Iron Fortification

Published: May 2020

What is the problem?

Iron is needed to produce hemoglobin and is an important component of many enzymes that are essential for growth of cells in the brain, muscles, and the immune system.1 Iron deficiency involves an insufficient supply of iron to cells following the depletion of the body's reserves and is caused by a poor diet, 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.4

Iron deficiency is the most common nutritional deficiency in the world and is especially prevalent among children in low-income countries.5

What is the program?

There are several strategies to reduce iron deficiency and anemia, including dietary change, control of infection, iron supplementation, and fortification of foods with iron.6 This intervention report focuses on fortification of staple foods with iron. However, it also draws heavily on evidence from iron supplementation programs because in some cases, we lack evidence on the effect of iron fortification directly and have to extrapolate based on effects from supplementation programs. (More information on iron supplementation is available on our page on iron supplementation for school-age children.)

There are a number of methods used to fortify foods, including mass fortification of staple foods, point-of-use fortification, and biofortification.7 Mass fortification of foods has been used with various vehicles, including staple foods (such as wheat flour, maize flour, and rice) and condiments (such as soy sauce, fish sauce, and salt). We focus on mass fortification of staple foods, in particular wheat flour, as this is the most commonly used medium in large-scale iron fortification programs because it is consumed in large quantities by entire populations.8 Iron fortification is often accompanied by fortification with other micronutrients, and the vast majority of iron fortification programs also fortify foods with folic acid.9

What is the evidence of effectiveness?

Below, we discuss the evidence for the impact of iron fortification on the following outcomes:

• Anemia and iron deficiency. There is reasonably strong evidence that fortification of staple foods leads to decreases in iron deficiency and anemia in the general population. The effect of iron supplementation is consistent with these positive effects but larger in magnitude.
• Cognitive outcomes. We did not identify any studies that measure the effect of iron fortification on cognitive outcomes. To estimate the effect of iron fortification on cognitive outcomes, we rely on evidence for the effect of iron supplementation on cognitive outcomes. We then adjust the effects found in these studies on supplementation downward to reflect the smaller effect of fortification, which provides a lower dosage of iron than supplementation, on iron deficiency. There is moderate evidence for a short-term effect of iron supplementation on cognitive outcomes for school-age children and evidence for no effect of iron supplementation on cognitive outcomes for children under 3. Evidence for the effect of iron supplementation on cognitive outcomes for adults is more limited, but our best guess is that the effect is similar in magnitude to the effect for school-age children. These estimated effects are concentrated among individuals with anemia at baseline.
• Income. We did not review any evidence directly linking iron supplementation and adult income for individuals receiving iron supplementation either as children or adults.
• Additional benefits. There is some evidence that iron supplementation for pregnant women leads to improved birth outcomes and long-term cognitive effects on children born to these women, once they enter school.
• Offsetting/negative effects. Iron fortification has been hypothesized to have a number of potential adverse effects, including increased risk of malaria, increased risk of non-malarial infections, iron overload and gastrointestinal effects. Our best guess is that these effects are small in magnitude, but we have some uncertainty about this.

In our cost-effectiveness analysis, we model the primary benefits of iron fortification as coming from its impact on (1) morbidity associated with iron deficiency and anemia and (2) adult income. (To measure effects on income, we rely on estimates from cross-sectional studies that relate IQ to income increases.) We do not include additional benefits or offsetting/negative effects.

We discuss evidence for iron fortification’s impact on each of these outcomes in more detail below.

Effect on iron deficiency and anemia

There is reasonably strong evidence that fortification of staple foods leads to decreases in iron deficiency and anemia in the general population. This evidence is corroborated by evidence on the impact of iron supplementation, though effects are larger for iron supplementation than fortification.10 This is expected because iron-fortified food generally has lower doses of iron than doses provided with iron supplements.11

We use the effects of iron fortification on iron deficiency and anemia in our cost-effectiveness analysis to assess morbidity gains from iron fortification for children. We also use the relative effects of iron supplementation vs. iron fortification on iron deficiency to extrapolate the effects of iron supplementation on cognitive outcomes to those of iron fortification.

Effect of iron fortification on iron deficiency and anemia

In our assessment of the effect of iron fortification on iron deficiency and anemia, we rely heavily on Gera, Sachdev, and Boy 2012, a meta-analysis of randomized and quasi-randomized trials of the effect of iron fortification on measures related to iron deficiency and anemia.12 The meta-analysis finds individuals in iron fortification treatment groups were 41% less likely to have anemia (95% confidence interval 29%-52%, 33 trials, n = 13,331)13 and 52% less likely to have iron deficiency (95% CI 38%-62%, n = 5,765), compared to individuals in control groups.14 Both child and adult participants were included among the studies included in the review.15

We have not thoroughly vetted this meta-analysis or reviewed any of the component studies. We also have not taken any effort to understand the quality of component studies (particularly quasi-randomized trials), variation in fortification interventions used, treatment populations included (i.e., children, pregnant women, adult males), or baseline iron deficiency or anemia rates.16 However, because of the large number of included studies, the highly plausible biological mechanism (see section above) and corroborating evidence from iron supplementation (see section below), we consider the evidence for iron fortification's impact on iron deficiency and anemia to be strong.

Effect of iron supplementation on iron deficiency and anemia

There is reasonably strong evidence for the impact of iron supplementation on iron deficiency and anemia for children. This is based on the following three meta-analyses, which we have not reviewed in depth.

• Low et al. 2013 is a Cochrane Collaboration meta-analysis of randomized and quasi-randomized controlled trials on the effect of daily iron supplementation for children age 5-12.17 It reports that children who received daily iron supplementation were 50% less likely to be anemic (95% CI 36%-61%, 7 trials, n = 1,763) and 79% less likely to have iron deficiency (95% CI 37%-93%, 4 trials, n = 1,020).18
• De-Regil et al. 2011 is a Cochrane Collaboration meta-analysis of randomized and quasi-randomized controlled trials of the effect of intermittent iron supplementation for children under 12.19 It reports that children who received intermittent supplementation were 49% less likely to be anemic (95% CI 28%-63%, 10 studies, n = 1,824) and 76% less likely to have iron deficiency (95% CI 9%-94%, 3 studies, n = 431).20
• Pasricha et al. 2013 conducts a meta-analysis of RCTs and estimates that children aged 4-23 months are 39% less likely to suffer from anemia (95% CI 26%-50%, 17 studies, n = 4,825) and 70% less likely to suffer from iron deficiency (95% CI 40%-85%, 9 studies, n = 2,464) after receiving iron supplementation.21

Evidence for adults is more limited and appears to focus primarily on pregnant women. Peña-Rosas et al. 2015, a Cochrane Collaboration meta-analysis, finds that daily oral iron supplementation of pregnant women reduces maternal anemia at term by 70% (54%-81%, 14 trials, n = 2,199) and iron deficiency at term by 57% (95% CI 34%-73%, 7 trials, n = 1,256).22 We have not reviewed this evidence in any depth. We were unable to find a meta-analysis that focuses on effects for non-pregnant adults.

Effect on cognitive outcomes

We have not identified any studies measuring cognitive effects of iron fortification on children or adults. As a result, the evidence in this section focuses on the effect of iron supplementation.

Overall, there is moderate-quality evidence that iron supplementation of primary-school-aged children (5-12 years) has positive effects on cognitive development in the short run for children who are anemic at baseline. There is no strong evidence of cognitive benefits for children under the age of 3 years in studies we identified.

Compared to the evidence for children, the evidence for adults is much more limited and the quality of randomized controlled trials (RCTs) varies widely. The available evidence does indicate a benefit of similar magnitude to the effect for children, but we have higher uncertainty about this effect.

We have not reviewed any studies measuring longer-term effects on cognitive outcomes for children or adults receiving supplementation.

In our cost-effectiveness model, we model the benefits of increases in cognitive skills as coming through potential effects on adult income (see below).

Short-run cognitive benefits for primary-school-aged children

Our assessment of short-run cognitive benefits to primary-school-aged children comes from Low et al. 2013, a Cochrane Collaboration meta-analysis of the effects of iron supplementation on cognitive development of children aged 5-12 years. The meta-analysis shows that children who had anemia at baseline had an increase in IQ of 4.55 points (95% CI 0.16-8.94, 3 studies, n = 186), compared to children in the control group. Although we are often skeptical of subgroup analyses, in this case, it has a clear and compelling biological rationale. Still, the small sample size for this sub-group analysis (186) gives us some uncertainty about the effect. There was no statistically significant effect overall in the full sample (not accounting for anemia status).23

We view this meta-analysis as moderate quality. Our in-depth assessment of Low et al. 2013 is here.

Short-run cognitive benefits for children under 3 years of age

There is no strong evidence of cognitive benefits for children under the age of 3 years in studies we identified.

Our review of evidence concerning short-run cognitive benefits of iron supplementation for children under 3 years of age is based on Wang et al. 2013.24

Wang et al. 2013 is a Cochrane Collaboration meta-analysis of the short-run effects of iron therapy on psychomotor development and cognitive function in iron deficient anemic children less than three years of age.25 The authors do not find evidence of positive effects of iron therapy on cognitive function in five studies in which outcome assessments were carried out between five and 11 days after commencement of therapy.26 However, the two included studies that collected data more than 30 days after commencement of therapy showed some evidence of positive effects on cognitive development.27

We do not have a good understanding of the tests used, how reliable they are as indicators of cognitive development of infants, or over what time period it is reasonable to expect effects of iron supplementation to show up in these tests. The authors note that the trials included in the review are at unclear risk of bias and that the effect of longer-term treatment remains unclear, with a need for more studies with long-term follow up.28

Short-run cognitive benefits for adults

Compared to the evidence for children, the evidence for iron supplementation in adults is much more limited (and the quality of RCTs varies widely), but it does suggest a benefit overall. We are uncertain whether this benefit is the same size in children and adults, but some evidence leads us to expect that it may be similar. Using a weighted average of available estimates that includes the estimates in children, we tentatively estimate that iron supplementation in adults with iron deficiency increases IQ by 0.35 standard deviations. We discuss this evidence in more detail here. However, these views are preliminary, and if we consider recommending significant additional funding to iron fortification programs, we would return to this evidence and consider it more carefully.

Effects on income

We have not reviewed any studies that assess the impact of iron supplementation or fortification on adult income.29 As a result, our cost-effectiveness analysis models this impact based on associations between cognitive skills and income in cross-sectional studies.30

Additional benefits

We also reviewed evidence for benefits of iron fortification due to improved birth outcomes and long-term benefits for children of mothers who received prenatal iron supplementation. We do not currently include these benefits in our cost-effectiveness model. While the evidence we reviewed does suggest there are some additional benefits through these two channels, we guess that the effects would not substantially change the cost-effectiveness of iron fortification in our model.

Effects on birth outcomes

There is moderate evidence that daily oral iron supplementation of pregnant women results in improved birth outcomes, such as reduced preterm birth and increased birthweight. Our main source of evidence for these effects is Peña-Rosas et al. 2015, a Cochrane Collaboration systematic review and meta-analysis of 44 RCTs.31

Peña-Rosas et al. 2015 estimates that women receiving iron supplementation are 16% less likely to deliver a baby with a weight less than 2500g (95% CI -3%-31%), 7% less likely to have a preterm birth (95% CI -3%-16%), and 49% less likely to have a very premature birth (95% CI 9%-71%).32 The authors also estimate that mothers receiving iron supplementation give birth to heavier babies on average but do not find evidence of a reduction in neonatal death, congenital anomalies, or maternal death.33

Long-run cognitive benefits for children of mothers receiving fortification

There is evidence from one RCT in rural Nepal that prenatal iron supplementation for mothers leads to improved cognitive outcomes for children.

We identified two studies with long-run follow-up data on cognitive development of children whose mothers were given iron supplements during pregnancy.

• Christian et al. 2010 is a long-run follow up of an RCT in rural Nepal, and finds evidence of positive effects of prenatal iron supplementation on cognitive development of children aged 7-9 years.34
• Zhou et al. 2006 is a long-run follow up of an RCT of non-anemic pregnant women in Australia. It does not find any effect of iron supplementation on IQ of children at age four.35

Although the results of Zhou et al. 2006 contrast with the findings of Christian et al. 2010, note that the studies were carried out in very different settings (Christian et al. 2010 in rural Nepal and Zhou et al. 2006 in Adelaide, Australia). In particular, all women recruited for Zhou et al. 2006 were non-anemic at baseline, and it’s likely that rates of iron deficiency and anemia were higher among women in the Christian et al. 2010 study.36 This is consistent with the findings of Low et al. 2013 (discussed above) that iron supplementation only seems to benefit people who are anemic at baseline.

Potential offsetting/negative impacts

Iron fortification has been hypothesized to have a number of potential adverse effects, which we describe below. Our best guess is that these effects are small in magnitude, but we have some uncertainty about this.

We exclude these offsetting effects from our cost-effectiveness analysis.

Increased risk of malaria

Our best guess is that iron supplementation and fortification do not have a meaningful effect on malaria risk.

Some researchers have hypothesized that iron status may be an important determinant of infection risk, particularly that low iron status may protect against malaria. Thus, they hypothesize that iron supplementation and fortification may increase the risk of malaria.37

A Cochrane review, Neuberger et al. 2016, concludes that iron supplementation leads to a slight decrease in the risk of malaria. Our preferred pooled estimate from Neuberger et al. 2016 finds that the relative risk of clinical malaria following iron supplementation is 0.97 (i.e., a 3% lower risk, 95% CI 0.91 to 1.03).38 However, our uncertainty is greater than that implied by Neuberger et al. 2016’s confidence interval for this pooled estimate. Therefore, we use a wider confidence interval (95% CI 0.84 to 1.10) that includes the possibility of larger negative effects of iron.39

Two observations continue to give us pause. The first is the inverse association between iron status and malaria infection risk in many observational studies. The second is the findings of Sazawal et al. 2006, a large RCT suggesting that iron plus folic acid supplementation leads to excess hospitalization or mortality risk in a malaria-endemic region with malaria treatment services.40 It remains possible that iron plus folic acid supplementation has larger adverse effects on malaria risk than either alone.

We have described our reasoning in more detail in our analysis of iron and infection and follow-up to that analysis.

Increased risk of non-malarial infections

Researchers also hypothesize that low iron status may protect against other infections beyond malaria.

In a medium-depth literature search, we identified three meta-analyses of RCTs examining the impact of iron supplementation on the risk of non-malaria infection (Gera and Sachdev 2002, Pasricha et al. 2013, and Neuberger et al. 2016). These meta-analyses suggest that iron supplementation can increase the risk of gastrointestinal illness such as diarrhea and vomiting, yet iron supplementation appears to have little or no effect on the overall rate of illness or on other prevalent categories of non-malaria illness including respiratory tract infections. We have not examined the studies underlying these meta-analyses so these conclusions remain somewhat uncertain.

The evidence base for fortification is considerably smaller than that for supplementation, suggesting that it may be more uncertain, and supplementation only had an impact on the risk of gastrointestinal illness. Given the lower doses of iron used in fortification, it seems unlikely that fortification would cause adverse effects not observed for supplementation. Overall, we do not believe current evidence provides compelling reasons to believe that iron fortification increases the risk of non-malaria infections.

We have described our analysis and conclusions in more detail here.

Iron overload

Iron fortification and supplementation programs can carry a risk of iron overload. Iron overload occurs when excess amounts of iron are absorbed or stored in the body and can lead to tissue damage in the liver, pancreas, and endocrine organs for individuals with heritable iron metabolism disorders.41 We have not come across any evidence on the prevalence and effects of iron overload in our reviews of the literature and are uncertain about how common this is. Our guess is that cases of severe iron overload are rare in iron fortification programs because the effective dose is far lower than in most supplementation programs. However, we would consider investigating iron overload in more depth if we recommended additional funding to iron fortification programs.

Iron supplementation and fortification may lead to high hemoglobin levels, which can result in negative birth outcomes.42 Peña-Rosas et al. 2015 finds weak evidence that pregnant women receiving daily oral iron supplementation are more likely to have hemoglobin levels greater than 130 g/L.43 However, the authors also find that iron supplementation is associated with improved birth outcomes, as discussed above.

Gastrointestinal side effects

There is moderate evidence that daily oral iron supplementation results in adverse side effects for menstruating women. Low et al. 2016, a Cochrane Collaboration systematic review and meta-analysis of 67 RCTs, finds evidence that women receiving iron supplementation were more likely to suffer from gastrointestinal side effects, loose stools or diarrhea, hard stools or constipation, and abdominal pain.44 Other systematic reviews find only very weak evidence of side effects for pregnant women and no evidence of side effects for children aged 5-12 years.45

We are uncertain whether these side effects are likely to have a significant effect on individuals' welfare, although they may represent a significant negative overall effect of a fortification program if they are widespread.

How cost-effective is it?

Based on a cost-effectiveness model we put together in November 2019 and updated with our most recent moral weights as of February 2021, we estimate that iron fortification is in the range of cost-effectiveness of the opportunities that we expect to direct marginal donations to (about 10x cash or higher, as of 2021).46 However, this estimate relies on several assumptions about which we have a high degree of uncertainty.

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.

Key uncertainties for the cost-effectiveness analysis are:

• Extrapolating increases in cognitive outcomes from iron supplementation to increases in cognitive outcomes from iron fortification. Because we did not find any evidence showing the effect of iron fortification on cognitive outcomes, we rely on estimates of the effect of iron supplementation on cognitive outcomes. We then adjust these estimates downward based on the ratio of the effect of fortification on iron deficiency to the effect of iron supplementation on iron deficiency. We have high uncertainty about the appropriateness of this adjustment.
• Extrapolating increases in cognitive outcomes to increases in income. Because we did not review any evidence showing the effect of iron fortification or supplementation on income, we rely on estimates from cross-sectional studies that relate IQ to income increases. We have a high uncertainty about this approach and the effect of iron on income. For children especially, these estimates rely on assumptions about the persistence of any cognitive skill gains due to iron supplementation. These assumptions are currently best guesses and not grounded in any empirical studies.
• Cost of iron fortification. Our current estimates of the cost of iron fortification come from two iron fortification charities we have investigated recently, but our impression is that costs of fortification will be highly dependent on the charity and setting.

We discuss key uncertainties and additional questions for further investigation in more detail below.

Is there room for more funding?

We have provided incubation grants to Fortify Health to support its whole wheat flour iron fortification program over two years in Maharashtra and West Bengal, India, and to Evidence Action to scope a project to provide technical assistance for the Indian government's work on large-scale school-based iron and folic acid supplementation targeting children and adolescents. We are aware of several organizations that we believe provide iron fortification programs, including some of our standout charities, and have conducted a review of some of them.47 However, we have not undertaken a comprehensive review of funding opportunities for iron fortification, and it is possible there are other organizations implementing iron fortification interventions that we have not listed.

Key questions for further investigation

• How does taking into account study quality for impact of iron supplementation and fortification on anemia-related outcomes influence effect size estimates? Studies on the impact of iron supplementation and fortification on anemia-related outcomes find that the size of impact varies based on study quality, and overall quality of studies in general seems to be low.48 The current cost-effectiveness analysis takes estimates at face value, without thorough consideration of quality. Incorporating quality into effect size calculations (e.g., using effect sizes from high-quality studies) may lead to downward estimates in effectiveness.
• How should we incorporate evidence from effectiveness (rather than efficacy) trials and evidence from recent trials of fortification of salt in India? Our impression is that the available evidence for fortification is based on tightly controlled, “efficacy” trials, rather than studies that aim to simulate the impact of fortification programs in the real-world, similar to those we might fund. There is at least one meta-analysis that compares findings from efficacy vs. effectiveness trials of iron fortification and finds that effect sizes are lower for the effectiveness trials (though the number of studies is extremely small).49 Additionally, a series of recent studies, described in Banerjee, Barnhardt, and Duflo 2018, find disappointing impacts of double fortification of salt programs in India, including some evidence that take-up of double fortified salt may fall over time.50
  If we investigate specific iron fortification charities, we plan to incorporate adjustments to the cost-effectiveness analysis to capture some mediating factors (e.g., ensuring costs reflect low take-up rates), but if there are other factors driving lower effects in effectiveness vs. efficacy trials, this would cause us to overestimate the effect of iron fortification programs.
• How serious are the effects of anemia on welfare, and how would effects change if we used anemia (rather than iron deficiency) as the main outcome for iron morbidity in cost-effectiveness analysis? In our current cost-effectiveness analysis, nearly two thirds of benefits come from anemia morbidity averted.51 This is based on Global Burden of Disease (GBD) data on years lived with disability (YLDs) due to iron deficiency. We have not reviewed how GBD calculates YLDs and therefore have high uncertainty about these parameters.52 An alternative approach to estimating morbidity effects would be to calculate the impact of iron fortification in mild, moderate, and severe anemia. The effects of iron fortification on moderate and severe cases of anemia are likely to be one of the most important effects of a fortification program, so the weight we place on reducing these cases is important for our assessment of how promising a program is likely to be. If fortification has differential effects on anemia based on severity and if morbidity varies based on severity, this could affect our estimated morbidity effects. We have not prioritized conducting an alternative cost-effectiveness analysis based on anemia, rather than iron deficiency, but may do so in the future. Finally, the value we place on anemia morbidity averted depends on our moral weights associated with one YLD. We may revisit this parameter in the near future, which may lead to changes in cost-effectiveness of iron fortification.
• Are there long-run cognitive benefits of iron fortification, how large are they, and what effect do they have on other outcomes? There is moderate evidence that iron supplementation improves the performance of school-aged children in cognitive tests in the short run. However, there is very little evidence on whether there are long-run cognitive benefits of iron supplementation or fortification. While our best guess is that 33% of cognitive skill gains from iron fortification persist into adulthood, this is highly speculative, and we do not have any evidence for this long-term effect.53 We also do not have a good understanding of how reliable the tests used in these studies are (in younger or older children); the length of time after which we should expect any cognitive benefits from iron supplementation or fortification to show up in these tests; and whether increased iron leads to long-term gains in income, either through improvements in cognitive skills or other mechanisms.54
• How large is the effect of iron fortification on adult income, and what drives this effect? Our cost-effectiveness model assumes iron fortification increases adult income through improvements in cognitive skills for children and adults. To translate gains in cognitive skills to gains in income, we rely on estimates from cross-sectional studies that relate IQ to income increases. It is also possible iron supplementation and fortification may lead to increases in income through improvements in physical productivity, in addition to cognitive gains. We have not undertaken a thorough scan of studies that try to estimate the effect of iron supplementation or fortification on income or productivity directly (i.e., by comparing income or productivity between individuals receiving iron supplementation or fortification to individuals not receiving iron supplementation or fortification), and it is possible that these studies could change our best guess of the effect of iron fortification on adult income. Currently, roughly one third of the cost-effectiveness of iron fortification comes from its impact on adult income,55 so adjustments to these parameters may have a moderate effect on our cost-effectiveness estimates.56
• How might the impact of iron fortification and supplementation in settings where fortification is implemented in the future differ from settings in studies? Effects on iron deficiency might differ for several reasons:
  1. The quantity of iron intake from fortified products consumed in the academic studies might be different to the level in future programs. This could be due to the amount of iron added to fortify foods or due to differences in relative iron content of iron-fortified foods and foods individuals would consume if iron-fortified foods weren’t available.
  2. Conditional on the quantity of iron intake, the amount of iron absorbed might differ between the meta-analysis and future programs, for several reasons:
     • Different fortification compounds and vehicles may have different absorption rates.
     • Certain substances inhibit the absorption of iron (e.g. tannins and phytates), and certain substances enhance the absorption of iron (e.g. ascorbic acid - i.e. vitamin C). The beneficiaries of future programs might consume different levels of inhibitors/enhancers alongside the fortified foods compared to the recipients in the academic studies.
     • It is possible that the level of absorption also depends on baseline levels of iron in the blood (absorption rates may be higher when initial iron levels are lower).
     • It is possible that the level of absorption also depends on how consistently iron-fortified food is consumed (i.e., daily vs. more intermittently).
  3. Conditional on the amount of iron absorbed, it is possible that iron has a greater effect on health outcomes (including averting risk of iron deficiency) for a lower initial iron status.

  Additional mediators mentioned in the literature include the effect of fortificants on taste and shelf life of fortified food, both of which may affect consumption of iron-fortified foods when made available.57 Plate wastage may also differ across contexts and mediate the effects of iron fortification.

• How would iron-fortified food be distributed across different individuals? Impacts of iron fortification and supplementation may vary by age, gender and other characteristics (e.g., baseline iron deficiency). The effectiveness of iron fortification will depend on whether fortified food is given to groups that have higher or lower benefits from iron fortified food. It is possible that the distribution of flour consumption across beneficiaries would be uneven in future implementation, such that a non-negligible portion of, say, iron-fortified flour is consumed by individuals who have already consumed their optimal dose of iron and so no longer receive additional health benefits.58
• Is the impact of iron-fortified food linear or nonlinear? We have not deeply investigated the shape of the relationship between iron absorption and health benefits (e.g., whether health benefits increase linearly with iron absorption, or whether absorption past a certain level confers diminishing marginal benefits). If the relationship between iron intake and health benefits is indeed concave in this way, it seems possible that some initially iron deficient people might consume a sufficiently large amount of iron that they are receiving limited (or no) benefits beyond a certain point, which would justify a downwards adjustment to our cost-effectiveness estimate. However, a concave relationship between iron intake and health benefits would also lead us to expect disproportionately larger health benefits (per unit of iron intake) for individuals who are consuming less than the average quantity of iron. This would suggest an upwards adjustment to our cost-effectiveness estimate. Determining how a) the drop-off in health benefits for people consuming more iron than average compares to b) the disproportionately greater health benefits for people consuming less iron than average, would require more detailed modeling than we've yet done of the actual distribution of fortified food consumption and of the shape of the relationship between iron intake and health benefits. Additionally, it seems possible that consumers do not purchase and consume all their food as fortified (if, e.g. they purchase from multiple markets, some of which may not stock fortified foods). This would mean that the average consumption per person is less than our model assumes, but that a proportionally larger number of beneficiaries are reached. Given a concave relationship between consumption and health benefits, this factor would also lead us to expect greater net health benefits overall.
• How appropriate is our adjustment for the relative benefits of fortification vs. supplementation in measuring cognitive effects? Because we did not identify any studies that measure the effect of iron fortification in cognitive outcomes, we use studies measuring the effect of supplementation on cognitive outcomes. We then adjust the effects found in these studies downward to reflect the smaller effect of fortification, which provides a lower dosage of iron than supplementation, on iron deficiency. The relative effect of fortification vs. supplementation on iron deficiency in meta-analyses we use in our cost-effectiveness analysis is 66%.59 However, the ratio of iron in fortification vs. supplements in those meta-analyses is just 16%.60 This may reflect non-linearities in effects of iron on health outcomes for individuals, but it’s also possible that we are overestimating the effect of fortification on cognitive outcomes and should adopt a lower conversation factor when translating the effects of supplementation on cognitive outcomes to fortification.
• What is the cost of iron fortification? Because our impression is that the cost of iron fortification per person will be specific to charity and context, we would plan to undertake a more thorough investigation of cost on a case-by-case basis if we review potential iron fortification charities.
• How would incorporating additional benefits of iron fortification influence cost-effectiveness? As discussed above, there is some evidence that iron may improve birth outcomes and long-term benefits for children of mothers who received prenatal iron supplementation. We do not currently include these benefits in our cost-effectiveness model. If they were included, they would likely increase our assessment of the cost-effectiveness of iron fortification.
• How would incorporating offsetting/negative effects of iron influence cost-effectiveness? As discussed above, iron fortification may lead to negative effects, such as increased risk of infection, iron overload and gastrointestinal side effects. We do not currently include these negative effects in our cost-effectiveness model. If they were included, they would likely decrease our assessment of the cost-effectiveness of iron fortification.
• Does fortification with additional nutrients provide additional impacts? Foods fortified with iron may also often be fortified with folic acid or B12, which may confer additional benefits. The current cost-effectiveness analysis excludes any additional benefits.
• Does effectiveness of iron fortification depend on worm prevalence and access to deworming drugs? Some reviews have suggested that hookworm and schistosomiasis can lead to anemia.61 This could suggest iron supplementation would be less effective in areas with access to deworming treatment. However, our review of deworming evidence suggests the impact of deworming on anemia is likely to be small.62
• Do income effects vary for men vs. women? Income effects may vary if (1) impact of fortification on cognitive outcomes is different for women and men and/or (2) labor market return to improved cognitive skill is different for women and men. We have not reviewed the evidence for these differential effects in any depth.

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• 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 7.

• 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 7.

• 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 7.
  • "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 6.

• 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 7.
  • "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 7.

• 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 6.
  • "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 7.

• 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.
  • "WHO has developed a comprehensive package of public health measures addressing all aspects of iron deficiency and anaemia. This package is being implemented in countries with high levels of iron deficiency and anaemia, malaria, helminth infections and schistosomiasis.
    • Increase iron intake. Dietary diversification including iron-rich foods and enhancement of iron absorption, food fortification and iron supplementation.
    • Control infection. Immunization and control programmes for malaria, hookworm and schistosomiasis.
    • Improve nutritional status. Prevention and control of other nutritional deficiencies, such as vitamin B12, folate and vitamin A."

    @WHO, micronutrient deficiencies@.

• 7
  • “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.
  • “Strategies to improve iron intake and alleviate iron-deficiency anaemia include mass and point-of-use fortification of foods with iron; dietary diversification to increase iron intake, absorption and utilisation; iron supplementation; and antihelminthic treatment.” Low et al. 2016, Pg 6.

• 8
  • "Mass targeted or market-driven food fortification with iron has been used with various vehicles: soy sauce, fish sauce, salt, milk, sugar, beverages, bouillon cubes, maize flour, and complementary foods (WHO/FAO 2006)...Since wheat flour is consumed in large quantities and throughout entire populations, it is by far the most commonly used medium in large-scale iron fortification programmes. There are over 79 countries with legislation to fortify wheat flour countries produced in industrial mills with vitamins and minerals. All the mandatory countries fortify wheat flour with at least iron and folic acid except Australia which does not include iron, and Congo, Venezuela, the United Kingdom, and the Philippines which do not include folic acid (FFI 2014)." Peña-Rosas et al. 2014, Pg 3.
  • "Fortification of maize flour and other sub-products produced from maize has been implemented in several settings around the world. Although there is less experience with fortification of maize flour than for wheat flour, mass fortification of maize flour with iron has been a reality for many years in several countries in the Americas (Dary 2002a; Garcia-Casal 2002) and Africa (voluntary fortification has been already introduced in Ghana, Kenya, Malawi and Mauritania, with mandatory fortification in South Africa (FFI 2012)." Pasricha et al. 2012, Pg 4.
  • Fortification of rice and seasonings is currently less common than wheat flour, though it is seen as promising, particularly in countries where rice is the dominant staple food crop:
    • "Rice is a globally produced, milled and traded staple food with an annual production and consumption worldwide of about 450million metric tons. It is the dominant staple food crop of around three billion people worldwide, providing up to 50% to 60% of their daily energy and protein intake (IRRI 2010)." Ashong et al. 2012, Pg 4.
    • "Wheat and maize flour fortification with iron alone, or in combination with folic acid and other micronutrients, has been implemented in more than 50 countries (CDC 2008; WHO 2009b) and is showing promising results in reducing anaemia and neural tube defects. Based on this experience, an increasing number of countries across the world are rapidly adopting fortification of rice as a means to fight malnutrition. Mandatory fortification of rice has been adopted in some countries, such as the Philippines, Costa Rica, Papua and Nicaragua (GAIN 2010). Fortified rice is sold in China using a multi-micronutrient formula and in Japan enriched rice has been on the market since 1981. The United States has a mandatory food standard for 'enriched rice', prescribing levels of thiamin, niacin, riboflavin, folic acid and iron to be added to rice for enrichment. Although this requirement only applies in order for rice to be labelled as 'enriched; (FDA 2001), 70% of the rice eaten in that country is enriched or fortified (American Rice Inc. 2004; A2Z Project 2008). In India, Brazil and Colombia, fortified rice is currently being distributed through public safety net programs." Ashong et al. 2012, Pg 6.
    • "The selection of the food for a fortification programme requires consideration of both dietary habits of the target population and the cost of the intervention. In some situations, fortification of condiments or seasonings (e.g. soy and fish sauces, or curry powder) may be a useful alternative if they are consumed consistently by most of the population, as is the case in many Asian and African countries, developed or not." Self et al. 2012, Pg 2.

• 9
  • Iron fortification can be, and often is, accompanied by other micronutrients, that may (i.e. folic acid, vitamin B12 or vitamin C) or may not enhance the effectiveness of the intervention (Zimmermann 2007). Peña-Rosas et al. 2014, Pg 3.
  • "There are over 79 countries with legislation to fortify wheat flour countries produced in industrial mills with vitamins and minerals. All the mandatory countries fortify wheat flour with at least iron and folic acid except Australia which does not include iron, and Congo, Venezuela, the United Kingdom, and the Philippines which do not include folic acid (FFI 2014)." Peña-Rosas et al. 2014, Pg 3.

• 10

  We also conducted a superficial review of a meta-analysis by De-Regil, Jefferds, and Peña‐Rosas 2017 on the effect of point-of-use iron fortification with micronutrient powders among preschool and school-age children. The meta-analysis also finds similar reductions in anemia prevalence and iron deficiency. We view this as providing further general support for the effect of iron on anemia-related outcomes, though we have not reviewed or vetted this meta-analysis or the component studies.

  • “In comparison with receiving no intervention or a placebo, children receiving iron‐containing MNP for point‐of‐use fortification of foods had lower risk of anaemia prevalence ratio (PR) 0.66, 95% confidence interval (CI) 0.49 to 0.88, 10 trials, 2448 children; moderate‐quality evidence) and iron deficiency (PR 0.35, 95% CI 0.27 to 0.47, 5 trials, 1364 children; moderate‐quality evidence) and had higher haemoglobin (mean difference (MD) 3.37 g/L, 95% CI 0.94 to 5.80, 11 trials, 2746 children; low‐quality evidence).” De-Regil, Jefferds, and Peña‐Rosas 2017, Pg 2.

• 11

  ”Aggregating annually, it appears as though on average roughly 12,269 mg of iron is delivered across the year in the iron supplementation studies, compared to 1,903 mg in the Gera et al. fortification meta-analysis.” GiveWell’s write-up on the adjusted estimate of effect size for iron fortification in Fortify Health's program.

• 12
  • “The predefined criteria for inclusion were randomized placebo-controlled trials with variations in design, including random allocation of individuals or clusters; multi-arm trials; factorial trials; and crossover trials for the first period of measurement only. Quasirandomized controlled trials were also eligible for inclusion.” Gera, Sachdev, and Boy 2012, Pg 310.
  • “The primary outcomes evaluated included 1) hemoglobin (g/dL), 2) anemia (%, as defined in individual trials), 3) serum ferritin (μg/L), 4) iron deficiency (%, as defined in individual trials), and 5) serum or plasma zinc (μmol/L).” Gera, Sachdev, and Boy 2012, Pg 310.

• 13
  • “Data pertaining to anemia were available from 33 trials conducted on 7606 subjects in the fortification group and 5725 control subjects at the end of the intervention period. The trial definition of anemia, which invariably accounted for age and sex differences for defining hemoglobin cutoff concentrations, was used for pooling the RR by random-effects model. A significantly lower RR of remaining anemic was observed at the end of fortification, namely 0.59 (95% CI: 0.48, 0.71; P < 0.001; I2 = 89.5%, Q test for heterogeneity = 304.94, P < 0.001).” Gera, Sachdev, and Boy 2012, Pg 313.
  • Sample size of 13,331 equals 7,606 plus 5,725.
  • 41% equals 1 - 0.59. For the 95% CI: 1 - 0.71 = 0.29; 1 - 0.48 = 0.52.

• 14
  • “Data pertaining to iron deficiency were available from 21 trials conducted on 3234 subjects in the intervention group and 2531 control subjects at the end of the intervention period. A significantly lower risk of being iron deficient was found (RR: 0.48, random-effects model; 95% CI: 0.38, 0.62; P < 0.001; I2 = 84.6%, Q test for heterogeneity = 130.25, P < 0.001).” Gera, Sachdev, and Boy 2012, Pg 313.
  • Sample size of 5,765 equals 3,234 plus 2,531.
  • 52% equals 1 - 0.48. For the 95% CI: 1 - 0.62 = 0.38; 1 - 0.38 = 0.62

• 15

  “Almost two-thirds of the analytic components were conducted exclusively in children (60 of 85), whereas the remaining also included adults (25 of 85).” Gera, Sachdev, and Boy 2012, Pg 311.

• 16

  We also identified four additional meta-analyses: Das et al. 2013, Hess, Tecklenburg, and Eichler 2016, Athe, Rao, and Nair 2013 and Garcia-Casal et al. 2018. Our impression is that they find effects broadly consistent with Gera, Sachdev, and Boy 2012, but we have not prioritized reviewing these additional meta-analyses in any depth.

• 17

  “We searched electronic databases (including MEDLINE and Embase) and other sources (July 2013) for randomized and quasi-randomized controlled trials involving daily iron supplementation in children aged 5–12 years. We combined the data using random effects meta-analysis.” Low et al. 2013, abstract.

• 18
  • Low et al. 2013, Pg E798, Table 3.
  • 50% equals 1 - 0.50. For the 95% CI: 1 - 0.64 = 0.36; 1 - 0.39 = 0.61.
  • 79% equals 1 - 0.21. For the 95% CI: 1 - 0.63 = 0.37; 1 - 0.07 = 0.93.

• 19

  “Randomised and quasi-randomised trials with either individual or cluster randomisation. Participants were children under the age of 12 years at the time of intervention with no specific health problems. The intervention assessed was intermittent iron supplementation compared with a placebo, no intervention or daily supplementation.” De-Regil et al. 2011, Pg 1.

• 20
  • De-Regil et al. 2011, Pg 4, Table: Summary of Findings for the Main Comparison.
  • 49% equals 1 - 0.51. For the 95% CI: 1 - 0.72 = 0.28; 1 - 0.37 = 0.63.
  • 76% equals 1 - 0.24. For the 95% CI: 1 - 0.91 = 0.09; 1 - 0.06 = 0.94.

• 21
  • “Of 9533 citations identified by the search strategy, 49 articles from 35 studies were eligible; these trials included 42,306 children. Only nine studies were judged to be at low risk of bias. In children receiving iron supplements, the risk ratio for anaemia was 0.61 (95% CI 0.50 to 0.74; 17 studies, n=4825), for iron deficiency was 0.30 (0.15 to 0.60; nine studies, n=2464), and for iron deficiency anaemia was 0.14 (0.10–0.22; six studies, n=2145)." Pasricha et al. 2013, Pg e77.
  • 39% equals 1 - 0.61. For the 95% CI: 1 - 0.74 = 0.26; 1 - 0.50 = 0.50.
  • 70% equals 1 - 0.30. For the 95% CI: 1 - 0.60 = 0.40; 1 - 0.15 = 0.85.

• 22

  “Preventive iron supplementation reduced maternal anaemia at term by 70% (risk ratio (RR) 0.30; 95% confidence interval (CI) 0.19 to 0.46, 14 trials, 2199 women, low quality evidence), iron‐deficiency anaemia at term (RR 0.33; 95% CI 0.16 to 0.69, six trials, 1088 women), and iron deficiency at term by 57% (RR 0.43; 95% CI 0.27 to 0.66, seven trials, 1256 women, low quality evidence).” Peña-Rosas et al. 2015, Pgs 1-2.

• 95% CI for maternal anemia at term: 1 - 0.46 = 0.54; 1 - 0.19 = 0.81.
• 95% CI for iron deficiency at term: 1 - 0.66 = 0.34; 1 - 0.27 = 0.73.

• 23

  “The most commonly reported global cognitive score was age-adjusted IQ. There was no overall benefit of iron supplementation on IQ scores (MD 5.47, 95% CI −3.24 to 4.18; p = 0.2, I2 = 97%, 5 studies, n = 1874). However, our subgroup 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, I2 = 28%, 3 studies, n = 186) (Appendix 3).” Low et al. 2013, Pgs E793, E796.

• 24

  Our impression is that two other meta-analyses, Pasricha et al. 2013 and Sachdev, Gera, and Nestel 2005, also find only very weak evidence of short run positive effects of iron supplementation on cognitive function of infants, though we have not reviewed these in detail.

  • ”We systematically reviewed the evidence for benefit and safety of daily iron supplementation in children aged 4–23 months...We identified no evidence of difference in mental (MD 1·65, 95% CI –0·63 to 3·94; six studies, n=1093) or psychomotor development (1·05, –1·36 to 3·46; six studies, n=1086).” Pasricha et al. 2013, Pg e77.
  • ”There is no convincing evidence that iron treatment has an effect on mental development in children below 27 months of age or on motor development.” Sachdev, Gera, and Nestel 2005. Pg 117.

• 25
  • "Objectives: To determine the effects of iron therapy on psychomotor development and cognitive function in iron deficient anaemic children less than three years of age." Wang et al. 2013, Pg. 1.
  • "Iron therapy can be administered to children less than three years of age with IDA orally (ferrous sulphate, ferrous fumarate, sodium iron ethylenediaminetetra-acetate and ferrous gluconate), intravenously (iron dextran, iron sucrose and ferric carboxymaltose) or intramuscularly (iron dextran) (Goddard 2011)." Wang et al. 2013, Pg 5.
  • "The iron was given in oral form in four trials (Aukett 1986; Idjradinata 1993; Lozoff 1982; Walter 1989), intramuscularly in three (Driva 1985; Honig 1978; Kimmons [pers comm]), and both intramuscularly and orally in one (Lozoff 1987)." Wang et al. 2013, Pg 9.

• 26
  • "There is no convincing evidence that iron treatment of young children with IDA has an effect on psychomotor development or cognitive function within 30 days after commencement of therapy." Wang et al. 2013, Pg 2.
  • ”Short-term effects of iron therapy. We included six trials (Driva 1985; Honig 1978; Kimmons [pers comm]; Lozoff 1982; Lozoff 1987; Walter 1989) reported in eight papers (Driva 1985; Honig 1978; Kimmons [pers comm]; Lozoff1982; Lozoff 1987; Walter 1989), which examined the effects of iron therapy on measures of psychomotor development within 30 days of commencement of therapy. The trials involveed [sic] 225 children with IDA. As described above, data from one study could not be included in the meta-analysis (Lozoff 1987). All studies included measures of development before and between 5 to 11 days after commencement of therapy and used the Bayley Scales of Infant Development in the assessment of outcome.” Wang et al. 2013, Pg 11.

• 27
  • "Two studies, including 160 randomised children with IDA, examined the effects of iron therapy on measures of psychomotor development and cognitive function more than 30 days after commencement of therapy. One of the studies reported the mean number of skills gained after two months of iron therapy using the Denver Developmental Screening Test. The intervention group gained 0.8 (95% CI -0.18 to 1.78, P value = 0.11, moderate quality of evidence) more skills on average than the control group. The other study reported that the difference in pre- to post-treatment change in Bayley Scale PDI between iron-treated and placebo groups after four months was 18.40 (95% CI 10.16 to 26.64, P value < 0.0001; moderate quality evidence) and in Bayley Scale MDI was 18.80 (95% CI 10.17 to 27.43, P value < 0.0001; moderate quality evidence).” Wang et al. 2013, Pg 2.
  • ”The Bayley Scale consists of two, age-standardised subscales, MDI [Mental Development Index] and PDI [Psychomotor Development Index].” Wang et al. 2013, Pg 9.
  • The standard deviation for Bayley Scale MDI scores in the control groups in each study ranged from 3.2 to 15.1. See Analysis 1.2, Wang et al. 2013, Pgs 25-26.

• 28
  • "In general, the trials included in this review were at unclear risk of bias. The 'Risk of bias' tables in the Characteristics of included studies tables give a comprehensive description of the risk of bias for each study. Figure 2 provides review authors' judgements about each risk of bias item presented as percentages across all included studies. Figure 3 provides review authors' judgements about each risk of bias item for each included study." Wang et al. 2013, Pg 9.
  • "The effect of longer-term treatment remains unclear. There is an urgent need for further large randomised controlled trials with long-term follow-up." Wang et al. 2013, Pg 2.

• 29
  • We have identified one study, Thomas et al. 2003, which measures the effect of an iron supplementation program for adults in Indonesia, but we have not prioritized a thorough review of this study and have not incorporated it into our cost-effectiveness estimates.
  • This study could potentially update our view of the effect of iron fortification on income, as well as on iron deficiency and anemia for adult men.
  • Abstract: “Iron deficiency is widespread throughout the developing world. We provide new evidence on the effect of iron deficiency on economic and social prosperity of older adults drawing on data from a random assignment treatment-control design intervention. The Work and Iron Status Evaluation is an on-going study following over 17,000 individuals in Central Java, Indonesia. Half the respondents receive a treatment of 120 mg of iron every week for a year; the controls receive a placebo. Compliance is monitored carefully. Results from the first six months of the intervention are presented for adults age 30 through 70 years. Males who were iron deficient prior to the intervention and who are assigned to the treatment are better off in terms of physical health, psycho-social health and economic success. These men are more likely to be working, sleep less, lose less work time to illness, are more energetic, more able to conduct physically arduous activities and their psycho-social health is better. There is evidence that economic productivity of these males also increased. Among iron-deficient males assigned to the treatment who were also self-employed prior to the baseline, hourly earnings rose substantially and so they earned more on a monthly basis. Benefits for women are in the same direction but the effects are more muted. The results provide unambiguous evidence in support of the hypothesis that health has a causal effect on economic prosperity of males during middle and older ages.” Thomas et al. 2003.

• 30

  See this cell of our iron fortification CEA for more detail (“Iron fortification” sheet, “Cognitive benefits in children” section, “Percentage increase in wages/consumption for every 1 point increase in IQ” row).

• 31
  • "We included randomised, cluster-randomised and quasi-randomised trials comparing the effects of daily oral prenatal supplements of iron, or iron + folic acid or iron + other vitamins and minerals supplements among pregnant women. We excluded studies that assessed the effects of multiple combinations of vitamins and minerals, except studies that examined the ’additional effect’ of iron or iron + folic acid supplements, i.e. when women in all arms of the trial were provided with the same other micronutrient supplements (with the exception of iron or iron + folic acid)." Peña-Rosas et al. 2015, Pg 9.
  • "We have included a range of interventions providing daily oral supplementation (e.g. tablets, capsules) containing iron alone, iron + folic acid or iron + other vitamins and minerals. The oral supplements forms include tablets or capsules (WHO 2008). Tablets (soluble tablets, effervescent tablets, tablets for use in the mouth, and modified-release tablets) are solid dosage forms containing one or more active ingredients." Peña-Rosas et al. 2015, Pg 9.
  • "In this updated review, we have included 61 and excluded 136 trials. Data from two new trials have been included (Korkmaz 2014; Liu 2012) and a trial that was included in the previous version of the review has now been excluded as it was not clear that the control and intervention groups were comparable, and both groups received iron (Hemminki 1991). We confirmed that seven trials are still ongoing. Forty-four trials involving 43,274 women contributed data for the comparisons in this review." Peña-Rosas et al. 2015, Pg 14.

• 32
  • "Overall, iron supplements reduced the prevalence of low birthweight (less than 2500 g) although using random-effects analysis the difference between groups did not reach statistical significance. Among 17,613 women in 11 trials, 8.4% of those who took daily iron supplementation during pregnancy had a baby with birthweight below 2500 g versus 10.2% of those who received no iron or placebo (average risk ratio (RR) 0.84; 95% confidence interval (CI) 0.69 to 1.03, evidence assessed as low quality) (Analysis 1.1)." Peña-Rosas et al. 2015, Pgs 24-25.
    • 16% equals 1 - 0.84. For 95% CI: 1 - 1.03 = -0.03; 1 - 0.69 = 0.31.
  • "Thirteen trials with 19,286 women provided data on preterm birth (before 37 week’s gestation); while women receiving iron supplements were less likely to experience premature delivery the difference between groups did not reach statistical significance (average RR 0.93; 95% CI 0.84 to 1.03, moderate quality evidence)." Peña-Rosas et al. 2015, Pg 26.
    • 7% equals 1 - 0.93. For 95% CI: 1 - 1.03 = -0.03; 1 - 0.84 = 0.16.
  • "Very premature birth (less than 34 weeks’ gestation). This outcome was reported in five trials with 3743 women; results suggest that babies born to mothers receiving iron were less likely to be born before 34 weeks’ gestation (average RR 0.51; 95% CI 0.29 to 0.91) (Analysis 1.59)." Peña-Rosas et al. 2015, Pg 28.
    • 49% equals 1 - 0.5. For 95% CI: 1 - 0.91 = 0.09; 1 - 0.29 = 0.71.

• 33
  • "Among infants born to 18,590 participants in 15 trials, women receiving supplements had slightly heavier newborns compared with women in the control group, but the difference between groups was not statistically significant. The mean difference (MD) in birthweight between those whose mothers had taken iron supplements and those whose mothers had not was 23.75 g (95% CI -3.02 to 50.51, moderate quality evidence) (Analysis 1.6)." Peña-Rosas et al. 2015, Pg 25.
  • "Four studies with 16,603 participants reported neonatal mortality and there was no clear evidence of any difference between groups (average RR 0.91; 95% CI 0.71 to 1.18, low quality evidence) (Analysis 1.16)." Peña-Rosas et al. 2015, Pg 27.
  • "Four studies with 14,636 women reported the number of infants with congenital anomalies; there was no clear evidence of any difference between groups (average RR 0.88; 95% CI 0.58 to 1.33) (Analysis 1.21)." Peña-Rosas et al. 2015, Pg 27.
  • "In two studies including 12,560 women, there was no clear difference between groups for maternal mortality (average RR 0.33; 95% CI 0.01 to 8.19, very low quality evidence) (Analysis 1.41)." Peña-Rosas et al. 2015, Pg 28.

• 34

  “Design, Setting, and Participants: Cohort follow-up of 676 children aged 7 to 9 years in June 2007–April 2009 who had been born to women in 4 of 5 groups of a community-based, double-blind, randomized controlled trial of prenatal micronutrient supplementation between 1999 and 2001 in rural Nepal. Study children were also in the placebo group of a subsequent preschool iron and zinc supplementation trial.
  Interventions: Women whose children were followed up had been randomly assigned to receive daily iron/folic acid, iron/folic acid/zinc, or multiple micronutrients containing these plus 11 other micronutrients, all with vitamin A, vs a control group of vitamin A alone from early pregnancy through 3 months postpartum. These children did not receive additional micronutrient supplementation other than biannual vitamin A supplementation...
  Results: The difference across outcomes was significant (Bonferroni-adjusted P < .001) for iron/folic acid vs control but not for other supplement groups. The mean UNIT T score in the iron/folic acid group was 51.7 (SD, 8.5) and in the control group was 48.2 (SD, 10.2), with an adjusted mean difference of 2.38 (95% confidence interval [CI], 0.06-4.70; P = .04). Differences were not significant between the control group and either the iron/folic acid/zinc (0.73; 95% CI, −0.95 to 2.42) or multiple micronutrient (1.00; 95% CI, −0.55 to 2.56) groups. In tests of executive function, scores were better in the iron/folic acid group relative to the control group for the Stroop test (adjusted mean difference in proportion who failed, −0.14; 95% CI, −0.23 to −0.04) and backward digit span (adjusted mean difference, 0.36; 95% CI, 0.01-0.71) but not for the go/no-go test. The MABC score was lower (better) in the iron/folic acid group compared with the control group but not after adjustment for confounders (mean difference, −1.47; 95% CI, −3.06 to 0.12; P = .07). Finger-tapping test scores were higher (mean difference, 2.05; 95% CI, 0.87-3.24; P = .001) in the iron/folic acid group.” Christian et al. 2010, abstract.

• 35
  • “In summary, 430 pregnant women receiving antenatal care at the Women's & Children's Hospital in Adelaide, Australia, were recruited to participate in the original trial during 1997–1999 (7). The participants were randomly allocated to receive either iron or placebo from 20 wk of gestation until birth. The dose of iron used in the trial was 20 mg/d, which was intended to increase the women's usual iron intake from ~12 mg/d (8) to the Recommended Dietary Intake for iron during pregnancy in Australia (22–36 mg/d) (9). The compliance rate was 86% for both groups based on tablet back-count and monthly phone calls (7)...The follow-up was conducted from May 2002 to January 2004, 4 y after birth." Zhou et al. 2006, Pg 1112-1113.
  • “RESULTS: The mean IQ was not significantly different (P = 0.980) between the children of the iron-supplemented mothers (109 +/- 11; n = 153) and the children of the mothers in the placebo group (109 +/- 11; n = 149). However, the percentage of children with an abnormal behavior score was higher in the iron group (24 of 151, or 16%) than in the placebo group (12 of 149, or 8%); the relative risk was 1.97 (95% CI: 1.03, 3.80; P = 0.037). There was no significant difference in the health of the mothers between groups, as assessed by the SF-36 Health Survey.” Zhou et al. 2006, abstract.
  • Zhou et al. 2006 is a follow up to a 2002 RCT described in Makrides et al. 2003, which states: “Women were excluded if they had preexisting anemia (defined as a hemoglobin concentration < 110 g/L),” Pg 146.

• 36
  • At the end of pregnancy, a small proportion of the women has iron deficiency anemia: "The proportion of women with iron deficiency anemia at the end of pregnancy was 1% (2 of 146) in the iron group and 11% (15 of 141) in the placebo group." Zhou et al. 2006, Pg 1112.
  • The authors note that their results may not extend to areas in which anemia is more common or severe: "Our findings are applicable to those of other industrialized countries because the dietary iron intake of pregnant women and the prevalence of IDA in pregnancy in our study population are similar to those of pregnant women in other industrialized countries (27, 28). However, our results may not be generalized to other populations in whom ID and anemia are more prevalent and more severe or undernutrition is common." Zhou et al. 2006, Pg 1116.
  • Zhou et al. 2006 is a follow up to a 2002 RCT described in Makrides et al. 2003, which states: “Women were excluded if they had preexisting anemia (defined as a hemoglobin concentration < 110 g/L),” Pg 146.
  • Christian et al. 2010 note: “We previously reported high prevalence rates of iron deficiency and anemia during pregnancy in this rural area of Nepal,” Pg 2720.

• 37

  “To minimize the risk of infection, the physiology of these children has adapted to actively exclude iron much of the time, which is validated by the fact that rare genetic variants in the hepcidin-ferroportin pathway lead to iron overload even in people on low-iron diets. Second, because so much evolutionary experience has been distilled into extensive genomic investment in mechanisms mediating the host-pathogen competition for iron, it may be hazardous to intentionally override such processes by administration of excess iron… If iron deficiency is protective, reversing such deficiency would be expected to enhance malaria susceptibility as previously demonstrated.” Prentice, Verhoef, and Cerami 2013, Pg 914.
  

• 38
  • Our preferred estimate comes from Neuberger et al. 2016, Pg 94, Analysis 3.1.
  • For more, see discussion in this writeup: "If we reject the rationale for the subgroup analysis, this leaves us with the overall pooled estimate (relative risk of clinical malaria of 0.93, 95% confidence interval 0.87 to 1.00). However, this pooled estimate excludes Sazawal et al. 2006 because its intervention included folic acid. Analysis 3.1 on the other hand includes the two largest trials conducted on the question (Sazawal et al. 2006 and Zlotkin et al. 2013) and reports a relative risk of 0.97 (95% confidence interval 0.91 to 1.03). Importantly, since the relative risk is less than one, it suggests that iron supplementation does not increase malaria risk in the average trial context."

• 39

  For more details, see the “Conclusions” section at the end of the writeup here.

• 40
  • ”Between Jan 1, 2002, and Aug 19, 2003, we did a randomised, double-masked, placebo-controlled trial on Pemba, the smaller of the two islands of the Zanzibar archipelago...Malaria is holoendemic with year-round transmission that is highest in June–September.” Sazawal et al. 2006, Pg 133.
  • ”Findings. The iron and folic acid-containing groups of the trial were stopped early on Aug 19, 2003, on the recommendation of the data and safety monitoring board. To this date, 24076 children contributed a follow-up of 25524 child-years. Those who received iron and folic acid with or without zinc were 12% (95% CI 2-23, p=0.02) more likely to die or need treatment in hospital for an adverse event and 11% (1-23%, p=0.03) more likely to be admitted to hospital; there were also 15% (7 to 41, p=0.19) more deaths in these groups.” Sazawal et al. 2006, Pg 133.
  • Commonly used antimalarial drugs interfere with folate metabolism of the malaria parasite, so it is possible that folic acid supplementation undermines their effectiveness.
    • ”With widespread emergence of chloroquine resistant P. falciparum infections, drugs targeting the critically important folate metabolism of malarial parasite have been frequently used [1]. In a double masked, placebo-controlled trial among preschool children in Pemba island (Tanzania), iron and folic acid supplementation (Fe/FA) based on earlier WHO guidelines [2] showed an increased risk of hospitalizations and death [3]. Children during this study were receiving sulfadoxine-pyrimethamine (SP), an antifolate antimalarial drug as a first-line treatment for malaria. Sulfadoxine is known to act by inhibition of dihydropteroate synthetase while pyrimethamine competitively inhibits dihydrofolate reductase thereby blocking the endogenous pathway whereby plasmodium parasites produce folate de novo. In addition, it blocks uptake of and/or utilization by malaria parasites of exogenous folic acid that may transiently occur in circulation following ingestion of high supplemental doses. It has been suggested that FA supplementation (at least in higher doses) during SP treatment could adversely affect the inhibitory effect of SP on parasite growth, by providing folate to the parasite [4].” Sazawal et al. 2014, Pg 1.
  • However, Sazawal et al. 2014 (a subgroup analysis of Sazawal et al. 2006) did not identify an association between folic acid supplementation, iron supplementation, and antimalarial treatment outcome in this context. This RCT used a relatively low dose of folic acid.
    • “In a double masked, placebo-controlled trial among preschool children in Pemba Island (Tanzania), iron and folic acid supplementation (Fe/FA) showed an increased risk of hospitalizations and death. In the present paper, we evaluated if folic acid supplementation reduced the efficacy of malaria treatment and thereby contributed to observed adverse effects. During the study, 1648 children had confirmed malarial episodes and received either sulphadoxine-pyrimethamine (SP) treatment and iron folic acid or SP treatment and placebo. These children were evaluated for recovery and incidence of hospitalization during the next 15, 30, and 140 days. Two groups did not differ in malarial episode or hospitalization rate on subsequent 15, 30, and 140 days. Altered efficacy of SP by folic acid was not observed and did not contribute to adverse events in the previous trial.” Sazawal et al. 2014, Pg 1.
    • "children (aged 1 to 35 months) were enrolled and randomly allocated to receive one of the four preparations: (a) iron (Fe) (12.5 mg/day) and folic acid (FA) (50 µg/day), or (b) Fe, FA and zinc (Zn) (10 mg/day), or (c) Zn alone or (d) placebo. Children 12 months received half the dose.” Sazawal et al. 2014, Pg 2.

• 41

  "As is the case with any fortification or supplementation programme involving iron, the largest potential risk of the program is secondary iron overload in certain individuals of the given fortified population (Pasricha 2012). Iron overload is observed in individuals who have heritable iron metabolism disorders which cause perturbed iron absorption and/or storage, leading to iron accumulation to subsequent tissue damage most commonly in the liver, pancreas and endocrine organs. The most common iron overload disorder is associated with mutations in the HFE gene, the gene for hereditary haemochromatosis. Other physiological conditions are also associated with iron overload including, thalassaemia, pyruvate kinase deficiency, and glucose-6-phosphate dehydrogenase deficiency, among others (Andrews 2000)." Peña-Rosas et al. 2014, Pg 5.

• 42

  "Haemoglobin levels greater than 130 g/L at sea level have also been associated with negative pregnancy outcomes (Hytten 1964; Hytten 1971; Murphy 1986; Scholl 1997; Steer 2000). Large epidemiologic retrospective studies (Murphy 1986; Steer 2000; Xiong 2000), and one prospective study in China (Zhou 1998), have shown that both low and high prenatal Hb concentrations are associated with increased risks for premature delivery and low birthweight." Peña-Rosas et al. 2015, Pg 8.

• 43
  • "Maternal high Hb concentrations (Hb greater than 130 g/L) at any time during second or third trimester. There was evidence from nine studies (2188 women) with estimable data that high Hb concentrations were more likely in the second and third trimesters in women who had received iron as part of supplements (average RR 2.37; 95% CI 1.34 to 4.21). There was high heterogeneity for this outcome ( heterogeneity: Tau2 = 0.57, I2 = 89%, Chi2 test for heterogeneity P < 0.00001 ) (Analysis 1.68).” Peña-Rosas et al. 2015, Pg 28.
  • "Maternal high Hb concentrations at term (defined as Hb greater than130 g/L at 37 weeks' gestation or more). Women who received iron were at higher risk of haemoconcentration at term (average RR 3.07; 95% CI 1.18 to 8.02; reported in eight studies 2156 women). Again, there was high heterogeneity for this outcome and results should be interpreted cautiously (heterogeneity: Tau2 = 1.34, I2 = 96%, Chi2 test for heterogeneity < 0.00001, 95% PI 0.19 to 39.15) (Analysis 1.69).” Peña-Rosas et al. 2015, Pg 28.

• 44

  "Seven trials recruiting 901 women reported on 'any side effect' and did not identify an overall increased prevalence of side effects from iron supplements (RR 2.14, 95% CI 0.94 to 4.86, low quality evidence). 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). 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); 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). Seven studies recruiting 1190 women identified evidence of an increased prevalence of abdominal pain among women randomised to iron (RR 1.55, 95% CI 0.99 to 2.41, low quality evidence). Eight studies recruiting 1214 women did not find any evidence of an increased prevalence of nausea among women randomised to iron (RR 1.19, 95% CI 0.78 to 1.82)." Low et al. 2016, Pg 2.

• 45
  • "One trial including 456 women (Charoenlarp 1988) suggests that women routinely receiving iron and folic acid supplementation are more likely to report any side effects; none of those receiving no supplementation reported side effects, however, the CI is very broad for this finding (RR 44.32; 95% CI 2.77 to 709.09) (Analysis 2.22), moderate quality evidence. This trial did not meet criteria for high methodological quality." Peña-Rosas et al. 2015, Pg 29.
  • "There was no difference in the number of children with gastrointestinal upset, constipation, vomiting or diarrhea or the rates of diarrhea between children who received iron supplementation or control (Appendix 4)." Low et al. 2013, Pg E797.

• 46

  See our cost-effectiveness analysis of iron fortification, “Iron fortification” sheet, “Iron fortification vs cash” row.

• 47

  The organizations are:

  • Food Fortification Initiative (current standout charity)
  • Project Healthy Children (current standout charity)
  • Global Alliance for Improved Nutrition (current standout charity)
  • Helen Keller International (current top charity for vitamin A supplementation)
  • PATH Ultra Rice

• 48

  Relevant studies and findings below:

  • Supplementation and anemia-related outcomes. The main morbidity outcome in the cost-effectiveness analysis is iron deficiency.
    • For iron supplementation, this evidence seems to be of “low” or “very low” quality, according to De-Regil et al. 2011, Pg 4, Table: Summary of Findings for the Main Comparison. Study quality appears to be low in general.
    • Low et al. 2013 find that when they include “only the 4 studies at low risk of bias, the beneficial effects of iron supplementation were no longer observed for hemoglobin, ferritin or iron deficiency.” Pg E798.
    • The number of trials reporting an effect on iron deficiency is also small. Low et al. 2013 and De-Regil et al. 2011, two of the key studies used to assess impacts on iron deficiency, rely on 4 trials (Low et al. 2013, Table 3, Pg E798) and 3 trials (De-Regil et al. 2011, Table: Summary of Findings for the Main Comparison, Pg 4), respectively. This is relevant because findings for impact on iron deficiency are used to adjust the impact of supplementation on cognitive outcomes.
  • Fortification and anemia-related outcomes. “Significant heterogeneity was observed for most of the evaluated outcomes. Sensitivity analyses and meta-regression for hemoglobin suggested a higher response with lower trial quality (suboptimal allocation concealment and blinding), use of condiments, and sodium iron edetate and a lower response when adults were included.” Gera, Sachdev, and Boy 2012, Pg 309.

• 49

  “In efficacy studies, DFS increased hemoglobin concentrations [standardized mean difference (SMD): 0.28; 95% CI: 0.11, 0.44; P < 0.001] and reduced the risk of anemia (RR: 0.59; 95% CI: 0.46, 0.77; P < 0.001) and IDA (RR 0.37; 95% CI: 0.25, 0.54; P < 0.001). In effectiveness studies, the effect size for hemoglobin was smaller but significant (SMD: 0.03; 95% CI: 0.01, 0.05; P < 0.01). Stratified analyses of efficacy studies by population subgroups indicated positive effects of DFS among women and school-age children. For the latter, DFS increased hemoglobin concentrations (SMD: 0.32; 95% CI: 0.03, 0.60; P < 0.05) and reduced the risk of anemia (SMD: 0.48; 95% CI: 0.34, 0.67; P < 0.001) and IDA (SMD: 0.37; 95% CI: 0.25, 0.54; P < 0.001). Hemoglobin concentrations, anemia prevalence and deworming at baseline, sample size, and study duration were not associated with effect sizes. The results indicate that DFS is efficacious in increasing hemoglobin concentrations and reducing the risk of anemia and IDA in LMIC populations. More effectiveness studies are needed.” Ramírez-Luzuriaga et al. 2018, abstract.

• 50

  “Although these results are only obtained in one setting and should be replicated, they are not encouraging for the prospect of DFS as a way to fight anemia in the general rural population. Our own previous work on decentralized flour fortification had equally disappointing impacts. Overall, the evidence in favor of food fortification as a scalable method to prevent anemia among the very poor is less than overwhelming.This contrasts with positive results of iron supplementation in the two major studies we reviewed...The issue with fortification may be that to make a notable difference for most people (sufficient to perhaps sustain their interest in the prod-uct), the iron dose must be large(r). But to be safe (and avoid poisoning due to over-consumption of iron), the concentration of iron supplementation in the food must be limited. With a single source of fortified food, and a diet that continues to be low in iron, the supplementation is perhaps insufficient to make enough of a difference for individuals to be willing to continue with the program. This of course further reduces impact, and ultimately makes the strategy non-viable.” Banerjee, Barnhardt, and Duflo 2018, Pg 146.

• "What is a bit worrisome is that take-up does appear to fall over time; many people tried it at least once but did not continue with the product. Fig. 2 shows that at the store level, purchases also fell over time. This suggests that the product does not have a slow diffusion curve that would eventually culminate in large adoption. Instead it seems that many people tried DFS, but gave it up after awhile." Banerjee, Barnhardt, and Duflo 2018, p. 134.

• 51

  See our Iron Fortification Cost Effectiveness Analysis, “Iron fortification” sheet, “Percent of cost-effectiveness coming from each component” section.

• 52

  We have done a review of DALY weights assigned to mild, moderate, and severe anemia and believe they provide reasonable measures of the morbidity effects of anemia, excluding cognitive effects. While we guess that DALYs associated with iron deficiency are derived from DALYs associated with anemia, we have not confirmed this or explored how these parameters are calculated.

• 53
  • See our iron fortification CEA, “Iron fortification” sheet, “Cognitive benefits in children” section, “Percent of cognitive benefit that is retained into adulthood” row.
  • The evidence we reviewed suggests iron supplementation in childhood does not yield substantial, permanent increases in cognitive ability. However, we also do not believe this evidence rules out the possibility that a portion of the cognitive benefit is permanent, though we are also not aware of evidence supporting this possibility. Our guess is that even if cognitive ability reverts to baseline after the end of iron supplementation or fortification, some benefit will remain in the form of learned information, skills, and social connections. This is highly speculative.
  • More discussion of the persistence of cognitive benefits of iron supplementation is here.

• 54

  We currently translate cognitive skill gains into income using cross-sectional studies and have high uncertainty about the parameter we use here. More detail can be found in this cell of our cost-effectiveness analysis iron fortification, “Iron fortification” sheet, “Cognitive benefits in children” section, “Percentage increase in wages/consumption for every 1 point increase in IQ” row.

• 55

  See our iron fortification CEA, “Iron fortification” sheet, “Percent of cost-effectiveness coming from each component” section, “Cognitive benefits in adults” row (also see the “Cognitive benefits in adults” section).

• 56

  Additional studies, which we have not reviewed but that could provide more information on the link between iron fortification or supplementation and income are below:

  • As discussed in above, we have identified one study, Thomas et al. 2003, that measures the effect of an iron supplementation program for adults in Indonesia, but we have not prioritized a thorough review of this study and have not incorporated it into our cost-effectiveness estimates. This study could potentially update our view of the effect of iron fortification on income, as well as on iron deficiency and anemia for adult men.
  • A review of anemia in low- and middle-income countries suggests there is evidence from trials of the effect of iron supplementation showing an effect on work productivity. We have not reviewed these studies.
    • “The association between iron deficiency and productivity has been extensively investigated. Iron's role in oxygen transport to muscles and other tissues, and its role in other metabolic pathways, show the direct route by which iron deficiency can reduce aerobic work capacity. This link has been supported by randomised field trials of iron supplementation and work productivity in developing countries, including rubber plantation workers in Indonesia, female tea-plantation workers in Sri Lanka, and female cotton-mill workers in China. In countries in which physical labour is prevalent, reduced work performance due to anaemia has substantial economic consequences.” Balarajan et al. 2011, Pg 2131.
  • There also may be additional studies, which have not reviewed, that provide evidence on the link between iron supplementation and outcomes, such as school attendance, that would provide stronger support for the effect of iron supplementation on income. An example, which we have not reviewed, is Chong et al. 2016.
    • “Do nutritional deficiencies contribute to the intergenerational persistence of poverty by reducing the earnings potential of future generations? To address this question, we made available supplemental iron pills at a health center in rural Peru and encouraged adolescents to take them via media messages. School administrative data provide novel evidence that reducing iron deficiency results in a large and significant improvement in school performance and aspirations for anemic students. Our findings demonstrate that combining low-cost outreach efforts and local supplementation programs can be an affordable and effective method of reducing rates of adolescent iron deficiency anemia.” Chong et al. 2016, abstract.

• 57

  “The success of iron-fortified food interventions depends on several factors, including the consumption pattern of the fortified food, effect of the fortificants on the taste and appearance of the food vehicle, shelf life of the fortified food, bioavailability of the iron fortificants, and the baseline iron status of the population (10, 11), which need greater evaluation for the success of this strategy.” Gera, Sachdev, and Boy 2012, Pg 309.

• 58

  “Fortification of commercialized food would thus leave marginalized households behind, which would be particularly unfortunate given that they are likely to be the most at risk for IDA.” Banerjee, Duflo, and Glennerster 2011, Pg 4.

• 59

  See our iron fortification CEA here.

• 60

  16% equals 1,903/12,269, based on the calculations described in this document: “Aggregating annually, it appears as though on average roughly 12,269 mg of iron is delivered across the year in the iron supplementation studies, compared to 1,903 mg in the Gera et al. fortification meta-analysis.”

• 61

  “Iron deficiency is thought to account for about half of the global cases of anemia and is associated with inadequate dietary iron and, in developing settings, hookworm and schistosomiasis.” Low et al. 2013, Pg E791.

• 62

  “The estimated effects of deworming on haemoglobin levels can vary significantly by context and by one's approach to selecting and combining studies. Our best guess is that any effects of deworming on haemoglobin levels are likely to be small.” GiveWell, Combination deworming.