Pharmacological and non-pharmacological interventions for non-respiratory sleep disturbance in children with neurodisabilities: a systematic review

Insomnia disorders

The ICSD-3 definition of insomnia is as follows: a persistent difficulty with sleep initiation, duration, consolidation or quality, which occurs despite adequate opportunity and circumstances for sleep and results in some form of daytime impairment. It comprises three subcategories: (1) chronic insomnia disorder, (2) short-term insomnia disorder and (3) other insomnia disorders. In children, chronic insomnia also includes behavioural insomnia disorders, the aetiology of which is located in the practices of parents around bedtime/settling and responding to night/early-morning wakings. 12 Behavioural insomnias are common in childhood, with an even higher prevalence among children with NDs. 14

Circadian rhythm sleep–wake disorders

Circadian rhythm sleep–wake disorders are characterised by abnormalities in the length, timing and/or regularity of the sleep–wake cycle relative to the day–night cycle. It is caused by genetic, neurological or visual pathway damage/disorders affecting circadian rhythms, including melatonin release. 14,15

Parasomnias

Parasomnias were included in the review because of the impact that they have on parents’ sleep. The ICSD-3 defines parasomnias as sleep-related occurrences that represent undesirable physical or cognitive experiences (e.g. sleep terrors, sleep walking) occurring out of sleep, during the transition from sleep to the awake state or from the awake state to sleep. They are more common in children than in adults. 16

The impacts of sleep disturbance

Sleep disturbance can have an impact on all members of the family: the child and their parents and siblings. Indeed, often it is the parents’ own sleep deprivation or poor sleep quality that precipitates them to seek help with their child’s sleep. 9,21 Child sleep problems are associated with poor outcomes for parents, such as heightened levels of parental stress and irritability,22,23 and for children, including poorer educational progress and daytime behaviour problems. 24 These outcomes in themselves increase demands on statutory services, as well as creating further additional support needs, such as respite care. 25,26 The wider association between sleep quality and economic consequences has also been described. 27,28 Parents consistently highlight the need for support with their child’s sleep problems,29,30 although, historically, little time has been allocated to training the relevant professionals to provide this kind of support. 31 Parents, practitioners and other stakeholders agree that research on sleep management interventions is a priority with respect to children with NDs. 32

Interventions for non-respiratory sleep disturbance

Interventions to address sleep disturbance among children with NDs examine both pharmacological and non-pharmacological approaches.

Pharmacological interventions act on an aspect of the physiological processes of sleep and/or the timing of the sleep–wake cycle; the most frequently used interventions are melatonin (a hormone playing a key role in the timing of the sleep–wake cycle), clonidine (which inhibits noradrenaline activity and hence has a soporific effect) and antihistamines [which inhibit neurotransmitters (histamines) that are involved in wakefulness/alertness]. 33–35 All are prescribed ‘off-label’. Other pharmacological interventions are used in relation to children’s sleep, such as medications to manage seizures and pain; however, these are outside the scope of this review because the primary purpose of the intervention is not sleep disturbance.

Non-pharmacological interventions address other causes of disturbances in sleep initiation, maintenance and/or scheduling and are wide-ranging in approach. Interventions that are available within and/or outside the NHS include:

• behavioural and cognitive behavioural interventions – addressing behavioural aspects of sleep including parents’ management of sleep behaviours and routines

• chronotherapy – intervening in the timing of sleep within the 24-hour cycle

• phototherapy (or ‘bright light therapy’) – using light exposure to effect changes in the circadian rhythm

• dietary interventions – removing stimulants and restricting to hypoallergenic food

• sensory interventions, including weighted blankets36 and ‘safe space’ bed tents37

• cranial osteopathy38

• changing the bedroom environment, for example by removing any televisions or other stimulatory materials and adjusting heating and/or lighting.

Current guidance on the management of sleep disturbance in children advocates that once clinical (e.g. pain or seizures) or respiratory reasons for sleep disturbance are excluded, behavioural approaches that seek to change parents’ responses to sleep-related problems should be the ‘first port of call’ for any child,33,39–41 with pharmacological intervention (and to date, this is typically melatonin) suggested in cases in which such approaches prove ineffective, which should be used alongside behavioural parent-directed approaches. 2,42

The justification for this is that, in common with children with typical development, the origins of sleep difficulties for many disabled children are behavioural, located in the way in which parents address and manage their child’s sleep. 4,43,44 The intensity of behavioural intervention depends on the complexity of the sleep problem and/or child/family-centred factors. Sleep problems that cannot be resolved through low-intensity approaches (e.g. simple information leaflets, verbal information/guidance during a routine appointment, one-off ‘sleep management workshops’) may require a more tailored and sustained approach involving a detailed assessment of the sleep problem, the creation of a bespoke sleep management strategy (based on behaviour modification principles) and time-limited (typically face-to-face) support as parents implement the strategy. In recent years, there has also been an increasing interest in using groups, as opposed to a series of one-to-one sessions, to deliver behavioural sleep support to parents. 45 Furthermore, online ‘self-directed’ sleep management interventions for adults are now available (e.g. Sleepio.com), and the management of sleep disturbance also appears within the curricula of newly available online parenting interventions for parents of children with typical development and disabilities (e.g. Stepping Stones Triple P). Constrained resources and wider changes in the way in which health care is delivered mean that it is likely that these newer modes of delivering behavioural sleep management intervention, such as groups and self-management, will increasingly be considered and used by clinicians and parents. 46 It was important, therefore, that this review examined evidence of the impact that the mode of delivery has on outcomes.

Population

Studies of children and young people with NDs who were experiencing non-respiratory sleep disturbances were eligible for inclusion in the review.

• Children and young people aged from 0 to 18 years were eligible. We did not expect to find many studies targeted at very young infants. Some previous reviews have used a lower age cut-off point of 3 months and others have not. Given the comprehensive nature of the review, we did not use a lower age cut-off point. ND was defined in accordance with the consensus definition developed by Morris et al. :17

  . . . congenital or acquired long-term conditions that are attributed to impairment of the brain and/or neuromuscular system and create functional limitations.

• Non-respiratory sleep disturbances, of any duration, related to the initiation, maintenance or scheduling of sleep, diagnosed by a health-care professional based on parental/carer or child report or sleep observation were eligible.

• Excluded non-respiratory sleep disorders were central disorders of hypersomnolence (in which daytime sleepiness is not caused by nocturnal sleep disturbance or misaligned circadian rhythms) and sleep-related movement disorders.

We excluded studies of respiratory-related sleep disturbances. However, NDs are complex conditions and sleep disturbances may have multifactorial causes. Therefore, we included studies in which the respiratory-related component was being controlled and the focus of the intervention was another cause of sleep disturbance. We also excluded studies in which the main focus of the intervention was not treatment of the sleep disturbance (e.g. interventions to control seizures when sleep outcomes were also reported) and studies of mixed populations of children with and without a ND, unless the results were reported separately for the two groups or the sample was predominantly (> 90%) children with a ND.

Intervention

NHS-relevant pharmacological and non-pharmacological interventions targeted at improving sleep initiation, maintenance, scheduling or sleep quality in any setting were eligible for inclusion. For pharmacological studies, ‘NHS relevant’ was defined as relating to drugs that are licensed for use for this indication in children or that are currently used for this purpose in the NHS. For non-pharmacological studies, ‘NHS relevant’ was defined as those interventions meeting current practice standards; for example, behavioural interventions that used punishment were excluded. Multicomponent interventions were eligible.

The NHS-relevant pharmacological interventions were melatonin, clonidine and antihistamines.

The NHS-relevant non-pharmacological interventions included (but were not restricted to):

• behavioural interventions delivered in a range of settings such as primary, secondary and tertiary or community, outpatient or inpatient that were delivered in groups or to individual children/families by health-care professionals

• self-help booklets, web-based packages and other online support

• behavioural/cognitive–behavioural interventions addressing behavioural aspects of sleep, including parents’ management of sleep behaviours and routines

• chronotherapy – intervening in the timing of sleep within the 24-hour cycle

• phototherapy (or ‘bright light therapy’) – using light exposure to effect changes in the circadian rhythm

• dietary interventions – removing stimulants, restricting to hypoallergenic food

• sensory interventions, including weighted blankets and ‘safe space’ bed tents

• cranial osteopathy

• changing the bedroom environment, for example by removing any televisions or other stimulatory materials and adjusting heating and/or lighting.

Comparator

Studies using no intervention, waiting list control, placebo or another NHS-relevant intervention were eligible for inclusion.

Outcomes

The following outcomes were assessed.

Primary outcomes:

• child’s sleep-related outcomes – parent-/carer- and child-reported outcomes relating to the initiation, maintenance, scheduling or quality of sleep (using measures such as sleep diaries, standardised scales, e.g. the Composite Sleep Disturbance Index or Epworth Sleepiness Scale) and objective measures such as actigraphy (used to calculate outcomes such as total sleep duration, time taken to fall asleep or sleep efficiency)

• parent sleep-related outcomes – quality of sleep

• measures of perceived parenting confidence and/or efficacy and/or understanding of sleep/sleep management (which are particularly relevant for parent training/behavioural interventions that seek to change the way that parents manage sleep disturbance).

Secondary outcomes:

• child-related quality of life, daytime behaviour and cognition

• parent/carer quality of life and well-being, including global quality of life (e.g. Short Form questionnaire – 36 items) and more specific outcomes such as physical well-being, mental well-being, and mental health (e.g. stress, depression)

• family functioning

• adverse events, including side effects from medication.

Data on uptake of the intervention, retention and intervention adherence were used as indicators of the acceptability and feasibility of the intervention. Quantitative or qualitative data on parents’/children’s experiences of receiving a sleep disturbance intervention included:

• the acceptability and feasibility of the intervention

• other experiences of receiving the intervention

• satisfaction with intervention outcomes and ‘fit’ with their priorities with regard to their child’s sleep disturbances; views/perspectives on the mechanisms by which outcomes were achieved.

Study design

Randomised controlled trials (RCTs) and non-randomised controlled studies, such as controlled before-and-after studies and cohort studies with a control group, were included. Both parallel and crossover RCTs were eligible for inclusion. Concerns have been expressed by others that a crossover design may be inappropriate owing to uncertainty about the duration of the effect of interventions on sleep patterns and circadian rhythm and, therefore, on the most appropriate duration for the washout period. 48 We agree with these concerns. However, given that the aim was to undertake a broad review and, as there were few RCTs likely to be available, we included crossover studies.

In order to achieve the second objective of the review, studies without a control group were included in the absence of controlled studies, that is, cohort studies and before-and-after studies. This was because they could include potentially promising interventions that were at an early stage of evaluation. Case studies were not eligible for inclusion.

Qualitative and quantitative studies were included if they reported data on parents’ or children’s experiences of receiving a sleep disturbance intervention (including intervention acceptability), such as the process of receiving the sleep intervention, satisfaction with intervention outcomes and ‘fit’ with their priorities with regard to their child’s sleep disturbances, and views/perspectives on the mechanisms by which outcomes were achieved. Data could be collected as part of studies of clinical effectiveness or studies that only sought to examine research questions on experiences and satisfaction.

Meta-analyses

Narrative synthesis

Although we planned to undertake separate quantitative and qualitative syntheses, this was to a large extent not possible, as few studies could be pooled. With the exception of the melatonin trials, there was a large degree of variability between studies evaluating different classes of interventions. For example, for behavioural interventions, there was wide variability in aspects of the interventions such as mode of delivery, duration and intensity of interventions, as well as in the comparators used. There was also variability in the conditions being studied, outcomes reported and the measures used to assess individual outcomes, follow-up times and types of data reported. Consequently, there were few instances in which it became appropriate to pool the data. Thus, it became necessary to adopt a principally narrative synthesis to report the findings. We present a narrative synthesis as our main analysis, with comparisons made for melatonin versus placebo, which were the only interventions that we judged could be appropriately compared.

Narrative synthesis was undertaken when quantitative synthesis was not appropriate or there were insufficient data, and applied mainly to the non-pharmacological interventions. When possible, we display outcomes in a forest plot, even when studies are not statistically pooled, to aid exploration of study results. When feasible, we investigated the subgroup characteristics outlined previously. Non-pharmacological studies were grouped by type of intervention (i.e. comprehensive parent-directed tailored, comprehensive parent-directed non-tailored or non-comprehensive) and comparator if heterogeneous. We explored outcomes by type of sleep disturbance with the aim of identifying effects that may be transferable to other NDs. Results are discussed in the context of ratings of risk of bias in the individual studies.

In terms of the qualitative data analysis, the topic areas that were subject to review were well defined; we therefore adopted a thematic approach to data extraction, analysis and synthesis. 60,73 To start, studies were grouped into pharmacological, behavioural and other non-pharmacological studies. For each, a descriptive report of relevant studies, and topic areas covered, was produced. The tabulated data were then scrutinised and analytical notes were made that summarised findings across studies with respect to the topic areas. Part of this process involved testing for contradictions in the evidence. 74

The synthesis interrogated such data, when available, to assist in identifying interventions that could be generalisable across conditions and those that are condition specific. 75,76 Factors taken into consideration in identifying promising interventions included feasibility of delivery of the intervention in a NHS setting, acceptability to children and families, evidence of clinical effectiveness or in the direction of clinical effectiveness based on CIs (taking into consideration the clinical significance of the estimates).

Protocol changes

During the course of the review, we identified numerous RCTs for the melatonin studies. We therefore decided to include only RCTs for this intervention. For all other interventions, we have included any design except case studies, as per the original protocol. Some studies reported multiple case studies that were not eligible for inclusion in the review. We made the decision to exclude uncontrolled studies with fewer than 10 participants.

Patient and public involvement

Three parents of children with NDs (two mothers, one father) acted as project advisors. They were recruited from a permanent parent consultation group of the chief investigator’s research unit. These parents were invited to the project team meetings, which were held three times over the course of study and were attended by the research team and all co-applicants. Each parent attended at least one meeting. They were also consulted, via e-mail, regarding the implications of the findings of the review. The children’s diagnoses included autism and rare, genetic conditions. At the first meeting, an early item on the agenda was a presentation of an overview of systematic reviews as a research method. Throughout the meetings, the parents were encouraged to share their experiences and opinions, and their contributions provided useful contextual information.

Study characteristics

Table 1 is a summary of the characteristics of the melatonin studies, and Appendix 5 provides further details. Of the 13 RCTs evaluating oral melatonin, which were undertaken in Canada, Italy, the Netherlands, the UK and the USA, 10 compared melatonin with placebo only; one compared melatonin, cognitive–behavioural therapy and a combination of the two with placebo; and two compared two regimens of melatonin (5 mg vs. 10 mg, and fast release vs. sustained release). Ten were crossover trials and three were parallel-group RCTs. Observed sample sizes ranged from 6 to 160 participants.

Assessment of risk of bias

A summary assessment of risk of bias for each RCT is provided in Table 1 and the full risk-of-bias assessment involving each bias domain is provided in Appendix 6 and Report Supplementary Material 1. One trial was rated as having a low risk of bias. 48 The ratings of risk of bias in the remaining RCTs were high or unclear; therefore, the findings from these studies may not be robust.

We could not locate a registered protocol for nine trials69,70,106,110,113–115,117,119 and one trial protocol was registered retrospectively,111 making it unclear whether or not the studies were free of selective reporting. Seven studies provided no, or little, detail regarding sequence generation;70,106,111,113,114,117,119 and four studies provided little or no detail regarding allocation concealment. 110,113,114,119 For three studies, how blinding was undertaken was unclear. 69,70,113 In three studies, the analysis of incomplete outcome data was not considered69,110 or was unclear. 114

Melatonin versus placebo

Eleven trials (n = 589 randomised participants) compared melatonin with placebo: eight crossover trials,69,70,106,113–115,117,119 two two-armed parallel-group trials,48,111 and one four-armed trial of oral melatonin, cognitive–behavioural therapy, oral melatonin plus cognitive–behavioural therapy and placebo. 110

The washout period used by the crossover trials varied. One had no washout period,119 one had a 1-month washout period106 and the remaining five trials had a washout period of between 3 and 7 days. 69,70,114,115,117 Camfield et al. 113 reported six ‘N of 1’ crossover trials with no washout period.

Six of the trials varied drug dosages depending on the child’s age and/or weight and tolerance of dosage (see Table 1). The dose ranges were 0.5–1 mg,113 0.5–12 mg,48 3–6 mg111 and 2–10 mg. 106 Fixed dosages were 3 mg (n = 2),110,119 5 mg (n = 4)69,70,114,117 and 9 mg. 115 Matched placebos were used except for in one trial,70 in which the placebo was not explicitly described, although in this trial the authors reported that each patient received a blister card of 30 days’ supply of medication.

The length of time that melatonin was prescribed for varied between studies: 10 days,70,117 2 weeks,114,119 4 weeks,69,111,115 5 weeks113 and 12 weeks. 48,106,110

The age of participants included in these trials ranged from 1 to 18 years, although the mean age across studies was broadly similar, ranging from 5.5 to 10.3 years (see Table 1). The ND that was represented varied. Four trials included children with a mixed range of neurodevelopmental disabilities,48,113,114,117 three trials included only children with ASC,69,106,110 two trials included children with ADHD,70,111 one trial included children with ASD and/or fragile X syndrome119 and one trial included children with epilepsy. 115

The type of sleep disturbances reported in the participants also varied. Most trials had more than one criterion for inclusion in the trial and included children with a mix of sleep disturbances (see Table 1) relating to sleep initiation48,69,70,106,110,111,113,117 and sleep maintenance. 48,69,106,110,113,117 However, two trials focused on a single sleep problem (‘sleep onset insomnia’111 and ‘initial insomnia’70) and one trial required a score of > 30 in the Sleep Behaviour Questionnaire. 115 Two studies did not specify the type of sleep problems eligible for inclusion. 114,119

Seven trials specified in their inclusion criteria that a preceding psychoeducational or behavioural sleep management intervention had to have been ineffective. 48,69,70,106,113,114,117 In five of these trials, guidance on sleep was provided as part of the trial in the form of a behaviour therapy advice booklet,48 tailored sleep hygiene advice,117 a sleep hygiene intervention,70 a sleep hygiene advice leaflet69 and behaviour management and parenting support. 106 In four of these trials, only children who continued to experience sleep problems were randomised. 48,70,106,117

Across these 11 trials, 19 sleep-related outcomes were measured (see Appendix 7). The most commonly measured outcomes were total sleep time (TST) (n = 11), sleep onset latency (SOL) (n = 10), number of night wakings (n = 6) and sleep efficiency (n = 5). Additional outcomes included arousals, bedtime, CSHQ, difficulty falling asleep, sleep onset, time from drug to sleep, longest sleep episode, the Sleep Behaviour Questionnaire, percentage of sleep stages, wake after sleep onset (WASO), nights without awakening, wake-up time, naptime, moving time, ‘interdaily stability’, ‘interdaily variability’ and ‘L5’ (average activity during the least active 5 hours). Definitions of outcome measures can be found in Appendix 7.

All trials had follow-up periods that commenced immediately following the completion of the intervention: 10 days,70,117 2 weeks,114,119 4 weeks,69,111,115 10 weeks113 or 12 weeks. 48,106,110

Global measures and composite scores

Total sleep time

All 11 trials48,69,70,106,110,111,113–115,117,119 (n = 589 randomised participants) assessed TST (see Appendix 7); four measured this using parent-reported sleep diaries only,69,106,113,114 whereas the remaining seven48,70,110,111,115,117,119 used both actigraphy and sleep diaries. However, of these, three report only actigraphy-measured TST data,110,111,119 as the sleep diaries were used purely to inform, or verify, actigraphy data. This follows existing guidance on the interpretation of actigraphy data. 134 The remaining four trials48,70,115,117 reported TST derived from both parent-completed sleep diaries and actigraphy data.

Data from seven trials using sleep diary-reported TST were pooled: six crossover trials with a washout period (n = 122 analysed participants),69,70,106,114,115,117 and one parallel-group trial (n = 110). 48 Note that in the forest plot (Figure 2), the sample sizes presented count participants in crossover trials twice (as being in the melatonin and placebo groups), so the figures reported in the text and shown in the figures may not match for this reason. There was a statistically significant increase in sleep diary-reported TST with melatonin compared with placebo (pooled MD 29.6 minutes, 95% CI 6.9 to 52.4 minutes; p = 0.01; see Figures 2 and 3). Statistical heterogeneity was high (I² = 97%) and this treatment effect is unlikely to be generalisable, although the effect estimates were all in the direction of benefit with melatonin. Heterogeneity was reduced when studies were stratified based on whether or not the study population was exclusively ASD or not (test for subgroup differences: p < 0.001; I² = 99%); there was a pooled MD of 64.7 minutes (95% CI 58.8 to 70.7 minutes, I² = 0%) for the studies of ASD (n = 24), and a smaller pooled MD of 15.9 minutes (95% CI 9.2 to 22.6 minutes, I² = 31%) for the studies of mixed or other populations (n = 208). There was only a single study (n = 9) in which participants had no prior sleep hygiene or behavioural intervention limiting the usefulness of this subgroup analysis; the overall results did not substantially change with removal of this study (pooled MD 33.0 minutes, 95% CI 8.6 to 57.4 minutes, n = 223; Figure 3). When the single trial rated as having a low risk of bias is considered alone, the increase in sleep time with melatonin was 13.2 minutes (95% CI –13.3 to 39.7 minutes). 48

FIGURE 2.

Sleep diary-reported TST: melatonin vs. placebo and ASD subgroup analysis. df, degrees of freedom; IV, instrumental variable.

FIGURE 3.

Sleep diary-reported TST: melatonin vs. placebo and prior intervention subgroup analysis. df, degrees of freedom; IV, instrumental variable.

The study of six ‘N of 1’ trials in six participants also reported sleep diary TST but, owing to the unusual trial design, could not be included in the meta-analysis. 113 The authors reported no ‘notable difference in sleep pattern or daytime behaviour between melatonin and placebo weeks’113 and provided raw data for each participant. From this, we calculated the MD between melatonin and placebo for parent-reported TST to be 13.9 minutes in favour of the melatonin group (95% CI –6.8 to 34.6 minutes; p = 0.14).

Five trials48,110,111,115,117 (n = 266 analysed participants) were pooled for actigraphy-measured TST, comprising two crossover trials with a washout period (n = 60)115,117 and three parallel-group trials (n = 206). 48,110,111 Weiss et al. 70 used actigraphy to measure TST post intervention and reported that there was no significant difference between melatonin and placebo, but the study did not provide data on this outcome to allow it to be included in the meta-analysis.

There was a statistically significant increase in actigraphy-measured TST with melatonin compared with placebo (pooled MD 31.9 minutes, 95% CI 14.8 to 49.1 minutes; p < 0.001) (Figure 4). Heterogeneity was high (I² = 76%) and this treatment effect is unlikely to be generalisable, although the effect estimates were all in the direction of benefit with melatonin. There was no statistically significant difference in effect between the studies in which participants received or did not receive a prior intervention (test for subgroup differences, p = 0.48; I² = 0%). Subgroup analysis by type of ND was not possible.

FIGURE 4.

Actigraphy-measured TST: melatonin vs. placebo. df, degrees of freedom; IV, instrumental variable.

One study without a washout period119 (n = 12 analysed participants) reported a MD in actigraphy-measured TST post intervention of 21 minutes between melatonin and placebo, favouring melatonin. Using non-parametric analysis methods, the authors report p-values of 0.0019 and 0.02 for this outcome, based on data sets produced using two different approaches for dealing with missing data (complete case and last observation carried forward). This outcome was also analysed using a paired t-test, giving a p-value of 0.057. We have estimated the 95% CI for the MD of 21 minutes as –0.7 to 42.7 minutes.

For TST based on polysomnography at 4 weeks immediately post intervention,115 there was no significant difference between melatonin and placebo, with a reported MD of 39.3 minutes (favouring placebo, 95% CI –34.7 to 113.3 minutes, n = 10).

Sleep efficiency

Five trials48,110,111,115,117 (n = 475 randomised participants) reported sleep efficiency (i.e. the ratio of TST to total time in bed): one trial used both actigraphy and parent report,117 three used actigraphy data only48,110,111 and one trial used polysomnography. 115

Cortesi et al. 110 also measured the percentage of children who achieved a sleep efficiency in the normative level of > 85% at the 12-week assessment.

Four trials48,110,117,135 (n = 255 analysed participants) for actigraphy-measured sleep efficiency were pooled, comprising three parallel trials (n = 205) and one crossover trial with a washout period (n = 50). There was no statistically significant difference in sleep efficiency with melatonin compared with placebo (pooled MD 4.76% favouring melatonin, 95% CI –0.95% to 10.47%; p = 0.10; Figure 5). Heterogeneity was high (I² = 94%) and this treatment effect is unlikely to be generalisable; although the trials did consistently report very small differences between groups in the proportion of time spent in bed asleep, these are unlikely to be clinically meaningful.

FIGURE 5.

Actigraphy-measured sleep efficiency: melatonin vs. placebo. df, degrees of freedom; IV, instrumental variable.

For the single trial117 reporting parent-reported sleep efficiency (n = 50 analysed participants), there was no statistically significant difference between groups (MD 0.30% favouring melatonin, 95% CI –0.90% to 1.49%; p = 0.62).

Cortesi et al. 110 reported the percentage of children who achieved a sleep efficiency in the normative range (> 85%) as 46.43% of the melatonin group compared with none of the placebo group.

Jain et al. 115 reported no difference in polysomnography-measured sleep efficiency (MD 3.8% favouring melatonin, 95% CI –2.5% to 10.1%, n = 10).

Sleep initiation

Sleep onset latency

Ten trials48,69,70,106,110,111,114,117,119 (n = 583 randomised participants) measured SOL, the time from bedtime to sleep onset time (see Appendix 7): three trials reported parent-reported SOL data only;69,106,114 two reported actigraphy-measured SOL data only;110,119 four reported both actigraphy-measured and parent-reported SOL data;48,70,111,117 and one used polysomnography- and actigraphy-measured data, but reported only the results of the polysomnography. 115 As with TST, trials reporting actigraphy data stated that it was informed, or verified, by parent-reported sleep diaries.

Cortesi et al. 110 also calculated the percentage of children who met either a standard sleep criterion for SOL of ≤ 30 minutes or a reduction of SOL by 50%. Wright et al. 106 used an additional measure of SOL defined as the duration of time between taking the medication and falling asleep.

For parent-reported/sleep diary SOL, six trials48,69,70,106,114,117 (n = 223 analysed participants) were pooled, comprising five crossover trials with a washout period (n = 110)69,70,106,114,117 and one parallel-group trial (n = 113). 48 There was a statistically significant decrease (favouring melatonin) in SOL for melatonin compared with placebo (pooled MD –35.6 minutes, 95% CI –50.9 to –20.3 minutes; p < 0.001; Figure 6). Heterogeneity was high (I² = 89%) and the treatment effect is unlikely to be generalisable, although the effect estimates were all in the direction of benefit with melatonin. There was a statistically significant difference in effect between the studies of children with ASD and those with mixed and other populations (test for subgroup differences, p < 0.001; I² = 93%). There was a larger difference in the ASD group between melatonin and placebo, with a mean reduction in favour of melatonin of 50.9 minutes (95% CI –55.5 to –46.2 minutes) compared with 27.41 minutes (95% CI –39.1 to –15.7 minutes) in the other group. Subgroup analysis by whether or not participants had received a prior intervention was not possible.

FIGURE 6.

Sleep diary-measured SOL: melatonin vs. placebo. df, degrees of freedom; IV, instrumental variable.

For actigraphy-measured SOL, five trials48,70,110,111,117 (n = 265 analysed participants) were pooled, comprising three parallel trials (n = 196)48,110,111 and two crossover trials with a washout period (n = 69). 70,117 There was a statistically significant decrease (favouring melatonin) in actigraphy-reported SOL (pooled MD –23.4 points, 95% CI –30.9 to –15.8 points; p < 0.001; Figure 7). There was moderate heterogeneity (I² = 48%). Based on the subgroup analysis, there was no statistically significant difference in effect between studies in which participants had or did not have a prior intervention (test for subgroup differences, p = 0.55; I² = 0%). A subgroup analysis based on neurodevelopmental condition was not possible.

FIGURE 7.

Actigraphy-measured SOL: melatonin vs. placebo. df, degrees of freedom; IV, instrumental variable.

For both sleep diary-measured and actigraphy-measured SOL, the single study rated as having a low risk of bias48 reported a statistically significant improvement with melatonin compared with placebo (see Figures 6 and 7).

The crossover study without a washout period119 (n = 12 analysed participants) reported a statistically significant decrease in mean SOL for the melatonin period, compared with the placebo period, using a non-parametric analysis (complete-case analysis, p = 0.02; last observation carried forward, p = 0.0001), but this difference is not significant when tested using a paired t-test (MD –28.08 minutes; p = 0.10; estimated 95% CI –2.5 to 58.7 minutes).

Cortesi et al. 110 used an additional indicator of SOL (the percentage of children who met a criterion of SOL of ≤ 30 minutes or a reduction of SOL by 50% post intervention) and reported that 39% of the melatonin group versus 0% of the placebo group achieved these changes (n = 66 analysed participants). Jain et al. 115 (n = 10), using polysomnography, reported that melatonin significantly reduced the mean SOL compared with placebo, with a reported MD of –11.4 minutes (95% CI –17.2 to –5.6 minutes).

Wright et al. 106 (n = 17) reported a significant decrease in SOL with melatonin compared with placebo [MD 51.7 minutes (SD 71.9 minutes; p = 0.012; estimated 95% CI 16.5 to 86.9 minutes)].

Sleep maintenance

Number of night wakings

Six trials69,106,113,114,117,119 (n = 142 randomised participants) reported the number of night wakings.

Four crossover trials with a washout period were pooled (n = 94 analysed participants). 69,106,114,117 There was no difference in the mean number of night wakings with melatonin compared with placebo (pooled MD –0.04 points, 95% CI –0.22 to 0.13 points; p = 0.61; Figure 8). Heterogeneity was high (I² = 84%), although the results were fairly consistent, with the exception of those of Dodge and Wilson. 114 Based on the subgroup analysis, there was no statistically significant difference in effect between studies based on ND (test for subgroup differences, p = 0.06; I² = 71%).

FIGURE 8.

Parent-reported number of night wakings: melatonin vs. placebo. df, degrees of freedom; IV, instrumental variable.

The crossover study without a washout period119 reported no significant difference for the melatonin period compared with the placebo period by either the non-parametric analyses or the paired t-test [MD by paired t-test –0.07 points (favours melatonin, p = 0.73; estimated 95% CI –0.44 to 0.30 points)]. Wasdell et al. 117 reported no statistically significant treatment difference (p = 0.48) for melatonin compared with placebo (estimated MD –0.41 points favouring melatonin, 95% CI –1.47 to 0.66 points).

Melatonin versus melatonin

Two crossover trials120,121 (n = 24 randomised participants) compared melatonin with melatonin. Jan et al. 121 compared controlled-release with fast-release melatonin, and Hancock et al. 120 compared a dose regimen of 5 mg with a dose regimen 10 mg of melatonin.

Jan et al. 121 did not have a washout period between the two intervention phases, whereas Hancock et al. 120 had a 2-week washout period. Hancock et al. 120 compared a fixed-dose regimen of 5 mg with 10 mg of melatonin regardless of the child’s age. The authors did not report whether or not the melatonin was controlled or fast release. The final average dose for controlled-release melatonin for Jan et al. 121 was 5.7 mg (range 2–12 mg), and the final average dose for fast-release melatonin was 7 mg (range 2–15 mg). Jan et al. 121 reported that the dosage for fast-release melatonin varied for each child depending on the dosage deemed by the trial team to be most effective for that child. However, the controlled-release melatonin was approximately 50% of the fast-release dose, which the authors stated was to avoid possible adverse side effects, as they had no previous information on the use of controlled-release melatonin in children. The duration of the intervention was 11 days for Jan et al. 121 and 2 weeks for Hancock et al. 120

The age of participants included in the trials ranged from 18 months to 31 years for Hancock et al. 120 (eligible participants < 18 years, n = 5, mean age 6.9 years); and from 4 to 21 years for Jan et al. 121 (eligible participants < 18 years, n = 15, mean age 9.3 years). Children in Hancock et al. 120 had severe neurodevelopmental difficulties, whereas the ND in the Jan et al. 121 study was tuberous sclerosis. The sleep disturbance in both studies focused on both sleep initiation and maintenance: in Hancock et al. 120 ‘severe sleep problems’, confirmed by a Quine sleep index score of at least 6 out of a possible 8, and for Jan et al. 121 ‘chronic wake–sleep disorders’.

In Jan et al.,121 the inclusion criterion was that children had already been treated with fast-release melatonin for > 3 months but slept for < 5–6 hours. No additional guidance or leaflets on sleep management were provided to parents in either of the trials.

Across both trials, four sleep-related outcomes were measured (see Appendix 8). Hancock et al. 120 measured TST, SOL and number of night wakings, whereas Jan et al. 121 measured ‘changes in sleep pattern’ as their only outcome. The results of these outcomes are summarised in Table 3 for participants aged < 18 years. Each outcome measure was reported by a single study. There was no evidence of benefit on any of the sleep-related outcomes for the RCT that compared controlled-release melatonin with fast-release melatonin121 or the RCT that compared a dose of 5 mg of melatonin with 10 mg of melatonin. 120

Adverse events

Eleven out of the 13 trials measured adverse events,48,70,106,110,111,114,115,117,119–121 which were collected and reported in different ways across the studies (Table 4).

One study reported adverse event data using the standardised assessment tool ‘treatment-emergent signs and symptoms’, which classified events into seven domains: somnolence, increased excitability, mood swings, seizures, rash, hypothermia and cough. 48 Signs and symptoms were graded as ‘no symptoms’, ‘mild symptoms’, ‘moderate symptoms’ and ‘severe symptoms’. Seriousness and causality were also assessed. In two studies,110,115 adverse events were determined at each in-person/telephone call visit by the study team and recorded in the participant’s chart; one study measured adverse events using study-specific questionnaires completed by parents;106 one reported using a standardised form;70 one reported using parent-completed questionnaires, in which the origin of the questionnaire was not reported;114 two reported measuring adverse events using open-ended interviews;111,117 one study reported only that adverse effects were reported by parents;120 and in one study it was unclear how the data were collected. 119

Three trials reported that no adverse events were observed or reported during the trial. 110,119,121 Further details of the adverse events reported can be found in Table 4. Overall, melatonin was tolerated and the adverse event profile appeared to be similar between the melatonin and placebo groups.

Summary

Eleven RCTs (eight crossover and three parallel trials) compared melatonin, of varying doses and duration, with placebo. The mean age of participants ranged from 5.5 to 10.3 years and some studies included children with a single ND, whereas others included mixed populations. Children had mostly sleep initiation and/or sleep maintenance problems and in the majority of studies had been offered a prior intervention, ranging from a sleep hygiene advice leaflet to behaviour management and parenting support. Only three child-related sleep outcomes were reported by more than half of the studies, with many of the additional outcomes assessed by a single study. None of the studies assessed parent-related outcomes.

One study was assessed as having a low risk of bias, with the remaining studies having an unclear or high risk of bias. When possible, studies were grouped in the synthesis by ND (ASD vs. mixed or other groups) and by whether or not they had received a prior intervention. However, the results of the subgroup analyses should be interpreted with caution, rather than be considered definitive, as they are based on summary data and are, therefore, observational rather than randomised comparisons as in a trial. In addition, some of the subgroups contained a particularly small number of studies.

There was evidence of benefit with melatonin compared with placebo, although the precise extent of the benefit, which children might benefit the most and the clinical importance of the benefit remain uncertain. The overall benefit was similar for diary-reported and actigraphy-recorded TST. Based on two small studies of children with ASD, there was a mean increase in diary-recorded TST of 64.78 minutes with melatonin compared with placebo (95% CI 58.8 to 70.7 minutes); for the five mixed or other ND studies, the mean increase was 15.9 minutes (95% CI 9.2 to 22.6 minutes). For the single study that was rated as having a low risk of bias (mixed population), the mean increase in TST was 13.2 minutes and the lower CI included the possibility of reduced sleep time (95% CI –13.3 to 39.7 minutes). The findings were similar for SOL. The benefit was greatest for the ASD studies in which there was a mean reduction of 50.9 minutes (95% CI –55.5 to –46.2 minutes) in diary-measured SOL, based on two small studies, whereas there was a smaller mean reduction of 27.4 minutes (95% CI –39.1 to –15.7 minutes) for the mixed and other population subgroup. For the single study with a low risk of bias (mixed population), the mean reduction in SOL was 37.5 minutes (95% CI –58.9 to –16.1 minutes). For other outcomes, there was some evidence of statistically significant benefit with melatonin for sleep initiation outcomes but not sleep maintenance outcomes, such as number of night wakings, although some of the single studies may not have been sufficiently powered to detect an effect.

A single RCT121 compared controlled-release and fast-release melatonin and one RCT120 compared a 5 mg and a 10 mg dose of melatonin, both with a high risk of bias. There was no evidence of benefit with either strategy.

Study characteristics

Twenty-six studies evaluated non-pharmacological interventions: 12 RCTs, one controlled before-and-after study and 13 uncontrolled before-and-after studies. Sample sizes ranged from 5 to 244 participants. Studies were conducted in Australia, Canada, China, Hong Kong, Israel, the UK and the USA. A summary of key characteristics is provided in Table 5 and further details are provided in Appendix 9.

We grouped studies, based on the intervention, into the following: parent-directed tailored interventions (n = 9), parent-directed non-tailored interventions (n = 8), non-comprehensive parent-directed interventions (n = 2) and ‘other’ non-pharmacological interventions (n = 7). Intervention and control details for non-pharmacological studies are outlined in Appendix 10.

Parent-directed interventions can be conceived as psychoeducational interventions that have the objective of ‘training’ parents to manage their child’s sleep disturbance by equipping them with the relevant knowledge and skills. These interventions vary in their intensity and different modes are used to deliver the training, including individual work, group work, teaching workshops and written material. Nineteen studies21,49,107,123–129,138,146,149,151,152,155,162,163 of parent-directed interventions were included in the review. The interventions varied considerably in terms of a number of characteristics. There was no consistency in the terminology used by study authors to describe the interventions, and the terms that were used to describe an intervention were not routinely defined. This was not unexpected. Generally, reporting of non-pharmacological interventions is acknowledged to be much poorer than for pharmacological studies. 164 However, it carries the risk of erroneous comparison of interventions or pooling of studies.

Therefore, a framework to describe the parent-directed interventions represented in this study was developed by the research team. It included intervention characteristics posited as being an ‘active ingredient’ of an intervention and/or having an impact on intervention effectiveness, for example, intensity, duration, mode of delivery and whether the intervention was condition specific or ND generic. There was incomplete reporting on these intervention characteristics across the studies. We defined tailored and non-tailored interventions as follows:

• Tailored – a face-to-face clinical assessment by a trained practitioner guides clinical decision-making regarding the management of a specific child’s sleep disturbance. A sleep management plan specific to the child/family is developed, and training in implementing that plan is delivered. There is extended ‘implementation support’, that is, ongoing support and advice as the parents implement changes to sleep management strategies and practices. The intervention is typically delivered on a one-to-one basis. However, an intervention that used teaching workshops and one-to-one work was also categorised as tailored123,124 because it fulfilled the criteria defined above.

• Non-tailored – the delivery of a standard ‘training curriculum’. The curriculum may include opportunities for a parent to be supported to operationalise the material learnt for their child’s sleep disturbance. Some implementation support may also be included. Among the studies included in this review, such interventions were delivered in a number of ways: written material, single-session workshops, group delivery and one-to-one work.

All but two of the parent-directed interventions were comprehensive in their content, that is, they included training across three topic areas: sleep and sleep processes, sleep hygiene and the management of specific problem behaviours (e.g. night wakings). The remaining two interventions, which were classified as non-comprehensive parent-directed interventions, focused on a single topic area related to managing sleep disturbance. One was concerned only with sleep hygiene training155 and the other focused on particular behavioural strategies to manage specific problem behaviours. 152

Disorder global measures and composite scores

Other global measures and composite scores

Several further composite scores and global outcome measures were reported by single studies. One RCT138 (n = 244) of a tailored parent-directed intervention compared with usual care reported a statistically significant reduction in parent-reported moderate or severe sleep problems (Table 8). There appeared to be improvement at follow-up in three further outcomes measured in two before-and-after studies (see Table 8). 21,123

Sleep initiation

Other sleep initiation outcomes

Two further before-and-after studies measured time to settle at night. One reported a statistically significant improvement in time to settle at night (MD –91.3 minutes, 95% CI –112.6 to –69.9 minutes)146 and the other did not report data for any sleep initiation outcomes. 126

Sleep maintenance

Other sleep maintenance outcomes

A variety of other outcomes related to sleep maintenance were reported by single studies. One RCT138 (n = 244) reported WASO (night waking duration and/or frequency after the child falls asleep) and found no evidence of a statistically significant difference between a tailored parent-directed intervention and usual care (Table 9). Another RCT125 (n = 27) comparing an extended versus brief intervention found that there was a greater reduction (i.e. now ‘no’ or only a ‘mild’ sleep problem) in sleep problems at 2 months for the extended intervention group compared with the brief intervention group. One before-and-after study146 reported statistically significant improvements in mean minutes per night the child was awake, and number of nights the child does not sleep in their own bed. Another before-and-after study126 reported measuring the number of nights per week that the child fell asleep in their own bed and the number of nights per week that the child co-slept; however, the authors reported insufficient data to determine the effects of the intervention on these outcomes (see Table 9).

Parent help-seeking for sleep problem

One RCT138 (n = 244) collected parent reports of other professional help sought for their child’s sleep. Parents of children in the intervention group were less likely than parents of children in the control group to seek help for their child’s sleep from a health professional (e.g. general practitioner, paediatrician or psychologist) (14% vs. 20% at 3 months), but this difference was not statistically significant.

School attendance

Two RCTs (n = 271) reported on school attendance, defined as the number of days missed from school. 125,138 Both reported only that there was no difference in this outcome between the intervention groups. 125,138

Parent-related outcomes

Three RCTs124,125,138 and one before-and-after study146 reported parent-carer-related outcomes. The outcomes measured and methods of assessment are summarised in Appendix 12.

Other parent-/carer-related outcomes of parent-directed tailored interventions

Two RCTs (n = 53)124,125 and one before-and-after study146 reported other parent-/carer-related outcomes of parent-directed tailored interventions. These data are summarised in Table 11. These outcomes focused on parental stress and morale124,146 and parent work attendance. 125

There was a statistically significant reduction (i.e. improvement) in the Parenting Stress Index – Short Form when comparing a parent-directed tailored intervention with a waiting list control. 124 Another RCT125 found a statistically significant difference in parent work attendance for an extended versus a brief version of a parent-directed tailored intervention.

The before-and-after study found both a statistically significant reduction in maternal stress, as measured by the Malaise Inventory, and an improvement in maternal morale, as measured by the Cantrill ladder, from pre to post intervention. 146

Summary

Nine studies evaluated parent-directed, comprehensive tailored interventions. 21,107,123–126,138,146 There were five RCTs,21,107,124,125,138 three of which107,124,138 were rated as having a high risk of bias and compared the intervention with usual care or other control, one125 of which was rated as having a high risk of bias and compared brief with extended versions of an intervention and another of which21 was rated as having a high risk of bias and compared different modes of delivering implementation support. There were also four before-and-after studies21,123,126,146 that were rated as having a high or an unclear risk of bias. The mean age of participants ranged from 2.7 to 12.1 years. The majority of studies21,123–126,138,146 included children with a mixed range of NDs, with three studies107,125,146 including children with a single condition. The majority of studies21,107,123,126,146 also included children with a mix of sleep disturbances, mainly sleep initiation and/or sleep maintenance problems.

Although all of the studies used face-to-face sessions with parents (at home or in a clinic) as the primary mode of delivery and were similar insofar as the content was classified as comprehensive, there was considerable variation in the duration of the intervention, the number of sessions delivered and the extent of implementation support when the sessions had finished, for example through follow-up telephone contact.

Overall, there was mixed evidence about the effects of parent-directed tailored interventions compared with usual care or other control, with limited evidence of benefit on more objective actigraphy child-related sleep outcomes and more evidence of benefit on parent-reported child outcomes and a few parent outcomes. Conclusions are hampered by the limited number of RCTs, the multitude of outcome measures and the risk of studies being underpowered to detect an effect. A single study138 was rated as having a low risk of bias for all domains except for blinding, as the outcomes may have been influenced by the lack of blinded outcome assessment. This RCT138 of a parent-directed comprehensive tailored intervention (with implementation support) compared with usual care, which provided the best available evidence identified, reported a small increase in TST in favour of the intervention, but the lower CI covered the possibility of worsening of TST (MD 10.9 minutes, 95% CI –19.0 to 40.8 minutes). A second RCT of a parent-directed comprehensive tailored intervention (with implementation support) compared with usual care had a similar finding (MD 26.0 minutes, 95% CI –35.1 to 87.1 minutes). 107 There was also no statistically significant improvement in other actigraphy-measured sleep outcomes with the intervention compared with control (sleep efficiency, WASO, SOL), measured by either or both studies. There was a statistically significant improvement in child sleep habits (CSHQ) and in parent-reported child sleep problems in one of these studies,138 as well as child behaviour and quality of life (parent-reported ADHD Rating Scale IV, PedsQL, Parent Daily Reporting of Morning and Evening Behaviour). The third RCT124 reported no statistically significant difference in child behaviour (Developmental Behaviour checklist). One RCT138 reported no statistically significant improvement in parental stress (DASS) with the intervention compared with control, whereas another RCT124 reported a statistically significant improvement (Parenting Stress Index – Short Form). The four before-and-after studies21,123,126,146 showed improvement across several child-related and parent-related outcomes.

Based on a single RCT,21 there was no statistically significant difference in the clinical effectiveness of home-delivered compared with telephone-based implementation support on child sleep outcomes (CSHQ) or parental outcomes (PSOC scale). Based on a single RCT,125 there was a statistically significant improvement in parental work attendance and parent-reported child sleep problems with an extended versus brief intervention but no difference for multiple other child-related and parent-related outcomes.

Child-related outcomes

The outcomes measured and methods of assessment are summarised in Appendix 14.

Parent outcomes

Several studies assessed parent outcomes. The outcome domains assessed were mental well-being,129,149,151 quality of sleep149,151 and parents’ sense of competence. 128,162,163

Summary

Eight studies49,127–129,149,151,162,163 evaluated parent-directed non-tailored interventions to manage sleep disturbance in children with NDs. We defined non-tailored interventions as those comprising the delivery of a standard ‘training curriculum’. All the non-tailored interventions were comprehensive in their content, covering material on sleep and sleep processes, sleep hygiene and the management of specific problem behaviours (e.g. night wakings). Within this set of interventions, the design of the curriculum may include opportunities for parents to be supported to operationalise the material learnt for their child’s sleep disturbance. Some implementation support (i.e. support to parents as they implement new ways of managing their child’s sleep disturbance) may also be included.

Compared with the tailored interventions reported in the previous section, the non-tailored interventions evaluated by studies included in this review were much more diverse in terms of mode of delivery [i.e. written material, group delivery (single vs. multiple sessions) and one-to-one work]. In addition, they differed in terms of the extent to which they could accommodate the specific information and training needs parents may have in terms of their own child’s condition and/or sleep problem. Furthermore, some included implementation support, but others did not. When implementation support was provided, it was always via telephone calls.

The eight studies included one RCT127 that compared intervention (written material) and no intervention and five before-and-after studies. 129,149,151,162,163 Three129,151,162 evaluated a group-delivered intervention comprising three or four sessions, one163 evaluated a single-session workshop and one evaluated an individually delivered intervention. 149 One RCT49 compared two modes of delivering the same training curriculum (written material vs. face-to-face session) with no intervention. The final RCT128 compared delivery of the same training curriculum via group and individual delivery. All the studies were rated as having a high risk of bias.

Four interventions127–129,151 were developed specifically for children with ASDs, and only children with these conditions were recruited to the studies. In the remaining four studies,49,149,162,163 the interventions were evaluated using samples of children with a range of NDs. The mean age of children recruited to the studies ranged from 2.0 to 8.9 years. The majority of studies reported that the children had problems with both sleep initiation and sleep maintenance.

The conclusions that can be drawn are limited, owing to the rating of the high risk of bias, the use of post-intervention follow-up time points and the risk of studies being underpowered to detect an effect. In addition, a large number of different outcome measures were used and these evaluated a range of outcome domains. We organise the findings in terms of mode of delivery and, when relevant, availability of implementation support.

A single trial evaluated the impact of an intervention comprising the provision of written information (and no implementation support) with no intervention. 127 There was no evidence of benefit at 2 weeks post intervention, as measured using actigraphy-collected sleep outcomes data (TST, Sleep Efficiency, SOL and WASO). Another three-armed trial49 compared the provision of written information or the delivery of the same material via a single face-to-face session with a waiting list control group. Neither active arm included the provision of implementation support. Evidence of benefit at 6 weeks post intervention, based on a parent-report measure (composite sleep disturbance score), was reported for both modes of intervention delivery compared with the control group (written information vs. control, MD 3.20, 95% CI 1.89 to 4.51; face-to-face delivery vs. control, MD 3.35, 95% CI 2.32 to 4.38). The study was not powered to detect a difference between the two active arms. No other child outcomes, or parent outcomes, were assessed by these studies. There is, therefore, mixed and very limited evidence regarding the impact that the provision of written information with no implementation support has on child sleep outcomes only. Given the differences in outcome measures, differences in post-intervention follow-up time points and the high risk of bias for both studies, it is not possible to draw further conclusions regarding this sort of intervention. Furthermore, no conclusions can be drawn regarding the relative benefits of written versus face-to-face delivery of training on sleep management.

One before-and-after study149 evaluated an intervention comprising a single face-to-face training session and implementation support available for up to 2 weeks after the session. The authors report significant improvements post intervention on non-standardised sleep outcome measures and a standardised measure of child behaviour (BPI) but data were not fully presented. Given the study limitations, no conclusions can be drawn from this evidence.

Two before-and-after studies evaluated multisession (n = 3 or 4) group-delivered interventions for which no implementation support was available after the group sessions were completed. 129,162 In one study, outcomes were reassessed immediately post intervention;129 in the other study, this took place 1 month post intervention. 162 Both studies report improvements in child sleep outcomes measured using the same standardised parent-report measure (CSHQ) (for Beresford et al. ,162 the pre- and post-intervention samples were not matched and the reported effect size was 0.2; for Reed et al. ,129 the MD was –6.89, with a 95% CI of –2.58 to –11.2) and, for one study (Beresford et al. 162), using achievement of parent-set sleep goals (progress towards goals, 93% of participants; no progress, 7% of participants). However, one of the studies129 also used actigraphy to collect sleep outcomes data (TST, SOL, WASO). No benefits were reported on these outcomes. Reed et al. 129 also reported evidence of benefit in terms of parent-reported child behaviour (RBS-R). A further before-and-after study151 also evaluated a multisession (n = 3) group-delivered intervention but also offered implementation support after the group sessions had finished via weekly telephone calls (duration unclear). This study also used the CSHQ to measure child sleep outcomes and reported significant improvements immediately post intervention (MD –3.34, 95% CI –1.4 to –5.3). Child behaviour outcomes were also assessed (CBCL and PCQ) and no benefits were reported. Beresford et al. 162 also report significant improvements in self-reported parental efficacy but not parenting satisfaction (PSOC scale); however, pre- and post-intervention samples were not matched so a MD and CI could not be calculated. Reed et al. 129 and Yu and Hong161 investigated parenting stress using the Parenting Stressing Index; neither study reported a change in this outcome between pre- and post-intervention time points. Yu and Hong161 also report no effect on parent-reported sleep quality (Pittsburgh Sleep Quality Index). Taken together, there is some limited evidence of benefit for group-delivered interventions in terms of parent-reported child sleep outcomes. We would again, however, note that these studies were rated as having a high risk of bias. It is not possible to draw further conclusions with respect to other child, or parent, outcomes.

A RCT128 compared delivery of the same training curriculum via a multisession (n = 2) group-delivered intervention and a single intervention; both arms included the same level of implementation support. No differences in outcomes (1 month post intervention) between the two modes of delivery were reported on actigraphy-derived sleep outcomes (TST, Sleep Efficiency, SOL and WASO) or parent-reported measures of child sleep (CSHQ and FISH), behaviour (CBCL and RBS-R) or quality of life (PedsQL). As this is a single study that was rated as having a high risk of bias, and it is not clear if it was adequately powered, no conclusions can be drawn.

The final mode of intervention delivery evaluated was a single workshop (5 hours) delivered to groups of up to 20 parents. 163 No implementation support was available. Parent-reported sleep outcome measures (CSHQ and attainment of parent-identified sleep goals) were readministered 3 months after the workshop. Benefits on these indicators were reported by the authors (PSOC-efficacy, effect size 0.82; PSOC-satisfaction, effect size 0.38). However, MD and CIs could not be calculated, as the data were not reported for a matched sample. Given that this mode of intervention delivery was evaluated by only a single study that was rated as having a high risk of bias, no further conclusions can be drawn.

Child sleep-related outcomes

Sleep maintenance

The RCT152 (n = 30) of the intervention restricted to training on principles of behaviour modification reported a variety of actigraphy-measured sleep maintenance outcomes.

There were statistically significant reductions in fragmentation index (percentage of immobile phases during sleep period that were ≤ 30 seconds of duration), movement during sleep and movement index (percentage of sleep period spent moving) for both groups from pre intervention to visit 4; however, the differences between the groups at follow-up were not statistically significant (Table 18). 152

Other child outcomes

The RCT152 (n = 30) comparing the intervention restricted to training on behaviour modification principles with an attentional-control-measured child daytime behaviour using the parent-completed, and teacher-completed, Aberrant Behavior Checklist (ABC) (Table 19). 179 No statistically significant differences on ABC subscales (parent, or teacher, report) between the intervention and control arms were found post intervention, except for the parent-reported stereotypies subscale.

The before-and-after study155 (n = 23) of an intervention training in sleep hygiene principles reported a statistically significant improvement in scores on an assessment tool capturing severity of ADHD symptoms.

Parent outcomes

The RCT152 (n = 30) comparing the intervention restricted to training on behaviour modification principles with an attentional control reported on a range of parent outcomes, including:

• maternal TST (actigraphy)

• maternal fragmentation index (actigraphy)

• maternal movement during sleep (actigraphy)

• maternal movement index (actigraphy)

• maternal daytime sleepiness (Epworth Sleepiness Scale)

• paternal daytime sleepiness (Epworth Sleepiness Scale)

• maternal satisfaction with their own sleep (six-point Likert scale)

• paternal satisfaction with their own sleep (six-point Likert scale)

• maternal stress (Malaise Inventory)

• paternal stress (Malaise Inventory)

• maternal perceived ability to control difficult sleep-related behaviour of their child (visual analogue scale)

• paternal perceived ability to control difficult sleep-related behaviour of their child (visual analogue scale)

• maternal perceptions of their partner’s ability to control difficult sleep-related behaviour of their child (visual analogue scale)

• paternal perceptions of their partner’s ability to control difficulty sleep-related behaviour of their child (visual analogue scale).

Further details of how these outcomes were measured are provided in Appendix 22. The data are summarised in Table 20.

We found no statistically significant differences between the groups at follow-up for any of these outcomes except father’s satisfaction with child’s sleep.

Measures of perceived confidence and/or efficacy and/or understanding of sleep/sleep management

Both the RCT152 and the before-and-after study155 reported on measures of perceived confidence and/or efficacy and/or understanding of sleep/sleep management.

The RCT152 reported on parents’ orientation to internal or external control beliefs as measured using the internality/externality control scale. These data are summarised in Table 21 and details of how these outcomes were measured are provided in Appendix 23. There were significant between-group differences for the father measures. The before-and-after study155 measured perceived confidence and efficacy using a parent satisfaction Likert-type scale. The authors narratively report that 87% of the responses were positive; however, it is unclear whether or not these positive responses related to child’s sleep and/or the intervention.

Summary

Two studies evaluated tailored interventions that were non-comprehensive in terms of their content. Thus, although comprehensive parent-directed interventions (tailored and non-tailored) covered material on sleep and sleep processes, sleep hygiene and the management of specific problem behaviours (e.g. night wakings), non-comprehensive interventions focused on just one of these aspects. Both non-comprehensive interventions were, however, tailored interventions, that is, the intervention was personalised to the specific child and family context.

A RCT152 evaluated a parent-directed intervention in which the content was restricted to behavioural principles of managing problem sleep behaviour. This intervention was delivered via a single face-to-face session followed by implementation support at least weekly for up to 3 months (duration as required). The comparator group was an attention control in which parents attended a single session with a practitioner (same duration as active arm, session content not described). We treated follow-up data collected 1 month after the face-to-face session as post-intervention outcomes. The sample included a range of NDs and the mean age of the children was 8.21 years. The rating of risk of bias was high.

Post intervention, an actigraphy-derived measure of sleep outcome (TST) was no different between the intervention and control arms, with similar findings for other actigraphy-derived measures (fragmentation index, movement during sleep and movement index). However, significant differences in scores post intervention on a parent-reported child sleep measure (Composite Sleep Index), favouring the intervention group, were found (MD –2.83, 95% CI –4.24 to –1.42). In addition, post intervention, fathers’ (but not mothers’) ratings of satisfaction with the child’s sleep (non-standardised measure) were higher for the intervention group than for the control group (MD –1.37, 95% CI –2.37 to 0.37).

The study also assessed child behaviour (parent and teacher report) using five subscales (inappropriate speech, hyperactivity, stereotypies, lethargy and irritability) of the ABC. Post intervention, no significant differences between the intervention and control arms were found on any subscale scores except parent-reported stereotypies. Here, a benefit to the intervention group was reported (MD –3.6, 95% CI –5.95 to 1.25).

In terms of mothers’ and fathers’ outcomes, sleep outcomes [actigraphy-derived (mothers only): TST, fragmentation index, movement during sleep; self-report: Epworth Sleepiness Scale, non-standardised measure of satisfaction with sleep] and other outcomes (psychological distress (Malaise Inventory), non-standardised measures of perceptions of own and partner’s ability to control child’s difficult sleep-related behaviour) were monitored. No differences between intervention and control arms were found post intervention for any of these outcomes.

Overall, given that there is just one trial – and it has a high risk of bias – no conclusions can be drawn regarding the effectiveness of parent-directed sleep management interventions in which the content was restricted to behavioural principles of managing problem sleep behaviour.

In the second non-comprehensive parent-directed intervention, the content was restricted to sleep hygiene. 155 This was evaluated using a before-and-after study design. The intervention, specific to children with ADHD, was delivered via a single session between parent and practitioner. No implementation support was offered. The ages of children recruited to the study were not reported. Risk of bias was high. Follow-up was 6 weeks post intervention.

Post intervention, scores on the parent-reported CSHQ had improved (MD 6.4, 95% CI 4.3 to 8.5). A measure of ADHD symptom severity was also used (Vanderbilt Assessment Scale), and improvements were also reported on this measure post intervention (Vanderbilt Assessment Scale questions 1–9, MD –3.87, 95% CI –7.37 to 0.37; Vanderbilt Assessment Scale questions 10–18, MD –2.91, 95% CI –4.81 to 1.01). (Changes in scores on a non-standardised measure of parent satisfaction were also reported, although it is unclear if this is capturing satisfaction with the child’s sleep and/or the intervention per se).

In terms of this intervention, given that the evidence is limited to a before-and-after study with a high risk of bias, no conclusions regarding its impact on children’s sleep or ADHD symptoms can be drawn.

Global measures and composite scores

Other global measures and composite scores

One RCT36 (n = 73) and two before-and-after studies161 (n = 38) reported further global measures and composite scores (Table 23). There was a statistically significant difference in Composite Sleep Disturbance Index score (but not sleep efficiency) with weighted blankets compared with placebo blanket. 36

Two before-and-after studies159,161 measured CSHQ total score (validated parent-reported assessment of child sleep, with higher scores indicating a greater severity of the sleeping disturbance),159,161 although one reported this only for baseline. 159 A statistically significant reduction in total CSHQ score was reported following acupuncture and ear-point taping post intervention. 161

Sleep initiation

Sleep maintenance

Other sleep maintenance outcomes

Two RCTs36,157 (n = 87) and one before-and-after study158 (n = 14) reported other outcomes related to sleep maintenance (Table 26). The before-and-after study evaluating light therapy and a behavioural programme reported sleep diary-measured ‘longest wake and sleep periods during a 24-hour cycle’. Data for this outcome were reported only graphically and it was not possible to estimate results from the graph. 158

One RCT narratively reported that all six of the participants who received the faded bedtime and response costs intervention and had problems with early waking at baseline had improved on this outcome during the last 10 days of treatment. In the control group, two out of the six participants reported improvements in early wakings, one worsened and three saw little or no change following bedtime scheduling. 157

There was no difference between the treatment groups at follow-up in Gringas et al. 36 in terms of time awake after sleep onset and the proportion of nights with one or more awakening.

Child-related quality of life, daytime behaviour and cognition

Two RCTs36,156 (n = 78) reported on child daytime behaviour using a sleep diary156 and the ABC. 36

There was no statistically significant difference in daytime behaviour and cognition for total ABC score or subscale scores between the weighted blanket group and the control blanket group at 4 weeks from baseline (MD –2.3, 95% CI –5.4 to 0.8). 36 Francis and Dempster156 used the sleep diary data to narratively describe anecdotal changes in child behaviour, but quantitative data were not reported.

Other outcomes

One RCT (n = 73) and one controlled before-and-after study (n = 78) reported other outcomes of interest. 36,160 The RCT reported that there were no significant differences for the total Sensory Behaviour Questionnaire or its subscales between the weighted blanket group and the control blanket group. 36 The controlled before-and-after study that compared essential fatty acid supplements with placebo reported a variety of other child-related outcomes at the end of the 10-week intervention period. 160 These data are summarised in Table 28.

Adverse events

Two out of the seven studies reported adverse events (Table 29). 36,160 One study36 reported how adverse events were measured, namely through parents reporting to a 24-hour telephone number and weekly face-to-face or telephone-based reviews with parents. Five studies did not report adverse events. 156–159,161

Summary

Seven studies evaluated seven types of non-pharmacological interventions. These interventions were all different from each other. Therefore, we summarise the findings from each study in turn.

Weighted blankets were evaluated using a crossover RCT, with a non-weighted blanket as the control intervention. 36 The intervention was developed for children with ASD, and all children recruited to the study had this diagnosis. They were aged between 5 and 16 years. The trial was rated as having a high risk of bias. Outcomes were measured over each 2-week treatment period. Data on 27 children in each arm were analysed.

No benefits in terms of TST and SOL (derived from actigraphy) or a number of other sleep outcomes derived from parent-completed sleep diaries (number of wakings/night, proportion of nights with more than one waking and total time awake after sleep onset) were reported for children in the weighted blanket group compared with the non-weighted blanket group. Similarly, no benefits from a weighted blanket were reported in terms of child behaviour (ABC) or increased sensitivities to sensory stimulation (Sensory Behaviour Questionnaire). There were no serious adverse events.

Valerian, a herb prepared in tablet form, was evaluated with a placebo using a RCT156 in a sample of five children with a range of NDs aged 7–14 years who had difficulties with sleep initiation and/or sleep maintenance. The rating of risk of bias was high.

At 2 weeks post intervention, there was no difference between arms in terms of TST, SOL and duration of time awake during the night. Parents’ perceptions of sleep quality (measured using a non-standardised visual analogue scale) did not differ significantly between trial arms post intervention. No other quantitative data on child outcomes were reported. Adverse events were not reported.

Essential fatty acid supplement preparation in tablet form was evaluated using a controlled before-and-after study. 160 All children (active arm, n = 40; placebo, n = 38), aged 9–12 years, recruited to the study were diagnosed with ADHD and were described as ‘sleep deprived’. The study was rated as having a high risk of bias.

At 10 weeks post intervention, scores on a non-standardised measure of sleep quality did not differ between active and placebo groups. A number of other parent-reported child outcomes were evaluated using non-standardised, parent-reported indicators (degree of fatigue in general during the day, level of good mood in general, level of ability to concentrate during the day and percentage of homework completed in general). No significant difference between active and placebo arms was found for these outcomes. Transient gastric problems were reported for some children in the active group.

An aquatic exercise programme for children with ASD (mean age 8.8 years) and ‘sleep dysfunction’ was evaluated using a before-and-after study design. 159 Eight children were recruited to the study. The study was rated as having a high risk of bias. The outcomes at 8 weeks post intervention were reviewed. Biweekly telephone interviews with parents were used to collect data, from which TST and SOL were calculated. Increased TST post intervention was reported (MD 83.3 minutes, 95% CI 17.55 to 149.09 minutes). No other changes to child sleep outcomes were reported. Adverse events were not reported.

Acupuncture and ear-point taping were also evaluated using a controlled before-and-after study design. 161 Thirty children (mean age 6.9 years) with sleep initiation or maintenance difficulties and/or an ‘abnormal sleep state’ were recruited to the study. All were described as having learning disabilities. It was not clear when post-intervention outcomes data were collected. The study was rated as having a high risk of bias. At post intervention, a significant improvement in scores on a parent-reported sleep outcome measure (CSHQ) was reported (MD –11.50, 95% CI –13.33 to –9.67).

A light therapy intervention combined with a programme of daytime schedules and activities was evaluated using a before-and-after study. 158 Fourteen children, aged 9 months to 4 years, were recruited to the study. They were described as having learning disabilities. The study was rated as having a high risk of bias. Outcomes were measured at 6 months post intervention. Five out of 14 children were reported to have ‘responded to treatment’ as measured by increases in TST (calculated from information collected by the study team during regular interviews with parents), which were reported to have improved post intervention. There were no serious adverse events.

Finally, the relative effectiveness of faded bedtime and response costs with bedtime scheduling was investigated using a parallel RCT. 157 The trial took place in an inpatient unit for children with very severe behaviour problems. The children (n = 14, 7 per arm) recruited to the trial had a range of NDs and sleep disturbances relating to sleep maintenance and ‘sleep consolidation’. They were aged 4–14 years. The trial was rated as having a high risk of bias. Outcomes were measured pre intervention and 10 days post intervention. Only narrative reports of sleep outcomes (based on observational data) are provided.

Overall, there is no evidence of benefit for weighted blankets, although we note that this was a single study that was rated as having a high risk of bias. Issues regarding study design and study bias mean that no conclusions can be drawn regarding the impact of the following interventions: valerian, fatty acid supplements, light therapy with daytime activities programme, acupuncture and ear-point taping, and an aquatic exercise programme. Finally, we note that the last two studies described157,158 were both reported almost 25 years ago, and no further studies replicating these interventions are reported. It is questionable whether or not they remain relevant or accepted approaches to managing sleep disturbance in children with NDs.

Quality appraisal

The quality appraisal of ‘family experience’ studies used the tool created by Hawker et al.,66 chosen because it was developed for use in reviews in which both qualitative and quantitative data are included and data in this review have been generated by studies using different paradigms. The tool was used in two ways. First, for studies (n = 2) in which a primary objective was to investigate family experience, and this is reported in a separate paper, a full quality appraisal was conducted (see Appendix 20). Second, for studies (n = 10) in which ‘family experience’ was a secondary study objective and was a minor element of evidence presented in any papers, the tool was used by the team to appraise, but not individually rate, the quality of the studies and evidence presented. One study106 reported data that were a part of routine data collection within a trial (i.e. the reason for study dropout). We did not subject this specific element of the study to a separate quality appraisal.

For the 10 studies36,49,107,123–129 for which ‘family experience’ was a secondary objective, the quality of studies and study reporting was very mixed. A number of issues were frequently noted that affected the quality of the ‘family experience’ objectives of these studies. First, family experience was sometimes not explicitly identified as a research objective. In addition, parent characteristics (e.g. gender, educational achievement, ethnicity and first language) were rarely reported. This is a significant omission, given that the majority of interventions represented in the ‘family experience’ data set were parent-directed interventions. Data collection tools were inadequately reported and/or study-specific tools were developed that, it would appear, had not undergone any piloting or been developed in consultation with parents. Descriptions of the analysis of family experience data were typically missing or very limited. Analyses were descriptive and opportunities to explore factors affecting experiences were not exploited. Based on the description of the data collection instruments, it appeared that, in some studies, not all findings were reported.

Findings

Findings on family experience can be found in Appendix 19.

Summary

Thirteen studies concerning family experience of sleep management interventions were identified, reporting 16 sleep management interventions in total. 36,49,106,107,122–130 All but one106 of the studies concerned non-pharmacological interventions: 14 were parent-directed interventions49,107,122–130 and one was a study of weighted blankets. 36 For these studies, data were predominantly quantitative (total n = 225) and typically collected using a questionnaire specifically designed for the study. One study124 supplemented questionnaire data through semistructured interviews with a subsample (n = 6) of study participants. A further study130 (n = 35), which investigated the family experience of four parent-directed sleep management interventions, used entirely qualitative methods. Study quality varied.

The pharmacological study106 reported data relevant to family experience106 concerning difficulties administering the medication. This was reported within the context of reporting on reasons for study withdrawal, rather than the study explicitly seeking to include an exploration of the family experience along with the evaluation of the medicine. 106

Therefore, the most extensive data set concerns parents’ experiences of receiving and implementing a sleep management intervention (11 studies21,49,107,123–129,149). The data were organised around five themes: parents’ experiences of accessing the intervention, parents’ experiences of implementing a sleep management strategy, parents’ views about the elements of the intervention that had an impact on the outcomes experienced, parents’ experiences as service users and recommending the intervention to others. Across all these themes, the data are very limited. There are a number of reasons for this. First, the pool of studies is very small. Second, many studies collected very few data. Third, studies typically used their own data collection instrument, thus hindering the pooling of data.

With these caveats, the following comments are made. There is very little evidence on parents’ experiences of accessing sleep management interventions. One study reported that parents believed that the time requirements associated with receiving a sleep management intervention could be a barrier to parents accessing an intervention. 124 Another found that the time-consuming nature of the intervention was a feature of the intervention that was ‘least liked’ by some study participants. 126 However, across all studies, only one participant is reported as finding the duration of the intervention too long. 126

Parents’ experiences of implementing a sleep management strategy were explored by five studies. 107,122,123,126,130 A consistent theme across all – although it was not universally reported by study participants – is the challenges and demands placed on parents as they implement the strategy. Despite this, all of the studies that asked parents if they would recommend the intervention to others reported unanimous or high levels of recommendation. On a related point, a further study144 reported exploring parents’ judgements as to their adherence to a sleep management strategy and it suggests that consistent adherence to sleep management interventions should not be assumed. Another study identified a range of factors that may further interfere with implementing a sleep management strategy. 130

Support with implementing a sleep management intervention was consistently identified by studies that offer data on elements of interventions that parents believe support positive outcomes. In terms of mode of delivery, both individual work and group delivery are identified as supporting positive outcomes: one offering the opportunity for a highly tailored intervention and the other offering peer support.

Principal findings: pharmacological interventions

There was evidence of benefit of melatonin compared with placebo, although the precise extent of the benefit, which children may benefit the most and the clinical importance of the benefit remain uncertain.

Discussion of principal findings: pharmacological interventions

This conclusion concurs with the issues raised by the team that conducted the only trial of (fast-release) melatonin rated as having a low risk of bias included in the review. 48 In it, the study sample comprised children with developmental delay and some with additional diagnoses, including epilepsy, autism or a specific genetic or chromosomal disorder. The authors note that ‘the sheer heterogeneity of the population studied has inevitably limited our ability to accurately estimate the impact of melatonin treatment for individual groups of patients with specific clinical (genetic), behavioural or developmental presentations’. 48

A core inclusion criterion for the Appleton et al. 48 trial was that a parent-directed intervention – in the form of an advice booklet – had not successfully addressed the presenting sleep disturbance. For over half of the children recruited to the trial (56%), this intervention did not sufficiently address the sleep disturbance and they were randomised to the melatonin or placebo arms. This finding does lend support to the argument, and based on understandings of types and aetiologies of sleep disturbance in children with NDs, that pharmacological and non-pharmacological approaches may both be required. It can also be taken to suggest that for some types of sleep disturbance, recourse to melatonin should occur only once attempts to change the way that a family may be managing the sleep disturbance have been tried.

Principal findings: parent-directed interventions

Studies of parent-directed interventions took two broad forms: (1) they were concerned with the clinical effectiveness of the intervention compared with no intervention or (2) they were testing different approaches to delivering the same intervention (e.g. varying mode of delivery or intensity of contact between the practitioner and the parent). There was variability between interventions in terms of intervention characteristics, such as mode of delivery, intensity, duration and availability of implementation support. Overall, the quality of the evidence was rated as having a high or unclear risk of bias in reporting and, therefore, the findings of these studies cannot be considered robust.

In terms of the tailored interventions, there was mixed evidence about the effects of these interventions on child (and parent) outcomes. There was limited evidence of benefit on more objective measures of sleep outcomes (actigraphy, verified or not with parent-completed sleep diaries). More evidence of benefit was found on parent-reported outcomes and a few parent outcomes. Conclusions are hampered by the limited number of RCTs, the multitude of outcome measures and the risk of studies being underpowered to detect an effect. Two small RCTs investigated specific intervention characteristics: mode of delivering implementation support21 and a brief versus extended (with implementation support) version of an intervention. 125 The rating of a high risk of study bias and the trials being underpowered mean that no conclusions can be drawn.

Compared with the tailored interventions, the non-tailored interventions evaluated were even more diverse in terms of a number of intervention characteristics, including mode of delivery [i.e. written material, group delivery (single vs. multiple sessions) and one-to-one work], the extent to which they accommodated parents’ individual learning and training needs and whether or not implementation support was available. Overall, the conclusions that can be drawn from this evidence are limited owing to the high risk of bias, the wide range in post-intervention follow-up time points and the risk of studies being underpowered to detect an effect. In addition, a large number of outcome measures were used, capturing a wide range of outcome domains.

There was mixed and very limited evidence regarding the impact that the provision of written information to parents had on managing their child’s sleep disturbance. No conclusions can be drawn regarding the relative benefits of written versus face-to-face delivery of sleep management training to parents. There is some limited evidence of benefit for group-delivered interventions in terms of parent-reported sleep outcomes (but not reported for more objective measures of sleep). A single RCT128 compared the individual delivery of an intervention via a single session with delivery of the same training via two group-delivered sessions. The rating of having a high risk of study bias and the trial being underpowered means that no conclusions can be drawn from the study findings. No RCTs were identified that evaluated a single-session workshop approach to delivering sleep management training to parents. It is useful to note that this mode of delivery is widely accessible to parents in the UK via statutory and non-statutory providers.

Two non-comprehensive parent-directed interventions are also reported by this study. The first is a trial (rated as having a high risk of bias) that evaluated an intervention in which the content was restricted to training on behavioural principles of managing problem behaviour compared with an attention control intervention. 152 The content of the second intervention was restricted to sleep hygiene principles and practices,155 which was evaluated using a before-and-after study design.

Discussion of principal findings: parent-directed interventions

It is relevant to briefly contextualise these findings on parent-directed interventions within the wider evidence base on the clinical effectiveness of parent-directed interventions for managing sleep in children with typical development. Here, a recent review, which identified 15 trials110,127,184–197 and 11 before-and-after studies,149,198–208 concluded that there was ‘moderate support’ for such interventions for young children (≤ 5 years). A paucity of trials that included older children and adolescents limited any conclusions being drawn with respect to these older age groups. 184 The authors recommend that, for young children who have typical development and are healthy, parent-directed interventions should be implemented with ‘no hesitation’. Furthermore, although noting the lack of evidence, the authors also recommend that they are used for older children and adolescents.

For children with NDs, however, additional factors may be at play in the development of behavioural insomnias, which may have implications for the content and scope of the training and advice given to parents, the duration of support parents may require to implement new sleep management approaches and strategies and the clinical effectiveness of a parent-directed intervention. 209 These include communication difficulties (both parental communication about bedtime and sleep and the child’s ability to understand sleep cues or communicate their needs),210,211 sensory sensitivities,209 cognitive delay and arousal associated with daytime behaviour problems. 212 This has implications for the design of future evaluations.

Parent-directed interventions as complex interventions: implications

Parent-directed interventions to manage sleep disturbance in children with NDs can be regarded as ‘complex intervention’, that is, they comprise a number of different interconnected elements. Early guidance, issued by the Medical Research Council on developing and evaluating complex interventions,213,214 has subsequently been developed and refined, including the need for intervention development and evaluation to be theory driven. 215 The theory underlying or informing an intervention will identify its ‘active ingredients’ and the factors that may moderate or mediate their therapeutic action. Although accepted as a fundamental feature of pharmacological studies, the notion of ‘active ingredients’ is as relevant and important to our understanding and evaluation of non-pharmacological interventions. 216,217 However, adoption of robust approaches to the evaluation of complex interventions, in which a theory of change has informed the study design and outcomes measured and the active ingredients are clearly defined and specified, remains patchy. 218

Specifying a theory of change, and the active ingredients, to complex interventions such as parent-delivered sleep management interventions requires looking not only at content of the ‘training’ delivered to parents, per se, but also at the features of the individuals involved in delivery, at the context, or mode, in which the training is delivered and in the implementation. 216,219 It would be fair to say that the influence of this thinking and methodological debate has, to date, had relatively little impact on evaluations of parent-directed, sleep management interventions for children with NDs. Behavioural theories (e.g. extinction, positive reinforcement) are explicitly identified as underpinning all the sleep management strategies on which parents were trained in the comprehensive parent-directed interventions and one of the non-comprehensive interventions. 152 In addition, the influence of social learning theory220 on choices about the techniques used to teach and train parents is apparent (e.g. the use of role-play, modelling, observation, group problem-solving). However, a theory of the process by which upskilling a parent in sleep management results in changes in a child’s sleep, and the factors that have an impact on that process, is left (relatively) undiscussed and unexplored. This is evidenced by the fact that only a small minority of the studies measured changes in parents’ knowledge of sleep management, perceived parenting confidence, collected data on parents’ characteristics and/or sought to assess the extent to which parents accurately or consistently applied their training.

The evidence reviewed regarding the ‘family experience’ of parent-directed sleep management interventions offers some, limited, insights into the process by which parent-directed interventions affect changes in the duration or quality of a child’s sleep and the factors that parents believe facilitate or hinder this process. However, the story appears complex. Thus, for example, although support with implementing new approaches to managing their child’s sleep disturbance was consistently identified as a valued or helpful aspect of the intervention received by parents, views on mode of delivery revealed that there were different benefits in group versus individual delivery. Exposure to other parents’ experiences and access to peer support were identified as supporting positive outcomes. In terms of individually delivered interventions, a key benefit reported by parents was the scope to personalise an intervention to the child and the family’s specific needs and context. It is also important to note that parents are likely to vary in their abilities, capacities and/or willingness to access the different modes of delivery. 221

Principal findings

There was no evidence that weighted blankets – an intervention that parents can purchase and use without professional supervision or receive via a prescription from statutory health services – were clinically effective. Issues of study design and ratings of high risk of study bias mean that no conclusions can be drawn regarding the impact of the following interventions: valerian, fatty acid supplements, light therapy with daytime activities programme, acupuncture and ear-point taping and the aquatic exercise programme.

Outcomes and outcome measurement

A number of issues need to be addressed in future research to generate robust and meaningful evidence that, in future reviews, can be subject to meta-analysis.

First, a large number of different child sleep outcomes and measurement tools were used by the studies included in this review. Our synthesis of the studies was partly hampered by this diversity of outcome measures in relation to both child sleep outcomes and other outcomes for children and their parents. Only TST was measured in the majority of studies and assessed in a similar way across studies. We would note that when evidence of benefit of a sleep management intervention was reported – and actigraphy and parent-report measures were used – benefit was more frequently observed with respect to parent-reported measures. It is not clear whether this is because of issues of objectivity versus subjectivity in outcome measurement or that these different measurement approaches are capturing qualitatively different outcomes.

Adverse events were reported in the majority of melatonin trials. However, the type of adverse event reported, data collection methods used and reporting of adverse events varied. Standardisation of the reporting and data collection methods for adverse events in future trials is important to understand the safety of pharmacological interventions. This also has relevance for non-pharmacological studies, in which interventions may have unintended consequences.

There were two additional issues: (1) variability in the outcome domains of interest, for example carer outcomes were assessed in some studies and not others and (2) variability in the measure used to assess specific outcome domains. Previous research has identified sleep as a key health outcome for children and young people with ND, their parents30 and health-care professionals. 222 However, based on searches of the Core Outcome Measures In Effectiveness database (www.comet-initiative.org; accessed 21 June 2017), no work has been undertaken to prioritise outcomes for children with NDs who experience sleep disturbances and their parents. A core outcome set would greatly assist the usefulness of research in this field, in which there are so many management options, allowing comparison between studies and also ensuring that the outcomes that are assessed are of relevance to children, their parents and also the health-care professionals involved in their care.

Second, further work with families to establish what constitutes a meaningful and worthwhile change in these outcome measures is important. Just one study49 adopted this approach, with a 50% reduction in the composite sleep disturbance score identified by parents participating in the study as the minimum change for the intervention to be considered worthwhile.

Meaningful and sufficient change may also have guided the duration of implementation support in interventions in which the duration of this was reported as variable, or needs-led,21,124,146 but the heuristic for ceasing implementation support was not explicitly reported. Furthermore, other studies reported an extended period of implementation support but it was not clear whether this duration was predetermined or simply what actually occurred when the intervention was delivered. An alternative, or additional, approach used by a small number of studies was the setting of parent-identified goals for their child’s sleep, with progress towards these goals tracked over follow-up time points. However, none of these studies used Goal Attainment Scaling methodology,223,224 which allows identification of, and tracking of progress towards, personalised intervention goals, with the creation of an aggregated score for each study participant, and allows robust comparisons between participants. This would appear to be a measurement approach worth considering in future research, alongside objective and other parent-reported outcome measures, as is the case in evaluations of complex interventions in other fields. 225

Third, consistency in follow-up time points based on an evidence-informed theory of change is required. This is particularly an issue for non-pharmacological interventions in which the implementation of newly acquired knowledge and skills in managing a child’s sleep may take time to have an effect. Thus, within the different types of parent-directed interventions, consensus is required as to the most clinically meaningful follow-up time points and whether or not evaluations should seek to also investigate maintenance of outcomes. This would also assist in comparisons between studies in future systematic reviews and meta-analyses.

Fourth, further work is required to identify other relevant child outcome measures and the time points at which such outcomes should be measured. Cognitive ability is an important example here. Little is understood about the benefits of (even small) cumulative gains in sleep in terms of arresting neuronal and cognitive loss. 226 Thus, the identification of appropriate follow-up time points and meaningful measures of cognition, an outcome that is challenging to accurately capture in children with severe learning disabilities, are essential. The selection of other child outcome measures also needs to be evidence based and informed by the intervention’s theory of change for that outcome.

Fifth, for parent-directed interventions, the development and application of a theory of change is required in the selection of appropriate outcomes. This is because children’s sleep outcomes will be mediated by the outcomes for parents achieved by the intervention, that is, the acquisition of new knowledge and understanding of sleep, and training in managing sleep disturbance. Furthermore, evidence from the wider literature on parenting interventions indicates that the extent to which these parent-centred outcomes are achieved are mediated/moderated by a number of factors, located in parent, practitioner and intervention characteristics. Only a minority of parent-directed interventions captured outcomes in this domain. Similarly, few studies report parent characteristics.

The design of evaluations

As we have noted earlier, evaluations need to be designed in such a way that the evidence generated addresses the key questions of what works, for whom and in what circumstances? Interestingly, a similar call for evidence has been made with respect to evaluation of similar interventions for children with typical development. 184 It would be informative to explore subgroup analyses within any future trials. In order to make any analyses more credible, it will be important to define these subgroups in advance, and the direction of effect, based on existing evidence. 227,228 Depending on the evaluation, subgroups may be in terms of sleep problem, child, parent or intervention characteristics.

In addition, for parent-directed interventions, RCTs need to incorporate measures of adherence and/or fidelity. These are loosely defined concepts. An evaluation of parent-directed interventions to manage autism symptoms usefully defined it as both the accuracy and comprehensiveness of the intervention delivered to the parents by the practitioner and the consistency and competency of the parent as they implement new approaches to managing their child’s sleep disturbance. 229 Our review of ‘family experience’ data identified that parents can find implementing a new sleep management strategy stressful and demanding. Only one study125 attempted to assess this in any way, relying on parents’ reports of the proportion of times that they implemented the new sleep management strategy. There are clearly significant challenges related to the feasibility and costs associated with measuring parent’s adherence and fidelity to a sleep management strategy given the time of day when parents will be implementing a sleep management strategy and the home setting. Methodological research will be required to inform incorporating this into study designs.

Finally, the final follow-up time point for most studies allowed consideration of short-term outcomes only. Future studies need to consider what longer-term follow-ups should be incorporated into study designs. Evidence on longer-term outcomes is particularly pertinent for parent-directed interventions that require significant investment in parents’, as well as practitioners’, time, physical and emotional resources (and potentially entail significant, if short-term, disruption to the family). If available, such evidence would support shared decision-making regarding the management of a child’s sleep disturbance.

Moving towards replication

At the moment, the evidence base predominantly comprises single evaluations of interventions. These are principally either investigations into the management of sleep disturbance by a particular clinic or are (typically) early evaluations of a newly developed intervention, prior to its implementation into routine practice. There are just two instances of some sort of replication study; however, in both,123,124,128,129 there are differences between the studies in the way the intervention was delivered. A taxonomy by which interventions should be defined and adherence to Template for Intervention Description and Replication (TIDieR) guidance164 in study reporting would support both replication and future evidence syntheses.

Search strategy

((((SU.EXACT(“Sleep disorders”) OR SU.EXACT(“Sleep problems”)) OR SU.EXACT(“Narcolepsy”)) OR ((“bed time*” NEAR/3 (dysfunction* OR disorder* OR difficult* OR disrupt* OR disturb* OR delay* OR problem*)) OR (bedtime* NEAR/3 (dysfunction* OR disorder* OR difficult* OR disrupt* OR disturb* OR delay* OR problem*)) OR (“bed time*” NEAR/3 (initial* OR pattern* OR routine* OR practice* OR maintain* OR intervention* OR schedule*)) OR (“bed time*” NEAR/3 (initial* OR pattern* OR routine* OR practice* OR maintain* OR intervention* OR schedule*))) OR ((night* NEAR/3 (dysfunction* OR disorder* OR difficult* OR disrupt* OR disturb* OR delay* OR problem*)) OR (night* NEAR/3 (settle* OR settling OR wake* OR awake OR wakeful* OR waking* OR awaking* OR awakening* OR wakening*)) OR (nocturnal NEAR/3 (dysfunction* OR disorder* OR difficult* OR disrupt* OR disturb* OR delay* OR problem*)) OR (nocturnal NEAR/3 (settle* OR settling OR wake* OR awake OR wakeful* OR waking* OR awaking* OR awakening* OR wakening*))) OR ((sleep* NEAR/3 (dysfunction* OR disorder* OR difficult* OR disrupt* OR disturb* OR delay* OR problem*)) OR (sleep* NEAR/3 (settle* OR settling OR wake* OR awake OR wakeful* OR waking* OR awaking* OR awakening* OR wakening*)) OR (sleep* NEAR/3 (initial* OR pattern* OR routine* OR practice* OR maintain* OR intervention* OR schedule*)) OR (sleepless* OR insomnia* OR parasomnia* OR “night terror*” OR nightterror* OR “night mare*” OR nightmare*) OR (“sleepwalk*” OR “nighthawk*” .) OR (sleepwalk* OR sleepwalk* OR “sleep walk*” OR somnambulism) OR (narcolepsy OR “nocturnal hyperkinesia”))) AND ((SU.EXACT(“Children”) OR SU.EXACT(“adolescentce”) OR SU.EXACT(“Infants”)) OR (adolescent* OR baby OR babies OR child OR children OR boy OR boys OR girl OR girls OR infant* OR infancy* OR juvenile* OR paediatric OR pediatric OR preschooler* OR schoolboy* OR schoolgirl* OR schoolchild* OR teens OR teenager* OR toddler* OR youth OR youths OR “young people” OR “young person*”))) AND (((SU.EXACT(“Developmentally disabled children”) OR SU.EXACT(“Developmentally delayed children”)) OR (SU.EXACT(“Developmental delays”) OR SU.EXACT(“Developmental disorders”)) OR SU.EXACT(“Angelman syndrome”) OR (SU.EXACT(“Attention deficit disorder”) OR SU.EXACT(“Attention deficit hyperactivity disorder”)) OR SU.EXACT(“Conduct disorders”) OR SU.EXACT(“Complex partial seizure disorder” OR “Epilepsy” OR “Idiopathic childhood epilepsy” OR “Landau-Kleffner syndrome” OR “Panayiotopoulos syndrome” OR “Temporal lobe epilepsy”) OR SU.EXACT(“Cerebral palsy”) OR SU.EXACT(“Down’s syndrome”) OR SU.EXACT(“Fragile X syndrome”) OR (SU.EXACT(“Prader - Willi syndrome”) OR SU.EXACT(“Prader-Willi syndrome”))) OR (SU.EXACT(“Rett syndrome”) OR SU.EXACT(“Smith-Magenis syndrome”) OR (SU.EXACT(“Williams-Beuren syndrome”) OR SU.EXACT(“Williams’ syndrome”)) OR (ADHD or “attention deficit” OR “angelman syndrome”) OR (autism or autistic or asperges* OR “cerebral palsy”) OR (“conduct disorder*” OR epilepsy or epileptic) OR (“Down* syndrome” OR “Fragile x syndrome”) OR (“Prader Willi Syndrome” OR “Prader-Willi Syndrome”) OR (“Rett syndrome” OR “Williams syndrome”)) OR (developmental NEAR/2 (disability* OR delay*)) OR neurodisability* OR (neurodevelopment* NEAR/3 (delay* OR disability* OR disease* OR disorder* OR dysfunction)) OR (neuromotor* NEAR/3 (delay* OR disability* OR disease* OR disorder* OR dysfunction)) OR (neuropsychiatr* NEAR/3 (delay* OR disability* OR disease* OR disorder* OR dysfunction)) OR (neuropsychol* NEAR/3 (delay* OR disability* OR disease* OR disorder* OR dysfunction)))

Search strategy

Search strategy

#1 MeSH descriptor: [Sleep Wake Disorders] explode all trees

#2 MeSH descriptor: [Sleep] explode all trees

#3 MeSH descriptor: [Somnambulism] explode all trees

#4 MeSH descriptor: [Narcolepsy] explode all trees

#5 sleep* near/3 (initiat* or pattern* or routine* or practice* or maintain* or intervention* or schedule*):ti,ab,kw or sleepless* or insomnia* or parasomnia* or “night terror*” or nightterror* or “night mare*” or nightmare*:ti,ab,kw or “sleep-wak*” or “night-wak*”:ti,ab,kw or “sleep-wak*” or “night-wak*” or sleepwalk* or “sleep-walk*” or “sleep walk*” or somnambulism:ti,ab,kw or narcolepsy or “nocturnal hyperkinesia”:ti,ab,kw (Word variations have been searched)

#6 nocturnal near/3 (dysfunction* or disorder* or difficult* or disrupt* or disturb* or delay* or problem*):ti,ab,kw or nocturnal near/3 (settle* or settling or wake* or awake or wakeful* or waking* or awaking* or awakening* or wakening*):ti,ab,kw or sleep* near/3 (dysfunction* or disorder* or difficult* or disrupt* or disturb* or delay* or problem*):ti,ab,kw or sleep* near/3 (settle* or settling or wake* or awake or wakeful* or waking* or awaking* or awakening* or wakening*):ti,ab,kw (Word variations have been searched)

#7 night* near/3 (dysfunction* or disorder* or difficult* or disrupt* or disturb* or delay* or problem*):ti,ab,kw or night* near/3 (settle* or settling or wake* or awake or wakeful* or waking* or awaking* or awakening* or wakening*):ti,ab,kw (Word variations have been searched)

#8 bed* near/3 (dysfunction* or disorder* or difficult* or disrupt* or disturb* or delay* or problem*):ti,ab,kw and bed* near/3 (settle* or settling or wake* or awake or wakeful* or waking* or awaking* or awakening* or wakening*):ti,ab,kw (Word variations have been searched)

#9 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8

#10 MeSH descriptor: [Child] explode all trees

#11 MeSH descriptor: [Adolescent] explode all trees

#12 MeSH descriptor: [Infant] explode all trees

#13 adolescen* or baby or babies or child or children or boy or boys or girl or girls or infant* or infanc* or juvenile* or paediatric or pediatric or preschooler* or schoolboy* or schoolgirl* or schoolchild* or teens or teenager* or toddler* or youth or youths or “young people” or “young person*”:ti,ab,kw (Word variations have been searched)

#14 #10 or #11 or #12 or #13

#15 #9 and #14

#16 MeSH descriptor: [Developmental Disabilities] explode all trees

#17 MeSH descriptor: [Child Development Disorders, Pervasive] explode all trees

#18 MeSH descriptor: [Angelman Syndrome] explode all trees

#19 MeSH descriptor: [Attention Deficit Disorder with Hyperactivity] explode all trees

#20 MeSH descriptor: [Attention Deficit and Disruptive Behavior Disorders] explode all trees

#21 MeSH descriptor: [Conduct Disorder] explode all trees

#22 MeSH descriptor: [Epilepsy] explode all trees

#23 MeSH descriptor: [Cerebral Palsy] explode all trees

#24 MeSH descriptor: [Down Syndrome] explode all trees

#25 MeSH descriptor: [Fragile X Syndrome] explode all trees

#26 MeSH descriptor: [Prader-Willi Syndrome] explode all trees

#27 MeSH descriptor: [Rett Syndrome] explode all trees

#28 MeSH descriptor: [Smith-Magenis Syndrome] explode all trees

#29 MeSH descriptor: [Williams Syndrome] explode all trees

#30 #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29

#31 ADHD or “attention deficit”:ti,ab,kw or “angelman syndrome”:ti,ab,kw or autism or autistic or asperger*:ti,ab,kw or “cerebral palsy”:ti,ab,kw or “conduct disorder*”:ti,ab,kw (Word variations have been searched)

#32 epilepsy or epileptic:ti,ab,kw or “Down* syndrome”:ti,ab,kw or “Fragile x syndrome”:ti,ab,kw or “Prader Willi Syndrome”:ti,ab,kw or “Rett syndrome”:ti,ab,kw (Word variations have been searched)

#33 “Smith-Magenis syndrome”:ti,ab,kw or “Williams syndrome”:ti,ab,kw (Word variations have been searched)

#34 developmental near/2 (disabilit* or delay*):ti,ab,kw or neurodisabilit*:ti,ab,kw or neurodevelopment* near/3 (delay* or disabilit* or disease* or disorder* or dysfunction*):ti,ab,kw or neuromotor* near/3 (delay* or disabilit* or disease* or disorder* or dysfunction*):ti,ab,kw (Word variations have been searched)

#35 neuropsychiatric* near/3 (delay* or disabilit* or disease* or disorder* or dysfunction*):ti,ab,kw or neuropsychol* near/3 (delay* or disabilit* or disease* or disorder* or dysfunction*):ti,ab,kw (Word variations have been searched)

#36 #31 or #32 or #33 or #34 or #35

#37 #30 or #36

#38 #15 and #37

Search strategy

Search strategy

1. exp Sleep Disorder/ (162,095)

2. Sleep/ (81,239)

3. Sleep Walking/ (1490)

4. Narcolepsy/ (6862)

5. ((bed time or bedtime$) adj3 (dysfunction$ or disorder$ or difficult$ or disrupt$ or disturb$ or delay$ or problem$)).ti,ab. (318)

6. ((bed time$ or bedtime$) adj3 (initiat$ or pattern$ or routine$ or practice$ or maintain$ or intervention$ or schedule$)).ti,ab. (282)

7. (night$ adj3 (dysfunction$ or disorder$ or difficult$ or disrupt$ or disturb$ or delay$ or problem$)).ti,ab. (2451)

8. (night$ adj3 (settle$1 or settling or wake$1 or awake or wakeful$ or waking$ or awaking$ or awakening$ or wakening$)).ti,ab. (3053)

9. (nocturnal$ adj3 (dysfunction$ or disorder$ or difficult$ or disrupt$ or disturb$ or delay$ or problem$)).ti,ab. (1558)

10. (nocturnal$ adj3 (settle$1 or settling or wake$1 or awake or wakeful$ or waking$ or awaking$ or awakening$ or wakening$)).ti,ab. (1279)

11. (sleep$ adj3 (settle$1 or settling or wake$1 or awake or wakeful$ or waking$ or awaking$ or awakening$ or wakening$)).ti,ab. (22,635)

12. (sleep$ adj3 (dysfunction$ or disorder or disorders or difficult$ or disrupt$ or disturb$ or delay$ or problem$)).ti,ab. (50,363)

13. (sleep$ adj3 (initiat$ or pattern$ or routine$ or practice$ or maintain$ or intervention$ or schedule$)).ti,ab. (13,975)

14. (sleepless$ or insomnia$ or parasomnia$ or night terror$ or nightterror$ or night mare$ or nightmare$).ti,ab. (29,033)

15. (sleep-wak$ or night-wak$).ti,ab. (11 to 232)

16. (sleepwalk$ or sleep-walk$ or sleep walk$ or somnambulism).ti,ab. (981)

17. (narcolepsy or nocturnal hyperkinesia).ti,ab. (5221)

18. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 (242,035)

19. exp Infant/ or exp Child/ or exp Adolescent/ (2,934,245)

20. (adolescen$ or baby or babies or child or children or boy or boys or girl or girls or infant$ or infanc$ or juvenile$ or paediatric or pediatric or preschooler$ or schoolboy$ or schoolgirl$ or schoolchild$ or teens or teenager$ or toddler$ or youth or youths or young people or young person$).ti,ab. (2,021,633)

21. 19 or 20 (3,492,441)

22. Childhood Disintegrative Disorder/ (128)

23. Developmental Disorder/ (28,670)

24. Asperger Syndrome/ (3660)

25. Attention Deficit Disorder/ or Attention Deficit Disorder with Hyperactivity/ or Attention Deficit Hyperactivity Disorder/ (43,642)

26. exp Autism/ (44,025)

27. Conduct Disorder/ (5234)

28. exp Epilepsy/ (194,464)

29. Cerebral Palsy/ (28,687)

30. Down Syndrome/ (29,198)

31. Fragile X Syndrome/ (6859)

32. Happy Puppet Syndrome/ (2139)

33. “Pervasive Developmental Disorder not otherwise specified”/ (790)

34. Prader-Willi Syndrome/ (4427)

35. Rett Syndrome/ (3903)

36. Smith Magenis Syndrome/ (480)

37. Williams Beuren Syndrome/ (2655)

38. (ADHD or attention deficit).ti,ab. (32,156)

39. angelman syndrome.ti,ab. (1370)

40. (autism or autistic or asperger$).ti,ab. (38,978)

41. cerebral palsy.ti,ab. (22,489)

42. conduct disorder$.ti,ab. (4762)

43. (epilepsy or epileptic).ti,ab. (137,265)

44. Down$ syndrome.ti,ab. (23,072)

45. Fragile x syndrome.ti,ab. (4278)

46. Prader Willi Syndrome.ti,ab. (3070)

47. Prader-Willi Syndrome.ti,ab. (3070)

48. Rett syndrome.ti,ab. (3072)

49. Smith-Magenis syndrome.ti,ab. (334)

50. Williams syndrome.ti,ab. (1688)

51. (developmental adj2 (disabilit$ or delay$)).ti,ab. (18,243)

52. neurodisabilit$.ti,ab. (271)

53. (neurodevelopment$ adj3 (delay$ or disabilit$ or disease$ or disorder$ or dysfunction$)).ti,ab. (8726)

54. (neuro-motor$ adj3 (delay$ or disabilit$ or disease$ or disorder$ or dysfunction$)).ti,ab. (20)

55. (neuromotor$ adj3 (delay$ or disabilit$ or disease$ or disorder$ or dysfunction$)).ti,ab. (428)

56. (neuropsychiatric$ adj3 (delay$ or disabilit$ or disease$ or disorder$ or dysfunction$)).ti,ab. (11,567)

57. (neuropsychol$ adj3 (delay$ or disabilit$ or disease$ or disorder$ or dysfunction$)).ti,ab. (2857)

58. 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 (415,764)

59. 18 and 21 and 58 (10,326)

60. (animal/ or nonhuman/) not exp human/ (4,938,572)

61. 59 not 60 (10,288)

Search strategy

1. ((bed time or bedtime$) adj3 (dysfunction$ or disorder$ or difficult$ or disrupt$ or disturb$ or delay$ or problem$)).ti,ab. (1)

2. ((bed time$ or bedtime$) adj3 (initiat$ or pattern$ or routine$ or practice$ or maintain$ or intervention$ or schedule$)).ti,ab. (4)

3. (night$ adj3 (dysfunction$ or disorder$ or difficult$ or disrupt$ or disturb$ or delay$ or problem$)).ti,ab. (43)

4. (night$ adj3 (settle$1 or settling or wake$1 or awake or wakeful$ or waking$ or awaking$ or awakening$ or wakening$)).ti,ab. (29)

5. (nocturnal$ adj3 (dysfunction$ or disorder$ or difficult$ or disrupt$ or disturb$ or delay$ or problem$)).ti,ab. (2)

6. (nocturnal$ adj3 (settle$1 or settling or wake$1 or awake or wakeful$ or waking$ or awaking$ or awakening$ or wakening$)).ti,ab. (1)

7. (sleep$ adj3 (settle$1 or settling or wake$1 or awake or wakeful$ or waking$ or awaking$ or awakening$ or wakening$)).ti,ab. (26)

8. (sleep$ adj3 (dysfunction$ or disorder or disorder$ or difficult$ or disrupt$ or disturb$ or delay$ or problem$)).ti,ab. (262)

9. (sleep$ adj3 (initiat$ or pattern$ or routine$ or practice$ or maintain$ or intervention$ or schedule$)).ti,ab. (77)

10. (sleepless$ or insomnia$ or parasomnia$ or night terror$ or nightterror$ or night mare$ or nightmare$).ti,ab. (202)

11. (sleep-wak$ or night-wak$).ti,ab. (14)

12. (sleepwalk$ or sleep-walk$ or sleep walk$ or somnambulism).ti,ab. (1)

13. (narcolepsy or nocturnal hyperkinesia).ti,ab. (4)

14. (adolescen$ or baby or babies or child or children or boy or boys or girl or girls or infant$ or infanc$ or juvenile$ or paediatric or pediatric or preschooler$ or schoolboy$ or schoolgirl$ or schoolchild$ or teens or teenager$ or toddler$ or youth or youths or young people or young person$).ti,ab. (36 to 213)

15. (ADHD or attention deficit).ti,ab. (200)

16. angelman syndrome.ti,ab. (0)

17. (autism or autistic or asperger$).ti,ab. (546)

18. cerebral palsy.ti,ab. (144)

19. conduct disorder$.ti,ab. (85)

20. (epilepsy or epileptic).ti,ab. (372)

21. Down$ syndrome.ti,ab. (255)

22. Fragile x syndrome.ti,ab. (12)

23. Prader Willi Syndrome.ti,ab. (3)

24. Prader-Willi Syndrome.ti,ab. (3)

25. Rett syndrome.ti,ab. (5)

26. Smith-Magenis syndrome.ti,ab. (0)

27. Williams syndrome.ti,ab. (0)

28. (developmental adj2 (disabilit$ or delay$)).ti,ab. (100)

29. neurodisabilit$.ti,ab. (13)

30. (neurodevelopment$ adj3 (delay$ or disabilit$ or disease$ or disorder$ or dysfunction$)).ti,ab. (31)

31. (neuro-motor$ adj3 (delay$ or disabilit$ or disease$ or disorder$ or dysfunction$)).ti,ab. (0)

32. (neuromotor$ adj3 (delay$ or disabilit$ or disease$ or disorder$ or dysfunction$)).ti,ab. (0)

33. (neuropsychiatric$ adj3 (delay$ or disabilit$ or disease$ or disorder$ or dysfunction$)).ti,ab. (24)

34. (neuropsychol$ adj3 (delay$ or disabilit$ or disease$ or disorder$ or dysfunction$)).ti,ab. (7)

35. or/1-13 (559)

36. or/15-34 (1671)

37. 14 and 35 and 36 (10)

Search strategy

1. exp Sleep Wake Disorders/ (67,333)

2. Sleep/ (41,262)

3. Somnambulism/ (561)

4. Narcolepsy/ (3034)

5. ((bed time or bedtime$) adj3 (dysfunction$ or disorder$ or difficult$ or disrupt$ or disturb$ or delay$ or problem$)).ti,ab. (175)

6. ((bed time$ or bedtime$) adj3 (initiat$ or pattern$ or routine$ or practice$ or maintain$ or intervention$ or schedule$)).ti,ab. (146)

7. (night$ adj3 (dysfunction$ or disorder$ or difficult$ or disrupt$ or disturb$ or delay$ or problem$)).ti,ab. (1573)

8. (night$ adj3 (settle$1 or settling or wake$1 or awake or wakeful$ or waking$ or awaking$ or awakening$ or wakening$)).ti,ab. (1850)

9. (nocturnal$ adj3 (dysfunction$ or disorder$ or difficult$ or disrupt$ or disturb$ or delay$ or problem$)).ti,ab. (1041)

10. (nocturnal$ adj3 (settle$1 or settling or wake$1 or awake or wakeful$ or waking$ or awaking$ or awakening$ or wakening$)).ti,ab. (811)

11. (sleep$ adj3 (settle$1 or settling or wake$1 or awake or wakeful$ or waking$ or awaking$ or awakening$ or wakening$)).ti,ab. (15,245)

12. (sleep$ adj3 (dysfunction$ or disorder or disorder$ or difficult$ or disrupt$ or disturb$ or delay$ or problem$)).ti,ab. (34,423)

13. (sleep$ adj3 (initiat$ or pattern$ or routine$ or practice$ or maintain$ or intervention$ or schedule$)).ti,ab. (8810)

14. (sleepless$ or insomnia$ or parasomnia$ or night terror$ or nightterror$ or night mare$ or nightmare$).ti,ab. (17,408)

15. (sleep-wak$ or night-wak$).ti,ab. (7703)

16. (sleepwalk$ or sleep-walk$ or sleep walk$ or somnambulism).ti,ab. (665)

17. (narcolepsy or nocturnal hyperkinesia).ti,ab. (3478)

18. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 (125,134)

19. exp Infant/ or exp Child/ or Adolescent/ (3,027,976)

20. (adolescen$ or baby or babies or child or children or boy or boys or girl or girls or infant$ or infanc$ or juvenile$ or paediatric or pediatric or preschooler$ or schoolboy$ or schoolgirl$ or schoolchild$ or teens or teenager$ or toddler$ or youth or youths or young people or young person$).ti,ab. (1,603,721)

21. 19 or 20 (3,390,703)

22. exp Child Development Disorders, Pervasive/ (23,521)

23. Developmental Disabilities/ (16,203)

24. Angelman Syndrome/ (996)

25. exp “attention deficit and disruptive behavior disorders”/ or attention deficit disorder with hyperactivity/ or asperger syndrome/ or autistic disorder/ (42,213)

26. Conduct Disorder/ (2623)

27. exp Epilepsy/ (138,055)

28. Cerebral Palsy/ (16,902)

29. Down Syndrome/ (21,645)

30. Fragile X Syndrome/ (4267)

31. Prader-Willi Syndrome/ (2411)

32. Rett Syndrome/ (1997)

33. Smith-Magenis Syndrome/ (107)

34. Williams Syndrome/ (1371)

35. (ADHD or attention deficit).ti,ab. (22,948)

36. angelman syndrome.ti,ab. (1106)

37. (autism or autistic or asperger$).ti,ab. (29,066)

38. cerebral palsy.ti,ab. (16,339)

39. conduct disorder$.ti,ab. (3664)

40. (epilepsy or epileptic).ti,ab. (92,832)

41. Down$ syndrome.ti,ab. (18,536)

42. Fragile x syndrome.ti,ab. (3622)

43. Prader Willi Syndrome.ti,ab. (2414)

44. Prader-Willi Syndrome.ti,ab. (2414)

45. Rett syndrome.ti,ab. (2494)

46. Smith-Magenis syndrome.ti,ab. (285)

47. Williams syndrome.ti,ab. (1375)

48. (developmental adj2 (disabilit$ or delay$)).ti,ab. (13,041)

49. neurodisabilit$.ti,ab. (135)

50. (neurodevelopment$ adj3 (delay$ or disabilit$ or disease$ or disorder$ or dysfunction$)).ti,ab. (6427)

51. (neuro-motor$ adj3 (delay$ or disabilit$ or disease$ or disorder$ or dysfunction$)).ti,ab. (11)

52. (neuromotor$ adj3 (delay$ or disabilit$ or disease$ or disorder$ or dysfunction$)).ti,ab. (304)

53. (neuropsychiatric$ adj3 (delay$ or disabilit$ or disease$ or disorder$ or dysfunction$)).ti,ab. (8341)

54. (neuropsychol$ adj3 (delay$ or disabilit$ or disease$ or disorder$ or dysfunction$)).ti,ab. (2022)

55. 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 (303,873)

56. 18 and 21 and 55 (4314)