the american college of obstetricians and gynecologists...

718 VOL. 118, NO. 3, SEPTEMBER 2011 OBSTETRICS & GYNECOLOGY

P RAC T I C EBUL L E T I N

the american college of obstetricians and gynecologistswomen’s health care physicians

BackgroundDeepveinthrombosis(DVT)andpulmonaryembolism(PE)arecollectivelyreferredtoasvenousthromboem-bolicevents.Approximately75–80%ofcasesofpreg-nancy-associated venous thromboembolism are causedbyDVT,and20–25%ofcasesarecausedbyPE(3,7,13).Onehalfoftheseeventsoccurduringpregnancyandonehalfoccurduringthepostpartumperiod(3–8).

Pregnancy-Associated Changes and Venous ThromboembolismPregnancyisassociatedwithphysiologicandanatomicchanges that increase the risk of thromboembolism,including hypercoagulability, increased venous stasis,decreasedvenousoutflow(14,15),compressionof theinferior vena cava and pelvic veins by the enlarginguterus(16),anddecreasedmobility(17–20).Pregnancy

altersthelevelsofcoagulationfactorsnormallyrespon-sibleforhemostasis.Theoveralleffectofthesechangesisanincreasedthrombogenicstate(seeTable1).WhenDVT occurs during pregnancy, it is more likely toinvolvetheleftlowerextremity(21–23).

Risk Factors Theriskofvenousthromboembolismmaybehigherinthe third trimester compared with the first and secondtrimesters (2), but the increased risk of venous throm-boembolismispresentfromthefirsttrimester(22,23),oftenbeforemanyoftheanatomicchangesofpregnancyoccur. The risk of venous thromboembolism is higherduringthepostpartumperiodthanitisduringpregnancy,especiallyduringthefirstweekpostpartum(1).

Themostimportantindividualriskfactorforvenousthromboembolisminpregnancyisapersonalhistoryofthrombosis.Theriskofrecurrentvenousthromboembo-

Thromboembolism in PregnancyPregnant women have a fourfold to fivefold increased risk of thromboembolism compared with nonpregnant women (1, 2). Approximately 80% of thromboembolic events in pregnancy are venous (3), with a prevalence of 0.5–2.0 per 1,000 pregnant women (4–9). Venous thromboembolism, including pulmonary embolism, accounts for 1.1 deaths per 100,000 deliveries (3), or 9 % of all maternal deaths in the United States (10). In the developing world, the leading cause of maternal death is hemorrhage (11); however, in developed nations, where hemorrhage is more often success-fully treated and prevented, thromboembolic disease is one of the leading causes of death (12).

The prevalence and severity of this condition during pregnancy and the peripartum period warrant special consider-ation of management and therapy. Such therapy includes the treatment of acute thrombotic events and prophylaxis for those at increased risk of thrombotic events. The purpose of this document is to provide information regarding the risk factors, diagnosis, management, and prevention of thromboembolism, particularly venous thromboembolism in pregnancy.

Number 123, September 2011 Replaces Practice Bulletin Number 19, August 2000

clinical management guidelines for obstetrician–gynecologists

Committee on Practice Bulletins—Obstetrics.ThisPracticeBulletinwasdevelopedbytheCommitteeonPracticeBulletins—Obstetricswiththeassis-tanceofAndraJames,MD.Theinformationisdesignedtoaidpractitionersinmakingdecisionsaboutappropriateobstetricandgynecologiccare.Theseguidelinesshouldnotbeconstruedasdictatinganexclusivecourseoftreatmentorprocedure.Variationsinpracticemaybewarrantedbasedontheneedsoftheindividualpatient,resources,andlimitationsuniquetotheinstitutionortypeofpractice.

VOL. 118, NO. 3, SEPTEMBER 2011 Practice BulletinThromboembolism in Pregnancy 719

lismduringpregnancyisincreasedthreefoldtofourfold(relative risk, 3.5; 95% confidence interval, 1.6–7.8),and 15–25% of all cases of venous thromboembolismin pregnancy are recurrent events (24). The next mostimportant individual risk factor for venous thrombo-embolism in pregnancy is the presence of a throm-bophilia (3, 23). Thrombophilia is present in 20–50%of women who experience venous thromboembolismduringpregnancyandthepostpartumperiod(25).Bothacquiredand inherited thrombophilias increase the riskofvenousthromboembolism(26).

Besides a personal history of thrombosis, otherrisk factors for the development of pregnancy-associ-ated venous thromboembolism include the physiologicchanges that accompany pregnancy and childbirth,medical factors (such as obesity, hemoglobinopathies,hypertension, and smoking), and pregnancy complica-tions(includingoperativedelivery)(3,6–8,17,27,28).

Anticoagulation Medications in PregnancyTheuseofanticoagulationtherapyinwomenduringpreg-nancywarrantsspecialconsiderationforbothmotherandfetus.Mostwomenwho requireanticoagulation therapybeforeconceptionwillneedtocontinuethistherapydur-ingpregnancyandthepostpartumperiod.Commonanti-coagulation medications include unfractionated heparin,

low molecular weight heparin (LMWH), and warfarin.The preferred anticoagulants in pregnancy are heparincompounds.

Heparin CompoundsNeitherunfractionatedheparinnorLMWHcrosses theplacenta(29,30)andbothareconsideredsafe inpreg-nancy(31).Uniqueconsiderationsregardingtheuseofanticoagulationtherapyinpregnancyincludea40–50%increase inmaternalbloodvolume;an increase inglo-merularfiltration,whichresultsinincreasedrenalexcre-tion of heparin compounds; and an increase in proteinbindingofheparin(32).Duringpregnancy,bothunfrac-tionatedheparinandLMWHhaveshorterhalf-livesandlowerpeakplasmaconcentrations,usuallynecessitatinghigherdosesandmorefrequentadministrationinordertomaintaineffectiveconcentrations(33–39).

There are few comparative studies of LMWH useinpregnancy,but innonpregnantpatients,LMWHhasbeenassociatedwithfeweradverseeffectsthanunfrac-tionated heparin (40). Potential advantages of LMWHinclude fewer bleeding episodes, a more predictabletherapeutic response, a lower risk of heparin-inducedthrombocytopenia,alongerhalf-life,andlessbonemin-eraldensityloss(31,41,42).

Importantly,neitherLMWHnorunfractionatedhep-arin is associated with significant bone loss when usedinprophylacticdosesduringpregnancy(43–45).Unfrac-tionated heparin, which is associated with increasedbruising at the injection sites, also has been associatedwith other skin reactions and serious allergic reactions(46). Moreover, unfractionated heparin is dispensed inmultiple-dose vials, which are potentially vulnerable tocontamination (47). Besides its greater cost, a relativedisadvantageofLMWHatthetimeofdeliveryisitslon-gerhalf-life,whichisanimportantconsiderationforbothneuraxialanesthesiaandperipartumbleedingrisk.

Warfarin Warfarin,acommonagentforlong-termanticoagulationtherapyoutsideofpregnancy,hasbeenassociatedwithpotentially harmful fetal effects, especially with first-trimesterexposure(48–54).Warfarinembryopathyhasbeen linkedwithexposureat6–12weeksofgestation,highlighting the importanceof earlypregnancycare insuchpatients(55).Therefore,formostwomenreceivingprolonged anticoagulation therapy who become preg-nant, it is recommended that unfractionated heparin orLMWHbeusedinplaceofwarfarin.

Althoughrarelyprescribedinpregnancy,warfarinisstillconsideredinpregnancyforwomenwithmechani-calheartvalvesbecauseoftheirhighriskofthrombosis

Table 1. Changes in the Normal Functioning of the Coagulation System During Pregnancy

Coagulant Factors Change in Pregnancy

Procoagulants

Fibrinogen Increased

FactorVII Increased

FactorVIII Increased

FactorX Increased

VonWillebrandfactor Increased

Plasminogenactivatorinhibitor-1 Increased

Plasminogenactivatorinhibitor-2 Increased

FactorII Nochange

FactorV Nochange

FactorIX Nochange

Anticoagulants

FreeProteinS Decreased

ProteinC Nochange

AntithrombinIII Nochange

Data from Bremme KA. Haemostatic changes in pregnancy. Best Practice &ResearchClinicalHaematology.2003;16:153–68andMedcalfRL,StasinopoulosSJ.Theundecidedserpin:theinsandoutsofplasminogenactivatorinhibitortype2.FEBSJ2005;272:4858–67.

720 Practice Bulletin Thromboembolism in Pregnancy OBSTETRICS & GYNECOLOGY

even with heparin or LMWH anticoagulation therapy(56).Themanagementofsuchwomenrequiresamulti-disciplinary care approach, and the decision regardingoptimalanticoagulationtherapymeritsadetaileddiscus-sionwiththepatientandherhealthcareprovidersregard-ingtherisksandbenefitsofthevarioustreatmentoptions.

Clinical Considerations and Recommendations

Whatistheappropriateevaluationofwomenwithapriorvenousthromboembolism?

Womenwithahistoryofthrombosiswhohavenothadacompleteevaluationofpossibleunderlyingetiologiesshould be tested for both antiphospholipid antibodies(57) and for inherited thrombophilias (58). The resultsof thrombophilia testinginwomenwithapriorvenousthromboembolism may alter the need for treatment ortheintensityoftreatmentfromaprophylactictoathera-peutic dose (also known as adjusted-dose or weight-baseddose)ofLMWHorunfractionatedheparin(59).

Howisavenousthromboembolismdiagnosedinpregnancy?

Deep Vein ThrombosisThetwomostcommoninitialsymptomsofDVT,presentinmore than80%ofwomenwithpregnancy-associatedDVT, are pain and swelling in an extremity (23). Adifferenceincalfcircumferenceof2cmormoreispar-ticularly suggestive of DVT in a lower extremity (60).When signs or symptoms suggest new-onset DVT, therecommendedinitialdiagnostictestiscompressionultra-sonographyoftheproximalveins(40).Whenresultsarenegativeandiliacveinthrombosisisnotsuspected,rou-tinesurveillancemaybeareasonableoption(seeFig.1).When results are negative or equivocal and iliac veinthrombosisissuspected,additionalconfirmatoryimagingwithmagnetic resonance imaging is recommended(61).Alternatively, depending on the clinical circumstances,empiricanticoagulationmaybeareasonableoption(seeFig.1).AlthoughmeasurementofD-dimerlevelsisause-fulscreeningtooltoexcludevenousthromboembolisminthe nonpregnant population, pregnancy is accompaniedbyaprogressiveincreaseinD-dimerlevels,evenahighD-dimerleveldoesnotpredictvenousthromboembolisminpregnancy(62–64).

Pulmonary EmbolismThe diagnosis of new-onset PE is similar to that inthe nonpregnant individual. Both ventilation–perfusion

scanning and computed tomographic (CT) angiogra-phy are associated with relatively low radiation expo-sure for the fetus (65). The concerns about maternalbreastradiationexposurewithCTangiographymustbeweighedagainstthepotentialconsequencesofwithhold-ing appropriate imaging and failing to make a properdiagnosis.Arecentstudyconcluded thatachestX-raycouldbeusedasadiscriminatortoreducethelikelihoodofnondiagnosticventilation–perfusionscanningandCTangiographyinthissetting(66).

Whoarecandidatesforanticoagulationtherapyduringpregnancy?

Therapeutic anticoagulation is recommended for allwomen with acute venous thromboembolism duringpregnancy. Other candidates for either prophylactic ortherapeutic anticoagulation during pregnancy includewomen with a history of thrombosis or those who areat significant risk of venous thromboembolism duringpregnancyorthepostpartumperiod,suchasthosewith

Suspect lowerextremity deep vein thrombosis

Compression ultrasonography of lower extremity or

extremities

Results

Negative or equivocal and

suspect iliac vessel process

Additional imaging studies

Presumptive anticoagulation

therapy

Results

Routine surveillance

Treat

Fig. 1.Diagnosisofdeepveinthrombosisduringpregnancy.FigureprovidedcourtesyofLeoR.Brancazio,MD.

Negative and do not suspect

iliac vessel process

Positive

Positive

Negative


high-risk acquired or inherited thrombophilias (seeTable2).

Despite the increased risk of venous thromboem-bolism during pregnancy and the postpartum period,routineanticoagulationtherapyforallpregnantwomenis not warranted (67, 68). Bleeding complications canarise from administration of unfractionated heparin orLMWH, and this complication should be consideredbeforeinitiatinganticoagulationtherapy(31,41,69,70).

Howshouldanticoagulationtherapybeadministered?

Thereareno large trials regarding theoptimaldoseofanticoagulants in pregnancy, and recommendations for

their use are based on case series and expert opinion.Therapeuticanticoagulationisrecommendedforwomenwith acute thromboembolism during the current preg-nancyorthoseathighriskofthrombosis,suchaswomenwithmechanicalheartvalves(40).Thedecisionregard-ing intensityof treatmentmaybe shapedbyother riskfactorssuchascesareandelivery,prolongedimmobility,obesity,andfamilyhistoryofthrombophiliasorvenousthromboembolism (see Table 3). For women with ahistoryof idiopathicthrombosisor thosewithtransientriskfactorswhoarenottakinganticoagulantsasalife-long treatment and have either no thrombophilia or alow-riskthrombophilia,expertsrecommendantepartumprophylacticanticoagulationorantepartumsurveillance

Table 2. Recommended Thromboprophylaxis for Pregnancies Complicated by Inherited Thrombophilias*

Clinical Scenario Antepartum Management Postpartum Management

Low-riskthrombophilia†withoutpreviousVTE Surveillancewithoutanticoagulation Surveillancewithoutanticoagulationtherapy therapyorprophylacticLMWHorUFH orpostpartumanticoagulationtherapyif thepatienthasadditionalrisksfactors‡

Low-riskthrombophilia†withasingleprevious Prophylacticorintermediate-doseLMWH/UFH PostpartumanticoagulationtherapyorepisodeofVTE––Notreceivinglong-term orsurveillancewithoutanticoagulation intermediate-doseLMWH/UFHanticoagulationtherapy therapy

High-riskthrombophilia§withoutpreviousVTE ProphylacticLMWHorUFH Postpartumanticoagulationtherapy

High-riskthrombophilia§withasingleprevious Prophylactic,intermediate-dose,oradjusted- PostpartumanticoagulationtherapyorepisodeofVTE––Notreceivinglong-term doseLMWH/UFHregimen intermediateoradjusted-doseLMWH/UFHforanticoagulationtherapy 6weeks(therapylevelshouldbeatleastas highasantepartumtreatment)

Nothrombophiliawithprevioussingle Surveillancewithoutanticoagulation PostpartumanticoagulationtherapyII

episodeofVTEassociatedwithtransient therapy riskfactorthatisnolongerpresent— Excludespregnancy-orestrogen-related riskfactor

Nothrombophiliawithprevioussingle Prophylactic-doseLMWHorUFHII PostpartumanticoagulationtherapyepisodeofVTEassociatedwithtransientrisk factorthatwaspregnancy-orestrogen-related

Nothrombophiliawithprevioussingleepisode Prophylactic-doseLMWHorUFHII PostpartumanticoagulationtherapyofVTEwithoutanassociatedriskfactor (idiopathic)—Notreceivinglong-termanticoagulationtherapy

Thrombophiliaornothrombophiliawithtwo Prophylacticortherapeutic-doseLMWH PostpartumanticoagulationtherapyormoreepisodesofVTE—Notreceivinglong- or ortermanticoagulationtherapy Prophylacticortherapeutic-doseUFH Therapeutic-doseLMWH/UFHfor6weeks

Thrombophiliaornothrombophiliawithtwo Therapeutic-doseLMWHorUFH Resumptionoflong-termanticoagulationormoreepisodesofVTE—Receivinglong-term therapyanticoagulationtherapy

Abbreviations:LMWH,lowmolecularweightheparin;UFH,unfractionatedheparin;VTE,venousthromboembolism.*Postpartum treatment levels should be greater or equal to antepartum treatment. Treatment of acute VTE and management of antiphospholipid syndrome areaddressedinotherPracticeBulletins.†Low-riskthrombophilia:factorVLeidenheterozygous;prothrombinG20210Aheterozygous;proteinCorproteinSdeficiency.‡First-degreerelativewithahistoryofathromboticepisodebeforeage50years,orothermajorthromboticriskfactors(eg,obesity,prolongedimmobility).§High-risk thrombophilia: antithrombin deficiency; double heterozygous for prothrombin G20210A mutation and factor V Leiden; factor V Leiden homozygous orprothrombinG20210Amutationhomozygous.||Surveillancewithoutanticoagulationissupportedasanalternativeapproachbysomeexperts.


66%ofwhomreceivedoncedailyLMWH(71).Anotherstudycomparingoncedailytinzaparinversustwicedailytinzaparinforthetreatmentofvenousthromboembolisminpregnancyfoundthatahigher-than-recommendeddos-agewasrequiredtomaintainanti-Xaactivityinthetargetrangeinwomenwhotooktinzaparinonlyonceaday(36).Anotherretrospectivestudyoftheonce-a-daytinzaparinregimen found two unusual thrombotic complicationsamong37pregnancies(72).Anyadjustmentforobesityisincorporatedintotherapeutic-doseregimens.Thereisnoevidenced-basedprotocolforadjustingprophylacticdosesinwomenwhoareobese,thusadjustmentscanbemadeonacase-by-casebasis.

Whichanticoagulantsshouldbeusedincasesofheparinallergy?

In cases of severe cutaneous allergies or heparin-induced thrombocytopenia in pregnancy, fondaparinux(asyntheticpentasaccharide)maybethepreferredanti-coagulantbecausedanaparoid,anLMWHwithminimalcross-reactivityinheparin-sensitivepatients,iscurrentlyunavailableintheUnitedStates(73).However,thereareinsufficientdatatojustifytheroutineuseoffondaparinuxas an alternative to heparins for prophylaxis of venousthromboembolisminpregnancy.Althougharecentretro-spectivestudycomparingfondaparinuxwithenoxaparinadministeredbetweenday6oftheconceptioncycleandcontinueduntil12weeksofgestationfoundnountowardeffectsoffondaparinuxonmotherorinfant(74),antico-agulantactivityhasbeendetectedinumbilicalcordbloodofexposedfetuses(75).

Howisnewlydiagnosedvenousthromboem-bolisminpregnancymanaged?

Management of newly diagnosed venous thromboem-bolismrequires therapeuticanticoagulationwitheitherunfractionatedheparinorLMWH(Table3).Hospital-ization for the initiation of anticoagulation therapymay be indicated in cases of hemodynamic instabil-ity, largeclots,ormaternalcomorbidities. Intravenousunfractionatedheparin canbe considered in the initialtreatment of PE and in situations in which delivery,surgery,orthrombolysis(indicatedforlife-threateningorlimb-threateningthromboembolism)maybenecessary.When patients appear to be hemodynamically stable,therapeuticLMWHcanbesubstitutedinanticipationofdischargefromthehospital.

Howshouldanticoagulationtherapybemonitoredduringpregnancy?

Dataareunclearregardingoptimalsurveillanceofanti-coagulation therapy during pregnancy. When used in

andpostpartumprophylaxis(40).Patientswithaninci-dentally discovered low-risk thrombophilia who havenothadapriorvenous thromboembolismcanbeman-agedantepartumwitheithersurveillanceorprophylacticLMWHorunfractionatedheparin,andinthepostpartumperiod with either LMWH and unfractionated heparinprophylaxis or with surveillance if the patient has noadditionalriskfactorsforDVT.

Basedonthepharmacokineticsoftheheparinagentsinpregnancy,therapeuticLMWHshouldbeadministeredonceortwicedailyandunfractionatedheparin,every12hours (Table 3) (34–38). A retrospective study of oncedaily versus twice daily doses of various heparins forvenous thromboembolism in pregnancy found no casesof recurrent venous thromboembolism in 126 women,

Table 3. Anticoagulation Regimens

Management Type Dosage

ProphylacticLMWH* Enoxaparin,40mgSConcedaily Dalteparin,5,000unitsSConcedaily Tinzaparin,4,500unitsSConcedaily

TherapeuticLMWH† Enoxaparin,1mg/kgevery12hours(Alsoreferredtoas Dalteparin,200units/kgoncedailyweight-adjusted, Tinzaparin,175units/kgoncedailyfull-treatmentdose) Dalteparin,100units/kgevery12hours

MinidoseprophylacticUFH UFH,5,000unitsSCevery12hours

ProphylacticUFH UFH,5,000–10,000unitsSCevery 12hours UFH,5,000–7,500unitsSCevery 12hoursinfirsttrimester UFH,7,500–10,000unitsSCevery 12hoursinthesecondtrimester UFH,10,000unitsSCevery12hours inthethirdtrimester,unlesstheaPTT iselevated

TherapeuticUFH UFH,10,000unitsormoreSCevery(Alsoreferredtoas 12hoursindosesadjustedtotargetweight-adjusted, aPTTinthetherapeuticrange(1.5–2.5,full-treatmentdose) 6hoursafterinjection)

Postpartumanticoagulation ProphylacticLMWH/UFHfor4–6weeks or VitaminKantagonistsfor4–6weeks withatargetINRof2.0–3.0,withinitial UFHorLMWHtherapyoverlapuntilthe INRis2.0ormorefor2days

Surveillance‡

Abbreviations:LMWH,lowmolecularweightheparin;SC,subcutaneously;UFH,unfractionatedheparin;aPTT,activatedpartialthromboplastintime;INR,inter-nationalnormalizedratio.*Althoughatextremesofbodyweight,modificationofdosemayberequired.†Maytargetananti-Xalevelinthetherapeuticrangeof0.6–1.0units/mLfortwicedailyregimen;slightlyhigherdosesmaybeneededforaonce-dailyregimen.‡Clinicalvigilanceandappropriateobjective investigationofwomenwithsymp-tomssuspiciousofdeepveinthrombosisorpulmonaryembolismmaybeneeded.


therapeuticdosestotreatorpreventvenousthromboem-bolism,itisnotclearwhetherthedoseofLMWHneedstobeadjusted.Onthebasisofsmallstudiesdemonstrat-ingtheneedforincreasedLMWHtomaintainantifactorXalevelsbetween0.6units/mLand1.0units/mL,someadvocate periodic measurement of antifactor Xa levels4–6hoursafterinjection,butotherstudieshaveshownthat fewwomenactually require increaseddoseswhenweight-baseddosesareused(40).Patientsconvertedtoasubcutaneoustherapeuticdoseofunfractionatedheparininthelastmonthofpregnancyshouldhaveanactivatedpartial thromboplastin time (aPTT) checked (aPTT of1.5–2.5,6hoursafterinjection)andtheirdoseofheparinadjustedtomaintaintheaPTTinthetherapeuticrange.

Patients receiving prophylactic anticoagulation donot require monitoring, but measurement of antifactorXalevelsoraPTTmaybewarrantedincasesinwhichprophylaxislevelsoutsideoftherecommendedrangeareclinically suspected (39). In one study, approximately40%ofwomen takingprophylacticLMWHhad levelsoutsideoftheprophylacticrange(39).

Guidelines recommend obtaining platelet countswheninitiatingtherapeuticunfractionatedheparintherapyinordertomonitorforheparin-inducedthrombocytopenia(76).Thedataarelessclearaboutmeasuringplateletlev-elswhen initiatingLMWH,butcase reportsofheparin-inducedthrombocytopeniahavebeendescribed(77).

Howisanticoagulationtherapymanagedatthetimeofdelivery?

Women receiving either therapeutic or prophylacticanticoagulationtherapymaybeconvertedfromLMWHtotheshorterhalf-lifeunfractionatedheparininthelastmonthofpregnancyorsoonerifdeliveryappearsimmi-nent. An alternative option may be to stop therapeuticanticoagulationandinducelaborwithin24hours,ifclin-icallyappropriate.Thepurposeofconversiontounfrac-tionatedheparinhaslesstodowithanyriskofmaternalbleedingatthetimeofdelivery,butrathertheriskofanepidural or spinal hematoma with regional anesthesia.TheAmericanSocietyofRegionalAnesthesiaandPainMedicineguidelines recommendwithholdingneuraxialblockade for 10–12 hours after the last prophylacticdose of LMWH or 24 hours after the last therapeuticdoseofLMWH(78).Theseguidelinessupport theuseofneuraxialanesthesiainpatientsreceivingdosagesof5,000unitsofunfractionatedheparintwicedaily,butthesafety inpatients receiving10,000units twicedailyormoreisunknown.Insuchcases, theAmericanSocietyofRegionalAnesthesiaandPainMedicinerecommendsassessmentonanindividualbasis(78).Ifawomangoesintolaborwhiletakingunfractionatedheparin,clearancecanbeverifiedbyanaPTT.Reversalofheparinisrarely

requiredandisnotindicatedwithaprophylacticdoseofheparin. For women in whom anticoagulation therapyhastemporarilybeendiscontinued,pneumaticcompres-sionsdevicesarerecommended.

ShouldpatientsundergoingcesareandeliveryreceiveDVTprophylaxis?

Cesarean delivery approximately doubles the risk ofvenousthromboembolism(6),butintheotherwisenormalpatient, this risk is still low (approximately 1 per 1,000patients) (79). Given this increased risk, and based onextrapolationfromperioperativedata,placementofpneu-matic compression devices before cesarean delivery isrecommendedforallwomennotalreadyreceivingthrom-boprophylaxis. Studies of routine thromboprophylaxisforcesareandeliveryhavebeensmallandnotadequatelypowered to assess a decrease in the risk of DVT or PEwith anticoagulation therapy (80–82). One publisheddecision analysis concluded that if thromboprophylaxiswas elected, pneumatic compression devices were pre-ferred to unfractionated heparin because of the risk ofbleeding complications and heparin-induced thrombocy-topenia (83). Another decision analysis concluded thatpneumaticcompressiondeviceswerecosteffectiveiftheincidence of postcesarean venous thromboembolism inthepopulationwasatleast6.8per1,000patients(84).

Forpatientsundergoingcesareandeliverywithaddi-tionalriskfactorsforthromboembolism,individualriskassessment may require thromboprophylaxis with bothpneumaticcompressiondevicesandunfractionatedhepa-rin or LMWH (40). However, cesarean delivery in theemergency setting should not be delayed because ofthetimingnecessarytoimplementthromboprophylaxis.Mostpatientsreceivingthromboprophylaxisduringpreg-nancywillbenefitfrompostpartumthromboprophylaxis,butthedoseandroutewillvarybyindication(85).

Additional measures should be considered for cer-tain women at particularly high risk of thrombosis atthe time of delivery. Women who have antithrombindeficiencymaybe candidates for antithrombin concen-tratesperipartum.WomenwhohavehadDVTinthe2–4weeksbeforedeliverymaybecandidatesforplacementofaretrievablevenacavalfilter,withremovalpostpar-tum(86,87).Otherwomenwhomaybecandidatesforvena caval filter placement during pregnancy includewomenwithrecurrentvenousthromboembolismdespitetherapeuticanticoagulation(87).

Whenistheoptimaltimetoresumeanti-coagulationtherapypostpartum?

The optimal time to restart anticoagulation therapypostpartum is unclear. A reasonable approach to mini-


mizebleedingcomplications is torestartunfractionatedheparinorLMWHnosoonerthan4–6hoursaftervagi-naldeliveryor6–12hoursaftercesareandelivery.Onestudyof95women treatedwithperipartumenoxaparincomparedwith303controlsfoundnosignificantincreaseintherateofseverepostpartumhemorrhagewhenenoxa-parinwas restartedbetween5hoursand24hoursaftera vaginal delivery and between 12 hours and 36 hoursafteracesareandelivery(88).Currentrecommendationsby American Society of Regional Anesthesia and PainMedicineareforresumptionofprophylacticLMWHnosoonerthan2hoursafterepiduralremoval(78).Becausetheoptimalintervalforresumptionoftherapeuticantico-agulationafterepiduralremovalisunclear,12hoursmaybeareasonableapproach.Whenreinstitutionofantico-agulationtherapyisplannedpostpartum,pneumaticcom-pressiondevicesshouldbeleftinplaceuntilthepatientisambulatoryanduntilanticoagulationtherapyisrestarted.

Womenwhorequiremorethan6weeksoftherapeu-ticanticoagulationmaybebridgedtowarfarin(89–91).Bridgingtowarfarinrequireswomentotaketwoantico-agulantssimultaneously.Forwomenwhorequireonly6weeksofanticoagulationtherapypostpartum,theutilityofwarfarinislimitedbecauseitfrequentlyrequires1–2weeks of administration before a therapeutic range isattained. Consequently, many patients opt to continueLMWHforthe6-weekperiod.Womenwhohaveexperi-encedvenousthromboembolismduringthecurrentpreg-nancy,especiallythoseinthethirdtrimester,willlikelyneedtocontinuetakingwarfarinformorethan6weeksafterdelivery;someexpertsrecommendtakingwarfarinforatleast3–6monthsdependingonthecircumstances(92).Becausewarfarin,LMWH,andunfractionatedhep-arindonotaccumulateinbreastmilkanddonotinduceananticoagulanteffectintheinfant,theseanticoagulantsarecompatiblewithbreastfeeding(89,93,94).

Whatpostpartumhormonalcontraceptiveoptionsareappropriateforwomenwiththrombophilias?

The risk of venous thromboembolism among womentakingestrogen-containingoralcontraceptivesincreases35-fold to99-foldandincreases16-foldamongwomenheterozygous for factor V Leiden and prothrombinG20210A mutations (95). The annual risk of venousthromboembolism is 5.7 per 10,000 among factor VLeidencarriersbut increases to28.5per10,000amongfactor V Leiden heterozygous women using estrogen-containingcontraceptives(relativerisk,34.7)(96).There-fore, alternative methods, such as intrauterine devices(including those containing progestin), progestin-onlypills or implants, and barrier methods should be used

(97).However,screeningallwomenforthrombophiliasbeforeinitiatingcombinationcontraceptionisnotrecom-mended(97–99).

Summary of Recommendations and ConclusionsThe following recommendation is basedongoodandconsistentscientificevidence(LevelA):

Whensignsor symptomssuggestnewonsetDVT,therecommendedinitialdiagnostictestiscompres-sionultrasonographyoftheproximalveins.

The followingrecommendationsandconclusionsarebasedonlimitedorinconsistentscientificevi-dence(LevelB):

Thepreferredanticoagulantsinpregnancyarehepa-rincompounds.

A reasonable approach to minimize postpartumbleedingcomplications is resumptionofanticoagu-lationtherapynosoonerthan4–6hoursaftervaginaldeliveryor6–12hoursaftercesareandelivery.

Becausewarfarin,LMWH,andunfractionatedhepa-rin do not accumulate in breast milk and do notinduce an anticoagulant effect in the infant, theseanticoagulantsarecompatiblewithbreastfeeding.

The following recommendations are based pri-marilyonconsensusandexpertopinion(LevelC):

Womenwithahistoryofthrombosiswhohavenothad a complete evaluation of possible underlyingetiologiesshouldbetestedforbothantiphospholipidantibodiesandforinheritedthrombophilias.

Therapeutic anticoagulation is recommended forwomenwithacutethromboembolismduringthecur-rentpregnancyorthoseathighriskofvenousthrom-boembolism,suchaswomenwithmechanicalheartvalves.

When reinstitution of anticoagulation therapy isplannedpostpartum,pneumaticcompressiondevicesshouldbeleftinplaceuntilthepatientisambulatoryanduntilanticoagulationtherapyisrestarted.

Womenreceivingeithertherapeuticorprophylacticanticoagulation may be converted from LMWH totheshorterhalf-lifeunfractionatedheparininthelastmonth of pregnancy or sooner if delivery appearsimminent.


Canada. Maternal Health Study Group of the CanadianPerinatal Surveillance System. J Obstet Gynaecol Can2009;31:611–20.(LevelII-3)

10. ClarkSL,BelfortMA,DildyGA,HerbstMA,MeyersJA,HankinsGD.Maternaldeathinthe21stcentury:causes,prevention, and relationship to cesarean delivery. Am JObstetGynecol2008;199:36.e1–5;discussion91–2.e7–11.(LevelII-3)

11. ProgramforAppropriateTechnologyinHealth(PATH).Postpartum hemorrhage prevention and treatment: post-partumhemorrhage.Availableat:http://www.pphpreven-tion.org/pph.php.RetrievedApril19,2011.(LevelIII)

12. ChangJ,Elam-EvansLD,BergCJ,HerndonJ,FlowersL,SeedKA,etal.Pregnancy-relatedmortalitysurveillance--UnitedStates,1991--1999.MMWRSurveillSumm2003;52:1–8.(LevelII-3)

13. Blanco-Molina A, Rota LL, Di Micco P, Brenner B,Trujillo-SantosJ,Ruiz-GamieteaA,etal.Venousthrom-boembolism during pregnancy, postpartum or duringcontraceptiveuse.RIETEInvestigators.ThrombHaemost2010;103:306–11.(LevelII-3)

14. GordonMC.Maternalphysiology.In:GabbeSG,NiebylJRandSimpsonJL,editors.Obstetrics:normalandprob-lem pregnancies. 5th ed. Philadelphia (PA): ChurchillLivingstone;2007.p.55–84.(LevelIII)

15. Macklon NS, Greer IA, Bowman AW. An ultrasoundstudy of gestational and postural changes in the deepvenous system of the leg in pregnancy. Br J ObstetGynaecol1997;104:191–7.(LevelIII)

16. WhittyJE,DombroswkiMP.Respiratorydiseasesinpreg-nancy. In: Gabbe SG, Niebyl JR and Simpson JL, edi-tors.Obstetrics:normalandproblempregnancies.5thed.Philadelphia(PA):ChurchillLivingstone;2007.p.939–63.(LevelIII)

17. Danilenko-DixonDR,HeitJA,SilversteinMD,YawnBP,PettersonTM,LohseCM,etal.Riskfactorsfordeepveinthrombosisandpulmonaryembolismduringpregnancyorpostpartum:apopulation-based,case-controlstudy.AmJObstetGynecol2001;184:104–10.(LevelII-3)

18. CarrMH,TowersCV,EastensonAR,PirconRA,IriyeBK,Adashek JA. Prolonged bedrest during pregnancy: doesthe risk of deep vein thrombosis warrant the use ofroutine heparin prophylaxis? J Matern Fetal Med 1997;6:264–7.(LevelII-3)

19. KovacevichGJ,GaichSA,LavinJP,HopkinsMP,CraneSS, Stewart J, et al. The prevalence of thromboemboliceventsamongwomenwithextendedbedrestprescribedas part of the treatment for premature labor or pretermpremature ruptureofmembranes.AmJObstetGynecol2000;182:1089–92.(LevelII-3)

20. Sikovanyecz J,OrvosH,PalA,KatonaM,EndreffyE,HorvathE,etal.Leidenmutation,bedrestandinfection:simultaneous triggersformaternaldeep-vein thrombosisandneonatal intracranialhemorrhage?FetalDiagnTher2004;19:275–7.(LevelIII)

21. ChanWS,SpencerFA,GinsbergJS.Anatomicdistribu-tionofdeepveinthrombosisinpregnancy.CMAJ2010;182:657–60.(LevelIII)

It is recommended towithholdneuraxialblockadefor10–12hoursafter the lastprophylacticdoseofLMWHor24hoursafter the last therapeuticdoseofLMWH.

Placementofpneumaticcompressiondevicesbeforecesarean delivery is recommended for all womennotalreadyreceivingthromboprophylaxis.

Proposed Performance MeasurePercentage of patients assessed for risk factors forthrombosisatthebeginningofpregnancy,duringpreg-nancy,andatthetimeofdelivery

References 1. Heit JA, Kobbervig CE, James AH, Petterson TM,

Bailey KR, Melton LJ III. Trends in the incidence ofvenous thromboembolism during pregnancy or postpar-tum:a30-yearpopulation-based study.Ann InternMed2005;143:697–706.(LevelII-3)

2. Pomp ER, Lenselink AM, Rosendaal FR, Doggen CJ.Pregnancy, the postpartum period and prothromboticdefects: risk of venous thrombosis in the MEGA study.JThrombHaemost2008;6:632–7.(LevelII-2)

3. James AH, Jamison MG, Brancazio LR, Myers ER.Venous thromboembolism during pregnancy and thepostpartumperiod:incidence,riskfactors,andmortality.AmJObstetGynecol2006;194:1311–5.(LevelII-3)

4. AndersenBS,SteffensenFH,SorensenHT,NielsenGL,Olsen J. The cumulative incidence of venous thrombo-embolismduringpregnancyandpuerperium--an11yearDanish population-based study of 63,300 pregnancies.ActaObstetGynecolScand1998;77:170–3.(LevelII-3)

5. Gherman RB, Goodwin TM, Leung B, Byrne JD,HethumumiR,MontoroM.Incidence,clinicalcharacter-istics,andtimingofobjectivelydiagnosedvenousthrom-boembolismduringpregnancy.ObstetGynecol1999;94:730–4.(LevelII-3)

6. LindqvistP,DahlbackB,MarsalK.Thromboticriskdur-ingpregnancy:apopulationstudy.ObstetGynecol1999;94:595–9.(LevelII-3)

7. SimpsonEL,LawrensonRA,NightingaleAL,FarmerRD.Venousthromboembolisminpregnancyandthepuerpe-rium:incidenceandadditionalriskfactorsfromaLondonperinataldatabase.BJOG2001;108:56–60.(LevelII-2)

8. JacobsenAF,SkjeldestadFE,SandsetPM.Incidenceandrisk patterns of venous thromboembolism in pregnancyandpuerperium--aregister-basedcase-controlstudy.AmJObstetGynecol2008;198:233.e1–233.e7.(LevelII-3)

9. Liu S, Rouleau J, Joseph KS, Sauve R, Liston RM,Young D, et al. Epidemiology of pregnancy-associatedvenous thromboembolism: a population-based study in


37. Norris LA, Bonnar J, Smith MP, Steer PJ, Savidge G.Low molecular weight heparin (tinzaparin) therapy formoderate risk thromboprophylaxis during pregnancy. Apharmacokineticstudy.ThrombHaemost2004;92:791–6.(LevelIII)

38. LebaudyC,HulotJS,AmouraZ,Costedoat-ChalumeauN,SerreauR,AnkriA, et al.Changes in enoxaparinphar-macokineticsduringpregnancyandimplicationsforanti-thrombotictherapeuticstrategy.ClinPharmacolTher2008;84:370–7.(LevelII-3)

39. FoxNS,LaughonSK,BenderSD,SaltzmanDH,RebarberA.Anti-factorXaplasmalevelsinpregnantwomenreceivinglowmolecularweightheparinthromboprophylaxis[pub-lishederratumappearsinObstetGynecol2009;113:742].ObstetGynecol2008;112:884–9.(LevelII-3)

40. Bates SM, Greer IA, Pabinger I, Sofaer S, Hirsh J.Venous thromboembolism, thrombophilia, antithrom-botictherapy,andpregnancy:AmericanCollegeofChestPhysiciansEvidence-BasedClinicalPracticeGuidelines.8th ed. American College of Chest Physicians. Chest2008;133:844S–86S.(LevelIII)

41. SansonBJ,LensingAW,PrinsMH,GinsbergJS,BarkaganZS,Lavenne-PardongeE,etal.Safetyof low-molecular-weightheparininpregnancy:asystematicreview.ThrombHaemost1999;81:668–72.(LevelIII)

42. PettilaV,LeinonenP,MarkkolaA,HiilesmaaV,KaajaR.Postpartum bone mineral density in women treated forthromboprophylaxiswithunfractionatedheparinorLMWheparin.ThrombHaemost2002;87:182–6.(LevelI)

43. Carlin AJ, Farquharson RG, Quenby SM, Topping J,Fraser WD. Prospective observational study of bonemineraldensityduringpregnancy:lowmolecularweightheparin versus control. Hum Reprod 2004;19:1211–4.(LevelII-2)

44. CaseleH,HaneyEI,JamesA,Rosene-MontellaK,CarsonM.Bone density changes in women who receive thrombo-prophylaxis in pregnancy. Am J Obstet Gynecol 2006;195:1109–13.(LevelI)

45. RodgerMA,KahnSR,CranneyA,HodsmanA,KovacsMJ,Clement AM, et al. Long-term dalteparin in pregnancynot associated with a decrease in bone mineral density:substudyofarandomizedcontrolledtrial.TIPPSinvesti-gators.JThrombHaemost2007;5:1600–6.(LevelI)

46. BlossomDB,KallenAJ,PatelPR,ElwardA,RobinsonL,Gao G, et al. Outbreak of adverse reactions associatedwith contaminated heparin [published erratum appearsinNEngl JMed2010;362:1056].NEngl JMed2008;359:2674–84.(LevelII-2)

47. YangCJ,ChenTC,LiaoLF,MaL,WangCS,LuPL,etal.NosocomialoutbreakoftwostrainsofBurkholderiacepa-ciacausedbycontaminatedheparin.JHospInfect2008;69:398–400.(LevelIII)

48. CotrufoM,DeFeoM,DeSantoLS,RomanoG,DellaCorteA,RenzulliA,etal.Riskofwarfarinduringpreg-nancywithmechanicalvalveprostheses.ObstetGynecol2002;99:35–40.(LevelIII)

49. Blickstein D, Blickstein I. The risk of fetal loss associ-atedwithwarfarinanticoagulation.IntJGynaecolObstet2002;78:221–5.(LevelIII)

22. Ray JG, Chan WS. Deep vein thrombosis during preg-nancyandthepuerperium:ameta-analysisoftheperiodofriskandthelegofpresentation.ObstetGynecolSurv1999;54:265–71.(Meta-analysis)

23. JamesAH,TapsonVF,GoldhaberSZ.Thrombosisdur-ing pregnancy and the postpartum period. Am J ObstetGynecol2005;193:216–9.(LevelIII)

24. Pabinger I, Grafenhofer H, Kyrle PA, Quehenberger P,MannhalterC,LechnerK,etal.Temporaryincreaseintheriskforrecurrenceduringpregnancyinwomenwithahis-toryofvenousthromboembolism.Blood2002;100:1060–2.(LevelII-3)

25. JamesAH.Venousthromboembolisminpregnancy.Arter-iosclerThrombVascBiol2009;29:326–31.(LevelIII)

26. RobertsonL,WuO,LanghorneP,TwaddleS,ClarkP,LoweGD,etal.Thrombophiliainpregnancy:asystem-aticreview.Thrombosis:RiskandEconomicAssessmentof Thrombophilia Screening (TREATS) Study. Br JHaematol2006;132:171–96.(Meta-analysis)

27. Larsen TB, Sorensen HT, Gislum M, Johnsen SP.Maternal smoking, obesity, and risk of venous throm-boembolism during pregnancy and the puerperium: apopulation-basednestedcase-controlstudy.ThrombRes2007;120:505–9.(LevelII-3)

28. Knight M. Antenatal pulmonary embolism: risk fac-tors, management and outcomes. UKOSS. BJOG 2008;115:453–61.(LevelII-3)

29. Flessa HC, Kapstrom AB, Glueck HI, Will JJ. Placentaltransportofheparin.AmJObstetGynecol1965;93:570–3.(LevelIII)

30. HarenbergJ,SchneiderD,HeilmannL,WolfH.Lackofanti-factorXaactivityinumbilicalcordveinsamplesaftersubcutaneousadministrationofheparinorlowmolecularmassheparininpregnantwomen.Haemostasis1993;23:314–20.(LevelI)

31. GreerIA,Nelson-PiercyC.Low-molecular-weighthepa-rins for thromboprophylaxis and treatment of venousthromboembolism in pregnancy: a systematic review ofsafetyandefficacy.Blood2005;106:401–7.(LevelIII)

32. James AH, Abel DE, Brancazio LR. Anticoagulants inpregnancy. Obstet Gynecol Surv 2006;61:59–69; quiz70–72.(LevelIII)

33. Brancazio LR, Roperti KA, Stierer R, Laifer SA.Pharmacokinetics and pharmacodynamics of subcutane-ousheparinduringtheearlythirdtrimesterofpregnancy.AmJObstetGynecol1995;173:1240–5.(LevelII-2)

34. CaseleHL,LaiferSA,WoelkersDA,VenkataramananR.Changes in the pharmacokinetics of the low-molecular-weightheparinenoxaparinsodiumduringpregnancy.AmJObstetGynecol1999;181:1113–7.(LevelIII)

35. BarbourLA,OjaJL,SchultzLK.Aprospectivetrialthatdemonstrates that dalteparin requirements increase inpregnancy tomaintain therapeutic levelsofanticoagula-tion.AmJObstetGynecol2004;191:1024–9.(LevelIII)

36. LykkeJA,GronlykkeT,Langhoff-RoosJ.Treatmentofdeepvenousthrombosisinpregnantwomen.ActaObstetGynecolScand2008;87:1248–51.(LevelIII)


lism in pregnancy: is it of any use? J Obstet Gynaecol2009;29:101–3.(LevelIII)

65. Chunilal SD, Bates SM. Venous thromboembolism inpregnancy:diagnosis,managementandprevention.ThrombHaemost2009;101:428–38.(LevelIII)

66. CahillAG,StoutMJ,MaconesGA,BhallaS.Diagnosingpulmonary embolism in pregnancy using computed-tomographicangiographyorventilation-perfusion.ObstetGynecol2009;114:124–9.(LevelII-3)

67. TooherR,GatesS,DowswellT,DavisLJ.Prophylaxisforvenousthromboembolicdiseaseinpregnancyandtheearlypostnatalperiod.CochraneDatabaseofSystematicReviews 2010, Issue 5. Art. No.: CD001689. DOI:10.1002/14651858.CD001689.pub2.(LevelIII)

68. CheYaakobCA,DzarrAA,IsmailAA,ZukyNikLahNA,Ho JJ. Anticoagulant therapy for deep vein thrombosis(DVT) in pregnancy. Cochrane Database of SystematicReviews 2010, Issue 6. Art. No.: CD007801. DOI:10.1002/14651858.CD007801.pub2.(LevelIII)

69. Lepercq J, Conard J, Borel-Derlon A, Darmon JY,BoudignatO,FrancoualC,etal.Venousthromboembo-lismduringpregnancy:aretrospectivestudyofenoxapa-rinsafetyin624pregnancies.BJOG2001;108:1134–40.(LevelII-3)

70. Ginsberg JS, Kowalchuk G, Hirsh J, Brill-Edwards P,BurrowsR.Heparin therapyduringpregnancy.Risks tothefetusandmother.ArchInternMed1989;149:2233–6.(LevelII-3)

71. VokeJ,KeidanJ,PavordS,SpencerNH,HuntBJ.Themanagement of antenatal venous thromboembolism inthe UK and Ireland: a prospective multicentre observa-tionalsurvey.BritishSocietyforHaematologyObstetricHaematology Group. Br J Haematol 2007;139:545–58.(LevelIII)

72. Ni Ainle F, Wong A, Appleby N, Byrne B, Regan C,Hassan T, et al. Efficacy and safety of once daily lowmolecularweightheparin(tinzaparinsodium)inhighriskpregnancy. Blood Coagul Fibrinolysis 2008;19:689–92.(LevelIII)

73. KnolHM,SchultingeL,ErwichJJ,MeijerK.Fondaparinuxasanalternativeanticoagulanttherapyduringpregnancy.JThrombHaemost2010;8:1876–9.(LevelIII)

74. Widmer M, Blum J, Hofmeyr GJ, Carroli G, Abdel-AleemH,LumbiganonP,etal.Misoprostolasanadjunctto standard uterotonics for treatment of post-partumhaemorrhage: a multicentre, double-blind randomisedtrial.Lancet2010;375:1808–13.(LevelI)

75. DempfleCE.Minortransplacentalpassageoffondaparinuxinvivo.NEnglJMed2004;350:1914–5.(LevelIII)

76. Warkentin TE, Greinacher A, Koster A, Lincoff AM.Treatmentandpreventionofheparin-inducedthrombocy-topenia:AmericanCollegeofChestPhysiciansEvidence-Based Clinical Practice Guidelines. 8th ed. AmericanCollegeofChestPhysicians.Chest2008;133:340S–80S.(LevelIII)

77. Walenga JM, Prechel M, Jeske WP, Bakhos M.Unfractionated heparin compared with low-molecular-

50. Nassar AH, Hobeika EM, Abd Essamad HM, Taher A,KhalilAM,UstaIM.Pregnancyoutcomeinwomenwithprostheticheartvalves.AmJObstetGynecol2004;191:1009–13.(LevelIII)

51. SadlerL,McCowanL,WhiteH,StewartA,BrackenM,NorthR.Pregnancyoutcomesandcardiaccomplicationsinwomenwithmechanical,bioprostheticandhomograftvalves.BJOG2000;107:245–53.(LevelIII)

52. MeschengieserSS,FondevilaCG,SantarelliMT,LazzariMA.Anticoagulationinpregnantwomenwithmechanicalheartvalveprostheses.Heart1999;82:23–6.(LevelIII)

53. Chen WW, Chan CS, Lee PK, Wang RY, Wong VC.Pregnancy in patients with prosthetic heart valves: anexperience with 45 pregnancies. Q J Med 1982;51:358–65.(LevelIII)

54. WesselingJ,VanDrielD,HeymansHS,RosendaalFR,Geven-BoereLM,SmrkovskyM,etal.Coumarinsduringpregnancy: long-term effects on growth and develop-mentofschool-agechildren.ThrombHaemost2001;85:609–13.(LevelII-2)

55. Iturbe-AlessioI,FonsecaMC,MutchinikO,SantosMA,ZajariasA,SalazarE.Risksofanticoagulant therapy inpregnantwomenwithartificialheartvalves.NEnglJMed1986;315:1390–3.(LevelII-2)

56. ElkayamU,BitarF.ValvularheartdiseaseandpregnancypartI:nativevalves.JAmCollCardiol2005;46:223–30.(LevelIII)

57. Antiphospolipidsyndrome.PracticeBulletinNo.118.Amer-ican College of Obstetricians and Gynecologists. ObstetGynecol2011;117:192–99.

58. Inherited thrombophilias inpregnancy.PracticeBulletinNo. 124. American College of Obstetricians and Gyne-cologists.ObstetGynecol2011;118:730–40.

59. Brill-EdwardsP,GinsbergJS,GentM,HirshJ,BurrowsR,Kearon C, et al. Safety of withholding heparin in preg-nantwomenwithahistoryofvenousthromboembolism.Recurrence of Clot in This Pregnancy Study Group.NEnglJMed2000;343:1439–44.(LevelII-2)

60. ChanWS,LeeA,SpencerFA,CrowtherM,RodgerM,Ramsay T, et al. Predicting deep venous thrombosisin pregnancy: out in “LEFt” field? [published erratumappears in Ann Intern Med 2009;151:516]. Ann InternMed2009;151:85–92.(LevelII-3)

61. Nijkeuter M, Ginsberg JS, Huisman MV. Diagnosis ofdeepvein thrombosisandpulmonaryembolisminpreg-nancy: a systematic review. J Thromb Haemost 2006;4:496–500.(Systematicreview)

62. KovacM,MikovicZ,RakicevicL,SrzenticS,MandicV,DjordjevicV,etal.TheuseofD-dimerwithnewcutoffcan be useful in diagnosis of venous thromboembo-lism in pregnancy. Eur J Obstet Gynecol Reprod Biol2010;148:27–30.(LevelIII)

63. ToMS,HuntBJ,Nelson-PiercyC.AnegativeD-dimerdoes not exclude venous thromboembolism (VTE) inpregnancy.JObstetGynaecol2008;28:222–3.(LevelIII)

64. Damodaram M, Kaladindi M, Luckit J, Yoong W.D-dimers as a screening test for venous thromboembo-


endometrial pathology in women with postmenopausalbleeding: a meta-analysis. Acta Obstet Gynecol Scand2002;81:799–816.(Meta-analysis)

88. Freedman RA, Bauer KA, Neuberg DS, Zwicker JI.Timing of postpartum enoxaparin administration andseverepostpartumhemorrhage.BloodCoagulFibrinolysis2008;19:55–9.(LevelII-3)

89. OrmeML,LewisPJ,deSwietM,SerlinMJ,SibeonR,Baty JD, et al. May mothers given warfarin breast-feedtheirinfants?BrMedJ1977;1:1564–5.(LevelIII)

90. Transferofdrugsandotherchemicals intohumanmilk.American Academy of Pediatrics Committee on Drugs.Pediatrics2001;108:776–89.(LevelIII)

91. McKenna R, Cole ER, Vasan U. Is warfarin sodiumcontraindicated in the lactating mother? J Pediatr 1983;103:325–7.(LevelIII)

92. JamesAH.Preventionandmanagementofvenousthrom-boembolisminpregnancy.AmJMed2007;120(suppl2):S26–34.(LevelIII)

93. Clark SL, Porter TF, West FG. Coumarin derivativesand breast-feeding. Obstet Gynecol 2000;95:938–40.(LevelIII)

94. RichterC,SitzmannJ,LangP,WeitzelH,HuchA,HuchR.Excretion of low molecular weight heparin in humanmilk.BrJClinPharmacol2001;52:708–10.(LevelIII)

95. GomesMP,DeitcherSR.Riskofvenousthromboembolicdiseaseassociatedwithhormonalcontraceptivesandhor-monereplacementtherapy:aclinicalreview.ArchInternMed2004;164:1965–76.(LevelIII)

96. VandenbrouckeJP,KosterT,BrietE,ReitsmaPH,BertinaRM,RosendaalFR.Increasedriskofvenousthrombosisinoral-contraceptiveuserswhoarecarriersoffactorVLeidenmutation.Lancet1994;344:1453–7.(LevelII-2)

97. U.S. medical eligibility criteria for contraceptive use,2010.CentersforDiseaseControlandPrevention(CDC).MMWRRecommRep2010;59(RR-4):1–86.(LevelIII)

98. PriceDT,RidkerPM.FactorVLeidenmutationandtherisksfor thromboembolicdisease:aclinicalperspective.AnnInternMed1997;127:895–903.(LevelIII)

99. Comp PC, Zacur HA. Contraceptive choices in womenwith coagulationdisorders.AmJObstetGynecol1993;168:1990–3.(LevelIII)

weightheparinasrelatedtoheparin-inducedthrombocy-topenia.CurrOpinPulmMed2005;11:385–91.(LevelIII)

78. HorlockerTT,WedelDJ,RowlingsonJC,EnnekingFK.Executive summary: regional anesthesia in the patientreceivingantithromboticorthrombolytictherapy:Ameri-can Society of Regional Anesthesia and Pain MedicineEvidence-Based Guideline. 3rd ed. American Collegeof Chest Physicians [published erratum appears in RegAnesth Pain Med 2010;35:226]. Reg Anesth Pain Med2010;35:102–5.(LevelIII)

79. MacklonNS,GreerIA.Venousthromboembolicdiseasein obstetrics and gynaecology: the Scottish experience.ScottMedJ1996;41:83–6.(LevelII-3)

80. Gates S, Brocklehurst P, Ayers S, Bowler U. Thrombo-prophylaxis and pregnancy: two randomized controlledpilot trials that used low-molecular-weight heparin.ThromboprophylaxisinPregnancyAdvisoryGroup.AmJObstetGynecol2004;191:1296–303.(LevelI)

81. EllisonJ,ThomsonAJ,ConkieJA,McCallF,WalkerD,Greer A. Thromboprophylaxis following caesarean sec-tion--a comparison of the antithrombotic properties ofthree lowmolecularweight heparins--dalteparin, enoxa-parinandtinzaparin.ThrombHaemost2001;86:1374–8.(LevelI)

82. BurrowsRF,GanET,GallusAS,WallaceEM,BurrowsEA.Arandomiseddouble-blindplacebocontrolledtrialoflowmolecular weight heparin as prophylaxis in preventingvenousthromboliceventsaftercaesareansection:apilotstudy.BJOG2001;108:835–9.(LevelI)

83. Quinones JN, James DN, Stamilio DM, Cleary KL,MaconesGA.Thromboprophylaxisaftercesareandeliv-ery:adecisionanalysis.ObstetGynecol2005;106:733–40.(LevelIII)

84. CaseleH,GrobmanWA.Cost-effectivenessofthrombo-prophylaxis with intermittent pneumatic compression atcesarean delivery. Obstet Gynecol 2006;108:535–40.(LevelIII)

85. Inherited thrombophilias inpregnancy.PracticeBulletinNo. 113. American College of Obstetricians and Gyne-cologists.ObstetGynecol2010;116:212–22.(LevelIII)

86. Imberti D, Prisco D. Retrievable vena cava filters: keyconsiderations.ThrombRes2008;122:442–9.(LevelIII)

87. Gupta JK, Chien PF, Voit D, Clark TJ, Khan KS.Ultrasonographic endometrial thickness for diagnosing


The MEDLINE database, the Cochrane Library, and theAmerican College of Obstetricians and Gynecologists’own internal resources anddocumentswereused to con-ductaliteraturesearchtolocaterelevantarticlespublishedbetween January 1985–December 2010. The search wasrestricted to articles published in the English language.Priority was given to articles reporting results of originalresearch, although review articles and commentaries alsowereconsulted.Abstractsofresearchpresentedatsympo-siaandscientificconferenceswerenotconsideredadequatefor inclusion in this document. Guidelines published byorganizationsorinstitutionssuchastheNationalInstitutesof Health and the American College of Obstetricians andGynecologistswerereviewed,andadditionalstudieswerelocated by reviewing bibliographies of identified articles.Whenreliable researchwasnotavailable,expertopinionsfromobstetrician–gynecologistswereused.

Studieswerereviewedandevaluatedforqualityaccordingto the method outlined by the U.S. Preventive ServicesTaskForce:

I Evidence obtained from at least one properlydesignedrandomizedcontrolledtrial.

II-1 Evidence obtained from well-designed controlledtrialswithoutrandomization.

II-2 Evidence obtained from well-designed cohort orcase–controlanalyticstudies,preferablyfrommorethanonecenterorresearchgroup.

II-3 Evidenceobtainedfrommultipletimeserieswithorwithouttheintervention.Dramaticresultsinuncon-trolled experiments also could be regarded as thistypeofevidence.

III Opinionsofrespectedauthorities,basedonclinicalexperience,descriptivestudies,orreportsofexpertcommittees.

Basedon thehighest levelofevidencefoundin thedata,recommendationsareprovidedandgradedaccordingtothefollowingcategories:

LevelA—Recommendationsarebasedongoodandcon-sistentscientificevidence.

LevelB—Recommendationsarebasedonlimitedorincon-sistentscientificevidence.

LevelC—Recommendations arebasedprimarilyoncon-sensusandexpertopinion.

CopyrightSeptember2011bytheAmericanCollegeofObstet-riciansandGynecologists.Allrightsreserved.Nopartof thispublication may be reproduced, stored in a retrieval system,posted on the Internet, or transmitted, in any form or by anymeans, electronic, mechanical, photocopying, recording, orotherwise,withoutpriorwrittenpermissionfromthepublisher.

Requests for authorization to make photocopies should bedirectedtoCopyrightClearanceCenter,222RosewoodDrive,Danvers,MA01923,(978)750-8400.

The American College of Obstetricians and Gynecologists 409 12th Street, SW, PO Box 96920, Washington, DC 20090-6920

Thromboembolisminpregnancy.PracticeBulletinNo.123.AmericanCollege of Obstetricians and Gynecologists. Obstet Gynecol 2011;118:718–29.

the american college of obstetricians and gynecologists...

Documents