Striking While the Iron is Hot: Understanding the Biological and Neurodevelopmental Effects of Iron Deficiency to Optimize Intervention in Early Childhood

Current Pediatrics Reports

Volumn 2, Issue 4, 2014, Pages 291-298

  Doom, Jenalee R ^a   Georgieff, Michael K ^a,b  

^a UNIVERSITY OF MINNESOTA   (United States)

^b UNIVERSITY OF MINNESOTA MEDICAL SCHOOL   (United States)

Author keywords

Infancy; Iron deficiency; Neurodevelopment; Nutritional interventions; Toddlerhood

Indexed keywords

EID: 84946498849     PISSN: None     EISSN: 21674841     Source Type: Journal    
DOI: 10.1007/s40124-014-0058-4     Document Type: Article

References (61)

1. Amin SB, Orlando M, Eddins A, MacDonald M, Monczynski C, Wang H. In utero iron status and auditory neural maturation in premature infants as evaluated by auditory brainstem response. J Pediatr. 2010;156(3):377–81. DOI: 10.1016/j.jpeds.2009.09.049
2. Siddappa AM, Georgieff MK, Wewerka S, Worca C, Nelson CA, deRegnier R-A. Auditory recognition memory in iron-deficient infants of diabetic mothers. Pediatr Res. 2004;55:1034–41. DOI: 10.1203/01.pdr.0000127021.38207.62
3. Kuzawa CW. Beyond feast-famine: brain evolution, human life history, and the metabolic syndrome. In: Muehlenbein M, editor. Human evolutionary biology. Cambridge: Cambridge University Press; 2010. p. 518–27. DOI: 10.1017/CBO9780511781193.037
4. Algarín C, Peirano P, Garrido M, Pizarro F, Lozoff B. Iron deficiency anemia in infancy: long-lasting effects on auditory and visual system functioning. Pediatr Res. 2003;53(2):217–23. DOI: 10.1203/01.PDR.0000047657.23156.55
5. Lozoff B, Klein NK, Nelson EC, McClish DK, Manuel M, Chacon ME. Behavior of infants with iron deficiency anemia. Child Dev. 1998;69:24–36. DOI: 10.1111/j.1467-8624.1998.tb06130.x
6. Lozoff B, Jimenez E, Hagen J, Mollen E, Wolf AW. Poorer behavioral and developmental outcome more than 10 years after treatment for iron deficiency in infancy. Pediatrics. 2000;105:E51. DOI: 10.1542/peds.105.4.e51
7. ∙ Georgieff MK. Long-term brain and behavioral consequences of early iron deficiency. Nutr Rev. 2011; 69:S43–8. This paper is a review of the long-term effects of pre- and post-natal ID in both humans and in model systems. Alterations in neurotransmitter systems and changes in gene expression are discussed.
8. Lukowski AF, Koss M, Burden MJ, et al. Iron deficiency in infancy and neurocognitive functioning at 19 years: evidence of long-term deficits in executive function and recognition memory. Neuroscience. 2010;13(2):54–70.
9. Youdim MBH, Green AR, Bloomfield MR, Mitchell BD, Heal DJ, Grahamesmith DG. The effects of iron deficiency on brain biogenic monoamine biochemistry and function in rats. Neuropharmacology. 1980;19:259–67. DOI: 10.1016/0028-3908(80)90148-3
10. Unger EL, Hurst AR, Georgieff MK, et al. Behavior and monoamine deficits in pre- and peri-natal iron deficiency are not corrected by early postnatal moderate or high iron diet in rats. J Nutr. 2012;142:2040–9. DOI: 10.3945/jn.112.162198
11. 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(2):141–53. DOI: 10.1002/dev.20049
12. Connor JR, Menzies SL. Relationship of iron to oligodendrocytes and myelination. Glia. 1996;17(2):83–93. DOI: 10.1002/(SICI)1098-1136(199606)17:2<83::AID-GLIA1>3.0.CO;2-7
13. Ortiz E, Pasquini JM, Thompson K, et al. Effect of manipulation of iron storage, transport, or availability on myelin composition and brain iron content in three different animal models. J Neurosci Res. 2004;2004(77):681–9. DOI: 10.1002/jnr.20207
14. Clardy SL, Wang X, Zhao W, et al. Acute and chronic effects of developmental iron deficiency on mRNA expression patterns in the brain. J Neural Transm Suppl. 2006;71:173–96. DOI: 10.1007/978-3-211-33328-0_19
15. 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(3):683–90.
16. Rao R, Tkac I, Townsend EL, Gruetter R, Georgieff MK. Perinatal iron deficiency alters the neurochemical profile of the developing rat hippocampus. J Nutr. 2003;133:3215–21.
17. De Ungria M, Rao R, Wobken JD, Luciana M, Nelson CA, Georgieff MK. Perinatal iron deficiency decreases cytochrome c oxidase activity in selective regions of neonatal rat brain. Pediatr Res. 2000;48:169–76. DOI: 10.1203/00006450-200008000-00009
18. Dallman PR. Biochemical basis for the manifestations of iron deficiency. Annu Rev Nutr. 1986;6:13–40. DOI: 10.1146/annurev.nu.06.070186.000305
19. Carlson ES, Tkac I, Magid R, et al. Iron is essential for neuron development and memory function in mouse hippocampus. J Nutr. 2009;139(4):672–9. DOI: 10.3945/jn.108.096354
20. ∙ Fretham SJB, Carlson ES, Wobken J, Tran PV, Petryk A, Georgieff MK. Temporal manipulation of transferrin receptor-1 dependent iron uptake identifies a sensitive period in mouse hippocampal neurodevelopment. Hippocampus. 2012;22:1691–1702. This article demonstrated that the spatial memory abnormalities seen with ID are due to neuronal iron deficiency and not to anemia and that there is a specific critical period for iron in the developing hippocampus.
21. Pisansky MT, Wickham RJ, Su J, et al. Iron deficiency with or without anemia impairs prepulse inhibition of the startle reflex. Hippocampus. 2013;23(10):952–62. DOI: 10.1002/hipo.22151
22. Schmidt AT, Waldow KJ, Grove WM, Salinas JA, Georgieff MK. Dissociating the long-term effects of fetal/neonatal iron deficiency on three types of learning in the rat. Behav Neurosci. 2007;2007(121):475–82. DOI: 10.1037/0735-7044.121.3.475
23. Carlson ES, Stead JDH, Neal CR, Petryk A, Georgieff MK. Perinatal iron deficiency results in altered developmental expression of genes mediating energy metabolism and neuronal morphogenesis in hippocampus. Hippocampus. 2007;17:679–91. DOI: 10.1002/hipo.20307
24. Tran PV, Dakoji S, Reise K, Storey K, Georgieff MK. Fetal iron deficiency alters the proteome of adult rat hippocampal synaptosome. Am J Physiol Regul Integr Comp Physiol. 2013;305:R1297–306. DOI: 10.1152/ajpregu.00292.2013
25. Insel BJ, Schaefer CA, McKeague IW, Susser ES, Brown AS. Maternal iron deficiency and the risk of schizophrenia in offspring. Arch Gen Psychiatry. 2008;65(10):1136–44. DOI: 10.1001/archpsyc.65.10.1136
26. Tran PV, Fretham SJB, Carlson ES, Georgieff MK. Long-term reduction of hippocampal BDNF activity following fetal-neonatal iron deficiency in adult rats. Pediatr Res. 2009;65(5):493–8. DOI: 10.1203/PDR.0b013e31819d90a1
27. ∙ Callahan LSN, Thibert KA, Wobken JD, Georgieff MK. Early life iron deficiency anemia alters the development and long-term expression of parvalbumin and perineuronal nets in the rat hippocampus. Dev Neurosci. 2013;35(5):427–236. This empirical paper documents decreased parvalbumin mRNA expression and protein levels in rodents who had experienced early life ID compared to iron sufficient controls, which is consistent with evidence of delayed hippocampal maturation and lower plasticity in adults who were formerly iron deficient.
28. Hensch TK. Critical period regulation. Annu Rev Neurosci. 2004;27:549–79. DOI: 10.1146/annurev.neuro.27.070203.144327
29. Hubel DH, Wiesel TN. Receptive fields, binocular interaction and functional architecture in the cat’s visual cortex. J Physiol. 1962;160:106–54.
30. Gluckman PD, Hanson MA. Living with the past: evolution, development, and patterns of disease. Science. 2004;305(5691):1733–6. DOI: 10.1126/science.1095292
31. ∙ Blegen MB, Kennedy BC, Thibert KA, Gewirtz JC, Tran PV, Georgieff MK. Multigenerational effects of fetal-neonatal iron deficiency on hippocampal BDNF signaling. Physiol Rep. 2013;1(5):1–10. This paper documents acute and chronic BDNF downregulation in formerly iron deficient F1 rats. However, iron sufficient F2 generation rats showed gene expression comparable to controls, suggesting that the effects of ID on BDNF expression are not multi-generational.
32. Roth TL, Sweatt JD. Epigenetic marking of the BDNF gene by early-life adverse experiences. Horm Behav. 2011;59(3):315–20. DOI: 10.1016/j.yhbeh.2010.05.005
33. Felt BT, Beard JL, Schallert T. Persistent neurochemical and behavioral abnormalities in adulthood despite early iron supplementation for perinatal iron deficiency anemia in rats. Behav Brain Res. 2006;171:261–70. DOI: 10.1016/j.bbr.2006.04.001
34. Schmidt AT, Alvarez GC, Grove WM, Rao R, Georgieff MK. Early iron deficiency enhances stimulus-response learning of adult rats in the context of competing spatial information. Dev Cog Neurosci. 2012;2(1):174–80. DOI: 10.1016/j.dcn.2011.07.014
35. Lozoff B, Beard J, Connor J, Felt B, Georgieff M, Schallert T. Long-lasting neural and behavioral effects of early iron deficiency in infancy. Nutr Rev. 2006;64:S34–43. DOI: 10.1301/nr.2006.may.S34-S43
36. Morse A, Beard JL, Jones B. Behavioral and neurochemical alterations in iron deficient mice. Proc Soc Exp Biol Med. 1999;220:147–52. DOI: 10.3181/00379727-220-44357
37. Armony-Sivan R, Eidelman AI, Lanir A, et al. Iron status and neurobehavioral development of premature infants. J Perinatal. 2004;24:757–62. DOI: 10.1038/sj.jp.7211178
38. Tamura T, Goldenberg RL, Hou J, et al. Cord serum ferritin concentrations and mental and psychomotor development of children at five years of age. J Pediatr. 2002;140(2):165–70. DOI: 10.1067/mpd.2002.120688
39. DeBoer T, Wewerka S, Bauer PJ, Georgieff MK, Nelson CA. Explicit memory performance in infants of diabetic mothers at 1 year of age. Dev Med Child Neurol. 2005;47:525–31. DOI: 10.1017/S0012162205001039
40. Ornoy A. Growth and neurodevelopmental outcome of children born to mothers with pregestational and gestational diabetes. Pediatr Endocrinol Rev. 2005;3(2):104–13.
41. Riggins T, Miller NC, Bauer PB, Georgieff MK, Nelson CA. Consequences of low neonatal iron status due to maternal diabetes mellitus on explicit memory performance in childhood. Dev Neuropsychol. 2009;34:762–79. DOI: 10.1080/87565640903265145
42. Angulo-Barroso RM, Schapiro L, Liang W, et al. Motor development in 9-month-old infants in relation to cultural differences and iron status. Dev Psychobiol. 2011;53:196–210. DOI: 10.1002/dev.20512
43. Peirano PD, Algarín CR, Chamorro RA, et al. Sleep alterations and iron deficiency anemia in infancy. Sleep Med. 2010;11(7):637–42. DOI: 10.1016/j.sleep.2010.03.014
44. ∙∙ Lozoff B, Smith JB, Kaciroti N, Clark KM, Guevara S, Jimenez E. Functional significance of early-life iron deficiency: outcomes at 25 years. J Pediatr. 2013;163:1260–1266. Lozoff and colleagues are the first to demonstrate effects of early-life iron deficiency at 25 years of age. Formerly iron deficient adults were more likely to have social and emotional problems, and they were less likely to complete secondary school, which was mediated by poorer cognitive functioning in adolescence.
45. 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(5):453–8. DOI: 10.1111/dmcn.12118
46. Christian P, Murray-Kolb LE, Khatry SK, et al. Prenatal micronutrient supplementation and intellectual and motor function in early school-aged children in Nepal. JAMA. 2010;304(24):2716–23. DOI: 10.1001/jama.2010.1861
47. Christian P, Morgan ME, Murray-Kolb L, et al. Preschool iron-folic acid and zinc supplementation in children exposed to iron-folic acid in utero confers no added cognitive benefit in early school-age. J Nutr. 2011;141(11):2042–8. DOI: 10.3945/jn.111.146480
48. Cusick SE, Georgieff MK. Nutrient supplementation and neurodevelopment: timing is the key. Arch Ped Adolesc Med. 2012;155:481–2.
49. ∙∙ Wachs TD, Georgieff M, Cusick S, McEwen B. Issues in the timing of integrated early interventions: contributions from nutrition, neuroscience and psychological research. Ann NY Acad Sci. 2014;1308:89–106. This paper is a review of the nutritional, neuroscientific, and psychological evidence for sensitive periods of development. Knowledge of these sensitive periods of development for different types of outcomes should inform interventions for children.
50. Cogswell ME, Parvanta I, Ickes L, Yip R, Brittenham. Iron supplementation during pregnancy, anemia, and birth weight: a randomized controlled trial. Am J Clin Nutr. 2003;78:773–81.
51. Lozoff B, De Andraca I, Castillo M, Smith JB, Walter T, Pino P. Behavioral and developmental effects of preventing iron-deficiency anemia in healthy full-term infants. Pediatrics. 2003;112(4):846–54.
52. Black MM, Baqui AH, Zaman K, et al. Iron and zinc supplementation promote motor development and exploratory behavior among Bangladeshi infants. Am J Clin Nutr. 2004;80(4):903–10.
53. Stoltzfus RJ, Kvalsvig JD, Chwaya HM, et al. Effects of iron supplementation and anthelmintic treatment on motor and language development of preschool children in Zanzibar: double blind, placebo controlled study. BMJ. 2001;323(7326):1389–93. DOI: 10.1136/bmj.323.7326.1389
54. Grantham-McGregor S, Ani C. A review of studies on the effect of iron deficiency on cognitive development in children. J Nutr. 2001;131:(2S–2):649S–666S; discussion 666S–668S.
55. Corapci F, Radan AE, Lozoff B. Iron deficiency in infancy and mother-child interaction at 5 years. J Behav Dev Pediatr. 2006;27:371–8. DOI: 10.1097/00004703-200610000-00001
56. Murray-Kolb LE, Khatry SK, Katz J, et al. Preschool micronutrient supplementation effects on intellectual and motor function in school-aged Nepalese children. Arch Pediatr Adolesc Med. 2012;166(5):404–10. DOI: 10.1001/archpediatrics.2012.37
57. ∙ Berglund SK, Westrup B, Hagglof B, Hernell O, Domellof M. Effects of iron supplementation of LBW infants on cognition and behavior at 3 years. Pediatrics. 2013;131:47–55. This iron supplementation intervention for marginally low birth weight infants indicates no improvements in cognitive function at 3 years but a significant improvement in behavior problems.
58. 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 1301 grams: neurocognitive development at 5.3 years’ corrected age. Pediatrics. 2007;120(3):538–46. DOI: 10.1542/peds.2007-0495
59. Fuglestad AJ, Georgieff MK, Iverson SL, et al. Iron deficiency after arrival is associated with general cognitive and behavioral impairment in post-institutionalized children adopted from Eastern Europe. Matern Child Health J. 2013;17:1080–7. DOI: 10.1007/s10995-012-1090-z
60. Doom JR, Gunnar MR, Georgieff MK, et al. Beyond stimulus deprivation: Iron deficiency and cognitive deficits in post-institutionalized children. Child Dev. 2014.
61. 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(5):696–702. DOI: 10.1016/j.jpeds.2007.09.048