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
ViewpointNeurological effects of iron supplementation in infancy: finding the balance between health and harm in iron-replete infants
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
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Cited by (25)
Essential trace elements in neurodevelopment: An updated narrative
2023, Vitamins and Minerals in Neurological DisordersRegional iron distribution and soluble ferroprotein profiles in the healthy human brain
2020, Progress in NeurobiologyCitation 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 SpectroscopyCitation 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 DiseasesCitation 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].