Hemorrhage After Manual Removal ofthe Placenta: Weighing Risk Factors

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Citation Perlman, Nicola. 2018. Hemorrhage After Manual Removal of thePlacenta: Weighing Risk Factors and the Role of the Third Stage ofLabor. Doctoral dissertation, Harvard Medical School.

Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:36923348

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Abstract:Introduction:Manualremovaloftheplacenta,oftenduetouterineatonyoranabnormallyadherentplacenta,canbeaccompaniedbyseverematernalpostpartumhemorrhage.Theobjectiveofthisstudywastoidentifyriskfactorsforpostpartumhemorrhagethatwouldallowtriagingofmostmorbidpatientspriortomanualremoval.Methods:ThiswasaretrospectivecasecontrolstudyofpatientswhohadundergonemanualremovaloftheplacentaaftervaginaldeliveryatBrighamandWomen’sHospitalbetweenJanuary1,2007andMay29,2015.Weevaluatedriskfactorsforpostpartumhemorrhageindependentlyandbypresumedcausativerole.Causativegroups(andriskfactors)includedAtony(multiplegestation,prolongedsecondstageoflabor,birthweight>4000g,parity>4,orBMI>40kg/m2),AbnormalPlacentation(>2priorD&Es,suspicionforaccretaonultrasound,ART,age>40years,priorcesarean,prioraccreta,priorretainedplacenta,prioruterinesurgery,resolvedlowlyingplacenta,orAshermanssyndrome),orOtherPostpartumHemorrhageRiskFactors(preeclampsia,acuteabruption,fibroids>6cm,orpretermdelivery).Riskfactorswerealsoclassifiedaseithermajor(concernforaccretaonultrasoundorsignsofabruptionatadmission)orminor(anyothervariable),andweanalyzedwhetheranyonemajorortwominorriskfactors,regardlessofcausativegrouping,wereassociatedwithpostpartumhemorrhageaftermanualremoval.Lengthofthirdstageoflaborwasanalyzedinrelationtopatientcharacteristics.Allsignificantvariableswereputintoamultivariableanalysistotestforconfounding.Results:Ofthe997womenidentifiedwithmanualremovaloftheplacentaduringourstudyperiod,172experiencedseverepostpartumhemorrhageandwereone-to-onematchedwithcontrolswithouthemorrhage.CasepatientsweremorelikelythancontrolstohaveanyoneriskfactorineithertheAtony(49%vs.37%respectively,p=0.01)orAbnormalPlacentationriskgroup(58%vs.38%,respectively,p<0.01)andadditionallyweremorelikelytohaveanyonemajorortwominorriskfactors(51%vs.26%controls;p>0.01).Postpartumhemorrhagepatientshadmanualremovaloftheplacentalaterinthethirdstageoflabor(p<0.01).Characteristicsassociatedwithrapidmanualremovaloftheplacentawithin30minutesafterdeliveryoftheinfantincludedcordavulsionandepiduralanalgesia(p<0.01),whereaschorioamnionitiswasassociatedwithdelayuntilmanualremoval(p=0.03).Increasinglengthofthirdstageofdeliveryshowedstrongassociationwithpostpartumhemorrhageinourmultivariateanalysis,alongwithriskfactorsforabnormalplacentation.Thoughsignificantintheunivariateanalysis,chorioamnionitis,ariskfactorforuterineatony,showednoassociationwithpostpartumhemorrhageaftercontrollingforotherfactorsinourmultivariableregression.Conclusion:Patientswithconcernforuterineatonyshouldhaverapidremovaloftheplacenta,regardlessofchorioamnionitisandepiduralanalgesia,inordertominimizeriskofpostpartumhemorrhage.Patientswithriskfactorsforabnormalplacentationorplacentaaccretamaynothaveriskofhemorrhagemitigatedbyrapidmanualdelivery.

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TableofContents:Contents: PageAbstract 2Glossary 4Introduction 5Methods 12Results 16Discussion 19Summary 24References 26Tables 29Figures 35

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GlossarylistingabbreviationsthatappearinyourthesisMROP:ManualremovaloftheplacentaPPH:PostpartumHemorrhageACOG:AmericanCollegeofObstetriciansandGynecologistsMAP:MorbidlyadherentplacentaDilationandCurettage:D&CDilationandEvacuation:D&EBodyMassIndex:BMIInVitroFertilization:IVFAssistedReproductiveTechnology:ART

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Introduction:

Postpartumhemorrhage(PPH),occurringinapproximately2-6%ofdeliveries,isamajor

causeofmaternalmortalityworldwide.(1-4)Inthelasttwodecades,therehasbeenan

observedincreaseinpostpartumhemorrhage,whichcurrentlyaccountsforoneofthe

mostcommonreasonsformaternalintensivecareunitadmission.(1,3)

Uterineatonyandretainedplacenta(includingplacentaaccreta)arethetwoleadingcauses

ofpostpartumhemorrhage.(1,3-6)Bothetiologiescanalsobeindicationsformanual

removaloftheplacenta(MROP),whichcanbefollowedbyseverebleeding.(1)While

studieshaveexaminedriskfactorsforPPH,rarelyhaveriskfactorsspecifictomanual

removalbeenproposed.Triagingpatientsaccordingtohemorrhageriskwithmanual

removaloftheplacentamayallowphysicianstoproactivelyavoidormanagethismorbid

complication.

Postpartumhemorrhage:

Postpartumhemorrhageisawidelyrecognizedcauseofmaternalmorbidityand

mortality.(4,7)AsoneoftheleadingcausesofIntensiveCareUnitadmissionfollowing

deliveryintheUnitedStates,thereisgreatinterestinexaminingriskfactorsandmethods

topreventmorbidityfromPPH.(7-10)ThetrendisparticularlyprescientintheUnited

States,butotherdevelopedcountrieshaveseenasimilarlyriseinPPH,notexplainedby

temporalchangesinriskfactors.(11,12)Andwhileevenindevelopedcountrieswith

resourcesandadequatepersonneltheriskofmorbidityfrommaternalhemorrhageishigh,

givingbirthindevelopingcountriesposesastaggeringriskofdeathduetocomplications.

Somereportscitematernalmorbidityratios(maternaldeathsper100,000livebirths)to

beashighasoneinsixforAfghanistanandSierraLeone,versusalowestestimateofonein

30,000inSweden.(13)

Theimportofpostpartumhemorrhageincontributingtomaternalmorbidityhascreateda

demandforbettersystemsforpredictingandtriagingmassivebloodlossatdelivery.(9)

Theepidemiologyofpostpartumhemorrhagehasbeenwellstudied.TheAmericanCollege

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ofObstetriciansandGynecologists(ACOG)warnsphysiciansintheirPracticeBulletinthat

primaryPPH,definedbytheCollegeasgreaterthan1000ccofbloodloss(arecentincrease

from500cc),occursin4-6%ofallpregnancies,citinga1991studybyCombsetalthatlists

PPHasaleadingcauseofmaternalmorbidityworldwide.(1,4)ResearchbyCallaghanetal

hasnotablyemphasizedthatwhilePPHisincreasing,maternaldeathfromPPHis

decreasingduetoincreasedratesoftransfusionandperipartumhysterectomy.(14-16)

However,whiledeathduringlaborhospitalizationhasdecreased,severematernal

morbidityhasinturnbecomeupto50timesmorecommon.(16)Itiswidelyrecognized

thatPPHisdueprimarilytopoorcontractionoftheuterus,oratony,followingdeliveryof

theinfant,andsecondarilytoretainedorabnormallyadherentplacentaduringthethird

stageoflabor.(1,4)Otherrecognizedcausesincludeinheritedoracquiredcoagulopathies,

andobstetricalcomplications—suchascervicallacerationsepisiotomies,anduterine

inversion.(4)

InordertoeffectivelyandefficientlytreatseverePPH,hospitalsandhealthcaresystems

areseekingtodevelopnovelwaystotriageandprepareforthisadverseoutcome.(4,17)

Riskscoresandalgorithmsarebecomingincreasinglycommonplace,andoftenemploya

multidisciplinaryteamincludingobstetricians,anesthesiologists,nursing,andpossibly

surgicalorradiologicsubspecialists.Riskpredictionmaybeparticularlyusefulinsettings

wheretreatmentmusthappenquicklyandinvolvesmanyteammembersandtreatment

modalities.Forinstance,whenapatientrequiresmanualextractionoftheplacentawith

subsequenttransfertotheoperatingroomwithseverepostpartumhemorrhage,setupof

cross-matchedbloodandsurgicalequipment,andearlynotificationofamultidisciplinary

hemorrhageteamwouldbeuseful.

VaginalDeliverywithManualExtractionofthePlacenta:

Manualremovaloftheplacenta,ormanuallycreatingacleavageplanebetweenthe

placentaandtheuterus,isgenerallyperformedinabsenceofdeliveryoftheplacenta

duringthethirdstageoflabor,andtypicallyafterothermanagementoptions(oxytocin,

uterinemassage,andcordtraction)havebeenexhausted.

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Accordingtotheliterature,retainedplacentarequiringmanualremovalisgenerally

assumedtobedueto(1)anatonicuteruswithpoorcontractiondisallowingnormal

contractileexpulsionoftheplacenta,(2)abnormalplacentationoraccreta,inwhichthe

placentahasinvadedintothematernalmyometrium,or(3)trappedorincarcerated

placenta,inwhichthecervixhasclosedpriortodeliveryoftheplacenta.(5,18)

Normalplacentationbeginswithblastocystimplantationintothematernalendometrium.

Inpreparationforthisimplantation,theendometriumdevelopsthedeciduaunderthe

influenceofprogesteroneandestrogenofearlypregnancy.Astheblastocystinvadesthis

decidua,thelayerofcellsformingthesurfaceoftheblastocystdevelopsintothechorionic

membrane.Cytotrophoblastcellsproliferatefromthechorionicmembraneandform

multinucleatedaggregatescalledsyncytiotrophoblastcells.Thesecellsformtheplacental

villi,withcytotrophoblastsatthecoreandsyncytiotrophoblastsformingtheepithelial

outerlayer,allowingfetal-maternalinterchangebetweenthevilli-decidualinteraction.

Afterthesecondstageoflabor,withdeliveryoftheinfant,bothahormonalcascadeaswell

asuterinecontractionsallowforseparationoftheselayersandexpulsionoftheplacenta.

Ifanypartofthisprocessisdisruptedthentheplacentamaynotdeliverspontaneouslyand

couldberetained.Forinstance,ifplacentalvillihaveinvadedbeyondthedeciduaandinto

thematernalmyometriumcausingadherentplacentaduetothisabnormalplacentation,

theplacentawillnotdetachinthethirdstage.Alternatively,inthesettingofpooruterine

contractionsduetoatony,theplacentamaynotbesubjecttoexpulsiveforcesrequiredfor

delivery.

Indevelopedcountries,retainedplacentaaffectsaround3%ofallvaginaldeliveries.(5,19).

RiskfactorsforretainedplacentarequiringMROPwereelucidatedbyEndlerand

colleaguesina2012casecontrolstudy.(20)Theauthorsshowedthattheseindependent

riskfactorsincludedpriorretainedplacenta,pretermdelivery,prolongeduseofoxytocin,

preeclampsia,twoormorepriormiscarriages,andoneormorepriorabortions.(20)The

authorsalsoshowedthatMROPwassignificantlyassociatedwithPPH.(20)Inafollowup

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studyEndleretalconfirmedtheseriskfactorsusingalargenationalregistrydatabaseas

cohort.(21)Theirfindingsshowedaparticularlystrongrelationshipbetweenpreeclampsia

andretainedplacenta,leadingtheauthorstohypothesizethatdisordersofplacentation

maybepositivelyassociatedwithMROP.(21)

Aprolongedthirdstageoflabor,ortimebetweendeliveryoftheinfantanddeliveryofthe

placenta,isalsorecognizedasasignificantriskfactorforpostpartumhemorrhage,and

studieshaveshownthatreducingthelengthofthirdstageoflaborviamanualextractionof

theplacentareducestheriskofpostpartumhemorrhage.(22-24)Inordertominimizethis

risk,failureofdeliveryoftheplacentainatimelymanneristhereforeacommonindication

forMROP.

IntheUS,however,thereisnooneguidelineformanagingMROP.(25)WhileACOG

recognizestheincreasedriskofPPHwithalongthirdstageoflaborandthusrecommends

activemanagement(withoxytocin,cordtraction,andmaternalefforttoexpelplacenta),

theydonotsuggestafirmtimelineformanualremoval.(4)Whilemajorityofplacentasare

spontaneouslyexpelledwellbefore30minutes,mostofthesparseliteratureonMROP

suggestsremovalinabsenceofspontaneousdeliveryatthistime.(5,25)

EventhoughthegeneralconsensusisthatMROPshouldbeattemptedinabsenceof

spontaneousdeliveryoftheplacentawithin30minutesofdeliveryoftheinfantorearlier

inthepresenceofPPH,thereislittledatatosupportthisguideline.(5,19)Inastudyby

Deneux-Tharauxetal,surveysfrom14Europeancountriesexhibitedwidevariationsin

waittimepriortoMROP,largelybycountrybutalsobyhospital.(19)Incountriessuchas

FinlandandDenmark,obstetricianstendedtowait60minutesormorepriortoMROP,

versusincountriessuchasSpainandFrance,whereprovidersremovedtheplacentaafter

30minutes.(19)Practicesalsovariedconsiderablydependingonwhetherornotthe

patientinquestionhadpriorepiduralanesthesia.(19)Similarly,theNationalInstitutefor

HealthandClinicalExcellence(NICE)suggestsawaittimeof30minutesintheUnited

KingdompriortoMROP,(26)whiletheWorldHealthOrganizationguidelinesproposea

waittimeof60minutes.(13)

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Ina1991studybyCombsetal,authorstriedtodefinehowdurationofthirdstageis

relatedtocomplications.(25)Inthestudytheyfoundthatthethirdstagehadalognormal

distribution,withameanlengthof6.8minutes,withonly3.3%ofdeliverieshavinggreater

agreaterthan30minutethirdstage.Interestingly,theauthorscalculatedthatthe

incidenceofPPH,transfusion,anddilationandcurettageremainedconstantduringthis

period,increasingonlyafter30minutesandplateauingat75minutesforbothmanually-

andspontaneously-deliveredplacentas.BecausePPHincidencedidnotincreaseuntilafter

30minutes,CombsetalrecommendedthistimingasguidanceforwhentoinitiateMROP.

AsubsequentstudybyDombrowskietalin1995triedtodeterminegestationalagespecific

dataforlengthofthirdstage,retainedplacenta,hemorrhage,andmanualremoval.(27)The

authorsfoundthatbothMROPandPPHdecreasedwithincreasinggestationalage,andthat

thetwowererelated.However,causalassociationcouldnotbedetermined.Alternatively,

whilenotstudyingmanualremovalperse,Rogersetal,in1998,foundthatactive

managementofthethirdstageresultedinsignificantlyreducedriskofPPH.(22)

LaterstudiesbyMagannetalsoughttostrengthentherelationshipbetweenlengthofthird

stageandPPH.In2005,Magannandcolleaguesundertookaprospectiveobservational

studyinwhichallwomendeliveringvaginallywereassessedforPPH.(24)Usingreceiver

operatingcharacteristiccurves,theauthorsshowedthatathirdstageoflaborlongerthan

18minuteswasassociatedwithasignificantriskofPPH.(24)Theauthorsfollowedupthis

paperin2012witharandomizedcontrolledtrialassigningvaginaldeliveriestomanual

removalateither10or15minutes(asopposedtothetraditional30)iftheplacentahad

notyetspontaneouslydelivered.(23)Thefindingssupportedtheauthors’initialstudy,

showingthatremovalat15minuteshadasignificantlygreaterlikelihoodofhemorrhage

comparedto10minutes,augmentingthediscussionofMROP’sappropriatetiming,and

indications.(23)

Intheir2014review,Urneretalemphasizethatguidelinesformanagementofretained

placentarequiringMROPdonotexist,asidefrompoorlydefinedtimelinesfor

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intervention.(5)TheauthorscitesimilarriskfactorsasthosestudiedbyEndleretal,and

additionallylistriskfactorsforinvasiveplacentaincludingpriorcesareansectionand

uterinesurgery.(5)Urnerandcolleaguessuggestthatroutinemanagementofretained

placentashouldinclude(inadditiontoMROPat30minutes)ultrasoundandamulti-

specialistteamapproach,aswellasfuturedevelopmentofstrictguidelinesforthethird

stageinordertoreducecomplicationssuchasseverePPH.(5)Corvielloetal,usingalarge

retrospectivecohortfromtheUnitedStates,echoedtheaboveriskfactors,particularly

stressingstillbirthasanindependentriskfactor,andproposingthatsomeintrinsic

pathophysiologyofintrauterinefetaldemiseleadstoincreasedriskofretained

placenta.(28)Titizandcolleaguessupportthesefindingsinalargecohortfrom

Australia.(2)

Whileabnormalplacentation,suchasaccreta,incretaorpercreta,isaknownsignificant

riskfactorforadherentplacentaatcesareansection,verylittlehasbeenwrittenonits

contributiontoretainedplacentaatvaginaldelivery.Thisconditionisbestunderstoodin

thesettingofplacentapreviawithpriorcesarean.(29,30)Inthisclinicalscenario,itis

recognizedthatlowlyingplacentaoverlyingauterinescarandprioruterinesurgeryare

majorriskfactorsforhemorrhagemorbidityatcesareandelivery.Becauseofit’s

associationwithlowlyingplacentaandcesarean,radiographicevidenceandclinical

suspicionforaccretaareoftenlackinginpatientswhopresentwithoutplacentaprevia,

whichincludesallpatientsundergoingavaginaldelivery.

Interestingly,ina2017paperbyBjurstrometal,theauthorsreportsixcasesoffailed

manualremovalatvaginaldeliveryduetoclinicallyadherentplacenta—referredtoas

morbidlyadherentplacenta,orMAP—onlyoneofwhichhadhistopathologicevidenceof

accreta.(31)Additionallyin2017,Roecaetalreported339patientswhocompleteda

pregnancywithpathologicallydiagnosedplacentaaccretawithouthysterectomywith39

returningforsubsequentpregnancy.(32)Ofthe39returningpatients,16underwent

manualremovaloftheplacenta.ThissuggeststhatthecontributionofaccretatoMROP

maybeunderrecognized.

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Themechanismsbehindandoutcomesofabnormallyadherentplacentaatvaginaldelivery

havenotbeenwellreported.Afewstudieshaveaddressedrelationshipsbetweenin

assistedreproductivetechnology(ART)andinvitrofertilization(IVF)anddisordersof

placentation,thoughitsrelationshiptoretainedplacentaandPPHhasnotbeenwell

defined.Firstreportedin2011,Esh-Broderetalshowedasignificantrelationshipbetween

IVFandplacentaaccreta,proposingenvironmentaldifferencesbetweentheendometrium

ofpatientsconceivingwithIVFandversusthosewithspontaneousconception.(33)In

2014,Ishiharaetalalsoconcludedviaretrospectiveanalysisthatcryopreservedblastocyst

transferwasassociatedwithbothaccretaandpregnancyinducedhypertension,though

theyhadlimitedabilitytocontrolforconfounding.(34)A2015studybyKaserand

colleaguesthat,aftercontrollingformultipleconfounders,cryopreservedembryotransfer

wassignificantlyassociatedwithplacentaaccreta,andproposedrelativelythinned

endometriumandlowerestradiollevelsaspotentialmechanisms.(3)

OthershaveevaluatedIVFwithrelationtothethirdstageoflabor.Elenisetal,ina2015

studyfromSweden,lookedspecificallyatoocytedonationIVFandtheriskofpoor

obstetricaloutcomesinotherwisehealthywomen.(35)Theauthorsfoundapositive

associationbetweenretainedplacentaandoocytedonation,aswellasbetweenPPHand

oocytedonation.(35)Finally,inarecent2016studybyAzizetal,seekingtodetermine

whetherornotlengthofthirdstagewasrelatedtoIVF,theauthorsconcludedthat

cryopreservedembryotransfer(donatedorautologous)withoutcontrolledovarian

hyperstimulationwasnotrelatedtolongerthirdstage,butdidsignificantlyincreasethe

riskforMROP.(36)

PurposeofInquiry:

WhileindividualriskfactorsforMROPhavebeenproposedandstudied,nostudyhas

determinedfactorsassociatedwithhemorrhagicmorbidityinthiscontext.Additionally,

becauseitismostlystudiedinthecontextofcesareanwithknownprevia,fewstudieshave

lookedatmorbidlyadherentplacentaandplacentaaccretariskfactors(particularly

resolvedlowlyingplacenta,prioruterinesurgery,historyofpreviousretainedplacenta,

priorcesareansection,andART)aspredictorsofPPHaftermanualextraction.Thegoalof

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thisstudywastodeterminepredictorsofprimary,severepostpartumhemorrhageafter

MROP,definedasanestimatedbloodloss(EBL)greaterthanorequalto1500ccoccurring

withinthefirst24hoursafterdelivery,needfortransfusion,greaterthanorequaltoa10

pointdropinhematocrit.(37)

Wehypothesizedthatonemajorriskfactorormultipleminorriskfactorsforpostpartum

hemorrhagewillincreaseriskofseverehemorrhageaftermanualextraction.Indefining

riskfactors,wegroupedvariablesaccordingtotheirassociationwithatony,invasive

placentation,orpostpartumhemorrhageintheabsenceoftheseotherfactors(other).Due

toworldwideincreaseduseofIVFandpathologicplacentaaccreta,andthepaucityof

researchconnectingthisproceduretothirdstageabnormalities,wewereparticularly

interestedinthisetiologyasariskfactorforPPH.(3)Wesecondarilyhypothesizedthat

patientswithriskfactorsforabnormalplacentationwouldshowthestrongestassociation

withPPH,basedontheseverityofthisconditionandlackoftimelyrecognitionand

managementatvaginaldelivery.

Elucidatingindependentriskfactorsforpostpartumhemorrhagewillallowobstetriciansto

betterprepareforandrecognizeseveremorbidityatvaginaldelivery,withthegoalof

reducingmaternalmorbidityandmortalityinbothdevelopedanddevelopingcountries.

Methods

Thisretrospectivecase-controlstudyhasbeenapprovedbyPartners/Brighamand

Women’sHospitalInstitutionalReviewBoard.Weusedbilling(ICD-9andCPT)codesin

ordertoidentifyallpatientswithvaginaldeliveriesbetweenJanuary1,2007andMay29,

2015whounderwentmanualremovaloftheplacenta(MROP).Thiswassupplemented

withdatafromourhospital’sofficialelectronicdeliveryrecord,whichcategorizesplacental

deliveriesas“manual”or“spontaneous.”Patientdatawascollectedfromelectronicand

papercharts.MROPwasdefinedasneedformanualcreationofaseparationplanebetween

uterusandplacentapostpartumforaneitherpartiallyorundeliveredplacenta.Two

authors(NPandDC)reviewedallchartstoconfirmmanualremoval.

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Whilepracticesvary,manualremovaloftheplacentaistypicallyattemptedifthepatient

hasnotdeliveredtheplacentawithin30minutes,ifadeliveredplacentaisvisually

incomplete,orifheavybleedingmandatesMROPsoonerthan30minutes.AtBrighamand

Women’sHospital,obstetriciansusetheirdiscretionindecidingwhentomanuallyextract

theplacenta.

Ourcasegroupincludedpatientsexperiencingseverehemorrhageaftermanualextraction.

Severepostpartumhemorrhagewasdefinedinthisstudyasestimatedbloodloss(EBL)

≥1500cc,hematocritdrop≥10percentagepoints,orbloodproducttransfusionforthe

indicationofhemorrhage.OurEBLdefinitionwasbasedontheliteratureshowingthat

patientswith>1500ccbloodlossexperiencethemostmorbidityandmortality

peripartum.(10)Ourcontrolgroupwasrandomlyselectedfromthosepatientswhodidnot

experienceseverepostpartumhemorrhage.Controlswereone-to-onematchedbasedon

yearofdeliveryinordertominimizebiasescausedbychangesinpracticeoverthecourse

ofthestudyperiod.Anypatientinthecohortwhodeliveredextramurally,priorto24

weeksgestationalage,orhaddelayedextractionoftheplacentaformorethan24hours

afterdeliverywasexcludedfromtheanalysis.

Wecollecteddetaileddemographic,medicalandhistoricaldataforeachsubject,including

age,bodymassindex(BMI)attheendofpregnancy,race,parity,numberofprior

spontaneousortherapeuticabortions(medicalorsurgical),priorhistoryofretained

placenta(placentarequiringmanualorsurgicalremovalinpriorpregnancy),andprior

historyofpathologically-confirmedplacentaaccreta.Surgicalhistoricalvariablesincluded

priorcesarean,dilationandcurettage(D&C)performedinthesettingofpregnancy

(spontaneousortherapeuticabortion,ortreatmentofpostpartumhemorrhageorretained

productsofconception),oruterinesurgicalprocedures(myomectomy,anyoperative

hysteroscopy,orendometrialablation).PriorD&Conanon-pregnantuterusoruterine

polypectomieswerenotconsidered.

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Alongwithdemographicsandhistoryabove,wecollectedcharacteristicsassociatedwith

currentpregnancy.TheseincludedconceptionachievedwithAssistedReproductive

Technology(ART;definedaseitherinvitrofertilizationorintracytoplasmicsperm

injection),multiplegestationinthecurrentpregnancy,aprolongedsecondstageoflabor

(timebetweenfullcervicaldilationof10cmanddeliveryoftheinfant),birthweightgreater

than4000g,signsofaccretaonultrasound(vascularlakes,lossofboundarybetween

placentaandmyometrium,absenceofsonolucentzone,orsignsofdeeperinvasionsuchas

percreta),resolvedlowlyingplacenta(definedasaplacentathathadcomewithin2cmor

coveredthecervicalosduringpregnancyviaultrasonographyrecords),Asherman

syndromeoruterinesynechiae(intrauterineadhesionsorbandsasindicatedby

ultrasound,hysteroscopy,orasnotedbypatient’sproviderinprenatalrecords),

preeclampsia(asindicatedbypatient’sproviderinprenatalrecords),acuteplacental

abruption(asmentionedbythepatientsprovider,orbyabnormallyheavybleedingat

presentation),fibroidsgreaterthan6cmonpregnancyultrasound,andgestationalage

(withpretermdeliverydefinedasdeliverypriorto37weeksgestationalage).

Wealsocollectedlaborvariablesofpresentpregnancyincludingoperativevaginaldelivery

(vacuumassistedorforcepsassistedvaginaldelivery)lowergenitaltractlaceration,degree

ofperineallaceration(asindicatedbyproviderinelectronicdeliveryrecord),episiotomy,

cordavulsion(completeseparationoftheumbilicalcordpriortodeliveryofplacenta,as

notedbydeliveryprovider),andchorioamnionitis(fevergreaterthan100.4Ftreatedwith

antibioticsduringfirstorsecondstageoflabor).

Pregnancyoutcomesandinterventionscollectedincludedatony(providernotedatonyin

chartorusedgreaterthanorequaltotwouterotonics—misoprostol,methylergonovine,

prostaglandinF-2α,oroxytocin),clinicalaccreta(providerreportedsuspectedclinical

accretaornotedabnormaladherenceoftheplacentatotheuterinewallwithunusually

difficultseparation),uterineinversion,hysterectomy,intrauterineballoonplacement,

uterinearteryembolization,needfordilationandcurettageincurrentpregnancy,intensive

careunitadmission,postpartumreadmission,andanypathologicaccretadiagnosis

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(definedasplacentalfibersadherenttothemyometriumwithabsentinterveningdecidua,

asindicatedbythepathologist).

Weanalyzedriskfactorsforhemorrhageaftermanualdeliverybothindividuallyand

groupedbasedontheirpresumedcausativeroleinPPHassociatedwithMROP.Thefirst

groupincludedvariablesassociatedwithatony,includingbirthweightgreaterthan4000g,

morbidobesity(BMIgreaterthan40kg/m2),chorioamnionitis,multiplegestations,high

parity(greaterthan4)andprolongedsecondstageoflabor(greaterthantwohours).The

nextgroupincludedvariablesassociatedwithabnormalplacentationorplacentaaccreta,

includingpreviouscesareandelivery,prioruterinesurgery,resolvedpreviaorlowlying

placentainthecurrentpregnancy,Ashermansyndromeoruterinesynechiae,historyof

pathologicaccreta,conceptionachievedviaART,ormorethan2priorD&Cproceduresas

definedabove.OurfinalgroupconsistedofotherPPHriskfactors,includinguterine

leiomyomagreaterthanorequalto6cm,acuteplacentalabruption,orpreeclampsia.(1,3,

20,37-43).

WealsoexaminedwhetheranyonemajorriskfactororanytwominorriskfactorsforPPH,

regardlessofgrouping,wereassociatedwithhemorrhage.Majorriskfactorsforsevere

hemorrhageweredefinedassignsofaccretaonantepartumradiographorpresenceof

acuteabruption.(40)Anyotherriskfactorwasconsideredminor.

Toanalyzetherelationshipbetweentimeandhemorrhage,werecordedeverysubject’s

durationofthirdstageoflabor,definedastimeinminutesbetweendeliveryoftheinfant

anddelivery(manuallyinourcohort)oftheplacenta,asofficiallyrecordedinthe

electronicdeliveryrecord.Toevaluatetherelationshipbetweenhemorrhageandduration

ofthethirdstage,wedividedtimeuntilplacentaldeliveryintothreecategories(</=30

minutes,30-60minutes,and>60minutes).Finally,tobetterunderstandtheroleoftimein

thedevelopmentofPPH,weexploredwhetherpatientandlaborcharacteristicswere

associatedwithvaryinglengthsofthirdstageviaourthreetimecategoriesabove.

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ThedataanalysisforthispaperwasgeneratedusingSASsoftware,version9.4.Copyright

©2016,SASInstituteInc.ContinuousvariableswereanalyzedwithWilcoxontests,while

categoricalvariableswereanalyzedwithconditionallogisticregressionorFisherExact

testsifavariablehadanullentry.P-valueslessthan0.05wereconsideredsignificantwith

two-tailedtests.Finally,inordertotestforindependentassociationsandcontrolfor

confounding,weenteredriskfactorvariablesintoastepwiselogisticregressionmodel.Any

variableassociatedwithhemorrhagewithap-valueof≤0.2wasincludedinthemodel.

Variableswereexcludedfromthemodeliffinalp-valueswere>0.35.

Results:

BetweenJanuary1,2007andJune30,2015,997womenwithmanualremovalofthe

placentawereidentified.Ofthesesubjects,172patientswereidentifiedashavingamajor

postpartumhemorrhage.Anadditional172matchedcontrolpatientswithMROPbut

withoutmajorPPHwererandomlyselectedfromtheremainingpatients.

Characteristicsofcase(severePPH)andcontrol(noPPH)groupsareshowninTable1.The

casegroupshowedlowermedianBMI(33.4vs.35.2,p<0.01),longersecondstageoflabor

(48kg/m2vs.38kg/m2;p=0.04),andlongerthirdstageoflabor(38minutesvs.23

minutes;p<0.01).Thecasegroupwasslightlyyoungerthanthecontrols(33.4yearsvs.

35.2years;p<0.01),andthemediannumberofpriorpregnancieswasoneless(0vs.1,

p<0.01).Theyalsotendedtodeliverunderepiduralanalgesialessfrequentlythanthe

controlgroup(145(85%)vs.159(93%),respectively,p=0.02).Ethnicity,priornumberof

abortions(boththerapeuticandspontaneous),operativevaginaldelivery,cordavulsion,

episiotomy,laceration(includinghighdegrees),andgestationalagedidnotsignificantly

differbetweenPPHandnoPPHgroups.

ObstetricaloutcomesforcaseandcontrolgroupsareshowninTable2.Averagebloodloss

inourseverePPHgroupwas1000cc(100-4000cc)andaveragehematocritdropwas

12.3%(0.3-23.3%).Inthecasegroup84patientsoutof173weretransfusedwithatleast

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onebloodproduct.Averagebloodloosinourcontrolgroupwas400cc(75-1400cc),and

averagehematocritdropwas4.1(0.1-9.7)andnopatienthadatransfusion(percase

inclusioncriteria).Hematocritdropdatawasfrequentlyunavailable,particularlyforour

controlgroup,oftenduetonoblooddrawpostpartum.

Ofthe172patientswithsignificantPPH,51%ofourPPHgroupwasnotedtohaveuterine

atonybyobstetriciansorproviders,incomparisonto12%ofournon-PPHcontrolgroup

(p<0.01).ThePPHgroupandthecontrolgroupdidnotdifferinratesofpathologicaccreta

diagnosis(17%vs.11%;p=0.09).Similarly,thepercentageofPPHpatientswithclinically

adherentplacenta(20%)didnotdifferfromthecontrolgroup(19%;p=0.79),nordidthey

differwhentheclinicalandpathologicdiagnoseswerecombined(34%intheaccretagroup

versus29%inthecontrolgroup,p=0.36).

Individualpredictorswithinthethreehemorrhageriskfactorcategoriesandtheir

associationswithourMROPwithPPHandcontrolgroupsareshowninTable3.Withinthe

Atonycategory,17%ofPPHpatientsexperiencedchorioamnionitis,versusthecontrol

groupwhichhad8%withchorioamnionitis(p=0.01).Multiplegestation(10%PPHvs.3%

controls;p=0.01)andasecondstageoflaborlongerthantwohours(28%PPHcasesvs.

17%controls;p<0.01)werealsosignificantlyassociatedwithPPH.Highbirthweight,high

parity,andmorbidobesitywerenotsignificantlydifferentbetweenthecaseandcontrol

groups.

WithintheAbnormalPlacentationgroup,prioruterinesurgery(24%casesvs.6%controls;

p<0.01),historyofretainedplacenta(13%casesvs.6%controls;p=0.03)andresolved

low-lyingplacenta(15%casesvs.8%controls;p=0.03)weresignificantlyassociatedwith

PPHafterMROP.ThepercentageofourPPHcasegroupwhounderwentART(19%)didnot

differfromtherespectivepercentageofcontrols(12%;p=0.09).Inourcasegroupthere

werefourpatients(2%)whohadapriorpathologicaccretawithouthysterectomy,versus

noneinourcontrolgroup(NS).Similarlythreepatients(2%)ofourcasegrouphad

evidenceofaccretaonultrasound,versusnoneinourcontrolgroup(NS).Noneofthe

potentialriskfactorsintheOtherPPHRiskFactorsgroup(largefibroids,acuteabruption,

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highorderlacerationorpreeclampsia)showedasignificantassociationwithPPHinthe

settingofMROP.

Casepatientsweresignificantlymorelikelythancontrolstohaveanyoneriskfactorin

eithertheAtony(49%vs.37%respectively,p=0.01)orAbnormalPlacentationriskgroup

(58%vs.38%,respectively,p<0.01,Table3).Similarly,PPHcasepatientswere

significantlymorelikelytohaveanyonemajor(signofaccretaonultrasoundorsignsof

abruptionatadmission)ortwominor(anyothervariable)riskfactors(51%vs.26%

controls;p>0.01)oranyriskfactorregardlessofgrouporseveritystratification(83%vs.

66%controls;p<0.01).

ThethirdstageoflaborbyquartileinourPPHcasegroupandournoPPHcontrolgroupis

showninTable4.WithinthePPHcasegroup,thirdstagerangedfrom1to213minutes,

with95%ofplacentaldeliveriesoccurringwithin2.5hoursandamedianof38minutes.

Thisvariedcomparedtothecontrolgroup,inwhich95%ofplacentasdeliveredwithin76

minutes,withamedianof23minutes.

Table5alsoshowsthelengthofthirdstageoflaborbrokendownbytimecategory(</=30

minutes,31-60minutes,and>60minutes).PatientsinthePPHcasegrouphadtheir

placentasmanuallyremovedlaterthancontrols.Withinthefirst30minutes,38%ofour

PPHcaseshadMROPversus68%ofcontrols.Between31and60minutes,30%ofPPH

casesand22%ofcontrolshadMROP.Finally,afterwaiting60minutes,32%ofthePPH

casegrouphadtheirplacentasdeliveredduringthistime,asopposedto10%ofthe

controls(p<0.01)Figure1illustratesthepercentageofcaseandcontrolpatientsdelivering

theirplacentasovertime.

Characteristicsofpatientsdeliveringatdifferentintervalsofthird-stageareshowninTable

5.Patientsexperiencingcordavulsionhadsignificantlyshortertime-to-deliveryintervals,

with24%of</=30minutemanualextractionsduetocordavulsion(p<0.01)(versusother

timeintervals),asdidpatientswithepiduralanalgesiawith93%of</=30minutemanual

extractionshavinganepidural(versus75%of>60minutedeliveries;p<0.01).Incontrast,

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chorioamnionitisduringlaborwassignificantlyassociatedwithalongerthirdstage,with

9%ofthe</=30minutedeliveries,10%ofthe31-60minutedeliveries,and24%ofthe>60

minutedeliveriesassociatedwithchorioamnionitisduringlabor(p=0.03).Ourthreetime

categoriesdidnotshowsignificantassociationwithatonyoraccreta,bothcharacteristics

tendedtohaveplacentaldeliveryearlierinourcohortsrangeofthirdstage.

ResultsfromourstepwiselogisticregressionareshowninTable6,whichshowsall

variablesretainedinthefinalmodel.Afteradjustingforsignificantvariablesinthe

univariateanalysis(lengthofthirdstageoflabor,prioruterinesurgery,maternalageby

year,multiparity,multiplegestations,BMIbyquartile,lowlyingplacenta,historyof

retainedplacenta,episiotomy,laceration,epiduralanesthesia,ART,prematurity,second

stageoflabor>2hours,cordavulsion,chorioamnionitis,andparity>4),chorioamnionitis,

cordavulsion,andparity>4felloutofthemodel.Increasinglengthofthirdstageshowed

thestrongestassociationtoPPH(OR=3.1,95%CI1.65-5.8295%)for3rdstageof31-60

minutesvs.</=30minutes,andOR=8.42,CI3.82-18.5995%CIfor3rdstage>60minutesvs.

</=30minutes).Abnormalplacentationpredictorsremainedindependentlyassociated

withPPH.Theseincludedprioruterinesurgery(OR=4.98,CI2.15-11.52),resolvedlow-

lyingplacenta(OR=3.31,95%CI1.43-7.64),andhistoryofretainedplacenta(OR=2.99,

95%CI1.13-7.94).Incontrast,oftheAtonyriskfactors,onlymultiplegestationsremained

significantinthemultivariablemodel(OR=7.66,95%CI2.2-26.72),whilehighBMI

appearedprotectiveratherthanariskfactor,withthe2ndBMIquartile(28.5kg/m2-37

kg/m2)moreassociatedwithPPHthanthe4th(45.5kg/m2–54kg/m2;OR=2.61,95%CI

1.25-5.45).Secondstagedurationgreaterthan2hourswasalsonotassociatedwithPPHin

themodel.

Discussion:

Thepurposeofthisstudywastodefinecharacteristicsassociatedwithmajorhemorrhage

intheeventofmanualextractionoftheplacenta.Ourresultsledustoconcludethatlength

oftimeuntildeliveryoftheplacentaisofgreatestimportinpreventingpostpartum

hemorrhageinthesettingofpotentialuterineatony.Wealsoconcludedthatpatientswith

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riskfactorsformorbidlyadherentplacentaareatriskofhemorrhagewithmanual

extraction,regardlessoflengthofthethirdstage.Thisinquiryisimportantfortriagingand

treatingmorbidpatientsonthelaboranddeliveryfloor.Ifcharacteristicsassociatedwith

massivehemorrhageareknownpriortoMROP,physicianscanadequatelyprepareby

transferringthemothertotheoperatingroom,callingfortypeandcrossedbloodproducts,

andnotifyingateamtrainedinsurgicalresponsetomassivebloodloss.

ThisstudyisuniqueinthatwecollectedbothhistoricalriskfactorsforPPHwithoutMROP

aswellasnovelriskfactorsrarelystudiedintheliterature,includingresolvedlowlying

placenta,priorhistoryofaretainedplacenta,andprioruterinesurgery.Wehypothesized

thatanyonemajorriskfactorormultipleminorriskfactorswouldbeassociatedwithan

increasedriskofsignificanthemorrhageaftermanualremovaloftheplacenta.This

hypothesisheldtruewithapproximatelyhalfofourseverepostpartumhemorrhage

patientshavinganyonemajorormultipleminorriskfactors,versusaboutafourthofour

controls.However,clinically,theseresultsshowthattriagingMROPpatientsviathese

criteriawillonlycatcharoundhalfofthepostpartumhemorrhagecases,andwillalso

incorrectlyidentifyatleastaquarterofpatientswhowillnotgoontohemorrhageafter

MROP.ThissuggeststhatinthesettingofMROP,mostpatients,regardlessofwhetherthey

experienceseverePPH,aremorbidapriori,andtraditionalriskstratificationforPPHmay

notbeasuseful.

Ofmoreusewasevaluatingtheroleoftimeinthethirdstageoflaborinrelationtorisk

factorsforthedevelopmentofatonyorabnormalplacentationandPPH.Weconfirmedthat

patientswithlongerthirdstagesoflabor—ordelayedmanualdeliveryoftheplacenta—

hadhigheroddsofexperiencingseverehemorrhage.Thisresultpersistedaftercontrolling

forpotentialconfounding.Wealsofoundthat,whenevaluatedcategorically,riskfactorsfor

atonyandabnormalplacentationwereassociatedwithPPH.However,withregardtoatony

riskfactors,onlymultiplegestationsremainedsignificantlyassociatedwithPPHinour

multivariableanalysis.Thesefindingssuggestthatatonyriskfactorsmaybemodulatedby

shorteningthetimeuntildeliveryoftheplacenta.Putanotherway,evenifapatienthas

exposuresassociatedwithatonyandPPH,timelydeliveryoftheplacentamaylessenor

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eveneliminateapatient’sriskofhemorrhage.Thefactthatmultiplegestationsremained

significantinthecontrolledanalysissuggeststhatatonyduetouterineover-distention

behavesdifferentlythanthatrelatedtoinflammation(asseenwithchorioamnionitis),and

maybelesssensitivetothirdstageduration.Thesefindingsarenovelandunreportedin

theliterature.

Incontrasttoatonyriskfactors,multipleindividualriskfactorsformorbidlyadherent

placentahadastrongassociationwithPPHwhenanalyzedinthemultivariableanalysis.

Theseincludedresolvedlowlyingplacenta,prioruterinesurgery,orhistoryofretained

placentainapriorpregnancy,butnotuseofARTorpriorcesareansection.Thisimplies

that,unlikewithatony,timeuntilmanualdeliveryoftheplacentaisnotaconfounderinthe

settingofriskfactorsforabnormalplacentation.Thus,ourdatasuggeststhatshortening

thethirdstageoflaborwhenaphysicianplansMROPduetoconcernforabnormal

placentationmaynothelplessenthemother’sriskofPPH.Thisisnottosaythatproviders

shoulddelaymanualremovalinthesettingofabnormallyadherentplacenta.Instead,a

morerapidmanualremovalmaynothelptoavoidmaternalhemorrhage.

OurfindingssupportpriorstudiesbyMagannetal(2005)andCombsetal(1991)that

linkedprolongedthirdstageoflaborwithPPH(24).Ourresultsexpanduponthesestudies,

suggestingthatevenfordeliveriesinwhichtheobstetricianchoosestomanuallyremove

theplacentaasopposedtowaitingforspontaneousdeliverywithoutintervention,timely

removalmayparticularlyreducehemorrhageinpatientswithcertainriskfactors,andthat

perhapsourlimitedguidelinesontimingshouldbereconsidered.

GiventheobservedimportanceofthirdstagedurationwithregardstoPPHrisk,we

exploredclinicalfactorsthatwereassociatedwithashortorlongertimeintervalfrom

deliveryofinfanttomanualdeliveryoftheplacenta.Weobservedthatumbilicalcord

avulsionandepiduralanalgesiawereassociatedwithashorterthirdstage,and

chorioamnionitiswithalongerthirdstage.Thisobservedrelationshipmightsuggestthat

avulsionofumbilicalcord,disallowingitsuseastractionontheplacenta,isoftenusedas

anindicationforrapidMROP,whilechorioamnionitisisnot,despiteitsrelationshipto

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atonyandPPH.Nootherriskfactorsinourstudywereindividuallyrelatedtoalongerthird

stageoflabor.

Therelationshipbetweenchorioamnionitisandalongerthirdstagemaybedueto

obstetricianswarinessofintroducingahandintotheuterusinthesettingofknown

intrapartuminfection,thusdelayingtimeuntilmanualremovalofaretainedplacenta.This

warinessmayexplainwhythisriskfactorforatonyaloneisrelatedtoprolongedthird

stageoflabor.Interpretingtheepiduralanalgesiarelationship,itispossiblethatphysicians

aremorelikelytoperformapotentiallyuncomfortableprocedurefaster(ratherthanwait

forpotentialspontaneousplacentaldelivery)underconditionsofanalgesia.Alternatively,

itmaybethatpatientswithoutanexistingepiduralmustwaitforeitherconscioussedation

orspinalanesthesiatobeplacedbeforeaphysiciancanattemptMROP,lengtheningtheir

thirdstageoflabor.

Whenconceivingofthisstudy,ARTwasavariableofparticularinterestduetoitsknown

associationwithplacentaaccreta,aconditionassociatedwithbothhemorrhagicmorbidity

andretainedplacentaduringdelivery.(3,33,34)WhilewefoundthatARTislikely

associatedwithMROP,asthe19%rateamongourpatientswithPPHand12%amongour

patientswithoutPPHreflectveryhighratesofARTinthisMROPpopulation.However,we

foundthatARTshowednosignificantrelationshiptoPPHinthisclinicalsetting.Thisis

likelybecausealthoughtheliteraturehasshownARTtobesignificantlyrelatedto

pathologicaccreta,ARTpregnanciesmaynotclinicallybemorelikelytohavehemorrhagic

morbidityduetoadherentplacenta.(3,33,34)Ofnote,standardizationofdefinitionsfor

placentaaccretadoesnotexist,andnotalladherentplacentasorpathologicaccretacause

massivehemorrhage,furtherconfusingthisrelationshipbetweenARTandmorbid

adherence.ThesefindingssupportAzizetal’sstudy,whichwhileshowinghigherratesof

MROPinARTpatients,alsoconcludedthatthereisnorelationshipbetweenARTand

hemorrhagiccomplicationsduringthethirdstageoflabor.(36)

AsopposedtoART,othervariableswithinourmorbidlyadherentplacentacategorywere

positivelyassociatedwithpostpartumhemorrhage.Thesesignificantexposuresincluded

23

resolvedlowlyingplacenta,priorretainedplacenta,andprioruterineprocedure—

variablesthatarenotgenerallyconsideredinstudiesofPPHriskintheliterature.A

clinicianplanningMROPinapatientwithanyoftheseriskfactorsforabnormal

placentationmaythuswanttoconsiderpreparingforhemorrhage.Interestingly,inthe

morbidlyadherentplacentacategory,priorcesareansectionwasnotassociatedwiththe

PPHgroup.Thisisstrikingincomparisontotheliterature,wherepriorcesareansectionis

associatedwithplacentaaccretainpatientswithprevia.Thissuggeststhatonlyinthe

settingofplacentalimplantationoveralowtransversecesareanscarispriorcesarean

associatedwithmorbidaccreta—generallynotthecasewithvaginaldeliveries.

Asecondaryfindingofinterestwasthehighrateofpathologicplacentaaccretainthe

cohort.Inourstudy,theoverallrateofplacentaaccretaonpathologyinboththecaseand

controlgroupswasaround20%.Thisismuchhigherthantherateinthegeneral

population(~0.2%)(44),andsuggeststhatthecontributionofabnormalplacentationto

manualextractionmaybehigherthanpreviouslyestimated.

Strengths,Limitations,andFurtherResearch

Ourstudydrawsstrengthfromouruseofdetailedchartreviewtocollectindividual

patients’data,whichallowedustoconfirmandconceiveofaccuratecriteriaforPPH

(>1500ccbloodloss,>/=10pointhematocritdrop,ortransfusion),ensuringthatourcase

groupcapturedtrueclinicalmorbidity.Ourdatacollectionadditionallyallowedusto

collectpreviouslyunstudiedexposures,sucharesolvedlow-lyingplacenta,prioruterine

surgery,andpriorretainedplacenta.ThisisincontrasttomostliteratureonPPHwhich

drawsriskfactorsfromlargenationaldatabasesanddischargecodingthatarenecessarily

limitedinavailablediagnoses.Additionally,ourrelativelylargenumberofcaseswith

severePPHinthesettingofmanualremovaloftheplacentaallowedustodetermine

significantrelationshipsbetweenmanyexposuresandPPH.

Amajorlimitationofourstudyisthatitwascompletedretrospectively,makingitdifficult

tofind,confirm,andstandardizealldata,andrestrictingchartreviewtowhatproviders

documented.Case-controlstudiesarealsolimitedbecausewhileexposuresandtheir

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relationshipstooutcomescanbedetermined,PPHincidencecannot.Additionally,while

hematocritdropwasusedascriteriaforwhetherornotapatienthemorrhaged,notall

patientshadpostpartumblooddraws,meaningthathematocritdropcouldnotbe

calculatedforsomeofourstudysubjects.Thismayhaveunderestimatedournumberof

caseswithseverePPH,biasingourhypothesistothenull.Finally,theindicationformanual

removalwasoftennotindicatedinthechart;thereforeweareunabletodefinitivelystate

whyaplacentawasremovedatagiventime.

Futureresearchshouldfocusonvalidatingourpredictionvariableswithastandardized

protocolforplacentamanagementanddeliveryinaprospectivetrial.Aretrospectivestudy

fromanotherinstitutionvalidatingourcriteriaintheirMROPpatientswithPPHwouldbe

usefulaswell.Consideringthedelayinmanualremovalinthesettingofchorioamnionitis,a

prospectivestudyexaminingthebalanceofriskofpostpartumhemorrhageversusriskof

infectiousmorbiditymaybeusefulaswell.Additionally,wecouldevaluatetheuseofother

modalitiesforpredictingandtriagingpatientslikelytohemorrhage,suchasbedside

ultrasoundorquantitativebloodloss,inordertofurtherhelpphysicianscontemplating

morbidityaftermanualextractionoftheplacenta.

Summary:

Themostimportantpredictorofhemorrhageaftermanualremovaloftheplacentais

lengthofthethirdstageoflabor.Majorandminorriskfactorsgroupedbyatonyand

morbidlyadherentplacentaareclinicallyusefulinpredictinghemorrhageafterMROP.If

manualremovaloftheplacentaseemslikely,patientswithriskfactorsforatonyshould

havetheirplacentasremovedinatimelyfashion,eveninthesettingofintrapartum

chorioamnionitis.Whileprovidersmayhesitatetomanuallyremoveaplacentawithout

epiduralanalgesiaorinthesettingofchorioamnionitis,earlierplacentaldeliveryislikely

beneficialinordertolessenriskofhemorrhagicmorbidity.

Incomparison,inthesettingofpatientsundergoingmanualremovalwithriskfactorsfor

morbidlyadherentplacenta,hemorrhageriskdidnotappeartobemitigatedbyfaster

removaloftheplacenta.Thissuggeststhatobstetriciansshouldconsiderassemblyof

25

appropriateteammembersandtypeandcrossedbloodproducts,andrequesttransferto

anoperatingroombeforeperformingmanualremovaloftheplacentainapatientwith

concernforabnormalplacentation.Finally,whilepatientswithretainedplacentahavea

highrateofARTuse,thisfactordoesnotappeartopredicthemorrhageriskinthisspecific

clinicalscenario.

Whiletimeappearstobethemostimportantfactorintriagingpatientsatriskforsevere

postpartumhemorrhageaftermanualremovaloftheplacenta,patientswithmultiple

gestation,resolvedlowlyingplacenta,prioruterinesurgery,orhistoryofpriorretained

placentashouldbeconsideredatriskforseverepostpartumhemorrhageevenwithtimely

manualremovaloftheplacenta.

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34. IshiharaO,ArakiR,KuwaharaA,ItakuraA,SaitoH,AdamsonGD.Impactoffrozen-thawedsingle-blastocysttransferonmaternalandneonataloutcome:ananalysisof277,042single-embryotransfercyclesfrom2008to2010inJapan.FertilSteril.2014;101(1):128-33.35. ElenisE,SvanbergAS,LampicC,SkalkidouA,AkerudH,SydsjoG.Adverseobstetricoutcomesinpregnanciesresultingfromoocytedonation:aretrospectivecohortcasestudyinSweden.BMCpregnancyandchildbirth.2015;15:247.36. AzizMM,GuirguisG,MarattoS,BenitoC,FormanEJ.Isthereanassociationbetweenassistedreproductivetechnologiesandtimeandcomplicationsofthethirdstageoflabor?ArchGynecolObstet.2016;293(6):1193-6.37. CommitteeonPracticeB-O.PracticeBulletinNo.183:PostpartumHemorrhage.Obstetricsandgynecology.2017;130(4):e168-e86.38. MehrabadiA,HutcheonJA,LiuS,BartholomewS,KramerMS,ListonRM,etal.Contributionofplacentaaccretatotheincidenceofpostpartumhemorrhageandseverepostpartumhemorrhage.Obstetricsandgynecology.2015;125(4):814-21.39. WettaLA,SzychowskiJM,SealsS,MancusoMS,BiggioJR,TitaAT.Riskfactorsforuterineatony/postpartumhemorrhagerequiringtreatmentaftervaginaldelivery.Americanjournalofobstetricsandgynecology.2013;209(1):51e1-6.40. DillaAJ,WatersJH,YazerMH.Clinicalvalidationofriskstratificationcriteriaforperipartumhemorrhage.Obstetricsandgynecology.2013;122(1):120-6.41. AllenVM,BaskettTF,O'ConnellCM,McKeenD,AllenAC.Maternalandperinataloutcomeswithincreasingdurationofthesecondstageoflabor.Obstetricsandgynecology.2009;113(6):1248-58.42. PracticeACoO.ACOGCommitteeopinion.Number266,January2002:placentaaccreta.Obstetricsandgynecology.2002;99(1):169-70.43. EshkoliT,WeintraubAY,SergienkoR,SheinerE.Placentaaccreta:riskfactors,perinataloutcomes,andconsequencesforsubsequentbirths.AmericanJournalofObstetrics&Gynecology.2013;208(3):219.e1-7.44. CommitteeonObstetricP.ACOGcommitteeopinion.Placentaaccreta.Number266,January2002.AmericanCollegeofObstetriciansandGynecologists.Internationaljournalofgynaecologyandobstetrics:theofficialorganoftheInternationalFederationofGynaecologyandObstetrics.2002;77(1):77-8.

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TablesandFigures:Table1:MaternalandlaboranddeliveryCharacteristicsinbothCase(PPH)andControl(noPPH)Groups.

a)D&E-DilationandEvacuationpreformedinthesettingofpriorpregnancies(spontaneousortherapeuticabortion,ortreatmentofpostpartumhemorrhageorretainedproductsofconception).b)WhilemedianpriornumberofD&Eprocedureswasthesameforcaseandcontrolgroup,overallourPPHcasegroupweresignificantlymorelikelytohavehadmoreD&Espriortoindexpregnancy.c)SAB–spontaneousabortion.d)TAB–therapeuticabortion,eitherwithmedicalorsurgicalintervention.

PPHN=172

noPPHN=172 P-Value

Age(years) 33.4(17.3-48.9)

35.2(17.0-50.4) <0.01

BMIatendofpregnancy(kg/m2) 28(20-54) 30(21-50) 0.02

Ethnicity 0.94White 110(64%) 105(61%) Black 23(13%) 27(16%) Hispanic 23(13%) 24(14%) Asian 15(9%) 14(8%) Other 1(1%) 2(1%) Parity 0(0-6) 1(0-6) <0.01Gestationalage(weeks) 38.8

(25.1-442.0)39.1

(24.7-41.9) 0.39

NumberofpriorD&Eaproceduresb 0(0-4) 0(0-4) <0.01

Priorcesarean 14(8%) 15(9%) 0.84Priorabortions(SABc/TABd) 0(0-6) 0(0-7) 0.79Epiduralanalgesia 145(85%) 159(93%) 0.02Operativevaginaldelivery 24(14%) 19(11%) 0.42Cordavulsion 24(14%) 34(20%) 0.16Episiotomy 16(9%) 9(5%) 0.15Laceration(any) 129(75%) 112(65%) 0.06Lengthof2ndStageofLabor(min) 48(1-345) 38(1-255) 0.04

Lengthof3rdStageofLabor(min) 38(1-213) 23(1-169) <0.01

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Table2:DeliveryoutcomesinbothCase(PPH)andControl(noPPH)groups. PPH

N=172noPPHN=172 P-Value

Estimatedbloodloss(cc) 1000(100-4000) 400(75-1400) n/a

Hematocritdrop(percent)

12.3(0.3-23.3) 4.1(0.1-9.7) n/a

Transfusion 84(49%) 0 n/aDilationandCurettage 103(60%) 14(8%) <0.01Uterineinversion 3(2%) 0 0.25Hysterectomy 8(5%) 0 <0.01BakriBalloon <0.01Placed 40(23%) 0 Failedplacement 3(2%) 1(1%) None 129(75%) 171(99%) Postpartumreadmission 15(9%) 3(2%) <0.01

DelayedPostpartumprocedure 16(10%) 10(6%) 0.18

Pathologicdiagnosisa Accreta 30/152(20%) 19/118(16%) 0.72Marginalorvelamentouscordinsertion

28/149(19%) 21/117(18%) 1

Infection/inflammation 29/149(19%) 19/117(16%) 0.73

a)Denominatorsintheindividualcellsreflectthenumberofsubjectsthathasaspecimensentforpathology.ForaccretathisreflectsaplacentaorD&Cspecimen.Fortheotherdiagnosesthisreflectsplacentaspecimensonly.

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Table3:RiskFactorassociationwithpostpartumhemorrhage,categorizedbyroleinthedevelopmentofretainedplacentaandPPH. PPH

N=172noPPHN=172 P-Value

Atony: Birthweight>4000g 12(7%) 14(8%) 0.67BMI>40kg/m2 5(3%) 11(6%) 0.14Chorioamnionitis 29(17%) 13(8%) 0.01Multiplegestations 17(10%) 5(3%) 0.012ndstage>2hr 49(28%) 29(17%) <0.01

Parity>4 1(1%) 5(3%) 0.14AnyAtonyRiskFactor 85(49%) 63(37%) 0.01AbnormalPlacentation Priorcesarean 14(8%) 15(9%) 0.84Prioruterinesurgerya 42(24%) 10(6%) <0.01Resolvedlowlyingplacentab 26(15%) 13(8%) 0.03

Ashermans/Synechiae 1(1%) 1(1%) 1Priorpathologicaccreta 4(2%) 0 0.99ART 33(19%) 21(12%) 0.09>2PriorD&C 5(3%) 9(5%) 0.29Signsofaccretaonultrasound 3(2%) 0 0.99

Priorretainedplacenta 23(13%) 11(6%) 0.03AnyabnormalplacentationRiskFactor 99(58%) 65(38%) <0.01

OtherPPHriskfactor Leiomyoma>=6cm 3(2%) 4(2%) 0.71AcuteAbruption 1(1%) 4(2%) 0.22Preeclampsia 17(10%) 13(8%) 0.43Laceration(highorder)c 9(5%) 4(2%) 0.15

AnyOtherPPHRiskFactor 28(16%) 25(15%) 0.66

RiskFactorsIndependentofgrouping

Anyriskfactor 143(83%) 114(66%) <0.01Onemajorortwominord 88(51%) 45(26%) <0.01

a)Prioruterinesurgeriesincludedmyomectomy,anyoperativehysteroscopy,orendometrialablation.

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b)Lowlyingplacentawasdefinedasultrasonographicdiagnosisofplacentapreviaortheplacentacomingwithin2cmofthecervicalosduringthecurrentpregnancy.c)Highorderlacerationsincluded3rdand4thdegreevaginaltearsafterdeliveryoftheinfant.d)Majorriskfactorsincludeacuteabruptionandradiologicsignsofaccreta.Allotherriskfactorsareincludedasminor.

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Table4:ThirdstageoflaborbycentilesinbothCase(PPH)andControl(noPPH)groups.Centiles PPH(minutes) NoPPH

(Minutes)Maximum 213 16995thpercentile 156 7675thpercentile 79 3850thpercentile 38 2325thpercentile 18 105thpercentile 6 5Minimum 1 1Table5:Characteristicsassociatedwith30minuteintervalcategoriesofthethirdstageoflabor.

</=30minutesN(%)

31-60minutesN(%)

>60minutesN(%)

P-Value

Postpartumhemorrhage 66(36%) 51(57%) 55(76%) <0.01Atony 53(29%) 33(37%) 21(29%) 0.37Accreta 55(30%) 23(26%) 30(42%) 0.08Cordavulsion 43(24%) 7(8%) 8(12%) <0.01Operativevaginaldelivery 25(14%) 8(9%) 10(14%) 0.51Multiplegestation 13(7%) 5(6%) 4(6%) 0.88Multiparous 106(58%) 53(60%) 31(43%) 0.06Historyofretainedplacenta 13(7%) 11(12%) 10(14%) 0.17Chorioamnionitis 16(9%) 9(10%) 17(24%) <0.01Epiduralanalgesia 171(93%) 81(91%) 54(75%) <0.01Prolonged2ndStagea 36(20%) 24(27%) 18(25%) 0.35a)Secondstageoflabor(timebetweenfullcervicaldilationanddeliveryoftheinfant)lastingmorethan2hours.

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Table6:Variablesassociatedwithpostpartumhemorrhageaftercontrollingforconfoundersa:

P-Value OR 95%CILengthof3rdstage <0.01 31-60vs.</=30(mins) 3.1 1.65-5.82>60vs.</=30(mins) 8.42 3.82-18.59Prioruterinesurgery <0.01 4.98 2.15-11.53Resolvedlowlyingplacenta <0.01 3.31 1.43-7.64LastpregnancyBMI(quartiles,kg/m2) <0.01 Q1vs.Q4 1.75 0.72-4.27Q2vs.Q4 2.61 1.25-5.45Q3vs.Q4 0.78 0.37-1.67Multiplegestations <0.01 7.66 2.2-26.72Age(year) 0.02 0.93 0.89-0.99Historyofretainedplacenta 0.03 2.99 1.13-7.94Laceration(highorder) 0.06 1.85 0.97-3.54Episiotomy 0.07 2.68 0.93-7.67Mutiparity 0.07 0.54 0.28-1.04Epiduralanalgesia 0.1 0.44 0.16-1.18ART 0.18 1.7 0.78-3.71Prematurity 0.23 1.53 0.76-3.08Prolonged2ndstage 0.38 1.38 0.67-2.84a)Chorioamnionitis,cordavulsion,andparity>4wereruninthismultivariableanalysisbutdidnotretainsignificance.

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Figures:Figure1:PercentageofCase(PPHa)andControl(NoPPHb)patientsdeliveringtheirplacentasovertime.

a)BluebarsrepresentCase(PPH)placentadeliveriesb)RedbarsrepresentControl(noPPH)placentadeliveries

0

5

10

15

20

25

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10 20 30 40 50 60 70 80 90 100110120130140150160170180190200210220

PercentageofCase(PPH)andControl(NoPPH)patientsdeliveringtheirplacentasovertime