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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 20  |  Issue : 1  |  Page : 8-14

Association between iron-deficiency anemia and febrile convulsion in children


Pediatrics Faculty of Medicine, Al-Azhar University, Asyut Branch and Public Health Department Faculty of Medicine, Assiut University, Asyut, Egypt

Date of Submission19-Dec-2020
Date of Decision27-Dec-2020
Date of Acceptance14-Jan-2021
Date of Web Publication4-Mar-2022

Correspondence Address:
Sarah M.H Rashwan
Pediatrics Faculty of Medicine, Al-Azhar University, Resident Physician, Center Street, Sohag, El-Maragh 82641
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/azmj.azmj_207_20

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  Abstract 


Background and aim Previous studies reported that iron-deficiency could be a risk factor for febrile seizure (FS), as the latter is more common in children younger than 2 years, and iron-deficiency anemia is also common in children of the same age. Yet, the relationship between iron deficiency and FS is not yet determined, and that is why this study was suggested. The aim of this study was to assess the association between iron-deficiency anemia and febrile convulsion (FC).
Patients and methods This study included 60 children aged 6 months to 5 years. These children were divided into three groups: a group of 20 patients with FC, a group of 20 patients with fever but without FC, and a group of 20 healthy children.
Results The main findings of this study were that there was a higher incidence of FSs found among children who received formula feeding. Furthermore, children with FSs had the lowest level of hematocrit, mean corpuscular volume, mean corpuscular hemoglobin concentration, and transferrin saturation values. However, iron-deficiency anemia was not associated with increased incidence of FCs.
Conclusion It can be concluded that formula feeding, low hematocrit, mean corpuscular volume, mean corpuscular hemoglobin concentration, and transferrin saturation are reinforcing factors for FSs.

Keywords: febrile convulsion, formula feeding, iron-deficiency anemia


How to cite this article:
Rashwan SM, Ahmed YE, Ibrahim AK, Kasem IE. Association between iron-deficiency anemia and febrile convulsion in children. Al-Azhar Assiut Med J 2022;20:8-14

How to cite this URL:
Rashwan SM, Ahmed YE, Ibrahim AK, Kasem IE. Association between iron-deficiency anemia and febrile convulsion in children. Al-Azhar Assiut Med J [serial online] 2022 [cited 2022 Jun 29];20:8-14. Available from: http://www.azmj.eg.net/text.asp?2022/20/1/8/339071




  Introduction Top


Febrile seizure (FS) is the most common convulsive disorder in children, which affects 2–5% of children aged 3–60 months [1]. Although FS is benign and rarely leads to brain damage, it causes emotional, physical, and mental damages, which are stressful for parents, and affects families’ quality of life [1],[2]. Many studies have tried to find its risk factors. Because of the relationship between FS and epilepsy in 2–4%, in the future, it can lead to hospitalization, costs for families and the society, and likelihood of recurrence (30 and 50% after the first and the second occurrences, respectively) [2].

Some recent studies have reported that iron-deficiency anemia could be a risk factor for FS, because the latter is more common in children under 2 years of age and iron-deficiency anemia is also common in children of the same age [3]. Owing to the presence of iron in hemoglobin structure, it plays a crucial role in the transport of oxygen to different tissues such as the brain [3]. Iron deficiency reduces the metabolism of some neurotransmitters, such as monoamine and aldehyde oxidase [4],[5].

Several lines of evidence led to the hypothesis that iron may have a role in the onset of a convulsion. However, the studies carried out so far have reported conflicting results. Some studies have reported that in the patients with iron deficiency, febrile convulsion (FC) is significantly higher than that in control group [6],[7],[8]. On the contrary, others concluded that the risk of FS in anemic children seems to be less than that in children without FS [9] and that iron deficiency can be a protective mechanism against convulsion threshold. Thus, iron supplements should be given with caution to the children [10]. Other studies have shown that iron deficiency plays no role in pediatric FS [11],[12].

As the relationship between iron-deficiency anemia and FS is still unclear, chance or other unknown factors can be considered as causes [13]. Considering the aforementioned results and as no study has been conducted on the mentioned relationship in Upper Egypt, the present study was carried out to compare the iron-deficiency anemia rates in children with FS with those in the febrile children without seizure and healthy children. The aim of this work was to investigate the association between iron-deficiency anemia and FC.


  Patients and methods Top


This was a case–control study, conducted in Maragha Central Hospital, Sohag University Hospital and Sohag General Hospital, in the period from February to August 2019. The target population was children attending outpatient pediatric clinics in the previously mentioned hospitals. Children aged 6 months to 5 years, and in case of convulsions, its type is generalized tonic–clonic convulsions, of duration less than 15 min, only one fit/24 h and of short postictal stupor, were included. Exclusion criteria were patients with clinical manifestations of central nervous system infection: meningeal irritation, ↑↑ ICT.

Sample size calculation was carried out using G*Power 3 software (Faul et al., 2007) [14]. A calculated minimum sample of 60 participants, divided into three equal groups (20 children with FC, a group of 20 children with fever but without FC, and a group of 20 healthy children), was needed to detect an effect size of 0.3 in the rate of iron-deficiency anemia among patients with FC, with an error probability of 0.05 and 80% power. Approval for this study was obtained from the Institutional review board (IRB) of Faculty of Medicine, Al Azhar (Asyut Branch) University before study execution. In addition, all participants’ caregivers received a written consent form. The informed consent was clear and indicated the purpose of the study, and their freedom to participate or withdraw at any time without any obligation. Furthermore, participants’ confidentiality and anonymity were assured by assigning each participant with a code number for the purpose of analysis only. The study was not based on any incentives or rewards for the participants. The study was in line with the Declaration of Helsinki.

All participants underwent full history taking (personal history, vaccination history, nutritional history, as well as past and family history), complete physical examination, and laboratory investigations (complete blood count, serum ferritin, serum iron, total iron-binding capacity, and transferrin saturation).

Statistical analysis

Data were revised, coded, processed, and analyzed using IBM-SPSS program (Statistical Package for Social Science) for Windows, version 20 (SPSS Inc., Chicago, Illinois, USA). Descriptive analysis included number and percentages for the qualitative data, and mean, SDs, and ranges for the quantitative data with parametric distribution and median with interquartile range for the quantitative data with nonparametric distribution. The appropriate tests of significance were conducted. χ2 test was used in the comparison between the groups with qualitative data. The comparison between more than two groups with quantitative data and parametric distribution was done by using analysis of variance test, and Kruskal–Wallis test was used in the comparison between more than two groups with quantitative data and nonparametric distribution. Significance was considered when P value less than 0.05.


  Results Top


The current study recruited 60 children (54% males and 46% females). The age ranged from 0.5 to 5 years, with a mean of 2.5±1.5 years. Their residence was rural in 65.6% of cases and urban in 34.4% of them. The majority (92%) gave history of taking iron supplements. For nutrition, 43% were breastfed, 36% received formula feeding, and 21% received both. Regarding the type of infection, 67% of children had infection (21% otitis media, 18% gastroenteritis, 16% pharyngitis, and 12% respiratory tract infection). [Table 1] shows that there were no statistically significant differences between the studied groups regarding sex, residence, or age (P>0.05). Likewise, no difference was found regarding iron supplementation history (P>0.05). On the contrary, there was a statistically significant difference between groups regarding infancy nutrition, that is, the highest percentage of the children in the FS group received formula feeding, without FS group received both breastfeeding and formula feeding, and the healthy group received breastfeeding ([Figure 1]). Moreover, there was a statistically significant difference among the three groups regarding the infectious disease type, with 100% of the children in the FS group having an infection, and the highest percentage of the children in the without FS group having gastroenteritis ([Table 2] and [Figure 2]).
Table 1 Comparison between groups regarding baseline data

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Figure 1 Infancy nitration nutrition in the three groups.

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Table 2 Comparison between groups regarding associated factors

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Figure 2 Infectious disease type in the three groups.

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[Table 3] illustrates that there was a significant statistical difference among the three groups in the hematocrit (HCT) value, with the FS group showing the lowest HCT value. Regarding the mean corpuscular volume (MCV) and the mean corpuscular hemoglobin concentration (MCHC), there was a significant statistical difference among the three groups, with the FS group showing the lowest MCV and MCHC values. No other significant statistical differences were found among the three groups concerning the remaining complete blood count results (white blood cells count, red blood cells count, hemoglobin, MCH, and platelets count). Regarding the iron-binding parameters, there was a significant statistical difference among the three groups concerning transferrin saturation with the highest mean saturation in the without FS group. No significant statistical difference was found among the three groups regarding serum ferritin, serum iron, or total iron binding capacity ([Table 4]). Moreover, [Table 5] demonstrates that there was no significant statistical difference between the group with FSs and the group without FSs regarding the presence of iron-deficiency anemia.
Table 3 Comparison between groups regarding complete blood count results

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Table 4 Comparison between groups regarding serum ferritin, serum iron, total iron-binding capacity, and transferrin saturation

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Table 5 Comparison between febrile seizure and without febrile seizure regarding iron-deficiency anemia

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  Discussion Top


FSs are seizures or convulsions that occur in children triggered by fever in the absence of an intracranial infection, hypoglycemia, or an acute electrolyte imbalance, which are the most common type of convulsions in children [15]. FSs usually occur in children between the ages of 6 months and 5 years, with the risk peaking in the second year of life and approximately one in every 25 children will have at least one FS [16]. The relationship between iron deficiency and FS is not yet determined [17] and that is why this study was executed.

The current study revealed that there were no significant statistical differences among the three groups regarding sex, residence place, or age. This balance in the baseline characteristics provides the basis for comparison between the study groups as it helps to minimize bias [18],[19],[20].

The current study revealed that no significant statistical difference existed among the three groups regarding the history of taking iron supplements and that none of the children in any of the three groups had a family history of seizure. Similar results concerning family history of seizure were reported by Barseem et al. [20], as they found no significant differences between the two groups regarding family history of FSs or epilepsy. This was disagreed with Ghasemi et al. [19] who found that the three groups included in their study showed significant difference in history of taking iron supplements with a high percentage of children giving history of taking iron supplements in the FS, febrile without seizure, and healthy groups (76, 69, and 89%, respectively). This difference could be attributed to the difference in the ethnic group, nutritional status, iron indices, and other confounding factors affecting the results.

It was proposed that lower doses of ferrous sulfate (15–20 mg), as an oral dose TDS, were as effective as traditional dosage (65 mg) with lower risk of side effects. An Iranian study showed that iron supplementation of low single dose was effective in managing iron-deficiency anemia. Moreover, a randomly selected sample of 193 adolescent girls aged 14–16 years were recruited for RCT (study group received 150 mg ferrous sulfate once weekly for 16 weeks and a placebo group). There was significant improvement in iron status in the study group (iron-deficiency anemia was resolved in the study group receiving the low-dose iron supplementation) [21].

Likewise, the current study revealed significant difference among the three groups regarding their infancy nutrition. This was contrasted by Ghasemi et al. [19] who found no significant statistical difference among the three groups regarding their pattern of infancy nutrition. This might be caused by that the high percentage of children giving history of depending on breastfeeding in the FS, febrile without seizure and healthy groups in their study (82, 82, and 74.7%, respectively) compared with 28.6, 35, and 65%, respectively, in this study [19].

Regarding the rates of infection among the study cohort, 100% of the children in the FS group had an infection other than gastroenteritis or respiratory tract infection, and the highest percentage of the children in the without FS group (55%) had gastroenteritis. This was in accordance with Sayed et al. [22], who performed their study on 90 children with FSs admitted to hospital to evaluate the diagnostic approaches for children with FSs admitted to Assiut University Children Hospital. They found that upper respiratory tract infection was the most common cause of febrile illness, occurring in 78% followed by gastroenteritis in 22% of cases.

The current study revealed a significant difference between groups in the HCT, HCT, and MCHC, with lower values in the FS group. Nearly similar results were reported by Barseem et al. [20], as they found significantly lower values of hemoglobin, MCV, MCHC, and HCT values in the case group compared with the control group, with no significant differences between both groups regarding red blood cell count and MCHC.

Furthermore, there was a significant difference concerning transferrin saturation, with the highest mean saturation in those without FS group. These results differ from those obtained by Papageorgiou and colleagues, who performed their study aiming to investigate any association between iron deficiency and FSs in European children. They performed their study on 100 children aged 6–60 months and found that plasma ferritin was significantly lower and total iron binding capacity significantly higher in the FS group [23]. Difference could be explained by the different ethnic origin and nutritional status of the included children.

Additionally, it was found that there was insignificant difference between the groups of with and without FSs regarding the presence of iron-deficiency anemia. This was in agreement with Jang et al. [23] with nearly similar results, where they performed their study on 63 cases of FSs and 65 controls with febrile illness but no seizures. Their objective was to examine the association between iron status and FSs in children in South Korea. They found that serum iron, plasma ferritin, and transferrin saturation were significantly lower in children with FSs compared with the controls, although iron-deficiency anemia was not associated with FSs [23]. The current findings contradicted what was found by Papageorgiou et al. [24], as they found that iron deficiency was more significantly frequent in cases than controls. Their conclusion was that European children with FSs have lower ferritin than those with fever alone and that iron status screening should be considered as routine for children presenting with or at high risk for FSs. Another study which showed the association between iron deficiency and FSs was the study conducted by Sharif et al. [17], as they found that the incidence of iron-deficiency anemia in the FC group was significantly higher than the nonconvulsing group, and they concluded that low serum iron and presence of anemia can serve as a reinforcing factor for the FS in children. Contradictory results were also reported by Yousefichaijan et al. [25] who found that the prevalence of anemia in the group with FCs was significantly lower than that in the control group with significantly higher blood indices compared with the control group. This was explained by that that iron deficiency can prevent FCs in children and probably increases the threshold of neuron excitation in fever.

Differences between the results of the present study and the other studies, as part of the controversial relationship found between iron deficiency and FSs along with inconsistent results reported in different studies, can be attributed to many factors. There are many confounding factors such as nutritional status, incidence of infection, cultural factors, and genetic background. It was 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. Furthermore, full-time day-care attendance (20 h per week or more) proved to be a risk factor as social history. Moreover, children with a history of ear discharge, frequent sore throats, or pneumonia were more likely to have had a FS. Viral infections, especially HHV-6, influenza A, and respiratory syncytial virus, also have an important role in the etiology. Moreover, children who have had vaccine-related seizures have an increased rate of recurrent FSs [3].

Furthermore, an important potential confounding on the results of these types of studies is the effect of ferritin as an acute-phase reactant agent, which can interfere with identifying the influence of iron status on FSs [23]. However, patients in the febrile groups were enrolled at the time of febrile illness, so it is supposed that the difference in ferritin level between these two groups would be significant.


  Conclusion and recommendations Top


Formula feeding, low HCT, MCV, MCHC, and transferrin saturation are reinforcing factors for FSs. That is why, this study recommended that pediatricians should encourage mothers to breastfeed their children and minimize the use of formula feeding to needy cases. Future researchers were recommended to carry on further investigation of the relationship between iron-deficiency anemia and FSs, study the correlation between formula feeding and FSs, and perform larger scale studies with wider scope focusing on issues not included in this study.

Acknowledgements

The authors express their profound appreciation and gratefulness for the Faculty of Medicine, Al Azhar (Assiut Branch) University, for facilitating the current work. The authors cordially acknowledge the participants’ caregivers who accepted to take part in this study. It would not have been possible to accomplish this research without their help and support.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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