrinogen,whilstallotherroutinePPH

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managementwasprovided.ClinicianswereblindedtotheFibtemresultbutdidknowthe

laboratoryfibrinogenwhenitbecameavailable(Fig.1).14

DespiteonlyamoderatecorrelationbetweenClaussfibrinogenandFibtem(r=0.59)thetwo

parametershadanalmostidenticalvalueforpredictingprogression.AstheClaussfibrinogenor

FibtemfelltheneedforanyRBCtransfusion,≥4unitsRBC,≥8unitsofbloodproducts

(RBC+FFP+platelets),useofaninvasiveprocedureorableed>2500mLincreased.Thelowerthe

fibrinogenorFibtemA5thehighertheproportionofwomenwithpooroutcomes(Fig.2).For

example,themedian(IQR)fibrinogenandFibtemA5ofwomenwhoreceived≥8unitsofblood

productswas2.1(1.8-3.4)g/Land12(7-17)mm,respectively,comparedwith3.9(3.2-4.5)and19

(17-23)inthosewhodidnot.FibtemA5<10mmwasassociatedwithmoreprolongedbleeding

(median127versus65minutes,p=0.02),longerinlevel2care(patientsneedingextendedpost-

operativecarewithenhancedinterventionsandmonitoring)(median24versus11hours,p<0.001)

andshortertimetofirstRBCtransfusion(p<0.001).Inaddition,thecombinationofalow

fibrinogen/Fibtem,withtheclinicalobservationthattherewason-goingPPHatrecruitment,wasa

strongerpredictorofthesepooroutcomesthaneitheralone.14

OBS-1confirmedthatalowfibrinogenorFibtemA5,measuredearlyduringaPPHwasassociated

withprogressionofPPH,howeveritremainedunknownwhethercorrectionoftheseparameters

wouldimproveoutcome.Furthermore,theappropriateclinicaltargetforfibrinogenorFibtemA5to

maintainhaemostasis,andthereforewhenfibrinogencontainingproductsshouldbeinfused,was

unknown.

AppropriateTriggersforFibrinogenreplacementduringPPH

InanauditreportcomparingaRotem-basedalgorithm(thatinfused3goffibrinogenconcentrateif

theFibtemwas<7mm,or<12mmwithseverebleeding,andFFPiftheExtemCTwas>100s)with

theUnit’spreviouspracticeoftreatingmajorPPHwithshockpacks(consistingof4RBC,4FFPand1

poolofplatelets):TheRotem-basedalgorithmwasassociatedwithalargereductioninFFP,

cryoprecipitateandplateletusage,fewerwomenneeded>5unitsRBC,orhadtransfusion

associatedcirculatoryoverloadoradmissiontoITU.39;40Whilethesedatawereretrospectiveandun-

randomized,theiroutcomesindicatethatROTEM-guidedtransfusionmanagementmaybesuperior

toanempiricmassivetransfusionapproachforPPH.Thereisnoinformationinthepaperabout

responsetimestoadministrationofbloodproductsafteradoptionoffibrinogenconcentrate

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infusions,althoughimmediateavailabilityoffibrinogenconcentratestoredontheirdeliverysuite

mayhavereducedresponsetimeandthereforeimprovedclinicaloutcomes.

Aprospective,double-blind,randomisedcontrolledtrial(RCT)ledbyWikkelsoeinvestigated

whetherinfusing2goffibrinogenconcentrateafter500-1000mLbloodloss,irrespectiveofplasma

fibrinogenlevel,reducedtheneedforRBCtransfusionandbloodloss.Nodifferenceinoutcomes

wasachievedwiththeempiricadministrationof2GfibrinogenconcentrateforPPHshowingthat

earlypre-emptive,formulaicfibrinogenreplacementwasnotindicated.Analysisfoundthatthe

averagefibrinogenlevelwhenfibrinogenconcentratehadbeeninfusionwasabout4.5g/Linboth

armsofthestudy,demonstratingthatthislevelisadequateforhaemostasisduringPPH.41The

resultsprovidegoodevidenceagainsttheuseofempiricfibrinogenreplacementduringPPHinthe

absenceofamonitoredlowplasmafibrinogenlevel,whileexposingmanywomentoplasma-derived

bloodproductsunnecessarily.

IntheObstetricBleedingStudy2(OBS-2)weusedFibtemA5andobservationofongoingbleedingto

guidefibrinogenandFFPreplacement.InOBS-1,aFibtemA5<16mm(fibrinogenabout3g/L),ina

womanwithongoingbleeding,hadbeenassociatedwithprogressiontomultiplepooroutomes14

andthiswassupportedbyotherobservationalstudies(Table1).OBS-2wasadouble-blind,placebo

controlledRCTwhichenrolledwomenwithPPH>1000-1500mL.Thestudyinvestigatedwhether

infusingfibrinogenconcentrate42ifFibtemA5was<16mmandbleedingwasongoingreducedblood

productusage.OBS-2alsoinvestigatedwhetheritwassafetowithholdFFPifFibtemA543was≥15

mmontheassumptionthatanormalfibrinogenwasasurrogateforadequatelevelsofother

coagulationfactors(Fig.3a).14;29;31

Therewasnostatisticallysignificantdifferenceinanyoutcomebetweenthefibrinogenandplacebo

(Normalsaline)groups,demonstratingthatafibrinogenofaround3g/Lisadequateforhaemostasis

duringPPH.44Pre-specifiedsubgroupanalyses43showedthatfibrinogen>2g/LorFibtemA5>12mm

wereadequateforhaemostasisdespiteseverePPH.However,ifFibtemA5orfibrinogenwas<12

mmor<2g/Latthetimeofrandomisation,womeninthefibrinogengroupreceivedfewerblood

productsandhadlowerbloodlossafterstudymedicationcomparedtoplacebo.44Theseexploratory

subgroupanalysesdidnotreachstatisticalsignificancepossiblyduetothesmallnumberofwomen

randomisedwithafibrinogen<2g/L.Howevertheseresults,inconjunctionwiththedatafrom

Mallaiah39,suggestthatanappropriateinterventionpointforinfusionoffibrinogenisaFibtemA5

<12mmorfibrinogen<2g/L,andastudyinvestigatingthisiswarranted.

Inourexperienceafibrinogenlevelbelow2g/Lisuncommonduringobstetrichaemorrhage.

Combiningdatafromconsecutivestudiesandobservationfromourinstitutionoverthelast8years

7

showsarateof1-2/1000deliveriesandasimilarincidencehasbeenobservedacrossallunitsin

Wales.InOBS-2,irrespectiveofbloodloss,womenwithaFibtemA5>15mmorwhohadstopped

bleeding,hadFFPwithheld(n=605).Median(IQR)bloodlosswas1500ml(1300-2000ml)andnone

ofthewomendevelopedhaemostaticimpairment21suggestingthathaemostaticimpairmentduring

PPHcanbeassessedaccuratelyusingVE-POCTs.

Thrombocytopeniaandplatelettransfusionduringpostpartumhaemorrhage

IthasbeensuggestedthatamassivetransfusionprotocolusedforPPHshouldinclude

platelets.18;20;45;46Guidelinesrecommendmaintainingtheplateletcountabove75x109/Lduring

PPH.8;9TherearelimiteddataontheincidenceandcausesofthrombocytopeniaduringPPH,

thereforeweanalysedthewomenrecruitedtotheOBS-1study.InmoderatetoseverePPH,

thrombocytopeniawasuncommon,with8/347(2.3%)womenhavingaplateletcount<75x109/L.

Twelvewomen(3.4%)receivedaplatelettransfusionandthesefellintotwogroups.Firstly,women

whowerethrombocytopenicbeforedeliveryduetopre-eclampsiaorpre-existingdiseasessuchas

immuneorinheritedthrombocytopeniaandsecondly,womenwithinitiallynormalplateletcounts

whoeitherhadaplacentalabruptionorbleeds>5000mL.47Thesefindingsweresupportedbythe

UKOSSsurveyofwomenwhoreceived≥8unitofRBC(medianbloodloss6000mL)wherethe

medianfirstplateletcounttakenduringthebleedwas131x109/Landlowestwas68x109/L,77%of

thesewomenreceivedaplatelettransfusion.Placentalabruptionwasassociatedwiththelargestfall

inplateletcount(137to54x109/L).30Thesereportssuggestthattheplateletcountisadequate

duringPPHinthevastmajorityofcases,andinclusionofplateletsinshockpackswouldresultin

manywomenreceivingunnecessaryplateletinfusions.

MeasurementofbloodlossafterdeliveryandduringPPH

EarlyrecognitionofPPHwithmeasuredratherthanestimatedbloodlossiscriticalbecauseclinicians

oftenunderestimatethevolumeofbleeding.48Measurementofbloodlossismoreaccurateandis

feasibleinroutinepractice,shouldbestartedaftereverydeliveryeveniftheinitiallossseems

normal49andisakeyrecommendationinRCOGguidance.8Weadoptedthepracticeofgravimetric

measurementofbloodlossonswabsandpadswiththeadditionofmeasuredbloodlossinconical

underbuttockdrapesandsuctionbottlesduringourstudiestostandardisepatientrecruitmentand

ensuretimelyescalationofcare.Measurementofbloodlossalonedoesnotleadtoimproved

outcomesduringPPH,50butwhenintegratedintoapathwaycanaidescalationofcare.20Inaddition,

escalationofcarealsoneedstotakeintoaccountotherfactorssuchasmaternalvitalsignsas

bleedingcanbeconcealedandtheapparentrateofbloodloss,althoughspecificguidanceisnot

available.

8

ImpactofObstetricBleedingStudiesonpracticeandevolvingqualityimprovement

Between2013and2015womenrecruitedtoOBS-2followedthestudybloodproductalgorithm(Fig

2a)andthosenotrecruitedweretreatedusingthelocalmajorobstetrichaemorrhageROTEM

algorithm(Fig3b).Since2010PPHoutcomedatahasbeencollectedatourinstitutionaspartofa

qualityimprovementinitiative.DuringOBS-2,RBCusagedecreasedby32%,FFPusageby86%and

thenumberofwomenreceiving5ormoreunitsRBCfellby86%(Fig4).Inaddition,bleeds≥2500ml

fellby83%andlevel3ITUadmissions(womenrequiringadvancedrespiratorysupport)duetoPPH

decreasedfromabout4/yeartononein3years(Fig4).Althoughtemporallyrelated,itisunlikely

thattheinterventionoffibrinogenadministrationwassolelyresponsiblefortheseimproved

outcomesasonly7womentreatedintheinterventionalarmhadafibrinogen<2g/L.Thisimplies

thatotherfactorsassociatedwithrunningthestudyandcomplyingwithprotocolswereinfluencing

maternaloutcomes.Inordertostandardiserecruitmenttothestudy,womenwereriskassessed,

bloodlosswasmeasuredratherthanestimatedandobstetriciansandanaesthetistsattendedthe

mother’sbedsidetoobtainconsentandtakestudybloodsasspecifiedinthestudyprotocol.

WhenOBS-2endedinNovember2015,itwasexpectedthatimprovedoutcomeswouldcontinue.

However,itrapidlybecameapparentthatthiswasnotthecaseandtheendofthestudycoincided

withanincreaseinlargehaemorrhagestoratessimilartobeforethestudy(Fig4).Asystematic

reviewof16largebleedsovera6monthperiodidentifiedcommonthemesincludingareturnto

estimatingbloodloss,themultidisciplinaryteamnotattendingthemother’sbedsideinatimely

fashionandPOCTsnotbeingperformedearlyinthecourseofthehaemorrhage.Thisresultedin

delayedrecognitionofadeterioratingpatientanddelayedescalationofobstetricintervention.

Qualityimprovementinitiativesinpostpartumhaemorrhage

In2011ShieldsdescribedaqualityimprovementprogrammethatstandardisedcareduringPPH.This

includedriskassessmentfollowedbyanescalating3-stageapproachbasedon500,1000and1500

mLbloodlossand/orclinicalsigns.Thisstepwise,prescriptiveapproachrequiredaccurate

contemporaneousmeasurementratherthanestimationofbloodlossandwasinitiatedafterevery

delivery.Theprotocolstipulatedthataseniormidwife,obstetricianandanaesthetistshouldattend

themother’sbedsidewhenbloodlossreached1000mL.At1500mLbloodloss,empiricalfixed-ratio

bloodproducttransfusionwasstartedbasedondataderivedfromtraumastudies.Thegroupnoted

thatPPHprogressedinfewerwomen,thenumberofbloodproductsusedfellandfewerwomen

9

developedcoagulopathy.19TheprotocolwasrolledoutacrossaregionbytheCaliforniaMaternal

QualityCareCollaborative(CMQCC)withsimilarresults.20Asimilarqualityimprovementprogramme

wasinitiatedbyTheAssociationofWomen’sHealth,ObstetricandNeonatalNurses(AWHONN).

BothCMQCCandAWHONNhaveextensiveinformationavailableontheirwebsites

(http://www.awhonn.org/?page=PPHandhttps://www.cmqcc.org/resources-tool-kits/toolkits/ob-

hemorrhage-toolkit).

Theseinitiativesoverlappedwithourexperiencesintermsofriskassessment,measuredbloodloss

andearlyescalationofobstetriccarebyseniorclinicians.Themaindifferencewastheapproachto

bloodproductreplacement,liberalfixed-ratioinfusionofbloodproductsbasedondataderivedfrom

trauma19;20versusVE-POCTstotargethaemostatictherapybasedonourprogrammeofresearch.It

isnotknownwhichoftheseapproachesresultsinbetteroutcomesandclinicaltrialsspecifically

addressingthevalueofVE-POCTsarerequiredtoaddressthis.

Understandingtheimpactofpointofcaretestsofcoagulationinpostpartumhaemorrhage

DuringOBS-2Rotem-guidedbloodproductreplacementwasintroducedintoroutinepracticeatour

centreforallpatients..Asexperienceincreasedandcliniciansacceptedtheresultsasclinically

reliable,managementofPPHchanged.IfearlyinthebleedtheRotemresultswerenormal,the

bleedingmustbeduetoaphysicalcause(atony,traumaorretainedplacentaltissue)andnot

coagulopathy.Thisknowledgefacilitatedearlytargetedescalationofobstetriccareand,ifnecessary,

involvementofamoreexperiencedcolleague.Ifcoagulationwasabnormalearlyinthebleedthe

motherwasimmediatelyidentifiedashighrisk.Earlycoagulopathyinsuchcasesraisessuspicionof

delayedresuscitation,placentalabruptionoramnioticfluidembolus.Themotherrequiredurgent

treatmentforcoagulopathy,almostalwayswithfibrinogenreplacement,andescalationofobstetric

managementtoaddresstheunderlyingcauseofbleeding.Thisbinaryclassificationhelpedtheteam

focusonthemostimportantclinicalproblemandourimpressionwasthatVE-POCTsfacilitated

behaviouralchangeofthemultidisciplinaryteam.

ANationalInstituteforHealthandCareExcellencereviewofVE-POCTduringPPHfocusedonlyon

bloodandbloodproductusage(https://www.nice.org.uk/guidance/dg13).Ourexperienceisthat

VE-POCTscanactasatriggeraroundwhichcarecanbestructuredbyencouragingcliniciansto

attendthebedsideearly.TheVE-POCTresultsinfluencedecisionmakingand,ifnormal,allowthe

obstetriciantofocusonmanagingtheobstetriccauseofbleedingwhiletheanaesthetist

10

concentratesonappropriateresuscitationandbloodproductreplacement.Ourobservation,

supportedbythefindingsfromOBS-2andotherretrospectiveobservationalstudies,27;28;39;40;44isthat

inthesmallnumberofwomenwhoareidentifiedashavingafibrinogen<2g/LorFibtemA5<12mm,

rapidcorrectionofhypofibrinogenaemiawithfibrinogenconcentrateimproveshaemostasisandis

advantageous,althoughlargeprospectivetrialsareneededtoverifythesefindings.

Localqualityimprovementinitiatives

Improvedlocalclinicaloutcomesmaybeaconsequenceofmultipleinter-relatedfactors.These

includedriskassessmentofallwomen,cumulativemeasurementofbloodlossandensuringthatan

experiencedmidwife,obstetricianandanaesthetistattendthemotherat1000mLbloodlosswith

ROTEMassessmentofcoagulationforallwomenweathertheywereenrolledintotheOBS-2study

ornot.Wedonotknowwhichoneoftheseinterventionsimprovesoutcomesanditislikelytobea

combinationofallofthesefactors.Overaoneyearperiod(2017,18monthsafterfinishingtheOBS

2trial)inourtertiaryreferralcentre,2.8/1000womenhadaPPH>2500mL,abloodtransfusionof≥5

unitsRBCorreceivedFFP.WhencomparedwiththepublisheddatafromHealthcareImprovement

Scotland,whereanoverallrateof6/1000wasreported,ourresultsfallbelow3standarddeviations

fromthemean.2WearecurrentlyseekingtoreplicatetheseimprovementsacrossWales.

AllWalesqualityimprovementprogramme:OBSCymru(ObstetricBleedingStrategyforWales

(Cymru))

OBSCymru(http://www.1000livesplus.wales.nhs.uk/obs-cymru)isaregisteredqualityimprovement

initiativethataimstoreducematernalmorbidityduetoPPHacrossWales.Waleshasapopulation

of3.1millionanddelivers30,000womenayearin12consultantledunits(CLU),withbetween500-

6000deliveriesperannumineachCLU.TheprojectaimstoreduceratesofmajorPPHandblood

transfusion,level3ICUcareandhysterectomyduetoPPH.

TheOBSCymruintervention

ThekeytoOBSCymruistolimitthenumberofmoderatebleedsthatprogresstosevere

haemorrhageandsoreducematernalmorbidity.Theprojectfocusedon4keyelementswhichdraw

onthequalityimprovementworkfromothergroups19;20andthelessonslearntfromourresearch

programme.

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1. Riskassessmentofallwomen:potentialriskfactorsforPPHareflaggedonadmissionto

deliverysuiteandwithon-goingriskassessmentduringlabour.

2. Cumulativegravimetricmeasurementofbloodlossaftereverydelivery:tofacilitate

escalationofcarewithspecificactionsrequiredat500,1000and1500mLbloodloss.

3. Multidisciplinarycarewithaseniormidwife,obstetricianandanaesthetistattendingthe

bedsideat1000mLbloodloss.

4. Rotem-guidedbloodproductreplacementusinganalgorithmderivedfromtheresultsof

OBS-2.

Thesethemesareembeddedintoclinicalpracticeusinganumberofinterventionsandtools

(availableathttp://www.1000livesplus.wales.nhs.uk/obs-cymru).APPHproformadescribingan

escalating4-stageapproachwasdevelopedandisplacedinallmothers’notesonadmissionto

deliverysuite.(Specificpaperworkwhichdescribesallactionsandinterventionswhichshouldoccur

asPPHprogressesandalsoactsasatemplateforscribingtheevents).

• Stage0:riskassessmentforallwomeninlabour(onadmissionandaslabourprogresses).

• Stage1:at>500mLafteravaginalbirthaseniormidwifeisinformed,thecauseofbleeding

assessedandinitialtreatmentinstituted.

• Stage2:at>1000mLaseniormidwife,obstetricianandanaesthetistattendthebedsideto

assessandescalatemanagementasappropriate.SamplesforRotem,bedsidelactateand

haemoglobin,FBCandcoagulationscreenaretakenandtranexamicacidisgiven.

• Stage3:at>1500mLwithon-goingbleedingtheconsultantobstetricianandanaesthetistare

informed.ThemajorobstetrichaemorrhageprotocolisactivatedandRotem-guidedblood

productreplacementinstitutedwhilstmedicalandsurgicaltreatmentsarecontinued.

ThisisacomplexinterventionandsoitsimpactisbeingassessedaccordingtoMedicalResearch

Councilguidance.51Thestep-wiseinterventionshavebeenincorporatedintoanallWalesPPH

guideline

(http://www.wisdom.wales.nhs.uk/sitesplus/documents/1183/Post%20Partum%20Haemorrhage_M

aternity%20Network%20Wales%20All%20Wales%20Guidelines_2017.pdf)andisbasedontheRoyal

CollegeofObstetricsandGynaecology(RCOG)green-topguidance8andincorporatingtheOBSCymru

approach.

DataarecollectedprospectivelyonallPPHs>1000mlinWalestobecomparedwithretrospective

datacollectedfromtheunits.ItistooearlytoassesswhetherkeymarkersofseverePPHare

changing;thisinformationwillbereportedatthecompletionoftheprojectin2019.

12

OBSCymruRotemguidedalgorithm

TheOBSCymruRotem-guidedbloodproductalgorithmisshowninfigure5http://www.oaa-

anaes.ac.uk/assets/_managed/cms/files/Guidelines/ROTEM%20Protocol.pdf.At1000mLbloodloss

withongoingbleedingFibtemA5andExtemCT,bedsidevenouslactateandhaemoglobinare

performedandFBCandcoagulationsenttothelaboratory.Intravenoustranexamicacidisgiven.The

WOMANtrialshowedthattranexamicacid,givenwithin3hoursofdelivery,reduceddeathdueto

bleedingwithoutanincreaseinthromboticorotheradverseevents,52ouralgorithmtherefore

infusestranexamicacidassoonasPPHisrecognisedoratthelatest1000mL.Therationaleforearly

Rotemtestingisnotonlytorapidlyidentifythesmallnumberofwomenwhoneedhaemostatic

support,buttoreassuretheobstetricianthatcoagulationisnormalandfocustreatmentonobstetric

causesofbleeding.Haemostaticbloodproductreplacementinitiallyfocusesonfibrinogen.IfFibtem

A5is≤12mmorClaussfibrinogen<2g/L,fibrinogenconcentrateisgiven.Fibrinogenconcentrateis

notlicensedforthisindicationintheUKandanalternative,asrecommendedbyRCOG,istoinfuse

cryoprecipitate.8TherecommendationsonfibrinogenreplacementarebasedondatafromOBS-2

andtheLiverpoolPPHalgorithm.39;40;44Thetargetistomaintainthefibrinogen>2g/Lwhichis

supportedinthe2016RCOGguideline.8;9IftheExtemCTisprolongedabovethenormalrange(75

secbasedonlocalvalidation)orthePT/aPTTisabovethenormalrange,afterfibrinogen

replacement,15ml/kgFFPisinfusedbasedonRCOGguidanceandOBS-2data.8;44Plateletsare

transfusedif<75x109/LbasedonRCOGguidance.8Becausecoagulopathycanevolverapidlyduring

PPHwerepeatRotemandlaboratorytestingevery500mLorevery30minutesduringongoing

bleeding,oratanytimeforclinicalconcern.Testsarerepeatedafterbloodproductsaregivento

assessresponse.

TheFuture–questionstobeaddressed.

TheroleofVE-POCTsinthemanagementofPPHremainsdebated53;54anddefinitiveevidenceis

lacking.Wehypothesisethatitisthecombinedeffectoftheearlyrecognitionofbleedingtriggering

timelyinterventionsincorporatingVE-POCTsandamanagementstrategyinvolvingthewhole

multidisciplinaryteamthatiskeytopreventingprogressionofPPHandminimisingmorbidity.A

studycomparingsuchanapproachutilisingearlyVE-POCT,withacceptedstandardcarebasedon

laboratorytestsofcoagulationisnownecessaryalthoughthiswouldnecessitatelargemulti-centre

studies.Itmayalsobepossibletopartiallyaddresssomeofthesequestionsbyspecificallystudying

highrisksurgicalproceduressuchaswomenhavingaCaesareansectionforplacentapreviaor

womenwhopresentwithabruption.

13

Dataonthecosteffectivenessofsuchanapproachisimportantifthisistobeusedmoregenerally

withinavarietyofhealthcaresettings.Wesuggestthatqualitativeassessmentoftheimpactofthe

interventiononteamdynamicsandbehaviourshouldalsobestudied.Amultinationalgroupof

interestedresearchersmayberequiredtoaddresstheseissues.

Funding

Thisreviewwaspreparedwithoutexternalfundingsupport.

Acknowledgements

Theauthorsthankthewomenwhohaveagreedtotakepartinthestudiesdescribedandthe

midwives,anaesthetistsandobstetricianswhohavehelptoenrolthesubjects.Theroleofeveryone

involvedinOBSCymruisgratefullyacknowledged.

Declarationsofinterest

PWChasreceivedresearchsupportfromCSLBehring,Werfen/TemInternationalandHaemonetics.

HehasactedasapaidconsultanttoCSLBehringandWerfen/TemInternational.

SFBhasreceivedsupportforqualityimprovementinitiativesfromWerfen/TemInternationaland

WelshGovernment.

LdeLhasreceivedresearchsupportfromWerfen/TemInternationalandHaemonetics.

REChasreceivedresearchsupportfromCSLBehring,Werfen/TemInternationalandHaemonetics.

ShehasreceivedsupportforqualityimprovementinitiativesfromWerfen/TemInternationaland

WelshGovernment.ShehasactedasapaidconsultanttoCSLBehringandWerfen/Tem

International.

14

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Table1:

Studiesinvestigatingtheassociationbetweenfibrinogenandprogressionofpostpartumhaemorrhage

Study N Studydesign Fibrinogeng/L Timeof

fibrinogenassayOutcomedefiningprogressionof

PPH

Descriptivestatisticreported

Noprogression

ofPPH

ProgressionofPPH

ROCAUC

(95%CI)Charbit31 129 Infusionof

uterotonicaftermanualexploration

ofuterus

Invasiveproceduretocontrolbleeding,fallinHb≥4g/Lor

≥4unitsRBC

Median(IQR)

4.4(3.7-5.1 3.3(2.5–4.2)

0.75(CInotreported)P<0.0001

Cortet32 738 DiagnosisofPPH Invasiveproceduretocontrolbleeding,fallinHb≥4g/L,≥4

unitsRBCoradmissiontooITU

Mean(SD) 4.2(1.2) 3.4(0.9) 0.66(0.64-0.68)

Poujade55 98 Variabletimebeforeembolisation

Successofradiologicalembolisation

Mean(SD) 2.9(1.3) 1.8(0.9) NR

Gayat34 257 Variabletimebeforeprocedure

Invasiveproceduretocontrolbleeding

Median(IQR) 2.7(2.1-3.5) 1.8(1.1-2.5) 0.83(±0.03)*

deLloyd33 240 Firstclinicalconcern

duringPPH≥2500mLbloodloss Mean(SD) 4.4(1.1)

3.1(1.0) 0.85

(0.78-0.93)Collins14 346 1000-1500mLblood

lossTransfusionof≥8unitsallogeneicbloodproducts

Median(IQR) 3.9(3.2-4.5) 2.1(1.8-3.4) 0.82(0.72-0.92)

Simon35 797 Beforebleedingstarted

PPHrequiringmanualuterineexploration,RBC

transfusionorfallinHb≥2g/L

Mean(SD) 4.9(1.0) 4.3(1.3) NR

StudiesareshownwhichinvestigatedtheassociationofClaussfibrinogen,takenearlyduringapostpartumhaemorrhageorbeforebleedingstarted,withprogressionofbleeding.VariablestudydesignswereemployedbutinallcasesalowClaussfibrinogenwasassociatedwithastatisticallysignificantlyincreasedriskofprogression.Thisdemonstratesthatfibrinogenlevelisausefulbiomarkerforpredictingprogressionofpostpartumhaemorrhage,however,dothetimerequiredtoobtainaresultit’sclinicalutilityislimited.NRnotreported,CIconfidenceinterval,ROCreceiveroperatingcharacteristicscurve,IQRinter-quartilerangeandSDstandarddeviation.*,inthisstudytheROCreferstoacompositepredictivetoolcombiningfibrinogen<2g/l,abnormalplacentalimplantation,PTratio<50%,heartrate>115beatsperminute,troponinraised.

20

Legendsforfigures

Figure1:StudydesignforOBS-1

Figure2:

Theproportionofwomenprogressingto>2500mLbloodloss(red),redbloodcelltransfusion(dark

blue),atleast4unitsredbloodcelltransfusion(lightblue)oraninvasiveproceduretocontrolthe

bleed(green)dependentonClaussfibrinogen(Fig2a)orFibtemA5(Fig2b)takenat1000-1500

bloodlossisshown.DataarederivedfromtheOBS1study.

Figure3:Rotemguidedbloodproductalgorithms

Figure2ashowthestudydesignandbloodproductalgorithmusedforwomenrecruitedintoOBS-2.

Figure2bshowsthebloodproductalgorithmusedforwomenwhowerenotenrolled.

Figure4:ChangesintransfusionpracticeacrosstimeinCardiff

Figure4ashowsthenumberofunitsofredbloodcells(RBC)(grey)andfreshfrozenplasma(FFP)

(black)transfusedforeachyearbetween2010and2017.TheOBS2studywasassociatedwitha

reductioninRBCandFFPtransfusionwhichincreasedafterthestudyfinishedandfellagainonce

OBSCymruwasinitiated.Figure4bshowsdataforthenumberofwomenwhoreceivedatleast5

unitsofRBC,representingasubgroupofveryseverepostpartumhaemorrhage.Asimilartemporal

trendwasobserved.

Figure5:OBSCyrmubloodproductalgorithm.

Studyentry1000mLPPHmeasuredorsuspected

PerformFibtem,APPT,PT,Claussfibrinogen,Hb

Fibtemperformedoutsideclinicalareasoclinicianswereblindedtoresults

AllusualObstetricinterventions

OrderbloodandbloodproductsifPPH>1500mL

Reacttolaboratoryresultsastheybecameavailable

Figure1

0102030405060708090100

<2g/L 2-3g/L 3-4g/L >4g/L

%ofw

omen

Concentrationoffibrinogen

>2500mLbloodloss

TransfusedanyRBC

Transfused≥4unitsRBC

Invasiveprocedure

Figure2b Figure2a

Figure3a

Figure3b

Figure4b Figure4a