1. Misoprostol for Preventing Postpartum Hemorrhage and for Postabortion Care Harshad Sanghvi Patricia Stephenson MAQ 2006 Mini University, 27 0ctober 2006

2. Session Objectives Describe the importance of PPH and postabortion complications as causes of maternal death. Describe the efficacy and safety of misoprostol for prevention of PPH and for medical management of postabortion care. Describe potential barriers to program implementation and scale up and ways to overcome them.

3. PPH: Magnitude of the Problem About 30% of all maternal deaths worldwide are due to bleeding. PPH is the most common cause of maternal death. Most of deaths due to bleeding occur postpartum.

4. Definition of PPH PPH : Blood loss greater than 500 ml Severe PPH: Blood loss greater than 1000 ml PPH : Blood loss greater than 500 ml Severe PPH: Blood loss greater than 1000 ml Any blood loss that causes a physiologic change that threatens a woman’s life

5. Incidence of PPH Blood Loss (n = 434) Mean + SE265.18 + 10.95 Range20 - 1600 Median200 Mode100 Acute PPH57 (13.2 %) Acute severe PPH 8 (1.8 %) Goudar, Eldavitch, Bellad, 2003

6. Etiology of PPH Uterine atony (~3/4 cases) Other Episiotomy Retained placenta Trauma - uterine rupture, inversion, cervical laceration, vaginal hematoma Postpartum infections Rarely : Coagulopathy

7. Risk Factors for PPH Preeclampsia, previous PPH, multiple gestation, arrest of descent, maternal hypotension, coagulation disorder, Asian or Hispanic, delivery with forceps or vacuum, augmented labor, nulliparity, multiparity, polyhydramnios, underlying anemia Up to 90% of women who experience PPH have no identifiable risk factors

8. Prevention of PPH Active management of third stage of labor (AMSTL) Uterotonic after birth of baby Controlled cord traction Fundal massage Restricting episiotomy & unnecessary obstetric interventions Prevention & treatment of anemia due to iron deficiency, hook worm, malaria

9. Active vs. Expectant Management Management of third stage of labor Blood Loss > 500 mls Blood loss > 1000 mls Expectant (n=3126) 13.6%2.6% Active (n=3158) 5.2%1.7% Relative risk0.38 (0.32-0.46)0.33(0.21-0.51) Number needed to treat 12 (10-15)57(42-89) Prendiville, Elbourne, McDonald, The Cochrane Library issue 3, 2003

10. Comparison of Uterotonics Programmatic considerations Oxytocin (IM) Ergometrine (IM) Misoprostol (PO or sublingual) Effectiveness++++++++ Need skilled provider yes no Suitable for home birth no yes Side effectsrarecommonrare Contraindicationsnone High BPnone Refrigeration needed yes no Therapeutic effect immediate within minutes

11. Misoprostol mystery madness (boo!)

12. Clinical demonstration study 1 Oral Misoprostol reduced PPH incidence to 6% Double-blind placebo controlled study 2 Oral Misoprostol reduced need for treatment of PPH from 8.4%  2.8% Rectal Misoprostol vs. Syntometrin for 3 rd stage 3 Similar reduction in length of 3 rd stage, postpartum blood loss and postpartum hemoglobin; Higher BP with Syntometrin Oral Misoprostol vs. Placebo 4 PPH: 7% vs 15% Need for therapeutic Oxytocin: 16% vs. 38% Misoprostol: Evidence 1: El-Refaey, 1997; 2: Hofmeyr, 1998; 3: Bamigboye, 1998; 4: Surbek, 1999

13. Double-blind placebo controlled WHO multi-center RCT: Oxytocin vs. Misoprostol in hospital 1 8 countries Oxytocin (n=9266); Misoprostol (n=9264) Severe PPH (1000cc): 3% vs. 4% Misoprostol – higher incidence of shivering Conclusion: Oxytocin preferred over Misoprostol Double blind placebo controlled RCT in rural Guinea Bissau: Misoprostol vs. Placebo Misoprostol alone reduces severe PPH (1000mls+) 11% vs. 17% RR 0.66 (0.44-0.98) More Evidence 1: Gulmezoglu,et al., Lancet 2001, H øj BMJ 2005

14. RCT of misoprostol compared to placebo for home birth in rural India Primary OutcomeMisoprostol (N= 812*) N (%) Placebo (N=808 ) N (%) Relative Risk (95% CI) P-value Postpartum Hemorrhage (blood loss  500 ml) 53 (6.5) 97 (12.0) 0.53 (0.39, 0.74) <0.0001 Severe Postpartum Hemorrhage (blood loss  1,000 ml) 2 (0.2) 10 (1.2) 0.20 (0.04, 0.91) <0.0001 A Randomized Placebo-Controlled Trial of Oral Misoprostol 600 mcg for Prevention of Postpartum Hemorrhage at Four Primary Health Center Areas of Belgaum District, Karnataka India Conclusive Evidence:

15. Blood Loss Distribution MPMPMPMP 95 th Percentile M: 500 ml P: 800 ml

16. Completed programs Indonesia, Gambia, Guinea Bissau New programs underway Pakistan, Nepal, Bangladesh, Kenya, Uganda, Afghanistan INDONESIA PROGRAM Safety: No women took medication at wrong time Acceptability: users said they would recommend it and purchase drug for future births Feasibility: 94% coverage with PPH prevention method achieved Effectiveness: 25% reduction in perceived excessive bleeding OR 0.76 ( 0.55 - 1.05) 45% reduction in need for referral for PPH 0.53 (0.24-1.12) Feasibility for Use at Homebirth

17. Treatment of PPH Even under the best circumstances, all PPH is not preventable Once severe PPH occurs, death can follow very rapidly

18. Clinical Interventions Basic EmOC Management of shock Uterotonics Bimanual compression Suturing of lacerations Aortic compression Manual removal of placenta Comprehensive EmOC Uterine artery ligation B-lynch procedure Hysterectomy Blood transfusion

19. Promising Interventions Home based Life Saving Skills Misoprostol Hydrostatic tamponade

20. Issues and Challenges Policy and supportive environment Supply chain logistics Human capacity and training Community involvement and mobilization Referral links

22. 13% of maternal deaths due to abortion. 15-20% of recognized pregnancies are miscarried or become nonviable. 20 million unsafe abortions occur each year. Postabortion Complications: Magnitude of the Problem

23. Definitions Early: before 12 weeks Late: between 12 & 20 weeks Threatened miscarriage: spotting or cramping in 1 st 20 weeks – usually with a viable continuing pregnancy Incomplete: expulsion of only part of the uterine contents or rupture of the membranes Complete: expulsion of all products of conception Missed: retention of a dead embryo or fetus

24. Treatment Options Surgery Manual vacuum aspiration (MVA) Electric/foot pump vacuum aspiration Sharp curettage Expectant management Medical management with misoprostol

25. Misoprostol: Indications Indication: Treatment of incomplete abortion and missed abortion for women with uterine size less than or equal to 12 weeks LMP Contraindications: Sepsis or pelvic infection Shock Suspicion of ectopic pregnancy IUD in place (remove)

26. Misoprostol 600 mcg MVARR (95% CI) Complete Evacuation 96.391.51.05 (0.98 -1.14) Complications0.9%9.8%0.01 (0.01-0.78) Acceptability94.2%94.7% Source: Weeks et al 2005 Increased bleeding for 6 hours, decreased pain with misoprostol Evidence: Uganda

27. Evidence: Vietnam: Dose Nguyen et al Contraception 2005 No difference in outcomes with single dose of 600mcg misoprostol or with two doses. Most (96%) women tolerated side effects of bleeding up to 4 days and cramping for a day

28. Misoprostol: Evidence Zhang et al NEJM 2005 RCT N=652 women compared 800 mcg misoprostol vaginally with vacuum aspiration for missed abortion. 84% of miso group and 97% of VA group had complete uterine evacuation by day 8 Both groups satisfied with treatment Miso instead of aspiration used in an outpatient setting reduces the costs of services

29. Evidence: Efficacy Success rates 66-100% for incomplete abortion using recommended dose of 600 mcg orally 60-93% for missed abortion using recommended dose of 800 mcg vaginally Highest success rates are achieved with extended follow up (7-14 days) to allow completion of expulsion

30. Evidence: Safety Side effects: (short lived) Nausea and vomiting Diarrhea Fever, chills Cramping Bleeding

31. Potential Advantages Misoprostol may help expand PAC services: in most resource constrained environments surgical services are not available beyond the district hospital. Availability of MVA and other surgical equipment is a significant bottleneck. Medical management may reduce the need for surgically trained health manpower. Lower cost; few side effects; most side effects mild and of short duration. Additional follow up required may provide opportunities for family planning counseling and services.

32. Drawbacks It is not for everyone. Even if indicated, some women will still require surgical treatment. Providers still need to be trained to correctly diagnose missed or incomplete abortion and rule out contraindications. Takes longer to evacuate the uterus and may require a follow up visit – women may be lost to follow up.

33. Issues and Challenges How do we: Expand PAC services to health centers and health posts? Train lower-level providers to safely administer misoprostol? Involve the community as a resource? Structure services to promote family planning? Overcome policy barriers of registration of misoprostol for off-label uses?