The Evidence for Use of Misoprostol in the Prevention and Treatment of Postpartum Hemorrhage

Rasha Dabash, MPH Gynuity Health Projects

MCHIP Meeting Dhaka, May 4, 2012

Why Misoprostol for PPH?

Conventional uterotonics (e.g. oxytocin) are the international standard of care for PPH but largely unavailable or not feasible in many settings.
Misoprostol may be easier to use, more widely available, lower in cost. Growing body of evidence to support efficacy and safety for prevention and treatment of PPH.

5 Scenarios for Use of Misoprostol in PPH Management

1. Prophylactic use for PPH prevention 2. First line treatment after prophylactic uterotonic 3. First line treatment after no prophylaxis 4. Adjunct treatment 5. Hybrid strategies: Secondary Prevention/Early liberal treatment (new idea)

Misoprostol for PPH prevention: Community-based RCTs

Study
Hoj et al 2005 Walraven et al 2005 Derman et al 2006

Context
Guinea-Bissau Midwives Rural health facility The Gambia TBAs homebirths India Midwives/ANMs PHCs/homebirths Pakistan TBAs homebirths

Methodology
RCT (n=661) 600g miso SL vs. placebo RCT (n=1229) 600g miso oral vs. oral ergo RCT (n=1620) 600g miso oral vs. placebo RCT (n=1116) 600g miso oral vs. placebo

Main Outcomes
severe PPH w/ miso

women experienced drop in Hb w/ miso

Acute PPH w/ miso Severe PPH w/ miso use of interventions w/ miso Acute PPH w/ miso women experienced drop in Hb w/ miso

Mobeen et al 2010

Increased incidence of shivering/fever in misoprostol arms in all studies

Scenarios 2 & 3: Misoprostol for PPH Treatment: Overview of Two Gynuity Non-Inferiority Trials
Purpose: To determine if 800 mcg sublingual misoprostol is similarly efficacious to 40 IU oxytocin delivered IV for the treatment of primary postpartum hemorrhage (PPH)

Double-blinded, placebo-controlled, randomized clinical trials in 5 countries (two settings): where women given oxytocin in third stage of labor where women not given oxytocin in third stage of labor
Sources: Blum J, Winikoff B, Raghavan S, et al. Treatment of post-partum haemorrhage with sublingual misoprostol versus oxytocin in women receiving prophylactic oxytocin: a double-blind, randomised, non-inferiority trial. Lancet Jan 2010; Winikoff B, Dabash R, Durocher J, et al. Treatment of post-partum haemorrhage with sublingual misoprostol versus oxytocin in women not exposed to oxytocin during labour: a double-blind, randomised, non-inferiority trial. Lancet Jan 2010;

Efficacy of 800 mcg sublingual misoprostol vs. 40 IU IV oxytocin in PPH treatment

# SCREENED

41,233
NO OXYTOCIN PROPHYLAXIS OXYTOCIN PROPHYLAXIS

31,039
ENROLLED

10,052
ENROLLED

809
MISO OXY MISO

977
OXY

407
BLEEDING CONTROLLED

402
BLEEDING CONTROLLED

488
BLEEDING CONTROLLED

490
BLEEDING CONTROLLED

363 (90.2%) 360 (95.5%)

440 (89.2%) 468 (89.6%)

Side Effects
With oxytocin prophylaxis: all minimal, no differences between 2 treatments with exception of fever & shivering With no oxytocin prophylaxis: all minimal, vomiting significantly more common with misoprostol, fever & shivering also more common with misoprostol
MISO

OXY

Oxytocin Prophylaxis

No Prophylaxis

SCENARIO 4: MISOPROSTOL AS ADJUNCT TREATMENT

Purpose: Determine if misoprostol is an effective adjunct treatment for primary PPH (due to uterine atony)

Four studies: Hofemyer, Zuberi, Walraven, Widmer

Summary of results:
Data show no benefit of simultaneous administration of

IV oxytocin + 600 mcg sublingual misoprostol over IV oxytocin alone for treatment of PPH
Significantly more fever in misoprostol arm

Implication of results: No reason to combine the two drugs as there is no added benefit, but more side effects

IMPLICATIONS
PROPHYLACTIC OXYTOCIN GIVEN Immediate Treatment of PPH IV OXYTOCIN FEASIBLE IV OXYTOCIN NOT FEASIBLE Either Drug Misoprostol Oxytocin Preferred Misoprostol NO PROPHYLACTIC OXYTOCIN GIVEN

Adjunct PPH Treatment No beneficial effect of Misoprostol

Last resort ??

All Drugs++

All Drugs++

Unanswered questions:
What is the impact of these strategies? Do they save lives? Program effectiveness of: misoprostol vs. oxytocin in Uniject outside of tertiary hospitals? misoprostol for PPH treatment at lower level facilities/ lower level providers? misoprostol when used for both prevention and treatment?

Is universal provision of misoprostol for PPH prevention cost-effective?

Universal Prevention vs. Treatment

Intervention 1: Treatment As Needed 1000 Deliveries Intervention 2: Universal Prophylaxis 1000 Deliveries Yes: 600 g oral Miso (3000 pills)

Prophylaxis Y/N? PPH Rate

No prophylaxis

12% PPH 120 PPH Cases

800 g SL Miso (480 pills)

6% PPH 60 PPH Cases

Bleeding controlled within 20 mins on site?

108

Additional interventions/ referral needed

12

60

Scenario 5: Hybrid Approach: Secondary Prevention/Liberal Treatment

9 out of 10 women who get prophylaxis dont need it Continuum of PP bleeding and provider practices Hybrid model: 800 mcg sublingual misoprostol administered before PPH (blood loss 350 mls)-or approx 25% of women (so over treating by 2X) Advantage: medicates fewer women, reduces side effects, and potentially reduces cost? Community studies underway/planned in India and Egypt comparing universal prophylaxis to secondary prevention

Thank You.