Program Strategies to Reduce Post-Partum Hemorrhage and Pre-Eclampsia/Eclampsia: A practical review of research findings

John Varallo, Khatidja Naithani, & Rehana Gubinon behalf of the MCHIP Maternal Health Team

Lunchtime RoundtableCORE Group Spring Meeting 2013

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Integrative reviews on PPH and PE/E recently published in BMC Pregnancy & Childbirth

Side effects of magnesium sulfate for PE/E management

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IS MgSO4 A DANGEROUS DRUG?

What is PE/E?

Pre-eclampsia / eclampsia (PE/E) is a life-threatening multisystem disorder

A common cause of maternal and perinatal morbidity and mortality 9% of maternal deaths in Asia / Africa 25% of maternal deaths in Latin America / Caribbean

Global focus on prevention, detection and management strategies Expansion of use of MgSO4

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Magnesium sulfate (MgSO4)

Drug of choice for prevention and management of eclamptic seizures

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Significantly more effective than diazepam or phenytoin in preventing seizures in PE/E MCETG, Magpie, Cochrane

Use re-affirmed in WHO Clinical Guidelines 2011

However…

Universal and consistent use of MgSO4 has been very slow to take hold

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Fear that MgSO4 is highly toxic

“We all know of many cases of death due to MgSO4 overdose.”

“We mustn’t let lower level workers use it due to toxicity”

“Hospitals and facilities should have calcium gluconate available to manage overdose”

“Magnesium sulfate is a dangerous drug!”

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Potential Side Effects of MgSO4

Minor - feeling of warmth, flushing, nausea and vomiting, muscle weakness, somnolence, dizziness, and irritation at the injection site

More serious Loss of patellar reflex (typically at a serum

concentration of >8 -10 mEq/L) Respiratory depression (>15 mEq/L)

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Research Questions Incidences of side effects of absent

patellar reflex and respiratory depression?

Frequency of use of Ca++ gluconate to counteract the effects of MgSO4 in response to detected side effects?

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Frequency of skipped or delayed doses of MgSO4 in response to development of side effects?

How many maternal deaths of women with severe PE/E have been reported to be attributed to toxicity of MgSO4 rather than from manifestations of the underlying disease?

Results Overview

Overall Outcome Rates all studies in 9556 subjects

Affected Patella Reflex

Respiratory Depression

Oliguria Skipped Dose

Calcium Gluconate

use

Incidence 1.6% 1.3% 2.5% 3.6% 0.2%

One maternal death reported by authors as due to MgSO4

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Results: Maternal death attributed to MgSO4

0.01% 1 / 9556 women in all groups Total maternal deaths (all causes) 91 / 9556Authors reported that cause was severe respiratory depression.

Woman’s serum magnesium was 24 mEq/L, which is well above therapeutic level

Death reported in small trial with 54 participants Magpie trial (n= 5055) had no deaths

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Estimates of clinical impact

Affected Patellar Reflex

Respiratory depression

Skipped or delayed dose

Calcium gluconate use

Incidence 1.6% 1.3% 3.6% 0.18%NNH: Number needed to harm

61 77 27 555

Scenario: Hospital delivers 5000 women annually. Assuming 5% rate of PE/E, 250 women annually will require MgSO4 in treatment

Frequency of 1 case

2.9 months 3.7 months 1.3 months 26.7 months

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Routine Monitoring of MgSO4 Use

Neurologic status (level of alertness and patellar reflexes)

Respiratory rate Urinary output (Oliguria is element of disease

process) Typical management of more serious side

effects: ↑ monitoring, delay next dose or suspend MgSO4 therapy, counteraction with calcium gluconate

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Monitoring of MgSO4 Use

Conclusions: MgSO4 is a safe drug

Findings indicate: Low incidence of severe side effects (1-2%) When adverse effects occur, delaying the next scheduled dose is generally sufficient to mitigate the effect. Maternal mortality directly attributable to use of MgSO4 was extremely rare.

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MgSO4 is NOT a dangerous drug

Conclusions: Policy and Practice

Severe PE/E should be diagnosed and treated with appropriate drugs, MgSO4 is anticonvulsant of choice

Women under treatment with MgSO4 need reasonable vigilance for side effects Simple protocols should be in place to manage

side effects All clinical leaders in maternal health should guide

adoption / use of MgSO4 as standard of care Including ensuring adequate supply of MgSO4

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Community-based distribution of misoprostol for PPH prevention

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Photo: Save the Children

What is PPH?

Blood loss >500mL in the first 24 hours after delivery

Severe PPH is loss of 1000mL or more.

Accurately quantifying blood loss is difficult in most clinical or home settings.

Many severely anemic women cannot tolerate even 500 mL blood loss

PPH: Leading Cause of Maternal Mortality

Hemorrhage is a leading cause of maternal deaths 35% of global

maternal deaths estimated 132,000

maternal deaths 14 million women in

developing countries experience PPH—26 women every minute

34%

31%

21%

0%

5%

10%

15%

20%

25%

30%

35%

40%

Africa Asia Latin America & theCaribbean

Sources: Khan et al., 2006; POPPHI, 2009; Taking Stock of Maternal, Newborn and Child Survival, 2000–2010 Decade Report

PPH Prevention

1. Active management of the third stage of labor (AMTSL) During deliveries with a skilled provider Prevents immediate PPH Associated with almost 60% reduction in PPH

occurrence1. Misoprostol

During home births without a skilled provider Community-based counseling and distribution of

misoprostol

Global Context

Inclusion on 2011 WHO Essential Drug List

Qualifications in 2012 WHO Recommendations “If a skilled attendant is not present, and

oxytocin is not available (such as at an unattended home birth), lay health workers should administer 600 mcg of oral misoprostol.”

“There is insufficient evidence to recommend the antenatal distribution of misoprostol to pregnant women for self-administration for the prevention of PPH.”

Evidentiary Gaps

2012 Cochrane review noted need for more information on:

Feasibility of misoprostol reaching the end-user (coverage)

Patient outcomes after use Adverse effects from misuse Outcomes useful to

policymakers, such as resource utilization

Research Questions

What is the range of implementation strategies for programs distributing misoprostol for the prevention of PPH at home births?

Which strategies achieve high distribution and coverage rates?

Do misoprostol programs adversely affect facility birth rates?

What is the incidence of adverse outcomes for misoprostol users, especially of mistimed administration before birth?

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Country # enrolled # took miso

Afghanistan 2 039 1 350

Bangladesh 53 897 46 561

Bangladesh 1 009 884

Bangladesh 19 497 9 228

Ethiopia 500 485

Gambia 630 630

Ghana 5 345 1 261

India 812 809

Indonesia 1 322 999Kenya 3 844 1 084Mozambique 11 927 4 781Nepal 18 761 13 969Nigeria 1 875 1 421Pakistan 534 533Pakistan 872 678Tanzania 12 511 1 826Zambia 5 574 233

Zambia 31 315 Not reported

18 studies or programs included

Not all enrolled women received misoprostol

86,732 women took misoprostol

12,615 were followed-up Results presented based on

number of women on whom condition was reported (i. e . , d a ta is inc o m p le te )

Results Overview

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When was misoprostol distributed?

Timing of Distribution # programs

(n =18)% of

programs

Any antenatal care visit (>12 weeks) 4 22.2%

Late pregnancy home visit (28–32 weeks) 4 22.2%

Late pregnancy antenatal care visit (>28 weeks) 3 16.7%

At home birth 10 55.6%

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Who distributed the misoprostol?

Distributing Cadre # programs (n

=18)% of

programs

Community health worker 5 27.8%

Traditional birth attendant 7 38.9%

Health workers/ANC providers 8 44.4%

Other (FP field worker, community drug keeper) 2 11.1%

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Who administered the misoprostol?

Person Administering# programs (n

=18)% of

programs

Self-administered 11 61.1%

Traditional birth attendant 9 50.0%

Community health worker 1 5.6%

SBA or semi-skilled health worker 3 16.7%

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Distribution rates: 21.0% – 96.6% % of women in target population who received misoprostol

Coverage rates: 16.2% – 93.8% % of women who delivered at home who used misoprostol

Only 10 of the 18 programs provided sufficient information to reliably calculate coverage rates

Measuring “Success”: Distribution and Coverage Rates

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Distribution Timing  Distributing Cadre Administration Method 

ANC DistributionHome Visit

(late pregnancy)

At home birth

Comm-unity

health worker

Traditional birth

attendant

Health worker/

ANC provider

SelfTraditional

birth attendant

SBA or semi-skilled health worker

Any visit Late visit

Distribution Rate or Rate Range

22.5–49.1%

21.0–26.7%

 54.5–96.6% 

22.5–83.6%

54.5–96.6%

25.9–86.5%

21.0–49.1%

21.0–96.6%

25.9–86.5% 22.5%

Coverage Rate or Rate Range

16.8–65.9%

16.2–35.9% 55.7–93.8% 16.8–

73.5%87.9–93.8%

35.9–73.5%

16.2–65.9% 

16.2–93.8%

35.9–73.5% 16.8% 

Distribution & Coverage Rates by Implementation Strategy

Distribution of misoprostol by community workers (TBAs or CHWs) during home visits late in pregnancy achieved greatest distribution and coverage, potentially more than double the coverage achieved by programs where distribution was through health workers or as a part of ANC services.

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Three programs (Nepal, Afghanistan and Zambia) reported the change in facility birth rate in program areas

Programs were not powered to measure a statistically significant change

In these three programs, facility birth rates increased in the target areas

No Adverse Change in Facility Birth Rates

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Low Incidence of Adverse Outcomes

Outcomes # of occurrences

(total # of women taking misoprostol at home

births)

Frequency

(Range)

Administration Prior to Birth

7 (12 615) 0.06% (0%–0.23%)

Total Maternal Deaths 51 (86 732) 0.06% (0%–1.72%)

Deaths due to PPH 24 (86 732) 0.03% (0.00%–0.16%)

Deaths attributed to misoprostol

0 (86 732) 0%

Perceived PPH 194 (72 534) 0.3% (0%–8.9%)

Other adverse outcomes requiring hospital referral 27 (86 732) 0.03% (0%–0.3%)

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If programs want high coverage, they should design programs with population coverage in mind, considering: In-home distribution, by CHWs or TBAs, and Self-administration with adequate education & counseling.

Mistimed self-administration is rare and should not be a reason to limit program development.

Limited available data suggest that programs do not counter national strategies to promote facility-based births.Our review suggests that ANC-only distribution

achieves 50% less coverage, so it likely does not protect those who need coverage the most.

Conclusions for Practice

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Continuing Program Evidence

Thank you!

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