Management of thromboembolic disease associated with pregnancy

The Journal of Maternal-Fetal Medicine 6:21–27 (1997)

Management of Thromboembolic DiseaseAssociated With Pregnancy

Wayne Evans, MD, Steven A. Laifer, MD,* Thomas J. McNanley, MD, andAndre Ruzycky, PhD

Department of Obstetrics, Gynecology, and Reproductive Sciences, Division ofMaternal-Fetal Medicine, University of Pittsburgh School of Medicine, Magee-

Womens Hospital, Pittsburgh, Pennsylvania

Abstract Our objective was to identify practice patterns of members of the Society of PerinatalObstetricians with regard to the management of thromboembolic disease in pregnant women.

We sent survey-questionnaires to members of the Society of Perinatal Obstetricians and requestedinformation on antepartum and postpartum management of four clinical case scenarios. We also requestedinformation on the evaluation of hypercoagulability and on the dosing and monitoring of heparin dur-ing pregnancy.

We received 515 responses after a single mailing (47%). Most respondents utilize some form of anticoagu-lation in pregnant women with a history of thromboembolic disease, although there was variation in theduration and intensity of anticoagulation. Nearly all respondents (96%) use full anticoagulation withheparin for pregnant women with prosthetic heart valves. Most respondents evaluate pregnant women forhypercoagulable disorders who present with a thromboembolism or have a history of thromboembolicdisease. There is considerable variation with respect to the dosing and monitoring of heparin therapyduring pregnancy.

Although most SPO members recommend anticoagulation in pregnant women with a history of venousthromboembolism, there is marked variation in the intensity, duration, and monitoring of heparin therapyin pregnant patients. Randomized prospective studies are needed to establish accurate recurrence risks andto evaluate the efficacy of anticoagulation in pregnant women with a history of venous thromboembolism.J. Matern.–Fetal Med. 6:21–27, 1997. q 1997 Wiley-Liss, Inc.

Key Words: thromboembolism; pregnancy; heparin; anticoagulation

INTRODUCTION nancy for the prevention of recurrent thromboembo-lism. The purpose of this study was to identify prevailingWomen with a history of thromboembolic diseasepractice approaches in the antipartum and puerperalare considered to be at increased risk for recurrentmanagement of anticoagulation therapy duringthromboembolism during pregnancy [1–3]. However,pregnancy.the true risk of recurrent thromboembolism during

pregnancy and/or the puerperium in women with a SUBJECTS AND METHODShistory of thromboembolism and without additional We sent surveys to all members of the Society ofrisk factors (hypercoagulable disorder) has not been Perinatal Obstetricians (SPO). The membership of theestablished. Only one small randomized study exists SPO comprises obstetricians with subspecialty trainingthat evaluated heparin for prevention of recurrent in maternal-fetal medicine and internal medicine spe-thromboembolism in pregnancy, and no statistical ben-efit was demonstrated [4]. Furthermore, there is limited

*Correspondence to: Steven A. Laifer, M.D., Magee-Womens Hospi-information on the pharmacokinetics of heparin duringtal, 300 Halket Street, Pittsburgh PA 15213-3180.

pregnancy. It is not surprising, therefore, to find diverse Received 18 August 1995; revised 25 March 1996; accepted 27March 1996.recommendations on the use of heparin during preg-

Q 1997 Wiley-Liss, Inc.

22 EVANS ET AL.

TABLE 1. Case 1a

No. %

1. What would be your antepartum management of this patient?No anticoagulation during pregnancy 69 13.8Prophylactic anticoagulation with minidose heparin during pregnancy 364 72.9Full anticoagulation with heparin during pregnancy 40 8.0Prophylactic anticoagulation with low-dose coumadin during pregnancy 2 0.4Full anticoagulation with coumadin during pregnancy 1 0.2Other 23 4.6

2. What would be your postpartum management of this patient?No anticoagulation 45 9.0Prophylactic anticoagulation with minidose heparin for 6 weeks 310 62.1Prophylactic anticoagulation with minidose heparin for 12 weeks 21 4.2Full anticoagulation with heparin for 6 weeks 13 2.6Full anticoagulation with heparin for 12 weeks 2 0.4Full anticoagulation with heparin followed by full anticoagulation with 61 12.2

coumadin for 6 weeksFull anticoagulation with heparin followed by full anticoagulation with 16 3.2

coumadin for 12 weeksOther 31 6.2

a A 25-year-old G1P0 presents for prenatal care at 8 weeks gestation. Her medical history is significant only fora well-documented lower extremity deep vein thrombosis 3 years earlier while taking oral contraceptives. Shewas treated with 10 days of intravenous heparin followed by coumadin for 6 months. She was also instructednever to use oral contraceptives in the future.

cialists who care for pregnant women with medical pert panels [5–8]. The recommendations from thesecomplications. We presented four case scenarios and expert panels are summarized in Table 6. The basisrequested information on antepartum and puerperal for these recommendations is that pregnancy and themanagement. We also included a questionnaire that puerperium are considered to be periods of increasedsought information on the evaluation of hypercoagula- risk for recurrent venous thromboembolism. The riskbility and on the monitoring and dosing of heparin. of a thromboembolic event in a pregnant women with

a past history is estimated to be approximately 12%.RESULTS

This risk estimate, however, is based on a retrospectiveWe received 515 responses after a single mailing patient questionnaire study that had serious flaws [9].

(47%). The four case scenarios and responses are pre- The investigators did not distinguish between superfi-sented in Tables 1–4, and the questionnaire and re- cial and deep venous thromboses, did not review medi-sponses are presented in Table 5. As can be seen in cal records to obtain objective verification of a recur-the tables, not all respondents answered each question. rent thrombotic event, provided no detailedThe mean response rate was 95% for the case presenta- information on pregnancy outcome, complications, ortions and 90% for the questions in the questionnaire, route of delivery, and did not specify whether recur-of those that responded. rences occurred antepartum or in the puerperium. Fur-

thermore, the study predated the ability to identifyDISCUSSIONhypercoagulable disorders. In a more recent retrospec-This survey illustrates that a majority of practitionerstive study in which a thromboembolic event was objec-will use some form of anticoagulation during pregnancytively documented, Tengborn et al. [10] found thatand the puerperium in pregnant women with a historythe risk of recurrent (deep) venous thromboembolismof thromboembolism. There is a lack of consensus how-during pregnancy was 6% (4/67) in patients withoutever, on the appropriate intensity of heparin anticoagu-a hypercoagulable disorder. Interestingly, in patientslation (prophylaxis vs. full dose), and on the precisereceiving heparin prophylaxis, the recurrence risk indosing and monitoring schedule of heparin therapy.women without a hypercoagulable disorder was 10%The practice of anticoagulation during pregnancy

and the puerperium has been endorsed by various ex- (2/20). Lao and colleagues prospectively followed 26

THROMBOEMBOLIC DISEASE AND PREGNANCY 23

TABLE 2. Case 2a

No. %

1. What would be your antepartum management of this patient?No anticoagulation during pregnancy 54 10.5Prophylactic anticoagulation with minidose heparin during pregnancy 354 71.5Full anticoagulation with heparin during pregnancy 66 13.3Prophylactic anticoagulation with low-dose coumadin during pregnancy 1 0.2Full anticoagulation with coumadin during pregnancy 0 0Other 23 4.4




a A 20-year-old G2 P1001 presents for prenatal care. Her medical and obstetrical history is significant for a well-documented lower extremity deep vein thrombosis 1 week after her previous uncomplicated full-term delivery.She was treated with 10 days of intravenous heparin and 6 months of coumadin. Her delivery was 2 years agoand she is now 6 weeks pregnant.

TABLE 3. Case 3a

No. %

1. What would be your antepartum management of this patient?No anticoagulation during pregnancy 15 3.0Prophylactic anticoagulation with minidose heparin during pregnancy 273 55.1Full anticoagulation with heparin during pregnancy 194 39.4Prophylactic anticoagulation with low-dose coumadin during pregnancy 0 0Full anticoagulation with coumadin during pregnancy 1 0.2Other 12 2.2




a A 37-year-old G5 P4004 presents for prenatal care at approximately 12 weeks gestation. She states that duringher last pregnancy 10 years ago she experienced a blood clot in her lung that had originated from her leg. Sheis currently on no medications.

patients with a history of venous thromboembolism tient was thought to have a recurrence, but her treat-ment was discontinued when a lung scan was performedduring pregnancy [11]. Patients were thromboprophy-

laxed during labor and the puerperium but received and was negative. There are no other prospective stud-ies that evaluate the risk of recurrent thromboembolismno treatment in the antepartum period. Only one pa-

24 EVANS ET AL.

TABLE 4. Case 4a

No. %

What would you advise this patient on anticoagulation during conceptionand pregnancy?

Continue coumadin anticoagulation 7 1.6Discontinue coumadin and initiate/maintain prophylactic anticoagulation 0 0

with minidose heparin during pregnancyDiscontinue coumadin and initiate/maintain full-dose anticoagulation with 420 95.9

heparin for duration of pregnancyOther 11 2.5a A 30-year-old G0 is seen for preconception counseling. Her medical history is significant for a history of mitralvalve disease requiring replacement with a mechanical valve 3 years ago. She has no exercise intolerance, appearshemodynamically stable, and her only medication is coumadin at 7.5 mg/day. She is interested in becomingpregnant and is seeking information on anticoagulation during pregnancy.

TABLE 5. General Questions

No. %

1. Do you perform a workup for hypercoagulability on all pregnant patients who present with athromboembolic event during pregnancy?

Yes 346 77.4No 101 22.6

2. Do you perform a workup for hypercoagulability on all pregnant patients with a history ofthromboembolic disease?

Yes 259 61.4No 163 38.6

3. When you perform a hypercoagulable evaluation, what tests do you request?Protein C 368 71.4Protein S 352 68.3Anti-thrombin III 417 80.9Lupus anticoagulant 453 87.9Other 71 13.7

4. When fully anticoagulating a patient with subcutaneous heparin, what prolongation of theaPTT do you attempt to achieve?

1.5–2.0 3 control 342 69.72.0–2.5 3 control 144 29.32.5–3.0 3 control 5 1.0

5. When fully anticoagulating a patient with subcutaneous heparin at 8-hour intervals, when doyou measure the aPTT?

2 h postinjection 44 8.94 h postinjection 156 31.76 h postinjection 150 30.5Immediately prior to next dose 142 28.9

6. When you use mini-dose heparin prophylaxis, what dose of heparin do you use and how oftendo you administer it?

5,000 U every 12 h 280 73.37,500 U every 12 h 64 16.85,000 U every 8 h 31 8.17,500 U every 8 h 7 1.8Other 108 28.3

a Incremental doses with advancing gestation (5,000 BID in first trimester, 7,500 BID in second trimester, 10,000BID in third trimester).


TABLE 6. Recommendations for Anticoagulation of Pregnant Women With aPrior History of Venous Thromboembolism

Expert panel Recommendation

NIH [5] Treat antenatally with low-dose heparin. The time of onsetof therapy is arbitrary. Postpartum patients should be man-aged with low-dose heparin and/or external pneumaticcompression according to the level of risk until fully ambu-latory.

American College of Chest Heparin (5,000 U Q12h or adjusted to produce a heparinPhysicians [6] level of 0.1–0.2 U/mL)) throughout pregnancy followed by

warfarin postpartum for 4 to 6 weeks. Alternatively, hepa-rin therapy could be withheld antepartum and the patientfollowed up by clinical surveillance and periodic imped-ance plethysmography or compressive ultrasound.

British Society for Initial dose of 5,000 IU 12 hourly by self-administered subcu-Haemotology [7] taneous injection. An increase in dose may be needed in

the last trimester to prolong the aPTT to 1.5 times an av-erage control at the mid-interval. The exact time at whichany prophylaxis is started will depend on the nature of therisk, the previous obstetric history, and the mother’s ownwishes, but it may be possible to delay drug treatment un-til late in pregnancy when the greatest risk of thromboem-bolism develops.

Maternal and Neonatal Women whose thrombotic history was not associated withHaemostasis Working Party pregnancy may be anticoagulated throughout pregnancy ifof the Haemostasis the past episode was severe but perhaps only during theand Thrombosis Task [8] third trimester or puerperium if the previous episode was

less serious. Before 36 weeks a dose of 7,500 IU/12 hourlymay be used, increasing to 10,000 IU/12 hourly at 36weeks and decreasing again to 7,500 IU/12 hourly postna-tally. Warfarin may be introduced immediately after deliv-ery but must be overlapped with heparin for at least thefirst 3 days until it is fully effective. Anticoagulationshould be continued at least until 6 weeks postpartum.

during pregnancy and/or the puerperium in women with pregnancy or use of oral contraceptives constitutesa group of higher risk women, and that a prior pulmo-with a history of thromboembolism and no additional

risk factors (i.e., hypercoagulable disorder). Further- nary embolism is of more concern in a subsequentpregnancy than a deep venous thrombosis. However,more, there is only one small randomized prospective

study that evaluated a therapeutic approach to pre- there is also very limited information to support theseclinical observations and no randomized studies thatventing recurrent thromboembolism during pregnancy

[4]. Forty patients with a history of thromboembolism have demonstrated that anticoagulation, either prophy-laxis or full dose heparin, is beneficial in these subgroupswere allocated to treatment with heparin (20 patients)

or no treatment (20 patients). One episode of thrombo- of women for the prevention of recurrent thromboem-bolism during pregnancy or the puerperium. Further-embolism occurred in the control group and none in

the heparin group. The difference was not statistically more, Ginsburg et al. demonstrated that the recurrenceof deep venous thrombosis is evenly distributed tempo-different, but the sample size was clearly insufficient

to make statistical conclusions [4]. Data to support the rally during the antepartum period [12].Given the paucity of accurate information, it is notrecommendations outlined in Table 6 are, therefore,

extremely limited. surprising, therefore, that clear guidelines for the pre-vention of recurrent thromboembolism during preg-This survey also illustrates that some clinicians feel

that the puerperium is the period of maximal risk of nancy do not exist and that management strategiesmay vary considerably. Prospective studies are neededrecurrence, that prior thromboembolism associated

26 EVANS ET AL.

to accurately define the true risk of recurrent thrombo- to similar doses of heparin in nonpregnant women [22].Their results support the use of higher doses of heparinembolism during pregnancy as well as to determine if

therapy for preventing recurrent thromboembolism is for prophylaxis and monitoring of the aPTT at 2–3 hafter subcutaneous injection of heparin in patients be-necessary and efficacious [13]. The importance of es-

tablishing the efficacy of thromboprophylaxis is based ing fully anticoagulated. Similarly, Dahlman et al. rec-ommend a prophylactic dose of heparin (240 IU/kgon the potential risks associated with the uniquely pro-

longed use of heparin during pregnancy and the puerpe- body weight/24 h in 2 divided doses) sufficient toachieve a plasma heparin concentration of 0.08–0.15rium. The principal risks of heparin include bleeding,

osteopenia, and thrombocytopenia [14–20]. Since the IU/mL measured 3 h after injection [23]. The findingsof Brancazio et al. also suggest that women who requireactivated partial thromboplastin time is usually not

prolonged with prophylactic doses of heparin, hemor- full-dose anticoagulation (prosthetic heart valves, hyp-ercoagulable disorder) should receive more frequentrhagic complications are infrequent. Heparin-induced

thrombocytopenia occurs in approximately 2% of pa- subcutaneous injections or perhaps might benefit fromthe continuous delivery of heparin via a subcutane-tients [19] and although usually mild and reversible,

can be severe when accompanied by paradoxical throm- ous pump.Given the potential risks associated with prolongedbosis and disseminated intravascular coagulation. Os-

teopenia does not appear to be dose dependent and use of heparin during pregnancy, we feel that prospec-tive randomized studies are required to properly evalu-may result in serious bone fractures. Recent studies

have demonstrated a 5–10% reduction in bone density ate the need for thromboprophylaxis in pregnantwomen with a history of thromboembolism. Most re-in patients receiving prophylactic doses of subcutane-

ous heparin. Although the heparin-induced osteopenia spondents to this survey stated their willingness toparticipate in multicenter randomized studies. Addi-appears reversible, vertebral crush fractures have been

observed in this group of patients [16–18]. Hemor- tional important areas of study include the use of lowmolecular weight heparin, which appears to be safe inrhagic complications have been reported in 2% of pa-

tients receiving high-intensity anticoagulation [15], pregnancy and may be a safer alternative when prophy-laxis is indicated in pregnancy [24], and further analysisand an additional concern includes persistent prolonga-

tion of the aPTT at the time of labor and delivery [20]. of the pharmacokinetics of heparin longitudinally dur-ing pregnancy and in women who receive heparin onWe have also observed subcutaneous infection and

abscesses in pregnant patients receiving subcutaneous a continual basis.heparin that necessitated temporary discontinuation of

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Management of thromboembolic disease associated with pregnancy