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Table 5 Systematic reviews/meta-analyses and intervention studies of the impact of heparin and other anti-coagulants in pregnancy on stillbirth and perinatal mortality

From: Reducing stillbirths: prevention and management of medical disorders and infections during pregnancy

Source Location and Type of Trial Intervention Stillbirths/Perinatal Outcomes
Reviews and meta-analyses
Anti-phospholipid antibodies    
Empson et al. 2005 [51] UK, USA, Italy, New Zealand, Finland. Meta-analysis (Cochrane). Aspirin: 13 RCTs (N = 849 women) included. Heparin: 8 RCTs included (Women with prior miscarriage and anti-phospholipid antibody-positive). N = 98 in trial of LMWH; N = 140 in trial of unfractionated heparin. To assess the impact on pregnancy loss of: 1. LMWH plus aspirin (intervention) vs. aspirin alone (controls). 2. Unfractionated heparin plus aspirin (intervention) vs. aspirin (controls). 3. Aspirin (intervention) vs. placebo or standard care (control) 1. Pregnancy loss: RR = 0.78 (95% CI: 0.39–1.57) [NS] [11/51 vs. 13/47 in intervention vs. control groups, respectively]. 2. Pregnancy loss: RR = 0.46 (95% CI: 0.29–0.71). [18/70 vs. 40/70 in intervention vs. control groups, respectively]. 3. Fetal loss (miscarriage+SB): RR = 1.05 (95% CI: 0.66–1.68) [NS] in intervention vs. control groups, respectively.
Di Nisio et al. 2005 [60] Finland, France. Meta-analysis (Cochrane). 1 quasi-RCT included (N = 20 women). 2 RCTs and quasi-RCTs (N = 74 women) included. To evaluate the efficacy and safety of anti-coagulant agents, such as aspirin compared to placebo and enoxaparin vs. aspirin, in women with a history of ≥ 2 spontaneous miscarriages or one later intrauterine fetal death without apparent causes other than inherited thrombophilias. 1. Assessed the impact of aspirin vs. no treatment on live birth rate. 2. Assessed the effects on live birth rate of subcutaneous enoxaparin (40 mg/daily) vs. aspirin (100 mg/daily) from the 8th week of amenorrhoea after positive pregnancy test. 1. Live-birth rate: RR = 1.00 (95% CI: 0.78–1.29) [NS] in intervention (aspirin) vs. control groups (placebo), respectively. 2. Live-birth rate: RR = 10.00 (95% CI: 1.56–64.20). [10/10 vs. 1/10 in enoxaparin vs. aspirin groups, respectively].
Gates et al. 2002 [62] UK, Finland. Meta-analysis (Cochrane). 3 RCTs included (N = 40 women). To assess the effects of unfractionated heparin (intervention) vs. no treatment (controls) on the incidence of venous thromboembolic disease. Fetal death (miscarriage + SB): RR = 1.00 (95% CI: 0.07–14.90) [NS] [1/20 vs. 1/20 in both groups].
Intervention studies
Anti-phospholipid antibodies    
Bar et al. 2000 [54] Israel. High Risk Pregnancy Clinic, tertiary hospital. Case series. Pregnant women (N = 46) with a history of recurrent abortions, intrauterine fetal death or IUGR and severe early-onset pre-eclampsia. Compared the impact of LMWH (enoxaparin sodium, 40 mg daily) in combination with low-dose aspirin (100 mg daily) in the first trimester (intervention group 1, n = 14) vs. the second trimester (intervention group 2, n = 17) vs. low-dose aspirin alone (controls). Abortions: 14% vs. 0% vs. 0% in intervention group 1, intervention group 2, and controls, respectively [NS]
Glasnovic et al. 2007 [55] Croatia. Case series with non-pregnant controls. Pregnant women (N = 62) with suspected anti-phospholipid syndrome (N = 36) vs. non-pregnant women (N = 26) with secondary anti-phospholipid syndrome and previous bad reproductive anamnesis. Studied the impact of treatment with LMWH plus low-dose aspirin during pregnancy. Fetal deaths: 0 in all groups.
Goel et al. 2006 [52] India (New Delhi). RCT. Pregnant women (N = 550) with poor obstetric history and raised anti-cardiolipin antibodies IgG. Compared the impact of a combination of low-dose aspirin (80 mg/day) and 5000 IU of unfractionated heparin subcutaneously every 12 hrs under hospital surveillance (intervention) vs. low-dose aspirin (80 mg/day; controls) on pregnancy outcomes. Live birth rate: 28/33 (84.8%) vs. 24/39 (61.5%) in intervention vs. control groups, respectively (P < 0.05).
Malinowski et al. 2003 [56] Poland (Lodz). RCT. Pregnant women (N = 148) suffering from recurrent abortion with presence of lupus anti-coagulant antibodies and/or high moderate concentration of anti-cardiolipin antibodies. Compared the impact of low-dose aspirin + LMWH simultaneously (Group 1) vs. LMWH 20 g daily (Group 2) vs. low-dose aspirin 75 mg daily (Group 3). Live birth (%): 92.5% vs. 81.1% vs. 89.3% in Groups 1, 2 and 3, respectively.
Noble et al. 2005 [57] USA. Academically based reproductive health centers. Prospective, controlled pilot study. Pregnant women (N = 50) with ≥ 3 pregnancy losses and positive anti-phospholipid antibody. Compared the impact of LMWH plus low-dose aspirin (Group 1) vs. unfractionated heparin plus low-dose aspirin (Group 2). Miscarriage: 4/25 (16%) vs. 5/25 (20%) in Group 1 and Group 2, respectively. P = 1.00) [NS] Live births: 21/25 (84%) vs. 20/25 (80%) in Group 1 and Group 2, respectively. (P = 1.00) [NS]
Stephenson et al. 2004 [53] Vancouver. Tertiary referral centre. RCT. Pregnant women (N = 28) with anti-phospholipid syndrome. Compared the impact of LMWH (dalteparin; intervention) vs. unfractionated heparin (control) preconceptionally or early in pregnancy on live birth rate. All women also received low-dose aspirin, initiated preconceptionally. Live birth rate: 9/13 (69%) vs. 4/13 (31%) in intervention vs. control groups, respectively.
Brenner, LIVE-ENOX Investigators 2005. [195] Israel. Multicentre. RCT. Pregnant women (N = 180) with thrombophilia and a history of recurrent pregnancy loss. Compared the impact of enoxaparin 80 mg/day (40 mg 2× daily; intervention) vs. enoxaparin 40 mg/day (40 mg 1× daily; controls). Live birth rate: 65/83 (78.3%) vs. 70/83 (84.3%) vs. in the intervention vs. comparison groups, respectively.
Dendrinos et al. 2007 [65] Greece (Athens). RCT. Women (N = 62) with a history of recurrent pregnancy loss and at least one factor of thrombophilic disorder. Compared the impact of 50 IU/kg of tinzaparin sodium daily (intervention) vs. 100 mg of aspirin daily (controls). New abortions: 6/31 vs. 11/31 in intervention vs. control groups, respectively; (P = 0.04).
Sarig et al. 2005 [196] Israel. Non-matched case-control study. Pregnant women (N = 87; N = 47 intervention, N = 40 controls with normal pregnancies) with thrombophilia and recurrent pregnancy loss. Compared the impact of LMWH (enoxaparin) 40 mg daily (intervention group 1) vs. 40 mg 2× daily (intervention group 2) vs. no treatment (controls). Live birth: 38/48 (79%) vs. 32/39 (82%) in groups 1 and 2, respectively [NS]
Unexplained prior losses    
Dolitzky et al. 2006 [70] Israel. University hospitals, general hospital, and community health clinic. Multi-centre randomised comparative cohort. Pregnant women (N = 107) with ≥ 3 consecutive 1st trimester miscarriages or ≥ 2 consecutive 2nd trimester miscarriages Compared the impact of LMWH enoxaparin (intervention) vs. aspirin (controls) on the live birth rate. Live birth rate: RR = 0.92 (95% CI: 0.58–1.46) [NS] [44/54 (81.5%) vs. 42/50 (84%) in intervention vs. control groups, respectively]. Live birth rate in primary aborters: [17/18 (94%) vs. 18/22 (81%) in intervention vs. control groups, respectively].
Cardiac indications    
Lee et al. 2007 [68] Korea (Daegu). Retrospective study. Pregnant women (N = 25) with mechanical heart valve replacement between 1997 and 2005. Compared the impact of LMWH nadroparin (7,500 U 2× daily) 6–12 wks of gestation and close-to-term only, and coumarin derivatives were used with aspirin at other times (exposed) vs. coumarin derivatives throughout pregnancy (unexposed). Fetal death (miscarriage + SB): 2/23 (8.7%) vs. 4/8 (50%) in the exposed and unexposed groups, respectively (P = 0.011).