The prevalence of epilepsy in the pediatric age group in developing countries can reach up to ten cases per 1000 children.1 Treatment with antiepileptic drugs is necessary for a long period in most patients2 and is associated with several adverse effects, such as gingival hyperplasia, gastrointestinal disorders, osteoporosis, osteomalacia, bone marrow toxicity, teratogenicity, hepatotoxicity, and nephrotoxicity, as well as endocrine, neurological, psychiatric, and dermatological disorders.3

Regarding vitamin D deficiency, a population-based study estimates a prevalence of 15% in the general pediatric population, with data referring to the United States.4 Considering the subjects using antiepileptic drugs, there is evidence that supports a prevalence above 70% in the pediatric population.5 Subclinical disease is characterized by biochemical abnormalities (reduced serum levels of calcium and 25-hydrovitamin D and high parathyroid hormone levels), reduction in bone mineral density and changes in bone biopsy findings.6,7 In a study conducted with members of the board of directors of the American Academy of Neurology, it was found that around 40% of pediatric neurologists routinely screen for bone mineral disease, 40% prescribe calcium and vitamin D to patients who already have the disease, and only 9% prophylactically prescribe calcium and vitamin D to subjects using antiepileptic drugs.7

The association between antiepileptic drug use and bone mineral disease was first reported in 1960.8 Since then, several studies have been performed aiming to understand the effect of antiepileptic drugs on bone metabolism, the factors that corroborate bone disease in individuals with epilepsy, and the real need for treatment and prevention in these patients.9–12

Taking into account the classification of antiepileptic drugs as inducers and non-inducers of cytochrome P450 (CYP450) enzyme system, some studies support the idea that the use of inducers is related to higher levels of vitamin D deficiency,12,13 since they can accelerate the hepatic metabolism of vitamin D, with a consequent reduction in its serum level.5

The current meta-analysis aims to measure the prevalence of vitamin D deficiency (measured through 25-hydroxyvitamin D) in pediatric patients using antiepileptic drugs, as well as to verify the prevalence of deficiency in subgroups, considering the study design, antiepileptic drugs used, and patients exclusively with epilepsy (without motor impairment).

The literature search, study selection based on title and abstract, and data extraction were carried out independently by two trained reviewers. A senior author was consulted in cases of disagreement. In case of duplicate articles, only one was considered. The report of this meta-analysis followed the recommendations proposed for the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines14 and is registered on the PROSPERO Platform (PROSPERO, University of York, England) under numberCRD42020143322.

The flowchart showing the search results and selection details is depicted in Fig. 1.17 During the search, 748 articles were found, of which 29 were relevant to the objectives of this study (Table 1).18–39 A total of 2368 children were included.

Figure 1.

Flowchart with the search results and selection details.

Adapted from Moher et al.17

(0.44MB).

The studies were carried out in 17 different countries, most of them located in the northern hemisphere. Turkey and India were the countries with the most publications. Regarding the cutoff point used to define 25-hydroxyvitamin D deficiency, they ranged from 10 to 20ng/mL, with the value of 20ng/mL being the most frequently used (13 studies).

Prevalenceof25-hydroxyvitamin D deficiency

Twenty-nine studies reported data to calculate the prevalence of 25-hydroxyvitamin D deficiency. The proportion of patients using antiepileptic drugs who developed deficiency in relation to the total number of patients was 0.32 (95% CI=0.25–0.41; I2=92%, p<0.01; Fig. 2). A funnel plot analysis showed the presence of publication bias.

Figure 2.

Forest plot of the total study sample and the proportion of 25-hydroxyvitamin D deficiency observed.

(0.59MB).

This meta-analysis summarized the data from 29 studies that assessed 25-hydroxyvitamin D deficiency in pediatric patients using antiepileptic drugs, comprising a total of 2368 patients. Approximately 760 had vitamin D deficiency at the time of assessment – a prevalence of 32%. This result is consistent with what the medical literature has shown for some decades, that the use of antiepileptic drugs may result in 25-hydroxyvitamin D deficiency and consequent worsening of bone health in patients with epilepsy.8,40

It is known that sun exposure and diet are some of the main factors involved in the metabolism and plasma concentrations of 25-hydroxyvitamin D. Therefore, a higher prevalence of 25-hydroxyvitamin D deficiency is expected in countries located at higher latitudes41 and in places with a diet low in vitamin D2 and D3.42 Taking into account that Turkey was the country that generated the most studies for this review, a reference for the 25-hydroxyvitamin D value in that population was sought. Hocaoglu-emre et al.43 evaluated a sample of 640 children living in Istanbul (Turkey) and found a mean 25-hydroxyvitamin D value of 25.95ng/mL and a deficiency prevalence of 5.6%, considering values <12ng/mL. This information suggests that the prevalence found in this meta-analysis may actually be related to the use of antiepileptic drugs.

Conditions that determine motor impairment, such as cerebral palsy, are also independently associated with bone disease.8 Aiming to exclude a possible confounding factor, a meta-analysis of the subgroup of patients exclusively with epilepsy was performed, i.e., those without motor disabilities. Unlike what some studies in the literature previously showed,28,32 the subgroup analysis showed no difference in the prevalence of 25-hydroxyvitamin D deficiency in relation to that performed for the total sample of studies. The fact that most patients included in the total analysis had only epilepsy contributed to this finding.

Another factor reported as a risk for 25-hydroxyvitamin D deficiency and worsening bone health in these patients is the use of hepatic metabolism-inducing antiepileptic drugs through CYP450.5,12,13 Therefore, an assessment of the prevalence of vitamin D deficiency was also carried out according to the subgroups related to the profile of the antiepileptic drugs used. The subgroup of patients who used antiepileptic drugs that were inducersshowed a higher prevalence of 25-hydroxyvitamin D (33%) compared to the subgroup that used antiepileptic drugs that were non-inducers (24%) and the subgroup that used antiepileptic drugs that were not metabolized through this system (25%).

Antiepileptic drugs can also be divided into potent (phenobarbital, phenytoin, and carbamazepine) or weak inducers (topiramate at doses above 200mg/day and oxcarbazepine)44; however, this subanalysis was not conducted in this study. It is likely that for each antiepileptic drug there is more than one mechanism responsible for its effect on bone metabolism,45 as well as that for each subject there is an individual response to the antiepileptic drug used, which is genetically determined.46

Considering the design of the articles included, all were observational studies. It is known that meta-analyses of observational studies have particular characteristics due to inherent biases and different study designs.14 In an attempt to make the analysis more homogeneous, sub-analyses were performed according to the type of study. In the analysis of the cohort studies, there was a prevalence of 25-hydroxyvitamin D deficiency of 52% and slightly less heterogeneity among the studies in comparison with the analysis of the cross-sectional studies, which maintained values similar to those observed in the evaluation in the total sample of the studies.

Regarding the analysis of the prevalence of 25-hydroxyvitamin D, disregarding the studies that showed no patients with 25-hydroxyvitamin D deficiency, it was observed that there was no difference in the value related to the heterogeneity when compared to the total sample. The possible explanations found for the lack of patients with deficiency in these studies were as follows: Rauchenzauner et al.22 included only monotherapy patients with non-enzyme-inducing antiepileptic drugs or minimally enzyme-inducing antiepileptic drugs; Krishnamoorthy et al.21 and Vera et al.29 did not disclose the cutoff point used for 25-hydroxyvitamin D deficiency and their studies have a small sample size; and finally, Razazizan et al.10 characterized their sample as monotherapy patients, who had normal physical activity and were adequately exposed to sunlight.

Finally, it is emphasized that the main innovation of this research was the outcome used. Previous meta-analyses used the bone mineral density outcome or considered the 25-hydroxyvitamin D variation with the use of the antiepileptic drug, which, despite being a significant data point, does not always result in clinical significance.8,47,48

Vitamin D deficiency and bone disease are neglected clinical situations in the context of long-term use of antiepileptic drugs in childhood. It can be observed that, even though there is a consistent pathophysiological basis for changes in the metabolism of 25-hydroxyvitamin D due to the use of medication, the data evidenced in this meta-analysis do not reliably indicate the existence of a related deficiency. However, as it is a complex, multifactorial disease, it is believed that efforts are still needed toward a better understanding of possible related factors in the process, as well as the standardization of vitamin D deficiency assessment parameters in the studies.

Taking into account the deleterious effects of vitamin D deficiency on bone health and, consequently, on the quality of life of these individuals, it is suggested to include the monitoring of 25-hydroxyvitamin D levels, supplementation with cholecalciferol, and treatment of the deficiency in25-hydroxyvitamin D when it exists. This approach is in line with the principle of not only treating epileptic seizures, but patients with epilepsy, who sometimes have motor impairments, are rarely exposed to sunlight, and do not consume a sufficient daily intake of vitamins D2 and D3. It is also suggested to consider patients using antiepileptic drugs that are cytochrome P450inducers as the group most at risk for developing vitamin D deficiency.

The authors declare no conflicts of interest.