Seizure 21 (2012) 603605

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Seizure
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Association between iron status and febrile seizures in children

Soheila Zareifar *, Hamid Reza Hosseinzadeh, Nader Cohan
Hematology Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran

A R T I C L E I N F O A B S T R A C T

Article history: Objectives: The aim of this study was to determine the association between iron status and febrile
Received 20 September 2011 seizures in children aged 6 months to 5 years.
Received in revised form 16 June 2012 Methods: This prospective casecontrol study enrolled 300 children who presented with febrile seizures
Accepted 18 June 2012
(case group) and 200 children who presented with a febrile illness without seizures (control group) from
March 2007 to January 2009. Hemoglobin, mean corpuscular volume and serum ferritin concentration
Keywords: were compared in the two groups in relation to age, sex and use of iron supplementation.
Iron
Results: Patients with febrile seizures were more frequently iron decient as dened by a serum ferritin
Febrile seizure
level below 20 ng/dl (56.6% vs. 24.8%, P = 0.0001). Mean hemoglobin concentration was 10.8 g/dl in the
Ferritin
Children control group and 11.7 g/dl in the case group (P < 0.05). The difference between groups in mean
corpuscular volume was not statistically signicant (75.5 vs. 74.4 , P < 0.130).
Conclusion: Low serum ferritin concentration and low iron status may be risk factors for the development
of febrile seizures.
2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

1. Introduction
Simple febrile seizures (SFSs) are the most common type of
seizure during childhood. The peak incidence is at the age of
approximately 18 months, occurring in 25% of all children.1
Because of their association with later epilepsy, many independent
risk factors (genetic factors, age, gender, fever, type and duration of
seizure, family and developmental history, multiple seizures,
perinatal exposure to antiretroviral drugs, history of maternal
smoking and alcohol consumption during pregnancy) have been
studied as potential predictors of recurrent febrile seizures.25
However, the data available in the literature are inconsistent.69
Iron plays a critical role in the metabolism of several
neurotransmitters, and in low iron status, aldehyde oxidases
and monoamine are reduced. In addition, the expression of
cytochrome C oxidase, a marker of neuronal metabolic activity, is
decreased in iron deciency.10 In developing countries, iron
deciency is one of the most prevalent nutritional problems,11
especially among infants aged between 6 and 24 months.1216 In
developing countries 4666% of all children under 4 years of age
are anemic, with half of the prevalence attributed to iron-
deciency anemia. Many studies have clearly demonstrated the
effect of iron on development, cognition, behavior and neurophys-
iology, and especially on brain metabolism, neurotransmitter
function and myelination.17 Iron-deciency anemia is common
* Corresponding author. Tel.: +98 7116473239; fax: +98 7116473239.
E-mail address: zareifars@sums.ac.ir (S. Zareifar).
during the second and third years of life and has been variably
associated with developmental and behavioral impairments,
hence it can inuence motor and cognitive skills.10,11 Because
iron is important for the function of various enzymes and
neurotransmitters in the central nervous system, low serum levels
of ferritin may lower the seizure threshold.18,19
We compared iron status in children with febrile seizures and a
control group in order to determine the relationship between iron
status and febrile seizures in pediatric patients in southern Iran.
2. Patients and methods
The study group consisted of 300 children with a rst febrile
seizure admitted to the pediatric emergency departments of Shiraz
University of Medical Sciences, Shiraz, southern Iran, between
March 2007 and January 2009. Written informed consent was
obtained from the parents of all patients for inclusion in the study,
which was approved by the Shiraz University of Medical Sciences
Ethics Committee. Simple febrile seizures were dened as seizure
occurring between the ages of 6 months and 5 years, associated
with a rectal temperature of at least 38.3 8C or an axillary
temperature of at least 37.8 8C documented either in the
emergency department or in the medical record, <15 min
duration, without evidence of central nervous system infection,
focal neurological signs or history of seizure, and occurring once in
the previous 24 h. The seizure was dened as complex if it lasted
>15 min, occurred more than once in 24 h or had focal features.
Children with developmental delay, denite neurological illness,
or a history of proved iron-deciency anemia, regular blood

1059-1311/$ see front matter 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.seizure.2012.06.010
604 S. Zareifar et al. / Seizure 21 (2012) 603605

transfusion or regular therapeutic doses of iron supplements were
excluded. A control group (n = 200) was selected randomly from
children admitted for febrile illnesses such as gastroenteritis, otitis
media or respiratory tract infections without seizure, previous
history of seizure or anticonvulsant therapy. Case and control
groups were comparable for age, gender, normal growth and
development, family history of febrile seizures, temperature at
presentation, white blood cell count and differential, and use of
iron supplementation. Age, sex, underlying illness, frequency and
duration of seizures were recorded for both groups. Because
ferritin is an acute-phase reactant protein in inammatory and
infectious processes, serum ferritin (SF) concentration was
measured by ELISA and double-checked 72 h after the onset of
the febrile illness. Anemia was dened as a decrease in mean
hemoglobin (Hb) level below 2 standard deviations of the normal
values for age, i.e. Hb < 10.5 g/dl for ages 624 months and
<11.5 g/dl for ages 25 years. Hemoglobin, mean corpuscular
volume (MCV), and SF concentration were compared in the case
and control groups.
3. Statistical analysis
The data were analyzed with the SPSS version 15 software
package for Windows (Chicago, IL, USA) by two-sample t-test.
Pearsons chi-squared test was used to calculate the differences in
proportions. Discrete variables are expressed as counts and
percentages. P values < 0.05 were considered signicant.
4. Results
Our results were based on 300 children with SFS (158 boys, 142
girls) and a control group of 200 children (72 boys, 128 girls). Table
1 shows the mean values of Hb, MCV and SF in case and control
groups. For this study we divided the sample into two age
subgroups of 6 months to 2 years (Table 2) and 25 years (Table 3).
The proportion of children with Hb < 10.5 g/dl was higher in both
control subgroups (P = 0.0001, Tables 2 and 3). Serum ferritin
concentration was signicantly lower in both case subgroups
(57.5% vs. 22% and 55.7% vs. 27.6%, P = 0.0001). The differences in
MCV were not signicant in either age subgroup. In children aged
6 months to 2 years (Table 2) and 25 years (Table 3), SF was
signicantly lower (P = 0.0001) in the SFS group.
In both age subgroups, the use of nontherapeutic doses of iron
supplements was more frequent in children with febrile illness
without seizure than in the case group with SFS (Tables 2 and 3).
5. Discussion
This study showed that patients with febrile seizures were
more frequently iron decient as dened by below-normal SF
levels. There is controversy regarding the role of iron status in
febrile convulsions, which are considered a benign seizure
syndrome distinct from epilepsy.1 Previous studies have reported
a relationship between iron-deciency anemia and convulsions in
patients with malaria.19 In addition, iron-deciency anemia can
cause developmental delay and behavioral disturbances early in
life, and correcting anemia early may reverse these processes.2022
Naveed and Billo showed that SF levels were signicantly lower in
children with febrile seizure compared to controls, and suggested
that children with iron deciency are more prone to febrile
seizures.23 Another study found that the incidence of febrile
seizures in patients with thalassemia was much lower than among
children in the general population.24 Thus, iron overload may be a
major factor in the brain metabolism that prevents febrile seizures.
Kobrinsky et al. also suggested that iron-deciency anemia raises
the threshold for febrile seizure,19 whereas Daoud et al. showed
that SF levels were signicantly lower in patients with a rst febrile
seizure than in patients with febrile illness without convulsions.18
Pisacane et al. reported an association between iron-deciency
anemia and febrile convulsions in Neapolitan children.2 In

Table 1
Mean age, hemoglobin, mean corpuscular volume and serum ferritin in children with simple febrile seizure (cases) and febrile illness without seizure (controls).

Data Cases (n = 300) Controls (n = 200) P value

Mean SD Mean SD

Age (months) 26.4 13.8 25.6 18.3 0.62

Hb (g/dl) 11.7 1.16 10.8 1.8 0.0001
MCV () 74.4 6.95 75.5 7.53 0.13
SF (ng/dl) 28.7 10.7 32.98 8.6 0.0001

Table 2
Characteristics of cases and controls at ages 6 months to 2 years.

Characteristic Cases (n = 139) Controls (n = 88) P value

Male (%) Female (%) Male (%) Female (%)

Hb < 10.5 (g/dl) 36.1 30.4 65.2 50.7 <0.0001

MCV < 70 () 34.8 17.9 34.1 19 0.15
SF < 30 (ng/dl) 51 64.1 13 31 <0.0001
Nontherapeutic iron supplement 71 66.7 87.9 86.2 <0.05

Table 3
Characteristics of cases and controls at ages 25 years.

Characteristic Cases (n = 151) Controls (n = 112) P value

Male (%) Female (%) Male (%) Female (%)

Hb < 11.5 (g/dl) 36.7 47.6 44.6 71.7 <0.0001

MCV < 75 () 32.2 45.5 31.9 16.2 <0.05
PF < 30 (ng/dl) 50.8 60.6 25.5 29.7 <0.0001
Nontherapeutic iron supplement 83.1 75.8 93.6 86.5 <0.05
 S. Zareifar et al. / Seizure 21 (2012) 603605
contrast, Momen and Hakimzadeh reported no relationship
between iron-deciency anemia and rst febrile convulsion in
children younger than 5 years of age in Iran.25 In another study in
Iran, Bidabadi and Mashouf reported that iron-deciency anemia
was less frequent among patients with febrile seizure than in
controls, and found no protective effect of iron deciency against
febrile convulsions.26 Pisacane et al., in their comparative study of
age- and sex-matched children, reported a signicantly higher
rate of iron-deciency anemia, dened on the basis of low serum
iron concentration, among children with febrile seizure than in
the control group.2 In children younger than 2 years of age, 30% of
those with febrile seizures had anemia compared to 14% in the
control group. However, SF levels were not measured in that
study.
In the present study the difference in MCV between the case
and control group overall and between children aged 6 months
to 2 years with and without SFS was not signicant, but it was
signicant in the 2-to-5 year old age group. Kobrinsky et al. also
reported that patients with febrile seizures were less frequently
iron decient as dened by elevated free erythrocyte protopor-
phyrin, but in their study, SF levels were not measured.19 Of the
indices of body iron status measured in the present study, SF
level was the only value that was signicantly lower in children
with SFS than in the control group a nding also reported by
Daoud et al.18 Although fever was present in all of our patients
in both groups, SF levels were measured 72 h after the onset of
the febrile illness. None of the patients in either group were
being treated for iron-deciency anemia on presentation, but
signicant numbers of patients in both groups sometimes used
non-therapeutic doses of iron supplements. We did not evaluate
the response to iron therapy in children in whom febrile
seizures recurred. Our results suggest that low SF levels may
play a role in febrile seizures.
6. Limitations
The main limitation of this study was the potential confounding
effect of ferritin as an acute-phase reactant agent, which can
interfere with the inuence of iron status on febrile seizures. This
limitation could be overcome by predicting the time when ferritin
level returned to its baseline value after the acute-phase reaction.
7. Conclusion
Low body iron status may decrease the threshold of seizure and
be a risk factor for the development of febrile seizures.
Conict of interest
None.
Acknowledgments
This study was supported by Shiraz University of Medical
Sciences research committee. We thank Shirin Parand and K.
605
Shashok (author AID in the Eastern Mediterranean) for improving
the use of English in the manuscript.
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