Seizure 52 (2017) 27–34

Contents lists available at ScienceDirect

Seizure
journal homepage: www.elsevier.com/locate/yseiz

Relationship between iron deficiency anemia and febrile seizures in

children: A systematic review and meta-analysis
Byung Ok Kwaka , Soo-Nyung Kimb , Ran Leec,*
a
Department of Microbiology, Konkuk University School of Medicine, Seoul, Republic of Korea
b
Department of Obstetrics and Gyneology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Republic of Korea
c
Department of Pediatrics, Konkuk University Medical Center, Konkuk University School of Medicine, 120-1 Neungdong-ro (Hwayang-dong), Gwangjin-gu,
Seoul 05030, Republic of Korea

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

Article history: Purpose: The association between iron deficiency anemia (IDA) and febrile seizures (FS) during childhood
Received 15 December 2016 is inconclusive due to inconsistent results reported in different studies. We performed a systematic
Received in revised form 24 July 2017 review and meta-analysis to determine an association between IDA and FS in children.
Accepted 14 September 2017
Methods: We searched PubMed, EMBASE, and Cochrane Library databases for studies published up to
Available online xxx
August 2015 using the following key words: [“iron deficiency” OR “iron status”] AND [“febrile seizure” OR
“febrile convulsion”] AND [“pediatric” OR “infant” OR “child”]. Pooled odds ratios (OR) and 95%
Keywords:
confidence intervals (CI) were calculated using standard meta-analysis techniques. Subgroup analysis
Iron deficiency anemia
Febrile seizure
also was performed.
Child Results: A total of 17 studies enrolling 2416 children with FS and 2387 controls were included in the meta-
analysis. The results indicated that IDA was significantly associated with FS (OR, 1.98; 95% CI, 1.26–3.13;
P = 0.003). Subgroup analyses evaluated the diagnostic indices for IDA including serum iron, plasma
ferritin, and mean corpuscular volume (MCV). The results indicated that IDA diagnosed on the basis of
plasma ferritin (OR, 3.78; 95% CI, 1.80–7.94; P < 0.001) or MCV (OR, 2.08; 95% CI, 1.36–3.17; P = 0.001) was
modestly associated with FS, whereas IDA diagnosed on the basis of two serum iron studies was not
associated with FS (OR, 0.57; 95% CI, 0.24–1.37; P = 0.210).
Conclusion: The results of this meta-analysis suggest that IDA is associated with an increased risk of FS in
children.
© 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

1. Introduction
Febrile seizure (FS) is the most common seizure type in young
children, which is not triggered by central nervous system
infection or metabolic disorders [1]. It usually occurs in infants
and children aged 6–60 months, and has 2–5% incidence of at least
one episode in this population. Iron deficiency anemia (IDA) is a
common nutritional deficiency in children with a prevalence of 1–
15% in the USA depending on ethnicity and socioeconomic status
[2,3], and a prevalence of 0.5–5% in South Korea [4]. Iron is
essential for proper growth and development, and iron deficiency
is reported to involve behavioural disorders, mental retardation,
and impaired immune function [5].
* Corresponding author.
E-mail address: 20050069@kuh.ac.kr (R. Lee).
The peak ages for FS and IDA coincide [6], and numerous studies
have been performed to determine an associative relationship.
However, individual studies have provided conflicting results with
other studies. Some studies reported an association between IDA
and FS [7–16], whereas other studies did not detect an association
[17,18]. A few studies even suggested a protective effect of IDA on FS
[19–21]. Systematic reviews and meta-analyses published in 2010
[22] and 2014 [23] examined the association between IDA and FS in
children aged 3 months to 6 years. However, the earlier study
included only a small number of published reports [22], and the
later study conducted subgroup analysis using limited criteria for
IDA (iron status, hemoglobin, and hematocrit) [23].
The primary aim of the present study was to determine whether
IDA and FS are associated in children by conducting a systematic
review and meta-analysis of all available literature. This study will
serve to update a previous literature review and include additional
data published since 2013. Our secondary aim was to provide a

http://dx.doi.org/10.1016/j.seizure.2017.09.009
1059-1311/© 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
28 B.O. Kwak et al. / Seizure 52 (2017) 27–34
more precise estimate of the relationship between IDA and FS by
performing subgroup analyses based on different diagnostic
indices for IDA.
2. Methods
2.1. Search strategy
We performed a meta-analysis according to the guidelines in
the Preferred Reporting Items for Systematic Reviews and Meta-
Analyses [24–27]. We searched PubMed and EMBASE databases
and the Cochrane Central Register of Controlled Trials (CENTRAL)
in the Cochrane Library database using the following terms: [“iron
deficiency” OR “iron status”] AND [“febrile seizure” OR “febrile
convulsion”] AND [“pediatric” OR “infant” OR “child”]. The
databases were searched up to 31 August, 2015, irrespective of
language. A clinical librarian with expertise in systematically
searching literature databases performed the searches. Titles and
abstracts were initially screened to identify relevant articles.
Subsequently, full-text articles were reviewed independently by
two authors (BOK and RL) to determine inclusion in this meta-
analysis. The reference lists in the retrieved papers were manually
searched to identify all relevant studies. Unpublished materials or
abstracts, and reports from scientific meetings were not included
in this meta-analysis.
2.2. Eligibility criteria
The selected studies were subjected to the following inclusion
criteria for this meta-analysis: (1) case-control or comparative
study designs with clear case and control groups; (2) subjects
included children aged 3 months to 6 years with febrile seizures;
(3) febrile seizures were compared with febrile illness without
seizure; (4) incidence of iron deficiency anemia was measured as
risk ratio or odds ratio (OR) with 95% confidence intervals (CI), or
provided sufficient data for these calculations.
Then, the selected studies were subjected to the following
exclusion criteria: (1) reports designed as case studies, single-arm
cohort studies, commentaries, letters, or editorials; (2) studies
enrolling cases and controls with non-febrile seizures, central
nervous system infections, neurological or hematological disor-
ders, or chronic multisystem diseases; (3) studies lacking specified
criteria for defining iron deficiency.
Fig. 1. Flow diagram of literature search and study selection procedure.
2.3. Data extraction
The following data were extracted from each study: first author,
publication year, study design, country, study period, age, gender,
criteria used to diagnose iron deficiency, sample size (cases and
controls), and incidence of iron deficiency in each group. Two
authors (BOK and RL) independently reviewed the full-text articles
of all selected studies and extracted data using a standard
extraction form. Any discrepancy in data interpretation was
resolved by discussion and consensus among the authors.
2.4. Quality assessment
The quality of each study was assessed for three categories
using the Newcastle-Ottawa scale (NOS) [28]: selection (0–4),
comparability (0–2), and exposure (case-control studies) or
outcome (cohort studies) (0–3). The following nine-star scoring
system was used to reflect the study quality: total score 0–4, low-
quality study; 5–7, moderate-quality study; and 8–9, high-quality
study. Two authors (BOK and RL) independently evaluated study
quality, and any disagreement was resolved by discussion and
consultation with the third author (SNK).
2.5. Data synthesis and analysis
In this meta-analysis, the overall OR and 95% CI were calculated
to generate pooled estimates for the relationship between IDA and
FS in children. Statistical heterogeneity was assessed using
Cochran’s Q test and the I2 statistic [29]. If substantial heterogene-
ity was detected using the Q test (P < 0.1) or I2 statistic (>50%), a
random-effects model (DerSimonian-Laird method) was used to
estimate the combined OR. Otherwise, a fixed-effects model
(Mantel-Haenszel method) was used for the meta-analysis.
Subgroup analysis was performed according to the definition of
IDA because the diagnostic criteria used in each study were
different. Subgroup analysis was planned a priori before data
collection and analysis. Sensitivity analysis was conducted by
sequentially eliminating each study from the meta-analysis to
determine the effect on the pooled OR and the robustness of the
conclusion. Cumulative analysis was conducted by sequentially
adding each study according to publication year to detect temporal
trends. Publication bias was evaluated using the Begg- Mazumdar
rank correlation test, Egger’s regression test, and fail-safe N test
[30–32]. A funnel plot was constructed to evaluate publication bias
 B.O. Kwak et al. / Seizure 52 (2017) 27–34 29

using the standard error and diagnostic OR [33]. All statistical
analyses were performed using Comprehensive Meta-Analysis
version 2.0 (Biostat, Englewood, NJ, USA). P < 0.05 was considered
as statistically significant. Data are presented according to a
checklist based on Meta-Analysis of Observational Studies in
Epidemiology [24].
3. Results
3.1. Literature search
The initial literature database search yielded 80 articles. After
reviewing abstracts and excluding duplicate or irrelevant articles,
30 full-text articles were assessed for eligibility. Subsequently, 13
of the 30 articles were excluded [22,23,34–44]: two were review
articles [22,23], one had no control group [37], two included an
afebrile healthy control group instead of febrile children as the
control group [34,36], and eight were incomplete studies that
provided insufficient data for statistical calculations [35,38–44].
Finally, 17 studies fulfilled the inclusion criteria and were included
in this meta-analysis [6–21,45]. A flow diagram of the study
selection is presented in Fig. 1.
3.2. Study characteristics
Study characteristics and quality assessment are presented in
Table 1. All studies included children aged 3 months to 6 years.
Most studies were conducted in Asia, including five in Iran
[13,17,18,20,21], four in Pakistan [9,11,12,14], two in India [10,15],
one in Korea [45], one in Jordan [8], one in the USA [19], one in Italy
[7], one in Canada [6], and one in Greece [16]. Each study used
different criteria to diagnose iron deficiency (ID) and IDA. Two
studies used serum iron level [20,21], four studies used plasma
ferritin [8,10,15,16] and the remaining 11 studies used mean
corpuscular volume (MCV) [6,7,9,11–14,17–19,45]. Quality assess-
ment was performed using the Newcastle-Ottawa Scale (Supple-
mental Table 1).
3.3. Meta-analysis of IDA and FS
A total of 2416 children with FS and 2387 children without FS
were included in this meta-analysis. IDA was reported in 851
(35.2%) cases and 707 (29.6%) controls, and was significantly
associated with FS, with a pooled OR of 1.98 (95% CI, 1.26–3.13;
P = 0.003) (Fig. 2A). Heterogeneity tests revealed that I2 = 89.987
(P < 0.001), indicative of heterogeneity; thus, a random-effects
model was used for meta-analysis.
Sensitivity analyses did not indicate significant changes in the
result with the sequential elimination of individual studies from
the meta-analysis (Fig. 2B), and a cumulative analysis showed
similar results over time (Fig. 2C). Egger’s regression test
(P = 0.006) and fail-safe N test (P < 0.001) indicated the presence
of publication bias, whereas the Begg-Mazumdar rank correlation
test showed no evidence of bias (P = 0.149). Inspection of the funnel
plot did not rule out publication bias (Fig. 3).
3.4. Subgroup analysis according to the criteria for diagnosing IDA
Subgroup analyses were performed according to the diagnostic
indices for IDA, such as serum iron, plasma ferritin, and MCV
(Fig. 4). A significant association was identified between FS and IDA
diagnosed from ferritin (OR, 3.78; 95% CI, 1.80–7.94; P < 0.001) or
MCV (OR, 2.08; 95% CI, 1.36–3.17; P = 0.001). By contrast, IDA
diagnosed using serum iron was not significantly associated with
FS (OR, 0.57; 95% CI, 0.24–1.37; P = 0.210). A random-effects model
was used for this meta-analysis because of heterogeneity in all
subgroup analyses (I2 < 0.001, P = 0.945; I2 = 52.535, P = 0.097;
I2 = 89.395, P < 0.001).
4. Discussion
The results of this study showed that IDA was significantly
associated with FS in children (OR, 1.98; 95% CI, 1.26–3.13;
P = 0.003). The subgroup meta-analysis according to the diagnostic
markers for IDA revealed a moderate association between IDA and

Table 1
Characteristics of the studies included in this meta-analysis.

First author Publication Country Age Definition of ID Sample size ID in ID in Quality

year cases controls, scorea
(months) (cases/ N (%) N (%)
controls)
Kobinsky [19] 1995 USA 6–36 MCV < 72 fL 26/24 4 (15.4) 7 (29.2) 4
Pisacane [7] 1996 Italy 6–24 MCV < 70 fL 146/146 44 (30.1) 21 (14.4) 6
Daoud [8] 2002 Jordan 3–72 Ferritin  30 mg/L 75/75 49 (65.3) 24 (32) 6
Naveed-ur-Rehman 2005 Pakistan 8–36 MCV < 70 fL 30/30 21(70) 9 (30) 5
[9]
Bidabadi [17] 2009 Iran 6–60 MCV < 70 fL (6–24 months), <75 fL (24– 200/200 88 (44) 96 (48) 5
60 months)
Hartfield [6] 2009 Canada 6–36 MCV < 70 fL 361/390 31 (8.6) 19 (4.9) 6
Vaswani [10] 2010 India 6–72 Ferritin  25 ng/mL 50/50 34 (68) 15 (30) 5
Jun [45] 2010 Korea 9–24 MCV < 70 fL 100/100 39 (39) 28 (28) 5
Sherjil [11] 2010 Pakistan 6–72 MCV < 65 fL 157/153 50 (31.8) 30 (19.6) 5
Amirsalari [18] 2010 Iran 9–60 MCV < 70 fL 132/88 5 (3.8) 6 (6.8) 5
Sattar [12] 2012 Pakistan 6–60 MCV < 72fL 90/90 56 (62.2) 18 (20) 5
Derakhshanfar [20] 2012 Iran 6–60 Serum iron < 40 mg/dL (<1 year) or <50 mg/dL 500/500 223 292 (58.4) 5
(>1 year) (44.6)
Yousefichaijan [21] 2014 Iran 6–72 Serum iron < 40 mg/dL (<1 year) or <50 mg/dL 191/191 43 (22.5) 65 (34.0) 5
(>1 year)
Ghasemi [13] 2014 Iran 5–60 MCV < 70 fL (6–24 months), <75 fL (24– 100/100 40 (40) 26 (26) 5
60 months)
Ashfaq [14] 2014 Pakistan 3–60 MCV < 70 fL 100/100 73 (73) 27 (27) 5
Srinivasa [15] 2014 India 6–60 Ferritin < 12 ng/mL 108/100 37 (34.3) 22 (22) 5
Papageorgiou [16] 2015 Greece 6–60 Ferritin < 30 ng/mL 50/50 12 (24) 2 (4) 6

Abbreviation: ID, iron deficiency.

a
Quality of each study was assessed using the Newcastle-Ottawa scale.
30 B.O. Kwak et al. / Seizure 52 (2017) 27–34

Fig. 2. Meta-analysis for the association between iron deficiency anemia and febrile seizures in children. Forest plot of the random-effects model (A), sensitivity analysis (B),
and cumulative analysis (C). Diamonds indicate the effect size of each study, which is proportional to the weight of each study.
 B.O. Kwak et al. / Seizure 52 (2017) 27–34 31

Fig. 3. Funnel plot of publication bias in the selection of studies for assessing the relationship between iron deficiency anemia and febrile seizure in children.

Fig. 4. Subgroup meta-analysis for the association between iron deficiency anemia (IDA) and febrile seizures in children according to diagnostic criteria of IDA. Diamonds
indicate the effect size of each study, which is proportional to the weight of each study.

FS based on plasma ferritin (OR, 3.78; 95% CI, 1.80–7.94; P < 0.001)
and MCV (OR, 2.08; 95% CI, 1.36–3.17; P = 0.001).
Iron is an essential nutrient for adequate growth and
development in children. Iron deficiency disrupts the function of
several organs, leading to anemia, abnormal growth and behavior,
mental retardation, altered thermoregulation, impaired physical
performance, and immune dysfunction [46].
Iron deficiency is also associated with neurological problems in
children, including growth disturbance, neurodevelopmental
delay, stroke, breath-holding spells, pseudotumor cerebri, and
impaired cognitive function [46]. Iron affects the enzymatic
reactions involved in DNA, RNA, and monoamine metabolism,
and the production and function of neurotransmitters [46,47].
Consequently, iron deficiency leads to abnormal iron metabolism,
myelination, and neurotransmitter activity in the brain. Animal
studies have shown that iron and iron regulatory proteins in the
brain are distributed heterogeneously during different neuro-
developmental stages, and that responses to iron deficiency varied
in young and adult rats [47,48]. Young rats at the same
neurodevelopmental stage as 6–12 month-old infants were fed
32 B.O. Kwak et al. / Seizure 52 (2017) 27–34
a low-iron diet for a short period, which led to a 25% decrease in
iron levels in the cortex, striatum, and hind-brain, and only a 5%
decrease in iron levels in the thalamus; the resumption of a high-
iron diet led to the prompt recovery of iron in essentially all brain
regions [46,48].
Iron deficiency is a risk factor for simple febrile seizures but not
for other types of acute seizures. However, iron deficiency is
associated with two other disorders that cause enhanced brain
excitability: restless leg syndrome (RLS) and attention deficit
hyperactivity disorder (ADHD). Family studies and genome-wide
association studies suggest that RLS is strongly associated with
reduced serum ferritin levels, and magnetic resonance imaging
(MRI) has shown reduced iron stores in the brains of many
patients. Low iron levels have also been measured in the thalamus
of children with ADHD using MRI, and the serum ferritin level has
been shown to predict the optimal dose of amphetamine needed to
treat ADHD [49].
The iron status can be associated with the general health status
of children in terms of nutrition, growth, and immunity. These
factors might influence directly on febrile seizures. Iron-deficiency
anemia increases the risk of preterm labor, low birthweight, and
infant mortality during the first two trimesters of pregnancy [50].
Yi Ning et al. reported that rats fed iron-deficient diets grew more
slowly and had a lower percentage of weight gain than rats fed a
control diet. Growth retardation was significant in iron-deficient
groups compared with iron-adequate groups [51]. Iron deficiency
also affects the capacity for an adequate immune response. Iron
plays an essential role in immunosurveillance, because of its
growth-promoting and differentiation-inducing properties for
immune cells and its interference with cell-mediated immune
effects or pathways and cytokine activities [52]. Especially,
cytokines are extensively important for the appropriate function
of both innate and adaptive immune response. Recent clinical and
experimental evidence has shown that pro-inflammatory cyto-
kines exacerbates brain damage after fever insult, suggesting that
it may also contribute to neuronal cell injury associated with
seizures. Furthermore, anti-inflammatory cytokines lessen sus-
ceptibility to febrile seizures [53].
The general health status of children may also be associated
with febrile seizures. Although there is no evidence of this
association at present, some studies have reported that chronic
malnutrition impacts head growth, and starvation is associated
with a gradual but severe decline in intellectual activities.
Furthermore, EEG rhythms tend to be slower during acute
malnutrition [54]. Yuelian Sun et al. reported that the association
of low birth weight and short gestational age with the risk of febrile
seizures was particularly strong within the first 5 years of life,
because the immature brain is more susceptible to seizures when
exposed to risk factors during prenatal life than the mature brain is
[50].
In the present study, we demonstrated an association between
IDA and FS in children using combined date from 17 studies.
Further studies that include the imaging of brain iron accumula-
tion in children with FS or the recurrence rate of FS after iron
supplementation are warranted to verify our observations.
The results of previous studies of the association between IDA
and FS have been inconsistent. Pisacane et al. [7] reported that iron
deficiency was more frequent in Italian children with FS (n = 146;
age range, 6–24 months) than in controls (OR, 2.6; 95% CI, 1.4–4.8).
A Canadian study by Hartfield et al. [6] reported an approximately
2-fold risk of ID in the FS group compared with controls (OR, 1.84;
95% CI, 1.02–3.31). Iron deficiency as a potential risk factor for FS
was reported in studies conducted in Jordan [8], Pakistan
[9,11,12,14], India [10,15], Iran [13], and Greece [16]. By contrast,
Amirsalari et al. [18] and Bidabadi et al. [17] reported no significant
differences in IDA in children with and without FS. Furthermore,
some studies have reported a protective effect of IDA on FS [19–21].
A small study by Kobrinsky et al. [19] that enrolled 26 children in
the USA suggested that iron deficiency may protect against the
development of FS. Recent studies in Iran [20,21] reported similar
conclusions. The inconsistent results of these studies may be
attributable to differences in sample sizes, age groups, diagnostic
criteria for IDA, nutritional state, socioeconomic status, and
ethnicity.
There are many confounding factors, such as nutritional status,
incidence of infection, cultural factors, and genetic background.
Richard et al. have reported that severe malnutrition (reduced
concentrations of albumin and plasma protein, hypokalemia and
hyponatremia, hypomagnesemia and hypocalcemia associated
with vitamin D deficiency) can lower the seizure threshold and
contribute to an increased prevalence of epilepsy in developing
countries. By the time hypomagnesemia occurs tissue and CSF
magnesium deficiency is usually severe because magnesium is
primarily an intracellular ion and neurological function is already
adversely affected [55]. Full-time day-care attendance (20 h per
week or more) is nearly as important a risk factor as social history.
Day-care attendance has been linked with an increased risk of
infectious disease, particularly respiratory infections, and diarrhea.
Children with a history of ear discharge, frequent sore throats, or
pneumonia were more likely to have had a febrile seizure [56].
Viral infections, especially HHV-6, influenza A, and respiratory
syncytial virus, have an important role in the etiology. Compared
with the rates of viral infections, bacteremia is an infrequent cause.
However, viral infections are frequently complicated by secondary
bacterial infection. Vaccines associated with an increased risk of
febrile seizures in the first 3 years of life include the measles-
mumps-rubella or measles-rubella and diphtheria-tetanus-per-
tussis vaccine. Children who have had vaccine-related seizures
have an increased rate of recurrent febrile seizures [57]. Almost any
type of epilepsy can be preceded by febrile seizures, and a few
epilepsy syndromes typically start with febrile seizures. Consider
generalized epilepsy with febrile seizures plus (GEFS+): Five genes
associated with GEFS+ have been identified to date: SCN1A, SCN2A,
and SCN1B, which encode the alpha-1, alpha-2, and beta-1 subunits
of the sodium channel, and GABRG2, GABRD and GABRB3, which
encode the gamma-2 subunit, the beta-3 subunit, and the delta
subunit of the GABAA receptor, respectively [58,59]. In our study,
we did not consider these confounding factors. This is a limitation
of our study.
Two meta-analyses have been performed to investigate the
association between IDA and FS. The earlier meta-analysis was
published in 2010 and showed that ID was associated with an
increased risk of FS (OR, 1.79; 95% CI, 1.03–3.09; P < 0.001); it
included 8 studies enrolling 1018 children with FS and 1049
controls [22]. A later meta-analysis reported that IDA was
associated with an increased risk of FS (OR, 1.52; 95% CI, 1.01–
2.28; P < 0.001) in regions with a low or moderate prevalence of
anemia (OR, 2.04; 95% CI, 1.46–2.85; P < 0.0001), but not in regions
with a high prevalence of anemia (OR, 0.56; 95% CI, 0.42–0.75;
P < 0.0001) [23].
Consistent with the previous meta-analyses, we found that IDA
was significantly associated with FS in children, with a pooled OR
of 1.98 (95% CI, 1.26–3.13; P = 0.003). Our subgroup analyses based
on the diagnostic markers for IDA identified an association
between IDA and FS based on plasma ferritin (OR, 3.78; 95% CI,
1.80–7.94; P < 0.001) and MCV (OR, 2.08; 95% CI, 1.36–3.17;
P = 0.001). A previous study [23] reported a significant association
between IDA and FS according to the iron status criterion for
anemia (OR 1.84; 95% CI, 1.02–3.33; P = 0.04), whereas no
association was identified according to hemoglobin and hemato-
crit criteria (OR, 1.26; 95% CI, 0.73–2.1; P = 0.4). Although we did not
analyze traditional diagnostic indices of iron status, such as total
 B.O. Kwak et al. / Seizure 52 (2017) 27–34
iron binding capacity (TIBC), transferrin saturation, and free
erythrocyte protoporphyrin (FEP), we elected to perform a
subgroup meta-analysis using the specific diagnostic markers of
plasma ferritin, serum iron, and MCV. We did not find a statistical
association between IDA defined by serum iron and FS (OR, 0.57;
95% CI, 0.24–1.37; P = 0.210); however, only two studies with
substantial heterogeneity (P < 0.001; I2 = 89.395%) were included
[20,21]. The inclusion of more studies is required to confirm these
relationships.
This study had some limitations. First, no randomized
controlled trials (RCT) were included in this meta-analysis, and
the quality of some of the included studies was insufficient.
Additional high-quality studies are required for further verifica-
tion. Second, we did not perform subgroup analyses according to
ethnicity or location. Previous meta-analyses have reported that
the association between IDA and FS was significant in regions with
a low-to-medium prevalence of IDA; however, this association is
confounded by other factors, such as genetics, nutritional state, or
socioeconomic status [23]. Most of the studies included in our
meta-analysis were conducted in Asia, particularly in Iran and
Pakistan, and we anticipate that the effect of IDA on FS could not be
precisely determined because of this confounder effect. Further
analyses should include non-Asian data or controlling for
confounders.
5. Conclusion
The combined data in this meta-analysis suggest that IDA is
associated with an increased risk of FS in children aged 3 months–6
years. Well-designed interventional studies are needed to evaluate
whether iron supplementation can prevent FS in this age group.
Conflict of interest statement
None.
Funding
This research did not receive grant support from funding
agencies in the public, commercial, or not-for-profit sectors.
Author contributions
BOK, SNK, and RL contributed to the study design, data
collection and analysis, manuscript preparation, and manuscript
approval.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.
seizure.2017.09.009.
References
[1] Hodgson ES, Glade GB, Harbaugh N, McInerny TK, Miller MR, Moyer VA, et al.
Febrile seizures: clinical practice guideline for the long-term management of
the child with simple febrile seizures. Pediatrics 2008;121:1281–6.
[2] Baker RD, Greer FR. Diagnosis and prevention of iron deficiency and iron-
deficiency anemia in infants and young children (0–3 years of age). Pediatrics
2010;126:1040–50.
[3] Cusick SE, Mei Z, Freedman DS, Looker AC, Ogden CL, Gunter E, et al.
Unexplained decline in the prevalence of anemia among US children and
women between 1988 and 1994 and 1999–2002. Am J Clin Nutr
2008;88:1611–7.
[4] Yang YJ, Kim SK, Hong YJ, Kim JG, Hyon IY, Hong KS, et al. The prevalence of iron
deficiency in preschool children. Korean J Pediatr Hematol Oncol 1998;5:14–20.
[5] Ghosh K. Non haematological effects of iron deficiency-a perspective. Indian J
Med Sci 2006;60:30.
33
[6] Hartfield DS, Tan J, Yager JY, Rosychuk RJ, Spady D, Haines C, et al. The
association between iron deficiency and febrile seizures in childhood. Clin
Pediatr 2009;48:420–6.
[7] Pisacane A, Sansone R, Impagliazzo N, Coppola A, Rolando P, D'apuzzo A, et al.
Iron deficiency anaemia and febrile convulsions: case-control study in
children under 2 years. Br Med J 1996;313:343–4.
[8] Daoud AS, Batieha A, Abu-Ekteish F, Gharaibeh N, Ajlouni S, Hijazi S. Iron
status: a possible risk factor for the first febrile seizure. Epilepsia
2002;43:740–3.
[9] Billoo A. Association between iron deficiency anemia and febrile seizures. J
Coll Physicians Surg Pak 2005;15:338–40.
[10] Vaswani RK, Dharaskar PG, Kulkarni S, Ghosh K. Iron deficiency as a risk factor
for first febrile seizure. Indian Pediatr 2010;47:437–9.
[11] Sherjil A, Saeed Z, Shehzad S, Amjad R. Iron deficiency anaemia—a risk factor
for febrile seizures in children. J Ayub Med Coll Abbottabad 2010;22:71–3.
[12] Sattar SA, Hameed MN, Tayya A. Iron deficiency: a possible cause of first febrile
seizure. Pak Pediatr J 2012;36:216–9.
[13] Ghasemi F, Valizadehi F. Iron-deficiency anemia in children with febrile
seizure: a case-control study. Iran J Child Neurol 2014;8:38.
[14] Ashfq M, Channa Y, Bader-U-Nisa. Frequency of iron deficiency anemia in
febrile seizures in children and comparison with febrile children without
seizures. Pak Pediatr J 2014;38:133–7.
[15] Srinivasa S, Reddy SP. Iron defeiciency anemia in children with simple febrile
seizures-a cohort study. Curr Pediatr 2014;18.
[16] Papageorgiou V, Vargiami E, Kontopoulos E, Kardaras P, Economou M,
Athanassiou-Mataxa M, et al. Association between iron deficiency and febrile
seizures. Eur J Paediatr Neurol 2015;19:591–6.
[17] Bidabadi E, Mashouf M. Association between iron deficiency anemia and first
febrile convulsion: a case–control study. Seizure 2009;18:347–51.
[18] Amirsalari S, Doust ZTK, Ahmadi M, Sabouri A, Kavemanesh Z, Afsharpeyman
S, et al. Relationship between iron deficiency anemia and febrile seizures. Iran J
Child Neurol 2010;4:27–30.
[19] Kobrinsky NL, Yager JY, Cheang MS, Yatscoff RW, Tenenbein M. Does iron
deficiency raise the seizure threshold? J Child Neurol 1995;10:105–9.
[20] Derakhshanfar H, Abaskhanian A, Alimohammadi H, ModanlooKordi M.
Association between iron deficiency anemia and febrile seizure in children.
Med Glas (Zenica) 2012;9:239–42.
[21] Yousefichaijan P, Eghbali A, Rafeie M, Sharafkhah M, Zolfi M, Firouzifar M. The
relationship between iron deficiency anemia and simple febrile convulsion in
children. J Pediatr Neurosci 2014;9:110.
[22] Idro R, Gwer S, Williams TN, Otieno T, Uyoga S, Fegan G, et al. Iron deficiency
and acute seizures: results from children living in rural Kenya and a meta-
analysis. PLoS One 2010;5:e14001.
[23] Habibian N, Alipour A, Rezaianzadeh A. Association between iron deficiency
anemia and febrile convulsion in 3-to 60-month-old children: a systematic
review and meta-analysis. Iran J Med Sci 2014;39:496.
[24] Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-
analysis of observational studies in epidemiology: a proposal for reporting.
JAMA 2000;283:2008–12.
[25] Moher D, Liberati A, Tetzalff J, Altman DG, Gruop RISMA. Preferred reporting
items for systematic reviews and meta-analyses: the PRISMA statement. PLoS
Med 2009;6:e1000097.
[26] Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al.
Preferred reporting items for systematic review and meta-analysis protocols
(PRISMA-P) 2015 statement. Syst Rev 2015;4:1.
[27] Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al.
Preferred reporting items for systematic review and meta-analysis protocols
(PRISMA-P) 2015: elaboration and explanation. BMJ 2015;349:g7647.
[28] Wells A, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et al. The
Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised
studies in meta-analyses. 3rd Symposium on systematic reviews: beyond the
basics. .
[29] Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in
meta-analyses. BMJ: Br Med J 2003;327:557.
[30] Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for
publication bias. Biometrics 1994;108:8–1101.
[31] Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a
simple, graphical test. BMJ 1997;315:629–34.
[32] Orwin RG. A fail-safe N for effect size in meta-analysis. J Educ Stat 1983;8:157–
9.
[33] Sterne JA, Egger M. Funnel plots for detecting bias in meta-analysis: guidelines
on choice of axis. J Clin Epidemiol 2001;54:1046–55.
[34] Fallah R, Tirandazi B, Karbasi SA, Golestan M. Iron deficiency and iron
deficiency anemia in children with febrile seizure. Iran J Pediatr Hematol Oncol
2013;3:200.
[35] Fallah R, Tirandazi B, Ferdosian F, Fadavi N. Iron deficiency and iron deficiency
anemia in children with first attack of seizure and on healthy control group: a
comparative study. Iran J Child Neurol 2014;8:18.
[36] Sadeghzadeh M, Asl PK, Mahboubi E. Iron status and febrile seizure-a case
control study in children less than 3 years. Iran J Child Neurol 2012;6:27.
[37] Waheed N, Butt MA. Iron status: is there a role in febrile seizures? J Ayub Med
Coll Abbottabad 2012;24:128–30.
[38] Im S, Ah JK, Choi BJ, Lee IG, Whang KT. The relationship between iron deficiency
anemia and febrile seizure. J Korean Child Neurol Soc 2003;11:55–60.
[39] Choudhury M, Zaman M, Mollah A, Hoque M, Fatmi L, Islam M, et al. Iron status
in children with febrile seizure. Mymensingh Med J 2013;22:275–80.
34 B.O. Kwak et al. / Seizure 52 (2017) 27–34
[40] Zareifar S, Hosseinzadeh HR, Cohan N. Association between iron status and
febrile seizures in children. Seizure 2012;21:603–5.
[41] Özaydın E, Arhan E, Cetinkaya B, Özdel S, Deg erliyurt A, Güven A, et al.
Differences in iron deficiency anemia and mean platelet volume between
children with simple and complex febrile seizures. Seizure 2012;21:211–4.
[42] Momen AA, Nikfar R, Karimi B. Evaluation of iron status in 9-month to 5-year-
old children with febrile seizures: a case-control study in the south west of
Iran. Iran J Child Neurol 2010;4:45–50.
[43] Omran MS, Tamaddoni A, Nasehi M, Babazadeh H, Navaei RA. Iron status in
febrile seizure: a case-control study. Iran J Child Neurol 2009;3:39–42.
[44] Heydarian F, Vatankhah H. The role of anemia in first simple febrile seizure in
children aged 6 months to 5 years old. Neurosciences (Riyadh) 2012;17:226–9.
[45] Jun YS, Bang HI, Yu ST, Shin SR, Choi DY. Relationship between iron deficiency
anemia and febrile convulsion in infants. Korean J Pediatr 2010;53:392–6.
[46] Beard JL. Iron biology in immune function, muscle metabolism and neuronal
functioning. J Nutr 2001;131:568S–80S.
[47] Erikson KM, Pinero DJ, Connor JR, Beard JL. Regional brain iron, ferritin and
transferrin concentrations during iron deficiency and iron repletion in
developing rats. J Nutr 1997;127:2030–8.
[48] Piñero DJ, Li N-Q, Connor JR, Beard JL. Variations in dietary iron alter brain iron
metabolism in developing rats. J Nutr 2000;130:254–63.
[49] Johnston MV. Iron deficiency, febrile seizures and brain development. Indian
Pediatr 2012;49:13–4.
[50] Sun Y, Vestergaard M, Pedersen CB, Christensen J, Basso O, Olsen J. Gestational
age, birth weight, intrauterine growth, and the risk of epilepsy. Am J Epidemiol
2007;167:262–70.
[51] Strube YNJ, Beard JL, Ross AC. Iron deficiency and marginal vitamin A
deficiency affect growth, hematological indices and the regulation of iron
metabolism genes in rats. J Nutr 2002;132:3607–15.
[52] Ekiz C, Agaoglu L, Karakas Z, Gurel N, Yalcin I. The effect of iron deficiency
anemia on the function of the immune system. Hematol J 2005;5:579–83.
[53] Yu N, Di Q, Hu Y, Zhang Y-f, Su L-y, Liu X-h, et al. A meta-analysis of pro-
inflammatory cytokines in the plasma of epileptic patients with recent seizure.
Neurosci Lett 2012;514:110–5.
[54] Pascual JM. Progressive brain disorders in childhood. Cambridge University
Press; 2017.
[55] Hackett R, Iype T. Malnutrition and childhood epilepsy in developing
countries. Seizure 2001;10:554–8.
[56] Bethune P, Gordon K, Dooley J, Camfield C, Camfield P. Which child will have a
febrile seizure? Am J Dis Child 1993;147:35–9.
[57] Millichap JG, Millichap JJ. Role of viral infections in the etiology of febrile
seizures. Pediatr Neurol 2006;35:165–72.
[58] Nakayama J. Progress in searching for the febrile seizure susceptibility genes.
Brain Dev 2009;31:359–65.
[59] Møller RS, Wuttke TV, Helbig I, Marini C, Johannesen KM, Brilstra EH, et al.
Mutations in GABRB3 From febrile seizures to epileptic encephalopathies.
Neurology 2017;88:483–92.