This protocol of overview of systematic reviews follows the guidelines of the Cochrane Handbook of Systematic Reviews of Interventions [48], and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) [49]. The eligibility criteria for the clinical question guiding this overview are presented in the PICOTSS (patient, intervention, comparators, outcomes, timing, setting, and study design) format (Table 1). We will also perform a supplementary systematic review to summarise the evidence of the adverse effects of massage on infants and children aged < 5 years. The methods of this review are based on the criteria of conducting systematic reviews of adverse events in the Cochrane Handbook of Systematic Reviews of Interventions [50], and the CRD’s guidance for undertaking reviews in health care [51]. Key points of the search eligibility and strategies are outlined in Table 2.
Criteria for considering reviews for inclusion
Types of studies
We will include published systematic reviews and randomised controlled trials (RCTs).
Types of participants
We will include systematic reviews in which participants are infants and children aged < 5 years.
Types of interventions
We will include systematic reviews that examine the effects and/or safety of massage therapy for infants and children aged < 5 years. Massage is defined as manipulations conducted on the soft tissue of a child’s body, which might include kneading, grasping, pressing, pushing, nipping, rotating, stretching, rubbing, and so forth [52]. This intervention can be used for treating or preventing diseases, improving the situation of medical conditions, promoting growth, health preservation, improving immunity, among others. We will include all types of massage therapies.
Types of comparisons
We will include systematic reviews of RCTs that compare the effects between massage therapy and other interventions, control interventions, or no intervention. The comparisons include waitlist control, placebo or sham controls, positive controls, pharmacological treatments, combinations of treatments, and usual or standard care. Studies comparing the effects of different kinds of massage therapies, or between massage and other complementary and alternative therapies, will be excluded.
Types of outcomes
Primary and secondary outcomes will not be limited due to the diversity of diseases and conditions. Where possible, when assessing study quality, we will consider the use of validated research tools to measure outcomes related to children and their caregivers.
Children
- Physical outcomes (e.g. blood pressure, pain assessment, pulse rate, weight change, length of hospital admission, readmission).
- Psychological outcomes (e.g. anxiety, depression, insomnia, fears, behavioural regression, self-esteem, mood, fears, and month-child attachment).
- Developmental outcomes (e.g. weight gain, intelligence, the ability to learn knowledge).
Caregivers
- Physical outcomes (e.g. blood pressure, pulse rate, weight change).
- Psychological outcomes (e.g. economic pressure, anxiety, depression, self-esteem, mood, fears)
Safety of interventions
- All adverse events (e.g. an increase in anxiety after receiving an intervention, high dropout rate) [50]
Timing
We will include systematic reviews of RCTs of any duration, treatment period, and treatment frequency.
Setting
We will include systematic reviews of RCTs that have been conducted in any setting. The intervention could be implemented anywhere, such as hospitals and at home. The therapists could be parents, caregivers, paediatricians, experts, practitioners, or other qualified personnel. The clinical trials could be pilot studies, feasibility studies, fully powered studies, or other phases. There are no limitations in other aspects of the setting.
Table 1. Eligibility criteria using the PICOTSS (Patients, Interventions, Comparators, Outcomes, Timing, Setting, and Study Design) format
|
Patients
· Infants and children aged < 5 years
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Intervention
· Massage therapy
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Comparators
· Waitlist control
· Placebo
· Positive controls
· Pharmacological treatments
· Combinations of treatments
· Usual care
· Standard care
|
Outcomes
· Children
§ Physical outcomes (e.g. pain assessment, pulse rate, length of hospital admission, readmission)
§ Psychosocial outcomes (e.g. anxiety, depression, insomnia, fears, behavioural regression)
§ Developmental outcomes (e.g. weight gain, intelligence, ability of learning knowledge)
· Caregivers
§ Physical outcomes (e.g. blood pressure)
§ Psychological outcomes (e.g. economic pressure, anxiety, depression)
· Safety of interventions
§ All adverse events (e.g. an increase in anxiety after receiving an intervention, high drop-out rate)
|
Timing
· Studies of any duration
|
Setting
· Studies of any setting
|
Study Design
· Systematic reviews with randomized controlled trials
|
Table 2. Key points of the protocol of systematic review of adverse events of massage for infants and children aged < 5 years
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Participants
· Infants and children aged < 5 years
|
Intervention
· Massage therapy
|
Comparators (if possible)
· Waitlist
· Placebo
· Positive controls
· Pharmacological treatments
· Combinations of treatments
· Usual care
· Standard care
|
Outcomes
· Any adverse events associated with the intervention
|
Timing
· Studies of any duration
|
Setting
· Studies of any setting
|
Study Design
· Randomized trials, cohort studies, case-control studies, case reports, and case series
|
Searching methods
· Useful information will be extracted from the included systematic reviews
· Free-text searching
· Index term attached with floating subheadings searching: MEDLINE and Embase
· Hand searching: google scholar
|
Data extraction
· Target condition
· Study type
· Number of participants
· Intervention setting
· Age of participants
· Adverse event
|
Data analysis
· Adverse events will be summarized and presented narratively
|
Assessment of risk of bias
· Cochrane risk-of-bias tool (RoB 2) for randomized trials [53]
· Non-randomized Studies of Interventions (ROBINS-I) tool for non-randomized studies [54]
|
Data synthesis
· Adverse events will be listed and summarized narratively
· High drop-out rate (20% or higher) will be considered as an adverse effect
|
Search methods for the identification of reviews
For objective 1, we will search the following databases, from inception to June 2020: Ovid MEDLINE, Embase, Health Technology Assessment Database (HTA), the Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (DARE), Allied and Complementary Medicine (AMED), China National Knowledge Infrastructure (CNKI), and Wanfang Data. The search includes six English databases and two Chinese databases, covering the major databases for international publications and literature published in Chinese. We have developed the searching strategies for the Embase database using free-text words and subheadings (Table 3), and search strategies for other databases will be built up accordingly. The following keywords will be used: (massag* OR touch OR tactile stimulation OR anmo OR acupressure OR tuina OR manipulat*) AND (newborn* OR child* OR baby OR babies OR infant* OR youth OR paediatric* OR paediatric* OR toddler* OR pre-school* OR pre-school*). To search the Chinese databases, the corresponding Chinese keywords will be used. We will contact the authors of the studies if necessary information is missing from the publications. References for the included studies will be searched for useful information. To address the on-going systematic reviews, we will also search the PROSPERO database to identify the registered relevant systematic reviews. We will not impose any time or language restrictions. Information on adverse effects from the included systematic reviews may not be comprehensive. To supplement this, the index term, free-text searching approach, and ‘Grey’ literature hand-searching will be used for identifying articles with information on adverse effects. We will extract data on infants and children aged < 5 years.
Table 3. Embase Search strategy
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Code
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Keywords
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1
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(massag* OR touch OR tactile stimulation OR anmo OR acupressure OR tuina OR manipulat*).mp
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2
|
exp massage/
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3
|
exp tactile stimulation/
|
4
|
exp acupressure/
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5
|
exp manipulative medicine/
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6
|
1 or 2 or 3 or 4 or 5
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7
|
(newborn* OR child* OR baby OR babies OR infant* OR youth OR pediatric* OR paediatric* OR toddler* OR preschool* OR pre-school*).mp
|
8
|
exp child/ or exp child care/
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9
|
exp newborn/ or exp newborn care/
|
10
|
exp infant care/ or exp infant/
|
11
|
exp juvenile/
|
12
|
exp pediatrics/
|
13
|
exp toddler/
|
14
|
exp preschool child/
|
15
|
7 or 8 or 9 or 10 or 11 or 12 or 13 or 14
|
16
|
exp “systematic review”/ or exp meta analysis/ or exp “review”/
|
17
|
6 and 15 and 16
|
For objective 2, we will extract information on the adverse effects from the included systematic reviews. In addition, we will search the following databases using both the index terms approach and the free-text searching approach from inception to June 2020: MEDLINE, Embase. Subheadings will be attached to the index term ‘massage’. The subheadings for donating data in MEDLINE and Embase databases will be used as follows: Massage/adverse effects (MEDLINE) and Massage/side effects (Embase). Text words for synonyms of ‘adverse effects’ and related terms will be searched using the following keywords from inception to June 2020: (massag* OR touch OR tactile stimulation OR anmo OR acupressure OR tuina OR manipulat*) AND (newborn* OR child* OR baby OR babies OR infant* OR youth OR paediatric* OR paediatric* OR toddler* OR pre-school* OR pre-school*) AND (safe OR safety OR side effect* OR undesirable effect* OR treatment emergent OR adverse effect*). We will also perform hand-searching for reports, conference proceedings, journals, and theses for useful information. Data on infants and children aged < 5 years will be extracted and summarised.
Data collection and analysis
Selection of reviews
Two authors (SCC and CSY) will independently screen the results of the electronic search by title and abstract. For both objectives, we will obtain the full-text report of the systematic reviews and studies deemed appropriate and uncertain, and subsequently apply the PICOTSS eligibility criteria to determine the final inclusion list. Studies that do not meet the inclusion criteria will be excluded. We will resolve disagreements between review authors through discussion or consultation with an additional reviewer (WFY) when necessary. We will provide a PRISMA flow diagram documenting the screening and review the selection process.
Data extraction and management
Two authors (SCC and CSY) will independently extract data using a standardised form. Discrepancies will be resolved by discussion or consultation with an additional reviewer (WFY) if necessary.
For objective 1, the data extraction form will include the following details:
- Target conditions
- Objectives of the systematic review
- Search time
- Number of included trials and participants
- Details of the participants
- Details of the interventions
- Details of comparison interventions
- Outcomes for which data were reported
- Adverse effects
- Review limitations
- Assessment of methodological quality and risk of bias of the included evidence
- GRADE judgements regarding the quality of evidence where present
- Meta-analysed pooled effect estimates for outcomes in reviews
For objective 2, we will extract the following details of the included studies:
- Target condition
- Study type
- Number of participants
- Intervention setting
- Age of participants
- Adverse event
- Published or not
Assessment of the methodological quality of the included reviews
Two authors (SCC and CSY) will be responsible for the methodological assessment. Discrepancies will be resolved by consensus between the two authors or by consulting a third reviewer (WFY) if necessary.
For objective 1, according to the requirement of the Cochrane handbook, both the methodological quality of the reviews included and the evidence quality of the individual studies included in the reviews must be assessed.
Quality of the included reviews
The methodological quality of the included systematic reviews will be assessed using the AMSTAR 2 (A Measurement Tool to Assess systematic Reviews 2) instrument [55, 56]. AMSTAR 2 assists in evaluating the quality of conducting systematic reviews using 16 distinct items, 7 of which are critical domains that can have an impact on the validity of a systematic review. The seven critical domains include protocol registration before the commencement of the review (item 2), comprehensiveness of the literature search strategy (item 4), justification of exclusion (item 7), risk of bias of the studies included in the reviews (item 9), appropriateness of meta-analytical methods (item 11), consideration of risk of bias when interpreting the results of the review (item 13), and assessment of the presence and likely impact of publication bias (item 15). Each AMSTAR item will be rated as ‘Yes’ (clearly done) or ‘No’ (clearly not done or without information) in light of the published systematic review. Some items provide a ‘partial Yes’ for responding to the situations that we think are worthy of partial adherence to the criteria. AMSTAR 2 assists users in identifying the potential influence of flaws or weaknesses in each domain. Quality of systematic reviews will be rated as ‘High’ (no or one non-critical weakness), ‘Moderate’ (more than one non-critical weakness), ‘Low’ (one critical flaw with or without non-critical weaknesses), or ‘Critical low’ (more than one critical flaw with or without non-critical weaknesses) [56].
Quality of evidence in the included reviews
We will assess the risk of bias of the individual trials included in the systematic reviews using the Cochrane collaboration’s tool (RoB 2) [53], which assesses the risk of bias of randomised trials in six domains as ‘Low risk’, ‘Unclear risk’, and ‘High risk’. These domains are selection bias, performance bias, detection bias, attrition bias, reporting bias, and other bias. The overall quality of evidence across studies for each significant outcome will be assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach [57]. The level of evidence will be determined by assessing the following aspects of the studies: number of studies, study design, risk of bias, inconsistency of the findings, imprecision, indirectness of the estimate, and other considerations, such as publication bias. A risk of bias (RoB) table and a summary of findings (SoF) table based on the methods described in the Cochrane Handbook for Systematic Reviews of Interventions will be built up to convey key information on the effects of massage intervention for each condition and the overall credibility of the information [48].
For objective 2, we will use the RoB 2 tool to assess the risk of bias of randomised trials [53] and the Non-randomized Studies of Interventions (ROBINS-I) tool for non-randomized studies [54]. Seven domains will be assessed in ROBINS-I, which are bias due to confounding factors, bias in the selection of participants for the study, bias in classification of interventions, bias due to deviations from intended interventions, bias due to missing data, bias in the measurement of outcomes, and bias in selection of the reported results. These domains will be rated as ‘Low risk’, ‘Moderate risk’, ‘Serious risk’, and ‘Critical bias’.
Data synthesis
We will report the results according to the Cochrane Handbook of Systematic Reviews of Interventions. A PRISMA flowchart will be used to present the process of study selection for both the overview and the systematic review. We will perform a qualitative synthesis for each universe of diseases, disorders, or other conditions. The universes will be classified according to the International Classification of Diseases, 11th version (ICD-11), which is the international standard for reporting diseases and health conditions [58].
The problem of double-counting data will be considered prudently because there might be two or more systematic reviews addressing the same question. To minimise the reduplicative information extracted from overlapping trials, the following strategies will be applied:
- If the qualities of these reviews are similar, we will select the one that contributes the most outcome data.
- If the outcomes of these reviews are completely overlapping, we will retain the one with the highest quality.
- If the outcomes of these reviews are partly overlapping, we will completely retain the highest-quality review and partly retain those with lower-quality.
- If the outcomes of these reviews do not overlap, we will retain all.
- If the outcomes of these reviews are completely overlapping and their qualities are similar, we will select the most recent.
We will present the effects of massage therapy based on the most comprehensive reviews with the highest quality. For the overlapping reviews that are not included in the intervention effects analysis, we will report their general information in a table to enable readers to obtain useful data. The AMSTAR 2 instrument, Cochrane RoB tool, and GRADE approach will be used to assess the quality of the reviews.
When possible, we will extract and report pooled effect estimates for meta-analysed outcomes for each review that meets the inclusion criteria. For dichotomous outcomes, relative risks (RRs) with 95% confidence intervals (CIs) will be pooled, while for continuous outcomes, mean differences (MDs) with 95% CIs for the same outcome measure or standardised mean differences (SMDs) with 95% CIs for different outcome measures will be expressed. For time-to-event data, hazard ratios (HRs) with 95% CIs will be expressed [48]. However, we will not compute an overview meta-estimate due to the heterogeneity in ages and outcomes between trials, the absence of essential data, and the lack of well-established quantification methods.
Adverse effects of massage therapy reported in the systematic reviews will be listed and summarised narratively. The mechanism of adverse effects of therapies for several conditions might be similar in different populations and settings [50]. Therefore, we will collect adverse effects regardless of the condition or how massage therapy was conducted. We will also collect information on adverse effects from the overlapping included systematic reviews. We will consider a high drop-out rate (≥20%) as an outcome measure in study reports for adverse effects, since withdrawal might be related to upsetting side effects, stress on subjects, or others [48, 59].
According to the results synthesised from the data on effects and safety issues, we will generate a figure to present the recommendation level of massage therapy for each included condition, considering the gender, age, and other factors. Since the mechanism of treatment effects might be similar on the same outcomes across different conditions, we will also generate a figure to summarise evidence for each outcome, if possible. Sufficient systematic review evidence will be the most important criterion for the generation of the final recommendation level figure, and all adverse effects for each condition will be emphasised and marked.
ETHICS AND DISSEMINATION
Results of this overview will be published in a peer-reviewed academic journal and presented at relevant national or international conferences. The study does not need ethical approval since it will not collect individual information.