2.1. Executive Guideline Steering Group (GSG)

The Executive GSG is an independent panel of 14 external experts and relevant stakeholders from the six WHO regions: African Region, Region of the Americas, Eastern Mediterranean Region, European Region, South-East Asia Region and Western Pacific Region. The Executive GSG advises WHO on the prioritization of new and existing PICO questions in maternal and perinatal health for development or updating of recommendations (13,14).

2.2. WHO Steering Group

The WHO Steering Group, comprising WHO staff members from the Department of Sexual and Reproductive Health and Research and the Department of Maternal, Newborn, Child and Adolescent Health and Ageing managed the process of updating the recommendations. The WHO Steering Group drafted the key recommendation questions in PICO format, engaged the systematic review teams and guideline methodologists (that is, the Evidence Synthesis Group [ESG]), as well as the members of the GDG and the External Review Group (ERG) (see below). In addition, the WHO Steering Group supervised the retrieval and syntheses of evidence, organized the GDG meetings, drafted and finalized the guideline document, and will also manage the guideline dissemination, implementation and impact assessment. The members of the WHO Steering Group are listed in Annex 1.

2.3. Guideline Development Group (GDG)

The WHO Steering Group identified a pool of approximately 50 experts and relevant stakeholders from the six WHO regions to constitute the WHO Maternal and Perinatal Health Guideline Development Group (MPH-GDG). This pool consists of a diverse group of experts who are skilled in the critical appraisal of research evidence, implementation of evidence-informed recommendations, guideline development methods, and clinical practice, policy and programmes relating to maternal and perinatal health. Members of the MPH-GDG are identified in a way that ensures geographic representation and gender balance, and there were no perceived or real conflicts of interest. Members’ expertise cuts across thematic areas within maternal and perinatal health.

From the MPH-GDG pool, 14 external experts and relevant stakeholders were invited to participate as members of the GDG for updating this recommendation. Those selected were a diverse group with expertise in research, guideline development methods, gender, equity and rights, clinical policy and programmes relating to PPH prevention and treatment.

The 14 GDG members for this recommendation were also selected in a way that ensured geographic representation and gender balance, and there were no important conflicts of interest. The GDG appraised the evidence that was used to inform the recommendation, advised on the interpretation of this evidence, formulated the final recommendation based on the draft prepared by the WHO Steering Group and reviewed and reached unanimous consensus for the recommendation in the final document. The members of the GDG are listed in Annex 1.

2.4. Evidence Synthesis Group (ESG)

WHO convened an ESG composed of guideline methodologists and systematic review teams to conduct or update systematic reviews, appraise the evidence and develop the Evidence to Decision (EtD) frameworks. A systematic review on this question was updated, supported by the Cochrane Pregnancy and Childbirth Group. The WHO Steering Group reviewed and provided input into the updated protocol and worked closely with the Cochrane Pregnancy and Childbirth Group to appraise the evidence using the GRADE methodology. Representatives of the Cochrane Pregnancy and Childbirth Group and a methodologist attended the GDG meeting to provide an overview of the available evidence and GRADE tables and to respond to technical queries from the GDG.

Systematic reviews of qualitative and cost-effectiveness studies were commissioned to generate evidence for other domains of the GRADE EtD frameworks. Researchers from the University of Central Lancashire, United Kingdom, conducted a systematic review of qualitative studies related to views and experiences of women and health-care providers on interventions for the prevention of PPH (17). A scoping search demonstrated that there were no cost-effectiveness studies on the use of this intervention. These reviews were conducted in collaboration with the WHO Steering Group, whose members worked closely with all members of the ESG to review the evidence and prepare the GRADE EtD frameworks. All members of the ESG attended the GDG meetings to provide an overview of the synthesized evidence and to respond to technical queries from the GDG. The members of the ESG are listed in Annex 1.

2.5. External partners and observers

Representatives of the United States Agency for International Development (USAID), the International Confederation of Midwives (ICM) and the International Federation of Gynecology and Obstetrics (FIGO) participated in the GDG meetings as observers. These organizations, with their long history of collaboration with WHO in maternal and perinatal health guideline dissemination and implementation, were identified as potential implementers of the recommendations. The list of observers who participated in the GDG meetings is included in Annex 1.

2.6. External Review Group (ERG)

The ERG included six technical experts with interests and expertise in the provision of evidence-based care to prevent and treat PPH. The group was geographically diverse and gender balanced, and the members had no important conflicts of interest. The experts reviewed the final document to identify any factual errors and commented on the clarity of language, contextual issues and implications for implementation. They ensured that the decision-making processes had considered and incorporated contextual values and the preferences of persons affected by the recommendations, health-care professionals and policy-makers. It was not within the remit of this group to change the recommendations that were formulated by the GDG. Members of the ERG are listed in Annex 1.

2.7. Identification of priority questions and outcomes

The priority outcomes were aligned with those from the 2012 WHO recommendations for prevention and treatment of postpartum haemorrhage (16). These outcomes were initially identified through a search of scientific databases for relevant, published systematic reviews and a prioritization of outcomes by the GDG for the 2012 guideline. After due consideration of the recently published core outcome set for prevention and treatment of PPH (18), three additional outcomes – maternal death, maternal well-being and maternal satisfaction – were included for this update to ensure that evidence synthesis and recommendation decision-making by the GDG were driven by outcomes that are important to women and to ensure that the final set of recommendations would be woman-centred. Additionally, three process outcomes were removed – reduction of time from decision-making to implementation, availability of drugs and treatment, and accuracy in blood loss assessment – as they were considered not relevant for this treatment intervention. All the outcomes were included in the scope of this document for evidence searching, retrieval, synthesis, grading and formulation of the recommendation. The list of priority outcomes is provided in Annex 2.

2.8. Evidence identification and retrieval

Evidence to support this update was derived from several sources by the ESG working in collaboration with the WHO Steering Group.

2.9. Certainty assessment and grading of the evidence

The certainty assessment of the body of evidence for each outcome was performed using the GRADE approach (20). Using this approach, the certainty of evidence for each outcome was rated as “high”, “moderate”, “low” or “very low”, based on a set of established criteria. The final rating of certainty of evidence was dependent on the factors briefly described below.

Study design limitations: The risk of bias was first examined at the level of each individual study and then across the studies contributing to the outcome. For randomized trials, certainty was first rated as “high” and then downgraded by one (“moderate”) or two (“low”) levels, depending on the minimum criteria met by the majority of the studies contributing to the outcome.

Inconsistency of the results: The similarity in the results for a given outcome was assessed by exploring the magnitude of differences in the direction and size of effects observed in different studies. The certainty of evidence was not downgraded when the directions of the findings were similar and confidence limits overlapped, whereas it was downgraded when the results were in different directions and confidence limits showed minimal or no overlap.

Indirectness: The certainty of evidence was downgraded when there were serious or very serious concerns regarding the directness of the evidence, that is, whether there were important differences between the research reported and the context for which the recommendation was being prepared. Such differences were related, for instance, to populations, interventions, comparisons or outcomes of interest.

Imprecision: This assessed the degree of uncertainty around the estimate of effect. As this is often a function of sample size and number of events, studies with relatively few participants or events, and thus wide confidence intervals around effect estimates, were downgraded for imprecision.

Publication bias: The certainty rating could also be affected by perceived or statistical evidence of bias to underestimate or overestimate the effect of an intervention as a result of selective publication based on study results. Downgrading evidence by one level was considered where there was strong suspicion of publication bias.

Certainty of evidence assessments are defined according to the GRADE approach:

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.
• Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
• Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect.
• Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.

The findings of the qualitative reviews were appraised for quality using the GRADE-CERQual tool (22). The GRADE-CERQual tool, which uses a similar conceptual approach to other GRADE tools, provides a transparent method for assessing and assigning the level of confidence that can be placed in evidence from reviews of qualitative research. The systematic review team used the GRADE-CERQual tool to assign a level of confidence (high, moderate, low and very low) to each review finding according to four components: methodological limitations of the individual studies; adequacy of data; coherence; and relevance to the review question of the individual studies contributing to a review finding. Findings from individual cost-effectiveness studies were reported narratively for each comparison of interest.

2.10. Formulation of the recommendation

The WHO Steering Group supervised and finalized the preparation of summary of findings tables and narrative evidence summaries in collaboration with the ESG using the GRADE EtD framework. EtD frameworks include explicit and systematic consideration of evidence on prioritized interventions in terms of specified domains: effects, values, resources, equity, acceptability and feasibility. For the priority questions, judgements were made on the impact of the intervention on each domain to inform and guide the decision-making process. Using the EtD framework template, the WHO Steering Group and ESG created summary documents for each priority question covering evidence on each domain:

• Effects: The evidence on the priority outcomes was summarized in this domain to answer the questions: “What are the desirable and undesirable effects of the intervention?” and “What is the certainty of the evidence on effects?” Where benefits clearly outweighed harms for outcomes that are highly valued by women, or vice versa, there was a greater likelihood of a clear judgement in favour of or against the intervention, respectively. Uncertainty about the net benefits or harms, or small net benefits, usually led to a judgement that did not favour the intervention or the comparator. The higher the certainty of the evidence of benefits across outcomes, the higher the likelihood of a judgement in favour of the intervention. In the absence of evidence of benefits, evidence of potential harm led to a recommendation against the intervention. Where the intervention showed evidence of potential harm and was also found to have evidence of important benefits, depending on the level of certainty and the likely impact of the harm, such evidence of potential harm was more likely to result in a context-specific recommendation, with the context explicitly stated within the recommendation.
• Values: This domain relates to the relative importance assigned to the outcomes associated with the intervention by those affected, how such importance varies within and across settings, and whether this importance is surrounded by any uncertainty. The question asked was: “Is there important uncertainty or variability in how much women value the main outcomes associated with the intervention?” When the intervention resulted in benefit for outcomes that most women consistently value (regardless of setting), this was more likely to lead to a judgement in favour of the intervention. This domain, together with the “effects” domain (see above), informed the “balance of effects” judgement.
• Resources: For this domain, the questions asked were: “What are the resources associated with the intervention?” and “Is the intervention cost-effective?” The resources required to implement UVI of oxytocin mainly include the costs of providing supplies, training, equipment and skilled human resources. A judgement in favour of or against the intervention was likely where the resource implications were clearly advantageous or disadvantageous, respectively.
• Acceptability: For this domain, the question was: “Is the intervention acceptable to women and health-care providers?” Qualitative evidence from systematic reviews exploring perceptions of PPH prevention and treatment by women and health-care providers has informed the judgements for this domain (17). The lower the acceptability, the lower the likelihood of a judgement in favour of the intervention.
• Feasibility: The feasibility of implementing this intervention depends on factors such as the resources, infrastructure and training requirements, and the perceptions of health-care providers responsible for administering it. The question addressed was: “Is it feasible for the relevant stakeholders to implement the intervention?” Qualitative evidence from systematic reviews exploring perceptions of PPH prevention and treatment by women and health-care providers was used to inform judgements for this domain (17). Where major barriers were identified, it was less likely that a judgement would be made in favour of the intervention.
• Equity: This domain encompasses evidence or considerations as to whether or not the intervention would reduce health inequities. Therefore, this domain addressed the question: “What is the anticipated impact of the intervention on equity?” The experiences and opinions of the GDG members were used to inform judgements for this domain. The intervention was likely to be recommended if its proven (or anticipated) effects reduce (or could reduce) health inequalities among different groups of women and their families.

For each of the above domains, additional evidence of potential harms or unintended consequences are described in the Additional considerations subsections. Such considerations were derived from studies that might not have directly addressed the priority question but provided pertinent information in the absence of direct evidence. These considerations were extracted from single studies, systematic reviews or other relevant sources.

The WHO Steering Group provided the EtD frameworks, including evidence summaries, summary of findings tables and other documents related to each recommendation, to the GDG members two weeks in advance of the GDG meeting. The GDG members were asked to review and provide comments (electronically) on the documents before the GDG meeting. During the GDG meeting (11–12 March 2020), which was conducted under the leadership of the GDG chairperson, the GDG members collectively reviewed the EtD frameworks and any comments received through preliminary feedback, and formulated the recommendations. The purpose of the meeting was to reach consensus on each recommendation, including its direction and in some instances the specific context, based on explicit consideration of the range of evidence presented in each EtD framework and the judgement of the GDG members. The GDG was asked to select one of the following categories for the recommendation:

• Recommended: This category indicates that the intervention should be implemented.
• Not recommended: This category indicates that the intervention should not be implemented.
• Recommended only in specific contexts (context-specific recommendation): This category indicates that the intervention is applicable only to the condition, setting or population specified in the recommendation and should only be implemented in these contexts.
• Recommended only in the context of rigorous research (research-context recommendation): This category indicates that there are important uncertainties about the intervention. With this category of recommendation, implementation can still be undertaken on a large scale, provided it takes the form of research that addresses unanswered questions and uncertainties related both to effectiveness of the intervention or option, and its acceptability and feasibility.

2.11. Management of declarations of interests

WHO has a robust process to protect the integrity of its normative work as well as to protect the integrity of individual experts with whom it collaborates. WHO requires that experts serving in an advisory role disclose any circumstances that could give rise to actual or ostensible conflicts of interest. The disclosure and the appropriate management of relevant financial and non-financial conflicts of interest of GDG members and other external experts and contributors are a critical part of guideline development at WHO. According to WHO regulations, all experts must declare their interests prior to participation in WHO guideline development processes and meetings according to the guidelines for declaration of interest (DOI) for WHO experts (15). All GDG members were therefore required to complete a standard WHO DOI form before engaging in the guideline development process and before participating in the guideline-related processes. The WHO Steering Group reviewed all DOI before finalizing the experts’ invitations to participate. Where any conflict of interest was declared, the WHO Steering Group determined whether such conflicts were serious enough to affect an expert’s objective judgement in the guideline and recommendation development process. To ensure consistency, the WHO Steering Group applied the criteria for assessing the severity of conflicts of interest as outlined in the WHO handbook for guideline development to all participating experts. All findings from the DOI statements received were managed in accordance with the WHO procedures to assure the work of WHO and the contributions of its experts is, actually and ostensibly, objective and independent. The names and biographies of individuals were published online four weeks prior to the meeting. Where a conflict of interest was not considered significant enough to pose any risk to the guideline development process or to reduce its credibility, the experts were only required to openly declare such conflicts of interest at the beginning of the GDG meeting, and no further actions were taken. Annex 3 shows a summary of the DOI statements and how conflicts of interest declared by invited experts were managed by the WHO Steering Group.

2.12. Decision-making during the GDG meeting

During the meeting, the GDG reviewed and discussed the evidence summary and sought clarification. In addition to evaluating the balance between the desirable and undesirable effects of the intervention and the overall certainty of the evidence, the GDG applied additional criteria based on the GRADE EtD framework to determine the direction and strength of the recommendation. These criteria included stakeholders’ values, resource implications, acceptability, feasibility and equity. Considerations were based on the experiences and opinions of the GDG members and supported by evidence from a literature search where available. EtD tables were used to describe and synthesize these considerations.

Decisions were made based on consensus, defined as the agreement by three quarters or more of the participants. None of the GDG members expressed opposition to the recommendation.

2.13. Document preparation

Prior to the online meeting, the WHO Steering Group prepared a draft version of the GRADE evidence profiles, the evidence summary and other documents relevant to the GDG’s deliberation. The draft documents were made available to the participants of the meeting two weeks before the meeting for their comments. During the meeting, these documents were modified in line with the participants’ deliberations and remarks. Following the meeting, members of the WHO Steering Group drafted a full guideline document to accurately reflect the deliberations and decisions of the participants. The draft document was sent electronically to the GDG and the ERG for their final review and approval.

2.14. Peer review

Following review and approval by GDG members, the final document was sent to eight external independent experts (comprising the ERG) who were not involved in the guideline panel for peer review. The WHO Steering Group evaluated the inputs of the peer reviewers for inclusion in this document. After the meeting and external peer review, the modifications made by the WHO Steering Group to the document consisted only of the correction of factual errors and improving language to address any lack of clarity.