doi: 10.1136/jcp.46.6.489 1993 46: 489-496 J Clin Pathol BMJ Publishing Group Ltd and Association of Clinical Pathologists Thrombosis Task. Working Party of the Haemostasis and pregnancy. Maternal and Neonatal haemostasis management of thrombosis associated with Guidelines on the prevention, investigation and http://jcp.bmj.com/content/46/6/489.citation Updated information and services can be found at: These include: References http://jcp.bmj.com/content/46/6/489.citation#related-urls Article cited in: service Email alerting box at the top right corner of the online article. Receive free email alerts when new articles cite this article. Sign up in the Notes http://group.bmj.com/group/rights-licensing/permissions To request permissions go to: http://journals.bmj.com/cgi/reprintform To order reprints go to: http://journals.bmj.com/cgi/ep To subscribe to BMJ go to: group.bmj.com on October 21, 2010 - Published by jcp.bmj.com Downloaded from
BMJ Publishing Group Ltd and Association of Clinical Pathologists Thrombosis Task.Working Party of the Haemostasis and pregnancy. Maternal and Neonatal haemostasismanagement of thrombosis associated with Guidelines on the prevention, investigation and
http://jcp.bmj.com/content/46/6/489.citationUpdated information and services can be found at:
Guidelines on the prevention, investigation andmanagement of thrombosis associated withpregnancy
Maternal and Neonatal Haemostasis Working Party of the Haemostasis and ThrombosisTask
Maternal andNeonatal HaemostasisWorking Party oftheHaemostasis andThrombosis TaskThe members of theWorking Party were:Chairman: Isobel DWalker (haematologist)Members: B T Colvin(haematologist)Elizabeth A Letsky(perinatal haematologist)R Rivers (neonatologist)R F Stevens (paediatrichaematologist)J J Walker (obstetrician)The members of theHaemostasis andThrombosis Task Forcewere:Chairman: B T ColvinSecretary: S J MachinT W BarrowcliffeM GreavesC A LudlamI J MackieF E PrestonP E RoseI D WalkerA WatersJ K WoodThese guidelines shouldbe read in conjunctionwith Guidelines on theUse and Monitoring ofHeparin Treatment(2nd revision 1993)Clin Pathol 46:97-103
and Guidelines onOral Anticoagulation(2nd edition 1990)Clin Pathol 43:177-83
both of which were alsoprepared by theHaemostasis andThrombosis Task Force.Correspondence to:Dr B T Colvin, Departmentof Haematology, The RoyalLondon Hospital, LondonEl 1BB.Accepted for publication18 December 1992
IntroductionAlthough the overall rate of fatal pulmonarythromboembolism has fallen over the past 30years, it is now the most common cause ofmaternal death during pregnancy in theUnited Kingdom.' The incidence of throm-boembolic complications, pulmonary throm-boembolism and deep vein thrombosispresenting during pregnancy is around 1 in1000 with a further 2 per 1000 women pre-senting in the puerperium.' This means thatan average obstetric unit will see between sixand 12 cases a year. Deep vein thrombosisand pulmonary thromboembolism are notjust associated with the risk of mortality;there is an increased morbidity in those thatsurvive. There is also an increased risk ofboth recurrent deep vein thrombosis anddeep vein insufficiency. This risk is greaterthan with similar events outside pregnancy.The prompt and accurate diagnosis of theseconditions is important. The diagnosis andmanagement of venous thrombotic disease inpregnancy is fraught with problems becauseof the fear, on the one hand, of damaging thefetus with irradiation or drugs, and on theother, of failing to prevent, or even causing,serious maternal morbidity with inadequateor inappropriate investigation or with thetreatment chosen. Because of these problems,all aspects of thrombosis diagnosis, preven-tion, and management must be fully dis-cussed with women affected and thesepatients should be encouraged to participatein decision making.
Investigation ofmaternal venousthromboembolic diseaseBecause both treatment and the lack of it maycarry significant risk, accurate diagnosis isimperative. Because the clinical diagnosis ofdeep vein thrombosis and pulmonaryembolism is difficult and frequently inaccu-rate,' there is a positive requirement for"objective" testing in pregnant women withsuspected deep vein thrombosis or pulmonarythromboembolism to minimise the exposureof mothers and their unborn children to thehazards of anticoagulant treatment. Anuncorroborated positive clinical diagnosismay lead needlessly to longterm complica-tions for women with respect to contracep-tion and the management of futurepregnancies.
In people who are not pregnant a multi-tude of tests are available to investigate forand accurately diagnose deep vein thrombosisand pulmonary thromboembolism. Contrastvenography and impedance plethysmography(IPG) are widely used and validated for thediagnosis of deep vein thrombosis.'4 Other"objective" tests for deep vein thrombosisdiagnosis include radioisotope venographyand fibrinogen leg scanning. More recently,Duplex ultrasound scanning and Dopplerultrasonography have been shown to be ofvalue and they are of particular interest foruse in obstetric patients.
At least two major problems require con-sideration with respect to the safety and suit-ability of these objective tests for use duringpregnancy: (a) the risks to the fetus of radio-logical procedures; and (b) the potentialunreliability of non-invasive tests during thelatter stages of pregnancy.
RISKS OF IN UTERO RADIATION EXPOSUREMost studies fail to show any increase in ter-atogenicity following in utero exposure to lowdoses of radiation.5 There may be a slightincrease in the relative risk of childhood can-cer but the absolute risk remains small.
It does, however, seem reasonable toassume that whatever the risks of in uteroirradiation they are likely to be dose related,and the fetus will be more susceptible in earlypregnancy. Every effort should therefore bemade to minimise fetal exposure to radiationparticularly before 12 weeks' gestation.Limited venography with abdominal shieldingexposes the fetus to much less radiation thancontrast venography without abdominalshielding. The diagnosis of suspected pul-monary embolism during pregnancy presentsfewer problems because pulmonary angio-graphy by the brachial route and ventilationand perfusion lung scanning each expose thefetus to very little radiation.
Screening by measuring the uptake of I"'labelled fibrinogen is contraindicatedthroughout pregnancy and the puerperiumbecause of the hazard to the fetus andneonate. In the antenatal period, the freelabel is trapped by the fetal thyroid and cancause hypothyroidism and carcinoma. It issecreted in high concentration in breast milkand the same risks therefore apply to breastfed infants.
Maternal and Neonatal Haemostasis Working Party of the Haemostasis and Thrombosis Task
RELIABILITY OF "OBJECTIVE" TESTS DURINGPREGNANCYAll of the non-invasive approaches to thediagnosis of thrombosis in pregnancy mayproduce false positive results during the laterstages of pregnancy. They can not differenti-ate extrinsic compression of the iliac veins orinferior vena cava by the gravid uterus fromvenous obstruction due to the presence of athrombus within the vessel. At present, con-trast venography remains the most reliablemethod for differentiating between intralumi-nal obstruction and extrinsic compression.
Furthermore, although a negative resultfrom a non-invasive test is likely to exclude aproximal vein thrombosis, none of the nonin-vasive tests is as reliable as venography forexcluding thrombosis in distal (calf) veins.
Equally, a negative result in a limitedvenogram (with abdominal screening) doesnot exclude iliac vein thrombosis.
OUTLINE OF INVESTIGATIONClinical history and examinationA diagnosis of deep vein thrombosis or pul-monary thromboembolism should be consid-ered in all patients presenting with increasingor persisting pain, swelling, or discolorationof a limb, or with sudden onset of chest painor breathlessness, particularly in thosepatients in whom the risk of venous thrombo-embolism may be increased (older or obesewomen and women who have had multiplepregnancies, or varicose veins, or a history orstrong family history of thrombosis, etc).
Objective testsMany maternity units, have access to Duplexultrasound scanning with (sometimes colour)Doppler flow facilities. Real time ultrasoundscanning can be used to visualise the deepvein system directly. In non-pregnant womenit has been shown to be sensitive andspecific.67 More recently, Greer et al showedsimilar accuracy in pregnant patients.8Compression ultrasonography, where the veinis compressed under ultrasound vision, candetect venous thrombosis in the proximalveins with a sensitivity of 94% and a select-ivity of 97%. It has limitations because it isunable to diagnose distal calf vein or an iso-lated iliac vein thrombosis. Doppler flowanalysis consists of listening for the normalvenous signal and the responses to respiratorymovement. It is also accurate in diagnosingproximal vein thrombosis but is less sensitiveto calf vein deep vein thrombosis. It is there-fore recommended that in cases of doubt,limited venography should still be performed.
In centres where IPG is routinely available,this can be performed initially. If the IPGgives a positive result during the first twotrimesters then it is reasonable to accept adiagnosis of deep vein thrombosis and treataccordingly. During the third trimester, apositive IPG requires further investigationusing limited venography. As with ultra-sound; a negative IPG excludes proximal veinthrombosis but not calf vein thrombi.The safety of not treating calf vein throm-
bosis in non-pregnant patients in whom theimpedance plethysmography remains negativehas been established,9 but the implications ofadopting a policy of non-treatment of calfvein thrombosis in pregnancy are not known.In theory, at least, venous stasis resultingfrom compression of the pelvic veins by theuterus may increase the risk of clinicallyimportant extension of calf vein thrombi dur-ing pregnancy. It is therefore suggested that ifthe impedance plethysmography is negative,or in any other case of doubt, limited venog-raphy to exclude calf vein thrombosis shouldbe performed before finally deciding not totreat.
Venography is the only technique thatgives information in all parts of the vasculartree. After limited venography, a positiveresult implies that treatment should be start-ed. If the limited venogram is negative thenfull venography is indicated to confirm orexclude iliac vein thrombosis because theradiation risk to the fetus is outweighed bythe risks of not treating a mother with venousthrombosis or unnecessarily treating one whohas no venous thrombotic disease.The diagnosis of pulmonary thromboem-
bolism during pregnancy may be easierbecause the radiation risk to the fetus is less.Initially, a chest x ray is required to excludeconditions which may clinically mimic pul-monary thromboembolism (pleurisy, pneu-mothorax, fractured rib). If the chest x-raypicture is non-diagnostic, ventilation and per-fusion lung scans should be performed. If theperfusion scan is negative pulmonary throm-boembolism can be excluded.10 If there is asegmental perfusion defect with normal venti-lation then it is reasonable to accept a highprobability of pulmonary thromboembolismand treat accordingly. If there is a subseg-mental perfusion defect with normal ventila-tion or matched perfusion and ventilationdefects, then the probability of pulmonarythromboembolism is only between 1040%10and in these cases pulmonary angiography(preferably by the brachial route) is necessaryto avoid treating unnecessarily a large per-centage of patients. This procedure carriesincreased risk to the fetus and should be usedonly if essential.
Laboratory investigationIt must be borne in mind that pregnancyitself alters the concentrations of haemostaticfactors, the procoagulants factor VII, factorVIII, and fibrinogen and the natural anticoag-ulant protein C increasing, particularly in thethird trimester, and both total and free pro-tein S decreasing from the first trimesteronwards. An acute thrombotic event may beassociated with very sharp reductions in theconcentrations of natural anticoagulants.
Pregnancy itself may be considered to be a"thrombotic risk" condition but all patientswith deep vein thrombosis or pulmonarythromboembolism require laboratory investi-gation to identify or exclude an underlyinghaemostatic defect. The investigations shouldinclude, in the first place, full blood count
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and platelet count, blood film, coagulationscreen (activated partial thromboplastin time,prothrombin time and thrombin time), func-tional assays of "natural anticoagulants"(antithrombin III, protein C, protein S) andtests for lupus inhibitors and other antiphos-pholipid antibodies.
It is difficult and sometimes impossible toconfirm or exclude an underlying throm-bophilic condition in a pregnant patient whorecently has had a DVT; therefore, follow upinvestigation of these patients when they are
not pregnant, not anticoagulated, and notsuffering an acute thrombotic event is recom-mended. A carefully taken family history andin some instances (for example, in antithrom-bin III, protein C, or protein S deficiency)testing family members may assist early diag-nosis and is essential to confirm the inheritednature of the defect.
Treatment ofthromboembolism inpregnancyCareful consideration must be given towhether a particular pregnant patient withthromboembolism should be managed in an
obstetric unit or in a medical ward. The finaldecision will depend on the extent and severi-ty of the thromboembolism and on theassessed needs of the pregnancy and the like-lihood of requiring immediate or urgentobstetric or neonatal care. Because of theseverity of the thrombotic event, some
patients may require transfer to a unit withspecialist diagnostic and backup facilities.Treatment must not be delayed if the clinicalsuspicion of thromboembolism is high, butobjective verification of the diagnosis must besought as soon as possible. If investigationsprove negative treatment can be stopped.
SURGERYLife threatening pulmonary embolism mayrequire surgical intervention. Patients whohave massive ileofemoral thrombosis shouldbe managed in centres where expert surgicalhelp is available if urgently needed. In thesecases the transfer of the patient to a unit withthe necessary facilities may be required. If thethrombus is free floating the risk of embolismis high. The use of caval filters can save lives.
THROMBOLYSISBecause of the risk of major haemorrhagefrom the placental site, the use of fibrinolyticagents is not recommended during pregnancyand should be avoided if delivery is immi-nent, or during the first few days after deliv-ery, unless surgical intervention is notpossible and fatal pulmonary embolism seemslikely.
Therapeutic anticoagulation inpregnancyAnticoagulant treatment during pregnancy isindicated for the treatment or prevention ofvenous thromboembolic disease and inpatients with valvular heart disease or pros-
thetic heart valves to prevent systemicembolism. The use of anticoagulants duringpregnancy is problematic and their introduc-tion or continuation must be carefully consid-ered in each patient.The oral anticoagulants, vitamin K antago-
nists, cross the placenta and potentially causeadverse effects in the fetus. Heparins do notseem to cross the placenta. But they have thepotential to cause adverse effects in themother.
WARFARINExposure to warfarin during organogenesismay be associated with embryopathy. Theincidence of embryopathic changes is verydifficult to estimate. Much of the publishedfindings on this topic comprise case reportsand are therefore subject to bias. In a smallprospective study Iturbe-Alessio et al reportedembryopathy in 10 out of 35 full term preg-nancies (29%; 95% confidence limits 15%-46%) after exposure to warfarin during thefirst trimester." Avoiding warfarin during theperiod from 6-12 weeks' gestation seems toreduce the risk of embryopathy considerablybut should not be regarded as abolishing therisk completely.
Patients receiving longterm oral anticoagu-lants should seek medical advice before preg-nancy so that the desirability and feasibility ofsubstituting heparin for the first trimester ofpregnancy can be considered. Patients whoconceive whilst taking warfarin should seekfurther medical advice as soon as a pregnancyis suspected.
It has also been suggested that central ner-vous system (CNS) abnormalities-due tointracranial haemorrhages and malforma-tions-occur increasingly often in the babiesof mothers taking warfarin at any stage oftheir pregnancy. On examining the publishedevidence, Ginsberg et al concluded that CNSabnormalities are a rare complication of war-farin treatment during pregnancy. 12 Theyreaffirm, however, that the use of oral antico-agulants in pregnancy is associated with anincreased rate of fetal wastage and congenitalmalformations.
Letsky states that the risk of fetal malfor-mation may be overstated because abnormali-ties seem to be uncommon in the UnitedKingdom and the risk is probably dose relat-ed."3 The risk of fetal damage must beweighted against the problems and risk ofconverting the mother to heparin.
Because of the risk of fetal intracranialhaemorrhage occurring during delivery, oralanticoagulants should be discontinued nolater than 36 weeks' gestation or two to threeweeks before expected delivery. Anti-coagulation should be maintained withheparin.
HEPARINThere is no evidence that either unfractionat-ed or low molecular weight heparins cross theplacenta. They would not therefore beexpected to cause direct adverse effects to thefetus. Previous reports that the use of heparin
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in pregnancy may be associated with a highrate of fetal loss are not supported onreview.'4 The fetal loss could be explained onthe basis of concomitant maternal morbidconditions which were responsible for adverseeffects. 12
Osteoporosis is a rare but much fearedcomplication of longterm heparin treat-ment.5 16 The available evidence suggests thatheparin associated bone demineralisation isdose and duration dependent,'7 but conclu-sive evidence about the risks of developingclinically important osteoporosis is difficult toobtain. Women taking 20 000 IU heparindaily for more than five months may be atincreased risk,'8 but the possibility that only asubgroup of patients is susceptible to theeffects of heparin on bone density must alsobe considered.'9 Originally it was postulatedthat heparin-induced bone changes were irre-versible but a more recent report suggeststhat bone density changes may be reversible.23There is no correlation between bone lossand the symptoms relating to it.21 Ginsberg etal concluded that heparin used for over onemonth is associated with a very small risk ofsymptomatic osteoporosis but causes a reduc-tion in bone density in the axial skeleton andlong bones.'9
Because of the degree of susceptibility tothese bone density changes, their reversibilityin individual patients and the possibility thataffected women may be at increased risk ofthe complications of osteoporosis followingthe menopause, it is recommended that wher-ever possible the dose and duration ofheparin treatment is minimised.
Thrombocytopenia is a rare complicationof heparin treatment in the United Kingdom.Two distinct groups are described: a mildsymptomless thrombocytopenia of earlyonset, probably due to a direct action ofheparin on platelets; and a delayed onset(from 6 to 10 days or more) associated, para-doxically, with thromboembolism. This sec-ond group has an immune basis and isassociated with an IgG heparin dependentantibody.22 The heparin must be discontinuedimmediately. A heparin from a differentsource or a low molecular weight heparin canbe substituted but this must be done withcaution since cross-reactivity may occur. Achange to oral anticoagulation may have to beconsidered.
Notwithstanding these potential complica-tions heparin remains the anticoagulant ofchoice for the prevention and management ofvenous thromboembolism in pregnancy.
MANAGEMENT OF ACUTE VENOUSTHROMBOEMBOLISMIn the United Kingdom the immediate man-agement of acute venous thrombosis orthromboembolism usually includes con-tinuous intravenous infusion of heparin, abolus of 5000 IU or up to 10 000 IU insevere pulmonary embolism, followed by acontinuous infusion starting with a dose of1000-2000 IU/hour.Whenever possible a platelet count and a
coagulation screen should be performedbefore treatment and the laboratory responseto the infusion should be checked four to sixhours after its start. The heparin dose shouldbe adjusted as necessary, repeating the labo-ratory monitoring four to six hours after anydose adjustment.
Antenatal patients require anticoagulationfor the remainder of their pregnancy. This isusually most conveniently and safely achievedby substituting self administered intermittentsubcutaneous heparin after six to ten days. Apreparation of heparin with a concentrationof 25 000 IU/ml should be used for subcuta-neous administration and the patient taughtto use a small volume syringe to ensure pre-cise dosage. A regimen of 10 000-15 000IU/12 hourly is usually adequate and safe butshould be monitored. Some studies haveshown that acute venous thrombosis may bemanaged from the outset with subcutaneousheparin 15 000 IU/12 hourly, but thisremains a less common practice in the UnitedKingdom.
If the patient has delivered, a vitamin Kantagonist, usually warfarin, can be startedaround three to five days after heparin hasbeen introduced and overlapped for three tofive days until the full effects of warfarin havebeen achieved. All patients should remaintaking anticoagulant treatment until at leastsix weeks after delivery.The newer low molecular weight heparins
are more expensive than standard unfraction-ated heparin but have certain theoreticaladvantages; for example, they have a longerhalf life. There is little experience of their usein pregnancy to support their widespread useat present but these agents are raising consid-erable interest and the results of further clini-cal trials are eagerly awaited.
LABORATORY MONITORING OF HEPARINTREATMENTIn the United Kingdom the most commonlyused test for monitoring treatment withunfractionated heparin is the activated partialthromboplastin time (APTT). Using theAPTT, antithrombotic activity requires a pro-longation of 1 5-2'0 times the midpoint ofthe normal range and usually the upper"safe" limit in those who are not pregnant isstated to be 2-5. This test does, however,have some limitations and a specific anti-Xaassay of heparin in plasma should be used inpatients where the response to heparin is dif-ficult to predict-for example in patients withantithrombin III deficiency-aiming toachieve a plasma heparin concentration of 0-2to 0 4 IU/ml which roughly corresponds withthe APIT range of 1-5-2.518 depending onthe APTT reagent used. During pregnancyhigh procoagulant concentrations in plasmaparticularly of FVIII and fibrinogen mayresult in low APTT values despite adequateplasma heparin concentrations. This shouldbe borne in mind particularly when treatingpatients in the third trimester, when it may bedifficult and even dangerous to try to achievehigh APTT values. In the situation of appar-
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ent heparin resistance, where large doses ofheparin fail to prolong the APTT into thetherapeutic range, anti-Xa assays may behelpful. If a low molecular weight heparin isused the AP'TT will not be prolonged and ananti-Xa assay must be used.The average plasma heparin concentration
achieved following subcutaneous injection isprobably somewhat lower than that achievedby giving the same dose of heparin by intra-venous infusion.2' The timing of monitoringrelative to heparin injection must be stan-dardised and APTT tests performed four tosix hours after injection permit optimal dosecontrol and adjustment.
Prophylactic anticoagulation in pregnancyPREVENTION OF CARDIAC/ARTERIALTHROMBOEMBOLISMPatients who are receiving long term oralanticoagulants because they have a prostheticheart valve present a particular problem dur-ing pregnancy as warfarin is known to causefetal abnormality. It has been shown that sub-stituting low dose subcutaneously adminis-tered heparin (5000 IU/12 hourly) for thevitamin K antagonist being taken before con-ception gives inadequate protection againstprosthetic valve thrombosis."Some authors recommend that in these
women continuous intravenous heparin infull therapeutic doses is substituted for war-farin during the period when the fetus is con-sidered to be most at risk of teratogenic drugeffects (6-12 weeks' gestation)." This policyobviously requires careful counselling beforeconception and easily available facilities forearly pregnancy diagnosis.Modem pregnancy tests can confirm con-
ception before the first missed menstrual peri-od. After careful pregnancy counsellingwomen are asked to attend as soon as a preg-nancy is suspected. If the pregnancy test ispositive, continuous intravenous heparintreatment may be substituted for warfarinuntil 12 weeks' gestation when warfarin maybe reintroduced. Early pregnancy tests, how-ever, do not guarantee fetal viability and atthis stage of pregnancy miscarriage rates arearound 15%. Ultrasound scans at 5-6 weeks'gestation give a more accurate assessment ofcontinuing pregnancy. Because of these prob-lems, many women with prosthetic valvescontinue to take warfarin throughout the firsttrimester, accepting the risk of teratogenicity.
Careful monitoring of warfarin treatmentusing the prothrombin time/InternationalNormalised Ratio (INR) is required more fre-quently than in non-pregnant patientsbecause of changing coagulation factor con-centrations and plasma volume. Continuousfull dose therapeutic intravenous heparinmust be substituted for oral anticoagulants ataround 36 weeks' gestation or two to threeweeks before the expected delivery. Warfarinmay be reintroduced immediately after deliv-ery either at the previous maintenance doseor at doses of 7 mg, 7 mg, and 5 mg, respec-tively, on the first three days. Heparin must
be continued in full doses for at least threedays until warfarin is fully effective.
PREVENTION OF VENOUS THROMBOEMBOLISMThrombosis prophylaxis during pregnancycan be considered in two broad groups: (1)Women with a history of thromboembolismbut no known underlying haemostatic abnor-mality and; (2) women with or without a his-tory of thrombotic disease who are known tohave an inherited "thrombophilic" abnormal-ity-for example, deficiency of antithrombinIII, protein C, or protein S, or acquiredthrombophilia due, for example, to thepresence in their plasma of antiphospholipidantibodies (such as lupus inhibitor or anti-cardiolipin antibodies).
Women with a thrombotic history but no knownthrombophilic abnormalityIt is very difficult to generalise about themanagement of these patients who are thesubject of a proposed international collabora-tive study comparing different managementstrategies (Ginsberg, personal communica-tion). Some authors concerned about therisks of anticoagulation during pregnancy rec-ommend that patients with a history of a sin-gle episode of thromboembolism and noadditional thrombosis "risk factors" aresupervised carefully antenatally and givenprophylactic anticoagulation intrapartum andfor six weeks post partum, statistically thetime when thrombosis is most likely tooccur.2 Other authors prefer a policy ofheparin prophylaxis throughout pregnancyusing self administered subcutaneous heparinin doses of 7500-10 000 IU/12 hourly.'4A policy somewhere between these two
extremes may be possible-delaying anti-coagulation until the puerperium in thosewomen in whom the past episode occurredpostnatally and introducing heparin four tosix weeks ahead of the stage at which throm-bosis occurred in those patients with a historyof thrombosis during pregnancy. Womenwhose thrombotic history was not associatedwith pregnancy may be anticoagulatedthroughout pregnancy if the past episode wassevere but perhaps only during the thirdtrimester or puerperium if the previousepisode was less serious. Before 36 weeks adose of 7500 IU/12 hourly may be used,increasing to 10 000 IU 12 hourly at 36 weeksand decreasing again to 7500 IU/12 hourlypostnatally. Monitoring to exclude excessivedegrees of anticoagulation and a periodicplatelet count are recommended. Warfarinmay be introduced immediately after deliverybut must be overlapped with or covered withheparin for at least the first three days until itis fully effective. Anticoagulation should becontinued at least until six weeks post par-tum. The management of each of thesewomen and each of their pregnancies must beindividually considered.
Women with known thrombophilic abnormalitiesAt present there is great interest in the man-agement of women who have been shown to
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have inherited deficiencies of antithrombinIII, protein C, or protein S or to haveacquired antiphospholipid antibodies, but inmany patients it remains extremely difficult togive clear advice.25 The use of prophylacticanticoagulation should not be an automaticconsequence of the knowledge that a womanhas reduced antithrombin III, protein C, orprotein S or has antiphospholipid antibodies.A careful history and family history must
be taken. A previous episode of thrombosis inconjunction with one of these defects wouldweight a decision in favour of prophylacticanticoagulation. The increased risk of throm-bosis associated with antithrombin III, pro-tein C, or protein S deficiency in pregnancyand the puerperium is difficult to assess butseems to be greater for antithrombin III defi-ciency than for protein C or protein S defi-ciency.26 Furthermore, it is quite clear, that atleast in non-pregnant patients the prevalenceof thromboembolism associated with anti-thrombin III deficiency is generally less inthose in whom functional defects affect onlythe heparin binding properties of the mole-cule than in those in whom there is loss orreduction in function at the active (anti-thrombin and anti-Xa) site. Characterisationof the subtype of inherited antithrombin IIIdeficiency may be clinically important inmaking decisions about the type and timingof intervention in affected women during andafter pregnancy but this requires furtherstudy.
In general, women with evidence of signifi-cantly reduced antithrombin activity shouldbe anticoagulated with heparin throughoutpregnancy and the puerperium whether ornot they have had a previous thromboticepisode and whether or not they are receivinglong term anticoagulation. Heparin should beself administered subcutaneously in dosessimilar to those used for the treatment ofvenous thrombosis 10 000-17 500 IU/12hourly, aiming to achieve an AP1T ratio of1-5-2-0 four to six hours after injection, butaccepting as pregnancy proceeds and factorVIII concentrations rise, that this may beimpossible to achieve when an anti-Xa assaymay be helpful. Regular monitoring to allowfor dose adjustment and check the plateletcount is essential.Women who have other inherited throm-
bophilic abnormalities and who have a historyof thrombosis also probably require anticoag-ulation during pregnancy and the puerperi-um. The time when this should be introducedis unclear but it has been suggested that if theprevious event was in late pregnancy or thepuerperium and if there have been no "spon-tanous" events, prophylactic doses of heparinsubcutaneously (5000-7500 IU/12 hourly)may suffice during the first and perhaps thesecond trimester. Full therapeutic doses ofheparin given subcutaneously should beintroduced to cover the third trimester andthe puerperium.2' At present it is very difficultto advise on the management of asympto-matic protein C or protein S deficient womenin pregnancy as no ideal regimen exists. Each
woman must be considered on an individualbasis, but women with a family history ofthrombosis probably merit prophylactic anti-coagulation as outlined above during preg-nancy.
Antiphospholipid antibodies are clinicallyimportant because they are associated withrecurrent fetal loss due to placental insuffi-ciency, and in some women a tendency torecurrent thrombosis. The management ofpregnancy in women with antiphospholipidantibodies is extremely difficult and currentlythe subject of study. As with inherited throm-bophilia it is impossible to identify whichwomen with laboratory evidence of antiphos-pholipid antibodies (lupus anticoagulant orincreased anticardiolipin antibodies) willdevelop clinical problems. If a woman hasantiphospholipid antibodies but no previoushistory of thromboembolism it may be worthtreating her with low dose aspirin (75 mg)daily until 36 weeks' gestation if she hasalready sustained fetal loss. It is currentlyrecommended that treatment is stopped at 36weeks because of the potential risk ofhaematoma formation associated with anepidural injection. This risk is probably over-stated and it is hoped that the large multi-centre studies on low dose aspirin inpregnancy will answer the problem. Inpatients with previous pregnancy loss, despiteprophylactic aspirin, the role of cortico-steroids, intravenous immunoglobulin, andheparin remains to be determined.
It is not considered, in general, justifiableto put patients without a history of thrombo-sis on longterm anticoagulants solely on thebasis of a laboratory finding of antiphospho-lipid antibodies. The combination of preg-nancy and antiphospholipid antibodies mayenhance the risk of thrombosis, but thedegree of this potential interaction is notknown. Women who are receiving longtermoral anticoagulants because of recurrentvenous thrombosis associated with antiphos-pholipid antibodies can be managed through-out pregnancy with subcutaneous heparin butmust be carefully counselled before concep-tion, and as with other patients receivinglongterm warfarin advised to seek medicaladvice as soon as a pregnancy is suspected.Women not receiving longterm anticoagu-lants but with a history of thrombosis shouldalso be considered as candidates for anticoag-ulation during pregnancy and the puerperi-um. The question of offering asymptomaticpatients, not receiving long term anticoagu-lants, anticoagulant cover during or afterpregnancy must be individually considered. Itis important to realise that for more than onereason these are high risk pregnancies requir-ing intensive maternal and fetal monitoring inspecialist units. At present it is suggested thatthey are best managed in centres with specialexpertise.28
PREPARATION FOR DELIVERYIt is valuable to aim for a planned delivery inpatients receiving anticoagulant treatment.Patients receiving full therapeutic doses of
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heparin must reduce their heparin dose onthe day of delivery-to 10 000-15 000 IU/24hours intravenously (or 5000-7500 IU/12hourly subcutaneously). Patients taking lowerprophylactic doses of heparin can continueprophylaxis throughout labour and delivery.
In all patients the APTT must be checkedto ensure it has normalised with reduction ordiscontinuation of heparin. Pregnant womenreceiving subcutaneous heparin may present amanagement problem at delivery becausethey may be at increased risk of bleeding ordeveloping haematomata if a prolongedAPTT persists for longer than anticipated, asmay happen in patients using heparin sub-cutaneously over a period of time.29Replacement of deficient inhibitors with con-centrates may be useful at the time of delivery(antithrombin III concentrate).'0
Planning the delivery of a patient receivingwarfarin is even more important. Everyattempt should be made to change to heparintwo to three weeks before labour or deliveryand no later than 36 weeks' gestation. Iflabour occurs or if delivery is contemplated ina mother still fully anticoagulated using war-farin, caesarean section should be consideredto protect the fetus from the possibility ofintracranial haemorrhage. If the INR isbetween 2-0-2-5 the risk of maternal bleedingduring operation is low, although a result ofaround 2-0 would be desirable. In patientswith an artificial heart valve it may be danger-ous to reduce the INR to below 2-0 in theabsence of anticoagulation. For womenwhose INR is in the therapeutic range vita-min K is contraindicated but should be givento the baby intravenously into the cord atdelivery. Fresh frozen plasma can be used forbleeding in either mother or baby and 2-3units should be made available: 10 ml/kg is asuitable dose of fresh frozen plasma for aneonate. Prothrombin complex concentratesmay be thrombogenic and should be consid-ered only in life-threatening haemorrhage.
If a patient is anticoagulated at the time ofdelivery, epidural analgesia is hazardous ashaematoma formation has been reported bothfollowing insertion and removal of the cannu-la. If anticoagulants have been discontinuedor if low dose prophylactic anticoagulants arebeing administered, providing the coagulationscreen is within normal limits, the plateletcount greater than 80 x 109/1, and the bleed-ing time normal it is probably safe to intro-duce an epidural catheter"3 but no consensusopinion has been achieved. Full discussionand cooperation with the anaesthetist isrequired in these situations and the relativebenefits and risks considered on an individualbasis.
After delivery heparin should be reintro-duced in a dose of 20 000-30 000 IU/day.Warfarin can be started immediately. Ifpreviously receiving warfarin, patients shouldbe restarted on their maintenance dosagebefore pregnancy. If starting warfarin for thefirst time, doses of 7 mg, 7 mg, and 5 mgshould be used respectively on the first threedays. Heparin must be continued for at least
three days until warfarin has become fullyeffective.
BREAST FEEDINGWarfarin has a high degree of protein bindingand is not secreted in any large quantity intobreast milk.'2 Mothers can therefore safelybreast feed while taking warfarin. Occa-sionally blood staining of the milk occurs inanticoagulated mothers. This is usually dueto local nipple trauma or mild infection.Neonates may be upset by the presence ofthis blood and it is often necessary to stopfeeding from the affected breast until bleed-ing stops. Expression of the milk is essentialto ensure continued production and patientcomfort.
LONG TERM FOLLOW UPIt is important that any patient started onanticoagulants during pregnancy or the puer-perium is followed up after delivery. A thera-peutic plan should be outlined. If thetreatment was started because of thromboem-bolism, further investigation may be neces-sary for complete diagnosis, andanticoagulation can usually be stopped sixweeks after birth. The implications of thediagnosis for future pregnancy and contracep-tion should be outlined. The plan for treat-ment of subsequent pregnancies should bediscussed before any such pregnancy isembarked on.
The advice contained in these guidelines is believed to repre-sent the state of the art at the time of going to press. It is poli-cy to revise the guidelines as new developments occur, but itmay not be possible to do this at the time of such changes andthe guidelines should always be used with due regard to cur-rent acceptable practice.Comments are invited to assist the review process. All cor-
respondence regarding the guidelines should be addressed to:BCSH Secretary, British Society for Haematology, 2 CarltonHouse Terrace, London SW1Y 5AF.
1 Turnbull A, Tindall VR, BeardR W, et al. Report onConfidential Enquiries into Matenal Deaths in Englandand Wales 1982-1984. London: HMSO 1989; 28-36.
2 Letsky EA. Thromboembolism during pregnancy. In:Coagulation problems in pregnancy. Current reviews inobstetrics and gynaecology. London: Churchill Living-stone, 1985: 29-61.
3 Barnes RW, Wu KK, Hoak JC. Fallibility of the clinicaldiagnosis of venous thrombosis. JAMA 1975;234:605-7.
4 Hull R, Taylor DW, Hirsh J, et al. Impedance plethys-mography: The relationship between venous filling andsensitivity and specificity for proximal vein thrombosis.Circulation 1978;58:898-902.
5 Ginsberg JS, Hirsh J, Rainbow AJ, Coates G. Risks to thefetus of radiologic procedures used in the diagnosis ofmaternal venous thromboembolic disease. ThrombHaemostas 1989a;61: 189-96.
6 Dauzat MM, Laroche JP, Charras C, et al. Real-time B-mode ultrasonography for better specificity in the non-invasive diagnosis of deep vein thrombosis. Y UltrasoundMed 1986;5:625-31.
7 Rosner NH, Doris PE. Diagnosis of femoropoplitealvenous thrombosis: comparison of duplex sonographyand plethysmography. Am J Roentgenol 1988;150:623-7.
8 Greer IA, Barry J, Mackon N, Allan PL. Diagnosis ofdeep vein thrombosis in pregnancy: a new role for diag-nostic ultrasound. BrJ Obstet Gynaecol 1990;97:53-7.
9 Hull R, Hirsh J, Carter C, et al. Diagnostic efficacy ofimpedance plethysmography for clinically suspecteddeep vein thrombosis. Ann Intern Med 1985a;102:21-8.
10 Hull R, Hirsh J, Carter C, et al. Diagnostic value of venti-lation-perfulsion lung scanning in patients with suspect-ed puimonary embolism. Chest 1985b;88:819-28.
11 Iturbe-Alessio I, Fonesca MC, Mutchinik 0, Santos MA,Zajarias A, Salazar E. Risks of anticoagulant therapy inpregnant women with artificial heart valves. N Engl JMed 1986;315:1390-3.
495
group.bmj.com on October 21, 2010 - Published by jcp.bmj.comDownloaded from
on bone density. Throm Haemostas 1990;64:286-9.20 Dahlman TC, Lindvall N, Hellgren M. Osteopenia in
pregnancy during longterm heparin treatment. A radio-logical study post partum. Br J Obstet Gynaecol1990;97:221-8.
21 de Swiet M, Dorington Ward P, Fidler J, et al. Prolongedheparin therapy in pregnancy causes bone demineralisa-tion (heparin induced osteopenia). Br J Obstet Gynaecol1983;90:1129-34.
22 Chong BH, Pitney WR, Castaldi PA. Heparin inducedthrombocytopenia. Association of thrombotic complica-tions with heparin-dependent IgG antibody that inducesthromboxane synthesis and platelet aggregation. Lancet1982;ii: 1246-9.
23 Andersson G, Fagrell B, Holmgren K, Johnsson H,Wilhelmsson S, Zetterquist S. Subcutaneous adminis-tration of heparin. A randomised comparison with intra-venous administration of heparin to patients with deepvein thrombosis. Thromb Res 1982;27:631 -9.
24 Dahlman TC, Hellgren MSE, Blomback M. Thrombosisprophylaxis in pregnancy with use of subcutaneousheparin adjusted by monitoring heparin concentrationin plasma. Am Obstet Gynecol 1989;161:420-5.
25 Walker ID. Management of thrombophilia in pregnancy.Blood Reviews 1991;5:227-33.
26 Conard J, Horellou MH, Van Dreden P, Lecompte T,Samama M. Thrombosis and pregnancy in congenitaldeficiencies in ATIII, protein C or protein S. Study of78 women. Thromb Haemostas 1990;63:319-20.
27 Haemostasis and Thrombosis Task Force. The BritishSociety for Haematology: Guidelines on the investiga-tion and management of thrombophilia. I7C/in Pathol1990;43:703-10.
28 Creagh MD, Greaves M. Lupus anticoagulant. Blood Rev1991;5:162-7.
29 Anderson DR, Ginsberg JS, Burrows R, Brill-Edwards P.Subcutaneous heparin therapy during pregnancy: a needfor concern at the time of delivery. Thromb Haemostas1991;65:248-50.
30 Hellgren M, Tengborn L, Abildgaard U. Pregnancy inwomen with congenital antithrombin III deficiency:experience of treatment with heparin and antithrombin.Gynaecol Obstet Invest 1982; 14:127-41.
31 Letsky EA. Haemostasis and epidural anaesthesia. Int 7ObstetAnaesthes 1991;1:51-4.
32 L'E Orme M, Lewis PJ, de Swiet M, et al. May mothersgiven warfarin breast feed their infants? Br Med .71977;i: 1564-5.
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