Iron Deficiency

Physical health can impact learning. I explored the connection between learning and iron deficiency in this paper from 2012.

Jennipher Spector

Independent Studies Unit

London Metropolitan University

May 28, 2012

‘A Case Study Exploring the Relationship between Iron Deficiency and Areas of Specific Cognitive Weakness in Childhood’

Introduction

The negative impact on psychomotor and cognitive development of iron-deficiency anemia in infancy has been well documented in more than a dozen studies over the last two decades (Walter, 2003). What is less researched and understood, however, is how mild iron deficiency affects cognitive development and function, and whether these effects can be reversed through iron supplementation. This study inquires into the possible relationship between mild iron deficiency and cognitive development specific to working memory, processing speed, and attention span, which are relative weaknesses in the case study subject, a 10-year-old boy. Following clinical blood work in July 2011 indicating iron deficiency in the subject, a psychoeducational assessment was conducted by an psychologist in September 2011 for the purpose of establishing baseline data. Shortly thereafter, iron supplementation was commenced according to recommendations from a pediatricians. After 18 weeks of iron supplementation, hematological screening was repeated to determine whether iron supplementation had been sufficient to return iron levels to normal. Once iron levels were determined to be within normal range, psychoeducational testing was conducted by the same psychologist. Results were then compared to results from September 2011 to determine whether iron supplementation had an effect upon cognitive areas previously determined to be areas of relative weakness – specifically, working memory, processing speed, and attention. The Literature Review section will explore the science of how and why iron deficiency affects cognitive ability and performance. It will also review previous studies aimed at determining whether these effects can be reversed following improvement of iron levels through iron supplementation. In the Methodology section, the design of the study will be discussed, as will the ethical considerations and rationale for the research approach. The Data Analysis section will compare haematology reports and psychoeducational reports conducted before and after iron supplementation. In the Discussion section, these results will be considered vis-à-vis research from the Literature Review. The limitations of this study will also be discussed, as will the implications for prevention and treatment of iron deficiency. Jennipher Spector Independent Studies Unit London Metropolitan University May 28, 2012 Literature Review Iron is necessary for several essential functions in the human body, including DNA synthesis, oxygen transport, and ATP (adenosine triphosphate) production. Iron is also required by enzymes involved in myelination and synthesis of neurotransmitters such as serotonin and dopamine (McCann and Ames, 2007), both of which are related to multiple cognitive functions, including learning and memory (Gonzalez-Burgos and Feria-Velasco, 2008). The accumulation of iron begins with the fetus in early pregnancy, increasing in the third trimester, and continuing throughout the lifespan. Unless the mother is severely anaemic, the infant is usually protected from iron deficiency for the first few months of life, but if sufficient iron is not provided in the diet, the infant eventually becomes vulnerable to iron deficiency. Insufficient dietary iron leads to biochemical changes in the blood and reduced concentrations of iron in bodily tissues. Iron deficiency anemia can result when iron concentrations are so low as to reduce serum hemoglobin (an iron-containing protein in red blood cells that transports oxygen) below the 98th percentile of a normally distributed population (McCann and Ames, 2007). The symptoms of iron deficiency anemia can include irritability, fatigue, headaches, abdominal pain, and impaired concentration and memory (A.D.A.M., 2011). If left untreated, iron deficiency anemia can impair growth, increase susceptibility to infections, and in extreme cases cause heart failure (Mayo Clinic, 2011). Iron deficiency (with or without anemia) is the most common nutritional disorder in humans, affecting about 20% of the global population (Cook and Finch, 1979 in Bruner, Joffe, Duggan, Casella, Brandt, 1996). Iron deficiency affects about two thirds of the developing world (United Nations Administrative Committee on Coordination Sub-Committee on Nutrition, 2000). In addition to developing countries, populations of lower socioeconomic status within industrialized countries are also disproportionately affected (Centers for Disease Control and Prevention, 2002). Although there can be other causes, including blood loss and impaired absorption, iron deficiency is typically the result of a lack of iron in the diet, and since heme iron from animal sources is absorbed two to three times more efficiently than non-heme iron from plant sources, it is more common in populations or individuals consuming less meat, dairy, and eggs (Centers for Disease Control and Prevention, 1998). Iron intake is not the only factor influencing blood iron levels, however. A study published in 2012 (Jahanshad, Kohannim, Hibar, Stein, McMahon, et al) indicates a genetic component in iron homeostasis. Specific genetic markers were found to influence both transferrin (the protein that transfers iron throughout the body) and brain microstructure (white matter fiber integrity), indicating that for some individuals or populations, iron deficiency may be influenced more by genetics than by diet. Jennipher Spector Independent Studies Unit London Metropolitan University May 28, 2012 Whether caused by genetics, diet, or socioeconomic factors, it is clear that iron deficiency anemia can cause significant detrimental effects on cognitive ability. Grantham-McGregor and Ani (2001) conclude that “longitudinal studies consistently indicate that children anemic in infancy continue to have poorer cognition, school achievement, and more behavior problems into middle childhood” (p. 649). The cognitive effects of iron deficiency without anemia are less well researched than the cognitive effects of anemia. One reason for this discrepancy is that iron deficiency without anemia is not detected by common screening procedures, despite the fact that it is more widespread than iron deficiency anemia (Lozoff, 2008). It is estimated that for every case of iron deficiency anemia found in a population, there are two cases of iron deficiency without anemia (Yip, 1994). McCann and Ames (2007) reviewed the research on the relationship between iron deficiency and cognitive and behavioral function. They concluded that: although most causal criteria are supported by at least some evidence from either human or animal studies, significant gaps suggest that it would be premature to conclude that a causal connection exists between iron deficiency per se during development and subsequent cognitive or behavioral performance... The literature is surprisingly uninformative on this extremely important topic, primarily because so few studies have been conducted (p. 941). While, as McCann and Ames suggest, the literature on the relationship between iron deficiency and cognitive impairment is inconclusive, it is still worthwhile to examine previous studies in order to identify patterns in the evidence base. Research over the past two decades can be divided into two categories: those that suggest that the cognitive effects of iron deficiency are irreversible despite correction of iron levels and those that suggest that the cognitive effects of iron deficiency can be improved following supplementation. Studies that fit into the former category will be examined first. 1. In a follow-up study, Costa Rican children diagnosed with and treated for iron deficiency during infancy were re-evaluated five and ten years later. When tested at both five and ten years after treatment, children who had severe, chronic iron deficiency in infancy scored lower on measures of mental and motor functioning than did children with normal iron levels during infancy. After controlling for background factors, differences Jennipher Spector Independent Studies Unit London Metropolitan University May 28, 2012 remained statistically significant in math and writing scores, motor functioning, and cognitive processes related to spatial memory, selective recall, and tachistoscopic threshold (visual attention). More of the formerly iron-deficient children had repeated a grade and/or been referred for special services or tutoring. Their parents and teachers rated their behavior as more problematic in several areas, agreeing in increased concerns about anxiety/depression, social problems, and attention problems (Lozoff, Jimenez, Hagen, Mollen, Wolf, 2000). 2. A longitudinal study of Chilean children concluded that iron deficiency anemia during infancy leads to mild auditory and visual dysfunctions that are still in effect four years after iron therapy (Algarin, Peirano, Garrido, Pizarro, Lozoff, 2003). [Fig. 1, below] Figure 1. Auditory and visual response times for anemic children following iron therapy and control children at 6 months and up to 4 years. The differences in speed of central conduction time in milliseconds are significant at all points (Algarin et al, 2003 in Walter, 2003). 3. A follow-up study of the previously-mentioned study of Chilean children by Algarin and colleagues in 2003 showed that although iron deficiency had been treated during infancy, memory deficits present four years later were still apparent when the children were ten years old (Congdon, Westerlund, Algarin, Peirano, Gregas, et al, 2012). The common factor in the above cases is that iron deficiency occurred during infancy. When iron deficiency occurs during infancy and early childhood, one well-researched theory summarized by Todorich and colleagues (Todorich, Pasquini, Garcia, Paez, Connor, 2009), points to an interruption in the process of myelination, which is dependent upon iron availability in the brain. Myelin is the material that forms the insulating plasma neuron around the axon of a neuron, facilitating efficient neurotransmission. Figure 2 (below) shows how myelin functions to speed up neurotransmission. Neurotransmission is more efficient and thus faster in myelinated than in unmyelinated fibers. Jennipher Spector Independent Studies Unit London Metropolitan University May 28, 2012 Figure 2. Impulse conduction in unmyelinated (top) and myelinated (bottom) fibers. Arrows show the flow of action currents in local circuits into the active region of the membrane. In unmyelinated fibers, the circuits flow through the adjacent piece of membrane, but in myelinated fibers the circuit flow jumps to the next node (Siegel, Agranoff, Albers, 1999). Myelin membranes are part of Schwann cells in the peripheral nervous system and oligodendrocytes in the central nervous system, concentrations of which is referred to as “white matter.” Oligodendrocytes are the primary iron-containing cells in the brain. Ironcontaining oligodendrocytes are found near neuronal cell bodies, along blood vessels, and are particularly abundant within white matter tracts. Iron is directly involved in myelin production since it is used in cholesterol and lipid biosynthesis and indirectly because it is required for oxidative metabolism (which occurs in oligodendrocytes at a higher rate than other brain cells). Iron deficiency may reduce iron acquisition by oligodendrocytes and thus the production of myelin (Connor and Menzies, 1996). The necessity of iron in myelin production has also been shown in studies demonstrating that decreased availability of iron in the diet is associated with hypomyelination (diseases involving substantial deficits in myelin deposition). Hypomyelination and the associated neurological effects persist long after iron deficiency has been corrected, (Todorich et al, 2009), implying that impairment of myelination within specific brain regions resulting from iron deficiency may be irreversible. The formation of a fully mature myelin may not be completed until adulthood in humans, but its growth is primarily concentrated in the first two years of life. Impaired myelination may thus explain cognitive discrepancies in children who experience iron deficiency in infancy, as well as why those effects appear to be irreversible after correction of iron deficiency through supplementation. The direct and important role of myelination in early motor development is well established (Algarin et al, 2003), and Algarin and colleagues further point to the spatial and temporal sequence of myelination during childhood as a possible explanation for differences in functioning of the visual and auditory systems, as well as behavioral and motor development differences in iron deficient children. Jennipher Spector Independent Studies Unit London Metropolitan University May 28, 2012 Because myelination occurs primarily in infancy, it is plausible that episodic iron deficiency after infancy may not have irreversible effects, or at least that its long-term effects after supplementation may be more subtle than the long-term effects of iron deficiency during infancy. This may perhaps be due in part to the sequence of myelination throughout the lifespan beginning with the most crucial functions such as motor development and ending with the subtler functions related to judgment. According to studies using MRI to map brain development, visual, auditory, and limbic cortices myelinate early; frontal and parietal neocortices continue myelination into adulthood; and posterior temporal cortices, primarily left hemisphere, which support language functions, have the longest maturation course (Sowell, Peterson, Thompson, Welcome, Henkenius, Toga, 2003). In the future, knowledge about specific points in human development when various regions of the brain myelinate could be applied to studies of iron deficient children at specific developmental stages for a better understanding of the relationship between myelination and iron deficiency. Until our understanding of the relationship between iron deficiency and myelination is fine-tuned, we could infer from MRI mapping and studies of iron deficient infants that iron deficiency during infancy has the most significant long-term effects on cognition and that these effects appear to be irreversible once the window for myelination of specific cortices has ended. While the results of studies examining the reversibility of cognitive impairment after iron deficiency during infancy are discouraging, the following studies indicate that when iron deficiency occurs after those first two critical years, the resulting cognitive impacts may in some cases be reversible following iron supplementation. 1. In a study of preschool children in Indonesia with both iron deficiency and anemia, cognitive performance related to visual attention and concept acquisition was suppressed. However, following 8 weeks of iron supplementation, cognitive weakness specific to visual attention and concept acquisition was reversed (Soewondo, Husaini, Pollilt, 1989). 2. Chinese preschoolers who had chronic iron deficiency anemia in infancy displayed less positive affect (positive emotions such as happiness), less frustration tolerance, more passive behavior, and more physical self-soothing in the stranger approach and delay of gratification scenarios. In contrast, the behavior and affect of children whose anemia was corrected before the age of 24 months were comparable to those of children who were nonacademic throughout infancy (Chang, Wang, Wang, Brouwer, Kok, et al, 2011). 3. After two months of iron supplementation, preschoolers in Greece with iron deficiency anemia showed an improvement in selective attention and discrimination cognitive Jennipher Spector Independent Studies Unit London Metropolitan University May 28, 2012 tests. (Metallinos-Katsaras, Valassi-Adam, Dewey, Lonnerdal, Stamoulakatou, Pollitt, 2004). 4. Two studies by Mexican neurophysiologists (Otero, Pliego-Rivero, Porcayo-Mercado, Mendieta-Alcántara, 2004 and Otero, Pliego-Rivero, Porcayo-Mercado, MendietaAlcántara, 2008) showed full recovery of working memory and attention to normal levels in previously iron deficient 8-10 year old children following iron supplementation. 5. In a study examining the effect of iron supplementation on iron deficient children aged 5-8 years diagnosed with ADHD, half of the 23 participants were given iron supplements and half were given a placebo. There was a progressive significant decrease in the ADHD Rating Scale after 12 weeks on iron but not on placebo (Konofal, Lecendreux, Deron, Marchand, Cortese, et al, 2008). 6. Iron deficient adolescent girls who received iron supplementation for eight weeks performed better on a test of verbal learning and memory than girls in the control group (iron deficient adolescent girls who did not receive iron supplementation) (Bruner et al, 1996). 7. In an randomized control study, increases in short term memory and attention span were significantly greater for the experimental group (iron deficient pregnant women given iron supplements for one month) than for the control group (iron deficient pregnant women not given iron supplements) (Groner, Holtzman, Charney, Mellits, 1985). 8. After treatment for iron deficiency in women ages 18-35, a significant improvement in serum ferritin was associated with a five- to seven-fold improvement in cognitive performance, while a significant improvement in hemoglobin was related to improved speed in completing the cognitive tasks (Murray-Kolb and Beard, 2007). These studies indicate that cognitive impairments resulting from iron deficiency that occurs after infancy can in fact be reversed following iron supplementation, possibly as a result of iron deficiency’s effect on dopamine neurotransmission. In a 2011 review of recent studies, Lozoff (2011) concluded that “pharmacologic and neuroimaging studies implicate...the mesocortical dopamine pathway.” Algarin and colleagues (2003) examine dopamine’s role in transmitting auditory and visual information as a possible explanation for its effect on higher-order cognitive and emotional functions negatively impacted by iron deficiency but reversible after iron supplementation. Studies by Otero and colleagues (2008) showing full recovery of working memory and attention to normal levels in previously iron deficient 8-10 year old children following iron supplementation hypothesized that: Jennipher Spector Independent Studies Unit London Metropolitan University May 28, 2012 Since iron is necessary for the synthesis of dopamine, dopaminergic neurotransmission is directly related to working memory systems... Biological and behavioral alterations related to dopaminergic neurotransmission have consistently been observed when brain iron reserves fall below 15% of normal values without anemia (Erikson et al 2000 and Nelson et al 1997). Basal ganglia and particularly the caudate nucleus and dopaminergic systems are importantly involved in attention processes (Beard et al 1994; Beard and Connor 2003; Erikson et al 2000 and 2001; Brozoski et al 1979; Durstewitz and Seamans 2002; Tanaka 2002; Costa et al 2003) and the highest brain iron deposits are located precisely in basal ganglia (p. 1739). Dopamine is involved in memory, learning, and attention as well as in motor control, hormonal regulation, stress responsivity, addiction, and emotional affect (Murray-Kolb and Beard, 2007). Furthermore, because of its possible effect on dopamine neurotransmission, iron deficiency has been suggested as a contributing factor to ADHD. In a 2004 study (Konofal, Lecendreux, Arnulf, and Mouren), ferritin (a protein that stores iron) levels were lower in children with ADHD than in controls. Lower ferritin levels were also related to more severe ADHD symptoms and greater cognitive deficits. The authors hypothesized that iron supplementation may reduce the symptoms of ADHD, and the following year a case study by Konofal and colleagues (Konofal, Cortese , Lecendreux, Arnulf, Mouren, 2005) examined the effect of iron supplementation in a three year old child with ADHD. After eight months of treatment, parents and teachers reported improvements in behavior, and The Conners’ Parent and Teacher Rating Scale raw total scores decreased to 19 and 13, respectively. In a study by Konofal and colleagues (Konofal, Lecendreux, Deron, Marchand, Cortese, et al, 2008) examining the effect of iron supplementation on iron deficient children with ADHD, half of the 23 participants were given iron supplements and half were given a placebo. There was a progressive significant decrease in the ADHD Rating Scale after 12 weeks on iron but not on placebo. In another attempt to understand the complex relationship between iron deficiency and cognitive development, studies reviewed by Fretham and colleagues (Fretham, Carlson, Georgieff, 2011) indicate that hippocampus-dependent memory appears and matures between 3 and 18 months of age, making memory an especially vulnerable function in iron deficient infants. However, whether alteration of dopamine metabolism due to early iron deficiency permanently alters hippocampal learning and memory function has not yet been determined. Recent studies on rats using genetic models offer an explanation of the role of iron in normal Jennipher Spector Independent Studies Unit London Metropolitan University May 28, 2012 hippocampal neuronal development as a means for understanding the negative impact of iron deficiency on learning and memory. The multiple studies reviewed by Fretham and colleagues (2011) suggest that iron is important for multiple interacting processes that affect overall regulation of numerous metabolic processes during early brain development. Finally, a study published this year offers new insight into the possible connection between iron deficiency and cognitive function. Using MRI to estimate iron content in various regions of the brain, a strong link was found between low iron in the thalamus of children diagnosed with ADHD as compared to those without ADHD (Cortese, Azoulay, Castellanos, Chalard, Lecendreux, et al, 2012). Although the role of the thalamus in symptoms of ADHD is poorly understood at this point, MRI studies point to morphological differences in the thalamus of children ages 8-18 with ADHD compared to those without ADHD (Ivanov, Bansal, Hao, Zhu, Kellendonk, et al, 2010). According to the research of Ivanov and colleagues, children ADHD showed smaller thalamic surface volume than children without ADHD. Also, children with ADHD who received stimulants had larger conventional thalamic volumes than children with ADHD who were not medicated. To date, there is not a study comparing attention quotients and thalamic volumes of iron deficient children with ADHD before and after supplementation to determine whether iron therapy has an effect on thalamic volumes and attention. In summary, it has not yet been definitively determined how and why iron deficiency affects cognitive development and function. Otero and colleagues (Otero, Pliego-Rivero, PorcayoMercado, Mendieta-Alcántara, 2008) describe the complex nature of iron deficiency’s effect on cognitive development as synergistically interacting mechanisms that directly and indirectly influence brain structure, biochemistry, and functional development. Our understanding of the effect of iron deficiency on cognitive development is incomplete, but ongoing inquiry into an issue that potentially affects 20% of the world’s population is continuing to progress. As researchers across disciplines work toward understanding the elusive relationship between iron deficiency and cognitive functions, the goal of prevention and treatment of iron deficiency and the associated detrimental effective effects become more likely. While this study does not propose to answer the questions that have plagued researchers for decades, it may offer further insight into the complex relationship between iron deficiency and cognitive function by applying theories explored in previous research to results of cognitive function following iron supplementation for an individual child. Methodology Jennipher Spector Independent Studies Unit London Metropolitan University May 28, 2012 Among the many forms of research, this project most clearly fits into the category of case study, defined by Merriam as an “in-depth description and analysis of a bounded system.” Because the data collected in this study focuses on an individual subject, the methodology most closely fits that of a single-case study. As such, “the starting and ending points are the comprehension of the case as a whole in its real-world context” (Scholz and Tietje, 2002). The core data in this study are quantitative, consisting of hematology reports performed in a lab and psychoeducational assessments carried out by a psychologist. More specifically, this single-case study fits Yin’s description of the longitudinal case in that the single case is studied at two or more points in time: “the theory of interest would likely specify how certain conditions change over time, and the desired time intervals would presumably reflect the anticipated stages at which the changes should reveal themselves.” In this study, cognitive ability and achievement is examined at intervals before and after iron supplementation over a nine-month period. The subject is the researcher’s son, a situation that presents both challenges and advantages within the context of this case study. Advantages include a deepened understanding of the subject’s academic and behavioural history, as well as close monitoring of the administration and effects of iron supplementation. Challenges include both ethical and logistical considerations. Specifically, the potential in this situation for personal bias and perceived bias could be heightened. As Yin (2009) points out, case study investigators are especially prone to using a case study to substantiate a preconceived position. Since the subject is the researcher’s child, it is reasonable for the parent to be hopeful that iron supplementation may positively affect areas of cognitive weakness. In order to avoid any potential bias, all cognitive assessments were carried out by a psychologist rather than by the researcher. The psychologist who was chosen to administer testing was not previously known by the researcher, and was selected due to her qualifications as a specialist in child psychology, her availability during the chosen period of time, and geographic proximity. This study was not discussed with the psychologist. In order to avoid a placebo effect, care was taken to avoid discussing the study in the presence of the subject. He was told that the iron monitoring and supplementation were necessary for correcting iron deficiency, and that iron deficiency may be related to the headaches which he had been experiencing (this connection was in fact suggested by his paediatrician). The possible connection to cognitive effects was not discussed directly with him or in his presence, and all efforts were made to avoid inadvertent awareness of the study at hand. Jennipher Spector Independent Studies Unit London Metropolitan University May 28, 2012 Ordinarily, ethical guidelines would compel the researcher to seek written consent from the research subject. However, considering the possibility of placebo in this study, consent could positively affect the outcome of both cognitive assessments and behavioural observations. Therefore, consent was not sought from the subject. Following Article 3 of the United Nations Convention on the Rights of the Child, “in all actions concerning children, the best interests of the child must be the primary consideration” (British Educational Research Association, 2004). Because this study was motivated with the best interests of the subject as the primary consideration, the methods of this study are well within ethical parameters. Cognitive testing and iron supplementation due to iron deficiency are both measures that are intended to be beneficial to the subject, regardless of whether it is part of a study. Therefore, measures to address both iron deficiency and cognitive weakness are justified for the benefit of the subject and are expected to have no negative effect. Excessive amounts of iron intake can result in liver toxicity. Therefore, care was taken to ensure that the dose of iron supplementation did not exceed the amount required to obtain blood iron levels within a normal range. Although a higher dose of iron may have resulted in faster and/or more significant improvements in cognitive and behavioural outcomes, the possibility of iron toxicity was considered a greater risk than the potential benefits of rapid blood iron increase. This study was conceived following a consultation with a developmental and behavioral pediatric specialist in Singapore on 8 June, 2011. Upon review of the subject’s physical symptoms (headaches, fatigue, irritability) and in light of areas of cognitive weaknesses (attention, processing speed, and working memory), the pediatricians recommended hematological screening to rule out iron deficiency or other irregularities. Once iron deficiency was identified, iron supplementation was recommended. Due to the timing of these events being amidst repatriation to the U.S., supplementation was postponed until after the family had resettled in their home and a new physician could be consulted. At that point, a baseline cognitive assessment was conducted by a psychologist and iron supplementation in the form of ferrous fumarate (as recommended by the physician) was commenced. After 18 weeks of iron supplementation (~15 mg ferrous fumarate daily in a multivitamin also containing vitamin C), follow-up hematologic screening was conducted, with iron supplementation continuing in order to maintain iron levels until follow-up cognitive testing could be scheduled. During this period of time, no supplemental tutors or therapists were engaged. Aside from being enrolled in regular public school, there were no additional enrichments that might have Jennipher Spector Independent Studies Unit London Metropolitan University May 28, 2012 affected cognitive or achievement test results. Additionally, no medications were given during this period that might have affected academic performance or behavior. Timeline for quantitative data collection Date Action 30-June-2011 Baseline hematology data collected 26-Sept-2011 Baseline cognitive assessment conducted 27-Sept-2011 Iron supplementation commenced 24-Jan-2012 Follow-up hematology data collected 29-Mar-2012 Follow-up cognitive assessment conducted Data Analysis Hematological screenings were conducted in Singapore in June 2011 and again in the U.S. in January 2012, approximately 7 months apart. After about 18 weeks of iron supplementation in the form of ferrous fumarate, serum iron increased 13 ug/dL and iron saturation increased 5%. Interestingly, the reference range for the two labs varies significantly. If the subject had been originally screened in the U.S., the consulting pediatricians would likely have not recommended iron supplementation, as the original hematological screening would have indicated serum iron and iron saturation within normal limits according to this U.S. lab’s reference range. Also, although serum iron and iron saturation increased following supplementation, both measures are still below the Singapore lab’s reference range, though well within the U.S. lab’s reference range. Public health implications of these variations will be addressed in the Discussion section. Date Measure Value Units Reference Range Jennipher Spector Independent Studies Unit London Metropolitan University May 28, 2012 30 June 2011 Iron, Serum 45 ug/dL 62-162 (Singapore lab) 24 Jan 2012 Iron, Serum 58 ug/dL 40-155 (U.S. lab) 30 June 2011 Iron Saturation 14 % 25-56 (Singapore lab) 24 Jan 2012 Iron Saturation 19 % 15-55 (U.S. lab) Following diagnosis of iron deficiency but prior to iron supplementation, a psychoeducational evaluation was conducted by a psychologist in September 2011 using the following tools:  Weschler Intelligence Scale for Children – 4 th edition (WISC-IV)  Weschler Individual Achievement Test – 3 rd edition (WIAT-III)  IVA+Plus After 18 weeks of iron supplementation resulting in increased blood iron and iron saturation, cognitive testing was performed in March 2012 by the same psychologist who administered testing in September 2011. IVA+Plus was repeated, as was WIAT-III. Due to the retest interval being too short, WISC-IV was replaced by DAS-II (Differential Abilities Scales – 2 nd Edition). The testing psychologist considered DAS-II to be an equivalent measure for processing speed and working memory, as the subtests within WISC-IV are quite similar. Results Jennipher Spector Independent Studies Unit London Metropolitan University May 28, 2012 The purpose of this study was to determine whether areas of relative cognitive weakness – attention, working memory, and processing speed – would improve after treating iron deficiency in the test subject. Iron supplementation for 18 weeks resulted in a 13 ug/dL increase in iron serum and 5% increase in iron saturation and an improvement in all areas of cognitive weakness under consideration – attention, working memory, and processing speed. Results of the psychoeducational assessments performed before and after iron supplementation are presented in the graphs below. Note that all measures reported below have a mean of 100 and a standard deviation of 15. WISC-IV and DAS-II: Cognitive ability measured before and after iron supplementation 75 80 85 90 95 100 105 110 Processing Speed Working Memory Before iron supplementation After iron supplementation IVA+Plus: Attention quotient measured before and after iron supplementation Jennipher Spector Independent Studies Unit London Metropolitan University May 28, 2012 0 10 20 30 40 50 60 70 80 90 100 Auditory Attention Visual Attention Sustained Auditory Attention Sustained Visual Attention Before After WIAT-III: Academic achievement measured before and after iron supplementation 75 80 85 90 95 100 105 110 Reading Comprehension and Fluency Written Expression Mathematics Math Fluency Oral Language Before After Discussion Jennipher Spector Independent Studies Unit London Metropolitan University May 28, 2012 Although the improvement of iron deficiency in the subject was nominal, all measures of cognitive ability (processing speed, working memory, and attention quotient) and academic achievement showed dramatic improvement. It is important to note, however, that two months passed between the time that follow-up hematology samples were drawn and followup psychoeducational testing was conducted. Since iron supplementation continued during those two months, it is reasonable to assume that iron levels were actually higher at the time of psychoeducational testing than was represented by hematology reports. Processing speed was initially measured at a standard score of 80 (using WISC-IV), which is in the 9th percentile and the low average range. Following supplementation, the standard score increased to 104 (using DAS-II), which is in the 61st percentile and the average range. This outcome can be compared to the previously-mentioned study in which iron deficient women ages 18-35 experienced improved processing speed following 16 weeks of iron supplementation (Murray-Kolb and Beard, 2007). Although the subjects of the Murray-Kolb and Beard study differ in age and gender from the subject of this study, the conclusion is relevant to this study: that “iron deficiency at any time in life may disrupt metabolic processes and subsequently change cognitive and behavioral functioning” (p. 778). As an explanation for initially impaired and subsequently improved processing speed, the authors support a connection between iron deficiency and impaired dopamine neurotransmission, which is then returned to normal following iron supplementation. The initial standard score for working memory (measured by WISC-IV) was 86, which is in the 18th percentile and the low average range. After supplementation, the standard score for working memory (measured by DAS-II) increased to 96, which is in the 39th percentile and the average range. This result most closely parallels the results of Otero and colleagues (Otero, Pliego-Rivero, Porcayo-Mercado, Mendieta-Alcántara, 2008) in which previously iron deficient 8-10 year old children showed full recovery of working memory to normal levels following iron supplementation. Like Murray-Kolb and Beard, Otero and colleagues propose that iron deficiency impedes dopamine neurotransmission, thus allowing for restoration of dopamine neurotransmission once iron levels are normalized. Attention was measured before and after iron supplementation by IVA+Plus, a computer-based test requiring the individual to respond or inhibit response to auditory and visual stimuli. Initial auditory attention quotient was 43 (very low range); after supplementation, auditory attention quotient was 87 (average range). Initial visual attention quotient was 77 (below average range); after supplementation, visual attention quotient was 95 (average range). Initial sustained auditory attention was 22 (extremely low range); after supplementation, sustained auditory Jennipher Spector Independent Studies Unit London Metropolitan University May 28, 2012 attention was 83 (below average). Initial sustained visual attention quotient was 54 (extremely low range); after supplementation, sustained visual attention quotient was 77 (below average). Results of this study are similar to previously-mentioned case study results obtained by Konofal and colleagues (2005) showing reduction of ADHD-related symptoms in a previously iron deficient three year old boy following iron supplementation. Similarly, in a control group comparison study by Konofal and colleagues (2008), previously iron deficient children diagnosed with ADHD who were given 80 mg iron/day over 12 weeks experienced a significant decrease in ADHD-related symptoms, while the control group (placebo) did not experience any decrease in symptoms. The authors described the effectiveness of iron therapy in iron deficient children with ADHD as comparable to stimulants. Since psychostimulants are believed to relieve ADHD symptoms by activating dopamine neurotransmission, Konofal and colleagues (2004) propose that iron supplementation might similarly improve dopamine activity with both ADHD and iron deficiency. Finally, although academic achievement was not a factor being considered in this study, results before and after iron supplementation show increases in all areas of academic achievement as measured by WIAT-III. The greatest increase was seen in Math Fluency, measured at a standard score of 81 (10th percentile) before supplementation and a standard score of 99 (4th percentile) after supplementation. This is not surprising, as a study of U.S. children ages 6-16 with iron deficiency had greater than twice the risk of scoring below average in math than did children with normal iron status (Halterman, Kaczorowski, Aligne, Auinger, Szilagyi, 2001). Since academic achievement is influenced by cognitive functions including working memory, processing speed, and attention, it is logical to assume that academic scores will increase with improved cognitive function. Indeed, research indicates a strong correlation between cognitive ability and academic achievement (Kaufman, Reynolds, Xin, Kaufman, McGrew, 2012). The primary limitation of this study is that the research sample is restricted to a single individual. It may be difficult, and possibly irresponsible, to universally generalize the results of a single case study to a broader audience, as each individual is unique and subject to the influences of an uncontrollable environment. Obviously, iron supplements should not be given to every child experiencing relative cognitive weakness in attention, working memory, and/or processing speed. As stated previously, excessive amounts of iron can be toxic. However, if the goal of scientific research is to make inferences that go beyond particular observations (King, Verba, Keohane, 1984), then it is incumbent upon the researcher to make an argument for the potential for generalization of this study. It may therefore be appropriate to apply the concept Jennipher Spector Independent Studies Unit London Metropolitan University May 28, 2012 of ‘natural generalization,’ in which common sense is used in determining whether the parameters between cases fit to a reasonable degree (Gomm, Hammersley, Foster, 2000). In determining whether this study should be generalized to other individuals with areas of cognitive weakness similar to the subject, non-cognitive indicators should be considered, such as symptoms of iron deficiency anemia, including irritability, fatigue, headaches, abdominal pain, and impaired concentration and memory (A.D.A.M., 2011), before commencing iron supplementation. Other associated symptoms of iron deficiency and iron deficiency anemia may include having spoon-shaped fingernails (koilonychia), the eating of non-food material (pica), a craving for ice (pagophagia), and abnormal temperature regulation (Institute of Medicine: Food and Nutrition Board, 2001). Other limitations which must be considered in determining the potential for generalization include the fact that that it is unknown how long iron deficiency had been present in the subject before being diagnosed. The subject was exclusively breast-fed for the first five months, with an increasingly diverse diet until weaning at 24 months. Since breast milk offers a highly bioavailable source of iron, even if the mother herself is iron deficient (Domellof, Lonnerdal, Dewey, Cohen, Hernell, 2004) it is unlikely that the subject became iron deficient during the first two years of life. As explained in the Literature Review, studies indicate that iron deficiency during the first two years is more likely to result in irreversible cognitive impairment. The fact that the subject was fed breast milk during the first two years, combined with the evidence indicating that previously impaired areas of cognitive function were significantly improved following improvement in iron status imply that the subject was not iron deficient during the first two years. Results of this study should therefore not be applied to cases where iron deficiency is likely during the first two years of development. Because of the possibility of accidental overdose from iron supplements, as well as gastrointestinal side-effects from even nominal quantities of iron supplements, public health initiatives should be focused on prevention rather than treatment of iron deficiency. Iron is normally sufficient in a balanced diet. However, there are a number of factors that influence iron absorption and bioavailability. Animal sources of food improve iron nutrition both by providing highly bioavailable heme iron and by enhancing non-heme iron absorption from plant sources when consumed in the same meal (Institute of Medicine: Food and Nutrition Board, 2001). The estimated overall iron bioavailability in the typical Western diet is 18%, whereas the estimated iron bioavailability from a typical vegetarian diet is 10%. Bioavailability can be as low as 5% with very strict vegetarianism and in developing countries where access to a variety of foods is limited. With a vegetarian diet, daily iron requirements can more easily be met if non- Jennipher Spector Independent Studies Unit London Metropolitan University May 28, 2012 heme sources of iron are consumed along with ascorbic acid, which enhances the absorption of non-heme iron. Also, it should be taken into consideration that calcium inhibits the absorption of both heme and non-heme iron (Institute of Medicine: Food and Nutrition Board, 2001). It is possible that some individuals may become iron deficient despite availability of iron-rich foods. In some cases this may be due to genetics, though it seems plausible that it could also be the result of being a “picky” or “fussy” eater. Although the cause of iron deficiency in the case study subject is unknown, it is suspected that sufficient iron was not obtained through the diet due to poor appetite and reluctance to eat many of the foods offered. If iron deficiency is suspected in a child who also has a limited diet, iron supplementation should be considered, especially in combination with ascorbic acid (vitamin C). Ideally, hematology testing should be conducted and iron supplementation should be supervised by a pediatricians. However, until the medical community becomes more aware of the connection between iron deficiency and cognitive function, it is incumbent upon parents to initiate action when iron deficiency is suspected. It is also important to take into consideration the differences in hematology reference ranges between labs when considering whether hematology reports indicate iron deficiency. As previously noted, if the baseline hematology report had been obtained at the same lab as was the follow-up hematology report, the consulting physician would not have recommended iron supplementation. For this reason, iron supplementation may be considered in cases where hematology results are in the lower end of the reference range. However, a physician should be consulted before commencing iron supplementation and hematology should be monitored longitudinally in order to prevent excessive iron intake. Conclusion In conclusion, this study showed the reversibility of cognitive weakness in the areas of working memory, processing speed, and attention following iron supplementation. While there may have been other factors affecting results, care was taken to avoid external influences, such as preventing placebo and avoiding other treatments or therapies that might have improved scores. Considering the apparent absence of other factors, the author concludes that improvements in cognitive and academic achievement scores are the result of improving blood iron levels through iron supplementation. 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