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.	陳子江, 林其德, 王謝桐, 等. 孕激素維持早期妊娠及防治流產的中國專家共識. 中華婦產科雜志, 2016, 51(7): 481-483.
2.	低分子肝素防治自然流產中國專家共識編寫組. 低分子肝素防治自然流產中國專家共識. 中華生殖與避孕雜志, 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.	劉宗花, 王謝桐. 低分子肝素治療自身免疫型復發性流產的作用機制及安全性. 山東醫藥, 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.	蔡仁變, 何曉彤, 林雪紅. 低分子肝素聯合小劑量阿司匹林治療復發性流產的效果及對凝血指標的影響. 中國實用醫藥, 2020, 15(23): 128-130.
10.	蔡燕, 李君. 低分子肝素治療妊娠期D-二聚體異常升高療效觀察. 中國藥業, 2018, 27(14): 73-75.
11.	杜秀雅, 馬華剛. 低分子肝素聯合黃體酮治療不明原因復發性自然流產臨床分析. 濰坊醫學院學報, 2014, 36(6): 465-466.
12.	高秀芹. 低分子肝素在復發性流產中的應用. 中外醫療, 2018, 37(30): 82-84.
13.	黃興華, 傘翠平. 低分子肝素結合主動免疫治療同種免疫性復發性自然流產的效果. 黑龍江醫藥科學, 2021, 44(2): 92-93.
14.	梁穎施, 陳惠禺, 黃俊杰, 等. 低分子肝素對復發性流產伴低滴度陽性抗β2糖蛋白Ⅰ抗體患者妊娠結局影響. 創傷與急危重病醫學, 2018, 6(2): 114-115,118.
15.	邱瑩, 黃膽. 阿司匹林聯合依諾肝素鈉治療血栓前狀態所致復發性流產的效果觀察. 當代醫藥論叢, 2020, 18(18): 13-14.
16.	辛秀. 那曲肝素鈣聯合阿司匹林治療復發性流產的效果及對患者血清TSP-1、sflt-1水平影響. 國際醫藥衛生導報, 2022, 28(9): 1288-1292.
17.	楊秀珍, 林志金, 張炯蘭. 低分子肝素在治療復發性流產中的臨床研究. 中外醫學研究, 2020, 18(22): 25-27.
18.	楊燕娥, 鄧舒靜, 李鳳妹, 等. 低分子肝素在復發性流產中的應用觀察. 大醫生, 2021, 6(16): 33-35.
19.	張書筠, 張弘, 王云潔, 等. 低分子肝素聯合阿司匹林治療抗磷脂抗體引起的復發性流產的臨床效果分析. 河北醫學, 2018, 24(3): 422-426.
20.	周仲元, 陳鴿子, 胡玥暘. 低分子肝素與黃體酮聯合葉酸治療復發性流產對患者淋巴細胞亞群、性激素及再妊娠結局影響. 中國計劃生育學雜志, 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.	Karada? C, Akar B, G?nen? 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, 張偉霞, 許倍銘, 等. 那屈肝素臨床應用藥學專家意見. 上海醫藥, 2022, 43(21): 12-17.

1. 陳子江, 林其德, 王謝桐, 等. 孕激素維持早期妊娠及防治流產的中國專家共識. 中華婦產科雜志, 2016, 51(7): 481-483.
2. 低分子肝素防治自然流產中國專家共識編寫組. 低分子肝素防治自然流產中國專家共識. 中華生殖與避孕雜志, 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. 劉宗花, 王謝桐. 低分子肝素治療自身免疫型復發性流產的作用機制及安全性. 山東醫藥, 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. 蔡仁變, 何曉彤, 林雪紅. 低分子肝素聯合小劑量阿司匹林治療復發性流產的效果及對凝血指標的影響. 中國實用醫藥, 2020, 15(23): 128-130.
10. 蔡燕, 李君. 低分子肝素治療妊娠期D-二聚體異常升高療效觀察. 中國藥業, 2018, 27(14): 73-75.
11. 杜秀雅, 馬華剛. 低分子肝素聯合黃體酮治療不明原因復發性自然流產臨床分析. 濰坊醫學院學報, 2014, 36(6): 465-466.
12. 高秀芹. 低分子肝素在復發性流產中的應用. 中外醫療, 2018, 37(30): 82-84.
13. 黃興華, 傘翠平. 低分子肝素結合主動免疫治療同種免疫性復發性自然流產的效果. 黑龍江醫藥科學, 2021, 44(2): 92-93.
14. 梁穎施, 陳惠禺, 黃俊杰, 等. 低分子肝素對復發性流產伴低滴度陽性抗β2糖蛋白Ⅰ抗體患者妊娠結局影響. 創傷與急危重病醫學, 2018, 6(2): 114-115,118.
15. 邱瑩, 黃膽. 阿司匹林聯合依諾肝素鈉治療血栓前狀態所致復發性流產的效果觀察. 當代醫藥論叢, 2020, 18(18): 13-14.
16. 辛秀. 那曲肝素鈣聯合阿司匹林治療復發性流產的效果及對患者血清TSP-1、sflt-1水平影響. 國際醫藥衛生導報, 2022, 28(9): 1288-1292.
17. 楊秀珍, 林志金, 張炯蘭. 低分子肝素在治療復發性流產中的臨床研究. 中外醫學研究, 2020, 18(22): 25-27.
18. 楊燕娥, 鄧舒靜, 李鳳妹, 等. 低分子肝素在復發性流產中的應用觀察. 大醫生, 2021, 6(16): 33-35.
19. 張書筠, 張弘, 王云潔, 等. 低分子肝素聯合阿司匹林治療抗磷脂抗體引起的復發性流產的臨床效果分析. 河北醫學, 2018, 24(3): 422-426.
20. 周仲元, 陳鴿子, 胡玥暘. 低分子肝素與黃體酮聯合葉酸治療復發性流產對患者淋巴細胞亞群、性激素及再妊娠結局影響. 中國計劃生育學雜志, 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. Karada? C, Akar B, G?nen? 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, 張偉霞, 許倍銘, 等. 那屈肝素臨床應用藥學專家意見. 上海醫藥, 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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