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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 ResearchChristiana Care, Newark, Delaware

Professor of Obstetrics and GynecologyThomas Jefferson University, Philadelphia, Pennsylvania

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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.

Global Scenario: 2008 EstimatesWHO, 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

1,700 14 4,300

Countries of Commonwealth of Independent States

1,500 40 40

World Total 358,000 260 140

Source: Trends in Maternal Mortality: 1990 – 2008. World Health Organization, 2010.

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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.

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Anemia More common in third world countries

Severe anemia - associated cause in > 50% of maternal deaths in the developing worldWomen 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

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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.

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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.

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Maternal Mortality Due to PPH in the Developing World

Poor access to skilled providers

Poor transport systems

Poor emergency services- Lack of blood/products

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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.

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Strategies for Reducing Postpartum Hemorrhage

Secondary to Atonic Uterus

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Active Management of the ThirdStage 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.

Active vs. Physiologic Management: Postpartum Hemorrhage

ActiveManagement

PhysiologicManagement

OR and 95% CI

Bristol Trial 50/846 (5.9%) 152/849 (17.9%)

3.13 (2.3-4.2)

HinchingbrookeTrial

51/748 (6.8%) 126/764 (16.5%)

2.42 (1.78-3.3)

Prendiville et al 1988; Rogers et al 1998.

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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).

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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.

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Uterotonic Drugs

Oxytocin-posterior pituitary extract

Ergometrine-preparation of ergot

Syntometrine-combination of oxytocin and ergometrine

Misoprostol-prostaglandin E1 analogue

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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

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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

Misoprostol vs. Injectable OxytocinStudy Risk ratio (95% CI) %

Weight

Amant et al. 3.00 (0.12, 72.77) 0.1Benchimol et al. 1.41 (0.68, 2.89) 3.4Caliskan et al. 0.92 (0.45, 1.89) 4.4Caliskan et al. 1.25 (0.62, 2.50) 4.0Cook et al. 1.92 (0.77, 4.77) 2.0El-refaey et al. 0.90 (0.37, 2.19) 2.9Gerstenfeld et al. 1.12 (0.56, 2.24) 4.0Gulmezoglu, A.M., et al. 1.39 (1.19, 1.63) 76.3Kundodyiwa, T.W. et al. 1.90 (0.64, 5.58) 1.4Ng, P.S., et al. 1.26 (0.34, 4.67) 1.2Oboro et al. 1.01 (0.06, 16.03) 0.3Overall 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

.5 2 10

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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.

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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

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Study Sponsors

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Global Network for Women’s & Children’sHealth Research, Site 8

J N Medical College, Belgaum, Karnataka India

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Key Elements of Study Protocol

Skilled birth attendant (6 months post high school)

Prophylactic uterotonic as intervention

Delivery of placentaExpectant Management

Quantitative measurement of blood loss

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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

Primary Outcome

Objective Measurement of Blood Loss

BRASSS-V®

Blood Collection Drape with Calibrated Receptacle

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BRASSS-V Blood Collection Drape with Calibrated Receptacle

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Primary Hypothesis

Misoprostol administered during the

third stage of labor will significantly

reduce the incidence of acute

postpartum hemorrhage by 50%.

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Study Sample

1600 women

800 – Misoprostol

800 - Placebo Delivering at home or at

sub-center

Normal vaginal deliveries Not deemed to be high-risk

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Study Sites

PHCs 4 Hirebagewadi, Bhendigeri, Neginhal, Yamakanmaradi

Sub Centers 19

Villages 43

Population 98,679

ANMs 19

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OB Clinic and Labor & Delivery

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Postpartum Unit and Research Storage Facility

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

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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) 1.2 (1.1)

Hemoglobin (gm/dl) [Mean (sd)] 9.61 (0.9) 9.62 (0.9)

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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

Primary Outcome: PPH Rates

Primary Outcome Misoprostol (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

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Oral Misoprostol in Preventing Postpartum Hemorrhage in Resource-

poor Communities: A Randomized Controlled Trial

Lancet 2006; 368: 1248-53.

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NNT

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

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

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1 2 3 4 Overall

Data Review Periods

% P

PH

Misoprostol Placebo

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

Maternal Side Effects

Misoprostol (n=812)

Placebo (n=805)

count (%) count (%)

Nausea 35 (4.3) 29 (3.6)

Vomiting 28 (3.5) 25 (3.1)

Diarrhea 9 (1.1) 5 (0.6)

Shivering 419 (51.8) 140 (17.4)

Fever 34 (4.2) 9 (1.1)

Neonatal Side Effects

Misoprostol (N=812)

Placebo (N=805)

Side Effects count (%) count (%)

Vomiting 26 ( 3.2) 40 ( 5.0)

Diarrhea 4 ( 0.5) 3 ( 0.4)

Fever 8 ( 1.0) 8 ( 1.0)

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WHO Recommendationsfor the Prevention of

Postpartum Hemorrhage

Misoprostol added to the essential medicine list,

2011

World Health Organization

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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.

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Confirmatory Trial Results

PPH (500ml) by 24%

in Hgb by 3 gms (47%)

Mobeen, N et al. BJOG, Oct. 2010.

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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

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Prevention of Pospartum Hemorrhage with Sublingual Misoprostol or Oxytocin: A

Double Blind Randomized Controlled Trial

Sample: Study group characteristics similar

Misoprostol Oxytocin pn=323 n=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.

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17 Countries for PPH prevention17 Countries for PPH prevention

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