Iron and Cognitive Development: What is the Evidence?

Iron and Cognitive Development: What Is the Evidence? 

Leila M. Larson, Kamija S. Phiri, Sant-Rayn Pasrichac

Key Messages

• Improvement in cognitive development in children is a key rationale for universal iron interventions in pregnancy and in children.
• Data supporting effects of universal iron interventions given either antenatally or in young children on cognitive development remain ambiguous, mainly because high-quality randomized controlled trials have not yet been done.
• Treatment of anemia with oral iron in primary-school-aged children and treatment of iron deficiency anemia with parenteral iron in young children induce marked benefits on cognitive performance, indicating that effects on cognitive performance in young children are plausible.

Keywords
Iron deficiency · Cognitive development · Children · Infants · Pregnancy · Anemia · Motor development · Evidence

Abstract

The theoretical irreversible damage that iron deficiency and iron deficiency anemia can exert on child development makes a compelling argument for action to alleviate the bur­den. However, a critical analysis of evidence from iron inter­ventions in early life is necessary to determine whether and how iron interventions improve cognitive outcomes. Key iron interventions used in clinical and public health practice include oral iron supplementation and, in young children, iron-containing multiple micronutrient powders. This article examines the evidence to answer 4 main questions. (1) Does antenatal iron supplementation influence long-term child cognitive development? (2) Does oral iron supplementation in preschool children improve short-term cognitive develop­ment? (3) Does oral iron supplementation in older children improve cognitive development? And (4), can provision of iron harm cognitive development? Early trials indicated ben­efit from parenteral iron in young children regardless of ane­mia status. There also appears to be evidence for benefit us­ing oral iron treatment on cognitive performance in anemic primary school children. However, antenatal and early child­hood oral iron intervention studies show inconsistent ef­fects on early and long-term childhood cognitive outcomes. These data suggest either that (a) effects from oral iron on cognitive development in young children are small or non­existent or that (b) heterogeneity between trials and the low quality of many studies make assessment of effect difficult. Importantly, few large, placebo-controlled trials in under-2-year-old children in low-income settings assessing effects of iron interventions on cognition have been performed; high-quality, placebo-controlled, adequately powered trials of universal iron interventions on cognitive performance in young children are urgently needed to justify policies of uni­versal iron intervention in this group. 

Introduction 
Anemia affects almost 300 million children worldwide [1], and iron deficiency (ID) has been considered the most important cause. Impairments in cognitive develop­ment caused by ID comprise perhaps the key rationale for alleviating the burden of anemia in children, and an im­portant justification for preventing anemia in pregnancy. International and national guidelines frequently recog­nize the importance of anemia in these groups and in­creasing attention is being paid to identifying resources to address it [2]. An association between impaired cogni­tive development and ID has long been recognized, and has underpinned the rationale for policy [3]. However, recent evidence synthesis has drawn attention to the lim­itations in our understanding of this topic. 

There is increasing recognition of the critical impor­tance of the first 1,000 days of a child’s existence (from conception to 2 years of age) on brain development. Hy­pothesized interactions between nutritional status and child development (e.g., Prado and Dewey [83]) may be direct or indirect ( Fig. 1 ). Whether and how these inter­actions exist for iron status remains uncertain. However, there has been enormous interest in optimizing iron stores during this sensitive period of rapid brain develop­ment [4] , and interventions which prevent or treat iron deficiency anemia (IDA) in pregnancy or in the first 2 years of life have been considered crucial to improving long-term outcomes in children [5] .

Types of Evidence 
What Do We Mean by “Evidence”? 
Information that can be used to inform clinical or pub­lic health policy should be derived from high-quality, ro­bust study designs. Evidence to justify an intervention can be classified according to well-established systems. For example, the GRADE (Grading of Recommendations As­sessment, Development and Evaluation) working group have established criteria to score the quality of informa­tion used to develop clinical recommendations. These sys­tems use an explicit system to score the evidence based on study design limitations, inconsistency of results between studies, indirectness of evidence, imprecision, and report­ing bias [6–8] . In most cases, only information from ran­domized controlled trials or systematic reviews can be considered as sufficient to provide strong recommenda­tions to implement an intervention (Fig. 2)  [6] .


Fig. 1. Hierarchy of evidence. 

Animal Studies 
Animal studies are appropriate for the determination of mechanisms but inadequate for discerning a clinically relevant effect in humans. As such, animal studies are not considered as “evidence.” Experimental evidence from animal studies suggests that fetal or neonatal ID impairs brain and especially hippocampal development [9] . Early ID has also been associated with defects in myelination and impairments in dopaminergic neurotransmission [10]. Effects of ID on development of these systems have been hypothesized to produce irreversible damage to cog­nitive performance.

Observational Studies 


Fig. 2. Hypothetical framework for associations between nutrition and child development. Adapted from Brown and Pollitt [82] and Prado and Dewey [83] . 

Observational studies start with a “low”-quality rating in GRADE. Several dozen observational studies have as­sessed associations between iron status and anemia in pregnancy or in infancy and compared these to cognitive outcomes in later childhood or even adulthood [11, 12] . The most important limitation of observational studies is confounding. Anemia often corresponds with impaired socioeconomic status, overall nutrition, and food security [13]; stunting [14] ; inflammation and infection (includ­ing malaria infection) [15] , exposure to indoor smoke [14], birth order, and psychosocial stimulation [16] . ID may also be associated with other confounders such as increased lead absorption [17] . Anemic or iron-deficient mothers may be less able to provide appropriate stimula­tion to their infants [18] . Anemic mothers may be at high­er risk of depression, which may impair mother-child interactions, impairing language and cognitive develop­ment. Whilst many studies make great efforts to adjust for these confounders in their analysis, it is implausible that all such confounders are completely removed. In addi­tion, reverse causality in observational studies may also explain some associations: for instance, more develop­mentally advanced children may engage more in self-feeding, or be provided with a greater iron-rich diet be­cause they appear more mature. Indirect explanations for relationships between ID and cognition include maternal depression, which can lead to poor mother-child interac­tion and disrupted infant attachment [19, 20]. 

Randomized Controlled Trials 
Double-blinded randomized controlled trials are the only way to definitively identify an effect of an interven­tion on an outcome. These studies provide information about the effect of an intervention on an outcome, rather than the effect of an exposure on an outcome, although analysis of effects of interventions can be substratified by exposure. Given the subjective methods for assessing child development outcomes (e.g., based on direct assess­ment of a child using a series of standardized tools, assess­ing milestones, or asking parents about perceptions of their child’s development) [21] , adequate blinding of both participants and their parents, as well as outcome assessors, is essential to generate high-quality evidence. Randomized controlled trials can be systematically iden­tified and data combined using a formal approach (“sys­tematic review and meta-analysis”). 

From the perspective of making recommendations for interventions, data from clinical trials in humans are es­sential. Here, we seek to critically evaluate the evidence for effects of iron interventions in (i) pregnancy, (ii) pre­school children, and (iii) older children in improving child development, with a view to understanding the po­tential benefits of these interventions on child develop­ment. 

Does Antenatal Iron Supplementation Influence Long-Term Child Cognitive Development? 
Several randomized controlled trials have evaluated effects of iron supplementation in pregnant mothers on developmental outcomes in children. Christian et al. [15] followed up a cohort of children who had been born to mothers randomized to iron-folic acid (IFA) supplemen­tation, IFA and zinc supplementation, iron-containing multiple micronutrients (MMNs), or control (all groups also received vitamin A) during pregnancy, and in whom the prevalence of anemia and ID had been high. At 7–9 years of age, compared to children of mothers who re­ceived control, children of mothers randomized to IFA, but not of mothers who received IFA with zinc or MMNs, had higher universal nonverbal intelligence test (UNIT) results (mean in control group 48.2, mean in IFA group 51.7, adjusted mean difference 2.38, p = 0.04), superior executive function tests, and better motor function [15] . The authors had noted an attenuation by zinc of the ben­efits of IFA on birth weight in the original trial and hy­pothesized that the addition of zinc may impair iron ab­sorption and hence the effectiveness of iron. 

A smaller trial in Australia compared cognitive perfor­mance at 4 years of age in children of mothers random­ized to iron or placebo during pregnancy, where IDA at delivery was uncommon (11% in the control arm) [22] . Cognitive performance was identical between groups. However, more children in the iron group had an abnor­mal behavior score (16%) than in the control group (8%) [23]. The authors subsequently followed the children to early school age (6–8 years of age) and again assessed be­havior. Whilst there were no differences in average par­ent- or teacher-reported behavioral or temperament scores, there was a higher incidence of teacher-rated peer problems in the iron group (8%) than in the placebo group (2%) (p = 0.026) [24]. 

A randomized controlled trial in Western China ran­domized 5,828 pregnant women to either IFA, MMNs, or folic acid alone, and assessed 1,305 infants using the Bayley Scales at 3, 6, and 12 months of age. There were no differences between children at 3 and 6 months, but at 12 months, children of mothers who had received MMNs had a higher mental development index score by 1.22 (compared with IFA) and 1.00 (compared with folic acid alone) (p = 0.02). There were no effects on motor devel­opment [25]. 

In contrast, a trial of antenatal MMNs compared to either daily or twice-weekly IFA in Vietnamese women found that at the age of 6 months, children born to moth­ers in the twice-weekly IFA group had a higher Bayley cognitive score (mean difference 1.89) than children born to the daily IFA group (p = 0.03), despite maternal ferritin levels being lower in this group [26] . No significant dif­ferences were found compared to the MMN group. 

Data from these trials were not included in Cochrane reviews or other key systematic reviews evaluating effects of iron supplementation in pregnancy [27, 28] or the United States Preventative Health Taskforce (USPSTF) review of iron supplementation in pregnancy [29] , al­though data from the Chinese study described above [30] were included in a Cochrane systematic review evaluating effects of antenatal MMNs [31] . Collectively, the clinical evidence does not appear to show that iron supplementa­tion in pregnancy causes improvements in long-term child mental development. 

Does Supplementation in Preschool Children Improve Short-Term Cognitive Development? 
A critical rationale for preventing anemia in pre­school children, and especially in children under 2 years, is the improvement of short- and long-term cognitive development [3, 32]. Several randomized controlled tri­als have addressed the effect of iron interventions, when compared to control, placebo, or no intervention, on cognitive development in children. Trials in children aged 6 months to 5 years evaluating effects of oral iron supplements or iron-containing multiple micronutrient powders (MNPs) on cognitive development are present­ed in Table 1 . Several of the key trials will be discussed here. 

Two early studies evaluated effects of parenteral (in­tramuscular) iron treatment of IDA [33] and nonanemic ID [34] on cognitive development (assessed with the Bay-ley Mental Development Index [MDI]). Within 8 days of treatment, compared with the placebo group, children treated with IDA showed marked improvements in MDI (mean gain 13.6 points), were found to become more alert and responsive, and had improved gross and fine motor coordination [33] . Among nonanemic ID children, iron improved MDI by 21.6 points, whereas in a control group of non-ID children, there was no benefit from iron [34]. These data provided early evidence that iron interven­tions improve cognitive performance in iron-deficient infants. 

Table 1. Randomized controlled trials comparing postnatal oral iron interventions (against control) on cognitive performance in preschool children




A population-based trial in 6-month-old infants was conducted in Indonesia, where 680 six-month-old infants were randomized to iron, zinc, iron and zinc, or placebo for 6 months. The trial found no benefit on mental devel­opment from iron or iron with zinc, compared to either placebo or zinc alone. There was a 3-point benefit from iron, but not iron with zinc, on motor development [35] . More recently, a large randomized trial in China compar­ing effects of prolonged iron supplementation to placebo in young infants (from the age of 6 weeks to 9 months) found that iron improved motor development. Effects on cognitive development, although included as an outcome in the trial registration, were not reported in this publica­tion [36]. 

A 2 × 2 factorial trial in Pakistan evaluated the effec­tiveness of (i) responsive stimulation (local health worker delivered messages to mothers about responsive care for development, age-appropriate play activities, and prob­lem solving), and (ii) enhanced nutrition, comprising training of health workers to deliver improved nutritional advice to mothers together with MNPs  [37] . Importantly, no placebo was used in this trial. Interventions were given to infants enrolled from birth to 23 months of age (MNPs were delivered starting at 6 months of age only). Children receiving enhanced nutri­tion (education and MNPs) had improved cognitive, lan­guage, and socio-emotional development at 12 months and improved language (but not other parameters) at 24 months; by the time the children turned 4 years, prosocial behaviors and motor development (which had not been affected by enhanced nutrition at 24 months) were high­er in the enhanced nutrition group, whereas effects on cognitive development were not seen [38] . Importantly, there were no effects from enhanced nutrition on hemo­globin concentration, and adherence to the intervention was limited [37] . Thus, this trial may have identified a transient early improvement in cognitive development which was not sustained throughout the intervention pe­riod, and the mechanism may not have been mediated directly via the effect of contents of the MNPs on anemia. 

In slightly older children, Stoltzfus et al. [39] random­ized 614 Tanzanian preschool children (6–59 months) to 12 months of iron supplementation (10 mg), antihelmin­thic therapy, a combination of the two, or placebo. The mean age at baseline was about 30 months. Motor and language milestones were assessed by parental report. In this group, nearly all children were anemic at baseline. Iron was found to improve motor scores in children who had been most anemic at baseline, but not overall. Iron improved language scores by 0.8 points on average (p = 0.011) [39] . The placebo-controlled design of the study meant the authors were able to conclude that iron im­proved child development. 
Several trials have attempted to address the effects of iron interventions in children younger than 6 months, ei­ther by fortifying infant formula or giving iron supplements to very young children. For example, a small trial gave oral iron supplements or placebo to term breastfed infants from 1 to 6 months of age, and found improvements from iron in visual acuity and psychomotor development but not mental development at 13 months of age [40] . Likewise, no improvements in mental development were reported in a trial comparing iron-fortified with low-iron formula in Ca­nadian children from very low-income households; bene­fits on motor development were seen at 9 and 12 months of 
age, but were attenuated by 15 months [41] .

Systematic reviews have summarized effects of iron supplementation on child cognitive development through meta-analysis. Pasri­cha et al. [42] meta-analyzed the effects of daily iron sup­plementation in children 4–23 months of age and found no clear evidence of benefit from iron on cognitive devel­opment at the end of the intervention (mean difference 1.65 [95% CI –0.63, 3.94], p = 0.16; 6 trials). Even when only studies at low risk of bias were included, the effect size was nonsignificant. Likewise, no benefit from iron was observed among children who had been anemic at baseline [42] . Thompson et al.  [43] assessed effects of dai­ly iron supplementation in 2- to 5-year-old children, and identified 4 trials including Stoltzfus described above, along with 2 other trials that did not clearly report overall effect sizes from iron on cognitive development. A previ­ous review of the effect of iron interventions in children (delivered through any mechanism) likewise was unable to identify a beneficial effect from iron on cognitive de­velopment in children under 27 months of age, although a benefit in older children was seen [44] . Wang et al.  [45] undertook a Cochrane review to assess effects of iron sup­plementation on cognitive development in iron-deficient anemic children under 3 years and did not find evidence that iron supplementation improved cognitive develop­ment (1.04 [–1.30, 3.39], p = 0.79) in this group. Larson and Yousafzai [46] meta-analyzed the effects of various nutritional supplementation regimens given postnatally to infants and children on cognitive development (com­bining trials giving iron, zinc, or MMN combinations of these) in low- and middle-income countries and reported that these did not significantly improve child develop­ment. Finally, the USPSTF analysis of evidence for iron interventions in high-income countries identified 4 ran­domized controlled trials, but was unable to find evidence of a benefit from iron on cognitive development [47] . Thus, evidence synthesis approaches have failed to iden­tify evidence of benefit from iron supplementation on cognitive development in children under 2 years of age. 

Perhaps more important than short-term cognitive performance are the effects of iron on long-term cogni­tive development. Two studies have evaluated the effects of iron interventions in the first 2 years of life on long­term cognitive outcomes. Murray-Kolb et al. [48] fol­lowed up a cohort of 735 Nepalese children who had been given daily doses of IFA, zinc, IFA with zinc, or placebo at the age of 12–35 months for a variable duration de­pending on age of enrolment. The children were assessed at the age of 7–9 years using tests of cognitive, executive, and motor function. The authors found that compared with children who had received placebo, there were no differences in children who had received IFA (with or without zinc) either before or after adjustment for con-founders. In the adjusted analysis, children who were giv­en IFA supplementation from 12 to 18 months of age (i.e., for the longest duration) performed worse (p = 0.02) on tests of executive function and fine motor function com­pared with children who did not receive IFA [48] . A sec­ond trial, in Thailand, followed up 560 of 609 children originally randomized at the age of 6 months to iron (10 mg), zinc, iron and zinc, or placebo given daily for 6 months. Children were followed up at the age of 9 years, when the authors found no differences overall or in any domain of the Wechsler Intelligence Scale for Children-III between the groups, or in the Raven’s Colored Pro­gressive Matrices score. Moreover, no differences in school performance in any subject (Thai, English, Math­ematics, or Science) were observed [49] . Collectively, these studies do not support the hypothesis that even quite sustained courses of iron supplementation in young children benefit cognitive performance in the long term. 

Failure to convincingly identify a benefit from iron on cognition may be because such a benefit does not exist – perhaps because iron at these doses and via this route does not impact on brain development, or, as hypothe­sized by some authors, because the effects from ID on early brain development are irreversible [50, 51] . How­ever, the “irreversible damage” hypothesis is not support­ed by the improvements seen in early trials of parenteral iron in iron-deficient infants [33, 34] . Alternatively, stud­ies have been undertaken in heterogeneous populations or populations where effects from iron may be unlikely to produce benefit. Several of the trials included in Table 1 were very short (<2 weeks) in duration. Several earlier, smaller trials conducted with small samples, using niche cognitive tests, and reported in ways that do not disclose the overall effect size from iron are perhaps better consid­ered as clinical experiments rather than as formal ran­domized controlled trials designed to generate evidence. 

Interactions between Cognitive and Psychomotor Development 
Although meta-analyses do not clearly demonstrate benefits from iron on psychomotor development (includ­ing gross and fine motor skills), several of the studies inves­tigating effects of iron in preschool-aged children identified benefits on psychomotor (rather than cognitive) develop­ment [35, 36, 52] . It is possible that benefits on psychomo-tor development may indirectly result in improved cogni­tive development. Using structural equation modeling, ob­servational studies in Indonesia and Tanzania considered that associations between nutrition and mental develop­ment were mediated by motor activity and motor develop­ment [53, 54] . Possible effects of benefits of motor develop­ment on mental development may be explained by the child having richer experiences, more stimulating situations, and improved interactions with others [55] . 

Does Iron Supplementation in Older Children Improve Cognitive Development? 
Several trials have evaluated effects of iron supplemen­tation in primary schoolchildren, and Low et al. [56] sum­marized these studies in a recent systematic review. The authors identified 9 studies conducted in primary school children aged 5–12 years, measuring cognitive testing. In­telligence quotient (IQ) was measured in 5 studies, whilst 3 studies used other author-adapted scales of cognitive performance, and 1 used school performance. Overall, compared with control, iron improved global cognitive scores (standardized mean difference 0.50 [0.11, 0.90], p = 0.01; 9 studies). This benefit was only seen among children who had been anemic at baseline (standardized mean difference 0.29 [0.07, 0.51], p = 0.01; 6 studies), but not in children who had been nonanemic at enrolment. There was no overall benefit from iron supplements in IQ in primary school children (mean difference 5.47 [–3.24, 4.18], p = 0.2; 5 studies), although among anemic chil­dren, iron supplements did improve IQ (mean difference 
4.55 [0.16, 8.94], p = 0.04; 3 studies). Thus, in contrast to trials undertaken in preschool children, treatment of anemia with iron supplementation in older children demon­strates a benefit on cognitive performance. 

These data are corroborated by other systematic re­views. Sachdev et al. [44] found a beneficial effect from iron interventions (oral or parenteral iron supplementa­tion, fortified formula milk or cereals) on IQ in children aged 8 years or older (standardized mean difference 0.41 [0.20, 0.62], p < 0.001) [45] . Likewise, Falkingham et al. 
[57] summarized 14 trials evaluating the effects of iron supplementation in older children, adolescents, and women on cognitive performance and found that iron improved IQ by 2.5 points (1.24, 3.76), although it had no effect in nonanemic individuals or on other outcomes in­cluding academic achievement, memory, or motor devel­opment [57] . 

Can Provision of Iron Harm Cognitive Development? 
There have been emerging concerns that provision of high concentrations of iron in fortification infant formu­la may impair long-term cognitive development. Lozoff et al. [58] followed up a cohort of Chilean infants who had been randomized in infancy to receive infant formula for­tified with either low (2.3 mg/L) or high (12.7 mg/L) lev­els of iron. After 6 months, children given the high-iron-fortified formula and/or iron supplements did not exhib­it improved cognitive or psychomotor development, but had approximately 5 days earlier age of crawling and had a delayed Fagan looking time, which the authors thought would predict impaired longer-term cognitive perfor­mance [58] . However, at the age of 10 years, the authors reassessed the children and found that those who had been randomized to the high-iron formula performed more poorly than their low-formula-receiving counter­parts on every outcome (IQ, p = 0.06;spatial memory, p = 0.02; arithmetic achievement, p = 0.07; visual-motor in­tegration, p = 0.046; visual perception, p = 0.06) [59] . A recent update to this cohort indicated a similar pattern of adverse performance in the high-iron-fortified group at the age of 16 years; of 9 cognitive tests performed, 4 showed poorer performance in the high-iron group; baseline hemoglobin did not interact with these effects [60].

Conclusions 
Improvements in long-term child development are perhaps the most important justification for universal iron (iron supplement or MNPs) interventions in young children and considered an important reason for pre­venting anemia in pregnancy. Whilst there is clear evi­dence for benefits of iron treatment on cognitive perfor­mance in anemic primary school children, in younger children, and especially in children under 2 years of age, evidence that oral iron interventions (supplements or mi-cronutrient powders) improve short- and long-term cog­nitive development remains scant. Benefits from paren­teral iron on cognition in iron-deficient and anemic in­fants have been reported in early trials and refute the contention that iron-induced brain damage is intractable, instead suggesting either that oral iron is ineffective or that quality trials have not yet been performed. Likewise, effects of iron in pregnancy on early and longer-term cog­nitive development remain ambiguous, with failure to demonstrate consistency or dose response. Heterogeneity may be due to differences in dose and duration of iron, timing of commencement of iron, population and epide­miology of anemia and ID, and adherence to interven­tions. 

Although numerous studies purporting to address these questions are available, the issue has still not been addressed in high-quality randomized controlled trials. Several recent trials evaluating effects of iron interven­tions (including MNPs) were not placebo controlled. Given the potentially subjective nature of cognitive as­sessments, blinding is essential, and non-placebo-con­trolled studies do not provide useful evidence for this outcome, regardless of the direction of the finding. We strongly discourage investigators from undertaking non-placebo-controlled trials in the future as they will not add to the literature. High-quality, dedicated, placebo-con­trolled, adequately powered trials of universal iron inter­ventions on cognitive performance in young children are urgently needed. In the interim, improvements in cogni­tive development cannot be used as a rationale for imple­menting universal iron interventions.

Disclosure Statement 
The authors have no conflicts of interest to declare. The writing of this article was supported by Nestlé Nutrition Institute. 

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