Efficacy of misoprostol for the treatment of postpartum hemorrhage: current knowledge and implications for health care planning

Figures & data

Table 1 Randomized controlled studies of misoprostol for the treatment of PPH

References	Study design/participants	Variable(s) of interest	Results
Lokugamage et al^Citation29	Single-blinded RCT to compare oxytocin and ergometrine combination to misoprostol N=64 with primary PPH due to atonic uterus with N=32 women in each arm	5 IU oxytocin and 500 µg ergometrine IM + 10 IU oxytocin diluted in 500 mL normal saline IV infusion compared to 800 µg rectal misoprostol	800 µg rectal misoprostol is effective in treating primary PPH Bleeding stopped within 20 minutes in 30 patients in the misoprostol group compared to 21 patients in the oxytocin + ergometrine group, with a 28.1% difference between the two groups (P=0.01) No significant difference in the clinical assessment of uterus contraction at 30 minutes or 60 minutes; misoprostol arm performed better at 120 minutes (P=0.05)
Hofmeyr et al^Citation30	Double-blind RCT to determine side effects and effectiveness of high-dose misoprostol for the treatment of PPH N=255 with N=117 in the misoprostol arm and N=121 in the placebo arm; both groups received active management of the third stage of labor; six women were excluded from analysis due to unknown randomization	1,000 µg misoprostol (oral, 200 µg; sublingual, 400 µg; and rectal, 400 µg) compared to placebo	Study was underpowered due to lower than expected incidence of primary outcome (>500 mL of blood loss) in the placebo group Blood loss ≥500 mL in 1 hour was 6/117 in the misoprostol group vs 11/120 in the placebo group (RR: 0.56; 95% CI: 0.21–1.46) Other proxy estimations of blood loss showed no significant differences between arms, including mean blood loss and Hb level on day 1 after birth <6 g/dL or blood transfusion Side effects significantly more frequent in the misoprostol group Five cases of serious morbidity in the misoprostol group, including three deaths
Walraven et al^Citation31	RCT to assess whether misoprostol is safe and confers additional benefits to routine treatment and after routine active management with uterotonics N=160 women with blood loss >500 mL after vaginal delivery with N=79 in the misoprostol arm and N=81 in the placebo arm	600 µg misoprostol (oral, 200 µg and sublingual, 400 µg) compared to placebo	Measured average additional blood loss after medication was 325 mL (95% CI: 265–384 mL) after misoprostol and 410 mL (95% CI: 323–498 mL) after placebo Shivering and mild temperature were common in the misoprostol arm Indicators including additional blood loss ≥500 mL (16.5% vs 28.4%) and ≥1,000 mL (2.5% vs 6.2%) and use of additional uterotonics (3.8% vs 6.2%) were always lower in the misoprostol arm
Zuberi et al^Citation32	Double-blind RCT to determine whether misoprostol provides additional benefits to a standard oxytocin regimen for the treatment of PPH N=71 women diagnosed with PPH after active management of the third stage of labor; N=39 in the placebo arm and N=32 in the misoprostol arm	600 µg of sublingual misoprostol Standard PPH treatment with IV oxytocin was given to all women in need	Study did reach the intended sample size due to much lower than expected PPH rate (<2%) Women in the misoprostol group had significantly lower blood loss; blood loss ≥500 mL (RR: 0.59; 95% CI: 10.12–2.99) Both postpartum drop in Hb and the use of additional interventions after treatment were lower in the misoprostol arm, but were not statistically significant Shivering and fever were commonly reported in the misoprostol arm
Blum et al^Citation33	Double-blind non-inferiority RCT in five countries to determine whether sublingual misoprostol is non-inferior to oxytocin in women who have received prophylactic oxytocin, with 6% margin of inferiority established as acceptable for clinical equivalence N=809 women with PPH with N=407 in the misoprostol arm and N=402 in the oxytocin arm	800 µg sublingual misoprostol compared to 40 IU IV oxytocin in women who have received after prophylactic oxytocin	Misoprostol is clinically equivalent to oxytocin when used to stop PPH in women who received prophylactic oxytocin during third stage of labor In the misoprostol arm, 89% of active bleeding controlled within 20 minutes vs oxytocin, 90% (RR: 0.99; 95% CI: 0.95, 1.04); additional blood loss of 300 mL or more after treatment (RR: 1.12; 95% CI: 0.92, 1.37) and additional uterotonics (RR: 0.86; 95% CI: 0.58, 1.28) Women in the misoprostol group were more likely to undergo intrauterine exploration under anesthesia; 9% vs 5% in the oxytocin arm (RR: 1.66; 95% CI: 1.00, 2.76)
Winikoff et al^Citation34	Double-blind non-inferiority RCT to determine whether sublingual misoprostol is non-inferior to oxytocin for women not exposed to prophylactic oxytocin N=978 women with PPH with N=488 in the misoprostol arm and N=490 in the oxytocin arm	800 µg sublingual misoprostol compared to 40 IU IV oxytocin in women	Misoprostol might be an appropriate first-line treatment for PPH in settings where oxytocin is not practical 90% of active bleeding controlled within 20 minutes in the misoprostol arm vs 96% in the oxytocin arm (RR: 0.94; 95% CI: 0.91, 0.98) 30% of women bled >300 mL in the misoprostol group vs 17% in the oxytocin group (RR: 1.78; 95% CI: 1.40, 2.26) Twice as many women were given additional uterotonics in the misoprostol group (RR: 1.98; 95% CI: 1.31, 2.99)
Widmer et al^Citation35	Double-blind RCT in five countries N=1422 women with PPH with N=705 in misoprostol arm and N=717 in placebo arm; both arms received standard uterotonics in addition to intervention	600 µg sublingual misoprostol compared to matching sublingual placebo Both arms received standard uterotonics in addition to intervention	Findings do not support the use of misoprostol in addition to standard uterotonics for the treatment of PPH Blood loss of >500 mL within 60 minutes after randomization was 14% in both arms (RR: 1.02; 95% CI: 0.79, 1.32) No significant differences were found between arms in blood loss of >100 mL within 60 minutes or 90 minutes and median blood loss; Hb concentration of <80 g/L within 24 hours

Abbreviations: Hb, hemoglobin; IM, intramuscular; IV, intravenous; PPH, postpartum hemorrhage; RCT, randomized controlled trial; RR, relative risk; CI, confidence interval.

Table 2 Non-randomized studies on the treatment of PPH with misoprostol

References	Study design/participants	Variable(s) of interest	Results
Prata et al^Citation36	Field intervention trial with control group to determine whether traditional birth attendants can diagnose and treat PPH N=849 women enrolled, with N=454 in the intervention arm and N=395 in the nonintervention arm	1,000 µg of misoprostol rectally to all women delivering vaginally with blood loss of 500 mL or more Referral to health facility in control sites	Eight women (2%) in the intervention area and 76 (19%) in the nonintervention area were referred to health facilities after delivery (OR: 0.1; 95% CI: 0.0–0.2) Of those referred, 1% from the intervention area and 95% from nonintervention area needed additional interventions due to PPH
Baruah and Cohn^Citation37	Retrospective cohort study with the control arm to assess the efficacy of rectal misoprostol as second-line therapy in the management of primary postpartum hemorrhage compared to methylergonovine N=40 in the study arm and N=18 in the control arm	800–1,000 µg of misoprostol rectally following initial oxytocin therapy compared to 0.2 mg methylergonovine maleate intramuscularly following oxytocin therapy	No significant difference between the two arms in the need for blood transfusion (methylergonovine maleate group, 0%, misoprostol group, 12.5%; P=0.11), the need for third-line medical therapy (methylergonovine maleate group, 55.5%, misoprostol group, 55%; P=0.961) or the need for any surgical intervention (methylergonovine maleate, 22.2%, misoprostol 12.5%; P=0.51)
Okonofua et al^Citation38	Cohort study design to investigate the efficacy of misoprostol sublingually to treat PPH in women experiencing PPH from uterine atony in three Nigerian hospitals N=131 women with PPH due to atonic uterus	800 µg of misoprostol immediately after the loss of 500 mL or more blood	15.3% of women required additional treatment with IV oxytocin and ergometrine after the initial administration of sublingual misoprostol 32.8% of women required blood transfusion, while all required IV infusion of saline and plasma expanders No maternal deaths, but five neonatal deaths and two stillbirths Results suggest that misoprostol is safe to be used in all levels of care for the primary treatment of PPH; there is a need for caution in recommending the use of misoprostol as first-line drug for the treatment of PPH in lower levels of care, since many women needed blood/blood products, the possibility of concomitant medical complications that providers need to address with women presenting with PPH, and need for follow-up care after severe PPH episode

Abbreviations: IV, intravenous; PPH, postpartum hemorrhage; CI, confidence interval.

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