Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia

Summary

Recurrent miscarriage affects 1–2% of women. In more than half of all recurrent miscarriage the cause still remains uncertain. Thrombophilia has been identified in about 50% of women with recurrent miscarriage and thromboprophylaxis has been suggested as an option of treatment. A randomised double-blind (for aspirin) multicentre trial was performed among 207 women with three or more consecutive first trimester (<13 weeks) miscarriages, two or more second trimester (13–24 weeks) miscarriages or one third trimester fetal loss combined with one first trimester miscarriage. Women were analysed for thrombophilia. After complete work-up, women were randomly allocated before seven weeks’ gestation to either enoxaparin 40 mg and placebo (n=68), enoxaparin 40 mg and aspirin 100 mg (n=63) or aspirin 100 mg (n=76). The primary outcome was live-birth rate. Secondary outcomes were pregnancy complications, neonatal outcome and adverse effects. The 0.92–1.48] was found for enoxaparin and placebo and 65% [RR 1.08, 95% CI 0.83–1.39] for enoxaparin and aspirin when compared to aspirin alone (61%, reference group). In the whole study group the live birth rate was 65% (95% CI 58.66–71.74) for women with three or more miscarriages (n=204). No difference in pregnancy complications, neonatal outcome or adverse effects was observed. No significant difference in live birth rate was found with enoxaparin treatment versus aspirin or a combination of both versus aspirin in women with recurrent miscarriage.

Keywords

Pregnancy - clinical trials - heparins/LMWH - thrombophilia

^* Trial registration number NCT0095962.

• References

• 1 Jauniaux E, Farquharson RG, Christiansen OB. et al. Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage. Hum Re-prod 2006; 21: 2216-2222.
• 2 Salat-Baroux J. Recurrent spontaneous abortions. Reprod Nutr Dev 1988; 28: 1555-1568.
• 3 Tulppala M, Palosuo T, Ramsay T. et al. A prospective study of 63 couples with a history of recurrent spontaneous abortion: contributing factors and outcome of subsequent pregnancies. Hum Reprod 1993; 8: 764-770.
• 4 Christiansen OB, Nybo Andersen AM, Bosch E. et al. Evidence-based investigations and treatments of recurrent pregnancy loss. Fertil Steril 2005; 83: 821-839.
• 5 Regan L, Rai R. Epidemiology and the medical causes of miscarriage. Baillieres Best Pract Res Clin Obstet Gynaecol 2000; 14: 839-854.
• 6 Rey E, Kahn SR, David M. et al. Thrombophilic disorders and fetal loss : a meta-analysis. Lancet 2003; 361: 901-908.
• 7 Rai R, Backos M, Baxter N. et al. Recurrent miscarriage--an aspirin a day?. Hum Reprod 2000; 15: 2220-2223.
• 8 Brenner B, Hoofman R, Blumenfeld Z. et al. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin. Thromb Haemost 2000; 83: 693-697.
• 9 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.
• 10 Kutteh WH. 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.
• 11 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). Br Med J 1997; 314: 253-257.
• 12 Kaandorp S, Di Nisio M, Goddijn M. et al. Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome. Cochrane Database Syst Rev 2009; 1: CD004734.
• 13 Mantha S, Bauer KA, Zwicker JI. Low molecular weight heparin to achieve live birth following unexplained pregnancy loss: a systematic review. J Thromb Haemost 2010; 8: 263-268.
• 14 Bose P, Black S, Kadyrov M. et al. Heparin and aspirin attenuate placental apoptosis in vitro: implications for early pregnancy failure. Am J Obstet Gynecol 2005; 192: 23-30.
• 15 Lin JP, Vlodavsky I. Heparin, heparan sulfate and heparanase in inflammatory reactions. Thromb Haemost 2009; 102: 823-828.
• 16 Johann S, Zoller C, Haas S. et al. Sulfated polysaccharide anticoagulants suppress natural killer cell activity in vitro. Thromb Haemost 1995; 74: 998-1002.
• 17 Girardi G, Redecha P, Salmon JE. Heparin prevents antiphospholid antibody-induced fetal loss by inhibiting complement activation. Nat Med 2004; 10: 1222-1226.
• 18 Clark P, Walker ID, Langhorne P. et al. SPIN (Scottish Pregnancy Intervention) study: a multicenter, randomized controlled trial of low-molecular-weight heparin and low-dose aspirin in women with recurrent miscarriage. Blood 2010; 115: 4162-4167.
• 19 Kaandorp SP, Goddijn M, van der Post JA. et al. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med 2010; 362: 1586-1596.
• 20 Badawy AM, Khiary M, Sherif LS. et al. Low-molecular weight heparin in patients with recurrent early miscarriages of unknown aetiology. J Obstet Gynaecol 2008; 28: 280-284.
• 21 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; 278: 33-38.
• 22 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.
• 23 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.
• 24 Laskin CA, Spitzer KA, Clark CA. 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.
• 25 Brigham SA, Conlon C, Farquharson RG. A longitudinal study of pregnancy outcome following idiopathic recurrent miscarriage. Hum Reprod 1999; 14: 2868-2871.
• 26 Jivraj S, Makris M, Saravelos S. et al. Pregnancy outcome in women with factor V Leiden and recurrent miscarriage. Br J Obstet Gynecol 2009; 116: 995-998.
• 27 Zain MM, Norman RJ. Impact of obesity on female fertility and fertility treatment. Womens Health (Lond Engl) 2008; 4: 183-194.
• 28 Metwally M, Saravelos SH, Ledger WL. et al. Body mass index and risk of miscarriage in women with recurrent miscarriage. Fertil Steril 2010; 94: 290-295.
• 29 Greer IA, Nelson-Piercy C. Low-molecular weight heparins for thrombophrophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 2005; 106: 401-407.