Transcript Center for Women’s Health - Foundation for the National

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
1
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.
2
Global Scenario: 2008 Estimates
WHO, UNICEF, UNFPA and the World Bank
Geographic Area
Developing
Regions
---------India
Maternal
Deaths
(Number)
Estimated Maternal
Mortality Ratio
(deaths per 100,000
live births)
Lifetime Risk
of Maternal
Death 1 in:
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
358,000
260
140
World Total
Source: Trends in Maternal Mortality: 1990 – 2008. World Health Organization, 2010.
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.
5
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
6
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.
7
Average Interval from Onset to Death

Ruptured uterus
24
hours

Antepartum hemorrhage
12
hours

Postpartum hemorrhage
hours
2
8
Maternal Mortality Due to PPH in the
Developing World

Poor access to skilled providers

Poor transport systems

Poor emergency services
- Lack of blood/products
9
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 19902008) due to:
-- reduction in home births
-- increased use of misoprostol
Reference: Trends in Maternal Mortality: 1990 – 2008. World
Health Organization, 2010.
10
Strategies for Reducing
Postpartum Hemorrhage
Secondary to Atonic Uterus
11
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.
12
Active vs. Physiologic Management:
Postpartum Hemorrhage
Active
Management
Physiologic
Management
OR and
95% CI
Bristol Trial
50/846 (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.
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).
14
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.
15
Uterotonic Drugs

Oxytocin-posterior pituitary
extract

Ergometrine-preparation of
ergot

Syntometrine-combination of
oxytocin and ergometrine

Misoprostol-prostaglandin E1
analogue
16
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
•
17
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 offlabel use according to United States
Pharmacopeia
Disadvantages
Shivering and fever frequent side
effects
 Takes longer to act compared to
injectable uterotonics

18
Study
Misoprostol vs. Injectable Oxytocin
Amant et al.
Risk ratio (95% CI)
% Weight
3.00 (0.12, 72.77)
0.1
Benchimol et al.
Caliskan et al.
Caliskan et al.
Cook et al.
El-refaey et al.
Gerstenfeld et al.
Gulmezoglu, A.M., et al.
Kundodyiwa, T.W. et al.
Ng, P.S., et al.
Oboro et al.
Overall
1.41 (0.68, 2.89)
0.92 (0.45, 1.89)
1.25 (0.62, 2.50)
1.92 (0.77, 4.77)
0.90 (0.37, 2.19)
1.12 (0.56, 2.24)
1.39 (1.19, 1.63)
1.90 (0.64, 5.58)
1.26 (0.34, 4.67)
1.01 (0.06, 16.03)
1.36 (1.19, 1.56)
.1
.5
2
3.4
4.4
4.0
2.0
2.9
4.0
76.3
1.4
1.2
0.3
100.0
10
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.
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.
20
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,  Shiva Goudar, MD
MPH
 Stacie Geller, PhD
 Bhala Kodkany, MD
 Stanley Edlavitch, PhD
 V.J. Naik, MD
 Ashlesha Patel, MD, MPH

21
Study Sponsors
22
Global Network for Women’s & Children’s
Health Research, Site 8
J N Medical College, Belgaum, Karnataka India
23
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
25
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
26
Primary
Outcome

Objective
Measurement of
Blood Loss

BRASSS-V®
Blood Collection
Drape with
Calibrated
Receptacle
BRASSS-V Blood Collection Drape
with Calibrated Receptacle
28
Primary Hypothesis
Misoprostol administered during the
third stage of labor will significantly
reduce the incidence of acute
postpartum hemorrhage by 50%.
29
Study Sample
 1600
women
800 – Misoprostol
800 - Placebo
 Delivering
at home or at
sub-center
 Normal
 Not
vaginal deliveries
deemed to be high-risk
30
Study Sites

PHCs
4
Hirebagewadi, Bhendigeri,
Neginhal, Yamakanmaradi

Sub Centers
19

Villages
43

Population

ANMs
98,679
19
31
32
OB Clinic and Labor & Delivery
33
Postpartum
Unit and
Research
Storage
Facility
34
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
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)
9.61 (0.9)
9.62 (0.9)
Hemoglobin (gm/dl) [Mean (sd)]
Obstetrical Indices
Misoprostol
Estimated GA at Delivery (weeks)
mean (sd)
Preterm Delivery (%)
Duration of Labor (hours)
38.9
(1.7)
173 (21.3)
7.97
Placebo
38.9
(1.8)
181 (22.4)
7.91
37
Primary Outcome: PPH Rates
Primary Outcome
Postpartum
Hemorrhage
(blood loss  500 ml)
Severe Postpartum
Hemorrhage
(blood loss  1,000 ml)
Misoprostol
(n= 812*)
n (%)
53 (6.5)
2 (0.2)
Placebo
(n=805)
n (%)
P-value
97 (12.0)
10 (1.2)
ss
0.0001
Oral Misoprostol in Preventing
Postpartum Hemorrhage in Resourcepoor Communities: A Randomized
Controlled Trial
Lancet 2006; 368: 1248-53.
39
NNT
One case of postpartum
hemorrhage was
prevented for every 18
women who received
misoprostol.
40
Postpartum Hemorrhage Rates for Data Review
Periods of Randomized Women by Treatment
20
17.7
18
Misoprostol
Placebo
16
14
12.3
12.0
% PPH
12
9.5
10
9.2
8.3
8
6.7
6.5
6.4
6
4
n=219
n=254
n=119
2
n=256
n=121
n=220
1.9
n=808
n=216
n=811
n=215
0
1
2
3
4
Overall
Data Review Periods
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
Placebo
count (%)
count (%)
Nausea
35 (4.3)
29 (3.6)
Vomiting
28 (3.5)
25 (3.1)
Diarrhea
9 (1.1)
5 (0.6)
419 (51.8)
140 (17.4)
34 (4.2)
9 (1.1)
(n=812)
Shivering
Fever
(n=805)
Neonatal Side Effects
Misoprostol
(N=812)
Placebo
(N=805)
Side Effects
count (%)
Vomiting
26 ( 3.2)
40 ( 5.0)
Diarrhea
4 ( 0.5)
3 ( 0.4)
Fever
8 ( 1.0)
8 ( 1.0)
count
(%)
WHO Recommendations
for the Prevention of
Postpartum Hemorrhage
Misoprostol added to the essential
medicine list, 2011
World Health Organization
44
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.
45
Confirmatory Trial Results

 PPH (500ml) by 24%

 in Hgb by 3 gms (47%)
Mobeen, N et al. BJOG, Oct. 2010.
46
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
47
instrumental deliveries
Prevention of Pospartum Hemorrhage with
Sublingual Misoprostol or Oxytocin: A
Double Blind Randomized Controlled Trial
Sample: Study group characteristics similar
Misoprostol
n=323
Oxytocin p
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.
48
17 Countries for PPH prevention
49
50