IRON DEFICIENCY ANEMIA IN CHILDREN RESIDING IN HIGH AND LOW-INCOME COUNTRIES: RISK FACTORS, PREVENTION, DIAGNOSIS AND THERAPY

Main Article Content

ELPIS MANTADAKIS
(*) Corresponding Author:

Abstract

Iron deficiency and iron deficiency anemia (IDA) affect approximately two billion people worldwide and most of them reside in low- and middle-income countries. In these countries, 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 that are 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 elderly 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 apparently associated with harmful effects on the overall incidence of infectious illnesses in sideropenic and/or anemic subjects. Further research is needed to clarify the risks and benefits of supplemental iron for children exposed to parasitic infections in the third world, and for children genetically predisposed to iron overload.


Downloads month by month

Downloads

Download data is not yet available.

Article Details

Author Biography

ELPIS MANTADAKIS, Democritus University of Thrace Faculty of Medicine

Associate Professor of Pediatrics and Pediatric /Oncology, Democritus University of Thrace Faculty of Medicine

References

1. 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 9789241596657. https://www.who.int/nutrition/publications/micronutrients/anaemia_iron_deficiency/9789241596657/en/
2. 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.
https://doi.org/10.1182/blood-2012-09-453522
3. Shaw 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
4. Rahman 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.
https://academic.oup.com/ajcn/article/103/2/495/4662868
5. Bailey RL, West KP Jr, Black RE. The epidemiology of global micronutrient deficiencies. Ann Nutr Metab. 2015;66 (Suppl 2):22-33.
https://doi.org/10.1159/000371618
6. Gupta 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
7. 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://www.karger.com/Article/Pdf/371357
8. 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
9. 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. 2011;183(12):E928-932.
https://doi.org/10.1503/cmaj.090290
10. Marx JJ. Iron deficiency in developed countries: prevalence, influence of lifestyle factors and hazards of prevention. Eur J Clin Nutr. 1997;51(8):491-494. https://doi.org/10.1038/sj.ejcn.1600440
11. 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.
https://doi.org/10.1016/S0140-6736(16)31678-6
12. Baker 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. 2010;126(5):1040-1050.
https://doi.org/10.1542/peds.2010-2576
13. Lozoff B, Georgieff MK. Iron deficiency and brain development. Semin Pediatr Neurol. 2006 Sep;13(3):158-165.
https://doi.org/10.1016/j.spen.2006.08.004
14. 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
15. 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
16. Howard H, Kamat D. Restless legs syndrome in children. Pediatr Ann. 2018;47(12):e504-506.
https://doi.org/10.3928/19382359-20181114-02
17. Houston 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.
http://dx.doi.org/10.1136/bmjopen-2017-019240
18. Brotanek JM, Gosz J, Weitzman M, Flores G. Secular trends in the prevalence of iron deficiency among US toddlers, 1976-2002. Arch Pediatr Adolesc Med. 2008;162(4):374-381.
http://doi.org/10.1001/archpedi.162.4.374
19. De Andrade Cairo RC, Rodrigues Silva L, Carneiro Bustani N, Ferreira Marques CD. Iron deficiency anemia in adolescents; a literature review. Nutr Hosp. 2014;29(6): 1240-1249.
https:// doi: 10.3305/nh.2014.29.6.7245.
20. 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
21. Zhang AS, Enns CA. Iron homeostasis: recently identified proteins provide insight into novel control mechanisms. J Biol Chem. 2009;284(2):711-715.
https://doi.org/10.1074/jbc.R800017200
22. Teucher 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.
https://doi.org/10.1024/0300-9831.74.6.403
23. Centers for Disease Control and Prevention. Recommendations to prevent and control iron deficiency in the United States. MMWR Recomm Rep. 1998;47(RR-3):1-29. https://www.cdc.gov/mmwr/preview/mmwrhtml/00051880.htm
24. Ginzburg YZ. Hepcidin-ferroportin axis in health and disease. Vitam Horm. 2019;110:17-45.
https://doi.org/10.1016/bs.vh.2019.01.002
25. Roth MP, Meynard D, Coppin H. Regulators of hepcidin expression. Vitam Horm. 2019;110:101-129.
https://doi.org/10.1016/bs.vh.2019.01.005
26. Weiss G, Ganz T, Goodnough LT. Anemia of inflammation. Blood. 2019;133(1):40-50.
https://doi.org/10.1182/blood-2018-06-856500
27. Olivares M, Walter T, Hertrampf E, Pizarro F. Anaemia and iron deficiency disease in children. Br Med Bull. 1999;55(3):534-543.
https://doi.org/10.1258/0007142991902600
28. Lynch 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://dx.doi.org/10.1177/15648265070284S413
29. Zlotkin 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. https://www.who.int/selection_medicines/committees/expert/22/applications/s10.1_micronutrient-powders.pdf?ua=1
30. Unicef. Product Specification Sheet. Multiple Micronutrient Powder (MNP) 15 Components.
https://www.unicef.org/supply/files/Micronutrient_pdr_15_component.pdf
31. Suchdev 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. https://doi.org/10.1002/14651858.CD008959.pub3
32. Weiss G. Dietary iron supplementation: a proinflammatory attack on the intestine? Gut. 2015;64(5):696-697.
http://dx.doi.org/10.1136/gutjnl-2014-308147
33. Jaeggi 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.
http://dx.doi.org/10.1136/gutjnl-2014-307720
34. Wieringa 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
35. Merryweather-Clarke AT, Pointon JJ, Shearman JD, Robson KJ. Global prevalence of putative haemochromatosis mutations. J Med Genet. 1997;34(4):275-278. http://dx.doi.org/10.1136/jmg.34.4.275
36. Wood MJ, 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
37. 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
38. Parkin PC, DeGroot J, Maguire JL, Birken CS, Zlotkin S. Severe iron-deficiency anaemia and feeding practices in young children. Public Health Nutr. 2016;19(4):716-722.
https://doi.org/10.1017/S1368980015001639
39. 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 Med. 1999;131(9):668-672.
https://doi.org/10.7326/0003-4819-131-9-199911020-00006
40. Loukas 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
41. Akin 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
42. Heeney MM, Finberg KE. Iron-refractory iron deficiency anemia (IRIDA). Hematol Oncol Clin North Am. 2014;28(4):637-652, v.
https://doi.org/10.1016/j.hoc.2014.04.009
43. Garofalo M, Abenhaim HA. Early versus delayed cord clamping in term and preterm births: a review. J Obstet Gynaecol Can. 2012;34(6):525-531.
https://doi.org/10.1016/S1701-2163(16)35268-9
44. Ziegler EE. Consumption of cow’s milk as a cause of iron deficiency in infants and toddlers. Nutr Rev. 2011;69 (Suppl 1):S37-42.
https://doi.org/10.1111/j.1753-4887.2011.00431.x
45. Cerami 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
46. Keung YK, Owen J. Iron deficiency and thrombosis: literature review. Clin Appl Thromb Hemost. 2004;10(4):387-391.
https://doi.org/10.1177/107602960401000412
47. Jolobe OM. Prevalence of hypochromia (without microcytosis) vs microcytosis (without hypochromia) in iron deficiency. Clin Lab Haematol. 2000;22(2):79-80. https://doi.org/10.1046/j.1365-2257.2000.00293.x
48. Wright 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.
http://dx.doi.org/10.1136/adc.2003.047407
49. Punnonen K, Irjala K, Rajamäki A. Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency. Blood. 1997;89(3):1052-1057. https://doi.org/10.1182/blood.v89.3.1052
50. Brugnara C. Iron deficiency and erythropoiesis: new diagnostic approaches. Clin Chem. 2003;49(10):1573-1578.
https://doi.org/10.1373/49.10.1573
51. Camaschella C. Iron deficiency: new insights into diagnosis and treatment. Hematology Am Soc Hematol Educ Program. 2015;2015:8-13.
https://doi.org/10.1182/asheducation-2015.1.8
52. Nosratnejad S, Barfar E, Hosseini H, Barooti E, Rashidian A. Cost-effectiveness of Anemia Screening in Vulnerable Groups: A Systematic Review. Int J Prev Med. 2014;5(7):813-819.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4124557/
53. 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. https://apps.who.int/iris/handle/10665/75368
54. Kemper AR, Fan T, Grossman DC, Phipps MG. Gaps in evidence regarding iron deficiency anemia in pregnant women and young children: summary of US Preventive Services Task Force recommendations. Am J Clin Nutr. 2017;106(Suppl 6):1555S-1558S.
https://doi.org/10.3945/ajcn.117.155788
55. Santiago 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
56. Nagpal J, Choudhury P. Iron formulations in pediatric practice. Indian Pediatr. 2004;41:807-815.
http://www.indianpediatrics.net/aug2004/aug-807-815.htm
57. Spottiswoode 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
58. Gera 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
59. Moretti 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
60. Okam 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
61. Camaschella C. Iron deficiency. Blood. 2019;133(1):30-39.
https://doi.org/10.1182/blood-2018-05-815944
62. Kruske 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
63. Zlotkin 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
64. Bopche 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.
https://www.indianpediatrics.net/oct2009/oct-883-885.htm
65. Sheikh 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.
http://www.pjmhsonline.com/2017/jan_march/pdf/259.pdf
66. Mahmood T, Khan TM, Khizar N. Comparison of ferrous sulphate with iron polymaltose in treating iron deficiency anaemia in children. JRMC. 2017;21:376-379. https://www.journalrmc.com/jrmc/volumes/16-COMPARISON%20OF%20FERROUS%20SULPHATE%20WITH%20IRON%20POLYMALTOSE%20(2).pdf
67. 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
68. Mehta BC. Ineffectiveness of iron polymaltose in treatment of iron deficiency anemia. J Assoc Physicians India. 2003;51:419-421. https://japi.org/April2003/Correspondence.htm#Ineffectiveness%20of%20Iron%20Polymaltose%20in%20Treatment%20of%20Iron%20Deficiency%20Anemia
69. Ruiz-Argüelles 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
70. Yasa 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://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206382/pdf/IJPED2011-524520.pdf
71. Haliotis 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 Ther. 1998;36:320-325. https://www.ncbi.nlm.nih.gov/pubmed/?term=Int+J+Clin+Pharmacol+Ther.+1998%3B36%3A320-325.+
72. Cancelo-Hidalgo 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
73. Rimon E, Kagansky N, Kagansky M, Mechnick L, Mashiah T, Namir M, Levy S. Are we giving too much iron? Low-dose iron therapy is effective in octogenarians. Am J Med. 2005;118:1142-1147.
https://doi.org/10.1016/j.amjmed.2005.01.065
74. Jacobs 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
75. Mattiello 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
76. Engle-Stone 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.
https://doi.org/10.3945/ajcn.116.142323