US and Russia Scientific Forum Meeting November 17, 2011 Postpartum Hemorrhage: The Leading Cause of Maternal Mortalit

1. US and Russia Scientific Forum MeetingNovember 17, 2011 Postpartum Hemorrhage: The Leading Cause of Maternal Mortality Richard J. Derman, MD, MPHChair, Department of Obstetrics and Gynecology Director, Institute for Women & Children’s Health Research Christiana Care, Newark, Delaware Professor of Obstetrics and Gynecology Thomas Jefferson University, Philadelphia, Pennsylvania

2. PPH’s Contribution to Mortality and Morbidity • PPH is the single most important cause of maternal death worldwide. • At least 30% of all worldwide maternal deaths are due to PPH. Note: Global maternal deaths in 2008 were estimated by WHO, UNICEF, UNFPA and the World Bank at 358,000 (but there was a range of uncertainty from 265,000 to 503,000). • Based upon estimates above, approximately 107,400 women bleed to death each year due to pregnancy-related hemorrhage • The maternal mortality ratio (deaths per 100,000 live births) varies substantially worldwide.

3. Global Scenario: 2008 EstimatesWHO, UNICEF, UNFPA and the World Bank Source: Trends in Maternal Mortality: 1990 – 2008. World Health Organization, 2010.

5. Motherhood in India • Mumtaz, the queen of Shah Jehan, may have died from postpartum hemorrhage while giving birth to her 14th child. The Taj Mahal was built in her memory. • Motherhood in India is about as safe now as it was in Europe 100 years ago. • In India, one maternal death occurs every 5 minutes. • Greater than 1 of 3 women in India deliver at home.

6. Anemia • More common in third world countries • Severe anemia - associated cause in > 50% of maternal deaths in the developing world Women already compromised by anemia are much more likely to die as a result of postpartum hemorrhage. • In many third world countries, women are not able to build their iron stores -- poor nutrition -- menstrual blood loss -- chronic infections -- repeated pregnancies • Most women in the third world enter pregnancy with little or no iron reserve

7. PPH Non-Predictable • Two-thirds of women who hemorrhage have no identifiable risk factors • Women who survive PPH often must receive blood transfusion -- risk of hepatitis or HIV Reference: F. Gary Cunningham, Kenneth J. Leveno, Steven L. Bloom, John C. Hauth, Dwight J. Rouse, Catherine Y. Spong. Williams Obstetrics, 23rd Edition. McGraw-Hill, 2010.

8. Average Interval from Onset to Death • Ruptured uterus 24 hours • Antepartum hemorrhage 12 hours • Postpartum hemorrhage 2 hours Maine D. Safe Motherhood Programs: Options and Issues, Center for Population & Family Health, Columbia University,1993.

9. Maternal Mortality Due to PPH in the Developing World • Poor access to skilled providers • Poor transport systems • Poor emergency services - Lack of blood/products

10. Millenium Development Goal 5 • Reduction of maternal mortality by 75% (1990-2015) • 5.5% reduction/year required • Only 13 of 137 countries are expected to reach goal • Reducing postpartum hemorrhage will be necessary to achieve goal • India has an accelerated rate of declining maternal mortality (-59% change 1990-2008) due to: -- reduction in home births -- increased use of misoprostol Reference: Trends in Maternal Mortality: 1990 – 2008. World Health Organization, 2010.

11. Strategies for Reducing Postpartum HemorrhageSecondary to Atonic Uterus

12. Active Management of the ThirdStage of Labor FIGO Joint Statement June, 2004. • Designed to speed the delivery of the placenta by increasing uterine contractions and thus averting uterine atony • Components • Administration of uterotonic agent (post cord-clamping) • Placenta delivered by controlled cord traction with counter-traction on the fundus • Uterine massage > delivery of placenta

13. Active vs. Physiologic Management: Postpartum Hemorrhage Prendiville et al 1988; Rogers et al 1998.

14. Active Management of the Third Stage of Labor without Controlled Cord Traction: A Randomized Non-inferiority Controlled Trial • Uterotonic use likely has greatest impact • Concern over controlled cord traction in rural areas among nonphysicians • If not significant change in bleeding, can recommend against the practice and expand AMTSL to lower level providers Gulmezoglu, M, et al., Reproductive Health, 2009 Jan, 6:2. (World Health Organization).

15. Uterine Massage • Few studies in literature • Confusion whether component of active management of 3rd stage • Initial blood loss may be higher because of expression of blood • Randomized trial implemented in Egypt and South Africa • Conclusion: “Uterine massage was less effective than oxytocin for reducing blood loss after delivery. When oxytocin was used, there was no additional benefit from uterine massage.” Abdel-Aleem H, et al. Int J Gynaecol Obstet 2010 Oct;111(1)32-6.

16. Uterotonic Drugs • Oxytocin-posterior pituitary extract • Ergometrine-preparation of ergot • Syntometrine-combination of oxytocin and ergometrine • Misoprostol-prostaglandin E1 analogue

17. Uterotonic Drugs: Oxytocin • Key Message: Oxytocin is the preferred drug when it can be stored properly and administered safety • Advantages • Acts within 2-5 minutes when given IM • Generally does not cause side effects • Disadvantages • More expensive than ergometrine, misoprostol • IM or IV preparations only • Not heat stable

18. Uterotonic Drugs: Misoprostol • Advantages • May be given orally • Low price • Long shelf life and easy to store • Heat stable • Prevention of PPH is an acceptable off-label use according to United States Pharmacopeia • Disadvantages • Shivering and fever frequent side effects • Takes longer to act compared to injectable uterotonics

19. .1 .5 2 10 Misoprostol vs. Injectable Oxytocin Study Risk ratio (95% CI) % Weight Amant et al. 3.00 (0.12, 72.77) 0.1 Benchimol et al. 1.41 (0.68, 2.89) 3.4 Caliskan et al. 0.92 (0.45, 1.89) 4.4 Caliskan et al. 1.25 (0.62, 2.50) 4.0 Cook et al. 1.92 (0.77, 4.77) 2.0 El-refaey et al. 0.90 (0.37, 2.19) 2.9 Gerstenfeld et al. 1.12 (0.56, 2.24) 4.0 Gulmezoglu, A.M., et al.1.39 (1.19, 1.63) 76.3 Kundodyiwa, T.W. et al. 1.90 (0.64, 5.58) 1.4 Ng, P.S., et al. 1.26 (0.34, 4.67) 1.2 Oboro et al. 1.01 (0.06, 16.03) 0.3 Overall 1.36 (1.19, 1.56) 100.0 All studies evaluating misoprostol vs. oxytocics with outcome blood loss N1000 mL. Mantel—Haenszel fixed effects model. Heterogeneity chi-squared=3.64 (df =10), p = 0.962. I-squared (variation in RR attributable to heterogeneity)=0.0%. Test of RR=1: z =4.41, p =0.000. Langenbach, C., Intl J GynOb, 2006.

20. First Randomized Community-based StudyEmploying Oral Misoprostol N=1229 (Gambia) • No placebo arm – standard of care, 2gms of oral ergometrine • Misoprostol performed 10% better (unknown effect of ergometrine) • Drop in Hgb, significantly greater in ergometrine group • 2 deaths from PPH (both in Misoprostol group) • Recommendation: await results from placebo-controlled trial Walraven, G et al., BJOG, Sept 2005.

21. A Randomized Placebo-Controlled Trial of Oral Misoprostol for Prevention of Postpartum Hemorrhage at Four Primary Health Centers of the Belgaum District, Karnataka India Richard J. Derman, MD, MPH Bhala Kodkany, MD V.J. Naik, MD Ashlesha Patel, MD, MPH Shiva Goudar, MD Stacie Geller, PhD Stanley Edlavitch, PhD

22. Study Sponsors

23. Global Network for Women’s & Children’sHealth Research, Site 8J N Medical College, Belgaum, Karnataka India

25. Key Elements of Study Protocol • Skilled birth attendant (6 months post high school) • Prophylactic uterotonic as intervention • Delivery of placenta • Expectant Management • Quantitative measurement of blood loss

26. Intervention Misoprostol vs Placebo, three 200 mcg tablets orally Administered within 5 minutes of clamping and cutting of the cord and cessation of cord pulsation

27. Primary Outcome Objective Measurement of Blood Loss BRASSS-V® Blood Collection Drape with Calibrated Receptacle

28. BRASSS-V Blood Collection Drape with Calibrated Receptacle

29. Primary Hypothesis Misoprostol administered during the third stage of labor will significantly reduce the incidence of acute postpartum hemorrhage by 50%.

30. Study Sample • 1600 women 800 – Misoprostol 800 - Placebo • Delivering at home or at sub-center • Normal vaginal deliveries • Not deemed to be high-risk

31. Study Sites PHCs 4 Hirebagewadi, Bhendigeri, Neginhal, Yamakanmaradi Sub Centers 19 Villages 43 Population 98,679 ANMs 19

33. OB Clinic and Labor & Delivery

34. Postpartum Unit and Research Storage Facility

36. Population Characteristics

37. Obstetrical Indices Misoprostol Placebo Estimated GA at Delivery (weeks) 38.9 38.9 mean (sd) (1.7) (1.8) Preterm Delivery (%) 173 (21.3) 181 (22.4) Duration of Labor (hours) 7.97 7.91

38. Primary Outcome: PPH Rates

39. Oral Misoprostol in Preventing Postpartum Hemorrhage in Resource-poor Communities: A Randomized Controlled Trial Lancet 2006; 368: 1248-53.

40. NNT One case of postpartum hemorrhage was prevented for every 18 women who received misoprostol.

41. 20 17.7 Misoprostol Placebo 18 16 14 12.3 12.0 12 9.5 % PPH 10 9.2 8.3 8 6.7 6.5 6.4 6 4 n=219 n=254 1.9 n=808 n=119 2 n=216 n=256 n=121 n=811 n=220 n=215 0 1 2 3 4 Overall Data Review Periods Postpartum Hemorrhage Rates for Data Review Periods of Randomized Women by Treatment Goudar SS, et al., Variation in the postpartum hemorrhage rate in a clinical trial of oral misoprostol. J Matern Fetal Neonatal Med. 2008 Aug; 21(8):559-64

42. Maternal Side Effects

43. Neonatal Side Effects

44. WHO Recommendations for the Prevention of Postpartum Hemorrhage Misoprostol added to the essential medicine list, 2011 World Health Organization

45. Confirmatory Study on Prophylactic Use of Oral Misoprostol (600 mcg) n=1119 • Conducted in rural Pakistan • Outcome measures similar to India study • Measured blood loss Gynuity Health Projects.

46. Confirmatory Trial Results •  PPH (500ml) by 24% •  in Hgb by 3 gms (47%) Mobeen, N et al. BJOG, Oct. 2010.

47. Prevention of Pospartum Hemorrhage with Sublingual Misoprostol or Oxytocin: A Double Blind Randomized Controlled Trial MB Bellad, D Tara, MS Ganachari, MD Mallapur, SS Goudar, BS Kodkany, NL Sloan, R Derman. June, 2011. Study Partners: KLE University, Jawaharlal Nehru Medical College & KLES Pharmacy College, Belgaum, Karnataka, India and Christiana Care Health Services • Double Blind Randomized Controlled Trial (RCT) • 400 µg powdered sublingual misoprostol v. 10 IU IM oxytocin • Eligibility criteria: Gestational age >28 weeks, singleton, cephalic presentation, normal spontaneous vaginal delivery (including episiotomy), Hb ≥ 8g/dl upon presentation. admitted to labor room in the KLE teaching hospital at JNMC, Belgaum • Exclusion criteria: Cesarean section and instrumental deliveries

48. Prevention of Pospartum Hemorrhage with Sublingual Misoprostol or Oxytocin: A Double Blind Randomized Controlled Trial Sample: Study group characteristics similar Misoprostol Oxytocin p n=323 n=329 Mean blood loss (ml) 192±122 371±135 ≤0.001 PPH 3.1% 9.1% ≤0.001 Hb decline ≥10% 9.0% 45.6% ≤0.001 • Blood loss > 1000 mls: None • Side effects: Misoprostol>oxytocin; Shivering most common; all transient and uncomplicated • Treatment PPH: Oxytocin>misoprostol. One woman in each group required transfusion, none died. • Conclusion: The effectiveness and ease of administration of sublingual misoprostol may be useful in busy and crowded labor rooms, or when a skilled delivery attendant is not promptly available to administer an injection.

49. 17 Countries for PPH prevention