- 1. Intermittent iron and folic acid supplementation in non-anaemic pregnant womeni Guideline: Intermittent iron and folic acid supplementation in non-anaemic pregnant women
- 2. Intermittent iron and folic acid supplementation in non-anaemic pregnant womenII WHO Library Cataloguing-in-Publication Data Guideline: Intermittent iron and folic acid supplementation in non-anaemic pregnant women. 1.Iron - administration and dosage. 2. Folic acid - administration and dosage. 3.Anaemia, Iron-deficiency- prevention and control. 4.Pregnancy. 5.Prenatal nutrition. 6.Dietary supplements. 7.Guidelines. I.World Health Organization. ISBN 978 92 4 150201 6 (NLM classification: WD 160) © World Health Organization 2012 All rights reserved. Publications of the World Health Organization are available on the WHO web site (www.who.int) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press through the WHO web site (http://www.who.int/about/licensing/copyright_form/en/index.html). 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 the World Health Organization 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 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 the World Health Organization in preference to others of a siprmilar 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 the World Health Organization 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 theWorld Health Organization be liable for damages arising from its use. Design and layout: Alberto March WHO. Guideline: Intermittent iron and folic acid supplementation in non-anaemic pregnant women. Geneva, World Health Organization, 2012. Suggested citation
- 3. iv Financial support iv Summary 1 Scope and purpose 2 Background 2 Summary of evidence 3 Recommendation 4 Remarks 5 Implications for future research 6 Dissemination, adaptation and implementation 7 Dissemination Adaptation and implementation Monitoring and evaluation of guideline implementation Guideline development process 8 Advisory groups Scope of the guideline, evidence appraisal and decision-making Management of conflicts of interest 10 Plans for updating the guideline 11 References 12 GRADE“Summary of findings”tables 14 Summary of the considerations by the Nutrition Guidance Expert Advisory Group for determining the strength of the recommendation 16 WHO Steering Committee for Nutrition Guidelines Development 17 Nutrition Guidance Expert Advisory Group – Micronutrients WHO Secretariat and external resource experts 18 External Experts and Stakeholders Panel – Micronutrients 22 Questions in Population, Intervention, Control, Outcomes (PICO) format 25 Annex 1 Annex 2 Annex 3 Annex 4 Annex 5 Annex 6
- 4. coordinated by Dr Luz Maria De-Regil under the supervision of Dr Juan Pablo Peña-Rosas, with technical input from Dr Metin Gulmezoglu, Dr Jose Martines, Dr Matthews Mathai and Dr Lisa Rogers. Thanks are due to Dr Regina Kulier and the staff at the Guidelines Review Committee Secretariat for their support throughout the process. Thanks are also due to Dr Davina Ghersi for her technical advice and assistance in the preparation of the technical consultations for this guideline and Mr Issa T. Matta and Mrs Chantal Streijffert Garon from the World Health Organization (WHO) Office of the Legal Counsel for their support in the management of conflicts of interest procedures. Ms Grace Rob and Mrs Paule Pillard from the Micronutrients Unit, Department of Nutrition for Health and Development, provided logistic support. WHO gratefully acknowledges the technical input of the members of the WHO Nutrition Steering Committee and the Nutrition Guidance Expert Advisory Group, especially the chairs of the meetings, Dr Janet King, Dr Rebecca Stoltzfus and Dr Rafael Flores-Ayala. WHO is also grateful to the Cochrane Pregnancy and Childbirth Group staff for their support during the development of the systematic review used to inform this guideline. WHO thanks the Government of Luxembourg for providing financial support for this work. Acknowledgements Financial support
- 5. Intermittent iron and folic acid supplementation in non-anaemic pregnant women1 Intermittent iron and folic acid supplementation in non-anaemic pregnant women It is estimated that 41.8% of pregnant women worldwide are anaemic. At least half of this anaemia burden is assumed to be due to iron deficiency. Member States have requested guidance from the World Health Organization (WHO) on the effectiveness and safety of different schemes of iron and folic acid supplementation in pregnant women as a public health measure to improve pregnancy outcomes in support of their efforts to achieve the Millennium Development Goals. WHO developed the present evidence-informed recommendations using the procedures outlined in the WHO handbook for guideline development. The steps in this process included: (i) identification of priority questions and outcomes; (ii) retrieval of the evidence; (iii) assessment and synthesis of the evidence; (iv) formulation of recommendations, including research priorities; and (v) planning for dissemination, implementation, impact evaluation and updating of the guideline. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was followed to prepare evidence profiles related to preselected topics, based on up- to-date systematic reviews. The guideline advisory group for nutrition interventions, the Nutrition Guidance Expert Advisory Group, comprises content experts, methodologists, representatives of potential stakeholders and consumers. These experts participated in several WHO technical consultations concerning this guideline, held in Geneva, Switzerland, and Amman, Jordan, in 2010 and 2011. Members of the External Experts and Stakeholders Panel were identified through a public call for comments, and this panel was involved throughout the guideline development process. Guideline advisory group members voted on the strength of the recommendation, taking into consideration: (i) desirable and undesirable effects of this intervention; (ii) the quality of the available evidence; (iii) values and preferences related to the interventions in different settings; and (iv) the cost of options available to health-care workers in different settings. All the members of the guideline advisory group completed a Declaration of Interests Form before each meeting. Intermittent iron and folic acid supplementation is recommended in non-anaemic pregnant women to prevent development of anaemia and to improve gestational outcomes (strong recommendation). The quality of the evidence for low birth weight, birth weight, premature birth, maternal anaemia at term, iron deficiency anaemia at term, and side-effects was very low. WHO Guideline 1 Summary 1 This publication is a WHO guideline. A WHO guideline is any document, whatever its title, containing WHO recommendations about health interventions, whether they be clinical, public health or policy interventions. A recommendation provides information about what policy-makers, health-care providers or patients should do. It implies a choice between different interventions that have an impact on health and that have ramifications for the use of resources. All publications containing WHO recommendations are approved by the WHO Guidelines Review Committee.
- 6. Intermittent iron and folic acid supplementation in non-anaemic pregnant women2 This guideline provides global, evidence-informed recommendations on intermittent iron and folic acid supplementation as a public health intervention for the purpose of improving pregnancy outcomes and reducing maternal anaemia in pregnancy. The guideline will help Member States and their partners in their efforts to make informed decisions on the appropriate nutrition actions to achieve the Millennium Development Goals, in particular, reduction of child mortality (MDG 4) and improvement in maternal health (MDG 5). The guideline is intended for a wide audience including policy-makers, their expert advisers and technical and programme staff at organizations involved in the design, implementation and scaling-up of nutrition actions for public health. This document presents the key recommendation and a summary of the supporting evidence. Further details of the evidence base are provided in Annex 1 and other documents listed in the references. It is estimated that 41.8% of pregnant women worldwide are anaemic (1). At least half of this anaemia burden is assumed to be due to iron deficiency (2), with the rest due to other conditions such as folate, vitamin B12 or vitamin A deficiencies, chronic inflammation, parasitic infections and inherited disorders. A pregnant woman is considered to be anaemic if her haemoglobin concentration during the first and third trimester of gestation is lower than 110 g/l, at sea level; in the second trimester of pregnancy, the haemoglobin concentration usually decreases by approximately 5 g/l (3). When anaemia is accompanied by an indication of iron deficiency (e.g. low ferritin levels), it is referred to as iron deficiency anaemia (2). Low haemoglobin concentrations indicative of moderate or severe anaemia during pregnancy have been associated with an increased risk of premature delivery, maternalandchildmortality,andinfectiousdiseases(4).Growthanddevelopmentmay also be affected (2), both in utero and in the long term (5). Conversely, haemoglobin concentrations greater than 130 g/l at sea level may also be associated with negative pregnancy outcomes such as premature delivery and low birth weight (6, 7). Interventions aimed at preventing iron deficiency and iron deficiency anaemia in pregnancy include iron supplementation, fortification of staple foods with iron, health and nutrition education, control of parasitic infections, and improvement in sanitation (8). Delayed umbilical cord clamping is also effective in preventing iron deficiency among infants and young children (9). During pregnancy, there is an increase in maternal iron requirements to support both maternal and fetal needs, and most women require additional iron intake to ensure sufficient iron stores at conception as well as during pregnancy to prevent iron deficiency (10). The use of daily iron and folic acid supplements throughout pregnancy has been the standard approach to cover this gap and in turn prevent and treat iron deficiency anaemia. Despite its proven efficacy, the use of daily iron supplementation has been limited in programme settings, possibly due to a lack of compliance because of common side-effects (e.g. nausea, constipation, dark stools or metallic taste), concerns about the safety of this intervention among women with an adequate iron intake, and variable availability of the supplements at community level (11). Scope and purpose Background
- 7. Intermittent iron and folic acid supplementation in non-anaemic pregnant women3 Intermittent use of oral iron supplements (i.e. once, twice or three times a week on non-consecutive days) has been proposed as an effective alternative to daily iron supplementation for prevention of anaemia in women of reproductive age, including those who are pregnant (12,13).The rationale behind this intervention has traditionally been that intestinal cells turn over every 5–6 days and have limited iron absorptive capacity. Thus intermittent provision of iron would expose only the new intestinal epithelial cells to this nutrient, which, in theory, should improve its absorption (14). This mechanism has recently been questioned. Intermittent supplementation also reduces oxidative stress and the other side-effects of daily supplementation (15, 16) and may minimize blockage of absorption of other minerals due to the high iron levels in the gut lumen and in the intestinal epithelial cells. Experience has shown that intermittent regimens may be more accepted by women, with increased adherence to supplementation programmes (17). An existing Cochrane systematic review (18) assessing the benefits and harms of iron supplementation alone or in combination with folic acid or other vitamins and minerals in pregnant women on neonatal and pregnancy outcomes was updated for this guideline. The updated review (19) compared the intermittent use of iron supplements alone, or in combination with folic acid or other micronutrients, with no intervention or placebo, and with the same supplements given on a daily basis to pregnant women living in a variety of settings, including malaria-endemic areas. The infant outcomes ranked as critical for decision-making by the Nutrition Guidance Expert Advisory Group members were low birth weight, weight at birth, prematurity, perinatal death and congenital anomalies including neural tube defects. The maternal outcomes considered critical were anaemia, iron deficiency and iron deficiency anaemia at term, as well as the presence of any side-effects, clinical malaria and infections during pregnancy.The potential effects of baseline anaemia prevalence, gestational age at the start of supplementation, malaria setting and the weekly dose of iron were also evaluated. The review included 21 trials, but only 18 trials (with 4072 women) contributed data to the review. The trials were carried out in the past two decades in countries across the globe (Argentina, Bangladesh, China, Guatemala, India, Indonesia, Iran, Malawi, Mexico, Pakistan, South Korea and Thailand). Most of the trials included both anaemic and non-anaemic women. All the studies were conducted in countries with some degree of malaria risk (20), however it was not clear from the reports whether malaria prevention and control programmes were in place at the time when these studies were conducted or whether concomitant malaria interventions were made available to the study participants. None of the studies included in the review compared the effects of intermittent ironsupplementationwiththeeffectsofnoironsupplementation.Thislikelyisbecause the studies involving intermittent supplementation were carried out in countries whose legislatures require all pregnant women to be given iron supplements. Summary of evidence
- 8. Intermittent iron and folic acid supplementation in non-anaemic pregnant women4 For the comparison between daily and intermittent regimens, the methodological qualityofthetrialsincludedintheanalysiswasmixed,withmoststudiesreportinghigh losses to follow-up. The total weekly iron dose in the arm that received intermittent supplements ranged from 80 mg to 200 mg of elemental iron as ferrous sulfate or ferrous fumarate per week, whereas the folic acid dose ranged from 400 μg (0.4 mg) to 3500 μg (3.5 mg) per week. There was no detectable difference between women taking iron supplements intermittently (alone or in combination with other micronutrients) and those receiving daily supplements with regard to maternal anaemia at term (average relative risk (RR) 1.22, 95% confidence interval (CI) 0.84–1.80, four studies), the risk of having a low birth weight (RR 0.96, 95% CI 0.61–1.52, seven studies) or a preterm (RR 1.82, 95% CI 0.75–4.40, four studies) baby and infant birth weight (mean difference –8.62 g; 95% CI 52.76 to 35.52 g, eight studies). There were no maternal deaths (six studies) or women with severe anaemia (six studies). Fewer side-effects were reported in women receiving intermittent rather than daily iron and folic acid supplements (RR 0.56; 95% CI 0.37–0.84, 11 studies). High haemoglobinconcentrations(morethan130g/l)duringthesecondandthirdtrimester of pregnancy were also less frequent among women using supplements intermittently (RR 0.48; 95% CI 0.35–0.67, 13 studies). The intervention seems to be equally effective among populations with different prevalences of anaemia, and in settings described as malaria endemic, and regardless ofwhetherthesupplementationwasinitiatedearlierorlaterthan20weeksofgestation or whether the dose of elemental iron per week was lower or higher than 120 mg. The quality of the evidence for low birth weight, birth weight, premature birth, maternal anaemia at term, iron deficiency at term, and side-effects was very low (Annex 1). Intermittent use of iron and folic acid supplements by non-anaemic pregnant women is recommended to prevent anaemia and improve gestational outcomes (strong recommendation)1, 2 . A suggested scheme for intermittent iron and folic acid supplementation in non- anaemic pregnant women is presented in Table 1. Recommendation 1 A strong recommendation is one for which the guideline development group is confident that the desirable effects of adherence outweigh the undesirable effects. The recommendation can be either in favour of or against an intervention. Implications of a strong recommendation for patients are that most people in their situation would want the recommended course of action and only a small proportion would not. Implications for clinicians are that most patients should receive the recommended course of action, and that adherence to this recommendation is a reasonable measure of good-quality care. With regard to policy-makers, a strong recommendation means that it can be adapted as a policy in most situations. 2 Considerations of the guideline advisory group for determining the strength of the recommendation are summarized in Annex 2.
- 9. Intermittent iron and folic acid supplementation in non-anaemic pregnant women5 Table 1 Suggested scheme for intermittent iron and folic acid supplementation in non- anaemic pregnant women a 120 mg of elemental iron equals 600 mg of ferrous sulfate heptahydrate, 360 mg of ferrous fumarate or 1000 mg of ferrous gluconate. b Haemoglobin concentrations should be measured prior to the start of supplementation to confirm non-anaemic status (3). Supplement composition Iron: 120 mg of elemental irona Folic acid: 2800 μg (2.8 mg) Frequency One supplement once a week Duration Throughout pregnancy. Iron and folic acid supplementation should begin as early as possible Target group Non-anaemicb pregnant adolescents and adult women Settings Countries where prevalence of anaemia among pregnant women is lower than 20%. • If a woman is diagnosed with anaemia at any time during pregnancy, she should be given daily iron and folic acid supplements throughout pregnancy as per current guidance (21). • The implementation of this recommendation may require a strong health system to facilitate confirmation of non-anaemic status prior to the start of supplementation and to monitor anaemia status throughout pregnancy. • As there is limited evidence for the effective dose of folic acid in intermittent supplementation, the recommendation for the folic acid dosage is based on the rationale of providing seven times the recommended daily supplemental dose during pregnancy. Folic acid requirements are increased in pregnancy because of the rapidly dividing cells in the fetus and increased urinary losses. As the neural tube closes by day 28 of pregnancy, by when pregnancy may not have been detected, folic acid supplementation after the first month of pregnancy may not prevent neural tube defects. However, it will contribute to other aspects of maternal and fetal health. • In malaria-endemic areas, iron and folic acid supplementation programmes should be implemented in conjunction with measures to prevent, diagnose and treat malaria during pregnancy (20, 22-23). Remarks
- 10. Intermittent iron and folic acid supplementation in non-anaemic pregnant women6 Implications for future research Discussion with the guideline advisory group members and stakeholders highlighted the limited evidence available in some areas, meriting further research on intermittent iron and folic acid supplementation in non-anaemic pregnant women, particularly in the following areas: • An iron supplementation programme may form part of an integrated programme of antenatal and neonatal care (24, 25) that promotes adequate gestational weight gain, screening of all women for anaemia at antenatal and postpartum visits, use of complementary measures to control and prevent anaemia (e.g. hookworm control), and a referral system to manage cases of severe anaemia. • The implementation of a behaviour change communication strategy to communicate the benefits of the intervention and management of side-effects, along with provision of high-quality products with appropriate packaging, is vital to improving the acceptability of and adherence to recommended supplementation schemes. The strategy can also serve to promote the use of dietary diversity and intake of food combinations that improve iron absorption. • Oralsupplementsareavailableascapsulesortablets(soluble,tablets,dissolvable and modified-release tablets) (26). Establishment of a quality assurance process is important to guarantee that supplements are manufactured, packaged and stored in a controlled and uncontaminated environment (27). • The selection of the most appropriate delivery platform should be context- specific,withtheaimofreachingthemostvulnerablepopulationsandensuring a timely and continuous supply of supplements. • the most effective and safe weekly dose of folic acid to improve folate status and improve pregnancy outcomes; • effects of other vitamins and minerals on haematological, nutritional and other health outcomes as well as the best formulation to provide multiple micronutrients on a weekly basis; • mechanisms through which intermittently delivered iron is absorbed and regulated by the intestinal cells; • potential use of slow-release formulations in terms of efficacy, cost and side- effects, in comparison with standard iron and folic acid tablets.
- 11. Intermittent iron and folic acid supplementation in non-anaemic pregnant women7 Dissemination The current guidelines will be disseminated through electronic media such as slide presentations, CD-ROMs and the World Wide Web, either through the World Health Organization (WHO) Micronutrients and United Nations Standing Committee on Nutrition (SCN) mailing lists, the WHO nutrition web site, or the WHO e-Library of Evidence for Nutrition Actions (eLENA). This library aims to compile and display WHO guidelines related to nutrition, along with complementary documents such as systematic reviews and other evidence that informed the guidelines, biological and behavioural rationales, and additional resources produced by Member States and global partners. The guideline will also be disseminated through a broad network of international partners, including WHO country and regional offices, ministries of health, WHO collaborating centres, universities, other United Nations agencies and nongovernmental organizations. It will also be published in the WHO Reproductive Health Library. Adaptation and implementation As this is a global guideline, it should be adapted to the context of each Member State. Prior to implementation, an intermittent iron supplementation programme should have well-defined objectives that take into account available resources, existing policies, suitable delivery platforms and suppliers, communication channels, and potential stakeholders. Ideally, iron and folic acid supplementation should be implemented as part of an integrated programme for antenatal and neonatal care. The implementation in this guideline may require a strong health system to facilitate the diagnosis of anaemia prior to starting supplementation and to monitor anaemia status throughout pregnancy. To ensure that WHO global guidelines and other evidence-informed recommendations for micronutrient interventions are better implemented in low- and middle-income countries, the Department of Nutrition for Health and Development works with the WHO Evidence-Informed Policy Network (EVIPNet) programme. EVIPNet promotes partnerships at country level between policy-makers, researchers and civil society to facilitate policy development and implementation through use of the best available evidence. Monitoring and evaluation of guideline implementation A plan for monitoring and evaluation with appropriate indicators is encouraged at all stages. The impact of this guideline can be evaluated within countries (i.e. monitoring and evaluation of the programmes implemented at scale) and across countries (i.e. the adoption and adaptation of the guidelines globally). The WHO Department of Nutrition for Health and Development, jointly with the Centers for Disease Control and Prevention (CDC) International Micronutrient Malnutrition Prevention and Control (IMMPaCt)programme,andwithinputfrominternationalpartners,developedageneric logic model for micronutrient interventions in public health to depict the plausible relationships between inputs and expected MDGs by applying the micronutrient programme evaluation theory (28). Member States can adjust the model and use it in combination with appropriate indicators, for designing, implementing, monitoring and evaluating the successful scaling-up of nutrition actions. Dissemination, adaptation and implementation
- 12. Intermittent iron and folic acid supplementation in non-anaemic pregnant women8 This guideline was developed in accordance with WHO evidence-informed guideline development procedures, as outlined in the WHO handbook for guideline development (29). Advisory groups The WHO Steering Committee for Nutrition Guidelines Development, led by the Department of Nutrition for Health and Development, was established in 2009 with representatives from all WHO departments with an interest in the provision of scientific nutrition advice, including Child and Adolescent Health and Development, Reproductive Health and Research, and the Global Malaria Programme. The Steering Committee guided the development of this guideline and provided overall supervision of the guideline development process (Annex 3). Two additional groups were formed: an advisory guideline group and an External Experts and Stakeholders Panel. The Nutrition Guidance Expert Advisory Group, was also established in 2009 (Annex 4). There were four subgroups: (i) Micronutrients, (ii) Diet and Health, (iii) Nutrition in Life course and Undernutrition, and (iv) Monitoring and Evaluation. Its role is to advise WHO on the choice of important outcomes for decision-making and in the interpretation of the evidence. The group includes experts from various WHO expert advisory panels and those identified through open calls for specialists, taking into consideration a balanced gender mix, multiple disciplinary areas of expertise and representation from all WHO regions. Efforts were made to include content experts, methodologists, representatives of potential stakeholders (such as managers and other health professionals involved in the health-care process) and consumers. Representatives of commercial organizations may not be members of a WHO guideline group. The External Experts and Stakeholders Panel was consulted on the scope of the guideline, the questions addressed and the choice of important outcomes for decision-making, as well as with regard to review of the completed draft guidelines (Annex 5). This was done through the WHO Micronutrients and SCN mailing lists that together include over 5500 subscribers, and through the WHO nutrition web site. Guideline development process For evaluation at global level, the WHO Department of Nutrition for Health and Development is developing a centralized platform, for sharing information on nutrition actions in public health practice implemented around the world. By sharing programmatic details, specific country adaptations and lessons learnt, this platform will provide examples of how guidelines are being translated into nutrition actions.
- 13. Intermittent iron and folic acid supplementation in non-anaemic pregnant women9 Scope of the guideline, evidence appraisal and decision-making An initial set of questions (and the components of the questions) to be addressed in the guideline was the critical starting point for formulating the recommendation. The questions were drafted by technical staff from the Micronutrients Unit, Department of Nutrition for Health and Development, based on policy and programme guidance needs of Member States and their partners. The population, intervention, control, outcomes (PICO) format was used (Annex 6). The questions were discussed and reviewed by the Steering Committee and feedback was received from 48 stakeholders. The first nutrition guideline advisory group meeting was held on 22–26 February 2010 in Geneva, Switzerland, to finalize the scope of the questions and rank the critical outcomes and populations of interest. The nutrition guideline advisory group – Micronutrients Subgroup discussed the relevance of the questions and modified them as needed. The guideline group members scored the relative importance of each outcome from 1 to 9 (where 7–9 indicated that the outcome was critical for a decision, 4–6 indicated that it was important and 1–3 indicated that it was not important). The final key questions on iron and folic acid supplementation in pregnant women, along with the outcomes that were identified as critical and important for decision-making, are listed in PICO format in Annex 6. WHO staff, in collaboration with researchers from other institutions, summarized and appraised the evidence, using the Cochrane methodology for randomized controlled trials1 . For identifying unpublished studies or studies still in progress, a standard procedure was followed to contact more than 10 international organizations working on micronutrient interventions. In addition, the International Clinical Trials Registry Platform (ICTRP), hosted at WHO, was systematically searched for any trials still in progress. No language restrictions were applied in the search. Evidence summaries were prepared according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the overall quality of the evidence (30). GRADE considers: the study design; the limitations of the studies in terms of their conduct and analysis; the consistency of the results across the available studies; the directness (or applicability and external validity) of the evidence with respect to the populations, interventions and settings where the proposed intervention may be used; and the precision of the summary estimate of the effect. Both the systematic review and the GRADE evidence profiles for each of the critical outcomes were used for drafting this guideline. The draft recommendation was reviewed by the WHO Nutrition Guidance Steering Committee and the nutrition guideline advisory group at a second consultation, held on 15–18 1 As part of the Cochrane pre-publication editorial process, reviews are commented on by external peers (an editor and two referees external to the editorial team) and the group’s statistical adviser (http://www.cochrane.org/ cochrane-reviews). The Cochrane handbook for systematic reviews of interventions describes in detail the process of preparing and maintaining Cochrane systematic reviews on the effects of health-care interventions.
- 14. Intermittent iron and folic acid supplementation in non-anaemic pregnant women10 November 2010 in Amman, Jordan, and at the third consultation, held on 14–16 March in Geneva, Switzerland, where the guideline advisory group also voted on the strength of the recommendation, taking into account: (i) desirable and undesirable effects of this intervention; (ii) the quality of the available evidence; (iii) values and preferences related to the intervention in different settings; and (iv) the cost of options available to health-care workers in different settings (Annex 2). Consensus was defined as agreement by simple majority of guideline group members. WHO staff present at the meeting as well as other external technical experts involved in the collection and grading of the evidence were not allowed to vote. One member voted against the use of intermittent iron and folic acid supplements as an alternative to daily supplementation in non-anaemic pregnant women. A public call for comments on the final draft guidelines was then released. Interested stakeholders became members of the External Experts and Stakeholders Panel but were only allowed to comment on the draft guideline after submitting a signed Declaration of Interests Form. Feedback was received from 15 stakeholders. WHO staff then finalized the guideline and submitted it for clearance by WHO before publication. Management of conflicts of interest AccordingtotherulesintheWHOBasicdocuments(31),allexpertsparticipatinginWHO meetings must declare any interest relevant to the meeting prior to their participation. The conflicts of interest statements for all guideline group members were reviewed by theresponsibletechnicalofficerandtherelevantdepartmentsbeforefinalizationofthe group composition and invitation to attend a guideline group meeting. All guideline group members and participants of the guideline development meetings submitted a Declaration of Interests Form along with their curriculum vitae before each meeting. In addition, they verbally declared potential conflicts of interest at the beginning of each meeting. The procedures for management of conflicts of interests strictly followed WHO Guidelines for declaration of interests (WHO experts) (32). The potential conflicts of interest declared by the members of the guideline group are summarized below. • Dr Héctor Bourges Rodriguez declared being chair of the executive board of the Danone Institute in Mexico (DIM), a non-profit organization promoting research and dissemination of scientific knowledge in nutrition, and receiving funds as chair honorarium from DIM. Some of the activities of the DIM may generally relate to nutrition and are funded by Danone Mexico, a food producer. • Dr Norm Campbell at the first meeting declared owning stock inViterra, a wheat pool for farmers that neither manufactures products nor undertakes activities relatedtothisguideline.In2011,DrCampbelldeclarednolongerowningstocks in this company. He serves as a Pan American Health Organization (PAHO) consultant and has been an adviser to Health Canada and Blood Pressure Canada, both of which are government agencies.
- 15. Intermittent iron and folic acid supplementation in non-anaemic pregnant women11 • Dr Emorn Wasantwisut declared serving as a technical/scientific adviser to the International Life Sciences Institute (ILSI)/South East Asia’s Food and Nutrients in Health and Disease Cluster and as a reviewer of technical documents and speaker for Mead Johnson Nutritionals. Her research unit received funds for research support from Sight and Life and the International Atomic Energy Agency (IAEA) for the use of stable isotopes to define interactions of vitamin A and iron. • Dr Beverley Biggs declared that the University of Melbourne received funding from the National Health and Medical Research Council (NHMRC) and Australian Research Council (ARC) for research on intermittent iron and folic acid supplementation in pregnancy, conducted in collaboration with the Research and Training Center for Community Development (RTCCD), the Key Centre for Women’s Health and the Murdoch Childrens Research Institute. This guideline will be reviewed in 2015. If new information is available at that time, a guideline review group will be convened to evaluate the new evidence and revise the recommendation if needed.The Department of Nutrition for Health and Development attheWHOheadquartersinGeneva,alongwithitsinternalpartners,willberesponsible for coordinating the guideline update following formal WHO handbook for guideline development (29) procedures. WHO welcomes suggestions regarding additional questions for evaluation in the guideline when it is due for review. Plans for updating the guideline
- 16. Intermittent iron and folic acid supplementation in non-anaemic pregnant women12 1. Worldwide prevalence of anaemia 1993–2005. WHO Global Database on Anaemia. Geneva, World Health Organization, 2008 (http://whqlibdoc.who.int/publications/2008/9789241596657_eng.pdf, accessed 7 June 2011). 2. WHO/UNICEF/UNU. Iron deficiency anaemia assessment, prevention, and cotrol: a guide for programme managers. Geneva, World Health Organization, 2001 (http://www.who.int/nutrition/publications/en/ida_assessment_prevention_control.pdf, accessed 7 June 2011). 3. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin and Mineral Nutrition Information System. Geneva, World Health Organization, 2011 (WHO/NMH/NHD/MNM/11.1; http://www.who.int/vmnis/indicators/haemoglobin.pdf, accessed 7 June 2011). 4. International Anemia Consultative Group. Report of the 2001 International Anemia Consultative Group Symposium. Why is iron important and what to do about it: a new perspective. Washington, DC, INACG Secretariat, 2002:1–50. 5. Lozoff B, Jimenez E, Smith JB. Double burden of iron deficiency in infancy and low socioeconomic status: a longitudinal analysis of cognitive test scores to age 19 years. Archives of Pediatrics and Adolescent Medicine, 2006, 160:1108–1113. 6. Murphy JF et al. Relation of haemoglobin levels in first and second trimesters to outcome. Lancet, 1986, 3:992–995. 7. Steer PJ. Maternal hemoglobin concentration and birth weight. American Journal of Clinical Nutrition, 2000, 71(Suppl. 5):S1285-S1287. 8. International Anaemia Consultative Group. Guidelines for the eradication of iron deficiency anaemia. A report of the International Nutritional Anaemia Consultative Group. Washington, DC, The Nutrition Foundation, 1977:1–29. 9. Chaparro C. Essential delivery care practices for maternal and newborn health and nutritition. Informational Bulletin. Washington, DC, Pan American Health Organization, 2007:1–4 (http://www.paho.org/english/ad/fch/ca/ca_delivery_care_practices_eng.pdf, accessed 7 June 2011). 10. Bothwell TH. Iron requirements in pregnancy and strategies to meet them. American Journal of Clinical Nutrition, 2000, 72(Suppl. 1):S257–S264. 11. Iron supplementation during pregnancy: why aren’t women complying? Geneva, World Health Organization, 1990 (WHO/MCH/90.5; (http://whqlibdoc.who.int/hq/1990/WHO_MCH_90.5.pdf, accessed 14 June 2011). 12. Chew F, Torun B, Viteri FE. Comparison of weekly and daily iron supplementation to pregnant women in Guatemala (supervised and unsupervised). FASEB Journal, 1996, 10:A4221. 13. Liu XN, Liu PY. The effectiveness of weekly iron supplementation regimen in improving the iron status of Chinese children and pregnant women. Biomedical and Environmental Sciences, 1996, 9:341–347. 14. Viteri FE et al. True absorption and retention of supplemental iron in women deficient when iron is administered every three days rather than daily to iron-normal and iron-deficient rats. Journal of Nutrition, 1995, 125:82–91. 15. Viteri FE, Berger J. Importance of pre-pregnancy and pregnancy iron status: can long-term weekly preventive iron and folic acid supplementation achieve desirable and safe status? Nutrition Reviews, 2005, 63:S65–S76. 16. Bhatla N. Comparison of effect of daily versus weekly iron supplementation during pregnancy on lipid peroxidation. Journal of Obstetrics and Gynaecology Research, 2009, 35(3):438–445. References
- 17. Intermittent iron and folic acid supplementation in non-anaemic pregnant women13 17. Casanueva E et al. Weekly iron as a safe alternative to daily supplementation for nonanemic pregnant women. Archives of Medical Research, 2006, 37:674–682. 18. Peña-Rosas JP, Viteri FE. Effects and safety of preventive oral iron or iron+folic acid supplementation for women during pregnancy. Cochrane Database of Systematic Reviews, 2009, (4):CD004736. 19. Peña-Rosas JP et al. Intermittent oral iron supplementation during pregnancy. Cochrane Database of Systematic Reviews, 2012, (7):CD009997 (http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009997/abstract;jsessionid=A5BF5B426BB3CC5F 1A34A77EA7235009.d02t02, accessed 14 July 2012). 20. Global malaria report 2010. Global Malaria Programme. Geneva, World Health Organization, 2010 (http://whqlibdoc.who.int/publications/2010/9789241564106_eng.pdf, accessed 7 June 2011). 21. Guideline: Daily iron supplementation in pregnancy. Geneva, World Health Organization, 2011, (in press) 22. Garner P, Gülmezoglu AM. Drugs for preventing malaria in pregnant women. Cochrane Database of Systematic Reviews, 2006, (4):CD000169 (http://www.thecochranelibrary.com/userfiles/ccoch/file/CD000169.pdf, accessed 14 June 2011). 23. Orton LC, Omari AAA. Drugs for treating uncomplicated malaria in pregnant women. Cochrane Database of Systematic Reviews, 2008, (4):CD004912 (http://www.thecochranelibrary.com/userfiles/ccoch/file/CD004912.pdf, accessed 7 June 2011). 24. WHO antenatal care randomized trial: manual for implementation of the new model. Geneva, World Health Organization, 2002 (http://whqlibdoc.who.int/hq/2001/WHO_RHR_01.30.pdf, accessed 7 June 2011). 25. Iron and folate supplementation. Integrated Management of Pregnancy and Childbirth (IMPAC). In: Standards for maternal and neonatal care, 1.8. Geneva, World Health Organization, 2006 (http://www.who.int/making_pregnancy_safer/publications/Standards1.8N.pdf, accessed 7 June 2011). 26. The international pharmacopoeia, 4th ed. Volumes 1 and 2. Geneva, World Health Organization, 2008 (http://apps.who.int/phint/en/p/about/, accessed 7 June 2011). 27. Quality assurance of pharmaceuticals: Meeting a major public health challenge. The WHO Expert Committee on Specifications for Pharmaceutical Preparations. Geneva, World Health Organization, 2007 (http://www.who.int/medicines/publications/brochure_pharma.pdf, accessed 7 June 2011). 28. WHO/CDC. Logic model for micronutrient interventions in public health. Vitamin and Mineral Nutrition Information System. Geneva, World Health Organization, 2011 (WHO/NMH/NHD/MNM/11.5; http://www.who.int/vmnis/toolkit/WHO-CDC_Logic_Model.pdf, accessed 7 June 2011). 29. WHO Handbook for guideline development. Guidelines Review Committee. Geneva, World Health Organization, 2012 (http://www.who.int/iris/bitstream/10665/75146/1/9789241548441_eng.pdf, accessed 30 July 2012). 30. Guyatt G et al. GRADE guidelines 1. Introduction – GRADE evidence profiles and summary of findings tables. Journal of Clinical Epidemiology, 2011, 64:383–394. 31. Basic documents, 47th ed. Geneva, World Health Organization, 2009 (http://apps.who.int/gb/bd/, accessed 19 May 2011). 32. Guidelines for declaration of interests (WHO experts). Geneva, World Health Organization, 2010.
- 18. of findings”tables Any intermittent oral iron supplementation versus any daily iron supplementation for women during pregnancy–infant outcomes Patient or population: women during pregnancy Settings: community settings Intervention: intermittent supplementation with iron alone or plus any other micronutrients Comparison: any intermittent oral iron supplementation versus any daily iron supplementation Relative effect Number of participants Quality of the evidence Outcomes (95% CI) (studies) (GRADE)* Comments Low birth weight (less than 2500 g) RR 0.96 1111 ⊕⊝⊝⊝ (0.61–1.52) (7 studies) very low 1 Birthweight (g) MD–8.62 10 608 ⊕⊝⊝⊝ (-52.76 to 35.52) (8 studies) very low2 Premature birth (less than 37 weeks of gestation) RR 1.82 382 ⊕⊝⊝⊝ (0.75–4.40) (4 studies) very low3 Neonatal death (death within first 28 days of life) Not estimable 0 See comment No studies reported data for this outcome (0 studies) Congenital anomalies (including neural tube defects) Not estimable 0 See comment No studies reported data for this outcome (0 studies) CI, confidence interval; RR, risk ratio * GRADE Working Group grades of evidence: High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Six of the studies contributing data had high levels of attrition, none had blinding and five had high or unclear risk of bias for allocation concealment. Proportion of events was low and there was some imprecision in the estimate. The results were consistent and statistical heterogeneity was nil (I2 = 0%). 2 Seven of the studies contributing data had high levels of attrition, none had blinding and five had high or unclear risk of bias for allocation concealment. 95% confidence intervals were wide for this outcome, although the results were consistent and statistical heterogeneity was nil (I2 = 0%). 3 Three of the included studies had high attrition, lacked blinding and had unclear or high risk of bias for allocation concealment. Proportion of events was low. The results were consistent and statistical heterogeneity was nil (I2 = 0%). For details of studies included in the review, see reference (19).
- 19. iron supplementation versus any daily iron supplementation for women during pregnancy–maternal outcomes Patient or population: women during pregnancy Settings: community settings Intervention: intermittent supplementation with iron alone or plus any other micronutrients Comparison: any intermittent oral iron supplementation versus any daily iron supplementation Relative effect Number of participants Quality of the evidence Outcomes (95% CI) (studies) (GRADE)* Comments Anaemia at term (haemoglobin lower than 110 g/l RR 1.22 676 ⊕⊝⊝⊝ at 37 weeks’gestation or more) (0.84–1.80) (4 studies) very low1 Iron deficiency at term (as defined by the trialists, Not estimable 0 See comment No studies reported data for this outcome based on any indicator of iron status at 37 weeks’ (0 studies) gestation or more) Iron deficiency anaemia at term RR 0.71 156 ⊕⊝⊝⊝ (as defined by the trialists) (0.08–6.63) (1 study) very low2 Maternal death Not estimable 0 See comment No studies reported data for this outcome (0 studies) Side-effects (any reported throughout the RR 0.56 1777 ⊕⊝⊝⊝ intervention period) (0.37–0.84) (11 studies) very low3 Severe anaemia at any time during second Not estimable 1240 See comment While this outcome was reported in six studies and third trimester (haemoglobin lower than 70g/l) (6 studies) there were no events Maternal clinical malaria Not estimable 0 See comment This outcome was not reported in any of the (0 studies) included studies Maternal infection during pregnancy Not estimable 0 See comment This outcome was not reported in any of the (0 studies) included studies CI, confidence interval; RR, risk ratio * GRADE Working Group grades of evidence: High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Half of the studies contributing data had high risk of bias for attrition, one had unclear allocation concealment. 95% confidence intervals were wide for all of these studies. The results were consistent and statistical heterogeneity was nil (I2 = 10%). 2 The single study contributing data had unclear methods to generate the random sequences and no blinding. 95% confidence intervals were wide. 3 Several studies were at high or unclear risk of allocation and attrition. The size and direction of treatment effect varied in these studies and heterogeneity was high (I2 = 87%). For details of studies included in the review, see reference (19).
- 20. Intermittent iron and folic acid supplementation in non-anaemic pregnant women16 Summary of the considerations by the Nutrition Guidance Expert Advisory Group for determining the strength of the recommendation Quality of evidence: Values and preferences: Trade-off between benefits and harm: Costs and feasibility: • The quality of the evidence was low and may be insufficient to support the use of intermittent supplementation in settings where daily iron and folic acid supplementation is standard practice • This may be a solution in areas with low prevalence of anaemia in pregnant women in whom daily programmes have failed to deliver • Intermittent iron and folic acid supplementation is likely to achieve higher coverage than daily supplementation. However, it requires screening for anaemia status of pregnant women, which is not common in most communities • Non-anaemic pregnant women can still be iron deficient; therefore intermittent iron supplementation may result in iron deficiency later on during pregnancy. If this intervention is combined with weekly iron supplementation in menstruating women, it may be more successful in preventing anaemia • Benefits outweigh harms but it is an area where more research is needed • Intermittent supplementation with iron and folic acid during pregnancy is presumably cheaper than daily supplementation and feasible in populations with low rates of iron deficiency or where daily iron supplementation is not available Annex 2
- 21. Intermittent iron and folic acid supplementation in non-anaemic pregnant women17 WHO Steering Committee for Nutrition Guidelines Development Dr Ala Alwan Acting Director Department of Chronic Diseases and Health Promotion Noncommunicable Diseases and Mental Health (NMH) Cluster Dr Francesco Branca Director Department of Nutrition for Health and Development Noncommunicable Diseases and Mental Health (NMH) Cluster Dr Ruediger Krech Director Department of Ethics, Equity, Trade and Human Rights Information, Evidence and Research (IER) Cluster Dr Knut Lonnroth Medical Officer The Stop TB Strategy HIV/AIDS, TB and Neglected Tropical Diseases (HTM) Cluster Dr Daniel Eduardo Lopez Acuna Director Department of Strategy, Policy and Resource Management Health Action in Crises (HAC) Cluster Dr Elizabeth Mason Director Department of Child and Adolescent Health and Development Family and Community Health (FCH) Cluster Dr Michael Mbizvo Director Department of Reproductive Health and Research Family and Community Health (FCH) Cluster Dr Jean-Marie Okwo-Bele Director Department of Immunization, Vaccines and Biologicals Family and Community Health (FCH) Cluster Dr Gottfried Otto Hirnschall Director Department of HIV/AIDS HIV/AIDS, TB and Neglected Tropical Diseases (HTM) Cluster Dr Tikki Pangestu Director Department of Research Policy and Cooperation Information, Evidence and Research (IER) Cluster Dr Isabelle Romieu Director Dietary Exposure Assessment Group, Nutrition and Metabolism Section International Agency for Research on Cancer (IARC) Lyons, France Dr Sergio Spinaci Associate Director Global Malaria Programme HIV/AIDS, TB and Neglected Tropical Diseases (HTM) Cluster Dr Willem Van Lerberghe Director Department of Health Policy, Development and Services Health Systems and Services (HSS) Cluster Dr Maged Younes Director Department of Food Safety, Zoonoses and Foodborne Diseases Health Security and Environment (HSE) Cluster Dr Nevio Zagaria Acting Director Department of Emergency Response and Recovery Operations Health Action in Crises (HAC) Cluster Annex 3
- 22. Intermittent iron and folic acid supplementation in non-anaemic pregnant women18 Nutrition Guidance Expert Advisory Group – Micronutrients, WHO Secretariat and external resource experts A. Nutrition Guidance Expert Advisory Group – Micronutrients (Note: the areas of expertise of each guideline group member are given in italics) Annex 4 Ms Deena Alasfoor Ministry of Health Muscat, Oman Health programme management, food legislations, surveillance in primary health care Dr Beverley-Ann Biggs International and Immigrant Health Group Department of Medicine University of Melbourne Parkville, Australia Micronutrients supplementation, clinical infectious diseases Dr Héctor Bourges Rodríguez Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubiran Mexico City, Mexico Nutritional biochemistry and metabolism research, food programmes, policy, and regulations Dr Norm Campbell Departments of Medicine Community Health Sciences and Physiology and Pharmacology University of Calgary Calgary, Canada Physiology and pharmacology, hypertension prevention and control Dr Rafael Flores-Ayala Centers for Disease Control and Prevention (CDC) Atlanta, United States of America Nutrition and human capital formation, nutrition and growth, impact of micronutrient interventions Professor Malik Goonewardene Department of Obstetrics and Gynaecology University of Ruhuna Galle, Sri Lanka Obstetrics and gynaecology, clinical practic Dr Junsheng Huo National Institute for Nutrition and Food Safety Chinese Center for Disease Control and Prevention Beijing, China Food fortification, food science and technology, standards and legislation Dr Janet C. King Children’s Hospital Oakland Research Institute Oakland, United States of America Micronutrients, maternal and child nutrition, dietary requirements Dr Marzia Lazzerini Department of Paediatrics and Unit of Research on Health Services and International Health Institute for Maternal and Child Health IRCCS Burlo Garofolo Trieste, Italy Paediatrics, malnutrition, infectious diseases Professor Malcolm E. Molyneux College of Medicine – University of Malawi Blantyre, Malawi Malaria, international tropical diseases research and practice Engineer Wisam Qarqash Jordan Health Communication Partnership Johns Hopkins University Bloomberg School of Public Health Amman, Jordan Design, implementation and evaluation of health communications and programmes Dr Daniel Raiten Office of Prevention Research and International Programs National Institutes of Health (NIH) Bethesda, United States of America Malaria, maternal and child health, human development research
- 23. Intermittent iron and folic acid supplementation in non-anaemic pregnant women19 B. WHO Dr Mahdi Ramsan Mohamed Research Triangle Institute (RTI) International Dar es Salaam, the United Republic of Tanzania Malaria control and prevention, neglected tropical diseases Dr Meera Shekar Health Nutrition Population Human Development Network (HDNHE) The World Bank Washington, DC, United States of America Costing of interventions in public health nutrition, programme implementation Dr Rebecca Joyce Stoltzfus Division of Nutritional Sciences Cornell University Ithaca, United States of America International nutrition and public health, iron and vitamin A nutrition, programme research Ms Carol Tom Central and Southern African Health Community (ECSA) Arusha, the United Republic of Tanzania Food fortification technical regulations and standards, policy harmonization Dr David Tovey The Cochrane Library Cochrane Editorial Unit London, England Systematic reviews, health communications, evidence for primary health care Mrs Vilma Qahoush Tyler UNICEF Regional Office for Central and Eastern Europe and Commonwealth of Independent States (CEE/CIS) Geneva, Switzerland Food fortification, public health programmes Dr Gunn Elisabeth Vist Department of Preventive and International Health Norwegian Knowledge Centre for the Health Services Oslo, Norway Systematic review methods and evidence assessment using GRADE methodology Dr Emorn Wasantwisut Mahidol University Nakhon Pathom, Thailand International nutrition, micronutrient biochemistry and metabolism Mr Joseph Ashong Intern (rapporteur) Micronutrients Unit Department of Nutrition for Health and Development Dr Maria del Carmen Casanovas Technical Officer Nutrition in the Life Course Unit Department of Nutrition for Health and Development Dr Bernadette Daelmans Medical Officer Newborn and Child Health and Development Unit Department of Child and Adolescent Health and Development Dr Luz Maria De-Regil Epidemiologist Micronutrients Unit Department of Nutrition for Health and Development Dr Chris Duncombe Medical Officer Anti-retroviral Treatment and HIV Care Unit Department of HIV/AIDS Dr Olivier Fontaine Medical Officer Newborn and Child Health and Development Unit Department of Child and Adolescent Health and Development
- 24. Intermittent iron and folic acid supplementation in non-anaemic pregnant women20 Dr Davina Ghersi Team Leader International Clinical Trials Registry Platform Department of Research Policy and Cooperation Dr Ahmet Metin Gulmezoglu Medical Officer Technical Cooperation with Countries for Sexual and Reproductive Health Department of Reproductive Health and Research Dr Regina Kulier Scientist Guideline Review Committee Secretariat Department of Research Policy and Cooperation Dr José Martines Coordinator Newborn and Child Health and Development Unit Department of Child and Adolescent Health and Development Dr Matthews Mathai Medical Officer Department of Making Pregnancy Safer Dr Mario Merialdi Coordinator Improving Maternal and Perinatal Health Unit Department of Reproductive Health and Research Dr Sant-Rayn Pasricha Intern (rapporteur) Micronutrients Unit Department of Nutrition for Health and Development Dr Juan Pablo Peña-Rosas Coordinator Micronutrients Unit Department of Nutrition for Health and Development Dr Aafje Rietveld Medical Officer Global Malaria Programme Dr Lisa Rogers Technical Officer Micronutrients Unit Department of Nutrition for Health and Development Mr Anand Sivasankara Kurup Technical Officer Social Determinants of Health Unit Department of Ethics, Equity, Trade and Human Rights Information Dr Joao Paulo Souza Medical Officer Technical Cooperation with Countries for Sexual and Reproductive Health Department of Reproductive Health and Research Dr Severin Von Xylander Medical Officer Department of Making Pregnancy Safer Dr Godfrey Xuereb Technical Officer Surveillance and Population-based Prevention Unit Department of Chronic Diseases and Health Promotion C. WHO regional offices Dr Abel Dushimimana Medical Officer Nutrition WHO Regional Office for Africa Brazzaville, Congo Dr Chessa Lutter Regional Adviser Child and Adolescent Health WHO Regional Office for the Americas/Pan American Health Organization Washington, DC, United States of America
- 25. Intermittent iron and folic acid supplementation in non-anaemic pregnant women21 Dr Kunal Bagchi Regional Adviser Nutrition and Food Safety WHO Regional Office for South-East Asia New Delhi, India Dr Joao Breda Noncommunicable Diseases and Environment WHO Regional Office for Europe Copenhagen, Denmark Dr Ayoub Al-Jawaldeh Regional Adviser Nutrition WHO Regional Office for the Eastern Mediterranean Cairo, Egypt Dr Tommaso Cavalli-Sforza Regional Adviser Nutrition WHO Regional Office for the Western Pacific Manila, Philippines D. External resource experts Dr Andreas Bluethner BASF SE Limburgerhof, Germany Dr Denise Coitinho Delmuè United Nations System Standing Committee on Nutrition (SCN) Geneva, Switzerland Professor Richard Hurrell Laboratory of Human Nutrition Swiss Federal Institute of Technology Zurich, Switzerland Dr Guansheng Ma National Institute for Nutrition and Food Safety Chinese Center for Disease Control and Prevention Beijing, China Dr Regina Moench-Pfanner Global Alliance for Improved Nutrition (GAIN) Geneva, Switzerland Ms Sorrel Namaste Office of Prevention Research and International Programs National Institutes of Health (NIH) Bethesda, United States of America Dr Lynnette Neufeld Micronutrient Initiative Ottawa, Canada Dr Juliana Ojukwu Department of Paediatrics Ebonyi State University Abakaliki, Nigeria Dr Mical Paul Infectious Diseases Unit Rabin Medical Center Belinson Hospital and Sackler Faculty of Medicine Tel Aviv University Petah-Tikva, Israel Mr Arnold Timmer United Nations Children’s Fund (UNICEF) New York, United States of America Dr Stanley Zlotkin Division of Gastroenterology, Hepatology and Nutrition The Hospital for Sick Children Toronto, Canada
- 26. Intermittent iron and folic acid supplementation in non-anaemic pregnant women22 External Experts and Stakeholders Panel – MicronutrientsAnnex 5 Dr Ahmadwali Aminee Micronutrient Initiative Kabul, Afghanistan Dr Mohamd Ayoya United Nations Children’s Fund (UNICEF) Port Au-Prince, Haiti Dr Salmeh Bahmanpour Shiraz University of Medical Sciences Shiraz, Iran (Islamic Republic of) Mr Eduard Baladia Spanish Association of Dieticians and Nutritionists Barcelona, Spain Dr Levan Baramidze Ministry of Labour Health and Social Affairs Tbilisi, Georgia Mr Julio Pedro Basulto Marset Spanish Association of Dieticians and Nutritionists Barcelona, Spain Dr Christine Stabell Benn Bandim Health Project Statens Serum Institut Copenhagen, Denmark Dr Jacques Berger Institut de Recherche pour le Développement Montpellier, France Dr R.J. Berry Centers for Disease Control and Prevention (CDC) Atlanta, United States of America Ms E.N. (Nienke) Blok Ministry of Health, Welfare and Sport The Hague, the Netherlands Ms Lucie Bohac Iodine Network Ottawa, Canada Dr Erick Boy-Gallego HarvestPlus Ottawa, Canada Dr Mario Bracco Albert Einstein Social Responsibility Israeli Institute São Paulo, Brazil Dr Gerard N. Burrow International Council of Iodine Deficiency Disorders Ottawa, Canada Dr Christine Clewes Global Alliance for Improved Nutrition Geneva, Switzerland Dr Bruce Cogill Global Alliance for Improved Nutrition Geneva, Switzerland Mr Hector Cori DSM Santiago, Chile Dr Maria Claret Costa Monteiro Hadler Federal University of Goiás Goiânia, Brazil Ms Nita Dalmiya United Nations Children’s Fund (UNICEF) New York, United States of America Professor Ian Darnton-Hill University of Sydney Sydney, Australia Professor Kathryn Dewey University of California Davis, United States of America Professor Michael Dibley Sydney School of Public Health University of Sydney Sydney, Australia Dr Marjoleine Dijkhuizen University of Copenhagen Copenhagen, Denmark Ms Tatyana El-Kour World Health Organization Amman, Jordan Dr Suzanne Filteau London School of Hygiene andTropical Medicine London, England Dr Rodolfo F. Florentino Nutrition Foundation of the Philippines Manila, Philippines
- 27. Intermittent iron and folic acid supplementation in non-anaemic pregnant women23 Dr Ann Fowler DSM Nutritional Products Rheinfelden, Switzerland Mr Joby George Save the Children Lilongwe, Malawi Dr Abdollah Ghavami School of Human Sciences London Metropolitan University London, England Dr Rosalind Gibson Department of Human Nutrition University of Otago Dunedin, New Zealand Mr Nils Grede World Food Programme Rome, Italy Ms Fofoa R. Gulugulu Public Health Unit Ministry of Health Funafuti, Tuvalu Dr Andrew Hall University of Westminster London, England Mr Richard L. Hanneman Salt Institute Alexandria, United States of America Ms Kimberly Harding Micronutrient Initiative Ottawa, Canada Dr Suzanne S. Harris International Life Sciences Institute (ILSI) Washington, DC, United States of America Dr Phil Harvey Philip Harvey Consulting Rockville, United States of America Dr Izzeldin S. Hussein International Council for Control of Iodine Deficiency Disorders Al Khuwair, Oman Dr Susan Jack University of Otago Dunedin, New Zealand Mr Quentin Johnson Food Fortification Quican Inc. Rockwood, Canada Mr Vinod Kapoor Independent Consultant on Fortification Panchkula, India Dr Klaus Kraemer Sight and Life Basel, Switzerland Dr Roland Kupka UNICEF Regional Office for West and Central Africa Dakar, Senegal Ms Ada Lauren Vitamin Angels Alliance Santa Barbara, United States of America Dr Daniel Lopez de Romaña Instituto de Nutrition y Tecnologia de Alimentos (INTA) Universidad de Chile Santiago, Chile Mrs Maria Manera Spanish Association of Dieticians and Nutritionists Girona, Spain Dr Homero Martinez RAND Corporation Santa Monica, United States of America Dr Zouhir Massen Faculty of Medicine University of Tlemcen Tlemcen, Algeria Dr Abdelmonim Medani Sudan Atomic Energy Khartoum, Sudan Dr María Teresa Murguía Peniche National Center for Child and Adolescent Health Mexico City, Mexico
- 28. Intermittent iron and folic acid supplementation in non-anaemic pregnant women24 Dr Sirimavo Nair University of Baroda Vadodara, India Dr Ruth Oniango African Journal of Food, Agriculture, Nutrition and Development (AJFAND) Nairobi, Kenya Dr Saskia Osendarp Science Leader Child Nutrition Unilever R&D Vlaardingen, the Netherlands Dr Jee Hyun Rah DSM-WFP Partnership DSM – Sight and Life Basel, Switzerland Mr Sherali Rahmatulloev Ministry of Health Dushanbe, Tajikistan Ms Anna Roesler Menzies School of Health Research/ Compass Women’s and Children’s Knowledge Hub for Health Chiang Mai, Thailand Professor Irwin Rosenberg Tufts University Boston, United States of America Professor Amal Mamoud Saeid Taha Faculty of Medicine University of Khartoum Khartoum, Sudan Dr Isabella Sagoe-Moses Ghana Health Service Accra, Ghana Dr Dia Sanou Department of Applied Human Nutrition Mount Saint Vincent University Halifax, Canada Dr Rameshwar Sarma St James School of Medicine Bonaire, the Netherlands Antilles Dr Andrew Seal University College London Centre for International Health and Development London, England Dr Magdy Shehata World Food Programme Cairo, Egypt Mr Georg Steiger DSM Nutritional Products DSM Life Science Products International Basel, Switzerland Professor Barbara Stoecker Oklahoma State University Oklahoma City, United States of America Dr Ismael Teta Micronutrient Initiative Ottawa, Canada Dr Ulla Uusitalo University of South Florida Tampa, United States of America Dr Hans Verhagen Centre for Nutrition and Health National Institute for Public Health and the Environment (RIVM) Bilthoven, the Netherlands Dr Hans Verhoef Wageningen University Wageningen, the Netherlands Dr Sheila Vir Chander Public Health Nutrition Development Centre New Delhi, India Dr Annie Wesley Micronutrient Initiative Ottawa, Canada Dr Frank Wieringa Institut de Recherche pour le Développement Montpellier, France Ms Caroline Wilkinson United Nations High Commission for Refugees Geneva, Switzerland Dr Pascale Yunis American University of Beirut Medical Center Beirut, Lebanon Dr Lingxia Zeng Xi’an JiaoTong University College of Medicine Xi’an, China
- 29. Intermittent iron and folic acid supplementation in non-anaemic pregnant women25 Questions in Population, Intervention, Control, Outcomes (PICO) format Population: Intervention: Control: Outcomes: Non-anaemic pregnant women Subpopulation: Critical • By malaria-endemic versus non-malaria-endemic area (no transmission or elimination achieved, susceptibility to epidemic malaria, year-round transmission with marked seasonal fluctuations, year-round transmission with consideration of Plasmodium falciparum and/or Plasmodium vivax) • By use of concurrent malarial measures, in particular, intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine- pyrimethamine (SP) • By human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) status: HIV positive versus HIV negative • By individual’s status of iron deficiency: iron deficiency versus non-iron deficiency • By individual’s status of anaemia: anaemic versus non-anaemic • By anaemia status of population: 20% or less versus 20–40% versus more than 40% Iron plus folic acid supplementation Subgroup analysis: Critical • By frequency: daily versus once weekly versus twice weekly versus other • By duration: 3 months or less versus more than 3 months • By nutrient: iron versus iron plus folic acid versus iron plus other micronutrients • By iron content • By folic acid content • No iron supplementation • Placebo • Same supplement without iron or folic acid on a daily basis Maternal Critical • Severe anaemia • Maternal mortality • Anaemia at term • Haemoglobin concentrations • Iron deficiency anaemia at term • Iron deficiency at term • Morbidity from malaria – incidence and severity (parasitaemia with or without symptoms) • Adverse effects Annex 6 Effects and safety of iron and folic acid supplementation in pregnant women a. Could iron and folic acid supplements given to pregnant women improve maternal and infant health outcomes? b. If so, at what dose, frequency and duration for the intervention, and in which settings?
- 30. Intermittent iron and folic acid supplementation in non-anaemic pregnant women26 Setting: Neonate/infant Critical • Neural tube defects • Iron deficiency anaemia at birth • Low birth weight: less than 2500 g • Birth weight • Iron deficiency at term • Length at birth • Anaemia at birth • Preterm birth: less than 37 weeks’gestation • Neonatal mortality: within 28 weeks after birth All settings
- 31. Intermittent iron and folic acid supplementation in non-anaemic pregnant women27 For more information, please contact: Department of Nutrition for Health and Development World Health Organization Avenue Appia 20, CH-1211 Geneva 27, Switzerland Fax: +41 22 791 4156 E-mail: [email protected] www.who.int/nutrition ISBN 978 92 4 1502016
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