Semin Vasc Med 2003; 03(1): 047-060
DOI: 10.1055/s-2003-38332
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Inherited Thrombophilia, Pregnancy, and Oral Contraceptive Use: Clinical Implications

Valerio De Stefano, Elena Rossi, Giuseppe Leone
  • Department of Hematology, Catholic University, Rome Italy
Further Information

Publication History

Publication Date:
27 March 2003 (online)


Inherited thrombophilia has been reported to be associated with an increased risk for complications of pregnancy, including venous thromboembolism (VTE) as well as preeclampsia (PEC), fetal loss (FL), fetal growth retardation (FGR), and abruptio placentae (AP), the latter probably due to inadequate placental perfusion. The estimate of risk largely depends on the kind of thrombophilia and on the criteria applied for the selection of the patients, producing in some cases contradictory results. Convincing evidence is available that deficiency of antithrombin III (AT), protein C (PC), and protein S (PS) is a risk factor for VTE and late FL. Factor VLeiden is associated with an increased risk for VTE, unexplained recurrent FL, late FL, and perhaps PEC; prothrombin G20210A is a weak risk factor for VTE. So far, the data available for FGR and AP are scarce. However, the absolute risk for VTE during pregnancy and puerperium is between 1 and 3%, in comparison with the baseline risk of 0.08%. Antithrombotic prophylaxis with subcutaneous heparin is warranted during puerperium in all women with thrombophilia and throughout all pregnancy in women at higher risk (AT deficiency, homozygosity for factor VLeiden, and perhaps PC and PS deficiencies); treatment with subcutaneous heparin for prevention of FL among women with thombophilia is under investigation. Presence of inherited thrombophilia increases the risk for VTE due to oral contraceptives up to an absolute risk of 3 per 1000 person-years, in comparison with the baseline risk of 3 to 6 per 10,000 person-years; the risk is further increased by first usage, the use of preparations containing third-generation progestins, and thrombophilia due to AT, PC, and PS deficiency as well as homozygous factor VLeiden and combined defects.


  • 1 Lane D A, Mannucci P M, Bauer K A. et al . Inherited thrombophilia: Part 1.  Thomb Haemost . 1996;  76 651-662
  • 2 Jordan F LJ, Nandorff A. The familial tendency in thromboembolic disease.  Acta Med Scand . 1956;  156 267-275
  • 3 Egeberg O. Inherited antithrombin deficiency causing thrombophilia.  Thromb Diath Haemorrh . 1965;  13 516-530
  • 4 Griffin J, Evatt B, Zimmerman T, Kleiss A, Wideman C. Deficiency of protein C in congenital thrombotic disease.  J Clin Invest . 1981;  68 1370-1373
  • 5 Comp P, Esmon C. Recurrent venous thromboembolism in patients with a partial deficiency of protein S.  N Engl J Med . 1984;  311 1525-1528
  • 6 Schwarz H P, Fischer M, Hopmeier P, Batard M, Griffin J. Plasma protein S deficiency in familial thrombotic disease.  Blood . 1984;  64 1297-1300
  • 7 De Stefano V, Finazzi G, Mannucci P M. Inherited thrombophilia: pathogenesis, clinical syndromes, and management.  Blood . 1996;  87 3531-3544
  • 8 Dahlback B, Carlsson M, Svensson P J. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C.  Proc Natl Acad Sci U S A . 1993;  90 1004-1008
  • 9 Koster T, Rosendaal F R, de Ronde H. et al . Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study.  Lancet . 1993;  342 1503-1506
  • 10 Svensson P J, Dahlback B. Resistance to activated protein C as a basis for venous thrombosis.  N Engl J Med . 1994;  330 517-522
  • 11 Bertina R M, Koeleman B PC, Koster T. et al . Mutation in blood coagulation factor V associated with resistance to activated protein C.  Nature . 1994;  369 64-67
  • 12 De Stefano V, Chiusolo P, Paciaroni K, Leone G. Epidemiology of factor V Leiden: clinical implications.  Semin Thromb Hemost . 1998;  24 367-379
  • 13 Poort S R, Rosendaal F R, Reitsma P H, Bertina R M. A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.  Blood . 1996;  88 3698-3703
  • 14 Rosendaal F R, Doggen C JM, Zivelin A. et al . Geographic distribution of the 20210 G to A prothrombin variant.  Thromb Haemost . 1998;  79 706-708
  • 15 Rosendaal F R. Venous thrombosis: a multicausal disease.  Lancet . 1999;  353 1167-1173
  • 16 Nordstrom M, Lindblad B, Bergqvist D, Kjellstrom T. A prospective study of the incidence of deep-vein thrombosis within a defined urban population.  J Intern Med . 1992;  232 155-160
  • 17 Anderson F A, Wheeler H B, Goldberg R J. et al . A population based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT study.  Arch Intern Med . 1991;  151 933-938
  • 18 Andersen B S, Steffensen F H, Sorensen H T, Nielsen G L, Olsen J. The cumulative incidence of venous thromboembolism during pregnancy and puerperium. An 11 year Danish population-based study of 63,300 pregnancies.  Acta Obstet Gynecol Scand . 1998;  77 170-173
  • 19 Mc Coll D M, Ramsay J E, Tait R C. et al . Risk factors for pregnancy associated venous thromboembolism.  Thromb Haemost . 1997;  78 1183-1188
  • 20 Rosendaal F R. Risk factors for venous thrombotic disease.  Thromb Haemost . 1999;  82 610-619
  • 21 Ray J C, Chan W S. Deep vein thrombosis during pregnancy and puerperium: a meta-analysis of the period of risk and the leg of presentation.  Obstet Gynecol Surv . 1999;  54 265-271
  • 22 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 1324-1328
  • 23 Martinelli I, De Stefano V, Taioli E. et al . Inherited thrombophilia and first venous thromboembolism during pregnancy and puerperium.  Thromb Haemost . 2002;  87 791-795
  • 24 Gerhardt A, Scharf R E, Beckmann M W. et al . Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium.  N Engl J Med . 2000;  342 374-380
  • 25 Conard J, Horellou M H, Van Dreden P, Lecompte T, Samama M. Thrombosis and pregnancy in congenital deficiencies in AT III, protein C or protein S: study of 78 women.  Thromb Haemost . 1990;  63 319-320
  • 26 De Stefano V, Leone G, Mastrangelo S, Tripodi A. et al . Thrombosis during pregnancy and surgery in patients with congenital deficiency of antithrombin III, protein C, protein S.  Thromb Haemost . 1994;  71 799-800
  • 27 Vicente V, Rodriguez C, Soto I, Fernandez M, Moraleda J M. Risk of thrombosis during pregnancy and post-partum in hereditary thrombophilia.  Am J Hematol . 1994;  46 151-152
  • 28 Pabinger I, Schneider B. Thrombotic risk in hereditary antithrombin III, protein C, or protein S deficiency. A cooperative, retrospective study.  Gesellschaft fur Thrombose- und Hamostaseforschung (GTH) Study Group on Natural Inhibitors. Arterioscler Thromb Vasc Biol . 1996;  16 742-748
  • 29 Friederich P W, Sanson B J, Simioni P. et al . Frequency of pregnancy-related venous thromboembolism in anticoagulant factor-deficient women: implications for prophylaxis.  Ann Intern Med . 1996;  125 955-960
  • 30 Dizon-Townson D S, Nelson L M, Jang H, Varner M W, Ward K. The incidence of factor V Leiden mutation in an obstetric population and its relationship to deep vein thrombosis.  Am J Obstet Gynecol . 1997;  176 883-886
  • 31 Lindqvist P G, Svensson P J, Marsaal K. et al . Activated protein C resistance (FV:Q506) and pregnancy.  Thromb Haemost . 1999;  81 532-537
  • 32 Murphy R P, Donoghue C, Nallen R J. et al . Prospective evaluation of the risk conferred by factor V Leiden and thermolabile methylenetetrahydrofolate reductase polymorphisms in pregnancy.  Arterioscler Thromb Vasc Biol . 2000;  20 266-270
  • 33 De Stefano V, Mastrangelo S, Paciaroni K. et al . Thrombotic risk during pregnancy and puerperium in women with APC-resistance. Effective subcutaneous heparin prophylaxis in a pregnant patient.  Thromb Haemost . 1995;  74 793-794
  • 34 Bokarewa M I, Bremme K, Blomback M. Arg506-Gln mutation in factor V and risk of thrombosis during pregnancy.  Br J Haematol . 1996;  92 473-478
  • 35 Hirsch D R, Mikkola K M, Marks P W. et al . Pulmonary embolism and deep venous thrombosis during pregnancy or oral contraceptive use: prevalence of factor V Leiden.  Am Heart J . 1996;  131 1145-1148
  • 36 Hallak M, Senderowicz J, Cassel A. et al . Activated protein C resistance (factor V Leiden) associated with thrombosis in pregnancy.  Am J Obstet Gynecol . 1997;  176 889-893
  • 37 McColl M D, Ellison J, Reid F. et al . Prothrombin 20210 G→A, MTHF C677T mutations in women with venous thromboembolism associated with pregnancy.  Br J Obstet Gynaecol . 2000;  107 565-569
  • 38 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
  • 39 Middeldorp S, Libourel E, Hamulyàk K, van der Meer J, Buller H. The risk of pregnancy-related venous thromboembolism in women who are homozygous for factor V Leiden.  Br J Haematol . 2001;  113 553-555
  • 40 Brill-Edwards P, Ginsberg J S, Gent M. et al . Safety of withholding heparin in pregnant women with a history of venous thromboembolism. Recurrence of Clots in This Pregnancy Study Group.  N Engl J Med . 2000;  343 1439-1444
  • 41 Abildgaard U, Viskjold F, Majak P. Hereditary antithrombin deficiency and pregnancy: venous thromboembolism despite prophylaxis with LMW heparin (Abst).  Thromb Haemost . 2001;  Suppl P1470
  • 42 Hellgren M, Tengborn L, Abildgaard U. Pregnancy in women with congenital antithrombin III deficiency: experience of treatment with heparin and antithrombin.  Gynecol Obstet Invest . 1982;  14 127-141
  • 43 De Stefano V, Leone G, De Carolis S. et al . Management of pregnancy in women with antithrombin III congenital defect: report of four cases.  Thromb Haemost . 1988;  59 193-196
  • 44 Kupferminc M J, Eldor A, Steinman N. et al . Increased frequency of genetic thrombophilia in women with complications of pregnancy.  N Engl J Med . 1999;  340 9-13
  • 45 Dovey D A, MacGillivray I. The classification and definition of hypertensive disorders of pregnancy.  Am J Obstet Gynecol . 1988;  158 892-898
  • 46 Weinstein L. Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy.  Am J Obstet Gynecol . 1982;  142 159-167
  • 47 Saftlas A F, Olson D R, Franks A L, Atrash H K, Pokras R. Epidemiology of preeclampsia and eclampsia in the United States, 1979-1986.  Am J Obstet Gynecol . 1990;  163 460-465
  • 48 Kupferminc M J, Fait G, Many A. et al . Severe preeclampsia and high frequency of genetic thrombophilic mutations.  Obstet Gynecol . 2000;  96 45-49
  • 49 De Groot J M C, Bloemenkamp K WM, Duvekot E J. et al . Preeclampsia and genetic risk factors for thrombosis: a case-control study.  Am J Obstet Gynecol . 1999;  181 975-980
  • 50 Dizon-Towson D S, Nelson L M, Easton K, Ward K. The factor V Leiden mutation may predispose women to severe preeclampsia.  Am J Obstet Gynecol . 1996;  175 902-905
  • 51 Grandone E, Margaglione M, Colaizzo D. et al . Factor V Leiden, C > T MTHFR polymorphism and genetic susceptibility to preeclampsia.  Thromb Haemost . 1997;  77 1052-1054
  • 52 Krauss T, Augustin H G, Osmers R. et al . Activated protein C resistance and factor V Leiden in patients with hemolysis, elevated liver enzymes, low platelets syndrome.  Obstet Gynecol . 1998;  92 457-460
  • 53 Nagy B, Toth T, Rigo Jr J. et al . Detection of factor V Leiden mutation in severe pre-eclamptic Hungarian women.  Clin Genet . 1998;  53 478-481
  • 54 van Pampus G M, Dekker G A, Wolf H. et al . High prevalence of hemostatic abnormalities in women with a history of severe preeclampsia.  Am J Obstet Gynecol . 1999;  180 1146-1150
  • 55 Grandone E, Margaglione M, Colaizzo D. et al . Prothrombotic genetic risk factors and the occurrence of gestational hypertension with or without proteinuria.  Thromb Hemost . 1999;  81 349-352
  • 56 O'Shaughnessy K M, Fu B, Ferraro F. et al . Factor V Leiden and thermolabile methylenetetrahydrofolate reductase gene variants in an East Anglian preeclampsia cohort.  Hypertension . 1999;  33 1338-1341
  • 57 Livingston J C, Barton J R, Park V. et al . Maternal and fetal inherited thrombophilias are not related to the development of severe preeclampsia.  Am J Obstet Gynecol . 2001;  185 153-157
  • 58 Ventura S J, Taffel S M, Mosher W D. Estimates of pregnancies and pregnancy rates for the United States, 1976-85.  Am J Public Health . 1988;  78 506-511
  • 59 Stirrat G M. Recurrent miscarriage. I. Definition and epidemiology.  Lancet . 1990;  336 673-675
  • 60 Samueloff A, Xenakis E M, Berkus M D, Huff R W, Langer O. Recurrent stillbirth: significance and characteristics.  J Reprod Med . 1993;  38 883-886
  • 61 Gris J C, Quere I, Monpeyroux F. et al . Case-control study of the frequency of thrombophilic disorders in couples with late foetal loss and no thrombotic antecedent. The Nimes Obstetricians and Haematologists Study(NOHA).  Thromb Haemos . 1999;  81 891-899
  • 62 Brenner B. Inherited thrombophilia and pregnancy loss.  Thromb Haemost . 1999;  82 634-640
  • 63 Preston F E, Rosendaal F R, Walker I D. et al . Increased fetal loss in women with heritable thrombophilia.  Lancet . 1996;  348 913-916
  • 64 Sanson B J, Friederich P W, Simioni P. et al . The risk of abortion and stillbirth in antithrombin-, protein C-, and protein S-deficient women.  Thromb Haemost . 1996;  75 387-388
  • 65 Gris J C, Ripart-Neveu S, Maugard C. et al . Retrospective evaluation of the prevalence of haemostasis abnormalities in unexplained primary early recurrent miscarriages. The Nimes Obstetricians and Haematologists (NOHA) Study.  Thromb Haemost . 1997;  77 1096-1103
  • 66 Meinardi J R, Middeldorp S, de Kam J P. et al . Increased risk for fetal loss in carriers of the factor V Leiden mutation.  Ann Intern Med . 1999;  130 736-739
  • 67 Tormene D, Simioni P, Prandoni P. et al . The risk of fetal loss in family members of probands with factor V Leiden mutation.  Thromb Haemost . 1999;  82 1237-1239
  • 68 Grandone E, Margaglione M, Colaizzo D. et al . Factor V Leiden is associated with repeated and recurrent unexplained fetal losses.  Thromb Haemost . 1997;  77 822-824
  • 69 Ridker P M, Miletich J P, Buring J E. et al . Factor V Leiden mutation as a risk factor for recurrent pregnancy loss.  Ann Intern Med . 1998;  128 1000-1003
  • 70 Brenner B, Sarig G, Weiner Z. et al . Thrombophilic polymorphisms are common in women with fetal loss without apparent cause.  Thromb Haemost . 1999;  82 6-9
  • 71 Souza S S, Ferriani R A, Pontes A G, Zago M A, Franco R F. Factor V Leiden and factor II G20210A mutations in patients with recurrent abortion.  Hum Reprod . 1999;  14 2448-2450
  • 72 Foka Z J, Lambropoulos A F, Saravelos H. et al . Factor V Leiden and prothrombin G20210A mutations, but not methylenetetrahydrofolate reductase C677T, are associated with recurrent miscarriages.  Hum Reprod . 2000;  15 458-462
  • 73 Younis J S, Brenner B, Ohel G. et al . Activated protein C resistance and factor V Leiden mutation can be associated with first- as well as second-trimester recurrent pregnancy loss.  Am J Reprod Immunol . 2000;  43 31-35
  • 74 Martinelli I, Taioli E, Cetin I. et al . Mutations in coagulation factors in women with unexplained late fetal loss.  N Engl J Med . 2000;  343 1015-1018
  • 75 Wramsby M L, Sten-Linder M, Bremme K. Primary habitual abortions are associated with high frequency of factor V Leiden mutation.  Fertil Steril . 2000;  74 987-991
  • 76 Kupferminc M J, Peri H, Zwang E. et al . High prevalence of the prothrombin gene mutation in women with intrauterine growth retardation, abruptio placentae and second trimester loss.  Acta Obstet Gynecol Scand . 2000;  79 963-967
  • 77 Martinelli P, Grandone E, Colaizzo D. et al . Familial thrombophilia and the occurrence of fetal growth restriction.  Haematologica . 2001;  86 428-431
  • 78 Wiener-Megnagi Z, Ben-Shlomo I, Goldberg Y, Shalev E. Resistance to activated protein C and the Leiden mutation: high prevalence in patients with abruptio placentae.  Am J Obstet Gynecol . 1998;  179 1565-1567
  • 79 Younis J S, Ohel G, Brenner B. et al . The effect of thromboprophylaxis on pregnancy outcome in patients with recurrent pregnancy loss associated with factor V Leiden mutation.  BJOG . 2000;  107 415-419
  • 80 Brenner B, Hoffman R, Blumenfeld Z, Weiner Z, Younis J S. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.  Thromb Haemost . 2000;  83 693-697
  • 81 Vandenbroucke J P, Rosing J, Bloemenkamp K WM. et al . Medical progress: oral contraceptives and the risk of venous thrombosis.  N Engl J Med . 2001;  344 1527-1535
  • 82 Kemmeren J K, Algra A, Grobbee D E. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis.  BMJ . 2001;  323 1-9
  • 83 Bloemenkamp K W, Rosendaal F R, Helmerhorst F M, Vandenbroucke J P. Higher risk of venous thrombosis during early use of oral contraceptives in women with inherited clotting factors.  Arch Intern Med . 2000;  160 49-52
  • 84 Pabinger I, Schneider B. Thrombotic risk of women with hereditary antithrombin III-, protein C- and protein S-deficiency taking oral contraceptive medication. The GTH Study Group on Natural Inhibitors.  Thromb Haemost . 1994;  71 548-552
  • 85 Vandenbroucke J P, Koster T, Briet E. et al . Increased risk of venous thrombosis in oral contraceptives users who are carriers of factor V Leiden mutation.  Lancet . 1994;  344 1453-1457
  • 86 Bloemenkamp K W, Rosendaal F R, Helmerhorst F M, Buller H R, Vandenbroucke J P. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen.  Lancet . 1995;  346 1593-1596
  • 87 Andersen B S, Olsen J, Nielsen G L. et al . Third generation oral contraceptives and heritable thrombophilia as risk factors of non-fatal venous thromboembolism.  Thromb Haemost . 1998;  79 28-31
  • 88 Martinelli I, Taioli E, Bucciarelli P, Akhavan S, Mannucci P M. Interaction between the G20210A mutation of the prothrombin gene and oral contraceptive use in deep vein thrombosis.  Arterioscler Thromb Vasc Biol . 1999;  19 700-703
  • 89 Spannagl M, Heinemann L A, Schramm W. Are factor V Leiden carriers who use oral contraceptives at extreme risk for venous thromboembolism?.  Eur J Contracept Reprod Health Care . 2000;  5 105-112
  • 90 Emmerich J, Rosendaal F R, Cattaneo M. et al . Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism. Pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism.  Thromb Haemost . 2001;  86 809-816
  • 91 Santamaria A, Mateo J, Oliver A. et al . Risk of thrombosis associated with oral contraceptives in women from 97 families with inherited thrombophilia: high risk of thrombosis in carriers of the G20210A mutation of the prothrombin gene.  Haematologica . 2001;  86 965-971
  • 92 Rintelen C, Mannhalter C, Ireland H. et al . Oral contraceptives enhance the risk of clinical manifestation of venous thrombosis at a young age in females homozygous for factor V Leiden.  Br J Haematol . 1996;  93 487-490
  • 93 Rosing J, Tans G, Nicolaes G A. et al . Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second- and third-generation oral contraceptives.  Br J Haematol . 1997;  97 233-238
  • 94 Martinelli I, Sacchi E, Landi G. et al . High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives.  N Engl J Med . 1998;  338 1793-1797
  • 95 Rosendaal F R, Helmerhorst F M, Vandenbroucke J P. Oral contraceptives, hormone replacement therapy and thrombosis.  Thromb Haemost . 2001;  86 112-123
  • 96 Hoibraaten E, Qvigstad E, Arnesen H. et al . Increased risk of recurrent venous thromboembolism during hormone replacement therapy. Results of the randomized, double-blind, placebo controlled estrogen in venous thromboembolism trial (EVTET).  Thromb Haemost . 2000;  84 961-967