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Effect of maternal iron deficiency anemia on fetal neural development

Abstract

Objective:

Perinatal iron deficiency may have deleterious consequences on fetal neural development. The present study was conducted to determine the effect of maternal iron deficiency anemia (IDA) on fetal hippocampal morphogenesis and production of brain-derived neurotrophic factor (BDNF).

Study design:

Seventy term, singleton neonates born to mothers with IDA (hemoglobin <110g/L and serum ferritin <12 μg/L) formed the study group. Twenty gestational age-matched neonates born to healthy mothers without IDA (hemoglobin ≥110 g/L and serum ferritin >12 μg/L) served as controls. Maternal and fetal inflammatory conditions, infections and neonates with perinatal asphyxia were excluded. Cord blood BDNF concentrations were estimated by enzyme-linked immunosorbent assay. Volumetric analysis of hippocampus (right, left and combined, corrected for total intracranial volume) was done by cranial magnetic resonance imaging on days 3–5 of life.

Results:

In the study group, 24 mothers had mild (hemoglobin 100.0–109.0 g/L), 24 had moderate (hemoglobin 70.0–99.0 g/L), and 22 had severe (hemoglobin <70.0 g/L) anemia. Both hippocampal volumes and serum BDNF concentrations of neonates born to iron-deficient mothers were significantly reduced compared to controls. A progressive decline in hippocampal volumes and BDNF concentrations was observed with increasing severity of maternal anemia. Pearson correlation showed significant correlations among maternal and cord blood hemoglobin, iron indices, hippocampal volumes and BDNF concentrations.

Conclusions:

Maternal IDA adversely affects hippocampal morphogenesis and fetal production of BDNF. The degree of affection is proportional to the severity of maternal anemia.

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References

  1. World Health Organization. Micronutrient deficiencies: prevention and control guidelines. Geneva, Switzerland: World Health Organization; 2015.

    Google Scholar 

  2. World Health Organization. The global prevalence of anaemia in 2011. Geneva, Switzerland: World Health Organization; 2015.

    Google Scholar 

  3. Stevens GA, Finucane MM, De-Regil LM, Paciorek CJ, Flaxman SR, Branca F, et al. Nutrition Impact Model Study Group (Anaemia). Global, regional, and national trends in haemoglobin concentration and prevalence of total and severe anaemia in children and pregnant and non-pregnant women for 1995-2011: a systematic analysis of population-representative data. Lancet Glob Health. 2013;1:e16–25.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Lozoff B, Beard J, Connor J, Barbara F, Georgieff M, Schallert T. Long-lasting neural and behavioral effects of iron deficiency in infancy. Nutr Rev. 2006;64:S34–S43.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Siddappa AM, Georgieff MK, Wewerka S, Worwa C, Nelson CA, Deregnier RA. Iron deficiency alters auditory recognition memory in newborn infants of diabetic mothers. Pediatr Res. 2004;55:1034–41.

    Article  CAS  PubMed  Google Scholar 

  6. Georgieff MK. The role of iron in neurodevelopment: fetal iron deficiency and the developing hippocampus. Biochem Soc Trans. 2008;36:1267–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. Ranade SC, Rose A, Rao M, Gallego J, Gressens P, Mani S. Different types of nutritional deficiencies affect different domains of spatial memory function checked in a radial arm maze. Neuroscience. 2008;152:859–66.

    Article  CAS  PubMed  Google Scholar 

  9. Rao R, Tkac I, Schmidt AT, Georgieff MK. Fetal and neonatal iron deficiency causes volume loss and alters the neurochemical profile of the adult rat hippocampus. Nutr Neurosci. 2011;14:59–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tran PV, Fretham SJ, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yamada K, Mizuno M, Nabeshima T. Role for brain-derived neurotrophic factor in learning and memory. Life Sci. 2002;70:735–44.

    Article  CAS  PubMed  Google Scholar 

  12. Cunha C, Brambilla R, Thomas KL. A simple role for BDNF in learning and memory? Front Mol Neurosci. 2010;3:1.

    PubMed  PubMed Central  Google Scholar 

  13. Tapia-Arancibia L, Rage F, Givalois L, Arancibia S. Physiology of BDNF: focus on hypothalamic function. Front Neuroendocrinol. 2004;25:77–107.

    Article  CAS  PubMed  Google Scholar 

  14. Nelson KB, Grether JK, Croen LA, Dambrosia JM, Dickens BF, Jelliffe LL, et al. Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation. Ann Neurol. 2001;49:597–606.

    Article  CAS  PubMed  Google Scholar 

  15. Taurines R, Segura M, Schecklmann M, Albantakis L, Grunblatt E, Walitza S, et al. Altered peripheral BDNF mRNA expression and BDNF protein concentrations in blood of children and adolescents with autism spectrum disorder. J Neural Transm. 2014;121:1117–28.

    Article  CAS  PubMed  Google Scholar 

  16. World Health Organization. Hemoglobin concentrations for the diagnosis of anemia and assessment of severity. In: Vitamin and mineral nutrition information system. World Health Organization: Geneva, Switzerland; 2011.

  17. Diagne I, Archambeaud MP, Diallo D, d’Oiron R, Yvart J, Tchernia G. [Erythrocyte indices and iron stores in cord blood.] [Article in French]. Arch Pediatr. 1995;2:208–14.

    Article  CAS  PubMed  Google Scholar 

  18. 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.

    Article  CAS  PubMed  Google Scholar 

  19. Jack CR Jr, Twomey CK, Zinsmeister AR, Sharbrough FW, Petersen RC, Cascino GD. Anterior temporal lobes and hippocampal formations: normative volumetric measurements from MR images in young adults. Radiology. 1989;172:549–54.

    Article  PubMed  Google Scholar 

  20. Jack CR Jr, Theodore WH, Cook M, McCarthy G. MRI-based hippocampal volumetrics: data acquisition, normal ranges, and optimal protocol. Magn Reson Imaging. 1995;13:1057–64.

    Article  PubMed  Google Scholar 

  21. Free SL, Bergin PS, Fish DR, Cook MJ, Shorvon SD, Stevens JM. Methods for normalization of hippocampal volumes measure with MR. AJNR Am J Neuroradiol. 1995;16:637–43.

    CAS  PubMed  Google Scholar 

  22. Wigglesworth JM, Baum H. Iron dependent enzymes in the brain. In: Youdim MBH, editor. Brain iron: neurochemical and behavioural aspects. New York, NY: Taylor and Francis; 1988. p. 25–66.

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  24. Sullivan EV, Pfefferbaum A, Swan GE, Carmelli D. Heritability of hippocampal size in elderly twin men: equivalent influence from genes and environment. Hippocampus. 2001;11:754–62.

    Article  CAS  PubMed  Google Scholar 

  25. Pfluger T, Weil S, Weis S, Vollmar C, Heiss D, Egger J, et al. Normative volumetric data of the developing hippocampus in children based on magnetic resonance imaging. Epilepsia. 1999;40:414–23.

    Article  CAS  PubMed  Google Scholar 

  26. Bohbot VD, Allen JJ, Nadel L. Memory deficits characterized by patterns of lesions to the hippocampus and parahippocampal cortex. Ann NY Acad Sci. 2000;911:355–68.

    Article  CAS  PubMed  Google Scholar 

  27. Thompson DK, Wood SJ, Doyle LW, Warfield SK, Lodygensky GA, Anderson PJ. Neonate hippocampal volumes: prematurity, perinatal predictors, and 2-year outcome. Ann Neurol. 2008;63:642–51.

    Article  PubMed  Google Scholar 

  28. Beauchamp MH, Thompson DK, Howard K, Doyle LW, Egan GF, Inder TE, et al. Preterm infant hippocampal volumes correlate with later working memory deficits. Brain. 2008;131:2986–94.

    Article  PubMed  Google Scholar 

  29. Chouthai NS, Sampurs J, Desai N, Smith GM. Changes of neurotrophin levels in umbilical cord blood from infants with different gestational ages and clinical conditions. Pediatr Res. 2003;53:965–9.

    Article  CAS  PubMed  Google Scholar 

  30. Tucker KL, Meyer M, Barde YA. Neurotrophins are required fornerve growth during development. Nat Neurosci. 2001;4:29–37.

    Article  CAS  PubMed  Google Scholar 

  31. Lu B, Figurov A. Role of neurotrophins in synapse development and plasticity. Rev Neurosci. 1997;8:1–12.

    Article  CAS  PubMed  Google Scholar 

  32. Takei N, Nawa H. Roles of neurotrophins on synaptic development and functions in the central nervous system. Hum Cell. 1998;11:157–65.

    CAS  PubMed  Google Scholar 

  33. Radka SF, Holst PA, Fritsche M, Altar CA. Presence of brain-derived neurotrophic factor in brain and human and rat but not mouse serum detected by a sensitive and specific immunoassay. Brain Res. 1996;709:122–301.

    Article  CAS  PubMed  Google Scholar 

  34. Chen GKR, Barde YA, Bonhoeffer T, Kossel A. Relative contribution of endogenous neurotrophins in hippocampal long-term potentiation. J Neurosci. 1999;19:7983–90.

    Article  CAS  PubMed  Google Scholar 

  35. Pollin RA, Fox WW. Fetal and neonatal physiology. Philadelphia: Saunders; 1998. p. 2106–7.

    Google Scholar 

  36. Karege F, Schwald M, Cisse M. Postnatal developmental profile of brain-derived neurotrophic factor in rat brain and platelets. Neurosci Lett. 2002;328:261–4.

    Article  CAS  PubMed  Google Scholar 

  37. Malamitsi-Puchner A, Economou E, Rigopoulou O, Boutsikou T. Perinatal changes of brain-derived neurotrophic factor in pre- and fullterm neonates. Early Hum Dev. 2004;76:17–22.

    Article  CAS  PubMed  Google Scholar 

  38. Han BH, Holtzman DM. BDNF protects the neonatal brain from hypoxic-ischemic injury in vivo via the ERK pathway. J Neurosci. 2000;20:5775–81.

    Article  CAS  PubMed  Google Scholar 

  39. Imam SS, Gad GI, Atef SH, Shawky MA. Cord blood brain derived neurotrophic factor: diagnostic and prognostic marker in fullterm newborns with perinatal asphyxia. Pak J Biol Sci. 2009;12:1498–504.

    Article  CAS  PubMed  Google Scholar 

  40. Felderhoff-Mueser U, Rutherford MA, Squier WV. Relationship between MR imaging and histopathologic findings of the brain in extremely sick preterm infants. AJNR Am J Neuroradiol. 1999;20:1349–57.

    CAS  PubMed  Google Scholar 

Download references

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Correspondence to Sriparna Basu.

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Basu, S., Kumar, D., Anupurba, S. et al. Effect of maternal iron deficiency anemia on fetal neural development. J Perinatol 38, 233–239 (2018). https://doi.org/10.1038/s41372-017-0023-5

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