Open access peer-reviewed chapter

Iron Deficiency Anaemia

Written By

Lingxia Zeng, Leilei Pei, Chao Li and Hong Yan

Submitted: 05 December 2016 Reviewed: 07 April 2017 Published: 20 December 2017

DOI: 10.5772/intechopen.69048

From the Edited Volume

Current Topics in Anemia

Edited by Jesmine Khan

Chapter metrics overview

2,159 Chapter Downloads

View Full Metrics

Abstract

Iron deficiency anaemia as the most common nutrition disorder has only marginal reduction globally during recent decades, with the highest burden in pregnant women and young children. Insufficient iron storage and/or excessive loss of iron are common causes of iron deficiency anaemia. Therefore, understanding the complexity of the regulatory network required to maintain iron homeostasis and identifying the functional variants associated with iron metabolism should be fundamental and crucial to control and treat the iron deficiency anaemia. Sensitive and inexpensive measures to distinguish iron deficiency anaemia from the other kinds of anaemia should be developed for precise treatment. Original disease treatments combined with oral or intravenous iron therapy are key approaches in clinical practices. The integrated, multifactorial and multi‐sectoral approach with food‐based strategy and iron supplementation as the leading public health inventions is required to achieve iron deficiency anaemia control target. This chapter will focus on the advanced knowledge associated with iron metabolism, disease burden and health consequences of iron deficiency anaemia in different life course, newly parameters development in the diagnosis of iron deficiency anaemia, therapy choice in clinical practice and public health strategies to reduce iron deficiencies in high‐burden areas.

Keywords

  • iron deficiency
  • iron deficiency anaemia
  • iron metabolism
  • hepcidin
  • iron supplementation
  • food fortification
  • ferritin
  • transferrin saturation

1. Introduction

As the most common nutrition disorder in both the developed and developing world, affecting more than two billion people, iron deficiency anaemia is recognized not only a clinical condition but also a serious public health issue, with pregnancy women and pre‐school‐age children at the highest risk [15]. The annual economic loss because of iron deficiency anaemia in 10 developing countries was estimated about 4% of gross domestic product [2]. Despite considerable economic and scientific advancement during recent decades, there has been only marginal reduction in the global prevalence of anaemia with more than 50% of cases caused by iron deficiency [2, 4].

This chapter will summarize the advanced knowledge associated with iron metabolism, health burden, newly parameters development in the diagnosis of iron deficiency anaemia, therapy choice and public health strategies to reduce iron deficiencies in high burden areas.

Advertisement

2. Iron metabolism and hepcidin, potential regulators associated with iron metabolism

2.1. Iron metabolism pathway

The absorption of dietary iron is a variable and dynamic process, depending on the two primary forms of haem and non‐haem iron. Haem is a component of haemoglobin and myoglobin and haem iron is complexed as ferrous iron (Fe2+) in the haem form, which is present in animal tissues such as meat, poultry, fish and shellfish [6]. Most of non‐haem iron (Fe3+ or ferric iron) is provided by the vegetarian diet (black tea, cacao, cereals, dried fruit etc.). Although haem iron could represent ∼40% of animal tissue iron and be better absorbed, it only accounts for less than 15% of total iron intake [7, 8]. In spite of the low absorption rate, the majority of the dietary iron is obtained from non‐haem iron. Studies have confirmed that animal tissues (meat, poultry and fish) and vitamin C and organic acids could enhance iron absorption, while high intake of phytates, tannins, calcium and zinc may tend to inhibit the absorption of iron [9, 10].

It is currently well known that most of dietary iron is absorbed by enterocytes of the duodenal lining. The first step to absorb iron is that the insoluble ferric iron (Fe3+) has to be converted into the ferrous form (Fe2+) by a brush border ferric reductase (duodenal cytochrome B, DCYTB) in the duodenum and upper jejunum. The ferrous iron is then transferred across the enterocyte membrane into the cell by divalent metal transporter 1 (DMT1). Afterwards, the iron is stored in these intestinal lining cells as ferritin which is accomplished by Fe3+ binding to apoferritin, or could be released into the body via the only known iron exporter ferroportin. Cooperated with either of the ferroxidases hephaestin (enterocytes) or ceruloplasmin (other cell types) that facilitate iron extraction from the ferroportin channel, ferroportin at the basolateral membrane transports Fe2+ that is subsequently loaded onto plasma transferrin (Tf) [11].

In blood, plasma iron‐loaded transferrin (Tf‐Fe2+) transports iron to all cells in a transferrin receptor‐mediated endocytotic process [6]. Iron‐loaded Tf binds to transferrin receptor 1 (TfR1), and their complex internalizes and enters into cells, wherein iron releases by pH‐dependent mechanism. As it provides most of the iron required for various functions of an organism, plasma transferrin plays a crucial role in iron metabolism. TfR1 is highly expressed on haemoglobin‐synthesizing erythroblasts. Most of plasma iron is used by bone marrow to synthesize haemoglobin in red blood precursors. Several other cell types, such as enterocytes, hepatocytes and reticuloendothelial macrophages, are considered to be major iron storage sites. Iron release from or store in enterocytes, hepatocytes and macrophages depends on plasma iron levels, to meet the physiological demand. In a review published in Cell, Hentze et al. carefully discussed these mechanisms and summarized them in a single figure (Figure 1) [11].

Figure 1.

Mechanism of systemic iron metabolism. Derived from: Hentze et al. [11].

2.2. Hepcidin and potential regulators associated with iron metabolism

In the human body, the iron homeostasis is tightly regulated to avoid both deficiency and excess. Hepcidin is a core regulator of the entry of iron into the circulation, which is a peptide hormone synthesized mainly in the liver, which was discovered in 2000. Previous studies have confirmed that hepcidin is not liver specific but also expressed in other tissues, such as the kidney, heart and lungs [12]. Hepcidin is first synthetized as an 84‐amino acid (aa) prepropeptide, and then further processed into 60–64‐aa prohepcidin. Finally, mature and biologically active 25‐aa hepcidin is produced by truncating the proregion from prohormon convertase furin [13]. When the hepcidin level is abnormally high, serum iron falls due to iron trapping in macrophages and liver cells, and decreased gut iron absorption by reducing iron transport across the gut mucosa (enterocytes). In the instances, it is clear that anaemia will develop due to lack of inadequate amount of serum iron being available for developing red cells. In the state in which the hepcidin level is abnormally low, on the contrary, iron overload occurs due to increased iron efflux from storage and gut iron absorption. Tandara et al. have discussed the mechanisms of hepcidin regulating iron homeostasis and summarized them in a single figure (Figure 2) [14].

Figure 2.

Maintenance of systemic iron homeostasis regulated by hepcidin. Derived from: Tandara and Salamunic [14].

So far, at least four major separate pathways in hepcidin regulation have been confirmed, such as regulation by iron status; dietary iron and iron stores; regulation by inflammation; regulation by hypoxia/anaemia and regulation by erythroid factors [15, 16]. These different regulatory inputs are integrated transcriptionally.

At the molecular level, it is not still completely clear that iron stores regulate hepcidin synthesis, but haemojuvelin (HJV), haemochromatosis protein (HFE) and transferrin receptor 2 (TfR2) have been proven to be upstream regulators of hepcidin. HFE acts as a bimodal switch between two sensors of the concentration of Tf‐Fe2+, TfR1 and TfR2, on the plasma membrane of hepatocytes [17]. HFE binds the ubiquitously expressed TfR1 at a site that overlaps the transferrin binding domain, and Tf‐Fe2+ thus competes with HFE binding to TfR1. By contrast, TfR2 can bind both HFE and Tf‐Fe2+ simultaneously [18]. Although HFE and TfR2 clearly contribute to hepcidin activation, the bone morphogenetic protein (BMP) signalling pathway is quantitatively the most critical. It has been proposed that HJV acts as co‐receptor that binds to bone morphogenetic protein (BMP) ligands and BMP type I and type II receptors on the cell surface. This complex (HJV‐BMP ligand‐BMP receptors) consequently induces an intracellular BMP signalling pathway which in turn activates the SMAD4 signalling pathway. The drosophila mothers against decapentaplegic (SMAD) complex translocate to nucleus and directly increases hepcidin gene transcription [1921]. BMP/SMAD signalling cascade of HJV is important for basal regulation of hepcidin transcription [22]. Thus, HJV is central for hepcidin expression, and the point of convergence of multiple regulatory inputs. Transmembrane protease, serine 6 (encoded by the TMPRSS6 gene) has been identified as an inhibitor of hepcidin activation by cleaving membrane HJV under normal conditions [11, 23, 24]. If TMPRSS6 gene mutations occur, hepcidin levels increase and result in insufficient iron absorption [25].

Hepcidin synthesis is also dramatically induced by infection and inflammation. In particular, interleukin 6 (IL‐6) is the central inducer of hepcidin synthesis during inflammation [14, 26, 27], which acts on hepatocytes and stimulates hepcidin production through signal transducer and activators of transcription (STAT3) signalling pathway [28]. Hepcidin mediated by IL‐6 often results in cellular iron retention and hypoferremia, thus anaemia develops due to restricted iron availability in haemoglobin synthesis [14]. In the condition in which anaemia/hypoxia develops, hepcidin gene expression decreases along with the increase of erythropoietin expression. Tissue hypoxia increased erythropoiesis and further suppress hepcidin expression. Several bone marrow‐derivated signal molecules that regulate the process of erythropoiesis mediating hepcidin have been found, including growth differentiation factor 15 (GDF15), twisted gastrulation protein homologue 1 (TWSG1), hypoxia inducible factors (HIF) and hormone erytropoetin [2931]. Furthermore, iron responsive element (IRE)/iron responsive proteins (IRP) system also tightly regulates cellular iron uptake and storage and coordinatively keeps cell iron homeostasis.

Iron responsive proteins 1 (IRP1) and 2 (IRP2) in cytoplasmic can sense the level of iron in transit pool and bind specifically to RNA stem‐loops (iron responsive element, IRE), and post‐transcriptionally modify the expression of proteins involved in iron metabolism [14].

2.3. Genetic variants associated with iron deficiency anaemia from genome‐wide association studies

The iron metabolism is tightly and precisely regulated by several interacting iron‐binding factors. The development of genome‐wide association studies (GWAS) has confirmed that the mutation of genes in iron metabolism, like transferrin, transferring receptors, matriptase‐2, hepcidin, may determine the phenotypic variation in iron homeostasis between individuals [32]. Mutations in the gene (HAMP) encoding hepcidin can increase iron absorption and lead to juvenile haemochromatosis [33]. Due to the same regulatory pathway, mutations in these genes, including those encoding HJV, HFE and TfR2, clearly result in iron loading syndromes [32].

However, limited information is available about gene variants associated with iron deficiency anaemia. The inherited disorders of iron metabolism played an important role in iron deficiency anaemia. For example, in two association studies of iron metabolism disorders, the SNP rs235756 in BMP2 brings about the decrease of serum ferritin level [34, 35]. Mutations in the DMT1 gene occur in patients with microcytic anaemia, low serum ferritin and liver iron overload [36]. Studies also showed that mutations in the matriptase gene (TMPRSS6) cause iron‐refractory iron deficiency anaemia [11]. It has been suggested that the mutation G277S of the TF gene alone does not affect iron absorption in iron deficient women and a combination of polymorphisms may be involved in iron metabolism [32, 37]. The recently determined mutation in the glutaredoxin 5 (GLRX5) gene leads to microcytic, hypochromic anaemia with iron overload and the presence of ringed sideroblasts in the bone marrow upon Perl’s staining [38]. According to the European Network of Rare Congenital Anaemia, 62 rare anaemia subtypes are shown recently, including haemolytic anaemia and anaemia arising from mutations in genes that control duodenal iron absorption (e.g. SLC11A2), systemic iron homoeostasis (e.g. TMPRSS6) or erythroid iron absorption and utilization [8]. The genetic forms of sideroblastic anaemia such as mutations in glutaredoxin 5, aminolevulinic acid synthetase 2 and ABCB7 genes provide the updated information.

Advertisement

3. Disease burden and adverse health consequences of iron deficiency anaemia in different life courses

3.1. Disease burden

WHO estimated that the highest prevalence of anaemia was in the population of pre‐school‐aged children, pregnant and non‐pregnant women, but lower for school‐aged children, men and the elderly [8]. Data in 2010 showed more than 2.2 billion people were affected by anaemia and global prevalence of anaemia was 32.9%, and iron deficiency was reported as the most common cause of anaemia [4]. WHO estimates that 50% of cases are due to iron deficiency, and regional disparities exist [4, 39]. In detail, results from studies conducted in the United States reported the prevalence of iron deficiency ranges from 4.5 to 18.0%. But the proportion of anaemia caused by iron deficiency in central Asia, south Asia and Andean Latin America were 64.7, 54.8 and 62.3%, respectively [8, 40].

In 2010, global anaemia causing 68.36 million years lived with disability (8.8% of total for all conditions) [4]. The distribution of anaemia prevalence was unbalanced across regions, central and West Africa and south Asia were the highest anaemia prevalence regions in middle‐ and low‐income areas, and high‐income areas had lowest anaemia prevalence (Table 1). In addition, this trend was similar among the higher risk population of anaemia (children under 5 years, pregnant women from 15 to 49 years, non‐pregnant women from 15 to 49 years) [5].

Prevalence of anaemia (%)
Children (<5 years)Non‐pregnant women (15–49 years)Pregnant women (15–49 years)
Middle‐ and low‐income areas
Central and west Africa714856
East Africa552836
South Africa462831
South Asia584752
East and southeast Asia252125
Central Asia, Middle East and north Africa383331
Oceania432836
Andean and central Latin America and Caribbean331927
Southern and tropical Latin America231831
Central and eastern Europe262224
High‐income areas111622

Table 1.

Distribution of anaemia prevalence in middle‐ and low‐income areas by different population.

3.2. Consequences of iron deficiency anaemia

The population of pre‐school‐aged children, pregnant and non‐pregnant women was the highest prevalence of anaemia [8], the consequences of iron deficiency anaemia among pre‐school‐aged children, pregnant and non‐pregnant women should be emphasized.

The consequences of iron deficiency of pregnant women are multiple. First, iron deficiency during pregnancy was significantly associated with increasing perinatal mortality. Evidence from six observational studies showed a combined odds ratio of 0.75 (association between anaemia and maternal mortality) associated with a 10 g/L increase in haemoglobin [41, 42]. In addition, the combined OR was 0.72 for perinatal mortality associated with a 10 g/L increase in haemoglobin [41, 42]. Another study (RCT) conducted in China found prenatal supplementation with iron‐folic acid was associated with a reduction in early neonatal mortality compared with prenatal folic acid supplementation only [43]. Second, many studies have determinate the association between iron deficiency anaemia and pre‐term and low birth weight [4446]. Evidence from a retrospective population‐based study showed maternal anaemia during pregnancy was risk factor for pre‐term delivery (OR = 1.2) and low birth weight (OR = 1.1) [44]. Results from a meta‐analysis reported that analysis of cohort studies showed a higher risk of pre‐term birth (OR = 1.21) and low birth weight (OR = 1.29) with anaemia in the first or second trimester of pregnancy [45]. Significant association between prenatal iron deficiency anaemia and low birth weight was also found in low and middle‐income counties [42]. Third, previous study reported that the fetal brain could be at risk when iron supply does not meet iron demand [47]. In addition, several observational studies reported the reverse effect of iron deficiency during pregnancy on intellectual development and motor development of children [48, 49]. One longitudinal study conducted in China found that prenatal iron deficiency anaemia in the third trimester is significantly associated with mental development of children [48]. Another prospective study conducted in Vietnam reported that prenatal iron deficiency anaemia hasadverse effects on child cognitive development [49].

Iron deficiency is more likely in women of reproductive age because of menstrual blood loss [50]. Results from some RCTs showed that iron improves cognitive ability, physical performance and mood in iron‐depleted non‐anaemia women [5153]. In detail, a study found iron supplementation improved physical performance and mood of female soldiers [51]. One study conducted in the United States reported iron status was significantly associated with cognitive ability in women of reproductive age. The iron‐sufficient women completed the cognitive tasks faster than women with iron deficiency anaemia, and got higher accuracy of cognitive function over a broad range of tasks [52]. Another study also reported the negative effect of maternal anaemia diagnosed postpartum on language comprehension of children [54].

Children under 5 years with iron deficiency anaemia test lower in social‐emotional, cognitive and motor development than control group children [47, 5559]. For motor development, an observational study conducted in African‐America found poorer motor function in iron deficiency infants [56]. Another longitudinal study found lower motor scores in infants with chronic iron deficiency anaemia. In addition, long‐term effect of chronic iron deficiency anaemia in infancy on motor development in early adolescence was exist, and even iron treatment at the age of 12–23 months did not prevent long‐term effect of iron deficiency in infancy on motor development [57]. A study conducted in the United States showed positive effect of iron status of infants at 9 months on gross motor development and motor coordination/sequencing [58]. For cognitive development, a meta‐analysis estimated that a 10 g/L haemoglobin increase was significantly associated with a 1.73 increase in IQ tests [41]. Another study found children with iron deficiency anaemia at 54–60 months age had lower score for verbal reasoning test compared to non‐anaemia children [59].

Iron deficiency anaemia is prevalent in the elderly, particularly after the age of 80 [60]. Chronic blood loss, micronutrient‐related anaemia and renal disease are important mechanisms for low haemoglobin level [61]. A cohort study conducted in Taiwan reported iron deficiency was significantly associated with cardiovascular disease and all‐cause mortality in elderly [62]. A prospective study conducted in Korea found anaemia was associated with physical functioning impairment and instrumental activities of daily living in elderly [63]. A Norwegian prospective study reported the significant association between low iron status and increasing risk of death from ischaemic heart disease [64]. Result from a cross‐sectional study conducted in England reported the significant relationship between iron status and symptoms of depression [65]. Many studies have extensively investigated the association between iron deficiency and productivity [42, 66], because the role of iron in oxygen transport to muscles and other tissues, and in other metabolic pathways by which iron deficiency can cause aerobic work capacity reduction [42]. Previous studies reported the positive effect of iron supplementation on work productivity of female cotton‐mill workers in China, female tea‐plantation workers in Sri Lanka and rubber plantation workers in Indonesia [66, 67]. Iron deficiency would cause work performance reduction and has substantial economic consequences accordingly in countries in which physical labour is prevalent [42, 67].

In summary, the consequences of iron deficiency anaemia in different populations were multiple. For pregnant women with iron deficiency anaemia, the effects were mainly on perinatal mortality, pre‐term birth, low birth weight, offspring intellectual development and motor development. For non‐pregnant women, the effects were mainly on cognitive ability, physical performance and mood. For infant, the effects were mainly focus on further social‐emotional, cognitive and motor development. For elderly, the effects were mostly on cardiovascular disease, all‐cause mortality, physical functioning impairment, instrumental activities of daily living, increasing risk of death from ischaemic heart disease and symptoms of depression. The effect of iron deficiency in adults on work productivity was also reported.

Advertisement

4. Standard diagnosis criteria of iron deficiency anaemia

At the population level, haemoglobin concentration is the most reliable indicator of anaemia. Meanwhile, measurement of haemoglobin concentration is frequently used as a proxy indicator of iron deficiency, because measurement of haemoglobin concentration is relatively inexpensive and easy. According to the criterion of World Health Organization, an adult man is considered as anaemic when the haemoglobin concentration is less than 130 g/L, whereas an adult woman is deemed anaemic when her haemoglobin concentration is less than 120 g/L, and this cut‐off should be lowered to 110 g/L if the woman is in pregnancy. This cut‐off threshold is 115 g/L between 5 and 11 years, and 110 g/L under 5 years (Table 2) [8, 68].

Children (0–14 years)Hb threshold (g/L)Adult (≥15 years)Hb threshold (g/L)
0.5–4 years110Non‐pregnant women120
5–11 years115Pregnant women110
12–14 years120Men130

Table 2.

Haemoglobin threshold in different population.

Patients with severe anaemia can be usually detected by clinical examination such as pallor of eyelids, tongue, palms and nail beds [8, 39, 69]. In poor areas where laboratory testing is not feasible, clinical examination should be regularly used to monitor women and children. As the frequency of conjunctivitis caused redness even in anaemia patients, palm pallor is preferred to eyelid pallor as a clinical sign for diagnosis of young children. But, clinical measures are more subjective and have more room for error accordingly compare to haemoglobin concentration [39].

Because of the complex diagnosis of iron deficiency, use of several indicators in combination could be better for us to assess iron deficiency [8]. First, red cell indices on full blood counts show a reduced mean cell volume, which corresponds to microcytosis, and a reduced mean cell haemoglobin, corresponding to hypochromia. But the thresholds are not commonly agreed [70]. Second, mean cell haemoglobin and volume are widely available, sensitive and inexpensive measures, but these indictors become abnormal only in longstanding iron deficiency. Moreover, mean cell volume could be normal if combined with nutrient deficiency [71].

Serum ferritin measurement is the most sensitive and specific test and widely used to identify iron deficiency [8, 39, 72], but it is spuriously elevate in malignancy, inflammatory conditions or liver disease. Serum ferritin below the cut‐off of 15 µg/L in patients older than 5 years could be diagnosed as iron deficiency [72]. However, results from previous study indicated that if the cut‐off of ferritin level increase to 30 µg/L, the diagnostic accuracy would be improved. The sensitivity would increase from 25 to 92% according, compared with the 12 µg/L (cut‐off value), and specificity was unchanged (98%) [73]. For the patients with malignant disease, acute and chronic inflammatory disorders and liver disease, cut‐off value equal or larger than 50 µg/L could still be iron deficient [4, 72]. Results from previous studies suggested cut‐off of 100 µg/L for patients with chronic kidney disease [74], and suggested increasing cut‐off to 200 µg/L in case of haemodialysis [75].

A low transferrin saturation level (less than 16%) also strongly indicates iron deficiency (iron supply insufficient to support normal erythropoiesis), but the threshold will increase to 20% in patients with inflammation. Because the serum iron will reduce with the increasing of total iron‐binding capacity if the patients with iron deficiency, and finally result in reduction in transferrin saturation [8, 39].

Serum soluble transferrin receptor (sTfR) is another useful biomarker in diagnosis of iron deficiency, and is not influenced by inflammation. The synthesis of transferrin receptors will increase if patients with iron deficiency and lead to an increase in sTfR accordingly [73]. But there are some limitations when using sTfR to determine iron deficiency. One of the limitations is that if the patients with disorders associated with increased erythropoiesis (haemolytic anaemia, chronic lymphocytic leukaemia), concentrations of sTfR can be raised accordingly. Another limitation is that the guidelines are only published in the UK, but standardized cut‐offs worldwide are still absent [75].

Recently, bone marrow aspiration is another option to assess iron stores, and thought of as the highly specific and not affected by inflammation for diagnosis of iron deficiency. But it is not used frequently only when other tests are conflicting or negative. As it is expensive and affected by recombinant human erythropoietin, it is uncomfortable for the patients [8, 39].

For diagnosis of iron deficiency anaemia, it is important to consider the whole picture rather than relying on single test results when determining the iron deficiency. The diagnosis of iron deficiency for the patients with inflammation is challenging and also cannot be determined on the basis of a single test result.

Advertisement

5. Therapy choice in clinical practices

The goals of treating iron deficiency anaemia are to treat its underlying cause and supply enough iron to normalize haemoglobin concentrations and replenish iron stores. Considering its cause and severity of iron deficiency anaemia, treatments may include dietary changes and supplements, medicines and surgery. Severe iron deficiency anaemia may require a blood transfusion, iron injections or intravenous (IV) iron therapy, which may need to be addressed in a hospital.

5.1. Oral iron therapy

Medical care starts with establishing the diagnosis and reason for the iron deficiency. Iron supplementation is used to prevent iron deficiency anaemia in at‐risk populations, or to treat patients with proven disease. Treatment with oral iron supplements is simple, inexpensive and a relatively effective way of treating iron deficient conditions. WHO has recommended daily iron supplementation with 60 mg of elemental iron to prevent iron deficiency in menstruating adolescent girls and women, and 2 mg/kg daily in children aged 0–5 years and 30 mg daily in children aged 5–12 years [7678]. In general, four common iron preparations are often adopted, i.e. ferrous sulphate, ferrous sulphate exsiccated, ferrous gluconate and ferrous fumarate. When side effects occur (dark stools, constipation, stomach irritation and heartburn), iron can be taken with meals, but doing so decreases absorption to 40% [8]. The best source of iron is red meat, especially beef and liver. The body tends to absorb iron from meat better than iron from non‐meat foods. However, some non‐meat foods can also help you raise your iron levels. Furthermore, Vitamin C helps the body absorb iron, whose good sources are vegetables and fruits, especially citrus fruits.

In most patients, the iron deficiency should be treated with oral iron therapy, and the underlying etiology should be corrected so the deficiency does not recur. However, there are cases that iron supplements are inappropriate to patients, for example, those who have a microcytic iron‐overloading disorder (e.g. thalassemia and sideroblastic anaemia).Therefore, it may be necessary to identify the etiology of the anaemia, such as gene mutation related to iron metabolism, occult blood loss undetected with chemical testing of stool specimens; for identification of a source of bleeding that requires endoscopic examinations or angiography; or for treatment of an underlying major illness (e.g. neoplasia and ulcerative colitis).

5.2. Intravenous (IV) iron therapy

The British Society of Gastroenterology guidelines suggest that all patients require iron supplementation and that parenteral iron can be used if oral preparations are not well tolerated. For therapeutic iron supplementation, treatment with IV iron in some clinical situations could present some advantages over oral iron, such as faster and higher increases of haemoglobin (Hb) levels and body iron stores. Friedrisch et al. suggest the main clinical indications for IV iron treatment, which contains post‐gastrectomy/bariatric surgery, anaemia of chronic kidney disease, intestinal malabsorption syndromes, anaemia associated to inflammatory diseases, inflammatory bowel diseases, anaemia of cancer, intolerance to oral iron or non‐compliance to an oral regimen, iron‐refractory iron deficiency anaemias and so on [79].

Recently, three new IV iron compounds (ferric carboxymaltose [FCM], iron isomaltoside 1000 [Monofer®] and Ferumoxytol [FeraHeme®]) have been released for clinical use in patients with Iron Deficiency Anaemia (IDA) [8082]. Do not administer IV iron therapy to patients who should be treated with oral iron, as anaphylaxis may result. Uncommonly, post‐menopausal women are unresponsive to iron supplementation, including parenteral iron, because they have primary defective iron reutilization due to androgen deficiency. This condition responds only to androgen replacement. Danazol is a reasonable choice for these patients, as it is less masculinizing.

Advertisement

6. Public health strategies to reduce iron deficiencies in high‐burden areas

Although the global anaemia burden has been actually improved and age‐standardized prevalence of anaemia was down from 33.3% in 1990 to 27% in 2013, according to the analysis based on 188 countries, 20 age groups, the total population with anaemia increased from 1.83 billion in 1990 to 1.93 billion in 2013 [2]. Developing countries account for more than 89% of the burden, with the greatest prevalence in central and western sub‐Saharan African and greatest number of case in South Asia. Children with the highest burden of anaemia consistently have improved less than adults [2]. Iron deficiency anaemia is the dominant cause of anaemia globally and in most populations, accounting for 62.6% of the total of anaemia cases, and IDA was also the greatest causes of anaemia‐related disability with 60% of total years lived with disability (YLD) [2, 83]. Monitoring and controlling IDA has been the crucial driver of reduced global anaemia burden since 1990 [2, 3]. Individual‐level and population‐level interventions targeted iron deficiency anaemia were implemented and the efficacy and effectiveness of these intervention strategies were also evaluated with a priority in high‐risk, high‐burden population such as pre‐school‐children and pregnant women. Especially, further actions on iron deficiency anaemia prevention and treatment are highly required in order to reach the global nutrition targets of a 50% reduction of anaemia in women of reproductive age by 2025 [84].

The World Health Organization (WHO) has published a series of guidelines that support policies for the prevention and control of iron deficiency anaemia targeted on population in highest burden of IDA [78, 8588]. The most common cause of iron deficiency anaemia in high‐burden areas is prolonged negative iron balance, caused by inadequate dietary iron intake or absorption, increased needs for iron during pregnancy or growth periods, and increased iron losses as a result of menstruation and parasitic infections [84].

Public health strategies to prevent and control iron deficiency anaemia include improvements in dietary diversity; food fortification with iron, folic acid and other micronutrients; distribution of iron‐containing supplements. The efficacy and effectiveness of different strategies were evaluated, based on the evidence from the community‐based large‐scale intervention studies.

Advertisement

6.1. Improvements in dietary diversity

Health education about food and nutrition such as dietary counselling is one of three recommended intervention strategies to decrease the IDA burden. Although dietary counselling commonly resulted in a better dietary intake profile in targeted subpopulation, such as breastfed for longer and had non‐human milk introduced later among infant, consumed more meat and had diets with better iron bioavailability in relation to the children or pregnant women; however, this kind of interventions was not sufficient to prevent occurrence of anaemia, ID or IDA in population with high IDA burden [8991].

6.2. Food fortification with iron

Food fortification as one of the leading public health interventions was recommended to prevent and control micronutrient deficiencies including iron deficiency and iron deficiency anaemia by adding the micronutrients containing iron to processed food vehicles, or home fortification. The choice of processed food vehicles varies widely by region and context, depending on the subpopulation targeted, food consumption and acceptability, food availability and sustainability, as well as the financial and technical concerns. The staple food is the most commonly used as vehicle of fortification, in addition, milk powder, beverages, biscuits, the most commonly used sauce, such as soy sauce, drink and water, can also be used as fortified foods [92104].

More than 80 countries have mandated fortification of wheat and maize flour with at least iron and folic acid in 2015 [93]. A review of efficacy and effectiveness of flour fortification programmes on iron status and anaemia found that flour fortification is associated with consistent reductions in low ferritin prevalence in women, but not in children. Further, a reduction in anaemia prevalence was observed in only one‐third of the subgroups of women and children studied [93].

A recently published review on the effect of multiple micro‐nutrients (MMN) containing iron‐fortified non‐dairy beverages among school‐aged children in low‐middle‐income counties showed a clear benefit of MMN fortified non‐dairy beverages intervention from 8 weeks to 6 months on anaemia (42% reduction in prevalence), iron deficiency (66% reduction in prevalence) and iron deficiency anaemia (83% reduction in prevalence) compared to iso‐caloric controls [99].

Biscuits have been identified to be an ideal vehicle for fortification for school‐aged children due to its convenience with regard to storage, distribution and long shelf life. A nutrition intervention trial conducted in India showed that iron‐fortified biscuits led to a significant enhancement in haemoglobin status of anaemic school children in rural areas [98]. Another study showed that maize porridge fortified with multi‐micronutrient powder contained low dose, highly bioavailable iron can reduce the prevalence of IDA in pre‐school children [102]. Home fortification with multi‐micronutrient powder with low dosages of bioavailable iron may therefore be a promising strategy to improve iron status among children.

A study involved 3029 students of the boarding schools in the 27 provinces in China showed that iron‐fortified soy sauce could be effective for the improvement of the haemoglobin level and reduce anaemia prevalence of boarding school students [97].

The beneficial of fortified complementary feeding supplement on the growth of young children aged 6–23 months have been confirmed by a large number of nutrition intervention programme conducted in population with low socio‐economic status. Furthermore, the risk of anaemia among young children was significantly reduced after the daily fortified complementary feeding supplement introduced to infant diet in rural area, which implied that fortified complementary feeding supplement could be a best intervention strategy target on young children anaemia [105112].

The successful implementation of food fortification programme commonly requires government‐driven and multi‐stakeholder participation, which has also become an obstacle to its sustainability.

6.3. Iron supplementation

Iron supplementation, provided in capsule, tablet or syrup form, is most suitable in contexts where certain subpopulation may not be reached, or when iron requirements may not be met by other intervention strategies.

A series of systematic reviews based on randomized control trial have been carried out to assess the effect of daily iron supplementation on haematologic and non‐haematologic outcomes in high‐burden subpopulations [113119]. In children aged 4–23 months, daily iron supplementation effectively reduces anaemia by 39%, iron deficiency by 70% and iron deficiency anaemia by 86% [117]. In 2–5‐year‐old children, daily iron supplementation increases haemoglobin and ferritin; however, the evidence on the effect of iron supplementation on anaemia, iron deficiency and iron deficiency anaemia is limited [114]. In primary‐school‐aged children (5–12‐year old), iron supplementation reduced the risk of anaemia by 50% and the risk of iron deficiency by 79% [116, 118].

The World Health Organization has published a series of iron supplementation guidelines, which provides global, evidence‐based recommendations on the daily or intermittent use of iron supplements for high‐burden subpopulation as a public health intervention to improve iron status and reduce the risk of iron deficiency anaemia in childhood, adolescence, pregnancy and lactation [8588]. WHO suggested iron supplementation scheme targeted on variety of subpopulation was summarized in Table 3. In summary, the establishment of effective strategies, an integrated, multifactorial and multi‐sectoral approach, is required to achieve IDA control target [84].

Target groupSupplementation compositionSupplement formFrequencyDurationSettings
Anaemic pregnant women120 mg of elemental iron and 400 µg folic acidDailyUntil women's Hb concentration rises to normal, then followed by the standard daily antenatal iron doseWhere prevalence of anaemia in pregnant women is 40% or higher
Non‐anaemic pregnant women30–60 mg of elemental iron and 400 µg folic acidDailyDuring pregnancyWhere prevalence of anaemia in pregnant women is 40% or higher
Non‐anaemic pregnant women120 mg of elemental iron and 2800 µg of folic acidweeklyDuring pregnancyWhere anaemia prevalence among pregnant women is less than 20%
Postpartum womeniron supplementation, alone or combination with folic acid6–12 weeks following deliveryWhere gestational anaemia is of public health concern
Infants and young children aged 6–23 months10–12.5 mg elemental ironDrops/syrupsDailyThree consecutive months in a yearWhere the prevalence of anaemia in infants and young children is 40% or higher
Pre‐school‐age children (24–59 months of age)30 mg elemental ironDrops/syrups/tabletsDailyThree consecutive months in a yearWhere the prevalence of anaemia in infants and young children is 40% or higher
Pre‐school‐age children (24–59 months of age)25 mg of elemental ironDrops/syrupsWeekly3 months of supplementation followed by 3 months of no supplementation after which the provision of supplements should restartWhere the prevalence of anaemia in pre‐school or school‐age children is 20% or higher
School‐age children (5–12 years of age)30–60 mg elemental ironTablets or capsulesDailyThree consecutive months in a yearWhere the prevalence of anaemia in infants and young children is 40% or higher
School‐age children (5–12 years of age)45 mg of elemental ironDrops/syrupsWeekly3 months of supplementation followed by 3 months of no supplementation after which the provision of supplements should restartWhere the prevalence of anaemia in pre‐school or school‐age children is 20% or higher
Menstruating adult women and adolescent girls (non‐pregnant females in the reproductive age group)30–60 mg elemental ironTabletsDailyThree consecutive months in a yearWhere the prevalence of anaemia in menstruating adult women and adolescent girls is 40% or higher

Table 3.

WHO suggested scheme daily iron supplementation in different subpopulation.

Advertisement

7. Conclusion—key results

Considering the complexity of the regulatory network required to maintain iron homeostasis, future fine‐mapping studies, including rare and uncommon variants, and functional studies should be undertaken to better characterize loci and to identify the functional variants directly influencing iron levels in iron deficiency anaemia.

New parameters which can give useful information about the iron availability for erythropoiesis and the erythropoietic activity of the bone marrow, and with stable to inflammatory conditions, should be developed for the early detection of iron deficiency, monitoring effect of iron supplementation and treatment, and discrimination the types of anaemia.

Intravenous iron formulation for rapid and high‐dose replenishment of depleted iron stores with very low immunogenic potential is ideal alternative choice for the treatment of iron deficiency anaemia. Iron supplementation and fortification, as two key public health strategies in reducing the iron deficiency anaemia burden, should be selected in terms of the certain population subgroups targeted. The establishment of effective strategies, an integrated, multifactorial and multi‐sectoral approach, is required to achieve IDA control target.

References

  1. 1. Khambalia AZ, Aimone AM, Zlotkin SH. Burden of anemia among indigenous populations. Nutrition Reviews. 2011;69(12):693-719. DOI: 10.1111/j.1753‐4887.2011.00437.x
  2. 2. Kassebaum NJ. The global burden of anemia. Hematology/Oncology Clinics of North America. 2016;30:247-308. DOI: 10.1016/j.hoc.2015.11.002
  3. 3. Global Burden of Disease Pediatrics Collaboration. Global and national burden of diseases and injuries among children and adolescents between 1990 and 2013‐findings from the global burden of disease 2013 study. JAMA Pediatrics. 2016;170(3):267-287. DOI: 10.1001/jamapediatrics.2015.4276
  4. 4. Kassebaum NJ, Jasrasaria R, Naghavi M, Wulf SK, Johns N, Lozano R, et al. A systematic analysis of global anemia burden from 1990 to 2010. Blood. 2014;123:615-624
  5. 5. Stevens GA, Finucane MM, De‐Regil LM, Paciorek CJ, Flaxman SR, Branca F, et al. Global, regional, and national trends in haemoglobin concentration and prevalence of total and severe anaemia in children and pregnant and non‐pregnant women for 1995-2011: A systematic analysis of population‐representative data. The Lancet Global Health. 2013;1(1):e16‐e25
  6. 6. McDermid JM, Lönnerdal B. Iron. Advances in Nutrition. 2012;3(4):532-533. DOI: 10.3945/an.112.002261
  7. 7. Hurrell R, Egli I. Iron bioavailability and dietary reference values. American Journal of Clinical Nutrition. 2010;91(5):1461S‐1467S. DOI: 10.3945/ajcn.2010.28674F
  8. 8. Lopez A, Cacoub P, Macdougall IC, Peyrin‐Biroulet L. Iron deficiency anaemia. Lancet. 2016;387(10021):907-916. DOI: 10.1016/S0140‐6736(15)60865‐0
  9. 9. Kibangou IB, Bouhallab S, Henry G, Bureau F, Allouche S, Blais A, et al. Milk proteins and iron absorption: Contrasting effects of different caseinophosphopeptides. Pediatric Research. 2005;58(4):731-734. DOI: 10.1203/01.PDR.0000180555.27710.46
  10. 10. Zimmermann MB, Chaouki N, Hurrell RF. Iron deficiency due to consumption of a habitual diet low in bioavailable iron: A longitudinal cohort study in Moroccan children. American Journal of Clinical Nutrition. 2005;81(1):115-121
  11. 11. Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: Regulation of mammalian iron metabolism. Cell. 2010;142(1):24-38. DOI: 10.1016/j.cell.2010.06.028
  12. 12. Kulaksiz H, Gherke DG, Rost A, Janetzko D, Kallinowski T, Bruckner B, et al. Prohepcidin: Expression and cell specific localisation in the liver and its regulation in hereditary haemochromatosis, chronic renall insufficiency, and renal anemia. Gut 2004;53:735-743. DOI: 10.1136/gut.2003.022863
  13. 13. Valore E, Ganz T. Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormon convertase furin. Blood Cells, Molecules and Diseases. 2008;40(1):132-138. DOI: 10.1016/j.bcmd.2007.07.009
  14. 14. Tandara L, Salamunic I. Iron metabolism: Current facts and future directions. Biochemical Medicine (Zagreb). 2012;22(3):311-328
  15. 15. Zhang AS, Enns CA. Molecular mechanisms of normal iron homeostasis. Hematology American Society of Hematology Education Program. 2009:207-214. doi: 10.1182/asheducation-2009.1.207.
  16. 16. Kemna EH, Kartikasari AE, van Tits LJ, Pickkers P, Tjalsma H, Swinkels DW. Regulation of hepcidin: Insights from biochemical analyses on human serum samples. Blood Cells, Molecules and Diseases. 2008;40(3):339-346. DOI: 10.1016/j.bcmd.2007.10.002
  17. 17. Goswami, T, and Andrews, NC. Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. Journal of Biological Chemistry. 2006;281(39):28494-28498. DOI: 10.1074/jbc.C600197200
  18. 18. Gao J, Chen J, Kramer M, Tsukamoto H, Zhang AS, Enns CA. Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin‐induced hepcidin expression. Cell Metabolism. 2009;9(3):217-227. DOI: 10.1016/j.cmet. 2009.01.010
  19. 19. Anderson GJ, Frazer DM, McLaren GD. Iron absorption and metabolism. Current Opinion in Gastroenterology. 2009;25(2):129-135. DOI: 10.1097/MOG.0b013e32831ef1f7
  20. 20. Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nature Genetics. 2006;38(5):531-539. DOI: 10.1038/ng1777
  21. 21. Wang RH, Li C, Xu X, Zheng Y, Xiao C, Zerfas P, et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metabolism. 2005;2(6):399-409. DOI: 10.1016/j.cmet.2005.10.010
  22. 22. Bartnikas TB, Fleming MD. Hemojuvelin is essential for transferrin‐dependent and transferrin‐independent hepcidin expression in mice. Haematologica. 2012;97(2):189-192. DOI: 10.3324/haematol.2011.054031
  23. 23. Hooper JD, Campagnolo L, Goodarzi G, Truong TN, Stuhlmann H, Quigley JP. Mouse matriptase‐2: Identification, characterization and comparative mRNA expression analysis with mouse hepsin in adult and embryonic tissues. Biochemical Journal 2003;373(Pt 3):689-702. DOI: 10.1042/BJ20030390
  24. 24. Silvestri L, Pagani A, Nai A, De Domenico I, Kaplan J, Camaschella C. The serine protease matriptase‐2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metabolism. 2008;8(6):502-511. DOI: 10.1016/j.cmet.2008.09.012
  25. 25. Kloss‐Brandstätter A, Erhart G, Lamina C, Meister B, Haun M, Coassin S, et al. Candidate gene sequencing of SLC11A2 and TMPRSS6 in a family with severe anaemia: Common SNPs, rare haplotypes, no causative mutation. PLoS One. 2012;7(4):e35015. DOI: 10.1371/journal.pone.0035015
  26. 26. Lee P, Peng H, Gelbart T, Beutler E. The IL‐6 and lipopolysaccharide‐induced transcription of hepcidin in HFE, transferrin receptor 2 and beta‐2‐microglobulin‐deficient hepatocytes. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(25):9263-9265. DOI: 10.1073/pnas.0403108101
  27. 27. Kemna EP, Nemeth E, van der Hoeven H, Pickkers, Swinkels D. Time course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS. Blood 2005;106(5):1864-1866. DOI: 10.1182/blood‐2005‐03‐1159
  28. 28. Wrighting D, Andrews NC. Interleukin‐6 induces hepcidin expression through STAT3. Blood 2006;108(9):3204-3209. DOI: 10.1182/blood‐2006‐06‐027631
  29. 29. Pinto JP, Ribeiro S, Pontes H, Thowfeequ S, Tosh D, Carvalho F, et al. Erythropoietin mediates hepcidin expression in hepatocytes through EPOR signaling and regulation of C/EBPalpha. Blood. 2008;111(12):5727-5733. DOI: 10.1182/blood‐2007‐08‐106195.
  30. 30. Tanno T, Bhanu NV, Oneal PA, Goh SH, Staker P, Lee YT, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Natural Medicines. 2007;13:1096-1101. DOI: 10.1038/nm1629
  31. 31. Tanno T, Porayette A, Orapan S, Noh SJ, Byrnes C, Bhupatiraju A, et al. Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood. 2009;114(1):181-186. DOI: 10.1182/blood‐2008‐12‐195503
  32. 32. Blanco‐Rojo R, Baeza‐Richer C, López‐Parra AM, Pérez‐Granados AM, Brichs A, Bertoncini S, et al. Four variants in transferrin and HFE genes as potential markers of iron deficiency anaemia risk: An association study in menstruating women. Nature Medicine (London). 2011;8:69. DOI: 10.1186/1743‐7075‐8‐69
  33. 33. Andreani M, Radio FC, Testi M, De Bernardo C, Troiano M, Majore S, et al. Association of hepcidin promoter c.‐582 A>G variant and iron overload in thalassemia major. Haematologica. 2009;94(9):1293-1296. DOI: 10.3324/haematol.2009.006270
  34. 34. Milet J, Dehais V, Bourgain C, Jouanolle AM, Mosser A, Perrin M, et al. Common variants in the BMP2, BMP4, and HJV genes of the hepcidin regulation pathway modulate HFE hemochromatosis penetrance. American Journal of Human Genetics. 2007;81(4):799-807. DOI: 10.1086/520001
  35. 35. Milet J, Le Gac G, Scotet V, Gourlaouen I, Thèze C, Mosser J, et al. A common SNP near BMP2 is associated with severity of the iron burden in HFE p.C282Y homozygous patients: A follow‐up study. Blood Cells, Molecules and Diseases. 2010;44(1):34-37. DOI: 10.1016/j.bcmd.2009.10.001
  36. 36. Beaumont C, Delaunay J, Hetet G, Grandchamp B, de Montalembert M, Tchernia G. Two new human DMT1 gene mutations in a patient with microcytic anaemia, low ferritinemia, and liver iron overload. Blood. 2006;107:4168-4170. DOI: 10.1182/blood‐2005‐10‐4269
  37. 37. Sarria B, Navas‐Carretero S, Lopez‐Parra AM, Perez‐Granados AM, Arroyo‐Pardo E, Roe MA, et al. The G277S transferrin mutation does not affect iron absorption in iron deficient women. European Journal of Nutrition. 2007;46(1):57-60. DOI: 10.1007/s00394‐006‐0631‐x
  38. 38. Ye H, Jeong SY, Ghosh MC, Kovtunovych G, Silvestri L, Ortillo D, et al. Glutaredoxin 5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts. Journal of Clinical Investigation. 2010;120(5):1749-1761. DOI: 10.1172/JCI40372
  39. 39. WHO. Iron Deficiency Anaemia Assessment, Prevention, and Control: A Guide for Programme Managers. Geneva: World Health Organization; 2001. Available from: http://apps.who.int/iris/bitstream/10665/66914/1/WHO_NHD_01.3.pdf. [Accessed: 15 March 2017]
  40. 40. Petry N, Olofin I, Hurrell RF, Boy E, Wirth JP, Moursi M, et al. The proportion of anemia associated with iron deficiency in low, medium, and high human development index countries: A systematic analysis of national surveys. Nutrients. 2016;8(11):693. DOI: 10.3390/nu8110693
  41. 41. Ezzati M, Lopez AD, Rodgers AA, Murray CJL. Comparative Quantification of Health Risks: Global and Regional Burden of Disease Attributable to Selected Major Risk Factors. Geneva, Switzerland: World Health Organization; 2004. Available from: http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.378.1301&rep=rep1&type=pdf. [Accessed: 15 March 2017]
  42. 42. Balarajan Y, Ramakrishnan U, Özaltin E, Shankar AH, Subramanian SV. Anaemia in low‐income and middle‐income countries. The Lancet. 2012;378(9809):2123-2135. DOI: http://dx.doi.org/10.1016/S0140‐6736(10)62304‐5
  43. 43. Zeng L, Cheng Y, Dang S, Yan H, Dibley MJ, Chang S, et al. Impact of micronutrient supplementation during pregnancy on birth weight, duration of gestation, and perinatal mortality in rural western China: Double blind cluster randomised controlled trial. British Medical Journal. 2008;337:a2001. DOI: https://doi.org/10.1136/bmj.a2001
  44. 44. Levy A, Fraser D, Katz M, Mazor M, Sheiner E. Maternal anemia during pregnancy is an independent risk factor for low birthweight and preterm delivery. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2005;122(2):182-186. DOI: 10.1016/j.ejogrb.2005.02.015
  45. 45. Haider BA, Olofin I, Wang M, Spiegelm an D, Ezzati M, Fawzi WW, et al. Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: Systematic review and meta‐analysis. British Medical Journal. 2013;346:f3443. DOI: 10.1136/bmj.f3443
  46. 46. Abu‐Saad K, Fraser D. Maternal nutrition and birth outcomes. Epidemiologic Reviews. 2010;32:5-25. DOI: https://doi.org/10.1093/epirev/mxq001
  47. 47. Lozoff B, Georgieff MK. Iron deficiency and brain development. Seminars in Pediatric Neurology. WB Saunders 2006;13(3):158-165. DOI: 10.1016/j.spen.2006.08.004
  48. 48. Chang S, Zeng L, Brouwer ID, Kok FJ, Yan H. Effect of iron deficiency anemia in pregnancy on child mental development in rural China. Pediatrics. 2013;131(3):e755‐e763. DOI: 10.1542/peds.2011‐3513
  49. 49. Tran TD, Biggs BA, Tran T, Simpson JA, Hanieh S, Dwyer T, et al. Impact on infants’ cognitive development of antenatal exposure to iron deficiency disorder and common mental disorders. PLoS One. 2013;8(9):e74876. DOI: 10.1371/journal.pone.0074876
  50. 50. Harvey LJ, Armah CN, Dainty JR, Foxall RJ, John Lewis D, Langford NJ, et al. Impact of menstrual blood loss and diet on iron deficiency among women in the UK. British Journal of Nutrition. 2005;94:557-564. DOI: https://doi.org/10.1079/BJN20051493
  51. 51. McClung JP, Karl JP, Cable SJ, Williams KW, Nindl BC, Young AJ, et al. Randomized, double‐blind, placebo‐controlled trial of iron supplementation in female soldiers during military training: Effects on iron status, physical performance, and mood. American Journal of Clinical Nutrition. 2009;90(1):124-131. DOI: 10.3945/ajcn.2009.27774
  52. 52. Murray‐Kolb LE, Beard JL. Iron treatment normalizes cognitive functioning in young women. American Journal of Clinical Nutrition. 2007;85(3):778-787
  53. 53. Pasricha SR, Drakesmith H, Black J, Hipgrave D, Biggs BA. Control of iron deficiency anemia in low‐and middle‐income countries. Blood. 2013;121(14):2607-2617. DOI: 10.1182/blood‐2012‐09‐453522
  54. 54. Hamadani JD, Tofail F, Hilaly A, Mehrin F, Shiraji S, Banu S, et al. Association of post-partum maternal morbidities with children's mental, psychomotor and language devel-opment in rural Bangladesh. Journal of Health, Population and Nutrition.2012 Jun;30(2):193-204
  55. 55. Lozoff B. Iron deficiency and child development. Food and Nutrition Bulletin 2007;28(4_suppl4):S560‐S571
  56. 56. Shafir T, Angulo‐Barroso R, Jing Y, Angelilli ML, Jacobson SW, Lozoff B. Iron deficiency and infant motor development. Early Human Development. 2008;84(7):479-485. DOI: 10.1016/j.earlhumdev.2007.12.009
  57. 57. Shafir T, Angulo‐Barroso R, Calatroni A, Jimenez E, Lozoff B. Effects of iron deficiency in infancy on patterns of motor development over time. Human Movement Science 2006;25(6):821-838. DOI: 10.1016/j.humov.2006.06.006
  58. 58. Shafir Liberzon T, Angulo‐Barroso R, Calatroni A, Angelilli ML, Jacobson SW, Lozoff B. Iron deficiency affects motor development in 9‐month‐old infants. Pediatric Research. 2005;57:1731
  59. 59. Gashu D, Stoecker BJ, Bougma K, Adish A, Haki GD, Marquis GS. Stunting, selenium deficiency and anemia are associated with poor cognitive performance in preschool children from rural Ethiopia. Nutrition Journal. 2016;15(1):38. DOI: 10.1186/s12937‐016‐0155‐z
  60. 60. Fairweather‐Tait SJ, Wawer AA, Gillings R, Jennings A, Myint PK. Iron status in the elderly. Mechanisms of Ageing and Development. 2014;136:22-28. DOI: 10.1016/j.mad.2013.11.005
  61. 61. Santos IS, Scazufca M, Lotufo PA, Menezes PR, Benseñor IM. Causes of recurrent or persistent anemia in older people from the results of the São Paulo Ageing & Health Study. Geriatrics & Gerontology International. 2013;13(1):204-208. DOI: 10.1111/j.1447‐0594.2012.00888.x
  62. 62. Hsu HS, Li CI, Liu CS, Lin CC, Huang KC, Li TC, et al. Iron deficiency is associated with increased risk for cardiovascular disease and all‐cause mortality in the elderly living in long‐term care facilities. Nutrition. 2013;29(5):737-743. DOI: 10.1016/j.nut.2012.10.015
  63. 63. Bang SM, Lee JO, Kim YJ, Lee KW, Lim S, Kim JH, et al. Anemia and activities of daily living in the Korean urban elderly population: Results from the Korean Longitudinal Study on Health and Aging (KLoSHA). Annals of Hematology. 2013;92(1):59-65. DOI: 10.1007/s00277‐012‐1563‐6
  64. 64. Mørkedal B, Laugsand LE, Romundstad PR, Vatten LJ. Mortality from ischaemic heart disease: Sex‐specific effects of transferrin saturation, serum iron, and total iron binding capacity. The HUNT study. European Journal of Cardiovascular Prevention & Rehabilitation. 2011;18(5):687-694. DOI: 10.1177/1741826710390134
  65. 65. Stewart R, Hirani V. Relationship between depressive symptoms, anemia, and iron status in older residents from a national survey population. Psychosomatic Medicine. 2012;74(2):208-213. DOI: 10.1097/PSY.0b013e3182414f7d
  66. 66. Haas JD, Brownlie T 4th. Iron deficiency and reduced work capacity: A critical review of the research to determine a causal relationship. Journal of Nutrition. 2001;131(2S‐2):676-688S; discussion 688-690S
  67. 67. Horton S, Ross J. The economics of iron deficiency. Food Policy. 2003;28:51-75. DOI: https://doi.org/10.1016/S0306‐9192(02)00070‐2
  68. 68. World Health Organization. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity [Internet]. 2011. Available from: http://www.who.int/nutrition/publications/micronutrients/indicators_haemoglobin/en/ [Accessed: 20 January 2017].
  69. 69. Huch Sr R. Iron Deficiency and Iron Deficiency Anaemia. Stuttgart: Thieme; 2006
  70. 70. Jolobe OM. Prevalence of hypochromia (without microcytosis) vs microcytosis (without hypochromia) in iron deficiency. Clinical and Laboratory Haematology. 2000;22:79-80. DOI: 10.1046/j.1365‐2257.2000.00293.x
  71. 71. Goddard AF, James MW, McIntyre AS, Scott BB, and the British Society of Gastroenterology. Guidelines for the management of iron deficiency anaemia. Gut. 2011;60:1309-1316
  72. 72. Guyatt GH, Oxman AD, Ali M, Willan A, McIlroy W, Patterson C. Laboratory diagnosis of iron‐deficiency anemia: An overview. Journal of General Internal Medicine. 1992;7:145-153. DOI: 10.1007/BF02598003
  73. 73. Mast AE, Blinder MA, Gronowski AM, Chumley C, Scott MG. Clinical utility of the soluble transferrin receptor and comparisonwith serum ferritin in several populations. Clinical Chemistry. 1998;44:45-51
  74. 74. Locatelli F, Aljama P, Bárány P, Canaud B, Carrera F, Eckardt KU, et al, and the European Best Practice Guidelines Working Group. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrology Dialysis Transplantation. 2004;19(suppl 2):ii1–ii47
  75. 75. Thomas DW, Hinchliff e RF, Briggs C, Macdougall IC, Littlewood T, Cavill I, and British Committee for Standards in Haematology. Guideline for the laboratory diagnosis of functional iron deficiency. British Journal of Haematology. 2013;161(5):639-648. DOI: 10.1111/bjh.12311
  76. 76. WHO. Guideline: Intermittent Iron and Folic Acid Supplementation in Menstruating Women. Geneva: World Health Organization; 2011. http://apps.who.int/iris/bitstream/10665/44649/1/9789241502023_eng.pdf
  77. 77. Fernández-Gaxiola AC, De-Regil LM. Intermittent iron supplementation for reducing anaemia and its associated impairments in menstruating women. The Cochrane Database of Systematic Reviews. 2011 Dec 7;(12):CD009218. doi: 10.1002/14651858.CD009218.pub2
  78. 78. WHO. Guideline: Intermittent Iron Supplementation for Preschool and School‐age Children. Geneva: World Health Organization; 2011. https://www.ncbi.nlm.nih.gov/books/NBK179850/
  79. 79. Friedrisch JR, Cançado RD. Intravenous ferric carboxymaltose for the treatment of iron deficiency anemia. Revista Brasileira de Hematologia e Hemoterapia. 2015;37(6):400-405. DOI: 10.1016/j.bjhh.2015.08.012
  80. 80. Lyseng‐Williamsom KA, Keating GM. Ferric carboxymaltose: A review of its use in iron‐deficiency anaemia. Drugs. 2009;69(6):739-756. DOI: 10.2165/00003495‐200969060‐00007
  81. 81. Jahn MR, Andreasen HB, Futterer S, Nawroth T, Schunemann V, Kolb U, et al. A comparative study of the physicochemical properties of iron isomaltoside 1000 (Monofer), a new intravenous iron preparation and its clinical implications. European Journal of Pharmaceutics and Biopharmaceutics. 2011;78(3):480-491. DOI: 10.1016/j.ejpb.2011.03.016
  82. 82. Lu M, Cohen MH, Rieves D, Pazdur R. FDA review of ferumoxytol (Feraheme) for the treatment of iron deficiency anemia in adults with chronic kidney disease. American Journal of Hematology. 2010;859(5):315-319
  83. 83. Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2163-2196
  84. 84. World Health Organization. Global Nutrition Targets 2025: Anaemia Policy Brief [Internet]. 2014. Available from: http://www.who.int/nutrition/publications/globaltargets2025_policybrief_anaemia/en/ [Accessed: 20 January 2017]
  85. 85. World Health Organization. WHO Recommendations on Antenatal Care for a Positive Pregnancy Experience [Internet]. 2016. Available from: http://www.who.int/reproductivehealth/publications/maternal_perinatal_health/anc‐positive‐pregnancy‐experience/en/ [Accessed: 20 January 2017]
  86. 86. World Health Organization. Guideline: Daily Iron Supplementation in Postpartum Women [Internet]. 2016. Available from: http://www.who.int/nutrition/publications/micronutrients/guidelines/daily_iron_supp_postpartum_women/en/ [Accessed: 20 January 2017]
  87. 87. World Health Organization. Guideline: Daily Iron Supplementation in Infants and Children [Internet]. 2016. Available from: http://www.who.int/nutrition/publications/micronutrients/guidelines/daily_iron_supp_childrens/en/ [Accessed: 20 January 2017]
  88. 88. World Health Organization. Guideline: Daily Iron Supplementation in Adult Women and Adolescent Girls [Internet]. 2016. Available from: http://www.who.int/nutrition/publications/micronutrients/guidelines/daily_iron_supp_womenandgirls/en/ [Accessed: 20 January 2017]
  89. 89. Bortolini GA, Vitolo MR. The impact of systematic dietary counseling during the first year of life on prevalence rates of anemia and iron deficiency at 12-16 months. Jornal de Pediatria (Rio de Janeiro). 2012;88(1):33-39. DOI: 10.2223/JPED.2156
  90. 90. Imdad A, Yakoob MY, Bhutta ZA. Impact of maternal education about complementary feeding and provision of complementary foods on child growth in developing countries. BMC Public Health. 2011;11(Suppl.3):S25. DOI: 10.1186/1471‐2458‐11‐S3‐S25
  91. 91. Mokori A, Hendriks SL, Oriskushaba P, Oelofse A. Changes in complementary feeding practices and nutrition status in returnee children aged 6-23 months in north Uganda. South African Journal of Clinical Nutrition. 2013;26(4):201-211
  92. 92. Cardoso MA, Augusto RA, Bortolini GA, Oliveira CSM, Tietzman DC, Sequeira LAS, et al. Effect of providing multiple micronutrients in powder through primary healthcare on anemia in young Brazilian children: A multicentre pragmatic controlled trial. PLoS ONE. 2016;11(3):e0151097. DOI: 10.1371/journal.pone.0151097
  93. 93. Pachon H, Spohrer R, Mei Z, and Serdula MK. Evidence of the effectiveness of flour fortification programs on iron status and anemia: A systematic review. Nutrition Reviews. 2015;73(11):780-795. DOI: 10.1093/nutrit/nuv037
  94. 94. Best C, Neufingerl N, Del Rosso JM, Transler C, Van den Briel T, Osendarp S. Can multi‐micronutrient food fortification improve the micronutrient status, growth, health, and cognition of school children? A systematic review. Nutrition Review. 2011;69:186-204
  95. 95. De‐Regil LM, Suchdev PS, Vist GE, Walleser S, Pena‐Rosas JP. Home fortification of foods with multiple micronutrient powders for health and nutrition in children under two years of age (review). Evidence Based Child Health. 2013;8:112-201
  96. 96. Yang Z, Huffman SL. Review of fortified food and beverage products for pregnant and lactating women and their impact on nutritional status. Maternal and Child Nutrition. 2011;7:19-43
  97. 97. Chen D, Sun J, Huang J, Wang L, Piao W, Tang Y, et al. Effects of the iron fortified soy sauce on improving student's anemia in boarding schools. Journal of Hygiene Research. 2016;45(2):221-225
  98. 98. Bal D, Nagesh K, Surendra HS, Chiradoni D, Gomathy G. Effect of Supplementation with iron fortified biscuits on the hemoglobin status of children in rural areas of Shimoga, Karnataka. Indian Journal of Pediatrics. 2015;82(3):253-259. DOI: 10.1007/s12098‐014‐1483‐7
  99. 99. Aaron GJ, Dror DK, Yang Z. Multiple‐Micronutrient fortified Non‐Dairy beverage interventions reduce the risk of anemia and iron deficiency in School‐Aged children in Low‐Middle income countries: A systematic review and Meta‐Analysis. Nutrients. 2015;7:3847-3868. DOI: 10.3390/nu7053847
  100. 100. Bilenko N, Fraser D, Vardy H, Belmaker I. Impact of multiple micronutrient supplementation (“Sprinkles”) on iron deficiency anemia in bedouin Arab and Jewish infants. Israel Medicine Association Journal. 2014;16:434-438
  101. 101. Almeida CA, De Mello ED, Ramos AP, Joao CA, Joao CR, Dutra‐de‐Oliveira JE. Assessment of drinking water fortification with iron plus ascorbic acid or ascorbic acid alone in daycare centers as a strategy to control Iron‐Deficiency anemia and iron deficiency: A randomized blind clinical study. Journal of Tropical Pediatrics. 2014;60(1): 40-46. DOI: 10.1093/tropej/fmt071
  102. 102. Macharia‐Mutie CW, Moretti D, Van den Briel N, Omusundi AM, Mwangi AM, Kok FJ, et al. Maize porridge enriched with a micronutrient powder containing Low‐Dose iron as NaFeEDTA but not amaranth grain flour reduces anemia and iron deficiency in Kenyan Preschool Children. Journal of Nutrition. 2012;142:1756-1763. DOI: 10.3945/in. 112.157578
  103. 103. Thankachan P, Selvam S, Surendran D, Chellan S, Pauline M, Abrams SA, et al. Efficacy of a multi micronutrient‐fortified drink in improving iron and micronutrient status among schoolchildren with low iron stores in India: A randomised, double‐masked placebo‐controlled trial. European Journal of Clinical Nutrition. 2013;67:36-41. DOI: 10.1038/ejcn.2012.188
  104. 104. Bokhari F, Derbyshire EJ, Hickling D, Li W, Brennan CS. A randomized trial investigating an iron‐rich bread as a prophylaxis against iron deficiency in pregnancy. International Journal of Food Sciences and Nutrition. 2012;63(4):461-467. DOI: 10.3109/09637486.2011.634790
  105. 105. Lazzerini M, Rubert L, Pani P. Specially formulated foods for treating children with moderate acute malnutrition in low‐ and middle‐income countries. Cochrane Database of Systematic Reviews. 2013(6). Art. No.: CD009584. DOI: 10.1002/14651858.CD009584.pub2
  106. 106. Sun J, Dai Y, Zhang S, Huang J, Yang Z, Huo J, Chen,C. Implementation of a programme to market a complementary food supplement (Ying Yang Bao) and impacts on anaemia and feeding practices in Shanxi, China. Maternal & Child Nutrition. 2011;7(Suppl 3):96-111
  107. 107. Phu PV, Hoan NV, Salvignol B, Trecge S, Wieringa FK, Dijkhuizen MA, et al. A six‐month intervention with two different types of Micronutrient‐Fortified complementary foods had distinct short‐ and long‐term effects on linear and ponderal growth of Vietnamese infants. The Journal of Nutrition. 2012;142:1735-1740. DOI: 10.3945/jn.111.154211
  108. 108. Campbell RK, Hurley KM, Shamim AA, Shaikh S, Chowdhury ZT, Mehra S, et al. Effect of complementary food supplementation on breastfeeding and home diet in rural Bangladeshi children. America Journal of Clinic Nutrition. 2016;104:1450-1458. DOI: 10.3945/ajcn.116.135509
  109. 109. Christian P, Shaikh S, Shamim AA, Mehra S, Wu L, Mitra M, et al. Effect of fortified complementary food supplementation on child growth in rural Bangladesh: A cluster‐randomized trial. International Journal of Epidemiology. 2015;44(6):1862-1876. DOI: 10.1093/ije/dyv155
  110. 110. Wang YY, Chen CM, Wang FZ, Jia M, Wang KA. Effects of nutrient fortified complementary food supplements on anemia of infants and young children in poor rural of Gansu. Biomedical and Environmental Sciences. 2009;22:194-200
  111. 111. Muslihah N, Khomsan A, Briawan D, Riyadi H. Complementary food supplementation with a small‐quantity of lipid‐based nutrient supplements prevents stunting in 6-12‐month‐old infants in rural West Madura Islan, Indonesia. Asia Pacific Journal of Clinical Nutrition. 2016;25(Suppl 1):S36‐S42. DOI: 10.6133/apjcn.122016.s9
  112. 112. Mangani C, Maleta K, Phuka J, Cheung YB, Thakalakwa C, Dewey K, et al. Effect of complementary feeding with lipid‐based nutrient supplements and corn‐soy blend on the incidence of stunting and linear growth among 6‐ to 18‐month‐old infants and children in rural Malawi. Maternal & Child Nutrition. 2015;11(Suppl. 4):132-143. DOI: 10.111/mcn.12068
  113. 113. Gera T, Sachdev HPS, Nestel P, Sachdev SS. Effect of iron supplementation on haemoglobin response in children: Systematic review of randomised controlled trials. Journal of Pediatric Gastroenterology and Nutrition. 2007;44(4):468-486
  114. 114. Thompson J, Biggs BA, Pasricha SR. Effects of daily iron supplementation in 2‐ to 5‐Year‐Old children: Systematic review and Meta‐analysis. Pediatrics. 2013;131(4):739-753. DOI: 10.1542/peds.2012‐2256
  115. 115. Neuberger A, Okebe J, Yahav D, Paul M. Oral iron supplements for children in malaria‐endemic areas (Review). Cochrane Database of Systematic Reviews. 2016;(2):CD006589. DOI: 10.1002/14651858.CD006589.pub4
  116. 116. Low M, Farrell A, Biggs BA, Pasricha SR. Effects of daily iron supplementation in primary‐school–aged children: Systematic review and meta‐analysis of randomized controlled trials. Canadian Medical Association Journal. 2013;185(17):E791‐E802. DOI: 10.1503/cmaj.130628
  117. 117. Pasricha SR, Hayes E, Kalumba K, Biggs BA. Effect of daily iron supplementation on health in children aged 4-23 months: A systematic review and meta‐analysis of randomised controlled trials. Lancet Global Health. 2013;1:e77‐e86
  118. 118. De‐Regil LM, Jefferds M, Sylvetsky AC, Dowswell T. Intermittent iron supplementation for improving nutrition and development in children under 12 years of age. Cochrane Database of Systematic Reviews. 2011;(12):CD009085. DOI: 10.1002/14651858.CD009085.pub2
  119. 119. Casey GJ, Montresor A, Cavalli‐Sforza LT, Thu H, Phu LB, Tinh TT, et al. Elimination of iron deficiency anemia and soil transmitted helminth infection: Evidence from a Fifty‐four month Iron‐Folic acid and De‐worming program. PLOS Neglected Tropical Diseases. 2013;7(4):e2146. DOI: 10.1371/journal.pntd.0002146

Written By

Lingxia Zeng, Leilei Pei, Chao Li and Hong Yan

Submitted: 05 December 2016 Reviewed: 07 April 2017 Published: 20 December 2017