Treatment of 51 Pregnancies with Danaparoid Because of Heparin

Blood Coagulation, Fibrinolysis and CellularHaemostasis

Treatment of 51 pregnancies withdanaparoidbecause of heparin intolerance

EdelgardLindhoff-Last1 ,Hans-Joachim Kreutzenbeck2 ,Harry N. Magnani3 1 Division ofVascular Medicine,Department of Internal Medicine,University Hospital Frankfurt, Germany 2 MedicalDepartment, Celltech, Essen, Germany 3 Clinical Consultant Marketing, OrganonBV, Oss,The Netherlands

Summary Pregnant patients withacute venous thrombosis or ahistoryof required (3/14) or an adverse eventled to atreatment discon- thrombosis mayneed alternative anticoagulation, when heparin tinuation (11/14).Four maternal bleeding events were recorded intolerance occurs. Onlylimited dataonthe useofthe hepari- during pregnancy, deliveryorpostpartum, twoofthemwere noiddanaparoid areavailable in literature.We reviewedthe use fatal duetoplacental problems.Three fetal deathswererec- of danaparoid in 51 pregnancies of 49 patients identified in litera- orded,all associated with maternal complications antedating da- turebetween 1981 and 2004.All patients had developed hepa- naparoiduse.Danaparoid cross-reactivity was suspectedin4 rin intolerance (32 duetoheparin-induced thrombocytopenia, HITpatientsand 5non-HITpatientswith skin reactions and was 19 mainlydue to heparin-induced skin rashes)and had acurrent confirmedserologicallyinone of the twoHIT patients tested.In and/or pasthistoryofthromboembolic complications.The initial none of fivefetal cordblood- andthree maternal breast milk- danaparoid doseregimens ranged from 1000 to 7500 U/day ad- samplesanti-Xa activity transferwas observed.Inconclusion da- ministereds.c.ori.v..Themedian duration of danaparoid use was naparoid can be usedasanalternativeantithrombotic agentin 10 weeks.Danaparoid was useduntil deliveryofahealthyinfant pregnant womenwith high thrombotic riskand intolerance to in 37 pregnancies. In the remaining 14 pregnancies it was heparins. stoppedearlier, becauseanticoagulant treatment was no longer

Keywords Pregnancy, heparin-induced thrombocytopenia,heparin-induced skin rash,danaparoid, heparin-intolerance ThrombHaemost 2005; 93: 63-9

Introduction Treatment alternatives forpregnant patients with heparinin- tolerance and ahigh risk of thrombosis are limited. Thus the pur- The antithromboticagent danaparoid is amixtureofglycosami- pose of our study wastoreviewthe efficacyand safety of dana- noglycans with an averagemolecular weight of 6000daltons.It paroid treatment in this clinicalsetting. mainlyconsistsofheparan sulphate (84%)and dermatan sulphate (12%)and inhibits factor Xa viaantithrombin (AT) and Methods thrombin via both AT and heparincofactor II.The ratio of anti- Xa to anti-IIa activity is approximately ≥ 22:1. Clinical develop- Literature search in Medline and Medscape wasperformed to ment of danaparoidfor thrombosis prophylaxis started in 1981. detect pregnancies treatedwith danaparoidbetween 1981 and

Its lowdegree of sulphation and absence of heparinare respon- 2004.The following terms were used for search: danaparoid, Or- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. sible forits lowpotential of cross-reactivity with heparin-in- garan, Lomoparan, heparinoid, Org10172, HIT, heparin, throm- ducedantiplatelet antibodies. Thereforeitwas used as an alter- bocytopenia, heparin-induced thrombocytopenia, lowmolecular native anticoagulant in patients with heparin-induced throm- weight heparin, lepirudin,argatroban,skin-necrosis, necrosis, bocytopenia(HIT), whowere enrolledinacompassionate-use pregnancy, thrombosis. programme (1, 2). It wasfirst approvedfor HITin1994 and is In addition unsolicitedpost-marketing reportsand the dana- availableinmanycountries world-wide. paroid compassionate-use programme were screened for preg-

Correspondence to: Received June 7, 2004 PD Dr.med. EdelgardLindhoff-Last Accepted after resubmission October 5, 2004 Division of VascularMedicine Department of InternalMedicine Prepublished onlineNovember 8, 2004 DOI:10.1160/TH04–06–0349 University Hospital Frankfurt Theodor-Stern-Kai 7 60590 Frankfurt/ Main,Germany Te l.: +49696301 5096, Fax: +49 69 6301 7219 E-mail: [email protected]

63 Lindhoff-Last, et al.: Treatment with danaparoidduring pregnancy

Ta ble1:Age and presenting clinical problems before startoftreatment.

nant patients. Case reports were only includediftheyprovided i.v.bolus of 750 Uwas usually applied) or for thrombosis treat- detailed information about intensity and duration of medication ment (i.v.bolus of 2500 Ufollowedbyaninfusion-rate of 400 and the outcome of danaparoidtreatment.Duplicatedcasere- U/h for 4h, then 300 U/h for 4hfollowedbyamaintenance infu- portswere excluded. sion rate of 150–200U/h) were used.

Confirmation of suspectedHIT Monitoring of anti-Xa activity SuspectedHIT wasconfirmed serologically usingthe platelet ag- Amidolytic anti-Xa activity wasmeasured in maternal plasma, gregation test (PAT)(3), the heparin-induced plateletactivation breast milkand fetal cordblood by modifications of the method assay(HIPAA) (4), theenzyme-linked immunoassay(ELISA) of Teienand Lie (7). (5) or the serotoninreleaseassay(SRA)(6). The same serologi- calmethods were used to test for danaparoidcrossreactivity.In Results This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. some patients with HITthe diagnostic method wasnot specified. Patientpopulation Confirmation of thromboembolic complications Fifty-one reportsofdanaparoid use in pregnancyin49women DVTwas confirmed by venographyorcompression ultrasound could be included. Twenty-onepregnancies were described in 19 and pulmonaryembolismbyhigh probability ventilation/perfu- independent publications (8–26), while 25 pregnancies were sion scans. One venous thrombosis wasdiagnosedbyclinical documented within the compassionate-use programme, which symptoms only. Arterial thrombosis wasidentified mainlyby includedfour published case-reports (13, 20–22). In addition, clinical evidenceofischemia and surgery,while computer to- five unsolicited post-marketing seriousadverse events, reported mographywas used fordiagnosis of intracranialarterial or ve- spontaneouslytoOrganonbetween 1981 and 2004,were in- nous thrombosis. cluded in the analysis. Thirty-twopregnancies in 30 womenwere associatedwith an Dosingofdanaparoid acuteorapasthistoryofHIT.Inthe remaining 19 pregnancies In most cases routine treatment regimens for thrombosis prophy- danaparoid wasstarted because of heparin intolerance (mainly laxis (750Us.c., b.d. or t.i.d.,inaddition to the first s.c. dose an skin reactions). Four patients had beenpreviouslytreated with

64 Lindhoff-Last, et al.: Treatment with danaparoidduring pregnancy

Ta ble2:Intensityand overallduration of danaparoid use.

danaparoid and in twoHIT patients danaparoidwas used during ean sections (12,14, 16, 17). In these patients danaparoid was twin pregnancies (10, 25). stopped24–48h pre-operatively and restarted 3–6hours post- Threepublications were excluded fromthe analysis, either operatively.The duration of danaparoid use after delivery varied because the number of treatedpatients, treatment intensity/du- from 4daysto6weeks (median 1week). ration and outcome remained unknown(27) or because of danaparoid use solelypost-partum (28, 29). Anti-Xa activity measurements Maternalblood Demographicdata Plasmaanti-Xa activities were reported in 22/51(43.1%) preg- Demographic data of patients before starting danaparoidtreat- nancies. During treatment of acute thrombosis the anti-Xaactiv- ment are summarised in Table1.Coagulation problems includ- ity wasbetween 0.4–0.6 U/ml and during long termthrombosis ing antithrombin- or protein S- deficiency, disseminated intrav- prophylaxis between0.1 –0.3 U/ml. In twopregnancies plasma ascular coagulation (DIC), heterozygote Factor VLeiden mu- anti-Xa levels were reported closetobleeding episodesand were tation, prothrombin mutation or antiphospholipid antibodies between 0.9–1.2 U/ml (9) in one case and 0.6 U/ml in the sec- were present in 45% (23/51) of pregnancies. All patients had ond case (unsolicited post-marketing report). either ahistoryofvenous or arterial thromboembolism in apre- viouspregnancyorpresentedwith arecent episode of throm- Cord blood andbreast milk boembolism. Cordblood of five infantswas testedatterm. No anti-Xa-activity could be detected (16, 20,22). In addition in threelactating Timing, intensity and duration of danaparoid use women(12, 24, 25) no anti-Xaactivity wasfound in breast milk Danaparoid treatment data are summarised in Tables 2and 3. despite maternal danaparoid blood levels of 0.15–0.45 U/ml. The initial dosing regimens varied from 1000 to 7500U/day.

In 26 pregnancies danaparoidwas started intravenouslytotreat Pregnancyoutcomes This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. acutethromboembolicevents. The remaining patients received In the 37 pregnancies carriedtotermduring or soon after dana- danaparoidfor thrombosis prophylaxis. paroid treatment wasstopped,anormal infant wasdelivered. Twelve patients were treated formore than 20 weeks during Twowomen died during caesariansections becauseofintra-op- their pregnancy. In 37 pregnancies danaparoidwas used until erative bleeding duetomisplaced placentas.Inthe remaining 14 vaginal delivery (n =23) or caesariansection (n =14). In the re- pregnancies danaparoid wasstopped prematurelyinthreecases, maining 14 pregnancies danaparoid treatment wasstopped when because it wasnolonger requiredand in twopatients becauseof the thrombotic problemwas under control (n =3), becauseof earlyfetal loss. In the remaining 9pregnancies danaparoid-treat- premature fetal loss (n =3)orbecauseofamaternal adverse ment wasdiscontinuedbecauseofconfirmed (n =1)orsus- event (plateletcount reduction: n=2, HELLP-syndrome: n=1, pected (n =8)cross-reactivity.Inone of these pregnancies thera- newskin rash: n=2orskin rash extension: n=3). Stopping and peutic termination of pregnancywas necessary. re-starting times of danaparoid use in relation to deliveries are summarized in Table3.Inone patient danaparoid treatment (750 Platelet countrecovery Us.c., b.d.) wascontinued throughout labour (22).Epiduralor Plateletcounts were reduced before startofdanaparoid in 11 of spinalanaesthesia wasusedwithoutcomplication in four caesar- 32 pregnancies associated with HIT. In all of these patients pla-

65 Lindhoff-Last, et al.: Treatment with danaparoidduring pregnancy

Ta ble3:Times of danaparoid discontinuation before delivery and restartingafter delivery.

teletcounts recovered to >150 x10 9 /ml within 7daysofdanapa- one with an event in both periods(Table4). Sevenpatients had roid treatment. morethan one adverse event.In18.8% of HITcases (6/32) and in 31.2% of non-HIT cases (6/19)anadverse event wasat- Adverse events tributedtodanaparoid use,but these did not include anyofthe Adverse eventswere reportedin25pregnancies: 22 with ante- fetal or maternal deaths. In 5non-HIT patients neworcontinued partum adverse events, 2with post-partum adverseevents and skin rashes occurred, while in the remaining non-HIT patient

Ta ble4:Adverse events (AE) during and afterdanaparoiduse. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

66 Lindhoff-Last, et al.: Treatment with danaparoidduring pregnancy progression of renalfailureand development of neurological babies were delivered by emergency caesarian section, butone of symptoms wasobserved. In the HIT- patients the following 6ad- these patients developedtransient hypertension and acentral verse eventswere attributedtodanaparoid. In onepatient skin scotoma post-operatively. necrosis developedatthe danaparoid-injections sites five days In twopatients, HELLP-syndrome wasdiagnosedduring after the termination of danaparoid-treatment during treatment pregnancy. One of these patients withahistoryofantiphospholi- with avitamin Kantagonist. In asecondpatient HELLP-syn- pid-syndrome and previous fetal loss wasadmitted after 26 drome wasobserved, while in anotherpatient anew platelet weeks of out-patient danaparoidtreatment becauseofHELLP- count reduction and positive in vitro-testing for HIT-antibody syndrome.Fetal development wasnormal and danaparoid and cross-reactivity occurred.Inthe remaining threepatients emerg- aspirin were replaced by aVKA. Twoserological tests for hepa- encylimb amputation wasnecessary in one woman, ahaemato- rin-induced antibodieswere negative.Threeweeks later, re- ma of the uterusdeveloped in the secondpatient, while anew tarded fetal growth wasdiagnosed, while herantiphospholipid- plateletcount reduction and deepveinthrombosis wasobserved antibody titreshad increased. Thepremature babywas delivered in the thirdpatient. by emergency caesarian section, butdeveloped afatal pulmon- Forfour pregnancies, adverse event causality wasnot men- aryhaemorrhage 2dayslater (21). tioned. The second patient presented withanartificialheartvalve and APLsyndrome.She wasswitched to aVKA and 4months Thromboembolic events later wasstarted on heparinbecauseofanuterine haematoma. In fourpatients with HITanew thromboembolic event (2 DVT However, severe thrombocytopenia developedinassociation and 2pulmonaryemboli) developedduring treatment with dana- with HELLP-syndrome and renal failure. Heparinwas changed paroid. In twoofthese patients the danaparoid dose wasin- to danaparoid, butrenal failureprogressed, and she developed creased,while the third patient wasstarted on avitamin Kantag- neurologicalsymptoms. Anormal infant wasdelivered by onist (VKA) and danaparoid wasdiscontinuedone week later, emergency caesarian section and both clinical status and renal when atherapeutic INRwas reached. Allthreepatients re- function improved thereafter (15). sponded favourably. The remaining HIT patient developedanew DVTand plateletcount reduction after 2weeks of danaparoid Newplatelet countreduction treatment. Danaparoidcross-reactivity wassuspected,but not In 5ofthe 32 HITpatients (15.6%) and none of the non-HIT pa- further investigated. Both eventsrecovered after switching to tients anew decrease in plateletcount wasobservedduring dana- lepirudin (11). paroid treatment. In one patient the plateletcount droppedafter 27 days of danaparoidtherapy. Her pre-treatment serum sample Non-fatalmajor bleedingcomplications wasfound to be positivefor danaparoid cross-reactivity and Asmall placental haematomadeveloped in one patient with an treatment wasimmediately withdrawn. The platelet count in- artificialheartvalve,who received high dose danaparoid treat- creased and there were no furthersequelae. In the other4cases ment (3760 Us.c., b.d.). The plasma anti-Xaactivity wasbe- no pre-treatment cross-reactivity tests were performed. In oneof tween 0.9and 1.2 U/ml, therefore the danaparoid dose wasre- these patients anew plateletcount reduction occurredafter 17 duced withoutfurther bleeding complications (9). weeks of treatment associatedwith aHELLP syndrome (see Apost-partum haemorrhage occurredinasecondcaseafter above)and 2serological checksfor cross-reactivity at that time useofdextran infusions during labour. Danaparoid (1250Us.c., were negative (21). In 2patients the plateletcount decreasedin b.d.) had already beendiscontinuedfivedaysbefore delivery. association with (pre)eclampsia after 20 and 28 weeks of treat- Subsequently danaparoid wasrestarted in combination with a ment, while in the fourthpatient thrombocytopenia occurred to- VKA on thefirst dayafter deliverywithoutany furtherprob- getherwith anew venous thromboembolic event after 12 days of lems. danaparoidtherapy(11). In all 5patients the plateletcount recovered after discontinuation of danaparoid. Skinreactions

In 5of17(29.4%) non-HIT patients presenting with aheparin in- Abortionorterminationofpregnancy This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. duced skin rash, the skin rash recurred or extendedduring dana- Amissedabortion wasdiagnosedafter twoweeks of danaparoid paroid therapy. In all patients cross-reactivity with danaparoid treatment in the 12th week of pregnancyinapatient with ahistory wassuspected. However, no re-challenge skin-tests were subse- of previous fetal losses due to systemic lupus erythematosus quently performed to confirmthe suspicion. (SLE). One HIT- patient, treatedwith aVKA during the post-partum Asecondpatient presented with phlegmasia coerulea period,developed skin necrosis at the antepartum danaparoidin- dolens.Aninferior vena cavalfilterwas inserted and heparinre- jection sites threedaysafter stop of danaparoidtreatment (20). placed by warfarin.VKA-induced gangrene occurredrequiring At thattime the patient’sprotein Clevel wasnormal. After skin fasciotomy. Postoperatively an infusionwith danaparoidwas debridement and grafting the area recovered despite continu- started,but despite increasing plateletcounts and the use of fibri- ation of VKA. nolytic therapythe gangrene progressed. Abelow knee amputation wasperformed and the 14 week pregnancywas termin- (Pre-)eclampsia and HELLP-syndrome ated. Three patientsdeveloped eclampsia or pre-eclampsia after 20, Athird patient with SLE, antiphospholipid-antibodies and a 28 and 30 weeks of danaparoiduse,respectively. Three normal historyofpreviousfetal lossesdeveloped aspontaneous abor-

67 Lindhoff-Last, et al.: Treatment with danaparoidduring pregnancy tion in the 16th week of pregnancy, 12 weeks after danaparoid ing three HIT patients and the presence of alternativereasonsfor treatment hadbeen initiated. Theaborted male fetus appeared plateletcount reduction and/or thrombosis during danaparoid normal and therewas no evidenceofthrombus or infarction of therapymakeitdifficulttoassess the real extent of initialcross- the placenta. reactivity and latersero-conversion. Furthermore the presenceof initial in vitro cross-reactivity of danaparoidwith HIT- antibodies Maternal deaths does not necessarilylead to clinical complications even during One patient, presentingwith lupusanticoagulant and pulmonary prolonged use(2, 33, 34). Besides the frequent needfor urgent embolism, developedHIT during treatment with unfractionated anticoagulation oftenprecludes waiting for the result of asero- heparin (UFH). She wasswitched to lowmolecular weight hepa- logical test (32). Complications induced by cross-reactivity of rinand VKA and developedasecondpulmonaryembolismand danaparoidinHIT patients can be avoided,when apre-treatment vaginal bleeding because of placenta praevia. An emergency plasma sample is serologically testedand regular plateletcount caesarian section wasperformed and asingle doseofdana-pa- monitoring is performed during danaparoid treatment. If cross- roid wasapplied for peri-operative thrombosis prophylaxis. reactivity with HIT- antibodiesisclinically suspected,the diag- Postoperatively she could not be resuscitatedbecauseofrespir- nosis should be confirmed by serological testing.Assoon as atoryproblems. Autopsyrevealed an atrio-septaldefect and his- sero-conversion is proven, danaparoidtreatment should be tological evidenceofpulmonaryhypertension. switchedtoanalternativeantithrombotic agent. The second patient had received 24 weeks of danaparoid Danaparoid cross-reactivity resulting in skin hypersensitiv- treatment (1250 –2250 Us.c. b.d.) before it wasstopped 5days ity reactions in non-HIT patients is less well understood.Inthe prior to delivery. Placental abruption occurred during labour present review29.4% (5/17) of the non-HIT patients with are- and severe bleeding started.The patient wasaJehovah’sWitness cent or currenthistoryofskin rash developedrecurrence or ex- and died several days laterafter refusing blood transfusion. tensionofthe rash during danaparoid therapy. Since onepatient wasalso sufferingfrom active SLEand no skin testing wasper- Discussion formedinany of these patients, it remains uncertain, whether the extendedornew skin rasheswere duetodanaparoid exposure.It The risk of thrombo-embolismisincreased in pregnancies with is known from the literature (35–39), thatdanaparoid can ‘cross- hereditaryoracquired coagulation disorders and/or ahistoryof react’inpatients alreadysensitized to heparins,but recurrence of deepvenous thrombosis. Therefore these patients are often skin rashes at injection sites during the first treatment days may treated with unfractionated or lowmolecular weight heparin. Al- not preclude continued successful use of danaparoid in these pa- though side-effects such as HIT (30)orskin rashes areuncom- tients (39, 40) with subsequent disappearanceofthe rash. This mon in pregnancy, theyshould be suspected wheneverthe patient maybedue to development of tolerance in at leastsome hyper- develops thrombocytopenia,thromboembolism or arash.Thedi- sensitive patients exposed to danaparoid. Thus, provided that agnosis of heparin-intolerance necessitatesanimmediate change skin reactions arenot severe or worsening, it is recommendedto of antithrombotic treatment and,sincedanaparoid did not show continue danaparoidinjections for 2–3 days in apatient with he- maternal or fetal toxicity in animalstudies(31), it has become in- parin inducedskin hypersensitivity.Ifthe skin reactions persist creasinglyusedasanalternativeantithrombotic in these patients. after this period of time, danaparoid must be stopped. The 49 patients identified in this reviewof51pregnancies had a Plasma anti-Xaactivity should be checked at weeklyto currentorpasthistoryofthrombosis with aneed forantithrom- monthly intervalsduring pregnancy. Anti-Xa activity does not botic therapy. All patients had developedheparin intolerance. In appear to cross theplacenta(16, 20, 22) nor to be secreted into addition 25 patients hadanincreased thromboticorbleeding risk breast milk(12, 24, 25).These findings do not prove,that dana- at presentation caused by avarietyofconcomitant disorders. In paroid does not cross the placenta or appear in breast milk, re- 72.5% (37/51) of these pregnancies danaparoid wasuseduntil spectively, sinceonlythe activity inducedbyits high antithrom- delivery resulting in the birth of normalliveinfants. bin affinity sub-fraction, whichis4%ofthe total preparation, is During treatment with danaparoid four HIT- patients devel- monitoredbythis assay. Howeverbecausethe molecularweight

opednew DVT. In three patients this could be handledbyin- and size of the othersubfractions of danaparoid aresimilarlydis- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. creasing the danaparoid dose or adding aVKA. Despite high le- tributedasthe high affinity material, thereisnoreason to sup- vels of anti-Xa activity and long duration of treatment in some pose that theycould be transferred into the fetusorthe breast patients onlyfew spontaneous bleeding problems occurred (9). milkingreater quantitiesthan the high affinity fraction. Even if Twopatients, whodeveloped fatalbleeding during caesarian sec- small amounts of danaparoid aresecreted into breastmilk, it is tion, hadplacental abnormalities, i.e.placenta praevia and unlikelytopose ahaemostatic problemfor the infant, since it abruptio placenta. During 12 additionalelectivecaesarian sec- would be hydrolysed and henceinactivatedbythe acid stomach tions no bleeding problemoccurred,when danaparoid was secretions (12,25). stopped6–48hours prior to surgeryand re-started 2–24hours In conclusion danaparoid canbeusedasanalternativeanti- post-operatively. thrombotic drug during pregnancies associated with heparin-in- Suspected clinical cross-reactivity with HITantibodies re- tolerance,but occasionallycross-reactivity remains aproblem. mains aproblemofdanaparoid treatment. Five newplatelet Highdose prophylactic treatment with danaparoid is able to pre- count reductions were reported,two of whichwere attributedto vent newthromboemboliccomplications,but some compli- danaparoid use. One of the twopatients tested, showedpositive cations of pregnancysuch as development of pre-eclampsia or cross-reactivity.Lack of serological confirmation in the remain- foetal loss due to lupusanticoagulant, SLE or antiphospholipid

68 Lindhoff-Last, et al.: Treatment with danaparoidduring pregnancy syndrome, arenot influenced. Since under-dosing of danaparoid Abbreviations in HIT- patients canlead to newthrombosis during the earlytreat- DVT: deep vein thrombosis,PE: pulmonaryembolism,ASD: atrial sep- ment days, it is advisabletouse the maximum recommended tal defect, AHV:artificial heartvalve, ICT:intra-cardiac thrombus,AT: dailydose for prophylaxis during the first 5–7daysunless safety antithrombin, PS: Protein S, APL: antiphospholipid syndrome, LA: is aproblem.Anti-Xa activity induced by danaparoid wasneither lupus anticoagulant, SLE: systemic lupuserythematosus,DIC: dis- observedinfetal cordblood nor in breastmilk. Therefore dana- seminated intravascular coagulation, TTP:thrombotic thrombocyto- penic purpura, FVL:factor VLeiden, FIIG 20210A:prothrombinmu- paroidcan be giventonursing mothers at least until vitamin K tation; AE:adverse events, HELLP:hemolysis,elevated liverenzymes antagonists are started and the INR is within the therapeutic and lowplateletcount range. Despite these encouraging results the number of pregnancies reported is still small.Therefore, danaparoid should onlybeused in pregnancyand the puerperium, if no other suitable antithrombotic drug is available.

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