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Semin Thromb Hemost 2007; 33(6): 597-603
DOI: 10.1055/s-2007-985756
Copyright © 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Do Thrombophilias Cause Placenta-Mediated Pregnancy Complications?

Marc A. Rodger1 , 2 , 3 , Michael Paidas4
  • 1Thrombosis Program, Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
  • 2Clinical Epidemiology Unit, Ottawa Health Research Institute, The Ottawa Hospital, Ottawa, Ottawa, Ontario, Canada
  • 3Department of Obstetrics and Gynecology, University of Ottawa, Ottawa, Ontario, Canada
  • 4Yale Women and Children's Center for Blood Disorders, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut
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Publication History

Publication Date:
04 September 2007 (online)

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ABSTRACT

There has been an sudden increase of knowledge about thrombophilias in the last decade as new thrombophilias are discovered and new associations are explored. It is now evident that thrombophilias are common and that the clinical consequences of having a thrombophilia do not appear to be limited to venous thromboembolism. The placenta-mediated pregnancy complications are also common (more than one in six pregnancies are affected) and include pregnancy loss, preeclampsia, placental abruption, and intrauterine growth restriction. These complications as a whole are the leading causes of maternal and neonatal morbidity in the developed world. Evidence has emerged to suggest that thrombophilic women may be at higher risk of developing these placenta-mediated pregnancy complications. However, is this evidence mature enough to claim that a causal association is proven? Is the evidence strong enough to recommend anticoagulant prophylaxis? We suggest that causality is not yet proven and that the data to support management with anticoagulant prophylaxis in thrombophilic pregnancies is too immature to consider this an established intervention.

KEYWORDS

Thrombophilia - intrauterine growth restriction (IUGR) - preeclampsia - pregnancy loss - placental abruption

REFERENCES

  • 1 van der Meer F J, Koster T, Vandenbroucke J P, Briet E, Rosendaal F R. The Leiden Thrombophilia Study (LETS).  Thromb Haemost. 1997;  78 631-635
    PubMedGoogle Scholar
  • 2 Rodeghiero F, Tosetto A. The epidemiology of inherited thrombophilia: the VITA Project. Vicenza Thrombophilia and Atherosclerosis project.  Thromb Haemost. 1997;  78(1) 636-640
    PubMedGoogle Scholar
  • 3 Souto J C, Coll I, Llobet D et al.. The prothrombin 20210A allele is the most prevalent genetic risk factor for venous thromboembolism in the Spanish population.  Thromb Haemost. 1998;  80 366-369
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Brown K, Luddington R, Williamson D, Baker P, Baglin T. Risk of venous thromboembolism associated with a G to A transition at position 20210 in the 3′-untranslated region of the prothrombin gene.  Br J Haematol. 1997;  98 907-909
    CrossrefPubMedGoogle Scholar
  • 5 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
    CrossrefPubMedGoogle Scholar
  • 6 Koster T, Blann A D, Briet E, Vandenbroucke J P, Rosendaal F R. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of DVT.  Lancet. 1995;  345 152-155
    CrossrefPubMedGoogle Scholar
  • 7 Kraaijenhagen R A, Anker P S, Koopman M MW et al.. High plasma concentration of Factor VIIIc is a major risk factor for venous thromboembolism.  Thromb Haemost. 2000;  83(1) 5-9
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Halbmayer W M, Haushofer A, Schon R et al.. The prevalence of moderate and severe FXII (Hageman factor) deficiency among the normal population: evaluation of the incidence of FXII deficiency among 300 healthy blood donors.  Thromb Haemost. 1994;  71 68-72
    PubMedGoogle Scholar
  • 9 den Heijer M, Koster T, Blom H J et al.. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis.  N Engl J Med. 1996;  334(12) 759-762
    Google Scholar
  • 10 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 1305-1307
    CrossrefPubMedGoogle Scholar
  • 11 Department of Health WO, Scottish Department of Health .Why mothers die. Report on confidential enquiries into maternal deaths in the United Kingdom 1994-1996. Drife J, Lewis G London; The Stationary Office 1998
  • 12 Berg C J, Atrash H K, Koonin L M, Tucker M. Pregnancy-related mortality in the United States, 1987-1990.  Obstet Gynecol. 1996;  88 161-167
    CrossrefPubMedGoogle Scholar
  • 13 Rusen I D, Liston R, Wen S W, Bartholomew S. Special Report on Maternal Mortality and Severe Morbidity in Canada Enhanced Surveillance: The Path to Prevention. Cat. No. H39-4/44-2004E. Minister of Public Works and Government Services Canada 2004
    Google Scholar
  • 14 Helewa M E, Burrows R F, Smith J, Williams K, Brain P, Rabkin S W. Report of the Canadian Hypertension Society Consensus Conference: 1. Definitions, evaluation and classification of hypertensive disorders in pregnancy.  CMAJ. 1997;  157 715-725
    PubMedGoogle Scholar
  • 15 Strauss R S. Adult functional outcome of those born small for gestational age: twenty-six-year follow-up of the 1970 British Birth Cohort.  JAMA. 2000;  283 625-632
    CrossrefPubMedGoogle Scholar
  • 16 Ghidini A, Salafia C M, Pezzullo J C. Placental vascular lesions and likelihood of diagnosis of preeclampsia.  Obstet Gynecol. 1997;  90(4 pt 1) 542-545
    CrossrefPubMedGoogle Scholar
  • 17 Salafia C M, Vintzileos A M, Silberman L, Bantham K F, Vogel C A. Placental pathology of idiopathic intrauterine growth retardation at term.  Am J Perinatol. 1992;  9(3) 179-184
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Salafia C M, Ernst L M, Pezzullo J C, Wolf E J, Rosenkrantz T S, Vintzileos A M. The very low birthweight infant: maternal complications leading to preterm birth, placental lesions, and intrauterine growth.  Am J Perinatol. 1995;  12(2) 106-110
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Salafia C M, Pezzullo J C, Lopez-Zeno J A, Simmens S, Minior V K, Vintzileos A M. Placental pathologic features of preterm preeclampsia.  Am J Obstet Gynecol. 1995;  173(4) 1097-1105
    CrossrefPubMedGoogle Scholar
  • 20 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
    CrossrefPubMedGoogle Scholar
  • 21 Li W, Zheng X, Gu J M et al.. Extraembryonic expression of EPCR is essential for embryonic viability.  Blood. 2005;  106(8) 2716-2722
    CrossrefPubMedGoogle Scholar
  • 22 Evans A S. Causation and disease: a chronological journey. The Thomas Parran Lecture.  Am J Epidemiol. 1978;  108(4) 249-258
    PubMedGoogle Scholar
  • 23 Parascandola M, Weed D L. Causation in epidemiology.  J Epidemiol Community Health. 2001;  55(12) 905-912
    CrossrefPubMedGoogle Scholar
  • 24 Hill A B. The environment and disease: association or causation?.  Proc R Soc Med. 1965;  58 295-300
    PubMedGoogle Scholar
  • 25 Thygesen L C, Andersen G S, Andersen H. A philosophical analysis of the Hill criteria.  J Epidemiol Community Health. 2005;  59(6) 512-516
    CrossrefPubMedGoogle Scholar
  • 26 Lin J, August P. Genetic thrombophilias and preeclampsia: a meta-analysis.  Obstet Gynecol. 2005;  105(1) 182-192
    CrossrefPubMedGoogle Scholar
  • 27 Wu O, Robertson L, Twaddle S et al.. Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study.  Health Technol Assess. 2006;  10 1-110
    PubMedGoogle Scholar
  • 28 Howley H E, Walker M, Rodger M A. A systematic review of the association between factor V Leiden or prothrombin gene variant and intrauterine growth restriction.  Am J Obstet Gynecol. 2005;  192 694-708
    CrossrefPubMedGoogle Scholar
  • 29 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
    CrossrefPubMedGoogle Scholar
  • 30 Rey E, Kahn S R, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis.  Lancet. 2003;  361(9361) 901-908
    CrossrefPubMedGoogle Scholar
  • 31 Burke W, Thomson E, Khoury M J et al.. Hereditary hemochromatosis. Gene discovery and its implications for population-based screening.  JAMA. 1998;  280 172-178
    CrossrefPubMedGoogle Scholar
  • 32 Infante-Rivard C, Rivard G E, Yotov W V et al.. Absence of association of thrombophilia polymorphisms with intrauterine growth restriction.  N Engl J Med. 2002;  347(1) 19-25
    CrossrefPubMedGoogle Scholar
  • 33 Meinardi J R, Middeldorp S, de Kam P J et al.. Increased risk for fetal loss in carriers of the factor V Leiden mutation.  Ann Intern Med. 1999;  130 736-739
    PubMedGoogle Scholar
  • 34 Preston F E, Rosendaal F R, Walker I D et al.. Increased fetal loss in women with heritable thrombophilia.  Lancet. 1996;  348 913-916
    CrossrefPubMedGoogle Scholar
  • 35 Redman C W. Current topic: pre-eclampsia and the placenta.  Placenta. 1991;  12(4) 301-308
    CrossrefPubMedGoogle Scholar
  • 36 Kramer M S. Determinants of low birth weight: methodological assessment and meta-analysis.  Bull World Health Organ. 1987;  65(5) 663-737
    PubMedGoogle Scholar
  • 37 Hills F A, Abrahams V M, Gonzalez-Timon B et al.. Heparin prevents programmed cell death in human trophoblast.  Mol Hum Reprod. 2006;  12(4) 237-243
    CrossrefPubMedGoogle Scholar
  • 38 Huhle G, Geberth M, Hoffmann U, Heene D L, Harenberg J. Management of heparin-associated thrombocytopenia in pregnancy with subcutaneous r-hirudin.  Gynecol Obstet Invest. 2000;  49(1) 67-69
    CrossrefPubMedGoogle Scholar
  • 39 Lepercq J, Conard J, Borel-Derlon A et al.. Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies.  BJOG. 2001;  108 1134-1140
    CrossrefPubMedGoogle Scholar
  • 40 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;  106 401-407
    CrossrefPubMedGoogle Scholar
  • 41 Howell R, Fidler J, Letsky E, de Swiet M. The risks of antenatal subcutaneous heparin prophylaxis: a controlled trial.  Br J Obstet Gynaecol. 1983;  90(12) 1124-1128
    PubMedGoogle Scholar
  • 42 Greer I A. The use of LMWH in pregnancies at risk: new evidence or perception?.  J Thromb Haemost. 2005;  3 781-782
    CrossrefPubMedGoogle Scholar
  • 43 Gates S, Brocklehurst P, Ayers S, Bowler U. Thromboprophylaxis and pregnancy: two randomized controlled pilot trials that used low-molecular-weight heparin.  Am J Obstet Gynecol. 2004;  191 1296-1303
    CrossrefPubMedGoogle Scholar
  • 44 McColl M D, Ramsay J E, Tait R C et al.. Risk factors for pregnancy associated venous thromboembolism.  Thromb Haemost. 1997;  78(4) 1183-1188
    PubMedGoogle Scholar
  • 45 Bates S M, Greer I A, Hirsh J, Ginsberg J S. Use of antithrombotic agents during pregnancy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.  Chest. 2004;  126(3 suppl) 627S-644S
    CrossrefPubMedGoogle Scholar
  • 46 Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies).  BMJ. 1997;  314 253-257
    CrossrefPubMedGoogle Scholar
  • 47 Kutteh W H. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone.  Am J Obstet Gynecol. 1996;  174(5) 1584-1589
    CrossrefPubMedGoogle Scholar
  • 48 Farquharson R G, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment.  Obstet Gynecol. 2002;  100 408-413
    CrossrefPubMedGoogle Scholar
  • 49 Empson M, Lassere M, Craig J, Scott J. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant.  Cochrane Database Syst Rev. 2005;  (2) CD002859
    PubMedGoogle Scholar
  • 50 Gris J-C, 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 3695-3699
    CrossrefPubMedGoogle Scholar
  • 51 Rodger M. Important publication missing key information.  Blood. 2004;  104(10) 3413-3414
    CrossrefPubMedGoogle Scholar
  • 52 Di Nisio M, Peters L, Middeldorp S. Anticoagulants for the treatment of recurrent pregnancy loss in women without antiphospholipid syndrome.  Cochrane Database Syst Rev. 2005;  (2) CD004734
    PubMedGoogle Scholar
  • 53 Walker M C, Ferguson S E, Allen V M. Heparin for pregnant women with acquired or inherited thrombophilias.  Cochrane Database Syst Rev. 2003;  (2) CD003580
    PubMedGoogle Scholar

Dr. Marc A Rodger

Division of Hematology, The Ottawa Hospital, General Campus

501 Smyth Rd., Ottawa, Ontario, Canada K1H 8L6

Email: mrodger@ohri.ca