Fluoride mouthrinses for preventing dental caries in children and adolescents
Abstract
Background
Fluoride mouthrinses have been used extensively as a caries‐preventive intervention in school‐based programmes and individually at home.
Objectives
To determine the effectiveness and safety of fluoride mouthrinses in the prevention of dental caries in children and to examine factors potentially modifying their effect.
Search methods
We searched the Cochrane Oral Health Group's Trials Register (May 2000), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2000, Issue 2), MEDLINE (1966 to January 2000), plus several other databases. We handsearched journals, reference lists of articles and contacted selected authors and manufacturers.
Selection criteria
Randomised or quasi‐randomised controlled trials with blind outcome assessment, comparing fluoride mouthrinse with placebo or no treatment in children up to 16 years during at least 1 year. The main outcome was caries increment measured by the change in decayed, missing and filled tooth surfaces (D(M)FS).
Data collection and analysis
Inclusion decisions, quality assessment and data extraction were duplicated in a random sample of one third of studies, and consensus achieved by discussion or a third party. Authors were contacted for missing data. The primary measure of effect was the prevented fraction (PF) that is the difference in mean caries increments between the treatment and control groups expressed as a percentage of the mean increment in the control group. Random‐effects meta‐analyses were performed where data could be pooled. Potential sources of heterogeneity were examined in random‐effects metaregression analyses.
Main results
Thirty‐six studies were included. For the 34 that contributed data for meta‐analysis (involving 14,600 children) the D(M)FS pooled PF was 26% (95% confidence interval (CI), 23% to 30%; P < 0.0001). Heterogeneity was not substantial, but confirmed statistically (P = 0.008). No significant association between estimates of D(M)FS prevented fractions and baseline caries severity, background exposure to fluorides, rinsing frequency and fluoride concentration was found in metaregression analyses. A funnel plot of the 34 studies indicated no relationship between prevented fraction and study precision. There is little information concerning possible adverse effects or acceptability of treatment in the included trials.
Authors' conclusions
This review suggests that the supervised regular use of fluoride mouthrinse at two main strengths and rinsing frequencies is associated with a clear reduction in caries increment in children. In populations with caries increment of 0.25 D(M)FS per year, 16 children will need to use a fluoride mouthrinse (rather than a non‐fluoride rinse) to avoid one D(M)FS; in populations with a caries increment of 2.14 D(M)FS per year, 2 children will need to rinse to avoid one D(M)FS. There is a need for complete reporting of side effects and acceptability data in fluoride mouthrinse trials.
PICOs
Plain language summary
Fluoride mouthrinses for preventing dental caries in children and adolescents
Regular supervised use of fluoride mouthrinses by children would reduce their tooth decay, even if they drink fluoridated water and use fluoridated toothpaste.
Fluoride is a mineral that prevents tooth decay (dental caries). Since widespread use of fluoride toothpastes and water fluoridation, the value of additional fluoride has been questioned. Fluoride mouthrinse is a concentrated solution that needs to be used regularly to have an effect. The review of trials found that regular use of fluoride mouthrinse reduces tooth decay in children, regardless of other fluoride sources. One in two children with high levels of tooth decay (and one in 16 with the lowest levels) would have less decay. However, more research is needed on adverse effects and acceptability of mouthrinses.
Authors' conclusions
Background
The prevention of dental caries in children and adolescents is generally regarded as a priority for dental services and considered more cost effective than its treatment (Burt 1998). Fluoride therapy has been the centrepiece of caries‐preventive strategies since the introduction of water fluoridation schemes over 5 decades ago (Murray 1991). These were introduced when caries was highly prevalent and severe, and when even modest prevention activities led to considerable reductions in disease levels. In the last 20 years, with the substantial decline in dental caries rates in many western countries, an increase in dental fluorosis levels in some countries, and intensive research on the mechanism of action of fluoride highlighting the primary importance of its topical effect, greater attention has been paid to the appropriate use of other fluoride‐based interventions (Glass 1982; Featherstone 1988; Ripa 1991; O'Mullane 1994; Marthaler 1996; Featherstone 1999).
The use of topically applied fluoride products in particular, which are much more concentrated than the fluoride in drinking water, has increased over recent decades. By definition, the term 'topically applied fluoride' is used to describe those delivery systems which provide fluoride to exposed surfaces of the dentition, at elevated concentrations, for a local protective effect, and are therefore not intended for ingestion. The most important anti‐caries effect of fluoride is considered to result from its action on the tooth/plaque interface, through promotion of remineralisation of early caries lesions and by reducing tooth enamel solubility (Featherstone 1988). Fluoride containing toothpastes (dentifrices), mouthrinses, gels and varnishes are the modalities most commonly used at present, either alone or in combination. Various products are marketed in different countries and a variety of caries‐preventive programmes based on these have been implemented. Toothpastes are by far the most widespread form of fluoride usage (Murray 1991a; Ripa 1991) and although the reasons for the decline in the prevalence of dental caries in children from different countries continues to be debated (Nadanovsky 1995; Krasse 1996; Marthaler 1996; de Liefde 1998), it has been mainly attributed to the gradual increase in, and regular home use of fluoride in toothpaste (Glass 1982; Ripa 1991; Rolla 1991; Marthaler 1994; O'Mullane 1994; Bratthall 1996).
At the same time, the lower caries prevalence now prevailing in many countries and the widespread availability of fluoride from multiple sources have raised the question of whether topically applied fluorides are still effective in reducing caries, and safe, mainly in terms of the potential risk of fluorosis (mottled enamel). This is particularly important as nearly all child populations in developed countries are exposed to some source of fluoride (notably in toothpaste), and adverse effects may be rare (such as acute fluoride toxicity) or more subtle (such as mild dental fluorosis).
The evidence on the effect of topical fluorides on the prevention of dental caries in children has been extensively reviewed in a number of traditional narrative reviews. A small number of reviews focusing on the evaluation of specific fluoride active agents within specific delivery systems have used a quantitative meta‐analytical approach to synthesise studies results (Clark 1985; Johnson 1993; Helfenstein 1994; Stamm 1995; van Rijkom 1998). However, a systematic quantitative evaluation of the available evidence on the effect of the main modalities of topically applied fluoride has never been undertaken.
This review is one in a series of systematic reviews of topical fluoride interventions and assesses the effectiveness of fluoride rinses in the prevention of dental caries in children.
Fluoride mouthrinses
Fluoride mouthrinses have been used extensively for the past 30 years to prevent dental caries in children. The use of rinses was especially widespread in organised school‐based programmes in countries experiencing high caries prevalence in the 1970s and 1980s. Doubts about the effectiveness of fluoride mouthrinse as a population strategy began in the mid 1980s in view of the decline in dental caries, and their presumed cost effectiveness was challenged (Stamm 1984; Disney 1990). The current view is that fluoride mouthrinsing programmes are only appropriate for high caries groups of children. While supervised, school‐based, weekly rinsing programmes using 900 ppm F solutions remain a popular procedure in America in non‐fluoridated communities (Horowitz 1996), in Scandinavia and in several other countries these have been discontinued based on the above‐noted caries decline and the widespread use of fluoride toothpastes (Seppa 1989). Mouthrinses containing 230 ppm F are available commercially for daily home use in some countries. Rinses containing 100 ppm F are also available for over the counter (OTC) sales and recommended for twice daily use. Fluoride mouthrinses have thus moved from being a tool mainly advocated in the public health setting and, through the force of commercial marketing, have gained greater prominence in the personal dental products market. By virtue of the widespread use of other oral mouthrinse products, from simple breath fresheners to products formulated to counter inflammatory periodontal (gum) diseases, it has been argued that the procedure could in fact be cost effective if those already using non‐fluoride mouthrinses convert to the use of fluoride rinses (Stamm 1993).
Although the procedure is not recommended for children under 6 years of age, due to the risk of acute and chronic fluoride ingestion, there are data implicating fluoride mouthrinse use by pre‐school children as a risk factor for dental fluorosis (enamel defects caused by young children chronically ingesting excessive amounts of fluoride during the period of tooth formation) because some young children might swallow substantial amounts (Ripa 1991; Stookey 1994). Accidental swallowing of the usual 10 ml rinse volume of a 0.05% (230 ppm F) NaF solution for daily use by a 5 to 6 year‐old child will result in ingestion of 2.3 mg of fluoride (the average dosage ingested would be twice the optimum level in a fluoridated area). Although this dose is far below the probable toxic dose (PTD) of fluoride, estimated to be 5 mg/kg body weight (Whitford 1992), or approximately 100 mg of fluoride for a 5 to 6 year‐old child (20 kg), this amount would be available in just 434 ml of the standard daily rinsing solution.
The effect of fluoride mouthrinses on the incidence of caries in children has been extensively investigated during the past four decades in a large number of clinical trials. Besides sodium fluoride solutions, mouthrinses containing other fluoride compounds in several concentrations and rinsing frequencies have been tested. The evidence from primary studies on the effectiveness of fluoride mouthrinses has been reviewed in numerous review articles and textbook chapters (Torell 1974; Birkeland 1978; Bohannan 1985; Leverett 1989; Ripa 1991; Ripa 1992; Petersson 1993). In one review article a meta‐analytical approach has been used to synthesise the results of US studies carried out in fluoride deficient communities (Stamm 1984). To date, no systematic reviews of the available evidence from clinical trials on the effectiveness and safety of fluoride mouthrinses have been reported.
Objectives
(1) To determine the effectiveness and safety of fluoride rinses in preventing dental caries in the child/adolescent population.
(2) To examine whether the effect of fluoride rinses is influenced by the level of caries severity.
(3) To examine whether the effect of fluoride rinses is influenced by the background exposure to fluoride in water (or salt), toothpastes or reported fluoride sources other than the study option(s).
(4) To examine whether the effect of fluoride rinses is influenced by fluoride concentration or application features, such as frequency of use.
Methods
Criteria for considering studies for this review
Types of studies
Randomised or quasi‐randomised controlled trials (RCTs) using or indicating blind outcome assessment, in which fluoride mouthrinse is compared concurrently to a placebo or no treatment group during at least 1 year/school year.
RCTs with open outcome assessment or no indication of blind assessment, or lasting less than 1 year/school year, or controlled trials where random or quasi‐random allocation is not used or indicated were excluded.
Types of participants
Children or adolescents aged 16 or less at the start of the study (irrespective of initial level of dental caries, background exposure to fluorides, dental treatment level, nationality, setting where intervention is received or time when it started).
Studies where participants were selected on the basis of special (general or oral) health conditions were excluded.
Types of interventions
Topical fluoride in the form of mouthrinses only, using any fluoride agent, at any concentration (ppm F), amount, frequency of use, duration of application, and with any technique of application, prior‐ or post‐application (in which the rinse is swished and expectorated, not swallowed). The control group is placebo or no treatment resulting in the following comparison: fluoride rinse compared with a placebo or no treatment.
Studies where the intervention consisted of any other caries preventive agent or procedure (e.g. other fluoride‐based measures, chlorhexidine, sealants, oral hygiene interventions, xylitol chewing gums, glass ionomers) used in addition to fluoride rinse were excluded.
Types of outcome measures
The primary outcome measure in this review is caries increment, as measured by 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 radiographically recorded at the dentine level of diagnosis. (SeeMethods for the different ways of reporting the decayed, (missing) and filled teeth or surfaces (D(M)FT/S) scores in clinical trials of caries preventives.)
The following outcomes were considered relevant: coronal dental caries and dental fillings, in both the permanent and the deciduous dentitions; tooth loss; dental pain/discomfort; specific side effects (fluorosis, tooth staining/discolouration, oral allergic reactions, adverse symptoms such as nausea, vomiting); unacceptability of preventive treatment as measured by drop outs during the trial (in non‐placebo controlled studies); use of health service resources (such as visits to dental care units, length of dental treatment time).
Studies reporting only on plaque/gingivitis, calculus, dentine hypersensitivity or fluoride physiological outcome measures (fluoride uptake by enamel or dentine, salivary secretion levels, etc.) were excluded.
Search methods for identification of studies
With a comprehensive search, we attempted to identify all relevant studies irrespective of language, from 1965 onwards.
Electronic searching
Up to 1998
Relevant studies were identified (for the series of topical fluoride reviews) by searching several databases from date of inception: MEDLINE (1966 to 1997), EMBASE (1980 to 1997), SCISEARCH (1981 to 1997), SSCISEARCH (1981 to 1997), ISTP (1982 to 1997), BIOSIS (1982 to 1997), CINAHL (1982 to 1997), ERIC (1966 to 1996), DISSERTATION ABSTRACTS (1981 to 1997) and LILACS/BBO (1982 to 1997). Two overlapping but complementary subject search phrases (Appendix 1) with very low specificity (but high sensitivity), using 'free text 'and 'controlled vocabulary', were formulated within Silverplatter MEDLINE around two main concepts, fluoride and caries, and combined with all three levels of the Cochrane Optimal Search Strategy for Randomised Controlled Trials (RCTs). These subject search phrases were customised for searching EMBASE and the other databases.
RCT filters were also adapted to search EMBASE, BIOSIS, SCISEARCH, DISSERTATION ABSTRACTS, and LILACS/BBO. All the strategies (subject search and methodological filters) developed to search each database are fully described in a report produced for the Systematic Reviews Training Unit (Marinho 1997), and are available on request. These were used for the development of a register of topical fluoride clinical trials for the systematic reviews, as the Cochrane Oral Health Group's Trials Register was not yet developed in 1997/98.
The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 1997, Issue 1), the Community of Science database (1998), which included ongoing trials funded by the National Institute of Dental Research (NIDR), the System for Information on Grey Literature in Europe (SIGLE) database (1980 to 1997), and OLDMEDLINE (1963 to 1965) were searched using the terms 'fluor' and 'carie' truncated. (Grey literature search had also been carried out by searching the Index to Scientific and Technical Proceedings (ISTP) and DISSERTATION ABSTRACTS.)
From 1999 to 2001
The strategy included in Appendix 2 was used to search LILACS/BBO in 1999 (1982 to 1998), where free text subject search terms were combined with a methodological filter for RCTs.
A supplementary and more specific subject search phrase (including 'free text' and 'controlled vocabulary' terms), refined exclusively for this review, formulated around three concepts: mouthrinse, fluoride and caries, was used to search Silverplatter MEDLINE (up to January 2000) without methodological filters (Appendix 3). This strategy was adapted to search the Cochrane Oral Health Group's Trials Register (up to May 2000), and has also been run on CENTRAL (The Cochrane Library 2000, Issue 2) to double‐check.
The metaRegister of Controlled Trials was searched in October 2001 for ongoing RCTs using the terms 'fluoride' and 'caries'.
Reference searching
All eligible trials retrieved from the searches, meta‐analyses and review articles were scanned for relevant references. Reviews had been identified mainly by a MEDLINE search strategy specifically carried out to provide information on available systematic reviews or meta‐analyses and on the scope of the literature on the topic, when the Cochrane Database of Systematic Reviews (CDSR), and the Database of Abstracts of Reviews of Effects (DARE) and NHS Economic Evaluation Database (NHSEED), were also searched. Reference lists of relevant chapters from preventive dentistry textbooks on topically applied fluoride interventions were also consulted.
Full‐text searching
Prospective handsearching of those journals (seven) identified as having the highest yield of eligible RCTs/controlled clinical trials (CCTs) were carried out, from January 1999 until January 2000: British Dental Journal, Caries Research, Community Dentistry and Oral Epidemiology, Journal of the American Dental Association, Journal of Dental Research, Journal of Public Health Dentistry and European Journal of Oral Sciences. The handsearch of Community Dentistry and Oral Epidemiology was undertaken (from 1990 to December 1999), as this was the journal with the highest yield of eligible reports.
Personal contact
Searching for unpublished studies (or 'grey' literature such as technical reports and dissertations, or studies published in languages other than English which may not have been indexed to major databases) started by contacting experts in the field of preventive dentistry. A letter was sent to the author(s) of each included study published during the last two decades in order to obtain information on possible unpublished studies eligible for inclusion. All the authors of studies who had been contacted in order to clarify reported information to enable assessment of eligibility or obtain missing data were also asked for unpublished studies.
Based on information extracted mainly from included studies, a list of manufacturers of fluoride mouthrinses was created for locating unpublished trials. Letters to manufacturers were sent out by the Cochrane Oral Health Group, in the hope that companies might be more responsive to contact from the editorial base than from individual reviewers. Six fluoride rinses manufacturers were contacted (October 2000) and information on any unpublished trials requested: Colgate‐Palmolive, Gaba AG, Johnson & Johnson, Oral‐B, Procter & Gamble, Warner‐Lambert.
Data collection and analysis
Identification of reports produced by the searches
Because multiple databases were searched, the downloaded set of records from each database, starting with MEDLINE, was imported to the bibliographic software package Reference Manager and merged into one core database to remove duplicate records and to facilitate retrieval of relevant articles. The records yielded from LILACS, BBO, CENTRAL, SIGLE and NIDR databases were not imported to Reference Manager and were scanned without the benefit of eliminating duplicates. The records produced by OLD MEDLINE and by the specific MEDLINE search performed without methodological filter were imported to Reference Manager for inspection, in a database separate from the core database. The records produced by searching the Cochrane Oral Health Group's Trials Register and the metaRegister of Controlled Trials were also checked outside Reference Manager.
All records electronically identified by the searches were printed off and scanned on the basis of title first, then by abstract (when this was available in English or in languages known by the reviewer) and/or keywords by one reviewer, Valeria Marinho (VM). Obviously irrelevant records were discarded and the full text of all remaining were obtained. Records were considered irrelevant according to study design/duration, participants, or interventions/comparisons (if it could be determined that the article was not a report of a randomised/quasi‐randomised controlled trial; or the trial was of less than 6 to 8 months duration; or the trial was exclusively in adults; or the trial did not address a fluoride rinse intervention; or the trial did not compare fluoride mouthrinse to placebo or no treatment).
All potentially relevant reports identified when searching other sources (reference lists of relevant studies, review articles and book chapters, journal handsearch, personal contact) were also obtained. (Reports that might be identified by contacting manufacturers will be obtained to feature in updates of this review.)
It was considered essential to identify and check all reports related to the same study; in case of any discrepancy, authors were contacted.
Selection of studies
With the inclusion criteria form previously prepared and pilot tested, one reviewer (VM) assessed all studies for inclusion in the review, and a second reviewer, Julian Higgins (JH), independently duplicated the process for a sample of those (approximately 30%). In addition, any study that could not be classified by the first reviewer was independently assessed by the second. A third reviewer was consulted, Stuart Logan (SL) or Aubrey Sheiham (AS), to resolve any disagreement. It was decided in advance to exclude any trial where agreement could not be reached (but this did not occur). Trial reports thought to be potentially relevant in languages not known by the reviewers were translated and the reviewer (VM) completed the inclusion form with reference to the translator. Attempts were made to contact authors of trials that could not be classified in order to ascertain whether inclusion criteria were met.
Data extraction
Data from all included studies were extracted by one reviewer (VM) using a pilot tested data extraction form. A second reviewer (JH) extracted data from a random sample of approximately one third of included studies. Again, data that could not be coded by the first reviewer were independently coded by the second, any disagreement was discussed and a third reviewer consulted to achieve consensus where necessary. (In future updates all reports will be data extracted and quality assessed in duplicate.) Data presented only in graphs and figures were extracted whenever possible, but were included only if two reviewers independently had the same result. Attempts were made to contact authors through an open‐ended request in order to obtain missing information or for clarification whenever necessary.
Additional information related to study methodology or quality that was extracted included: study duration (years of follow up); comparability of baseline characteristics: methods used pre‐randomisation in sizing/balancing (stratification based on relevant variables) or used post‐randomisation in analysing/adjusting for possible differences in prognostic factors between groups; objectivity/reliability of primary outcome measurement (diagnostic methods and thresholds/definitions used and included, and monitoring of diagnostic errors); any co‐intervention and/or contamination. Information on sponsoring institutions and manufacturers involved was also recorded.
Characteristics related to participants that were extracted included: age (range) at start, caries severity at start (average DMFS, DFS, or other measure), background exposure to other fluoride sources (in water, topical applications, etc.), year study began, location where study was conducted (country), setting where participants were recruited, and dental treatment level (F/DMF). Characteristics of the intervention that were extracted included: mode of application (how the intervention was delivered), methods (technique/device) of application, prior‐ and post‐application, fluoride active agents and concentrations used, frequency and duration of application, and amount applied.
Different ways of assessing/reporting caries increment in the trials (change from baseline as measured by the DMF index) were recorded separately and/or combined according to the components of the index chosen and units of measurement (DMFT/S, or DFT/S, or DT/S, or FT/S), types of tooth/surface considered (permanent/deciduous teeth/surfaces, first molar teeth, approximal surfaces, etc.), state of tooth eruption considered (erupted and/or erupting teeth or surface), diagnostic thresholds used (cavitated/dentine lesions, non‐cavitated incipient lesions), methods of examination adopted (clinical and/or radiographic), and approaches adopted to account or not for reversals in caries increment (in a net or observed/crude caries increment respectively). In addition, caries increments have been recorded whenever the authors reported them (various follow ups).
As we were aware that caries increment could be reported differently in different trials we developed a set of a priori rules to choose the primary outcome data for analysis from each study: data on permanent teeth would be chosen over data on deciduous teeth; data on surface level would be chosen over data on tooth level; DFS data would be chosen over DMFS data, and this would be chosen over DS or FS; data for 'all surface types combined' would be chosen over data for 'specific types' only; data for 'all erupted and erupting teeth combined' would be chosen over data for 'erupted' only, and this over data for 'erupting' only; data from 'clinical and radiological examinations combined' would be chosen over data from 'clinical' only, and this over 'radiological' only; data for dentinal/cavitated caries lesions would be chosen over data for enamel/non‐cavitated lesions; net caries increment data would be chosen over crude (observed) increment data; and follow up nearest to 3 years (often the one at the end of the treatment period) would be chosen over all other lengths of follow up, unless otherwise stated. When no specification was 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 were assumed.
The Characteristics of included studies table provides a description of all the main outcome data reported from each study with the primary measure chosen featuring at the top. Where assessments of caries increments were made during a post‐intervention follow‐up period, the length of time over which outcomes were measured after the intervention ended was noted. All other relevant outcomes assessed/reported in the trials are also listed in this table.
Quality assessment
The methodological quality of the included studies was assessed according to the criteria for concealment of treatment allocation described in the Cochrane Reviewers' Handbook (Clarke 2000) used in the Cochrane Review Manager software (RevMan). Allocation concealment for each trial was rated as belonging to one of three categories.
(A) Adequately concealed (an adequate method to conceal allocation is described).
(B) Concealment unclear ('random' allocation stated/indicated but the actual allocation concealment method is not described or an apparently adequate concealment scheme is reported but there is uncertainty about whether allocation is adequately concealed).
(C) Inadequately concealed (an inadequate method of allocation concealment is described).
Excluded: random (or quasi‐random) allocation clearly not used in the trial, or 'random' allocation not stated and not implied/possible.
Blinding of main outcome assessment was also rated according to the following three categories defined for the topical fluoride reviews.
(A) Double‐blind (blind outcome assessment and use of placebo described).
(B) Single‐blind (blind outcome assessment stated and no placebo used).
(C) Blinding indicated (blind outcome assessment not stated but likely in any element/phase of outcome assessment, e.g. clinical and/or radiographic examinations performed independently of previous results, or radiographic examinations performed independently of clinical examinations with results reported separately/added later, or examiners clearly not involved in giving treatment, or use of placebo described) or reported but unclear (blind outcome assessment reported but there is information that leads to suspicion/uncertainty about whether the examination was blind).
Excluded: clearly open outcome assessment used or blind outcome assessment not reported and unlikely (no description of an examination performed independently of previous results, of x‐rays registered independently of clinical examination, of use of a placebo, and of examiners clearly not involved in giving treatment).
One reviewer (VM) assessed the quality of all included studies. A second reviewer (JH) duplicated the process for a random sample of approximately one third of those. Any disagreement was discussed and where necessary a third reviewer was consulted to achieve consensus. Where uncertainty could not be resolved an effort was made to contact authors directly to clarify the method used to conceal allocation or whether assessment of the main outcome had been carried out blind.
Checking of interobserver reliability was limited to these validity assessments.
Other methodological characteristics of the trials such as completeness of follow up (proportion excluded) and handling of exclusions (extent to which reasons for attrition are explicitly reported, or losses are independent of treatment allocated) were not used as thresholds for inclusion. However, all assessments of study quality are described in the table of included studies, and were coded for possible use in metaregression/sensitivity analyses.
Data analyses
Handling of missing main outcome data
It was decided that missing standard deviations for caries increments that were not revealed by contacting the original researchers would be inputed through linear regression of log standard deviations on log mean caries increments. This is a suitable approach for caries prevention studies since, as caries increments follow an approximate Poisson distribution, they are closely related (similar) to their standard deviations (van Rijkom 1998).
Handling of results of studies (main outcome) with more than one treatment arm
In the studies with more than one relevant intervention group and a common control group, such as those comparing different active fluoride agents or concentrations of fluoride ions to a placebo/no treatment group, raw results (the numbers, mean caries increments and standard deviations) from all relevant experimental groups were combined in order to obtain a measure of treatment effect. This enables the inclusion of all relevant data in the primary meta‐analysis, although may slightly compromise the secondary investigations of dose response.
Choice of measure of effect and meta‐analyses of main outcome
The chosen measure of treatment effect was 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 caries increment (where discrete counts are considered to approximate to a continuous scale and are treated as continuous data) this measure was considered more appropriate than the mean difference or standardised mean difference, since it allows combination of different ways of measuring caries increment and a meaningful investigation of heterogeneity between trials. It is also simple to interpret. The meta‐analyses were conducted as inverse variance weighted averages. Variances were estimated using the formula presented in Dubey 1965 which was more suitable for use in a weighted average, and for large sample sizes the approximation should be reasonable. Random‐effects meta‐analyses were performed throughout.
With the use of prevented fraction, it was not possible to perform the main outcome analyses in RevMan/MetaView. However, the raw results of the studies (mean/SD/n) were entered in RevMan and mean differences were presented without meta‐analyses. Where meta‐analyses using standardised mean differences yielded materially similar results to those using prevented fractions, we have also presented these within MetaView. Deciduous and permanent teeth are analysed separately throughout.
For illustrative purposes the results were also presented as the number of children needed to treat (NNT) to prevent one carious teeth/surface. These were calculated by combining the overall prevented fraction with an estimate of the caries increment in the control groups of the individual studies.
Assessment of heterogeneity and investigation of reasons for heterogeneity
Heterogeneity was assessed by inspection of a graphical display of the estimated treatment effects from the trials along with their 95% confidence intervals and by formal tests of homogeneity undertaken prior to each meta‐analysis (Thompson 1999).
In addition to aspects of study quality, three potential sources of heterogeneity were specified a priori as investigations of these formed part of the primary objectives of the review. We hypothesised that: (1) the effect of fluoride mouthrinses differs according to the baseline levels of caries severity; (2) the effect of fluoride mouthrinses differs according to exposure to other fluoride sources (in water, in toothpastes, etc.); and (3) the effect of fluoride mouthrinses differs according to concentration of fluoride and frequency of application. The association of these factors with estimated effects (D(M)FS PFs) were examined by performing random‐effects metaregression analyses in Stata version 6.0 (Stata Corporation, USA) using the program Metareg (Sharp 1998).
To allow such investigation, relevant data were dealt with as follows: data on 'baseline levels of caries' were calculated from the study sample analysed (final sample) and in connection with the caries increment index chosen, unless otherwise stated, and were averaged among all relevant study groups. Data on 'background exposure to other fluoride sources' combined data on the use of fluoride toothpaste and the consumption of fluoridated water (or salt) and were grouped into two categories: one for studies which were based on samples provided with non‐fluoride toothpaste and which were from non‐fluoridated areas (non‐exposed), and another for studies based on samples using fluoride toothpaste or studies in fluoridated communities or both. When use or non‐use of fluoride toothpaste was not clearly indicated in studies carried out in developed countries, it was assumed that fluoride toothpaste was widely used from the middle of the 1970s (Ripa 1989); this information was sought from authors (or obtained from other sources) when missing from studies carried out in other locations. When data on the year a study had begun was not provided this was calculated as a 'probable date' by subtracting the duration of the study (in years) plus one extra year, from the publication date of the study. Data on 'concentration applied' and 'frequency of rinsing' have not been categorised, but a 'total intensity of application per year' covariate was produced by multiplying frequency of application (per year) by fluoride concentration of mouthrinse applied (in ppm F). In multiple arm studies we averaged this intensity score over fluoride treatment groups. Incomplete data for frequency of mouthrinsing was dealt with as follows: in studies of supervised daily rinse at school where participants were provided with mouthrinse for home use, rinsing frequency of 365 times a year was to be assumed if not precisely reported. Rinsing frequency of 320 times a year was assumed in studies of 'unsupervised' daily rinse at home (even if instructions to rinse more than once a day were given); frequency of 160 times (days) a year was assumed when it was not precisely reported in studies of supervised daily rinse at school where children were not provided with any rinse for home use; frequency of 30 times a year was assumed for weekly rinse at school, and of 17 times a year for fortnightly rinse at school.
Further potential sources of heterogeneity were investigated by metaregression. These 'post hoc' analyses are clearly identified and the results should be treated with caution. Sensitivity analyses were performed where appropriate.
Investigation of publication and other biases
A funnel plot (plots of effect estimates versus the inverse of their standard errors) was drawn. Asymmetry of the funnel plot may indicate publication bias and other biases related to sample size, though may also represent a true relationship between trial size and effect size. A formal investigation of the degree of asymmetry was performed using the method proposed by Egger et al (Egger 1997).
Measures of effect and meta‐analysis of other outcomes
For outcomes other than caries increment, continuous data were to be analysed according to differences in mean treatment effects and their standard deviations. Dichotomous outcome data were analysed by calculating risk ratios (RR) or, for adverse effects of fluoride treatment, risk differences (RD). RevMan was used for estimation of overall treatment effects. Again, a random‐effects model was used to calculate a pooled estimate of effect. As a general rule only (relevant) outcomes with useable data are shown in the analyses tables.
Results
Description of studies
Search results
Searching the core database in Reference Manager (using 'mouthwash*' or 'rins*' or 'sodium fluoride*' or 'amine fluoride*' or 'amine fluoride solution' or 'acidulated fluorophosphate*' or 'acidulated phosphate fluoride*' or 'fluorophosphate*' or 'stannous fluoride*' as keywords combined with 'rins' or 'wash' or 'fluoride solution' in titles and notes) retrieved 2263 records from MEDLINE, EMBASE, BIOSIS, SCISEARCH, SSCISEARCH, CINAHL, ERIC, ISTP and DISSERTATION ABSTRACTS. There were 211 records scanned outside Reference Manager produced by searching LILACS (48 records), BBO (47 records), CENTRAL (86 records), SIGLE (6 records), and NIDR/Community of Science Database (24 records). When LILACS and BBO were searched for the second time with a modified search strategy the yield was 210 records (142 and 68 records respectively) also scanned outside Reference Manager. Searching OLDMEDLINE produced 545 records. Thus, 3229 records yielded by the original electronic searches for topical fluoride trials were scanned, but many of these were duplicates not merged in the core database. The specific MEDLINE search for fluoride mouthrinse trials performed without a randomised controlled trial (RCT) filter produced 763 records, and the search performed in the Cochrane Oral Health Group's Trials Register produced 139 records. The search for ongoing studies in the metaRegister of Controlled Trials produced five records.
Searching other non‐electronic sources (reference lists of potentially relevant reports, review articles or book chapters, journals, and contacting authors) produced 112 additional records for inspection. One of the six manufacturers of fluoride mouthrinses contacted, GABA, provided a list of 409 records from a search performed in GALIDENT (Database of GABA Library in Dentistry) using the keyword 'amine fluoride'. However, search results from these and, if provided, from other manufacturers will be taken into account in updates of this review.
From the search results above a total of 282 records were considered potentially eligible, and sought for further assessment.
Study selection results
Two hundred and eighty‐two reports were sought for detailed assessment for inclusion, of which nine full text reports could not be obtained (most of these were incomplete references to non‐English reports). One hundred and forty‐four reports were considered immediately irrelevant for this review, either due to the types of study design described (historical controls or other non‐experimental designs) or as a result of the types of intervention compared with, or used in addition to fluoride mouthrinse (including head‐to‐head studies without a placebo or no treatment group). Ninety‐two studies (129 reports) are considered/cited in this review. These comprise 60 reports relating to 36 included studies, 55 reports relating to 43 excluded studies, and 14 reports relating to 13 studies waiting assessment, either because they require translation (seven reports in Swedish of seven studies, two reports in Russian of one study, and one report/study each in Danish, Hungarian, Japanese, and Thai), or because additional information could not be obtained yet for one study in abstract form (Kawall 1981). There were no reports of ongoing studies.
Listed either under excluded or included studies are 27 non‐English reports (21 studies). Two of these studies (two non‐English reports) were excluded either on the basis of the English abstract alone or due to the availability of a full text English report of the same study, and one report/study was included based on an English publication related to the same study. There remained 24 non‐English reports that have been fully assessed (18 studies): 11 in Portuguese (by the contact reviewer), five in Spanish (by the contact reviewer), three in German (by a German translator, with the reviewer), three in Russian (by a Russian translator, with the reviewer), two in Japanese (by a Japanese translator, with the reviewer).
Excluded studies
SeeCharacteristics of excluded studies table for the description of reasons for rejecting each study.
The 43 studies in this section were excluded for a variety of reasons. Seven studies were clearly not randomised/quasi‐randomised. Five studies used open outcome assessment. One study randomised two clusters, each to one of the two study arms. Five studies did not mention or indicate random/quasi‐random allocation nor blind outcome assessment, two studies did not mention random/quasi‐random allocation and did not mention or indicate blind outcome assessment, and two other studies did not mention random/quasi‐random allocation nor blind outcome assessment. Two studies did not mention random or quasi‐random allocation (but used/indicated blind outcome assessment); the attempt to contact the author(s) of these studies was unsuccessful and they were excluded. In one study, the length of follow up was 6 months and relevant outcomes were not reported.
Sixteen studies had other active agents or other interventions in addition to fluoride mouthrinse: eight of these did not state or indicate blind outcome assessment and/or random or quasi‐random allocation; two others had only one cluster for each study arm, another was not randomised/quasi‐randomised and the length of follow up for the main outcome assessment was less than 1 year/school year; and another had an 'inappropriate placebo' (not an inactive treatment). In two studies, the fluoride solution was swallowed after rinsing.
Included studies
SeeCharacteristics of included studies table for details of each study.
There are 36 trials included. The study conducted by Horowitz 1971 has been treated as two independent trials, since the results for the two age groups in the study have been reported separately as distinct studies. There were also completely distinct studies published as such concomitantly by the same author: Koch 1967a and Koch 1967b. All 60 reports were published between 1965 and 1998. The 36 trials were conducted between 1962 and 1994: 10 in the 1960s, 19 in the 1970s, six in the 1980s, and one in the 1990s. Thirteen trials were conducted in USA, four in UK, five in Sweden, two in Denmark, two in Canada, two in New Zealand, three in Brazil, and one in each of the following countries: Finland, The Netherlands, South Africa, Chile and Puerto Rico. Fifteen studies had more than one publication, one of these had seven published reports. Nine studies acknowledged assistance (product provision, etc.) and/or financial support from fluoride mouthrinse manufacturers. Of a total of 18 studies whose authors were sent request letters for unpublished information, replies related to 11 studies were obtained.
Design and methods
Fifteen studies had more than one fluoride mouthrinse treatment group compared to a control (multitreatment studies); among these one trial had two treatment groups and two placebo control groups. Six trials used a factorial design to investigate the effects of multiple topical fluoride interventions. With regard to type of control group used, four trials used a no treatment control group, and the remaining 32 used a placebo control group. The study duration (indicated by the total length of follow up as well as the treatment duration) ranged from 2 to 3 years among included trials; only three lasted less than 2 years (1.6 years). Studies were large with only three trials allocating less than 100 children to relevant groups. The total number of children participating in the trials (given by the sample analysed at the end of the trial periods) was 15,171 and ranged from 95 in the smallest trial to 1238 in the largest trial (on average, 421 participants per trial). All participants were recruited from school settings.
Participants
All included trials reported that the participants were aged 14 or less at the start, with similar numbers from both sexes (where these data were reported). The ages of the children at the start of the trials ranged from 5 to 14 years (where these data were reported); at least 18 trials included children who were 12, at least five trials included 5/6 year‐olds. Caries prevalence at baseline, reported in all but two of the studies, ranged from 0.94 to 14.7 D(M)FS. With regard to 'background exposure to other fluoride sources', all but two studies reported exposure or not to water fluoridation: four studies were conducted in fluoridated communities and 30 studies were not. Among the studies conducted in non‐fluoridated areas, no (or very low) exposure to fluoride toothpaste or to other fluoride sources was clearly reported in eight studies, and substantial exposure to fluoride toothpaste (over 95%) was reported in six studies; exposure or not to fluoride toothpaste had to be assumed in 16 studies based on study location and year started, as described above. Information on dental treatment level was reported in the study conducted in Denmark, in one of the two studies conducted in Canada, and in one study from USA.
Interventions
All 36 included trials reported supervised use of mouthrinse in school programmes (two of which also tested their use at home). Rinsing with sodium fluoride (NaF) was tested in 32 trials, acidulated phosphate fluoride (APF) in four trials, stannous fluoride (SnF2) in two, and sodium monofluorophosphate (SMFP), amine fluoride (AmF) and amonium fluoride (NH4F) were each tested in a different study. The fluoride concentration used in the mouthrinses ranged from 100 ppm F (0.02% NaF) to 3000 ppm F (0.66% NaF), and the frequency of application ranged from 3 to 330 times a year, but these were unusually low and high concentrations and frequencies. The concentration of 230 ppm F (180 and 250 ppm F in a few studies) was used in 18 studies, and the concentration of 900 ppm F (1000 ppm F in a few studies) was used in 19 studies. It can be seen that when rinsing was performed once a week or once every 2 weeks, a rinse usually employing 900 ppm F was used (16 trials). Conversely, when rinsing was performed once (or twice) a day, the fluoride concentration used was 230 ppm F, or around this concentration (13 trials). The only study (Duany 1981) where information on rinsing frequency was not available is likely to have used daily rinses for all three low concentrations of fluoride tested (this was one of the four studies testing the 100 ppm F rinsing solutions). The usual amounts of mouthrinse used per application was 5 or 10 ml, and usual rinsing time was 1 or 2 minutes (reported in 21 studies). The performance of some form of prior tooth prophylaxis (brushing without paste or with a non‐fluoride paste before rinsing) was reported in four studies (not considered a separate intervention on its own).
Outcome measures
Caries increment: All but two of the 36 trials reported caries increment data (or data from which these could be derived) at the tooth surface level (D(M)FS), and 13 trials reported caries increment at the tooth level (D(M)FT); d(e/m)fs/d data were not reported in any trial. With regard to the components of the DMFS index used (and types of teeth/surfaces assessed), 20 trials reported DMFS data (one trial for premolars and molars only and 19 trials for all tooth surface types), and 16 trials reported DFS data (one trial for approximal surfaces of premolars and molars only and 15 trials for all tooth surface types). No choice had to be made between DMFS or DFS data in any one trial. Sixteen trials presented D(M)FS data at more than one follow‐up time (which ranged from 1.6 to 3 years); follow up of either 2 or 3 years was reported in 26 trials. In three trials, assessments of D(M)FS increments were also made during a post‐intervention follow‐up period.
Clinical (35 trials) and radiographic (20 trials) examinations provided the definition of different stages or grades of caries lesions. These have been grouped into two basic grades for each method of examination: NCA = non‐cavitated incipient enamel lesions clinically visible as white spots or discoloured fissures; CA = lesions showing loss of enamel continuity that can be recorded clinically (undermined enamel, softened floor/walls) or showing frank cavitation; ER = any radiolucency in enamel/enamel‐dentine junction; DR = radiolucency into dentine. Many trials presented results using one caries grade only (usually CA/ER or CA/DR), others either did not report the grade, or reported caries increment data at both levels of diagnosis, in which case CA was chosen. Data on the state of tooth eruption considered were not clearly specified in many trials.
Other dental caries data reported: caries incidence/attack rate (five trials), proportion of children developing new caries (three trials).
Data on adverse effects: stain score (one trial), proportion of children with tooth staining (two trials, incomplete data), signs of sensitivity in oral soft tissue (two trials, with the following statement in one: "'no cases of mucosal hypersensitivity after periodical examinations of every subject"; no baseline data given in the other), any side effects (three trials, none of which with complete or useable data, and with the following statement in all three: "no adverse side effects observed"). Fluorosis data have not been reported in any of the trials.
Data for unacceptability of treatment (as measured by drop outs/exclusions) were reported in two of the non‐placebo controlled trials. Actual unacceptability to the taste was reported in one trial, with the following statement: "only an insignificant number withdrew because of unacceptance to the taste".
Risk of bias in included studies
Based on 28 studies included in the topical fluoride reviews and randomly selected for assessment of reproducibility and agreement between two reviewers, interrater reliability was excellent (89%) for both allocation concealment and blinding, and agreement was good for allocation (Kappa = 0.61) and very good for blinding (Kappa = 0.73).
There were clear differences in the quality of the studies in this review (using the reported information and additional information obtained from investigators).
Allocation concealment
Three of the trials which described the randomisation process could be coded A (e.g. adequate concealment of allocation). Twenty‐nine included trials were described as randomised but provided no description of the allocation process and were coded B. Four trials were quasi‐randomised and coded C.
Blinding
Twenty‐nine trials were classified as double‐blind (score A). Single‐blinding (blind dental caries assessment but no placebo used) was described in three trials (score B). Blind outcome assessment was unclear/indicated in four trials (score C), one of which was a non‐placebo controlled trial.
Follow up and withdrawals
All the participants considered at the end of each study as a proportion of all the participants present at start in all studies was 65% (12,980 analysed out of 20,066 randomised); this excludes six studies with no data by group on participants randomised. Drop out rates could not be obtained for four of the 36 included studies. There was considerable variation in drop out rates ranging from 10% at 3 years to 62% at 2.5 years.
Reasons for exclusions (when given) included moving away, absent for follow‐up examinations, and refusal to participate or poor compliance. A few trials reported the numbers excluded according to reason for attrition.
Other methodological features
Type of randomisation: stratified random allocation was used in at least 22 trials.
Units of randomisation: cluster randomisation was used in one trial (Ruiken 1987) where schools were used as units of randomisation and children used as units of analysis. Individuals were allocated to study arms in all other trials, and each participant's caries incidence, over a period of time was used as the unit of analysis.
Baseline comparisons and handling of any differences: one trial did not report any baseline data, another described as 'balanced' (for which randomisation may have succeeded to produce nearly exact balance) did not report any of the actual values for the baseline characteristics (such as initial caries levels). Some degree of imbalance was reported in a few trials (for characteristics considered most influential, usually initial caries levels) and generally either described as not significant or that adjustment had resulted in trivial differences in effect estimates.
Objectivity/reliability of primary outcome measurement: diagnostic methods used (clinical or radiographic) were described in all studies, but thresholds/definitions used for caries and monitoring of diagnostic errors were not always reported (see 'Notes' in the Characteristics of included studies table for methodological features assessed).
Effects of interventions
Effect of fluoride mouthrinse on dental caries increment
The effects of fluoride mouthrinses on dental caries increment (as measured by the DMF index) were reported in a variety of ways in the included studies. Where appropriate and possible these have been combined to produce pooled estimates as described in the Methods section. The results are reported separately here for:
(1) decayed, (missing) and filled surface prevented fraction (D(M)FS PF);
(2) decayed, (missing) and filled teeth prevented fraction (D(M)FT PF);
(3) D(M)FS and D(M)FT pooled using a standardised mean difference (SMD).
Estimates of the effects of fluoride mouthrinse on caries increment in deciduous teeth/surfaces (as measured by the dmf index) could not be produced for this review, as there was no study contributing data.
Two included studies (Brandt 1972; de Liefde 1989) did not contribute data suitable for meta‐analysis, although they are retained in the review. Standard deviations (SD) of mean caries increment data (new D(M)FS) were (partly) missing in 12 of the 34 studies which contributed data (Bastos 1989; DePaola 1977; Driscoll 1982; Finn 1975; Gallagher 1974; Heidmann 1992; Laswell 1975; McConchie 1977; Moreira 1972; Poulsen 1984; Ruiken 1987; van Wyk 1986). From the analysis of the 179 available treatment arms for the topical fluoride reviews with complete information (as of October 1999) we derived a regression equation log (SD caries increment) = 0.64 + 0.55 log (mean caries increment), (R2 = 77%). This equation was used to estimate missing standard deviations from mean D(M)FS increments for the meta‐analyses. Similarly, this same regression equation was used to estimate missing standard deviation data for three of the 13 trials reporting D(M)FT data (Bastos 1989; Finn 1975; McConchie 1977).
(1) Effect on tooth surfaces: D(M)FS PF
For all 34 trials combined, the D(M)FS PF pooled estimate was 0.26 (95% confidence interval (CI), 0.23 to 0.30; P < 0.0001), suggesting a substantial benefit from the use of fluoride mouthrinse. The CIs are relatively narrow, and although not substantial, heterogeneity in results could be observed statistically (Q = 55.62 on 33 degrees of freedom, P = 0.008).
For each study, the D(M)FS PF and 95% CIs can be viewed in the Additional tables; the results of the random‐effects meta‐analysis of D(M)FS PFs (performed in Stata) are presented in Additional Table 1: Meta‐analyses of prevented fractions. A forest plot showing the effects of fluoride mouthrinses (PFs and 95% CIs) on D(M)FS increments resulting from this meta‐analysis is available on the Cochrane Oral Health Group web site (www.ohg.cochrane.org).
| Analysis | Number of studies | RE estimate | 95% CI | Meta‐analysis P‐value | Heterogeneity test |
| D(M)FS ‐ all studies | 34 | 26% | 23% to 30% | P < 0.0001 | Q = 55.62 (33 df); P = 0.008 |
| D(M)FT ‐ all studies | 13 | 24% | 18% to 30% | P < 0.0001 | Q = 26.04 (12 df); P = 0.011 |
Metaregression and sensitivity analyses: D(M)FS PF
Univariate metaregression suggested no significant association between estimates of D(M)FS prevented fractions and the pre‐specified factors: baseline caries severity, background exposure to fluoridated water, background exposure to fluoride toothpaste, background exposure to any fluoride source, fluoride concentration, or rinsing frequency. There was an association of 'total intensity of application per year' (frequency times concentration) with the prevented fraction, but it became non‐significant when the trial of DePaola 1977, a study with high influence (an outlier), was excluded from the analysis.
Further univariate metaregression analyses showed no significant association between estimates of D(M)FS prevented fractions and allocation concealment (random/quasi‐random), blinding of outcome assessment (blind/blind likely or unclear), type of control group (placebo/no treatment), drop out rate, or length of follow up (duration of study).
Other potential effect modifiers have not been investigated (e.g. mode of mouthrinse use, since virtually all trials were conducted in school settings under supervision).
Metaregression results for potential effect modifiers, are given in Additional Table 2: Random‐effects metaregression analyses of prevented fractions: D(M)FS. It should be noted that the influential study by DePaola 1977 is omitted from the analysis intensity of application with prevented fraction.
| Characteristic | Number of studies | Slope estimate | 95% CI | Slope interpretation | P‐value |
| Mean baseline caries | 33 | 0.3% | (‐0.7% to 1.3%) | Increase in PF per unit increase in mean baseline caries | 0.6 |
| Fluoridated water area | 32 | 7% | (‐3.9% to 17.8%) | Higher PF in presence of water fluoridation | 0.2 |
| Fluoride dentrifice use | 32 | ‐0.7% | (‐9.5% to 8%) | Lower PF in presence of fluoride dentifrice use | 0.9 |
| Background fluorides | 32 | 1.4% | (‐6.3% to 9%) | Higher PF in presence of background fluoride | 0.7 |
| Rinsing frequency | 33 | 1% | (‐3.3% to 5.5%) | Increase in PF per 100 extra applications/year | 0.6 |
| Fluoride concentration in solution | 34 | 1% | (‐3.7% to 5.7%) | Increase in PF per 1000 ppm F | 0.7 |
| Intensity (freq times conc) | 32 (excludes DePaola 1977) | 11.5% | (‐10% to 33%) | Increase in PF equivalent to doubling from 100 to 200 applications and increasing by 1000 ppmF | 0.3 |
| Allocation concealment | 34 | ‐7% | (‐18% to 5%) | Lower PF with adequately concealed allocation | 0.3 |
| Blind outcome assessment | 34 | 8% | (‐11% to 13%) | Higher PF with blind outcome assessment indicated (not clearly stated) | 0.9 |
| Double blinding | 34 | 3.5% | (‐5.4% to 13%) | Higher PF with lack of double‐blinding | 0.4 |
| Control group | 34 | 6.3% | (‐4.2% to 17%) | Higher PF for no‐treatment compared with placebo | 0.2 |
| Drop out | 31 | 0.6% | (‐1.8% to 3%) | Increase in PF per 10 drop outs | 0.6 |
| Length of follow up | 34 | 0.2% | (‐6.9% to 7.4%) | Increase in PF per extra year of follow up | 0.9 |
We performed a sensitivity analysis for the main meta‐analysis of D(M)FS prevented fraction, to take account of the additional uncertainty related to the cluster randomised trial by Ruiken 1987. We inflated the variance of the prevented fraction estimate by an amount equal to (1 + (m‐1) * ICC), where m is the average cluster size and ICC the intraclass correlation coefficient. A conservative value of 0.1 for the ICC was used since we could not find an ICC from this or any similar trial. The D(M)FS PF pooled estimate was 0.26 (95% CI, 0.23 to 0.30; P < 0.0001). These results are identical to the analysis ignoring the cluster randomised design, since the estimate for this trial is similar to the meta‐analysis result and altering its weight has minimal effect.
We performed another sensitivity analysis by excluding one trial (Spets‐Happonen 1991) in which a non‐fluoride active agent was present in both fluoride and control groups, making the trial different in this way from all others that had been included. The D(M)FS PF pooled estimate resulting from the exclusion of this trial was again identical to the analysis that includes it. This is a small trial that carries little weight and had minimal effect in a meta‐analysis that includes so many larger studies.
In order to illustrate the magnitude of the effect, numbers of children needed to treat (NNT) to prevent one D(M)FS were calculated based on the pooled D(M)FS PF and on the caries increments in the control groups of the trials that contributed data to the meta‐analysis. The overall caries‐inhibiting effect (%PF) derived from the pooled results of the 34 trials was 26% (95% CI, 23% to 30%); the caries increments ranged from 0.25 to 7.02 D(M)FS per year. In populations with a caries increment of 0.25 D(M)FS per year (at the lowest end of the results seen in the included studies), this implies an absolute caries reduction of 0.065 D(M)FS per year, equivalent to an NNT of 16 (95% CI, 14 to 18): i.e. 16 children need to rinse with a fluoride mouthrinse (rather than a non‐fluoride mouthrinse) to avoid one D(M)FS. In populations with a caries increment of 2.14 D(M)FS per year (at the mid range of the results seen in the included studies), this implies an absolute caries reduction of 0.56 D(M)FS per year, equivalent to an NNT of 1.8 (95% CI, 1.6 to 2): i.e. two children need to rinse with a fluoride mouthrinse to avoid one D(M)FS.
Funnel plot and test for funnel plot asymmetry: D(M)FS PF
A funnel plot of the 34 trials reporting D(M)FS PFs does not look asymmetrical, and the weighted regression test for asymmetry (Egger 1997) was not statistically significant (asymmetry intercept (95% CI) = ‐0.84 (‐2.02 to 0.35) (P = 0.16)). There is, therefore, no evidence of bias using this method.
The funnel plot is available on the Cochrane Oral Health Group web site (www.ohg.cochrane.org).
(2) Effect on whole teeth: D(M)FT PF
Thirteen trials reported data which allowed the calculation of the D(M)FT PF. All 13 are also included in the analysis of D(M)FS PF. The results of this analysis are very similar to those reported above.
The pooled estimate of D(M)FT PF was 0.24 (95% CI, 0.18 to 0.30; P < 0.0001), suggesting, again, a substantial benefit of fluoride mouthrinse, within relatively narrow CIs. Heterogeneity between trials (Q = 26.04 on 12 degrees of freedom, P = 0.01) was not substantial, although statistically significant.
For each study, the D(M)FT PF and 95% CI can be viewed in the Additional tables. The results of the random‐effects meta‐analysis of D(M)FT PFs performed in Stata are also presented in Additional Table 1: Meta‐analyses of prevented fractions.
(3) Alternative treatment effect measure: Standardised mean difference (SMD)
Due to the character of D(M)FS data, mean caries increments are closely related to their SDs (they are about the same). Thus, meta‐analyses using SMDs (the difference between two means divided by an estimate of the within group standard deviation) yielded materially similar results to those using PFs (the difference in mean caries increments between the treatment and control groups divided by the mean increment in the control group). We therefore decided to present D(M)FS and D(M)FT SMDs in RevMan, since it was not possible to present the main outcome analyses with PFs in MetaView/RevMan.
For the 34 trials, the pooled D(M)FS SMD estimate was 0.30 (95% CI, 0.24 to 0.36; P < 0.0001). There was heterogeneity between trials (Chi2 = 93.00 on 33 degrees of freedom, P < 0.0001). The results of this analysis are similar to that of the random effects meta‐analysis of D(M)FS PF (the slight inconsistency may well be due to differences between caries increment rates and standard deviations in some of the arms of the included studies).
The pooled estimate of D(M)FT SMD based on the 13 trials that contributed data was 0.28 (95% CI, 0.20 to 0.37; P < 0.0001). There was statistically significant heterogeneity (Chi2 = 26.13 on 12 degrees of freedom, P = 0.01). These results are also consistent with those found in the random‐effects meta‐analysis of D(M)FT PF.
Effect on deciduous dentition
None of the included trials reported on caries increment in deciduous teeth/surfaces.
Effect of fluoride mouthrinse on other outcomes
A few trials report data for other relevant outcomes (see 'Outcome measures' under Description of studies). Some of these are simply other measures/indices for dental caries increment in permanent teeth/surfaces and require no further consideration; three trials report on the proportion of children developing new caries. Meta‐analyses results for the proportion of children developing new caries are presented below. The few trials that report on adverse effects give no useable or incomplete data for analysis. Data for unacceptability of treatment (as measured by drop outs) were reported in two of the non‐placebo controlled trials. Meta‐analyses results for these are also described below.
Proportion of children developing new caries
Three trials reported results on the proportion of children developing one or more new caries (Finn 1975; Heidmann 1992; Torell 1965). The pooled estimate (random‐effects meta‐analysis) of the odds ratio was 0.61, with no heterogeneity in the results (95% CI, 0.41 to 0.90; Chi2 for heterogeneity 3.76 on 2 degrees of freedom, P = 0.15). This corresponds to an NNT to prevent one child from developing caries of 9 (95% CI, 6 to 39) in a population with a caries risk the same as that found in the control groups in these trials (nine children using fluoride mouthrinse for 2 to 3 years will prevent new caries development in one child).
Unacceptability of treatment (drop outs/exclusions)
The pooled estimate of the odds ratio of dropping out from the mouthrinse as opposed to the non‐treatment arm in the two non‐placebo controlled trials that reported drop outs (Craig 1981; Moreira 1981) was 1.26 (95% CI, 0.60 to 2.64). There was no heterogeneity in these results (Chi2 = 1.43 on 1 degree of freedom, P < 0.23).
Discussion
The main aim of this review was to estimate the effects on dental caries of using fluoride mouthrinse in children compared to placebo or no treatment. Over 14,600 children were included in the trials comparing a fluoride mouthrinse with a placebo or no treatment. For almost all children the fluoride rinse they received was a sodium fluoride (NaF) formulation, provided in supervised school‐based mouthrinsing programmes, often either on a daily or weekly/fortnightly basis. Fluoride mouthrinsing at these two rinse frequencies and two main different strengths (230 ppm F/900 ppm F) has proven a versatile method of self applied topical fluoride use, and an effective method when used regularly over time under supervision.
An average caries reduction in terms of decayed, missing and filled tooth surfaces (DMFS) of about 26% can be expected from the use of this method. The meta‐analysis of the 34 studies assessing the effect of fluoride mouthrinse on the permanent dentition suggests that this reduction falls within narrow confidence intervals (23 to 30%). This would correspond to a number needed to treat (NNT) of 1.8 to avoid one D(M)FS per year in a child population with a caries increment of 2.14 D(M)FS per year (in the middle range of control group rates for included studies), or an NNT of 15.4 for children from a population with a caries increment of 0.25 D(M)FS per year (at the lowest end of the observed range). This means that two children need to rinse with a fluoride mouthrinse (rather than a non‐fluoride mouthrinse) to prevent one decayed, missing or filled tooth surface, in a child population with a high caries increment per year. In populations with caries increment as low as 0.25 D(M)FS per year, 16 children will need to use a fluoride mouthrinse to avoid one D(M)FS.
A secondary aim of this review was to examine whether there was any relationship between the caries‐preventive effectiveness of fluoride mouthrinse and a number of factors including the initial level of caries severity, background exposure to fluoride, and fluoride concentration and frequency of use. We were unable to detect a clear relationship between any of these factors and the magnitude of the treatment effect in spite of substantial variation between trials in these factors. This result should, however, be interpreted with caution. Even a meta‐analysis including 34 trials has limited power to detect such relationships and, like all analyses of observational data, is subject to the problem of potential confounding. For some factors such as 'background exposure to fluoride' there is, in addition, the problem of potential misclassification due to the poor quality of the reported data on exposure to fluoride other than in water. We were forced to make a number of assumptions, for instance classifying 'use of fluoride toothpaste' for 16 of the studies on the basis of the year when the study was conducted and its location. We were also forced to treat this as a dichotomous variable (before/after mid 1970s), although it is likely that use of fluoridated toothpaste gradually increased during the 1960s, 1970s, and 1980s. Similarly we grouped exposure to fluoride in toothpaste and fluoride in water into a single dichotomous variable which is likely to group studies whose participants had quite different levels of baseline exposure. These problems may bias any estimates of effect towards the null hypothesis. Nevertheless, these results suggest that fluoride mouthrinse may still be of benefit after the advent of fluoride toothpaste, and in both fluoridated and non‐fluoridated areas.
We did observe a significantly greater treatment effect with increased total intensity (frequency times concentration) of mouthrinse application. Although plausible, this relationship was however dependent on the inclusion of one study with particularly powerful effects (DePaola 1977). After exclusion of this study in a sensitivity analysis no significant association was seen with this factor. It should be noted that in the majority of studies where mouthrinse was performed once a week (or once every 2 weeks), a rinse employing higher fluoride concentrations (usually 900 ppm F) was used (16 trials). Conversely, in most studies where rinsing was performed once (or twice) a day a lower fluoride concentration (usually 230 ppm F) was used (13 trials). Moreover, in five multiarm studies investigating both combinations of concentrations‐frequencies (and in seven studies testing the two main fluoride concentrations) we averaged this intensity score over fluoride treatment groups to combine study results, a decision that may have slightly affected this particular investigation of heterogeneity (and that of dose‐response). Nevertheless, looking specifically at the effectiveness of the two most commonly used fluoride mouthrinse regimens there might be little to choose when the weaker (low concentration) is used as a daily rinse and the stronger (high concentration) as a weekly or fortnightly rinse. This does not necessarily imply that when both concentrations are used daily, or both are used as weekly/fortnightly rinses, they will have a similar effect. A weaker solution may well give poorer results when used less frequently. More robust investigations of these aspects of the intervention require direct, head‐to‐head comparisons of different fluoride concentrations, frequencies and intensities, which were not within the scope of this review.
We made a thorough attempt to investigate sources of heterogeneity in this review, examining factors related to participants, interventions and study quality. None of the factors investigated was clearly related to heterogeneity. Even though the type of control group (placebo/no treatment) might represent a strong indicator of study quality and source of heterogeneity in the topical fluoride reviews (Marinho 2002), a relationship between type of control group and prevented fraction was not observed in this review, possibly due to the fact that only four non‐placebo controlled trials were included. Moreover, it should be pointed out that a generally high attrition rate has been observed across the fluoride rinse trials (mean of 32%). Overall only 65% of all the participants at start remained at the end of the studies and results are often based on compliant subjects who actually completed the study. Thus, the issue of longer term compliance should not be disregarded when administering such procedure.
We performed a sensitivity analysis for the main meta‐analysis to take account of the additional uncertainty we should have about the cluster randomised trial by Ruiken et al (Ruiken 1987). This showed results (PF) identical to the analysis ignoring the cluster randomised design since the estimate for this trial is similar to the meta‐analysis result and altering its weight has minimal effect.
A degree of funnel plot asymmetry may be suggested by visual inspection, but the Egger test provided no evidence of a significant relationship between trial size and effect estimate.
We found little information about the effects of fluoride mouthrinses on other outcomes such as the proportion of children developing new caries or on acceptability of fluoride rinsing. We found little useful information about some possible adverse effects of the procedure. This lack of direct evidence from clinical trials on relevant outcomes other than caries increment makes it more difficult for clinicians and policy makers to weigh the benefits of fluoride mouthrinse use in preventing caries against possible shortcomings of the procedure, be it provided in community dental health programmes or in the home environment.
| Study | Prevented fraction | 95% c.i. |
| Ashley 1977 | 14% | (1% to 27%) |
| Bastos 1989 | 28% | (18% to 39%) |
| Blinkhorn 1983 | 24 | (11% to 38%) |
| Craig 1981 | 32% | (‐4% to 67%) |
| DePaola 1977 | 42% | (32% to 51%) |
| DePaola 1980 | 22% | (5% to 38%) |
| Driscoll 1982 | 38% | (21% to 54%) |
| Duany 1981 | 13% | (‐5% to 31%) |
| Finn 1975 | 17% | (4% to 29%) |
| Gallagher 1974 | 14% | (5% to 23%) |
| Heidmann 1992 | 5% | (‐19% to 30%) |
| Heifetz 1973 | 32% | (20% to 45%) |
| Heifetz 1982 | 35% | (20% to 50%) |
| Horowitz 1971 | 16% | (‐17% to 50%) |
| Horowitz 1971a | 43% | (19% to 68%) |
| Koch 1967 | 23% | (13% to 34%) |
| Koch 1967a | 25% | (9% to 41%) |
| Koch 1967b | 2% | (‐21% to 25%) |
| Laswell 1975 | 35% | (10% to 60%) |
| McConchie 1977 | 18% | (7% to 29%) |
| Molina 1987 | 30% | (16% to 44%) |
| Moreira 1972 | 17% | (‐6% to 39%) |
| Moreira 1981 | 25% | (8% to 42%) |
| Packer 1975 | 35% | (6% to 64%) |
| Petersson 1998 | 14% | (‐30% to 59%) |
| Poulsen 1984 | 12% | (‐10% to 34%) |
| Radike 1973 | 33% | (22% to 44%) |
| Ringelberg 1979 | 23% | (7% to 39%) |
| Ringelberg 1982 | 22% | (6% to 39%) |
| Rugg‐Gunn 1973 | 36% | (27% to 44%) |
| Ruiken 1987 | 33% | (16% to 49%) |
| Spets‐Happonen 1991 | 26% | (‐17% to 70%) |
| Torell 1965 | 35% | (26% to 43%) |
| van Wyk 1986 | 30% | (20% to 40%) |
Comparison 1 Fluoride mouthrinse versus placebo/no‐treatment, Outcome 1 D(M)FS increment (prevented fraction) ‐ nearest to 3 years (34 trials).
| Study | Prevented fraction | 95% c.i. |
| Bastos 1989 | 34% | (21% to 48%) |
| Blinkhorn 1983 | 25% | (12% to 37%) |
| Finn 1975 | 22% | (6% to 37%) |
| Horowitz 1971 | 25% | (‐8% to 58%) |
| Horowitz 1971a | 52% | (26% to 77%) |
| Koch 1967 | 11% | (1% to 21%) |
| Koch 1967a | 13% | (‐10% to 35%) |
| Koch 1967b | ‐4% | (‐29% to 21%) |
| McConchie 1977 | 18% | (3% to 33%) |
| Molina 1987 | 26% | (11% to 40%) |
| Radike 1973 | 31% | (20% to 42%) |
| Ringelberg 1979 | 18% | (3% to 33%) |
| Rugg‐Gunn 1973 | 32% | (24% to 40%) |
Comparison 1 Fluoride mouthrinse versus placebo/no‐treatment, Outcome 2 D(M)FT increment (prevented fraction) ‐ nearest to 3 years (13 trials).
Comparison 1 Fluoride mouthrinse versus placebo/no‐treatment, Outcome 3 D(M)FS increment (SMD) ‐ nearest to 3 years (34 trials).
Comparison 1 Fluoride mouthrinse versus placebo/no‐treatment, Outcome 4 D(M)FT increment (SMD) ‐ nearest to 3 years (13 trials).
Comparison 1 Fluoride mouthrinse versus placebo/no‐treatment, Outcome 5 Developing one or more new caries (3 trials).
Comparison 1 Fluoride mouthrinse versus placebo/no‐treatment, Outcome 6 Unacceptability of treatment as measured by leaving study early (2 trials).
| Analysis | Number of studies | RE estimate | 95% CI | Meta‐analysis P‐value | Heterogeneity test |
| D(M)FS ‐ all studies | 34 | 26% | 23% to 30% | P < 0.0001 | Q = 55.62 (33 df); P = 0.008 |
| D(M)FT ‐ all studies | 13 | 24% | 18% to 30% | P < 0.0001 | Q = 26.04 (12 df); P = 0.011 |
| Characteristic | Number of studies | Slope estimate | 95% CI | Slope interpretation | P‐value |
| Mean baseline caries | 33 | 0.3% | (‐0.7% to 1.3%) | Increase in PF per unit increase in mean baseline caries | 0.6 |
| Fluoridated water area | 32 | 7% | (‐3.9% to 17.8%) | Higher PF in presence of water fluoridation | 0.2 |
| Fluoride dentrifice use | 32 | ‐0.7% | (‐9.5% to 8%) | Lower PF in presence of fluoride dentifrice use | 0.9 |
| Background fluorides | 32 | 1.4% | (‐6.3% to 9%) | Higher PF in presence of background fluoride | 0.7 |
| Rinsing frequency | 33 | 1% | (‐3.3% to 5.5%) | Increase in PF per 100 extra applications/year | 0.6 |
| Fluoride concentration in solution | 34 | 1% | (‐3.7% to 5.7%) | Increase in PF per 1000 ppm F | 0.7 |
| Intensity (freq times conc) | 32 (excludes DePaola 1977) | 11.5% | (‐10% to 33%) | Increase in PF equivalent to doubling from 100 to 200 applications and increasing by 1000 ppmF | 0.3 |
| Allocation concealment | 34 | ‐7% | (‐18% to 5%) | Lower PF with adequately concealed allocation | 0.3 |
| Blind outcome assessment | 34 | 8% | (‐11% to 13%) | Higher PF with blind outcome assessment indicated (not clearly stated) | 0.9 |
| Double blinding | 34 | 3.5% | (‐5.4% to 13%) | Higher PF with lack of double‐blinding | 0.4 |
| Control group | 34 | 6.3% | (‐4.2% to 17%) | Higher PF for no‐treatment compared with placebo | 0.2 |
| Drop out | 31 | 0.6% | (‐1.8% to 3%) | Increase in PF per 10 drop outs | 0.6 |
| Length of follow up | 34 | 0.2% | (‐6.9% to 7.4%) | Increase in PF per extra year of follow up | 0.9 |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 D(M)FS increment (prevented fraction) ‐ nearest to 3 years (34 trials) Show forest plot | Other data | No numeric data | ||
| 2 D(M)FT increment (prevented fraction) ‐ nearest to 3 years (13 trials) Show forest plot | Other data | No numeric data | ||
| 3 D(M)FS increment (SMD) ‐ nearest to 3 years (34 trials) Show forest plot | 34 | 14663 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.30 [‐0.36, ‐0.24] |
| 4 D(M)FT increment (SMD) ‐ nearest to 3 years (13 trials) Show forest plot | 13 | 5105 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.28 [‐0.37, ‐0.20] |
| 5 Developing one or more new caries (3 trials) Show forest plot | 3 | 1805 | Odds Ratio (M‐H, Random, 95% CI) | 0.61 [0.41, 0.90] |
| 6 Unacceptability of treatment as measured by leaving study early (2 trials) Show forest plot | 2 | 315 | Odds Ratio (M‐H, Random, 95% CI) | 1.26 [0.60, 2.64] |
