Keywords
autism spectrum disorder - melatonin - children - meta-analysis
Introduction
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with a prevalence
of approximately 1.7% in the general population.[1] ASD is mainly manifested as a language disorder, social disorder, and stereotyped
interest orientation and belongs to a subtype of pervasive developmental disorder.[2] Studies have shown that children with ASD are more likely to have sleep problems
than children without ASD (11–37%), with a prevalence ranging from 50 to 80%.[3]
[4]
[5] Sleep disturbance is often described as onset of insomnia or difficulty initiating
and maintaining sleep.[6] The severity and frequency of insomnia are associated with higher levels of maternal
stress, negative attitudes toward children, and increased rates of behavioral problems
and autism symptoms in children.[7] Therefore, effective interventions are required for the treatment of insomnia.
Melatonin, also known as the pineal hormone, is an indole hormone secreted by the
pineal gland and plays an important role in regulating the circadian rhythm of the
body.[8] Evidence suggests that sleep disturbances in children with ASD are associated with
a disturbed melatonin secretion.[9]
[10] As a result, some studies have recommended the use of melatonin to treat sleep problems
in children with neurodevelopmental disorders. However, due to the results of different
studies, conclusions regarding the efficacy of melatonin are varied. Therefore, this
study explored the efficacy of melatonin in the treatment of insomnia in children
with ASD through a meta-analysis to provide a clinical reference.
Methods
The Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) guidelines
were used to conduct the meta-analysis ([Supplementary Table S1], available in the online version only).
Literature Search Strategy
A systematic literature search was conducted using PubMed, Embase, and Web of Science
databases. The search strategies were as follows: “autism spectrum disorder,” “ASD,”
“Autistic Disorder,” “melatonin,” “Rozerem,” etc. The retrieval time is April 20,
2022, and the language limit is English. In addition, this study also conducted a
manual search of the paper version of the literature and screened the relevant reviews
and references of the included literature, hoping to obtain more studies that can
be used for meta-analysis. The detailed search strategy is described in [Supplementary Material 1] (available in the online version only).
Inclusion and Exclusion Criteria
The inclusion criteria were as follows: 1. The study was a randomized controlled study;
2. the subjects were children diagnosed with ASD; 3. melatonin was used in the experimental
group and placebo in the control group for the intervention; and 4. at least with
one reported outcome (total sleep time, sleep onset latency, and number of awakenings).
The exclusion criteria were as follows: (1) non-authoritative studies such as reviews,
conference abstracts, and reviews; (2) studies that did not use melatonin; and (3)
repeated publications or the same data used in multiple articles, only included studies
with the most complete information, and the rest were excluded.
Study Selection and Data Extraction
Two investigators (X.M. and L.F.) independently screened the literature according
to the inclusion and exclusion criteria. After identifying the literature included
in the analysis, data extraction was performed independently according to a pre-designed
table. The extracted information included the first author, year of publication, basic
characteristics of the research participants (sample size, age, etc.), intervention
measures, intervention time, and study outcomes. After both have completed the above
data extraction work, they exchange and review the extraction forms.
The quality of the literature was assessed using Cochrane quality assessment criteria.
Judgments were made independently by two investigators, and if disagreements occurred,
a consensus was reached through discussion.
Statistical Analysis
Statistical analysis was performed using the Stata 15.0 software. A generic inverse
variance method was used to calculate the estimated pooled standardized mean differences
(SMD) with 95% confidence interval (CI) for the outcomes. I
2 statistic was used to assess the heterogeneity of the included RCTs. If I
2 <50%, data were analyzed using a fixed-effects model; otherwise, data were analyzed
using a random-effects model. Publication bias was quantitatively assessed using Egger's
test.
Results
A flow chart of literature screening is shown in [Fig. 1]. A total of 988 articles were searched in the PubMed, Embase, and Web of Science
databases. After excluding duplicate studies, a total of 626 articles remained. After
browsing titles and abstracts, 613 papers that did not meet the inclusion criteria
were excluded. Nine of the remaining 13 papers were removed after reading the full
text. Finally, four studies were included in the meta-analysis.[11]
[12]
[13]
[14] The results of the quality evaluation of the included studies are shown in [Fig. 2].
Fig. 1 Flow diagram of the systematic review selection process.
Fig. 2 Risk of bias (RoB) summary: review authors' judgments about each RoB item for each
included study.
Overall, the studies involved 238 children aged 2 to 17.5 years. Children receive
melatonin at doses between 1 and 10 mg. Treatment duration is 4 to 13 weeks. [Table 1] provides an overview of the baseline data, treatment drugs, and outcome indicators
reported in the literature.
Table 1
Basic information included in the study
|
Study
|
Sample size
|
Age (Year)
|
Interventions
|
Intervention time
|
Sleep diary or actigraph record
|
Outcomes
|
|
Garstang and Wallis 2006
|
11
|
4–16 y
|
5 mg melatonin
|
4 wk
|
Sleep diary
|
Total sleep time, sleep onset latency, number of awakenings
|
|
Wright et al 2011
|
22
|
3–16 y
|
2–10 mg melatonin
|
12 wk
|
Sleep diary
|
Total sleep time, sleep onset latency, number of awakenings
|
|
Cortesi et al 2012
|
80
|
4–10 y
|
1 mg fast-release and 2 mg controlled-release melatonin
|
12 wk
|
Both diary and actigraph
|
Total sleep time, sleep onset latency, number of awakenings
|
|
Gringras et al 2017
|
125
|
2–17.5 y
|
2 mg escalated to 5 mg prolonged-release melatonin
|
13 wk
|
Both diary and actigraph
|
Total sleep time and sleep onset latency
|
Sleep Onset Latency
Four studies reported the effects of melatonin on sleep onset latency in children
with ASD. There was significant heterogeneity among the studies (p< 0.001, I
2 = 83.3%); therefore, a random-effects model was selected. The results of the meta-analysis
showed that the experimental group had a better effect on shortening the sleep onset
latency of children with ASD than the control group, and the difference was statistically
significant (SMD = − 1.34, 95% CI: −2.19 to −0.48, [Fig. 3]).
Fig. 3 Forest plot comparing efficacy of melatonin over control in sleep onset latency in
children with ASD. ASD, autism spectrum disorder.
Number of Awakenings
Data on the effect of melatonin on the number of awakenings in children with ASD were
extracted from three studies. There was significant heterogeneity between the studies
(p <0.001, I
2 = 94.5%); therefore, a random-effects model was selected. The results showed that
the experimental group had a better effect in reducing the number of awakenings in
children with ASD than the control group, and the difference was statistically significant
(SMD = − 2.35, 95% CI: −4.62 to −0.08, [Fig. 4]).
Fig. 4 Forest plot comparing efficacy of melatonin over control in number of awakenings
in children with ASD. ASD, autism spectrum disorder.
Total Sleep Time
Four studies reported data on melatonin for the total sleep time in children with
ASD. A random-effects model was selected because of the significant heterogeneity
between studies (p <0.001, I
2 = 85.7%). The results showed that, compared with the control group, ASD children
in the experimental group had longer total sleep time, and the difference was statistically
significant (SMD = 1.42, 95% CI: 0.5–2.33, [Fig. 5]).
Fig. 5 Forest plot comparing efficacy of melatonin over control in total sleep time in children
with ASD. ASD, autism spectrum disorder.
Publication Bias and Sensitivity Analysis
Egger's test showed that the p-values for each outcome measure were greater than 0.05, suggesting that there was
no significant publication bias among the included studies ([Supplementary Fig. S1], available in the online version only). In addition, sensitivity analysis showed
that the pooled results were stable ([Supplementary Fig. S2], available in the online version only).
Discussion
The study found that children with ASD had a higher prevalence of insomnia than normally
developing children, ranging from 40 to 86%.[15]
[16]
[17]
[18] For children with ASD, insomnia not only exacerbates some core symptoms but may
also affect the effectiveness of rehabilitation training. For example, Ming found
that insomnia in children with ASD was significantly associated with mood disturbances
and gastrointestinal abnormalities.[19] Some studies have also found an association between sleep problems and developmental
regression in ASD.[20] Therefore, addressing insomnia in children with ASD and improving their sleep quality
have become the most important issues in clinical interventions for children with
ASD. Melatonin is commonly used for insomnia in children, has favorable side effects,
is cost-efficient and readily available, and is often effective for sleep disturbances.[21] This meta-analysis systematically evaluated the efficacy of melatonin in the treatment
of insomnia in children with ASD. This study found that melatonin significantly shortened
sleep onset latency, reduced the number of awakenings, and prolonged the total sleep
time in children with ASD.
There is growing evidence that sleep disturbances in children and adolescents with
ASD are associated with arousal dysregulation and sensory hyper-responsiveness and
require a sedation strategy to improve their sleep.[1] Furthermore, insomnia in children with ASD is thought to be associated with abnormal
melatonin levels.[22] Melatonin is a hormone mainly secreted by the pineal gland, and its endogenous circadian
rhythm is influenced by light/dark conditions.[23] Extensive research has shown that melatonin not only plays a key role in regulating
the sleep/wake cycle but also has potent antioxidant and anti-inflammatory properties
and is involved in immune responses and neuroprotection.[24]
[25] This study confirmed the role of melatonin in the regulation of the sleep/wake cycle.
In this study, we found that melatonin was effective in relieving insomnia in children
with ASD, shortened sleep onset latency, reduced the number of nighttime awakenings,
and prolonged the total sleep time.
There is no consensus on the optimal dose of melatonin for promoting sleep in children.
Malow et al reported that 1 to 3 mg of melatonin supplementation was well tolerated
and improved sleep delay in most children with ASD.[26] The doses of melatonin in the included studies ranged from 2 to 10 mg. In this study,
melatonin doses ranging from 2 to 10 mg were included, and the results showed that
at this dose range, melatonin improved sleep, children had more regular and appropriate
bedtimes, children sleep for a longer period of time, and the number of nighttime
awakenings was significantly reduced. Due to the small number of included studies,
subgroup analysis based on dose differences could not be performed. Therefore, large-scale
clinical trials are required to verify these findings.
This study had some limitations. First, the included studies were few, and the source
of heterogeneity could not be explored through quantitative methods, such as subgroup
analysis and meta-regression. Second, the intervention measures used were inconsistent.
Although the experimental groups in the included studies all used melatonin for intervention,
the dose of melatonin was not strictly limited; therefore, there were certain differences
in the intervention measures. Finally, although significant results were obtained,
the small number of included studies may have reduced the accuracy of the results,
requiring larger-sample studies to verify the results.
Conclusion
There is some evidence that melatonin is beneficial in the treatment of insomnia in
children with ASD by reducing sleep onset latency, reducing the number of nighttime
awakenings, and increasing total sleep time compared to controls. However, due to
the limited number of studies included in this study, more and larger studies are
needed to verify this.
