Mütterliche Thrombophilie und wiederholte Fehlgeburten – gibt es eine evidenzbasierte Indikation für Heparin als Rezidivprophylaxe?

Zusammenfassung

Hintergrund Wiederholte Fehlgeburten, auch wiederholte Spontanaborte (WSA) genannt, werden von 1 – 5% der Paare erlebt und weisen eine multifaktorielle Genese auf. Erworbene und angeborene Thrombophilien werden als hämostaseologische Risikofaktoren in der Pathogenese diskutiert.

Methode Die Übersichtsarbeit basiert auf einer selektiven Literaturrecherche in PubMed. Auf die aktuelle Evidenzlage zu WSA beim Antiphospholipidsyndrom und den hereditären Thrombophilien wird besonders hingewiesen.

Ergebnisse Das Antiphospholipidsyndrom (APS) ist eine erworbene, autoimmun-vermittelte Thrombophilie, bei der wiederholte Fehlgeburten zu den klinischen Klassifikationskriterien gehören. Von den serologischen Kriterien hat sich der Nachweis des Lupusantikoagulans als wichtigster Risikofaktor für die Entwicklung von Schwangerschaftskomplikationen herauskristallisiert. Der kombinierte Einsatz von niedrigdosiertem ASS mit Heparin zeigte einen deutlichen Vorteil hinsichtlich des Schwangerschaftsausgangs bei APS-bedingten Fehlgeburten. Bei einigen angeborenen Thrombophilien besteht auch eine erhöhte Risikoassoziation mit der Entstehung von WSA, wenn auch geringer als beim APS. Der Analogschluss zum Antiphospholipidsyndrom bezüglich des Einsatzes von Heparin zur Abortprophylaxe wird durch die aktuellen Analysen nicht hinreichend unterstützt. Daten zu seltenen, kombinierten bzw. homozygoten Thrombophilien bez. Fehlgeburten sind unzureichend.

Schlussfolgerung Anders als beim Antiphospholipidsyndrom stellen wiederholte Spontanaborte für sich bei mütterlicher hereditärer Thrombophilie nach aktueller Studienlage keine Indikation zur prophylaktischen Heparingabe in einer Folgeschwangerschaft dar. Unabhängig davon bestimmt das maternale Risiko für thromboembolische Ereignisse die Indikation für eine Thromboseprophylaxe in der Schwangerschaft.

Schlüsselwörter

Abort - Präeklampsie - Schwangerschaft

• References/Literatur

• 1 WHO. Recommended definitions, terminology and format for statistical tables related to the perinatal period and use of a new certificate for cause of perinatal deaths. Acta Obstet Gynecol Scand 1977; 56: 247-253
• 2 Rai R, Regan L. Recurrent miscarriage. Lancet 2006; 368: 601-611
• 3 Practice Committee of American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril 2013; 99: 63
• 4 Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril 2012; 98: 1103-1111
• 5 Specker C. Antiphospholipid syndrome. Z Rheumatol 2016; 75: 570-574
• 6 Miyakis S, Lockshin MD, Atsumi T. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295-306
• 7 Cervera R, Piette JC, Font J. et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002; 46: 1019-1027
• 8 Rai R, 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
• 9 Chighizola CB, Andreoli L, de Jesus GR. et al. The association between antiphospholipid antibodies and pregnancy morbidity, stroke, myocardial infarction, and deep vein thrombosis: a critical review of the literature. Lupus 2015; 24: 980-984
• 10 Abou-Nassar K, Carrier M, Ramsay T. et al. The association between antiphospholipid antibodies and placenta mediated complications: a systematic review and meta-analysis. Thromb Res 2011; 128: 77-85
• 11 Andreoli L, Chighizola CB, Banzato A. et al. Estimated frequency of antiphospholipid antibodies in patients with pregnancy morbidity, stroke, myocardial infarction, and deep vein thrombosis: a critical review of the literature. Arthritis Care Res (Hoboken) 2013; 65: 1869-1873
• 12 Yelnik CM, Laskin CA, Porter TF. et al. Lupus anticoagulant is the main predictor of adverse pregnancy outcomes in aPL-positive patients: validation of PROMISSE study results. Lupus Sci Med 2016; 3: e000131
• 13 Opatrny L, David M, Kahn SR. et al. Association between antiphospholipid antibodies and recurrent fetal loss in women without autoimmune disease: a metaanalysis. J Rheumatol 2006; 33: 2214-2221
• 14 Viall CA, Chamley LW. Histopathology in the placentae of women with antiphospholipid antibodies: a systematic review of the literature. Autoimmun Rev 2015; 14: 446-471
• 15 Ostensen M, Andreoli L, Brucato A. et al. State of the art: reproduction and pregnancy in rheumatic diseases. Autoimmun Rev 2015; 14: 376-386
• 16 Empson M, Lassere M, Craig J. et al. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev 2005; (02) CD002859
• 17 Mak A, Cheung MW, Cheak AA. 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) 2010; 49: 281-288
• 18 Bouvier S, Cochery-Nouvellon E, Lavigne-Lissalde G. et al. Comparative incidence of pregnancy outcomes in treated obstetric antiphospholipid syndrome: the NOH-APS observational study. Blood 2014; 123: 404-413
• 19 Andreoli L, Bertsias GK, Agmon-Levin N. et al. EULAR recommendations for womenʼs health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Ann Rheum Dis 2017; 76: 476-485
• 20 Girardi G, Redecha P, Salmon JE. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat Med 2004; 10: 1222-1226
• 21 Alvarez AM, Balcázar N, San Martín S. et al. Modulation of antiphospholipid antibodies-induced trophoblast damage by different drugs used to prevent pregnancy morbidity associated with antiphospholipid syndrome. Am J Reprod Immunol 2017; 77: e12634
• 22 Ruffatti A, Salvan E, Del Ross T. et al. Treatment strategies and pregnancy outcomes in antiphospholipid syndrome patients with thrombosis and triple antiphospholipid positivity. A European multicentre retrospective study. Thromb Haemost 2014; 112: 727-735
• 23 Sciascia S, Branch DW, Levy RA. et al. The efficacy of hydroxychloroquine in altering pregnancy outcome in women with antiphospholipid antibodies. Evidence and clinical judgment. Thromb Haemost 2016; 115: 285-290
• 24 Cohen H, Hunt BJ, Efthymiou M. et al. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol 2016; 3: e426-e436
• 25 Willeke A, Gerdsen F, Bauersachs RM. et al. Rationelle Thrombophiliediagnostik. Deutsches Ärzteblatt 2002; 31 – 32: 2111-2118
• 26 Roberts LN, Patel RK, Arya R. Venous thromboembolism and ethnicity. Br J Haematol 2009; 146: 369-383
• 27 Rey E, Kahn SR, David M. et al. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361: 901-908
• 28 Robertson L, Wu O, Langhorne P. et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2006; 132: 171-196
• 29 Rodger MA, Betancourt MT, 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
• 30 Baumann K, Beuter-Winkler P, Hackethal A. et al. Maternal factor V Leiden and prothrombin mutations do not seem to contribute to the occurrence of two or more than two consecutive miscarriages in Caucasian patients. Am J Reprod Immunol 2013; 70: 518-521
• 31 Skeith L, Carrier M, Kaaja R. et al. A meta-analysis of low-molecular-weight heparin to prevent pregnancy loss in women with inherited thrombophilia. Blood 2016; 127: 1650-1655
• 32 de Jong PG, Quenby S, Bloemenkamp KW. et al. ALIFE2 study: low-molecular-weight heparin for women with recurrent miscarriage and inherited thrombophilia–study protocol for a randomized controlled trial. Trials 2015; 16: 208
• 33 Rodger MA, Gris JC, de Vries JIP. et al. Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trials. Lancet 2016; 388: 2629-2641
• 34 Bujold E, Roberge S, Lacasse Y. et al. Prevention of preeclampsia and intrauterine growth restriction with Aspirin started in early pregnancy. Obstet Gynecol 2010; 116: 402-414
• 35 Roberge S, Nicolaides K, Demers S. et al. The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis. Am J Obstet Gynecol 2017; 216: 110-120.e6
• 36 Schisterman EF, Silver RM, Lecher LL. et al. Preconception low-dose aspirin and pregnancy outcomes: results from the EAGeR randomised trial. Lancet 2014; 384: 29-36
• 37 Toth B, Würfel W, Bohlmann MK. et al. Recurrent miscarriage: diagnostic and therapeutic procedures. Guideline of the DGGG (S1-Level, AWMF Registry No. 015/050, December 2013). Geburtsh Frauenheilk 2015; 75: 1117-1129
• 38 Bates SM, Greer IA, Middeldorp S. et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e691S-e736S
• 39 Gynaecologists, RCOG. The investigation and treatment of couples with recurrent firsttrimester and second-trimester miscarriage. RCOG Green-top Guideline No. 17, 2011. Last update April 2011 Online: http://www.nice.org.uk/accreditation
• 40 Heit J, Kobbervig CE, James AH. et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005; 143: 697-706
• 41 Encke A, Haas S, Kopp I. et al. S3-Leitlinie Prophylaxe der venösen Thromboembolie (VTE). AWMF; 2015 Online http://www.awmf.org/leitlinien/detail/ll/003-001.html Stand 15.10.2015
• 42 Marik PE, Plante LA. Venous thromboembolic disease and pregnancy. N Engl J Med 2008; 359: 2025-2033