Misoprostol for PPH: An Update on Gynuity’s collaborative body of research An Update: March 2008

Misoprostol for PPH Prevention in Collaboration with Aga Khan Network Study design: Double-blind, placebo-controlled, randomized, community-based study Study area: 78 villages, 83 TBAs in Chitral, NWFP, Pakistan Study arms: a) 600 µg oral misoprostol (n = 800) or b) placebo resembling misoprostol (n = 800) Collaborators: Aga Khan University, Aga Khan Health Services/Pakistan, Aga Khan Foundation

Outcome Measures Research Questions Is there a clinically meaningful difference in postpartum hemorrhage or mean blood loss? Will the intervention reduce anemia? Are the side effects tolerable for women? PPH (blood loss ≥ 500 mL) change in Hb ≥ 2 g/dL Secondary outcome measures Primary outcome measures severe PPH (blood loss ≥ 1000 mL) intermediate PPH (≥ 750 mL) mean blood loss anemia (< 9 g/dL & < 11 g/dL)

Misoprostol for PPH Prevention in rural Pakistan Safety: No serious adverse events to date Status of recruitment: 1,060 of 1400 enrolled (revised sample size) Launch: Sept 2005 Time to completion: August 08 Data available: Oct/Nov 08

Postpartum blood loss (n = 314) Blood loss (ml) mean ± sd *315.4 ± range

Distribution of blood loss

Hemoglobin levels Warm months (April – Oct) Cold months (Nov – March) Pre-delivery Hb g/dl mean ± sd (n=398) 12.8 ± ± 1.9 Postpartum Hb g/dl mean ± sd Range (n=166) 11.1 ± (n=158) 11.9 ± Mean change in Hb g/dl mean ± sd 1.4 ± 1.9

Side effects reported % (n) Shivering10.4 (34) Chills8.9 (29) Nausea3.1 (10) Headache2.1 (7) Fatigue2.1 (7) Fainting1.5 (5) Vomiting0.9 (3) Fever0.9 (3)

Treatment of Primary PPH Objective: To determine if misoprostol is as effective as oxytocin for treatment of primary PPH due to atonic uterus in two types of settings: 1) where uterotonics given during third stage of labor, 2) where no uterotonics given during third stage of labor Study design: Hospital-based, double-blind, placebo- controlled, randomized trial. Study arms: 1) 800 µg sublingual misoprostol, 2) 40 IU IV oxytocin Research countries: Burkina Faso, Ecuador, Egypt, Turkey and Vietnam

Treatment of Primary PPH Time to completion: Recruitment ended Jan 18, 2008 Data available: Data entry and cleaning ongoing, unclean data: Mar/April 08

Total screened & enrolled StudyTotal screenedTotal enrolled A9, B30, A + B40,4251,773

Adjunct PPH Treatment in Collaboration with WHO Objective: To determine if a combined regimen (misoprostol + injectable uterotonics) is a better treatment for PPH than injectable uterotonics alone Study design: Hospital-based, double-blinded placebo-controlled, randomized study Study arms: 1) 600 µg sublingual misoprostol, or 2) placebo Collaborators: World Health Organization and WHO Collaborating Centres in Argentina, Egypt, South Africa, Thailand & Vietnam

Outcome Measures Primary outcome Blood loss ≥ 500 mL at 60 & 90 minutes Secondary outcomes Side effects Need for blood transfusion Hb 24 h after delivery Blood loss ≥ 1000 mL at 60 & 90 minutes Mean blood loss at 60 & 90 minutes Use of additional uterotonics after randomization Maternal death, severe morbidity

Adjunct PPH Treatment Efficacy: Unknown -study blinded. DSMB report Dec 07: “We congratulate the trial organizers and collaborators on the progress and conduct of the trial... Based on the results so far, we recommend to continue and finish the study without modifications... There are great variations in rates between centres and bigger effects in some than others, but probably due to small numbers. Nothing that will affect the validity of the results of the study” Safety: No serious adverse events. Time to completion: Recruitment expected to end June/July 2008

Adjunct PPH Treatment in collaboration with Aga Khan Network Objective: To determine if a combined regimen (misoprostol + injectable uterotonics) is a better treatment for PPH than injectable uterotonics alone Study design: Hospital-based, double-blinded placebo-controlled, randomized study Study arms: 1) 600 µg sublingual misoprostol, 2) placebo Collaborators: AKU, AK-F, and AKHS/P Hospitals in Karachi, Pakistan

Adjunct PPH Treatment Safety: No serious adverse events Time to completion: Recruitment ended April 2007 Data available: Draft paper ready for submission

Outcomes MISOPLACEBO n=29n=32p-value Postpartum blood loss after study treatment Total blood loss post-treatment (ml) mean ± sd175 ± ± Blood loss ≥500ml post-treatment %(n) 7.4 (2)12.5 (4)0.678 Postpartum hemoglobin measures Post-delivery Hb mean ± sd9.0 ± ± Drop in Hb mean ± sd2.0 ± ± Postpartum Hb ≥ 2 g/dL lower than pre-delivery Hb %(n)41.4 (12)56.3 (18)0.183

Outcomes MISOPLACEBO n=29n=32p-value Additional interventions Amount of IV fluids given ml 75.9 (22)53.1 (17) > 1000 ml 24.1 (7)46.9 (15) Blood transfusion %(n)17.2 (5)18.8 (6)0.573 Uterine packing done %(n)6.9 (2)18.8 (6)0.162 Balloon tamponade used %(n)0.0 (0)3.1 (1)0.525 Referrals for additional PPH care %(n)3.4 (1)3.2 (1)0.737

Adjunct PPH Prevention In Collaboration with Effective Care Research Unit, South Africa Objective: To determine if a combined regimen (400 µg misoprostol + 10 IU oxytocin) is better than 10 IU oxytocin for PPH prevention Study design: Hospital-based, double-blinded placebo-controlled, randomized study Study arms: 1) 400 µg sublingual misoprostol, 2) placebo Collaborators: Effective Care Research Unit, East London, South Africa. Several centres will participate. South Africa, Nigeria & Uganda

Outcome Measures Research Question: Will the addition of misoprostol 400µg sublingually augment the effectiveness of current routine active management of the third stage of labour? Primary outcome Measured blood loss of 500mls or more within 1 hour after enrolment Secondary outcomes side-effects blood loss  1000 mls after enrolment mean blood loss after enrolment blood transfusion maternal morbidity and mortality

Adjunct PPH Prevention Efficacy: Unknown. This study is still blinded. Safety: No serious adverse events. Time to completion: Recruitment ended Sept 2007 Data available: Data being cleaned. Full data set expected to be ready for unblinding Mar 08. Data available for sharing thereafter.

Other ongoing efforts in our free time Paper nearing submission on review of relationship of prophylaxis and AMSTL on bleeding: a meta-analysis Materials development on PPH based on study results in collaboration with FCI – targeting policy maker, provider and user audiences Completed Instructions for Use on PPH Prevention – now being translated into various languages Developing policy piece… PPH prevention vs. treatment: where is the money best spent? Paper on AMSTL using screening data from large PPH txt study Study on methods of blood loss: Drape vs. Dry/Wet Weight Meetings with pharmaceutical companies re collaboration on using PPH treatment data for registration of misoprostol for PPH (the dossier..)

Thank You!