# Zinc supplementation in pregnancy
Zinc is a trace element found in many foods, particularly in meat, but also in dairy products, legumes and unrefined cereals; diets low in bioavailable zinc are those in which animal protein is low and intake of cereals is high (1). Zinc is not stored in the body, so physiological needs must be met by dietary intake alone (2). In pregnant women, the average physiological requirement of zinc is estimated to double in the third trimester and almost triple during lactation (2). Therefore, many pregnant women are potentially at risk of zinc deficiency through inadequate dietary intake, exacerbated by the increased nutritional demands of pregnancy and lactation. In addition, routine iron supplementation may prevent women from meeting their zinc requirements by competing with zinc for absorption (3). This may also occur with calcium supplements and foods fortified with inorganic calcium salts (1).
Zinc plays an important role in many biological processes that contribute to human growth and development. Among children, the prevalence of stunting has been used as an indicator of zinc deficiency (1, 3). Zinc deficiency increases susceptibility to infections, and supplementing zinc among children in disadvantaged populations has been shown to reduce the incidence of diarrhoea and pneumonia (1-5). The World Health Organization (WHO) and the United Nations Children's Fund (UNICEF) recommend zinc supplementation is given along with oral rehydration salts for the clinical management of diarrhoea in children (6).
In pregnancy, zinc deficiency has been linked to prolonged labour, postpartum haemorrhage, pre-eclampsia, preterm birth and post-term pregnancies (7); however, these associations have not been well established. This evidence-to-decision (EtD) framework presents research evidence on the effects and other considerations relevant to recommendations on antenatal zinc supplements compared with no zinc supplements or placebo.

# The updated recommendation in the context of the WHO antenatal care guideline
In 2016, the following recommendation on antenatal zinc supplementation was made: "Zinc supplementation for pregnant women is only recommended in the context of rigorous research" (8). The Guideline Development Group (GDG) made this recommendation because it felt that the evidence on the intervention was incomplete and that more research was necessary. Since the publication of the 2016 WHO antenatal care (ANC) guideline, the systematic review, on which the 2016 recommendation was based, has been updated to include four additional trials (9); hence the need to re-evaluate the evidence.

# Rationale and objectives
As part of the WHO's normative work on supporting evidence-informed policies and practices and its living guidelines approach (10), the Department of Sexual and Reproductive Health and Research (SHR), the Department of Maternal, Newborn, Child and Adolescent Health and Ageing (MCA) and the Department of Nutrition and Food Safety (NFS) prioritized the updating of this recommendation on zinc supplements following the advice of the Executive Guideline Steering Group (GSG) in response to the identification of updated evidence on this intervention.

# Target audience
The recommendation in this global guideline is intended to inform the development of relevant national and local health policies and clinical protocols. Therefore, the target audience of this guideline includes national and local public health policy-makers, implementers and managers of national and local maternal and child health programmes, concerned nongovernmental and other organizations, professional societies involved in the planning and management of maternal and child health services, health professionals (including obstetricians, midwives, nurses, nutritionists and general medical practitioners), researchers, and academic staff involved in training health professionals.

# Scope of the recommendations
This updated recommendation is relevant to all pregnant women and adolescent girls receiving ANC in any health-care facility or community-based setting and to their fetuses and newborns. The guideline question was prioritized during the WHO 2016 ANC guideline development process. In 2019, the recommendation was prioritized for updating in the context of WHO's living guideline commitment (10). The outcomes of interests are, therefore, the same as those prioritized for the ANC guideline relevant to nutritional interventions (Box 1).
This recommendation is an update of one of 49 recommendations that were published in WHO recommendations on antenatal care for a positive pregnancy experience (8). The recommendation was developed initially using the standardized operating procedures described in the WHO handbook for guideline development (11). In summary, the process included: (i) identification of priority question and outcomes, (ii) retrieval of evidence, (iii) assessment and synthesis of the evidence, (iv) formulation of recommendation, and (v) planning for the implementation, dissemination, impact evaluation and updating of the recommendation. This recommendation was identified by the Executive GSG as a high priority for updating in response to new evidence on this question.

# Contributors to the guideline Executive Guideline Steering Group
The Executive GSG is an independent panel of external experts and relevant stakeholders from the six WHO regions. This group advises WHO on the prioritization of new and existing questions in maternal and perinatal health for recommendation development or updating.

# WHO Steering Group
The WHO Steering Group that managed the updating process comprised the same staff members from the Departments of SRH, MCA and NFS as the WHO ANC guideline of 2016 (see Annex 1 for the list of members).
The WHO Steering Group drafted the priority question in PICO (population, intervention, comparator, outcome) format and identified individuals to be invited to participate as guideline methodologists, and in the guideline development and external review groups. In addition, the WHO Steering Group supervised the evidence retrieval and synthesis, organized the technical consultation and finalized the guideline document. Additionally, WHO regional office representatives for sexual and reproductive health were invited to all GDG sessions and provided comments on the updated recommendation document. The WHO Steering Group in collaboration with WHO regional offices will oversee the dissemination of the updated recommendation.

# Guideline Development Group
The WHO Steering Group identified and invited 12 external experts and stakeholders from the six WHO regions to constitute the GDG, ensuring representation, gender balance and no important conflicts of interest. These experts also served in the GDG for the WHO ANC guideline's nutrition recommendations of 2016. They were a diverse group of individuals with expertise in research, guideline development methods and clinical policy and programmes relating to ANC interventions, plus a patient/consumer representative. The GDG appraised the evidence used to inform the recommendation, advised on the interpretation of this evidence and formulated the final recommendation during an online GDG meeting on 13 January 2021. In addition, GDG members reviewed and approved the final guideline document before its submission to the WHO Guidelines Review Committee for approval. A list of the GDG members can be found in Annex 1.

# External Review Group
The External Review Group (ERG) was a geographically and gender-balanced group with no important conflicts of interest (see Annex 2). There were four members, including technical experts and other stakeholders with interests in the provision of evidence-informed ANC. This group peer-reviewed the draft version of the guideline document to identify any factual errors and comment on the clarity of the language, contextual issues and implications for implementation. The group ensured that the guideline decision-making processes had considered and incorporated the contextual values and preferences of people affected by the recommendation, including pregnant women and adolescent girls, health-care professionals and policy-makers. It was not within the ERG's remit to change the recommendation formulated by the GDG.

# Systematic review team and guideline methodologists
The managing editors of the Cochrane pregnancy and childbirth group coordinated the updating of the quantitative systematic review and facilitated collaboration between systematic review authors and guideline methodologists. Working closely with the WHO Steering Group, methodologists from The Evidence-based Medicine Consultancy in the United Kingdom of Great Britain and Northern Ireland appraised the quantitative evidence using WHO's standardized operating procedures for GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology (12). Two qualitative-evidence experts from the University of Central Lancashire in the United Kingdom systematically reviewed qualitative studies related to women's and health professionals' views on ANC, and synthesized this evidence.

# External partners and observers
Six representatives of the ICM, UNFPA, USAID, UNICEF and the Bill & Melinda Gates Foundation were invited to the final GDG meeting to serve as observers. All these organizations are potential implementers of the proposed guideline with a history of collaboration with the WHO in guideline dissemination and implementation.
Observers do not participate in the formulation of recommendations.

# Declaration of interests by external contributors
WHO requires that experts serving in an advisory role disclose any circumstances that could give rise to actual or ostensible conflicts of interest. In accordance with the WHO guidelines for declaration of interests (WHO Experts) ( 13), all GDG members and other external collaborators were asked to declare in writing any competing interests (whether academic, financial or other) at the time of the invitation to participate in the ANC guideline development process. The standard WHO form for declaration of interest (DOI) was completed and signed by each expert. The WHO Steering Group reviewed all the DOI forms before finalizing experts' invitations to participate. Where any conflicts of interest were declared, the WHO Steering Group determined whether they were serious enough to affect the individual's ability to make objective judgements about the evidence or recommendation. To ensure consistency, the WHO Steering Group applied the criteria for assessing the severity of a conflict of interest in the WHO handbook for guideline development (11).
All findings from DOI statements were managed in accordance with the WHO DOI guidelines on a case-bycase 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 expert was only required to declare such a conflict at the GDG meeting, and no further action was taken. A summary of the DOI statements and information on how conflicts of interest were managed are included in Annex 2. To strengthen public trust and transparency in connection with WHO meetings involving the provision of expert advice in developing technical norms and standards, the names and brief biographies of individuals considered for participation in this guideline together, with a description of the objectives of relevant meetings, were made public ahead of the planned online GDG meeting, to allow time for public notice and comment.

# Identifying priority questions and outcomes
The priority question and outcomes were aligned with those of the ANC guideline. This question and outcomes were originally informed through an extensive scoping exercise of existing clinical practice guidelines relevant to routine ANC, supplemented by searching the Cochrane Database of Systematic Reviews for existing key systematic reviews relevant to ANC. Critical and important outcomes were informed by these reviews, and by a WHO-commissioned scoping qualitative review of what women want during pregnancy (14). The findings of the latter revealed that pregnant women want a positive pregnancy experience, defined as maintaining physical and sociocultural normality; maintaining a healthy pregnancy and baby; having an effective transition to positive labour and birth; and achieving a positive motherhood. This composite outcome of a positive pregnancy experience became the overarching principle of ANC guideline recommendations.

# Evidence identification and retrieval
Evidence to support this recommendation was derived from a number of sources by the methodologists working closely with the WHO Steering Group. An updated systematic review was the primary source of evidence on the effectiveness of oral antenatal zinc supplementation. Earlier versions of this review -in which evidence on effectiveness was derived from randomized controlled trial (RCT) data assessed and synthesized using standardized Cochrane methodology -supported the ANC guideline recommendation of 2016. The up-to-date RevMan file was retrieved from the Cochrane pregnancy and childbirth group and customized to reflect the key comparisons, GDG-specified subgroup analyses, and outcomes relevant to the ANC guideline. Evidence was evaluated according to standard operating procedures approved by the WHO Steering Group, and evidence profiles (in the form of GRADE tables) were prepared, including assessments of the certainty of the evidence, for the comparisons of interest.
Two qualitative systematic reviews commissioned by the WHO Steering Group for the 2016 guideline development process informed the values, acceptability and feasibility criteria of the EtD frameworks to inform the recommendation (see below for more information, under section 2.6 -Preparation of the evidence summary) (14,15). Additionally, systematic reviews of cost-effectiveness were sought through PubMed searches of the literature.

# Quality assessment and grading of the evidence
The GRADE approach (12) was used to appraise the certainty of quantitative evidence, meaning that the certainty of evidence for each outcome was rated as "high", "moderate", "low", or "very low" based on a set of established criteria. As a baseline, the evidence from the systematic reviews was rated "high certainty" because it was derived from RCTs; this rating was then downgraded according to considerations of risk of bias, inconsistency, imprecision, indirectness and publication bias or other considerations.
Qualitative evidence was derived from a qualitative evidence synthesis performed for the WHO 2016 ANC guideline (14,15). Previously subjected to a quality appraisal using the GRADE-CERQual (Confidence in the Evidence from Reviews of Qualitative research) tool, the evidence was not regraded for this updated recommendation. The GRADE-CERQual tool, which uses a similar approach conceptually to other GRADE tools, rates the level of confidence that can be placed in qualitative evidence synthesis according to four components: methodological limitations of the individual studies, adequacy of data and coherence and relevance of the findings to the review question (16).

# Preparation of the evidence summary
The WHO Steering Group supervised and finalized the preparation of the evidence summary and profile, in collaboration with the guideline methodologists, using the DECIDE (Developing and Evaluating Communication strategies to Support Informed Decisions and Practice based on Evidence) framework. DECIDE is an EtD tool that includes explicit and systematic consideration of research evidence on interventions according to six criteria, namely effects, values, resources, equity, acceptability and feasibility (17). These six EtD criteria were populated with the research evidence, where available; in addition, information from other sources was described in the additional considerations subsections of each criterion. The certainty of the graded evidence on intervention effectiveness was systematically interpreted in EtD frameworks according to guidance from the Cochrane group on effective practice and organization of care (18).

# Formulation of the recommendation
GDG members and other participants were provided with the evidence summary in advance of the online GDG meeting held on 13 January 2021, organized by the WHO Steering Group from Geneva, Switzerland. During the technical consultation, under the leadership of the GDG chair, the GDG members reviewed, discussed and made judgements on the impact of the intervention for each of the EtD criteria. GDG judgements were summarized in a table, before finalizing the recommendation and remarks. The intervention could be recommended, not recommended, or recommended only under certain conditions (in specific contexts, with targeted monitoring and evaluation, in the context of rigorous research).

# Decision-making process
The online GDG meeting was guided by a clear protocol, designed to allow the recommendation to be formulated through a process of group discussion, until consensus was reached. The final adoption of the recommendation and, if necessary, the context in which the recommendation would apply were confirmed by unanimous consensus (i.e. full agreement among all GDG members).

# Guideline preparation and peer review
Following the online GDG meeting, members of the WHO Steering Group, assisted by methodologists, drafted a full guideline document to accurately reflect the deliberations and decisions of participants. A preliminary version of the document was sent electronically to the participants and the ERG for final review and technical comments.
The WHO Steering Group carefully evaluated the input of the peer reviewers for inclusion in the guideline document and made revisions to the guideline draft as needed. After the GDG meetings and peer review process, further modifications to the guideline by the WHO Steering Group were limited to corrections of factual errors and improvements in language to address any lack of clarity. The document was then submitted for executive clearance according to established WHO publication procedures.

# Evidence and recommendation on antenatal zinc supplementation
This section provides the WHO recommendation adopted by the GDG on antenatal zinc supplementation with its corresponding evidence summary. Evidence on the effectiveness of zinc supplementation is further detailed in GRADE tables in Annex 3. To ensure that the recommendation is correctly understood, additional remarks reflecting the summary of the discussion by the GDG are included below the recommendation.

# WHO recommendation on antenatal zinc supplementation
Zinc supplementation for pregnant women is recommended only in the context of rigorous research.
- This Guideline Development Group agreed to retain the WHO recommendation found in the 2016 WHO antenatal care guideline (8). - WHO does not recommend zinc supplementation as part of routine antenatal care. It is recommended only in the context of rigorous research to improve our knowledge of its effect on maternal and newborn health outcomes.
Research is particularly needed on how zinc status is impacted by other nutritional supplementation (e.g. iron and/or calcium) given as part of routine antenatal care. Additionally, research is needed on the efficacy of zinc supplementation -provided either alone or with other nutritional supplements (e.g. iron, folic acid and calcium, according to national guidelines/standard of care) -on maternal and neonatal outcomes. Multiple doses of zinc, iron and/or calcium may need to be evaluated based on the current national standard of care. Research on the effectiveness or the implementation of zinc supplementation is not identified as a priority at this time. - Pregnant women should be encouraged and supported to receive adequate nutrition, which is best achieved through a healthy, balanced diet, and to refer to guidelines on healthy eating (19).

# The priority question
For pregnant women (population), does zinc supplementation (intervention) compared with no zinc supplementation (comparator) improve maternal and perinatal health outcomes (outcome)?

# Effects of the intervention
What are the anticipated effects of antenatal zinc supplements compared with no zinc supplements (or placebo)?

# Research evidence
The following evidence was derived from a systematic review (9) that updated evidence from a review published in 2015 (7). The updated review includes data from four additional trials, so that there was a total of 25 RCTs, involving more than 18 000 pregnant women. Studies were carried out in Bangladesh (two studies), Chile, China, Denmark, Egypt, Ghana, Indonesia (two studies), the Islamic Republic of Iran (three studies), Nepal, Pakistan, Peru (two studies), South Africa, United Republic of Tanzania, the United Kingdom (three studies) and the United States of America (four studies). The dose of daily zinc supplementation ranged from 5 mg to 50 mg of zinc per day, although in one trial some women received up to 90 mg of zinc per day. Eleven trials compared zinc supplementation with placebo. There was a wide variation in the size of trials (56 women recruited in the smallest, 4926 women in the largest) and in women's nutritional and zinc status at trial entry. Women's gestational age at recruitment and the duration of supplementation also varied across trials (before conception in one trial, in the first or second trimester in most trials, after 26 weeks' gestation in two trials, and up to 6 months postpartum in one trial), as did compliance with treatment.

# Maternal outcomes
Pre-eclampsia: The evidence suggests that zinc supplementation may make little or no difference to preeclampsia compared with no zinc supplements (six trials, 2568 women; risk ratio, RR, 0.93, 95% confidence interval, CI, 0.62 to 1.42; low-certainty evidence, downgraded due to design limitations and imprecision).

# Maternal infection:
The evidence suggests that zinc supplementation may make little or no difference to maternal infection compared with no zinc supplements (four trials, 1891 women; RR 0.94, 95% CI 0.72 to 1.23; low-certainty evidence, downgraded due to design limitations and imprecision).
Side-effects: Side-effects were not generally reported in trials.
The evidence on caesarean section was of very low certainty and there were no relevant data on maternal anaemia, maternal mortality, gestational diabetes mellitus or positive pregnancy experience.

# Fetal/neonatal outcomes
Small for gestational age: Zinc supplementation probably makes little or no difference to the small for gestational age outcome compared with no zinc supplements (nine trials, 5330 babies; RR, 1.02, 95% confidence interval, CI, 0.92 to 1.12; moderate-certainty evidence, downgraded due to design limitations).

# Summary of effects
Low-certainty evidence suggests that zinc supplementation may have little or no effect on pre-eclampsia and maternal infections; there is insufficient evidence available for other maternal outcomes. In addition, lowcertainty evidence suggests that supplementation may have little or no effect on any of the important fetal and neonatal outcomes.

# Additional considerations
- WHO recommends iron and folic acid supplementation containing 30 mg to 60 mg of iron and 0.4 mg of folic acid for all pregnant women, and calcium supplementation for women with low dietary intake and those at risk of pre-eclampsia; these supplements may potentially reduce the bioavailability of zinc (1).

# Desirable effects
How substantial are the desirable anticipated effects of zinc supplements compared with no zinc supplements?
Judgement  Don't know  Varies  Trivial  Small  Moderate  Large
Rationale for judgement: There appears to be no clear improvement in pregnancy outcomes.

# Undesirable effects
How substantial are the undesirable anticipated effects of zinc supplements compared with no zinc supplements?
Judgement  Don't know  Varies  Trivial  Small  Moderate  Large
Rationale for judgement: There was no evidence suggesting harm but adverse events were generally not reported in the studies.

# Certainty of the evidence

# What is the overall certainty of the evidence of effects of zinc supplements compared with no zinc supplements?
 No included studies  Very low  Low  Moderate  High
Rationale for judgement: Low certainty was the most common GRADE rating.

# Is there important uncertainty about, or variability in, how much women (and their families) value the main outcomes associated with zinc supplements?
A scoping review of what women want from ANC informed the outcomes for the WHO ANC guideline (14). Evidence showed that women from various resource settings valued having a positive pregnancy experience comprising three equally important components, namely effective clinical practices (interventions and tests), relevant and timely information, and psychosocial and emotional support, each provided by practitioners with good clinical and interpersonal skills within a well-functioning health system (high confidence in the evidence). Rationale for judgement: The low-certainty evidence suggests that there are neither benefits nor harms with zinc supplements.
How large are the resource requirements (costs)?

# Research evidence
No research evidence on the costs and cost-effectiveness of implementing zinc supplementation was found.

# Main resource requirements
The main resource requirement is probably the cost of the supplements. The UNICEF Supply Catalogue pricing accessed on 3 June 2021 gave an indicative price of US$ 1.34 for a blister pack of 100 tablets of 20 mg each, which is equivalent to US$ 3.20 for six-month supply (20). However, to ensure that women received relevant and accurate information about the supplements, staff training would be required, which would also have cost implications.

# Additional considerations
- The cost-effectiveness of zinc supplements for pregnant women is uncertain because the systematic review found no strong evidence of their effectiveness in relation to the pregnancy outcomes evaluated. - To have an impact on child mortality, it has been suggested that food fortification may be the most cost-effective strategy to supplement zinc among populations with a high prevalence of zinc deficiency (3).

# Resources required

# Large savings
Rationale for judgement: The cost of zinc supplements is similar to that of iron and folic acid supplements, and, if implemented, may double the cost of micronutrient supplements provided to women during pregnancy.

# Certainty of evidence on required resources
What is the certainty of the evidence on costs? Rationale for judgement: The evidence did not show zinc supplementation to be effective, so cost-effectiveness cannot be evaluated.
What would be the impact of zinc supplements compared with no zinc supplements on health equity?

# Research evidence

# Additional considerations
- Nutritional deficiencies are common in low-and middle-income countries (LMICs). Effective interventions to improve the nutritional status of pregnant women and girls in these settings could help to address health inequalities by preventing illnesses related to vitamin and mineral deficiencies.
 Don't know  Varies  Reduced  Probably reduced  Probably no impact  Probably increased  Increased
Rationale for judgement: There is no clear evidence of the effectiveness of zinc supplementation for pregnancy outcomes; the effectiveness of zinc supplementation on general maternal health in LMICs was not a prioritized guideline outcome.

# Would zinc supplements be acceptable to key stakeholders?

# Research evidence
A systematic review of qualitative research exploring women's views and experiences of ANC suggests that women tend to view ANC as a source of knowledge and information and generally appreciate any advice (including dietary or nutritional) that may lead to a healthy baby and a positive pregnancy experience (high confidence in the evidence) (15).
The same review explored health professionals' views of ANC, and suggests that health professionals are keen to offer general health-care advice and specific pregnancy-related information (low confidence in the evidence) but sometimes feel they do not have the appropriate training, and the resources and time to deliver the service in the informative, supportive and caring manner that women want (high confidence in the evidence) (15).

# Additional considerations
 Don't know  Varies  No  Probably No  Probably Yes  Yes
Rationale for judgement: If zinc supplementation improved pregnancy outcomes, supplementation would probably be acceptable. However, as there is no clear evidence of effectiveness, it may not be acceptable.
Would zinc supplementation be feasible to implement?

# Research evidence
Evidence derived from a qualitative evidence synthesis conducted to support the WHO ANC guideline development shows that where there are likely to be additional costs associated with supplementation (high confidence in the evidence), women may be less likely to engage with services (15). In addition, in a number of LMIC settings, providers felt that a lack of resources, both in terms of the availability of recommended supplements and the lack of suitably trained staff to deliver nutritional information, was an issue, which may limit the implementation of this intervention (high confidence in the evidence).

# Additional considerations
- On the demand side, if zinc supplements are free and available, routine supplementation may be feasible. On the supply side, however, there may be several considerations to take into account, such as changes in regulatory norms and policies (e.g. tariffs, labelling, imports, government oversight, etc.), how sustainable the production is (local or imported) and how to guarantee product availability. - In addition, the lack of effectiveness of this intervention suggests that it would not be feasible in LMICs where healthcare expenditure is constrained.
 Don't know  Varies  No  Probably No  Probably Yes  Yes
Rationale for judgement: There is no clear evidence of effectiveness.

# Summary of GDG judgements on antenatal zinc supplementation (18)

# Draft implementation considerations

# Research gaps
- The GDG agreed that more research on the efficacy of zinc supplementation in pregnancy was needed and that trials of zinc supplementation should consider other nutritional supplements (e.g. iron and/or calcium) that women may be receiving as part of routine ANC. As iron supplementation is recommended in all settings, and calcium supplementation is recommended in settings with low dietary intake as part of routine ANC, research is needed to evaluate the interactions among these nutrients in relation to maternal and newborn outcomes.
In settings providing iron and folic acid as part of routine ANC, trials on zinc supplementation should include several doses of zinc along with either 30 mg and/or 60 mg of elemental iron, according to national guidance.
Information should be recorded carefully on the timing of the different supplements, whether taken at the same time or different times of the day, along with an assessment of the feasibility and acceptability of taking multiple supplements at different times in these trials.

# Dissemination and implementation of the recommendation 4.1 Recommendation dissemination
This updated global guideline will be available online for download and also as a printed publication. Online versions will be available on the WHO websites and other online platforms developed by the WHO Departments of SRH, NFS and MCA, and through the WHO ANC portal 1 and the WHO Reproductive Health Library and WHO e-Library of Evidence for Nutrition Actions. 2 Print versions will be distributed to WHO regional and country offices, ministries of health, WHO collaborating centres, nongovernmental organization partners, among others, using the same distribution list that was developed for the WHO ANC guideline. The updated recommendation and updated derivative products, in particular the WHO Antenatal Care Recommendations Adaptation Toolkit and its instruction manual, will be disseminated during meetings and scientific conferences attended by WHO staff (21). Social media channels will also be used. The executive summary and recommendation from this publication will be translated into the six United Nations languages for dissemination through the WHO regional offices and during meetings organized or attended by WHO staff.

# Implementation considerations and applicability issues
This updated recommendation supersedes the WHO ANC guideline recommendation on zinc supplementation that was issued in 2016 (recommendation A6) (8). The GDG agreed that there were no new implementation considerations or applicability issues specific to this recommendation, as it was recommended in a research context. Monitoring of the uptake and impact of this updated recommendation will be integrated into that of the 2016 WHO ANC guideline (8). For implementation considerations related to WHO recommendations on antenatal care for a positive pregnancy experience in general, please refer to this guideline and associated derivative products, which are available on the WHO websites.

# Research implications
The GDG agreed that more research on the efficacy of zinc supplementation in pregnancy is needed and that trials of zinc supplementation should consider other nutritional supplements (e.g. iron and/or calcium) that women may be receiving as part of routine ANC. As iron supplementation is recommended in all settings and calcium supplementation is recommended in settings with low dietary intake as part of routine ANC, research is needed to evaluate the interactions among these nutrients in relation to maternal and newborn outcomes.
In settings providing iron and folic acid as part of routine ANC, trials on zinc supplementation should include several doses of zinc along with 30 mg and/or 60 mg of elemental iron, according to national guidance.
Information should be recorded carefully on the timing of the different supplements, whether taken at the same time or different times of the day, along with an assessment of the feasibility and acceptability of taking multiple supplements at different times in these trials.
6 Updating the guideline WHO convenes the Executive GSG biannually to review WHO's current portfolio of maternal and perinatal health recommendations, and to advise on the prioritization of new and existing questions for recommendation development and updating. WHO will monitor the publication of new randomized trials on this topic. Any concern about the validity of the recommendation will be promptly communicated via the guideline website, 3 and plans will be made to update the recommendation, as necessary. WHO will prioritize its independent normative guidance informed by the strategic shifts embedded in its Constitution and the Thirteenth General Programme of Work 2019-2023.
All technical products developed during the process of developing this recommendation, including the Cochrane RevMan 4 file customized for priority outcomes, and the basis for quality ratings within the GRADE process, will be archived in the departmental shared folder for future reference and use.
Evidence from studies with moderate risk of bias and design limitations.
Confidence interval is imprecise.
More than 50% of the pooled effect from studies with moderate risk of bias and design limitations.