Gynuity Health Projects

Programs

Postpartum Hemorrhage

Overview

Postpartum hemorrhage (PPH) is a major cause of maternal death and accounts for more than one quarter of all such deaths in low-resource regions of the world. Since 2004, Gynuity Health Projects has been collaborating with partners to conduct clinical and programmatic research, generate and synthesize evidence to inform policy and practice, and provide technical assistance to governments and other key stakeholders in order to address gaps in PPH care. We focus especially on developing and translating the scientific evidence on misoprostol into effective policies, programs and practices for PPH prevention and treatment.

Research
Gynuity assesses technologies, in particular misoprostol, and interventions that are appropriate for PPH care in low-resource environments and community settings. We design and evaluate service delivery and program approaches to: a) improve the availability and use of low cost technologies for the management of PPH; and b) facilitate timely and effective PPH treatment options across multiple levels of care.

The Role Of Misoprostol For PPH Management
Uterotonic medicines stimulate contractions of the uterus after delivery and can help to control excessive blood loss caused by uterine atony, the most common cause of PPH. Oxytocin, the gold standard uterotonic, requires cold storage, intravenous or intramuscular administration, and skilled providers – factors that can complicate its use in certain settings. Misoprostol comes in tablet form, is stable at room temperature, and does not require any special skills, equipment, or facilities for its use. These advantages make it a valuable uterotonic for use in low-resource and community settings. Large pivotal trials (Mobeen 2011, Blum 2010, Winikoff 2010, Widmer 2010) have helped to advance knowledge about misoprostol’s safety, efficacy and effectiveness; to establish evidence-based and internationally-recognized regimens for PPH prevention (600mcg oral) and PPH treatment (800mcg sublingual); and to support community-level research clarifying the different ways for integrating misoprostol into PPH programs.

Refining The Role Of Uterotonics For PPH Prophylaxis At The Community Level
Misoprostol is associated with significant reductions in PPH when administered prophylactically. A study conducted in Pakistan showed that a single 600mcg oral dose of misoprostol reduced the incidence of measured blood loss (>500mL) by a quarter (Mobeen 2011), supporting earlier findings which established the safety and effectiveness of the same regimen for the prevention of PPH (Hoj 2005, Derman 2006, Walvaren 2005). More recent research sets out to evaluate the role of misoprostol and oxytocin for PPH prophylaxis at the community level.

Prophylactic administration of misoprostol and oxytocin in Unijectby lower level providers where access to standard injectable uterotonics is limited
A cluster randomized controlled trial conducted in rural Senegal compares the programmatic effectiveness and feasibility of misoprostol (600mcg oral) and oxytocin in Uniject™ (a pre-filled, single dose, non-reusable, intramuscular injection, 10 IU) when given prophylactically by auxiliary midwives (matrones) to women delivering at health huts. The study shows that oxytocin in Uniject™ and misoprostol are equally effective in reducing the incidence of PPH in this environment. Ease of use, higher acceptability, and fewer logistical challenges make misoprostol a more adaptable and appropriate intervention option in this setting (Diop 2016). Based on the findings from this study, Senegal has revised its national guidelines to recognize matrones and authorize the provision of misoprostol for PPH prophylaxis in all deliveries in health huts.

Antenatal distribution of misoprostol for self-administration to prevent PPH
A randomized controlled trial implemented in rural Uganda shows that misoprostol distributed in advance to pregnant women for self-use to prevent PPH can be appropriately taken by women delivering at home (Weeks 2015). In countries with a high proportion of non-facility deliveries, the advance distribution model can increase the number of women who have access to a uterotonic to prevent PPH.

Beyond Prophylaxis: Generating Evidence On Misoprostol For PPH Management At The Community Level
Two hospital-based trials conducted by Gynuity and partners in five countries provide the largest body of evidence to date on misoprostol’s efficacy for treating PPH (Winikoff 2010, Blum 2010). They show that a single 800mcg sublingual dose of misoprostol is a safe, effective and acceptable first-line treatment for PPH. Evidence generated from these studies has supported changes to international recommendations on misoprostol for the treatment of PPH [WHO 2012, FIGO 2012, FIGO/ICM 2014, WHO Essential Medicines List (EML) 2015]. A series of community studies build on the evidence and set out to clarify different ways for extending misoprostol use for PPH management into all levels of care.

Universal prophylaxis followed by treatment with misoprostol if PPH occurs
Double-blind placebo-controlled randomized trials conducted in Pakistan and Afghanistan determine the safety and feasibility of misoprostol (800mcg sublingual) as treatment for PPH in women who received misoprostol (600mcg oral) as PPH prophylaxis. Traditional birth attendants (TBAs) in Pakistan and community health workers (CHWs) in Afghanistan were trained to recognize heavy bleeding and to administer a treatment dose of misoprostol, followed by referral. The prophylactic dose of the drug was administered by TBAs in Pakistan and by the women themselves in Afghanistan. The studies show that the provision of misoprostol to treat PPH in women who have already received a prophylaxis dose is safe and can be managed by community level providers.

First aid treatment with misoprostol following home and community deliveries
A double-blind, randomized parallel-group study assesses the impact of adding a treatment dose of misoprostol (800mcg sublingual) as ‘first aid’ to the standard of care, referral alone. Nurse-midwives in Egypt administered first aid emergency care using misoprostol to women suspected to have heavy bleeding during home or Primary Health Unit deliveries. The study examines rates of transfer to a higher level of care. The research shows that the “first aid” approach to managing PPH is safe and feasible and can be easily implemented by birth attendants in lieu of routine reliance on referral alone given the barriers to transfer.

Family first aid approach: self-administration of misoprostol to treat PPH in the home
A study in Sind Province, southeastern Pakistan, assesses the impact of antenatal distribution of misoprostol (200mcg x 4 tablets) to women and families as first aid to treat PPH following home births. Antenatal counseling to women and their families about the use of this medicine provides a platform to educate communities about danger signs and symptoms that warrant timely care. This approach can equip women and their families with ‘first aid’ treatment in response to perceived heavy bleeding following home births.

Secondary prevention: early treatment with misoprostol for women with above-average postpartum blood loss
While ‘universal prophylaxis’ with misoprostol is known to reduce the incidence of PPH, it requires medicating every woman who gives birth, is resource-intensive, and does not eliminate the need for treatment strategies. Two cluster-randomized non-inferiority community trials conducted in India (Ragahavan 2016) and Egypt compare the administration of misoprostol either as prophylaxis (600mcg oral) to all women immediately after delivery or as an “early treatment” dose (800mcg sublingual) only to women with above-average blood loss (approximately 350-500mL). The research shows that secondary prevention of PPH with misoprostol is no worse than (‘non inferior to’) universal prophylaxis. In addition to medicating substantially fewer women, thereby exposing them to fewer side effects, the secondary prevention approach has the potential to improve acceptability, cost and sustainability.

Monitoring And Evaluation Of National PPH Initiatives And Programs
Gynuity collaborates with program agencies, donors and governments to conduct monitoring and evaluation of national PPH initiatives and programs. Findings from evaluations undertaken in countries such as Nepal, Senegal and Niger provide important insight for these and other countries committed to improving the quality and reach of their PPH programs.

Country Program: Nepal
Nepal’s program of community-based distribution of misoprostol for PPH prevention enlists female community health volunteers (FCHVs), trained to provide counseling and to dispense misoprostol to pregnant women to self-administer at the time of their delivery as a prophylaxis. A Gynuity-sponsored evaluation of the national program revealed widespread shortages in the advance distribution of misoprostol, with only 13% of women receiving the drug. This was due to challenges in the national commodity distribution system that resulted in severe shortages at health facilities and among FCHVs. The evaluation found that when women were given misoprostol, however, a majority who delivered at home used it for PPH prevention.

Country Program: Senegal
A community study comparing misoprostol and oxytocin in Uniject™ found both interventions work equally well when given as prophylaxis by auxiliary midwives (matrones) to women delivering in health huts. Ease of use, higher acceptability and fewer logistical challenges make misoprostol a more appropriate option in this setting (Diop 2016). Senegal subsequently changed its national guidelines to allow for misoprostol use by auxiliary midwives in health huts nationwide. An evaluation by Gynuity and ChildFund Senegal documents the scale-up of the national community strategy for PPH prevention in selected regions and examines outcomes such as feasibility and misoprostol distribution in community settings. Findings are based on data collected from health hut assessments, interviews with auxiliary midwives and women, as well as in depth interviews with community members.

Country Program: Niger
An evaluation of Niger’s national PPH program assesses coverage, knowledge, use, and acceptability of the initiative’s newly-introduced technologies: misoprostol for PPH prevention and treatment; the use of the uterine balloon tamponade when medical management fails; and the application of the non-pneumatic anti-shock garment. The program includes training, supply and provision of PPH prevention and treatment services at all levels of the health system.

Addressing Outstanding Research Questions On PPH And Its Management
Important questions on PPH and its management remain unanswered. Gynuity conducts research to fill gaps in knowledge and create new evidence-based science on PPH prevention and treatment.

(Re)defining PPH and new triggers for PPH intervention
Uncertainties remain about the amount of blood loss that are of greatest importance in triggering intervention and predicting severe maternal outcomes after childbirth. Shock index, a calculated variable of heart rate to systolic blood pressure, has been identified as a promising clinical parameter for evaluating the severity of PPH. Research in Latin America explores the relationship between postpartum bleeding patterns, clinical signs/symptoms, and hemodynamic changes during the immediate postpartum period in order to identify new clinical indicators that could facilitate early diagnosis and management of PPH. This research, along with data from several large PPH studies, allows for a more in-depth exploration of which PPH indicators and outcomes matter and has led to re-consideration of commonly used PPH definitions and markers of excess bleeding (i.e. postpartum blood loss ≥500mL).

High fever incidence in Latin America following PPH treatment with misoprostol
In prior studies conducted in multiple countries, unusual rates of high fever (­> 40.0°C) were found only in women from one site (Quito, Ecuador) following the use of misoprostol (800mcg sublingual) to treat PPH. Similar high rates of misoprostol-induced fever were not found elsewhere. (Winikoff 2010, Blum 2010) Additional research in Latin America sets out to understand better the relationship between misoprostol and high fever and to determine the role of genetic factors leading to the increase in fever.

Route of administration for oxytocin for PPH prevention
Variable routes are used for oxytocin administration after childbirth yet there is little understanding about the impact that different routes may have on postpartum blood loss. Research sets forth to compare the effect of intravenous (IV) infusion, IV bolus and intramuscular (IM) injection of oxytocin to prevent PPH in order to address this evidence gap and increase awareness about the clinical and programmatic implications of route of administration in PPH management more generally. Studies confirm that IV routes of administration (including infusion and bolus) reduce blood loss compared to IM injection.

When Uterotonics Are Not Enough: Additional Strategies To Address Gaps In PPH Care
Some women do not respond to uterotonics and require additional interventions beyond uterotonics to stop postpartum bleeding. Interventions, such as blood transfusion and surgical procedures, are often not immediately available or feasible outside of tertiary care centers in low-resource regions. Gynuity implements research to evaluate simple, low-cost interventions for use when women fail to respond to uterotonics (such as oxytocin and misoprostol).

Use of uterine balloon tamponade (UBT) in low resource settings
There is limited evidence on the use of UBT outside of tertiary care centers in high resource settings. A prospective, randomized stepped wedge evaluation assesses the potential reduction in PPH-related mortality and invasive procedures for PPH following the introduction of a locally assembled condom UBT in referral facilities in Uganda, Senegal, and Egypt. A cohort analysis assesses the safety and acceptability of UBT among women diagnosed with PPH.

Oral tranexamic acid (TXA) as adjunct to misoprostol for treatment of PPH
TXA, an anti-fibrinolytic agent, has been shown to be successful in managing bleeding in trauma patients during surgery and has shown promise in use in obstetrics. The wide availability of TXA in tablet form and its stability at room temperature suggest feasibility for use as part of a package of PPH treatment options in lower level health facilities and home births. A placebo-controlled trial assesses the efficacy and tolerability of oral TXA when used as an adjunct to misoprostol for treatment of PPH.

Enhancing the effectiveness of PPH care
While access to appropriate technologies for managing PPH is critical, the poor quality of obstetric care, including management of PPH at mid to lower level referral facilities, has emerged as a key barrier to improving the safety of births for women in low resource countries. A better understanding of how care is provided and where the major barriers to effective PPH care are, may be important to improving programs and maternal health outcomes. Qualitative and quantitative assessments, including delivery observations, are being carried out in settings where UBT research is being implemented to better understand components of effective PPH care.

Training and Education
Gynuity’s training efforts focus on supporting the introduction of technologies and interventions that are appropriate and useful for PPH at all levels of care. We develop training modules that summarize the latest evidence-based findings on misoprostol and other technologies for PPH management as well as monitoring tools geared towards different levels of providers and low literacy audiences. In addition to collaborating with partner agencies on national training programs, we organize technical consultations to guide national health care programs and service delivery organizations seeking to incorporate misoprostol for PPH indications into their programs of work.

Technical Assistance
Gynuity provides technical assistance to agencies and governments to increase their knowledge of research findings on misoprostol for PPH, develop misoprostol-focused programs for implementation, and prepare monitoring and evaluation components to their programs. Our efforts in this area support the integration of evidence-based practices for PPH management and the inclusion of misoprostol for PPH into national essential drugs lists, service delivery guidelines, and training curricula.

Policy and Advocacy
Gynuity works closely with international and regional partners —including FIGO, WHO and the FCI Program of Management Sciences for Health— to advance better understanding, use and acceptance of misoprostol for PPH through advocacy and policy change. Evidence generated through our research helps inform the advocacy agenda. We pursue policy change by preparing and submitting applications for misoprostol for PPH to be included on the World Health Organization’s Model List of Essential Medicines (WHO EML), and advocating for its inclusion to national-level essential drugs lists, country-level norms and clinical guidelines. We collaborate with pharmaceutical companies to push for greater availability of quality misoprostol products for PPH.

Key milestones clarifying the role of misoprostol for PPH indications

  • Misoprostol added to the WHO EML for the prevention of PPH (2011) and treatment of PPH (2015).
  • Joint statement issued by the International Confederation of Midwives (ICM) and the International Federation of Gynecology and Obstetrics (FIGO) recommending misoprostol for the treatment of PPH in low resource settings (2014).
  • European Medicines Agency approved the first misoprostol product, Hemoprostol, for the treatment of PPH (2014).
  • International guidelines issued by WHO and FIGO recommending misoprostol for the prevention and treatment of PPH (2012).

Materials Development
To address issues of access of misoprostol for PPH care from all perspectives, Gynuity develops informational and educational materials in multiple languages for use by a range of audiences. In addition to publishing study results in peer-reviewed scientific journals, we synthesize evidence into user-friendly formats to highlight evidence-based research findings that inform policymakers and program implementers and that assist organizations and health facilities to educate providers, families and women on how to use misoprostol for PPH care. The materials include an Instructions for Use brochure series that outlines regimen options for the prevention and treatment of PPH using misoprostol and pamphlets that contain pictorial panels targeted to an illiterate or low literate audience. We create short films to highlight the programmatic realities that exist in many settings as well as showcase the different service delivery models for PPH in our studies.

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