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Table 6 Observational studies on 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
Observational studies
Antiphospholipid antibodies
Carp et al. 2003 [58] Israel. Cohort study. Pregnant women (N = 85) with ≥ 3 consecutive pregnancy losses and a hereditary thrombophilia who conceived (N = 85 delivered; N = 38 miscarried). Compared the impact of enoxaparin 40 mg (intervention) vs. no treatment (controls) on pregnancy outcomes. Live births: OR = 3.03 (95% CI: 1.12–8.36); P < 0.02. [26/37 (70.2%) vs. 21/48 (43.8%) in intervention vs. control groups, respectively]. (Among primary aborters) Live birth rate: OR = 9.75 (95% CI: 1.59–52.48; P < 0.008). (Among primary aborters ≥ 5 miscarriages) Live birth rate: 61.6% vs. 18.2% in intervention vs. control groups, respectively [NS].
Franklin and Kutteh 2002 [197] USA. 2 centres. Prospective cohort study. Pregnant women (N = 79) with ≥ 2 consecutive pregnancy losses and anti-phospholipid antibodies (2 intervention groups: group 1 had recurrent pregnancy loss + anti-phospolipid antibodies; group 2 had other positive anti-phospholipid antibodies). Compared the impact of heparin and aspirin (intervention) vs. aspirin alone (group 3; controls). Intervention group 1 was treated with heparin and aspirin; intervention group 2 was treated with heparin or aspirin; group 3 received aspirin alone. Viable infants: 19/25 (76%) vs. 18/28 (64%) vs. 12/26 (46%) in groups 1, 2 and 3, respectively (P = 0.03 for group 1 vs. group 3).
Ruffatti et al. 1997 [59] Italy (Padova). Prospective cohort study. Pregnant women (N = 53) with ≥ 2 consecutive miscarriages during first trimester and/or 1 fetal death during last two trimesters. Compared the pregnancy success rate with calcium heparin alone, self-administered subcutaneously 3× daily at dosages 15,000–37,500 IU vs. rate prior to therapy. Live birth: 100% vs. 24.52% in the calcium heparin vs. prior to therapy (P < 0.0001). Malformations: 0/53 30/37 examined placentas (81.08%) showed signs of thrombotic events.
Thrombophilias
Deligiannidis et al. 2007 [66] Greece. Cohort study. Pregnant women (N = 52) with thrombophilia. Compared the impact of LMWH plus low-dose aspirin (intervention) vs. no treatment (controls). Fetal death (miscarriage+SB): OR = 0.10 (95% CI: 0.002–0.98). [1/29 vs. 17/23 in intervention vs. control groups, respectively].
Folkeringa et al. 2007 [63] Netherlands. Prospective, family cohort study. Pregnant women (N = 376) with (N = 37) and without (N = 18) hereditary deficiencies of antithrombin protein C or protein S. Compared the impact of thromboprophylaxis with unfractionated or LMWH < 16 wks and > 36 wks of gestation, and a vitamin K antagonist from 16–36 wks and after delivery (intervention #1) vs. no treatment (controls). Additionally compared same treatment in women deficient for antithrombin protein C or protein S (intervention #2) vs. no treatment in non-deficient women (controls). Fetal death (miscarriage + SB): adj. RR = 0.07 (95% CI: 0.001–0.7, P = 0.02) in intervention #1 group vs. controls, respectively. Fetal death (miscarriage+SB): 0% in deficient women with thromboprophylaxis versus 45% in deficient women without (P = 0.001) and 7% in non-deficient women without thromboprophylaxis (P = 0.37).
Cardiac indications
Kawamata et al. 2007 [69] Japan. Retrospective study. Women (N = 12; N = 16 pregnancies) with mechanical heart valve replacement. Assessed the impact of changing warfarin treatment to heparin at 6–13 wks of gestational age; administration continuously adjusted according to the activated partial thromboplastin time level up to the time of delivery. Fetal death (miscarriage + SB): 1/16 (at 30 wks).
Kim et al. 2007 [67] South Korea (Seoul). Retrospective study. Women (N = 27; N = 41 pregnancies) with a mechanical valve replacement. Compared the impact among three groups: group 1 (N = 5) took warfarin throughout the pregnancy, group 2 (N = 18) took heparin throughout the pregnancy, and group 3 (N = 18) took heparin in the 1st trimester and warfarin from 12–20 wks gestation. SBR: 2/5 (40%) vs. 1/18 (5.6%) vs. 8/18 (44.4%) in groups 1, 2, and 3, respectively.
Safety    
Sorensen et al. 2000 [71] Denmark. Population-based. Retrospective cohort study using national databases. Pregnant women receiving LMWH (N = 66) or no drugs (N = 17,259) between 1991–98. Compared the impact of LMWH (exposed) vs. no prescriptive drugs (unexposed). SBR: 0/66 (0%) vs. 204/17,259 (1.2%) in the exposed vs. unexposed groups, respectively. Pre-term: OR = 2.11 (95% CI: 0.96–4.65) [NS] LBW and malformations: no increased risk.