Effektivität und Sicherheit der niedermolekularen Heparine bei Schwangeren mit wiederholtem Spontanabort (> 3 Aborte). Vergleichsstudie mit intravenösen Immunglobulinen (IVIG)

Zusammenfassung

Studiendesign: In einer retrospektiven Studie verglichen wir den Schwangerschaftsverlauf von 117 Frauen mit Thrombophilie und 117 Frauen ohne Thrombophilie, anatomische und genetische Ursachen (immunologisch bedingter Abort) nach > 3 Aborten. Methoden: Die Frauen mit Thrombophilie erhielten 5000 IE Dalteparin täglich oder in Kombination mit 100 mg Aspirin ab Diagnosestellung der Schwangerschaft. Schwangere mit immunologisch bedingten Aborten gaben wir 0,2 g/kg Immunglobuline bis maximal der 30. SSW. Die Gabe von Aspirin wurde in der 35. SSW beendet; Dalteparin verabreichten wir bis zur Geburt und bis 6 Wochen post partum. Wir erfassten die Häufigkeit der Fehlgeburten, die späten Schwangerschaftskomplikationen (Frühgeburt, fetale Retardierung, Präeklampsie) sowie die Nebenwirkungen der Therapien. Resultate: Die Lebendgeburtsrate in der IVIG-Gruppe war mit 85 % vergleichbar mit der Thrombophilie-behandelten Gruppe (78,6 %). Spät auftretende Komplikationen lagen in der IVIG-Gruppe bei 21,6 % und in der Thrombophilie-Gruppe bei 47,9 %. Die substanzspezifischen Nebenwirkungen sahen wir selten. Schlussfolgerung: Eine Dosisanpassung des Dalteparin war im Verlauf der Schwangerschaften nicht notwendig, da die Anti-Xa-Spiegel unverändert blieben.

Abstract

Objective: To compare the most efficacious therapeutic regimes - intravenous immunoglobulin (IVIG), low molecular weight heparins (LMWH) or LMWH and aspirin - in cases with thrombophilia or antiphospholipid syndrome (APLS) in women prone to immunological abortion and women with a history of recurrent spontaneous abortion (> 3 abortions). Methods: We observed 117 women with > 3 abortions and thrombophilia and 117 women with the same history and immunological abortion. The women received Dalteparin 5000 anti-Xa units alone or in combination with 100 mg aspirin. The other group received 0.2 mg/kg IVIG every 4 weeks until the 30th week of gestation. Aspirin was stopped in the 35th week of gestation and LMWH shortly before delivery and continued up to 6 weeks after delivery. The incidence of abortion, the late pregnancy outcome and the side effects of LMWH and IVIG were recorded. Results: The characteristics of both groups were similar with respect to general parameters. The birth rate in the IVIG group was comparable (85.0 %) to the thrombophilia group (78.8 %). The pregnancy complication rate was higher in the group with thrombophilia (47.9 %) vs. IVIG (21.6 %). Conclusions: The study indicates that IVIG may prevent miscarriages in patients in whom of thrombophilic, anatomical and genetic factors were excluded. Dalteparin is safe and effective for the prevention of miscarriage in cases with hereditary thrombophilic defects and APLS. The anti-Xa values remained unchanged during pregnancy and a dosage adaptation was not needed. Side effects of Dalteparin and IVIG were rare.

Angeborene thrombophile Defekte - Antiphospholipid‐Syndrom - wiederholter Spontanabort (WSA) - intravenöse Immunglobuline (IVIG) - niedermolekulare Heparine (NMH) - Dalteparin

hereditary thrombophilia - antiphospholipid syndrome - recurrent spontaneous abortion - intravenous Immunoglobulin (IVIG) - low molecular weight heparin (LMWH) - Dalteparin

Literatur

• 1 Bar J, Cohen-Sacher B, Hod M. Low-molecular-weight heparin for thrombophilia in pregnant women.  Int J Gynaecol Obstet. 2000;  69 209-213
• 2 Bar J, Lahav J, Kapustian V, Orvieto R, Yairi Y, Peled Y, Ben-Rafael Z, Hod M. Effect of thrombophylaxis on pregnancy outcome in women with thrombophilia.  Arch Perinat Med. 1999;  1 35-37
• 3 Bates S H, 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;  126 627-644
• 4 Blombäck M, Bremme K, Hellgren M, Siegbahn A, Lindberg H. Thromboprophylaxis with low molecular mass heparin, Fragmin (Dalteparin), during pregnancy - a longitudinal safety study.  Blood Coag Fibrinolysis. 1998;  9 1-9
• 5 Bounemeaux H, de Moerloose P. Is laboratory monitoring of low-molecular-weight heparin therapy necessary? No.  J Thromb Hemost. 2004;  4 551-554
• 6 Branch D W, Flint Porter T, Paiodas M J, Belford M A, Gonik B. Obstetric uses of intravenous immunoglobulin: Successes, failures, and promises.  J Allergy Clin Immunol. 2001;  108 133-138
• 7 Brenner B. LIVE-ENOX investigators . Efficacy and safety of two doses of Enoxaparin in pregnant women with thrombophilia and recurrent pregnancy loss: the LIVE-ENOX Study (abstract).  Blood. 2002;  100 702a
• 8 Brenner B. Thrombophilia and pregnancy.  Clin Adv Hematol Oncol. 2003;  1 351-355
• 9 Brenner B, Nowak-Göttl U, Kosch A, Manco-Johnson M, Laposata M. Diagnostic studies for thrombophilia in women on hormonal therapy and during pregnancy, and children.  Arch Pathol Lab Med. 2002;  126 1296-1303
• 10 Brenner B. Antithrombotic prophylaxis for women with thrombophilia and pregnancy complications - Yes.  J Thromb Haemost. 2003;  1 2070-2072
• 11 Brenner B. Maternal anticoagulant prophylaxis for prevention of pregnancy loss in women with thrombophilia.  J Thromb Haemost. 2003;  1 416-417
• 12 Brenner B. Clinical management of thrombophilia-related placental vascular complications.  Blood. 2004;  103 4003-4009
• 13 Buchholz T, Lohse P, Rogenhofer N, Kosian E, Pihusch R, Thaler C J. Polymorphisms in the ACE and PAI‐1 genes are associated with recurrent spontaneous abortion.  Hum Reprod. 2003;  11 2473-2477
• 14 Bussen S, Mulofinger L, Frambach T, Steck T, Dietl J. Molekulargenetische und plasmatische Untersuchungen des Gerinnungssystems bei Frauen mit habitueller Abortneigung.  Geburtsh Frauenheilk. 2004;  64 1061-1067
• 15 Carlin A J, Fahjrquharson R G, Quenby S M, Tropping J, Fraser W D. Prospective observational study of bone mineral density during pregnancy: low molecular weight heparin versus control.  Hum Reprod. 2004;  19 1211-1214
• 16 Carp H, Dolitzky M, Inbal A. Thromboprophylaxis improves the live birth rate in women with consecutive recurrent miscarriages and hereditary thrombophilia.  J Thromb Haemost. 2002;  1 433-438
• 17 Carp H J, Toder V, Gazit E, Ahiron R, Torchinski A, Mashiach S, Shoenfeld Y. Further experience with intravenous immunoglobulin in women with recurrent miscarriage and poor prognosis.  Am J Reprod Immunol. 2001;  46 268-273
• 18 Carp H J, Torchinsky Fein A, Toder V. Hormones, cytokines and fetal anomalies in habitual abortion.  Gynecol Endocrinol. 2001;  15 472-483
• 19 Carp H J. Recurrent pregnancy loss: Towards more accurate diagnosis and treatment.  IMAJ. 2001;  3 528-532
• 20 Carp H JA, Asherson R A, Shoenfeld Y. Intravenous Immuno-globulin in pregnancies complicated by the Antiphospholipid Syndrome: What is its role?.  J Clin Rheumatol. 2001;  7 291-294
• 21 Christiansen O B, Nielsen H S, Kolte A, Pedersen A T. Research methodology and epidemiology of relevance in recurrent pregnancy loss.  Semin Reprod Med. 2006;  24 5-16
• 22 Daya S, Gunby J, Clark D A. Intravenous immunoglobulin therapy for recurrent spontaneous abortion: a metaanalysis.  Am J Reprod Immunol. 1998;  39 69-76
• 23 Empson M, Lassere M, Craig J C, Scott J R. Recurrent pregnancy loss with Antiphospholipid antibody: a systematic review of therapeutic trials.  Obstet Gynecol. 2002;  99 135-144
• 24 Farquharson R G, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment.  Obstet Gynecol. 2002;  100 408-413
• 25 Franklin R D, Kutteh W H. Antiphospholipid antibodies (APA) and recurrent pregnancy loss treating a unique APA positive population.  Human Reprod. 2002;  17 2981-2985
• 26 Grandone E, Brancaccio V, Colaizzo B S. Preventing adverse obstetric outcomes in women with genetic thrombophilia.  Fertil Steril. 2002;  78 371-375
• 27 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
• 28 Gris J-C, Mercier E, Quere I, Lavigne-Lissalde G, Cochery-Nouvellon E, Hoffet M, Ripart-Neveu S, Tailland M L, Dauzat M, Mares P. Low molecular weight heparin versus low dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder.  Blood. 2004;  103 3695-3699
• 29 Harenberg J. Is laboratory monitoring of low-molecular-weight heparin therapy necessary? Yes.  J Thromb Hemost. 2004;  2 547-550
• 30 Heilmann L, Rath W, Pollow K. The influence of antiphospholipid antibodies on the pregnancy outcome of patients with recurrent spontaneous abortion.  Clin Appl Thromb Hemost. 2001;  7 281-285
• 31 Heilmann L, Rath W. Thombophilie in der Schwangerschaft. Bremen, London, Boston; Unimed 2002
• 32 Kling C, Steinmann J, Magez J, Westphal E, Kabelitz D. Akute Nebenwirkungen der allogenen Lymphozyten-Immunisierung.  Geburtsh Frauenheilk. 2005;  65 404-413
• 33 Kovalevsky G, Gracia C R, Berlin J A, Sammel M D, Barnhart K T. Evaluation of the association between hereditary thrombophilia and recurrent pregnancy loss. A Meta-analysis.  Arch Intern Med. 2004;  164 558-563
• 34 Kutteh W H, Ermel L D. A clinical trial for the treatment of antiphospholipid antibody-associated recurrent pregnancy loss with low dose heparin and aspirin.  Am J Reprod Immunology. 1996;  35 402-407
• 35 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
• 36 Kwak J Y, Quilty E A, Gilman-Sachs A. Intravenous immunoglobulin infusion therapy in women with recurrent spontaneous abortions of immune aetiologies.  J Reprod Immunol. 1995;  28 175-188
• 37 Laposata M, Green D, Van Cott E NM, Barrowcliffe T W, Goodnight S H, Sosolik R C. College of American Pathologists Conference XXXI on Laboratory monitoring of anticoagulant therapy. The clinical use and laboratory monitoring of low molecular - weight heparin, danparoid, hirudin and related components, and argatroban.  Arch Pathol Lab Med. 1998;  122 799-807
• 38 Lindqvist P G, Merlo J. The natural course of women with recurrent fetal loss.  J Thromb Haemost. 2006;  4 896-897
• 39 Lissalde-Lavigne G, Fabbro-Peary P, Cochery-Nouvellon E, Mercier E, Ripart-Neveu S S, Balducchi J P, Daures J P, Perneger T, Quere I, Dauzat M, Mares P, Gris J C. Factor V Leiden and Prothrombin G20210A Polymorphismus as a risk factors for miscarriage during a first intended pregnancy: the matched case-control “NOHA first” study.  J Thromb Haemost. 2005;  3 2178-2184
• 40 Menge S, Müller-Lantzsch C, Keck C, Tempfer C. Habituelle Aborte - ein aktueller Überblick über Ursachen und therapeutische Möglichkeiten.  Geburtsh Frauenheilk. 2004;  64 574-583
• 41 Miykakis S, Lockshin M D, Atsumi T, Branch D W, Brey R L, Cervera R, Derksen R HWM, De Groot P G, Koike T, Meroni P L, Reber G, Shoehfeld Y, Tincani A, Vlachoyiannopoulos P G, Krilis S. International Consensus Statement on an update of the classification criteria for definite antiphospholipid Syndrome (APS).  J Thromb Haemost. 2006;  4 295-306
• 42 Müller-Eckhardt G, Lattermann A. Nachweis von HLA-Antigenen, HLA-Antikörpern und Histokompatibilität. Müller-Eckhardt C Transfusionsmedizin. Berlin, Heidelberg, New York; Springer 1996
• 43 Noens L AE. Intravenous immunoglobulin for treatment of recurrent miscarriage. Dalakas MC, Späth PJ Intravenous Immunoglobulin in the third Millennium. Boca Raton, London, New York, Washington; Parthenon Pub 2006
• 44 Orgad S, Loewnthal R, Gazit E, Sadtzki S, Novikov I, Carp H J. The prognostic value of antipaternale antibodies and leukocyte immunizations on the proportion of live births in couples with consecutive recurrent miscarriages.  Human Reprod. 1999;  14 2974-2979
• 45 Pattison N S, Chamley L W, Birsdall M, Zanderigo A M, Liddell H S, McDougall J. 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
• 46 Pautzner R, Dulitzki M, Langevitz P, Livneh A, Kenett R, Many A. Low molecular weight heparin and wafarin in the treatment of patients with antiphospholipid syndrome during pregnancy.  Thromb Haemost. 2001;  86 1379-1384
• 47 Piazza M. Immunoglobulin transmits hepatitis C. True or false?.  Hepatology. 1999;  29 299-300
• 48 Prandoni P, Siragusa S, Girolami B, Fabris F. The incidence of heparin-induced thrombocytopenia in medical patients treated with low molecular-weight heparin: a prospective cohort study.  Blood. 2005;  108 3049-3054
• 49 Quenby S M, Farquharson R G. Predicting recurring miscarriage: what is important?.  Obstet Gynecol. 1993;  82 132-134
• 50 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
• 51 Rey E, Kahn S R, David M, Shrier I. Thrombophilic disorders and fetal loss: a metaanalysis.  Lancet. 2003;  361 901-908
• 52 Riyazi N, Leeda M, de Vries J L. Low molecular weight heparin combined with aspirin in pregnant women with thrombophilia and history of preeclampsia or fetal growth restriction: a preliminary study.  Eur J Obstet Gynecol Reprod Biol. 1998;  80 49-54
• 53 Robertson L, Wu O, Langhorne P, Twaddle S, Clark P, Lowe G DO, Walker I D, Greaves M, Brenkel I, Regan L, Greer I A. Thrombosis Risk Economic Assessment of thrombophilia screening (TREATS) study . Thrombophilia in pregnancy: a systematic review.  Brit J Haematology. 2005;  132 171-196
• 54 Samama M M. Contemporary laboratory monitoring of low molecular heparins.  Thromb Haemost. 1995;  15 119-123
• 55 Scott J R, Branch W D. Immunology of early pregnancy loss:.  Contemporary Ob/Gyn. 1998;  43 40-56
• 56 Stephenson M D, Ballem P J, Tsang P, Purkiss S, Ensworth S T, Houlihan E, Ensom M HH. 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
• 57 Stricker R B, Steinleitner A, Winger E E. Intravenous immunoglobulin (IVIG) therapy for immunologic abortion.  Clin Appl Immunology Rev. 2002;  2 187-199
• 58 Stricker R B, Winger E E. Update on treatment of immunologic abortion with low-dose intravenous immunoglobulin.  Am J Reprod Immunology. 2005;  54 390-396
• 59 Tzafettas J, Petropoulos P, Psarra A, Delkos D, Papaloukas C, Giannoulis H, Kalogiros G, Gkoutzioulis F. Early antiplatelet antithrombotic therapy in patients with a history of recurrent miscarriages of known and unknown aetiology.  Eur J Obstet Gynecol Reprod Biol. 2005;  120 22-26
• 60 Tempfer C, Schneeberger C, Riener E-K, Hefler L A, Keck C. Assoziationsstudien von Polymorphismen zur Risikoevaluierung in der Schwangerschaft - Literaturübersicht und Metaanalyse.  Geburtsh Frauenheilk. 2004;  64 1080-1089
• 61 Valensise H, Vaquero E, de Carolis C, Stipa E, Perricone R, Arduini D, Romanini C. Normal fetal growth in woman with antiphospholipid syndrome treated with high-dose intravenous immunoglobulin (IVIG).  Prenatal Diagnosis. 1995;  15 509-517
• 62 Vaquero E, Lazzarin N, Velensise H, Menghini S, di Pierro G, Cesa F, Romanini C. Pregnancy outcome in recurrent spontaneous abortion associates with antiphospholipid antibodies: A comparative study of intravenous immunoglobulin versus prednisone plus low dose aspirin.  Am J Reprod Immunol. 2001;  45 174-179
• 63 von Wolff M, Strowitzki T. Habituelle Aborte - ein multifaktorielles Krankheitsbild.  Gynäkol Endokrin. 2004;  3 7-17
• 64 Wilson A, Gharafi E, Koike T, Lockshin M, Branch D W, Piete J C, Brey R, Derksen R, Harris H N, Hughes G RV, Triplett D A, Khamashta M A. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome.  Arthr Rheumatol. 1999;  42 1309-1311
• 65 Yamada H, Kishida T, Kobayashi N, Katz E H, Aoski N, Fujimoto S. Massive immunoglobulin treatment in women with four or more recurrent spontaneous primary abortions of unexplained aetiology.  Human Reprod. 1998;  13 2620-2623
• 66 Younis J S, Ohel G, Brenner B. The effect of thromboprophylaxis on pregnancy outcome in patients with recurrent pregnancy loss associated with factor V Leiden mutation.  BJOG. 2000;  107 415-419
• 67 Zenclussen A C, Gentile T, Margni R, Kortebani G, Mazzolli A. Asymmetric antibodies and pregnancy.  Amer J Reprod Immunol. 2001;  45 289-294
• 68 Zetterberg H. Methylenetetrahydrofolate reductase and transcobalamin genetic polymorphisms in human spontaneous abortion: biological and clinical implications.  Reprod Biol and Endocrinol. 2004;  2 1-8