Fluoride toothpastes of different concentrations for preventing dental caries in children and adolescents
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine the relative effectiveness of fluoride toothpastes of different concentrations in preventing dental caries in children and adolescents.
Background
Description of the condition
Caries (dental decay) is a dynamic process in which tooth mineral is lost and gained in a continuous process of de‐ and re‐mineralisation. Aside from the pain arising from the carious lesions themselves, there is also the emotional distress of the disease and the potential consequences of medical intervention. Affected teeth cannot always be saved and may have to be extracted. This has particular consequences for young children, for whom general anaesthesia may be required. There is an associated social impact of this disease in terms of absence from school for the children and absence from work for their carers. There are also important financial implications for this disease with a substantial proportion of healthcare budgets being spent every year on treating caries.
Whilst in some areas of the developed world there has been evidence of a reduction in the prevalence and severity of dental caries in recent years, social inequalities in dental health exist, with many individuals and communities having a clinically significant burden of preventable dental disease. Whilst some success has been achieved in a reduction in caries in adults, challenges remain in the prevention of caries in young children, and in reducing inequalities in this population.
The link between fluoride and oral health dates back to the 1930s. Nearly 80 years on and fluoride remains one of dentistry's key strategies for the prevention of dental caries. At the 8th World Congress on Preventive Dentistry (Liverpool, 2005) members of the International Association for Dental Research, the World Health Organization (WHO), the European Association of Dental Public Health and the British Association for the Study of Community Dentistry put forward a call for action in the 'Liverpool Declaration' (IADR/WHO/BASCD 2005). They outlined nine areas of work that should be addressed by the year 2020, one of which was the need for countries to ensure the availability of appropriate and affordable fluoride programmes for the prevention of tooth decay. This has recently been reinforced by the findings of a Global Consultation on Oral Health through Fluoride (2006) which suggests that promoting dental health by using fluoride will "improve quality of life and enhance achievement of the Millennium Development Goals by reducing the high dental disease burden of populations, especially children in disadvantaged populations" (FDI World Dental Federation 2006).
Description of the intervention
There are two main methods of fluoride delivery ‐ topical or systemic. There continues to be considerable debate regarding systemic fluoride delivery through for example fluoridated water or milk. The beneficial effects of topical fluoride agents have been examined in a series of high quality Cochrane systematic reviews (Marinho 2002; Marinho a 2002; Marinho 2003; Marinho a 2003; Marinho b 2003; Marinho 2004; Marinho a 2004). In particular, evidence for the use of fluoride toothpastes is unequivocal (Marinho b 2003). Summarising all available placebo‐controlled evidence from randomised controlled trials (RCTs), the review concluded that fluoride toothpastes are efficacious in preventing caries when compared to non‐fluoride toothpastes. However, recommendations as to the fluoride concentrations suitable for use with young children are less clear. The review concluded that the effect of fluoride toothpaste on caries prevention increased according to some factors, which included higher fluoride concentration. However, comparisons of toothpastes of differing fluoride concentration were not explicitly (directly) evaluated. This review aims to critically appraise the RCTs comparing toothpastes of different concentrations with a view to establishing the most appropriate concentration for children and adolescents. This review is being conducted alongside a Cochrane review looking at the effect of topical fluoride (including that from toothpaste) on dental fluorosis which will attempt to quantify the risk of high levels of fluoride and inform this risk/benefit debate (Wong 2009).
Why it is important to do this review
The objectives of the WHO Global Oral Health Programme are detailed in a WHO report (Petersen 2003) and summarised in a global policy document (Petersen 2009) with one of the priority action areas being the effective use of fluoride. Prevention and effective use of fluoride toothpaste is the recommended strategy for oral health in young children in a recent Lancet editorial (Lancet 2009), although it is acknowledged that its cost prohibits its widespread use in many low‐income and middle‐income countries.Following on from this it is important that recommendations concerning the use of fluoride toothpaste in young children are evidence based. The recently published document 'Delivering Better Oral Health: An Evidence‐Based Toolkit' from the Department of Health in the UK (DoH 2007) on fluoride concentration in toothpaste has cited evidence from the Cochrane systematic review (Marinho b 2003), a single RCT (Davies 2002) and three published reviews of fluoride toothpastes for caries prevention in children and adolescents (Ammari 2003; Steiner 2004; Twetman 2003). This toolkit recommends that for preventing caries in children aged up to 3 years "only a smear of toothpaste containing no less than 1000 ppm fluoride" be used, and for all children aged 3 to 6 years "a pea‐sized amount of toothpaste containing 1350–1500 ppm fluoride" be used. For children older than 6 years, fluoridated toothpaste of 1350 ppm or above is recommended. The table of key references cited in the toolkit provides "further relevant references" pertaining to fluoride concentration:
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"Toothpastes containing 1450 ppm fluoride offers more caries‐preventive effect than toothpaste containing 440 ppm fluoride" and
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"Toothpastes containing 1450 ppm fluoride offers more caries‐preventive effect than toothpaste containing 1000 ppm fluoride".
Evidence to support the former recommendation is the Cochrane systematic review of placebo‐controlled trials (Marinho b 2003) and a single long‐term RCT based in deprived areas of the North of England (Davies 2002). Whilst the Cochrane systematic review concluded that the effect of fluoride toothpaste on caries prevention increased according to higher fluoride concentration amongst other factors, this was not explicitly evaluated and no optimum level of fluoride concentration for caries prevention was given.
Evidence to support the second recommendation comes from meta‐analyses in reviews carried out in 2003 and 2004 (Ammari 2003; Steiner 2004; Twetman 2003). The reviews differ in their methods, though none have been undertaken as Cochrane systematic reviews. Not all reviews have included an assessment of the quality of trials, and some of the included studies are cluster‐randomised, with no evidence that this has been taken into account in the analysis. Many important details of the review research process go unreported in these publications. For instance, it is unclear whether a protocol was written prior to undertaking the review, and search criteria are not fully documented. Additionally, important information on methods of analysis of the concentration‐response effectiveness has been omitted or has been undertaken sometimes narratively. The comparisons made in the reviews are:
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250 ppm relative to 1000 ppm (n = 4 trials) (Steiner 2004);
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250 ppm relative to 1000 ppm (n = 6 trials) and 500‐550 ppm relative to 1000‐1055 ppm (n = 2 trials narrative only) (Ammari 2003);
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placebo toothpaste compared to placebo, < 1000 ppm relative to 1000‐1100 ppm (n = 4 trials) 1500 ppm relative to 1000‐1100 ppm (n = 9 trials) (Twetman 2003).
Recently published clinical guidelines (EAPD 2008) on the prevention of early childhood caries from the European Academy of Paediatric Dentistry state that "children's teeth should be brushed daily with a smear of fluoride toothpaste as soon as they erupt" though no explicit fluoride concentration is given. In a comment on the recommendation, based on previous reviews (Ammari 2003; Twetman 2003), the authors of the guidelines state that "there is no evidence of a caries‐preventive effect from low‐fluoride toothpaste".
A further published meta‐analysis examined the caries‐preventive effect of higher level fluoride toothpastes of 1700 ppm, 2200 ppm, 2800 ppm relative to 1100 ppm (Bartizek 2001). This meta‐analysis was based on a single multicentre randomised controlled trial. No Cochrane systematic review including trials of active interventions, i.e. fluoride toothpastes of different concentrations, and placebo‐controlled trials has been undertaken.
A systematic review addressing all the available evidence on the concentration of fluoride in toothpastes using appropriate statistical methodologies will help to clarify the optimal concentration of fluoride needed to achieve caries prevention in young children and adolescents.
Traditional approaches to meta‐analysis have focused on direct (head to head) pairwise comparisons within RCTs. However, when many different interventions exist, the number of pairwise comparisons becomes prohibitive and interpretation difficult. For example when there are six interventions to be compared, this will result in 15 distinct pairwise combinations. Combining similar fluoride levels may be a solution, but this runs the risk of obscuring subtle concentration‐related differences in effect. Adjusted indirect comparisons can be made between trials with a common comparator. Further, with advances in statistical methodologies, it is possible to combine both direct and indirect evidence from RCTs in what the Cochrane Handbook for Systematic Reviews of Interventions refers to as multiple treatments meta‐analysis (Higgins 2008). This methodology is sometimes known in the literature as network meta‐analysis or mixed treatment comparisons (MTC). Such a technique refers to a meta‐analysis of multiple interventions, and can involve both direct and indirect treatment comparisons. This has been used to evaluate many different interventions including for example self monitoring of diabetes (Jansen 2006) and stroke prevention treatments (Cooper 2006), and is suitable for both binary and continuous outcome measures. The research will therefore incorporate a substantial statistical and methodological component and will advance knowledge in this area. A systematic review addressing all the available evidence on the concentration of fluoride in toothpastes will help to clarify the optimal concentration of fluoride needed to achieve caries prevention while limiting objectionable enamel fluorosis, since the risk of fluorosis in young children has been associated with the use of fluoride toothpaste.
The aim of this review is to provide a clear and robust summary of the research evidence on the effects of fluoride toothpastes of different concentrations for dental health in children and adolescents.
Objectives
To determine the relative effectiveness of fluoride toothpastes of different concentrations in preventing dental caries in children and adolescents.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials and cluster‐randomised trials with a minimum duration of 1 year. Split‐mouth studies will be excluded.
Types of participants
Children and adolescents. Trials of children or adolescents aged 16 years or less at the start of the study will be included (irrespective of initial level of dental caries, background exposure to fluorides, dental treatment level, nationality, setting where the intervention is received or time when the intervention started).
Types of interventions
Trials making a comparison between at least two fluoride toothpastes of differing concentration, or fluoride toothpaste and placebo toothpaste. Fluoride agents combined or not in the following formulations:
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Sodium fluoride (NaF)
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Sodium monofluorosphate (SMFP)
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Stannous fluoride (SnF2)
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Acidulated phosphate fluoride (APF)
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Amine fluoride (AmF).
These may be formulated with any compatible abrasive system and are considered at any fluoride concentration (ppm), frequency of use, amount or duration of application, and with any technique of toothbrushing or post‐toothbrushing procedure. Studies where the intervention group alone or both the intervention and control groups received any additional active agent(s) or caries preventive measure(s) as part of the study (e.g. chlorhexidine agent, other fluoride‐based procedures, oral hygiene procedures, sealants, xylitol chewing gums, glass ionomers) in addition to fluoride toothpaste or placebo toothpaste will not be included. Studies where participants are receiving additional measures as part of their routine oral care such as oral hygiene advice, supervised brushing, fissure sealants will be included. It is acknowledged in advance that the comparison of certain levels of fluoride toothpastes may be sparse, and direct and indirect comparisons will be undertaken.
SeeFigure 1.
Illustration of potential indirect comparison, using placebo toothpastes as common comparator, and fluoride toothpastes of 1000 ppm and 1500 ppm.
Types of outcome measures
Primary outcomes
The primary outcome measure is caries increment as measured by either:
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change from baseline in the decayed, (missing) and filled surface (D(M)FS) index, in all permanent teeth erupted at start and erupting over the course of the study (dental caries is defined here as being clinically and radiologically recorded at the dentine level of diagnosis);
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change from baseline in the decayed, (missing/extraction indicated), and filled surface d(e/m)fs index, in deciduous tooth surfaces;
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change in per cent caries free;
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change in the proportion developing new caries.
Secondary outcomes
The secondary outcome will be adverse effects such as irritation, dental staining etc.
Search methods for identification of studies
The searches will attempt to identify all relevant trials irrespective of language. We aim to have all papers not published in English translated. Similarly, there will be no restriction with regard to status of publication and both published and unpublished studies wil be sought.
Electronic searches
The following databases will be searched:
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Cochrane Oral Health Group's Trials Register
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Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library current issue)
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MEDLINE (OVID) (from 1966 to the present)
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EMBASE (OVID) (from 1974 to the present)
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CINAHL (OVID)
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CANCERLIT (via PubMed)
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SIGLE
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LILACS.
Sensitive search strategies will be developed using a combination of free text and controlled vocabulary. The strategy for MEDLINE (OVID) is presented in Appendix 1. This will be run with the Cochrane Highly Sensitive Search Strategy (CHSSS) for identifying randomised trials in MEDLINE: sensitivity maximising version (2008 revision) as referenced in Chapter 6.4.11.1 and detailed in box 6.4.c of the Cochrane Handbook for Systematic Reviews of Interventions 5.0.1 (updated September 2008) (Higgins 2008).
Searching other resources
Previously published systematic reviews of fluoride toothpastes will also be screened to identify any reports that meet the inclusion criteria (Ammari 2003; Bartizek 2001; Clarkson 1993; Steiner 2004Twetman 2003). The Cochrane fluoride toothpaste systematic review (Marinho b 2003) is currently being updated and any relevant trials located through the update will be incorporated into this review.
Data collection and analysis
Selection of studies
The titles and abstracts (when available) of all reports identified through the electronic searches will be scanned independently by two of the review authors. For studies appearing to meet the inclusion criteria, or for which there are insufficient data in the title and abstract to make a clear decision, the full report will be obtained. The full reports obtained from all the electronic and other methods of searching will be assessed independently by the review authors to establish whether the studies meet the inclusion criteria. Disagreements will be resolved by discussion. All studies meeting the inclusion criteria will be assessed for quality and data extracted. Studies rejected at this or subsequent stages will be recorded in the 'Characteristics of excluded studies' table, and reasons for exclusion recorded.
Data extraction and management
Data extraction will be undertaken independently and in duplicate by three review authors (Helen Worthington (HW), Priscilla Appelbe (PA) and Tanya Walsh (TW)) using a piloted data extraction form. In order to undertake multiple treatments meta‐analysis, it is important that trials are homogeneous in terms of key characteristics. The following information will be extracted:
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Article information: author, journal, year of publication
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Study information: country of origin, duration of data collection (months), date of baseline collection[1], dates of data collection, number of centres, location (e.g. school‐based), other sources of fluoride exposure[2], duration of intervention, individual or cluster‐randomisation
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Intervention: level and type of fluoride, abrasive system
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Assessment: teeth included, criteria for clinical diagnosis, calculation of change/increment
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Frequency of brushing, supervised brushing, number of examiners and calibration details, method of clinical assessment
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Participant information: age at baseline, initial number, baseline caries, per cent caries free, mean DMFS (standard deviation (SD)/standard error (SE)), mean DMFT (SD/SE)
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Outcome information: final caries and number, per cent caries free, mean DMFS (SD/SE), mean DMFT (SD/SE), increment and number, level of compliance
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Adverse effects: e.g. soft tissue damage, dental stain, irritation, none‐reported.
[1] When data on the study start are not provided a 'probable date' will be calculated by subtracting the duration of the study (in years) plus 1 extra year, from the publication date of the study.
[2] Background exposure to other fluoride sources will encompass data on the use (outside the trial) of topical fluorides/fluoride rinses or even fluoride toothpastes (in studies where the intervention was tested under supervision at school and no supply of any toothpaste had been provided for home use) and the consumption of fluoridated water/salt/tablets. Background use of other fluorides (rinses, gels, tablets, etc) should be clearly reported as used by the majority in a study to be considered as such, and exposure to water/salt fluoridation should be above 0.3 ppm F.
Assessment of risk of bias in included studies
All trials to be included in the analyses will be assessed for quality independently and in duplicate as part of the data extraction process with reference to the Cochrane Handbook for Systematic Reviews of Interventions 5.0.1 (Higgins 2008). Included trials will be assessed on the following:
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Adequate sequence generation: Yes, No, Unclear
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Allocation concealment: Yes, No, Unclear
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Blinding: Yes, No, Unclear
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Incomplete outcome data addressed: Yes, No, Unclear
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Free of selective outcome reporting (e.g. DMFT or DMFS or both reported?): Yes, No, Unclear
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Free of other sources of bias: Yes, No, Unclear.
'Yes' indicates a low risk of bias, 'No' indicates high risk of bias and 'Unclear' indicates either lack of information or uncertainty over the potential for bias.
Following assessment a risk of bias table will be completed.
Measures of treatment effect
Data on 'baseline levels of caries' will be calculated from the study sample analysed (final sample) and in connection with the caries increment index chosen unless otherwise stated. The prevented fraction (PF) will be the primary estimate of effect. The PF is expressed as the mean increment in the controls minus the mean increment in the treated group divided by the mean increment in the controls i.e. the caries increment in the treatment group expressed as a percentage of the control group. This will be calculated for D(M)FS and D(M)FT. Variances will be estimated using the formula presented in Dubey (Dubey 1965), along with confidence intervals.
This PF is considered to be more appropriate than the absolute mean difference or standardized mean difference as it allows for the combination of different ways in which caries increments are measured across studies. For completeness and to compare results with earlier publications, the standardized mean difference will also be calculated and raw values (mean, SD, n) will also be presented.
Dealing with missing data
Following the data extraction and quality assessment process, trial investigators will be contacted in order to obtain further information of any unclear or missing data. For the main outcome data, missing standard deviations for caries increments not revealed through contact with the original researchers will be imputed through linear regression of log (standard deviations) on log (mean caries) increments.
Data synthesis
It is acknowledged that caries increment could be reported differently in different trials. To account for this the choice of primary outcome will follow the hierarchy presented in the Cochrane systematic review of placebo‐controlled trials (Marinho b 2003):
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data on surface level will be chosen over data on tooth level
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DFS data will be chosen over DMFS data, and these will be chosen over DS or FS
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data for 'all surface types combined' will be chosen over data for 'specific types' only
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data for 'all erupted and erupting teeth combined' will be chosen over data for 'erupted' only, and these over data for 'erupting' only
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data from 'clinical and radiological examinations combined' will be chosen over data from 'clinical' only, and these over 'radiological' only
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data for dentinal/cavitated caries lesions will be chosen over data for enamel/non‐cavitated lesions
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net caries increment data will be chosen over crude (observed) increment data
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follow up nearest to 3 years (often the one at the end of the study period) will be chosen over all other lengths of follow up, unless otherwise stated.
A graphical representation of the taxonomy of interventions and review of the study characteristics will be undertaken, along with an assessment of underlying assumptions to determine the feasibility of conducting a multiple treatments meta‐analysis. Statistical analysis will be carried out using the WinBugs package using a random‐effects model for the multiple treatments meta‐analysis for the prevented fraction data and standardized mean difference. This will be undertaken for both D(M)FS and D(M)FT. Deciduous and permanent teeth will be analysed separately throughout.
Subgroup analysis and investigation of heterogeneity
If data allow, random‐effects meta‐regression with toothbrushing method (i.e. performed under supervision or not), will be undertaken as this was a clinically important effect modifier in previous reviews (Marinho b 2003; Twetman 2003), along with baseline caries and year of randomisation.
Illustration of potential indirect comparison, using placebo toothpastes as common comparator, and fluoride toothpastes of 1000 ppm and 1500 ppm.
