Iron deficiency in preschool children with autistic spectrum disorders

Iron deficiency in preschool children with autistic spectrum disorders

Research in Autism Spectrum Disorders 4 (2010) 639–644 Contents lists available at ScienceDirect Research in Autism Spectrum Disorders Journal homep...

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Research in Autism Spectrum Disorders 4 (2010) 639–644

Contents lists available at ScienceDirect

Research in Autism Spectrum Disorders Journal homepage: http://ees.elsevier.com/RASD/default.asp

Iron deficiency in preschool children with autistic spectrum disorders ¨ mer Faruk Akc¸a b, Ayhan Bilgic¸ a,*, Kag˘an Gu¨rkan b, Serhat Tu¨rkog˘lu c, O b b Birim Gu¨nay Kılıc¸ , Runa Uslu a

Malatya Government Hospital, Department of Child and Adolescent Psychiatry, Malatya Devlet Hastanesi, 44300 Malatya, Turkey Ankara University School of Medicine, Department of Child and Adolescent Psychiatry, Ankara U¨niversitesi Tip Faku¨ltesi Cocuk ve Ergen Psikiyatrisi AD, 06100 Cebeci, Ankara, Turkey c Dr. Sami Ulus Children’s Health and Disease Education and Research Hospital, Department of Child and Adolescent Psychiatry, Dr. Sami Ulus Devlet Hastanesi, 06080 Altındag˘, Ankara, Turkey b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 6 December 2009 Accepted 23 December 2009

Iron deficiency (ID) cause negative outcomes on psychomotor and behavioral development of infants and young children. Children with autistic spectrum disorders (ASD) are under risk for ID and this condition may increase the severity of psychomotor and behavioral problems, some of which already inherently exist in these children. In the present study, the frequency of ID and the association between ID and autistic symptoms, developmental level, and behavioral problems in preschool children attending a clinic for ASD (N = 31) were evaluated. No association was observed between ID and the severity of autistic symptoms, developmental level and behavioral problems. ID was detected in 32.3% (N = 10) of the children based on serum ferritin level. In this study, the negative impact of low serum ferritin in ASD has not been confirmed. On the other hand, the rate of ID was considerably high in this sample of children with ASD compared to normative data of preschool children. Further studies with larger samples are needed to clarify the relationship between ID and clinical variables associated with ASD. ß 2009 Elsevier Ltd. All rights reserved.

Keywords: Iron deficiency Ferritin Autistic spectrum disorders Preschool children Behavioral problems

The frequency of iron deficiency (ID) and iron deficiency anaemia (IDA) was reported to be high in children with autistic spectrum disorders (ASD) (Dosman et al., 2006; Latif, Heinz, & Cook, 2002). Previously, low iron intake (Cornish, 1998) and malabsorption (Wakefield et al., 1998) were considered as causes of ID in these children. However, it was shown that serum ferritin concentration return to normal level with iron supplementation (Dosman et al., 2007) and this finding support the notion that ID is associated with low iron intake in children with ASD. The high frequency of low iron intake in these children is thought to be associated with feeding difficulties and food selectivity (Cornish, 1998). Iron has a vital importance for proper function of some enzymes that are engaged in myelinization process and in monoamine neurotransmitter synthesis (Lozoff, 2007; McCann & Ames, 2007). It has a distribution in the brain in a parallel way with dopamine and intensively exists in the basal ganglia (Hill & Switzer, 1984; Youdim & Yehuda, 2000). It was shown in studies conducted with rodents that ID causes the decrease in the amount of proteins involved in energy metabolism, the slowing of dendritic growth and the reduction in the intensity of neural metabolites in hippocampus (Lozoff, 2007; McCann & Ames, 2007). The reported unfavourable consequences of ID on learning process, attention, memory and psychomotor functions might be associated with the functional deficits in these biological processes (Lozoff, 2007; Lozoff, Wolf, & Jimenez,

* Corresponding author. Tel.: +90 422 3261569. E-mail addresses: [email protected] (A. Bilgic¸), [email protected] (K. Gu¨rkan), [email protected] (S. Tu¨rkog˘lu), [email protected] (a), [email protected] (B.G. Kılıc¸), [email protected] (R. Uslu). 1750-9467/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.rasd.2009.12.008

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1996). It seems that the presence of ID without anaemia is sufficient for occurrence of these functional disturbances (Akman et al., 2004; Otero, Aguirre, Porcayo, & Fernandez, 1999). Besides, it is possible that children with anaemia explore the environment less and move less compared to their healthy counterparts and that may preclude them to receive sufficient stimulus and developing new skills (Abbott, 1998). The negative impacts of ID, especially early in life, on psychomotor and neurologic development do not seem to be reversible by iron supplementation and ID may cause permanent hazards in brain (Connor & Menzies, 1996; Lozoff, 2007; Roncagliolo, Garrido, Walter, Peirano, & Lozoff, 1998). There are many studies in the literature regarding the association between unfavourable psychomotor development and increased behavioral problems and ID/IDA (Idjradinata & Pollitt, 1993; Lozoff et al., 1987, 1996; Lozoff, Jimenez, Hagen, Mollen, & Wolf, 2000). Thus, it is reasonable to consider that insufficient iron intake may increase the severity of psychomotor retardation and behavioral problems, some of which already inherently exist in these children. Relatively more frequent emergence of insufficient iron intake in preschool children (Thane, Bates, & Prentice, 2003) and possible permanent impairments related to ID early in life (Connor & Menzies, 1996; Lozoff, 2007; Roncagliolo et al., 1998) suggest that children with ASD in this age range may have greater risk for ID and associated impairments. In this study, it was aimed to investigate the association between autistic symptoms, developmental level and behavioral problems and ID in preschool children with ASD. Another aim was to determine the frequency of ID and IDA in this group of children. 1. Materials and methods 1.1. Participants The sample consisted of children with ASD, with an age range of 18–60 months, who referred to Ankara University Department of Child and Adolescent Psychiatry. Children with a chronic neurological condition or physical illness other than ASD and children using continual medications because of behavioral problems or any other reasons were excluded. The study was approved by the Ankara University Ethical Committee. The nature and purpose of the study was explained to all parents. The parents who agreed to participate in the study read the patient information sheet and provided written informed consent. At first, 36 referred families were approached for the study; two of them refused to participate and three children were excluded based on exclusion/inclusion criteria. 1.2. Instruments 1.2.1. Childhood Autism Rating Scale (CARS) The Childhood Autism Rating Scale (CARS) consists of 15 items, which are rated on a scale of 1–4, with all the items contributing equally to one total score (Schopler, Reichler, Devellis, & Daly, 1980). Children were evaluated with CARS via family interviews and child observations. Items of the scale are concerned with interpersonal relationships, imitation, emotional response, body use, object use, adaptation to change, visual response, listening response, taste and smell responses, use of touch, fear/nervousness, verbal communication, non-verbal communication, activity level, level of intellectual response, and general impressions. The cut-off points for autism is 30. The interval from 30 to 36.5 points indicates mild-moderate autism, and scores between 37 and 60 indicate severe autism. For the Turkish version of the scale, item-total correlation (except item 14) ranges between 0.60 and 0.91, and item analysis indicates that all items (except item 14) differentiate children with mild to severe autism and its internal reliability coefficient is 0.86 (Sucuoglu, Oktem, Akkok, & Gokler,1996). 1.2.2. Autism Behavior Checklist (AuBC) The Autism Behavior Checklist (AuBC) is primarily used to define severity and frequency of autistic symptoms in school children (Krug, Arick, & Almond, 1980), but it was also shown to be useful in young children. It may be rated by caregivers or teachers of the children. The checklist consists of 57 questions, divided into five categories: Sensory, Relating (social skills), Body and Object Use, Language, and Social and Self Help. For the Turkish version of the AuBC total score, alpha coefficient and split half reliability were 0.92 (Yilmaz-Irmak, Tekinsav-Sutcu, Aydin, & Sorias, 2007). Findings suggested that the validity and the reliability of AuBC were satisfactory for the Turkish sample. 1.2.3. Aberrant Behavior Checklist (AbBC) The Aberrant Behavior Checklist (AbBC) was originally developed to assess treatment effects in people with intellectual disability (Aman, Singh, Stewart, & Field, 1985). The AbBC has also been found to be useful for evaluating inappropriate and maladaptive behaviors. It has 58 items that are rated on a four-point scale ranging from 0 (‘‘not at all a problem’’) to 3 (‘‘the problem is severe in degree’’) by caregivers or teachers of the patients. The scoring of items generates five subscales as follows: (I) Irritability, Agitation, Crying; (II) Lethargy, Social Withdrawal; (III) Stereotypic Behavior; (IV) Hyperactivity, Noncompliance; (V) Inappropriate Speech. The Turkish translation and adaptation of the AbBC was conducted with 10–24 years old individuals with intellectual disability (Sucuoglu, 2003). Adaptation study of AbBC for 1–4 years old children was performed later; to do this, three items were rewritten to be congruent with this age range (Karabekiroglu & Aman, 2009). Internal consistencies for all AbBC subscales were found to be moderate to high. Cronbach’s alpha values were as follows: (I)

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Irritability, Agitation, Crying: 0.90; (II) Lethargy, Social Withdrawal: 0.81; (III) Stereotypic Behavior: 0.83; (IV) Hyperactivity, Non-compliance: 0.89; (V) Inappropriate Speech: 0.68. 1.2.4. Ankara Developmental Screening Inventory (ADSI) The Ankara Developmental Screening Inventory (ADSI) was developed for assessing developmental levels of 0–6 years old Turkish children taking into consideration culture specific features (Savasir, Sezgin, & Erol, 1994). It was included a total of 154 questions for the caregiver and the child according to the age groups of children. The questions represent the different areas of development. The inventory divided into four categories: cognitive language score, fine motor ability score, gross motor ability score, and social and self-care skills score. The total of these four scores yields the general developmental score. The raw scores are then converted to standard T scores, which are compared with the normative data belonging to children within the same age range. 1.3. Procedure ASD diagnosis was made according to DSM-IV-TR (American Psychiatric Association, 1994) criteria using to information gathered by history taking, one-way mirror observation and videotaping of parent-child interaction, and CARS and checklists. One of the authors (R.U.), who have an extensive experience in both infant psychiatry and ASD fields, reviewed all the data and confirmed the ASD diagnoses. Twenty-four of the children were diagnosed as autism and 7 of them as PDD-NOS based on the DSM-IV-TR criteria. CARS and AuBC were used to determine the severity of the autistic symptoms. The severity of behavioral problems was rated by AbBC. Developmental assessments were conducted by an expert psychologist using ADSI, who was specifically trained and experienced in the administration of this tool. Developmental delay levels were defined by dividing the developmental level score determined by ADSI to normative data which are matched for their age. AuBC and AbBC were administered to the mother primarily; in case the mother was unavailable, then other caregivers were asked to fill out the sheets. Serum ferritin level was taken as an indicator of ID, because ID is the only cause of low ferritin concentration. In addition, serum ferritin level reliably shows iron levels in body tissues including brain and is also an early precursor of ID (Worwood, 1997). Since ferritin is an acute phase reactant, if there was an active or recent infection within the last 2 weeks, the evaluation was postponed to the next visit (one month later). Moreover, to make an accurate diagnosis of IDA, mean corpuscular volume and, serum iron level and total iron binding capacity were also estimated along with serum ferritin and haemoglobin concentration, considering the possibility of the increase in the serum ferritin level owing to medical conditions, which may not be showing clinical signs. Based on the cut-off points in preschoolers used by the Centers for Disease Control and Prevention (2002), we took serum ferritin levels <10 mg/L and haemoglobin levels <110 g/L as indicators of ID and anaemia, respectively. 1.4. Statistical analysis All analyses were performed with SPSS, Version 11.0 for Windows (Chicago, IL, USA). Descriptive analyses of haematological values were conducted. Pearson’s correlation analysis was used in order to examine the correlation between the serum ferritin level and autistic symptoms, developmental level and behavioral problems. The significance was set at a level of 0.05 (two tailed). 2. Results The mean age of the children was 40.26  11.70 months, and the study group consisted of 27 (87.1%) boys and 4 (12.9%) girls. Serum ferritin levels varied between 4 and 56 mg/L, and haemoglobin concentrations were between 106 and 140 g/L. Ten children (32.3%) had a ferritin level below 10 mg/L, which is accepted as a cut-off point for diagnosis of the ID for preschool children. On the other hand, two children (6.5%) had a haemoglobin concentration level below 110 g/L which is the cut-off point for diagnosis of IDA for children in this age range. In all patients who had ID and IDA, mean corpuscular volume, Table 1 Red blood cell indices in preschool children with autistic spectrum disorders (N = 31). Red blood cell indices

Mean  SS

Ferritin (mg/L) Hemoglobin (g/L) MCV (fL) Serum iron (mg/dL) TIBC (mg/dL)

19.9  14.03 (32.3%)a 126  9.5 (6.5%)a 76.5  7.08 62.4  29.1 371.6  52.4

a Percentage of children with serum concentration of ferritin < 10 mg/L, hemoglobin < 110 mg/L, MCV: mean corpuscular volume, and TIBC: total iron binding capacity.

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Table 2 Mean CARS, AuBC, AbBC and ADSI scores in preschool children with autistic spectrum disorders (N = 31). Psychometric assessments

Mean  SS

CARS

40.40  7.08

AuBC Total Sensory Relating Body and object use Language Social and self-care

67.74  27.0 8.90  6.71 16.87  8.86 15.00  10.11 14.45  5.93 12.61  5.49

AbBC Total Irritability, Agitation, Crying Lethargy, Social Withdrawal Stereotypic Behavior Hyperactivity, Non-compliance Inappropriate Speech

51.32  25.84 12.58  7.83 12.32  8.03 6.42  4.73 18.45  10.04 2.13  1.94

ADSI Total score/normative data (%) Cognitive language score/normative data (%) Fine motor score/normative data (%) Gross motor score/normative data (%) Social and Self Help score/normative data (%)

48.62  15.47 45.57  18.19 49.91  15.59 72.21  27.51 46.99  16.80

CARS: Childhood Autism Rating Scale; AuBC: Autism Behavior Checklist; AbBC: Aberrant Behavior Checklist; ADSI: Ankara Developmental Screening Inventory.

serum iron levels and total iron binding capacity were compatible with their condition. Red blood cell indices of the patients are shown in Table 1. There was no association between autistic symptom severity as defined by CARS and AuBC and developmental delay level which was defined by ADSI, and serum ferritin levels (p > 0.05). Similarly, there was no significant association between behavioral problems based on AbBC scores and serum ferritin levels (p > 0.05). Results of the psychometric assessment of the children are presented in Table 2. 3. Discussion In some of the recent studies, it was reported that ID and IDA were frequently presented in children with autism (Dosman et al., 2006, 2007; Latif et al., 2002). These studies suggested that ID may be more severe in autistic children who have more symptoms in communication domain and it may cause sleep problems (Dosman et al., 2006, 2007). It was proposed that ID is associated with narrow food selection, and because this problem is more evident in preschool children ID and IDA are more frequent in this age group (Cornish, 1998; Dosman et al., 2007). Based on these ideas, in the present study, the association between serum ferritin level and autistic symptomatology, developmental retardation and behavioral problems and the frequency of ID and IDA were examined in a group of 18–60 months old children with ASD. There was no association between serum ferritin level and autistic symptom scores in our study. We found two reports of Dosman et al. (2006, 2007) related to this issue. In one of these studies, they reported a correlation between low serum ferritin levels and high Autism Diagnostic Observation Schedule (ADOS) communication domain scores in 1–10-year-old children with ASD (Dosman et al., 2006). In another study, they found no correlation between serum ferritin levels and ADOS and Autism Diagnostic Interview-Revised (ADI-R) scores in preschool children, but an inverse correlation between ferritin levels and ADOS communication domain scores in school children (Dosman et al., 2007). The authors suggested that these findings are indicative of more severely impaired communication, which could reflect more restricted diets in impaired children, or that behavioral difficulties are exacerbated by iron deficiency (Dosman et al., 2006). In our study, no association was observed between serum ferritin levels and the severity of developmental delay set by ADSI. The association between mental-motor retardation and ID and IDA was widely investigated in the literature. The overall results of the studies predominantly suggested an association between ID/IDA and mental-motor retardation and cognitive impairments (Hurtado, Claussen, & Scott, 1999; Idjradinata & Pollitt, 1993; Lozoff et al., 1987, 1996, 2000). However, findings of the studies were not fully consistent and there are also some studies that could not document an association (Deinard, List, Linddren, Hunt, & Chang, 1986; Hurtado et al., 1999; Johnson & McGowan, 1983). Likewise, based on our data, it does not seem possible to say whether ID/IDA was a cause or a result. Given the wide acceptance of harmful effects of ID on brain development, the presence of higher frequency of behavioral problems is an expected condition in children with ID. A considerable amount of studies were conducted related to behavioral problems caused by ID and IDA in children who have not another underlying illness. The overall results of these

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studies suggested that ID caused behavioral problems resulting in fewer interactions and impaired learning in these children (Grant et al., 2007; Grantham-Mcgregor & Ani, 2001; Lozoff, 2007). Besides, an association between IDA and some specific behavioral problems such as breathe holding spells and restless legs syndrome was documented (Connor et al., 2003; Daoud, Batieha, Al-Sheyyab, Abuekteish, & Hijazi, 1997). However, there is no clear consistency across studies that examined the association between ID/IDA and behavioral problems, and there are some studies reporting no such association (Johnson & McGowan, 1983). On the other hand, the association between ID and behavioral problems were not investigated in children with ASD except an open label study that examined the effect of iron supplementation on sleep problems (Dosman et al., 2007). In our study, we found no association between serum ferritin levels and behavioral problems. This finding may be resulted from a real lack of association between ID and behavioral problems determined by AbBC or it may stem from the small sample size. ID was detected in 32.3% and IDA in 6.5% of the children in our study. There is no population-based study regarding the frequency of ID and IDA in preschool children in Turkey. The prevalence of ID and IDA in school children was reported as 5.5% and 5% respectively, in a study conducted in S¸anlıurfa, that one of the big cities of Turkey (Koc¸, Baz, Kesen, & Erel, 2006). Although it is asserted that the prevalence of ID may reach as much as 40%–50% in developing countries (Grant et al., 2007; Wu, Lesperance, & Bernsteın, 2002), this study suggested that the prevalence of ID in Turkey is similar to developed countries. Considering the prevalence of ID in preschool children in the USA as 5% (Centers for Disease Control & Prevention, 2002), we can say that children with ASD are under great risk for ID, as 32.3% of our sample have ID in the present study in compatible with findings of previous studies regarding this issue (Dosman et al., 2006; Latif et al., 2002). Major limitations of the present study are small sample size and the lack of a control group. Small sample size may account for the lack of association between ID and some of the clinical variables. Lack of a comparison group prevents the ability to reach a more definitive result related to frequency of ID/IDA in children with ASD. Another limitation may be the inclusion of children with ASD as a single group without splitting them up into subtypes. 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