Safety of low-molecular-weight heparin in pregnancy: a systematic review_Chinese Journal of Evidence-Based Medicine

Authors：

ZHANG Chuan ^1,2,3 , ZHANG Li ^3,4 , LI Yongqin ⁵ , LIU Dan ^1,2,3 , ZENG Linan ^1,2,3 ,  ZHANG Lingli ^1,2,3

1. Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu 610041, P.R.China;
2. Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu 610041, P.R.China;
3. Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, P.R.China;
4. Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu 610041, P.R.China;
5. West China School of Pharmacy, Sichuan University, Chengdu 610041, P.R.China;

Corresponding author：

ZHANG Lingli, Email: zhanglingli@scu.edu.cn

Keywords：

Low molecular weight heparin; Pregnancy; Safety; Systematic review; Meta-analysis; Randomized controlled trial; Cohort study

DOI：

10.7507/1672-2531.202107078

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Objective To systematically review the safety of low molecular weight heparin (LMWH) in pregnancy. Methods PubMed, EMbase, The Cochrane Library, WanFang Data, VIP, and CNKI databases were electronically searched to collect randomized controlled trials (RCTs) and cohort studies on the safety of LMWH in pregnancy from inception to March 30^th, 2020. Two reviewers independently screened literature, extracted data, and assessed the risk of bias of included studies. Meta-analysis was then performed using RevMan 5.3 software. Results A total of 77 RCTs and 13 cohort studies were included. The results of meta-analysis showed that LMWH increased the incidence of postpartum hemorrhage (RR=1.50, 95%CI 1.00 to 2.25, P=0.05). However, there was no significant difference. The incidence of hematological adverse events was different from the results of RCTs and cohort studies. The results of RCT subgroup analysis showed that LMWH increased ecchymosis at the injection site (RR=1.60, 95%CI 1.24 to 2.08, P=0.000 4). However, the incidence of overall skin system adverse events did not increase significantly. LMWH reduced the incidence of cardiovascular adverse events (RR=0.18, 95%CI 0.07 to 0.46, P=0.000 3). LMWH failed to increase the occurrence of fetal congenital malformations, digestive system, central nervous system, skeletal system, and systemic adverse events. Conclusions Current evidence suggests that LMWH is relatively safe to use during pregnancy. However, whether it increases postpartum hemorrhage and hematological adverse events is unclear. Due to limited quality and quantity of the included studies, more high-quality studies are required to verify the above conclusions.

Citation： ZHANG Chuan, ZHANG Li, LI Yongqin, LIU Dan, ZENG Linan, ZHANG Lingli. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Chinese Journal of Evidence-Based Medicine, 2021, 21(11): 1259-1268. doi: 10.7507/1672-2531.202107078 Copy

1.	American College of Obstetricians and Gynecologists' Committee on Practice Bulletins-Obstetrics. ACOG practice bulletin No. 196:thromboembolism in pregnancy. Obstet Gynecol, 2018, 132(1): e1-e17.
2.	Queensland Health. Queensland clinical guidelines (No. MN14.9-V5 -R19): venous thromboembolism (VTE) in pregnancy and the puerperium. Available at:https://www.health.qld.gov.au/qcg.
3.	Shomer E, Katzenell S, Zipori Y, et al. Microvesicles of pregnant women receiving low molecular weight heparin improve trophoblast function. Thromb Res, 2016, 137: 141-147.
4.	Dias ATB, Modesto TB, Oliveira SA. Effectiveness of the use of low molecular heparin in patients with repetition abortion history: systematic review and meta-analysis. JBRA Assist Reprod, 2021, 25(1): 10-27.
5.	Urban G, Vergani P, Tironi R, et al. Antithrombotic prophylaxis in multiparous women with preeclampsia or intrauterine growth retardation in an antecedent pregnancy. Int J Fertil Womens Med, 2007, 52(2-3): 59-67.
6.	Forestier F, Daffos F, Capella-Pavlovsky M. Low molecular weight heparin (PK 10169) does not cross the placenta during the second trimester of pregnancy study by direct fetal blood sampling under ultrasound. Thromb Res, 1984, 34(6): 557-560.
7.	Ensom MH, Stephenson MD. Pharmacokinetics of low molecular weight heparin and unfractionated heparin in pregnancy. J Soc Gynecol Investig, 2004, 11(6): 377-383.
8.	Schindewolf M, Gobst C, Kroll H, et al. High incidence of heparin-induced allergic delayed-type hypersensitivity reactions in pregnancy. J Allergy Clin Immunol, 2013, 132(1): 131-139.
9.	Sirico A, Saccone G, Maruotti GM, et al. Low molecular weight heparin use during pregnancy and risk of postpartum hemorrhage: a systematic review and meta-analysis. J Matern Fetal Neonatal Med, 2019, 32(11): 1893-1900.
10.	Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions (version 5. 1. 0). The Cochrane Collaboration, 2011, Availableat: //www.cochrane-handbook.org.
11.	Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol, 2010, 25(9): 603-605.
12.	Gates S, Brocklehurst P, Ayers S, et al. Thromboprophylaxis and pregnancy: two randomized controlled pilot trials that used low-molecular-weight heparin. Am J Obstet Gynecol, 2004, 191(4): 1296-1303.
13.	Rodger MA, Kahn SR, Cranney A, et al. Long-term dalteparin in pregnancy not associated with a decrease in bone mineral density: substudy of a randomized controlled trial. J Thromb Haemost, 2007, 5(8): 1600-1606.
14.	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.
15.	李伏福, 周运花. 阿司匹林联合低分子肝素治疗复发性流产的研究. 中国现代药物应用, 2019, 13(3): 129-131.
16.	Gris JC, Chauleur C, Faillie JL, et al. Enoxaparin for the secondary prevention of placental vascular complications in women with abruptio placentae. The pilot randomised controlled NOH-AP trial. Thromb Haemost, 2010, 104(4): 771-779.
17.	Kaandorp SP, Goddijn M, Post J, et al. Aspirin alone or combined with low-molecular-weight heparin in women with unexplained recurrent miscarriage, a randomised placebo-controlled trial. Hum Reprod, 2010, 25: i28-i29.
18.	黄灿丽. 低分子肝素钙治疗复发性流产的研究. 医药前沿, 2013, (11): 28-29.
19.	陈铸. 对53例原因不明的复发性流产患者使用肝素进行治疗的效果分析. 当代医药论丛, 2015, (6): 161-162.
20.	张高, 程玲慧. 低分子肝素与小剂量阿司匹林联合可有效治疗复发性流产. 基因组学与应用生物学, 2017, 36(4): 1348-1354.
21.	蔡燕琴. 低分子肝素钙联合小剂量阿司匹林治疗D-二聚体升高的复发性流产的应用观察. 中国现代药物应用, 2016, 10(11): 217-218.
22.	高珊珊. 低分子肝素与阿司匹林治疗习惯性流产的疗效观察. 现代诊断与治疗, 2017, 28(19): 3599-3600.
23.	黄珊珊, 罗奕巾. 低分子肝素钙治疗病理性高凝复发性流产的价值. 海峡药学, 2017, 29(7): 160-161.
24.	吴飞. 低分子肝素联合阿司匹林治疗高龄复发性流产的效果观察. 中国妇幼健康研究, 2017, (S1): 499-500.
25.	蔡春燕, 杨燕珍. 低分子肝素钙治疗复发性流产的效果分析. 河南医学研究, 2018, 27(10): 1815-1816.
26.	黄珊珊. 低分子肝素钙治疗高凝状态复发性流产的疗效观察. 广东医学. 2018, (S1): 227-228.
27.	李亚. 低分子肝素与阿司匹林联合治疗习惯性流产的疗效观察. 临床合理用药杂志, 2018, 11(23): 61-62.
28.	刘金兰. 伴D-二聚体升高的复发性流产患者中应用低分子肝素钙治疗的临床效果. 现代诊断与治疗, 2018, 29(8): 1264-1265.
29.	王女嬴. 低分子肝素钠治疗D-二聚体升高复发性流产的观察. 医学食疗与健康, 2018, (5): 8-9.
30.	许庭郁. 低分子肝素联合阿司匹林对复发性流产的治疗效果分析. 海峡药学, 2018, 30(10): 205-206.
31.	周磊清, 张蓉, 宣毅飞. 低分子肝素皮下注射与小剂量阿司匹林联合治疗不明原因复发性流产的临床观察. 现代医院, 2018, 18(11): 1658-1660.
32.	黄静. 低分子肝素联合阿司匹林对复发性流产的疗效观察. 临床医药文献电子杂志, 2019, 6(93): 67.
33.	龙静, 刘洁玲, 韩朝辉, 等. 低分子肝素治疗ART妊娠后复发性流产的效果及对激素水平, 凝血功能的影响. 中国计划生育学杂志, 2019, 27(3): 339-341,345.
34.	曾国富, 章芸, 李梅桂, 等. 低分子肝素联合主动免疫治疗不明原因复发性自然流产的临床研究. 北方药学, 2019, 16(11): 119-120.
35.	段芙蓉, 刘晓媛. 低分子肝素联合阿司匹林治疗高龄复发性流产的临床效果. 临床医学研究与实践, 2019, 4(3): 32-33.
36.	方丽丽, 张庆. 阿司匹林和低分子肝素治疗习惯性流产临床疗效评价. 母婴世界, 2019, (24): 141.
37.	李素青. 阿司匹林与低分子肝素联用对患者习惯性流产的临床疗效与安全性评价. 抗感染药学, 2019, 16(5): 881-884.
38.	梁荣丽, 罗宋. 低分子肝素联合小剂量阿司匹林对原因不明复发性流产患者血栓前状态及免疫功能的影响. 中国计划生育学杂志, 2019, 27(2): 184-188.
39.	聂桂琴. 阿司匹林联合低分子肝素治疗习惯性流产的效果评价. 养生保健指南, 2019, (51): 218.
40.	邵敏佳. 低分子肝素联合阿司匹林对复发性流产的治疗效果分析. 医药前沿, 2019, 9(28): 141-142.
41.	屠金枝, 熊俊娜, 殷勤. 阿司匹林联合低分子肝素治疗习惯性流产的疗效观察. 养生保健指南, 2019, (34): 280.
42.	王先梅. 阿司匹林联合低分子肝素治疗习惯性流产临床效果观察. 医药前沿, 2019, 9(3): 93-94.
43.	张新乐, 赵白信, 王雪锋, 等. 低分子肝素对反复自然流产子宫动脉血流和凝血-纤溶指标的影响及疗效观察. 中国合理用药探索, 2019, 16(5): 104-107.
44.	张艳艳. 低分子肝素对复发性流产孕妇性激素, 免疫功能及保胎成功率的影响. 中国妇幼保健, 2019, 34(13): 3037-3039.
45.	郑桂英, 张粉叶, 谷世敏, 等. 黄体酮联合低分子肝素钠治疗复发性流产临床评价. 中国药业, 2019, 28(18): 75-77.
46.	骆英. 黄体酮联合低分子肝素钠治疗复发性流产的效果观察. 临床合理用药杂志, 2020, 13(29): 85-86.
47.	马莉, 徐慧军. 寿胎丸联合肝素治疗抗磷脂抗体阳性复发性流产的疗效观察. 世界最新医学信息文摘(连续型电子期刊), 2020, 20(18): 86-87.
48.	徐娟. 阿司匹林和低分子肝素治疗习惯性流产临床疗效评价. 世界复合医学, 2020, 6(8): 168-170.
49.	赵娜. 阿司匹林和低分子肝素治疗习惯性流产临床疗效及对抗体清除率影响. 临床研究, 2020, 28(4): 40-41.
50.	张欣, 王琇, 张丽. 低分子肝素对反复种植失败合并易栓症患者妊娠结局的影响观察. 中国药师, 2020, 23(9): 1792-1794.
51.	陈翠娜. 阿司匹林联合低分子肝素钙治疗血栓前状态致早期习惯性流产的临床疗效分析. 当代医学, 2020, 26(25): 98-100.
52.	顾惠英. 阿司匹林肠溶片与低分子肝素治疗习惯性流产的效果和安全性分析. 名医, 2020, (9): 334-335.
53.	李晶晶. 低分子肝素联合丙种球蛋白治疗复发性流产临床疗效观察. 现代诊断与治疗, 2020, 31(10): 1571-1572.
54.	林海玉. 阿司匹林联合低分子肝素在习惯性流产临床治疗中应用的效果分析. 系统医学, 2020, 5(14): 103-105.
55.	邱文芳, 温泉, 刘素梅. 阿司匹林和低分子肝素治疗习惯性流产的临床疗效评价. 当代医学, 2020, 26(32): 20-22.
56.	苏群凤. 低分子肝素钙与阿司匹林治疗高龄复发性流产. 世界最新医学信息文摘, 2020, 20(57): 131-132.
57.	王东霞. 低分子肝素钠联合阿司匹林治疗复发性流产的效果分析. 临床医学工程, 2020, 27(6): 797-798.
58.	魏明. 阿司匹林联合低分子肝素对高凝状态复发性流产患者妊娠结局的影响. 黑龙江医药科学, 2020, 43(6): 42-43.
59.	袁少飞, 高峰丽, 郭海军, 等. 阿司匹林联合低分子肝素对血栓前状态致复发性流产的临床疗效和安全性研究. 中国处方药, 2020, 18(11): 126-128.
60.	朱益静, 符圆圆, 孔彩霞, 等. 黄体酮联合低分子肝素钠治疗复发性流产的疗效分析. 广西医学, 2020, 42(6): 698-702.
61.	颜颖. 阿司匹林肠溶片与低分子肝素治疗习惯性流产的效果与安全性观察. 吉林医学, 2021, 42(3): 661-663.
62.	叶聘. 阿司匹林联合低分子肝素在习惯性流产治疗中的应用效果. 临床医学, 2021, 41(3): 96-98.
63.	李伟娜. 阿司匹林联合低分子肝素治疗高凝状态复发性流产的效果观察. 广州医药, 2021, 52(2): 131-134.
64.	钱晶晶, 陈鸳鸳. 低分子肝素钙治疗子宫动脉阻力指数增高的复发性流产患者的疗效及对妊娠结局的影响. 中国妇幼保健, 2021, 36(6): 1336-1338.
65.	袁少飞, 高峰丽, 郭海军, 等. 阿司匹林和低分子肝素对高龄复发性流产患者抗体清除率和保胎成功率的影响. 中外医疗, 2021, 40(7): 110-112.
66.	徐丽琼. 低分子肝素钠联合地屈孕酮在先兆流产治疗中的临床应用. 健康之友, 2020, (16): 287.
67.	李晓飞. 低分子肝素钙联合地屈孕酮治疗对先兆流产患者妊娠结局的影响. 内科, 2017, 12(5): 674-676.
68.	李清醒. 低分子肝素钠联合地屈孕酮治疗先兆流产效果观察. 深圳中西医结合杂志, 2018, 28(18): 121-122.
69.	王文娣, 朱学喆, 王慧峰. 低分子肝素钠联合地屈孕酮在治疗先兆流产中的应用效果. 医学美学美容, 2019, 28(16): 58.
70.	仰莉苹. 低分子肝素钠联合地屈孕酮治疗先兆流产的疗效和安全性. 饮食保健, 2019, 6(26): 58-59.
71.	胡金菊. 低分子肝素钠联合地屈孕酮对先兆流产患者的影响. 实用中西医结合临床, 2020, 20(3): 35-36.
72.	蒋艳华, 冯洁, 钟建玲. 低分子肝素钠联合低剂量黄体酮治疗先兆流产的临床疗效探究. 中国现代药物应用, 2020, 14(7): 169-171.
73.	涂荧花. 低分子肝素钠辅助地屈孕酮治疗先兆流产的效果观察. 医学理论与实践, 2020, 33(15): 2521-2522.
74.	朱琳. 低分子肝素钠联合间苯三酚治疗先兆流产的临床疗效. 临床合理用药杂志, 2020, 13(36): 116-118.
75.	Rey E, Garneau P, David M, et al. Dalteparin for the prevention of recurrence of placental-mediated complications of pregnancy in women without thrombophilia: a pilot randomized controlled trial. J Thromb Haemost, 2009, 7(1): 58-64.
76.	周叶, 邢秀月, 张潍, 等. 低分子肝素对子痫前期孕妇肾损害的保护作用. 西南国防医药, 2017, 27(6): 612-614.
77.	谭西施. 低分子肝素钠在妊娠期高血压患者治疗中的应用观察. 基层医学论坛, 2017, 21(10): 1224-1225.
78.	张玉敏. 低分子肝素钠联合硫酸镁治疗妊娠期高血压综合征患者的效果. 中国民康医学, 2017, 29(2): 25-26.
79.	吴丽琴, 孙玉娟, 苏翠珍, 等. 低分子量肝素钠注射液联合硫酸镁注射液和拉贝洛尔片治疗重度妊娠期高血压综合征的临床研究. 中国临床药理学杂志, 2019, 35(3): 216-219.
80.	刘展, 孙克佳, 秦丹. 低分子肝素联合拉贝洛尔治疗早发型重度子痫前期患者的疗效分析. 中国合理用药探索, 2019, 16(10): 164-166.
81.	傅红. 拉贝洛尔联合依诺肝素治疗妊娠期高血压疾病疗效观察. 医学临床研究, 2019, 36(9): 1677-1679,1683.
82.	Llurba E, Bella M, Burgos J, et al. Early prophylactic enoxaparin for the prevention of preeclampsia and intrauterine growth restriction: a randomized trial. Fetal Diagn Ther, 2020, 47(11): 824-833.
83.	宋晓辉, 吴琼琼, 陈丽华. 阿司匹林联合低分子肝素治疗重度子痫前期的效果观察. 中国实用医刊, 2020, 47(3): 112-115.
84.	单丽娟, 兰淑海. 低分子肝素辅助治疗对重度子痫前期患者胎盘缺氧的效果评价. 吉林医学, 2020, 41(12): 2911-2912.
85.	周月云, 张庆娥, 董晶晶, 等. 低分子肝素用于妊娠期高血压疾病治疗效果探究. 心血管外科杂志(电子版), 2020, 9(3): 82.
86.	Shirazi M, Naeiji Z, Sharbaf FR, et al. Therapeutic role of enoxaparin in intra-uterine growth restriction: a randomized clinical trial. J Gynecol Obstet Hum Reprod, 2021, 50(8): 102070.
87.	陈亚秋. 低分子肝素在妊娠晚期羊水过少治疗中的用药安全性研究. 医药前沿, 2018, 8(34): 106.
88.	Qublan H, Amarin Z, Dabbas M, et al. Low-molecular-weight heparin in the treatment of recurrent IVF-ET failure and thrombophilia: a prospective randomized placebo-controlled trial. Hum Fertil (Camb), 2008, 11(4): 246-253.
89.	Andersen AS, Berthelsen JG, Bergholt T. Venous thromboembolism in pregnancy: prophylaxis and treatment with low molecular weight heparin. Acta Obstet Gynecol Scand, 2010, 89(1): 15-21.
90.	Roshani S, Cohn DM, Stehouwer AC, et al. Incidence of postpartum haemorrhage in women receiving therapeutic doses of low-molecular-weight heparin: results of a retrospective cohort study. BMJ Open, 2011, 1(2): e000257.
91.	Galambosi PJ, Kaaja RJ, Stefanovic V, et al. Safety of low-molecular-weight heparin during pregnancy: a retrospective controlled cohort study. Eur J Obstet Gynecol Reprod Biol, 2012, 163(2): 154-159.
92.	Knol HM, Schultinge L, Veeger NJ, et al. The risk of postpartum hemorrhage in women using high dose of low-molecular-weight heparins during pregnancy. Thromb Res, 2012, 130(3): 334-338.
93.	Lindqvist PG, Dahlbäck B. Bleeding complications associated with low molecular weight heparin prophylaxis during pregnancy. Thromb Haemost, 2000, 84(1): 140-141.
94.	Arbuthnot C, Browne R, Nicole S, et al. A double centre retrospective study into rates of postpartum haemorrhage in women on low molecular weight heparin. Br J Haematol, 2017, 176(1): 141-143.
95.	Yuksel H, Kayatas S, Boza AT, et al. Low molecular weight heparin use in unexplained recurrent miscarriage. Pak J Med Sci, 2014, 30(6): 1232-1237.
96.	周淑君. 低分子肝素和阿司匹林对复发性流产患者血浆纤溶酶原激活物抑制剂-1和组织型纤溶酶原活化因子水平的影响. 中国基层医药, 2016, 23(18): 2740-2743.
97.	Shlomo M, Gorodischer R, Daniel S, et al. The fetal safety of enoxaparin use during pregnancy: a population-based retrospective cohort study. Drug Saf, 2017, 40(11): 1147-1155.
98.	郭仲杰, 刘春霞, 郭晓霞, 等. 依诺肝素与磺达肝癸钠用于复发性流产患者妊娠期抗凝治疗的对比. 当代医学, 2020, 26(30): 5-8.
99.	李慧, 吴小妹, 周玉华. 低分子肝素钠联合地屈孕酮治疗先兆流产的临床观察. 中国药房, 2017, 28(18): 2499-2502.
100.	谭焕仪. 达肝素钠注射液辅助治疗先兆流产的可行性及安全性. 数理医药学杂志, 2019, 32(11): 1677-1678.
101.	Boilot T, Raia-Barjat T, Ollier E, et al. Influence of anticoagulant therapy during pregnancy on the peripartum and anesthesia delivery terms. Gynecol Obstet Fertil, 2015, 43(7-8): 502-508.
102.	Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood, 2005, 106(2): 401-407.
103.	Kominiarek MA, Angelopoulos SM, Shapiro NL, et al. Low-molecular-weight heparin in pregnancy: peripartum bleeding complications. J Perinatol, 2007, 27(6): 329-334.
104.	Jacobson B, Rambiritch V, Paek D, et al. Safety and efficacy of enoxaparin in pregnancy: a systematic review and meta-analysis. Adv Ther, 2020, 37(1): 27-40.
105.	Byrd LM, Shiach CR, Hay CR, et al. Osteopenic fractures in pregnancy: is low molecular weight heparin (LMWH) implicated. J Obstet Gynaecol, 2008, 28(5): 539-542.
106.	Goëb V, Strotz V, Verdet M, et al. Post-partum sacral fracture associated with heparin treatment. Clin Rheumatol, 2008, 27(Suppl 2): S51-53.
107.	Lefkou E, Khamashta M, Hampson G, et al. Review: Low-molecular-weight heparin-induced osteoporosis and osteoporotic fractures: a myth or an existing entity. Lupus, 2010, 19(1): 3-12.
108.	Ozdemir D, Tam AA, Dirikoc A, et al. Postpartum osteoporosis and vertebral fractures in two patients treated with enoxaparin during pregnancy. Osteoporos Int, 2015, 26(1): 415-418.
109.	Ekim A. Postpartum osteoporosis and thoracic vertebral fracture in a patient treated with heparin during pregnancy. J Clin Anal Med, 2016, 7: 154-157.
110.	Ozturk G, Akpinar P, Karamanlioglu AD, et al. Pregnancy-related osteoporotic vertebral compression fractures in two patients treated with low-molecular-weight heparin during pregnancy: case reports. Gynecol Endocrinol, 2018, 34(5): 378-380.
111.	Hardcastle SA, Yahya F, Bhalla AK. Pregnancy-associated osteoporosis: a UK case series and literature review. Osteoporos Int, 2019, 30(5): 939-948.
112.	Carlin AJ, Farquharson RG, Quenby SM, et al. Prospective observational study of bone mineral density during pregnancy: low molecular weight heparin versus control. Hum Reprod, 2004, 19(5): 1211-1214.

1. American College of Obstetricians and Gynecologists' Committee on Practice Bulletins-Obstetrics. ACOG practice bulletin No. 196:thromboembolism in pregnancy. Obstet Gynecol, 2018, 132(1): e1-e17.
2. Queensland Health. Queensland clinical guidelines (No. MN14.9-V5 -R19): venous thromboembolism (VTE) in pregnancy and the puerperium. Available at:https://www.health.qld.gov.au/qcg.
3. Shomer E, Katzenell S, Zipori Y, et al. Microvesicles of pregnant women receiving low molecular weight heparin improve trophoblast function. Thromb Res, 2016, 137: 141-147.
4. Dias ATB, Modesto TB, Oliveira SA. Effectiveness of the use of low molecular heparin in patients with repetition abortion history: systematic review and meta-analysis. JBRA Assist Reprod, 2021, 25(1): 10-27.
5. Urban G, Vergani P, Tironi R, et al. Antithrombotic prophylaxis in multiparous women with preeclampsia or intrauterine growth retardation in an antecedent pregnancy. Int J Fertil Womens Med, 2007, 52(2-3): 59-67.
6. Forestier F, Daffos F, Capella-Pavlovsky M. Low molecular weight heparin (PK 10169) does not cross the placenta during the second trimester of pregnancy study by direct fetal blood sampling under ultrasound. Thromb Res, 1984, 34(6): 557-560.
7. Ensom MH, Stephenson MD. Pharmacokinetics of low molecular weight heparin and unfractionated heparin in pregnancy. J Soc Gynecol Investig, 2004, 11(6): 377-383.
8. Schindewolf M, Gobst C, Kroll H, et al. High incidence of heparin-induced allergic delayed-type hypersensitivity reactions in pregnancy. J Allergy Clin Immunol, 2013, 132(1): 131-139.
9. Sirico A, Saccone G, Maruotti GM, et al. Low molecular weight heparin use during pregnancy and risk of postpartum hemorrhage: a systematic review and meta-analysis. J Matern Fetal Neonatal Med, 2019, 32(11): 1893-1900.
10. Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions (version 5. 1. 0). The Cochrane Collaboration, 2011, Availableat: //www.cochrane-handbook.org.
11. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol, 2010, 25(9): 603-605.
12. Gates S, Brocklehurst P, Ayers S, et al. Thromboprophylaxis and pregnancy: two randomized controlled pilot trials that used low-molecular-weight heparin. Am J Obstet Gynecol, 2004, 191(4): 1296-1303.
13. Rodger MA, Kahn SR, Cranney A, et al. Long-term dalteparin in pregnancy not associated with a decrease in bone mineral density: substudy of a randomized controlled trial. J Thromb Haemost, 2007, 5(8): 1600-1606.
14. 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.
15. 李伏福, 周运花. 阿司匹林联合低分子肝素治疗复发性流产的研究. 中国现代药物应用, 2019, 13(3): 129-131.
16. Gris JC, Chauleur C, Faillie JL, et al. Enoxaparin for the secondary prevention of placental vascular complications in women with abruptio placentae. The pilot randomised controlled NOH-AP trial. Thromb Haemost, 2010, 104(4): 771-779.
17. Kaandorp SP, Goddijn M, Post J, et al. Aspirin alone or combined with low-molecular-weight heparin in women with unexplained recurrent miscarriage, a randomised placebo-controlled trial. Hum Reprod, 2010, 25: i28-i29.
18. 黄灿丽. 低分子肝素钙治疗复发性流产的研究. 医药前沿, 2013, (11): 28-29.
19. 陈铸. 对53例原因不明的复发性流产患者使用肝素进行治疗的效果分析. 当代医药论丛, 2015, (6): 161-162.
20. 张高, 程玲慧. 低分子肝素与小剂量阿司匹林联合可有效治疗复发性流产. 基因组学与应用生物学, 2017, 36(4): 1348-1354.
21. 蔡燕琴. 低分子肝素钙联合小剂量阿司匹林治疗D-二聚体升高的复发性流产的应用观察. 中国现代药物应用, 2016, 10(11): 217-218.
22. 高珊珊. 低分子肝素与阿司匹林治疗习惯性流产的疗效观察. 现代诊断与治疗, 2017, 28(19): 3599-3600.
23. 黄珊珊, 罗奕巾. 低分子肝素钙治疗病理性高凝复发性流产的价值. 海峡药学, 2017, 29(7): 160-161.
24. 吴飞. 低分子肝素联合阿司匹林治疗高龄复发性流产的效果观察. 中国妇幼健康研究, 2017, (S1): 499-500.
25. 蔡春燕, 杨燕珍. 低分子肝素钙治疗复发性流产的效果分析. 河南医学研究, 2018, 27(10): 1815-1816.
26. 黄珊珊. 低分子肝素钙治疗高凝状态复发性流产的疗效观察. 广东医学. 2018, (S1): 227-228.
27. 李亚. 低分子肝素与阿司匹林联合治疗习惯性流产的疗效观察. 临床合理用药杂志, 2018, 11(23): 61-62.
28. 刘金兰. 伴D-二聚体升高的复发性流产患者中应用低分子肝素钙治疗的临床效果. 现代诊断与治疗, 2018, 29(8): 1264-1265.
29. 王女嬴. 低分子肝素钠治疗D-二聚体升高复发性流产的观察. 医学食疗与健康, 2018, (5): 8-9.
30. 许庭郁. 低分子肝素联合阿司匹林对复发性流产的治疗效果分析. 海峡药学, 2018, 30(10): 205-206.
31. 周磊清, 张蓉, 宣毅飞. 低分子肝素皮下注射与小剂量阿司匹林联合治疗不明原因复发性流产的临床观察. 现代医院, 2018, 18(11): 1658-1660.
32. 黄静. 低分子肝素联合阿司匹林对复发性流产的疗效观察. 临床医药文献电子杂志, 2019, 6(93): 67.
33. 龙静, 刘洁玲, 韩朝辉, 等. 低分子肝素治疗ART妊娠后复发性流产的效果及对激素水平, 凝血功能的影响. 中国计划生育学杂志, 2019, 27(3): 339-341,345.
34. 曾国富, 章芸, 李梅桂, 等. 低分子肝素联合主动免疫治疗不明原因复发性自然流产的临床研究. 北方药学, 2019, 16(11): 119-120.
35. 段芙蓉, 刘晓媛. 低分子肝素联合阿司匹林治疗高龄复发性流产的临床效果. 临床医学研究与实践, 2019, 4(3): 32-33.
36. 方丽丽, 张庆. 阿司匹林和低分子肝素治疗习惯性流产临床疗效评价. 母婴世界, 2019, (24): 141.
37. 李素青. 阿司匹林与低分子肝素联用对患者习惯性流产的临床疗效与安全性评价. 抗感染药学, 2019, 16(5): 881-884.
38. 梁荣丽, 罗宋. 低分子肝素联合小剂量阿司匹林对原因不明复发性流产患者血栓前状态及免疫功能的影响. 中国计划生育学杂志, 2019, 27(2): 184-188.
39. 聂桂琴. 阿司匹林联合低分子肝素治疗习惯性流产的效果评价. 养生保健指南, 2019, (51): 218.
40. 邵敏佳. 低分子肝素联合阿司匹林对复发性流产的治疗效果分析. 医药前沿, 2019, 9(28): 141-142.
41. 屠金枝, 熊俊娜, 殷勤. 阿司匹林联合低分子肝素治疗习惯性流产的疗效观察. 养生保健指南, 2019, (34): 280.
42. 王先梅. 阿司匹林联合低分子肝素治疗习惯性流产临床效果观察. 医药前沿, 2019, 9(3): 93-94.
43. 张新乐, 赵白信, 王雪锋, 等. 低分子肝素对反复自然流产子宫动脉血流和凝血-纤溶指标的影响及疗效观察. 中国合理用药探索, 2019, 16(5): 104-107.
44. 张艳艳. 低分子肝素对复发性流产孕妇性激素, 免疫功能及保胎成功率的影响. 中国妇幼保健, 2019, 34(13): 3037-3039.
45. 郑桂英, 张粉叶, 谷世敏, 等. 黄体酮联合低分子肝素钠治疗复发性流产临床评价. 中国药业, 2019, 28(18): 75-77.
46. 骆英. 黄体酮联合低分子肝素钠治疗复发性流产的效果观察. 临床合理用药杂志, 2020, 13(29): 85-86.
47. 马莉, 徐慧军. 寿胎丸联合肝素治疗抗磷脂抗体阳性复发性流产的疗效观察. 世界最新医学信息文摘(连续型电子期刊), 2020, 20(18): 86-87.
48. 徐娟. 阿司匹林和低分子肝素治疗习惯性流产临床疗效评价. 世界复合医学, 2020, 6(8): 168-170.
49. 赵娜. 阿司匹林和低分子肝素治疗习惯性流产临床疗效及对抗体清除率影响. 临床研究, 2020, 28(4): 40-41.
50. 张欣, 王琇, 张丽. 低分子肝素对反复种植失败合并易栓症患者妊娠结局的影响观察. 中国药师, 2020, 23(9): 1792-1794.
51. 陈翠娜. 阿司匹林联合低分子肝素钙治疗血栓前状态致早期习惯性流产的临床疗效分析. 当代医学, 2020, 26(25): 98-100.
52. 顾惠英. 阿司匹林肠溶片与低分子肝素治疗习惯性流产的效果和安全性分析. 名医, 2020, (9): 334-335.
53. 李晶晶. 低分子肝素联合丙种球蛋白治疗复发性流产临床疗效观察. 现代诊断与治疗, 2020, 31(10): 1571-1572.
54. 林海玉. 阿司匹林联合低分子肝素在习惯性流产临床治疗中应用的效果分析. 系统医学, 2020, 5(14): 103-105.
55. 邱文芳, 温泉, 刘素梅. 阿司匹林和低分子肝素治疗习惯性流产的临床疗效评价. 当代医学, 2020, 26(32): 20-22.
56. 苏群凤. 低分子肝素钙与阿司匹林治疗高龄复发性流产. 世界最新医学信息文摘, 2020, 20(57): 131-132.
57. 王东霞. 低分子肝素钠联合阿司匹林治疗复发性流产的效果分析. 临床医学工程, 2020, 27(6): 797-798.
58. 魏明. 阿司匹林联合低分子肝素对高凝状态复发性流产患者妊娠结局的影响. 黑龙江医药科学, 2020, 43(6): 42-43.
59. 袁少飞, 高峰丽, 郭海军, 等. 阿司匹林联合低分子肝素对血栓前状态致复发性流产的临床疗效和安全性研究. 中国处方药, 2020, 18(11): 126-128.
60. 朱益静, 符圆圆, 孔彩霞, 等. 黄体酮联合低分子肝素钠治疗复发性流产的疗效分析. 广西医学, 2020, 42(6): 698-702.
61. 颜颖. 阿司匹林肠溶片与低分子肝素治疗习惯性流产的效果与安全性观察. 吉林医学, 2021, 42(3): 661-663.
62. 叶聘. 阿司匹林联合低分子肝素在习惯性流产治疗中的应用效果. 临床医学, 2021, 41(3): 96-98.
63. 李伟娜. 阿司匹林联合低分子肝素治疗高凝状态复发性流产的效果观察. 广州医药, 2021, 52(2): 131-134.
64. 钱晶晶, 陈鸳鸳. 低分子肝素钙治疗子宫动脉阻力指数增高的复发性流产患者的疗效及对妊娠结局的影响. 中国妇幼保健, 2021, 36(6): 1336-1338.
65. 袁少飞, 高峰丽, 郭海军, 等. 阿司匹林和低分子肝素对高龄复发性流产患者抗体清除率和保胎成功率的影响. 中外医疗, 2021, 40(7): 110-112.
66. 徐丽琼. 低分子肝素钠联合地屈孕酮在先兆流产治疗中的临床应用. 健康之友, 2020, (16): 287.
67. 李晓飞. 低分子肝素钙联合地屈孕酮治疗对先兆流产患者妊娠结局的影响. 内科, 2017, 12(5): 674-676.
68. 李清醒. 低分子肝素钠联合地屈孕酮治疗先兆流产效果观察. 深圳中西医结合杂志, 2018, 28(18): 121-122.
69. 王文娣, 朱学喆, 王慧峰. 低分子肝素钠联合地屈孕酮在治疗先兆流产中的应用效果. 医学美学美容, 2019, 28(16): 58.
70. 仰莉苹. 低分子肝素钠联合地屈孕酮治疗先兆流产的疗效和安全性. 饮食保健, 2019, 6(26): 58-59.
71. 胡金菊. 低分子肝素钠联合地屈孕酮对先兆流产患者的影响. 实用中西医结合临床, 2020, 20(3): 35-36.
72. 蒋艳华, 冯洁, 钟建玲. 低分子肝素钠联合低剂量黄体酮治疗先兆流产的临床疗效探究. 中国现代药物应用, 2020, 14(7): 169-171.
73. 涂荧花. 低分子肝素钠辅助地屈孕酮治疗先兆流产的效果观察. 医学理论与实践, 2020, 33(15): 2521-2522.
74. 朱琳. 低分子肝素钠联合间苯三酚治疗先兆流产的临床疗效. 临床合理用药杂志, 2020, 13(36): 116-118.
75. Rey E, Garneau P, David M, et al. Dalteparin for the prevention of recurrence of placental-mediated complications of pregnancy in women without thrombophilia: a pilot randomized controlled trial. J Thromb Haemost, 2009, 7(1): 58-64.
76. 周叶, 邢秀月, 张潍, 等. 低分子肝素对子痫前期孕妇肾损害的保护作用. 西南国防医药, 2017, 27(6): 612-614.
77. 谭西施. 低分子肝素钠在妊娠期高血压患者治疗中的应用观察. 基层医学论坛, 2017, 21(10): 1224-1225.
78. 张玉敏. 低分子肝素钠联合硫酸镁治疗妊娠期高血压综合征患者的效果. 中国民康医学, 2017, 29(2): 25-26.
79. 吴丽琴, 孙玉娟, 苏翠珍, 等. 低分子量肝素钠注射液联合硫酸镁注射液和拉贝洛尔片治疗重度妊娠期高血压综合征的临床研究. 中国临床药理学杂志, 2019, 35(3): 216-219.
80. 刘展, 孙克佳, 秦丹. 低分子肝素联合拉贝洛尔治疗早发型重度子痫前期患者的疗效分析. 中国合理用药探索, 2019, 16(10): 164-166.
81. 傅红. 拉贝洛尔联合依诺肝素治疗妊娠期高血压疾病疗效观察. 医学临床研究, 2019, 36(9): 1677-1679,1683.
82. Llurba E, Bella M, Burgos J, et al. Early prophylactic enoxaparin for the prevention of preeclampsia and intrauterine growth restriction: a randomized trial. Fetal Diagn Ther, 2020, 47(11): 824-833.
83. 宋晓辉, 吴琼琼, 陈丽华. 阿司匹林联合低分子肝素治疗重度子痫前期的效果观察. 中国实用医刊, 2020, 47(3): 112-115.
84. 单丽娟, 兰淑海. 低分子肝素辅助治疗对重度子痫前期患者胎盘缺氧的效果评价. 吉林医学, 2020, 41(12): 2911-2912.
85. 周月云, 张庆娥, 董晶晶, 等. 低分子肝素用于妊娠期高血压疾病治疗效果探究. 心血管外科杂志(电子版), 2020, 9(3): 82.
86. Shirazi M, Naeiji Z, Sharbaf FR, et al. Therapeutic role of enoxaparin in intra-uterine growth restriction: a randomized clinical trial. J Gynecol Obstet Hum Reprod, 2021, 50(8): 102070.
87. 陈亚秋. 低分子肝素在妊娠晚期羊水过少治疗中的用药安全性研究. 医药前沿, 2018, 8(34): 106.
88. Qublan H, Amarin Z, Dabbas M, et al. Low-molecular-weight heparin in the treatment of recurrent IVF-ET failure and thrombophilia: a prospective randomized placebo-controlled trial. Hum Fertil (Camb), 2008, 11(4): 246-253.
89. Andersen AS, Berthelsen JG, Bergholt T. Venous thromboembolism in pregnancy: prophylaxis and treatment with low molecular weight heparin. Acta Obstet Gynecol Scand, 2010, 89(1): 15-21.
90. Roshani S, Cohn DM, Stehouwer AC, et al. Incidence of postpartum haemorrhage in women receiving therapeutic doses of low-molecular-weight heparin: results of a retrospective cohort study. BMJ Open, 2011, 1(2): e000257.
91. Galambosi PJ, Kaaja RJ, Stefanovic V, et al. Safety of low-molecular-weight heparin during pregnancy: a retrospective controlled cohort study. Eur J Obstet Gynecol Reprod Biol, 2012, 163(2): 154-159.
92. Knol HM, Schultinge L, Veeger NJ, et al. The risk of postpartum hemorrhage in women using high dose of low-molecular-weight heparins during pregnancy. Thromb Res, 2012, 130(3): 334-338.
93. Lindqvist PG, Dahlbäck B. Bleeding complications associated with low molecular weight heparin prophylaxis during pregnancy. Thromb Haemost, 2000, 84(1): 140-141.
94. Arbuthnot C, Browne R, Nicole S, et al. A double centre retrospective study into rates of postpartum haemorrhage in women on low molecular weight heparin. Br J Haematol, 2017, 176(1): 141-143.
95. Yuksel H, Kayatas S, Boza AT, et al. Low molecular weight heparin use in unexplained recurrent miscarriage. Pak J Med Sci, 2014, 30(6): 1232-1237.
96. 周淑君. 低分子肝素和阿司匹林对复发性流产患者血浆纤溶酶原激活物抑制剂-1和组织型纤溶酶原活化因子水平的影响. 中国基层医药, 2016, 23(18): 2740-2743.
97. Shlomo M, Gorodischer R, Daniel S, et al. The fetal safety of enoxaparin use during pregnancy: a population-based retrospective cohort study. Drug Saf, 2017, 40(11): 1147-1155.
98. 郭仲杰, 刘春霞, 郭晓霞, 等. 依诺肝素与磺达肝癸钠用于复发性流产患者妊娠期抗凝治疗的对比. 当代医学, 2020, 26(30): 5-8.
99. 李慧, 吴小妹, 周玉华. 低分子肝素钠联合地屈孕酮治疗先兆流产的临床观察. 中国药房, 2017, 28(18): 2499-2502.
100. 谭焕仪. 达肝素钠注射液辅助治疗先兆流产的可行性及安全性. 数理医药学杂志, 2019, 32(11): 1677-1678.
101. Boilot T, Raia-Barjat T, Ollier E, et al. Influence of anticoagulant therapy during pregnancy on the peripartum and anesthesia delivery terms. Gynecol Obstet Fertil, 2015, 43(7-8): 502-508.
102. Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood, 2005, 106(2): 401-407.
103. Kominiarek MA, Angelopoulos SM, Shapiro NL, et al. Low-molecular-weight heparin in pregnancy: peripartum bleeding complications. J Perinatol, 2007, 27(6): 329-334.
104. Jacobson B, Rambiritch V, Paek D, et al. Safety and efficacy of enoxaparin in pregnancy: a systematic review and meta-analysis. Adv Ther, 2020, 37(1): 27-40.
105. Byrd LM, Shiach CR, Hay CR, et al. Osteopenic fractures in pregnancy: is low molecular weight heparin (LMWH) implicated. J Obstet Gynaecol, 2008, 28(5): 539-542.
106. Goëb V, Strotz V, Verdet M, et al. Post-partum sacral fracture associated with heparin treatment. Clin Rheumatol, 2008, 27(Suppl 2): S51-53.
107. Lefkou E, Khamashta M, Hampson G, et al. Review: Low-molecular-weight heparin-induced osteoporosis and osteoporotic fractures: a myth or an existing entity. Lupus, 2010, 19(1): 3-12.
108. Ozdemir D, Tam AA, Dirikoc A, et al. Postpartum osteoporosis and vertebral fractures in two patients treated with enoxaparin during pregnancy. Osteoporos Int, 2015, 26(1): 415-418.
109. Ekim A. Postpartum osteoporosis and thoracic vertebral fracture in a patient treated with heparin during pregnancy. J Clin Anal Med, 2016, 7: 154-157.
110. Ozturk G, Akpinar P, Karamanlioglu AD, et al. Pregnancy-related osteoporotic vertebral compression fractures in two patients treated with low-molecular-weight heparin during pregnancy: case reports. Gynecol Endocrinol, 2018, 34(5): 378-380.
111. Hardcastle SA, Yahya F, Bhalla AK. Pregnancy-associated osteoporosis: a UK case series and literature review. Osteoporos Int, 2019, 30(5): 939-948.
112. Carlin AJ, Farquharson RG, Quenby SM, et al. Prospective observational study of bone mineral density during pregnancy: low molecular weight heparin versus control. Hum Reprod, 2004, 19(5): 1211-1214.

Chinese Journal of Evidence-Based Medicine

Safety of low-molecular-weight heparin in pregnancy: a systematic review

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content