Antithrombotic Treatment for Recurrent Miscarriage: Bayesian Network Meta-Analysis and Systematic Review

Abstract

Combined use of heparin and aspirin is frequently prescribed for treatment of recurrent miscarriage (RM) in patients with antiphospholipid syndrome (APS), or in those without apparent cause of RM other than thrombophilia; however, this strategy is largely based on expert opinion and has not been well studied. The option for the use of different antithrombotic therapies to improve live birth remains unclear. In this network meta-analysis, we incorporated direct and indirect evidence to evaluate effects of different antithrombotic treatments on prevention of pregnancy losses.We searched PubMed and Embase for randomized clinical trials comparing effects of at least 2 antithrombotic treatments on live birth in RM patients published from 1965 through the early of May 2015. Potential risk bias of eligible trials was evaluated according to the Cochrane Collaboration guidelines. Bayesian network meta-analysis was used to estimate relative effects on live birth.A total of 19 trials involving 2391 RM patients with or without thrombophilia and 543 with APS were included. No beneficial effect of antithrombotic treatment was observed either in RM patients with or without thrombophilia or in patients with APS; however, for patients with or without thrombophilia, low molecular weight heparin therapy had the greatest probability (61.48%) of being the best option in terms of live birth; for patients with APS, unfractionated heparin plus aspirin was the superior treatment for RM with the highest possibility (75.15%) of being top 2 places for reducing pregnancy losses. Aspirin was inferior in both groups.Our results do not support the use of combined low molecular weight heparin and aspirin for RM treatment, and suggested aspirin may have negative effects for lowering the risk of pregnancy loss.

FIGURE 1

Flow diagram of the database search and trial selection process.

FIGURE 2

Network among eligible treatments in patients with or without thrombophilia and patients with APS. The node size indicates the sample size in the treatment group that the node stands for; the thickness of the link represents the sample size of the direct comparisons. APS = antiphospholipid syndrome, LMWH = low molecular weight heparin, UFH = unfractionated heparin.

FIGURE 3

Forest plot for OR of live birth based on Bayesian network and traditional pair-wise meta-analyses in patients with or without thrombophilia. The black squares represent the pooled effect estimates, which mean the OR of live birth between the corresponding pair of drugs, whereas the horizontal lines depict the 95% credible intervals in Bayesian network meta-analysis and 95% confidence intervals in traditional pair-wise meta-analysis. LMWH = low molecular weight heparin, OR = odds ratio, UFH = unfractionated heparin.

FIGURE 4

Rank and cumulative probabilities of different antithrombotic treatments in patients with or without thrombophilia based on the protective effects on live birth. The horizontal axis represents the positions that the corresponding drug may rank at based on the protective effects on the outcome of live birth, whereas the vertical axis means the probabilities or the cumulative probabilities of the drug being ranked at the corresponding positions on the horizontal axis. For example, as the figure shows, the probabilities of aspirin being at first, second, third, and the last place for the protective effects on live birth are 0.5%, 2.4%, 15.07%, 82.03%, respectively, and the cumulative probabilities are 0.5%, 2.9%, 17.97%, 100%, respectively. LMWH = low molecular weight heparin.

FIGURE 5

Forest plot for OR of live birth based on Bayesian network and traditional pair-wise meta-analyses in patients with APS. The black squares represent the pooled effect estimates, which mean the OR of live birth between the corresponding pair of drugs, whereas the horizontal lines depict the 95% credible intervals in Bayesian network meta-analysis and 95% confidence intervals in traditional pair-wise meta-analysis. APS = antiphospholipid syndrome, LMWH = low molecular weight heparin, OR = odds ratio, UFH = unfractionated heparin.

FIGURE 6

Rank and cumulative probabilities of different antithrombotic treatments in patients with antiphospholipid syndrome based on the protective effects on live birth. The horizontal axis represents the positions that the corresponding drug may rank at based on the protective effects on the outcome of live birth, whereas the vertical axis means the probabilities or the cumulative probabilities of the drug being ranked at the corresponding positions on the horizontal axis. LMWH = low molecular weight heparin, UFH = unfractionated heparin.