Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Inherited thrombophilias in pregnancy

Charles J Lockwood, MD, MHCM
Kenneth A Bauer, MD
Section Editors
Lawrence LK Leung, MD
Vincenzo Berghella, MD
Deputy Editor
Vanessa A Barss, MD, FACOG


Inherited thrombophilias are genetic conditions that increase the risk of thromboembolic disease. During pregnancy, the thrombogenic potential of these inherited disorders is enhanced because of the hypercoagulable state produced by normal pregnancy-associated physiologic changes in several coagulation factors [1-3]:

Resistance to activated protein C increases in the second and third trimesters

Protein S activity decreases due to reductions in total and free protein S antigen

Fibrinogen and factors II, VII, VIII, and X increase

Levels and activity of the fibrinolytic inhibitors, thrombin activatable fibrinolytic inhibitor (TAFI), plasminogen activator inhibitor type 1 (PAI-1) and PAI-2 increase


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Aug 2017. | This topic last updated: Aug 04, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Lockwood CJ. Heritable coagulopathies in pregnancy. Obstet Gynecol Surv 1999; 54:754.
  2. Walker MC, Garner PR, Keely EJ, et al. Changes in activated protein C resistance during normal pregnancy. Am J Obstet Gynecol 1997; 177:162.
  3. Comp PC, Thurnau GR, Welsh J, Esmon CT. Functional and immunologic protein S levels are decreased during pregnancy. Blood 1986; 68:881.
  4. Kupferminc MJ, Yair D, Bornstein NM, et al. Transient focal neurological deficits during pregnancy in carriers of inherited thrombophilia. Stroke 2000; 31:892.
  5. Greer IA. The challenge of thrombophilia in maternal-fetal medicine. N Engl J Med 2000; 342:424.
  6. Domagala TB, Adamek L, Nizankowska E, et al. Mutations C677T and A1298C of the 5,10-methylenetetrahydrofolate reductase gene and fasting plasma homocysteine levels are not associated with the increased risk of venous thromboembolic disease. Blood Coagul Fibrinolysis 2002; 13:423.
  7. McColl MD, Ellison J, Reid F, et al. Prothrombin 20210 G-->A, MTHFR C677T mutations in women with venous thromboembolism associated with pregnancy. BJOG 2000; 107:565.
  8. American College of Obstetricians and Gynecologists Women's Health Care Physicians. ACOG Practice Bulletin No. 138: Inherited thrombophilias in pregnancy. Obstet Gynecol 2013; 122:706. Reaffirmed 2017.
  9. 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.
  10. McColl MD, Ramsay JE, Tait RC, et al. Risk factors for pregnancy associated venous thromboembolism. Thromb Haemost 1997; 78:1183.
  11. 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.
  12. 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.
  13. Jacobsen AF, Dahm A, Bergrem A, et al. Risk of venous thrombosis in pregnancy among carriers of the factor V Leiden and the prothrombin gene G20210A polymorphisms. J Thromb Haemost 2010; 8:2443.
  14. Folkeringa N, Brouwer JL, Korteweg FJ, et al. High risk of pregnancy-related venous thromboembolism in women with multiple thrombophilic defects. Br J Haematol 2007; 138:110.
  15. Marik PE, Plante LA. Venous thromboembolic disease and pregnancy. N Engl J Med 2008; 359:2025.
  16. Haemostasis and Thrombosis Task Force, British Committee for Standards in Haematology. Investigation and management of heritable thrombophilia. Br J Haematol 2001; 114:512.
  17. Zotz RB, Gerhardt A, Scharf RE. Inherited thrombophilia and gestational venous thromboembolism. Best Pract Res Clin Haematol 2003; 16:243.
  18. Dizon-Townson D, Miller C, Sibai B, et al. The relationship of the factor V Leiden mutation and pregnancy outcomes for mother and fetus. Obstet Gynecol 2005; 106:517.
  19. Said JM, Higgins JR, Moses EK, et al. Inherited thrombophilia polymorphisms and pregnancy outcomes in nulliparous women. Obstet Gynecol 2010; 115:5.
  20. Murphy RP, Donoghue C, Nallen RJ, et al. Prospective evaluation of the risk conferred by factor V Leiden and thermolabile methylenetetrahydrofolate reductase polymorphisms in pregnancy. Arterioscler Thromb Vasc Biol 2000; 20:266.
  21. Clark P, Walker ID, Govan L, et al. The GOAL study: a prospective examination of the impact of factor V Leiden and ABO(H) blood groups on haemorrhagic and thrombotic pregnancy outcomes. Br J Haematol 2008; 140:236.
  22. Rodger MA, Hague WM, Kingdom J, et al. Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open-label randomised trial. Lancet 2014; 384:1673.
  23. Lindqvist PG, Svensson PJ, Marsaál K, et al. Activated protein C resistance (FV:Q506) and pregnancy. Thromb Haemost 1999; 81:532.
  24. Silver RM, Zhao Y, Spong CY, et al. Prothrombin gene G20210A mutation and obstetric complications. Obstet Gynecol 2010; 115:14.
  25. Kjellberg U, van Rooijen M, Bremme K, Hellgren M. Factor V Leiden mutation and pregnancy-related complications. Am J Obstet Gynecol 2010; 203:469.e1.
  26. Robertson L, Wu O, Langhorne P, et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2006; 132:171.
  27. Kosmas IP, Tatsioni A, Ioannidis JP. Association of Leiden mutation in factor V gene with hypertension in pregnancy and pre-eclampsia: a meta-analysis. J Hypertens 2003; 21:1221.
  28. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361:901.
  29. Preston FE, Rosendaal FR, Walker ID, et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348:913.
  30. Kocher O, Cirovic C, Malynn E, et al. Obstetric complications in patients with hereditary thrombophilia identified using the LCx microparticle enzyme immunoassay: a controlled study of 5,000 patients. Am J Clin Pathol 2007; 127:68.
  31. Sottilotta G, Oriana V, Latella C, et al. Genetic prothrombotic risk factors in women with unexplained pregnancy loss. Thromb Res 2006; 117:681.
  32. Roqué H, Paidas MJ, Funai EF, et al. Maternal thrombophilias are not associated with early pregnancy loss. Thromb Haemost 2004; 91:290.
  33. Rodger MA, Betancourt MT, Clark P, et al. The association of factor V leiden and prothrombin gene mutation and placenta-mediated pregnancy complications: a systematic review and meta-analysis of prospective cohort studies. PLoS Med 2010; 7:e1000292.
  34. Silver RM, Saade GR, Thorsten V, et al. Factor V Leiden, prothrombin G20210A, and methylene tetrahydrofolate reductase mutations and stillbirth: the Stillbirth Collaborative Research Network. Am J Obstet Gynecol 2016; 215:468.e1.
  35. Bouvier S, Cochery-Nouvellon E, Lavigne-Lissalde G, et al. Comparative incidence of pregnancy outcomes in thrombophilia-positive women from the NOH-APS observational study. Blood 2014; 123:414.
  36. Rodesch F, Simon P, Donner C, Jauniaux E. Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy. Obstet Gynecol 1992; 80:283.
  37. Jaffe R. Investigation of abnormal first-trimester gestations by color Doppler imaging. J Clin Ultrasound 1993; 21:521.
  38. Watson AL, Skepper JN, Jauniaux E, Burton GJ. Susceptibility of human placental syncytiotrophoblastic mitochondria to oxygen-mediated damage in relation to gestational age. J Clin Endocrinol Metab 1998; 83:1697.
  39. Facco F, You W, Grobman W. Genetic thrombophilias and intrauterine growth restriction: a meta-analysis. Obstet Gynecol 2009; 113:1206.
  40. Alfirevic Z, Roberts D, Martlew V. How strong is the association between maternal thrombophilia and adverse pregnancy outcome? A systematic review. Eur J Obstet Gynecol Reprod Biol 2002; 101:6.
  41. Dudding TE, Attia J. The association between adverse pregnancy outcomes and maternal factor V Leiden genotype: a meta-analysis. Thromb Haemost 2004; 91:700.
  42. Lin J, August P. Genetic thrombophilias and preeclampsia: a meta-analysis. Obstet Gynecol 2005; 105:182.
  43. Dudding T, Heron J, Thakkinstian A, et al. Factor V Leiden is associated with pre-eclampsia but not with fetal growth restriction: a genetic association study and meta-analysis. J Thromb Haemost 2008; 6:1869.
  44. D'Elia AV, Driul L, Giacomello R, et al. Frequency of factor V, prothrombin and methylenetetrahydrofolate reductase gene variants in preeclampsia. Gynecol Obstet Invest 2002; 53:84.
  45. Morrison ER, Miedzybrodzka ZH, Campbell DM, et al. Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension: results from a large population-based study and systematic review. Thromb Haemost 2002; 87:779.
  46. Kahn SR, Platt R, McNamara H, et al. Inherited thrombophilia and preeclampsia within a multicenter cohort: the Montreal Preeclampsia Study. Am J Obstet Gynecol 2009; 200:151.e1.
  47. Vollset SE, Refsum H, Irgens LM, et al. Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine study. Am J Clin Nutr 2000; 71:962.
  48. Nurk E, Tell GS, Refsum H, et al. Associations between maternal methylenetetrahydrofolate reductase polymorphisms and adverse outcomes of pregnancy: the Hordaland Homocysteine Study. Am J Med 2004; 117:26.
  49. von Kries R, Junker R, Oberle D, et al. Foetal growth restriction in children with prothrombotic risk factors. Thromb Haemost 2001; 86:1012.
  50. Göpel W, Kim D, Gortner L. Prothrombotic mutations as a risk factor for preterm birth. Lancet 1999; 353:1411.
  51. Schlembach, D, Beinder, E, Zingsem, J, et al. Association of maternal and/or fetal factor V Leiden and G20210A prothrombin mutation with HELLP syndrome and intrauterine growth restriction. Clin Sci (Lond) 2003; 105:279.
  52. Dizon-Townson DS, Meline L, Nelson LM, et al. Fetal carriers of the factor V Leiden mutation are prone to miscarriage and placental infarction. Am J Obstet Gynecol 1997; 177:402.
  53. Gibson CS, MacLennan AH, Hague WM, et al. Associations between inherited thrombophilias, gestational age, and cerebral palsy. Am J Obstet Gynecol 2005; 193:1437.
  54. Gibson CS, MacLennan AH, Janssen NG, et al. Associations between fetal inherited thrombophilia and adverse pregnancy outcomes. Am J Obstet Gynecol 2006; 194:947.e1.
  55. Clark P, Twaddle S, Walker ID, et al. Cost-effectiveness of screening for the factor V Leiden mutation in pregnant women. Lancet 2002; 359:1919.
  56. Brill-Edwards P, Ginsberg JS, Gent M, et al. Safety of withholding heparin in pregnant women with a history of venous thromboembolism. Recurrence of Clot in This Pregnancy Study Group. N Engl J Med 2000; 343:1439.
  57. Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e691S.
  58. Thrombosis and Embolism during Pregnancy and the Puerperium, Reducing the Risk (Green-top 37a) http://www.rcog.org.uk/womens-health/clinical-guidance/reducing-risk-of-thrombosis-greentop37a (Accessed on May 11, 2012).
  59. Kaandorp SP, van Mens TE, Middeldorp S, et al. Time to conception and time to live birth in women with unexplained recurrent miscarriage. Hum Reprod 2014; 29:1146.
  60. Steinvil A, Raz R, Berliner S, et al. Association of common thrombophilias and antiphospholipid antibodies with success rate of in vitro fertilisation. Thromb Haemost 2012; 108:1192.
  61. Girling J, de Swiet M. Inherited thrombophilia and pregnancy. Curr Opin Obstet Gynecol 1998; 10:135.
  62. Girling JC, de Swiet M. Thromboembolism in pregnancy: an overview. Curr Opin Obstet Gynecol 1996; 8:458.
  63. Paidas MJ, Ku DH, Lee MJ, et al. Protein Z, protein S levels are lower in patients with thrombophilia and subsequent pregnancy complications. J Thromb Haemost 2005; 3:497.
  64. Saha P, Stott D, Atalla R. Haemostatic changes in the puerperium '6 weeks postpartum' (HIP Study) - implication for maternal thromboembolism. BJOG 2009; 116:1602.
  65. Hellgren M. Hemostasis during normal pregnancy and puerperium. Semin Thromb Hemost 2003; 29:125.
  66. Lijfering WM, Mulder R, ten Kate MK, et al. Clinical relevance of decreased free protein S levels: results from a retrospective family cohort study involving 1143 relatives. Blood 2009; 113:1225.
  67. Pintao MC, Ribeiro DD, Bezemer ID, et al. Protein S levels and the risk of venous thrombosis: results from the MEGA case-control study. Blood 2013; 122:3210.
  68. Basaran A, Deren Ö, Buyukasik Y, Basaran M. Free protein s reference ranges in gravidas without hereditary and acquired thrombophilia. Indian J Hematol Blood Transfus 2015; 31:286.
  69. Den Heijer M, Lewington S, Clarke R. Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies. J Thromb Haemost 2005; 3:292.
  70. Bønaa KH, Njølstad I, Ueland PM, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006; 354:1578.
  71. Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006; 354:1567.
  72. den Heijer M, Willems HP, Blom HJ, et al. Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism: A randomized, placebo-controlled, double-blind trial. Blood 2007; 109:139.
  73. van der Meer FJ, Koster T, Vandenbroucke JP, et al. The Leiden Thrombophilia Study (LETS). Thromb Haemost 1997; 78:631.
  74. Ma J, Stampfer MJ, Hennekens CH, et al. Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infarction in US physicians. Circulation 1996; 94:2410.
  75. Ray JG, Shmorgun D, Chan WS. Common C677T polymorphism of the methylenetetrahydrofolate reductase gene and the risk of venous thromboembolism: meta-analysis of 31 studies. Pathophysiol Haemost Thromb 2002; 32:51.
  76. Brattström L, Wilcken DE, Ohrvik J, Brudin L. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta-analysis. Circulation 1998; 98:2520.
  77. Ren A, Wang J. Methylenetetrahydrofolate reductase C677T polymorphism and the risk of unexplained recurrent pregnancy loss: a meta-analysis. Fertil Steril 2006; 86:1716.
  78. James A, Committee on Practice Bulletins—Obstetrics. Practice bulletin no. 123: thromboembolism in pregnancy. Obstet Gynecol 2011; 118:718. Reaffirmed 2017.
  79. 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.
  80. 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.
  81. Gerhardt A, Scharf RE, Greer IA, Zotz RB. Hereditary risk factors of thrombophilia and probability of venous thromboembolism during pregnancy and the puerperium. Blood 2016.
  82. Simioni P, Tormene D, Prandoni P, Girolami A. Pregnancy-related recurrent events in thrombophilic women with previous venous thromboembolism. Thromb Haemost 2001; 86:929.
  83. Lockwood CJ. Inherited thrombophilias in pregnant patients: detection and treatment paradigm. Obstet Gynecol 2002; 99:333.
  84. Warren JE, Simonsen SE, Branch DW, et al. Thromboprophylaxis and pregnancy outcomes in asymptomatic women with inherited thrombophilias. Am J Obstet Gynecol 2009; 200:281.e1.
  85. Heyl PS, Sappenfield WM, Burch D, et al. Pregnancy-related deaths due to pulmonary embolism: findings from two state-based mortality reviews. Matern Child Health J 2013; 17:1230.
  86. de Vries JI, van Pampus MG, Hague WM, et al. Low-molecular-weight heparin added to aspirin in the prevention of recurrent early-onset pre-eclampsia in women with inheritable thrombophilia: the FRUIT-RCT. J Thromb Haemost 2012; 10:64.
  87. Abheiden C, Van Hoorn ME, Hague WM, et al. Does low-molecular-weight heparin influence fetal growth or uterine and umbilical arterial Doppler in women with a history of early-onset uteroplacental insufficiency and an inheritable thrombophilia? Secondary randomised controlled trial results. BJOG 2016; 123:797.
  88. Gris JC, Mercier E, Quéré I, et al. Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder. Blood 2004; 103:3695.
  89. Folkeringa N, Brouwer JL, Korteweg FJ, et al. Reduction of high fetal loss rate by anticoagulant treatment during pregnancy in antithrombin, protein C or protein S deficient women. Br J Haematol 2007; 136:656.
  90. Badawy AM, Khiary M, Sherif LS, et al. Low-molecular weight heparin in patients with recurrent early miscarriages of unknown aetiology. J Obstet Gynaecol 2008; 28:280.
  91. Dolitzky M, Inbal A, Segal Y, et al. A randomized study of thromboprophylaxis in women with unexplained consecutive recurrent miscarriages. Fertil Steril 2006; 86:362.
  92. Fawzy M, Shokeir T, El-Tatongy M, et al. Treatment options and pregnancy outcome in women with idiopathic recurrent miscarriage: a randomized placebo-controlled study. Arch Gynecol Obstet 2008; 278:33.
  93. Laskin CA, Spitzer KA, Clark CA, et al. Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA Trial. J Rheumatol 2009; 36:279.
  94. Abou-Nassar K, Kovacs MJ, Kahn SR, et al. The effect of dalteparin on coagulation activation during pregnancy in women with thrombophilia. A randomized trial. Thromb Haemost 2007; 98:163.
  95. Skeith L, Carrier M, Kaaja R, et al. A meta-analysis of low-molecular-weight heparin to prevent pregnancy loss in women with inherited thrombophilia. Blood 2016; 127:1650.
  96. de Jong PG, Kaandorp S, Di Nisio M, et al. Aspirin and/or heparin for women with unexplained recurrent miscarriage with or without inherited thrombophilia. Cochrane Database Syst Rev 2014; :CD004734.