Guideline development process

Publication Details

This guideline was developed in accordance with the WHO evidence-informed guideline development procedures outlined in the WHO handbook for guideline development (66). The steps in this process included: (i) identification of priority questions and outcomes; (ii) retrieval of the evidence; (iii) assessment and synthesis of the evidence; (iv) formulation of normative statements, including research priorities; (v) planning for dissemination; (vi) equity, human rights, implementation, regulatory, and ethical considerations; and (vii) impact evaluation and updating of the guideline.

In 2015, WHO initiated a review of global guidelines on haemoglobin cutoffs to define anaemia. The activities included retrieving, summarizing, and assessing the currently available evidence to inform updated WHO normative statements on the use and interpretation of haemoglobin concentrations for assessing anaemia in individuals and in populations.

A WHO Steering Committee (Annex 4), led by the Department of Nutrition and Food Safety, was established with representatives from relevant WHO departments with an interest in the provision of scientific nutrition advice. Advisers from the WHO regions participated in the meetings of the GDG as part of the Steering Committee. The Steering Committee guided and provided overall supervision of this guideline development process. Two additional groups were formed: the GDG and a systematic reviews team.

The GDG was established in 2019 (Annex 5) and comprised 14 experts with a range of technical skills, diverse perspectives, wide geographical representation, and gender balance. They consisted of content experts, methodologists, and representatives of potential stakeholder and beneficiaries. The list of members of the GDG came from suggestions from all WHO departments with an interest in the provision of scientific nutrition advice; WHO expert advisory panels (67); members of previous guideline development groups; and those identified through a call for experts published on the WHO Nutrition website and distributed to the WHO Nutrition mailing list.

The GDG consisted of experts in nutrition, micronutrients, maternal and child nutrition, public health, epidemiology, clinical practice, malaria, infectious diseases, health equity, behaviour science, programme evaluation, haematology, diagnostic methods, biomarkers for anaemia, bioethics, genetics, haemoglobinopathies, blood donation, transfusion, and blood safety. Its role was to advise WHO on: (i) the scope of the guidelines and priority questions for which systematic reviews of evidence were commissioned; (ii) the choice of important outcomes for decision-making; (iii) the interpretation of evidence with explicit consideration of the overall balance of risks and benefits; and (iv) the formulation of final drafting of the normative statements, taking into account existing evidence as well as diverse values and preferences.

As resource persons, the systematic reviews team members, participated in the guideline development process by presenting evidence and identifying research priorities. They participated only in the open meetings and were informed that they were not allowed to participate in the decision-making process (Annex 6).

Five technical experts were invited to peer-review the draft guideline. The final draft guideline was peer-reviewed by four content experts, who provided technical feedback (Annex 7). These peer-reviewers were identified through various expert panels within and outside WHO. Peer-reviewers are not involved in the guideline development process (66) and are only asked to provide comments on the final draft guideline. Their role is to identify any errors or missing data and to comment on clarity, setting-specific issues, and implications for implementation, not to change the normative statements formulated by the GDG. Reviews from such individuals or organizations on a draft guideline may be helpful in anticipating and dealing with controversy, improving the clarity of the final document, and promoting engagement with all stakeholders.

This document is a WHO guideline and, after executive clearance, represents the decisions, policy, or views of WHO.

Scoping the guideline, evidence appraisal, and decision-making

WHO started this project for updating haemoglobin cutoffs to define anaemia in individuals and populations by convening a prioritization exercise via a two-stage international consultation. Six subtopics were established: physiology of anaemia; haemoglobin cutoffs for different population groups; definition of anaemia across clinical and environmental contexts; approach to development of anaemia cutoffs; laboratory, equipment, regulatory, and diagnostic considerations; and implementation of WHO’s haemoglobin threshold guidelines.

Based on the identified subtopics and the normative needs identified at various technical meetings organized by WHO, 17 background papers were commissioned (3, 26–29, 46, 68–79), and the available evidence was presented to the GDG, after input from the WHO Steering Committee to advise and support this normative work.

The first GDG meeting, held in Spain on 6–8 November 2019, developed and prioritized PICO questions and identified topics for further discussions, technical meetings, or research.

The PICO questions were drafted by technical staff at the Department of Nutrition and Food Safety, based on the policy and programme guidance needs of Member States and their partners, although the questions related to the review of haemoglobin cutoffs and adjustment factors to diagnose anaemia did not always fit the format or cover all domains of the evidence-to-decision frameworks.

The evidence was searched systematically for all PICO questions. WHO documents and databases (Cumulative Index to Nursing and Allied Health Literature, Cochrane Library, Google Scholar, Medline, Ovid, PubMed, ScienceDirect, and Scopus) were searched. Databases of clinical trials and WHO databases were searched for ongoing studies, and the grey literature was also reviewed. The search was performed without time or language limitations and snowballing was used with selected reviews and systematic reviews to identify additional references. Due to the nature of the PICO questions and the guideline objective of reviewing cutoffs to define anaemia in individuals and populations, the identification of geographically diverse datasets of raw data for setting cutoffs and reviewing adjustments was prioritized.

The questions were discussed and reviewed by the WHO Steering Committee and the GDG and were modified as needed. The GDG scored the relative importance of each outcome from one to nine (where a score of seven, eight, or nine indicated that the outcome was critical for a decision; a score of four, five, or six indicated that it was important; and a score of three, two, or one indicated that it was not important). A special issue of 17 papers in the Annals of the New York Academy of Sciences, including systematic or desk reviews on the priority questions, was the basis for developing the final PICO questions after the first GDG meeting (3, 26–29, 46, 68–79). The key questions, along with the outcomes that were identified as critical for decision-making, are listed in PICO format in Annex 2.

WHO convened three technical meetings after the first GDG meeting in 2019 to address several key issues that had been identified as needing addressing before the need for adjustments to account for differences in settings and populations could be considered.

  • In October 2020, a technical meeting on considered adjustments of haemoglobin concentrations to define anaemia by elevation above sea level and smoking.
  • In April 2021, a technical meeting was held on considerations to determine haemoglobin concentrations to define anaemia in the lifecycle, particularly during pregnancy and to discuss the basis for the revision of the cutoffs to define anaemia focusing on a statistical approach and/or a functional/clinical outcomes approach.
  • In December 2021, a third technical meeting considered the role of infection, inflammation, and genetic ancestry as potential determinants for adjustments of haemoglobin concentrations to define anaemia, especially at the population level. This meeting also addressed considerations about blood sampling and analytical methods used for haemoglobin determinations.

Participants of these technical meetings were instructed to declare any interest relevant to the meeting, prior to their participation. At the beginning of each meeting, conflicts of interest were addressed and publicly declared, with no significant conflicts recorded.

The series of second GDG meetings was held virtually on 1–3 June, 15–17 June, and 29 June–1 July 2022. The objectives were to:

  • formulate normative statements on the use and interpretation of haemoglobin concentrations for assessing anaemia status in individuals and populations and determine their strength, taking into account benefits, harms, values and preferences, feasibility, equity, ethics, acceptability, resource requirements, and other factors, as appropriate;
  • define implications for further research and gaps; and
  • discuss implementation and evaluation considerations of the guideline.

The evidence that informed the haemoglobin cutoffs to define anaemia in individuals and populations was based on a commissioned haemoglobin concentration analysis of healthy population databases (18), general population databases (18–22), and systematic reviews (48). For identification of unpublished studies or studies still in progress, a standard procedure was followed to contact more than 10 international organizations working on anaemia prevention and control interventions. In addition, the ClinicalTrials.gov online database of the National Library of Medicine, United States of America (80), and the International Clinical Trials Registry Platform (81), which is hosted by WHO, were systematically searched for trials in progress. No language restrictions were applied in the search.

When possible, since some of the questions did not apply to this format due to their intrinsic nature, evidence summaries and profiles were prepared according to the GRADE approach, to assess the overall certainty of the evidence (82, 83). GRADE considers: the study design; the limitations of the studies in terms of their conduct and analysis; the consistency of the results across the available studies; the directness (or applicability and external validity) of the evidence with respect to the populations, interventions, and settings where the proposed intervention may be used; and the precision of the summary estimate of the effect. The GRADE approach could only be used for a subsection of the questions.

The GDG interpreted the evidence, taking in consideration the Developing and Evaluating Communication Strategies to support Informed Decisions and Practice based on Evidence (DECIDE) framework (84). DECIDE is an evidence-to-decision tool that includes intervention effects, values, resources, equity, acceptability, and feasibility criteria to guide the formulation of the normative statements (85, 86).

The certainty of the direct evidence for the critical outcomes was moderate, and for three of the questions was considered very low. The GRADE summary of findings table for the response of haemoglobin concentrations to nutrition interventions in infants, children and adolescents is shown in Annex 1. Readers are directed to the overview of reviews (48) for other tables on interventions and population groups.

The draft normative statements were discussed and voted on at the second GDG meetings, including judgements on harms and benefits and taking into account: (i) desirable and undesirable effects; (ii) the certainty of the available evidence; (iii) values and preferences related to the intervention in different settings; and (iv) the cost and feasibility of the intervention in different settings (Annex 3). The WHO Secretariat (Annex 8) gathered and circulated a summary of the results to the GDG.

If there was no unanimous consensus (primary decision rule), more time was given for deliberations and a second round of online balloting took place. If no unanimous agreement was reached, a two thirds vote of the GDG was required for approval of the proposed normative statements (secondary decision rule). Divergent opinions could be recorded in the guideline. The results from voting forms are kept on file by WHO for up to 5 years. WHO staff present at the meeting, as well as the systematic reviews teams involved in the collection and grading of the evidence, did not participate in the consensus-building process. Two co-chairs with expertise in managing group processes and interpreting evidence were nominated at the opening of each consultation, and the GDG approved their nomination. Members of the WHO Secretariat were available at all times, to help guide the overall meeting process, but did not vote and did not have veto power.

Deliberations on haemoglobin cutoffs for infants and children aged 6–59 months

During the series of second GDG meetings, while addressing the cutoffs to define anaemia in individuals (Table 2), there was discussion about cutoffs for infants and children 6–59 months and a proposal from some members of the GDG was presented. The GDG voted in favour of this new proposal of having a single cutoff of <105 g/dL for the whole 6–59-month age group. This differed from the WHO proposal of separate cutoffs for the age groups 6–23 months and 24–59 months, which was based on there being a consistent difference in haemoglobin concentrations between the two age groups. This raised concerns from some GDG members because: the proposed single cutoff was based on a completely unsupported and separate analysis from Braat et al. (18); the evidence was mixed; and the criteria for the definition health were unclear and inconsistent.

During the drafting of this guideline, and after discussions within the WHO Nutrition and Food Safety Department, it was found that in the analysis of the evidence in Braat et al. (18) and in other publications (19, 20), there is indeed a consistent difference in haemoglobin concentrations between the two age groups. In the data from the Comprehensive National Nutrition Survey in India (19), the difference between the two age groups is 9 g/L, under the assumptions that: (i) the number of boys and girls is the same; (ii) the data children aged 1 year and 2 years can be averaged to represent 6–23 months; and (iii) the data for children aged 3 years, 4 years, and 5 years can be averaged to represent 24–59 months. For the data in Addo et al. (20), the difference between the two age groups is 5 g/L, under the assumption that the sample size for the 22 surveys is one third for 6–23 months age group and two thirds for the 24–59 months age group. These findings were supported by the analysis of an additional database from Ecuador by the Braat et al. authors, which was obtained after the GDG meeting in July 2023. These new data were held to the same health inclusion criteria as the other databases in the original Braat et al. analysis (18).

Within WHO, there was also discussion about the significance and implications of a single haemoglobin cutoff for infants and children from 6 months to 5 years of age, when there are noted differences in growth and nutrient requirements. The relatively large increase (10 g/L) in cutoffs (i.e. from <105 to <115 d/L between the ages of from 59 months and 5 years was also noted. It was felt that the current evidence and physiological changes occurring in these children supported separation cutoffs for infants and children 6–23 months, 24–59 months, allowing for changes in cutoffs to occur in a transitioned manner. The WHO proposed cutoff presents a gradual increase from 105 g/L at 23 months, to 110 g/L at 59 months, and to 115 g/L from 5 years of age. By contrast, with the original GDG proposal, the cutoff for a 4.5-year-old child would be 105 g/L and would increase to 115 g/L (10 g/L increase) 6 months later when the child reaches 5 years of age.

A third GDG meeting was convened on 8 June 2023 to discuss the rationale of the WHO proposal to separate haemoglobin cutoffs for children from 6 to 59 months of age into two groups (6–23 months, and 24–59 months). The rationale was: (i) to maintain consistency with the health criteria used for defining the other age groups; (ii) analysis of other publications reviewed during the second GDG meeting (18–20) also showed consistent differences in haemoglobin concentrations between children 6–23 months and 24–59 months, ranging between 5 g/L and 9 g/L; (iii) there are noted differences in growth and nutrient requirements between those two age groups; and (iv) additional analysis by Braat and colleagues obtained after the GDG meeting in July 2022 supported the separation of the age groups.

Seven GDG members participated in the online meeting and voted. The proposal and presentations were sent to the four members unable to attend the meeting, along with a request to vote. The result was: yes, eight votes; no, one vote; no answer, two votes.

Management of competing interests

According to the processes recommended in the WHO handbook for guideline development (66), all experts participating in WHO meetings must declare any interest relevant to the meeting, prior to their participation. The responsible technical officer and the WHO Steering Committee reviewed the declarations-of-interest statements for all GDG members, before finalization of the group composition and invitation to attend a GDG meeting.

All participants, members of the GDG, and systematic reviews teams of the guideline development meetings, submitted a declaration-of-interests form, along with their curriculum vitae, before each meeting. Participants of these meetings participated in their individual capacity and not as institutional representatives. In addition, they verbally declared any interests that could be perceived to affect their objectivity and independence in providing advice to WHO at the beginning of each meeting. The procedures for management of competing interests strictly followed the Guidelines for declaration of interests (WHO experts) (87). The management of the perceived or real conflicts of interest declared by the members of the GDG that are relevant to this guideline was as follows.1

Dr Rachel Hammonds declared she has worked as a consultant for UNICEF in Kenya to highlight the importance of testing and treating women of reproductive age for anaemia. She was asked to verbally disclose this to the other participants at the start of the GDG meetings.

Dr Crystal Karakochuck declared she has worked as a consultant for WHO in themes related to anaemia. She was asked to verbally disclose this to the other participants at the start of the GDG meetings.

Dr Harshpal Singh Sachdev declared he has done research and published substantially on anaemia, including a recent publication on haemoglobin thresholds in Indian children and adolescents. He was asked to verbally disclose this to the other participants at the start of the GDG meetings.

Dr Melissa F. Young declared she has received funding for research on anaemia. She was asked to verbally disclose this to the other participants at the start of the GDG meetings.

The names of the GDG members, along with a description of the objectives of the meeting, were published on the WHO website prior to the first GDG meeting (88), for public notice and comment. No additional information on any interests or biases relating to the individuals being considered for membership of the GDG were brought to light from the public notice.

Footnotes

1

A conflict-of-interest analysis must be performed whenever WHO relies on the independent advice of an expert in order to take a decision or to provide recommendations to Member States or other stakeholders. The term “conflict of interest” means any interest declared by an expert that may affect or be reasonably perceived to affect the expert’s objectivity and independence in providing advice to WHO. WHO’s conflict-of-interest rules are designed to avoid potentially compromising situations that could undermine or otherwise affect the work of the expert, the committee, or the activity in which the expert is involved, or WHO as a whole. Consequently, the scope of the inquiry is any interest that could reasonably be perceived to affect the functions that the expert is performing.