The recommendations were first developed using standardized operating procedures in accordance with the process described in the WHO handbook for guideline development (9). In summary, the process included:
- (i)
identification of the priority question and critical outcomes;
- (ii)
retrieval of evidence;
- (iii)
assessment and synthesis of evidence;
- (iv)
formulation of the recommendations; and
- (v)
planning for the dissemination, implementation, impact evaluation and updating of the recommendations.
WHO recommendations on the use of antihypertensive drugs for severe hypertension in pregnancy were identified by the Executive GSG as a high priority for updating in response to new, potentially important evidence on this question. Six main groups were involved in this process, with their specific roles described in the following sections.
Contributors to the guideline
Executive Guideline Steering Group (Executive 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, South-East Asia Region, European Region, Eastern Mediterranean Region, and Western Pacific Region. The Executive GSG advises WHO on the prioritization of new and existing questions in maternal and perinatal health for recommendation development or updating (10).
WHO Steering Group
The WHO Steering Group, comprising WHO staff members from the Department of Reproductive Health and Research (RHR) and the Department of Maternal, Newborn, Child and Adolescent Health (MCA) managed the updating process. The Group drafted the key recommendation questions in PICO format, identified the systematic review team and guideline methodologist, as well as the guideline development and external review groups. In addition, the WHO Steering Group supervised the syntheses and retrieval of evidence, organized the Guideline Development Group meeting, drafted and finalized the guideline document, and managed the guideline dissemination, implementation and impact assessment. The members of the WHO Steering Group are listed in Annex 1.
Guideline Development Group
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 (MPHGDG). This pool consists of a diverse group of experts who are skilled in critical appraisal of research evidence, implementation of evidence-based 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 are no significant conflicts of interest. Members’ expertise cuts across thematic areas within maternal and perinatal health.
From the MPH-GDG pool, 16 external experts and relevant stakeholders were invited to constitute the Guideline Development Group (GDG) for updating these recommendations. Those selected were a diverse group of individuals with expertise in research, guideline development methods, and clinical policy and programmes relating to maternal and perinatal health.
In accordance with WHO guidelines, the GDG members were selected in a way that ensured geographic representation and gender balance and there were no important conflicts of interest The Group appraised the evidence that was used to inform the recommendations, advised on the interpretation of this evidence, formulated the final recommendations based on the draft prepared by the Steering Group, and reviewed and approved the final document. The members of this Group are listed in Annex 1.
External Review Group
This Group included eight technical experts with interest and expertise in the provision of evidence- based obstetric care. None of its members declared a conflict of interest. The Group reviewed the final document to identify any errors of fact and commented on the clarity of the language, contextual issues and implications for implementation. The Group ensured that the decision-making processes have considered and incorporated contextual values and preferences of potential users of the recommendations, healthcare providers and policy makers. They did not change the recommendations that were formulated by the GDG. The members of the External Review Group are presented in Annex 1.
Systematic review team and guideline methodologists
A Cochrane 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 protocol and worked closely with the Cochrane Pregnancy and Childbirth Group to appraise the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Representatives of the Cochrane Pregnancy and Childbirth Group attended the GDG meeting to provide an overview of the available evidence and GRADE tables and to respond to technical queries from the GDG.
External partners and observers
Representatives of the United States Agency for International Development (USAID), the Maternal and Child Survival Programme (MCSP)/Jhpiego, the Bill & Melinda Gates Foundation (BMGF), the International Confederation of Midwives (ICM), the International Federation of Gynaecology and Obstetrics (FIGO) and Population Council participated in the GDG meeting as observers. These organizations, with a long history of collaboration with the RHR Department in guideline dissemination and implementation, are implementers of the recommendations. The list of observers who participated in the GDG meeting is presented in Annex 1.
Identification of critical outcomes
The critical and important outcomes were aligned with the prioritized outcomes from the WHO recommendations on prevention and treatment of pre-eclampsia and eclampsia (7). These outcomes were initially identified through a search of key sources of relevant, published, systematic reviews and a prioritization of outcomes by the 2011 GDG panel. All outcomes were included in the scope of this document for evidence searching, retrieval, grading and formulation of the recommendations. The list of outcomes is provided in Annex 2.
Evidence identification and retrieval
A Cochrane systematic review was updated by the Cochrane Pregnancy and Childbirth Group. This systematic review was the primary source of evidence for these recommendations.
Randomized controlled trials (RCT) relevant to the key question were screened by the review authors, and data on relevant outcomes and comparisons were fed into Review Manager (RevMan) software. The RevMan file was retrieved from the Cochrane Pregnancy and Childbirth Group and customized to reflect the key comparisons and outcomes (those that were not relevant to the recommendations were excluded). Then the RevMan file was exported to GRADE profiler software (GRADEpro) and GRADE criteria were used to critically appraise the retrieved scientific evidence. Finally, evidence profiles (in the form of GRADE tables) were prepared for comparisons of interest, including the assessment and judgements for each outcome and the estimated risks.
Certainty assessment and grading of the evidence
The certainty assessment of the body of evidence for each outcome was performed using the GRADE approach (11). 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 individual study and then across 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 direction 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 recommendations were 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
Formulation of recommendations
The WHO Steering Group used the evidence profiles to summarise evidence on effects on the pre- specified outcomes. The evidence summary and corresponding GRADE tables, other related documents for assessment of values and preferences, resource requirements and cost-effectiveness, acceptability, feasibility and equity were provided in advance to meeting participants, who were invited to submit their comments electronically in advance of the meeting.
The GDG members and other participants were then invited to attend an online GDG meeting (see Annex 1 for the list of participants) organized by the Steering Group on 2 May 2018. During the meeting, the GDG members reviewed and discussed the balance between the desirable and undesirable effects of the intervention and the overall certainty of supporting evidence, values and preferences of stakeholders, resource requirements and cost-effectiveness, acceptability, feasibility and equity, before finalizing the recommendations and remarks.
Declaration of interests by external contributors
According to WHO regulations, all experts must declare their interests prior to participation in WHO guideline development processes and meetings. All GDG members were therefore required to complete a standard WHO Declaration of Interest (DOI) form before engaging in the guideline development process and before participating in the guideline-related meeting. The WHO Steering Group reviewed each declaration before finalizing the experts’ invitations to participate. Where any conflict of interest was declared, the Steering Group determined whether such conflicts were serious enough to affect the expert’s objective judgement on the guideline development process. To ensure consistency, the Steering Group applied the criteria for assessing the severity of conflict of interests in the WHO Handbook for Guideline Development to all participating experts. All findings from the received DOI statements were managed in accordance with the WHO DOI guidelines on a case-by-case basis and communicated to the experts. Where a conflict of interest was not considered significant enough to pose any risk to the guideline development process or reduce its credibility, the experts were only required to openly declare such conflict 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 the conflicts of interest declared by the experts were managed by the Steering Group.
Decision-making during the Guideline Development Group 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 evidence-to-decision framework to determine the direction and strength of the recommendations. These criteria included stakeholders’ values, resource implications, acceptability, feasibility and equity. Considerations were based on the experience and opinions of members of the GDG and supported by evidence from a literature search where available. Evidence-to-decision 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 recommendations.
Document preparation
Prior to the online meeting, the WHO Steering Group prepared a draft version of the GRADE evidence profiles, evidence summary and other documents relevant to the deliberation of the GDG. 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 recommendation document to accurately reflect the deliberations and decisions of the participants. The draft document was sent electronically to GDG members and the External Review Group for final review and approval.
Peer review
Following review and approval by GDG members and the External Review Group, the final document was sent to eight external independent experts 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 correcting factual errors and improving language to address any lack of clarity.
