Tavasoli et al. BMC Pediatrics(2024) 24:518
https://doi.org/10.1186/s12887-024-04968-9

BMC Pediatrics

RESEARCH

Open Access

Evaluating the serum levels of zinc, copper,
magnesium, and 25-hydroxy vitamin D
in children with idiopathic drug-resistant
epilepsy; a cross-sectional study
Azita Tavasoli1, Ladan Afsharkhas1*

and Behnaz Parvini2

Abstract
Background Drug-resistant epilepsy is defined as failure of seizure control in spite of using 2 or 3 proper antiepileptic
drugs in appropriate time. Mineral elements play important roles in neuronal function; it is believed that mineral
deficiency may lead to complications through seizure management. In the present study, serum levels of zinc (Zn),copper (Cu), magnesium (Mg), calcium (Ca), and 25-hydroxy vitamin D (Vit D) in drug-resistant-epilepsy (DRE) patientswere evaluated and compared with the controlled patients.
Methods In this cross-sectional study, epileptic patients were included and categorized into two groups of DRE
and well-controlled patients. Patients’ serum samples were analysed to evaluate Zn, Cu, Mg, Ca, and Vit D levels. The
primary objective was comparison of serum levels of different trace elements between the groups.
Results Sixty-four epileptic children including 33 DRE and 31 well-controlled children entered the study. The DRE
children showed a significantly earlier onset of disease compared to the other group (p = 0.014). Comparing thefrequency of developmental delay between the groups, the results showed this complication was significantly
more frequent in the DRE group (p < 0.001). Concerning serum elements, the results showed a significantly higher
concentration of Zn in the well-controlled group than the DRE group (p = 0.007). On the other hand, no significant
differences were observed between the groups regarding the means of Vit D, Ca, Cu, and Mg levels (p > 0.05).
Conclusion The results of the present study delineated that drug-resistant epilepsy patients had earlier onset of
disease and were at higher risk of neurodevelopmental delay compared with well-controlled-epilepsy patients. A
significant lower serum levels of Zn were also observed in drug-resistant-epilepsy patients. This finding may suggest
the role of zinc supplementation in help to better control of drug-resistant seizures, as well as, the importance ofserum zinc monitoring in epileptic patients.
Keywords Drug-resistant epilepsy, Seizures, Trace element, Child*Correspondence:
Ladan Afsharkhas
drafshar1neuro@gmail.com
1
Pediatric Neurologist, Department of Pediatric Neurology, Ali AsgharChildren’s Hospital, Iran University of Medical Sciences, Tehran, Iran2
Department of Pediatrics, Ali Asghar Children’s Hospital, Iran University of
Medical Sciences, Tehran, Iran
© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you
give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified thelicensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it.The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to thematerial. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation
or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http://
creativecommons.org/licenses/by-nc-nd/4.0/.

Tavasoli et al. BMC Pediatrics(2024) 24:518

Introduction
Epilepsy is one of the most frequent neurological disorders associated with abnormal electrical currents. Thisdisorder is defined as recurrent occurrence of unprovoked seizures; if two or more unprovoked seizures happen at intervals more than 24 h the diagnosis of epilepsy
is done. Totally 51 million people around the world are
suffering from this disease, and about 3–4% of children
experience at least an epileptic attack in their lifetime[1–3]. Although the etiology of disease remains unknown
in some cases, several factors such as structural, infectious, immunological, metabolic, or genetic disturbances
are involved [4, 5]. Depending on the type and durationof seizures, epilepsy can cause neuronal death, neuronal
injury, and alteration of neuronal network, resulting inlong term consequences [6].
The first generation or new antiepileptic drugs like carbamazepine, clonazepam, phenobarbital, valproic acideither as monotherapy or multi-drug regimens are prescribed for children to manage their epileptic seizures[7]. Drug-resistant epilepsy (DRE) is an epilepsy thatshows resistance to treatment despite the use of 2 or 3
properly chosen antiepileptic drugs with appropriate
dosage and duration. Moreover, in the definition of DRE,
the frequency of seizures and patient’s follow-up period
are considered as the important factors [3]. As, basedon Berg and Shinnar definition, DRE is diagnosed whenmore than one seizure attack is occurred per month for
18 months and no seizure free period is existed for morethan 3 consecutive months [3]. DRE problem may relate
to advanced damages in structure and microvasculatureof nervous system. In addition, increased levels of oxidative stress and inflammatory agents can affect functionof drug transporters resulting in DRE [8]. Other mechanisms like alterations in neural sprouting, neurogenesis,
voltage-gated ion channels, neurotransmitter receptors
and their sensitives, as well as epileptogenesis pattern
may be involved [9]. It was reported that about 20% of
patients are drug resistant and continue to experience
seizure attacks despite using antiepileptic drugs withproper dose and duration [7, 10]. To manage this complication, the number of antiepileptic drugs, the frequencyof seizure, and the patient’s follow-up should be considered as the important factors [3].
Evidence has shown the potential role of minerals andmicro-nutrients deficiencies on nervous system disorders
through affecting voltage and transmitter-gated channels,
signal transduction, as well as enzymatic and biologicalactivities [11, 12]. On the other hand, the possible antiepileptic effects of several minerals and micro-nutrientslike magnesium, vitamin B6, B12, E, and D have beenshown [13]. An investigation demonstrated significantly
lower levels of serum selenium (Se) and copper (Cu) inwell-controlled and drug-resistant epileptic children

Page 2 of 7

compared to the age and sex-matched controls [14]. The
other study has shown that macro and micro-nutrient
intakes were significantly lower in patients with uncontrolled seizures compared with those with controlled seizures [15]. Comparing serum calcium (Ca), magnesium(Mg), zinc (Zn), and Cu concentrations in seizures-controlled and DRE patients, the results of a study demonstrated a significantly lower level of serum Zn in patients
who did not respond to the antiepileptic treatments[16]. This finding was confirmed by the other investigation, and the authors revealed a significant relationshipbetween low levels of serum Zn and intractable epilepsy
in 35 patients aged 6 months to 15 years [3].
The prevalence of epilepsy in Iran is still high (1%) [17],and further investigations are needed to assess the etiology or management of DRE. As literatures have shown
the role of trace elements on neuronal function; it is supposed that mineral deficiency may lead to neurologicalcomplications through resistance to treatment. Hence, by
the present study we aimed to compare serum levels of
Zn, Cu, Mg, Ca, and 25-hydroxy vitamin D (Vit D) in thewell-controlled and DRE patients to show any potential
role of trace elements on DRE occurrence.

Materials and methods
A cross-sectional study was conducted at Ali AsgharChildren’s Hospital which is affiliated with the Iran University of Medical Sciences (Tehran, Iran). All epileptic children aged 1–17 years who attended our centerfrom 2019 to 2021 entered the study. According to literature [3], patients with at least a seizure attack during recent six months, despite consuming two or more
antiepileptic drugs for a year were considered as the
DRE group. The other patients with controlled seizure
during the treatment period were included in the study
as the well-controlled group. Exclusion criteria were
symptomatic seizures due to nervous system infections,
neurodegenerative diseases, metabolic diseases, structural complications (like tumors); symptomatic Cu, Ca,or Zn deficiency; a positive history of systemic disorderaffecting trace elements values (such as Wilson disease,chronic renal or hepatic diseases, malnutrition and acrodermatitis enteropathica); taking supplementation or
drugs containing Zn, Cu, Mg, and Ca during recent six
months.
All participants’ demographic and clinical data wereextracted from the medical records and gathered in achecklist. These data included age, sex, familial historyof epilepsy, consumed medicines, type of seizure, treatment duration, and the time of the first seizure. Other
demographic characteristics such as geographic area andsocioeconomic status were identical between the groups.
A dietary intake history was also taken. Accordingly, allTavasoli et al. BMC Pediatrics(2024) 24:518

Page 3 of 7

participants were on balanced diet and none of them had
dietary restriction for medical purposes.
Evaluating serum levels of elements, including Zn, Cu,
Mg, Ca, and Vit D, 6 ml of peripheral venous blood was
drowned, centrifuged, stored at -70 o C, and sent to thelaboratory. The levels of Zn, Cu, Ca, and Mg were measured using the Atomic absorption spectrophotometry
method. Vit D measurement was also carried out using
a Radioimmune assay kit (IDS Co., United Kingdom).
Based on the evidence [18–22], normal ranges of elements were considered as follows (Table 1).
Sample size

According to the results of a former investigation performed by Prasad et al., [16] the means of Zn levels in
the controlled epilepsy and drug-resistant groups were
10.38 ± 2.99 and 12.62 ± 3.30.
µg/dl. Using the following sample size formula, considering α error 0.05, and the power of 80%, the sample size
was estimated at 32 in each group.
2n=(s21 + s22 ) + (z1− α2 + z1−β )(x̄1 − x̄2 )2S1 = 2.99; S2 = 3.30
X1 = 10.38; X2 = 12.62
Z1-α/2 = 1.96
Z1-β = 0.85
Statistical analysis

Data analysis was performed using the Statistical Package for the Social Science (SPSS Inc., Chicago, USA),version 27.0. The quantitative variables in the study arepresented in mean ± SD (variables with normal distribution) or median and interquartile range (variables without normal distribution). Qualitative variables are also
shown in number (%). The Chi-square test was used tocompare qualitative variables like sex, familial history,
developmental delay, used drugs, and type of seizure
between the groups. The Independent T-test was implemented to analyze the quantitative variables (patients’ages and serum elements) between the groups. Variables
without normal distribution (age at onset of the epilepsy
and treatment duration) were also analyzed using theTable 1 Normal ranges of different trace elements
Serum elements
Zinc (µg/dl)
Copper (µg/dl)
Magnesium (mg/dl)
Calcium (mg/dl)
25-hydroxy vitamin D (ng/ml)

Normal range
Female70–11480–155
1.5–2.3
8.8–10.8> 30

Male
72.6–127
70–150
1.5–2.3
8.8–10.8> 30

Mann-Witney test. The correlations between treatment
duration and serum elements were reported using theSpearman correlation. A p-value less than 0.05 was considered the significant level.
Ethical consideration

The present study was approved based on the Helsinki
Declaration by the Ethics Board of the Iran Universityof Medical Sciences (ID Code: IUMS;2854;1395.4.26).
Before enrolment, parents or legal guardians of children
were informed about the project, and then they wereasked for written consent. The participants were assured
about their right to discontinue and exit from the study.
No cost was imposed, and all data were considered
confidential.

Results
Sixty-four epileptic children including 33 (52%) DRE
and 31 (48%) well-controlled epilepsy children entered
the study. Of all participants, 36 (56%) were male. Myoclonic and Tonic-clonic were the most common types of
seizures in the DRE and well-controlled patients, respectively. The physical examination of patients did not reveal
any signs of inadequate dietary intake such as malnutrition or acrodermatitis enteropathica.
Concerning the consumed drugs, 21 subjects of
the well-controlled group used a single-drug regimen as follows; 6 patients took Phenobarbital (5 mg/
kg/day), 5 patients took Levetiracetam (20–40 mg/kg/day), 5 patients took Valproate sodium (20 mg/kg/day),4 patients took Carbamazepine (20 mg/kg/day), and 1
took Topiramate (5 mg/kg/day). The other patients inthe well-controlled group used multiple drugs, of them
9 received two and 4 received three drugs. The duration of treatment was one to two years. Additionally,
all patients in the DRE group consumed a high dose ofmultiple-drug regimen depending on seizure type; 22, 8,
and 3 patients used three, four, and five drugs, respectively. The most common combinations were Valproate
sodium (20 mg/kg/day), Clobazam (1 mg/kg/day), andTopiramate (7–9 mg/kg/day), followed by Phenobarbital(5 mg/kg/day), clobazam (1 mg/kg/day), and Levetiracetam (40 mg/kg/day), as well as Vigabatrin (100 mg/kg/day), Levetiracetam (40 mg/kg/day), and Phenobarbital(5 mg/kg/day). The multiple-drug regimen in this groupof patients varied in terms of medications and treatment
duration (longer than a year).
As comparative data are shown in Table 2, the DRE
children showed significantly earlier onset of disease
compared to the other group (p = 0.014). The treatment
period in the DRE group was more prolonged comparedto the treatment duration in the well-controlled group(p < 0.001). The majority of DRE children (75%) showedneurodevelopmental delay. Comparing the frequency

Tavasoli et al. BMC Pediatrics(2024) 24:518

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Table 2 Comparison of demographic and clinical characteristics between the case and control groups

Age (year): mean ± SD
Gender (%)

Male
FemaleFamily History (%)
Yes
NoDevelopmental Delay (%)
Yes
No
Drug (%)
Single drug
Multiple drugs
Seizure type (%)
Atonic
Focal
Myoclonic
Tonic
Tonic-clonicAge at onset epilepsy (year): median (IQR)
Treatment duration (year): median (IQR)

Well-controlled epilepsy groupn = 31
6.32 ± 4.29
17 (47.20)
14 (50.00)
10 (58.80)
21 (44.70)
8 (25.00)
23 (71.90)
18 (100)
13 (28.30)
7 (46.70)
5 (41.70)
1 (12.50)
1 (33.30)
17 (65.40)
4.00 (5.00)
1.60 (0.40)

Drug-resistant epilepsy groupn = 33
6.34 ± 3.89
19 (52.80)
14 (50.00)
7 (41.20)
26 (55.30)
24 (75.00)
9 (28.10)
0 (0.00)
33 (71.70)
8 (53.30)
7 (58.30)
7 (87.50)
2 (66.70)
9 (34.60)
1.00 (3.29)
3.60 (3.60)

p-value
0.990
0.512
0.237
< 0.001< 0.001
0.106

0.014
< 0.001

SD: Standard deviation, IQR: interquartile range

Table 3 Comparison of serum levels of Zinc, Calcium, Magnesium, copper, and vitamin D between the groups

Zinc
Calcium
Magnesium
CopperVitamin D

Well-controlled epilepsy (n = 31)
mean ± SD
95.22 ± 14.26
9.35 ± 0.50
1.92 ± 0.17
119.00 ± 18.15
41.91 ± 16.90

Drug-resistant epilepsy (n = 33)
mean ± SD
84.76 ± 15.78
9.32 ± 0.61
1.93 ± 0.20
113.83 ± 23.12
45.43 ± 17.10

p-value
0.007
0.828
0.874
0.325
0.410

SD: Standard deviation

Table 4 Correlations between treatment duration with serum levels of Zinc, Calcium, Magnesium, copper, and Vitamin D in thegroupsControlled epilepsy
Correlation with Treatment duration Score
P value
Resistant epilepsy
Correlation with Treatment duration Score
P value

Zinc

Calcium

Magnesium

CopperVitamin D-0.018
0.923

0.28
0.12

0.16
0.36

0.031
0.896

0.35
0.051

-0.27
0.129

-0.14
0.428

0.32
0.065

-0.04
0.792

-0.05
0.771

of developmental delay between the groups, the results
showed this complication was significantly more frequent in the DRE group (p < 0.001). More children in the
DRE group consumed multiple-drug regimens comparedto the patients in the well-controlled group (71.70% vs.
28.30%; p < 0.001). The mean age of DRE children was
higher than the well-controlled subjects but the difference was not statistically significant(p = 0.990). No differences were also observed between the groups regarding
participants’ genders (p = 0.512) and seizure types(p = 0.106). More patients in the well-controlled group
had a familial history of epilepsy; however, the difference between the groups was not statistically significant(p = 0.237). Detailed data are presented in Table 2.

Concerning serum elements, the results showed a significantly higher concentration of Zn in the well-controlled group than the DRE group (p = 0.007). On theother hand, no significant differences were observed
between the groups regarding to means of Vit D, Ca, Cu,
and Mg levels (p > 0.05). Data are shown in Table 3.
Table 4 shows the correlations between the length of
the treatment period and serum elements in both groups.
According to the results, no statistically significant correlations were observed between the duration of the treatment period with serum levels of Zn, Ca, Mg, Cu, and Vit
D in the studied groups (p > 0.05).

Tavasoli et al. BMC Pediatrics(2024) 24:518

Discussion
Literatures have shown no significant improvement ofseizure attacks in one-fifth to one-fourth of epileptic
patients despite use of 2–3 antiepileptic drugs [3, 23]. The
present study assessed the possible relationships between
drug resistance in epileptic patients and concentrationsof serum trace elements.
The results of present study showed that the mean ofserum Zn in DRE patients was significantly lower thanthe other group. These findings may suggest the role ofzinc supplementation in better control of drug-resistantseizures, as well as, the importance of serum zinc monitoring in patients who have refractory epilepsy. Evidence
has demonstrated the modulatory effects of Zn on neural excitability; Zn is a modulator of the glutamic aciddecarboxylase and is involved in the production andactivity of the gamma-aminobutyric acid (GABA) an
inhibitory neurotransmitter [24]. Moreover, the activation of N-Methyl-D-Aspartate (NMDA as an excitatoryneurotransmitter) receptors has been shown by low levels of serum Zn [24]. The principal modulatory effects of
Zn on NMDA receptors occur through two manners ofvoltage-dependent and non-dependent channel blockage
at various concentrations. Zn binds to the aminoterminal domain of GLUN2 A subunit of NMDA receptors todecrease the probability of ion channel opening throughthe increment of proton inhibition. Mutation of GLUN2
can alter the sensitivity of NMDA receptors to Zn andresults drug-resistant epilepsies [25]. Zn as a cofactor also has inhibitory effects on neuronal T-type calcium channels [14]. Doboszewska et al. reported a highlevel of Zn in mossy fibers of hippocampus, which thisregion of brain is critical for epilepsy occurrence andits drug-resistant forms [26]. Excitotoxicity-evoked seizures are resulted from brain inflammation and increased
pro-inflammatory cytokines, including IL-1beta. The
functions of IL-1beta are diminished by Zn throughblocking glutamate receptors [27]. According to Baraka
et al. study, proper doses of Zn could diminish seizures
by reducing inflammatory and pro-inflammatory factors
such as interleukin-1 β and oxidative stress in rats [28].
Furthermore, extracellular signaling effect of Zn exerts
via some post-synaptic receptors like protein-coupled
receptor 39. Activation of such receptors may increase
intracellular calcium release, resulting in upregulation ofpotassium-chloride (K+-Cl) cotransporters, increase of
K+-dependent Cl− efflux in the post-synaptic neurons,
promotion of GABA A receptor-mediated cell hyperpolarization, and excitotoxicity inhibition [28]. Thesemechanisms may explain the modulatory role of Zn in
the control of seizure attacks.
Moreover, Zn is a major component of the superoxidase dismutase, an antioxidant enzyme that detoxifies
the oxidative radicals which are responsible in neuronal

Page 5 of 7

membrane instability and epileptogenesis [3]. In accordance with our findings, Prasad et al. [16] compared
serum minerals in epileptic patients with and without
response to antiepileptic drugs. Their results showedsignificantly lower levels of serum Zn in non-responder
patients compared to the responder patients (10.38 ± 2.99
vs. 12.62 ± 3.30 µmol/L; p < 0.05); however, considering serum Ca, Mg, and Cu, the differences between thegroups were not statistically significant. Kheradmand
et al. [3] also showed Zn deficiency was significantly
more frequent among patients with DRE compared withpatients with controlled epilepsy (70% vs. 20%; p < 0.001).
In line with our finding, Elshorbagy et al. [29] confirmed
the role of Zn supplementation in the reduction of seizures among patients with idiopathic intractable epilepsy.
On the contrary to Zn levels, a significant difference was
not observed between the groups concerning serum Cu
concentrations (p = 0. 81). Inconsistent with our results,
Chakrabarty et al. [14] demonstrated no significant difference in serum Zn concentrations between the twogroups of patients with drug-refractory and well-controlled epilepsy (643 ± 149 vs. 607 ± 110; p = 0.13).
Based on the results, no significant differences wereobserved between the groups regarding serum Ca, Cu,
and Mg levels. Concerning the means of Vit D level, nodifference was also observed between the groups. Seasonal-related variables were not considered in the study
because the samples were collected over a long period
and the seasonal conditions were the same for bothgroups. Our finding may also associate with no notable seasonal variation in our geographic area, affecting
patients’ Vit D status [30]. On the other hand, evidence
has revealed the role of several factors (seasonal change,
duration of sunlight exposure, duration of UV exposure,physical activity, pigments of skin) on serum Vit D levels[30, 31].
According to the results of the present study, DRE
patients showed significantly earlier onset of disease
and longer treatment period compared with the wellcontrolled group. Compatible with our findings, otherinvestigations [32, 33] showed early onset of seizure asa significant risk factor for DRE; Karaoğlu et al. showed
the age at onset of seizure in DRE case was significantly
lower than drug-responsive subjects (1.85 vs. 4.92 years;
p < 0.001). Yilmaz et al. also revealed age of epilepsy
onset < 12 month in 54.5% of drug resistant and 28.4% of
drug responsive epilepsy patients (p < 0.001).
Comparing the frequency of developmental delay
between the groups, our results showed this complication was significantly more frequent among DRE
patients. Consistent to our results, Karaoğlu et al. [32]showed a significant correlation between motor andmental abnormalities with development of DRE in 200
epileptic children. The other study by Gavrilovic et al.

Tavasoli et al. BMC Pediatrics(2024) 24:518[34] demonstrated that the mean of cognitive score in
103 DRE patients was significantly lower than 52 drugresponsive-epilepsy cases (p < 0.001).
Compatible with other investigations [9, 35], the results
showed significantly more children in the DRE groupconsumed multiple-drug regimens compared to thepatients in the well-controlled group. Prescribing more
medications in this group of patients help to act against
more than one target-based epileptogenic mechanisms[36]. Evidence has confirmed that DRE patients use
three or more medications, excluding diazepam, while
drug-responsive-epilepsy patients receive less than threeantiepileptic drugs. DRE patients added or switchedalternative drugs 3.6 to 3.7 times more than their nonrefractory counterparts [35].
According to the results, we could not find any significant correlations between the duration of treatment
period with serum levels of Zn, Ca, Mg, Cu, and Vit D
in the studied groups. It seems several factors like prescribed drugs, consuming supplements, duration of disease, and treatment period may be involved factors [37].
In summary, the results showed early onset of disease
and risk of developmental delay in DRE patients. Moreover, lower serum Zn levels may be observed in DRE
compared with controlled epilepsy. Accordingly, monitoring of this trace element seems beneficial and should
be considered. On the other hand, it should be noticed
that the present study had several limitations regarding small sample size, and including few variables. For
instance, data on patients consuming different drugs
were insufficient to show possibly statistical correlations
between the drugs and serum elements levels. Although
all included patients were on a well-balanced diet consisting of vegetables, meat and/or dairy foods, which had
sufficient dietary diversity of micronutrients, the quantitative analyses regarding trace elements in their diet were
not performed. Additionally, this is a cross-sectional
study, and the causality cannot be confirmed. Designing
future investigations with a larger samples size and considering more variables like different demographic characteristics, life style, nutritional habits, seasonal factors,
types of neurodevelopmental abnormalities (in motor or
cognitive domains), para clinic findings, the history ofstatus epilepticus, neonatal, or febrile seizures, as well as
detailed data regarding consumed drugs and the rout of
usage could provide more informative data.

Conclusion
The results delineated that drug-resistant-epilepsy
patients had earlier onset of disease and were at higher
risk of neurodevelopmental delay compared with wellcontrolled epilepsy patients. A significant lower serum
levels of Zn were also observed in drug-resistant-epilepsy patients. This finding may suggest the role of Zn

Page 6 of 7

supplementation in help to better control of drug-resistant seizures, as well as, the importance of serum zincmonitoring in epileptic patients. Further investigations
are needed to determine the potential cut-off serum zinclevel for drug-resistant epilepsy. Furthermore, a succeeding study is suggested to measure trace elements levels
before and after antiepileptic treatment to show possible
relationship between trace elements levels and drugs.
Abbreviations
Cu	Copper
Zn	ZincMg	Magnesium
Ca	Calcium
Vit D	25-hydroxy vitamin D
DRE	Drug-resistant-epilepsy
Acknowledgements
This study was supported by Iran University of Medical Sciences. The authors
appreciate their support. The authors also thank to Dr. Zahra Farahani from thematernal, fetal, and neonatal Research Center of Tehran University of Medical
Sciences for her kind collaboration.
Author contributions
Dr. A. T. and Dr. L. A. carried out the design, coordinated the study, andparticipated in most of the experiments. MS. B.P. carried out analysis of data
and research. All authors have prepared the manuscript, read, and approved
the content of it.
Funding
This study was supported by the Iran University of Medical Sciences.
Data availability
The datasets related to our study are available from the corresponding author
upon reasonable request.

Declarations
Ethics approval and consent to participate
Ethics approval was obtained from the institutional review board of Iran
University of Medical Sciences according to the Helsinki declaration. Written
informed consent was obtained from the participants’ parents or legal
guardians of the minors included in the study.
Consent for publication
Written informed consent for publication of personal or clinical details was
obtained from the parents or legal guardians of any participant under the ageof 18.
Competing interests
The authors declare no competing interests.
Received: 9 April 2024 / Accepted: 24 July 2024

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