WHO recommendation on Calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications
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WHO recommendation on Calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications
WHO recommendation on Calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications
WHO recommendation on calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications ISBN 978-92-4-000311-8 (electronic version) ISBN 978-92-4-000312-5 (print version) © World Health Organization 2020 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. WHO recommendation on calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications. Geneva: World Health Organization; 2020. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/about/licensing. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use.
WHO recommendation on Calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications iii
Contents
Acknowledgements iv
Acronyms and abbreviations v
Executive Summary 1
1. Background 3
2. Methods 4
3. Recommendation and supporting evidence 10
4. Dissemination and implementation of the recommendation 12
5. Research implications 13
6. Applicability issues 13
7. Updating the recommendation 14
References 15
Annex 1. External experts and WHO staff involved in the preparation of the guideline 17
Annex 2. Priority outcomes for decision-making 21
Annex 3. Summary and management of declared interests from GDG members 22
Annex 4. Evidence-to-decision framework 24iv WHO recommendation on Calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications
Acknowledgements
The Department of Sexual and Reproductive Health and Research, the Department of
Maternal, Newborn, Child and Adolescent Health and Ageing, and the Department of
Nutrition and Food Safety of the World Health Organization (WHO) gratefully acknowledge the
contributions of many individuals and organizations to the updating of this recommendation.
Work on this update was coordinated by Joshua Vogel, Abiodun Adanikin and Olufemi
Oladapo of the WHO Department of Sexual and Reproductive Health and Research.
WHO extends its sincere thanks to Ebun Adejuyigbe, Shabina Ariff, Jemima Dennis-
Antwi, Luz Maria De-Regil, Christine East, Lynn Freedman, Pisake Lumbiganon,
Anita Maepioh, Shireen Meher, James Neilson, Hiromi Obara, Cristina Palacios,
Rachel Plachcinski, Zahida Qureshi, Kathleen Rasmussen, Niveen Abu Rmeileh and
Eleni Tsigas who served as members of the Guideline Development Group (GDG),
and to Zahida Qureshi (Chair) and James Neilson (Vice-Chair) for leading the meeting.
We also thank Caroline Homer, Hadiza Galadanci, Jashodhara Gupta, Jack Moodley,
M Jeeva Sankar, Shakila Thangaratinam, Saraswathi Vedam and Hayfaa Wahabi who
were members of the External Review Group. WHO also gratefully acknowledges the
contribution of the members of the Executive Guideline Steering Group.
Leanne Jones, Frances Kellie and Myfanwy Williams reviewed the scientific evidence,
prepared the Grading of Recommendations Assessment, Development and Evaluation
(GRADE) tables and drafted the narrative summary of evidence. Joshua Vogel,
Abiodun Adanikin and Olufemi Oladapo revised the narrative summaries and double-
checked the corresponding GRADE tables and prepared the evidence-to-decision
(EtD) frameworks. Abiodun Adanikin, Fernando Althabe, Ana Pilar Betrán, Mercedes
Bonet, Maurice Bucagu, Fran McConville, Olufemi Oladapo, Juan Pablo Peña-Rosas,
Anayda Portela, Lisa Rogers, Özge Tuncalp and Joshua Vogel commented on a
preliminary draft document before discussions and deliberations by the WHO Guideline
Development Group members. The External Review Group peer reviewed the final
document prior to executive clearance by WHO and publication.
We acknowledge the various organizations that were represented by observers, including
Deborah Armbruster and Mary-Ellen Stanton (United States Agency for International
Development), Kathleen Hill (Maternal and Child Survival Program/Jhpiego), Jeff Smith
(Bill & Melinda Gates Foundation), Ingela Wiklund (International Confederation of Midwives),
Gerard Visser (International Federation of Gynaecology and Obstetrics) and Charlotte
Warren (Ending Eclampsia Project, Population Council). We also appreciate the contributions
of WHO Regional Offices’ staff – Nino Berdzuli, Bremen De Mucio, Chandani Anoma
Jayathilaka, Ramez Khairi Mahaini, Léopold Ouedraogo, Howard Sobel and Claudio Sosa.
WHO acknowledges the financial support for this work received from the United States
Agency for International Development and the UNDP/UNFPA/UNICEF/WHO/World
Bank Special Programme of Research, Development and Research Training in Human
Reproduction (HRP), a cosponsored program executed by the WHO. WHO emphasizes
that donors do not participate in any decision related to the guideline development
process, including the composition of research questions, membership of the guideline
development groups, conducting and interpretation of systematic reviews, or formulation
of the recommendation. The views of the funding bodies have not influenced the content
of this recommendation.WHO recommendation on Calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications v
Acronyms and abbreviations
ANC Antenatal care
BMGF Bill & Melinda Gates Foundation
CI Confidence interval
DOI Declaration of Interest
EtD Evidence-to-decision
FIGO International Federation of Gynaecology and Obstetrics
FWC Family, Women’s and Children’s Health (a WHO cluster)
GDG Guideline Development Group
GRC Guidelines Review Committee
GRADE Grading of Recommendations, Assessment, Development and Evaluation
GREAT Guideline development, Research priorities, Evidence synthesis, Applicability of
evidence, Transfer of knowledge (a WHO project)
GSG Executive Guideline Steering Group
HELLP Haemolysis, elevated liver enzymes, low platelets
ICM International Confederation of Midwives
ICU Intensive care unit
LMIC Low and middle-income country
MAP Mean arterial pressure
MCA [WHO Department of] Maternal, Newborn, Child and Adolescent Health and Ageing
MCSP Maternal and Child Survival Programme
MPH Maternal and Perinatal Health (a unit in WHO’s Department of Sexual and
Reproductive Health and Research)
NFS [WHO Department of] Nutrition and Food Safety
NICU Neonatal intensive care unit
NNT Number needed to treat
PICO Population (P), intervention (I), comparison (C), outcome (O)
RCT Randomized controlled trial
RR Relative risk
SDG Sustainable Development Goals
SoF Summary of findings
SRH [WHO Department of] Sexual and Reproductive Health and Research
UN United Nations
UNFPA United Nations Population Fund
USAID United States Agency for International Development
WHO World Health Organizationvi WHO recommendation on Calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications
WHO recommendation on Calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications 1
Executive Summary
Introduction help in increasing capacity in countries to respond
to their needs on interventions before and/or early
Hypertensive disorders of pregnancy are a significant
in pregnancy to prevent the risk of pre-eclampsia
cause of severe morbidity, long-term disability
during pregnancy, and to prioritize essential actions
and death among both mothers and their babies.
in national health policies, strategies and plans.
Worldwide, they account for approximately 14% of all
maternal deaths. Among the hypertensive disorders
that complicate pregnancy, pre-eclampsia and Guideline development methods
eclampsia stand out as major causes of maternal and
The development of this recommendation was guided
perinatal mortality and morbidity. Most of the deaths
by standardized operating procedures in accordance
due to pre-eclampsia and eclampsia are avoidable
with the process described in the WHO handbook
through the provision of timely and effective care
for guideline development. The recommendation was
to the women presenting with these complications.
initially developed using this process, namely:
Improving care for women during pregnancy and
around the time of childbirth to prevent and treat (i) identification of the priority question and
pre-eclampsia and eclampsia are necessary steps critical outcomes;
towards the achievement of the health targets of (ii) retrieval of evidence;
the Sustainable Development Goals (SDGs). Efforts
to prevent and reduce morbidity and mortality due (iii) assessment and synthesis of evidence;
to these conditions can help address the profound (iv) formulation of the recommendation; and
inequities in maternal and perinatal health globally. To
(v) planning for the dissemination,
achieve this, healthcare providers, health managers,
implementation, impact evaluation and
policy-makers and other stakeholders need up-to-
updating of the recommendation.
date and evidence-informed recommendations to
guide clinical policies and practices. The scientific evidence supporting the
recommendation was synthesized using the
In 2019, the Executive Guideline Steering Group
Grading of Recommendations, Assessment,
(GSG) on WHO maternal and perinatal health
Development and Evaluation (GRADE) approach. An
recommendations prioritized the development
updated systematic review was used to prepare the
of a new WHO recommendation on calcium
evidence profiles for the prioritized question. WHO
supplementation before and/or early in pregnancy
convened an online meeting on 31 July 2019 where
for preventing hypertensive disorders of pregnancy,
the Guideline Development Group (GDG) members
in response to the publication of a multi-country
reviewed, deliberated and achieved consensus on
trial evaluating the use of pre-pregnancy calcium
the strength and direction of the recommendation
supplementation.
presented herein. Through a structured process, the
GDG reviewed the balance between the desirable
Target audience and undesirable effects and the overall certainty
of supporting evidence, values and preferences of
The primary audience of this recommendation
stakeholders, resource requirements and cost-
includes health professionals who are responsible
effectiveness, acceptability, feasibility and equity.
for developing national and local health protocols
(particularly those related to pre-eclampsia and
eclampsia, and nutrition for non-pregnant and Recommendation
pregnant women and adolescent girls), and those
The GDG reviewed the balance between the
directly providing care to pregnant women and their
desirable and undesirable effects and the
newborns, including midwives, nurses, general
overall quality of supporting evidence, values
medical practitioners, obstetricians, managers of
and preferences of stakeholders, resource
maternal and child health programmes, and relevant
requirements and cost-effectiveness, acceptability,
staff in ministries of health, in all settings. It aims to2 WHO recommendation on Calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications
feasibility and equity. The GDG issued a new is correctly understood and applied in practice,
recommendation on pre-pregnancy calcium guideline users may want to refer to the remarks,
supplementation, with remarks and implementation as well as to the evidence summary, including the
considerations. To ensure that the recommendation considerations on implementation.
Table 1: WHO recommendation on pre-pregnancy calcium supplementation for the prevention of
pre-eclampsia and its complications
Pre-pregnancy calcium supplementation for the prevention of pre-eclampsia and its
complications is recommended only in the context of rigorous research.
(Recommendation in research context)
Justification
• Low-certainty evidence suggests that starting calcium supplementation before and/or early
in pregnancy (compared to placebo or no treatment) may make little or no difference to
women’s risk of developing hypertensive disorders during pregnancy. The estimate of effect
of this intervention on the outcome “pre-eclampsia and/or pregnancy loss and/or stillbirth
at any gestational age” included the possibility of a risk reduction, but the 95% confidence
interval touched the line of no effect. There is a possibility of clinical benefit for those women
with greater than 80% compliance with calcium supplementation. However, this is uncertain
and needs further research. The maternal adverse effects of the intervention are not known.
• The acceptability of calcium supplementation by women may vary – while women may value
nutritional interventions that can lead to a healthy baby and a positive pregnancy experience, calcium
tablets can be large, have a powdery texture and be unpalatable to consume. Feasibility may also be
limited in settings where calcium is not always available due to logistical or staff constraints or cost.
In addition, limited access to pre-conception healthcare services may be a barrier to the provision of
calcium supplements prior to pregnancy. The cost-effectiveness of this intervention is not known.
Remarks
• The GDG noted that in 2018 WHO revalidated the recommendation that in populations with
low dietary calcium intake, daily calcium supplementation (1.5–2.0 g oral elemental calcium) is
recommended for pregnant women to reduce the risk of pre-eclampsia (1). However, there is
insufficient evidence to determine with precision at what gestational age calcium supplementation
should be commenced in order to confer this benefit. The 2018 recommendation specified that
stakeholders may wish to commence calcium supplementation at the first antenatal care contact,
in order to optimize compliance with this regimen. Evidence review on initiation of calcium
supplementation before pregnancy and continuing through pregnancy, however, shows that
it remains uncertain whether this will confer additional health benefits, and further research is
required.
• Food fortification of staple foods with calcium may be an important public health intervention
in settings where dietary calcium intake is low. Dietary counselling of all women who are
considering pregnancy should promote adequate calcium intake through locally available,
calcium-rich foods. Adequate calcium intake could be easily achieved by the incorporation of
dairy products in the diet on a daily basis. However, dairy products are not part of all regular
diets, or are not available in certain populations. Likewise, a high-salt diet decreases body-
calcium retention compared to a diet that is low in salt. Caffeine and protein can also induce
hypercalciuria, but to a much lesser extent. This has become more important in recent years
due to the consumption of caffeine-containing beverages such as soda and energy drinks.WHO recommendation on Calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications 3
1. Background
An estimated 295 000 women and adolescent Hypertensive disorders of pregnancy are a
girls died as a result of pregnancy and childbirth- significant cause of severe morbidity, long-
related complications in 2017, around 99% of term disability and death among both mothers
which occurred in low-resource settings (2). and their babies. Worldwide, they account for
Haemorrhage, hypertensive disorders and sepsis approximately 14% of all maternal deaths (8).
are responsible for more than half of all maternal Among the hypertensive disorders that complicate
deaths worldwide. Thus, improving the quality of pregnancy, pre-eclampsia and eclampsia stand
maternal healthcare for women is a necessary out as major causes of maternal and perinatal
step towards achievement of the health targets of mortality and morbidity. The majority of deaths
the Sustainable Development Goals (SDGs) and due to pre-eclampsia and eclampsia would be
the targets and indicators of WHO’s Thirteenth avoidable through the provision of timely and
General Programme of Work, particularly effective care to women presenting with these
for achieving universal health coverage (3). complications. Efforts to prevent and reduce
International human rights law includes pre-eclampsia and eclampsia-associated
fundamental commitments of states to enable morbidity and mortality could reduce the profound
women and adolescent girls to survive pregnancy inequities in maternal health globally.
and childbirth, as part of their enjoyment of sexual
and reproductive health and rights, and living a life
of dignity (4). The World Health Organization (WHO)
Rationale and objectives
envisions a world where “every pregnant woman WHO has established a novel process for
and newborn receives quality care throughout the prioritizing and updating maternal and perinatal
pregnancy, childbirth and the postnatal period” (5). health recommendations, whereby an Executive
Guideline Steering Group (GSG) oversees a
There is evidence that effective interventions systematic prioritization of maternal and perinatal
exist at reasonable cost for the prevention or health recommendations in most urgent need of
treatment of virtually all life-threatening maternal updating (9). Recommendations were prioritized,
complications (6). Almost two thirds of the global based on changes or important new uncertainties
maternal and neonatal disease burden could be in the underlying evidence base on benefits,
alleviated through optimal adaptation and uptake harms, values placed on outcomes, acceptability,
of existing research findings (7). To provide good- feasibility, equity, resource use, cost-effectiveness,
quality care, healthcare providers at all levels of or factors affecting implementation. The Executive
maternal healthcare services, particularly in low GSG prioritized the development of a new WHO
and middle-income countries (LMICs) need to recommendation on pre-pregnancy calcium
have access to appropriate medicines and health supplementation for preventing hypertensive
products, and training in relevant procedures. disorders of pregnancy, in response to the
Healthcare providers, health managers, publication of a multi-country trial evaluating the
policymakers and other stakeholders also need use of this intervention (10). The primary goal of
up-to-date, evidence-informed recommendations this recommendation is to improve the quality
to guide clinical policies and practices in order of care and outcomes for pregnant women and
to optimize quality of care, and enable improved women intending to become pregnant, particularly
healthcare outcomes. Efforts to prevent and those related to prevention of pre-eclampsia,
reduce morbidity and mortality in pregnancy and eclampsia and resulting complications.
childbirth could reduce the profound inequities in
maternal and perinatal health globally.4 WHO recommendation on Calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications
Target audience Persons affected by the
The primary audience includes health
recommendation
professionals who are responsible for developing The population affected by this recommendation
national and local health guidelines and protocols includes women (particularly those intending to
(particularly those related to nutrition in pregnancy become pregnant and those women at higher
and pre-eclampsia and eclampsia) and those risk of gestational hypertensive disorders) in low,
directly providing care to women during labour middle or high-income settings (11).
and childbirth, including midwives, nurses, general
medical practitioners, obstetricians, managers
of maternal and child health programmes, and
relevant staff in ministries of health, in all settings. 2. Methods
This recommendation may be of interest to The recommendation was developed using
professional societies involved in the care of standardized operating procedures in accordance
pregnant women, nongovernmental organizations with the process described in the WHO handbook
concerned with promoting people-centred for guideline development (12). In summary, the
pre-conception and maternal care, and process included:
implementers of maternal and child health and (i) identification of the priority question and
nutrition programmes. It aims to help in increasing critical outcomes;
capacity in the countries to respond to their needs
(ii) retrieval of evidence;
on interventions before and/or early in pregnancy
to prevent the risk of pre-eclampsia during (iii) assessment and synthesis of evidence;
pregnancy, and to prioritize essential actions in
(iv) formulation of the recommendation; and
national health policies, strategies and plans.
(v) planning for the dissemination, implementation,
impact evaluation and updating of the
Scope of the recommendation recommendation.
Framed using the Population (P), Intervention (I),
In 2017, early/pre-pregnancy calcium
Comparison (C), Outcome (O) (PICO) format, the
supplementation was identified by the Executive
questions for this recommendation were:
GSG as a high priority for development of a
• In pregnant women and women intending recommendation, in response to new, potentially
to become pregnant (P), does starting important evidence on this question (10, 13). Six
calcium supplementation before and/or main groups were involved in this process, with
early in pregnancy (I), compared to placebo their specific roles described in the following
or no calcium supplementation before and/ sections.
or early in pregnancy (C), improve maternal
and perinatal outcomes (O), including the
onset of pre-eclampsia? Contributors to the guideline
o If yes, in what populations of women/ Executive guideline steering group (Executive
pregnant women is pre-pregnancy GSG) for updating WHO maternal and perinatal
calcium supplementation most health recommendations (2017–2019)
beneficial?
The Executive GSG is an independent panel of 14
o What dosing regimen of calcium external experts and relevant stakeholders from
supplementation is most beneficial? the six WHO regions: African Region, Region of
the Americas, South-East Asia Region, EuropeanWHO recommendation on Calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications 5
Region, Eastern Mediterranean Region and From the MPH-GDG pool, 17 external experts and
Western Pacific Region. The Executive GSG relevant stakeholders were invited to participate
advises WHO on the prioritization of new and as members of the GDG for updating this
existing questions in maternal and perinatal health recommendation. Those selected were a diverse
for recommendation development or updating (13). group with expertise in research, guideline
development methods, gender, equity and
rights, clinical policy and programmes relating
WHO Steering Group
to pre-eclampsia and eclampsia prevention and
The WHO Steering Group, comprising WHO staff treatment, as well as implementation of essential
members from the Department of Sexual and nutrition actions.
Reproductive Health and Research (SRH), the
Department of Maternal, Newborn, Child and The 17 GDG members for this recommendation
Adolescent Health and Ageing (MCA), and the were also selected in a way that ensured
Department of Nutrition and Food Safety (NFS) geographic representation and gender balance,
managed the updating process. The Group and there were no important conflicts of interest.
drafted the key recommendation questions in The GDG appraised the evidence that was used
PICO format, identified the systematic review to inform the recommendation, advised on the
team and guideline methodologists, as well as the interpretation of this evidence, formulated the final
guideline development and external review groups. recommendation based on the draft prepared by
In addition, the WHO Steering Group supervised the Steering Group, and reviewed and reached
the syntheses and retrieval of evidence, organized unanimous consensus for the recommendation in
the GDG meeting, drafted and finalized the the final document. The members of the GDG are
guideline document, and managed the guideline listed in Annex 1.
dissemination, implementation and impact
assessment. The members of the WHO Steering
External Review Group
Group are listed in Annex 1.
An External Review Group included eight
technical experts with interest and expertise in
Guideline Development Group the provision of evidence-informed obstetric
The WHO Steering Group identified a pool and nutrition care, as well as gender, equity
of approximately 50 experts and relevant and rights. None of its members declared
stakeholders from the six WHO regions to a conflict of interest. The experts reviewed
constitute the WHO Maternal and Perinatal the final document to identify any factual
Health Guideline Development Group (MPH- errors and commented on the clarity of
GDG). This pool is a diverse group of experts language, contextual issues and implications
who are skilled in the critical appraisal for implementation. They ensured that the
of research evidence, implementation of decision-making processes had considered
evidence-informed recommendations, guideline and incorporated contextual values and
development methods, and clinical practice, the preferences of potential users of the
policy and programmes relating to maternal and recommendations, healthcare professionals
perinatal health. Members of the MPH-GDG and policy makers. They did not change the
are identified in a way that ensures geographic recommendation that was formulated by
representation and gender balance, and there the GDG. The names and affiliations of the
were no perceived or real conflicts of interest. external reviewers are provided here as an
Members’ expertise cuts across thematic areas acknowledgement and by no means indicate
within maternal and perinatal health and nutrition their endorsement of the recommendations in
during pregnancy. this guideline. The acknowledgement of the6 WHO recommendation on Calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications
reviewers does not necessarily represent the 2011 GDG panel. All the outcomes were included
views, decisions or policies of the institutions in the scope of this document for evidence
with which they are affiliated. The members of searching, retrieval, grading and formulation
the External Review Group are listed in Annex 1. of the recommendation. The list of critical and
important outcomes is provided in Annex 2.
Evidence Synthesis Group
A Cochrane systematic review on this question
Evidence identification and retrieval
was updated, supported by the Cochrane A Cochrane systematic review was updated in
Pregnancy and Childbirth Group. The WHO 2019 with the support of the Cochrane Pregnancy
Steering Group reviewed and provided input into and Childbirth Group (15). This systematic review
the updated protocol and worked closely with was the primary source of evidence for this
the Cochrane Pregnancy and Childbirth Group recommendation.
to appraise the evidence using the Grading of
Recommendations Assessment, Development Randomized controlled trials relevant to the key
and Evaluation (GRADE) methodology. question were screened by the review authors,
Representatives of the Cochrane Pregnancy and and data on relevant outcomes and comparisons
Childbirth Group and methodologists attended were entered into Review Manager 5 (RevMan)
the GDG meeting to provide an overview of the software. The RevMan file was retrieved from
available evidence and GRADE tables and to the Cochrane Pregnancy and Childbirth Group
respond to technical queries from the GDG. and customized to reflect the key comparisons
and outcomes (those that were not relevant to
the recommendation were excluded). Then the
External partners and observers RevMan file was exported to GRADE profiler
Representatives of the United States Agency software (GRADEpro) and GRADE criteria were
for International Development (USAID), the Bill & used to critically appraise the retrieved scientific
Melinda Gates Foundation (BMGF), the International evidence (16). Finally, evidence profiles (in the
Confederation of Midwives (ICM), the International form of GRADE summary of findings tables) were
Federation of Gynaecology and Obstetrics (FIGO) prepared for comparisons of interest, including
and the Population Council participated in the the assessment and judgements for each
GDG meeting as observers. These organizations, outcome and the estimated risks (17).
with a long history of collaboration with various
WHO departments and programmes in guideline
Certainty assessment and grading of
dissemination and implementation, are among the
the evidence
implementers of the recommendation. The list of
observers who participated in the GDG meeting is The certainty assessment of the body of evidence
included in Annex 1. for each outcome was performed using the
GRADE approach (18). Using this approach, the
certainty of evidence for each outcome was rated
Identification of critical outcomes as ‘high’, ‘moderate’, ‘low’ or ‘very low’ based
The critical and important outcomes were aligned on a set of established criteria. The final rating
with the prioritized outcomes from the 2011 WHO of certainty of evidence was dependent on the
recommendations on prevention and treatment factors briefly described below.
of pre-eclampsia and eclampsia (14). These
Study design limitations: The risk of bias was
outcomes were initially identified through a search
first examined at the level of each individual study
of key sources of relevant, published, systematic
and then across the studies contributing to the
reviews and a prioritization of outcomes by theWHO recommendation on Calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications 7
outcome. For randomized trials, certainty was • Moderate certainty: We are moderately
first rated as ‘high’ and then downgraded by one confident in the effect estimate. The true
(‘moderate’) or two (‘low’) levels, depending on effect is likely to be close to the estimate of
the minimum criteria met by the majority of the the effect, but there is a possibility that it is
studies contributing to the outcome. substantially different;
Inconsistency of the results: The similarity in • Low certainty: Our confidence in the
the results for a given outcome was assessed effect estimate is limited. The true effect
by exploring the magnitude of differences in the may be substantially different from the
direction and size of effects observed in different estimate of the effect; and
studies. The certainty of evidence was not
downgraded when the directions of the findings • Very low certainty: We have very little
were similar and confidence limits overlapped, confidence in the effect estimate. The true
whereas it was downgraded when the results effect is likely to be substantially different
were in different directions and confidence limits from the estimate of effect.
showed minimal or no overlap.
Indirectness: The certainty of evidence was Formulation of recommendations
downgraded when there were serious or very
The WHO Steering Group supervised and
serious concerns regarding the directness of the
finalized the preparation of summary of findings
evidence, that is, whether there were important
tables and narrative evidence summaries in
differences between the research reported and
collaboration with the Evidence Synthesis Group
the context for which the recommendation was
using the GRADE evidence-to-decision (EtD)
being prepared. Such differences were related,
framework. EtD frameworks include explicit and
for instance, to populations, interventions,
systematic consideration of evidence on prioritized
comparisons or outcomes of interest.
interventions in terms of specified domains:
effects, values, resources, equity, acceptability and
Imprecision: This assessed the degree of
feasibility. For the priority questions, judgements
uncertainty around the estimate of effect. As this
were made on the impact of the intervention on each
is often a function of sample size and number of
domain, in order to inform and guide the decision-
events, the studies with relatively few participants
making process. Using the EtD framework template,
or events, and thus wide confidence intervals
the WHO Steering Group and ESG created summary
around effect estimates, were downgraded for
documents for each priority question covering
imprecision.
evidence on each domain, as described below.
Publication bias: The certainty rating could also • Effects: The evidence on the priority
be affected by perceived or statistical evidence outcomes was summarized in this domain
of bias to underestimate or overestimate the to answer the questions: “What are the
effect of an intervention as a result of selective desirable and undesirable effects of the
publication based on study results. Downgrading intervention?” and “What is the certainty of
evidence by one level was considered where the evidence on effects?” Where benefits
there was strong suspicion of publication bias. clearly outweighed harms for outcomes
that are highly valued by women, or vice
Certainty of evidence assessments are defined
versa, there was a greater likelihood of
according to the GRADE approach:
a clear judgement in favour of or against
• High certainty: We are very confident the intervention, respectively. Uncertainty
that the true effect lies close to that of the about the net benefits or harms, or small
estimate of the effect; net benefits, usually led to a judgement8 WHO recommendation on Calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications
that did not favour the intervention or the • Acceptability: For this domain, the question
comparator. The higher the certainty of was: “Is the intervention acceptable to
the evidence of benefits across outcomes, women and healthcare providers?” Qualitative
the higher the likelihood of a judgement in evidence from systematic reviews on women’s
favour of the intervention. In the absence of and providers’ views and experiences with
evidence of benefits, evidence of potential routine antenatal care services (19) informed
harm led to a recommendation against the judgements for this domain. The lower
the intervention. Where the intervention the acceptability, the lower the likelihood of a
that showed evidence of potential harm judgement in favour of the intervention.
was also found to have evidence of
important benefits, depending on the level • Feasibility: The feasibility of implementing
of certainty and the likely impact of the this intervention depends on factors
harm, such evidence of potential harm was such as the resources, infrastructure
more likely to result to a context-specific and training requirements, and the
recommendation, with the context explicitly perceptions of healthcare providers
stated within the recommendation. responsible for administering it. The
question addressed was: “Is it feasible for
• Values: This domain relates to the relative the relevant stakeholders to implement the
importance assigned to the outcomes intervention?” Qualitative evidence from
associated with the intervention by those the systematic reviews on women’s and
affected, how such importance varies providers’ views and experiences with
within and across settings, and whether antenatal care services was used to inform
this importance is surrounded by any judgements for this domain (19). Where
uncertainty. The question asked was: “Is major barriers were identified, it was less
there important uncertainty or variability in likely that a judgement would be made in
how much women value the main outcomes favour of the intervention.
associated with the intervention?” When
the intervention resulted in benefit for • Equity: This domain encompasses evidence
outcomes that most women consistently or considerations as to whether or not the
value (regardless of setting), this was more intervention would reduce health inequities.
likely to lead to a judgement in favour of the Therefore, this domain addressed the
intervention. This domain, together with the question: “What is the anticipated impact of
“effects” domain (see above), informed the the intervention on equity?” The findings of
“balance of effects” judgement. a systematic review on inequities in calcium
intake globally (11), as well as the experiences
• Resources: For this domain, the questions and opinions of the GDG members, were used
asked were: “What are the resources to inform judgements for this domain. The
associated with the intervention?” and intervention was likely to be recommended
“Is the intervention cost-effective?” if its proven (or anticipated) effects reduce
The resources required to implement (or could reduce) health inequalities among
pre-pregnancy calcium supplementation different groups of women and their families.
mainly include the costs of providing
supplies, training, equipment and skilled For each of the above domains, additional evidence
human resources. A judgement in favour of potential harms or unintended consequences
of or against the intervention was likely is described in the “additional considerations”
where the resource implications were subsections. Such considerations were derived
clearly advantageous or disadvantageous, from studies that might not have directly addressed
respectively. the priority question, but which provided pertinentWHO recommendation on Calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications 9
information in the absence of direct evidence. on a large scale, provided that it takes the
These were extracted from single studies, form of research that is able to address
systematic reviews or other relevant sources. unanswered questions and uncertainties,
related both to effectiveness of the
The WHO Steering Group provided the EtD intervention or option, and its acceptability
frameworks, including evidence summaries, and feasibility.
summary of findings (SoF) tables and other
documents related to each recommendation, to
GDG members two weeks in advance of the GDG Management of declaration of
meeting. The GDG members were asked to review interests
and provide comments (electronically) on the
WHO has a robust process to protect the integrity
documents before the GDG meeting. During the
of WHO in its normative work as well as to protect
GDG meeting (31 July 2019), which was conducted
the integrity of individual experts the Organization
online under the leadership of the GDG chairperson,
collaborates with. WHO requires that experts serving
the GDG members collectively reviewed the
in an advisory role disclose any circumstances
EtD frameworks and any comments received
that could give rise to actual or ostensible conflict
through preliminary feedback, and formulated the
of interest. The disclosure and appropriate
recommendations. The purpose of the meeting
management of relevant financial and non-financial
was to reach consensus on each recommendation,
conflicts of interest of GDG members and other
including its direction and, in some instances, the
external experts and contributors is a critical part of
specific context, based on explicit consideration
guideline development at WHO. According to WHO
of the range of evidence presented in each
regulations, all experts must declare their interests
EtD framework and the judgement of the GDG
prior to participation in WHO guideline development
members. The GDG was asked to select one of the
processes and meetings according to the Guidelines
following categories for the recommendation:
for declarations of interest (WHO experts) (20).
• Recommended: This category
indicates that the intervention should be All GDG members were therefore required to
implemented. complete a standard WHO Declaration of Interest
(DOI) form before engaging in the guideline
• Not recommended: This category development process and before participating
indicates that the intervention should not in the guideline-related processes. The WHO
be implemented. Steering Group reviewed all declarations before
finalizing the experts’ invitations to participate.
• Recommended only in specific contexts
Where any conflict of interest was declared, the
(“context-specific recommendation”):
Steering Group determined whether such conflicts
This category indicates that the
were serious enough to affect an expert’s objective
intervention is applicable only to the
judgement in the guideline and recommendation
condition, setting or population specified in
development process. To ensure consistency, the
the recommendation, and should only be
Steering Group applied the criteria for assessing
implemented in these contexts.
the severity of conflict of interests as outlined in
the WHO Handbook for Guideline Development to
• Recommended only in the context of
all participating experts.
rigorous research (“research-context
recommendation”): This category
All findings from the DOI statements received were
indicates that there are important
managed in accordance with the WHO procedures
uncertainties about the intervention.
to assure the work of WHO and the contributions
With this category of recommendation,
of its experts is, actually and ostensibly, objective
implementation can still be undertaken
and independent. The names and biographies of10 WHO recommendation on Calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications
individuals were published online two weeks prior accurately reflect the deliberations and decisions
to the meeting. Where a conflict of interest was not of the participants. The draft document was sent
considered significant enough to pose any risk to electronically to GDG members and the External
the guideline development process or to reduce its Review Group for their final review and approval.
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.
Peer review
Annex 3 shows a summary of the DOI statements Following review and approval by GDG members,
and how conflicts of interest declared by invited the final document was sent to eight external
experts were managed by the Steering Group. independent experts (External Review Group)
who were not involved in the guideline panel for
peer review. The WHO Steering Group evaluated
Decision-making during the GDG the inputs of the peer reviewers for inclusion in
meeting this document. After the meeting and external
During the meeting, the GDG reviewed and peer review, the modifications made by the WHO
discussed the evidence summary and sought Steering Group to the document consisted only
clarification. In addition to evaluating the balance of the correction of factual errors and improving
between the desirable and undesirable effects language to address any lack of clarity.
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. 3. Recommendation and
These criteria included stakeholders’ values, supporting evidence
resource implications, acceptability, feasibility
and equity. Considerations were based on the The following section outlines the
experience and opinions of members of the GDG recommendation and the corresponding narrative
and supported by evidence from a literature summary of evidence for the prioritized question.
search where available. EtD tables were used to The evidence-to-decision (EtD) table, summarizing
describe and synthesize these considerations. the balance between the desirable and
undesirable effects and the overall certainty of
Decisions were made based on consensus, defined the supporting evidence, values and preferences
as the agreement by three quarters or more of the of stakeholders, resource requirements, cost-
participants. None of the GDG members expressed effectiveness, acceptability, feasibility and equity
opposition to the recommendation. that were considered in determining the strength
and direction of the recommendation, is presented
Document preparation in the EtD framework (Annex 4).
Prior to the online meeting, the WHO Steering The following recommendation was adopted
Group prepared a draft version of the GRADE by the GDG. Evidence on the effectiveness of
evidence profiles, the evidence summary and other this intervention was derived from the updated
documents relevant to the GDG’s deliberation. Cochrane systematic review and was summarized
The draft documents were made available to the in GRADE tables (Annex 4). The certainty of the
participants of the meeting two weeks before the supporting evidence was rated as ‘moderate’ for
meeting for their comments. During the meeting, most of the critical outcomes.
these documents were modified in line with the
participants’ deliberations and remarks. Following To ensure that the recommendation is correctly
the meeting, members of the WHO Steering understood and appropriately implemented
Group drafted a full guideline document to in practice, additional ‘remarks’ reflecting theWHO recommendation on Calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications 11
Table 1: WHO recommendation on pre-pregnancy calcium supplementation for the prevention of
pre-eclampsia and its complications
Pre-pregnancy calcium supplementation for the prevention of pre-eclampsia and its
complications is recommended only in the context of rigorous research.
(Recommendation in research context)
Justification
• Low-certainty evidence suggests that starting calcium supplementation before and/or early
in pregnancy (compared to placebo or no treatment) may make little or no difference to
women’s risk of developing hypertensive disorders during pregnancy. The estimate of effect
of this intervention on the outcome “pre-eclampsia and/or pregnancy loss and/or stillbirth
at any gestational age” included the possibility of a risk reduction, but the 95% confidence
interval touched the line of no effect. There is a possibility of clinical benefit for those women
with greater than 80% compliance with calcium supplementation. However, this is uncertain
and needs further research. The maternal adverse effects of the intervention are not known.
• The acceptability of calcium supplementation by women may vary – while women may value
nutritional interventions that can lead to a healthy baby and a positive pregnancy experience, calcium
tablets can be large, have a powdery texture and be unpalatable to consume. Feasibility may also be
limited in settings where calcium is not always available due to logistical or staff constraints or cost.
In addition, limited access to pre-conception healthcare services may be a barrier to the provision of
calcium supplements prior to pregnancy. The cost-effectiveness of this intervention is not known.
Remarks
• The GDG noted that in 2018 WHO revalidated the recommendation that in populations with
low dietary calcium intake, daily calcium supplementation (1.5–2.0 g oral elemental calcium) is
recommended for pregnant women to reduce the risk of pre-eclampsia (1). However, there is
insufficient evidence to determine with precision at what gestational age calcium supplementation
should be commenced in order to confer this benefit. The 2018 recommendation specified that
stakeholders may wish to commence calcium supplementation at the first antenatal care contact,
in order to optimize compliance with this regimen. Evidence review on initiation of calcium
supplementation before pregnancy and continuing through pregnancy, however, shows that
it remains uncertain whether this will confer additional health benefits, and further research is
required.
• Food fortification of staple foods with calcium may be an important public health intervention
in settings where dietary calcium intake is low. Dietary counselling of all women who are
considering pregnancy should promote adequate calcium intake through locally available,
calcium-rich foods. Adequate calcium intake could be easily achieved by the incorporation of
dairy products in the diet on a daily basis. However, dairy products are not part of all regular
diets, or are not available in certain populations. Likewise, a high-salt diet decreases body-
calcium retention compared to a diet that is low in salt. Caffeine and protein can also induce
hypercalciuria, but to a much lesser extent. This has become more important in recent years
due to the consumption of caffeine-containing beverages such as soda and energy drinks.12 WHO recommendation on Calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications
summary of the discussion by the GDG are office willing to translate the full recommendation
included under the recommendation. into any of these languages.
Implementation research
4. Dissemination and considerations
• Pre-pregnancy calcium supplementation
implementation of the is recommended only in the context of
recommendation rigorous research. This rating category
indicates that there are important
The dissemination and implementation of this uncertainties about this intervention. The
recommendation is to be considered by all actors implementation can still be undertaken
at the international, national and local levels at a large scale, provided that it takes the
involved in the provision of care for women. As a form of research that is able to address
recommendation for rigorous research, there is a unanswered questions and uncertainties
need to further evaluate the benefits and harms of related to effectiveness, as well as
this intervention in a research context. However, acceptability and feasibility.
it remains critical to ensure that the 2018 WHO
recommendation on calcium supplementation • To assess effectiveness, rigorous research
during pregnancy (in populations with low dietary should – at least – compare women who
calcium intake) (1) is translated into antenatal are exposed to calcium supplementation
care packages and programmes at country and prior to pregnancy with women who are
health-facility levels (where appropriate). not, and include a baseline assessment.
These comparison groups should be as
similar as possible to ensure that the effect
Recommendation dissemination and of pre-pregnancy calcium supplementation
evaluation is assessed, rather than the effect of other
The recommendation will be disseminated factors. Randomized trials are the most
through WHO regional and country offices, effective way to do this, but if these are
ministries of health, professional organizations, not possible, then interrupted time series
WHO collaborating centres, other United Nations analyses or controlled before-and-after
agencies and nongovernmental organizations, studies can be considered. Programmes
among others. This recommendation will also that are evaluated without a comparison
be available on the WHO website, the WHO group or baseline assessment are at high
Reproductive Health Library (www.who.int/rhl) risk of bias, and may not measure the true
and WHO e-Library of Evidence for Nutrition effect of this intervention.
Actions (eLENA) (www.who.int/elena). Updated
• Relevant stakeholders (particularly those
recommendations are also routinely disseminated
involved in programmes to improve calcium
during meetings or scientific conferences
intake during pregnancy) should be
attended by WHO maternal and perinatal health
informed that there is currently insufficient
staff.
evidence to recommend in favour of or
The recommendation document will be translated against the use of pre-pregnancy calcium
into the six UN languages and disseminated supplementation for the prevention of
through the WHO regional offices. Technical pre-eclampsia and its complications.
assistance will be provided to any WHO regional
• Women who opt to use calcium
supplements before pregnancy for health
benefits for themselves and/or their babiesWHO recommendation on Calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications 13
should be well supported and informed of • What is the feasibility and acceptability of
the uncertainties regarding the benefits pre-pregnancy calcium supplementation to
and possible harms of this intervention. improve maternal and perinatal outcomes?
• This recommendation should not detract
from the importance of good nutrition
for all women through all public health 6. Applicability issues
strategies. The implementation of the
WHO recommendation on calcium
supplementation during pregnancy (in Anticipated impact on the
populations with low dietary calcium intake) organization of care and resources
to reduce the risk of pre-eclampsia should If a pre-pregnancy calcium supplementation
also not be negatively affected. Specific programme targeting non-pregnant women
guidance related to the implementation of and adolescent girls is implemented, resources
calcium supplementation during pregnancy are required for sustainable procurement and
is available in the 2018 recommendation stocks of calcium tablets, as well as updated
document (1). The WHO antenatal care training curricula and provision of training to
guidelines outline the 2016 WHO antenatal relevant health workers. The WHO model list
care model, which includes timing, of essential medicines (EML) (22) currently lists
content and frequency of antenatal care calcium tablets containing 500 mg (elemental
contacts (21). In populations where calcium calcium) in section 27 (Vitamins and minerals).
supplementation during pregnancy is Calcium is included in two different dosage
implemented, the need for, and compliance forms – calcium tablets should be available in a
with, calcium supplementation should be 500 mg (elemental) dose. Essential medicines
considered at all antenatal care contacts. are intended to be available within the context
of functioning health systems at all times in
adequate amounts, in the appropriate dosage
forms, with assured quality, and at a price the
5. Research implications individual and the community can afford (23).
The GDG identified important knowledge gaps
that need to be addressed through primary Monitoring and evaluating guideline
research, which may have an impact on this implementation
recommendation. The following questions were If a pre-pregnancy calcium supplementation
identified as those that demand urgent priority: programme targeting non-pregnant women
• In pregnant women and non-pregnant and adolescent girls is implemented, it should
women intending to become pregnant, be monitored at the health-service level as
does pre-pregnancy calcium provision or part of broader efforts to monitor and improve
supplementation improve maternal and the quality of primary healthcare, particularly
perinatal outcomes, including the onset of women, maternal and newborn care. For
pre-eclampsia and its complications? example, interrupted time series, clinical audits
or criterion-based clinical audits can be used
o In what populations of women/pregnant to obtain relevant data related to pre-eclampsia
women is pre-pregnancy calcium and eclampsia. Clearly defined review criteria
supplementation or provision most and indicators are needed; these could be
beneficial? associated with locally agreed targets and
aligned with the standards and indicators
o What dosing regimen (including dose,
described in the WHO document Standards for
frequency and time of initiation) of
calcium supplementation is most
beneficial?You can also read
