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How Effective are Treatments for Unexplained Recurrent Miscarriage?


  • Recurrent pregnancy loss (RPL) is unexplained in approximately 50% of cases  
    • RPL is estimated to vary between 0.5% and 2.3% in different populations 
    • RPL definitions are not consistent as some define RPL as ≥3 losses before gestational week 22 while some use ≥2 losses  
  • Evidence based treatment is limited but there have been several suggested treatments that includes  
    • Acetylsalicylic acid | Low molecular weight heparin | Progesterone | Intravenous immunoglobulin | Corticosteroids | Leukocyte immune therapy | Pre-implantation genetic screening | tender loving care  
  • Roepke et al. (Acta Obstetricia et Gynecologica Scandinavica, 2018) contrasted treatment efficacies in women with unexplained recurrent pregnancy loss


  • Systematic review and meta-analysis 
  • Literary search included 21 randomized controlled trials (RCTs) with women who had ≥3 miscarriages and treated with one of the following 
    • Acetylsalicylic acid 
    • Low molecular weight heparin 
    • Progesterone 
    • Intravenous immunoglobulin 
    • Leukocyte immune therapy 
  • Outcomes 
    • Live birth; at gestational age ≥ 22 completed weeks 
    • Complications or side effects 
  • Only studies with outcome of live birth and/or complication were included 
  • The study quality was assessed and data was extracted independently by at least two authors 


  • There was no significant difference in live birth rates between acetylsalicylic acid, low molecular weight heparin or placebo 
  • Meta-analysis of low molecular weight heparin vs. control found no significant differences in live birth rate 
    • Risk ratio (RR) 1.47 (95% CI, 0.83-2.61) 
  • Treatment with progesterone starting in the luteal phase seemed effective in increasing live birth rate 
    • RR 1.18 (95% CI 1.09-1.27)  
    • There was no benefit to progesterone when started after conception 
  • Intravenous immunoglobulin showed no effect on live birth rate compared with placebo 
    • RR 1.07 (95% CI 0.91-1.26) 
  • Paternal immunization compared with autologous immunization showed a significant difference in outcome, although the studies were small and at high risk of bias 
    • RR 1.8 (95% CI 1.34-2.41) 


  • While the studies had strengths, the authors acknowledge that  
    • Not including large RCTs that used a ≥2 losses definition rather than 3 could impact results  
    • Overall, studies suffer from low quality and bias   
    • Progesterone administered at ovulation and continued through the luteal phase was the only significant treatment for idiopathic recurrent pregnancy loss 
  • They suggest that treatments for recurrent pregnancy loss should be used within the context of RCTs 

Learn More – Primary Sources: 

Treatment efficacy for idiopathic recurrent pregnancy loss – a systematic review and meta-analyses.