Description of the condition
Dental caries affects 60% to 90% of children as well as the majority of adults (Petersen 2003). The condition has been defined as an indigenous infection caused by cariogenic bacteria (Sato 1996). Although a variety of bacteria have been implicated in the caries process, Streptococcus mutans (a gram-positive bacteria) has been identified as the primary pathogen (Marsh 1992). The development of dental caries is a dynamic process, and four factors need to be present simultaneously (Qualtrough 2005):
- a fermentable carbohydrate (dietary sugars);
- bacteria (in dental plaque/biofilm);
- a susceptible tooth surface;
- sufficient time for the preceding factors to interact.
If there is time (inadequate oral hygiene measures) then bacteria in the oral cavity will build up, adhere to tooth surfaces and interact with saliva to form a biofilm (Reese 2007). Acid is subsequently derived from the metabolic processes within this biofilm (the main driver for this is the availability of dietary sugars, namely sucrose) leading to a reduction in pH. Subsequently mineral is lost from the tooth surface (demineralisation); as the availability of dietary sugars depletes and the pH increases then remineralisation occurs (Manji 1991). The net result of this is the maintenance of an intact tooth. However, the frequent intake of dietary sugars leads to an imbalance in demineralisation and remineralisation in favour of the former, this leads to the formation of a carious lesion (Bowen 1978). The diagnosis of dental caries is based on clinical and, where appropriate, radiographic examination.
An estimation of the depth of demineralisation (extent of the carious lesion) and a judgement of whether the lesion is active dictates its management (Nyvad 1997). Management may be operative or non-operative (preventative) (Pitts 2004).
Operative management consists of removal of demineralised dental tissue and replacement with a synthetic material to prevent the continuation of the carious process. This restorative process can result in the repeated need for repair and/or replacement of the restoration, and with each intervention greater tooth loss inevitably occurs. Eventually the tooth may become unrestorable leading to its loss. This has been referred to as the restorative staircase (Sharif 2010).
Prevention of caries can avoid the initiation of this process. Preventative strategies are focused on reducing one or all of the four factors required for the development of dental caries (listed above). Several Cochrane reviews have evaluated the effectiveness of antimicrobial therapy, dental floss, fissure sealants, dietary advice and fluorides in the prevention of dental caries (Harris 2012; Hiiri 2010; Pereira-Ceni 2009; Sambunjak 2011). The most widely reported preventive measure has been the use of fluorides (Benson 2004; Marinho 2003; Marinho 2009; Walsh 2010). Fluoride inhibits demineralisation when it is present as a solution; it also aids remineralisation and has been reported to be a bacteriostatic agent (Featherstone 1999).
Description of the intervention
Xylitol is a naturally occurring 5-carbon polyol sugar of crystalline structure derived from corn and hardwood. It occurs in many fruits and plants (Jones 1979). It achieves equal sweetness to sucrose without resulting in a physiological requirement for insulin production, consequently xylitol is used as a sucrose substitute in many diabetic food products (Brunzell 1978). In addition, xylitol is not fermentable by the majority of oral cariogenic bacteria and it has also been shown to have antibacterial properties, thus it is recommended for use as an alternative to sucrose without contributing to the development of dental caries (Azarpazhooh 2011). The main reported adverse side effect of xylitol is its laxative effect (Wang 1981).
Xylitol has been produced in a variety of preparations including gum, syrup, lozenges, sprays, mouthwashes, gels, toothpaste, candies and varnishes (Alanen 2000; Ly 2006; Makinen 1982, Milgrom 2009; Pereira-Ceni 2009). In this review we are specifically interested in xylitol-containing gels, toothpastes, varnishes, mouthrinses, chewing gums and sprays.
How the intervention might work
Xylitol inhibits the growth and metabolism of cariogenic bacteria; it is most effective against Streptococcus mutans (Vadeboncoeur 1983), the primary bacteria responsible for the dental caries process (Marsh 1992). Xylitol becomes involved in bacterial metabolism and forms xylitol–5–phosphate, which in turn inhibits glycolytic enzymes and bacterial growth.
In addition, the presence of xylitol-5-phosphate results in the failure of cariogenic bacteria to adhere to dental surfaces (Trahan 1995). Previous research has shown that 1% and 5% xylitol concentrations have resulted in significant reductions in oral cariogenic bacteria (Azarpazhooh 2011). Interestingly, xylitol has been shown to reduce the occurrence of acute otitis media in children up to the age of 12 years, this has been attributed to a reduction in bacteria from the oral cavity (Azarpazhooh 2011).
Why it is important to do this review
The dental caries process and its management has the potential to cause pain, infection and may even lead to the development of dental anxiety, in addition it can be costly (Skaret 1998; Stephen 1978). Experience of dental caries has been shown to adversely affect oral health related quality of life outcomes (Chen 1996). Reviewing the available evidence regarding the effectiveness of xylitol-containing products for preventing dental caries is therefore essential.
Summary of previous systematic reviews
Previous reviews relating to this topic have been published. However, none of them offer a robust methodology comprehensively evaluating the effectiveness of xylitol for preventing dental caries. Two reviews, both narrative in nature, compared xylitol to sorbitol (Burt 2006; Gales 2000). A further narrative review considered xylitol in sweeteners and gum only (van Loveren 2004). Two reviews (Deshpande 2008; Mickenautsch 2012) also studied xylitol in chewing gum for the prevention of dental caries; one further review considered the use of xylitol as a dietary supplement in the form of candies and lozenges (Antonio 2011); however, all three reviews restricted their search to the English language. Interestingly, xylitol has also been compared to fluoride (Ly 2008) but the authors of this review limited the product types for inclusion and the literature search was restricted to one database only.
To assess the effects of different xylitol-containing products on preventing dental caries in children and adolescents.
In this review we are specifically interested in xylitol-containing gels, toothpastes, varnishes, mouthrinses, chewing gums and sprays.
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs), including cluster randomised trials but excluding cross-over trials. Cross-over trials are inappropriate for studies with caries as an outcome.
Types of participants
Inclusion criteria: children and adolescents below 18 years of age who have permanent or deciduous teeth, or both.
Exclusion criteria: studies in which the majority of participants are undergoing fixed or removable orthodontic treatment, the intervention is provided for less than one year, and groups of children are selected as they have underlying health conditions.
Types of interventions
Xylitol-containing gels, toothpastes, varnishes, mouthrinses, chewing gums and sprays will be compared with placebo or no intervention (which includes routine care). We will also include trials comparing one xylitol-containing product with another. The interventions must be provided for at least one year.
Types of outcome measures
Change in dental caries increment (dental caries is defined as clinical or radiographic lesions or both recorded at the dentine level), determined by change from baseline in the following.
- Decayed-missing-filled tooth surfaces (DMFS) and decayed-missing-filled teeth (DMFT) d(e)fs d(e)ft indices. Data on permanent and deciduous teeth will be analysed separately. The summary statistics for the indices will be those for all permanent and deciduous teeth erupted at the start and erupting over the course of the study.
- Number of children with and without dental caries increment.
- Pain and discomfort.
- Quality of life (QOL).
- Patient satisfaction.
- Cost (including use of health service resources (such as visits to dental care units, length of dental treatment time)).
- Adverse effects, gastrointestinal complaints.
- Adverse effects, any specific adverse effects related to any clinically diagnosed reactions to any of the active interventions.
Search methods for identification of studies
For the identification of studies to be included or considered for this review, we will develop detailed search strategies for each database searched. These will be based on the search strategy developed for MEDLINE (Appendix 1) but revised appropriately for each database to take account of differences in controlled vocabulary and syntax rules. The subject search will use a combination of controlled vocabulary and free text terms.
The search strategy will combine the subject search with the Cochrane Highly Sensitive Search Strategy (CHSSS) for identifying reports of randomised controlled trials (2008 revision) (as published in box 6.4.c in theCochrane Handbook for Systematic Reviews of Interventions, version 5.1.0, updated March 2011) (Higgins 2011).
We will not place any restrictions on language or date of publication when searching the electronic databases.
Any non-English papers identified will be translated and assessed for eligibility.
We will search the following electronic databases:
- the Cochrane Oral Health Group's Trials Register (to present);
- the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, current issue);
- MEDLINE via OVID (1946 to present) (Appendix 1);
- EMBASE via OVID (1980 to present);
- CINAHL via EBSCOhost (1980 to present);
- Web of Science Conference Proceedings (1990 to present);
- ProQuest Dissertations and Theses (1861 to present).
Searching other resources
Only handsearching done as part of the Cochrane Worldwide Handsearching Programme and uploaded to CENTRAL will be included. See the Cochrane Masterlist for details of the journal issues searched to date.
To identify possible unpublished or ongoing studies, experts and organisations known in this field will be contacted.
The reference lists of any potentially included clinical trials will be examined to help identify additional studies not identified by the electronic searches.
We will search the US National Institutes of Health register of clinical trials to identify ongoing studies (ClinicalTrials.gov).
Data collection and analysis
Selection of studies
Two review authors (Mohammad O Sharif (MOS) and Farooq Ahmed (FA)) will independently assess the abstracts of retrieved studies. Full copies of studies deemed to be relevant, potentially relevant or for which there is insufficient information in the title and abstract to make a clear decision will be obtained. Full text papers will be assessed independently by MOS and FA and any disagreements on the eligibility of studies will be resolved through discussion and consensus. If necessary, a third review author (Helen Worthington (HW)) will be consulted.
Any studies not fulfilling the inclusion criteria will be excluded and the reasons for exclusion will be noted in a Characteristics of excluded studies table.
Data extraction and management
As highlighted in a previous Cochrane review (Marinho 2013), dental caries increment can be reported differently in different trials. The set of a priori rules developed by the authors for that review will be adopted to choose the primary outcome data for analysis from each study: data on surface level will be chosen over data on tooth level, decayed-filled tooth surfaces (DFS) data will be chosen over decayed-missing-filled tooth surfaces (DMFS) data, and these will be chosen over decayed-filled (DF) or filled tooth surfaces (FS); data for 'all surface types combined' will be chosen over data for 'specific types' only; data for 'all erupted and erupting teeth combined' will be chosen over data for 'erupted' only, and these over data for 'erupting' only; data from 'clinical and radiological examinations combined' will be chosen over data from 'clinical' only, and these over 'radiological' only; data for dentinal or cavitated caries lesions will be chosen over data for enamel or non-cavitated lesions; net caries increment data will be chosen over crude (observed) increment data; and follow-up nearest to three years (often the one at the end of the treatment period) will be chosen over all other lengths of follow-up, unless otherwise stated. When no specification is provided with regard to the methods of examination adopted, diagnostic thresholds used, groups of teeth and types of tooth eruption recorded, and approaches for reversals adopted the primary choices described above will be assumed.
Study details and outcomes data will be collected independently and in duplicate by two review authors (MOS and FA) using a predetermined form designed for this purpose. These will be entered into a Characteristics of included studies table and outcome data will be entered into additional tables or as forest plots in Review Manager (RevMan) (RevMan 2012), any disagreements will be discussed. If necessary, a third review author (HW) will be consulted to resolve any inconsistencies.
The following details will be extracted.
- Trial methods: (a) method of allocation; (b) masking of participants and outcomes; (c) exclusion of participants after randomisation and proportion of losses at follow-up.
- Setting and when trial conducted.
- Participants: (a) country of origin; (b) sample size; (c) age; (d) gender; (e) inclusion and exclusion criteria (symptoms and duration, information on diagnosis verification).
- Intervention and control: type and procedural information.
- Outcomes: primary and secondary outcomes will be outlined in the Types of outcome measures section of the review. Data will be collected at all time points.
If stated, the sources of funding of any of the included studies will be recorded.
This information will be utilised to assess the clinical diversity and generalizability of any included trials.
Assessment of risk of bias in included studies
Studies identified for inclusion in this review will be assessed independently by two review authors (MOS and FA) who will grade them using a simple contingency form following the domain-based evaluation described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The independent evaluations will subsequently be compared and discussed, and disagreements will be resolved. If necessary, a third review author (HW) will be consulted to resolve any disagreements.
The authors will assess the following domains:
- sequence generation;
- allocation concealment;
- blinding of participants and personnel;
- blinding of outcome assessors;
- incomplete outcome data;
- selective outcome reporting;
- other bias.
The assessments for each included study will be reported in the corresponding sections of the risk of bias tables in RevMan (RevMan 2012).
The authors will also categorise the overall risk of bias of individual studies. In making the assessment, consideration will be given to the relative importance of different domains, and individual studies will be categorised as being at: low, high or unclear risk of bias according to the following:
- low risk of bias (plausible bias unlikely to seriously alter the results) if all criteria were met;
- unclear risk of bias (plausible bias that raises some doubt about the results) if one or more criteria were assessed as unclear; or
- high risk of bias (plausible bias that seriously weakens confidence in the results) if one or more criteria were not met.
Measures of treatment effect
The following section has been taken from the fluoride varnish Cochrane review as it was considered appropriate for this review (Marinho 2013).
For the dental caries outcomes
The chosen measure of treatment effect is the prevented fraction (PF), that is mean increment in the controls minus mean increment in the treated group divided by mean increment in the controls. For an outcome such as dental caries increment (where discrete counts are considered to approximate to a continuous scale and are treated as continuous outcome) this measure is considered more appropriate than the mean difference or standardised mean difference since it allows combination of different ways of measuring dental caries increment and a meaningful investigation of heterogeneity between trials. It is also simple to interpret.
For dichotomous outcomes, the estimate of effect of an intervention will be expressed as risk ratios (RR) together with 95% confidence intervals (CIs). For continuous outcomes, mean differences and standard deviations will be used to summarise the data for each group using mean differences and 95% CIs.
Unit of analysis issues
We will use mean dental caries increments which have been calculated for each patient. We will include cluster randomised trials and will use the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions to take the clustering into account if the published report has not done so. We will excluded cross-over trials as they are inappropriate for the primary outcome, dental caries.
Dealing with missing data
All trial authors will be contacted to retrieve missing data when necessary. If agreement cannot be reached then data will be excluded until clarification is available. For missing standard deviations relating to caries increments we will use the approach adopted in the topical fluoride reviews (Marinho 2013): these will be imputed through linear regression of log standard deviations on log mean caries increments where appropriate. This is a suitable approach for dental caries prevention studies since, as they follow an approximate Poisson distribution, dental caries increments are closely related (similar) to their standard deviations (van Rijkom 1998). Otherwise methods in section 7.7.3 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) will be used to estimate missing standard deviations.
Assessment of heterogeneity
If sufficient trials are included, clinical heterogeneity will be assessed by examining the characteristics of the studies, the similarity between the types of participants, the interventions and the outcomes as specified in the criteria for included studies. Statistical heterogeneity will be assessed using a Chi
In the event that there are insufficient clinically homogeneous trials for any specific intervention, or insufficient study data, a narrative synthesis will be presented.
Assessment of reporting biases
If sufficient trials are identified for inclusion, publication bias will be assessed according to the recommendations on testing for funnel plot asymmetry (Egger 1997) as described in section 10.4.3.1 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If asymmetry is identified, other possible causes will be assessed.
Only if there are studies of similar comparisons reporting the same outcome measures will a meta-analysis be conducted.
Dental caries increments
The meta-analyses will be conducted as inverse variance weighted averages. Variances will be estimated using the formula presented in Dubey 1965, which is more suitable for use in a weighted average and for large sample sizes the approximation should be reasonable. Random-effects model meta-analyses will be performed throughout (unless there are less than four studies in a meta-analysis, in which case a fixed-effect model will be used).
If meta-analyses using standardised mean differences yield materially similar results to those using prevented fractions, we will also present these. Deciduous and permanent teeth would be analysed separately throughout.
Risk ratios will be combined for dichotomous data, and mean differences for continuous data, using random-effects models.
Subgroup analysis and investigation of heterogeneity
The following subgroup analyses are planned for the dental caries increments.
- Preparation type (toothpastes, mouthrinses, chewing gum etc).
- Doses and concentration of preparations.
If a sufficient number of studies with similar characteristics are included, sensitivity analyses will be undertaken to assess the robustness of the results by excluding studies with unclear or inadequate allocation concealment, unclear or inadequate blinding of outcomes assessment, and unclear or inadequate completeness of follow-up.
Presentation of main results
A summary of findings table will be developed for the primary outcomes of this review using GRADEPro software. The quality of the body of evidence will be assessed with reference to the overall risk of bias of the included studies, the directness of the evidence, the inconsistency of the results, the precision of the estimates, the risk of publication bias, the magnitude of the effect, and whether or not there is evidence of a dose-response relationship. The quality of the body of evidence for each of the primary outcomes will be categorised as high, moderate, low or very low.
Appendix 1. MEDLINE (OVID) search strategy
1. (teeth adj5 (cavit$ or caries or carious or decay$ or lesion$ or deminerali$ or reminerali$)).mp.
2. (tooth adj5 (cavit$ or caries or carious or decay$ or lesion$ or deminerali$ or reminerali$)).mp.
3. (dental adj5 (cavit$ or caries or carious or decay$ or lesion$ or deminerali$ or reminerali$)).mp.
4. (enamel adj5 (cavit$ or caries or carious or decay$ or lesion$ or deminerali$ or reminerali$)).mp.
5. (dentin adj5 (cavit$ or caries or carious or decay$ or lesion$ or deminerali$ or reminerali$)).mp.
6. (root adj5 (cavit$ or caries or carious or decay$ or lesion$ or deminerali$ or reminerali$)).mp.
7. exp TOOTH DEMINERALIZATION/
8. Dental plaque index/
9. (("dental plaque" or DMF or DFS or DFT or DMFT) adj2 (index or indices)).mp.
10. Dental plaque/
11. ((dental or tooth or teeth) adj3 plaque).mp.
13. exp Sugar Alcohols/
14. ("sugar alcohol$" or polyol$).mp.
15. Sweetening Agents/
20. 12 and 19
The above search will be linked with the Cochrane Highly Sensitive Search Strategy (CHSSS) for identifying reports of randomised controlled trials (2008 revision) (as published in box 6.4.c in theCochrane Handbook for Systematic Reviews of Interventions, version 5.1.0, updated March 2011) (Higgins 2011).
1. randomized controlled trial.pt.
2. controlled clinical trial.pt.
5. drug therapy.fs.
10. exp animals/ not humans.sh.
11. 9 not 10
Contributions of authors
Conceiving the idea: Mohammad O Sharif (MOS) and Helen Worthington (HW).
Writing the protocol: MOS, Farooq Ahmed (FA) and HW.
Declarations of interest
There are no financial conflicts of interest and the review authors declare that they do not have any associations with any parties who may have vested interests in the results of this review.
Sources of support
- The University of Manchester, UK.
- Manchester Academic Health Sciences Centre (MAHSC), UK.The Cochrane Oral Health Group is supported by MAHSC and the NIHR Manchester Biomedical Research Centre
- Cochrane Oral Health Group Global Alliance, UK.All reviews in the Cochrane Oral Health Group are supported by Global Alliance member organisations (British Orthodontic Society, UK; British Society of Paediatric Dentistry, UK; British Society of Periodontology, UK; Canadian Dental Hygienists Association, Canada; National Center for Dental Hygiene Research & Practice, USA; New York University College of Dentistry, USA; and Royal College of Surgeons of Edinburgh, UK) providing funding for the editorial process (http://ohg.cochrane.org/)
- National Institute for Health Research (NIHR), UK.CRG funding acknowledgement:
The NIHR is the largest single funder of the Cochrane Oral Health GroupDisclaimer:
The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health