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Abstract

Iron is an important micronutrient which participates in the complex processes of brain development, maturation and functioning. During early brain development, iron deficiency affects myelinisation and neurotransmitter metabolism, and consequently alters the brain function. Severe sideropenia is accompanied by iron-deficiency (sideropenic) anaemia. The hematopoietic system’s priority of using iron leads to an even greater risk of brain development and function disorders. In fact, pronounced iron deficiency in the neonatal and breast-feeding period creates a permanent deficit in cognitive and social achievements, and success in life in general, which suggests that there is a critical period in which a sufficient amount of iron presents a prerequisite for basic brain development processes. A large number of infants with iron-deficiency anaemia caused by undernutrition or parasitic diseases makes this problem a high-priority topic and highlights the key role of primary and secondary prevention.

Keywords: iron, iron-deficiency anaemia, early brain development, infant

Introduction

Throughout the course of one’s life, the brain figures as a dynamic structure which is constantly being remodelled under the influence of internal and external factors. During the final trimester of pregnancy, the foetal brain undergoes rapid growth which continues during the infant’s first years. In infancy, the brain triples in weight (from 350 to 1000g) and continues developing rapidly during the first 2–3 years, when it reaches 80% of its adult weight. Although foundations for future development of intelligence, vision and speech are created during the first years, basic developmental processes begin at the moment of conception. Neural organisation and differentiation, synaptogenesis, glial cell proliferation, biochemical neuron differentiation, neurotransmitter synthesis and myelinisation all begin in the prenatal period. Brain development follows a genetically controlled, hierarchical sequence which may be interrupted by negative epigenetic effects. Depending on the phase in which these harmful influences occur, characteristic changes are made. Negative epigenetic effects occurring within the first trimester of pregnancy may cause anencephaly, meningocele or other neural tube closure defects. Negative epigenetic effects occurring after the fifth month may cause mental retardation, autism or similar higher brain functions disorders.

The plasticity of the brain in early infancy protects it from external influences and allows it to adapt to unfavourable conditions (e.g. undernutrition). However, the efficiency of its adaptability depends on the period in which harmful factors first appear, their duration and severity. Nutrition is certainly one of the most important factors in brain growth and development. The negative influence of undernutrition is most prominent in the period of rapid brain development. This is a period of extreme brain sensitivity. Harmful factors which occur at that time have a considerable negative effect on brain development and function. Although the rapid development phase is a period in which the brain is very sensitive to a lack of nutrients, it is also a period in which the brain shows the highest degree of plasticity and, consequently, the ability to compensate for structural and functional damage. The deficiency of certain macro- and micronutrients has a particularly large impact on brain development. These primarily include proteins, certain types of fat, iron, zinc, copper, iodine, selenium, vitamin A, choline and folate. The impact of the deficiency of any nutrient on brain development is determined by the period in which the deficiency occurs, its degree and duration. The specific influence of the deficiency of a given nutrient depends on the physiological processes in individual parts of the brain, in which the nutrient participates, and is manifested as a neurological function disorder in that specific area. For instance, iron deficiency affects myelinisation, monoamine neutransmitter synthesis and hippocampus metabolism during infancy. Reductions in speed (myelinisation), changes in motor control, affect (monoamines) and memory (hippocampus) (1, 2) all bear witness to these influences. Unfortunately, general undernutrition (linked with a deficiency of a large number of macro- and micronutrients) is globally widespread.

Iron Deficiency

Iron deficiency (sideropenia) is common among pregnant women and infants. There are several stages of iron deficiency: the first stage includes a decline in iron storage due to reduced availability; the second stage is iron deficiency (without anaemia) due to low iron storage, which has not yet affected haemoglobin synthesis; the third stage is iron-deficiency anaemia. Between 1 and 2 billion people worldwide suffer from iron-deficiency anaemia (sideropenic anaemia) (3). In the US, this condition affects 9% of children aged 1–2, 3% of children aged 3–5, 2% of children aged 6–11, and 9–11% of adolescent girls and women of generative age (4). Numerous studies have shown that iron-deficiency anaemia in pregnancy (especially its severe types) creates a significant risk of reducing foetal iron storage (5). The amount of iron in the mother’s milk is not sufficient to satisfy the infant’s iron needs during the first year, and iron supplements for breastfeeding mothers has not produced satisfactory results. The general conclusion is that iron should be administered to all breastfed infants after the sixth month, and to all prematurely born infants and infants born at low birth weight after the second month (6, 7). Frequent pregnancy disorders, such as intrauterine growth restriction and gestational diabetes mellitus, increase the risk of iron deficiency in the late foetal and early neonatal period.

The most reliable biochemical indicator of the first stage of iron deficiency is serum ferritin. In the second stage, reduced ferritin levels are accompanied by a reduction in serum iron and an increase in total iron binding capacity (TIBC). The third stage of iron deficiency features haematological symptoms of anaemia: reduced haemoglobin, mean corpuscular volume (MCV), reticulocyte number and increased red cell distribution width (RDW) (8). Infants born to mothers suffering from iron-deficiency anaemia have lower ferritin levels and are more prone to anaemia (5). Low ferritin levels in pregnant women suffering from preanaemia correlate with low ferritin levels in their newborns (9). Infants born with low ferritin levels have reduced foetal iron supplies, which can create a risk of postnatal sideropenia and can consequently damage brain development. The most common cause of foetal iron deficiency is maternal iron deficiency. As previously mentioned, maternal anaemia creates complications in 30–50% of pregnancies in developing countries. In contrast, in developed countries where iron supplements are routinely administered, the same complications occur in fewer than 1% of pregnancies.

During the foetal and neonatal period, iron is primarily built into erythrocytes, and only then into all the other tissues, including the brain. If iron supplies are not sufficient to satisfy the needs of all organ systems, the risk of brain damage exists even among non-anaemic infants (i.e. in cases of sideropenia without sideropenic anaemia) (10). When compared to a control group, infants suffering from sideropenic anaemia are less successful in tests of cognitive, motor, socio-emotional and neurophysiological development. Iron therapy does not always have satisfactory long-term results. Recent randomised studies suggest that it is important to begin administering iron supplements as early as possible, before the damage becomes severe and chronic. This will enable the prevention and reparation of numerous disorders (11). Considering the high frequency of sideropenia, potential infant brain development damage due to iron deficiency and lower results in cognitive development are alarming, both at the individual and social level.

Role of iron in the brain: research on animals and humans

The brain contains a system for integrating iron from plasma (transferrin receptor), a mechanism for iron transfer (trasferrin – Tf) (12), a mechanism for accumulating iron in the cells (H and L ferritin isomorphs) and functional iron storage located in each cell (13, 14, 15). The blood-brain barrier enables efficient regulation of the transfer of iron from the plasma into the cerebrospinal fluid, where the choroid plexus also functions as an iron transport regulator both within and outside the brain. As the brain matures, the function of the blood-brain barrier also changes and matures. Basal ganglia, substantia nigra and deep cerebellar nuclei contain the most iron. The distribution of iron in the brain of a child or adolescent can be determined via magnetic resonance (16, 17). The highest concentrations of iron are found in the globus pallidus, caudate nucleus, putamen and substantia nigra (18). Interestingly enough, substantia nigra only becomes rich in iron once the person reaches the age of 12 to 15 (17). Iron concentration in the brain is highest at birth, then drops during the first year, until it starts growing again at the age when myelinisation begins and Tf mRNA expression increases (18, 19, 20). This dynamic underscores the importance of the timing of iron deficiency. These biological tests are the first indicators to provide an explanation for the observation that infants with iron-deficiency anaemia experience arrested development due to a biological disorder. The fact that all existing studies based on clinical observations conducted after iron supplement therapy reveal that functions were never fully recovered, despite the fact that normal levels or iron have subsequently been reached, leads us to conclude that there is a critical period of brain development when ample amounts of iron are necessary for normal growth and development. As a rule, this is a brief period after which corrections of specific deficits (in this case, iron) no longer result in the establishment of a normal development process. This critical period is present only in infancy; in contrast, in cases of adult and adolescent iron-deficiency anaemia, iron supplements bring about complete behaviour and cognitive ability normalisation (21).

Dopaminergic pathways develop swiftly during early postnatal life. This development is characterised by a rapid increase in the number of dopamine transporters and receptors which lasts until early puberty. Development of the neural network activates other monoamine transporters and receptors as well, and their numbers increase until puberty and adulthood. This type of monoamine dynamic plays an important part in the organisation of axon development and the formation of synapses in the period of early brain growth; later (with age), it assumes its traditional role of neurotransmission. The role iron and other micronutrients play in eliminating excess neural compounds has not been entirely explained yet, nor has the influence of iron in brain biology on individual developmental functions. Numerous studies conducted in the past four decades explore the role of iron in neurotransmitter metabolism. They all suggest that iron is an indispensable component of numerous enzymes which participate in neurotransmitter synthesis (22, 23), such as tryptophan hydroxylase (serotonin synthesis) and serotonin hydroxylase (norepinephrine and dopamine synthesis). Furthermore, iron is a cofactor in ribonucleotide reductase and the basis for numerous reactions of electronic transfer in lipid and brain energy metabolism. It also plays an important role in monoamine oxidase activity (the enzyme responsible for the proper breakdown of these neurotransmitters) (23). The indirect mechanism which enables cell iron to influence monoamine metabolism has yet to be studied, although recent work on cell culture provides support for the theory that these are extremely important processes of crucial importance for the normal development and function of the brain (24). Experiments conducted on pheochromocytoma (PC12 cell culture) and neuroblastoma cells suggest a link between iron levels and expressions of dopamine and norepinephrine transporters. These studies were the first to prove a connection between cellular iron and monoamine metabolism (25).

The role of iron in rodent myelination has been known for several decades (26–34). The latest studies reveal several possible mechanisms of the impact of iron deficiency and indicate changes in lipid and phospholipid synthesis (with an effect on the myelin structure) in the entire brain (35), as well as in its specific regions (29–31). In both the entire brain and the myelin fractions, the lipid system remains unchanged even in adulthood, regardless of the fact that normal iron levels have subsequently been reached (35, 36). Changes in the (m)RNA responsible for transcribing the basic myelin protein (BMP) have also been noted (37). In the event of changes in the BMP composition, changes in the (m)RNA are present up to 6 months after iron therapy (38).

Different diet models with reduced iron intake were used in studies of early iron-deficiency anaemia, which included monitoring changes in iron-deficiency anaemia in rodent mothers, foetuses and rat pups. The degree of sideropenia in these models effects brain development by changing the gene expression and protein profile of the whole brain or its individual parts. In response to sideropenia, an increase of transferrin receptors, divalent metal transporter gene activity and protein expression in the pup brain occurs, commensurate to the degree of sideropenia (39–41). Results of research conducted on the brains of a smaller group of non-breastfed rat pups suffering from moderate anaemia during gestation and lactation showed significant changes in more than 300 transcripts, in the sense of an increase and reduction in their regulation (their ratio being more or less the same) (37). More important is the fact that five genes remained unchanged (in the sense of their reduced activity), even in 180-day old pups. These genes are responsible for cytoskeleton stability and synapse functioning. The expression of the regulatory gene for microtubule-associated protein 2 synthesis is altered and causes disturbance in the hippocampus protein distribution in adult rats after a case of early iron-deficiency anaemia (32). This type of structural change can damage the synapse and cause long-term behaviour changes following iron-deficiency anaemia.

The majority of randomly controlled studies of early iron supplementation (42–51) provide evidence to support the positive influence of iron. In research conducted in developed countries, its influence on motor functions ranged from 0.27 to 0.39 SD, while its influence on socio-emotional functions ranged from 0.30 to 0.41 SD (52). Only one study focused on its positive influence on cognitive functions (44). It was conducted on two groups of healthy infants: the first group received iron supplements (n=1123), while the second did not (n=534). At the age of 12 months, 3.1% of infants from the first group and 22.6% of infants from the second group developed iron-deficiency anaemia. Using the Fagan Test of Infant Intelligence and the Bayley Scales of Infant and Toddler Development, significant differences between the two groups of infants were discovered. The group which did not receive iron supplements expressed less positive emotions and was less involved in social interactions or interactions with the primary caregiver. Infants from this group were also more difficult to calm down with words or toys. Generally speaking, these infants were less prone to responding positively to external stimuli, which, the authors of the study conclude, reduces the potential benefits of external stimuli on early brain development.

Neurological effects of early childhood sideropenia  

Development disorder

The majority of studies on the effect of infant sideropenia on infant development and behaviour has been conducted among infants aged 6 to 24 months, when sideropenia is most frequent. Results of research conducted in different parts of the world indicate lower cognitive, motor and/or social/emotional functions among children suffering from iron-deficiency anaemia in infancy, compared to healthy infants (52–54).

Lozoff et al. conducted extensive research on the influence of iron deficiency on neuromotor development on a group of healthy children in Costa Rica (53). The initial research (55), conducted among 191 healthy children aged 12 to 23 months, measured haemoglobin and iron levels in serum. Bayley Scales of Infant and Toddler Development were used to evaluate psychomotor status prior to therapy, as well as one week and then three months after the commencement of iron therapy. Prior to commencing therapy, all children with haemoglobin levels below 10 g/l had significantly lower results in mental and motor development. No significant changes were noted after a week of therapy. After three months of therapy, anaemia was improved among all children, but 64% of them still suffered from sideropenia. After three months of therapy, results of psychomotor ability tests remained significantly lower, even among the 36% of children with improved sideropenia. Further research showed that extending the iron therapy to six months did not improve cognitive deficits. In their next study, Lozoff et al. demonstrate that the differences described above persist when the research is conducted among children aged 5, and from 11 to 14 (56). Their results indicate that differences in motor skills, frequent repeating of school years, anxiety/depression, social issues, attention disorder and extremely low results on cognitive tests persist in adolescence (until the age of 19), despite iron therapy which succeeded in improving iron-deficiency anaemia in infancy (57). The latest meta-analyses point to the long-term effects on the intelligence quotient, which is 1.73 points lower for each 10 g/l-lower haemoglobin level (58).

Infant sideropenia unaccompanied by anaemia also causes neuromotor development disorders, but behaviour disorders have not been noted. Disorders in adolescence are barely noticeable and reversible (59).

In older children, sideropenia causes cognitive disorders. Preschool children with and without anaemia suffer from attention disorders which lead to higher brain function disorders (60).

Syncope

A recently published retrospective study shows that a group of 106 children below the age of 19 with neurologically mediated syncope had lower serum ferritin, transferrin saturation and haemoglobin levels compared to children with other types of syncope. Children with neurologically mediated syncope also suffered from sideropenia (15%), anaemia (11%) or iron-deficiency anaemia (7%). Reduced iron supplies probably cause a dysfunction of enzymes which take part in catecholamine synthesis and resorption. This might explain why syncope is so common among adolescent girls (61).

Childhood stroke

A childhood stroke is very rare. Existing literature suggests 2 to 3 cases in 100,000 children a year. The cause is unknown for 20–36% of ischemic strokes and 16% of hemorrhagic strokes. The link between sideropenia and a stroke has been detected among both children and adults. Three possible causes of stroke include thrombocytosis, hypercoagulability and hypoxia. The stroke is usually clinically manifested as hemiplegia. The bilateral spread can also be manifested as consciousness disturbance. The patient can display behavioural or mood disorders, as well as focal and multifocal convulsions.

In a retrospective study of 15 children affected by a stroke and 143 control cases, Maguire et al. showed that iron-deficiency is more frequent among children affected by a stroke (53% compared to 9% of control cases) (55, 62).

Affective respiratory crisis

Affective respiratory crisis

An affective respiratory crisis is also linked to sideropenia. The emotional component certainly initiates a sequence of events which leads to severe hypoxia, loss of consciousness and occasionally convulsions. Anaemia certainly contributes to a reduction in oxygenation and facilitates the cascades of further processes. Holowatch analysed haemoglobin levels and compared a group of 160 children suffering from affective respiratory crises (aged 3 months to 3 years) with a group of 192 children suffering from febrile convulsions and a group of 572 children hospitalised for other reasons. Haemoglobin levels lower than 79 g/l were found among 23.5% of children with affective respiratory crises, 2.6% of children with febrile convulsions and 6.9% of children hospitalised on other grounds (63).

Boon attempted to determine whether iron therapy reduces the frequency of affective respiratory crises. He found it to be useful (NNT=2) and concluded that improvement is more likely to occur among children suffering from iron-deficiency anaemia (64).

Schizophrenia

A group of researchers at the New York State Psychiatry Institute followed a group of 6,872 children whose mothers had average haemoglobin levels during pregnancy, over the course of 22 years. The frequency of schizophrenia among the research subjects was 0.8%. Schizophrenia was four times more frequent among children whose mothers had an average haemoglobin level below 10 g/l, compared to children whose mothers had an average haemoglobin level above 12 g/l. In a discussion of the possible causes for this situation, the authors point to sideropenia (65).

Conclusion

Iron is important for normal brain development. Animal testing indicates that iron is important for normal brain development and myelinisation. Iron deficiency during pregnancy and lactation causes irreversible damage to brain development and function, which may be manifested as arrested cognitive and social development. This highlights the importance of preventing iron deficiency among women of generative age, during pregnancy and breastfeeding, and among infants (especially during the first two years), as well as the importance of following the preventive measures programme of the Compulsory Health Insurance Act, which requires capillary haemoglobin check-ups at the age of 6 and 12 months, and 2, 4 and 6 years (66). In risk situations, check-ups are necessary according to indication, and generally occur earlier and more frequently than those prescribed by in programme.

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