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The Association Between Iron Deficiency and Febrile Seizures in Childhood Dawn S. Hartfield, Jonathan Tan, Jerome Y. Yager, Rhonda J. Rosychuk, Don Spady, Christina Haines and William R. Craig Clin Pediatr (Phila) 2009; 48; 420 originally published online Feb 19, 2009; DOI: 10.1177/0009922809331800 The online version of this article can be found at: http://cpj.sagepub.com/cgi/content/abstract/48/4/420
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The Association Between Iron Deficiency and Febrile Seizures in Childhood
Clinical Pediatrics Volume 48 Number 4 May 2009 420-426 © 2009 Sage Publications 10.1177/0009922809331800 http://clp.sagepub.com hosted at http://online.sagepub.com
Dawn S. Hartfield, MD, MPH, Jonathan Tan, Jerome Y. Yager, MD, Rhonda J. Rosychuk, PhD, Don Spady, MD, Christina Haines, MSc, and William R. Craig , MDCM Purpose. The purpose of this study was to determine the association between iron deficiency and febrile seizures in a large cohort of children aged 6 to 36 months. Methods. A retrospective case control study with 361 patients who presented with febrile seizures to the emergency department and 390 otherwise healthy controls who presented with a febrile illness to the emergency department were reviewed to determine iron status using the MCV, RDW, and hemoglobin. Results. A total of 9% of cases had iron deficiency (ID) and 6%
F
ebrile seizures are defined by the National Institute of Health as “an event in infancy or childhood usually occurring between three months and five years of age, associated with fever but without evidence of intracranial infection or defined cause for the seizure.”1 They are the most common cause of convulsions in childhood, occurring in 2% to 4% of North American children.2 Simple febrile seizures are the most common form and are single, brief, and generalized. Complex febrile seizures are focal, From the Department of Pediatrics, University of Alberta, Edmonton, Canada. Dr Hartfield was the principal investigator and was involved in initiating the research question, study design, data analysis, and manuscript preparation. Jonathan Tan assisted with data extraction, data entry, and analysis. Dr Yager was involved in developing the research question, study design, and critical appraisal of the work. Dr Craig was involved in study design, data entry, analysis, and interpretation of results. Christina Haines, Dr Rosychuk, and Dr Spady were involved in the statistical design and analysis respectively. Address correspondence to: Dawn H. Hartfield, Department of Pediatrics, Room 8213 Aberhart Centre 1, 11402 University Avenue NW, University of Alberta, Edmonton, Alberta, Canada T6G 2J3; e-mail:
[email protected].
had iron deficiency anemia (IDA), compared to 5% and 4% of controls respectively. The conditional logistic regression odds ratio for ID in patients with febrile seizures was 1.84 (95% CI, 1.02-3.31). Conclusion. Children with febrile seizures were almost twice as likely to be iron deficient as those with febrile illness alone. The results suggest that screening for ID should be considered in children presenting with febrile seizure. Keywords: febrile seizure; iron deficiency; anemia
last longer than 15 minutes, or include more than 1 seizure associated with the febrile illness. The peak age of febrile seizures is 18 months, with recurrent episodes occurring in one third of patients.3 Although frightening to caregivers, febrile seizures are benign, and the risk of subsequent epilepsy following simple febrile seizures is no greater than that for the general population. Currently identified risk factors for febrile seizure include having a first- or second-degree relative with a history of febrile seizure, maternal smoking in pregnancy, low birth weight, neonatal stay of >30 days, attendance at day care, increased number of febrile illnesses, fever greater than 39.4°C, and particular infectious illnesses.4 Iron deficiency (ID) is the most common nutritional deficiency and affects up to 9% of children 1 to 2 years of age according to the third National Health and Nutrition Examination Survey from the United States.5 Canadian data are limited to small studies of discrete populations, with rates of iron deficiency anemia (IDA) ranging from 1.5% to 52%.6-11 The peak age for ID is between 1 and 2 years, which coincides with the peak incidence for febrile seizures.5
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Iron Deficiency and Febrile Seizures in Childhood / Hartfield et al 421
Table 1. Previous Publications Examining the Relationship Between Febrile Seizures and Iron Deficiency Author
Study Design 15
Age Range (Months)
Number of Patients Cases = 26; controls = 25
Kobrinsky et al
Case-control study (retrospective)
6–36
Pisacane et al16
Case-control study (retrospective)
6–24
Daoud et al17
Case-control (retrospective)
3–72
Naveed-ur and Billoo18
Case-control (retrospective)
8–36
Diagnostic Criteria for ID/IDA
Conclusion
FEP > 0.50 ng/L, MCH < Children with febrile 24 pg, MCV < 72 fL, seizures were less ferritin < 20 µg/L, likely to be iron hemoglobin < 110 g/L, deficient (no odds hematocrit < 0.320 ratio [OR] L/L, and/or platelets > reported) 550 × 109/L Cases = 146; Children with febrile Hemoglobin < 105 g/L, controls = 146 seizures were more MCV < 70 fL, and likely to be iron serum iron < 5.4 deficient than µmol/L controls; OR 2.6 (1.4-4.8) Cases = 75; Plasma ferritin was No a priori definition controls = 75 lower in cases provided; lab values than controls; compared: hemoglobin larger study < 110 g/L, MCV < 72 needed to examine fL, MCH < 24 pg, the association (no ferritin > 30 µg/L OR reported) Cases = 30; IDA was more Hemoglobin < 100 g/L, controls = 30 common in cases MCV < 70 fL, MCH < than controls 24 pg, hematocrit < (P < .05 for all 30%, or ferritin < 10 univariable µg/L definitions)
Note: IDA, iron deficiency anemia; FEP, free erythrocyte protoporphyrin; MCH, mean corpuscular hemoglobin; MCV, mean cell volume.
Iron has been found to act as a cofactor in a number of enzymatic reactions at the cellular level, and it effects neurotransmitter production and function, hormone function, and DNA replication.12,13 Deficiency of iron, therefore, results in disruption of normal cell and organ function. The most clinically obvious consequence of ID is anemia, but virtually every organ system is affected, resulting in changes in cognitive and behavioral performance, impaired physical growth, and impairment of immune function.13 ID is associated with neurological problems in young children, including developmental delay, stroke, breath-holding spells, and pseudotumor cerebri.14 Four small studies have been published investigating a possible relationship between ID and febrile seizures, with varying results.15-18 Three of the studies found that ID was associated with febrile seizures,16-18 whereas the fourth found that those with ID were less likely to have a febrile seizure15 (Table 1). Factors that may have
contributed to these contrary results include small patient numbers and different diagnostic criteria for the diagnosis of ID in the setting of a febrile illness. Given the known association of ID with other neurological disorders in children and the contrary results of the previous work done, we sought to clarify the current controversy regarding the relationship between ID and febrile seizures in children. The purpose of this retrospective study was to determine in a large cohort of patients the iron status of children 6 to 36 months of age presenting with febrile seizures compared with age-matched controls presenting with fever alone.
Patients and Methods This was a retrospective case-controlled study including patients from January 2001 to May 2006 who presented to the Stollery Children’s Hospital, Edmonton, Alberta, Canada. Charts of patients presenting to the
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422 Clinical Pediatrics / Vol. 48, No. 4, May 2009
emergency room with febrile seizure between ages 6 and 36 months were examined. Children included as cases were those diagnosed with a febrile seizure (simple or complex) and having a complete blood count (CBC) done during their emergency room visit. The diagnosis of febrile seizure was made by the pediatric emergency physician or by a pediatric neurologist. Controls were patients who presented with a febrile illness without a seizure and had a CBC done. Controls were group matched to cases on age (6-18 months; 19-36 months). The groups were not matched on gender, because there are no gender differences seen in ID in children of this age5 or in febrile seizures.19 The 2 age groups were broad in range to enable data collection and matching. Clinically, the rates of ID and febrile seizures were anticipated to be uniform enough within the age range to not affect results. Patients excluded were those with (a) develop mental delay, (b) CNS infection, (c) a past history of nonfebrile seizures, (d) chronic multisystem disease, or (e) an underlying blood disorder. Information was gathered from the patient’s chart with respect to age, gender, personal and family history of seizure, developmental status, birth history, and hematology results. Statistical Analysis Systems (SAS) and the Statistical Package for the Social Sciences (SPSS) were used to perform analyses. Ethics approval was obtained from the Human Research Ethics Board at the University of Alberta in Edmonton, Alberta, Canada.
Diagnosis of Iron Deficiency The diagnosis of ID in children is challenging. The gold standard for diagnosis is a trial of iron therapy.20 A low mean cell volume (MCV) reflects microcytosis that is seen with ID. The red cell distribution width (RDW) reflects anisocytosis, the variance of cell size that increases with ID.20 The RDW is the first parameter to be affected in ID, even prior to changes in ferritin, serum iron levels, TIBC (total iron binding capacity), transferrin saturation, FEP (free erythrocyte protoporphyrin), cell size, and hemoglobin level.21 Several studies have found that the RDW alone or in combination with MCV is an effective screening tool for ID in children and often superior to other measures.22-29 Kim et al25 found that the sensitivity of RDW was 83.3% and specificity was 57.7% in diagnosing IDA. For MCV, they found the
sensitivity and specificity to be 99% and 53.8%, respectively. A combination using both MCV and RDW resulted in a positive predictive value of 97.8% in the diagnosis of IDA. Traditional measures of iron status (ferritin, serum iron, TIBC, transferrin saturation, and FEP) are influenced by infection and are therefore not reliable indicators of iron status in the setting of acute infection.30 MCV and RDW are not affected by acute infections typical of early childhood.25 Therefore, the iron status of patients was determined using the definition of ID as a MCV < 70 fL and RDW > 15.6%. Anemia was diagnosed when the hemoglobin was
