The Long-term Effects of Iron Deficiency in Early Infancy on Neurodevelopment
DOI:
https://doi.org/10.12775/JEHS.2024.70.51104Keywords
neurodevelopment, infantile, iron, deficiencyAbstract
Introduction and Purpose: Iron deficiency alongside anaemia is one of the most significant global health concerns with potentially long-lasting implications on child development and health outcomes. The period of infancy represents a crucial phase of central nervous system maturation, rendering infants particularly susceptible to the adverse effects of iron deficiency. It is therefore crucial to pay close attention to this issue. The aim of this review is to elucidate the neurological implications of iron deficiency in infancy and emphasize the necessity of implementing preventive strategies to safeguard child development.
State of Knowledge: Iron deficiency in infancy can result in impairments of brain development. Extensive research highlights the influence of this micronutrient on various physiological processes, including the synthesis of neurotransmitters, neuronal metabolism, myelination, synaptogenesis and gene expression. Furthermore, iron deficiency during infancy is associated with adverse developmental outcomes, including cognitive, motor, and socioemotional deficits. Long-term follow-up studies have elucidated the enduring neurological consequences of iron deficiency in infancy, with effects extending into childhood and beyond.
Summary: Given that the changes that occur during the infantile period are often irreversible and have long-lasting implications for future development, it is of the utmost importance to prioritize prevention strategies.
References
J. E. Fairman and M. Wang, “Iron Deficiency and Other Types of Anemia in Infants and Children,” 2016. [Online]. Available: www.aafp.org/afp.
R. D. Baker et al., “Clinical report - Diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young children (0-3 years of age),” Pediatrics, vol. 126, no. 5, pp. 1040–1050, Nov. 2010, doi: 10.1542/peds.2010-2576.
V. Mattiello, M. Schmugge, H. Hengartner, N. von der Weid, and R. Renella, “Diagnosis and management of iron deficiency in children with or without anemia: consensus recommendations of the SPOG Pediatric Hematology Working Group,” European Journal of Pediatrics, vol. 179, no. 4. Springer, pp. 527–545, Apr. 01, 2020. doi: 10.1007/s00431-020-03597-5.
W. M. Gardner et al., “Prevalence, years lived with disability, and trends in anaemia burden by severity and cause, 1990–2021: findings from the Global Burden of Disease Study 2021,” Lancet Haematol, vol. 10, no. 9, pp. e713–e734, Sep. 2023, doi: 10.1016/S2352-3026(23)00160-6.
Geneva: World Health Organization, “DAILY IRON SUPPLEMENTATION in infants and children GUIDELINE,” 2016.
A. Kumar, E. Sharma, A. Marley, M. A. Samaan, and M. J. Brookes, “Iron deficiency anaemia: Pathophysiology, assessment, practical management,” BMJ Open Gastroenterology, vol. 9, no. 1. BMJ Publishing Group, Jan. 07, 2022. doi: 10.1136/bmjgast-2021-000759.
S. Ni, Y. Yuan, Y. Kuang, and X. Li, “Iron Metabolism and Immune Regulation,” Frontiers in Immunology, vol. 13. Frontiers Media S.A., Mar. 23, 2022. doi: 10.3389/fimmu.2022.816282.
United Nations World Health Organization, “Iron Deficiency Anaemia: Assesment, Prevention and Control: a Guide for Programme Managers,” 2001.
B. Felt et al., “Iron deficiency in infancy predicts altered serum prolactin response 10 years later,” Pediatr Res, vol. 60, no. 5, pp. 513–517, Nov. 2006, doi: 10.1203/01.PDR.0000242848.45999.7b.
S. McCann, M. P. Amadó, and S. E. Moore, “The role of iron in brain development: A systematic review,” Nutrients, vol. 12, no. 7. MDPI AG, pp. 1–23, 2020. doi: 10.3390/nu12072001.
S. E. Cusick and M. K. Georgieff, “The Role of Nutrition in Brain Development: The Golden Opportunity of the ‘First 1000 Days,’” Journal of Pediatrics, vol. 175, pp. 16–21, Aug. 2016, doi: 10.1016/j.jpeds.2016.05.013.
S. R. Pasricha, J. Tye-Din, M. U. Muckenthaler, and D. W. Swinkels, “Iron deficiency,” The Lancet, vol. 397, no. 10270. Lancet Publishing Group, pp. 233–248, Jan. 16, 2021. doi: 10.1016/S0140-6736(20)32594-0.
Geneva: World Health Organization, “WHO guideline on use of ferritin concentrations to assess iron status in individuals and populations.,” 2020.
M. Hermoso et al., “The effect of iron on cognitive development and function in infants, children and adolescents: A systematic review,” Annals of Nutrition and Metabolism, vol. 59, no. 2–4. pp. 154–165, Dec. 2011. doi: 10.1159/000334490.
B. Lozoff, J. Beard, J. Connor, B. Felt, M. Georgieff, and T. Schallert, “Long-Lasting Neural and Behavioral Effects of Iron Deficiency in Infancy,” Nutr Rev, pp. 34–43, 2006, doi: 10.1301/nr.2006.may.S34.
J. Beard, K. M. Erikson, and B. C. Jones, “Neonatal Iron Deficiency Results in Irreversible Changes in Dopamine Function in Rats,” Journal of Nutrition, vol. 133, pp. 1174–1179, 2003, [Online]. Available: https://academic.oup.com/jn/article-abstract/133/4/1174/4688294
Y. Wang, Y. Wu, T. Li, X. Wang, and C. Zhu, “Iron Metabolism and Brain Development in Premature Infants,” Front Physiol, vol. 10, Apr. 2019, doi: 10.3389/fphys.2019.00463.
E. S. Carlson, J. D. H. Stead, C. R. Neal, A. Petryk, and M. K. Georgieff, “Perinatal iron deficiency results in altered developmental expression of genes mediating energy metabolism and neuronal morphogenesis in hippocampus,” Hippocampus, vol. 17, no. 8, pp. 679–691, 2007, doi: 10.1002/hipo.20307.
M. Deungria, R. Rao, J. D. Wobken, M. Luciana, C. A. Nelson, and M. K. Georgieff, “Perinatal Iron Deficiency Decreases Cytochrome c Oxidase (CytOx) Activity in Selected Regions of Neonatal Rat Brain,” Pediatr Res, 2000, doi: 10.1093/jn/133.4.1174.
J. Zheng, J. Liu, and W. Yang, “Association of iron-deficiency anemia and non-iron-deficiency anemia with neurobehavioral development in children aged 6–24 months,” Nutrients, vol. 13, no. 10, Oct. 2021, doi: 10.3390/nu13103423.
R. Rao, I. Tkac, E. L. Townsend, R. Gruetter, and M. K. Georgieff, “Perinatal Iron Deficiency Alters the Neurochemical Profile of the Developing Rat Hippocampus,” American Society for Nutritional Sciences, vol. 133, pp. 3215–3221, 2003, [Online]. Available: https://academic.oup.com/jn/article-abstract/133/10/3215/4687551
K. L. Ward et al., “Ingestive Behavior and Neurosciences Gestational and Lactational Iron Deficiency Alters the Developing Striatal Metabolome and Associated Behaviors in Young Rats,” J. Nutr, vol. 137, pp. 1043–1049, 2007, [Online]. Available: https://academic.oup.com/jn/article-abstract/137/4/1043/4664608
J. A. Estrada, I. Contreras, F. B. Pliego-Rivero, and G. A. Otero, “Molecular mechanisms of cognitive impairment in iron deficiency: Alterations in brain-derived neurotrophic factor and insulin-like growth factor expression and function in the central nervous system,” Nutritional Neuroscience, vol. 17, no. 5. Maney Publishing, pp. 193–206, 2014. doi: 10.1179/1476830513Y.0000000084.
M. K. Georgieff, “Iron deficiency in pregnancy,” American Journal of Obstetrics and Gynecology, vol. 223, no. 4. Mosby Inc., pp. 516–524, Oct. 01, 2020. doi: 10.1016/j.ajog.2020.03.006.
G. L. Wehby, “Living on higher ground reduces child neurodevelopment - Evidence from South America,” Journal of Pediatrics, vol. 162, no. 3, 2013, doi: 10.1016/j.jpeds.2012.09.011.
M. Roncagliolo, M. Garrido, T. Walter, P. Peirano, and B. Lozoff, “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, pp. 683–690, 1998.
E. L. Congdon et al., “Iron deficiency in infancy is associated with altered neural correlates of recognition memory at 10 years,” Journal of Pediatrics, vol. 160, no. 6, pp. 1027–1033, Jun. 2012, doi: 10.1016/j.jpeds.2011.12.011.
A. F. Lukowski 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, vol. 13, no. 2, pp. 54–70, 2010, doi: 10.1179/147683010X12611460763689.
H. E. Krieger, A. H. Claussen, and K. G. Scott, “Early childhood anemia and mild or moderate mental retardation,” Am J Clin Nutr, pp. 115–9, 1999, doi: 10.1093/ajcn/69.1.115.
B. Beltrán-Navarro, E. Matute, E. Vásquez-Garibay, and D. Zarabozo, “Effect of chronic iron deficiency on neuropsychological domains in infants,” J Child Neurol, vol. 27, no. 3, pp. 297–303, Mar. 2012, doi: 10.1177/0883073811416867.
H. Szajewska, M. Ruszczynski, and A. Chmielewska, “Effects of iron supplementation in nonanemic pregnant women, infants, and young children on the mental performance and psychomotor development of children: A systematic review of randomized controlled trials,” American Journal of Clinical Nutrition, vol. 91, no. 6. pp. 1684–1690, Jun. 01, 2010. doi: 10.3945/ajcn.2010.29191.
S. McCann, M. P. Amadó, and S. E. Moore, “The role of iron in brain development: A systematic review,” Nutrients, vol. 12, no. 7. MDPI AG, pp. 1–23, 2020. doi: 10.3390/nu12072001.
T. Shafir, R. Angulo-Barroso, Y. Jing, M. L. Angelilli, S. W. Jacobson, and B. Lozoff, “Iron deficiency and infant motor development,” Early Hum Dev, vol. 84, no. 7, pp. 479–485, Jul. 2008, doi: 10.1016/j.earlhumdev.2007.12.009.
D. C. C. Santos et al., “Timing, duration, and severity of iron deficiency in early development and motor outcomes at 9 months,” Eur J Clin Nutr, vol. 72, no. 3, pp. 332–341, Mar. 2018, doi: 10.1038/s41430-017-0015-8.
B. Wang, S. Zhan, T. Gong, and L. Lee, “Iron therapy for improving psychomotor development and cognitive function in children under the age of three with iron deficiency anaemia,” Cochrane Database of Systematic Reviews, vol. 2013, no. 6. John Wiley and Sons Ltd, Jun. 06, 2013. doi: 10.1002/14651858.CD001444.pub2.
M. K. Georgieff, “Long-term brain and behavioral consequences of early iron deficiency,” Nutr Rev, vol. 69, no. SUPPL. 1, 2011, doi: 10.1111/j.1753-4887.2011.00432.x.
P. T. Tseng et al., “Peripheral iron levels in children with attention-deficit hyperactivity disorder: A systematic review and meta-analysis,” Scientific Reports, vol. 8, no. 1. Nature Publishing Group, Dec. 01, 2018. doi: 10.1038/s41598-017-19096-x.
Y. Wang, L. Huang, L. Zhang, Y. Qu, and D. Mu, “Iron status in attention-deficit/hyperactivity disorder: A systematic review and meta-analysis,” PLoS ONE, vol. 12, no. 1. Public Library of Science, Jan. 01, 2017. doi: 10.1371/journal.pone.0169145.
P. L. East, J. R. Doom, E. Blanco, R. Burrows, B. Lozoff, and S. Gahagan, “Iron Deficiency in Infancy and Sluggish Cognitive Tempo and ADHD Symptoms in Childhood and Adolescence,” Journal of Clinical Child and Adolescent Psychology, vol. 52, no. 2, pp. 259–270, 2023, doi: 10.1080/15374416.2021.1969653.
J. R. Doom, B. Richards, G. Caballero, J. Delva, S. Gahagan, and B. Lozoff, “Infant Iron Deficiency and Iron Supplementation Predict Adolescent Internalizing, Externalizing, and Social Problems,” Journal of Pediatrics, vol. 195, pp. 199-205.e2, Apr. 2018, doi: 10.1016/j.jpeds.2017.12.008.
B. Lozoff, E. Jimenez, J. Hagen, E. Mollen, and A. W. Wolf, “Poorer Behavioral and Developmental Outcome More Than 10 Years After Treatment for Iron Deficiency in Infancy,” 2000. [Online]. Available: http://www.pediatrics.org/
B. Lozoff, J. B. Smith, N. Kaciroti, K. M. Clark, S. Guevara, and E. Jimenez, “Functional significance of early-life iron deficiency: Outcomes at 25 years,” Journal of Pediatrics, vol. 163, no. 5, pp. 1260–1266, Nov. 2013, doi: 10.1016/j.jpeds.2013.05.015.
P. East, E. Delker, B. Lozoff, J. Delva, M. Castillo, and S. Gahagan, “Associations Among Infant Iron Deficiency, Childhood Emotion and Attention Regulation, and Adolescent Problem Behaviors,” Child Dev, vol. 89, no. 2, pp. 593–608, Mar. 2018, doi: 10.1111/cdev.12765.
J. R. Doom, S. Gahagan, P. L. East, P. Encina, J. Delva, and B. Lozoff, “Adolescent Internalizing, Externalizing, and Social Problems Following Iron Deficiency at 12–18 Months: The Role of Maternal Responsiveness,” Child Dev, vol. 91, no. 3, pp. e545–e562, May 2020, doi: 10.1111/cdev.13266.
A. A. Zehetner, N. Orr, A. Buckmaster, K. Williams, and D. M. Wheeler, “Iron supplementation for breath-holding attacks in children,” Cochrane Database of Systematic Reviews, May 2010, doi: 10.1002/14651858.cd008132.pub2.
R. Jain, D. Omanakuttan, A. Singh, and M. Jajoo, “Effect of iron supplementation in children with breath holding spells,” J Paediatr Child Health, vol. 53, no. 8, pp. 749–753, Aug. 2017, doi: 10.1111/jpc.13556.
R. Sulviani, W. Kamarullah, S. Dermawan, and H. Susanto, “Anemia and Poor Iron Indices Are Associated With Susceptibility to Febrile Seizures in Children: A Systematic Review and Meta-analysis,” J Child Neurol, vol. 38, no. 3–4, pp. 186–197, Mar. 2023, doi: 10.1177/08830738231170333.
A. S. Daoud, A. Batieha, F. Abu-Ekteish, N. Gharaibeh, S. Ajlouni, and S. Hijazi, “Iron status: A possible risk factor for the first febrile seizure,” Epilepsia, vol. 43, no. 7, pp. 740–743, 2002, doi: 10.1046/j.1528-1157.2002.32501.x.
N. L. Kobrinsky, J. Y. Yager, M. S. Cheang, R. W. Yatscoff, and M. Tenenbein, “Does Iron Deficiency Raise the Seizure Threshold?,” J Child Neurol, vol. 10, no. 2, pp. 105–109, 1995, doi: 10.1177/088307389501000207.
P. Yousefichaijan, A. Eghbali, M. Rafeie, M. Sharafkhah, M. Zolfi, and M. Firouzifar, “The relationship between iron deficiency anemia and simple febrile convulsion in children,” J Pediatr Neurosci, vol. 9, no. 2, p. 110, 2014, doi: 10.4103/1817-1745.139276.
H. N. Jang, H. S. Yoon, and E. H. Lee, “Prospective case control study of iron deficiency and the risk of febrile seizures in children in South Korea,” BMC Pediatr, vol. 19, no. 1, Sep. 2019, doi: 10.1186/s12887-019-1675-4.
S. Tong and E. Vichinsky, “Iron deficiency: Implications before anemia,” Pediatr Rev, vol. 42, no. 1, pp. 11–18, Jan. 2021, doi: 10.1542/PIR.2018-0134.
V. Mattiello, M. Schmugge, H. Hengartner, N. von der Weid, and R. Renella, “Diagnosis and management of iron deficiency in children with or without anemia: consensus recommendations of the SPOG Pediatric Hematology Working Group,” European Journal of Pediatrics, vol. 179, no. 4. Springer, pp. 527–545, Apr. 01, 2020. doi: 10.1007/s00431-020-03597-5.
S. Sundararajan and H. Rabe, “Prevention of iron deficiency anemia in infants and toddlers,” Pediatric Research, vol. 89, no. 1. Springer Nature, pp. 63–73, Jan. 01, 2021. doi: 10.1038/s41390-020-0907-5.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2024 Anna Korczak, Emilia Wójcik, Ewa Olek, Olga Łopacińska, Katarzyna Stańczyk, Aleksandra Korn, Justyna Jędrzejczyk, Oliwia Szewczyk, Katarzyna Burda, Karolina Czarnecka
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
The periodical offers access to content in the Open Access system under the Creative Commons Attribution-NonCommercial-ShareAlike 4.0
Stats
Number of views and downloads: 346
Number of citations: 0
