A systematic literature review of the relation between iron status/anemia in pregnancy and offspring neurodevelopment



The fetal brain starts developing early and animal studies have suggested that iron plays several roles for the development, but results from epidemiological studies investigating associations between gestational iron and offspring neurodevelopment are inconsistent.


To systematically examine results from observational studies and RCTs on gestational iron and offspring neurodevelopment, with focus on the importance of four domains: iron status indicators, exposure timing, neurodevelopmental outcomes, and offspring age.


PRISMA guidelines were followed. Embase, PsychInfo, Scopus, and The Cochrane library were searched in September 2017 and February 2018. Overall, 3307 articles were identified and 108 retrieved for full-text assessment. Pre-specified eligibility criteria were used to select studies and 27 articles were included;19 observational and 8 RCTs.


Iron status in pregnancy was associated with offspring behavior, cognition, and academic achievement. The direction of associations with behavioral outcomes were unclear and the conclusions related to cognition and academic achievement were based on few studies, only. Little evidence was found for associations with motor development. Observed associations were shown to persist beyond infancy into adolescence, and results depended on iron status indicator type but not on the timing of exposure.


We conclude that there is some evidence that low pregnancy iron, possibly particularly in the 3rd trimester, may be associated with adverse offspring neurodevelopment. As most previous research used Hemoglobin, inferring results to iron deficiency should be done with caution. No conclusions could be reached regarding associations beyond early childhood, and supplementation with iron during pregnancy did not seem to influence offspring neurodevelopment.

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  1. 1.

    World Health Organization. WHO | Micronutrient deficiencies [http://www.who.int/nutrition/topics/ida/en/]. World Health Organization, 2015.

  2. 2.

    United Nations Children’s Fund. Iron Deficiency Anaemia Assessment, Prevention, and Control A guide for programme managers. 2001;1–114.

  3. 3.

    World Health Organization. WHO recommendations on antenatal care for a positive pregnancy experience. WHO Rep. 2016;1–120.

  4. 4.

    World Health Organization. The Global Prevalence of Anaemia in 2011. WHO Rep. 2011;1–44.

  5. 5.

    World Health Organization. Evaluating the public health significance of micronutrient malnutrition. In. Allen L, de Benoist B, Dary O, Hurrell R, editors. Guidelines on food fortification with micronutrients. Geneva: Switzerland; 2006;41–92.

  6. 6.

    Connor JR, Menzies SL. Altered cellular distribution of iron in the central nervous system of myelin deficient rats. Neuroscience. 1990;34:265–71.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Kwik-Uribe CL, Gietzen D, German JB, Golub MS, Keen CL. Chronic marginal iron intakes during early development in mice result in persistent changes in dopamine metabolism and myelin composition. J Nutr. 2000;130:2821–30.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Nelson C, Erikson K, Piñero DJ, Beard JL. In vivo dopamine metabolism is altered in iron-deficient anemic rats. J Nutr. 1997;127:2282–8.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Erikson KM, Shihabi ZK, Aschner JL, Aschner M. Manganese accumulates in iron-deficient rat brain regions in a heterogeneous fashion and is associated with neurochemical alterations. Biol Trace Elem Res. 2002;87:143–56.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Beard JL, Connor JR. Iron status and neural functioning. Annu Rev Nutr. 2003;23:41–58.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Tran PV, Fretham SJB, Carlson ES, Georgieff MK. Long-term reduction of hippocampal brain-derived neurotrophic factor activity after fetal-neonatal iron deficiency in adult rats. Pediatr Res. 2009;65:493–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Georgieff MK. Iron in the brain. Neoreviews. 2006;7:e344–52.

    Article  Google Scholar 

  13. 13.

    Ibi M, Sawada H, Nakanishi M, Kume T, Katsuki H, Kaneko S, et al. Protective effects of 1α,25-(OH)2D3 against the neurotoxicity of glutamate and reactive oxygen species in mesencephalic culture. Neuropharmacology. 2001;40:761–71.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Srivastava DPP, Waters EMM, Mermelstein PGG, Kram r EAA, Shors TJJ, Liu F. Rapid estrogen signaling in the brain: implications for the fine-tuning of neuronal circuitry. J Neurosci. 2011;31:16056–63.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Li D. Effects of iron deficiency on iron distribution and gamma-aminobutyric acid (GABA) metabolism in young rat brain tissues. Hokkaido Igaku Zasshi. 1998;73:215–25.

    CAS  PubMed  Google Scholar 

  16. 16.

    Taneja V, Mishra K, Agarwal KN. Effect of early iron deficiency in rat on the gamma-aminobutyric acid shunt in brain. J Neurochem. 1986;46:1670–4.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Connor JR, Menzies SL, Burdo JRBP. Iron and iron management proteins in neurobiology. Pediatr Neurol. 2001;25:118–29.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Beard JL, Connor JR, Jones BC. Iron in the brain. Nutr Rev. 1993;51:157–70.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Niillard SA. Ribonucleotide reductase in developing brain. J Biol Chem. 1972;247:2395–400.

    Google Scholar 

  20. 20.

    Lozoff B, Georgieff MK. Iron deficiency and brain development. Semin Pediatr Neurol. 2006;13:158–65.

    PubMed  Article  Google Scholar 

  21. 21.

    Stiles J, Jernigan TL. The basics of brain development. Neuropsychol Rev. 2010;20:327–48.

    PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Honda K, Casadesus G, Petersen RB, Perry G, Smith MA. Oxidative stress and redox-active iron in Alzheimer’s Disease. Ann N Y Acad Sci. 2004;1012:179–82.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Iglesias L, Canals J, Arija V. Effects of prenatal iron status on child neurodevelopment and behavior: a systematic review. Crit Rev Food Sci Nutr. 2018;58:1604–14.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Veena SR, Gale CR, Krishnaveni GV, Kehoe SH, Srinivasan K, Fall CH. Association between maternal nutritional status in pregnancy and offspring cognitive function during childhood and adolescence; a systematic review. BMC Pregnancy Childbirth. 2016;16:220.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. 25.

    Higgins JPT GSS. Cochrane Handbook for Systematic Reviews of Interventions | Cochrane Training [http://training.cochrane.org/handbook]. The Cochrane Collaboration. 2013.

  26. 26.

    Downs SHH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Heal. 1998;52:377–84.

    CAS  Article  Google Scholar 

  27. 27.

    NIH - National Library of Medicine. Pregnancy Trimesters - National Library of Medicine - PubMed Health [https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0023078/].

  28. 28.

    Ellman LM, Vinogradov S, Kremen WS, Poole JH, Kern DM, Deicken RF, et al. Low maternal hemoglobin during pregnancy and diminished neuromotor and neurocognitive performance in offspring with schizophrenia. Schizophr Res. 2012;138:81–7.

    PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Vaughn J, Brown J, Carter JP. The effects of maternal anemia on infant behavior. J Natl Med Assoc. 1986;78:963–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Zhou SJ, Gibson RA, Crowther CA, Baghurst P, Makrides M. Effect of iron supplementation during pregnancy on the intelligence quotient and behavior of children at 4 y of age: Long-term follow-up of a randomized controlled trial. Am J Clin Nutr. 2006;83:1112–7.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Parsons A, Zhou S, Spurrier N, Makrides M. Effect of iron supplementation during pregnancy on the behaviour of children at early school age: long-term follow-up of a randomised controlled trial. Br J Nutr. 2008;99:1133–9.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Li Q, Yan H, Zeng L, Cheng Y, Liang W, Dang S, et al. Effects of maternal multimicronutrient supplementation on the mental development of infants in rural western China: Follow-up evaluation of a double-blind, randomized, controlled trial. Pediatrics. 2009;123:e685–92.

    PubMed  Article  Google Scholar 

  33. 33.

    Chang S, Zeng L, Brouwer ID, Kok FJ. Effect of iron deficiency anemia in pregnancy on child mental development in rural China. Pediatrics. 2013;131:e755–63.

    PubMed  Article  Google Scholar 

  34. 34.

    Li C, Zeng L, Wang D, Yang W, Dang S, Zhou J, et al. Prenatal micronutrient supplementation is not associated with intellectual development of young school-aged children. J Nutr. 2015;145:1844–9.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    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.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Angulo-Barroso R, Li M, Santos D, 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.

    PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Tofail F, Persson L, Arifeen S, Hamadani J, Mehrin F, Ridout D, et al. Effects of prenatal food and micronutrient supplementation on infant development: a randomized trial from the maternal and infant nutrition interventions, Matlab (MIMIMat) study. Am J Clin Nutr. 2008;87:704–11.

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Tran TD, Tran T, Simpson JA, Tran HT, Nguyen TT, Hanieh S, et al. Infant motor development in rural Vietnam and intrauterine exposures to anaemia, iron deficiency and common mental disorders: a prospective community-based study. BMC Pregnancy Childbirth. 2014;14:8.

    PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Naeye RL, Peters EC. Antenatal hypoxia and low IQ values. Am J Dis Child. 1987;141:50–4.

    CAS  PubMed  Google Scholar 

  40. 40.

    Fararouei M, Robertson C, Whittaker J, Sovio U, Ruokonen A, Pouta A, et al. Maternal Hb during pregnancy and offspring’s educational achievement: a prospective cohort study over 30 years. Br J Nutr. 2010;104:1363–8.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Oyemade UJ, Cole OJ, Johnson AA, Knight EM, Westney OE, Laryea H, et al. Prenatal predictors of performance on the Brazelton Neonatal Behavioral Assessment Scale. J Nutr. 1994;124(6 Suppl):1000S–1005S.

    CAS  PubMed  Google Scholar 

  42. 42.

    Menon KC, Ferguson EL, Thomson CD, Gray AR, Zodpey S, Saraf A, et al. Effects of anemia at different stages of gestation on infant outcomes. Nutrition. 2016;32:61–5.

    PubMed  Article  Google Scholar 

  43. 43.

    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;46:141–53.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Aranda N, Hernández-Martínez C, Arija V, Ribot B, Canals J. Haemoconcentration risk at the end of pregnancy: effects on neonatal behaviour. Public Health Nutr. 2017;20:1405–13.

    PubMed  Article  Google Scholar 

  45. 45.

    Mireku M, Davidson L, Koura G, Ouédraogo S, Boivin M, Xiong X, et al. Prenatal hemoglobin levels and early cognitive and motor functions of one-year-old children. Pediatrics. 2015;136:e76–83.

    PubMed  Article  Google Scholar 

  46. 46.

    Hernández-Martínez C, Canals J, Aranda N, Ribot B, Escribano J, Arija V. Effects of iron deficiency on neonatal behavior at different stages of pregnancy. Early Hum Dev. 2011;87:165–9.

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Tran TD, Biggs B-A, Tran TD, Simpson JA, Hanieh S, Dwyer T. Impact on infants’ cognitive development of antenatal exposure to iron deficiency disorder and common mental disorders. PLoS ONE. 2013;8:e74876.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Berglund SK, Torres-Espinola FJ, Garcia-Valdes L, Segura MT, Martinez-Zaldivar C, Padilla C. et al. The impacts of maternal iron deficiency and being overweight during pregnancy on neurodevelopment of the offspring. Br J Nutr. 2017;118:533–40.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Lynch S. The rationale for selecting and standardizing iron status indicators. World Health Organization. 2012.

  50. 50.

    Mireku MO, Davidson LL, Boivin MJ, Zoumenou R, Massougbodji A, Cot M, et al. Prenatal iron deficiency, neonatal ferritin, and infant cognitive function. Pediatrics. 2016;138:e20161319.

    PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Wachs TD, Georgieff M, Cusick S, McEwen BS. Issues in the timing of integrated early interventions: contributions from nutrition, neuroscience, and psychological research. Ann N Y Acad Sci. 2014;1308:89–106.

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Morath DJ, Mayer-Pröschel M. Iron deficiency during embryogenesis and consequences for oligodendrocyte generation in vivo. Dev Neurosci. 2002;24:197–207.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Doom JR, Georgieff MK. Striking while the iron is hot: Understanding the biological and neurodevelopmental effects of iron deficiency to optimize intervention in early childhood. Curr Pediatr Rep. 2014;2:291–8.

    PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Beard L, Kretchmer N, Beard JL, Carlson S. The role of nutrition in the development of normal cognition. Am J Clin Nutr. 1996;63:997S–1001S.

    PubMed  Article  Google Scholar 

  55. 55.

    Bailey L, West KP, Black RP. The epidemiology of global micronutrient deficiencies. Ann Nutr Metab. 2015;66:22–33.

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Jones SM, Darling-Churchill KE, Halle TG. Assessing early childhood social and emotional development: Key conceptual and measurement issues. J Appl Dev Psychol. 2016;45:42–8.

    Article  Google Scholar 

  57. 57.

    Brown VJ. Reproductive toxicity: too much of a good thing? Environ Health Perspect. 2006;114:A578.

    PubMed Central  Article  PubMed  Google Scholar 

  58. 58.

    Taylor R, Fealy S, Bisquera A, Smith R, Collins C, Evans T-J, et al. Effects of nutritional interventions during pregnancy on infant and child cognitive outcomes: a systematic review and meta-analysis. Nutrients. 2017;9:1265.

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  59. 59.

    Fernald LC, Kariger P, Engle P, Raikes A. Examining early child development in low-income countries: a toolkit for the assessment of children in the first five years of life. The World Bank, 2009;1–133.

  60. 60.

    Pollitt E, Triana N. Stability, Predictive Validity, and Sensitivity of Mental and Motor Development Scales and Pre-School Cognitive Tests among Low-Income Children in Developing Countries. Food Nutr Bull. 1999;20:45–52.

    Article  Google Scholar 

  61. 61.

    Dji. Country Classification System. Dow Jones Indexes. 2011;1–3.

  62. 62.

    Yang L, Ren AG, Liu JM, Ye RW, Hong SX. Influence of hemoglobin level during early gestation on the development of cognition of pre-school children. Zhonghua Liu Xing Bing Xue Za Zhi. 2010;31:1353–8.

    CAS  PubMed  Google Scholar 

  63. 63.

    Wasserman GA, Graziano JH, Factor-Litvak P, Popovac D, Morina N, Musabegovic A, et al. Consequences of lead exposure and iron supplementation on childhood development at age 4 years. Neurotoxicol Teratol. 1994;16:233–40.

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Wasserman G, Graziano JH, Factor-Litvak P, Popovac D, Morina N, Musabegovic A, et al. Independent effects of lead exposure and iron deficiency anemia on developmental outcome at age 2 years. J Pediatr. 1992;121(5 Pt 1):695–703.

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Rioux FM, Bélanger-Plourde J, Leblanc PL, Vigneau F. Relationship Between Maternal DHA and Iron Status And Infants' Cognitive Performance. Canadian Journal of Dietetic Practice and Research. 2011;72:e140–e146.

    Google Scholar 

  66. 66.

    Lewis SJ, Bonilla C, Brion M-J, Lawlor DA, Gunnell D, Ben-Shlomo Y. et al. Maternal iron levels early in pregnancy are not associated with offspring IQ score at age 8, findings from a Mendelian randomization study. European Journal of Clinical Nutrition. 2014;68:496–502.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Prado EL, Abbeddou S, Adu-Afarwuah S, Arimond M, Ashorn M, Ashorn U. et al. Predictors and pathways of language and motor development in four prospective cohorts of young children in Ghana, Malawi, and Burkina Faso. Journal of Child Psychology and Psychiatry. 2017;58:1264–1275.

    PubMed  Article  Google Scholar 

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We acknowledge the contribution of the statistician Volkert Siersma from the University of Copenhagen to our work through providing statistical help and Gabriel Gulis from the University of Southern Denmark for supervising the writing process.


Twelve months of under-graduate research stipend was received from the Lundbeck Foundation.

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JJ, IOS, and BLH were responsible for project conception and developed the overall research plan. JJ and MS conducted the search. JJ analyzed data. JJ, IOS, and BLH wrote the paper. JJ had primary responsibility for final content. All authors read and approved the final manuscript.

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Correspondence to Berit L. Heitmann.

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Janbek, J., Sarki, M., Specht, I.O. et al. A systematic literature review of the relation between iron status/anemia in pregnancy and offspring neurodevelopment. Eur J Clin Nutr 73, 1561–1578 (2019). https://doi.org/10.1038/s41430-019-0400-6

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