Professional Documents
Culture Documents
Tomas Walter
S104 Food and Nutrition Bulletin, vol. 24, no. 4 (supplement) © 2003, The United Nations University.
Effect of iron deficiency anemia in infancy and childhood S105
TABLE 1. Mental scale items (12 months) TABLE 2. Motor scale items (12 months)
Infants passing (%) Infants passing (%)
Description (item no.) Anemic Control p value Description (item no.) Anemic Control p value
Pushes car along (99) 56 77 NS Walks with help (42) 85 97 NS
Turns book pages (103) 69 83 NS Sits from standing (43) 67 97 0.01
Imitates words (mama, Pat-a-cake (44) 82 97 NS
dada) (106)
Stands alone (45) 64 93 0.02
At 12 months 13 47 0.01
At 15 months 75 100 0.07 Walks alone (46) 38 67 0.05
central nervous system development in 6-month-old of similar effects in the human infant has posed many
infants that lasts at least to 4 years of age and suggests methodologic challenges. During the last 20 years,
the benefits of studying other processes that are rapidly research on the effects of IDA and iron therapy on
myelinating during the first 2 years of life. infant development has depended heavily on stand-
ardized tests of infant development, which have serious
Sleep studies and autonomic nervous system limitations and bear unknown relations to central nerv-
development ous system functions. By measuring auditory-evoked
potentials, we provide more direct evidence of central
Maturational patterns of heart rate variability (HRV) nervous system alterations in infants with IDA. Such
provide noninvasive tools for the investigation neurophysiologic measurements had not been previ-
of central nervous integrity during early human ously conducted in the iron-deficient infant.
development and are likely to reflect brain function Changes in auditory brainstem-evoked potentials
alterations earlier and more closely than tests of or responses (ABRS) are particularly relevant to study
behavior and psychomotor development. Patterns of in infants with IDA. ABRS consist of a succession of
heart rate and HRV were measured in 18 anemic 6- five to seven waves recorded at the scalp within the
month-old infants and corresponding control infants first 10 milliseconds after stimulation. Development
from polygraphic recordings during quiet and active changes in ABRS have been carefully studied. There
sleep and wakefulness [32, 33]. Iron-deficient anemic are well-established developmental progressions from
infants presented lower amplitude in all sleep-wake birth until stable values are reached at 18 to 24 months,
states. It was proposed that delayed myelination of with decreases in the absolute and interpeak latencies,
the vagal nerve results in decreased parasympathetic decrease in duration, and increase in amplitude [21–23].
influences that may underlie behavioral effects in iron Latency changes have been related to increases in
deficiency in infancy. conduction velocity during axonal myelination. Other
changes, such as increase in amplitude and reduction
Reliance on animal studies in duration, are probably due to improvements in
synchronization at the axonal or synaptic levels. Thus,
The many challenges of studying the central nervous these developmental progressions are occurring during
system in human infants has meant that direct evidence the age period when iron deficiency is most common.
of central nervous system effects has had to come
from animal studies. That evidence is increasingly
compelling. In addition to earlier research on iron’s role Conclusions
in central nervous system neurotransmitter function
[34–38], recent work shows that brain iron is essential Behavioral studies have consistently shown that
for normal myelination [27–31, 39, 40]. In rats, there IDA has adverse effects. Perhaps the most important
is an influx of transferrin and iron into the brain in the implication of our findings, however, is that they may
immediate postnatal period. As iron and its transport further generate plausible and testable hypotheses
and storage compounds are redistributed in the brain, about the effects of iron deficiency on the developing
myelinogenesis and iron uptake are at their peak. Iron central nervous system. Many parts of the brain are
and its related proteins concentrate in oligodendrocytes becoming myelinated in the first 2 years of life, when
and become more concentrated in white than in gray iron deficiency is most prevalent. We are obtaining
matter (the majority of brain iron is found in this more direct and indirect non-invasive measures
myelin fraction). Oligodendrocytes synthesize fatty of myelination in the human. With the hypothesis
acids and cholesterol for myelin production, a process of impaired myelination in early IDA, it should be
that requires iron. Furthermore, animal studies have possible to design studies with specific measures, using
consistently found a lasting deficit in brain iron when techniques such as positron emission tomography
IDA occurs early in development [9–11]. Although (PET) scan imaging, evoked and spontaneous
only two studies of iron deficiency in animal models potentials, and, eventually, behavioral progressions
examined myelination directly, both found iron- known to depend on myelination. Such hypothesis-
deficient rats to be hypomyelinated [29, 40]. driven research would be a substantial advance over
previous studies of iron-deficient infants, which has
Challenges in designing clinical studies largely depended on global tests of development.
Thus, these studies suggest new, promising directions
The results of these and other animal studies indicate for understanding more specific central nervous system
that IDA during brain growth has long-lasting effects mechanisms by which IDA could alter infant behavior
on the central nervous system. Yet obtaining evidence and development.
Effect of iron deficiency anemia in infancy and childhood S109
References
1. Lozoff B, Brittenham GM, Viteri FE, Wolf AW, Urrutia 307–16.
JJ. The effects of short-term oral iron therapy on 20. Walter T. Effect of iron-deficiency anaemia on cognitive
developmental deficits in iron-deficient anemic infants. skills in infancy and childhood. Baillieres Clin Haematol
J Pediatr 1982;100:351–7. 1994;7:815–27.
2. Walter T, De Andraca I, Chadud P, Perales C. Iron 21. Roncagliolo M, Garrido M, Walter T, Peirano P, Lozoff B.
deficiency anemia: adverse effects on infant psychomotor Evidence of altered central nervous system development
development. Pediatrics 1986;84:7–17. in infants with iron deficiency anemia at 6 mo: delayed
3. Bayley N. Bayley Scales of Infant Development. New maturation of auditory brainstem responses. Am J Clin
York: Psychological Corporation, 1969. Nutr 1998;68:683–90.
4. Lozoff B, Wolf AW, Jimenez E. Iron-deficiency anemia 22. Roncagliolo M, Peirano P, Walter T, Garrido M, Lozoff B.
and infant development: Effects of extended oral-iron Auditory brainstem responses in iron deficient anemic
therapy. J Pediatr 1996;129:382–9. infants. Electroenceph Clin Neurophysiol 1997;103:63.
5. Pollitt E. The developmental and probabilistic nature of 23. Algarin C, Peirano P, Garrido M, Pizarro F, Lozoff B.
the functional consequences of iron-deficiency anemia Iron deficiency anemia in infancy: long-lasting effects
in children. J Nutr 2001;131:669S-675S. on auditory and visual system functioning. Pediatr Res
6. Idjradinata P, Pollitt E. Reversal of developmental 2003;53:217–23.
delays in iron-deficient anaemic infants treated with 24. Angulo-Kinzler RM, Peirano P, Lin E, Algarin C, Garrido
iron. Lancet 1993;341:1–4. M, Lozoff B. Twenty-four-hour motor activity in human
7. Stoltzfus RJ, Kvalsvig JD, Chwaya HM, et al. Effects of infants with and without iron deficiency anemia. Early
iron supplementation and anthelmintic treatment on Hum Dev 2002;70:85–101.
motor and language development of preschool children 25. Angulo-Kinzler RM, Peirano P, Lin E, Garrido M, Lozoff
in Zanzibar: double blind, placebo controlled study. BMJ B. Spontaneous motor activity in human infants with
2001;323:1389–93. iron-deficiency anemia. Early Hum Dev 2002;66:67–79.
8. Pollitt E, Metallinos-Katsaras E. Iron deficiency and 26. Peirano P, Algarin C, Garrido M, Pizarro F, Roncagliolo
behavior Constructs, methods, and validity of findings. M, Lozoff B. Interaction of iron deficiency anemia and
In: Wurtman RJ, Wurtman JJ, eds. Nutrition and the neurofunctions in cognitive development. Nestle Nutr
Brain. New York: Raven Press, 1990;101–146. Workshop Ser Clin Perform Programme 2001:19–35;
9. Dallman PR. Biochemical basis for the manifestations discussion 35–9.
of iron deficiency. Ann Rev Nutr 1986;6:13–40. 27. Beard JL, Connor JD, Jones BC. Brain iron: location and
10. Dallman PR, Siimes M, Manies EC. Brain iron: Persistent function. Progress in Food Nutr Sci 1993;17:183–221.
deficiency following short-term iron deprivation in the 28. Beard JL, Connor JR, Jones BC. Iron in the brain. Nutr
young rat. Br J Haematol 1975;31:209–15. Rev 1993;51:157–70.
11. Dallman PR, Spirito RA. Brain iron in the rat: Extremely 29. Connor JR, Menzies SL. Altered cellular distribution of
slow turnover in normal rats may explain long-lasting iron in the central nervous system of myelin deficient
effects of early iron deficiency. J Nutr 1977;107:1075– rats. Neuroscience 1990;34:265–71.
81. 30. Connor JR, Menzies SL, St Martin SM, Mufson EJ.
12. Aukett MA, Parks YA, Scott PH, Wharton BA. Treatment Cellular distribution of transferrin, ferritin, and iron in
with iron increases weight gain and psychomotor normal and aged human brains. J Neurosci Res 1990;
development. Arch Dis Child 1986;61:849–57. 27:595–611.
13. Lozoff B. Behavioral alterations in iron deficiency. Adv 31. Gerber MR, Connor JR. Do oligodendrocytes mediate
Pediatr 1988;35:331–59. iron regulation in the human brain? Ann Neurol 1989;
14. Lozoff B, Brittenham GM. Behavioral aspects of iron 26(1):95–8.
deficiency. Prog Hematol 1986;14:23–53. 32. Peirano P, Lacombe J, Kastler B, Guillon G, Vicente G,
15. Lozoff B, De Andraca I, Castillo M, Smith JB, Walter Monod N. Night sleep heart rate patterns recorded by
T, Pino P. Behavorial and developmental effects of cardiopneumography at home in normal and at-risk for
preventing iron deficiency anemia in healthy full-term SIDS infants. Early Hum Dev 1988;17:175–86.
infants. Pediatrics 2003;112:846–54. 33. Peirano P, Williamson A, Garrido M, Rojas P, Ehijo
16. Moffatt MEK, Longstaffe S, Besant J, Dureski C. A, Lozoff B. Iron-deficiency anemia delays in the
Prevention of iron deficiency and psychomotor decline development of the autonomic nervous system in
in high risk infants through iron fortified infant infants. Sleep Res 1996:24A.
formula: A randomized clinical trial. J Pediatr 1994; 34. Ben-Shachar D, Ashkenazi R, Youdim MBH. Long-term
125:527–34. consequence of early iron-deficiency on dopaminergic
17. Lozoff B, Jimenez E, Wolf A, Klein N. Long-term effect of neurotransmission in rats. Int J Dev Neurosci 1986;4:
iron deficiency anemia in infancy. Pediatrics 1989:16A. 81–8.
18. De Andraca I, Walter T, Castillo M, P P, Rivera F, Cobo 35. Youdim MBH. Neuropharmacological and neuro-
C. Iron deficiency anemia in infancy and its effects biochemical aspects of iron deficiency. In: Dobbing J,
upon psychological development at prechool age: a ed. Brain, behaviour, and iron in the infant diet. London:
longitudinal study. Nestle Found 1990:54–62. Springer-Verlag, 1990;83–106.
19. Walter T. Impact of iron deficiency on cognition in 36. Youdim MBH. Brain iron metabolism biochemical
infancy and childhood. Eur J Clin Nutr 1993;47(5): and behavioral aspects in relation to dopaminergic
S110 T. Walter
neurotransmission. In: Lagoth A, ed. Handbook of 39. Lin HH, Connor JR. The development of the
neurochemistry. New York: Plenum Press, 1985; 731– transferrin-transferrin receptor system in relation to
55. astrocytes, MBP and galactocerebroside in normal and
37. Youdim MBH, Ben-Shachar D, Yehuda S. Putative myelin-deficient rat optic nerves. Brain Res Dev Brain
biological mechanisms of the effect of iron deficiency Res 1989;49:281–93.
on brain biochemistry and behavior. Am J Clin Nutr 40. Roskams AJ, Connor JR. Iron, transferrin, and ferritin
1989;50:607–17. in the rat brain during development and aging. J
38. Youdim MBH, Yehuda S. Iron deficiency induces reversal Neurochem 1994;63:709–16.
of dopamine dependent circadian cycles: Differential
response to d-Amphetamine and TRH. Peptides 1985;
6:851–5.