1. To AMTSL or Not to AMTSL: That is the Question Deborah Armbruster, Senior Maternal Health and Newborn Advisor Bureau for Global Health, USAID CSHGP’s Partners Meeting, October 12, 2011 Photo: Peg Marshall Misoprostol: moving on… and the remaining issues Maternal Health Commodities: what’s a UN Commission got to do with it? What’s new: POSTPARTUM HEMORRHAGE

2. Agenda Rationale and background for the AMTSL trial Finding from the AMTSL trial What will be the impact of the trial ? Misoprostol and WHO’s Essential Medicine List USAID support for expansion of misoprostol – safely and effectively MH and MCH Commodities… and the UN Commission… and then there’s Merck

3. What is AMTSL? Active Management of the Third Stage of Labor Administration of a uterotonic agent (oxytocin is the drug of choice) within one minute after birth of the baby and after ruling out the presence of another baby Controlled cord traction with counter-traction to support the uterus Uterine massage after delivery of the placenta

4. AMTSL trial ACTIVE MANAGEMENT OF THE THIRD STAGE OF LABOUR WITHOUT CONTROLLED CORD TRACTION: A RANDOMIZED NON-INFERIORITY CONTROLLED TRIAL HRP Trial: A65554

5. Rationale PPH is a major cause of maternal death. AMTSL is associated with over 60% reduction of the risk of PPH. AMTSL components are: administration of oxytocin soon after delivery of the baby, controlled cord traction (CCT), delayed cord clamping and cutting and uterine massage. WHO guidelines recommend the use of the full AMTSL package, while acknowledging the lack of evidence on the effectiveness of some individual components. CCT is a procedure that requires manual skills and it is recommended for use by skilled birth attendants only. If CCT does not have a meaningful impact on blood loss then it could be omitted and a simplified package focusing mainly on the uterotonic could be recommended.

6. Objective The primary objective was to determine whether the simplified package of oxytocin 10 IU IM/IV, without CCT, is not less effective than the full AMTSL package with regard to reducing blood loss ≥ 1000 ml in the third stage of labour. If this hypothesis is proven, the simplified package without CCT could be adopted, with the advantage of not requiring training to acquire the manual skill to perform this task.

7. Study design Hospital-based, multicentre, randomized, non-inferiority controlled trial. Participating countries: Argentina, Egypt, India, Kenya, the Philippines, South Africa, Thailand, Uganda. (16 hospitals, 2 PHC centres) Sample size ~ 25,000 women Recruitment period: June 2009 – November 2010 Participants: - inclusion criteria: women expecting to deliver vaginally - exclusion criteria: advanced first stage of labour, women too distressed to give consent, minors without guardian, planned caesarean section, multiple pregnancies, birth considered abortion. Interventions: - experimental arm: "simplified package" (Placental delivery WITHOUT controlled cord traction. i.e. maternal effort, gravidity) - control arm: "full package" (Placental delivery WITH controlled cord traction )

8. Trial outcomes The risk of severe postpartum haemorrhage is not increased The blood loss reduction with CCT is clinically not significant

9. Trial outcomes But, there was an increase in the need of manual removal of placenta This effect is clustered in Philippines, where ergotamine is widely used for Prevention of PPH: excluding Philippines data, there is no additional risk of manual removal of placenta

10. Non-inferiority analysis graph showing where the 95%CI for the Risk Ratio for the primary outcome Blood loss≥1000ml lies with respect to the point of no difference and to the preset non- inferiority margin for the RR, Δ=1·3

11. Non-inferiority analysis graph showing where the 95%CI for the Risk Difference for the primary outcome Blood loss≥1000ml lies with respect to point of no difference and to the preset non-inferiority margin for the Risk Difference, Δ=0·45

12. Main findings CCT has minimal added value in terms of reducing blood loss over and above the uterotonic Oxytocin 10 IU IM injection after delivery of the baby should be regarded as the primary intervention for prevention of PPH In settings where SBA are not available and oxytocin is used as routine uterotonic for prevention of PPH, CCT could be safely omitted during the third stage of labour In setting where SBA are available, oxytocin is used as routine uterotonic for prevention of PPH, practising CCT may shorten the duration of the third stage of labour without additional harms or benefits Even when there is good adherence to a hands-off management of the umbilical cord and the placenta, about 6% of women will eventually require CCT. Thus, teaching of CCT for health professionals should continue

13. Implications for research The findings of this trial strengthen the need to focus on strategies to scale up the use of oxytocin in peripheral levels of health system as the primary component of AMTSL. It is timely to conduct a rigorous evaluation of the preventive and therapeutic use of uterine massage.

14. Impact Impact is potentially huge –Decreased cost (less training) –Increased use of uterotonics beyond SBAs –Increased emphasis on ensuring quality drugs are available –Increased ease to measure progress (coverage by uterotonics) Requires global dialogue and consensus on the “message from trial –WHO guidance likely Mr. 2012 Questions remain: –Should preservice schools teach AMTSL –Should providers,trained in AMTSL, be expected to use AMTSL

15. Misoprostol is an effective uterotonic to prevent and treat postpartum hemorrhage Prevention WHO multi-centre trial 2001 – RR of >1000 ml blood loss was 2.9% - oxytocin group to 4.0% - miso group [95% CI 0.6 – 1.6] Derman 2006 (NICHD) community-based RCT – placebo found 47% decrease in PPH with miso Mobeen 2010 (Gynuity) community-based RCT – placebo found 24% decrease in PPH with miso WHO guidelines – 600 µg oral, when oxytocin not available WHO Essential Medicine List – miso added for PPH indications Treatment Blum 2009 (Gynuity) oxytocin 96.5% vs miso 90% effective WHO guidelines – 800 µg sublingual, 3 rd line drug

16. USAID is supporting the expansion of access to misoprostol-- safely and effectively Challenges/ControversiesWay Forward WHO has concerns about safety of dose and use by women and provision by TBAs A review of new evidence by WHO and an update in PPH prevention guidelines, including new evidence on misoprostol, will occur in March 2012 Challenges with drug procurement. USAID linked up with NGOs to procure drugs for pilots. This is no longer possible as program scale up USAID is working to identify other procurement mechanism(s), e.g. UNFPA, Clinton Foundation Issues with quality of drugUSAID will support careful review of GMP of manufacturers before procurement and will provide list to countries.

17. Work on uterotonic drugs as part of PPH prevention and treatment activities Reproductive Health Supplies Coalition – includes 3 MH commodities Maternal Health Supplies in Bangladesh (PAI) Maternal Health Supplies in Uganda (PAI) Misoprostol research Oxytocin in Uniject Maternal Health Supplies Working Group - (PAI – funded by MHTF) Ghana, Indonesia, Peru and Guatemala Uterotonic drug quality studies Misoprostol quality studies MH and MCH Commodities… and the UN Commission… and then there’s Merck In the beginning… Studies MH Supplies Work. Gr UN Commission USAID developed “Safe Birth Essential Meds and Products concept paper Unicef and Norway are developing similar concept for MCH… but include a UN Commission The organizations join forces with UNFPA, WHO, Gates, CHAI, Dfid Merck for Mothers is announced