Micronutrients and Brain Development

  • Davide MatteiEmail author
  • Angelo Pietrobelli
Nutrition and the Brain (J Nasser, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Nutrition and the Brain


Purpose of Review

This review summarizes the most recent evidence regarding the effects of micronutrients on brain development.

Recent Findings

Emerging evidence indicates that nutrition in the early life can profoundly influence neurodevelopment, affecting later life health outcomes, neurocognitive performances, and disease risks. Inadequate early life nutrition has been associated with some neuropsychiatric disorders. Epigenetic mechanisms could play a crucial role, imprinting the genomes in early life making the individual more susceptible to develop diseases later in life.


Children adequately nourished are more likely to reach their developmental potential in cognitive, motor, and socioemotional abilities, with positive societal repercussions. Data from further clinical trials are needed before more definitive conclusions can be drawn regarding the efficacy of dietary interventions for improving neurocognitive and social outcomes and preventing some neuropsychiatric illnesses. Nevertheless, it is reasonable to make recommendations to our patients to adopt certain dietary habits to optimize early life nutritional status in order to avoid long-term adverse consequences. Strategies of prevention should focus on ensuring more quality food to preconceptional, pregnant, lactating women and to children in their early life, not only in those areas where malnutrition is common but also in developed countries.


First 1000 days Brain development Neurodevelopment Micronutrients Micronutrient deficiencies Iron Iodine Zinc Epigenetics Neurocognitive performances Neuropsychiatric diseases 


Compliance with Ethical Standards

Conflict of Interest

Davide Mattei and Angelo Pietrobelli declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Pietrobelli A, Agosti M, MeNu Group. Nutrition in the first 1000 days: ten practices to minimize obesity emerging from published science. Int J Environ Res Public Health. 2017;14:1491.
  2. 2.
    Barks A, Hall AM, Tran PV, Georgieff MK. Iron as a model nutrient for understanding the nutritional origins of neuropsychiatric disease. Pediatr Res. 2018;85:176–82. Scholar
  3. 3.
    Pereira-da-Silva L, Rêgo C, Pietrobelli A. The diet of preschool children in the Mediterranean countries of the European Union: a systematic review. Int J Environ Res Public Health. 2016;13:572.
  4. 4.
    Prado EL, Dewey KG. Nutrition and brain development in early life. Nutr Rev. 2014;72:267–84.
  5. 5.
    Levi RS, Sanderson IR. Dietary regulation of gene expression. Curr Opin Gastroenterol. 2004;20:139–42.CrossRefGoogle Scholar
  6. 6.
    Canani RB, Costanzo MD, Leone L, Bedogni G, Brambilla P, Cianfarani S, et al. Epigenetic mechanisms elicited by nutrition in early life. Nutr Res Rev. 2011;24:198–205. Scholar
  7. 7.
    Roseboom T, de Rooij S, Painter R. The Dutch famine and its long-term consequences for adult health. Early Hum Dev. 2006;82:485–91. Scholar
  8. 8.
    •• Georgieff MK, Brunette KE, Tran PV. Early life nutrition and neural plasticity. Dev Psychopathol. 2015;27:411–23. This is an excellent paper about neural plasticity and nutrient effects on brain development. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Bale TL, Baram TZ, Brown AS, Goldstein JM, Insel TR, McCarthy MM, et al. Early life programming and neurodevelopmental disorders. Biol Psychiatry. 2010;68:314–9. Scholar
  10. 10.
    Walker SP, Wachs TD, Gardner JM, Lozoff B, Wasserman GA, Pollitt E, et al. Child development: risk factors for adverse outcomes in developing countries. Lancet. 2007;369:145–57. Scholar
  11. 11.
    Stiles J, Jernigan TL. The basics of brain development. Neuropsychol Rev. 2010;20:327–48. Scholar
  12. 12.
    Silbereis JC, Pochareddy S, Zhu Y, Li M, Sestan N. The cellular and molecular landscapes of the developing human central nervous system. Neuron. 2016;89:248–68. Scholar
  13. 13.
    Fox SE, Levitt P, Nelson CA. How the timing and quality of early experiences influence the development of brain architecture. Child Dev. 2010;81:28–40. Scholar
  14. 14.
    Bornstein MH. Sensitive periods in development: structural characteristics and causal interpretations. Psychol Bull. 1989;105:179–97.CrossRefGoogle Scholar
  15. 15.
    Colombo J. The critical period concept: research, methodology, and theoretical issues. Psychol Bull. 1982;91:260–75.CrossRefGoogle Scholar
  16. 16.
    •• 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. This is an excellent review about recent evidence on nutrition effects on brain development. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Jorgenson LA, Wobken JD, Georgieff MK. Perinatal iron deficiency alters apical dendritic growth in hippocampal CA1 pyramidal neurons. Dev Neurosci. 2003;25:412–20. Scholar
  18. 18.
    Tyagi E, Zhuang Y, Agrawal R, Ying Z, Gomez-Pinilla F. Interactive actions of Bdnf methylation and cell metabolism for building neural resilience under the influence of diet. Neurobiol Dis. 2015;73:307–18. Scholar
  19. 19.
    Zeisel S. Choline, other methyl-donors and epigenetics. Nutrients. 2017;9:445.
  20. 20.
    Ly A, Ishiguro L, Kim D, Im D, Kim S-E, Sohn K-J, et al. Maternal folic acid supplementation modulates DNA methylation and gene expression in the rat offspring in a gestation period-dependent and organ-specific manner. J Nutr Biochem. 2016;33:103–10. Scholar
  21. 21.
    • Barks A, SJB F, Georgieff MK, Tran PV. Early-life neuronal-specific iron deficiency alters the adult mouse hippocampal transcriptome. J Nutr. 2018;148:1521–8. This is an excellent paper about epigenetic changes induced by early life malnutrition. CrossRefPubMedGoogle Scholar
  22. 22.
    Susser ES, Lin SP. Schizophrenia after prenatal exposure to the Dutch Hunger Winter of 1944-1945. Arch Gen Psychiatry. 1992;49:983–8.CrossRefGoogle Scholar
  23. 23.
    Susser E, Neugebauer R, Hoek HW, Brown AS, Lin S, Labovitz D, et al. Schizophrenia after prenatal famine. Further evidence. Arch Gen Psychiatry. 1996;53:25–31.CrossRefGoogle Scholar
  24. 24.
    St Clair D, Xu M, Wang P, Yu Y, Fang Y, Zhang F, et al. Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959-1961. JAMA. 2005;294:557–62. Scholar
  25. 25.
    Kundakovic M, Jaric I. The epigenetic link between prenatal ad-verse environments and neurodevelopmental disorders. Genes (Basel). 2017;8:104.
  26. 26.
    Toledo-Rodriguez M, Lotfipour S, Leonard G, Perron M, Richer L, Veillette S, et al. Maternal smoking during pregnancy is associated with epigenetic modifications of the brain-derived neurotrophic factor-6 exon in adolescent offspring. Am J Med Genet B Neuropsychiatr Genet. 2010;153B:1350–4. Scholar
  27. 27.
    Kundakovic M, Gudsnuk K, Franks B, Madrid J, Miller RL, Perera FP, et al. Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure. Proc Natl Acad Sci U S A. 2013;110:9956–61. Scholar
  28. 28.
    Sarris J, Logan AC, Akbaraly TN, Amminger GP, Balanzá-Martínez V, Freeman MP, et al. Nutritional medicine as mainstream in psychiatry. Lancet Psychiatry. 2015;2:271–4. Scholar
  29. 29.
    • Barnard ND, Willett WC, Ding EL. The misuse of meta-analysis in nutrition research. JAMA. 2017;318:1435–6. This is an excellent paper about meta-analysis and the potential consequences on diet and health policies. CrossRefPubMedGoogle Scholar
  30. 30.
    •• Georgieff MK, Ramel SE, Cusick SE. Nutritional influences on brain development. Acta Paediatr. 2018;107:1310–21. This is an excellent review about effects of nutrient on neurodevelopment. CrossRefPubMedGoogle Scholar
  31. 31.
    Marangoni F, Cetin I, Verduci E, Canzone G, Giovannini M, Scollo P, et al. Maternal diet and nutrient requirements in pregnancy and breastfeeding. An Italian consensus document. Nutrients. 2016;8:629.
  32. 32.
    Società di Nutrizione Umana (SINU). LARN—Livelli di Assunzione di Riferimento di Nutrienti ed Energia per la Popolazione Italiana; IV Revisione. Milano: SICS; 2014. p. 1–655.Google Scholar
  33. 33.
    Ross AC, Taylor CL, Yaktine AL, et al. Dietary reference intakes for calciumand vitaminD. Institute ofMedicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. National Academies Press (US); 2011. Summary tables.Google Scholar
  34. 34.
    Greminger AR, Lee DL, Shrager P, Mayer-Pröschel M. Gestational iron deficiency differentially alters the structure and function of white and gray matter brain regions of developing rats. J Nutr. 2014;144:1058–66. Scholar
  35. 35.
    Carlson ES, Tkac I, Magid R, O’Connor MB, Andrews NC, Schallert T, et al. Iron is essential for neuron development and memory function in mouse hippocampus. J Nutr. 2009;139:672–9. Scholar
  36. 36.
    Tran PV, Kennedy BC, Lien Y-C, Simmons RA, Georgieff MK. Fetal iron deficiency induces chromatin remodeling at the Bdnf locus in adult rat hippocampus. Am J Physiol Regul Integr Comp Physiol. 2015;308:R276–82. Scholar
  37. 37.
    Lozoff B, Beard J, Connor J, Felt B, Georgieff M, Schallert T. Long-lasting neural and behavioral effects of iron deficiency in infancy. Nutr Rev. 2006;64:S34–91. Scholar
  38. 38.
    McLean E, Cogswell M, Egli I, Wojdyla D, de Benoist B. Worldwide prevalence of anaemia, WHO Vitamin and Mineral Nutrition Information System, 1993-2005. Public Health Nutr. 2009;12:444–54. Scholar
  39. 39.
    Georgieff MK. Long-term brain and behavioral consequences of early iron deficiency. Nutr Rev. 2011;69:S43–8. Scholar
  40. 40.
    Cusick SE, Georgieff MK. Nutrient supplementation and neurodevelopment: timing is the key. Arch Pediatr Adolesc Med. 2012;166:481–2. Scholar
  41. 41.
    Christian P, Murray-Kolb LE, Khatry SK, Katz J, Schaefer BA, Cole PM, et al. Prenatal micronutrient supplementation and intellectual and motor function in early school-aged children in Nepal. JAMA. 2010;304:2716–23. Scholar
  42. 42.
    Christian P, Morgan ME, Murray-Kolb L, LeClerq SC, Khatry SK, Schaefer B, 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;141:2042–8. Scholar
  43. 43.
    Murray-Kolb LE, Khatry SK, Katz J, Schaefer BA, Cole PM, LeClerq SC, et al. Preschool micronutrient supplementation effects on intellectual and motor function in school-aged Nepalese children. Arch Pediatr Adolesc Med. 2012;166:404–10. Scholar
  44. 44.
    Nguyen PH, Gonzalez-Casanova I, Young MF, Truong TV, Hoang H, Nguyen H, et al. Preconception micronutrient supplementation with iron and folic acid compared with folic acid alone affects linear growth and fine motor development at 2 years of age: a randomized controlled trial in Vietnam. J Nutr. 2017;147:1593–601. Scholar
  45. 45.
    Angulo-Barroso RM, Li M, Santos DCC, Bian Y, Sturza J, Jiang Y, et al. Iron supplementation in pregnancy or infancy and motor development: a randomized controlled trial. Pediatrics. 2016;137:e20153547. Scholar
  46. 46.
    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;167:1226–32. Scholar
  47. 47.
    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;55:453–8. Scholar
  48. 48.
    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. Scholar
  49. 49.
    Lozoff B, Castillo M, Clark KM, Smith JB. Iron-fortified vs low-iron infant formula: developmental outcome at 10 years. Arch Pediatr Adolesc Med. 2012;166:208–15. Scholar
  50. 50.
    Kc A, Rana N, Målqvist M, Jarawka Ranneberg L, Subedi K, Andersson O. Effects of delayed umbilical cord clamping vs early clamping on anemia in infants at 8 and 12 months: a randomized clinical trial. JAMA Pediatr. 2017;171:264–70. Scholar
  51. 51.
    Lozoff B, Jimenez E, Wolf AW. Long-term developmental outcome of infants with iron deficiency. N Engl J Med. 1991;325:687–94. Scholar
  52. 52.
    Tamura T, Goldenberg RL, Hou J, Johnston KE, Cliver SP, Ramey SL, et al. Cord serum ferritin concentrations and mental and psychomotor development of children at five years of age. J Pediatr. 2002;140:165–70. Scholar
  53. 53.
    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. Scholar
  54. 54.
    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;163:1260–6. Scholar
  55. 55.
    Insel BJ, Schaefer CA, McKeague IW, Susser ES, Brown AS. Maternal iron deficiency and the risk of schizophrenia in offspring. Arch Gen Psychiatry. 2008;65:1136–44. Scholar
  56. 56.
    Schmidt RJ, Tancredi DJ, Krakowiak P, Hansen RL, Ozonoff S. Maternal intake of supplemental iron and risk of autism spectrum disorder. Am J Epidemiol. 2014;180:890–900. Scholar
  57. 57.
    Schachtschneider KM, Liu Y, Rund LA, Madsen O, Johnson RW, Groenen MA, et al. Impact of neonatal iron deficiency on hippocampal DNA methylation and gene transcription in a porcine biomedical model of cognitive development. BMC Genomics. 2016;17:856. Scholar
  58. 58.
    Pharoah P, Buttfield IH, Hetzel BS. Neurological damage to the fetus resulting from severe iodine deficiency during pregnancy. Int J Epidemiol. 2012;41:589–92. Scholar
  59. 59.
    Thilly CH, Delange F, Lagasse R, Bourdoux P, Ramioul L, Berquist H, et al. Fetal hypothyroidism and maternal thyroid status in severe endemic goiter. J Clin Endocrinol Metab. 1978;47:354–60. Scholar
  60. 60.
    Moog NK, Entringer S, Heim C, Wadhwa PD, Kathmann N, Buss C. Influence of maternal thyroid hormones during gestation on fetal brain development. Neuroscience. 2017;342:68–100. Scholar
  61. 61.
    Mohan V, Sinha RA, Pathak A, Rastogi L, Kumar P, Pal A, et al. Maternal thyroid hormone deficiency affects the fetal neocorticogenesis by reducing the proliferating pool, rate of neurogenesis and indirect neurogenesis. Exp Neurol. 2012;237:477–88. Scholar
  62. 62.
    •• Velasco I, Bath SC, Rayman MP. Iodine as essential nutrient during the first 1000 days of life. Nutrients. 2018;10:290. This is an excellent review about iodine effects on brain development.
  63. 63.
    Furnica RM, Lazarus JH, Gruson D, Daumerie C. Update on a new controversy in endocrinology: isolated maternal hypothyroxinemia. J Endocrinol Investig. 2015;38:117–23. Scholar
  64. 64.
    Henrichs J, Ghassabian A, Peeters RP, Tiemeier H. Maternal hypothyroxinemia and effects on cognitive functioning in childhood: how and why? Clin Endocrinol. 2013;79:152–62. Scholar
  65. 65.
    Hynes KL, Otahal P, Hay I, Burgess JR. Mild iodine deficiency during pregnancy is associated with reduced educational outcomes in the offspring: 9-year follow-up of the gestational iodine cohort. J Clin Endocrinol Metab. 2013;98:1954–62. Scholar
  66. 66.
    Abel MH, Caspersen IH, Meltzer HM, Haugen M, Brandlistuen RE, Aase H, et al. Suboptimal maternal iodine intake is associated with impaired child neurodevelopment at 3 years of age in the Norwegian mother and child cohort study. J Nutr. 2017;147:1314–24. Scholar
  67. 67.
    Min H, Dong J, Wang Y, Wang Y, Teng W, Xi Q, et al. Maternal hypothyroxinemia-induced neurodevelopmental impairments in the progeny. Mol Neurobiol. 2016;53:1613–24. Scholar
  68. 68.
    Lavado-Autric R, Ausó E, García-Velasco JV, Arufe M del C, Escobar del Rey F, Berbel P, et al. Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. J Clin Invest. 2003;111:1073–82. Scholar
  69. 69.
    Bath SC, Steer CD, Golding J, Emmett P, Rayman MP. Effect of inadequate iodine status in UK pregnant women on cognitive outcomes in their children: results from the Avon Longitudinal Study of Parents and Children (ALSPAC). Lancet. 2013;382:331–7. Scholar
  70. 70.
    Markhus MW, Dahl L, Moe V, Abel MH, Brantsæter AL, Øyen J, et al. Maternal iodine status is associated with offspring language skills in infancy and toddlerhood. Nutrients. 2018;10:1270.
  71. 71.
    van Mil NH, Tiemeier H, Bongers-Schokking JJ, Ghassabian A, Hofman A, Hooijkaas H, et al. Low urinary iodine excretion during early pregnancy is associated with alterations in executive functioning in children. J Nutr. 2012;142:2167–74. Scholar
  72. 72.
    Gowachirapant S, Jaiswal N, Melse-Boonstra A, Galetti V, Stinca S, Mackenzie I, et al. Effect of iodine supplementation in pregnant women on child neurodevelopment: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017;5:853–63. Scholar
  73. 73.
    AbelMH, Ystrom E, Caspersen IH, Meltzer HM, Aase H, Torheim LE, et al. Maternal iodine intake and offspring attention-deficit/hyperactivity disorder: results froma large prospective cohort study. Nutrients. 2017;9:1239.
  74. 74.
    Román GC, Ghassabian A, Bongers-Schokking JJ, Jaddoe VWV, Hofman A, de Rijke YB, et al. Association of gestational maternal hypothyroxinemia and increased autism risk. Ann Neurol. 2013;74:733–42. Scholar
  75. 75.
    Sandstead HH. Zinc deficiency. A public health problem? Am J Dis Child. 1991;145:853–9.CrossRefGoogle Scholar
  76. 76.
    Sandstead HHWO. Atwater memorial lecture. Zinc: essentiality for brain development and function. Nutr Rev. 1985;43:129–37.CrossRefGoogle Scholar
  77. 77.
    Black MM. Zinc deficiency and child development. Am J Clin Nutr. 1998;68:464S–9S.CrossRefGoogle Scholar
  78. 78.
    Mathur NB, Agarwal DK. Zinc supplementation in preterm neonates and neurological development, a randomized controlled trial. Indian Pediatr. 2015;52:951–5.CrossRefGoogle Scholar
  79. 79.
    Fuglestad AJ, Kroupina MG, Johnson DE, Georgieff MK. Micronutrient status and neurodevelopment in internationally adopted children. Acta Paediatr. 2016;105:e67–76. Scholar
  80. 80.
    Siegel EH, Kordas K, Stoltzfus RJ, Katz J, Khatry SK, LeClerq SC, et al. Inconsistent effects of iron-folic acid and/or zinc supplementation on the cognitive development of infants. J Health Popul Nutr. 2011;29:593–604.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Locks LM, Manji KP, McDonald CM, Kupka R, Kisenge R, Aboud S, et al. The effect of daily zinc and/or multivitamin supplements on early childhood development in Tanzania: results from a randomized controlled trial. Matern Child Nutr. 2017;13:e12306.
  82. 82.
    Colombo J, Zavaleta N, Kannass KN, Lazarte F, Albornoz C, Kapa LL, et al. Zinc supplementation sustained normative neurodevelopment in a randomized, controlled trial of Peruvian infants aged 6-18 months. J Nutr. 2014;144:1298–305. Scholar
  83. 83.
    Pfaender S, Grabrucker AM. Characterization of biometal profiles in neurological disorders. Metallomics. 2014;6:960–77. Scholar
  84. 84.
    Yasuda H, Tsutsui T. Assessment of infantile mineral imbalances in autism spectrum disorders (ASDs). Int J Environ Res Public Health. 2013;10:6027–43. Scholar
  85. 85.
    Elbaz F, Zahra S, Hanafy H. Magnesium, zinc and copper estimation in children with attention deficit hyperactivity disorder (ADHD). Egypt J Med Human Genet. 2017;18(2):153–63.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Pediatric DivisionUniversity of VeronaVeronaItaly
  2. 2.Pennington Biomedical Research CenterBaton RougeUSA

Personalised recommendations