Iron Deficiency Anemia in Children Residing in High and Low-Income Countries: Risk Factors, Prevention, Diagnosis and Therapy
1 Department of Pediatrics, Hematology/ Oncology Unit, University General Hospital of Alexandroupolis, Thrace, Greece.
2 Democritus University of Thrace Faculty of Medicine, Alexandroupolis, Thrace, Greece.
Received: May 5, 2020
Accepted: June 12, 2020
Mediterr J Hematol Infect Dis 2020, 12(1): e2020041 DOI 10.4084/MJHID.2020.041
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deficiency and iron-deficiency anemia (IDA) affects approximately two
billion people worldwide, and most of them reside in low- and
middle-income countries. In these nations, additional causes of anemia
include parasitic infections like malaria, other nutritional
deficiencies, chronic diseases, hemoglobinopathies, and lead poisoning.
Maternal anemia in resource-poor nations is associated with low birth
weight, increased perinatal mortality, and decreased work productivity.
Maintaining a normal iron balance in these settings is challenging, as
iron-rich foods with good bioavailability are of animal origin and
either expensive and/or available in short supply. Apart from
infrequent consumption of meat, inadequate vitamin C intake, and diets
rich in inhibitors of iron absorption are additional important risk
factors for IDA in low-income countries. In-home iron fortification of
complementary foods with micronutrient powders has been shown to
effectively reduce the risk of iron deficiency and IDA in infants and
young children in developing countries but is associated with
unfavorable changes in gut flora and induction of intestinal
inflammation that may lead to diarrhea and hospitalization. In
developed countries, iron deficiency is the only frequent micronutrient
deficiency. In the industrialized world, IDA is more common in infants
beyond the sixth month of life, in adolescent females with heavy
menstrual bleeding, in women of childbearing age and older people.
Other special at-risk populations for IDA in developed countries are
regular blood donors, endurance athletes, and vegetarians. Several
medicinal ferrous or ferric oral iron products exist, and their use is
not associated with harmful effects on the overall incidence of
infectious illnesses in sideropenic and/or anemic subjects. However,
further research is needed to clarify the risks and benefits of
supplemental iron for children exposed to parasitic infections in
low-income countries, and for children genetically predisposed to iron
Nevertheless, IDA is also frequently identified in certain high-risk groups in developed countries, like infants and toddlers, adolescent females, women of childbearing age, and the elderly. In industrialized countries, iron deficiency is the only frequent micronutrient deficiency. In the U.S., it is estimated that at least 2.7% of toddlers one to two years old suffer from IDA. A review of 44 studies conducted in 19 European countries showed that 2-25% of infants aged 6-12 months were iron deficient, with a higher prevalence in those who were socioeconomically deprived and in those who were drinking cow’s milk during their first year of life. In children aged 12-36 months, prevalence rates of iron deficiency varied between 3% and 48%, while the prevalence of IDA in both age groups was up to 50% in Eastern but below 5% in Western Europe. On the other hand, up to 40% of preschool children in low- and middle-income countries are estimated to be iron deficient and/or anemic. Special populations at risk for IDA in developed countries include indigenous people, newly arrived immigrants, refugees, regular blood donors, endurance athletes and vegetarians.[9,10]
IDA is the ultimate result of untreated iron deficiency, and globally iron deficiency ranks number nine among 26 modifiable risk factors for death included in the Global Burden of Disease project. Regardless of the presence of symptoms, patients with IDA should be treated as early as possible because they are at risk for organ ischemia and further worsening of the anemia unless the underlying cause is relieved, and the bone marrow iron stores refilled. Likewise, children with iron deficiency alone should be treated because sideropenia is associated with long-lasting neurocognitive impairments, decreased learning ability, and altered motor function.[12,13] Febrile seizures, breath-holding spells, and restless leg syndrome have also been shown to be much more prevalent in people with iron deficiency.[14-16] In adolescent and young adult females, isolated iron deficiency is associated with fatigue and cold intolerance that is relieved with appropriate oral iron therapy.
The worldwide prevalence of anemia has slightly decreased in the past 20 years, but the situation remains concerning in Central and Western Africa. In the U.S., despite the decline in iron deficiency prevalence among infants, black, and underprivileged children, iron deficiency prevalence did not change much in toddlers between 1976 and 2002 and remained high in certain groups such as Hispanic, younger and overweight toddlers. In developing countries, the prevalence of anemia (not just IDA) in younger children is close to 50%, and as previously said, about half of this anemia is considered to be due to iron deficiency. This proportion is lower in countries with anemia prevalence more than 40% (see below) and in countries with a very high burden of infectious diseases, where inflammation is a primary contributor to anemia. In developed countries and beyond the fifth year of life, IDA is less common in children of school age and becomes a frequent problem again in adolescent females with heavy menstrual bleeding, pubertal growth spurt, and poor diets, as well as in women of childbearing age and older people.
Dietary Absorption of Iron
Dietary iron exists in two forms, i.e., as heme iron derived from hemoglobin and myoglobin in meat and as nonheme iron that can be extracted from plants and dairy foods. The bioavailability of heme iron is substantially higher (up to 25%), but even in developed countries, most dietary iron is absorbed in the form of nonheme iron. The bioavailability of the latter is only 5-10% and is adversely affected by consumption of phytates in cereals and vegetables, and the consumption of polyphenols, tannins, and oxalates that are contained in vegetables, some fruits, legumes, coffee, and tea. Vitamin C increases the absorption of dietary iron. Table 1 shows plant foods that reduce iron absorption, while Table 2 displays the daily recommended iron requirements by age.
|Table 1. Plant foods that reduce iron absorption.|
|Table 2. Recommended dietary allowance (RDA) for iron by age (modified from reference 23).|
IDA results from a reduction of the body’s iron content due to blood loss, inadequate iron supply, decreased absorption of iron, or a combination of the above factors. Inflammation diverts iron from the bone marrow, where erythropoiesis takes place to storage sites of the reticuloendothelial system in the liver and spleen, leading to iron-restricted erythropoiesis and anemia. The peptide hepcidin is the master regulator of intestinal iron absorption and tissue iron distribution by inducing degradation of the cellular iron exporter ferroportin. Ferroportin transfers iron into plasma after its absorption from the basolateral surface of the enterocytes, and stored iron from macrophages and hepatocytes that recycle heme from senescent erythrocytes. Any infectious disease and/or inflammatory condition upregulates hepcidin expression through interleukin 6 (IL-6) and decreases iron absorption. The upregulated IL-6 is responsible for the characteristic hyposideremic response to acute inflammation. Hence, chronic heart failure, chronic kidney disease, inflammatory bowel diseases, autoimmune rheumatic diseases, and obesity-a frequently overlooked inflammatory condition that is almost exclusively limited in developed countries-are associated with decreased iron absorption. Hepcidin blood levels are indeed higher in obese than normal-weight individuals, and this limits iron absorption, hinters iron fortification and leads to increased sequestration of iron in macrophages.
Risk Factors and Prevention of IDA
Under these circumstances, the fortification of foods with iron is considered as the most cost-effective approach in reducing the prevalence of iron deficiency and its anemia. Fortification of foods implies the addition of iron-containing substances to the product recipe, either as isolated compounds (e.g., iron salts or chelates) or as iron-rich ingredients (e.g., meat or its derivatives). The choice depends on the desired product characteristics, including taste and color, and maybe restricted by cost and availability. Because of iron’s oxidation-reduction properties, it can lead to chemical instability in the food matrix. Thus, the industry uses insoluble, poorly soluble, or strongly chelated iron compounds, all of which have limited chemical reactivity. However, both solubility and chemical availability are necessary for the effective absorption of nonheme iron.
WHO guidelines suggest in infants and toddlers 6-23 months of age fortification of complementary foods with iron-containing micronutrient powders (MNPs), which should include 12.5 mg of elemental iron per sachet, preferably as coated ferrous fumarate, corresponding to 37.5 mg of ferrous fumarate or 62.5 mg of ferrous sulfate heptahydrate or other equivalent amounts in the various iron compounds. In children 6-12 months old, sodium iron EDTA (NaFeEDTA) is not recommended. The same guidelines suggest fortification of complementary foods with iron-containing MNPs in children 2-12 years, including 12.5 mg of elemental iron for children aged 2-4 years and 12.5 to 30 mg elemental iron for children 5-12 years of age. If NaFeEDTA is selected as a source of iron, the dose of elemental iron should be reduced by 3-6 mg due to its higher bioavailability. The UNICEF’s MNP product contains 10 mg of iron per sachet, as coated ferrous fumarate, NaFeEDTA or ferrous bis-glycinate.
In-home iron fortification of complementary foods with MNPs has been shown to effectively reduce the risk of iron deficiency in children less than two years of age in low-income countries without changing their customary diet. Unfortunately, MNPs are associated with unfavorable changes in gut flora and induction of intestinal inflammation that may lead to diarrhea and increased risk of hospitalization.[32,33] Moreover, the benefits of this intervention on survival or the developmental outcomes of infants and toddlers are unclear. Thus, MNPs cannot be considered as an ideal substitute for meat.
Another major problem with universal iron fortification is the risk of iron overload in people with hereditary hemochromatosis and hemoglobinopathies. Hereditary hemochromatosis is the most common autosomal recessive disorder in Caucasians, with a prevalence of 1 in 300 to 500 individuals. The worldwide frequency of the H63D mutation in the HFE protein is about 8.1%, and of the C282Y mutation 1.9%. Men are affected with hemochromatosis around 2 to 3 times as often as women, and iron overload usually appears after the age of 40 years in men and after the age of 50 years in women because menstruation increases iron removal. Hemochromatosis has the same prevalence in Europe, Australia, and other Western countries, but is less common among patients of African descent. Thus, Caucasians have a six times higher risk of developing the disease than blacks. Therefore, universal iron fortification of foods may be safe in Africa but might be hazardous in countries with a predominantly Caucasian population, although more research is needed to confirm or refute this concern.
In developed countries, dietary mistakes and gastrointestinal and genital blood loss are the most common etiologies of IDA. In industrialized nations, incorrect dietary habits such as prolonged breastfeeding without iron supplementation beyond the fourth month of life, decreased consumption of iron-fortified milk, the introduction of fresh cow’s milk before the first birthday, cow’s milk consumption > 500 mL/day, daytime bottle use beyond the twelfth month of life, bottle use in bed, preferred consumption of poultry over red meat, and vegan diets are associated with IDA. Moreover, celiac disease, symptomatic giardiasis, gastrectomy, decreased gastric acidity, and inadequate oral iron intake for cultural or religious reasons are causes of iron deficiency and IDA through decreased iron supply.[37,38] On the other hand, prolonged and/or heavy menses, use of intrauterine devices over contraceptive pills for birth control, traumatic or operative blood loss, blood donation, inflammatory bowel diseases, gastrointestinal bleeding due to antithrombotic, antiplatelet or non-steroidal anti-inflammatory drugs and congenital or acquired bleeding disorders predispose to iron deficiency and IDA due to blood loss. In all countries, long-lasting Helicobacter pylori infections, and in developing countries, hookworm infestation and schistosomiasis are additional risk factors for IDA. Regarding hookworm infection, it is one of the most common tropical diseases in the world, and despite its frequent association with IDA in developing countries, it often remains untreated. Iron refractory iron deficiency anemia (IRIDA) is a rare autosomal recessive disorder of iron metabolism characterized by IDA unresponsive to oral iron but partially responsive to parenteral iron therapy. IRIDA is caused by mutations in the TPMRSS6 gene and is a very infrequent cause of IDA in all countries. Table 3a summarizes known risk factors for IDA based on etiology and Table 3b main risk factors for IDA in low-and high-income countries.
|Table 3a. Risk factors for IDA by cause.|
|Table 3b. Main risk factors for IDA in low-income and developed countries.|
Although the total body iron content is regulated by iron absorption and is highly conserved, rapid body growth, menstruation, and pregnancy require additional iron supply. Premature neonates are also frequently iron deficient because most of the iron accumulates during the third trimester of pregnancy. Thus, the prevention of IDA in children is feasible by avoiding breastfeeding without the administration of iron supplements beyond the fourth month of life, in addition to using infant formulas high in elemental iron (>6.7mg/L) and consuming meat products. Delayed cord clamping increases the neonate’s body iron stores and may decrease the risk of IDA in the first six months of life. Consumption of large amounts of fresh cow’s milk by infants and toddlers negatively affects their iron stores because of its low iron content, the frequent occurrence of occult gastrointestinal bleeding associated with cow’s milk, and the inhibition of nonheme iron absorption by the casein and calcium of milk.
For the prevention of IDA, the American Academy of Pediatrics recommends infants born at <37 weeks’ gestation who breastfeed should receive elemental iron at 2 mg/kg/day, as medicinal iron or iron-fortified milk or complementary foods starting after the first month and extending through twelve months of life. Exclusively breastfed term infants should receive an iron supplement of 1 mg/kg/day, starting at four months and continued until iron-containing complementary foods have been introduced. Term infants who receive iron-fortified formula do not require medicinal iron unless they have other risk factors for IDA. Properly fed toddlers do not require medicinal iron supplements in developed countries. However, if the diet has low iron content, medicinal or over the counter supplements containing iron alone or along with vitamins and other minerals are effective.
Diagnosis of IDA
From a biochemical perspective, IDA is characterized by low serum iron, low serum ferritin, decreased transferrin saturation, increased total iron-binding capacity, elevated soluble serum transferrin receptors (sTfR), elevated serum zinc protoporphyrin (ZnPP) and low serum hepcidin-25, the active form of hepcidin. Ferritin can be misleading in children with IDA and concurrent infections, as it is an acute-phase protein. Unfortunately, measurements of sTfR and ZnPP are not widely available and are expensive, while hepcidin is almost exclusively used for research purposes considering the lack of a gold standard measurement assay and pending resolution of the international efforts for harmonization.
In the last two decades, the percentage of hypochromic erythrocytes and especially CHr (hemoglobin content of reticulocytes or RET-He) have emerged as reliable indicators of IDA and response to iron therapy.[49,50] CHr measures the functional iron available for erythropoiesis over the previous three days and is an early indicator of iron-restricted erythropoiesis, i.e., the second stage of iron deficiency before the development of overt anemia. Moreover, CHr, unlike ferritin, is not affected by inflammation. A pediatric Italian study showed that CHr along with absolute reticulocyte count was able to detect among patients with IDA the early responders to oral iron therapy so that unresponsive children could be offered alternative therapies.
Table 4 summarizes the standard hematologic and biochemical features of IDA. It should be emphasized that the estimates of the prevalence of iron deficiency and IDA that are available from low-income countries are mostly indirect since only hemoglobin is measured with simple field-based techniques, while ferritin or other indicators of iron status are not routinely determined due to cost.
|Table 4. Hematologic and biochemical features of IDA.|
IDA Screening Recommendations
WHO recommends targeted screening for IDA in children and pregnant women prior to iron administration if anemia prevalence is >5% and guidelines for the management of iron-deficient patients exist. The American Academy of Pediatrics recommends universal screening of infants for IDA at one year of age because it considers the condition to be highly prevalent and easily treatable. In contrast, the U.S. Preventive Services Task Force considers there is insufficient evidence to recommend for or against routine screening for IDA in asymptomatic children 6-12 months old but recommends such screening in all pregnant women. Finally, the Centers for Disease Control and Prevention recommends targeted screening for selected children at high-risk for IDA, such as premature infants, infants living in poverty, refugees, those fed a low-iron or unfortified formula, or who continue to breastfeed without iron supplementation after six months. We also believe that targeted rather than universal screening for IDA may be more cost-effective, but high-quality scientific evidence is clearly missing.
Treatment of IDA with Oral Iron Products
|Table 5. Available oral iron medicinal products for prevention and treatment of iron deficiency and IDA.|
Oral iron supplementation in third world countries is associated with increased risk of parasitemia in children with malaria, but this side effect is insignificant in areas where concrete malaria surveillance and control exist. Moreover, a systematic review of 28 randomized controlled clinical trials of iron supplementation or fortified formula milk or cereals in children did not show any apparent harmful effect on the overall incidence of infectious illnesses, although it slightly increased the risk of diarrhea.
Oral iron supplements acutely elevate serum hepcidin levels, but the duration and extent of the increase, its dependence on the administered iron dose, and its effects on iron absorption have only recently been studied in humans. Moretti et al. recruited 54 iron-deficient but non-anemic young women. By using radiolabeled iron, they showed that with increasing dose, the fractional absorption of oral iron significantly decreased, while absolute absorption increased. A six-fold increase in iron dose, i.e., from 40 to 240 mg, resulted in only a threefold increase in iron absorption. Providing lower doses, i.e., 40 to 80 mg of elemental iron and avoiding twice-daily dosing, maximized fractional absorption. These results were confirmed by two studies funded by the Swiss National Science Foundation that showed that in iron-depleted women, the administration of iron supplements daily as divided doses increases serum hepcidin and reduces iron absorption. Hence, providing iron supplements in single doses and on alternate days optimizes iron absorption and might be a better dosing regimen, although further investigations are required in anemic, not just sideropenic patients.
Several issues require consideration when choosing oral iron therapy. First, a product with good bioavailability needs to be chosen. Second, a clinically effective and well-tolerated dose should be used. Finally, the number of daily doses should be minimized in order to improve compliance with lengthy oral iron therapy. Unless the patient continues to bleed or cannot adequately absorb iron, oral iron therapy is expected to increase the hemoglobin after two to three weeks with full correction of IDA by two months unless the anemia was particularly severe at the start of therapy. A less than 1 g/dL increase in hemoglobin after two weeks of therapy is a frequently used criterion for assessing response to oral iron therapy, although, in all patients with IDA, oral therapy should be continued for several months after anemia is corrected to replenish body iron stores.
The existing dosing recommendations for all oral iron products in children are mainly empirical. Few clinical studies exist comparing different oral iron products. Kruske et al. performed a randomized, unblinded clinical trial in children < 6 years of age with anemia in an aboriginal community in Australia. Oral F.S. was prescribed at 3 mg/kg/day as a single daily unsupervised dose and was compared to twice weekly supervised administration over three months. Remarkably enough, oral F.S. as directly observed twice-weekly treatment was superior to unsupervised daily therapy. Zlotkin et al. performed a randomized study of liquid F.S. for two months in 557 anemic children aged 6-24 months in rural Ghana. Patients received 40 mg of elemental iron once daily versus 40 mg in three divided doses. Successful treatment of IDA occurred in 61% of those receiving a single dose versus 56% of the three times daily group. Side effects were minimal and did not differ between the two groups. Bopche et al. assessed the clinical response and side effects of F.S. and IPC in 118 children with IDA. All patients were given elemental iron 6 mg/kg/day in three divided doses. Patients who received F.S. had significantly higher hemoglobin and fewer residual complaints compared to those who received IPC. However, gastrointestinal side effects were more common with F.S. (7.6% versus 17%). Sheikh et al. randomized 70 toddlers with IDA to receive F.S. or IPC at 6 mg/kg/day of elemental iron in three divided doses. Response and compliance with therapy were similar in both groups. Mahmood et al randomized 170 children with IDA to receive F.S. or IPC at 6 mg/kg/day once daily for four weeks. Rise in hemoglobin was significantly higher in children treated with F.S. (87.1% versus 70.6%). Powers et al randomized 80 infants and children aged 9 to 48 months with nutritional IDA to 3 mg/kg/day of elemental iron once daily for three months as either F.S. or IPC drops. The mean hemoglobin increased 1g/dL more in those who received F.S., and the proportion of children with complete resolution of IDA at the end of therapy was also significantly higher in the F.S. group (29% versus 6%). Both iron products were well-tolerated, but there were significantly more reports of diarrhea in the IPC group. Mehta described a case series of patients from India who failed to respond to oral IPC therapy, while the same patients responded well to oral administration of ferrous fumarate. Ruiz-Arguelles also showed that among 240 adults with IDA who received oral IPC, 31% failed to respond. Yasa et al. randomized 103 children aged >6 months with IDA to IPC once daily or F.S. twice daily at 5 mg/kg/day. Efficacy was comparable, but IPC was associated with fewer gastrointestinal adverse events and better treatment acceptability. Investigators from Greece randomized 100 children with iron deficiency or IDA to receive iron protein succinylate or IPC at 4 mg/kg/day elemental iron to a maximum daily dose of 80 mg for two months. Both drugs were well tolerated, but iron protein succinylate led to a faster hematologic response. Cancelo-Hidalgo et al. performed a systematic review of the tolerability of different iron supplements and found that ferrous fumarate had the highest rate of adverse events (47%) followed by F.S. and ferrous gluconate (32% and 30.9% respectively). Among all oral iron products, ferrous glycine sulfate, iron protein succinylate, and F.S. combined with mucoproteose were those better tolerated. Regarding liposomal (sucrosomial) iron, a multicenter study of the Associazione Italiana Emato-Oncologia Pediatrica documented its excellent tolerance, i.e., the complete absence of gastrointestinal side effects, but the limited number of patients with mild IDA treated limits the conclusions that can be drawn regarding the clinical efficacy of this formulation in children.
Based on the above-limited data, for infants and children with IDA we recommend therapy with oral F.S., 3 mg/kg in elemental iron, administered once daily (oral drops in infants, syrup in younger children, tablets in older ones). Higher doses of F.S. up to 4-6 mg/kg/day in divided doses are unlikely to be more effective and are associated with more frequent gastrointestinal intolerance. If F.S. is not tolerated, IPC can be used (oral drops, syrup or tablets) at a daily dose of 3-5 mg/kg in one or two doses with meals, but the response is slower compared to F.S. It is crucial to educate parents of children with IDA that for optimal absorption, F.S. should be given 30 minutes to two hours before or after meals with water or orange juice and that milk products should be avoided because they substantially decrease the absorption of elemental iron. IPC products can be used as an alternative in children who demonstrate gastrointestinal intolerance to F.S. Since the iron in IPC products is complex-bound, ionic interactions with food are unlikely,  and the medication can be ingested with a meal or shortly thereafter which is a practical advantage in infants. Iron protein succinylate and iron acetyl aspartylate, both available in single-dose potable vials of 80 mg, should be used in patients who cannot tolerate cheaper oral iron products. Finally, more studies of the innovative oral sucrosomial and the other liposomal oral iron products are required in order to document their efficacy in children with IDA.
The recommended duration of oral iron therapy is usually three months, but the duration should be adjusted to achieve normalization of hemoglobin, MCV, MCH, reticulocyte count, and serum ferritin. In addition, dietary modifications to address the underlying mechanisms of IDA are essential. More specifically, the amount of consumed milk should be limited to no more than 500 mL/day in toddlers, and rational consumption of meat products should be promoted.
Parenteral Iron Therapy
|Table 6. Indications for intravenous iron therapy in children.|
- Worldwide prevalence of anaemia 1993-2005: WHO
global database on anaemia, Edited by: de Benoist B, McLean E, Egli I,
Cogswell M. WHO Library Cataloguing-in-Publication Data. ISBN
- 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.
JG, Friedman JF. Iron deficiency anemia: focus on infectious diseases
in lesser developed countries. Anemia. 2011;2011:260380.
https://doi.org/10.1155/2011/260380 PMid:21738863 PMCid:PMC3124144
MM, Abe SK, Rahman MS, Kanda M, Narita S, Bilano V, Ota E, Gilmour S,
Shibuya K. Maternal anemia and risk of adverse birth and health
outcomes in low- and middle-income countries: systematic review and
meta-analysis. Am J Clin Nutr. 2016;103(2):495-504.
RL, West K.P. Jr, Black RE. The epidemiology of global micronutrient
deficiencies. Ann Nutr Metab. 2015;66 (Suppl 2):22-33.
PM, Perrine CG, Mei Z, Scanlon KS. Iron, anemia, and iron deficiency
anemia among young children in the United States. Nutrients. 2016;8(6).
pii: E330. https://doi.org/10.3390/nu8060330 PMid:27249004
- Eussen S, Alles M,
Uijterschout L, Brus F, van der Horst-Graat J. Iron intake and status
of children aged 6-36 months in Europe: a systematic review. Ann Nutr
Metab. 2015;66(2-3):80-92. https://doi.org/10.1159/000371357
- Armitage AE, Moretti D. The
importance of iron status for young children in low- and middle-income
countries: a narrative review. Pharmaceuticals (Basel). 2019;12(2).
pii: E59. https://doi.org/10.3390/ph12020059 PMid:30995720
- Swinkels H, Pottie K,
Tugwell P, Rashid M, Narasiah L; Canadian Collaboration for Immigrant
and Refugee Health (CCIRH). Development of guidelines for recently
arrived immigrants and refugees to Canada: Delphi consensus on
selecting preventable and treatable conditions. CMAJ.
- Marx JJ.
Iron deficiency in developed countries: prevalence, influence of
lifestyle factors and hazards of prevention. Eur J Clin Nutr.
- GBD 2015 Disease and
Injury Incidence and Prevalence Collaborators. Global, regional, and
national incidence, prevalence, and years lived with disability for 310
diseases and injuries, 1990-2015: a systematic analysis for the Global
Burden of Disease Study 2015. Lancet. 2016;388(10053):1545-1602.
RD, Greer FR. Committee on Nutrition American Academy of Pediatrics.
Diagnosis and prevention of iron deficiency and iron-deficiency anemia
in infants and young children (0-3 years of age). Pediatrics.
- Lozoff B, Georgieff MK.
Iron deficiency and brain development. Semin Pediatr Neurol. 2006
- Jang HN, Yoon HS, Lee EH.
Prospective case control study of iron deficiency and the risk of
febrile seizures in children in South Korea. BMC Pediatr.
2019;19(1):309. https://doi.org/10.1186/s12887-019-1675-4 PMid:31484495
- Tomoum H, Habeeb N,
Elagouza I, Mobarez H. Paediatric breath-holding spells are associated
with autonomic dysfunction and iron deficiency may play a role. Acta
Paediatr. 2018;107(4):653-657. https://doi.org/10.1111/apa.14177
- Howard H, Kamat D.
Restless legs syndrome in children. Pediatr Ann. 2018;47(12):e504-506.
BL, Hurrie D, Graham J, Perija B, Rimmer E, Rabbani R, Bernstein CN,
Turgeon AF, Fergusson DA, Houston DS, Abou-Setta AM, Zarychanski R.
Efficacy of iron supplementation on fatigue and physical capacity in
non-anaemic iron-deficient adults: a systematic review of randomised
controlled trials. BMJ Open. 2018;8(4):e019240.
- Brotanek JM, Gosz J,
Weitzman M, Flores G. Secular trends in the prevalence of iron
deficiency among U.S. toddlers, 1976-2002. Arch Pediatr Adolesc Med.
- De Andrade Cairo RC,
Rodrigues Silva L, Carneiro Bustani N, Ferreira Marques CD. Iron
deficiency anemia in adolescents; a literature review. Nutr Hosp.
- Powers JM,
Buchanan GR. Disorders of iron metabolism: new diagnostic and treatment
approaches to iron deficiency. Hematol Oncol Clin North Am.
2019;33:393-408. https://doi.org/10.1016/j.hoc.2019.01.006 PMid:31030809
AS, Enns CA. Iron homeostasis: recently identified proteins provide
insight into novel control mechanisms. J Biol Chem.
B, Olivares M, Cori H. Enhancers of iron absorption: ascorbic acid and
other organic acids. Int J Vitam Nutr Res. 2004;74(6):403-419.
for Disease Control and Prevention. Recommendations to prevent and
control iron deficiency in the United States. MMWR Recomm Rep.
YZ. Hepcidin-ferroportin axis in health and disease. Vitam Horm.
2019;110:17-45. https://doi.org/10.1016/bs.vh.2019.01.002 PMid:30798811
MP, Meynard D, Coppin H. Regulators of hepcidin expression. Vitam Horm.
- Weiss G, Ganz T, Goodnough
LT. Anemia of inflammation. Blood. 2019;133(1):40-50.
- Olivares M, Walter T,
Hertrampf E, Pizarro F. Anaemia and iron deficiency disease in
children. Br Med Bull. 1999;55(3):534-543.
S, Stoltzfus R, Rawat R. Critical review of strategies to prevent and
control iron deficiency in children. Food Nutr Bull. 2007;28(Suppl
4):S610-620. https://doi.org/10.1177/15648265070284S413 PMid:18297898
S, PenaRosas JP, Velazquez FB. WHO Department of Nutrition for Health
and Development. Multiple Micronutrient Powders for Point-of-Use
Fortification of Foods Consumed by Infants and Children 6-23 Months of
Age and Children Aged 2-12 Years. November 29, 2018.
- Unicef. Multiple micronutrient pdr,sach./PAC-30.
PS, Jefferds MED, Ota E, da Silva Lopes K, De-Regil LM. Home
fortification of foods with multiple micronutrient powders for health
and nutrition in children under two years of age. Cochrane Database
Syst Rev. 2020;2:CD008959.
G. Dietary iron supplementation: a proinflammatory attack on the
intestine? Gut. 2015;64(5):696-697.
T, Kortman GA, Moretti D, Chassard C, Holding P, Dostal A, Boekhorst J,
Timmerman HM, Swinkels DW, Tjalsma H, Njenga J, Mwangi A, Kvalsvig J,
Lacroix C, Zimmermann MB. Iron fortification adversely affects the gut
microbiome, increases pathogen abundance and induces intestinal
inflammation in Kenyan infants. Gut. 2015;64(5):731-742.
FT. Micronutrient powders to combat anemia in young children: does it
work? BMC Med. 2017;15(1):99. https://doi.org/10.1186/s12916-017-0867-8
AT, Pointon JJ, Shearman JD, Robson KJ. Global prevalence of putative
haemochromatosis mutations. J Med Genet. 1997;34(4):275-278.
https://doi.org/10.1136/jmg.34.4.275 PMid:9138148 PMCid:PMC1050911
M.J., Skoien R, Powell LW. The global burden of iron overload. Hepatol
Int. 2009;3(3):434-444. https://doi.org/10.1007/s12072-009-9144-z
- Burke RM,
Leon JS, Suchdev PS. Identification, prevention and treatment of iron
deficiency during the first 1000 days. Nutrients. 2014;6(10):4093-4114.
https://doi.org/10.3390/nu6104093 PMid:25310252 PMCid:PMC4210909
PC, DeGroot J, Maguire JL, Birken CS, Zlotkin S. Severe iron-deficiency
anaemia and feeding practices in young children. Public Health Nutr.
- Annibale B, Marignani M,
Monarca B, Antonelli G, Marcheggiano A, Martino G, Mandelli F, Caprilli
R, Delle Fave G. Reversal of iron deficiency anemia after Helicobacter
pylori eradication in patients with asymptomatic gastritis. Ann Intern
A, Hotez PJ, Diemert D, Yazdanbakhsh M, McCarthy JS, Correa-Oliveira R,
Croese J, Bethony JM. Hookworm infection. Nat Rev Dis Primers.
2016;2:16088. https://doi.org/10.1038/nrdp.2016.88 PMid:27929101
M, Sarbay H, Guler S, Balci YI, Polat A. Response to parenteral iron
therapy distinguish unexplained refractory iron deficiency anemia from
iron-refractory iron deficiency anemia. Int J Lab Hematol.
2016;38:167-171. https://doi.org/10.1111/ijlh.12462 PMid:26818204
MM, Finberg KE. Iron-refractory iron deficiency anemia (IRIDA). Hematol
Oncol Clin North Am. 2014;28(4):637-652, v.
M, Abenhaim HA. Early versus delayed cord clamping in term and preterm
births: a review. J Obstet Gynaecol Can. 2012;34(6):525-531.
EE. Consumption of cow's milk as a cause of iron deficiency in infants
and toddlers. Nutr Rev. 2011;69 (Suppl 1):S37-42.
C. Iron nutriture of the fetus, neonate, infant, and child. Ann Nutr
Metab. 2017;71 (Suppl 3):8-14. https://doi.org/10.1159/000481447
- Keung YK,
Owen J. Iron deficiency and thrombosis: literature review. Clin Appl
Thromb Hemost. 2004;10(4):387-391.
CM, Kelly J, Trail A, Parkinson KN, Summerfield G. The diagnosis of
borderline iron deficiency: results of a therapeutic trial. Arch Dis
Child. 2004;89(11):1028-1031. https://doi.org/10.1136/adc.2003.047407
D, Nemeth E, Swinkels DW. Hepcidin in the diagnosis of iron disorders.
- Brugnara C. Iron
deficiency and erythropoiesis: new diagnostic approaches. Clin Chem.
2003;49(10):1573-1578. https://doi.org/10.1373/49.10.1573 PMid:14500582
C. Iron deficiency: new insights into diagnosis and treatment.
Hematology Am Soc Hematol Educ Program. 2015;2015:8-13.
E, Giraudo MT, Davitto M, Ansaldi G, Mondino A, Garbarini L, Franzil A,
Mazzone R, Russo G, Ramenghi U. Reticulocyte parameters: markers of
early response to oral treatment in children with severe
iron-deficiency anemia. J Pediatr Hematol Oncol. 2012;34(6):e249‐e252.
S, Barfar E, Hosseini H, Barooti E, Rashidian A. Cost-effectiveness of
Anemia Screening in Vulnerable Groups: A Systematic Review. Int J Prev
- Assessing the
iron status of populations: report of a joint World Health
Organization/ Centers for Disease Control and Prevention technical
consultation on the assessment of iron status at the population level,
Geneva, Switzerland, 6-8 April 2004. Geneva: World Health Organization,
Centers for Disease Control and Prevention; 2005.
AR, Fan T, Grossman DC, Phipps MG. Gaps in evidence regarding iron
deficiency anemia in pregnant women and young children: summary of U.S.
Preventive Services Task Force recommendations. Am J Clin Nutr.
2017;106(Suppl 6):1555S-1558S. https://doi.org/10.3945/ajcn.117.155788
P. Ferrous versus ferric oral iron formulations for the treatment of
iron deficiency: a clinical overview. Scientific World Journal.
2012;2012:846824. https://doi.org/10.1100/2012/846824 PMid:22654638 PMCid:PMC3354642
- Nagpal J, Choudhury P. Iron formulations in pediatric practice. Indian Pediatr. 2004;41:807-815.
A, Brilli E, Fogli S, Beconcini D, Carpi S, Tarantino G, Zambito Y.
Sucrosomial® iron absorption studied by in vitro and ex-vivo models.
Eur J Pharm Sci. 2018;111:425‐431. https://doi.org/10.1016/j.ejps.2017.10.021 PMid:29055735
K.M., Banjar ZM, Hariri AH, Hassan AH. Solid lipid nanoparticles loaded
with iron to overcome barriers for treatment of iron deficiency anemia.
Drug Des Devel Ther. 2015;9:313‐320. https://doi.org/10.2147/DDDT.S77702 PMid:25609917 PMCid:PMC4293289
GO, Pereira DI, Tempest B, Ilyas H, Flynn AC, Aslam MF, Simpson RJ,
Powell JJ. A nanoparticulate ferritin-core mimetic is well taken up by
HuTu 80 duodenal cells and its absorption in mice is regulated by body
iron. J Nutr. 2014;144(12):1896‐1902. https://doi.org/10.3945/jn.114.201715 PMid:25342699 PMCid:PMC4230207
N, Fried M, Drakesmith H, Duffy PE. Implications of malaria on iron
deficiency control strategies. Adv Nutr. 2012;3(4):570-578. https://doi.org/10.3945/an.111.001156 PMid:22797994 PMCid:PMC3649728
T, Sachdev HP. Effect of iron supplementation on incidence of
infectious illness in children: systematic review. BMJ.
2002;325(7373):1142. https://doi.org/10.1136/bmj.325.7373.1142 PMid:12433763 PMCid:PMC133452
D, Goede JS, Zeder C, Jiskra M, Chatzinakou V, Tjalsma H,
Melse-Boonstra A, Brittenham G, Swinkels DW, Zimmermann MB. Oral iron
supplements increase hepcidin and decrease iron absorption from daily
or twice-daily doses in iron-depleted young women. Blood.
2015;126:1981-1989. https://doi.org/10.1182/blood-2015-05-642223 PMid:26289639
- Stoffel NU, Cercamondi CI, Brittenham G, Zeder C, Geurts-Moespot AJ, Swinkels DW, Moretti D, Zimmermann MB. Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: two open-label, randomised controlled trials. Lancet Haematol. 2017;4(11):e524‐e533. https://doi.org/10.1016/S2352-3026(17)30182-5
MM, Koch TA, Tran MH. Iron supplementation, response in iron-deficiency
anemia: Analysis of five trials. Am J Med. 2017;130:991.e1-991.e8. https://doi.org/10.1016/j.amjmed.2017.03.045 PMid:28454902
- Camaschella C. Iron deficiency. Blood. 2019;133(1):30-39. https://doi.org/10.1182/blood-2018-05-815944 PMid:30401704
SG, Ruben AR, Brewster DR. An iron treatment trial in an aboriginal
community: improving non-adherence. J Paediatr Child Health.
1999;35:153-158. https://doi.org/10.1046/j.1440-1754.1999.t01-1-00351.x PMid:10365352
S, Arthur P, Antwi KY, Yeung G. Randomized, controlled trial of single
versus 3-times-daily ferrous sulfate drops for treatment of anemia.
Pediatrics. 2001;108:613-616. https://doi.org/10.1542/peds.108.3.613 PMid:11533326
AV, Dwivedi R, Mishra R, Patel GS. Ferrous sulfate versus iron
polymaltose complex for treatment of iron deficiency anemia in
children. Indian Pediatr. 2009;46:883-885.
MA, Shah M, Shakir MU. Comparison of efficacy of ferrous sulfate and
iron polymaltose complex in the treatment of childhood iron deficiency
anemia. PJMHS. 2017;11: 259-261.
T, Khan TM, Khizar N. Comparison of ferrous sulphate with iron
polymaltose in treating iron deficiency anaemia in children. JRMC.
- Powers JM, Buchanan GR,
Adix L, Zhang S, Gao A, McCavit TL. Effect of low-dose ferrous sulfate
vs iron polysaccharide complex on hemoglobin concentration in young
children with nutritional iron-deficiency anemia: A randomized clinical
trial. JAMA. 2017;317:2297-2304. https://doi.org/10.1001/jama.2017.6846 PMid:28609534 PMCid:PMC5815003
- Mehta BC. Ineffectiveness of iron polymaltose in treatment of iron deficiency anemia. J Assoc Physicians India. 2003;51:419-421.
GJ, Díaz-Hernández A, Manzano C, Ruiz-Delgado GJ. Ineffectiveness of
oral iron hydroxide polymaltose in iron-deficiency anemia. Hematology.
2007;12:255-256. https://doi.org/10.1080/10245330701214160 PMid:17558703
B, Agaoglu L, Unuvar E. Efficacy, tolerability, and acceptability of
iron hydroxide polymaltose complex versus ferrous sulfate: a randomized
trial in pediatric patients with iron deficiency anemia. Int J Pediatr.
2011;2011:524520. https://doi.org/10.1155/2011/524520 PMid:22121379 PMCid:PMC3206382
FA, Papanastasiou DA. Comparative study of tolerability and efficacy of
iron protein succinylate versus iron hydroxide polymaltose complex in
the treatment of iron deficiency in children. Int J Clin Pharmacol
MJ, Castelo-Branco C, Palacios S, Haya-Palazuelos J, Ciria-Recasens M,
Manasanch J, Pérez-Edo L. Tolerability of different oral iron
supplements: a systematic review. Curr Med Res Opin. 2013;29:291-303. https://doi.org/10.1185/03007995.2012.761599 PMid:23252877
G, Guardabasso V, Romano F, Corti P, Samperi P, Condorelli A, Sainati
L, Maruzzi M, Facchini E, Fasoli S, Giona F, Caselli D, Pizzato C,
Marinoni M, Boscarol G, Bartoni E, Casciana ML, Tucci F, Calposini I,
Notarangelo LD, Giordano P, Ramenghi U, Colombatti R. Monitoring oral
iron therapy in children with iron deficiency anemia: an observational,
prospective, multicenter study of AIEOP patients (Associazione Italiana
Emato-Oncologia Pediatrica). Ann Hematol. 2020;99(3):413‐420. https://doi.org/10.1007/s00277-020-03906-w PMid:31965272
V, Schmugge M, Hengartner H, von der Weid N, Renella R. SPOG Pediatric
Hematology Working Group. Diagnosis and management of iron deficiency
in children with or without anemia: consensus recommendations of the
SPOG Pediatric Hematology Working Group. Eur J Pediatr.
2020;179(4):527-545. https://doi.org/10.1007/s00431-020-03597-5 PMid:32020331
P, Wood L, Bird AR. Erythrocytes: better tolerance of iron polymaltose
complex compared with ferrous sulphate in the treatment of anaemia.
Hematology. 2000;5:77-83. https://doi.org/10.1080/10245332.2000.11746490 PMid:11399604
- Bircher AJ, Auerbach M. Hypersensitivity from intravenous iron products. Immunol Allergy Clin North Am. 2014;34(3):707‐xi. https://doi.org/10.1016/j.iac.2014.04.013 PMid:25017687
- Mantadakis E. Advances in pediatric intravenous iron therapy. Pediatr Blood Cancer. 2016;63(1):11‐16. https://doi.org/10.1002/pbc.25752 PMid:26376214
R, Aaron GJ, Huang J, Wirth JP, Namaste SM, Williams AM, Peerson JM,
Rohner F, Varadhan R, Addo OY, Temple V, Rayco-Solon P, Macdonald B,
Suchdev PS. Predictors of anemia in preschool children: Biomarkers
Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA)
project. Am J Clin Nutr. 2017;106(Suppl 1):402S-415S.