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Iron Supplementation for School-Age Children

This is an interim intervention report. We have spent limited time to form an initial view of this program and, at this point, our views are preliminary. We plan to consider undertaking additional work on this program in the future.

Summary

  • What is iron deficiency? Iron deficiency is an insufficient supply of iron to cells, which can adversely affect their function. Iron deficiency is the most common cause of anemia and can lead to a range of adverse physical and cognitive effects.
  • Which programs tackle this problem? Iron supplementation and iron fortification are the most common interventions that address iron deficiency. Iron supplementation can be administered orally, intravenously, or intramuscularly, although daily or weekly oral iron supplementation is the most common method. Iron fortification programs usually involve mandatory, centralized mass fortification of staple foods, such as wheat flour. This report focuses on iron supplementation for school-age children.
  • What evidence do we have of the effects of these programs? There is strong evidence that iron supplementation reduces cases of anemia. There is weak to moderate quality evidence that iron supplementation, with or without folic acid, increases cognitive ability. However, there is uncertain evidence that iron supplementation programs may increase malaria risk, and evidence that it has adverse gastrointestinal side effects such as constipation and diarrhea.
  • How cost-effective are iron supplementation programs? Iron supplementation programs may be in the same range of cost-effectiveness as our other priority programs in contexts with low malaria prevalence, but our cost-effectiveness estimates involve several highly uncertain assumptions and key factors about which we need more information.
  • Bottom line: This program appears promising, and we are open to considering charities that work to scale up iron supplementation in contexts with low malaria prevalence.


Published: April 2019

What is the problem?

Iron is needed to produce the oxygen-carrying molecule hemoglobin, and is an important component of many enzymes that are essential for the growth and function of many tissues.1 Iron deficiency is an insufficient supply of iron to cells following the depletion of the body's reserves, and is caused by insufficient dietary iron absorption, increased requirement for iron, or loss of iron due to blood loss or parasitic infections.2

Iron deficiency is the most common cause of anemia, a condition in which hemoglobin production is diminished, and is believed to contribute to at least half of the global burden of anemia.3 Iron deficiency and iron deficiency anemia have been associated with a range of adverse physical, psychological, and cognitive effects, and are significant risk factors in illness and death, although not all of these associations have been validated by randomized controlled trials.4 Iron deficiency is the most common nutritional deficiency in the world, and is most prevalent among children and women of reproductive age in low-income countries.5

What is the program?

There are several strategies to reduce iron deficiency, including dietary change, breeding staple crops with intrinsically higher levels of iron, control of infection, iron supplementation, and fortification of foods with iron.6

This report focuses on iron supplementation programs for school-age children, in part because this is most relevant to a GiveWell Incubation Grant to Evidence Action to support an iron and folic acid supplementation program.

Iron supplementation is the oral consumption of iron-containing compounds, typically in pill form. Ferrous sulfate is the most common compound used in studies to date, but other common compounds include ferrous gluconate and fumarate.7 In studies to date, recipients typically take the iron supplement daily, 2-3 days per week, or once per week.8

Does the program have strong evidence of effectiveness?

In summary:

  • There is strong evidence that iron supplementation reduces anemia in school-age children.
  • There is weak to moderate quality evidence that iron supplementation improves cognitive ability in school-age children while they receive supplementation. We believe it is unlikely that iron supplementation permanently increases cognitive ability in children, but our speculative best guess is that it has persistent indirect benefits.
  • There is suggestive evidence that iron supplementation may increase cases of malaria in some contexts.

Effects on anemia

There is strong evidence that iron supplementation reduces anemia in school-age children.

Below, we discuss two meta-analyses: De-Regil et al. 2011, a meta-analysis of 33 randomized or quasi-randomized trials of intermittent iron supplementation (i.e., supplementation occuring 1-3 times per week) provided to children from birth to 12 years of age,9 and Low et al. 2013, a meta-analysis of 7 randomized controlled trials (RCTs) of daily iron supplementation provided to children 5-12 years old.10

A Cochrane Collaboration meta-analysis (De-Regil et al. 2011) of 33 randomized or quasi-randomized trials on intermittent iron supplementation (i.e., supplementation one, two, or three times a week on nonconsecutive days) concludes:11

In comparison with receiving no intervention or a placebo, children receiving iron supplements intermittently have a lower risk of anaemia (average risk ratio (RR) 0.51, 95% confidence interval (CI) 0.37 to 0.72, ten studies) and iron deficiency (RR 0.24, 95% CI 0.06 to 0.91, three studies) and have higher haemoglobin (mean difference (MD) 5.20 g/L, 95% CI 2.51 to 7.88, 19 studies) and ferritin concentrations (MD 14.17 μg/L, 95% CI 3.53 to 24.81, five studies).

Intermittent supplementation was as effective as daily supplementation in improving haemoglobin (MD −0.60 g/L, 95% CI −1.54 to 0.35, 19 studies) and ferritin concentrations (MD −4.19 μg/L, 95% CI −9.42 to 1.05, 10 studies), but increased the risk of anaemia in comparison with daily iron supplementation (RR 1.23, 95% CI 1.04 to1.47, six studies). Data on adherence were scarce and it tended to be higher among those children receiving intermittent supplementation, although this result was not statistically significant.

Low et al. 2013 conducted a meta-analysis of seven randomized controlled trials on 1,763 children 5-12 years old, and estimates that iron supplementation reduces cases of anemia by about 50% (95% confidence interval 39% to 64%).12

We have not yet vetted the above meta-analyses. However, because of the apparently large number of randomized controlled trials included in the analyses and the highly plausible biological mechanism (see section above), we consider the evidence for iron supplementation's impact on anemia to be strong.

We have not yet thoroughly investigated whether iron supplementation has different effects on mild, moderate, and severe anemia.

Effects on cognitive ability

There is weak to moderate quality evidence that iron supplementation improves cognitive ability in school-age children while they receive supplementation. We believe it is unlikely that iron supplementation permanently increases cognitive ability in children, but our speculative best guess is that it has persistent indirect benefits.

Short-term cognitive effects

Iron deficiency may adversely affect cognitive ability in children.13

Low et al. 2013 is the most recent meta-analysis we are aware of that assesses the effects of iron supplementation on cognitive ability in children aged 5-12 years. The authors pre-registered their methodology and conducted an extensive search for studies for inclusion in the review.14 Low et al. 2013 includes nine randomized controlled trials that report cognitive outcomes, all in low- or middle- income countries, and it assessed risk of bias by using the Cochrane risk of bias assessment tool.15 However, the authors concluded that no studies reporting cognitive outcomes were at low overall risk of bias, so we interpret these results with caution.16

Low et al. 2013 estimates an increase in the standardized mean difference (SMD) of several measures of global cognitive performance among children receiving iron supplementation in nine studies (SMD 0.50, 95% CI 0.11 to 0.90).17

Focusing on intelligence quotient (IQ), a specific measure of global cognitive performance, Low et al. 2013 does not report evidence of an increase in average IQ scores for all children receiving supplementation (MD 5.47, 95% CI –3.24 to 14.18), but does for those who are anemic at baseline (MD 4.55, 95% CI 0.16 to 8.94).18 Since the standard deviation of IQ is 15 by definition,19 this corresponds to a SMD of about 0.30.20 This finding rests on only three studies, all of which represented children who had moderate anemia on average.21

We have not yet reviewed the key underlying studies in Low et al. 2013 in depth or thoroughly analyzed which outcome grouping we should consider most reliable (e.g., whether to focus on IQ tests vs. all cognitive tests, and whether to focus on results from children who were anemic at baseline vs. all children).

Long-term cognitive effects

We believe the direct cognitive benefits of iron supplementation in childhood and adolescence are unlikely to be permanent. However, our speculative best guess is that there is an indirect permanent benefit of supplementation.

Our research on this question is preliminary and relatively speculative (see footnote for more details).22

Are there any potential negative impacts of the program?

We have not yet thoroughly investigated potential negative impacts of iron supplementation. However, one uncertain possibility is that iron supplementation may increase the risk of acquiring malaria. There is also evidence that iron supplementation increases the risk of undesired gastrointestinal side effects such as constipation and diarrhea.

Malaria risk

Iron is required by many pathogens for their survival, including Plasmodium falciparum, which causes the greatest number and most dangerous forms of malaria infections.23 There is some evidence that iron deficiency may reduce malaria infection risk, and that iron supplementation or fortification may therefore increase cases of malaria, although there is ongoing debate on this question.24

Neuberger et al 2016, a Cochrane Collaboration meta-analysis on this topic, concluded that, “In areas where there are prevention and management services for malaria, iron (with or without folic acid) may reduce clinical malaria (RR [risk ratio] 0.91, 95% CI [confidence interval] 0.84 to 0.97; seven trials, 5586 participants, low quality evidence), while in areas where such services are unavailable, iron (with or without folic acid) may increase the incidence of malaria, although the lower CIs indicate no difference (RR 1.16, 95% CI 1.02 to 1.31; nine trials, 19,086 participants, low quality evidence).”25 However, when pooling all studies on clinical malaria risk, Neuberger et al 2016 did not find evidence that iron supplementation increases risk.26

We have not yet deeply reviewed the evidence on whether iron supplementation increases malaria risk in malarial areas without malaria prevention and management services. We are also uncertain how the quality of malaria prevention and management services in charity-relevant contexts compares with the services that were provided as part of studies included in the meta-analysis.

We spoke with Dr. Mical Paul, one of the coauthors of Neuberger et al 2016, who agreed that it is reasonable to be concerned that iron programs (specifically fortification programs) could increase risk of malaria in regions with high malaria burden and weak malaria prevention and management services.27

Gastrointestinal side effects

A Cochrane Collaboration meta-analysis, Low et al. 2016, quantifies gastrointestinal side effects caused by iron supplementation in menstruating women. It reports that:

  • ”Five studies recruiting 521 women identified an increased prevalence of gastrointestinal side effects in women taking iron (RR 1.99, 95% CI 1.26 to 3.12, low quality evidence).”28
  • ”Six studies recruiting 604 women identified an increased prevalence of loose stools/diarrhoea (RR 2.13, 95% CI 1.10, 4.11, high quality evidence).”29
  • ”Eight studies recruiting 1036 women identified an increased prevalence of hard stools/constipation (RR 2.07, 95% CI 1.35 to 3.17, high quality evidence).”30

Neuberger et al 2016, a second Cochrane Collaboration meta-analysis, also reports higher diarrhea risk in children receiving iron supplements in malaria-endemic areas, although this was only evident when pooling iron supplementation trials with trials that administered both iron and zinc.31

We have not yet reviewed these findings in depth.

Is the program cost-effective?

A preliminary cost-effectiveness model for this intervention is available here. Iron supplementation programs may be in the same range of cost-effectiveness as our other priority programs in contexts with low malaria prevalence, but our cost-effectiveness estimates involve several highly uncertain assumptions and key factors about which we need more information.

Note that our cost-effectiveness analyses are simplified models that do not take into account a number of factors. There are limitations to this kind of cost-effectiveness analysis, and we believe that cost-effectiveness estimates such as these should not be taken literally due to the significant uncertainty around them. We provide these estimates (a) for comparative purposes and (b) because working on them helps us ensure that we are thinking through as many of the relevant issues as possible.

Major uncertainties in our current cost-effectiveness model of iron supplementation include:

  • What is the magnitude of long-term benefits due to cognitive effects of iron supplementation? We currently discount the short-term cognitive benefits as estimated in studies by about 60% (i.e., we include less than half of the estimated short-term benefits in our model) due to concerns that the short-term effects will not persist in the long term. However, we do not have an evidence basis for this specific figure and so we are highly uncertain about it. How much to discount for these kinds of concerns is a difficult judgment call.32
  • How valuable is it to avert cases of anemia? We rely on conventional Global Burden of Disease (GBD) disability weights for mild, moderate, and severe anemia. We have done some simple sanity checks on these weights, e.g. by reviewing the methodology behind the current and past GBD weights for anemia, reviewing evidence on anemia's effect on physical performance, making comparisons between anemia and other illnesses that have similar disability weights, and imagining what disability weight we would assign if we were not anchored on the GBD weight.33 This work did not lead us to have substantial disagreements with the current GBD disability weight.
  • How should one account for costs such as teachers' time in administering the program? Our current cost-effectiveness model does not capture the cost of teachers' time in implementing this program, under the assumption that the opportunity cost of that time is likely very low. If we ultimately see this cost as high, this could meaningfully change our view on the cost-effectiveness of iron supplementation.

Does the program have room for more funding?

We have not yet carefully quantified the magnitude of room for more funding in this area, but we expect there is a large funding gap for related work. We are aware of a number of charities working on anemia-related interventions, such as current standout charities (as of April 2019) Food Fortification Initiative, Project Healthy Children, and Global Alliance for Improved Nutrition, and Incubation Grant recipients Evidence Action and Fortify Health.

Questions for further investigation

Below, we list areas we may research if we deepen our investigation of this program:

  • What is the relationship between anemia and iron-deficiency anemia? Iron deficiency is a major cause of anemia, but anemia can also be caused by infection and other factors.34 In our cost-effectiveness analysis, we use population prevalence data on iron-deficiency anemia because we have been unable to find anemia prevalence data for the relevant age group. However, our estimate of the effectiveness of iron supplementation refers to anemia rather than iron-deficiency anemia. We account for this discrepancy with an external validity adjustment, but we may be able to refine this adjustment with further investigation. The relationship between the two conditions may also depend on the setting.
  • Would our conclusions change if we examined the primary studies underlying the meta-analyses we cite? In most cases in this report, we have taken the findings of high-quality meta-analyses at face value. In past investigations, we have sometimes found that a closer examination of primary studies underlying high-quality meta-analyses changes our conclusions, often because the data are not as pertinent as we initially believed.
  • Does iron supplementation have different effects on mild, moderate, and severe anemia?
  • How severe are the side effects of iron supplementation, and in addition to negative health effects do they lead to decreased uptake of iron programs?

Sources

Document Source
De-Regil et al. 2011 Source
GiveWell, Key judgment calls in iron supplementation CEA Source
GiveWell's non-verbatim summary of a conversation with Mical Paul, July 13, 2017 Source
Low et al. 2013 Source
Low et al. 2016 Source
Neuberger et al 2016 Source
Peña-Rosas et al 2014 Source
Peña-Rosas et al 2015 Source
WHO, Anaemia Source
Wikipedia, "Intelligence quotient" Source
  • 1.

    "Iron is an important mineral needed to produce haemoglobin. It is also a component of many enzymes that are essential for proper cell development and cell growth of the brain, muscle, and the immune system (Beard 2001). It is a component of the peroxidase and nitrous oxide-generating enzymes that participate in the immune response to infections and is probably involved in regulating the production and action of cytokines (mediators of immune function released during early stages of infection). Since free iron is toxic to cells, it is stored as ferritin, an intracellular protein." Neuberger et al 2016, Pg. 5.

  • 2.

    "Iron deficiency involves an insufficient supply of iron to the cells following depletion of the body’s reserves. Its main causes are a diet poor in absorbable iron, an increased requirement for iron (e.g. during pregnancy) not covered through the diet, a loss of iron due to parasitic infections, particularly hookworm, and other blood losses (Crompton 2002; INACG 2002a)." Peña-Rosas et al 2015, Pg. 4.

  • 3.
    • "Chronic iron deficiency frequently turns into iron-deficiency anaemia. While iron deficiency is the most common cause of anaemia, other causes such as acute and chronic infections that cause inflammation; deficiencies of folate and of vitamins B 2 , B 12 , A, and C; and genetically inherited traits such as thalassaemia and drepanocytosis (sickle-cell anaemia) may be independent or superimposed causal factors (WHO 2001; WHO 2015a)." Peña-Rosas et al 2015, Pg. 4.
    • "Over 1.6 billion people worldwide have anaemia, a condition in which haemoglobin production is diminished. Women of menstruating age account for approximately a third of all cases of anaemia across the globe (WHO/CDC 2008). The most recent estimates suggest that 29% of non-pregnant women worldwide are anaemic (Stevens 2013). Iron deficiency is believed to contribute to at least half the global burden of anaemia, especially in non-malaria-endemic countries (Stoltzfus 2001). Iron deficiency is thus considered the most prevalent nutritional deficiency in the world." Low et al. 2016, Pg. 5.
  • 4.
    • "As well as being critical to the production of haemoglobin, iron has a critical role in many other aspects of human physiology as it is involved in a range of oxidation-reduction enzymatic reactions in the muscle and nervous tissue (Andrews 1999), as well as other organs. Iron deficiency and iron-deficiency anaemia have been associated with a range of adverse physical, psychological, and cognitive effects. Animal models suggest a role for iron in brain development and function, with iron depletion being associated with dysregulated neurotransmitter levels (Lozoff 2007), and some, but not all, clinical studies have shown associations between iron supplementation and improvement in cognitive performance (Murray-Kolb 2007) and mood and well being, with a reduction in fatigue (Verdon 2003). Observational studies have suggested that iron deficiency in the absence of anaemia impairs exercise performance in women (Scholz 1997), while some, but not all, interventional studies of iron supplementation among the same population have shown variable improvements in maximal and submaximal exercise performance (Brownlie 2002; LaManca 1993), endurance (Brownlie 2004; Hinton 2000), and muscle fatigue (Brutsaert 2003). There may also be associations between iron status and haemoglobin concentrations and work productivity (Li 1994: Scholz 1997; Wolgemuth 1982). When anaemia is severe, it may cause lethargy, fatigue, irritability, pallor, breathlessness and reduced tolerance for exertion." Low et al. 2016, Pg. 6.
    • "The consequences of iron-deficiency anaemia are serious, and can include diminished intellectual and productive capacity (Hunt 2002), and possibly increased susceptibility to infections (Oppenheimer 2001)." Peña-Rosas et al 2015, Pg. 4.
    • "Based on estimates of iron-deficiency anaemia as a risk factor for death, iron deficiency has been estimated to cause 726,000 deaths in the perinatal and childhood periods globally, with the greatest toll in Southeast Asia and in Africa (WHO 2004; FAO/WHO 2005). Experimental and observational studies have linked iron deficiency to adverse effects on child development, including impairments of cognitive, emotional, and motor development (Pollitt 1993; Grantham-McGregor 2001; Gewa 2009), growth (Lawless 1994), immune function, and increased risk of infection (Berger 2000; Beard 2001)." Neuberger et al 2016, Pg. 5.
  • 5.
    • "Over 1.6 billion people worldwide have anaemia, a condition in which haemoglobin production is diminished. Women of menstruating age account for approximately a third of all cases of anaemia across the globe (WHO/CDC 2008). The most recent estimates suggest that 29% of non-pregnant women worldwide are anaemic (Stevens 2013). Iron deficiency is believed to contribute to at least half the global burden of anaemia, especially in non-malaria-endemic countries (Stoltzfus 2001). Iron deficiency is thus considered the most prevalent nutritional deficiency in the world." Low et al. 2016, Pg. 5.
    • "Childhood anaemia is a major, widespread public health problem in sub-Saharan Africa and other low-income areas (WHO 2008a; Kassebaum 2014). The highest prevalence of anaemia is found among children younger than five years of age who are living in low-income countries (Kassebaum 2014)." Neuberger et al 2016, Pg. 5.
  • 6.
    • "There are several strategies to reduce and/or treat iron deficiency and iron-deficiency anaemia: dietary modification and diversification that aims to increase the content and bioavailability of iron in the diet (FAO/CAB International 2011); preventive or intermittent iron supplementation through tablets, syrups or drops; blood transfusion, indicated only for very severe anaemia; biofortification through conventional plant breeding or genetic engineering that increases the iron content or its bioavailability in edible plants and vegetables; and fortification with iron compounds of staple foods (typically maize, soy and wheat flour) (WHO/FAO 2006)." Peña-Rosas et al 2014, Pg. 2.
  • 7.

    Low et al. 2013, Table 1, Pgs. E794-796

  • 8.

    “Nine trials included arms where children were supplemented with iron twice a week and in two studies children were provided with iron every other day. The rest of the studies provided iron supplements once weekly.” De-Regil et al. 2011, Pg. 15.

  • 9.
    • "The provision of daily iron supplements is a widely used strategy for improving iron status in children but its effectiveness has been limited due to its side effects, which can include nausea, constipation or staining of the teeth. As a consequence, intermittent iron supplementation (one, two or three times a week on nonconsecutive days) has been proposed as an effective and safer alternative to daily supplementation" Pg. 2, De-Regil et al. 2011
    • "We included randomised and quasi-randomised studies with randomisation at either an individual or cluster level. We defined quasi-randomised trials as trials which use systematic methods to allocate participants to treatment groups, such as alternation, assignment based on date of birth or case record number (Higgins 2011). We did not include cross-over trials nor other types of evidence (for example, cohort or case-control studies) in the meta-analysis but we have considered such evidence in the discussion where relevant." Pgs. 7-8, De-Regil et al. 2011.
    • "We included 33 trials, involving 13,114 children (~49% females) from 20 countries in Latin America, Africa and Asia. The methodological quality of the trials was mixed." Pg. 2, De-Regil et al. 2011
    • "The intervention assessed was intermittent iron supplementation compared with a placebo, no intervention or daily supplementation." Pg. 2, De-Regil et al. 2011
    • "Objectives—To assess the effects of intermittent iron supplementation, alone or in combination with other vitamins and minerals, on nutritional and developmental outcomes in children from birth to 12 years of age compared with a placebo, no intervention or daily supplementation." Pg. 2, De-Regil et al. 2011
  • 10.

    "We included randomized controlled trials that included primary-school–aged children (5–12 yr) who were randomly assigned to daily (≥ 5 d/wk) oral iron supplementation or control. We included studies that did not specifically recruit participants from this age range if the mean or median age of participants was between 5 and 12 years, if more than 75% of participants were aged 5–12 years, or if most of the study’s recruitment age range overlapped 5–12 years. We excluded studies that included only children with a known developmental disability or a condition that substantially altered iron metabolism, including severe anemia. We included trials involving participants from all countries and socioeconomic backgrounds." Pg. E792, Low et al. 2013.

  • 11.
    • "We included 33 trials, involving 13,114 children (~49% females) from 20 countries in Latin America, Africa and Asia. The methodological quality of the trials was mixed." Pg. 2, De-Regil et al. 2011
    • "We included randomised and quasi-randomised studies with randomisation at either an individual or cluster level. We defined quasi-randomised trials as trials which use systematic methods to allocate participants to treatment groups, such as alternation, assignment based on date of birth or case record number (Higgins 2011). We did not include cross-over trials nor other types of evidence (for example, cohort or case-control studies) in the meta-analysis but we have considered such evidence in the discussion where relevant." Pgs. 7-8, De-Regil et al. 2011.
    • "The provision of daily iron supplements is a widely used strategy for improving iron status in children but its effectiveness has been limited due to its side effects, which can include nausea, constipation or staining of the teeth. As a consequence, intermittent iron supplementation (one, two or three times a week on nonconsecutive days) has been proposed as an effective and safer alternative to daily supplementation" Pg. 2, De-Regil et al. 2011
    • Blockquotes are from Pgs. 2-4, De-Regil et al. 2011
  • 12.

    See row eight of Table 3, Low et al. 2013, Pg. E798.

  • 13.
    • "Iron is also present in the brain in relatively large amounts and is involved in neurotransmitter function (Burhans 2005); an adequate supply may contribute to maintaining normal cognitive and psychological health, although the mechanisms are not completely elucidated as yet." Low et al. 2016
    • "Iron deficiency may adversely affect the cognitive performance, development and physical growth of infants (WHO 2001; Black 2011) even in the long term (Lozoff 2006)." Peña-Rosas et al 2015, Pg. 5.
    • "In observational studies, iron deficiency has been associated with impaired cognitive and physical development. It has been estimated that each 10 g/L decrement in hemoglobin reduces future intelligence quotient (IQ) by 1.73 points." Low et al. 2013, Pg. E791.
  • 14.
    • The authors pre-registered their review methodology: "The protocol for our systematic review and meta-analysis is registered with PROSPERO (www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42011001208). We included outcomes that could be used to inform guidelines for anemia control." Low et al. 2013, Pg. E792
    • The authors conducted an extensive search for studies for inclusion in the review: "We searched the following electronic databases: Scopus, MEDLINE, Embase, Cochrane Central Register of Controlled Trials, ProQuest Digital Theses, the Australian Digital Theses Program
      database, WHO regional databases and OpenGrey. We reviewed the references of the identified articles and of previous systematic reviews. There was no language restriction applied. The search strategy for Scopus is presented in Appendix 1. We performed the searches on July 4, 2013, for all databases except Embase (searched in June 2011). We searched the World Health Organization's International Clinical Trials Registry Platform in July 2013 for potentially eligible ongoing trials." Low et al. 2013, Pg. E792
  • 15.

    "We assessed the risk of bias by use of the Cochrane risk of bias assessment tool, which addresses selection, performance, attrition, detection and reporting bias through the evaluation of reported sequence generation, allocation concealment, blinding, incomplete outcome data and selective outcome reporting. We used sensitivity analysis to examine the effects of removing studies with a high risk of bias (studies with poor or unclear randomization or allocation concealment, and poor or unclear blinding or high or imbalanced losses to follow-up) from the analysis. For outcomes that had more than 10 included trials, we examined funnel plots for evidence of publication bias." Low et al. 2013, page E792.

  • 16.
    • "No studies reporting cognitive outcomes were at low overall risk of bias." Low et al. 2013, page E793.
    • Table 2 Low et al. 2013, page E798, shows the authors' assessment of the risk of bias of each paper included in their review across six key domains. Though not explicitly reported in the paper, it appears that the authors classified each of these studies as having an 'unclear overall risk of bias'.
  • 17.
    • A number of different tests of cognitive performance were used in the individual studies: "Global cognitive performance was reported in 9 studies: 5 studies used IQ (tests: Raven Progressive Matrices, Wechsler Intelligence Scale for Children [WISC], Test of Non-verbal Intelligence 2nd Edition), 3 studies used author-adapted scales of global cognitive performance (visual memory, digit span, mazes test, clerical task tests with maximum scores of 40), and 1 study used overall school performance." Low et al. 2013, Pg. E793
    • "Children who received iron supplementation had higher global cognitive scores at the end of the intervention compared with children who received the control (SMD 0.50, 95% confidence interval [CI] 0.11 to 0.90; p = 0.01, I 2 = 93%, 9 studies, n = 2355) (Figure 2). This beneficial effect was seen among children who were anemic at baseline (SMD 0.29, 95% CI 0.07 to 0.51; p = 0.01, I 2 = 22%, 6 studies, n = 487) but not among those without anemia (SMD 0.01, 95% CI –0.10 to 0.11; p = 0.9, I 2 = 0%, 4 studies, n = 1361) (test for subgroup difference: p = 0.05)." Low et al. 2013, Pg. E793
  • 18.

    "There was no overall benefit of iron supplementation on IQ scores (MD 5.47, 95% CI –3.24 to 4.18; p = 0.2, I 2 = 97%, 5 studies, n = 1874). However, our sub-group analysis showed that children who had anemia at baseline had significant improvements in their IQ after iron supplementation compared with children who received the control (MD 4.55, 95% CI 0.16 to 8.94; p = 0.04, I 2 = 28%, 3 studies, n = 186) (Appendix 3)." Low et al. 2013, Pg. E793, E796

  • 19.

    “When current IQ tests were developed, the median raw score of the norming sample is defined as IQ 100 and scores each standard deviation (SD) up or down are defined as 15 IQ points greater or less,[3] although this was not always so historically.” Wikipedia, "Intelligence quotient"

  • 20.

    4.55 / 15 = 0.3033

  • 21.

    “Average hemoglobin levels are in the moderate anemia range in all three studies.” GiveWell, Key judgment calls in iron supplementation CEA, Pg. 15. Also see the table on Pg. 15.

  • 22.

    For more details, see GiveWell, Key judgment calls in iron supplementation CEA.

  • 23.

    "Malaria is a leading cause of morbidity and mortality in children in sub-Saharan Africa (Breman 2001; WHO 2008b). Most infections are caused by the most virulent parasite species, Plasmodium falciparum (WHO 2008b), which is transmitted to humans by the bite of an infected female Anopheles mosquito." Neuberger et al 2016, Pg. 6.

  • 24.

    "There is an ongoing debate on whether iron deficiency offers protection from malaria and whether an excess of iron increases the risk of malaria or severe malaria (Oppenheimer 2001; Stoltzfus 2010; Suchdev 2010; Oppenheimer 2012). Iron is required by many pathogens for their survival and pathogenicity (killing ability) (Beard 2001). Removal of free circulating iron seems to be an important part of the host (human) response to infection. The theory that iron deficiency may be an important defence mechanism has been termed "nutritional immunity" (Kochan 1973). The erythrocytic form of the Plasmodium parasite requires free iron (which is lacking in an iron-deficient person). In one observational study iron deficiency was associated with a small, albeit significant, degree of protection from episodes of clinical malaria in a cohort of young children living on the Kenyan coast (Nyakeriga 2004)." Neuberger et al 2016, Pg. 6.

  • 25.

    Pg. 2, Neuberger et al 2016.

  • 26.

    “Overall, iron does not cause an excess of clinical malaria (risk ratio (RR) 0.93, 95%confidence intervals (CI) 0.87 to 1.00; 14 trials, 7168 children, high quality evidence).” Neuberger et al 2016, abstract.

  • 27.

    "Dr. Paul believes that it is reasonable to be concerned that iron fortification could increase risk of malaria in regions with high malaria burden and weak malaria prevention and management services. However, these risks should be weighed against the likely benefits. Regarding daily oral iron supplementation, the World Health Organization (WHO) guidelines suggest that, “In malaria-endemic areas, the provision of iron supplementation in infants and children should be done in conjunction with public health measures to prevent, diagnose and treat malaria (strong recommendation, high quality of evidence).” (http://who.int/nutrition/publications/micronutrients/guidelines/summar y_daily_iron_supp_children.pdf)" Pgs. 1-2, GiveWell's non-verbatim summary of a conversation with Mical Paul, July 13, 2017.

  • 28.

    Low et al. 2016, abstract.

  • 29.

    Low et al. 2016, abstract.

  • 30.

    Low et al. 2016, abstract.

  • 31.

    Neuberger et al 2016, analysis 1.17, Pg. 98.

  • 32.
    For more information, see GiveWell, Key judgment calls in iron supplementation CEA.
  • 33.

    See GiveWell, Key judgment calls in iron supplementation CEA, Pgs. 7-11.

  • 34.

    “Iron deficiency is thought to be the most common cause of anaemia globally, although other conditions, such as folate, vitamin B12 and vitamin A deficiencies, chronic inflammation, parasitic infections, and inherited disorders can all cause anaemia.” WHO, Anaemia