WHO recommendation on Calcium supplementation before pregnancy for the prevention of pre-eclampsia and its complications

Page created by Janice Spencer
 
CONTINUE READING
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                                                       24
iv   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 Organization
vi   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 to
2   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, European
WHO 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 the
6   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 the
WHO 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 judgement
8   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 pertinent
WHO 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 of
10   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 the
WHO 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 babies
WHO 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