Iron is a key nutrient and is essential for the developing fetus, neonate, infant, and child. Iron requirements are high during early stages of life because it is critically important for the production of new red blood cells and muscle cells as well as brain development. Neonates, infants, and children obtain iron from dietary sources including breast milk (lactoferrin) and heme- and non-heme-containing foods. Iron deficiency (ID) is the most common micronutrient deficiency in children and pregnant women worldwide. ID and iron deficiency anemia (IDA) can affect growth and energy levels as well as motor and cognitive performance in the developing child. The fetus is completely dependent on maternal iron crossing through the placenta and, although it is generally well protected against deficiency at birth, ID in mothers can increase the risk of ID and IDA in their children as early as 4 months. This review will discuss the uses of iron, iron requirements, and the sources of iron from conception through childhood. In addition, it will describe the prevalence and clinical manifestations of ID and IDA in children and discuss recommendations for iron supplementation of children and pregnant women.

1.
Mahoney DH: Iron deficiency in infants and young children: screening, prevention, clinical manifestations, and diagnosis; in Motil KJ, Drutz JE, Hoppin AG (eds): UpToDate.
2.
Global Burden of Disease Pediatrics Collaboration, Kyu HH, Pinho C, Wagner JA, Brown JC, Bertozzi-Villa A, et al: 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 Pediatr 2016;170:267-287.
3.
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
4.
Engle-Stone R, Aaron GJ, Huang J, Wirth JP, Namaste SM, Williams AM, et al: Predictors of anemia in preschool children: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project. Am J Clin Nutr 2017;106:402S-415S.
5.
Lozoff B: Iron deficiency and child development. Food Nutr Bull 2007;28:S560-S571.
6.
Clark KM, Li M, Zhu B, Liang F, Shao J, Zhang Y, et al: Breastfeeding, mixed, or formula feeding at 9 months of age and the prevalence of iron deficiency and iron deficiency anemia in two cohorts of infants in China. J Pediatr 2017;181:56-61.
7.
Geng F, Mai X, Zhan J, Xu L, Zhao Z, Georgieff M, et al: Impact of fetal-neonatal iron deficiency on recognition memory at 2 months of age. J Pediatr 2015;167:1226-1232.
8.
Bates-Eamer N, Carin B, Lee M, Lim W, Kapila M: Post-2015 Development Agenda: Goals, Targets And Indicators - Special Report. 2015.
9.
United Nations Standing Committee on Nutrition: Nutrition and the Post-2015 Sustainable Development Goals. A Technical Note. October 2014.
10.
Golden MH: Specific deficiencies versus growth failure: type I and type II nutrients. SCN News 1995;10-14.
11.
Low M, Farrell A, Biggs B-A, Pasricha S-R: Effects of daily iron supplementation in primary-school-aged children: systematic review and meta-analysis of randomized controlled trials. CMAJ 2013;185:E791-E802.
12.
Falkingham M, Abdelhamid A, Curtis P, Fairweather-Tait S, Dye L, Hooper L: The effects of oral iron supplementation on cognition in older children and adults: a systematic review and meta-analysis. Nutr J 2010; 9:4.
13.
Larson LM, Phiri KS, Pasricha S-R: Iron and cognitive development: what is the evidence. Ann Nutr Metab 2017;71(suppl 3):25-38.
14.
Wachs TD, Georgieff M, Cusick S, McEwen BS: Issues in the timing of integrated early interventions: contributions from nutrition, neuroscience, and psychological research. Ann NY Acad Sci 2014;1308:89-106.
15.
Cusick SE, Georgieff MK: The role of nutrition in brain development: the golden opportunity of the “first 1000 days.” J Pediatr 2016;175:16-21.
16.
Burden MJ, Westerlund AJ, Armony-Sivan R, Nelson CA, Jacobson SW, Lozoff B, et al: An event-related potential study of attention and recognition memory in infants with iron-deficiency anemia. Pediatrics 2007;120:e336-e345.
17.
Geng F, Mai X, Zhan J, Xu L, Zhao Z, Georgieff M, et al: Impact of fetal-neonatal iron deficiency on recognition memory at 2 months of age. J Pediatr 2015;167:1226-1232.
18.
Algarin C, Karunakaran KD, Reyes S, Morales C, Lozoff B, Peirano P, et al: Differences on brain connectivity in adulthood are present in subjects with iron deficiency anemia in infancy. Front Aging Neurosci 2017;9:54.
19.
Roncagliolo M, Garrido M, Walter T, Peirano P, Lozoff B: Evidence of altered central nervous system development in infants with iron deficiency anemia at 6 mo: delayed maturation of auditory brainstem responses. Am J Clin Nutr 1998;68:683-690.
20.
Wachs TD, Pollitt E, Cueto S, Jacoby E, Creed-Kanashiro H: Relation of neonatal iron status to individual variability in neonatal temperament. Dev Psychobiol 2005;46:141-153.
21.
Lozoff B, Clark KM, Jing Y, Armony-Sivan R, Angelilli ML, Jacobson SW: Dose-response relationships between iron deficiency with or without anemia and infant social-emotional behavior. J Pediatr 2008;152:696-702, 702.31-33.
22.
Algarín C, Nelson CA, Peirano P, Westerlund A, Reyes S, Lozoff B: Iron-deficiency anemia in infancy and poorer cognitive inhibitory control at age 10 years. Dev Med Child Neurol 2013;55:453-458.
23.
Steinmacher J, Pohlandt F, Bode H, Sander S, Kron M, Franz AR: Randomized trial of early versus late enteral iron supplementation in infants with a birth weight of less than 1,301 g: neurocognitive development at 5.3 years' corrected age. Pediatrics 2007;120:538-546.
24.
Wang B, Zhan S, Gong T, Lee L: Iron therapy for improving psychomotor development and cognitive function in children under the age of three with iron deficiency anaemia. Cochrane Database Syst Rev 2013;6: CD001444.
25.
Pasricha S-R, Hayes E, Kalumba K, Biggs B-A: Effect of daily iron supplementation on health in children aged 4-23 months: a systematic review and meta-analysis of randomised controlled trials. Lancet Glob Health 2013;1:e77-e86.
26.
Lukowski AF, Koss M, Burden MJ, Jonides J, Nelson CA, Kaciroti N, et al: Iron deficiency in infancy and neurocognitive functioning at 19 years: evidence of long-term deficits in executive function and recognition memory. Nutr Neurosci 2010;13:54-70.
27.
Thibault H, Galan P, Selz F, Preziosi P, Olivier C, Badoual J, et al: The immune response in iron-deficient young children: effect of iron supplementation on cell-mediated immunity. Eur J Pediatr 1993;152:120-124.
28.
Galan P, Thibault H, Preziosi P, Hercberg S: Interleukin 2 production in iron-deficient children. Biol Trace Elem Res 1992;32:421-426.
29.
Hassan TH, Badr MA, Karam NA, Zkaria M, El Saadany HF, Abdel Rahman DM, et al: Impact of iron deficiency anemia on the function of the immune system in children. Medicine (Baltimore) 2016;95:e5395.
30.
Gwamaka M, Kurtis JD, Sorensen BE, Holte S, Morrison R, Mutabingwa TK, et al: Iron deficiency protects against severe Plasmodium falciparum malaria and death in young children. Clin Infect Dis 2012;54:1137-1144.
31.
Jonker FAM, Calis JCJ, van Hensbroek MB, Phiri K, Geskus RB, Brabin BJ, et al: Iron status predicts malaria risk in Malawian preschool children. PLoS One 2012;7:e42670.
32.
Nyakeriga AM, Troye-Blomberg M, Dorfman JR, Alexander ND, Bäck R, Kortok M, et al: Iron deficiency and malaria among children living on the coast of Kenya. J Infect Dis 2004;190:439-447.
33.
Kabyemela ER, Fried M, Kurtis JD, Mutabingwa TK, Duffy PE: Decreased susceptibility to Plasmodium falciparum infection in pregnant women with iron deficiency. J Infect Dis 2008;198:163-166.
34.
Senga EL, Harper G, Koshy G, Kazembe PN, Brabin BJ: Reduced risk for placental malaria in iron deficient women. Malar J 2011;10:47.
35.
Prentice AM: Clinical implications of new insights into hepcidin-mediated regulation of iron absorption and metabolism. Ann Nutr Metab 2017;71(suppl 3):40-48.
36.
Rowland TW, Kelleher JF: Iron deficiency in athletes. Insights from high school swimmers. Am J Dis Child 1960 1989;143:197-200.
37.
Rowland TW, Deisroth MB, Green GM, Kelleher JF: The effect of iron therapy on the exercise capacity of nonanemic iron-deficient adolescent runners. Am J Dis Child 1960 1988;142:165-169.
38.
Krebs NF, Lozoff B, Georgieff MK: Neurodevelopment: the impact of nutrition and inflammation during infancy in low-resource settings. Pediatrics 2017;139:S50-S58.
39.
Widdowson EM, Spray CM: Chemical development in utero. Arch Dis Child 1951;26:205-214.
40.
Wang C-Y, Jenkitkasemwong S, Duarte S, Sparkman BK, Shawki A, Mackenzie B, et al: ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading. J Biol Chem 2012;287:34032-34043.
41.
Hojyo S, Fukada T, Shimoda S, Ohashi W, Bin B-H, Koseki H, et al: The zinc transporter SLC39A14/ZIP14 controls G-protein coupled receptor-mediated signaling required for systemic growth. PLoS One 2011;6: e18059.
42.
Cao C, Pressman EK, Cooper EM, Guillet R, Westerman M, O'Brien KO: Placental heme receptor LRP1 correlates with the heme exporter FLVCR1 and neonatal iron status. Reproduction 2014;148:295-302.
43.
Cao C, Fleming MD: The placenta: the forgotten essential organ of iron transport. Nutr Rev 2016;74:421-431.
44.
Allen LH: Anemia and iron deficiency: effects on pregnancy outcome. Am J Clin Nutr 2000;71:1280S-1284S.
45.
Young MF, Griffin I, Pressman E, McIntyre AW, Cooper E, McNanley T, et al: Maternal hepcidin is associated with placental transfer of iron derived from dietary heme and nonheme sources. J Nutr 2012;142:33-39.
46.
Koenig MD, Tussing-Humphreys L, Day J, Cadwell B, Nemeth E: Hepcidin and iron homeostasis during pregnancy. Nutrients 2014;6:3062-3083.
47.
Jobarteh ML, McArdle HJ, Holtrop G, Sise EA, Prentice AM, Moore SE: mRNA levels of placental iron and zinc transporter genes are upregulated in Gambian women with low iron and zinc status. J Nutr 2017;147:1401-1409.
48.
Di Renzo GC, Spano F, Giardina I, Brillo E, Clerici G, Roura LC: Iron deficiency anemia in pregnancy. Womens Health (Lond) 2015;11:891-900.
49.
Mwangi MN, Prentice AM, Verhoef H: Safety and benefits of antenatal oral iron supplementation in low-income countries: a review. Br J Haematol 2017;177:884-895.
50.
Recommendations to prevent and control iron deficiency in the United States. Centers for Disease Control and Prevention. MMWR Recomm Rep 1998;47:1-29.
51.
WHO: WHO recommendations on antenatal care for a positive pregnancy experience. Available from: http://www.who.int/reproductivehealth/publications/maternal_perinatal_health/anc-positive-pregnancy-experience/en/ (accessed February 10, 2017).
52.
Dietary reference values for food energy and nutrients for the United Kingdom. Report of the Panel on Dietary Reference Values of the Committee on Medical Aspects of Food Policy. Rep Health Soc Subj (Lond) 1991;41:1-210.
53.
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. Lancet Glob Health 2013;1:e16-e25.
54.
Mwangi MN, Roth JM, Smit MR, Trijsburg L, Mwangi AM, Demir AY, et al: Effect of Daily antenatal iron supplementation on Plasmodium infection in Kenyan women: a randomized clinical trial. JAMA 2015;314:1009-1020.
55.
Andersson O, Domellöf M, Andersson D, Hellström-Westas L: Effects of delayed cord clamping on neurodevelopment and infection at four months of age: a randomised trial. Acta Paediatr 1992 2013;102:525-531.
56.
World Health Organization: Guideline: Delayed Umbilical Cord Clamping for Improved Maternal and Infant Health and Nutrition Outcomes. Geneva, World Health Organization, 2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK310511/ (accessed August 28, 2017).
57.
Bayer K: Delayed umbilical cord clamping in the 21st century: indications for practice. Adv Neonatal Care 2016;16:68-73.
58.
Committee on Obstetric Practice, American College of Obstetricians and Gynecologists: Committee Opinion No.543: Timing of umbilical cord clamping after birth. Obstet Gynecol 2012;120:1522-1526.
59.
Martin CR, Ling P-R, Blackburn GL: Review of infant feeding: key features of breast milk and infant formula. Nutrients 2016;8:279.
60.
Mills RJ, Davies MW: Enteral iron supplementation in preterm and low birth weight infants. Cochrane Database Syst Rev 2012; CD005095.
61.
Institute of Medicine; Food and Nutrition Board: Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc: A Report of the Panel on Micronutrients. Washington, DC, National Academies Press, 2001.
62.
Siimes MA, Vuori E, Kuitunen P: Breast milk iron - a declining concentration during the course of lactation. Acta Paediatr Scand 1979;68:29-31.
63.
Kumar A, Rai AK, Basu S, Dash D, Singh JS: Cord blood and breast milk iron status in maternal anemia. Pediatrics 2008;121:e673-e677.
64.
Andreas NJ, Kampmann B, Mehring Le-Doare K: Human breast milk: a review on its composition and bioactivity. Early Hum Dev 2015;91:629-635.
65.
Ward PP, Uribe-Luna S, Conneely OM: Lactoferrin and host defense. Biochem Cell Biol Biochim Biol Cell 2002;80:95-102.
66.
Wally J, Buchanan SK: A structural comparison of human serum transferrin and human lactoferrin. Biometals 2007;20:249-262.
67.
Lin L, Pantapalangkoor P, Tan B, Bruhn KW, Ho T, Nielsen T, et al: Transferrin iron starvation therapy for lethal bacterial and fungal infections. J Infect Dis 2014;201:254-264.
68.
Jiang R, Lopez V, Kelleher SL, Lönnerdal B: Apo- and holo-lactoferrin are both internalized by lactoferrin receptor via clathrin-mediated endocytosis but differentially affect ERK-signaling and cell proliferation in Caco-2 cells. J Cell Physiol 2011;226:3022-3031.
69.
Lönnerdal B, Bryant A: Absorption of iron from recombinant human lactoferrin in young US women. Am J Clin Nutr 2006;83:305-309.
70.
Berglund SK, Westrup B, Hägglöf B, Hernell O, Domellöf M: Effects of iron supplementation of LBW infants on cognition and behavior at 3 years. Pediatrics 2013;131:47-55.
71.
MacQueen BC, Baer VL, Scott DM, Ling CY, O'Brien EA, Boyer C, et al: Iron supplements for infants at risk for iron deficiency. Glob Pediatr Health 2017;4:2333794X17703836.
72.
McGuire S: World Health Organization. Comprehensive Implementation Plan on Maternal, Infant, and Young Child Nutrition. Geneva, Switzerland, 2014. Adv Nutr 2015;6:134-135.
73.
Breastfeeding and the use of human milk. American Academy of Pediatrics, Work Group on Breastfeeding. Breastfeed Rev 1998;6:31-36.
74.
Schanler RJ: Nutritional composition of human milk and preterm formula for the premature infant; in Abrams SA, Hoppin AG (eds): UpToDate, 2016.
75.
Schanler RJ, Garza C: Plasma amino acid differences in very low birth weight infants fed either human milk or whey-dominant cow milk formula. Pediatr Res 1987;21:301-305.
76.
Agostoni C, Decsi T, Fewtrell M, Goulet O, Kolacek S, Koletzko B, et al: Complementary feeding: a commentary by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr 2008;46:99-110.
77.
Gupta S, Agarwal R, Aggarwal KC, Chellani H, Duggal A, Arya S, et al: Complementary feeding at 4 versus 6 months of age for preterm infants born at less than 34 weeks of gestation: a randomised, open-label, multicentre trial. Lancet Glob Health 2017;5:e501-e511.
78.
Walter T, Dallman PR, Pizarro F, Velozo L, Peña G, Bartholmey SJ, et al: Effectiveness of iron-fortified infant cereal in prevention of iron deficiency anemia. Pediatrics 1993;91:976-982.
79.
Subar AF, Krebs-Smith SM, Cook A, Kahle LL: Dietary sources of nutrients among US children, 1989-1991. Pediatrics 1998;102:913-923.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.