Deep vein thrombosis in pregnancy: Epidemiology, pathogenesis, and diagnosis
- David R Schwartz, MD
David R Schwartz, MD
- Associate Professor of Clinical Medicine
- Section Chief, Critical Care
- NYU Medical Center
- Atul Malhotra, MD
Atul Malhotra, MD
- Kenneth M Moser Professor, Department of Medicine
- University of California, San Diego
- Steven E Weinberger, MD
Steven E Weinberger, MD
- Adjunct Professor of Medicine
- University of Pennsylvania School of Medicine
- Executive Vice President and CEO
- American College of Physicians
- Section Editors
- Lawrence LK Leung, MD
Lawrence LK Leung, MD
- Editor-in-Chief — Hematology
- Section Editor — Disorders of Hemostasis and Coagulation
- Professor of Medicine
- Stanford University School of Medicine
- Charles J Lockwood, MD, MHCM
Charles J Lockwood, MD, MHCM
- Section Editor — Obstetrics
- Senior Vice President, USF Health
- Dean, Morsani College of Medicine
- Professor, Obstetrics and Gynecology
- University of South Florida
- Jess Mandel, MD
Jess Mandel, MD
- Section Editor — Pulmonary Vascular Disease
- Professor of Medicine
- University of California, San Diego
Pregnancy and the puerperium (postpartum period) are well-established risk factors for venous thromboembolism (VTE), which occurs with a prevalence of 1 in 1600 [1-7]. The overlap with symptoms of pregnancy may impair clinical suspicion making diagnosis of VTE more challenging.
VTE can manifest during pregnancy as an isolated lower extremity deep venous thrombosis (DVT) or clot can break off from the lower extremities and travel to the lung to present as a pulmonary embolus (PE) [8-10]. PE is the seventh leading cause of maternal mortality, responsible for 9 percent of maternal deaths [11-13]. Thus, the detection of DVT during pregnancy is critical to preventing deaths from PE.
The epidemiology, pathogenesis, and diagnosis of DVT during pregnancy and the puerperium will be reviewed here. The epidemiology, pathogenesis, and diagnosis of PE, as well as the prevention and treatment of DVT and PE during pregnancy are discussed separately. (See "Pulmonary embolism in pregnancy: Epidemiology, pathogenesis, and diagnosis" and "Deep vein thrombosis and pulmonary embolism in pregnancy: Prevention" and "Deep vein thrombosis and pulmonary embolism in pregnancy: Treatment" and "Use of anticoagulants during pregnancy and postpartum".)
The overall prevalence of VTE in pregnancy is low. In the United States, VTE is diagnosed during 1 in 500 to 2000 pregnancies (absolute incidence; 0.025 to 0.1 percent) [1-6]. In a retrospective case-control study of 395,335 pregnant women at 24 weeks of gestation, the incidence of VTE was 85 per 100,000 pregnancies . A population-based inception cohort study over a 30 year period detected an overall incidence of VTE of 200 per 100,000 woman-years . DVT was three times more common than PE .
Similar rates are observed in Europe [2,5]. In one retrospective study of over 72,000 deliveries, the incidence of DVT was 0.71 per 1000 deliveries (95% CI 0.5-0.9) with 0.5 (95% CI 0.34-0.66) and 0.21 (95% CI 0.11-0.31) occurring antenatally and postnatally, respectively . The incidence of PE was 0.15 per 1000 deliveries (95% CI 0.06-0.24) with 0.07 (95% CI 0.01-0.13) and 0.08 (95% CI 0.02-0.14) occurring antenatally and postnatally, respectively .
- Marik PE, Plante LA. Venous thromboembolic disease and pregnancy. N Engl J Med 2008; 359:2025.
- Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet 1999; 353:1258.
- Prevention of venous thrombosis and pulmonary embolism. NIH Consensus Development. JAMA 1986; 256:744.
- Kujovich JL. Hormones and pregnancy: thromboembolic risks for women. Br J Haematol 2004; 126:443.
- 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.
- Morris JM, Algert CS, Roberts CL. Incidence and risk factors for pulmonary embolism in the postpartum period. J Thromb Haemost 2010; 8:998.
- James AH, Jamison MG, Brancazio LR, Myers ER. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol 2006; 194:1311.
- Bourjeily G, Paidas M, Khalil H, et al. Pulmonary embolism in pregnancy. Lancet 2010; 375:500.
- Brown HL, Hiett AK. Deep vein thrombosis and pulmonary embolism in pregnancy: diagnosis, complications, and management. Clin Obstet Gynecol 2010; 53:345.
- Arya R. How I manage venous thromboembolism in pregnancy. Br J Haematol 2011; 153:698.
- Chang J, Elam-Evans LD, Berg CJ, et al. Pregnancy-related mortality surveillance--United States, 1991--1999. MMWR Surveill Summ 2003; 52:1.
- The National Institute for Clinical Excellence. Why mothers die 2000–2002 — report on confidential enquiries into maternal deaths in the United Kingdom. London: Royal College of Obstetricians and Gynaecologists Press, 2003.
- 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.
- Simpson EL, Lawrenson RA, Nightingale AL, Farmer RD. Venous thromboembolism in pregnancy and the puerperium: incidence and additional risk factors from a London perinatal database. BJOG 2001; 108:56.
- McColl MD, Ramsay JE, Tait RC, et al. Risk factors for pregnancy associated venous thromboembolism. Thromb Haemost 1997; 78:1183.
- Sachs BP, Brown DA, Driscoll SG, et al. Maternal mortality in Massachusetts. Trends and prevention. N Engl J Med 1987; 316:667.
- MacKAy AP, Berg CJ, Liu X, et al. Changes in pregnancy mortality ascertainment: United States, 1999-2005. Obstet Gynecol 2011; 118:104.
- http://www.cdc.gov/reproductivehealth/maternalinfanthealth/pmss.html (Accessed on November 15, 2013).
- Blondon M, Harrington LB, Righini M, et al. Racial and ethnic differences in the risk of postpartum venous thromboembolism: a population-based, case-control study. J Thromb Haemost 2014; 12:2002.
- Treffers PE, Huidekoper BL, Weenink GH, Kloosterman GJ. Epidemiological observations of thrombo-embolic disease during pregnancy and in the puerperium, in 56,022 women. Int J Gynaecol Obstet 1983; 21:327.
- Ghaji N, Boulet SL, Tepper N, Hooper WC. Trends in venous thromboembolism among pregnancy-related hospitalizations, United States, 1994-2009. Am J Obstet Gynecol 2013; 209:433.e1.
- Ginsberg JS, Brill-Edwards P, Burrows RF, et al. Venous thrombosis during pregnancy: leg and trimester of presentation. Thromb Haemost 1992; 67:519.
- Rutherford S, Montoro M, McGehee W, Strong T. Thromboembolic disease associated with pregnancy: an 11-year review. Am J Obstet Gynecol 1991; 164(Suppl):286.
- Kierkegaard A. Incidence and diagnosis of deep vein thrombosis associated with pregnancy. Acta Obstet Gynecol Scand 1983; 62:239.
- Stein PD, Hull RD, Kayali F, et al. Venous thromboembolism in pregnancy: 21-year trends. Am J Med 2004; 117:121.
- 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.
- Sultan AA, West J, Tata LJ, et al. Risk of first venous thromboembolism in and around pregnancy: a population-based cohort study. Br J Haematol 2012; 156:366.
- Sultan AA, Tata LJ, West J, et al. Risk factors for first venous thromboembolism around pregnancy: a population-based cohort study from the United Kingdom. Blood 2013; 121:3953.
- Abdul Sultan A, West J, Tata LJ, et al. Risk of first venous thromboembolism in pregnant women in hospital: population based cohort study from England. BMJ 2013; 347:f6099.
- Kamel H, Navi BB, Sriram N, et al. Risk of a thrombotic event after the 6-week postpartum period. N Engl J Med 2014; 370:1307.
- Tepper NK, Boulet SL, Whiteman MK, et al. Postpartum venous thromboembolism: incidence and risk factors. Obstet Gynecol 2014; 123:987.
- Abdul Sultan A, Grainge MJ, West J, et al. Impact of risk factors on the timing of first postpartum venous thromboembolism: a population-based cohort study from England. Blood 2014; 124:2872.
- Haemostasis and Thrombosis Task Force, British Committee for Standards in Haematology. Investigation and management of heritable thrombophilia. Br J Haematol 2001; 114:512.
- Chan WS, Spencer FA, Ginsberg JS. Anatomic distribution of deep vein thrombosis in pregnancy. CMAJ 2010; 182:657.
- Cockett FB, Thomas ML, Negus D. Iliac vein compression.--Its relation to iliofemoral thrombosis and the post-thrombotic syndrome. Br Med J 1967; 2:14.
- Hull RD, Raskob GE, Carter CJ. Serial impedance plethysmography in pregnant patients with clinically suspected deep-vein thrombosis. Clinical validity of negative findings. Ann Intern Med 1990; 112:663.
- Kearon C, Ginsberg JS, Hirsh J. The role of venous ultrasonography in the diagnosis of suspected deep venous thrombosis and pulmonary embolism. Ann Intern Med 1998; 129:1044.
- Friederich PW, Sanson BJ, Simioni P, et al. Frequency of pregnancy-related venous thromboembolism in anticoagulant factor-deficient women: implications for prophylaxis. Ann Intern Med 1996; 125:955.
- Grandone E, Margaglione M, Colaizzo D, et al. Genetic susceptibility to pregnancy-related venous thromboembolism: roles of factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations. Am J Obstet Gynecol 1998; 179:1324.
- Dizon-Townson DS, Nelson LM, Jang H, et al. The incidence of the factor V Leiden mutation in an obstetric population and its relationship to deep vein thrombosis. Am J Obstet Gynecol 1997; 176:883.
- Gerhardt A, Scharf RE, Beckmann MW, et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 2000; 342:374.
- Bergrem A, Dahm AE, Jacobsen AF, et al. Differential haemostatic risk factors for pregnancy-related deep-vein thrombosis and pulmonary embolism: a population-based case-control study. Thromb Haemost 2012; 108:1165.
- Zotz RB, Gerhardt A, Scharf RE. Inherited thrombophilia and gestational venous thromboembolism. Best Pract Res Clin Haematol 2003; 16:243.
- Branch DW, Silver RM, Blackwell JL, et al. Outcome of treated pregnancies in women with antiphospholipid syndrome: an update of the Utah experience. Obstet Gynecol 1992; 80:614.
- GOODRICH SM, WOOD JE. PERIPHERAL VENOUS DISTENSIBILITY AND VELOCITY OF VENOUS BLOOD FLOW DURING PREGNANCY OR DURING ORAL CONTRACEPTIVE THERAPY. Am J Obstet Gynecol 1964; 90:740.
- Wright H, Osborn S, Edmunds D. Changes in the rate of flow of venous blood in the leg during pregnancy, measured with radioactive sodium. Surg Gynecol Obstet 1950; 90:481.
- Macklon NS, Greer IA, Bowman AW. An ultrasound study of gestational and postural changes in the deep venous system of the leg in pregnancy. Br J Obstet Gynaecol 1997; 104:191.
- Hellgren M, Blombäck M. Studies on blood coagulation and fibrinolysis in pregnancy, during delivery and in the puerperium. I. Normal condition. Gynecol Obstet Invest 1981; 12:141.
- American College of Obstetricians and Gynecologists. Thromboembolism in pregnancy. ACOG Practice Bulletin 19. ACOG 2000; Washington, DC.
- Walker MC, Garner PR, Keely EJ, et al. Changes in activated protein C resistance during normal pregnancy. Am J Obstet Gynecol 1997; 177:162.
- Bergrem A, Dahm AE, Jacobsen AF, et al. Resistance to activated protein C is a risk factor for pregnancy-related venous thrombosis in the absence of the F5 rs6025 (factor V Leiden) polymorphism. Br J Haematol 2011; 154:241.
- Kruithof EK, Tran-Thang C, Gudinchet A, et al. Fibrinolysis in pregnancy: a study of plasminogen activator inhibitors. Blood 1987; 69:460.
- Gerbasi FR, Bottoms S, Farag A, Mammen E. Increased intravascular coagulation associated with pregnancy. Obstet Gynecol 1990; 75:385.
- Lee RV, McComb LE, Mezzadri FC. Pregnant patients, painful legs: the obstetrician's dilemma. Obstet Gynecol Surv 1990; 45:290.
- Bergqvist A, Bergqvist D, Hallböök T. Deep vein thrombosis during pregnancy. A prospective study. Acta Obstet Gynecol Scand 1983; 62:443.
- Kline JA, Williams GW, Hernandez-Nino J. D-dimer concentrations in normal pregnancy: new diagnostic thresholds are needed. Clin Chem 2005; 51:825.
- Chan WS, Chunilal S, Lee A, et al. A red blood cell agglutination D-dimer test to exclude deep venous thrombosis in pregnancy. Ann Intern Med 2007; 147:165.
- Chan WS, Lee A, Spencer FA, et al. D-dimer testing in pregnant patients: towards determining the next 'level' in the diagnosis of deep vein thrombosis. J Thromb Haemost 2010; 8:1004.
- Kovac M, Mikovic Z, Rakicevic L, et al. The use of D-dimer with new cutoff can be useful in diagnosis of venous thromboembolism in pregnancy. Eur J Obstet Gynecol Reprod Biol 2010; 148:27.
- Polak JF, Wilkinson DL. Ultrasonographic diagnosis of symptomatic deep venous thrombosis in pregnancy. Am J Obstet Gynecol 1991; 165:625.
- Lohr JM, Kerr TM, Lutter KS, et al. Lower extremity calf thrombosis: to treat or not to treat? J Vasc Surg 1991; 14:618.
- Wells PS, Hirsh J, Anderson DR, et al. Comparison of the accuracy of impedance plethysmography and compression ultrasonography in outpatients with clinically suspected deep vein thrombosis. A two centre paired-design prospective trial. Thromb Haemost 1995; 74:1423.
- Heijboer H, Cogo A, Büller HR, et al. Detection of deep vein thrombosis with impedance plethysmography and real-time compression ultrasonography in hospitalized patients. Arch Intern Med 1992; 152:1901.
- Chan WS, Spencer FA, Lee AY, et al. Safety of withholding anticoagulation in pregnant women with suspected deep vein thrombosis following negative serial compression ultrasound and iliac vein imaging. CMAJ 2013; 185:E194.
- Le Gal G, Prins AM, Righini M, et al. Diagnostic value of a negative single complete compression ultrasound of the lower limbs to exclude the diagnosis of deep venous thrombosis in pregnant or postpartum women: a retrospective hospital-based study. Thromb Res 2006; 118:691.
- Raţiu A, Navolan D, Spătariu I, et al. Diagnostic value of a negative single color duplex ultrasound in deep vein thrombosis suspicion during pregnancy. Rev Med Chir Soc Med Nat Iasi 2010; 114:454.
- Carpenter JP, Holland GA, Baum RA, et al. Magnetic resonance venography for the detection of deep venous thrombosis: comparison with contrast venography and duplex Doppler ultrasonography. J Vasc Surg 1993; 18:734.
- Spritzer CE, Evans AC, Kay HH. Magnetic resonance imaging of deep venous thrombosis in pregnant women with lower extremity edema. Obstet Gynecol 1995; 85:603.
- Torkzad MR, Bremme K, Hellgren M, et al. Magnetic resonance imaging and ultrasonography in diagnosis of pelvic vein thrombosis during pregnancy. Thromb Res 2010; 126:107.
- Hull R, Hirsh J, Sackett DL, et al. Clinical validity of a negative venogram in patients with clinically suspected venous thrombosis. Circulation 1981; 64:622.
- Lensing AW, Büller HR, Prandoni P, et al. Contrast venography, the gold standard for the diagnosis of deep-vein thrombosis: improvement in observer agreement. Thromb Haemost 1992; 67:8.
- Bates SM, Jaeschke R, Stevens SM, et al. Diagnosis of DVT: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e351S.
- Chan WS, Lee A, Spencer FA, et al. Predicting deep venous thrombosis in pregnancy: out in "LEFt" field? Ann Intern Med 2009; 151:85.
- Righini M, Jobic C, Boehlen F, et al. Predicting deep venous thrombosis in pregnancy: external validation of the LEFT clinical prediction rule. Haematologica 2013; 98:545.
- RISK FACTORS
- Timing during pregnancy
- Anatomic location of DVT
- Inherited thrombophilias
- Endothelial injury
- CLINICAL PRESENTATION
- LABORATORY TESTING
- Compression ultrasonography
- Serial compression ultrasonography
- Magnetic resonance venography
- Ascending contrast venography
- DIAGNOSTIC ALGORITHM
- Pretest probability
- - Wells score
- - LEFt clinical prediction rule
- - D-dimer
- Compressive ultrasound and subsequent testing
- - Positive CUS
- - Negative CUS
- DIFFERENTIAL DIAGNOSIS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS