Comment: The quality of evidence is downgraded by inconsistency (unexplained variability in results.
A meta-analysis included 5 RCT analyzing the effect of heparin (unfractionated heparin or low molecular weight heparin LMWH) plus aspirin compared with aspirin alone on the live-birth rate in women with a history of at least two miscarriages and antiphospholipid antibodies. The pooled effect of unfractionated heparin and low molecular weight heparin was evaluable in three and two randomized controlled studies, respectively, with regard to live births, which was the major outcome. Overall, treatment effects were in favor of heparin against first-trimester losses (OR 0.39, 95% CI 0.24 to 0.65, number needed to treat (NNT) 6). More specifically, unfractionated heparin displayed a significant effect (OR 0.26, 95% CI 0.14-0.48; 3 trials, NNT 4), while the pooled effect of LMWH was insignificant (OR 0.70, 95% CI 0.34 to 1.45; 2 trials). Combination therapy of either unfractionated heparin or LMWH with aspirin failed to display any significant effect in the prevention of late-pregnancy losses.
A prospective, multicenter RCT compared low-molecular-weight (LMW) heparin plus low-dose aspirin with intravenous immunoglobulin (IVIG) in the treatment of antiphospholipid antibody syndrome in women with recurrent spontaneous abortions before 10 weeks of gestation (85 patients aged 18-39 years). The women treated with LMW heparin plus low-dose aspirin had a higher rate of live births (29/40, 72.5%) than those treated with IVIG (15/38, 39.5%); OR 1.80; 95% CI 1.14 to 2.84; P=0.007).
A Cochrane review included 13 studies with a total of 849 subjects. The quality was not high; 50% had clear evidence of allocation concealment. Participant characteristics varied between trials. Unfractionated heparin combined with aspirin (two trials; n = 140) significantly reduced pregnancy loss compared to aspirin alone (relative risk (RR) 0.46, 95% confidence interval (CI) 0.29 to 0.71). Low molecular weight heparin (LMWH) combined with aspirin compared to aspirin (one trial; n = 98) did not significantly reduce pregnancy loss (RR 0.78, 95% CI 0.39 to 1.57). There was no advantage in high-dose, over low-dose, unfractionated heparin (one trial; n = 50). Three trials of aspirin alone (n = 135) showed no significant reduction in pregnancy loss (RR 1.05, 95% CI 0.66 to 1.68). Prednisone and aspirin (three trials; n = 286) resulted in a significant increase in prematurity when compared to placebo, aspirin, and heparin combined with aspirin, and an increase in gestational diabetes, but no significant benefit. Intravenous immunoglobulin +/- unfractionated heparin and aspirin (two trials; n = 58) was associated with an increased risk of pregnancy loss or premature birth when compared to unfractionated heparin or LMWH combined with aspirin (RR 2.51, 95% CI 1.27 to 4.95). When compared to prednisone and aspirin, intravenous immunoglobulin (one trial; n = 82) was not significantly different in outcomes.