Efficacy and safety of different low-molecular-weight heparins in improving pregnancy outcomes in patients with recurrent abortion: a network meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

CHEN Linhua , MA Wanjun ,  WANG Wanyu

Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, P. R. China;

Corresponding author：

WANG Wanyu, Email: wanyu15810@163.com

Keywords：

Recurrent abortion; Live birth; Low molecular weight heparin; Network meta-analysis; Randomized controlled trial

DOI：

10.7507/1672-2531.202211001

Video：

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Objective To systematically evaluate the efficacy and safety of different low-molecular-weight heparins (LMWHs) in improving pregnancy outcomes in patients with recurrent abortion. Methods The PubMed, EMbase, Cochrane Library, CBM, CNKI, VIP and WanFang Data databases were electronically searched to collect randomized controlled trials (RCTs) related to the objectives from inception to July 2022. Two reviewers independently screened literature, extracted data and assessed the risk of bias of the included studies. Meta-analysis was then performed by using Stata 16.0 software. Results A total of 25 RCTs involving 4 631 patients were included. Enoxaparin, dalteparin, nadroparin, and tinzaparin were included. The results of network meta-analysis showed that the live birth rate of the tinzaparin was higher than that of enoxaparin and dalteparin. The live birth rate in nadroparin was higher than that in enoxaparin and dalteparin. The cumulative sorting probability showed that tinzaparin ranked best for improving the live birth rate, nadroparin ranked best for reducing the miscarriage rate, and enoxaparin ranked best for reducing the preterm birth rate. Conclusion Current evidence suggests that tinzaparin and nadroparin may be the best choice for improving pregnancy outcomes in patients with recurrent abortion. Due to the limited quality and quantity of the included studies, more high quality studies are needed to verify the above conclusion.

Citation： CHEN Linhua, MA Wanjun, WANG Wanyu. Efficacy and safety of different low-molecular-weight heparins in improving pregnancy outcomes in patients with recurrent abortion: a network meta-analysis. Chinese Journal of Evidence-Based Medicine, 2023, 23(7): 790-796. doi: 10.7507/1672-2531.202211001 Copy

1.	陈子江, 林其德, 王谢桐, 等. 孕激素维持早期妊娠及防治流产的中国专家共识. 中华妇产科杂志, 2016, 51(7): 481-483.
2.	低分子肝素防治自然流产中国专家共识编写组. 低分子肝素防治自然流产中国专家共识. 中华生殖与避孕杂志, 2018, 38(9): 701-708.
3.	Jeve YB, Davies W. Evidence-based management of recurrent miscarriages. J Hum Reprod Sci, 2014, 7(3): 159-169.
4.	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(13): 1650-1655.
5.	刘宗花, 王谢桐. 低分子肝素治疗自身免疫型复发性流产的作用机制及安全性. 山东医药, 2007, 47(20): 114-115.
6.	Jiang F, Hu X, Jiang K, et al. The role of low molecular weight heparin on recurrent pregnancy loss: a systematic review and meta-analysis. Taiwan J Obstet Gynecol, 2021, 60(1): 1-8.
7.	Guerrini M, Bisio A. Low-molecular-weight heparins: differential characterization/physical characterization. Handb Exp Pharmacol, 2012, (207): 127-157.
8.	Cumpston M, Li T, Page MJ, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane handbook for systematic reviews of interventions. Cochrane Database Syst Rev, 2019, 10: ED000142.
9.	蔡仁变, 何晓彤, 林雪红. 低分子肝素联合小剂量阿司匹林治疗复发性流产的效果及对凝血指标的影响. 中国实用医药, 2020, 15(23): 128-130.
10.	蔡燕, 李君. 低分子肝素治疗妊娠期D-二聚体异常升高疗效观察. 中国药业, 2018, 27(14): 73-75.
11.	杜秀雅, 马华刚. 低分子肝素联合黄体酮治疗不明原因复发性自然流产临床分析. 潍坊医学院学报, 2014, 36(6): 465-466.
12.	高秀芹. 低分子肝素在复发性流产中的应用. 中外医疗, 2018, 37(30): 82-84.
13.	黄兴华, 伞翠平. 低分子肝素结合主动免疫治疗同种免疫性复发性自然流产的效果. 黑龙江医药科学, 2021, 44(2): 92-93.
14.	梁颖施, 陈惠禺, 黄俊杰, 等. 低分子肝素对复发性流产伴低滴度阳性抗β2糖蛋白Ⅰ抗体患者妊娠结局影响. 创伤与急危重病医学, 2018, 6(2): 114-115,118.
15.	邱莹, 黄胆. 阿司匹林联合依诺肝素钠治疗血栓前状态所致复发性流产的效果观察. 当代医药论丛, 2020, 18(18): 13-14.
16.	辛秀. 那曲肝素钙联合阿司匹林治疗复发性流产的效果及对患者血清TSP-1、sflt-1水平影响. 国际医药卫生导报, 2022, 28(9): 1288-1292.
17.	杨秀珍, 林志金, 张炯兰. 低分子肝素在治疗复发性流产中的临床研究. 中外医学研究, 2020, 18(22): 25-27.
18.	杨燕娥, 邓舒静, 李凤妹, 等. 低分子肝素在复发性流产中的应用观察. 大医生, 2021, 6(16): 33-35.
19.	张书筠, 张弘, 王云洁, 等. 低分子肝素联合阿司匹林治疗抗磷脂抗体引起的复发性流产的临床效果分析. 河北医学, 2018, 24(3): 422-426.
20.	周仲元, 陈鸽子, 胡玥暘. 低分子肝素与黄体酮联合叶酸治疗复发性流产对患者淋巴细胞亚群、性激素及再妊娠结局影响. 中国计划生育学杂志, 2021, 29(10): 2051-2055.
21.	Fouda UM, Sayed AM, Abdou AM, et al. Enoxaparin versus unfractionated heparin in the management of recurrent abortion secondary to antiphospholipid syndrome. Int J Gynaecol Obstet, 2011, 112(3): 211-215.
22.	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(3): 280-284.
23.	Bao SH, Sheng SL, Liao H, et al. Use of D-dimer measurement to guide anticoagulant treatment in recurrent pregnancy loss associated with antiphospholipid syndrome. Am J Reprod Immunol, 2017, 78(6): 1-12.
24.	Elmahashi MO, Elbareg AM, Essadi FM, et al. Low dose aspirin and low-molecular-weight heparin in the treatment of pregnant Libyan women with recurrent miscarriage. BMC Res Notes, 2014, 7: 23.
25.	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(1): 33-38.
26.	Pasquier E, de Saint Martin L, Bohec C, et al. Enoxaparin for prevention of unexplained recurrent miscarriage: a multicenter randomized double-blind placebo-controlled trial. Blood, 2015, 125(14): 2200-2205.
27.	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(17): 1586-1596.
28.	Karadağ C, Akar B, Gönenç G, et al. Aspirin, low molecular weight heparin, or both in preventing pregnancy complications in women with recurrent pregnancy loss and factor V Leiden mutation. J Matern Fetal Neonatal Med, 2020, 33(11): 1934-1939.
29.	Khan ES, Basharat A, Jamil M, et al. Preventive role of low-molecular-weight heparin in unexplained recurrent pregnancy loss. Clin Appl Thromb Hemost, 2017, 23(1): 17-19.
30.	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(2): 279-287.
31.	Shaaban OM, Abbas AM, Zahran KM, et al. Low-molecular-weight heparin for the treatment of unexplained recurrent miscarriage with negative antiphospholipid antibodies: a randomized controlled trial. Clin Appl Thromb Hemost, 2017, 23(6): 567-572.
32.	Visser J, Ulander VM, Helmerhorst FM, et al. Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia. HABENOX:a randomised multicentre trial. Thromb Haemost, 2011, 105(2): 295-301.
33.	Schleussner E, Kamin G, Seliger G, et al. Low-molecular-weight heparin for women with unexplained recurrent pregnancy loss: a multicenter trial with a minimization randomization scheme. Ann Intern Med, 2015, 162(9): 601-609.
34.	Jeske WP, Walenga JM, Hoppensteadt DA, et al. Differentiating low-molecular-weight heparins based on chemical, biological, and pharmacologic properties: implications for the development of generic versions of low-molecular-weight heparins. Semin Thromb Hemost, 2008, 34(1): 74-85.
35.	Beretta G, Gelmini F, Merlino M, et al. A simplified screening procedure for determination of total N-NO groups (TNG) and nitrite (NO2-) in commercial low-molecular-weight heparins (LMWH) by selective chemical denitrosation followed by high-sensitivity chemiluminescence detection (NO-analyzer, NOA). J Pharm Biomed Anal, 2009, 49(5): 1179-1184.
36.	Li JP, Vlodavsky I. Heparin, heparan sulfate and heparanase in inflammatory reactions. Thromb Haemost, 2009, 102(5): 823-828.
37.	徐蕾, 张伟霞, 许倍铭, 等. 那屈肝素临床应用药学专家意见. 上海医药, 2022, 43(21): 12-17.

1. 陈子江, 林其德, 王谢桐, 等. 孕激素维持早期妊娠及防治流产的中国专家共识. 中华妇产科杂志, 2016, 51(7): 481-483.
2. 低分子肝素防治自然流产中国专家共识编写组. 低分子肝素防治自然流产中国专家共识. 中华生殖与避孕杂志, 2018, 38(9): 701-708.
3. Jeve YB, Davies W. Evidence-based management of recurrent miscarriages. J Hum Reprod Sci, 2014, 7(3): 159-169.
4. 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(13): 1650-1655.
5. 刘宗花, 王谢桐. 低分子肝素治疗自身免疫型复发性流产的作用机制及安全性. 山东医药, 2007, 47(20): 114-115.
6. Jiang F, Hu X, Jiang K, et al. The role of low molecular weight heparin on recurrent pregnancy loss: a systematic review and meta-analysis. Taiwan J Obstet Gynecol, 2021, 60(1): 1-8.
7. Guerrini M, Bisio A. Low-molecular-weight heparins: differential characterization/physical characterization. Handb Exp Pharmacol, 2012, (207): 127-157.
8. Cumpston M, Li T, Page MJ, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane handbook for systematic reviews of interventions. Cochrane Database Syst Rev, 2019, 10: ED000142.
9. 蔡仁变, 何晓彤, 林雪红. 低分子肝素联合小剂量阿司匹林治疗复发性流产的效果及对凝血指标的影响. 中国实用医药, 2020, 15(23): 128-130.
10. 蔡燕, 李君. 低分子肝素治疗妊娠期D-二聚体异常升高疗效观察. 中国药业, 2018, 27(14): 73-75.
11. 杜秀雅, 马华刚. 低分子肝素联合黄体酮治疗不明原因复发性自然流产临床分析. 潍坊医学院学报, 2014, 36(6): 465-466.
12. 高秀芹. 低分子肝素在复发性流产中的应用. 中外医疗, 2018, 37(30): 82-84.
13. 黄兴华, 伞翠平. 低分子肝素结合主动免疫治疗同种免疫性复发性自然流产的效果. 黑龙江医药科学, 2021, 44(2): 92-93.
14. 梁颖施, 陈惠禺, 黄俊杰, 等. 低分子肝素对复发性流产伴低滴度阳性抗β2糖蛋白Ⅰ抗体患者妊娠结局影响. 创伤与急危重病医学, 2018, 6(2): 114-115,118.
15. 邱莹, 黄胆. 阿司匹林联合依诺肝素钠治疗血栓前状态所致复发性流产的效果观察. 当代医药论丛, 2020, 18(18): 13-14.
16. 辛秀. 那曲肝素钙联合阿司匹林治疗复发性流产的效果及对患者血清TSP-1、sflt-1水平影响. 国际医药卫生导报, 2022, 28(9): 1288-1292.
17. 杨秀珍, 林志金, 张炯兰. 低分子肝素在治疗复发性流产中的临床研究. 中外医学研究, 2020, 18(22): 25-27.
18. 杨燕娥, 邓舒静, 李凤妹, 等. 低分子肝素在复发性流产中的应用观察. 大医生, 2021, 6(16): 33-35.
19. 张书筠, 张弘, 王云洁, 等. 低分子肝素联合阿司匹林治疗抗磷脂抗体引起的复发性流产的临床效果分析. 河北医学, 2018, 24(3): 422-426.
20. 周仲元, 陈鸽子, 胡玥暘. 低分子肝素与黄体酮联合叶酸治疗复发性流产对患者淋巴细胞亚群、性激素及再妊娠结局影响. 中国计划生育学杂志, 2021, 29(10): 2051-2055.
21. Fouda UM, Sayed AM, Abdou AM, et al. Enoxaparin versus unfractionated heparin in the management of recurrent abortion secondary to antiphospholipid syndrome. Int J Gynaecol Obstet, 2011, 112(3): 211-215.
22. 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(3): 280-284.
23. Bao SH, Sheng SL, Liao H, et al. Use of D-dimer measurement to guide anticoagulant treatment in recurrent pregnancy loss associated with antiphospholipid syndrome. Am J Reprod Immunol, 2017, 78(6): 1-12.
24. Elmahashi MO, Elbareg AM, Essadi FM, et al. Low dose aspirin and low-molecular-weight heparin in the treatment of pregnant Libyan women with recurrent miscarriage. BMC Res Notes, 2014, 7: 23.
25. 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(1): 33-38.
26. Pasquier E, de Saint Martin L, Bohec C, et al. Enoxaparin for prevention of unexplained recurrent miscarriage: a multicenter randomized double-blind placebo-controlled trial. Blood, 2015, 125(14): 2200-2205.
27. 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(17): 1586-1596.
28. Karadağ C, Akar B, Gönenç G, et al. Aspirin, low molecular weight heparin, or both in preventing pregnancy complications in women with recurrent pregnancy loss and factor V Leiden mutation. J Matern Fetal Neonatal Med, 2020, 33(11): 1934-1939.
29. Khan ES, Basharat A, Jamil M, et al. Preventive role of low-molecular-weight heparin in unexplained recurrent pregnancy loss. Clin Appl Thromb Hemost, 2017, 23(1): 17-19.
30. 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(2): 279-287.
31. Shaaban OM, Abbas AM, Zahran KM, et al. Low-molecular-weight heparin for the treatment of unexplained recurrent miscarriage with negative antiphospholipid antibodies: a randomized controlled trial. Clin Appl Thromb Hemost, 2017, 23(6): 567-572.
32. Visser J, Ulander VM, Helmerhorst FM, et al. Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia. HABENOX:a randomised multicentre trial. Thromb Haemost, 2011, 105(2): 295-301.
33. Schleussner E, Kamin G, Seliger G, et al. Low-molecular-weight heparin for women with unexplained recurrent pregnancy loss: a multicenter trial with a minimization randomization scheme. Ann Intern Med, 2015, 162(9): 601-609.
34. Jeske WP, Walenga JM, Hoppensteadt DA, et al. Differentiating low-molecular-weight heparins based on chemical, biological, and pharmacologic properties: implications for the development of generic versions of low-molecular-weight heparins. Semin Thromb Hemost, 2008, 34(1): 74-85.
35. Beretta G, Gelmini F, Merlino M, et al. A simplified screening procedure for determination of total N-NO groups (TNG) and nitrite (NO2-) in commercial low-molecular-weight heparins (LMWH) by selective chemical denitrosation followed by high-sensitivity chemiluminescence detection (NO-analyzer, NOA). J Pharm Biomed Anal, 2009, 49(5): 1179-1184.
36. Li JP, Vlodavsky I. Heparin, heparan sulfate and heparanase in inflammatory reactions. Thromb Haemost, 2009, 102(5): 823-828.
37. 徐蕾, 张伟霞, 许倍铭, 等. 那屈肝素临床应用药学专家意见. 上海医药, 2022, 43(21): 12-17.

Chinese Journal of Evidence-Based Medicine

Efficacy and safety of different low-molecular-weight heparins in improving pregnancy outcomes in patients with recurrent abortion: a network meta-analysis

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