Die Anwendung von niedermolekularen Heparinen in der Schwangerschaft

Zusammenfassung

Niedermolekulare Heparine ersetzen in zunehmendem Maße die unfraktionierten Heparine auch in der Schwangerschaft. Aufgrund der vorliegenden Daten ist eine angenäherte Komplikationsrate von 11,6 % bei 1884 Beobachtungen mit niedermolekularen Heparinen in der Schwangerschaft zu beobachten. Vaginale Blutungen traten bei ca. 3,4 %, venöse Thrombosen bei 1,7 %, Aborte bei 3 %, Frakturen bei 0,1 % und ein HIT II bei 0,05 % der Schwangeren auf. Die Einteilung in 3 Risikogruppen hat sich aus praktisch/klinischen Gesichtspunkten angeboten. Während Schwangere mit niedrigem Thromboserisiko allein einer postpartualen Prophylaxe bedürfen, sollten Frauen mit mittlerem Risiko in der gesamten Schwangerschaft mit einem niedermolekularen Heparin behandelt werden. Bei einer kleinen Gruppe von Schwangeren mit hohem Risiko ist dagegen eine therapeutische Dosis der niedermolekularen Heparine zu empfehlen. Das Antiphospholipidsyndrom ist mit einer hohen geburtshilflichen Komplikationsrate verbunden und erfordert eine enge Zusammenarbeit mit einem hämostaseologisch erfahrenen Labor.

Summary

Anticoagulant therapy for thromboprophylaxis in pregnancy usually consists of non-fractionated heparin (UFH) in a dose of 10,000 IU twice daily or of low molecular weight heparin (LMWH). The potential advantages of LMWH are based on the plasma half-life and on their 90 - 95 % bioavailability after s.c. administration. The complication rate of a pooled evaluation of patients treated during pregnancy with LMWH was 3.4 % for vaginal bleeding, 1.7 % for deep vein thrombosis, 3 % for spontaneous abortion, 0.1 % for osteoporotic fracture and 0.05 % for HIT II. Management of patients with hereditary hypercoagulable state in pregnancy is controversial because of the scarcity of data to guide decision making and because of inconsistencies among the available data . The working group of GTH “thrombophilia in pregnancy” recommended guidelines for the management of women who receive antithrombotic therapy for prophylaxis of venous thrombosis and pregnancy complications. Low-risk patients receiving post partum antithrombotic therapy, women with moderate risk LMWH from the first diagnosis of the pregnancy and patients with higher risk received “therapeutic doses” of LMWH. Patients with antiphospholipid antibody syndrome (APS) are associated with a high rate of adverse pregnancy complications and should be referred to a unit that specializes in the management of acquired thrombophilia in pregnancy.

Literatur

• 1 Committee opinion A COG. Anticoagulation with low molecular weight heparin during pregnancy.  Internat J Gyn Obstet. 1999;  65 89-90
• 2 ACOG Practice Bulletin No. 19, August 2000. Thromboembolism in pregnancy. 
• 3 Arnaout M S, Kazma H, Khalil A. et al . Is there a safe anticoagulation protocol for pregnant women with prostetic valves?.  Clin Exp Obstet Gynaecol. 1998;  25 101-104
• 4 Bachmann F, Beck E, Holfeld P. et al . Antikoagulation während der Schwangerschaft und im Wochenbett (Schweizerische Konsensus-Konferenz).  Frauenarzt. 1999;  40 1412-1421, 1537-1547
• 5 Backos M, Rai R, Thomas E. et al . Bone density changes in pregnant women treated with heparin: a prospective, longitudinal study.  Hum Reprod. 1999;  14 2876-2880
• 6 Backos M, Rai R, Baxter N. et al . Pregnancy complications in women with recurrent miscarriage associated with antiphospholipid antibodies treated with low dose aspirin and heparin.  Brit J Obstet Gynaecol. 1999;  106 102-107
• 7 Bisadze V O, Alexandrow B A, Genievskaya M G, Starchenko K V, Likova N S, Setchenov I M. Impact of LMWH (Fraxiparin) on some indices of maternal and newborne hemostasis.  Thromb Haemost. 1999;  Suppl. 680 (abstract)
• 8 Bisadze V O, Alyautdin O S, Makatsaria A D. Longterm use of LMWH (Fraxiparine) in pregnance with cardiac pathology.  Thromb Haemost. 1999;  Suppl. 680 (abstract)
• 9 Branch D W, Silver R M, Blackwell J L, Reading J C, Scott J R. Outcome in treated pregnancies in women with antiphospholipid syndrome: an update of the Utah Experience.  Obstet Gynecol. 1992;  80 614-620
• 10 Branch D W, Silver R M. Criteria for antiphospholipd syndrome: early pregnancy loss, fetal loss, or recurrent pregnancy loss?.  Lupus. 1996;  5 409-413
• 11 Branch D W, Porter T F. Autoimmune disorder. James DK, Steer PJ, Weimer CP, Gonik B High risk pregnancy. W. B. Saunders 1999
• 12 Branch D W, Peaceman A M, Druzin M. et al . A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy.  Am J Obstet Gynecol. 2000;  182 122-127
• 13 Brill-Edwards P, Ginsberg J S, Gent M, Hirsch J, Burrows R, Kearon C, Geerts W, Kovacs M, Weitz J I, Robinson S, Whittom R, Couture G. Safety of withholding heparin in pregnant women with a history of venous thromboembolism.  N Engl J Med. 2000;  343 1439-1444
• 14 Büller A R. Persönliche Mitteilung. 1999
• 15 Chan W S, Ray J G. Low molecular weight heparin use during pregnancy: Issues of safety and practicality.  Obstet Gynecol Survey. 1999;  54 649-654
• 16 Chan W S. What is the optimal management of pregnant women with valvular heart disease in pregnancy?.  Haemostasis. 1999;  29 (Suppl. 1) 105-106
• 17 Chan W S, Anand S, Ginsberg J S. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of literature.  Arch Intern Med. 2000;  160 191-196
• 18 Chong B H. Danaparoid for the treatment of heparin induced thrombocytopenia. Warkentin ThE, Greinacher A Heparin induced thrombocytopenia. New York, Basel; Marcel Dekker, Inc. 2000
• 19 Christiansen O B. Epidemiological, immunogenetic and immunotherapeutic aspects of unexplained recurrent miscarriage. Thesis Kobenhavn. 1997
• 20 Clark A L, Branch D W, Silver R M, Harris E N, Pierangeli S, Spinnato J A. Pregnancy complicated by the antiphospholipid syndrome: Outcomes with intravenous Immunoglobulin therapy.  Obstet Gynecol. 1999;  93 437-441
• 21 Coulam C B. Immunotherapy for recurrent spontaneous abortion Early Pregnancy.  Biology and Medicine. 1995;  1 13-26
• 22 Cowchock S. Prevention of fetal death in the antiphospholipid antibody syndrom.  Lupus. 1996;  5 467-472
• 23 Cowchock S. Treatment of antiphospholipid syndrome in pregnancy.  Lupus. 1998;  7 95-97
• 24 Crowther M A, Spitzer K, Julian J, Ginsberg J, Johnston M, Crowther R, Laskin C. Pharmacokinetic profile of a low molecular weight heparin (Reviparin) in pregnant patients: A prospective study.  Thrombos Res. 2000;  98 133-136
• 25 Dalsgaard J. Treatment of venous thromboembolism with Tinzaparin during pregnancy.  Ann Haematol. 1999;  78 A3
• 26 de Swiet M. Maternal mortality: Confidential enquiries into maternal deaths in the United Kingdom.  Am J Obstet Gynaecol. 2000;  182 760-766
• 27 Frewin R, Chisholm M. Anticoagulation of women with prosthetic heart valves during pregnancy.  Brit J Obstet Gynaecol. 1998;  105 683-686
• 28 Gerhardt A, Scharf R E, Beckmann M W. et al . Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium.  N Engl J Med. 2000;  342 374-380
• 29 Ginsberg J S. Thromboembolism and pregnancy.  Thromb Haemost. 1999;  82 620-624
• 30 Ginsberg J S, Hirsh J. Anticoagulants during pregnancy.  Ann Rev Med. 1989;  40 79-86
• 31 Ginsberg J S, Hirsh J. Use of antithrombotic agents during pregnancy.  Chest. 1998;  114 524-530
• 32 Girling J C, deSwiet M. Thromboembolism in pregnancy: an overview.  Current Obstet Gynecol. 1996;  8 458-463
• 33 Goldhaber S Z. Invited commentary.  Am Thorac Surg. 2000;  69 265-266
• 34 Gordon C, Kilby M D. Use of intravenous immunoglobulin therapy in pregnancy in systemic lupus erythematosus and antiphospholipid antibody syndrom.  Lupus. 1998;  7 429-433
• 35 Grandone E, Margaglione M, Colaizzo D. Genetic susceptibility to pregnancy-related venous thromboembolism: Roles of factor V Leiden, prothrombin G20210 A, and methylenetrahydrofolate reductase C677 T mutations.  Am J Obstet Gynecol. 1998;  179 1324-1328
• 36 Greer J A. The special case of venous thromboembolism in pregnancy.  Haemostasis. 1998;  28 22-34
• 37 Greer I A. Thrombosis in pregnancy: maternal and fetal issues.  Lancet. 1999;  353 1258-1265
• 38 Greinacher A, Eckardt Th, Mußmann J, Müller-Eckardt C. Pregnancy complicated by heparin associated thrombocytopenia: Management by a prospectively in vitro selected heparinoid (ORG 10, 172).  Thromb Res. 1993;  71 123-126
• 39 Greinacher A, Warkentin T E. Treatment of heparin induced thrombocytopenia: An Overview. Warkentin ThE, Greinacher A Heparin induced Thrombocytopenia. New York, Basel; M. Dekker, Inc. 2000
• 40 Harenberg J, Leber G, Zimmermann R, Schmidt W. Thromboembolieprophylaxe mit niedermolekularem Heparin in der Schwangerschaft.  Geburtsh Frauenheilk. 1987;  47 15-18
• 41 Harenberg J. Heparinprophylaxe in der Schwangerschaft - wann und womit?.  Gynecol Prax. 2000;  24 623-631
• 42 Harris E N, Pierangeli S S. Utilization of intravenous immunoglobulin therapy to treat recurrent pregnancy loss in the antiphospholipid syndrome: a review.  Scand J Rheumatol. 1998;  27 (Suppl 107) 97-102
• 43 Heilmann L. Niedermolekulare Heparine in der Frauenheilkunde.  Haemostaseologie. 2001;  21 (in press)
• 44 Heilmann L, Schneider D M, v. Tempelhoff G F, Kuse S. Antiphospholipid-antibodies and other thrombophilic defects in patients with a history of early onset severe preeclampsia or HELLP-Syndrome.  Geburtsh Frauenheilk. 1999;  59 95-100
• 45 Huhle G, Geberth M, Hoffmann U, Heene D L, Harenberg J. Management of heparin associated thrombozytopenia in pregnancy with subcutan Hirudin.  Gynecol Obstet Invest. 2000;  49 67-69
• 46 Hunt B J, Doughty H A, Majumdar G. et al . Thromboprophylaxis with low molecular-weight heparin (Fragmin) in high risk pregnancies.  Thromb Haemost. 1997;  77 39-43
• 47 Katano K, Aoki K, Sasa H, Ogasawara M, Matsuura E, Yagami Y. Beta-2-Glykoprotein-1-dependent anticardiolipin antibodies as a predictor of adverse pregnancy outcomes in healthy pregnant women.  Hum Reprod. 1996;  11 509-512
• 48 Khamashta M A, Hughes G RV. Detection and importance of anticardiolipin antibodies.  J Clin Pathol. 1993;  46 104-107
• 49 Khamashta M A. Primary prevention of thrombosis in subjects with positive antiphospholipid antibodies.  J Autoimmunity. 2000;  15 249-253
• 50 Kutteh W H. Recurrent pregnancy loss: an update.  Curr Opin Obstet Gynecol. 1999;  11 435-439
• 51 Laskin C, Ginsberg J S, Farine D, Crowthers M, Spitzer K, Solominka C, Ryan G, Seaward G, Ritchie K. Low molecular weight heparin and ASA-therapy in women with autoantibodies and unexplained recurrent fetal loss.  Am J Obstet Gynecol. 1997;  176 125 (abstract)
• 52 Lee L H, Liaun P CY. Low molecular weight heparin for thromboprophylaxis during pregnancy in 2 patients with mechanical mitral valves replacement.  Thromb Haemost. 1996;  76 628-629
• 53 Lev-Ran O, Kramer A, Gurevitch J. et al . Low-molecular-weight heparin for prosthetic heart valves: treatment failure.  Ann Thorac Surg. 2000;  69 264-266
• 54 Lima F, Khamashta M A, Buranan N MM, Kerslake S, Hunt B J, Hughes G RV. A study of sixty pregnancies in patients with the antiphospholipid syndrome.  Clin Exp Rheumatol. 1996;  14 131-136
• 55 Lindhoff-Last E, Sohn Ch, Ehrly A M, Bauersachs R M. Aktuelles Management der Thromboembolie in Schwangerschaft und Wochenbett.  Zbl Gynäkol. 2000;  122 4-17
• 56 Macchi L, Sarfati R, Guicheteau M, Chamlian. et al . Thromboembolic prophylaxis with danaparoid (Orgaran) in a high-thrombosis-risk pregnant women with the history of heparin induced thrombocytopenia (HIT) and Widal's disease.  Clin Appl Thrombosis/Haemostasis. 2000;  6 187-189
• 57 McColl M D, Walker I D, Greer I A. The role of inherited thrombophilia in venous thromboembolism associated with pregnancy.  Brit J Obstet Gynaecol. 1999;  106 756-766
• 58 McColl M D, Ramsay J E, Tait R C. et al . Risk factors for pregnancy associated venous thromboembolism.  Thromb Haemost. 1997;  78 1183-1188
• 59 Meschengieser S, Salviu J, Lazzari M. Low molecular weight heparin (LMWH) in pregnant patients with prosthetic heart valves.  Thromb Haemost. 1999;  Suppl 184-185
• 60 Messmore A L, Kundur R, Wehrmacher W, Scanlon P. Anticoagulant therapie of pregnant patients with prostetic heart valves: Rationale for a clinical trial of low-molecular weight heparin.  Clin Appl Thrombosis/Haemostasis. 1999;  5 73-77
• 61 Montalescot G, Polle V, Collet J P. et al . Low-molecular-weight heparin after mechanical heart valve replacement.  Circulation. 2000;  101 1083-1086
• 62 Pregnancy loss study group . Randomized, placebo controlled trial of intravenous immune globulin (IVIG) in antiphospholipid syndrome (APS) in pregnancy: A progress report.  Lupus. 1996;  5 553 (abstract)
• 63 Pregnancy loss study group . A multicenter, randomized, double-blind pilot study of IVIG therapy during pregnancy in women with antiphospholipid syndrome.  Lupus. 1998;  7 (Suppl. 2) 196 (abstract)
• 64 Rai R S, Clifford K, Cohen H, Regan L. High prospective fetal loss rate in untreated pregnancies of women with recurrent miscarriage and antiphospholipid antibodies.  Hum Reprod. 1995;  10 3301-3304
• 65 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).  Brit Med J. 1997;  314 253-257
• 66 Rai R S, Regan L. Antiphospholipid-syndrome and pregnancy loss.  Hosp Med. 1998;  59 637-639
• 67 Reber G, Arvieux J, Comby E, Degenne D, de Moerlove P, Sanmarco M, Potron G. Multicenter evaluation of nine comercal kids for the quantification of anticardiolipin antibodies.  Thromb Haemost. 1995;  73 444-452
• 68 Rosendaal F R. Risk factors for venous thrombotic disease.  Thromb Haemost. 1999;  82 610-619
• 69 Rutherford S E, Phelan J P. Thromboembolic disease in pregnancy.  Clin Perinatol. 1986;  13 719-739
• 70 Sanson B J, Lensing A WA, Prins M H. et al . Safety of low-molecular-weight heparin in pregnancy: A systematic review.  Thromb Haemost. 1999;  81 668-672
• 71 Sarret M, Toulemonde F. Meta-analysis with LMWH's. Sarret M, Kher A, Toulemonde F Low-molecular weight heparin therapy. New York, Basel; M. Dekker, Inc. 1999
• 72 Schneider D M, v. Tempelhoff G F, Heilmann L. Retrospective evaluation of the safety and efficacy of low molecular weight heparin as thromboprophylaxis during pregnancy.  Am J Obstet Gynecol. 1997;  177 1567-1568
• 73 Sherer Y, Levy Y, Shoenfeld Y. Intravenous immunoglobulin therapy of antiphospholipid syndrom.  Rheumatology. 2000;  39 421-426
• 74 Sorensen H T, Johnsen S P, Larsen H, Pedersen L, Nielsen G L, Moller M. Birth outcomes in pregnant women treated with low-molecular-weight heparin.  Acta Obstet Gynecol Scand. 2000;  79 655-659
• 75 Spinnato J A, Clark A L, Pierangeli S S, Harris E N. Intravenous immunoglobulin therapy for the antiphospholipid syndrome in pregnancy.  Am J Obstet Gynecol. 1995;  172 690-694
• 76 Stein J, Blanck K, Löhrs B, Scholz S, Thaler C J. In-vitro- und In-vivo-Effekte polyvalenter Immunglobuline bei Patientinnen mit rezidivierenden Spontanaborten und antipaternalen non-HLA-Antikörpern.  Geburtsh Frauenheilk. 2000;  60 251-256
• 77 Wapner R J, Cowchock F S, Shapiro S S. Successful treatment in two women with antiphospholipid antibodies and refractory pregnancy losses with intravenous immunoglobulin infusions.  Amer J Obstet Gynecol. 1989;  161 1271-1272
• 78 Warkentin T E, Levine M N, Hirsh J, Horsewood P, Roberts R S, Gent M, Kelton J G. Heparin induced thrombozytopenia in patients treated with low molecular weight heparin or unfractionated heparin.  N Engl J Med. 1995;  332 1330-1335
• 79 Wilson W A, Gharavi A E, Koike T, Lockshin M D. et al . International consensus statement on preliminary classification criteria for definite antiphospholipid syndrom.  Arthritis & Rheumatism. 1999;  42 1309-1311
• 80 Winkler M, Rath W. Thromboembolische Komplikationen in Schwangerschaft und Wochenbett.  Geburtsh Frauenheilk. 2000;  60 XXV-XXVIII