Venous thromboembolism in pregnancy: diagnosis, management and prevention

Sanjeev D. Chunilal; Shannon M. Bates

doi:10.1160/TH08-08-0526

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2009; 101(03): 428-438
DOI: 10.1160/TH08-08-0526

Clinical Focus

Schattauer GmbH

Venous thromboembolism in pregnancy: diagnosis, management and prevention

Sanjeev D. Chunilal

¹Department of Hematology, North Shore Hospital, Takapuna, Auckland, New Zealand

,

Shannon M. Bates

²Department of Medicine, McMaster University, Hamilton, Ontario, Canada

› Author Affiliations

Abstract

Summary

A pregnant woman has a two- to five-fold higher risk of venous thromboembolism (VTE) than a non-pregnant woman of the same age and, in developed countries, she is more likely to die from fatal pulmonary embolism (PE) than from obstetric haemorrhage. The increased VTE risk is mediated through normal physiological changes of pregnancy including alterations in haemostasis that favour coagulation, reduced fibrinolysis and pooling and stasis of blood in the lower limbs. Thrombophilia, smoking, obesity, immobility and postpartum factors such as infection, bleeding and emergency surgery (including emergency caesarian section) also increase the risk of pregnancy-related VTE. The diagnosis of VTE can be safely established with acceptable radiation exposure to the fetus using readily available imaging modalities such as ultrasound, ventilation perfusion lung scanning and computed tomographic pulmonary angiography. However, the optimal diagnostic strategies still remain to be determined. If there is no contraindication to anticoagulation, commencing treatment prior to objective confirmation should be strongly considered. For the mother and fetus, effective and safe treatment is readily available with low-molecular-weight heparin (LMWH), but optimal dosing of these agents in pregnancy remains controversial. Emerging data support antepartum LMWH prophylaxis for women with previous VTE if the event was unprovoked or in the presence of thrombophilia. On the other hand, women with prior provoked VTE and no thrombophilia or women with asymptomatic thrombophilia (but a family history of VTE) can safely be managed with antepartum surveillance. Postpartum prophylaxis is recommended for women with prior VTE or thrombophilia (and a family history of VTE).

Keywords

Pregnancy - venous thromboembolism (VTE) - thrombophilia - low-molecular-weight heparin (LMWH)

Full Text

References

References
1 Lewis G. The Confidential Enquiry into Maternal and Child Health (CEMACH). Saving Mothers’ Lives: reviewing maternal deaths to make motherhood safer-2003–2005. The Seventh Report on Confidential Enquiries into Maternal Deaths in the United Kingdom. London: CEMACH; 2007
2 Chang J, Elam-Evans LD, Berg CJ. et al. Pregnancy-related mortality surveillance United States, 1991–1999. MMWR Surveill Summ 2003; 52: 1-8.
3 Pomp ER, Lenselink AM, Rosendaal FR. et al. Pregnancy, the post partum period and prothrombotic defect: risk of venous thrombosis in the MEGA study. J Thromb Haemost 2008; 6: 632-637.
4 Gherman RB, Goodwin TM, Leung B. et al. Incidence, clinical characteristics, and timing of objectively diagnosed venous thromboembolism during pregnancy. Obstet Gynecol 1999; 94: 730-734.
5 James AH, Jamison MG, Brancazio LR. et al. Venous thromboembolism during pregnancy and the postpartum period: Incidence, risk factors, and mortality. Am J Obstet Gynecol 2006; 194: 1311-1315.
6 Voral S, Ghosh K, Shetty S. et al. Deep venous thrombosis in the antenatal period in a large cohort of pregnancies from western India. Thromb J 2007; 5: 9.
7 Ray JG, Chan WS. Deep vein thrombosis during pregnancy and the puerperium: a meta-analysis of the period of risk and the leg of presentation. Obstet Gynecol Surv 1999; 54: 265-271.
8 Heit JA, Kobbervig CE, James AH. et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: A 30 year population based study. Ann Intern Med 2005; 143: 697-706.
9 Ikard RW, Ueland K, Folse R. Lower limb venous dynamics in pregnant women. Surg Gynecol Obstet 1971; 132: 483-488.
10 Berqvist A, Berqvist D, Hailbook T. Deep vein thrombosis during pregnancy: a prospective study. Acta Obstet Gynecol Scand 1983; 62: 443-448.
11 Sterling Y, Woolf L, North WRS. et al. Haemostasis in normal pregnancy. Thromb Haemost 1984; 52: 176-182.
12 Koster T, Blann AD, Briët E. et al. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345: 152-155.
13 Brill-Edwards PA, Ginsberg JS, Gent M. et al. Safety of withholding heparin in pregnant women with a history of venous thromboembolism. N Engl J Med 2000; 343: 1439-1444.
14 Crowther M, Roberts J, Roberts R. et al. Fibrinolytic Variables in Patients with Recurrent Venous Thrombosis: a Prospective Cohort. Study Thromb Haemost 2001; 85: 390-394.
15 Prins M, Hirsh J. A critical review of the evidence supporting a relationship between impaired fibrinolytic activity and venous thromboembolism. Arch Intern Med 1991; 151: 1721-1731.
16 Kher A, Bauersachs R, Nielsen JD. The management of thrombosis in pregnancy: role of low molecular-weight heparin. Thromb Haemost 2007; 97: 505-513.
17 Macklon NS, Greer IA, Bowman AW. An ultra-sound study of gestational and postural changes in the deep venous system of the leg in pregnancy. Br J Obstet Gynecol 1997; 102: 191-197.
18 Goodrich SM, Wood JE. Peripheral venous distensibility and velocity of venous blood during pregnancy or during oral contraceptive therapy. Am J Obstet Gynecol 1964; 90: 740-744.
19 Royal College of Obstetricians and Gynaecologists.. Thromboprophylaxis during pregnancy, labour and after normal vaginal delivery. Guideline No.37. London RCOG; 2004.
20 Jacobsen AF, Skjeldestad FE, Sandset PM. Ante-and postnatal risk factors of venous thrombosis: a hospital-based case-control study. J Thromb Haemost 2008; 6: 905-912.
21 Robertson L, Wu O, Langhorne P. et al. Thrombophilia and pregnancy: a systematic review. Brit J Haematol 2005; 132: 171-196.
22 Martinelli I, Battaglioli T, De Stefano V. et al. The risk of first venous thromboembolism during pregnancy and puerperium in double heterozygotes for factor V Leiden and prothrombin G20210A. J Thromb Haemost 2008; 6: 494-498.
23 Ginsberg JS, Hirsh J, Rainbow AJ. et al. Risks to the fetus of radiologic procedures used in the diagnosis of maternal venous thromboembolic disease. Thromb Haemost 1989; 61: 189-196.
24 Nijkeuter M, Geleijns J, De Roos A. et al. Diagnosing pulmonary embolism in pregnancy: rationalizing fetal radiation exposure in radiological procedures. J Thromb Haemost 2004; 2: 1857-1858.
25 Ries LAG, Smith MA, Gurney JG. et al. Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975–1995, National Cancer Institute, SEER Program. NIH Pub. No. 99–4649. Bethesda, MD, 1999.
26 Cook VJ, Kyriou J. Radiation from CT and perfusion scanning in pregnancy. Br Med J 2005; 331: 350.
27 Law J, Faulkner K. Cancers detected and induced, and associated risk and benefit, in a breast screening programme. Brit J Radiol 2001; 74: 1121-1127.
28 Scarsbrook AF, Evans AL, Owen AR. et al. Diagnosis of suspected venous thromboembolic disease in pregnancy. Clin Rad 2006; 61: 1-12.
29 Barrellier MT, Lezin B, Monsallier JM. Isolated deep vein thrombosis. A study of 48 cases seen in 7 years among 18 297 echo Doppler evaluation of the lower limb. J Mal Vasc 2001; 26: 290-298.
30 Chan WS, Chunilal SD, Lee AYY. et al. A red cell agglutination D-dimer test to exclude deep vein thrombosis in pregnancy. Ann Intern Med 2007; 147: 165-170.
31 Wells PS, Anderson DR, Rodger M. et al. Evaluation of D-dimer in the diagnosis of suspected deep vein thrombosis. N Eng J Med 2003; 349: 1227-1235.
32 Chan WS, Chunilal SD, Bates SM. et al. The prevalence of a positive soluble fibrin and D-dimer results in healthy asymptomatic pregnant women. Blood 1999; 94: 20a (Abstract).
33 Kearon C, Ginsberg JS, Douketis J. et al. Management of suspected deep venous thrombosis in out-patients by using clinical assessment and D-dimer testing. Ann Intern Med 2001; 135: 108-111.
34 Lensing AW, Prandoni P, Brandjes D. et al. Detection of deep-vein thrombosis by real-time B-mode ultrasonography. N Engl J Med 1989; 320: 342-345.
35 Fraser DGW, Moody AR, Morgan MS. et al. Diagnosis of lower-limb deep venous thrombosis: a prospective blinded study of magnetic resonance direct thrombus imaging. Ann Intern Med 2002; 136: 89-98.
36 Cham MD, Yankelevitz DF, Shaham D. et al. Deep venous thrombosis: detection by using indirect CT venography. Radiology 2000; 216: 744-751.
37 Rademaker J, Griesshaber V, Hidajat N. et al. Combined CT pulmonary angiography and venography for diagnosis of pulmonary embolism and deep vein thrombosis: radiation dose. J Thoracic Imag 2001; 16: 297-299.
38 Wells PS, Ginsberg JS, Anderson DR. et al. Use of a clinical model for safe management of patients with suspected pulmonary embolism. Ann Intern Med 1998; 129: 997-1005.
39 Hull RD, Raskob GE, Ginsberg JS. et al. A noninvasive strategy for the treatment of patients with suspected pulmonary embolism. Arch Intern Med 1994; 154: 289-297.
40 Chan WS, Ray JG, Murray S. et al. Suspected pulmonary embolism in pregnancy: clinical presentation, results of lung scanning, and subsequent maternal and pediatric outcomes. Arch Intern Med 2002; 162: 1170-1175.
41 Balan KK, Critchley M, Vedavathy KK. et al. The value of ventilation perfusion imaging in pregnancy. Br J Radiol 1997; 70: 338-340.
42 Anderson DR, Kahn SR, Rodger MA. et al. Computed tomographic pulmonary angiography versus ventilation-perfusion lung scanning in patients with suspected pulmonary embolism: a randomized controlled trial. J Am Med Assoc 2007; 298: 2743-2753.
43 Ginsberg JS, Hirsh J, Turner CD. et al. Risks to the fetus of anticoagulant therapy during pregnancy. Thromb Haemost 1989; 61: 197-203.
44 Sanson BJ, Lensing AW, Prins MH. et al. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost 1999; 81: 668-672.
45 Iturbe-Alessio I, Fonseca MC, Mutchinik O. et al. Risk of anticoagulant therapy in pregnant women with prosthetic heart valves. N Engl J Med 1988; 315: 1390-1393.
46 Hall JG, Pauli R, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980; 68: 122-141.
47 Wesseling J, Van Driel D, Heymans HSA. et al. Coumarins during pregnancy: Long term effects on growth and development of school age children. Thomb Haemost 2001; 85: 609-613.
48 Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature. Arch Intern Med 2000; 160: 191-196.
49 Hirsh J, Cade JF, O’Sullivan EF. Clinical experience with anticoagulant therapy during pregnancy. Br Med J 1970; 31: 270-273.
50 Levine M, Gent M, Hirsh J. et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996; 334: 677-681.
51 Voke J, Keidan J, Pavord S. et al. The management of antepartum venous thromboembolism in the UK and Ireland: a prospective multicenter observational survey. Brit J Haematol 2007; 139: 545-558.
52 Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 2005; 106: 401-407.
53 Kominiarek MA, Angelopoulos SM, Shapiro NL. et al.. Low-molecular-weight heparin in pregnancy: peripartum bleeding complications. J Perinatol 2007; 27: 329-334.
54 Dahlman TC. Osteoporotic fractures and the recurrence of thromboembolism during pregnancy and the puerperium in 184 women undergoing thrombprophylaxis with heparin. Am J Obstet Gynecol 1993; 168: 1265-1270.
55 Pettila V, Leinonen P, Marrkova A. et al. Postpartum bone mineral density in women treated for thrombprophylaxis with unfractionated heparin or low molecular weight heparin. Thromb Haemost 2002; 87: 182-183.
56 Carlin AJ, Farquharson RG, Quenby SM. et al. Prospective observational study of bone mineral density during pregnancy: low molecular weight heparin versus control. Hum Reprod 2004; 19: 1211-1214.
57 Warkentin TE, Levine MN, Hirsh J. et al. Heparin-induced thrombocytopenia in patients treated with low molecular weight heparin or unfractionated heparin. N Eng J Med 1995; 332: 1330-1335.
58 Warkentin TE, Greinacher A, Koster A. et al. Treatment and Prevention of Heparin-Induced Thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2008; 133: 340S-380S.
59 de Valk HW, Banga JD, Wester JW. et al. Comparing subcutaneous Danaparoid with intravenous unfractionated heparin for the treatment of venous thromboembolism: a randomized controlled trial. Ann Intern Med 1991; 123: 1-9.
60 Lindhoff-Last E, Kreutzenbeck HJ, Magnani HN. Treatment of 51 pregnancies with Danaparoid because of heparin intolerance. Thromb Haemost 2005; 93: 63-69.
61 Anderson DR, Ginsberg JS, Brill-Edwards P. et al. The use of an indwelling Teflon catheter for subcutaneous heparin administration during pregnancy: a randomized cross-over trial. Arch Intern Med 1993; 153: 841-844.
62 van Dongen CJ, van den Belt AG, Prins MH. et al. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev 2004; 4: CD001100.
63 Weitz J. Low molecular weight heparins. N Engl J Med 1997; 337: 688-698.
64 Raschke RA, Reilly BM, Guidry JR. et al. The weight-based heparin dosing compared with a “standard care” nomogram: a randomized controlled trial. Ann Intern Med 1993; 119: 874-881.
65 Cruickshank MK, Levine MN, Hirsh J. et al. A standard heparin nomogram for the management of heparin therapy. Arch Intern Med 1991; 151: 333-337.
66 Chunilal SD, Young E, Johnston MA. et al. The APTT response of pregnant plasma to unfractionated heparin. Thromb Haemost 2002; 87: 92-97.
67 Levine MN, Hirsh J, Gent M. et al. A randomized trial comparing activated thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin. Arch Intern Med 1994; 154: 49-56.
68 Wan S, Quinlan DJ, Agnelli G. et al. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation 2004; 110: 744-749.
69 Ahearn GS, Hadjiliadis D. Govert et al. Massive pulmonary embolism during pregnancy successfully treated with recombinant tissue plasminogen activator: a case report and review of treatment options. Arch Intern Med 2002; 162: 1221-1227.
70 Pfeifer GW. Distribution and placental transfer of 131-I streptokinase. Australas Ann Med 1970; 19 (01) 17-18.
71 Salas SP, Marshall G, Gutiérrez BL. et al. Time course of maternal plasma volume and hormonal changes in women with pre-eclampsia or fetal growth restriction. Hypertension 2006; 47: 203-208.
72 Barbour L, Oja JL, Schultz LK. A prospective trial that demonstrates that dalteparin requirements increase in pregnancy to maintain therapeutic level of anticoagulation. Am J Obstet Gynecol 2004; 191: 1024-1029.
73 Whitfield CR. Normal pregnancy. In: Dewhurst’s textbook of Obstetrics and Gynaecology for postgraduates. 5^th Ed. Oxford: Blackwell Scientific Publication; 1995. pp. 107-108.
74 Bates SM, Ginsberg JS. How I treat: how we manage venous thromboembolism during pregnancy. Blood 2002; 100: 3470-3478.
75 Bates SM, Greer IA, Pabinger I. et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: Evidence-Based Clinical Practice Guidelines American College of Chest Physicians. Chest 2008; 133: 844-886.
76 Anderson DR, Ginsberg JS, Burrows R. et al. Subcutaneous heparin therapy during pregnancy; a need for concern at the time of delivery. Thromb Haemost 1991; 65: 248-250.
77 Wittmaack FM, Greer FR, Fitz Simmons J. Neonatal depression after a protamine sulfate injection: a case report. J Reprod Med 1994; 39: 655-656.
78 Kovacs MJ, Levine MN, Keeney M. et al. Anti-Xa effect of a low molecular weight heparin (dalteparin) does not accumulate in extended duration therapy for venous thromboembolism in cancer patients. Thromb Haemost 2005; 93: 1185-1188.
79 O’Donnell MJ, Kearon CJ, Johnson J. et al. Brief communication: preoperative anticoagulant activity after bridging low-molecular-weight heparin for temporary interruption of warfarin. Ann Intern Med 2007; 146: 184-187.
80 Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 188S-203S.
81 Campbell IA, Bentley DP, Prescott RJ. et al. Anticoagulation for three versus six months in patients with deep vein thrombosis or pulmonary embolism, or both: randomised trial. Br Med J 2007; 31: 674-681.
82 Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. N Engl J Med 1997; 336: 1506-1511.
83 De Stefano V, Martinelli I, Rossi E. et al. The risk of recurrent venous thromboembolism in pregnancy and puerperium without antithrombotic prophylaxis. Br J Haematol 2006; 135: 386-391.
84 Pabinger I, Grafenhofer H. Kaider, et al. Risk of pregnancy-associated recurrent venous thromboembolism in women with a history of venous thrombosis. J Thromb Haemost 2005; 3: 949-954.
85 White RH, Chan WS, Zhou H. et al. Recurrent venous thromboembolism after pregnancy-associated versus unprovoked thromboembolism. Thromb Haemost 2008; 100: 246-252.
86 Vossen CY, Conard J, Fontcuberta J. et al. Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect: the European Prospective Cohort on Thrombophilia (EPCOT). J Thromb Haemost 2005; 3: 459-464.
87 Folkeringa N, Brouwer JLP, Korteweg FJ. et al. High risk of pregnancy-related venous thromboembolism in women with multiple thrombophilic defects. Brit J Haematol 2007; 138: 110-116.
88 Martinelli I, Legnani C, Bucciarelli P. et al. Risk of pregnancy-related venous thrombosis in carriers of severe inherited thrombophilia. Thromb Haemost 2001; 86: 800-803.
89 Demers C, Ginsberg JS, Hirsh J. et al. Thrombosis in antithrombin-III-deficient persons report of a large kindred and literature review. Ann Intern Med 1992; 116: 754-761.
90 McColl M, Ramsay JE, Tait RC. et al. Risk factors for pregnancy associated venous thromboembolism. Thromb Haemost 1997; 8: 1183-1188.
91 Lensen RP, Bertina RM, de Ronde H. et al. Venous thrombotic risk in family members of unselected individuals with factor V Leiden. Thromb Haemost 2000; 83: 817-821.
92 Dizon-Townson D, Miller C, Sibai B. et al. The relationship of the factor V Leiden mutation and pregnancy outcomes for the mother and fetus. Obstet Gynecol 2005; 106: 517-524.