Anticoagulants for the Treatment of Recurrent Pregnancy Loss in Women without Antiphospholipid Syndrome_Chinese Journal of Evidence-Based Medicine

Authors：

Marcello Di Nisio

1. Department of Medicine and Aging, School of Medicine, and Aging Research Center, Ce.S.I., "Gabriele D’Annunzio" University Foundation, Via dei Vestini, 66013 , Chieti, Italy2. Academic Medical Center, Department of Obstetrics and Gynaecology, P.O. Box 22660, 1100 DD Amsterdam3. Academic Medical Center, Department of Vascular Medicine F4-276, P.O. Box 22660, 1100 DD Amsterdam;

Corresponding author：

Keywords：

Anticoagulants; Treatment; Recurrent pregnancy loss

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Objective 　To evaluate the efficacy and safety of anticoagulant agents, such as aspirin and heparin, in women with a history of at least two spontaneous miscarriages or one later intrauterine fetal death without apparent causes other than inherited thrombophilias.
Methods 　We searched the Cochrane Pregnancy and Childbirth Group trials register (March 2004), the Central Register of Controlled Trials (The Cochrane Library, Issue 1, 2004), MEDLINE (January 1966 to March 2004), and EMBASE (1980 to March 2004). We scanned bibliographies of all located articles for any unidentified articles. Randomised and quasi-randomised controlled trials that assessed the effect of anticoagulant treatment on the live-birth rate in women with a history of at least two spontaneous miscarriages or one later intrauterine fetal death without apparent causes other than inherited thrombophilias were eligible. Interventions included aspirin, unfractionated heparin, and low molecular weight heparin for the prevention of birth loss. One treatment could be compared with another or with placebo. Two authors assessed the trials for inclusion in the review and extracted the data. Data were entered into the Review Manager software and double checked.
Results 　Two studies (242 participants) were included in the review and for both of them data were extracted for the subgroups of women fulfiling the inclusion criteria of the review. In one study, 54 pregnant women with recurrent spontaneous abortion without detectable anticardiolipin antibodies were randomised to low-dose aspirin or placebo. Similar live-birth rates were observed with aspirin and placebo [relative risk (RR) 1.00, 95% confidence interval (CI) 0.78 to 1.29]. In another study, a subgroup of 20 women who had had a previous fetal loss after the 20th week and had a thrombophilic defect were randomised to enoxaparin or aspirin. Enoxaparin treatment resulted in an increased live-birth rate, as compared to low-dose aspirin, RR 10.00, 95% CI 1.56 to 64.20).
Conclusions 　The evidence on the efficacy and safety of thromboprophylaxis with aspirin and heparin in women with a history of at least two spontaneous miscarriages or one later intrauterine fetal death without apparent causes other than inherited thrombophilias is too limited to recommend the use of anticoagulants in this setting. Large, randomised, placebo-controlled trials are urgently needed.

Citation： Marcello Di Nisio,Louisette W,Peters,Saskia Middeldorp. Anticoagulants for the Treatment of Recurrent Pregnancy Loss in Women without Antiphospholipid Syndrome. Chinese Journal of Evidence-Based Medicine, 2005, 05(9): 658-666. doi: Copy

1.	Everett C. Incidence and outcome of bleeding before the 20th week of pregnancy: prospective study from general practice[J]. BMJ, 1997; 315(7099): 32-34.
2.	Huisjes HJ. Spontaneous abortion[M]. London: Churchill Livingstone, 1984.
3.	Clifford K, Rai R, Watson H, Regan L. An informative protocol for the investigation of recurrent miscarriage: preliminary experience of 500 consecutive cases[J]. Human Reproduction, 1994; 9(7): 1328-1332.
4.	Cook CL, Pridman DD. Recurrent pregnancy loss[J]. Current Opinion in Obstetrics and Gynecology, 1995; 7(5): 357-366.
5.	Stirrat GM. Recurrent miscarriage: definition and epidemiology[J]. Lancet, 1990; 336(8716): 673-675.
6.	NHMRC. Report on Maternal Deaths in Australia 1994-96[M]. Canberra. 2001.
7.	Goyaux N, Alihonou E, Diadhiou F, Leke R, Thonneau PF. Complications of induced abortion and miscarriage in three African Countries: a hospital-based study among WHO collaborating centres[J]. Acta Obstetricia et Gynecologica Scandinavica, 2001; 80(6): 568-573.
8.	Lee C, Slade P. Miscarriage as a traumatic event: a review of the literature and new implications for intervention[J]. Journal of Psychosomatic Research, 1996; 40(3): 235-244.
9.	Stern JJ, Dorfmann AD, Gutierrez-Najar AJ, Cerrillo M, Coulam CB. Frequency of abnormal karyotypes among abortuses from women with and without a history of recurrent spontaneous abortion[J]. Fertility and Sterility, 1996; 65(2): 250-253.
10.	Preston FE, Rosendaal FR, Walker ID, Briet E, Berntorp E, Conard J, Fontcuberta J, Makris M, Mariani G, Noteboom W, Pabinger I, Legnani C, Scharrer I, Schulman S, van der Meer FJ. Increased fetal loss in women with heritable thrombophilia[J]. Lancet, 1996; 348(9032): 913-916.
11.	Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A, Fait G, Lessing JB. Increased frequency of genetic thrombophilia in women with complications of pregnancy[J]. New England Journal of Medicine, 1999; 340(1): 9-13.
12.	Rushton DI. Placental pathology in spontaneous miscarriage. In: Beard RW, Sharp F, editor(s). Early pregnancy loss: mechanisms and treatment[M]. London: RCOG, 1988:149-158.
13.	Dizon TD, Meline L, Nelson LM, Varner M, Ward K. Fetal carriers of the factor V Leiden mutation are prone to miscarriage and placental infarction[J]. American Journal of Obstetrics and Gynecology, 1997; 177(2): 402-405.
14.	Rai RS, Regan L, Chitolie A, Donald JG, Cohen H. Placental thrombosis and second trimester miscarriage in association with activated protein C resistance[J]. British Journal of Obstetrics and Gynaecology, 1996; 103(8): 842-844.
15.	Mousa HA, Alfirevic Z. Do placental lesions reflect thrombophilia state in women with adverse pregnancy outcome?[J]. Human Reproduction, 2000; 15(8): 1830-1833.
16.	Rai RS, Regan L, Clifford K, Pickering W, Dave M, Mackie I, McNally T, Cohen H. Antiphospholipid antibodies and beta2-glycoprotein-I in 500 women with recurrent miscarriage: results of a comprehensive approach[J]. Human Reproduction, 1995; 10(8): 2001-2005.
17.	Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis[J]. Lancet, 2003; 361(9361): 901-908.
18.	Carp H, Dolitzky M, Tur-Kaspa, Inbal A. Hereditary thrombophilias are not associated with a decreased live birth rate in women with recurrent miscarriage[J]. Fertility and Sterility, 2002; 78(1): 58-62.
19.	Hohlagschwandtner M, Unfried G, Heinze G, Huber JC, Nagele F, Tempfer C. Combined thrombophilic polymorphisms in women with idiopathic recurrent miscarriage[J]. Fertility and Sterility, 2003; 79(5): 1141-1148.
20.	Brenner B, Sarig G, Weiner Z, Younis J, Blumenfeld Z, Lanir N. Thrombophilic polymorphisms are common in women with fetal loss without apparent cause[J]. Thrombosis and Haemostasis, 1999; 82(1): 6-9.
21.	Finan RR, Tamin H, Ameen G, Sharida HE, Raschid M, Almawl WY. Prevalence of factor V G1691A (factor V-Leiden) and prothrombin G20210A gene mutations in a recurrent miscarriage population[J]. American Journal of Hematology, 2002; 71(4): 300-305.
22.	Ginsberg JS, Greer I, Hirsh J. Use of antithrombotic agents during pregnancy[J]. Chest, 2001; 119(Supp l): 122-131.
23.	Meinardi JR, Middeldorp S, de Kam PJ, Koopman MM, van Pampus EC, Hamulyak K, Prins MH, Buller HR, van der Meer J. Increased risk for fetal loss in carriers of the factor V Leiden[J]. Annals of Internal Medicine, 1999; 130(9): 736-739.
24.	Sanson BJ, Friederich PW, Simioni P, Zanardi S, Hilsman MV, Girolami A, ten Cate JW, Prins MH. The risk of abortion and stillbirth in antithrombin-, protein C-, and protein S-deficient women[J]. Thrombosis and Haemostasis, 1996; 75(3): 387-388.
25.	Levine JS, Branch W, Rauch J. The antiphospholipid syndrome[J]. New England Journal of Medicine, 2002; 346(10): 752-763.
26.	Infante-Reviard C, David M, Gauthier R, Rivard GE. Lupus anticoagulants, anticardiolipin antibodies, and fetal loss. A case-control study[J]. New England Journal of Medicine, 1991; 325(15): 1063-1066.
27.	Lockshin MD. Pregnancy loss in the antiphospholipid syndrome[J]. Thrombosis and Haemostasis, 1999; 82(2): 641-648.
28.	Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone[J]. American Journal of Obstetrics and Gynecology, 1996; 174(5): 1584-1589.
29.	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)[J]. BMJ, 1997; 314(7076): 253-257.
30.	Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment[J]. Obstetrics & Gynecology, 2002; 100(3): 408-413.
31.	Empson M, Lassere M, Craig J, Scott J. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant[M/CD]. In: The Cochrane Database of Systematic Reviews, 2, 2005. 10.1002/14651858.CD002859. Hoboken, New Jersey: John Wiley & Sons.
32.	Oates-Whitehead RM, Haas DM, Carrier JAK. Progestogen for preventing miscarriage[M/CD]. In: The Cochrane Database of Systematic Reviews, 4, 2003. 10.1002/14651858.CD003511. Hoboken, New Jersey: John Wiley & Sons.
33.	Scott JR. Immunotherapy for recurrent miscarriage[M/CD]. In: The Cochrane Database of Systematic Reviews, 1, 2003. 10.1002/14651858.CD000112. Hoboken, New Jersey: John Wiley & Sons.
34.	Rai R, Backos M, Baxter N, Chilcott I, Regan L. Recurrent miscarriage-an aspirin a day[J]? Human Reproduction, 2000; 15(10): 2220-2223.
35.	Sanson BJ, Lensing AW, Prins MH, Ginsberg JS, Barkagan ZS, Lavenne-Pardonge E. Safety of low-molecular-weight heparin in pregnancy. A systematic review[J]. Thrombosis and Haemostasis, 1999; 81(5): 668-672.
36.	Walker MC, Ferguson SE, Allen VM. Heparin for pregnant women with acquired or inherited thrombophilias[M/CD]. In: The Cochrane Database of Systematic Reviews, 2, 2003. 10.1002/14651858.CD003580. Hoboken, New Jersey: John Wiley & Sons.
37.	Clarke M, Oxman AD. Cochrane Reviewers Handbook 4.1.5 [Updated April 2002][M/CD]. In: The Cochrane Library. Issue 2, 2002. Oxford: Update Software.
38.	Review Manager (RevMan). 4.1 for Windows Edition[Z]. Oxford, England: The Cochrane Collaboration, 2000.
39.	Gris JC, Mercier E, Quere I, Lavigne-Lissalde G, Cochery-Nouvellon E, Hoffet M, Ripart-Neveu S, Tailland ML, Dauzat M, Mares P. Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder[J]. Blood, 2004; 103(10): 3695-3699.
40.	Tulppala M, Marttunen M, Soderstrom-Anttila V, Ailus K, Palosuo T, Ylikorkala O. Low dose aspirin in the prevention of miscarriage in women with unexplained or autoimmune related recurrent miscarriage: effect on prostacyclin and thromboxane A2 production[J]. Human Reproduction, 1997; 12(1): 191.Tulppala M, Marttunen M, Soderstrom-Anttila V, Foudila T, Ailus K, Palosuo T, Ylikorkala O. Low-dose aspirin in the prevention of miscarriage in women with unexplained or autoimmune related recurrent miscarriage: effect on prostacyclin and thromboxane A2 production[J]. Human Reproduction, 1997; 12(7): 1567-1572.
41.	Bar J, Cohen-Sacher B, Hod M, Blickstein D, Lahav J, Merlob P. Low-molecular-weight heparin for thrombophilia in pregnant women[J]. International Journal of Gynecology & Obstetrics, 2000; 69(3): 209-213.
42.	Bar J, Mashiah R, Cohen-Sacher B, Hod M, Orvieto R, Ben-Rafael Z, Lahav J. Effect of thromboprophylaxis on uterine and fetal circulation in pregnant women with a history of pregnancy complications[J]. Thrombosis Research, 2001; 101(4): 235-241.
43.	Bick RL. Recurrent miscarriage syndrome due to blood coagulation protein/platelet defects: prevalence, treatment and outcome results. DRW Metroplex Recurrent Syndrome Cooperative Group[J]. Clinical and applied thrombosis/hemostasis, 2000; 6(3): 115-125.
44.	Brenner B, Hoffman, Blumenfeld Z, Weiner Z, Younis JS. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin[J]. Thrombosis and Haemostasis, 2000; 83(5): 693-697.
45.	Brenner B., Hoffman R., Carp H., Dulitsky M., Samueloff A., Yohal D., Bar Y., Thaler I., Yarom I., Ellis M., Varon D., Tal Y., Blumenfeld Z., Segal S., Kupferminc M., Younis J., LIVE-ENOX INVESTIGATORS. Efficacy and safety of two doses of enoxaparin in pregnant women with thrombophilia and recurrent pregnancy loss: the LIVE-ENOX study[J]. Journal of Thrombosis and Haemostasis, 2003; 1(Suppl 1): Abstract number: OC084.
46.	Carp H, Dolitzky M, Inbal A. Thromboprophylaxis improves the live birth rate in women with consecutive recurrent miscarriages and hereditary thrombophilia[J]. Journal of Thrombosis and Haemostasis, 2003; 1(3): 433-438.
47.	Grandone E, Brancaccio V, Colaizzo D, Scianname N, Pavone G, Di Minno G, Margaglione M. Preventing adverse obstetric outcomes in women with genetic thrombophilia[J]. Fertility and Sterility, 2002; 78(2): 371-375.
48.	Gris J-C, Neveu S, Tailland M-L, Courtieu C, Mares P, Schved J-F. Use of a low-molecular-weight heparin (enoxaparin) or of a phenformin-like substance (moroxydine chloride) in primary early recurrent aborters with an impaired fibrinolytic capacity[J]. Thrombosis and Haemostasis, 1995; 73(3): 362-367.
49.	Li D-K, Liu L, Odouli R. Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population based cohort study[J]. BMJ, 2003; 327(7411): 368-372.
50.	Ogasawara MS, Iinuma Y, Aoki K, Katano K, Ozaki Y, Suzumori K. Low-dose aspirin is effective for treatment of recurrent miscarriage in patients with decreased coagulation factor XII[J]. Fertility and Sterility, 2001; 76(1): 203-214.
51.	Reznikoff-Etievant MF, Cayol V, Zou GM, Abuaf N, Robert A, Johanet C, Milliez J. Habitual abortions in 678 healthy patients: investigation and prevention[J]. Human Reproduction, 1999;14(8): 2106-2109.
52.	Sarig G., Aharon A., Lanir N., Goshen H., Drugan A., Blumenfeld Z., Brenner B. Modulation of systemic and placental hemostatic mechanisms by enoxaparin in women with gestational vascular complications[J]. Journal of Thrombosis and Haemostasis, 2003; 1(Suppl 1): Abstract number: OC083.
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1. Everett C. Incidence and outcome of bleeding before the 20th week of pregnancy: prospective study from general practice[J]. BMJ, 1997; 315(7099): 32-34.
2. Huisjes HJ. Spontaneous abortion[M]. London: Churchill Livingstone, 1984.
3. Clifford K, Rai R, Watson H, Regan L. An informative protocol for the investigation of recurrent miscarriage: preliminary experience of 500 consecutive cases[J]. Human Reproduction, 1994; 9(7): 1328-1332.
4. Cook CL, Pridman DD. Recurrent pregnancy loss[J]. Current Opinion in Obstetrics and Gynecology, 1995; 7(5): 357-366.
5. Stirrat GM. Recurrent miscarriage: definition and epidemiology[J]. Lancet, 1990; 336(8716): 673-675.
6. NHMRC. Report on Maternal Deaths in Australia 1994-96[M]. Canberra. 2001.
7. Goyaux N, Alihonou E, Diadhiou F, Leke R, Thonneau PF. Complications of induced abortion and miscarriage in three African Countries: a hospital-based study among WHO collaborating centres[J]. Acta Obstetricia et Gynecologica Scandinavica, 2001; 80(6): 568-573.
8. Lee C, Slade P. Miscarriage as a traumatic event: a review of the literature and new implications for intervention[J]. Journal of Psychosomatic Research, 1996; 40(3): 235-244.
9. Stern JJ, Dorfmann AD, Gutierrez-Najar AJ, Cerrillo M, Coulam CB. Frequency of abnormal karyotypes among abortuses from women with and without a history of recurrent spontaneous abortion[J]. Fertility and Sterility, 1996; 65(2): 250-253.
10. Preston FE, Rosendaal FR, Walker ID, Briet E, Berntorp E, Conard J, Fontcuberta J, Makris M, Mariani G, Noteboom W, Pabinger I, Legnani C, Scharrer I, Schulman S, van der Meer FJ. Increased fetal loss in women with heritable thrombophilia[J]. Lancet, 1996; 348(9032): 913-916.
11. Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A, Fait G, Lessing JB. Increased frequency of genetic thrombophilia in women with complications of pregnancy[J]. New England Journal of Medicine, 1999; 340(1): 9-13.
12. Rushton DI. Placental pathology in spontaneous miscarriage. In: Beard RW, Sharp F, editor(s). Early pregnancy loss: mechanisms and treatment[M]. London: RCOG, 1988:149-158.
13. Dizon TD, Meline L, Nelson LM, Varner M, Ward K. Fetal carriers of the factor V Leiden mutation are prone to miscarriage and placental infarction[J]. American Journal of Obstetrics and Gynecology, 1997; 177(2): 402-405.
14. Rai RS, Regan L, Chitolie A, Donald JG, Cohen H. Placental thrombosis and second trimester miscarriage in association with activated protein C resistance[J]. British Journal of Obstetrics and Gynaecology, 1996; 103(8): 842-844.
15. Mousa HA, Alfirevic Z. Do placental lesions reflect thrombophilia state in women with adverse pregnancy outcome?[J]. Human Reproduction, 2000; 15(8): 1830-1833.
16. Rai RS, Regan L, Clifford K, Pickering W, Dave M, Mackie I, McNally T, Cohen H. Antiphospholipid antibodies and beta2-glycoprotein-I in 500 women with recurrent miscarriage: results of a comprehensive approach[J]. Human Reproduction, 1995; 10(8): 2001-2005.
17. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis[J]. Lancet, 2003; 361(9361): 901-908.
18. Carp H, Dolitzky M, Tur-Kaspa, Inbal A. Hereditary thrombophilias are not associated with a decreased live birth rate in women with recurrent miscarriage[J]. Fertility and Sterility, 2002; 78(1): 58-62.
19. Hohlagschwandtner M, Unfried G, Heinze G, Huber JC, Nagele F, Tempfer C. Combined thrombophilic polymorphisms in women with idiopathic recurrent miscarriage[J]. Fertility and Sterility, 2003; 79(5): 1141-1148.
20. Brenner B, Sarig G, Weiner Z, Younis J, Blumenfeld Z, Lanir N. Thrombophilic polymorphisms are common in women with fetal loss without apparent cause[J]. Thrombosis and Haemostasis, 1999; 82(1): 6-9.
21. Finan RR, Tamin H, Ameen G, Sharida HE, Raschid M, Almawl WY. Prevalence of factor V G1691A (factor V-Leiden) and prothrombin G20210A gene mutations in a recurrent miscarriage population[J]. American Journal of Hematology, 2002; 71(4): 300-305.
22. Ginsberg JS, Greer I, Hirsh J. Use of antithrombotic agents during pregnancy[J]. Chest, 2001; 119(Supp l): 122-131.
23. Meinardi JR, Middeldorp S, de Kam PJ, Koopman MM, van Pampus EC, Hamulyak K, Prins MH, Buller HR, van der Meer J. Increased risk for fetal loss in carriers of the factor V Leiden[J]. Annals of Internal Medicine, 1999; 130(9): 736-739.
24. Sanson BJ, Friederich PW, Simioni P, Zanardi S, Hilsman MV, Girolami A, ten Cate JW, Prins MH. The risk of abortion and stillbirth in antithrombin-, protein C-, and protein S-deficient women[J]. Thrombosis and Haemostasis, 1996; 75(3): 387-388.
25. Levine JS, Branch W, Rauch J. The antiphospholipid syndrome[J]. New England Journal of Medicine, 2002; 346(10): 752-763.
26. Infante-Reviard C, David M, Gauthier R, Rivard GE. Lupus anticoagulants, anticardiolipin antibodies, and fetal loss. A case-control study[J]. New England Journal of Medicine, 1991; 325(15): 1063-1066.
27. Lockshin MD. Pregnancy loss in the antiphospholipid syndrome[J]. Thrombosis and Haemostasis, 1999; 82(2): 641-648.
28. Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone[J]. American Journal of Obstetrics and Gynecology, 1996; 174(5): 1584-1589.
29. 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)[J]. BMJ, 1997; 314(7076): 253-257.
30. Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment[J]. Obstetrics & Gynecology, 2002; 100(3): 408-413.
31. Empson M, Lassere M, Craig J, Scott J. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant[M/CD]. In: The Cochrane Database of Systematic Reviews, 2, 2005. 10.1002/14651858.CD002859. Hoboken, New Jersey: John Wiley & Sons.
32. Oates-Whitehead RM, Haas DM, Carrier JAK. Progestogen for preventing miscarriage[M/CD]. In: The Cochrane Database of Systematic Reviews, 4, 2003. 10.1002/14651858.CD003511. Hoboken, New Jersey: John Wiley & Sons.
33. Scott JR. Immunotherapy for recurrent miscarriage[M/CD]. In: The Cochrane Database of Systematic Reviews, 1, 2003. 10.1002/14651858.CD000112. Hoboken, New Jersey: John Wiley & Sons.
34. Rai R, Backos M, Baxter N, Chilcott I, Regan L. Recurrent miscarriage-an aspirin a day[J]? Human Reproduction, 2000; 15(10): 2220-2223.
35. Sanson BJ, Lensing AW, Prins MH, Ginsberg JS, Barkagan ZS, Lavenne-Pardonge E. Safety of low-molecular-weight heparin in pregnancy. A systematic review[J]. Thrombosis and Haemostasis, 1999; 81(5): 668-672.
36. Walker MC, Ferguson SE, Allen VM. Heparin for pregnant women with acquired or inherited thrombophilias[M/CD]. In: The Cochrane Database of Systematic Reviews, 2, 2003. 10.1002/14651858.CD003580. Hoboken, New Jersey: John Wiley & Sons.
37. Clarke M, Oxman AD. Cochrane Reviewers Handbook 4.1.5 [Updated April 2002][M/CD]. In: The Cochrane Library. Issue 2, 2002. Oxford: Update Software.
38. Review Manager (RevMan). 4.1 for Windows Edition[Z]. Oxford, England: The Cochrane Collaboration, 2000.
39. Gris JC, Mercier E, Quere I, Lavigne-Lissalde G, Cochery-Nouvellon E, Hoffet M, Ripart-Neveu S, Tailland ML, Dauzat M, Mares P. Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder[J]. Blood, 2004; 103(10): 3695-3699.
40. Tulppala M, Marttunen M, Soderstrom-Anttila V, Ailus K, Palosuo T, Ylikorkala O. Low dose aspirin in the prevention of miscarriage in women with unexplained or autoimmune related recurrent miscarriage: effect on prostacyclin and thromboxane A2 production[J]. Human Reproduction, 1997; 12(1): 191.Tulppala M, Marttunen M, Soderstrom-Anttila V, Foudila T, Ailus K, Palosuo T, Ylikorkala O. Low-dose aspirin in the prevention of miscarriage in women with unexplained or autoimmune related recurrent miscarriage: effect on prostacyclin and thromboxane A2 production[J]. Human Reproduction, 1997; 12(7): 1567-1572.
41. Bar J, Cohen-Sacher B, Hod M, Blickstein D, Lahav J, Merlob P. Low-molecular-weight heparin for thrombophilia in pregnant women[J]. International Journal of Gynecology & Obstetrics, 2000; 69(3): 209-213.
42. Bar J, Mashiah R, Cohen-Sacher B, Hod M, Orvieto R, Ben-Rafael Z, Lahav J. Effect of thromboprophylaxis on uterine and fetal circulation in pregnant women with a history of pregnancy complications[J]. Thrombosis Research, 2001; 101(4): 235-241.
43. Bick RL. Recurrent miscarriage syndrome due to blood coagulation protein/platelet defects: prevalence, treatment and outcome results. DRW Metroplex Recurrent Syndrome Cooperative Group[J]. Clinical and applied thrombosis/hemostasis, 2000; 6(3): 115-125.
44. Brenner B, Hoffman, Blumenfeld Z, Weiner Z, Younis JS. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin[J]. Thrombosis and Haemostasis, 2000; 83(5): 693-697.
45. Brenner B., Hoffman R., Carp H., Dulitsky M., Samueloff A., Yohal D., Bar Y., Thaler I., Yarom I., Ellis M., Varon D., Tal Y., Blumenfeld Z., Segal S., Kupferminc M., Younis J., LIVE-ENOX INVESTIGATORS. Efficacy and safety of two doses of enoxaparin in pregnant women with thrombophilia and recurrent pregnancy loss: the LIVE-ENOX study[J]. Journal of Thrombosis and Haemostasis, 2003; 1(Suppl 1): Abstract number: OC084.
46. Carp H, Dolitzky M, Inbal A. Thromboprophylaxis improves the live birth rate in women with consecutive recurrent miscarriages and hereditary thrombophilia[J]. Journal of Thrombosis and Haemostasis, 2003; 1(3): 433-438.
47. Grandone E, Brancaccio V, Colaizzo D, Scianname N, Pavone G, Di Minno G, Margaglione M. Preventing adverse obstetric outcomes in women with genetic thrombophilia[J]. Fertility and Sterility, 2002; 78(2): 371-375.
48. Gris J-C, Neveu S, Tailland M-L, Courtieu C, Mares P, Schved J-F. Use of a low-molecular-weight heparin (enoxaparin) or of a phenformin-like substance (moroxydine chloride) in primary early recurrent aborters with an impaired fibrinolytic capacity[J]. Thrombosis and Haemostasis, 1995; 73(3): 362-367.
49. Li D-K, Liu L, Odouli R. Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population based cohort study[J]. BMJ, 2003; 327(7411): 368-372.
50. Ogasawara MS, Iinuma Y, Aoki K, Katano K, Ozaki Y, Suzumori K. Low-dose aspirin is effective for treatment of recurrent miscarriage in patients with decreased coagulation factor XII[J]. Fertility and Sterility, 2001; 76(1): 203-214.
51. Reznikoff-Etievant MF, Cayol V, Zou GM, Abuaf N, Robert A, Johanet C, Milliez J. Habitual abortions in 678 healthy patients: investigation and prevention[J]. Human Reproduction, 1999;14(8): 2106-2109.
52. Sarig G., Aharon A., Lanir N., Goshen H., Drugan A., Blumenfeld Z., Brenner B. Modulation of systemic and placental hemostatic mechanisms by enoxaparin in women with gestational vascular complications[J]. Journal of Thrombosis and Haemostasis, 2003; 1(Suppl 1): Abstract number: OC083.
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Chinese Journal of Evidence-Based Medicine

Anticoagulants for the Treatment of Recurrent Pregnancy Loss in Women without Antiphospholipid Syndrome

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