Thrombophilie und Schwangerschaftskomplikationen

 

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Zusammenfassung

Die Ergebnisse zahlreicher zumeist retrospektiver Studien der vergangenen 15 Jahre weisen auf einen Zusammenhang zwischen der Entwicklung schwerwiegender Schwangerschaftskomplikationen (SSK) und genetisch determinierten und erworbenen Thrombophilien hin. Die auf niedrigem Evidenzniveau basierenden aktuellen Empfehlungen internationaler Expertengruppen (American College of Chest Physicians, Pregnancy and Thrombosis Working Group, Royal College of Obstetricians and Gynaecologists) zur Indikation einer Thrombophilieabklärung und Antikoagulanziengabe bei Schwangeren mit SSK – außerhalb thrombotischer Ereignisse – sind uneinheitlich, da für eine abschließende Beurteilung prospektive Studien mit ausreichender statistischer Power unter Einbeziehung homogener Patientengruppen und Anwendung multivariater Analysemodelle einschließlich standardisierter Komplikationsterminologien fehlen. Obgleich ein gesichertes Interaktionsmodell für den Pathomechanismus einer Thrombophilie und Ausbildung einer SSK gegenwärtig nicht verfügbar ist, stellen 75 % aller befragten Pränatalabteilungen in England bei Frauen mit Spät- oder wiederholten Aborten sowie Abruptio placentae die Indikation zu einer Thrombophilieabklärung und machen den Einsatz einer Antikoagulanziengabe zur Prävention einer SSK in der Folgeschwangerschaft davon abhängig. Es war das Ziel der vorliegenden Übersichtsarbeit, unter Berücksichtigung aktueller prospektiver Untersuchungen die Studienlage zur Thrombophilie bei SSK und Antikoagulanziengabe zur Prävention einer SSK kritisch zu beurteilen sowie Empfehlungen zum praktischen Vorgehen zu erarbeiten.

Abstract

Results obtained in the last 15 years from a number of retrospective trials provide evidence that there is an association between adverse pregnancy outcomes (APO) such as early/late (recurrent) abortion, preeclampsia, intrauterine fetal growth retardation, or abruptio placentae and the presence of inherited or acquired thrombophilic defects. Although revised international recommendations (American College of Chest Physicians, Pregnancy and Thrombosis Working Group, Royal College of Obstetricians and Gynaecologists) for the investigation and management of thrombophilia in patients with APO apart from thrombosis have been published recently, they are inconsistent and based on limited evidence due to the lack of prospective trials performed in homogeneous groups of patients using multivariate analysis and uniform terminologies for APO. However, according to a recent British survey, 75 % of participating prenatal units perform routine thrombophilia screening in women with APO, and the results guide the decision to administer anticoagulant medication to prevent APO in subsequent pregnancies. A summary of current study results of thrombophilia-associated APO and the prevention of APO (apart from thrombosis) using anticoagulants was carried out, and more recent prospective trials are considered. Recommendations for thrombophilia screening in APO as well as the use of anticoagulants for the prevention of APO are discussed.

Literatur

• 1 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
• 2 Bates S M, Greer I A, Pabinger I American College of Chest Physicians et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).  Chest. 2008;  133 (6 Suppl.) 844S-886S
  CrossrefPubMedGoogle Scholar
• 3 Duhl A J, Paidas M J, Ural S H for the pregnancy and thrombosis working group et al. Antithrombotic therapy and pregnancy: consensus report and recommendations for prevention and treatment of venous thromboembolism and adverse pregnancy outcomes.  Am J Obstet Gynecol. 2007;  197 457e1-457e21
  CrossrefPubMedGoogle Scholar
• 4 Kent N, Leduc L, Crane J et al. Prevention and treatment of venous thrombembolism (VTE) in obstetrics. SCOG Clinical Practice Guidelines.  J SOGC. 2000;  22 736-749
  PubMedGoogle Scholar
• 5 Rodger M A, Paidas M, McLintock C et al. Inherited thrombophilia and pregnancy complications revisited.  Obstet Gynecol. 2008;  112 320-324
  CrossrefPubMedGoogle Scholar
• 6 Norrie G, Farquharson R G, Greaves M. Screening and treatment for heritable thrombophilia in pregnancy failure: inconsistencies among UK early pregnancy units.  Br J Haematol. 2009;  144 241-244
  CrossrefPubMedGoogle Scholar
• 7 Dargaud Y, Rugeri L, Vergnes M C et al. A risk score for the management of pregnant women with increased risk of venous thromboembolism: a multicentre prospective study.  Br J Haematol. 2009;  145 825-835
  CrossrefPubMedGoogle Scholar
• 8 Chauleur C, Galanaud J P, Alonso S et al. Observational study of pregnant women with a previous spontaneous abortion before the 10th gestation week with and without antiphospholipid antibodies.  J Thromb Haemost. 2010;  8 699-706
  CrossrefPubMedGoogle Scholar
• 9 Lindqvist P G, Svensson P J, Marsaál K et al. Activated protein C resistance (FV : Q506) and pregnancy.  Thromb Haemost. 1999;  81 532-537
  PubMedGoogle Scholar
• 10 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;  36 279-287
  CrossrefPubMedGoogle Scholar
• 11 Said J M, Higgins J R, Moses E K et al. Inherited thrombophilia polymorphisms and pregnancy outcomes in nulliparous women.  Obstet Gynecol. 2010;  115 5-13
  CrossrefPubMedGoogle Scholar
• 12 Kramer M S, Kahn S R, Rozen R et al. Vasculopathic and thrombophilic risk factors for spontaneous preterm birth.  Int J Epidemiol. 2009;  38 715-723
  CrossrefPubMedGoogle Scholar
• 13 Kahn S R, 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.e1-151.e9
  PubMedGoogle Scholar
• 14 Silver R M, Zhao Y, Spong C Y Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (NICHD MFMU) Network et al. Prothrombin gene G20210A mutation and obstetric complications.  Obstet Gynecol. 2010;  115 14-20
  CrossrefPubMedGoogle Scholar
• 15 Jaslow C R, Carney J L, Kutteh W H. Diagnostic factors identified in 1020 women with two versus three or more recurrent pregnancy losses.  Fertil Steril. 2010;  93 1234-1243
  CrossrefPubMedGoogle Scholar
• 16 Dugoff L, Cuckle H S, Hobbins J C FaSTER Trial Research Consortium et al. Prediction of patient-specific risk for fetal loss using maternal characteristics and first- and second-trimester maternal serum Down syndrome markers.  Am J Obstet Gynecol. 2008;  199 290.e1-290.e6
  PubMedGoogle Scholar
• 17 Quenby S M, Farquharson R G. Predicting recurring miscarriage: what is important?.  Obstet Gynecol. 1993;  82 132-138
  PubMedGoogle Scholar
• 18 Christiansen O B, Steffensen R, Nielsen H S et al. Multifactorial etiology of recurrent miscarriage and its scientific and clinical implications.  Gynecol Obstet Invest. 2008;  66 257-267
  CrossrefPubMedGoogle Scholar
• 19 Heyl W, Rath W, Heilmann L. Hämostaseveränderungen in der normalen Schwangerschaft.. Rath W, Heilmann L Gerinnungsstörungen in Gynäkologie und Geburtshilfe.. Stuttgart, New York: Thieme; 1999: 115-117
  Google Scholar
• 20 Jindal P, Regan L, Fourkala E O et al. Placental pathology of recurrent spontaneous abortion: the role of histopathological examination of products of conception in routine clinical practice: a mini review.  Hum Reprod. 2007;  22 313-316
  PubMedGoogle Scholar
• 21 Mousa H A, Alfirevic Z. Do placental lesions reflect thrombophilia state in women with adverse pregnancy outcome.  Human Reproduc. 2000;  15 1830-1833
  PubMedGoogle Scholar
• 22 Rey E, Garneau P, David M et al. Dalteparin for the prevention of recurrence of placental-mediated complications of pregnancy in women without thrombophilia: a pilot randomized controlled trial.  J Thromb Haemost. 2009;  7 58-64
  CrossrefPubMedGoogle Scholar
• 23 Dendrinos S, Kalogirou I, Makrakis E et al. Safety and effectiveness of tinzaparin sodium in the management of recurrent pregnancy loss.  Clin Exp Obstet Gynecol. 2007;  34 143-145
  PubMedGoogle Scholar
• 24 Leduc L, Dubois E, Takser L et al. Dalteparin and low-dose aspirin in the prevention of adverse obstetric outcomes in women with inherited thrombophilia.  J Obstet Gynaecol Can. 2007;  29 787-793
  PubMedGoogle Scholar
• 25 Sergio F, Maria Clara D, Gabriella F et al. Prophylaxis of recurrent preeclampsia: low-molecular-weight heparin plus low-dose aspirin versus low-dose aspirin alone.  Hypertens Pregnancy. 2006;  25 115-127
  CrossrefPubMedGoogle Scholar
• 26 Georgiades P, Ferguson-Smith A C, Burton G J. Comparative developmental anatomy of the murine and human definitive placentae.  Placenta. 2002;  23 3-19
  CrossrefPubMedGoogle Scholar
• 27 Sood R, Kalloway S, Mast A E et al. Fetomaternal cross talk in the placental vascular bed: control of coagulation by trophoblast cells.  Blood. 2006;  107 3173-3180
  CrossrefPubMedGoogle Scholar
• 28 Aharon A, Brenner B, Katz T et al. Tissue factor and tissue factor pathway inhibitor levels in Trophoblast cells: implications for placental hemostasis.  Thromb Haemost. 2004;  92 776-786
  PubMedGoogle Scholar
• 29 Erlich J, Parry G C, Fearns C et al. Tissue factor is required for uterine hemostasis and maintenance of the placental labyrinth during gestation.  Proc Natl Acad Sci USA. 1999;  96 8138-8143
  CrossrefPubMedGoogle Scholar
• 30 Isermann B, Sood R, Pawlinski R et al. The thrombomodulin-protein C system is essential for the maintenance of pregnancy.  Nat Med. 2003;  9 331-337
  CrossrefPubMedGoogle Scholar
• 31 Weiler-Guettler H, Christie P D, Beeler D L et al. A targeted point mutation in thrombomodulin generates viable mice with a prethrombotic state.  J Clin Invest. 1998;  101 1983-1991
  CrossrefPubMedGoogle Scholar
• 32 Stortoni P, Cecati M, Giannubilo S R et al. Placental thrombomodulin expression in recurrent miscarriage.  Reprod Biol Endocrinol. 2010;  8 1
  CrossrefPubMedGoogle Scholar
• 33 Ball E, Bulmer J N, Ayis S et al. Late sporadic miscarriage is associated with abnormalities in spiral artery transformation and trophoblast invasion.  J Pathol. 2006;  208 535-542
  CrossrefPubMedGoogle Scholar
• 34 Lyall F. Mechanisms regulating cytotrophoblast invasion in normal pregnancy and pre-eclampsia.  Aust N Z J Obstet Gynaecol. 2006;  46 266-273
  CrossrefPubMedGoogle Scholar
• 35 Kim Y M, Bujold E, Chaiworapongsa T et al. Failure of physiologic transformation of the spiral arteries in patients with preterm labor and intact membranes.  Am J Obstet Gynecol. 2003;  189 1063-1069
  CrossrefPubMedGoogle Scholar
• 36 Brosens J J, Pijnenborg R, Brosens I A. The myometrial junctional zone spiral arteries in normal and abnormal pregnancies: a review of the literature.  Am J Obstet Gynecol. 2002;  187 1416-1423
  CrossrefPubMedGoogle Scholar
• 37 Gerbasi F R, Bottoms S S, Farag A et al. Increased intravascular coagulation associated with pregnancy.  Obstet Gynecol. 1990;  75 385-389
  PubMedGoogle Scholar
• 38 von Tempelhoff G F, Velten E, Yilmaz A et al. Blood rheology at term in normal pregnancy and in patients with adverse outcome events.  Clin Hemorheol Microcirc. 2009;  42 127-139
  PubMedGoogle Scholar
• 39 Sibai B, Dekker G, Kupferminc M. Pre-eclampsia.  Lancet. 2005;  365 785-799
  CrossrefPubMedGoogle Scholar
• 40 Hung T H, Skepper J N, Charnock-Jones D S et al. Hypoxia-reoxygenation: a potent inducer of apoptotic changes in the human placenta and possible etiological factor in preeclampsia.  Circ Res. 2002;  90 1274-1281
  CrossrefPubMedGoogle Scholar
• 41 Hempstock J, Jauniaux E, Greenwold N et al. The contribution of placental oxidative stress to early pregnancy failure.  Hum Pathol. 2003;  34 1265-1275
  CrossrefPubMedGoogle Scholar
• 42 Burton G J, Jauniaux E. Placental oxidative stress: from miscarriage to preeclampsia.  J Soc Gynecol Investig. 2004;  11 342-352
  CrossrefPubMedGoogle Scholar
• 43 Greaves M. Pathogenesis and management of antiphospholipid syndrome.  Thromb Res. 2009;  123 (Suppl. 2) S4-S9
  CrossrefPubMedGoogle Scholar
• 44 Rand J H, Wu X X. Antibody-mediated interference with annexins in the antiphospholipid syndrome.  Thromb Res. 2004;  114 383-389
  CrossrefPubMedGoogle Scholar
• 45 Hulstein J J, Lenting P J, de Laat B et al. Beta2-glycoprotein I inhibits von Willebrand factor dependent platelet adhesion and aggregation.  Blood. 2007;  110 1483-1491
  CrossrefPubMedGoogle Scholar
• 46 Rote N S. Antiphospholipid antibodies and recurrent pregnancy loss.  Am J Reprod Immunol. 1996;  35 394-401
  CrossrefPubMedGoogle Scholar
• 47 Shamonki J M, Salmon J E, Hyjek E et al. Excessive complement activation is associated with placental injury in patients with antiphospholipid antibodies.  Am J Obstet Gynecol. 2007;  196 167.e1-167.e5
  CrossrefPubMedGoogle Scholar
• 48 Laude I, Rongières-Bertrand C, Boyer-Neumann C et al. Circulating procoagulant microparticles in women with unexplained pregnancy loss: a new insight.  Thromb Haemost. 2001;  85 18-21
  PubMedGoogle Scholar
• 49 Lissalde-Lavigne G, Fabbro-Peray P, Cochery-Nouvellon E et al. Factor V Leiden and prothrombin G20210A polymorphisms as risk factors for miscarriage during a first intended pregnancy: the matched case-control ‘NOHA first study.  J Thromb Haemost. 2005;  3 2178-2184
  CrossrefPubMedGoogle Scholar
• 50 Stirrat G M. Recurrent miscarriage. II: Clinical associations, causes, and management.  Lancet. 1990;  336 728-733
  CrossrefPubMedGoogle Scholar
• 51 Smith L F, Ewings P D, Quinlan C. Incidence of pregnancy after expectant, medical, or surgical management of spontaneous first trimester miscarriage: long term follow-up of miscarriage treatment (MIST) randomised controlled trial.  BMJ. 2009;  339 b3827
  CrossrefPubMedGoogle Scholar
• 52 Zegers-Hochschild F, Adamson D, de Mouzon J on behalf of ICMART and WHO; The International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) et al. Revised glossary on ART terminology, 2009.  Human Reproduction. 2009;  24 2683-2687
  CrossrefPubMedGoogle Scholar
• 53 Carreras L O, Vermylen J, Spitz B et al. Lupus anticoagulant and inhibition of prostacyclin formation in patients with repeated abortion, intrauterine growth retardation and intrauterine death.  Br J Obstet Gynaecol. 1981;  88 890-894
  PubMedGoogle Scholar
• 54 Yasuda M, Takakuwa K, Tokunaga A et al. Prospective studies of the association between anticardiolipin antibody and outcome of pregnancy.  Obstet Gynecol. 1995;  86 555-559
  CrossrefPubMedGoogle Scholar
• 55 Rai R S, Clifford K, Cohen H et al. High prospective fetal loss rate in untreated pregnancies of women with recurrent miscarriage and antiphospholipid antibodies.  Hum Reprod. 1995;  10 3301-3304
  PubMedGoogle Scholar
• 56 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
• 57 Higashino M, Takakuwa K, Arakawa M et al. Anti-cardiolipin antibody and anti-cardiolipin beta-2-glycoprotein I antibody in patients with recurrent fetal miscarriage.  J Perinat Med. 1998;  26 384-389
  CrossrefPubMedGoogle Scholar
• 58 Pabinger I, Nemes L, Rintelen C et al. Pregnancy-associated risk for venous thromboembolism and pregnancy outcome in women homozygous for factor V Leiden.  Hematol J. 2000;  1 37-41
  CrossrefPubMedGoogle Scholar
• 59 Kist W J, Janssen N G, Kalk J J et al. Thrombophilias and adverse pregnancy outcome – a confounded problem!.  Thromb Haemost. 2008;  99 77-85
  PubMedGoogle Scholar
• 60 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
  CrossrefPubMedGoogle Scholar
• 61 Rai R, Shlebak A, Cohen H et al. Factor V Leiden and acquired activated protein C resistance among 1000 women with recurrent miscarriage.  Hum Reprod. 2001;  16 961-965
  CrossrefPubMedGoogle Scholar
• 62 Tal J, Schliamser L M, Leibovitz Z et al. A possible role for activated protein C resistance in patients with first and second trimester pregnancy failure.  Hum Reprod. 1999;  14 1624-1627
  CrossrefPubMedGoogle Scholar
• 63 Rodger M A, Betancourt M T, 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
  CrossrefPubMedGoogle Scholar
• 64 Jivraj S, Rai R, Underwood J et al. Genetic thrombophilic mutations among couples with recurrent miscarriage.  Hum Reprod. 2006;  21 1161-1165
  CrossrefPubMedGoogle Scholar
• 65 Report of the National High Blood Pressure Education program. Working group report on high blood pressure in pregnancy.  Am J Obstet Gynecol. 2000;  183 181-192
  PubMedGoogle Scholar
• 66 ACOG Committee on Practice Bulletins – Obstetrics . ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002.  Obstet Gynecol. 2002;  99 159-167
  CrossrefPubMedGoogle Scholar
• 67 Prasmusinto D, Skrablin S, Fimmers R et al. Ethnic differences in the association of factor V Leiden mutation and the C677T methylenetetrahydrofolate reductase gene polymorphism with preeclampsia.  Eur J Obstet Gynecol Reprod Biol. 2004;  112 162-169
  CrossrefPubMedGoogle Scholar
• 68 Kobashi G, Yamada H, Asano T et al. The factor V Leiden mutation is not a common cause of pregnancy-induced hypertension in Japan.  Semin Thromb Hemost. 1999;  25 487-489
  Article in Thieme ConnectPubMedGoogle Scholar
• 69 Hira B, Pegoraro R J, Rom L et al. Absence of factor V leiden, thrombomodulin and prothrombin gene variants in black South African women with pre-eclampsia and eclampsia.  BJOG. 2003;  110 327-328
  PubMedGoogle Scholar
• 70 Mello G, Parretti E, Marozio L et al. Thrombophilia is significantly associated with severe preeclampsia. Results of a large scale, care-controlled study.  Hypertension. 2005;  46 1270-1274
  CrossrefPubMedGoogle Scholar
• 71 Facchinetti F, Marozio L, Frusca T et al. Maternal thrombophilia and the risk of recurrence of preeclampsia.  Am J Obstet Gynecol. 2009;  200 46.e1-46.e5
  PubMedGoogle Scholar
• 72 Cowchock S, Reece E A. Organizing Group of the Antiphospholipid Antibody Treatment Trial . Do low-risk pregnant women with antiphospholipid antibodies need to be treated?.  Am J Obstet Gynecol. 1997;  176 1099-1100
  CrossrefPubMedGoogle Scholar
• 73 Tulppala M, Marttunen M, Söderstrom-Anttila V et al. Low-dose aspirin in prevention of miscarriage in women with unexplained or autoimmune related recurrent miscarriage: effect on prostacyclin and thromboxane A2 production.  Hum Reprod. 1997;  12 1567-1572
  CrossrefPubMedGoogle Scholar
• 74 Pattison N S, Chamley L W, Birdsall M et al. Does aspirin have a role in improving pregnancy outcome for women with the antiphospholipid syndrome? A randomized controlled trial.  Am J Obstet Gynecol. 2000;  183 1008-1012
  CrossrefPubMedGoogle Scholar
• 75 Laskin C A, Bombardier C, Hannah M E et al. Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss.  N Engl J Med. 1997;  337 148-153
  CrossrefPubMedGoogle Scholar
• 76 Rai R, Cohen H, Dave M et al. 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
• 77 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 1584-1589
  CrossrefPubMedGoogle Scholar
• 77a Kutteh W H, Ermel L D. A clinical trial for the treatment of antiphospholipid antibody-associated recurrent pregnancy loss with lower dose heparin and aspirin.  Am J Reprod Immunol. 1996;  35 402-407
  CrossrefPubMedGoogle Scholar
• 78 Franklin R D, Kutteh W H. Antiphospholipid antibodies (APA) and recurrent pregnancy loss: treating a unique APA positive population.  Hum Reprod. 2002;  17 2981-2985
  CrossrefPubMedGoogle Scholar
• 78a Triolo G, Ferrante A, Ciccia F et al. Randomized study of subcutaneous low molecular weight heparin plus aspirin versus intravenous immunoglobulin in the treatment of recurrent fetal loss associated with antiphospholipid antibodies.  Arthritis Rheum. 2003;  48 728-731
  CrossrefPubMedGoogle Scholar
• 78b Farquharson R G, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment.  Obstet Gynecol. 2002;  100 408-413 Erratum in: Obstet Gynecol. 2002;  100 1361
  CrossrefPubMedGoogle Scholar
• 79 Stephenson M D, Ballem P J, Tsang P et al. Treatment of antiphospholipid antibody syndrome (APS) in pregnancy: a randomized pilot trial comparing low molecular weight heparin to unfractionated heparin.  J Obstet Gynaecol Can. 2004;  26 729-734
  PubMedGoogle Scholar
• 80 Noble L S, Kutteh W H, Lashey N et al. Antiphospholipid antibodies associated with recurrent pregnancy loss: prospective, multicenter, controlled pilot study comparing treatment with low-molecular-weight heparin versus unfractionated heparin.  Fertil Steril. 2005;  83 684-690
  CrossrefPubMedGoogle Scholar
• 81 Ghosh K, Shetty S, Vora S et al. Successful pregnancy outcome in women with bad obstetric history and recurrent fetal loss due to thrombophilia: effect of unfractionated heparin and low-molecular weight heparin.  Clin Appl Thromb Hemost. 2008;  14 174-179
  CrossrefPubMedGoogle Scholar
• 82 Mak A, Cheung M W, Cheak A A et al. Combination of heparin and aspirin is superior to aspirin alone in enhancing live births in patients with recurrent pregnancy loss and positive anti-phospholipid antibodies: a meta-analysis of randomized controlled trials and meta-regression.  Rheumatology (Oxford). 2009;  49 281-288
  PubMedGoogle Scholar
• 82a Dolitzky M, Inbal A, Segal Y et al. A randomized study of thromboprophylaxis in women with unexplained consecutive recurrent miscarriages.  Fertil Steril. 2006;  86 362-366
  CrossrefPubMedGoogle Scholar
• 83 Clark P, Walker I D, Langhorne P et al. The Scottish Pregnancy Intervention Study: a multicentre randomised controlled trial of low molecular weight heparin and low dose aspirin in women with recurrent miscarriage.  Blood. 2010;  115 4162-4167
  CrossrefPubMedGoogle Scholar
• 84 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 1586-1596
  CrossrefPubMedGoogle Scholar
• 85 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;  27 33-38
  PubMedGoogle Scholar
• 86 Badawy A M, Khiary M, Sherif L S et al. Low-molecular weight heparin in patients with recurrent early miscarriages of unknown aetiology.  J Obstet Gynaecol. 2008;  28 280-284
  CrossrefPubMedGoogle Scholar
• 87 Brenner B, Hoffman R, Blumenfeld Z et al. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.  Thromb Haemost. 2000;  83 693-697
  PubMedGoogle Scholar
• 88 Carp H, Dolitzky M, Inbal A. Thromboprophylaxis improves the live birth rate in women with consecutive recurrent miscarriages and hereditary thrombophilia.  J Thromb Haemost. 2003;  1 433-438
  CrossrefPubMedGoogle Scholar
• 89 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
• 90 Grandone E, De Stefano V, Rossi E et al. Antithrombotic prophylaxis during pregnancy in women with deficiency of natural anticoagulants.  Blood Coagul Fibrinolysis. 2008;  19 226-230
  CrossrefPubMedGoogle Scholar
• 91 Kalk J J, Huisjes A J, de Groot C J et al. Recurrence rate of pre-eclampsia in women with thrombophilia influenced by low-molecular-weight heparin treatment?.  Neth J Med. 2004;  62 83-87
  PubMedGoogle Scholar
• 91a Tzafettas J, Petropoulos P, Psarra A et al. Early antiplatelet and antithrombotic therapy in patients with a history of recurrent miscarriages of known and unknown aetiology.  Eur J Obstet Gynecol Reprod Biol. 2005;  120 22-226
  CrossrefPubMedGoogle Scholar
• 92 Nelson-Piercy C, MacCallum P, MacKillop L et al. Reducing the risk of thrombosis and ambolism during pregnancy and the puerperium. Sec. Ed. Thromboprophylaxis during pregnancy, labour and after vaginal delivery 2004; Settings standards to improve women's health (Royal College of Obstetricians and Gynaecologists).  Green-top Guidelines. 2009;  37 1-35
  PubMedGoogle Scholar
• 93 The Scottish Intercollegiate Guidelines Network .Prophylaxis of venous thromboembolism, A national clinical guideline.. No 62. Edinburgh: SIGN; 2002
  Google Scholar
• 94 Qublan H, Amarin Z, Dabbas M et al. Low-molecular-weight heparin in the treatment of recurrent IVF-ET failure and thrombophilia: a prospective randomized placebo-controlled trial.  Hum Fertil (Camb). 2008;  11 246-253
  CrossrefPubMedGoogle Scholar
• 95 Halbmayer W M, Feichtinger W, Kindermann C et al. Recurrent miscarriage or failed in-vitro fertilization: antibodies against annexin V, cardiolipin, beta-2-glycoprotein-1 and APC-resistance.  Hamostaseologie. 2005;  25 391-393
  PubMedGoogle Scholar
• 96 Nelson S M, Greer I A. The potential role of heparin in assisted conception.  Hum Reprod Update. 2008;  14 623-645
  CrossrefPubMedGoogle Scholar

Priv. Doz. Dr. med. Georg-Friedrich von Tempelhoff, FCATH

Abt. Gynäkologie und Geburtshilfe
Klinikum Aschaffenburg (Lehrkrankenhaus der Maximilians-Universität Würzburg)

Am Hasenkopf 1

63739 Aschaffenburg

Email: g-f.von.tempelhoff@gmx.de