Introductions from John, Khatidja & Rehana We’re here on behalf of the entire MCHIP Maternal Health Team, led by Jeff Smith. At this roundtable, we’ll be discussing the findings of two recent publications that were led by Jeff Smith and that discuss two key maternal health commodities: magnesium sulfate for the management of pre-clampsia/eclampsia, or PE/E, and misoprostol for the prevention of postpartum hemorrhage, or PPH. We’ll be highlighting the findings that are most relevant for program managers and the steps that programs can take to incorporate these lessons into their work. As you all know, PPH and PE/E continue to be leading causes of maternal mortality in developing countries, so we think it’s helpful to have this forum to discuss them together.
Both of the articles we’re discussing were published earlier this year in BMC Pregnancy and Childbirth . They’re available for free online, and we also have copies available here. Both articles were collaborations with Venture Strategies International, or VSI, in Berkeley, California, and the PE/E article has an author from the Johns Hopkins Bloomberg School of Public Health. Judith Fullerton, a nurse-midwife and independent consultant, is the one who suggested the “integrative review” design. For those who aren’t familiar with “integrative reviews,” they’re similar to systematic reviews in that they use a pre-defined literature search strategy, but they include grey literature in addition to peer-reviewed literature, so they’re a more useful way to find and evaluate operational evidence that isn’t often published in peer-reviewed literature. We’ll talk about each article for approximately 15 minutes and then leave 30 minutes for discussion. John and Khatidja will take the first article, which examines the safety of magnesium sulfate for PE/E. Rehana will take the second article, on community-based distribution of misoprostol for the prevention of PPH at home birth.
As with any drug, we have to balance the risk of side effects with potential benefits. But we also have to have good data on side effects to appropriately estimate risk. This picture depicts a woman suffering from severe pre-eclampsia, and therefore a candidate for magnesium sulfate.
MgSO4 is an anti-convulsant. We have a copy of the 2011 WHO Clinical Guidelines here for anyone who is interested.
This shows countries’ uptake of four maternal health commodities: oxytocin and misoprostol for PPH, and magnesium sulfate and diazepam for severe PE/E. Many countries (those with both green and purple bars above the line) include both MgSO4 and diazepam as their national policy standard for severe PE/E, which creates confusion and resistance among providers who are more comfortable using diazepam, even though magnesium sulfate is the drug of choice. We are working to make magnesium sulfate the sole national standard for PE/E.
These are some common statements we hear about magnesium sulfate in the countries in which we work. Overdose and toxicity is a big concern -- but this can usually be addressed by simply delaying the next scheduled dose. The goal of our review was to systematically identify any data that might support or refute these claims.
From our review of the clinical literature on magnesium sulfate, we knew that these are the potential side effects of magnesium sulfate.
Based on the potential known side effects, we came up with these research questions and designed our literature search strategy around them. We searched for all types of prospective clinical studies where (1) magnesium sulfate was used to manage pre-eclampsia or eclampsia, (2) the study was conducted in a developing country, and (3) the study recorded the incidence of any adverse side effect resulting from magnesium sulfate use.
We included a total of 24 studies, which in the aggregate administered magnesium sulfate to 9556 women and recorded adverse events. This chart presents the overall incidence of five adverse events: affected patella reflex, respiratory depression, oliguria, skipped dose, and calcium gluconate use. As you can see, the incidence of each is extremely low!
There was only one maternal death attributed to magnesium sulfate use among the 9556 women using magnesium sulfate in these 24 studies. There were 90 maternal deaths attributed to other causes. The one attributed death was in a small trial, of a woman who had an extremely elevated serum magnesium level. A large trial with over 5000 participants reported no deaths attributed to magnesium sulfate use.
Taking the incidence rates from the previous slide, we show here the frequency of having one case experiencing these side effects in a hospital that delivers 5000 women annually and where the prevalence of PE/E is 5%, the average global prevalence. Again, these effects are rare. [John to provide explanation of the NNH row if needed.]
To manage the side effects that do occur, a few simple routine monitoring steps can be taken, including a neurologic and respiratory status check and measurement of urinary output. All of these should be performed anyway for patients with severe PE/E! For more serious side effects, magnesium sulfate therapy can be delayed or suspended, or calcium gluconate can be administered.
These picture show a patient with severe PE being monitored.
Our review concluded that magnesium sulfate should be considered a safe drug, with a low incidence of severe side effects and almost no attributable mortality. Side effects can usually be managed by simply delaying the next scheduled dose.
Our findings call for increased awareness of magnesium sulfate as the drug of choice to manage severe PE/E, and for better understanding of the actual incidence of its side effects and ways to best manage them. Clinical leaders and program staff should enable the use of magnesium sulfate as the standard of care for PE/E, a significant cause of maternal mortality.
Specifically reported for 25 study groups. Overall incidence among all 9556 women was 1.3%, with the incidence ranging from 0-8.2%. In the three studies that reported very high incidences of absent patellar reflex, the incidence of respiratory depression was less than 1%.
Use of calcium gluconate reported for 12 of the 34 subject groups. Administered only 17 times, resulting in an overall rate among 9,556 women of less than 0.2%. In one study, Ca gluconate was administered following a dosing error which resulted in administration of 4g of MgSO4 in one hour instead of four hours.
We now turn to the second article, on implementation strategies for community-based distribution of misoprostol for PPH prevention. As you all know, community-based care is essential to reach those women who don’t come to facilities. This review asked the question: what do we know about ways in which misoprostol has been distributed at the community level for the prevention of PPH at home births, which often make up the majority of births in developing countries?
First, a brief primer on PPH. It is very difficult to determine and treat PPH in most clinical settings in developing countries, let alone at home births, so we need PREVENTION .
PPH is the leading cause of maternal mortality—accounting for more than 1/3 of global maternal deaths--and disproportionately affects the developing world. Women in sub-Saharan Africa have a 1 in 39 lifetime risk of dying from pregnancy or childbirth, contrasted with 1 in 3800 in developed countries.
There are two strategies that we know prevent PPH: active management of the third stage of labor and administration of misoprostol immediately after birth. Misoprostol is the only one of the two that is possible without a skilled provider present. It can be distributed before birth and administered either by the women herself or by a person attending the birth, such as a TBA. It’s most commonly distributed as a small package of three sea-blue tablets, each 200mcg for a total dose of 600mcg.
In 2011, WHO reversed its previous position not to include misoprostol on its Model List of Essential Medicines for the prevention of PPH. In 2012, however, the WHO qualified its endorsement of misoprostol for PPH prevention by recommending its administration by CHWs but not by self-administration. The WHO stated that there was insufficient evidence to distribute misoprostol to pregnant women through antenatal care for self-administration at birth. We have a copy of these 2012 WHO Recommendations for anyone interested.
There was also a 2012 Cochrane review that requested more information on misoprostol coverage and adverse outcomes.
MCHIP and VSI were aware of a number of programs that were using community-based distribution of misoprostol both by CHWs and for self-administration at home births. We asked ourselves, what information could we collect and publish about these programs to give WHO and the global community the information they needed to feel comfortable recommending advance distribution of misoprostol for use at home births? We chose these research questions to inform our literature search strategy—only literature that was responsive to at least one of these questions was included in our review. In addition to publishing the integrative review answering these research questions, MCHIP is working closely with WHO to prepare a database of evidence on projects that are predominately using self-administration.
Through our integrative review, we identified 18 studies or programs in 14 separate countries, which had administered misoprostol to more than 86,000 women. Some of those programs were designed to follow up with a small subsample of women to obtain information about use, so we tried to identify the subpopulation of misoprostol users on whom follow-up data was collected and found 12,615 women across these 18 programs.
We found three main types of program design characteristics, what we’ve called “implementation strategies”: the timing of distributing, the person distributing the misoprostol, and the person administering the misoprostol. Some programs used more than one strategy, such as programs that distributed misoprostol at ANC and then, as a catch-all, to women at home birth. This shows the range of timing choices that programs reported using: at any ANC visit after 12 weeks, at a late pregnancy home visit, at a late ANC visit, or at the home birth itself.
This shows the range of cadres that the programs reported using—again, some programs used more than one distribution strategy and cadre, such as health workers at ANC visits and then TBAs at birth.
This shows the range of persons permitted by the program to administer the misoprostol. A majority of the programs allowed self-administration, which gave us useful information responding directly to the WHO’s concerns.
We decided that one way to measure the success of these programs was to determine how well they got misoprostol into the hands of pregnant women or providers who could use it, what we called the “distribution rate,” and also how well they got pregnant women to actually take it, what we called the “coverage rate.” More specifically, we defined the “distribution rate” as the proportion of pregnant women in a program’s catchment area who received misoprostol for PPH prevention. We defined the “coverage rate” as the proportion of women who delivered at home in the catchment area (actual or estimated) who used misoprostol for PPH prevention. As you might expect, a number of the program reports did not contain definite information about these specific numerators and denominators. In fact, only 10 of the 18 programs contained sufficient information to calculate at least one of these two rates. Part of the intent of this review was to suggest the type of data that we think programs should collect so we can build a sufficient evidence base.
When we disaggregated the few distribution and coverage rates that we could collect, we found that distribution by community workers late at home visits late in pregnancy achieved the greatest distribution and coverage. If more programs collected this information, we would have more data points to cross-reference.
One common concern about community-based misoprostol programs is that giving women misoprostol will encourage them to deliver at home and not come to facilities. The programs we reviewed did not contain much concrete data to support or refute that claim, but the three programs that did try to measure a change in facility use among misoprostol users found an increase in facility birth rates in the target areas.
Similar to magnesium sulfate, concerns persist about adverse outcomes in women using misoprostol, so we collected whatever information was available on these outcomes in the program reports. There appears to be a very low incidence of these outcomes, including the PPH that misoprostol is designed to prevent, in women using misoprostol. While there were a total of 51 deaths attributed to misoprostol among the more than 86,000 users, no maternal death was attributed to misoprostol . To the specific concern that women might take the drug at the incorrect time, and particularly taking it before birth occurs, we found that only 7 out of more than 12,000 women, or just 0.06%, reported this happening. Associating those cases with their program implementation strategies, we found that: More cases reported when distributed at any ANC visit compared to home distribution, and More cases when distributed by health worker or ANC provider compared with distribution by any other distributing cadre. Incorrect administration might not be an issue that requires ANC distribution or distribution by a skilled health provider.
Misoprostol is safe and effective for PPH prevention at home births. Programs need to be designed with population coverage in mind and consider using home visits for distribution and allowing self-administration with appropriate education and counseling. Distributing misoprostol at ANC visits only, as the WHO currently recommends, is not likely to achieve the coverage needed to protect women at home births.
We conclude with the story of our first misoprostol client, Alice, this past August in South Sudan, a country with an MMR above 2000. Alice took the 3 misoprostol tablets given to her by an attendant immediately after the delivery of the baby. She explained that she was examined on the abdomen after baby was born and, before delivery of the placenta, swallowed the misoprostol tablets with a glass of water. Alice reported that she experienced coldness, was covered by a blanket for a short time and the coldness disappeared. She had little bleeding which was normal. She is now happy with her baby. We’re continuing to gather evidence to show that community-based distribution of misoprostol works. We encourage all of you who work on misoprostol programs to look at our recommendations for the data that we think should be collected and get this data into the peer-reviewed or grey literature.
If you don’t have time to read the entire articles, we have 2-page briefs with us about each one. You can also find these briefs and other information about our PE/E and PPH programs at www.mchip.net.
Program Strategies to Reduce Post-Partum Hemorrhage and Pre-Eclampsia_John Varallo_Khatidja Naithani_Rehana Gubin_4.24.13
ProgramStrategies to Reduce Post-PartumHemorrhage and Pre-Eclampsia/Eclampsia: A practicalreview of research findingsJohn Varallo, Khatidja Naithani, & Rehana Gubinon behalf of the MCHIPMaternal Health TeamLunchtime RoundtableCORE Group Spring Meeting 20131
Integrative reviews on PPH and PE/Erecently published in BMC Pregnancy &Childbirth
Side effects of magnesiumsulfate forPE/E management3IS MgSO4 ADANGEROUSDRUG?
What is PE/E? Pre-eclampsia / eclampsia (PE/E) is a life-threatening multisystem disorder A common cause of maternal and perinatalmorbidity and mortality 9% of maternal deaths in Asia / Africa 25% of maternal deaths in Latin America / Caribbean Global focus on prevention, detection andmanagement strategies Expansion of use of MgSO44
Magnesiumsulfate (MgSO4) Drug of choice for prevention and managementof eclamptic seizures5 Significantly more effectivethan diazepam orphenytoin in preventingseizures in PE/E MCETG, Magpie, Cochrane Use re-affirmed in WHOClinical Guidelines 2011
However… Universal and consistent use of MgSO4 hasbeen very slow to take hold6
Fearthat MgSO4 is highly toxic “We all know of many cases of death due toMgSO4 overdose.” “We mustn’t let lower level workers use it due totoxicity” “Hospitals and facilities should have calciumgluconate available to manage overdose” “Magnesium sulfate is a dangerous drug!”7
Potential Side Effects of MgSO4 Minor - feeling of warmth, flushing, nauseaand vomiting, muscle weakness,somnolence, dizziness, and irritation at theinjection site More serious Loss of patellar reflex (typically at a serumconcentration of >8 -10 mEq/L) Respiratory depression (>15 mEq/L)8
Research Questions Incidences of side effects of absentpatellar reflex and respiratorydepression? Frequency of use of Ca++gluconate to counteract the effectsof MgSO4 in response to detectedside effects?9 Frequency of skipped or delayed doses of MgSO4 inresponse to development of side effects? How many maternal deaths of women with severe PE/Ehave been reported to be attributed to toxicity of MgSO4rather than from manifestations of the underlyingdisease?
Results OverviewOverall Outcome Rates all studies in 9556 subjectsAffectedPatellaReflexRespiratoryDepressionOliguria SkippedDoseCalciumGluconateuseIncidence 1.6% 1.3% 2.5% 3.6% 0.2%One maternal death reported by authors as due to MgSO410
Results:Maternal death attributed to MgSO40.01%1 / 9556 women in all groupsTotal maternal deaths (all causes) 91 / 9556Authors reported that cause was severe respiratorydepression. 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 deaths11
Estimates of clinical impactAffectedPatellarReflexRespiratorydepressionSkipped ordelayed doseCalciumgluconate useIncidence 1.6% 1.3% 3.6% 0.18%NNH:Numberneeded toharm61 77 27 555Scenario: Hospital delivers 5000 women annually. Assuming 5% rate of PE/E,250 women annually will require MgSO4 in treatmentFrequency of1 case2.9 months 3.7 months 1.3 months 26.7 months12
Routine Monitoring of MgSO4 Use Neurologic status (level of alertness andpatellar reflexes) Respiratory rate Urinary output (Oliguria is element of diseaseprocess) Typical management of more serious sideeffects: ↑ monitoring, delay next dose orsuspend MgSO4 therapy, counteraction withcalcium gluconate13
Conclusions:MgSO4 is a safe drugFindings indicate:Low incidence of severe side effects (1-2%)When adverse effects occur, delaying the nextscheduled dose is generally sufficient to mitigatethe effect.Maternal mortality directly attributable to use ofMgSO4 was extremely rare.15MgSO4 is NOT a dangerous drug
Conclusions:Policy and Practice Severe PE/E should be diagnosed and treatedwith appropriate drugs, MgSO4 is anticonvulsant of choice Women under treatment with MgSO4 needreasonable vigilance for side effects Simple protocols should be in place to manageside effects All clinical leaders in maternal health should guideadoption / use of MgSO4 as standard of care Including ensuring adequate supply of MgSO416
Community-based distribution ofmisoprostol forPPHprevention26Photo: Save the Children
What is PPH? Blood loss >500mL in thefirst 24 hours afterdelivery Severe PPH is loss of1000mL or more. Accurately quantifyingblood loss is difficult inmost clinical or homesettings. Many severely anemicwomen cannot tolerateeven 500 mL blood loss
PPH: Leading Cause of MaternalMortality Hemorrhage is a leadingcause of maternal deaths 35% of globalmaternal deaths estimated 132,000maternal deaths 14 million women indeveloping countriesexperience PPH—26women every minute34%31%21%0%5%10%15%20%25%30%35%40%Africa Asia Latin America & theCaribbeanSources: Khan et al., 2006; POPPHI, 2009;Taking Stock of Maternal, Newborn and ChildSurvival, 2000–2010 Decade Report
PPHPrevention1. Active management of the third stage of labor(AMTSL) During deliveries with a skilled provider Prevents immediate PPH Associated with almost 60% reduction in PPHoccurrence1. Misoprostol During home births without a skilled provider Community-based counseling and distribution ofmisoprostol
Global Context Inclusion on 2011 WHO Essential DrugList Qualifications in 2012 WHORecommendations “If a skilled attendant is not present, andoxytocin is not available (such as at anunattended home birth), lay healthworkers should administer 600 mcgof oral misoprostol.” “There is insufficient evidence torecommend the antenatal distribution ofmisoprostol to pregnant women for self-administration for the prevention ofPPH.”
Evidentiary Gaps2012 Cochrane review notedneed for more informationon: Feasibility of misoprostolreaching the end-user (coverage) Patient outcomes after use Adverse effects from misuse Outcomes useful topolicymakers, such as resourceutilization
Research Questions What is the range of implementationstrategies for programs distributing misoprostolfor the prevention of PPH at home births? Which strategies achieve high distributionand coverage rates? Do misoprostol programs adversely affectfacility birth rates? What is the incidence of adverse outcomes formisoprostol users, especially of mistimedadministration before birth?
33Country # enrolled # tookmisoAfghanistan 2 039 1 350Bangladesh 53 897 46 561Bangladesh 1 009 884Bangladesh 19 497 9 228Ethiopia 500 485Gambia 630 630Ghana 5 345 1 261India 812 809Indonesia 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 233Zambia 31 315 Not reported 18 studies or programsincluded Not all enrolled womenreceived misoprostol 86,732 women tookmisoprostol 12,615 were followed-up Results presented based onnumber of women on whomcondition was reported (i. e . ,data is inco m ple te )Results Overview
34When was misoprostol distributed?Timing of Distribution# programs(n =18)% ofprogramsAny antenatal care visit (>12weeks)4 22.2%Late pregnancy home visit(28–32 weeks)4 22.2%Late pregnancy antenatalcare visit (>28 weeks)3 16.7%At home birth 10 55.6%
35Who distributed the misoprostol?Distributing Cadre# programs (n=18)% ofprogramsCommunity 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%
36Who administered the misoprostol?Person Administering# programs (n=18)% ofprogramsSelf-administered 11 61.1%Traditional birth attendant 9 50.0%Community health worker 1 5.6%SBA or semi-skilled healthworker3 16.7%
37 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 sufficientinformation to reliably calculate coverage ratesMeasuring “Success”: Distributionand Coverage Rates
38Distribution Timing Distributing Cadre Administration Method ANC DistributionHome Visit(latepregnancy)At homebirthComm-unityhealthworkerTraditionalbirthattendantHealthworker/ANCproviderSelfTraditionalbirthattendantSBA orsemi-skilledhealthworkerAny visit Late visitDistributionRate orRateRange22.5–49.1%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%CoverageRate orRateRange16.8–65.9%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 byImplementation StrategyDistribution of misoprostol by community workers (TBAs orCHWs) during home visits late in pregnancy achieved greatestdistribution and coverage, potentially more than double thecoverage achieved by programs where distribution was throughhealth workers or as a part of ANC services.
39 Three programs (Nepal,Afghanistan and Zambia)reported the change in facilitybirth rate in program areas Programs were not powered tomeasure a statisticallysignificant change In these three programs, facilitybirth rates increasedin thetarget areasNo Adverse Change in Facility BirthRates
40Low Incidence of Adverse OutcomesOutcomes # of occurrences(total # of women takingmisoprostol at homebirths)Frequency(Range)Administration PriortoBirth7 (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 tomisoprostol0 (86 732) 0%Perceived PPH 194 (72 534) 0.3% (0%–8.9%)Otheradverse outcomesrequiring hospital referral 27 (86 732) 0.03% (0%–0.3%)
41 If programs want high coverage, they should designprograms 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 areason to limit program development. Limited available data suggest that programs do not counternational strategies to promote facility-based births.Ourreview suggests that ANC-only distributionachieves 50% less coverage, so it likely does notprotect those who need coverage the most.Conclusions forPractice