Viewpoint
Neurological effects of iron supplementation in infancy: finding the balance between health and harm in iron-replete infants

https://doi.org/10.1016/S2352-4642(17)30159-1Get rights and content

Summary

Iron mediates many biochemical processes in neural networks that proliferate during brain development. Insufficient iron causes irreversible neurodevelopmental deficits, and most high-income countries recommend that infants older than 4–6 months receive additional iron via food fortification or supplementation to prevent iron-deficiency anaemia. Now that the prevalence of iron-deficiency anaemia in children has decreased to less than 10% in most developed countries, concerns that the recommended intakes far exceed those required to prevent iron-deficiency anaemia have been raised, and emerging evidence suggests that iron overexposure could be linked to adverse outcomes later in life. In this Viewpoint, we discuss the importance of iron for neurodevelopment, investigate the biochemical markers used to assess iron stores, summarise the disparity in public health policies among high-income countries, and discuss the potential association between iron overexposure and adverse neurological outcomes later in life. We present a case for new studies to establish the optimal amount of iron that both prevents deficiency and reduces the potential risk of long-term negative health outcomes.

Introduction

Iron-deficiency anaemia, particularly in infancy, can have severe negative health effects. Symptoms include fatigue, headache, paleness, stomatitis, restless legs syndrome, koilonychia, bowel irritation, and impaired glucose metabolism.1, 2 The burden of disease is high, spanning lost productivity to infant and maternal mortality.3 Iron is essential for neurodevelopment,4 and policies designed to reduce the prevalence of iron-deficiency anaemia in children are a crowning achievement of preventive medicine. However, the effectiveness of iron supplementation appears to be situation dependent, with little evidence of the overall benefit in low-income and middle-income countries,5 and even less in Organisation for Economic Co-operation and Development (OECD) countries.6 The WHO's 2016 guideline for iron supplementation in infants and children7 recommends supplementing infants for only three consecutive months a year, and only in areas where the prevalence of anaemia is greater than 40%. However, the evidence of benefit is often at odds with public health guidelines on a country-by-country basis.

Existing policies have received criticism because of emerging evidence of negative long-term effects of excessive iron exposure during neurodevelopment. WHO states that obtaining additional data on the safety of iron supplementation, including effects in children who do not have anaemia or are not iron deficient, should be a research priority.7 In this Viewpoint, we critically appraise the evidence surrounding iron supplementation. Highlighting the potential negative outcomes of overexposure, we emphasise the paucity of compelling evidence supporting or refuting the need for iron supplementation programmes, necessitating the need to revisit public health policies with new evidence-based studies. We propose that a potential middle ground should be pursued for iron supplementation or fortification, or both, in children that are iron replete that prevents iron-deficiency anaemia, while mitigating the risk of adverse neurodevelopmental outcomes later in life.

Section snippets

Dietary iron and brain iron concentrations

Several processes that are unique to the brain rely on iron redox chemistry (panel 1). Iron concentrations are compartmentalised and regulated to prevent reactions with byproducts of mitochondrial respiration that drive oxidative stress (figure 1).

Uptake of iron into the brain following blood–brain barrier maturation has been assumed to be independent of dietary iron intake in adults; however, rodent studies8 have shown that iron concentration in the brain increases by about 30% in healthy rats

Iron deficiency versus iron-deficiency anaemia

The clinical distinction between iron deficiency and iron-deficiency anaemia is of great importance with respect to clinical management. Bermejo and García-López define iron deficiency as “the decrease of the total content of iron in the body” and iron-deficiency anaemia as “when [iron deficiency] is sufficiently severe to reduce erythropoiesis”.30 Iron deficiency affects approximately 2 billion people worldwide,31 with iron-deficiency anaemia being the most common cause of anaemia.3

Treating iron deficiency and iron-deficiency anaemia in infants

For iron deficiency and iron-deficiency anaemia, iron supplementation and fortification of food products remains a primary point-of-care strategy for addressing these conditions in areas of high prevalence—ie, in many low-income and middle-income countries.3

However, in many high-income countries, fortification of infant formula has been commonplace for decades. The Australian Institute for Health and Welfare reports that 96% of infants in Australia are initially breastfed, but only 39% are

Short-term adverse health effects

Iron supplementation can cause adverse health events, even in populations that are clinically anaemic. In her overview of clinical, pathological, and therapeutic aspects of iron-deficiency anaemia, Camaschella33 identified nausea, vomiting, constipation, and dysgeusia as the most common acute side-effects of iron supplementation. Intravenous iron therapy has a similar side-effect profile, in addition to pruritus, myalgia, and other localised sources of pain.73 A systematic review and

Conclusion

As the collective understanding of iron biochemistry grew throughout the 20th century, the importance of maintaning an iron-replete biological system became apparent, with awareness of the role of nutrition and signs and symptoms of anaemia increasing worldwide. Accordingly, ensuring that a population has sufficient access to dietary iron is an ongoing public health endeavour. However, unlike other essential micronutrients that have well described toxic effects when in excess, such as manganese

Search strategy and selection criteria

We identified references for this Viewpoint through searches of PubMed and Google Scholar with the search terms “iron supplementation”, “iron fortification”, “iron deficiency an[a]emia”, “brain iron”, and related terms from Jan 1, 1900, to June 30, 2017. Articles were also identified through searches of the authors' own collections. Only papers published in English were reviewed. The final reference list was generated on the basis of originality and relevance to the broad scope of this

References (97)

  • MB Zimmermann et al.

    Nutritional iron deficiency

    Lancet

    (2007)
  • JK Friel et al.

    A double-masked, randomized control trial of iron supplementation in early infancy in healthy term breast-fed infants

    J Pediatr

    (2003)
  • RE Kleinman

    Expert recommendations on iron fortification in infants

    J Pediatr

    (2015)
  • M Domellöf et al.

    Iron absorption in breast-fed infants: effects of age, iron status, iron supplements, and complementary foods

    Am J Clin Nutr

    (2002)
  • EA Szymlek-Gay et al.

    α-Lactalbumin and casein-glycomacropeptide do not affect iron absorption from formula in healthy term infants

    J Nutr

    (2012)
  • C Ke et al.

    Iron metabolism in infants: influence of bovine lactoferrin from iron-fortified formula

    Nutrition

    (2015)
  • O Hernell et al.

    Iron status of infants fed low-iron formula: no effect of added bovine lactoferrin or nucleotides

    Am J Clin Nutr

    (2002)
  • G Bjørklund et al.

    Interactions of iron with manganese, zinc, chromium, and selenium as related to prophylaxis and treatment of iron deficiency

    J Trace Elem Med Biol

    (2017)
  • M Shayeghi et al.

    Identification of an intestinal heme transporter

    Cell

    (2005)
  • F Pizarro et al.

    The effect of proteins from animal source foods on heme iron bioavailability in humans

    Food Chem

    (2016)
  • SE Cusick et al.

    Delaying iron therapy until 28 days after antimalarial treatment is associated with greater iron incorporation and equivalent hematologic recovery after 56 days in children: a randomized controlled trial

    J Nutr

    (2016)
  • L Malan et al.

    Iron and a mixture of DHA and EPA supplementation, alone and in combination, affect bioactive lipid signalling and morbidity of iron deficient South African school children in a two-by-two randomised controlled trial

    Prostaglandins Leukot Essent Fatty Acids

    (2016)
  • K Chen et al.

    Effect of bovine lactoferrin from iron-fortified formulas on diarrhea and respiratory tract infections of weaned infants in a randomized controlled trial

    Nutrition

    (2016)
  • S Soofi et al.

    Effect of provision of daily zinc and iron with several micronutrients on growth and morbidity among young children in Pakistan: a cluster-randomised trial

    Lancet

    (2013)
  • LL Iannotti et al.

    Iron supplementation in early childhood: health benefits and risks

    Am J Clin Nutr

    (2006)
  • P Idjradinata et al.

    Adverse effect of iron supplementation on weight gain of iron-replete young children

    Lancet

    (1994)
  • T Tamura et al.

    Cord serum ferritin concentrations and mental and psychomotor development of children at five years of age

    J Pediatr

    (2002)
  • M Domellöf et al.

    Iron supplementation of breast-fed Honduran and Swedish infants from 4 to 9 months of age

    J Pediatr

    (2001)
  • D Kaur et al.

    Increased murine neonatal iron intake results in Parkinson-like neurodegeneration with age

    Neurobiol Aging

    (2007)
  • AT Soliman et al.

    Iron deficiency anemia and glucose metabolism

    Acta Biomed

    (2017)
  • M Domellöf et al.

    Iron requirements of infants and toddlers

    J Pediatr Gastroenterol Nutr

    (2014)
  • WHO guideline: daily iron supplementation in infants and children

    (2016)
  • J-H Chen et al.

    Imbalance of iron influx and efflux causes brain iron accumulation over time in the healthy adult rat

    Metallomics

    (2014)
  • LA Atkins et al.

    Iron intakes of Australian infants and toddlers: findings from the Melbourne Infant Feeding, Activity and Nutrition Trial (InFANT) Program

    Br J Nutr

    (2016)
  • RD Baker et al.

    Diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young children (0–3 years of age)

    Pediatrics

    (2010)
  • D Holland et al.

    Structural growth trajectories and rates of change in the first 3 months of infant brain development

    JAMA Neurol

    (2014)
  • RL Leibel et al.

    Iron deficiency: behavior and brain biochemistry

  • P Christian et al.

    Prenatal micronutrient supplementation and intellectual and motor function in early school-aged children in Nepal

    JAMA

    (2010)
  • MO Mireku et al.

    Prenatal iron deficiency, neonatal ferritin, and infant cognitive function

    Pediatrics

    (2016)
  • NA Alwan et al.

    Maternal iron status in pregnancy and long-term health outcomes in the offspring

    J Pediatr Genet

    (2015)
  • C Cai et al.

    Gene expression profiles suggest iron transport pathway in the lactating human epithelial cell

    J Pediatr Gastroenterol Nutr

    (2017)
  • RM Angulo-Barroso et al.

    Iron supplementation in pregnancy or infancy and motor development: a randomized controlled trial

    Pediatrics

    (2016)
  • C Jardí et al.

    Influence of breastfeeding and iron status on mental and psychomotor development during the first year of life

    Infant Behav Dev

    (2017)
  • O Andersson et al.

    Effect of delayed cord clamping on neurodevelopment at 4 years of age: a randomized clinical trial

    JAMA Pediatr

    (2015)
  • MK Georgieff

    Long-term brain and behavioral consequences of early iron deficiency

    Nutr Rev

    (2011)
  • B Wang et al.

    Iron therapy for improving psychomotor development and cognitive function in children under the age of three with iron deficiency anaemia

    Cochrane Database Syst Rev

    (2013)
  • P East et al.

    Associations among infant iron deficiency, childhood emotion and attention regulation, and adolescent problem behaviors

    Child Dev

    (2017)
  • B Lozoff et al.

    Behavioral and developmental effects of preventing iron-deficiency anemia in healthy full-term infants

    Pediatrics

    (2003)
  • Cited by (25)

    • Essential trace elements in neurodevelopment: An updated narrative

      2023, Vitamins and Minerals in Neurological Disorders
    • Regional iron distribution and soluble ferroprotein profiles in the healthy human brain

      2020, Progress in Neurobiology
      Citation Excerpt :

      Additionally, the mean age of the Allen Human Brain Atlas donors was 42.5 ± 13.4 years, compared to the 74.0 ± 12.7 mean age of brains used here to directly assess iron levels. Brain iron content and expression of iron regulatory proteins (particularly transferrin and ferritin) increases with age (Ward et al., 2014), and with an estimated half-life in the brain of over 10 years (Chen et al., 2014) periods of high iron intake may introduce an additional source of variation (Hare et al., 2015a, 2018), recently shown using stable isotope tracing studies in adult rats (Chen et al., 2013). To our knowledge the impact of differential iron uptake on regional compartmentalisation and subsequent protein expression has not been investigated.

    • From niche methods to necessary tools: The growing importance of analytical atomic spectrometry in metal imaging in neuroscience

      2019, Spectrochimica Acta - Part B Atomic Spectroscopy
      Citation Excerpt :

      Metal deficiency in the brain can have equally harmful effects. Iron deficiency anemia during critical periods of infant development can cause irreversible neurological deficits [27], several genetic disorders of metal metabolism results in decreased levels of essential metals in the brain (e.g. Menkes disease [28]), and Cu deficiency (as well as elevated Fe) has been identified as a feature of neurodegenerative processes in Parkinson's disease [29]. In the latter case this decrease in cellular Cu of degenerating neurons has been associated with dysfunction of SOD1 [30–32], further reducing the capacity of cells to compensate for the pathological increase in reactive Fe and the subsequent elevated rate of ROS production.

    • Haemoglobin variants, iron status and anaemia in Sri Lankan adolescents with low red cell indices: A cross sectional survey

      2018, Blood Cells, Molecules, and Diseases
      Citation Excerpt :

      This risks possible deleterious effects of increased iron availability [24] which include impaired cognitive development in young children [25] and adverse effects on the gut microbiome [26].

    View all citing articles on Scopus
    View full text