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Semin Reprod Med 2011; 29(6): 540-547
DOI: 10.1055/s-0031-1293207
© Thieme Medical Publishers

Testing for Inherited Thrombophilia in Recurrent Miscarriage

Paulien G. de Jong1 , Mariëtte Goddijn2 , Saskia Middeldorp1
  • 1Department of Vascular Medicine, Center for Reproductive Medicine, Academic Medical Center, Amsterdam, The Netherlands
  • 2Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Academic Medical Center, Amsterdam, The Netherlands
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Publication History

Publication Date:
08 December 2011 (online)

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ABSTRACT

Approximately 1–5% of women trying to conceive experience recurrent miscarriage, and in 50% of these women, the cause of the preceding miscarriages is unknown. Inherited thrombophilias such as factor V Leiden mutation, prothrombin gene mutation (PT 20210A), and deficiencies of natural anticoagulants protein C, protein S, and antithrombin are associated with recurrent miscarriage. Knowledge of the association between inherited thrombophilia and recurrent miscarriage and of potential treatment options for improving chances of a live birth could tempt physicians to test for inherited thrombophilia in women with recurrent miscarriage. However, the strength of the association between inherited thrombophilia and recurrent miscarriage is not very strong, and more importantly, no evidence indicates that the use of anticoagulants improves the chance of live birth in these women. With the current state of evidence, testing for inherited thrombophilia should not lead to altered clinical management and therefore, should not be performed routinely in women with recurrent miscarriage but only in the context of scientific studies.

KEYWORDS

Pregnancy - inherited thrombophilia - adverse pregnancy outcome - recurrent miscarriage

REFERENCES

  • 1 Farquharson R G, Jauniaux E, Exalto N. ESHRE Special Interest Group for Early Pregnancy (SIGEP) . Updated and revised nomenclature for description of early pregnancy events.  Hum Reprod. 2005;  20 (11) 3008-3011
    Google Scholar
  • 2 Kaandorp S P, Goddijn M, van der Post J A et al.. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage.  N Engl J Med. 2010;  362 (17) 1586-1596
    Google Scholar
  • 3 van den Boogaard E, Kaandorp S P, Franssen M T et al.. Consecutive or non-consecutive recurrent miscarriage: is there any difference in carrier status?.  Hum Reprod. 2010;  25 (6) 1411-1414
    Google Scholar
  • 4 Regan L, Rai R. Epidemiology and the medical causes of miscarriage.  Best Pract Res Clin Obstet Gynaecol. 2000;  14 (5) 839-854
    Google Scholar
  • 5 Poland B J, Miller J R, Jones D C, Trimble B K. Reproductive counseling in patients who have had a spontaneous abortion.  Am J Obstet Gynecol. 1977;  127 (7) 685-691
    Google Scholar
  • 6 Sierra S, Stephenson M. Genetics of recurrent pregnancy loss.  Semin Reprod Med. 2006;  24 (1) 17-24
    Google Scholar
  • 7 Rai R, Regan L. Recurrent miscarriage.  Lancet. 2006;  368 (9535) 601-611
    Google Scholar
  • 8 Rey E, Kahn S R, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis.  Lancet. 2003;  361 (9361) 901-908
    Google Scholar
  • 9 Robertson L, Wu O, Langhorne P Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study et al. Thrombophilia in pregnancy: a systematic review.  Br J Haematol. 2006;  132 (2) 171-196
    Google Scholar
  • 10 Morrison E R, Miedzybrodzka Z H, Campbell D M 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 (5) 779-785
    Google Scholar
  • 11 Ridker P M, Miletich J P, Hennekens C H, Buring J E. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening.  JAMA. 1997;  277 (16) 1305-1307
    Google Scholar
  • 12 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 (10) 3698-3703
    Google Scholar
  • 13 Lockwood C J. Inherited thrombophilias in pregnant patients.  Prenat Neonatal Med. 2001;  6 3-14
    Google Scholar
  • 14 Bank I, van de Poel M H, Coppens M et al.. Absolute annual incidences of first events of venous thromboembolism and arterial vascular events in individuals with elevated FVIII:c. A prospective family cohort study.  Thromb Haemost. 2007;  98 (5) 1040-1044
    Google Scholar
  • 15 Kamphuisen P W, Lensen R, Houwing-Duistermaat J J et al.. Heritability of elevated factor VIII antigen levels in factor V Leiden families with thrombophilia.  Br J Haematol. 2000;  109 (3) 519-522
    Google Scholar
  • 16 Rosendaal F R, Koster T, Vandenbroucke J P, Reitsma P H. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance).  Blood. 1995;  85 (6) 1504-1508
    Google Scholar
  • 17 Coppens M, Kaandorp S P, Middeldorp S. Inherited thrombophilias.  Obstet Gynecol Clin North Am. 2006;  33 (3) 357-374
    Google Scholar
  • 18 Middeldorp S, van Hylckama Vlieg A. Does thrombophilia testing help in the clinical management of patients?.  Br J Haematol. 2008;  143 (3) 321-335
    Google Scholar
  • 19 Cohn D M, Roshani S, Middeldorp S. Thrombophilia and venous thromboembolism: implications for testing.  Semin Thromb Hemost. 2007;  33 (6) 573-581
    Google Scholar
  • 20 Hellgren M. Hemostasis during normal pregnancy and puerperium.  Semin Thromb Hemost. 2003;  29 (2) 125-130
    Google Scholar
  • 21 Kujovich J L. Thrombophilia and pregnancy complications.  Am J Obstet Gynecol. 2004;  191 (2) 412-424
    Google Scholar
  • 22 Salmon J E, Girardi G, Lockshin M D. The antiphospholipid syndrome as a disorder initiated by inflammation: implications for the therapy of pregnant patients.  Nat Clin Pract Rheumatol. 2007;  3 (3) 140-147; quiz 1, 187
    Google Scholar
  • 23 Quenby S, Mountfield S, Cartwright J E, Whitley G S, Chamley L, Vince G. Antiphospholipid antibodies prevent extravillous trophoblast differentiation.  Fertil Steril. 2005;  83 (3) 691-698
    Google Scholar
  • 24 Bose P, Black S, Kadyrov M et al.. Heparin and aspirin attenuate placental apoptosis in vitro: implications for early pregnancy failure.  Am J Obstet Gynecol. 2005;  192 (1) 23-30
    Google Scholar
  • 25 Isermann B, Sood R, Pawlinski R et al.. The thrombomodulin-protein C system is essential for the maintenance of pregnancy.  Nat Med. 2003;  9 (3) 331-337
    Google Scholar
  • 26 Ivanov P D, Komsa-Penkova R S, Konova E I, Kovacheva K S, Simeonova M N, Popov J D. Association of inherited thrombophilia with embryonic and postembryonic recurrent pregnancy loss.  Blood Coagul Fibrinolysis. 2009;  20 (2) 134-140
    Google Scholar
  • 27 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 (1) 6-14
    Google Scholar
  • 28 Hirsh J, Warkentin T E, Shaughnessy S G et al.. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety.  Chest. 2001;  119 (1, Suppl) 64S-94S
    Google Scholar
  • 29 Badawy A M, Khiary M, Sherif L S, Hassan M, Ragab A, Abdelall I. Low-molecular weight heparin in patients with recurrent early miscarriages of unknown aetiology.  J Obstet Gynaecol. 2008;  28 (3) 280-284
    Google Scholar
  • 30 Fawzy M, Shokeir T, El-Tatongy M, Warda O, El-Refaiey A A, Mosbah A. Treatment options and pregnancy outcome in women with idiopathic recurrent miscarriage: a randomized placebo-controlled study.  Arch Gynecol Obstet. 2008;  278 (1) 33-38
    Google Scholar
  • 31 Clark P, Walker I D, Langhorne P Scottish Pregnancy Intervention Study (SPIN) collaborators et al. SPIN (Scottish Pregnancy Intervention) study: a multicenter, randomized controlled trial of low-molecular-weight heparin and low-dose aspirin in women with recurrent miscarriage.  Blood. 2010;  115 (21) 4162-4167
    Google Scholar
  • 32 Laskin C A, Spitzer K A, Clark C A et al.. Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA Trial.  J Rheumatol. 2009;  36 (2) 279-287
    Google Scholar
  • 33 Visser J, Ulander V M, Helmerhorst F M et al.. Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia. HABENOX: a randomised multicentre trial.  Thromb Haemost. 2011;  105 (2) 295-301
    Google Scholar
  • 34 Greer I A, 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 (2) 401-407
    Google Scholar
  • 35 Byrd L, Shiach C, Johnston T, Hay C. Osteopenic fractures in pregnancy: is low molecular weight heparin (LMWH) implicated?.  J Obstet Gynaecol. 2008;  28 (5) 539-542
    Google Scholar
  • 36 Bank I, Libourel E J, Middeldorp S, Van Der Meer J, Büller H R. High rate of skin complications due to low-molecular-weight heparins in pregnant women.  J Thromb Haemost. 2003;  1 (4) 859-861
    Google Scholar
  • 37 Machin S J. Pros and cons of thrombophilia testing: cons.  J Thromb Haemost. 2003;  1 (3) 412-413
    Google Scholar
  • 38 Cohn D M, Vansenne F, Kaptein A A, De Borgie C A, Middeldorp S. The psychological impact of testing for thrombophilia: a systematic review.  J Thromb Haemost. 2008;  6 (7) 1099-1104
    Google Scholar
  • 39 Hellmann E A, Leslie N D, Moll S. Knowledge and educational needs of individuals with the factor V Leiden mutation.  J Thromb Haemost. 2003;  1 (11) 2335-2339
    Google Scholar
  • 40 Lindqvist P G, Dahlbäck B. Reactions to awareness of activated protein C resistance carriership: a descriptive study of 270 women.  Acta Obstet Gynecol Scand. 2003;  82 (5) 467-470
    Google Scholar
  • 41 Dolitzky M, Inbal A, Segal Y, Weiss A, Brenner B, Carp H. A randomized study of thromboprophylaxis in women with unexplained consecutive recurrent miscarriages.  Fertil Steril. 2006;  86 (2) 362-366
    Google Scholar

Paulien de JongM.D. 

Academic Medical Center

Amsterdam, Netherlands

Email: p.g.dejong@amc.uva.nl