BACKGROUND AND PURPOSE: 

• WHO (2012) recommends all women giving birth should be offered uterotonics during the third stage of labor to prevent PPH 
  • Oxytocin 10 IU (intramuscular/intravenous) is drug of choice 
  • Alternatives include other injectable uterotonics and misoprostol where oxytocin is unavailable 
• Gallos et al. (Cochrane Database Syst Rev, 2018) compared the efficacy and side-effect profile of treatments for PPH 

METHODS: 

• Systematic review and meta-analysis 
• Database search consisted of RCT comparisons or cluster trials of effectiveness or side-effects of uterotonic drugs for preventing PPH 
• At least three review authors independently assess studies to avoid bias 
• Interventions assessed 
  • Oxytocin 
  • Ergometrine 
  • Misoprostol  
  • Carbetocin 
  • Combination of drugs (dosing varied)
    • Combination ‘usually’ 500 mcg of ergometrine plus 5 IU oxytocin 
    • Misoprostol and oxytocin regimens varied more widely
• Primary outcome 
  • Identify and rank most effective uterotonic medications to prevent PPH ≥ 500 ml and PPH ≥ 1000 mL 
• Data was stratified based on the following  
  • Mode of birth | Prior risk of PPH | Healthcare setting | Dosage | Regimen | Route of drug administration 

RESULTS:  

• 140 RCTs were included, totaling 88,947 subjects 
• When oxytocin alone is compared to placebo
  • PPH ≥ 500 mL: relative risk (RR) 0.56 (95% CI, 0.46 to 0.68)
  • PPH ≥ 1,000 mL: RR 0.60 (95% CI, 0.51 to 0.72)
• The three most effective drugs for prevention of PPH ≥ 500 mL compared to oxytocin alone were 
  • Ergometrine plus oxytocin: RR 0.69 (95% CI, 0.57 to 0.83; moderate-quality evidence) 
  • Carbetocin:  RR 0.72 (95% CI, 0.52 to 1.00; very low-quality evidence) 
  • Misoprostol plus oxytocin: RR 0.73 (95% CI, 0.60 to 0.90; moderate-quality evidence) 
• The authors calculate that while 10.5% of women receiving oxytocin would experience PPH ≥ 500mL, the following would occur using these 3 regimens  
  • Ergometrine plus oxytocin: 7.2% 
  • Carbetocin: 7.6%  
  • Misoprostol plus oxytocin: 7.7%  
• The results for PPH ≥1000mL were similar to PPH ≥ 500mL results when compared to oxytocin alone, with ergometrine plus oxytocin being consistently significant (carbetocin and misoprostol plus oxytocin trending)   
  • Ergometrine plus oxytocin combination: RR 0.77 (95% CI, 0.61 to 0.95; high-quality evidence)  
  • Carbetocin: RR 0.70 (95% CI, 0.38 to 1.28; low-quality evidence)  
  • Misoprostol plus oxytocin combination: RR 0.90 (95% CI 0.72 to 1.14; moderate-quality evidence) 
• There were no significant differences between all drugs for maternal deaths or severe morbidity  
• Poorest side-effect rankings when compared to oxytocin alone  
  • Ergometrine plus oxytocin combination 
    • Vomiting: 1.9% versus 0.6% 
    • Hypertension: 1.2% versus 0.7% 
  • Misoprostol plus oxytocin combination 
    • Fever: 11.4% versus 3.6%  
• The authors looked at additional outcomes and found that all agents except ergometrine were effective for preventing blood transfusion when compared with placebo or no treatment
  • Misoprostol plus oxytocin was the only intervention more effective when compared with oxytocin alone
  • The misoprostol plus oxytocin combination likewise was the only intervention that was more effective compared to oxytocin when assessing change in hemoglobin

CONCLUSION: 

• Two combination treatments (oxytocin with either ergometrine or misoprostol) had greater efficacy than oxytocin alone, but introduced more side effects 
• Carbetocin was also more efficient than oxytocin alone and did not lead to more side effects; however, the evidence is poor for many studies including carbetocin and conclusions need to be verified 
• Oxytocin, the WHO recommended treatment, while associated with decreased risk of PPH, may not be the most efficient treatment

Learn More – Primary Sources: 

Uterotonic agents for preventing postpartum haemorrhage: a network meta-analysis. 

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