A meta‐analysis: Does vitamin D play a promising role in sleep disorders?

Abstract Background Sleep disorders, one of the most common problems in the general population, have been related to a series of harmful health consequences. Vitamin D appears to be associated with sleep disorders. However, the difference in vitamin D levels between sleep disorder subjects and people without a sleep disorder is unclear. Simultaneously, the influence of vitamin D replenishment on sleep disorders remains controversial. Methods PubMed, MEDLINE, Web of Science, and Cochrane Library were searched for literatures published until October 2019. Using a random effects model, a meta‐analysis was conducted to calculate the standard mean difference to evaluate the difference in vitamin D concentrations between sleep disorder subjects and normal people and the efficacy of vitamin D supplementation on sleep disorders. Results Our study found that the serum vitamin D levels in the sleep disorder subjects were lower than that in the normal people (SMD = −0.75 ng/ml, 95% CI = −0.93, −0.57 ng/ml). Moreover, the Pittsburgh Sleep Quality Index (PSQI)in the subjects with vitamin D supplementation was lower than that in the controls (SMD = −0.45, 95% CI = −0.76, −0.13). Conclusions Vitamin D could play a promising role in sleep disorders. More data are required to confirm the efficacy of vitamin D supplementation for improving sleep disorders.

leg dyskinesia, and restless legs syndrome, cause sleep deprivation (Tufik, Andersen, Bittencourt, & Mello, 2009). Sleep disorders have been related to a series of adverse health consequences, involving an elevated risk of hypertension, diabetes, and other chronic diseases (Institute of Medicine Committee on Sleep & Research, 2006;Riemann, 2009). Studies have shown that the prevalence of sleep disorders tends to rise with age. Almost 41% of elderly people have sleep disorders with insomnia (Tsou, 2013). Young people today also experience a number of sleep disorders, which may impact academic performance, health, and mood (Gaultney, 2010). Similarly, sleep problems are currently common in children, with approximately 25% have experienced sleep problems (McDonagh, Holmes, & Hsu, 2019).
As a fat-soluble vitamin, vitamin D not only plays a role in regulating bone homeostasis but also is involved in the presentation and severity of sleep disorders Kulie, Groff, Redmer, Hounshell, & Schrager, 2010). Vitamin D target neurons are supposed to be participated in sleep regulation, and its receptors have been found in the hypothalamus and other brain regions, which are related to the regulation of sleep-wake cycle (Gominak & Stumpf, 2012;Saper, Scammell, & Lu, 2005). Previous studies have shown that abnormally low concentrations of vitamin D are general in patients seeking sleep medication and may be the causes or contributors to sleep disorder (McCarty et al., 2014). Furthermore, Majid's study has shown that the vitamin D supplementation improves sleep quality and raises sleep duration in subjects with sleep disorders (Majid, Ahmad, Bizhan, Hosein, & Mohammad, 2018). However, the results of other studies are not consistent with it (Gunduz et al., 2016;Shiue, 2013). The dispute remains existed between vitamin D and sleep disorders. Therefore, a meta-analysis was performed evaluating the difference in vitamin D between sleep disorder people and normal people. Additionally, the meta-analysis also evaluated all related randomized control trials (RCTs) with a focus on the influence of vitamin D supplementation on sleep disorders.

| Sources and methods of data retrieval
Literatures of PubMed, MEDLINE, Web of Science, and Cochrane Library were searched from these database inceptions until October 2019. We analyzed differences in vitamin D concentrations between people with sleep disorders and normal subjects. Meanwhile, sleep quality can be evaluated by the Pittsburgh Sleep Quality Index (PSQI) questionnaire, which consists of 19 items involving seven-factor scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping pills, and daytime dysfunction. And higher scores indicate poorer sleep quality (Buysse, Reynolds, Monk, Berman, & Kupfer, 1989). Therefore, the change in the PSQI score in response to supplementation with vitamin D was also evaluated. The following terms were used for the literature search: vitamin D, cholecalciferol, ergocalciferol, sleep quality, sleep disorders, and Pittsburgh Sleep Quality Index (PSQI).
The search strategy performed is detailed in Table 1. The location, assay method, sleep disorder types, study types, intervention dose and time of vitamin D, and other related factors were also evaluated.

| Inclusion criteria
The inclusion criteria were as follows: (a

| Data abstraction
All included literatures were assessed, and the following data were extracted: first author, nationality, publication year, numbers, mean age, and gender of case/supplementation groups and controls. We also extracted data on the assay method of vitamin D, sleep disorder types, and vitamin D levels in the subjects with sleep disorders and controls.
Moreover, the intervention time and dose and the PSQI score in the vitamin D supplementation groups and controls were also extracted.

| Statistical analysis
Statistical analysis was performed using the statistical software  TA B L E 2 (Continued) effects model. Cochran's Q statistic and the I 2 statistic were used to evaluate the statistical heterogeneity (Kochran, 1954). p < .05 was defined significant for heterogeneity (Higgins, Thompson, Deeks, & Altman, 2003

| Differences in vitamin D concentrations between sleep disorders and controls
We performed a meta-analysis of the serum vitamin D con-  High quality: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.
Abbreviations: CI, confidence interval; SMD, standard mean deviation. a Results for vitamin D levels of subjects with sleep disorders compared with controls.
b Upgraded by one level due to all the results of the included studies were almost identical(subjects with sleep disorders had lower vitamin D levels). c Upgraded by one level due to sleep disorders were associated with vitamin D levels(The more serious the sleep disorder, the lower the vitamin D levels).

TA B L E 4 The Summary of Findings (SoF) with GRADE system (vitamin D levels)
the average serum vitamin D concentrations were lower than those of the controls ( Figure S1). Simultaneously, a subgroup analysis was conducted based on the assay method, and the studies were separated into three methods: CI, EI, and other. The average serum vitamin D concentrations were lower than those of the controls in all three groups ( Figure S2). The main types of sleep disorders in the included studies were OSAS (mild), OSAS (moderate), OSAS (severe), OSAS (unclassified), restless legs syndrome, and other. The average serum vitamin D concentrations were lower in all of the groups compared to those of the controls except for the OSAS (mild) group ( Figure S3). Moreover, we separated the studies into two groups (case-control study and cross-sectional study) based on the included study types. For the two groups, statistically significant differences with the controls were observed ( Figure S4).

| Effect of vitamin D supplementation on sleep disorders
For the 4 papers evaluating the change in the PSQI score, 2 studies were performed in Asia (Ghaderi et al., 2017;Majid et al., 2018), and the remaining studies (Huang et al., 2013;Mason et al., 2016) (n = 2) F I G U R E 2 Forest plot of the vitamin D concentration in the sleep disorders vs. control groups were conducted in America. The intervention time was ≤2 months in 1 paper (Majid et al., 2018) and >2 months in 3 studies (Ghaderi et al., 2017;Huang et al., 2013;Mason et al., 2016). The serum vitamin D concentrations after intervention were sufficient (Majid et al., 2018;Mason et al., 2016) in 2 papers and insufficient in the others (Ghaderi et al., 2017;Huang et al., 2013). The basic situation of the subjects is shown in Table 3 and Table S2.
The risk of bias within individual studies for evaluating the change in the PSQI score is shown in Figure 3 and Table S2. All 4 studies were randomized and had complete outcome data (Ghaderi et al., 2017;Huang et al., 2013;Majid et al., 2018;Mason et al., 2016). Additionally, 3 trials might have controlled the reporting bias via registering in a clinical trial registry (Ghaderi et al., 2017;Majid et al., 2018;Mason et al., 2016). The methods of allocation concealment and blinding of participants and study personnel were properly described in 3 studies (Ghaderi et al., 2017;Majid et al., 2018;Mason et al., 2016). Two studies conducted the methods of blinding of the outcome (Majid et al., 2018;Mason et al., 2016). Moreover, no commercial company was involved and no conflict of interest existed in all the studies, so the studies were considered free of potential bias (Ghaderi et al., 2017;Huang et al., 2013;Majid et al., 2018;Mason et al., 2016). Similarly, the GRADE system was conducted to determine the quality of evidence (Table 6).
We Moreover, the subgroup analysis was conducted based on the region, intervention time, and serum vitamin D concentration after intervention. Details are shown in Table 7. Studies were separated into two regions based on the geographical study area. For the Asia group, the PSQI was lower than that of the controls. However, the researches in America did not indicate differences in the PSQI between the supplementation subjects and control subjects ( Figure   S5). Simultaneously, the studies were separated into two groups based on the intervention time: ≤2 months and >2 months. The PSQI was lower than that of the controls in the ≤2 months' group, while the studies in the >2 months' group did not indicate differences between the supplementation and control subjects ( Figure   S6). Additionally, all subjects were separated into two groups based on their serum vitamin D levels after intervention ( Figure S7).

| D ISCUSS I ON
Sleep disorders bring a heavy burden on the healthcare system. The personal average annual medical expense may increase by $2000 due to chronic sleep disorders (Xie et al., 2017). It has been reported that vitamin D deficiency is related to a higher risk of sleep disorders  . However, it is controversial whether supplementation with vitamin D is truly beneficial to improving sleep quality.
This meta-analysis found that vitamin D concentrations in sleep disorders were significantly lower than those in normal controls. In addition, vitamin D supplementation can effectively improve sleep quality. Although the specific mechanism of the role of vitamin D on sleep disorders has not yet been illustrated, some potential mechanisms have been considered. Low concentrations of vitamin D can disrupt sleep by creating and developing myopathic pain (Lee, Greenfield, & Campbell, 2009). Meanwhile, as central sleep regulators, inflammatory mediators (including TNF-α and IL-1) and prostaglandin D2 indicated negative correlation with vitamin D levels.
Inflammatory mediators and prostaglandin D2 were increased in cases of vitamin D deficiency, thus leading to sleep disorders, including OSAS. Therefore, vitamin D supplementation could effectively improve sleep quality (Barcelo et al., 2007;Bellia et al., 2013;Khoo et al., 2011).
When we analyzed the outcomes of the vitamin D concentrations and the PSQI score in the included papers, a high level of heterogeneity was found in both outcomes, so we conducted a subgroup analysis to determine the source of heterogeneity. The subgroup analysis of the region indicated that the heterogeneity was decreased in both results. Therefore, we concluded that different regions could be the source of heterogeneity in the included studies. In addition, the PSQI was significantly lower in the vitamin D supplementation subjects than in the control subjects for the Asia group, while there was no significant difference for the America group. Several decades ago, as one of the industrialized countries, America had undertaken fortification of milk and other food products with vitamin D (Marwaha & Dabas, 2019). Therefore, there may be other factors or diseases that cause sleep disorders in Americans.
In contrast, in Asian countries, urbanization is likely to be related to lifestyle changes, lower physical activity, an increase in indoor living, and lack of sun exposure, thus leading to an increase in vitamin D deficiency (Mithal, Bansal, Kyer, & Ebeling, 2014). Additionally, in different areas of Asia, nutritional status and sunlight exposure are diversity; hence, the vitamin D supplementation may be more necessary for Asian people (Lau et al., 2006). Furthermore, due to Turkey's special geographical location (across Eurasia), we took it as a subgroup when we analyzed the differences in vitamin D concentrations between the sleep disorders and control subjects by subgroup analysis based on region. We considered the combination of east and F I G U R E 3 Risk of within-study bias (RCT) High quality: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.
Abbreviations: CI, confidence interval; RCT, randomized controlled trial; SMD, standard mean deviation. a All subjects were followed up range 8 weeks to 12 months.
b Results for PSQI score of treatments compared with controls (including PSQI score of postsupplementation compared with presupplementation in the treatments).

TA B L E 6
The Summary of Findings (SoF) with GRADE system (PSQI score) F I G U R E 4 Forest plot of the PSQI in the vitamin D supplementation vs. control groups west in various fields, and the complexity of race may be the reason for the high heterogeneity in the Eurasia group.
Comparing the subjects with sleep disorders with the control group at the vitamin D level, the results indicated that OSAS severity may correlate with vitamin D levels. As one of the major sleep disorders, the more serious the disease is, the lower the level of vitamin D.
The result is similar to the K's study (Archontogeorgis, Nena, Papanas, Zissimopoulos, et al., 2018). Although the mechanism of vitamin D insufficiency or deficiency in OSAS is inadequately understood, several possible pathogeneses indicated that they may affect each other.
OSAS subjects are probably to have excessive daytime sleepiness or obesity, thus reducing the outdoor activities and sunlight exposure, leading to the decrease in vitamin D synthesis (Igelstrom, Emtner, Lindberg, & Asenlof, 2013 According to the results of the vitamin D supplementation, the studies in >2 months did not demonstrate differences between the supplementation and control subjects. The reason may be that the guidelines for vitamin D supplementation in people with sleep disorders were lacking. We could only refer to the existing supplemental guidelines, which suggested 50,000 IU once a week for 8 weeks for clinical management of vitamin D deficiency in adults (Cesareo et al., 2018) (since only one group in the included studies was 50,000 IU/week, we were unable to perform the subgroup analysis according to intervention dose). Therefore, considering the small sample size, more RCTs are required to assess the relationship be-

| CON CLUS IONS
Vitamin D could play a promising role in sleep disorders. Considering several limitations found in this meta-analysis, more data from RCTs are required to confirm the efficacy of vitamin D supplementation for improving sleep disorders.

CO N FLI C T O F I NTE R E S T
The authors declare that they have no competing interests.

AUTH O R S ' CO NTR I B UTI O N S
BL, WC, and SY made the study design; SY, ZT, HZ, and YP conducted the study; SY, ZT, CW, and NY analyzed the data and wrote the manuscript; SY, ZT, YG, and HW participated amending the manuscript. SY and ZT contributed equally to this work. All authors agreed with the final version of the manuscript.

S TU D I E S I N VO LV I N G H U M A N S U BJ EC TS
Although the study involves human subjects, it is a meta-analysis based on evaluating published research data. Therefore, no ethical issues are involved.