Misoprostol for Preventing Postpartum Hemorrhage and for

Postabortion Care

Harshad SanghviPatricia Stephenson

MAQ 2006 Mini University, 27 0ctober 2006

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.

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.

Definition of PPHDefinition 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

Incidence of PPH

Blood Loss (n = 434)Blood Loss (n = 434)

Mean + SE 265.18 + 10.95

Range 20 - 1600

Median 200

Mode 100

Acute PPH 57 (13.2 %)

Acute severe PPH

8 (1.8 %)

Goudar, Eldavitch, Bellad, 2003

Etiology of PPH

Uterine atony (~3/4 cases)

Other •Episiotomy•Retained placenta•Trauma - uterine rupture, inversion,

cervical laceration, vaginal hematoma•Postpartum infections•Rarely : Coagulopathy

Risk Factors for PPH

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

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

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

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 risk 0.38 (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

Comparison of Uterotonics

Programmatic considerations

Oxytocin (IM)

Ergometrine(IM)

Misoprostol (PO or

sublingual)

Effectiveness +++ ++ +++

Need skilled provider

yes yes no

Suitable for home birth

no no yes

Side effects rare common rare

Contraindications

none High BP none

Refrigeration needed

yes yes no

Therapeutic effect

immediate

immediate within minutes

Misoprostol mystery madness (boo!)

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 3rd stage 3

Similar reduction in length of 3rd 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

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, Høj BMJ 2005

RCT of misoprostol compared to placebo for home birth in rural India

Primary Outcome Misoprostol

(N= 812*)

N (%)

Placebo

(N=808)

N (%)

RelativeRisk

(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 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 IndiaPrevention of Postpartum Hemorrhage at Four Primary Health Center Areas of Belgaum District, Karnataka India

Conclusive Evidence:

Blood Loss Distribution

MM PP

9595thth Percentile Percentile

M: 500 mlM: 500 ml

P: 800 mlP: 800 ml

Completed programs• Indonesia, Gambia,

Guinea BissauNew 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

Treatment of PPH

Even under the best circumstances, all PPH is not preventable

Once severe PPH occurs, death can follow very rapidly

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

Promising Interventions

Home based Life Saving Skills

MisoprostolHydrostatic tamponade

Issues and Challenges

Policy and supportive environmentSupply chain logisticsHuman capacity and trainingCommunity involvement and mobilizationReferral links

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

Definitions

Early: before 12 weeksLate: between 12 & 20 weeksThreatened miscarriage: spotting or cramping in 1st 20 weeks – usually with a viable continuing pregnancyIncomplete: expulsion of only part of the uterine contents or rupture of the membranesComplete: expulsion of all products of conceptionMissed: retention of a dead embryo or fetus

Treatment Options

SurgeryManual vacuum aspiration (MVA)Electric/foot pump vacuum aspirationSharp curettage

Expectant managementMedical management with misoprostol

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 infectionShockSuspicion of ectopic pregnancyIUD in place (remove)

Misoprostol 600 mcg

MVA RR(95% CI)

Complete Evacuation

96.3 91.5 1.05(0.98 -1.14)

Complications

0.9% 9.8% 0.01(0.01-0.78)

Acceptability

94.2% 94.7%

Source: Weeks et al 2005Increased bleeding for 6 hours, decreased pain with misoprostol

Evidence: Uganda

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

Misoprostol: Evidence

Zhang et al NEJM 2005RCT 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 8Both groups satisfied with treatmentMiso instead of aspiration used in an outpatient setting reduces the costs of services

Evidence: Efficacy

Success rates66-100% for incomplete abortion using recommended dose of 600 mcg orally60-93% for missed abortion using recommended dose of 800 mcg vaginallyHighest success rates are achieved with extended follow up (7-14 days) to allow completion of expulsion

Evidence: Safety

Side effects: (short lived)Nausea and vomitingDiarrheaFever, chillsCrampingBleeding

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.

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.

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?