Perinatal iron deficiency and neurocognitive development

“As the incidence of both these conditions is increasing worldwide (Beck et al., 2010; Martin et al., 2010; Danaei et al., 2011), it is likely that iron deficiency in infants will become an even greater concern in the future.”

“This phase of rapid growth represents a sensitive period, wherein environmental insults alter neurodevelopment (McEwen, 1999).”

“Like dendritic arbor structure, a spine’s morphology can impact its function (Spruston, 2008).”

“The SERT, which is responsible for re-uptake of serotonin within the brain, is the predominant mechanism controlling strength and duration of serotonergic neurotransmission (Gaspar et al., 2003).”

“Most likely Tf (secreted by the choroid plexus, which is another point of regulation) is the primary method for the distribution of iron in the brain (Beard, 2001); however, it is also possible for iron to be transported by binding to ferritin (Piñero and Connor, 2000).”

“It was previously thought that neonates were protected from iron deficiency, in all but the most severe cases of maternal anemia, due to mobilization of iron stores accumulated in utero (Allen, 2000).”

“…human brain and cognitive development is of particular interest because the brain growth spurt that begins in the last one-third of pregnancy continues the first 2 years after birth due to dendritic growth, synaptogenesis, and glial cell proliferation (Courchesne et al., 2000; Gogtay et al., 2006).”

“Neonatal iron deficiency is also greater in infants born prematurely or of a diabetic mother (Lozoff et al., 2006).”

“Neurogenesis in the hippocampal dentate gyrus also persists in the neonatal period (and throughout adulthood), and recent evidence indicates lingering neurogenesis in different cortical regions, including the prefrontal cortex in human infants (Sanai et al., 2011; Feliciano and Bordey, 2012).”

“IRON UTILIZATION WITHIN THE BRAIN So what are some potential mechanisms underlying iron deficiency-related deficits in cognition? Iron is important for erythropoiesis, formation of hemoglobin and myoglobin, gene transcription, cellular enzyme reactions, and important oxidation-reduction actions (Lieu et al., 2001).”

“After 6 months of age, the blood-brain barrier is a major control point for the entry of iron into the brain, although the choroid plexus (the vasculature responsible for producing cerebrospinal fluid) is also a location of regulation for iron entry (Beard and Connor, 2003).”

“The anemic infants also showed deficits in language capability and coordination (Walter et al., 1989).”

“…when 12–18 month old infants that were diagnosed with iron deficiency anemia were given an oral iron intervention, Bayley Scales of Infant Development scores significantly improved compared to those given a placebo, even after only 4 months of supplementation (Idjradinata and Pollitt, 1993).”

“The large increase in iron deficiency in pregnant women in developing countries may be due to poor nutrition education and lack of iron supplements (Pasricha et al., 2013).”

“In developing countries, approximately 12% of children under 5 will die from a micronutrient deficiency (Ahmed et al., 2012).”

“Increased latency of auditory brain stem potentials and visual evoked potentials (indirect markers of myelination) has been reported in iron deficient children (Roncagliolo et al., 1998; Algarín et al., 2003).”

“This coincides with the onset of myelination and an increase in transferring mRNA levels in brain (Connor et al., 1987; Connor and Menzies, 1996; Roncagliolo et al., 1998).”

“Five year old children, who were born either iron deficient, scored lower on tests of language ability, fine-motor skills, and tractability, when compared to children who were iron sufficient at birth (Tamura et al., 2002).”

“Iron-deficient animals develop ADHD-like behavior that has been linked to the dopaminergic system (Lahat et al., 2011).”

“…test, Intra-Extra-dimensional Shift, Stockings of Cambridge, Spatial Working Memory, Rapid Visual Information Processing, Pattern Recognition Memory, and Spatial Recognition Memory) at the age of 19 years old, when compared to teens that were iron sufficient during infancy (Lukowski et al., 2010).”

“Hippocampal-dependent memory appears and matures between 3–18 months of age (Nelson, 1995).”

“Neurotransmitter synthesis begins during embryogenesis (Figure 1; Herlenius and Lagercrantz, 2001).”

“These in turn modulate factors that facilitate elongation and branching by promoting or reducing actin polymerization (Ackermann and Matus, 2003; Sekino et al., 2007).”

“It has also been demonstrated that infants with low serum ferritin concentrations have abnormal auditory recognition memory (Siddappa et al., 2004).”

“However, it is now documented that even mild iron deficiency in the mother reduces iron stores in the fetus, resulting in a neonatal iron-deficient condition (Rao and Georgieff, 2002).”

“Smaller spine heads could reduce conduction velocity resulting in less coordinated input to the soma as well as represent smaller post-synaptic density which could also affect signal transmission (Hodgkin, 1954).”

“Additionally, rats that were iron deficient in the perinatal period displayed deficits in myelinogenesis at adulthood, even though iron stores were replete (Ortiz et al., 2004).”

“The results showed an improved scores within the Mental Development Index for the iron supplemented group (Oski and Honig, 1978), which resulted in a surge of interest in this topic (Yehuda et al., 2010).”

“In Chile, infants 3 months of age, were given either iron fortified formula or control diet for 12 months (Walter et al., 1983).”

“This process is not restricted to early developmental periods because it is also necessary for reshaping neural circuitry during experience-dependent learning throughout life (i.e., synaptic plasticity; Figure 1; Bagot et al., 2009).”

“However, it is now documented that even mild iron deficiency in the mother reduces iron stores in the fetus, resulting in a neonatal iron-deficient condition (Rao and Georgieff, 2002).”

“In industrialized countries like the United States, the incidence of iron deficiency is increasing, probably due in part to the increase in the number of children and adults who are overweight or obese (inflammation disrupts iron homeostasis) (Del Giudice et al., 2009).”

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“Studies in Indonesia found that 8 weeks of oral supplementation of iron in anemic preschool aged children reduced deficits in visual attention and concept acquisition compared to children who were not given supplementation (Soewondo et al., 1989).”

“…appears to have a programming effect on the physiologic mechanisms responsible for iron homeostasis resulting in offspring that are more likely to develop iron deficiency in the future regardless of adequate nutrition (De Pee et al., 2002; Georgieff et al., 2002; Emamghorashi and Heidari, 2004.”

“At birth, the blood-brain barrier is incompletely developed: it prevents iron transport proteins from diffusing into the brain but it lacks the ability to transfer iron from the blood into the brain parenchyma (Collard, 2009).”

“This is vital because the neonatal gut is developmentally immature and infants are unable to regulate iron absorption until 6–9 months of age (Domellöf et al., 2002).”

“The rate of iron entry into the brain is increased during iron deficiency (Taylor et al., 1991), which is due to an increased amount of Tf receptors present on the cells of the blood-brain barrier (van Gelder et al.”

“In rodents, iron deficiency is associated with delayed development of surface righting, bar hold, forelimb placing, and negative geotaxis (Beard et al., 2006).”

“Other studies demonstrate that serotonin transporter (SERT) and norepinephrine transporter densities are also altered by iron deficiency (Burhans et al., 2005).”

“For example, iron deficiency in the perinatal period is associated with altered expression of genes critical for hippocampal development and function (Carlson et al., 2007).”

“However, it is now documented that even mild iron deficiency in the mother reduces iron stores in the fetus, resulting in a neonatal iron-deficient condition (Rao and Georgieff, 2002).”

“Also in Indonesia, when 12–18 month old infants that were diagnosed with iron deficiency anemia were given an oral iron intervention, Bayley Scales of Infant Development scores significantly improved compared to those given a placebo, even after only 4 months of supplementation (Idjradinata and Pollitt, 1993).”

“Studies done in rat pups showed that iron regulatory proteins, which are involved with the regulation of Tf receptor, were not readily expressed until post-natal day 15, when peak myelination occurs in the rat (Siddappa et al., 2002).”

“Iron deficient diets also resulted in cognitive deficits in the Morris Water Maze, a hippocampal-dependent task which requires the rat to develop a spatial map of the area surrounding the pool in order to reach a hidden platform (Yehuda and Youdim, 1989).”

“…months infants that were iron sufficient showed greater attentional response to the mother’s face and greater updating of memory to the stranger’s face, while iron deficient infants did not show this response until 12 months of age, suggesting a delay in cognitive development (Burden et al., 2007).”

“At post-natal day 15, CA1 pyramidal neurons in rats that underwent a period of iron deficiency in utero showed reduced dendritic branching and smaller spine head diameters (Brunette et al., 2010).”

“SERT is expressed more during development than in adulthood (Daws and Gould, 2011).”

“Multiple studies have shown that iron status in infants born to iron deficient mothers is still abnormally low 9 months after birth despite being provided adequate dietary iron (Georgieff et al., 2002; Geltman et al., 2004).”

“During prenatal development iron accumulates in the brain so levels are highest immediately after birth (Siddappa et al., 2003).”

“…premature and had low ferritin levels at birth performed significantly worse on tests involving spatial cognition and processing of auditory signals when tested at 9 to 10 years of age, even though their hemoglobin levels had returned to normal (Armony-Sivan et al., 2004; Yehuda and Yehuda, 2006).”

“Young rats whose mothers were fed an iron-deficient diet and who were born with iron deficiency, showed decreased brain-derived neurotrophic factor (BDNF) levels, down-regulation of BDNF target genes, and altered neuronal differentiation (Tran et al., 2008).”

“MATERNAL IRON DEFICIENCY AND IRON DEFICIENCY ANEMIA: EFFECTS ON NEONATAL IRON STATUS As iron is concerned, the developing fetus was once considered a “perfect parasite,” able to acquire sufficient iron from the mother even when she was iron deficient (Young et al., 2012).”

“…deficits in both passive avoidance, where the rat had to inhibit its activity (i.e., not leave a platform and enter a chamber) in order to avoid shock, and active avoidance (i.e., where rats had to move into another chamber of the testing area in order to avoid shock) (Weinberg et al., 1979, 1981).”

“Similar deficits were observed in a water Y-maze (where the rat had two choices and a dry platform was placed at the end of the arm of the correct choice as a reward), including increased incorrect arm entries and a longer time to reach the platform (Yehuda et al., 1986), both of which indicate cognitive deficits.”

“Fear conditioning (as measured by heart rate deceleration in a cage where the rat had been shocked previously, as well as exposure to a tone that was played during the shock in a novel cage) was also impaired in iron deficient rats (McEchron et al., 2005).”

“The authors would also like to thank Jennifer Rytych for her input and help with the content of this article.”

“This coincides with the onset of myelination and an increase in transferring mRNA levels in brain (Connor et al., 1987; Connor and Menzies, 1996; Roncagliolo et al., 1998).”

“Dopamine is important for regulating cognition and emotion, reward and pleasure, movement, and hormone release (Dunnett et al., 2005).”

“In a Brazilian community, iron deficiency anemia in infants (average age 11.6 months) reached nearly 26% (Konstantyner et al., 2012); and in Canada, the rate of iron deficiency anemia in Cree Indian infants (average age 9 months) was nearly 32% (Willows et al., 2000).”

“Neurogenesis in the hippocampal dentate gyrus also persists in the neonatal period (and throughout adulthood), and recent evidence indicates lingering neurogenesis in different cortical regions, including the prefrontal cortex in human infants (Sanai et al., 2011; Feliciano and Bordey, 2012).”

“Thus, in critical developmental periods environmental insults that inhibit neurogenesis or alter neuron maturation will likely affect present and future behavior.”

“Oligodendrocytes synthesize fatty acids and Frontiers in Human Neuroscience www.frontiersin.org September 2013 | Volume 7 | Article 585 | 7 cholesterol for myelin (Mackler et al., 1979; McKay et al., 1983).”

“Multiple studies have shown that iron status in infants born to iron deficient mothers is still abnormally low 9 months after birth despite being provided adequate dietary iron (Georgieff et al., 2002; Geltman et al., 2004).”

“6 months) reached nearly 26% (Konstantyner et al., 2012); and in Canada, the rate of iron deficiency anemia in Cree Indian infants (average age 9 months) was nearly 32% (Willows et al.”

“…premature and had low ferritin levels at birth performed significantly worse on tests involving spatial cognition and processing of auditory signals when tested at 9 to 10 years of age, even though their hemoglobin levels had returned to normal (Armony-Sivan et al., 2004; Yehuda and Yehuda, 2006).”

“The authors would also like to thank Jennifer Rytych for her input and help with the content of this article.”

“…appears to have a programming effect on the physiologic mechanisms responsible for iron homeostasis resulting in offspring that are more likely to develop iron deficiency in the future regardless of adequate nutrition (De Pee et al., 2002; Georgieff et al., 2002; Emamghorashi and Heidari, 2004.”

“Another study was carried out to investigate the effects of perinatal iron deficiency on hippocampal development in mice (Ranade et al., 2013).”

“stages, where the dysfunction may affect memory and learning ability [171].”