Iron Supplement Who
Iron Supplement Who
Iron Supplement Who
WHO | Guideline
Suggested citation
WHO | Guideline
WHO. Guideline: Daily iron and folic acid supplementation in pregnant women.
Geneva, World Health Organization, 2012.
II
Contents
Acknowledgements
iv
Financial support
iv
Summary
Background
Summary of evidence
Recommendation
Remarks
Dissemination
Adaptation and implementation
Monitoring and evaluation of guideline implementation
Guideline development process
Advisory groups
10
10
References
11
Annex 1
13
Annex 2
17
Annex 3
18
Annex 4
19
Annex 5
23
Annex 6
2
7
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III
Acknowledgements
This guideline was coordinated by Dr Luz Maria De-Regil under the supervision of
Dr Juan Pablo Pea-Rosas, with technical input from Dr Metin Gulmezoglu, Dr Jose
Martines, Dr Matthews Mathai and Dr Lisa Rogers. Thanks are due to 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 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 FloresAyala. 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.
Financial support
WHO | Guideline
WHO thanks the Government of Luxembourg for providing financial support for this
work.
IV
WHO Guideline1
Summary
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 daily 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 upto-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 in
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 intervention 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.
Daily oral iron and folic acid supplementation is recommended as part of the
antenatal care to reduce the risk of low birth weight, maternal anaemia and iron
deficiency (strong recommendation). The overall quality of the evidence for iron
supplementation versus no iron was moderate for low birth weight, preterm birth,
maternal anaemia at term and maternal iron deficiency at term. The evidence was of
low quality for birth weight, neonatal death, congenital anomalies, maternal death,
maternal severe anaemia, and infections during pregnancy; whereas it was of very low
quality for side-effects.
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.
WHO | Guideline
Background
It is estimated that 41.8% of pregnant women worldwide are anaemic (1). At least half of
this burden is assumed to be due to iron deficiency (2), with the rest due to conditions
such as folate, vitamin B12 or vitamin A deficiency, 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 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,
maternal and child mortality, and infectious diseases (4). Iron deficiency anaemia may
affect growth and development both in utero (2) and in the long term (5). 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, women need to consume additional
iron to ensure they have sufficient iron stores to prevent iron deficiency (10). Therefore,
in most low- and middle-income countries, iron supplements are used extensively by
pregnant women to prevent and correct iron deficiency and anaemia during gestation.
A standard supplemental dose of 60 mg of elemental iron was first established
in 1959, based on estimates of iron requirements in pregnant women (11); this dose
has since been endorsed by several expert consultations (4, 12, 13). A prophylactic
dose of 300 g (0.3 mg) per day throughout pregnancy was suggested in 1968 by
the World Health Organization (WHO). The supplemental dose was increased to 400 g
(0.4 mg) of folic acid per day in 1998 following publication of several studies supporting
WHO | Guideline
the periconceptional use of this nutrient in the prevention of neural tube defects. This
dose was deemed to provide more folic acid than required to produce an optimal
haemoglobin response in pregnant women. If supplementation is started after the
first trimester of pregnancy it will not help prevent birth defects (13).
Gastrointestinal distress is a common observation in women consuming
large amounts of supplemental iron, particularly on an empty stomach. Thus
gastrointestinal side-effects are considered as the critical adverse effect on which to
base the tolerable upper level of intake for iron. Use of high-dose iron supplements is
commonly associated with constipation and other gastrointestinal effects, including
nausea, vomiting and diarrhoea, with the frequency and severity depending on the
amount of elemental iron released in the stomach.
Summary of evidence
An existing Cochrane systematic review (14) assessing the benefits and harms of iron
supplementation in healthy pregnant women was updated for this guideline. The
updated review (15) compared the daily provision of iron supplements alone or in
combination with folic acid or other micronutrients with no intervention, placebo or
versus the use of the same supplements but without iron (e.g. only folic acid) among
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 were low birth weight, weight at birth, prematurity,
perinatal death and congenital anomalies, including neural tube defects. The maternal
outcomes considered were anaemia, iron deficiency and iron deficiency anaemia at
term, as well as the presence of any side-effects, clinical malaria or infections during
pregnancy. The potential effects of baseline anaemia status, gestational age at the start
of supplementation, malaria setting and the daily dose of iron were also evaluated.
The review included 60 randomized controlled trials with 27 402 women from
30 different countries in all continents. Only 43 trials contributed data to the review,
albeit not all of them reported on all the outcomes; 16 of the trials were of high quality
according to the pre-established criteria. Twenty-three studies were conducted in
countries that in 2011 had some malaria risk in parts of the country. In some of these
countries/territories, malaria is present only in certain areas or up to a particular altitude.
Only two of these studies reported malaria outcomes. It was not always 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.
Overall, women taking daily iron supplements were less likely to have low birth
weight babies compared with controls (average relative risk (RR) 0.81, 95% confidence
interval (CI) 0.68 0.97, 11 studies) and the mean birth weight was 30.81g greater for
those infants whose mothers received iron during pregnancy (95% CI 5.94 55.68 g, 14
studies). There was no significant effect on preterm birth or neonatal death.
WHO | Guideline
Daily iron supplementation reduced the risk of maternal anaemia at term by 70%
(RR 0.30, 95% CI 0.19 0.46, 14 trials) and iron deficiency at term by 57% (RR 0.43, 95%
CI 0.27 0.66, seven studies), but it had no significant effect on the risk of infections
during pregnancy (RR 1.16, 95% CI 0.83 1.63, two studies). Women receiving iron had
8.88 g more haemoglobin per litre at or near term (95% CI 6.96 10.80, 19 studies)
than those who did not receive iron. At the same time, women who received iron
supplements tended to report more frequently side-effects (RR 2.36, 95% CI 0.96 to
5.82, 11 studies) and were at increased risk of high haemoglobin concentrations (i.e.
greater than 130 mg/L) during the second and third trimesters of pregnancy (RR 2.26,
95% CI 1.40 3.66, 10 studies).
The intervention seems to be effective among populations with different
prevalences of anaemia, and in settings described as malaria-endemic, when compared
with settings where malaria is sporadic or absent, and regardless of whether the
supplementation was initiated earlier or later than 20 weeks of gestation or whether
the daily dose of elemental iron was 30 mg or less, 3159 mg, or 60 mg or higher.
However, women receiving 60 mg of iron or more were more likely to have haemoglobin
concentrations above 130 g/L and report side effects (RR 6.52, 95% CI 1.13, 37.69) than
dose women receiving 30 mg per day or less (RR 1.01, 95% CI 0.84 1.21).
The overall quality of the evidence for iron supplementation versus no iron was
moderate for low birth weight, preterm birth, maternal anaemia at term and maternal
iron deficiency at term. The evidence was of low quality for birth weight, neonatal
death, congenital anomalies, maternal death, maternal severe anaemia, and infections
during pregnancy; whereas it was of very low quality for side-effects (Annex 1).
Recommendation
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 desire
the recommended course of action and only a small proportion would not. For clinicians, the implications are that most
patients should receive the recommended course of action, and 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.
Considerations of the guideline advisory group for determining the strength of the recommendation are summarized
in Annex 2.
WHO | Guideline
Table 1
Suggested scheme for daily iron and folic acid supplementation in pregnant
women
Supplement composition
Frequency
Duration
Target group
Settings
All settings
a
30 mg of elemental iron equals 150 mg of ferrous sulfate heptahydrate, 90 mg of ferrous fumarate or 250 mg of
ferrous gluconate.
Remarks
WHO | Guideline
Implications for
future research
Dissemination,
adaptation and
implementation
WHO | Guideline
An iron and folic acid supplementation programme should ideally form part
of an integrated programme of antenatal and neonatal care (20, 21) 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.
Discussion with the guideline development group and stakeholders highlighted the
limited evidence available in some areas, meriting further research on daily iron and folic
acid supplementation in pregnant women, in particular, in the following areas:
side-effects, as they are often poorly defined and reported (e.g. there is no
information on intensity or frequency of most side-effects);
Dissemination
The current guideline will be disseminated through electronic media such as slide
presentations, CD-ROMs and the World Wide Web, either through or the WHO
nutrition web site, the WHO Micronutrients and United Nations Standing Committee
on Nutrition (SCN) mailing lists, 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
Guideline
development process
WHO | Guideline
Advisory groups
The WHO Steering Committee for Nutrition Guidelines Development, led by the
Department of Nutrition for Health and Development and the Department of Research
Policy and Cooperation, 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 established in 2009 (Annex 4).
It has 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 decisionmaking, as well as with regard to review of the completed draft guideline (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.
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 at 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 meeting with the Nutrition Guidance Expert Advisory Group was held on
2226 February 2010 in Geneva, Switzerland, to finalize the scope of the questions and
rank the critical outcomes and populations of interest. The nutrition guideline expert
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 79 indicated that the outcome was
critical for a decision, 46 indicated that it was important and 13 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 for decisionmaking are listed in PICO format in Annex 6.
WHO | Guideline
1
As part of the Cochrane pre-publication editorial process, this review was commented on by three external
peers (an editor, and two referees who are external to the editorial team) and the groups 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.
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Management of
conflicts of interest
WHO | Guideline
According to the rules in the WHO Basic documents (27), all experts participating in WHO
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
the responsible technical officer and the relevant departments before finalization of the
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) (28). The potential conflicts of interest
declared by the members of the guideline group are summarized below.
This guideline will be reviewed in 2016. 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
at the WHO headquarters in Geneva, along with its internal partners, will be responsible
for coordinating the guideline update, following formal WHO handbook for guideline
development (25) procedures. WHO welcomes suggestions regarding additional
questions for evaluation in the guideline when it is due for review.
10
References
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World Health Organization, 2008 (http://whqlibdoc.who.int/publications/2008/9789241596657_eng.pdf,
accessed 1 December 2012).
2. WHO/UNICEF/UNU. Iron deficiency anaemia assessment, prevention, and control: a guide for programme
managers. Geneva, World Health Organization, 2001
(http://www.who.int/nutrition/publications/en/ida_assessment_prevention_control.pdf, accessed
1 December 2012).
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Nutrition Information System. Geneva, World Health Organization, 2011 (WHO/NMH/NHD/MNM/11.1;
http://www.who.int/vmnis/indicators/haemoglobin.pdf, accessed 1 December 2012).
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Symposium. Why is iron important and what to do about it: a new perspective. Washington, DC, INACG
Secretariat, 2002:150.
5. Lozoff B, Jimenez E, Smith JB. Double burden of iron deficiency in infancy and low socioeconomic status: a
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Informational Bulletin. Washington, DC, Pan American Health Organization, 2007:14
(http://www.paho.org/english/ad/fch/ca/ca_delivery_care_practices_eng.pdf, accessed 1 December 2012).
10. Bothwell TH. Iron requirements in pregnancy and strategies to meet them. American Journal of Clinical
Nutrition, 2000, 72(Suppl. 1):S257S264.
11. Iron deficiency anaemias: Report of a WHO study group. Geneva, World Health Organization, 1959
(WHO Technical Report Series, No. 182; http://whqlibdoc.who.int/trs/WHO_TRS_182.pdf, accessed
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1 December 2012).
13. Stoltzfus R, Dreyfuss M. Guidelines for the use of iron supplements to prevent and treat iron deficiency
anaemia. Washington, DC, ILSI Press, 1998
(http://www.who.int/nutrition/publications/micronutrients/guidelines_for_Iron_supplementation.pdf,
accessed 1 December 2012).
14. Pea-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.
15. Pea-Rosas et al. Daily oral iron supplementation during pregnancy. Cochrane Database of Systematic
Reviews, 2012, Issue 12 . Art. No.: CD004736. DOI: 10.1002/14651858.CD004736.pub4
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16. UNICEF, WHO, UNU. Composition of a multi-micronutrient supplement to be used in pilot programmes among
pregnant women in developing countries: report of a United Nations Childrens Fund (UNICEF), World Health
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accessed 1 December 2012).
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Systematic Reviews, 2006, (4):CD000169.
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Systematic Reviews, 2008, (4):CD004912.
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21. 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://cdrwww.who.int/reproductivehealth/publications/maternal_perinatal_health/iron_folate_
supplementation.pdf, accessed 1 December 2012).
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(http://apps.who.int/phint/en/p/about, accessed 1 December 2012).
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(http://www.who.int/medicines/publications/brochure_pharma.pdf, accessed 1 December 2012)
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Information System. Geneva, World Health Organization, 2011 (WHO/NMH/NHD/MNM/11.5;
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25. WHO handbook for guideline development. Geneva, World Health Organization, 2012
(http://apps.who.int/iris/bitstream/10665/75146/1/9789241548441_eng.pdf, accessed 1 December 2012).
26. Guyatt G et al. GRADE guidelines 1. Introduction GRADE evidence profiles and summary of findings
tables. Journal of Clinical Epidemiology, 2011, 64:383394.
27. Basic documents, 47th ed. Geneva, World Health Organization, 2009 (http://apps.who.int/gb/bd, accessed 1
December 2012).
28. Guidelines for declaration of interests (WHO experts). Geneva, World Health Organization, 2010.
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13
Daily iron and folic acid supplementation in pregnant women
Relative effect
Number of participants Quality of the evidence
(95% CI)
(studies)
(GRADE)*
Comments
Outcomes
Low birth weight (less than 2500 g)
RR 0.81
8 480
(0.68 0.97)
(11 studies)
moderate1
Birth weight (g)
The mean difference
9 385
(g) between
(14 studies)
low2
groups was 30.81
(5.94 55.68)
Preterm birth (less than 37 weeks of gestation)
RR 0.88
10 148
(0.77 1.01)
(13 studies)
moderate3
Neonatal death (within 28 days after birth)
RR 0.90
7 465
(0.68 1.19)
(4 studies)
low4
Congenital anomalies
RR 0.86
2 702
(0.55 1.35)
(3 studies)
low5
(Continued overleaf)
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14
Daily iron and folic acid supplementation in pregnant women
Relative effect
Number of participants Quality of the evidence
Outcomes
(95% CI)
(studies)
(GRADE)*
Comments
Maternal anaemia at term (Hb less than 110 g/L
RR 0.30
2 199
at 37 weeks gestation or more)
(0.19 0.46)
(14 studies)
moderate6
Maternal iron deficiency at term (as defined by
RR 0.43
1 256
trialists, based on any indicator of iron status at 37
(0.27 0.66)
(7 studies)
moderate7
weeks gestation or more)
Maternal death (death while pregnant or within 42
Not estimable
47
days of termination of pregnancy)
(1 study)
low8
Side-effects (any reported throughout the
RR 2.36
4 418
intervention period)
(0.96 5.82)
(11 studies)
very low9
Maternal severe anaemia at any time during
RR 0.22
2 125
(0.01 3.20)
(9 studies)
low10
2nd or 3rd trimester (Hb less than 70 g/L)
Infection during pregnancy (including urinary tract
infections and others)
RR 1.16
(0.83 1.63)
3 421
(2 studies)
low11
WHO | Guideline
Any supplements containing iron and folic acid versus same supplements without iron and folic acid, no treatment or placebo for pregnant women
Patient or population: Pregnant women
Settings: All settings including malaria-endemic areas
Intervention: Any supplements containing iron versus no treatment/placebo or the same supplements without iron and folic acid
15
Daily iron and folic acid supplementation in pregnant women
Relative effect
Number of participants Quality of the evidence
Outcomes
(95% CI)
(studies)
(GRADE)*
Comments
Low birthweight (less than 2500 g)
RR 1.07
1 311
(0.31 3.74)
(2 studies)
very low1
Birth weight (g)
The mean difference
1 365
(g) between the
(2 studies)
very low2
groups was 57.73
(7.66 107.79)
Preterm birth (less than 37 weeks of gestation)
RR 1.55
1 497
(0.40 6.00)
(3 studies)
very low3
Neonatal death (within 28 days after birth)
RR 0.81
1 793
(0.51 1.30)
(3 studies)
low4
Congenital anomalies
RR 0.70
1 652
(0.35 1.40)
(1 study)
very low5
CI: confidence interval; RR: average risk ratio; Hb: haemoglobin.
*GRADE Working Group grades of evidence
High quality: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate quality: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low quality: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.
Very low quality: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.
One out of the two trials was considered at high risk of bias. Low heterogeneity (29%) but inconsistency in the magnitude and direction of the effect. Wide confidence intervals.
One out of the two trials was considered at high risk of bias. Very low heterogeneity (2%) but inconsistency in the magnitude and direction of the effect. Wide confidence intervals.
3
Two out of the three trials were considered at high risk of bias. Moderate heterogeneity (34%). Wide confidence intervals.
4
Two of the three trials were considered at low risk of bias. Nil heterogeneity (0%). Wide confidence intervals.
5
A single high-quality trial assessed this outcome, reporting low number of events for both study arms. Wide confidence intervals.
1
2
(Continued overleaf)
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16
Daily iron and folic acid supplementation in pregnant women
Relative effect
Number of participants Quality of the evidence
Outcomes
(95% CI)
(studies)
(GRADE)*
Comments
Maternal anaemia at term (Hb less than 110 g/L
RR 0.34 346
at 37 weeks gestation or more)
(0.21 0.54)
(3 studies)
high6
Maternal iron deficiency at term (as defined by
RR 0.24 131
trialists, based on any indicator of iron status at 37
(0.06 0.99)
(1 study)
low7
weeks gestation or more)
Maternal death (death while pregnant or within 42
Not estimable
131
days of termination of pregnancy)
(1 study)
low8
Side-effects (any reported throughout the
RR 44.32
456
intervention period)
(2.77 709.09)
(1 study)
low9
Maternal severe anaemia at any time during
RR 0.12 506
(0.02 0.63)
(4 studies)
low10
2nd or 3rd trimester (Hb less than 70 g/L)
Infection during pregnancy (including urinary tract
infections and others)
RR 1.00 48
(0.15 6.53)
(1 study)
low11
Annex 2
Quality of evidence:
Trade-off between
benefits and harm:
WHO | Guideline
17
Annex 3
Dr Ruediger Krech
Director
Department of Ethics, Equity, Trade and
Human Rights
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 Knut Lonnroth
Medical Officer
The Stop TB Strategy
HIV/AIDS, TB and Neglected Tropical Diseases
(HTM) Cluster
Dr Sergio Spinaci
Associate Director
Global Malaria Programme
HIV/AIDS, TB and Neglected Tropical
Diseases (HTM) Cluster
Dr Elizabeth Mason
Director
Department of Child and Adolescent Health
and Development
Family and Community Health (FCH) Cluster
Dr Maged Younes
Director
Department of Food Safety, Zoonoses and
Foodborne Diseases
Health Security and Environment (HSE)
Cluster
Dr Michael Mbizvo
Director
Department of Reproductive Health and
Research
Family and Community Health (FCH) Cluster
Dr Nevio Zagaria
Acting Director
Department of Emergency Response and
Recovery Operations
Health Action in Crises (HAC) Cluster
Dr Jean-Marie Okwo-Bele
Director
Department of Immunization, Vaccines and
Biologicals
Family and Community Health (FCH) Cluster
WHO | Guideline
18
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 Hctor Bourges Rodrguez
Instituto Nacional de Ciencias Medicas y
Nutricin 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 practice
WHO | Guideline
19
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
Childrens 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
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
B. WHO
WHO | Guideline
Mr Joseph Ashong
Intern (rapporteur)
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 Bernadette Daelmans
Medical Officer
Newborn and Child Health and Development
Unit
Department of Child and Adolescent Health
and Development
Dr Olivier Fontaine
Medical Officer
Newborn and Child Health and
Development Unit
Department of Child and Adolescent
Health and Development
20
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 Jos 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
WHO | Guideline
21
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
Dr Kunal Bagchi
Dr Kunal Bagchi
Regional Adviser
Nutrition and Food Safety
WHO Regional Office for South-East Asia
New Delhi, India
Dr Ayoub Al-Jawaldeh
Regional Adviser
Nutrition
WHO Regional Office for the Eastern
Mediterranean
Cairo, Egypt
Dr Joao Breda
Noncommunicable Diseases and Environment
WHO Regional Office for Europe
Copenhagen, Denmark
Dr Tommaso Cavalli-Sforza
Regional Adviser
Nutrition
WHO Regional Office for the Western Pacific
Manila, Philippines
D. Experts extrieurs
Dr Andreas Bluethner
BASF SE
Limburgerhof, Germany
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
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
WHO | Guideline
22
Mr Arnold Timmer
United Nations Childrens Fund (UNICEF)
New York, United States of America
Dr Stanley Zlotkin
Division of Gastroenterology, Hepatology
and Nutrition
The Hospital for Sick Children
Toronto, Canada
Annex 5
Dr Erick Boy-Gallego
HarvestPlus
Ottawa, Canada
Dr Mohamd Ayoya
United Nations Childrens Fund (UNICEF)
Port Au-Prince, Haiti
Dr Mario Bracco
Albert Einstein Social Responsibility Israeli
Institute
So Paulo, Brazil
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
Dveloppement
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
WHO | Guideline
23
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 Gois
Goinia, Brazil
Ms Nita Dalmiya
United Nations Childrens 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 S. Harris
International Life Sciences Institute (ILSI)
Washington, DC, United States of America
Dr Suzanne Filteau
London School of Hygiene and Tropical
Medicine
London, England
Dr Phil Harvey
Philip Harvey Consulting
Rockville, United States of America
Dr Rodolfo F. Florentino
Nutrition Foundation of the Philippines
Manila, Philippines
Dr Izzeldin S. Hussein
International Council for Control of Iodine
Deficiency Disorders
Al Khuwair, Oman
Dr Ann Fowler
DSM Nutritional Products
Rheinfelden, Switzerland
Dr Susan Jack
University of Otago
Dunedin, New Zealand
Mr Joby George
Save the Children
Lilongwe, Malawi
Mr Quentin Johnson
Food Fortification
Quican Inc.
Rockwood, Canada
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
WHO | Guideline
24
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 Romaa
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 Mara Teresa Murgua Peniche
National Center for Child and Adolescent
Health
Mexico City, Mexico
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
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
Mr Sherali Rahmatulloev
Ministry of Health
Dushanbe, Tajikistan
Dr Ismael Teta
Micronutrient Initiative
Ottawa, Canada
Ms Anna Roesler
Menzies School of Health Research/
Compass Womens and Childrens Knowledge
Hub for Health
Chiang Mai, Thailand
Dr Ulla Uusitalo
University of South Florida
Tampa, United States of America
WHO | Guideline
25
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 Dveloppement
Montpellier, France
WHO | Guideline
26
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
Xian JiaoTong University College of Medicine
Xian, China
Annex 6
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 individuals status of iron deficiency: iron deficiency versus no iron
deficiency
By individuals status of anaemia: anaemia versus no anaemia
By anaemia status of population: 20% or less versus 2040% versus
more than 40%
Intervention:
Control :
No iron supplementation
Placebo
Same supplement without iron or folic acid
Outcomes:
Maternal
Critical
Severe anaemia
Maternal mortality
Anaemia
Haemoglobin concentrations
Iron deficiency anaemia
Iron deficiency
Morbidity from malaria incidence and severity (parasitaemia with
or without symptoms)
Adverse effects
Neonate/infant
Critical
Anaemia
Iron deficiency
Iron deficiency anaemia
Neural tube defects
Low birth weight: less than 2500 g
Birth weight
Length at birth
Cognitive performance
Gestational age: less than 34 weeks versus less than 37 weeks versus
no prematurity
Mortality
Setting:
WHO | Guideline
27
All settings
Daily iron and folic acid supplementation in pregnant women
www.who.int/nutrition
WHO | Guideline
29