|Year : 2017 | Volume
| Issue : 2 | Page : 68-73
Risk factors for febrile seizures in Benghazi, Libya: a case–control study
Amenh B Yousif1, Lamia M Hafez2, Fatma S Benkhaial1
1 Family and Community Medicine Department, Faculty of Medicine, Benghazi University, Benghazi, Libya
2 Regional Center for Food and Feed, Agriculture Research Center, Alexandria, Egypt
|Date of Submission||06-Aug-2017|
|Date of Acceptance||14-Oct-2017|
|Date of Web Publication||17-Jan-2018|
Lamia M Hafez
Associate Professor Regional Center for Food and Feed, Agriculture Research Center, Alexandria, 21616
Source of Support: None, Conflict of Interest: None
Background Febrile seizures (FS) are the most common seizures of childhood, occurring in 2–5% of children at 6 months to 5 years of age. The risk factors for FS include developmental delay, delayed discharge from the neonatal ICU, viral infections, a family history of FS, possibly iron deficiencies, and nonexclusive breastfeeding.
Aim This study was carried out to identify and quantify the risk factors for FS in Libyan children.
Patients and methods A case–control study was carried out including one hundred patients with FS aged 6–60 months, admitted to Benghazi Paediatrics Hospital, Libya, who were matched with another 100 children with fever, but without seizure of the same age as the control group. The control group was enrolled randomly and the study was carried out over 8 months from 1 October 2016 to 31 May 2017. Data were collected using a pretested questionnaire. Blood samples were collected from both cases and controls and a complete blood count was performed. χ2-Test was used to assess the significance of the risk factors. Univariate and multivariate logistic regression analyses were carried out to determine the strength of associations at a 5% level of significance.
Results The majority of cases and the children in the control group were between 6 months and less than 25 months of age. It was found that 93% of the cases and 87% of the children in the control group had a temperature higher than 38°C. The most common types of FS for cases were simple FS, which was recorded in 86% of cases, and complex FS, recorded in 14% of cases. A positive family history of FS was reported in 48% of cases compared with 22% of the children in the control group [odds ratio (OR)=3.27, 95% confidence interval (CI): 1.77–6.05, P<0.001]. Iron-deficiency anemia was reported in 73% of cases compared with 33% of controls, and this was found to be a strong significant risk factor for FS (OR=5.48, 95% CI: 2.99–10.07, P<0.001). Furthermore, nonexclusive breast-feeding was reported in 66% of cases compared with 32% of controls (OR=4.12, 95% CI: 2.28–7.43, P<0.001); prematurity was reported in 29% of cases compared with 11% of children in the control group (OR=3.30, 95% CI: 1.54–7.07, P<0.001).
Conclusion The results of the present study indicated that iron-deficiency anemia, nonexclusive breast-feeding, and a family history of FS and prematurity were the most important risk factors for FS. This study recommends educational programs for modifiable risk factors, encourages exclusive breast feeding in the first 6 months, and early diagnosis and treatment for iron-deficiency anemia in children.
Keywords: anemia, Benghazi, children, febrile seizures, nonexclusive breast feeding, risk factors
|How to cite this article:|
Yousif AB, Hafez LM, Benkhaial FS. Risk factors for febrile seizures in Benghazi, Libya: a case–control study. Alex J Pediatr 2017;30:68-73
|How to cite this URL:|
Yousif AB, Hafez LM, Benkhaial FS. Risk factors for febrile seizures in Benghazi, Libya: a case–control study. Alex J Pediatr [serial online] 2017 [cited 2018 Dec 18];30:68-73. Available from: http://www.ajp.eg.net/text.asp?2017/30/2/68/223455
| Introduction|| |
Febrile seizures (FS) are a type of seizure accompanied by fever with temperature higher than or equal to 38°C, without central nervous system infection, that occur in infants and children at 6 months to 60 months of age. FS occur in 2–5% of all children and, as such, are the most common convulsive event in children younger than 60 months of age .
FS are typically divided into two types: simple febrile seizure and complex febrile seizure. Simple febrile seizure is one that is generalized, occurs once over a 24-h period, and lasts less than 15 min; 70–75% of FS are simple. FS is considered complex if it is focal or localized to a specific part of the body, duration longer than 15 min but less than 30 min, or involves recurrence of seizures in a 24-h period; 20–25% of FS are complex .
It is suggested that FS is an age-dependent response of the immature brain to fever as studies on animal models have suggested that during the brain maturation process, there is an enhanced neuronal excitability . This postulation is supported by the fact that most FS (65–85%) occur between 6 months and 3 years of age, with the peak incidence at 18 months ,,.
Despite its benign nature, the FS is one of the most common reasons for admission to pediatric emergency worldwide. In most of the patients, fever occurs because of upper respiratory system and urinary tract infection .
The most consistently identified risk factor for FS is the presence of a close family history of FS. The risk may be increased by an underlying brain disorder, premature birth, delayed discharge from the neonatal ICU, and developmental delay. Any viral or bacterial illness may induce FS. Generally, at least 50% of children who present with FS will have no identified risk factors . Perinatal factors and iron-deficiency anemia were suspected to be risk factors associated with FS .
Iron deficiency (ID) is the most common nutritional deficiency and affects up to 9% of children 1–2 years of age according to the Third National Health and Nutrition Examination Survey from the USA. The peak age for ID is between 1 and 2 years, which coincides with the peak incidence for FS .
Iron is needed for brain energy metabolism, metabolism of neurotransmitters, and for myelination. Thus, ID may alter the seizure threshold of a child ,. Iron is essential for proper neurogenesis, as well as for differentiation of certain brain cells, and also for functioning of oligodendrocytes, which are responsible for producing myelin. These cells are particularly sensitive to iron deprivation, which will lead to an altered composition and amount of myelin in the white matter .
Exclusive breastfeeding is recommended up to 6 months of age, with continued breastfeeding along with appropriate complementary foods up to 2 years of age or beyond. In most countries, the rates of exclusive breastfeeding under 6 months of age are below 50%. This finding signals the need to modify breastfeeding support strategies to specific patterns recorded in each country . Brain development occurs most rapidly in the early years of life, in which the breast milk plays an important role because of its essential nutrient components, such as long-chain polyunsaturated fatty acid, cholesterol, and gangliosides, which are found in small amounts or even do not exist in formula milk. Studies also show that breastfeeding is associated with better IQ levels, development in total brain volume, and the development of brain white matter in children . It was found that breast-feeding duration in children with their first FS was significantly lower than those of healthy children .
Efforts have to be made to identify the risk factors associated with FS in different countries.
| Aim|| |
The aim of this study was to identify and quantify the potential risk factors for FS in Libyan children.
| Patients and methods|| |
A case–control study was carried out including a total of 200 patients. One hundred cases with FS aged 6–60 months were selected from Benghazi Paediatric Hospital, Libya. They were matched with 100 children with febrile illness without seizures (same age range). They were selected randomly from the same hospital as the control group from 1 October 2016 to 31 May 2017.
Inclusion criteria of the cases and control group were as follows:
- Libyan children with an age range from 6 to 60 months were selected from Paediatrics Hospital in Benghazi, Libya.
- Diagnostic criteria for FS (on the basis of American Academy of Paediatrics Clinical Practice Guidelines) included seizures associated with fever; children were healthy without any evidence of central nervous system infection or metabolic disorders as indicated by assessment of history, clinical examination, and record review .
- A control group in the same age with febrile illness without a history of seizures was selected.
Exclusion criteria of the cases and control group were as follows:
- Children with central nervous system infections.
- Children with previous febrile seizures.
- Previous medical history of epilepsy.
- Inborn error metabolism.
- Organic cause of seizures.
- Data were collected using a pretested questionnaire including age, sex, family history of febrile seizure, educational level of mother, previous medical history, and history of exclusive breastfeeding in the first 6 months, obstetric history, history of prematurity, mode of delivery, and history of neonatal ICU (NICU) admission.
- A full systemic examination was performed by the pediatrician and axillary temperature was taken for both groups.
- Laboratory evaluation: Blood samples were obtained from both the case and the control group and a complete blood count was performed for both groups. The cut-off level of hemoglobin values below (11 g/dl) was considered anemic according to the WHO definition .
A pilot study was carried out using the designed questionnaire at the beginning of the study.
- The collected data were handled and analyzed using SPSS software, version 16 (SPSS Inc., Chicago, Illinois, USA).
- Data were described using number and percentage.
- Comparison between cases and controls was performed using the χ2-test at a 5% level of significance. Odds ratio (OR) was used to quantify risk factors.
- Risk factors with a P value less than 0.05 in univariate analysis were subjected to a multivariate logistic regression analysis and adjusted OR was calculated.
Ethical approval was obtained from the Faculty of Medicine, Benghazi University, and the Paediatric Hospital to carry out the research and written informed consent was obtained from all parents for inclusion in the study.
| Results|| |
The majority of cases and control groups were between 6 months and less than 25 months ([Table 1]).
It was found that 93% of the cases and 87% of the children in the control group had temperature higher than 38°C and there was no significant difference between the two groups ([Table 2]). Most common types of FS for cases in the present study were simple FS (86%), whereas complex FS was present in 14%.
|Table 2 Distribution of the groups studied according to the grades of temperature|
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[Table 3] shows the sex, mother’s education, and family history of FS for the studied groups. In the cases group, 60% were males, whereas in the control group, 54% were males. A positive family history of FS was reported in 48% of cases compared with 22% of the children in the control group [OR=3.27, 95% confidence interval (CI): 1.77–6.05, P<0.001]. This finding could be considered a risk factor for FS, children with a positive family history had three times higher risk of developing FS than children who did not have a family history of FS. Furthermore, mother’s education in 42% of cases were less than secondary level compared to 38% in control group, without statistical significance.
|Table 3 Distribution of the groups studied according to their sex, mothers’ education, and family history of febrile seizures|
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Iron-deficiency anemia was reported in 73% of cases compared with 33% of the children in the control group, and this was found to be a strong risk factor for FS (OR=5.48, 95% CI: 2.99–10.07, P<0.001) ([Table 4]). It seems that anemic children had five times higher risk of developing FS than those with normal hemoglobin levels. Furthermore, nonexclusive breast-feeding was reported in 66% of cases compared with 32% of the children in the control group (OR=4.12, 95% CI: 2.28–7.43, P<0.001). It seems that the risk of developing FS in nonexclusive breastfeeding children was four times higher than those with exclusive breast-feeding in the first 6 months.
|Table 4 Distribution of cases and the control group according to the history of breast feeding and iron-deficiency anemia|
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[Table 5] shows the perinatal risk factors of the studied groups. Prematurity was reported in 29% of cases compared with 11% in the control group (OR=3.30, 95% CI: 1.54–7.07, P<0.001). Infants with premature birth had three times higher risk of developing FS than those with full-term delivery. The present study showed that there were no associations between mode of delivery, NICU admission, and increased risk for FS (OR=0.66, 95% CI: 0.38–1.16, P<0.15; OR=1.05, 95% CI: 0.56–1.97, P<0.87, respectively).
|Table 5 Distribution of cases and the control group according to perinatal history|
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The most common significant risk factors found in the current study, which were assessed by logistic regression analysis, were ID anemia (OR=5.48, 95% CI: 2.99–10.07), nonexclusive breastfeeding (OR=4.12, 95% CI: 2.28–7.43), prematurity (OR=3.30, 95% CI: 1.54–7.07), and family history of FS (OR=3.27, 95% CI: 1.77–6.05, respectively) ([Table 6]). The estimated odds ratios of logistic regression analysis were not materially changed after adjustment.
|Table 6 Multivariate regression analysis of significant risk factors for febrile seizures|
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| Discussion|| |
In the present study, it was found that the majority of cases of FS occurred in the second year of life (13 to <25 months), with the peak age at 18 months, which is similar to the finding in other studies ,,. FS are age dependent and age should be considered critical for developing FS. A unique age specificity of the maturing brain’s sensitivity to fever because of enhanced neuronal excitability during the normal brain maturation had been suggested . In the present study, most cases had temperature higher than 38°C; this was similar to a study carried out in Zawia, Libya . The most common types of FS included in the present study were simple FS, reported in 86% of cases; this finding was similar to that obtained in another study in Tunisia . In the current study, 60% of the cases were males whereas in the control group, 54% were males. The male sex predominance is well documented , but there was no satisfactory explanation for this sex predominance .
About 48% of cases were found to have a positive family history of FS compared with control group (22%), and this with statistically significant (P<0.001). This finding is in agreement with the study carried out in Jordan that reported a strong evidence of positive family history as a risk factor for FS . In case–control study carried out to determine the risk factors of FS among children in the United Arab Emirates, family history of FS was the only significant predictor for FS . A similar finding reported that a family history of FS is a significant factor for diagnosis . In the present study, educational level of the mother was not found to be a significant risk factor and this was in agreement with the finding of the Brazil study .
In the present study, 73% of cases were anemic compared with 33% of the children in the control group. ID anemia was found to be a strong significant risk factor (OR=5.48, P<0.001). The present study had documented that anemic children had five times higher risk of developing FS than nonanemic children. The association between anemia and FS was studied by other authors who confirmed this association ,. Other studies also concluded that the risk of FS occurred in anemic children than nonanemic children . This was in agreement with the results of a case–control study from Italy, in which the author suggests that fever can worsen the negative effect of anemia on the brain and a seizure occurs consequently . Furthermore, a recent study carried out in Egypt reported that FS is more common in anemic children and ID anemia seems to be an important risk factor for the development of FS .
In the present study, prematurity was found to be a significant risk factor. This was also found in other studies ,,. The risk of FS increases with decreasing birth weight and gestational age at birth, indicating that perinatal risk factors play a causal role .
The current study found that nonexclusive breastfeeding was reported in 66% of cases compared with 32% of the children in the control group (OR=4.12, P<0.001). It seems that the risk for developing FS in nonbreastfed children is four times higher than those with exclusive breastfeeding in the first 6 months; this was similar to the results of another observational study . It could be suggested that exclusive breastfeeding in the first 6 months of life may protect children from developing FS . The protective mechanism of breastfeeding has not yet been clarified, but it was suggested that the contents of polyunsaturated fatty acids such as arachidonic acid and docosahexaenoic acid, cholesterol, and sialic acid play an important role in brain development and stabilization of neuronal membranes by the neuroprotective mechanism and increasing the seizure threshold ,. Also, it can be explained by the fact that the gastroenteritis and respiratory infections are much lower in breastfed children, with little possibility of developing fever ,. Also, frequent contact between the mother and the baby, and their affectionate relation can improve developmental skills, which are a marker for brain development ,.
In the present study, mode of delivery and admission to NICU were not found to be significant risk factors for FS; this was in agreement with a study carried out in Taiwan . However, admission to NICU was found to be a risk factor for FS in other studies; the risk may be increased by delaying discharge from NICU .
| Conclusion|| |
The most frequent significant risk factors for FS were ID anemia, nonexclusive breast feeding, prematurity, and a positive family history.
The limitations of this study were the difficulty in the clinical evaluation of children with FS and the inaccurate information provided by the family.
- Educational programs focusing on the modifiable risk factors are required especially to improve maternal child health services through health education and encouraging exclusive breast feeding in the first 6 months.
- It is recommended to attend antenatal care regularly for early diagnosis of women with preterm labor to minimize premature birth.
- Improve awareness of parents with a positive family history of FS to follow-up their children.
- Guidelines and protocols in primary healthcare for the early diagnosis and treatment of children with ID anemia should be available.
The authors are very grateful to all children and their parents for generously agreeing to take part in the present study, and also thank the laboratory team for comprehensive efforts that resulted in a significant improvement of this study and all doctors and nurses of pediatric hospital for their assistance and expert contribution.
The authors alone are responsible for the content and writing of the paper.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
American Academy of Pediatrics. Neurodiagnostic evaluation of the child with a simple febrile seizure. Pediatrics 2011; 127:389–394.
Whelan H, Harmelink M, Chou E, Sallowm D, Khan N, Patil R et al.
Complex febrile seizures − a systematic review. Dis Mon 2017; 63:5–23.
Jensen FE, Sanchez RM. Why does the developing brain demonstrate heightened susceptibility to febrile and other provoked seizures? In: Baram TZ, Shinnar S, editors. Febrile seizures. San Diego, CA: Academic Press; 2002. pp. 153–168.
Verity CM, Butler NR, Golding J. Febrile convulsions in a national cohort followed up from birth. II-Medical history and intellectual ability at 5 years of age. Br Med J Clin Res Ed 1985; 290:1311–1315.
Forsgren L, Sidenvall R, Blomquist HK, Heijbel J. A prospective incidence study of febrile convulsions. Acta Pediatr 1990; 79:550–557.
Hauser WA. The prevalence and incidence of convulsive disorders in children. Epilepsia 1994; 35(Suppl 2):S1–S6.
Waruiru C, Appleton R. Febrile seizures: an update. Arch Dis Child 2004; 89:751–756.
Waheed N, Butt MA. Iron status: is there a role in febrile seizures? J Ayub Med Coll Abbottabad 2012; 24:128–130.
Beard J. Iron deficiency alters brain development and functioning. J Nutr 2003; 133:1468–1472.
Batra J, Seth PK. Effect of iron deficiency on developing rat brain. Indian J Clin Biochemist 2002; 17:108–114.
Looker AC, Dallman PR, Carroll MD. Prevalence of iron deficiency in the United States. JAMA 1997; 277:973–976.
Özaydın E, Arhan E, Cetinkaya B, Özdel S, Değerliyurt A, Güven A et al.
Differences in iron deficiency anemia and mean platelet volume between children with simple and complex febrile seizures. Seizure 2012; 21:211–214.
Victora CG, Bahl R, Barros AJ, Franca GV, Horton S, Krasevec J, Murch S et al.
Breastfeeding in the 21st century: epidemiology, mechanisms, lifelong effect. Lancet 2016; 387:475–490.
Issacs EB, Fischl BR, Quinn BT, Chong WK, Gadian DG, Lucas A. Impact of breast milk on intelligence quotient, brain size, and white matter development. Pediatr Res 2010; 67:357–362.
Farivar KH, Tairani AB. The protective effect of breast feeding in febrile seizures. J Iran Children 1996; 9:49–55.
American Academy of Pediatrics Steering Committee on Quality Improvement and Management, Subcommittee on Febrile Seizures. Febrile seizures: clinical practice guideline for the long-term management of the child with simple febrile seizures. Pediatrics 2008; 121:1281–1286.
De Mayaer EM, Dallman P, Gurney JM. Preventing and controlling iron deficiency anemia through primary health care. Geneva: WHO; 1989. p. 25.
Eskandarifar A, Fatolahpor A, Asadi G, Ghaderi E. The risk factors in children with simple and complex febrile seizures: an epidemiological study. Int J Pediatr 2017; 5:5137–5144.
Annegers JF, Hauser WA, Shirts SB. Factors prognostic of unprovoked seizures after febrile convulsions. N Engl J Med 1987; 316:493–498.
Offringa M, Hazebroek-Kampschreur AA, Derksen-Lubsen O. Prevalence of febrile seizures in Dutch school children. Paediatr Perinat Epidemiol 1991; 5:181–188.
AL-Zwaini EJ, AL-Ani S, AL-Khalidi MJ, AL-Ta’ie MF. Risk factors for febrile seizures: a matched case control study. Iraqi PG Med J 2006; 5:353–358.
Elgerbi A. Factors that may anticipate febrile convulsion. Univ Bull 2014; 16:111–120.
Sfaihi L, Maaloul I, Kmiha S. Febrile seizures: an epidemiological and outcome study of 482 cases. Childs Nerv Syst 2012; 28:1779–1784.
Pal DK, Kugler SL, Mandelbaum DE. Phenotypic features of familial febrile seizures: case control study. Neurology 2003; 60:410–414.
Guelletle EM. The child who convulses with fever. Pediatr Clin N Am 1974; 21:467–481.
Daoud A. Febrile convulsion: review and update. J Pediatr Neurol 2004; 2:9–14.
Gururaj AK, Bener A, Al-Suweidi EK, Al-Tatari HM, Khadir AE. Predictors of febrile seizure: a matched case-control study. J Trop Pediatr 2001; 47:361–362.
Mohsenipour R, Saidi M, Rahmani P. Assessment of causative factors of febrile seizure related to a group of children in Iran. Biomed Res 2017; 28:1548–1552.
Dalbem JS, Siqueira H, Mariano ME, Regina PA. Febrile seizures: population based study. J pediatr 2015; 91:529–534.
Naveed R, Billo AG. Association between iron deficiency anemia and febrile seizures. J Coll Physicians Surg Pak 2005; 15:338–340.
Daoud AS, Batieha A, Abu-Ekteish F. Iron status: a possible risk factor for the first febrile seizures. Epilepsia 2002; 43:740–743.
Talebiun A, Momtazmanesh N, Mosavi G, Khojasteh M. Relationship between febrile seizure and anemia. Iran J Pediatr 2006; 165:79–82.
Piscan A, Sansone R, Impaglizzo N. Iron deficiency anemia and febrile convulsion: case control study in children under 2 years. BMJ 1996; 313:34.
Khalefa AM, Algendi RA, Hammad KS, Elsayed AH. Evaluation of iron status in children with first febrile seizures. Nat Sci 2017; 15:92–95.
Al-sweidi E, Bener A, Uduman S. Risk factor for febrile seizures. Neuroscince 1992; 4:269–274.
Forsgren L, Sidenvall R, Blomquis HK. Pre- and perinatal factors in febrile convulsions. Acta Paediatr Scand 1991; 80:218–225.
Ellatiff A, Garawany H. Risk factors of febrile disease among preschool children in Alexandria. J Egypt Public Health Assoc 2002; 77:156–172.
Vestergaard M, Christensen J. Register-based studies on febrile seizures in Denmark. Brain Dev 2009; 31:372–377.
Abolfazl M, Ayazi P, Fallahi M, Javadi A. Risk factors of the first febrile seizures in Iranian children. Inter J Pediatr 2010; 4:862897.
Akhondian J, Ivari RE. The incidence of febrile convulsion in exclusively breast-fed children. MJIRI 2006; 19:319–322.
Taha AY, Jeffrey MA, Taha NM, Bala S, Burnham WM. Acute administration of docosahexaenoic acid increases resistance to pentylenetetrazol-induced seizures in rats. Epilepsy Behav 2010; 17:336–343.
Emmett PM, Rogers IS. Properties of human milk and their relationship with maternal nutrition. Early Hum Dev 1997; 49:S7–S28.
Lang S. Breast feeding special care babies. 2nd ed. UK: Harcourt; 2002.
Heird WC. The feeding of infants and children [chapter 41]. In: Behrman RE, Kliegman RM, Henson HB, editors. Nelson text book of pediatrics. 17th ed. Philadelphia, PA: W.B. Saunders; 2004.
Yavin E, Brand A, Green P. DHA abundance in brain: biodevice to combat oxidative stress. Nutr Neurosci 2002; 5:149–157.
Cheruku SR, Montgomery-Downs HE, Farkas SL, Thoman EB, Lammi-Keefe CJ. Higher maternal plasma DHA during pregnancy is associated with more mature. Neonatal sleep-state-patterning. Am J Clin Nutr 2002; 76:608–613.
Huang CC, Wang ST, Chang YC, Huang M, Chan Chi Y, Tsai J. Risk factors for first febrile convulsion in children: a population study in Southern Taiwan. Epilepsia 1999; 40:719–725.
Sharawat IK, Singh J, Dawman L, Singh A. Evaluation of risk factors associated with first episode febrile seizure. J Clin Diag Res 2016; 10:10–13.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]