Introduction
Headache is among the most common health problems in children and adolescents, yet it is often underrecognized as a medical concern. An epidemiological survey involving 9,000 students found that over one-third of children older than 7 years and one-half older than 15 years reported experiencing headaches [1,2]. Recent meta-analytic findings indicate a 62% prevalence of primary headaches among children and adolescents. Prevalence estimates by subtype are 8% for migraine without aura, 3% for migraine with aura, and 17% for tension-type headache [3].
It is crucial to differentiate primary headaches from secondary headaches caused by acute infections, life-threatening cerebral hemorrhages, or brain tumors, as the latter may require distinct management approaches. Treatment for primary headaches typically includes lifestyle modifications, acute symptomatic relief, and preventive therapies [4-6].
Basic tests such as complete blood count, thyroid function tests, and measurement of vitamin D levels are commonly performed to identify treatable causes of pediatric headaches. However, plasma folate levels are often overlooked in routine evaluations. Recent adult studies have shown that folic acid supplementation effectively reduces headache frequency and severity in patients with low folate levels, suggesting that folic acid may help alleviate headache symptoms by reducing homocysteine levels [7-10].
During critical growth phases in children, vitamin B plays an essential role as a cofactor in maintaining homocysteine homeostasis through the methylation cycle [8]. Folic acid, as a vitamin B rather than a pharmacological agent like topiramate or flunarizine, is generally easier to explain to patients and caregivers. This often results in improved treatment adherence and fewer adverse effects compared to other preventive medications [11].
Therefore, in this study, we reviewed cases of pediatric patients diagnosed with primary headache at the Department of Pediatrics and Adolescents, National Health Insurance Service Ilsan Hospital. We analyzed whether plasma folate levels were associated with headache frequency and whether folic acid supplementation in children with low folate levels led to reduced headache frequency and pain severity.
Materials and Methods
1. Study population
In this retrospective study, we analyzed pediatric patients aged 6 to 18 years who visited the pediatric outpatient department at National Health Insurance Service Ilsan Hospital for headache evaluation between January 2021 and December 2024. Among children diagnosed with primary headache, only those with plasma folate levels below 4.0 ng/mL were included. Patients with concurrent iron deficiency anemia requiring iron supplementation were excluded. Diagnoses of primary and secondary headaches, including migraine and tension-type headache, were based on the International Classification of Headache Disorders (ICHD-3). Patients who had abnormal findings on brain magnetic resonance imaging (MRI) or electroencephalography and were diagnosed with secondary headache were excluded from the study.
2. Data collection
The medical records of enrolled pediatric patients were retrospectively reviewed to collect data on age, sex, age at initial visit to National Health Insurance Service Ilsan Hospital, history of neurological disorders, family history of headache, and levels of anxiety and depression, which were assessed using the Revised Children’s Manifest Anxiety Scale (RCMAS) and the Children’s Depression Inventory (CDI), respectively. Time of headache onset and location of headache were examined, and pain severity was quantified using a visual analog scale (VAS). Additional data were collected regarding headache patterns and the presence and characteristics of aura.
Hematologic evaluations related to headaches included complete blood count with hemoglobin level, thyroid function tests, screening for iron deficiency anemia, and measurement of plasma folate levels. Physical examinations included measurements of body weight, height, and head circumference. Percentiles were calculated based on age-matched reference values to determine if the measurements fell below the 3rd percentile or above the 97th percentile. If head circumference exceeded the 97th percentile, brain MRI was performed to rule out structural abnormalities. For patients with visual aura, electroencephalography was conducted to investigate potential organic causes. Blood pressure was remeasured if initially found to exceed the 97th percentile, and patients with persistently elevated blood pressure were excluded. Patients whose primary concern was headache but who were determined during history-taking to primarily have dizziness or syncope were also excluded.
Patients with plasma folate levels ≤4.0 ng/mL were prescribed oral folic acid at a dose of 1.0 mg. Two months after supplementation, changes in headache frequency and VAS pain scores were assessed at the outpatient clinic. The primary outcome was defined as a reduction in headache frequency or pain intensity following folic acid supplementation. Patients with a ≥50% reduction in either headache frequency or pain severity were classified as responders, while those who did not meet this criterion were considered non-responders. Statistical analyses were conducted within each group to determine whether changes in headache frequency or pain severity were significant.
This study was approved by the Institutional Review Board of the National Health Insurance Service Ilsan Hospital (IRB No. NHMC 2021-09-012). Written informed consent by the patients was waived due to a retrospective nature of our study.
3. Statistical analysis
Collected data were analyzed using SPSS version 26 (IBM Corp., Armonk, NY, USA). The chi-square test was used to evaluate associations between categorical variables and recurrent headaches.
To compare means between the migraine and tension-type headache groups, an independent samples t-test was used for normally distributed data, while the Mann-Whitney U test was used for non-normally distributed data. Frequencies were compared between the two groups using either the chi-square test or the Fisher exact test.
Within each group, the Wilcoxon signed-rank test was used to assess changes in headache frequency and severity following treatment. A P value of less than 0.05 was considered to indicate statistical significance for all analyses.
Results
1. Baseline characteristics
From January 2021 to November 2024, a total of 82 pediatric patients under the age of 18 presenting with a chief concern of headache were found to have plasma folate levels below 4.0 ng/mL. Following 2 months of folic acid supplementation, 60 patients (73.2%) were classified as responders, displaying a reduction of ≥50% in headache intensity or frequency, whereas 22 patients (26.8%) were considered non-responders.
The median age was 15.7 years (interquartile range [IQR], 14.0 to 16.5) in the responder group and 14.7 years (IQR, 12.6 to 17.1) in the non-responder group, with no significant difference between groups (P=0.65). Gender distribution did not differ significantly between groups (P=0.18), and girls accounted for 56.1% of the total patient population. The frequency and intensity of headache were not significantly different between the responder and non-responder groups. Both groups had poorly controlled headaches, with a median frequency of 5.0 days/week and a mean VAS score of 6.2.
Folate levels did not significantly differ between responders (mean, 4.10 ng/mL) and non-responders (mean, 3.99 ng/mL; P=0.42). Additionally, no significant differences were observed between groups in RCMAS and CDI scores, which reflect anxiety and depression levels (Table 1).
2. Effect of folic acid supplementation in responder and non-responder groups
Among patients with low folate levels, over 2 months of folic acid supplementation, headache intensity in the responder group decreased significantly from a median of 6.0 (IQR, 5.0 to 7.0) to 1.5 (IQR, 0 to 2.9; P<0.001) (Fig. 1A). Conversely, headache intensity in the non-responder group displayed no significant change, with a median of 5.0 (IQR, 4.8 to 8.0) after treatment (P=0.07) (Fig. 1B).
Similarly, headache frequency significantly decreased in the responder group from a median of 6.0 days/week (IQR, 3.5 to 7.0) to 0.5 days/week (IQR, 0 to 2.0; P<0.001) (Fig. 2A). In contrast, the non-responder group showed no significant change, with a post-treatment median of 5.0 days/week (IQR, 1.8 to 7.0; P=0.08) (Fig. 2B).
Plasma folate levels were measured after 2 months of treatment in 41 patients—30 responders and 11 non-responders. Post-treatment folate levels showed no significant differences between groups, similar to pretreatment levels. Folate levels increased by approximately 12 to 16.2±6.6 ng/mL in responders (Fig. 3A) and by about 7 to 11.2±3.6 ng/mL in non-responders (Fig. 3B).
3. Comparison of treatment response by headache type
Within the responder group, 40 patients (66.7%) were diagnosed with migraine. Of the 24 patients who had migraine with aura, 22 belonged to the responder group. Eighteen of the 25 patients with migraine without aura also responded to folic acid supplementation, although the difference from the non-responder group was not statistically significant. In contrast, tension-type headache was significantly more prevalent in the non-responder group (13 patients, 59.1%) than in the responder group (P=0.004) (Table 2).
Discussion
Headache is one of the most frequently reported neurological symptoms in children and adolescents, and its prevalence increases with age [1,2]. Previous studies have estimated that primary headaches affect 10% to 20% of school-aged children and more than 50% of individuals under 20 years old [12]. Among headaches, migraine is a major subtype, typically characterized by unilateral pain and often associated with disabling symptoms. Although the precise pathophysiology of migraine remains unclear, genetic predisposition appears to play a meaningful role. Proposed mechanisms include neuroinflammatory processes, vascular dysregulation, and central sensitization [13]. Additionally, hormonal influences—particularly involving estrogen and progesterone—have been implicated in the higher prevalence of migraine among women. This hormonal relationship may also explain the increased frequency of migraine episodes observed during menstruation in some female patients [14].
Management of childhood migraines should begin with avoidance of known triggers and alleviation of academic or psychosocial stressors. Dietary modifications, such as reducing the intake of caffeine-containing beverages, are also recommended to improve headache control. If lifestyle modifications and acute symptomatic treatment fail to sufficiently reduce headache frequency or severity, preventive pharmacological therapy should be considered [15].
Lea et al. [9] demonstrated that lowering plasma homocysteine levels through vitamin supplementation—specifically, 25 mg of vitamin B6 (pyridoxine), 2 mg of vitamin B9 (folic acid), and 400 mcg of vitamin B12 (cyanocobalamin)—significantly reduced migraine burden in adult patients. In their study, the median frequency of headaches decreased from 6 to 1.8 days/week, and the median pain intensity was reduced from a VAS score of 6.5 to 4.5 [9].
Compared with previous studies in adults, folic acid supplementation in this pediatric study appeared to more effectively reduce headache frequency. Notably, children exhibited an average increase of approximately 10 ng/mL in plasma folate levels after just 2 months of supplementation with 1.0 mg of folic acid, which is greater than typically observed in adult populations.
A study by Menon et al. [11] demonstrated that patients with methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) gene variants exhibited greater responsiveness to folic acid treatment, with a corresponding reduction in homocysteine levels, supporting the therapeutic rationale for folate supplementation [11,16]. However, in the present study, although folate levels increased in the non-responder group after treatment, no clinical improvement was observed. This may be attributable to the fact that approximately 75% of patients in the non-responder group were diagnosed with tension-type headaches. Unlike migraines, tension-type headaches, which are linked to psychosocial and environmental factors, often display limited responsiveness to folic acid supplementation [17].
In this study, all pediatric patients received 1 mg of folic acid daily. However, Menon et al. [11] reported that a 1 mg dose was less effective than a 2 mg dose in adult patients, suggesting that dosage may influence treatment outcomes. Although homocysteine levels must be measured to determine whether the administered dose is appropriate and biochemically effective, this study was limited by an inability to assess homocysteine concentrations. Nevertheless, follow-up testing conducted 3 months after treatment revealed an increase of ≥10 ng/mL in plasma folate levels in most patients, indicating a significant biological response to supplementation.
These findings may reflect differences in endogenous responses to folic acid supplementation, particularly in patients with MTHFR or MTRR gene variants. Folic acid deficiency can result from various factors, including inadequate dietary intake, increased physiological demands, intestinal malabsorption, and the use of medications that interfere with folate metabolism. The recommended daily folate intake for adolescents is 400 μg (0.4 mg as folic acid), whereas higher amounts—up to 600 μg (0.6 mg as folic acid)—are required during pregnancy or lactation. Total body folate stores are estimated to be approximately 5 mg [18]. Evidence suggests that folic acid metabolism differs from that of naturally occurring folates, and under certain circumstances, excessive folic acid intake may have toxic effects [19].
This study had several limitations. The retrospective analysis was conducted at a single institution with a limited patient population. Additionally, all patients received a fixed dose of 1 mg of folic acid. However, Menon et al. [11] reported that a 1 mg dose was less effective than a 2 mg dose in adult patients, raising questions regarding the adequacy of a 1 mg dose in children. Measurement of homocysteine levels would have provided key evidence regarding the appropriateness of the dosage; however, this was not performed in the present study.
In conclusion, this study demonstrated that folic acid supplementation effectively reduced headache severity and frequency in children with low folate levels, at least in the short term. These findings suggest that evaluating folate levels may be warranted as part of the initial assessment in children presenting with headaches.
PDF Links
PubReader
ePub Link
XML Download
Full text via DOI
Cited
