1. 1 US and Russia Scientific Forum Meeting November 17, 2011 Postpartum Hemorrhage: The Leading Cause of Maternal Mortality Richard J. Derman, MD, MPH Chair, 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. 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 Estimates WHO, UNICEF, UNFPA and the World Bank Geographic Area Maternal Deaths (Number) Estimated Maternal Mortality Ratio (deaths per 100,000 live births) Lifetime Risk of Maternal Death 1 in: Developing Regions ---------- India 355,000 ----------- 63,000 [20 yr. ago 136,000] 290 ----------------- 230 [20 yr. ago 540] 120 ------------ 140 [20 yr. ago 48] Developed Regions 1,700144,300 Countries of Commonwealth of Independent States 1,50040 World Total358,000260140 Source: Trends in Maternal Mortality: 1990 – 2008. World Health Organization, 2010.

5. 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. 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. 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, 23 rd Edition. McGraw-Hill, 2010.

8. 8 Average Interval from Onset to Death Ruptured uterus24 hours Antepartum hemorrhage12 hours Postpartum hemorrhage2 hours Maine D. Safe Motherhood Programs: Options and Issues, Center for Population & Family Health, Columbia University,1993.

9. 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. 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. 11 Strategies for Reducing Postpartum Hemorrhage Secondary to Atonic Uterus

12. 12 Active Management of the Third Stage of Labor 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 FIGO Joint Statement June, 2004.

13. Active vs. Physiologic Management: Postpartum Hemorrhage Active Management Physiologic Management OR and 95% CI Bristol Trial50/846 (5.9%)152/849 (17.9%) 3.13 (2.3-4.2) Hinchingbrooke Trial 51/748 (6.8%)126/764 (16.5%) 2.42 (1.78-3.3) Prendiville et al 1988; Rogers et al 1998.

14. 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. 15 Uterine Massage Few studies in literature Confusion whether component of active management of 3 rd 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. 16 Uterotonic Drugs Oxytocin-posterior pituitary extract Ergometrine-preparation of ergot Syntometrine-combination of oxytocin and ergometrine Misoprostol-prostaglandin E1 analogue

17. 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. 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. Misoprostol vs. Injectable Oxytocin StudyRisk 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..1.5210

20. 20 First Randomized Community-based Study Employing 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. 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. 22 Study Sponsors

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

25. 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. 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. 28 BRASSS-V Blood Collection Drape with Calibrated Receptacle

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

30. 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. 31 Study Sites PHCs 4 Hirebagewadi, Bhendigeri, Neginhal, Yamakanmaradi Sub Centers 19 Villages 43 Population 98,679 ANMs 19

32. 32

33. 33 OB Clinic and Labor & Delivery

34. 34 Postpartum Unit and Research Storage Facility

35. Total Number Screened 4248 Total Number Ineligible at Initial Screening 1599 Not Planning to Deliver in Home or Sub-center 1556 Normal Vaginal Delivery Not Likely 22 Other Condition(s) Make Current Pregnancy High-risk 12 Consent Form Not Signed 9 Total Number Eligible at Initial Screening 2649 Total Eligible at Initial Screening & Not Randomized 1029 Became Ineligible Prior to Third Stage Labor 476 Refusal 176 ANM not present at delivery 324 Study Medication Not Available 53 Total Number Randomized Study Duration 33 months 1620

36. Population Characteristics Misoprostol (N=812) Placebo (N=805) Age [Mean (sd)]23.3 (3.3)23.2 (3.2) Literacy [Count (%)]511 (62.9)511 (63.2) Prenatal Visits [Mean (min-max)]3.45 (1-8)3.5 (1-10) Gravida [Mean (sd)]2.2 (1.1)2.3 (1.1) Parity [Mean (sd)]1.2 (1.1) Hemoglobin (gm/dl) [Mean (sd)]9.61 (0.9)9.62 (0.9)

37. 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 Primary OutcomeMisoprostol (n= 812*) n (%) Placebo (n=805) n (%) P-value Postpartum Hemorrhage (blood loss  500 ml) 53 (6.5) 97 (12.0)0.0001 Severe Postpartum Hemorrhage (blood loss  1,000 ml) 2 (0.2) 10 (1.2) ss

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

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

41. Postpartum Hemorrhage Rates for Data Review Periods of Randomized Women by Treatment 6.7 9.5 8.3 1.9 6.4 17.7 12.3 9.2 6.5 12.0 0 2 4 6 8 10 12 14 16 18 20 1234 Overall Data Review Periods % PPH MisoprostolPlacebo n=256 n=220 n=254 n=219 n=121 n=119 n=215 n=216 n=811 n=808 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 Misoprostol (n=812) Placebo (n=805) count (%) Nausea35 (4.3)29 (3.6) Vomiting28 (3.5)25 (3.1) Diarrhea9 (1.1)5 (0.6) Shivering419 (51.8)140 (17.4) Fever34 (4.2)9 (1.1)

43. Neonatal Side Effects Misoprostol (N=812) Placebo (N=805) Side Effects count (%) Vomiting26 ( 3.2)40 ( 5.0) Diarrhea4 ( 0.5)3 ( 0.4) Fever8 ( 1.0)

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

45. 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. 46 Confirmatory Trial Results  PPH (500ml) by 24%  in Hgb by 3 gms (47%) Mobeen, N et al. BJOG, Oct. 2010.

47. 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. 48 Prevention of Pospartum Hemorrhage with Sublingual Misoprostol or Oxytocin: A Double Blind Randomized Controlled Trial Sample: Study group characteristics similar MisoprostolOxytocinp n=323n=329 Mean blood loss (ml)192±122371±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. 49 17 Countries for PPH prevention

50. 50