The study by de Ungria and colleagues makes several important contributions. It furthers our understanding of iron's role in the developing brain, bridges basic brain research and developmental cognitive neuroscience, and focuses attention on perinatal iron deficiency. Each of these areas is noteworthy.
In the last decade there has been an exciting burst of research on iron's role during brain development. Recent work in the rodent model shows that brain iron is essential for normal myelination (1–4). In the rat, there is an influx of transferrin and iron into the brain in the immediate postnatal period. As iron and its transport and storage compounds are redistributed in the brain, myelinogenesis and iron uptake are at their peak. In addition, the regulatory genes and proteins controlling these processes are starting to be characterized. Older research also pointed to iron's role in CNS neurotransmitter function, especially implicating the D2 receptor of the dopaminergic system (see reviews (5, 6). After almost 20 y of little or no new work, there now are modern studies in this area, confirming dopaminergic alterations in iron deficiency (7, 8) and indicating that the neurotransmitter story is likely to be more complex.
The study by de Ungria et al. adds neuronal metabolism to the list of CNS functions impaired by early iron deficiency. The investigators used cytochrome c oxidase (CytOx), an iron-dependent enzyme involved in oxidative phosphorylation, as a quantifiable marker of neuronal metabolic activity. They systematically assessed regional differences in brain iron concentration and CytOx activity in young rats born to dams on iron-deficient or iron-sufficient diets throughout gestation and early lactation. The result that neuronal metabolism was most markedly reduced in all regions of the hippocampus is important and novel. This finding extends our appreciation of the vulnerability of the developing hippocampus. Hippocampal changes have now been described in a wide variety of early insults, including hypoxia-ischemia or hypoglycemia (9–12), several developmental neurotoxins (13), and nutrient deficiencies, such as lack of iron. However, the absence of correlation between reductions in iron concentration and CytOx activity in the de Ungria study was an unexpected result that raises further questions. If differing amounts of available iron do not account for differences in reduced CytOx activity, then what is the mechanism? What are the connections, if any, between the functions of iron in the hippocampus and myelination or neurotransmitter function?
Differential effects on the hippocampus appeared specific in this study. However, the hippocampus is not the only area of the brain affected by early iron deficiency. For instance, the nucleus accumbens showed normal CytOx activity in the de Ungria study, but a decrease in dopamine D2 receptor levels in this structure was reported in earlier research in the post-weanling iron-deficient rat (14). Such observations are reminders of the multiple roles that iron plays in the developing CNS, the importance of systematic investigation of different brain regions, and the need for further studies that carefully vary the developmental stage at which iron deficiency occurs and its effects are assessed.
The study makes a contribution beyond showing that neuronal metabolism is affected by iron deficiency. It is an interesting and powerful demonstration of the fruitfulness of interdisciplinary perspectives. Although other studies also demonstrate such cross-fertilization (eg linking slower nerve conduction in iron-deficient infants to basic science work on iron's role in myelination (15), the productive back-and-forth between the bedside and the laboratory is exceptionally well-illustrated by the team involved in the de Ungria study. The study's fundamental hypothesis was that perinatal iron deficiency would differentially reduce neuronal metabolic activity in areas of the brain involved in memory processing. This hypothesis grew out of a close collaboration between Georgieff, a neonatologist, Nelson, a developmental psychologist, and their colleagues in a variety of disciplines. Georgieff and associates had observed that newborn infants of diabetic mothers (IDMs) had lower levels of iron in liver, heart, and brain (16), postulating that abnormal maternal glucose metabolism created chronic fetal hypoxemia, with concomitant increase in red cell mass and depletion of iron stores. Nelson's expertise in the development of memory (17) led them to wonder whether decreased brain iron might affect memory functions that depend on certain developing brain regions, especially the hippocampus. The group has been pursuing related studies of these issues, using advanced basic science techniques in the rodent model to answer mechanistic questions and applying sophisticated developmental cognitive neuroscience approaches to assess memory functions in human infants with particular perinatal risks (18, 19). Thus, the result of this multidisciplinary collaboration is sophisticated clinically derived, hypothesis-driven CNS research that breaks new ground in nutrition, brain development, and behavior.
The study's observation of the vulnerability of the developing hippocampus to early iron deficiency, combined with earlier work showing lasting deficits in brain iron in the rodent model (20–24), may also help make sense of some previous research findings. Rodents that were iron deficient in early development appear to have lasting difficulty with spatial navigation (23), a capacity considered to entail normal hippocampal functioning. Young adolescents who were iron deficient as infants show poorer spatial memory (25), which might also relate to the role of the hippocampus in spatial tasks (26). These studies did not include “hippocampal” tasks specifically, but future research should certainly do so, given the findings of the de Ungria study.
A third important contribution of studies such as the one by de Ungria et al. is to focus attention on prenatal and perinatal iron deficiency. Recent research in rodents, primates, and humans points to impaired iron transport across the placenta in several prenatal conditions. Examples include diabetes mellitus, prenatal alcohol exposure, intrauterine growth retardation, and maternal stress (16, 27, 28). In some of these conditions, there is direct evidence of decreased brain iron (16, 27) or iron-deficiency anemia in the offspring (28). There are also iron alterations in perinatal hypoxia-ischemia (29, 30), and perinatal iron deficiency increases the vulnerability of the rat hippocampus to hypoxia-ischemia (29). Taken together, these studies raise the possibility that iron deficiency plays an important role in the adverse outcomes observed in these conditions.
These studies also demand that we rethink the traditional dogma that the human fetus suffers few ill effects of maternal iron deficiency, unless severe. Infants born to mothers with nutritional iron deficiency in pregnancy are rarely anemic, but they may have lower iron stores and/or develop iron deficiency sooner postnatally (see reviews (31, 32). There is now solid evidence that brain iron deficiency can occur even with a normal Hb level. In young animals of every species tested to do date, iron is prioritized to the red cells over all other organs, including brain (16, 33–35). If the developing human hippocampus and other CNS functions are vulnerable to perinatal iron deficiency, as the de Ungria study shows in the rat, there are major public health implications. WHO estimates that more than 30% of pregnant women in developing countries has iron-deficiency anemia (36), and one in four to five babies develops iron-deficiency anemia (37, 38). Anemia is a late manifestation of iron deficiency, and iron deficiency without anemia is even more widespread. If subtle effects of iron deficiency in infancy lay the ground for later problems in cognitive and behavioral functioning, then a large unrecognized population of children could be at risk due to perinatal iron deficiency, a nutritional problem that can be prevented or treated.
References
Connor JR, Benkovic SA 1992 Iron regulation in the brain: histochemical, biochemical, and molecular considerations. Ann Neurol 32: S51–S61.
Connor JR, Menzies SL 1990 Altered cellular distribution of iron in the central nervous system of myelin deficient rats. Neuroscience 34: 265–271.
Larkin EC, Rao GA 1990 Importance of fetal and neonatal iron: adequacy for normal development of central nervous system. In: Dobbing J (ed) Brain, Behaviour, and Iron in the Infant Diet. Springer-Verlag, London, 43–62.
Yu GS, Steinkirchner TM, Rao GA, Larkin EC 1986 Effect of prenatal iron deficiency on myelination in rat pups. Am J Pathol 125: 620–624.
Youdim MBH 1990 Neuropharmacological and neurobiochemical aspects of iron deficiency. In: Dobbing J (ed) Brain, Behaviour, and Iron in the Infant Diet. Springer-Verlag, London, 83–106.
Beard JL, Connor JR, Jones BC 1993 Iron in the brain. Nutr Rev 51: 157–170.
Beard JL, Chen Q, Connor J, Jones BC 1994 Altered monamine metabolism in caudate-putamen of iron-deficient rats. Pharmacol Biochem Behav 48: 621–624.
Nelson CA, Erikson K, Pinero DJ, Beard JL 1997 In vivo dopamine metabolism is altered in iron-deficient anemic rats. J Nutr 127: 2282–2288.
Barks JD, Sun R, Malinak C, Silverstein FS 1995 Gp120, an HIV-1 protein increases susceptibility to hypoglycemic and ischemic brain injury in perinatal rats. Exp Neurol 132: 123–133.
Nelson C, Silverstein FS 1994 Acute disruption of cytochrome oxidase activity in brain in a perinatal rat stroke model. Pediatr Res 36: 12–19.
Towfighi J, Mauger D, Vannucci R, Vannucci S 1997 Influence of age on the cerebral lesions in an immature rat model of cerebral hypoxia-ischemia: a light microscopic study. Dev Brain Res 100: 149–160.
Yager J, Shualb A, Thornhill J 1996 The effect of age on susceptibility to brain damage in a model of global hemispheric hypoxia-ischemia. Dev Brain Res 93: 143–154.
Walsh TJ, Emerich DF 1988 The hippocampus as a common target of neurotoxic agents. Toxicology 49: 219–225.
Youdim MBH, Sills MA, Heydorn WE, Creed GJ, Jacobowitz DM 1986 Iron deficiency alters discrete proteins in rat caudate nucleus and nucleus accumbens. J Neurochem 47: 794–799.
Roncagliolo M, Garrido M, Walter T, Peirano P, Lozoff B 1998 Evidence of altered central nervous system development in infants with iron deficiency anemia at 6 mo: delayed maturation of auditory brain stem responses. Am J Clin Nutr 68: 683–690.
Petry CD, Eaton MA, Wobken JD, Mills MM, Johnson DE, Georgieff MK 1992 Iron deficiency of liver, heart, and brain in newborn infants of diabetic mothers. J Pediatr 121: 109–114.
Nelson CA 1995 The ontogeny of human memory: a cognitive neuroscience perspective. Dev Psychol 31: 723–738.
deRegnier R-AO, Georgieff MK, Nelson CA 1997 Cognitive event-related potentials in four-month-old infants at risk for neurodevelopmental impairments. Dev Psychobiol 30: 11–28.
DeRegnier R-A, Nelson CA, Thomas K, Wewerka S, Georgieff MK 2000 Neurophysiologic evaluation of auditory recognition memory in healthy newborn infants and infants of diabetic mothers. J Pediatr, in press.
Dallman PR, Siimes M, Manies EC 1975 Brain iron: persistent deficiency following short-term iron deprivation in the young rat. Br J Haematol 31: 209–215.
Findlay E, Reid RL, Ng KT, Armstrong SM 1981 The effect of iron deficiency during development on passive avoidance learning in the adult rat. Physiol Behav 27: 1089–1096.
Weinberg J, Levine S, Dallman PR 1979 Long-term consequences of early iron deficiency in the rat. Pharmacol Biochem Behav 11: 631–638.
Felt BT, Lozoff B 1996 Brain iron and behavior of rats are not normalized by treatment of iron deficiency anemia during early development. J Nutr 126: 693–701.
Chen Q, Connor JR, Beard JL 1995 Brain iron, transferrin and ferritin concentrations are altered in developing iron-deficient rats. J Nutr 125: 1529–1535.
Lozoff B, Jimenez E, Hagen J, Mollen E, Wolf AW 2000 Poorer behavioral and developmental outcome more than 10 years after treatment for iron deficiency in infancy. Pediatrics 105: E51
Uecker A, Nadel L 1996 Spatial locations gone awry: object and spatial memory deficits in children with fetal alcohol syndrome. Neuropsychologia 34: 209–223.
Connor JR 1994 Iron acquisition and expression of iron regulatory proteins in the developing brain: manipulation by ethanol exposure, iron deprivation and cellular dysfunction. Dev Neurosci 16: 233–247.
Coe CL, Lubach GR 1998 Novel mechanism accounting for prenatal effects on the development of infant immunity. PNIRS Abstracts 12– 12
Rao R, de Ungria M, Sullivan D, Wu P, Wobken JD, Nelson CA, Georgieff MK 1999 Perinatal brain iron deficiency increases the vulnerability of rat hippocampus to hypoxic ischemic insult. J Nutr 129: 199–206.
Palmer C, Menzies SL, Roberts RL, Pavlik G, Connor JR 1999 Changes in iron histochemistry after hypoxic-ischemic brain injury in the neonatal rat. J Neuroscience Res 56: 60–71.
Ryan AS 1997 Iron-deficiency anemia in infant development: implications for growth, cognitive development, resistance to infection, and iron supplementation. Yearbook Phys Anthropol 40: 25–62.
Allen LH 1997 Pregnancy and iron deficiency: unresolved issues. Nutr Rev 55: 91–101.
Georgieff MK, Schmidt RL, Mills MM, Radmer WJ, Widness JA 1992 Fetal iron and cytochrome c status after intrauterine hypoxemia and erythropoietin administration. Am J Physiol 268: R485–R491.
Guiang SFI, Georgieff MK, Schmidt RL, Lambert DJ, Widness JA 1997 Intravenous iron supplementation effect on tissue iron and hemoproteins in chronically phlebotomized lambs. Am J Physiol 273: R2124–R2131.
Georgieff MK, Landon MB, Mills MM, Hedlund BE, Faassen AE, Schmidt RL, Ophoven JJ, Widness JA 1990 Abnormal iron distribution in infants of diabetic mothers: spectrum and maternal antecedents. J Pediatr 117: 455–461.
WHO/UNICEF/Joint Committee on Health Policy Strategic approach to operationalizing selected end-decade goals: reduction of iron deficiency anaemia. UNICEF-WHO Joint Committee on Health Policy editor. JCHP30/95/4.5 1–8. 1994 Geneva WHO.
Freire WB 1997 Strategies of the Pan American Health Organization/World Health Organization for the control of iron deficiency in Latin America. Nutr Rev 55: 183–188.
deMaeyer E, Adiels-Tegman M 1985 The prevalence of anaemia in the world. World Health Stat Q 38: 302–316.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lozoff, B. Perinatal Iron Deficiency and the Developing Brain. Pediatr Res 48, 137–139 (2000). https://doi.org/10.1203/00006450-200008000-00003
Issue Date:
DOI: https://doi.org/10.1203/00006450-200008000-00003
This article is cited by
-
Iron Availability Compromises Not Only Oligodendrocytes But Also Astrocytes and Microglial Cells
Molecular Neurobiology (2018)
-
Combating Iron Deficiency in Children
The Indian Journal of Pediatrics (2013)
-
Ernährung Frühgeborener nach der Entlassung
Monatsschrift Kinderheilkunde (2012)
-
Iron Deficiency: Beyond Anemia
The Indian Journal of Pediatrics (2011)
-
Increased Hippocampal Expression of the Divalent Metal Transporter 1 (DMT1) mRNA Variants 1B and +IRE and DMT1 Protein After NMDA-Receptor Stimulation or Spatial Memory Training
Neurotoxicity Research (2010)