Fluoride toothpastes for preventing dental caries in children and adolescents

Valeria CC Marinho; Julian Higgins; Stuart Logan; Aubrey Sheiham (deceased)

doi:10.1002/14651858.CD002278

. 2003 Jan 20;2003(1):CD002278. doi: 10.1002/14651858.CD002278

Fluoride toothpastes for preventing dental caries in children and adolescents

Valeria CC Marinho ^1,^✉, Julian Higgins ², Stuart Logan ³, Aubrey Sheiham (deceased) ⁴

Editor: Cochrane Oral Health Group

PMCID: PMC8439270 PMID: 12535435

Abstract

Background

Fluoride toothpastes have been widely used for over 3 decades and remain a benchmark intervention for the prevention of dental caries.

Objectives

To determine the effectiveness and safety of fluoride toothpastes in the prevention of 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 toothpaste with placebo 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 caries increments between the treatment and control groups expressed as a percentage of the 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

Seventy‐four studies were included. For the 70 that contributed data for meta‐analysis (involving 42,300 children) the D(M)FS pooled PF was 24% (95% confidence interval (CI), 21 to 28%; P < 0.0001). This means that 1.6 children need to brush with a fluoride toothpaste (rather than a non‐fluoride toothpaste) to prevent one D(M)FS in populations with caries increment of 2.6 D(M)FS per year. In populations with caries increment of 1.1 D(M)FS per year, 3.7 children will need to use a fluoride toothpaste to avoid one D(M)FS. There was clear heterogeneity, confirmed statistically (P < 0.0001). The effect of fluoride toothpaste increased with higher baseline levels of D(M)FS, higher fluoride concentration, higher frequency of use, and supervised brushing, but was not influenced by exposure to water fluoridation. There is little information concerning the deciduous dentition or adverse effects (fluorosis).

Authors' conclusions

Supported by more than half a century of research, the benefits of fluoride toothpastes are firmly established. Taken together, the trials are of relatively high quality, and provide clear evidence that fluoride toothpastes are efficacious in preventing caries.

Plain language summary

Fluoride toothpastes for preventing dental caries in children and adolescents

Children who brush their teeth at least once a day with a toothpaste that contains fluoride will have less tooth decay.  Tooth decay (dental caries) is painful, expensive to treat and can sometimes lead to serious damage to teeth. Fluoride is a mineral that prevents tooth decay. The review of trials found that children aged 5 to 16 years who used a fluoridated toothpaste had fewer decayed, missing and filled permanent teeth after three years (regardless of whether their drinking water was fluoridated). Twice a day use increases the benefit. No conclusion could be reached about the risk that using fluoride toothpastes could mottle teeth (fluorosis), an effect of chronic ingestion of excessive amounts of fluoride when children are young.

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 remineralization 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 programs 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 topical 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 topical fluorides has never been undertaken.

This review is one in a series of systematic reviews of topical fluoride interventions and assesses the effectiveness of fluoride toothpastes in the prevention of dental caries in children.

Fluoride toothpastes (dentifrices)

Toothbrushing with fluoride toothpaste is by far the most common form of caries control in use today. The intensive promotion of fluoride toothpastes by the oral healthcare industry has been a major factor in their increased use, and, in the developed world, since the 1980s, nearly all commercially available toothpaste formulations contain fluoride. Various fluoride compounds have been used alone or combined in the formulations, including sodium fluoride, sodium monofluorophosphate, amine fluoride and stannous fluoride, and, according to each manufacturer's specifications these must be compatible with other basic ingredients, especially abrasive systems (which account for almost half of the entire toothpaste formulation). Fluoride toothpastes must be differentiated from fluoride prophylactic pastes, since their fluoride concentrations, methods and frequencies of application differ, as well as amounts of abrasives in their formulation (abrasives account for almost the entire content of a prophylactic paste). In addition, although some toothpastes are available in the translucent form of gel, they are different from fluoride gels, which have higher fluoride levels, no abrasives and are applied much less frequently, usually by a professional.

Consensus among researchers and public health authorities places fluoride toothpaste as the method of choice for preventing caries, as it is convenient and culturally approved, widespread, and it is commonly linked to the decline in caries prevalence in many countries. There is an argument that the effect of fluoride toothpastes are underestimated in 'short term' clinical trials of two to three years duration, as these are used throughout life. In addition, it is argued that the use of fluoride toothpaste in fluoridated areas offers more protection than either alone. However, concern has been expressed that dental fluorosis, enamel defects caused by young children chronically ingesting excessive amounts of fluoride during the period of tooth formation (up to the age of 6 years), is increasing in both fluoridated and non‐fluoridated communities, and the early use of fluoride toothpastes by young children may be an important risk factor (Horowitz 1992; Stookey 1994; Ellwood 1995).

The usual concentration of fluoride in toothpastes is 1000/1100 parts per million (ppm F); toothpastes with higher (1500 ppm F) and lower than conventional fluoride levels (around 500 ppm F) are available in many countries. While the evidence of the effectiveness of low fluoride‐containing toothpastes in reducing dental caries appears to be conflicting, toothpastes containing higher concentrations of fluoride confer greater protection against caries (Stephen 1988; O'Mullane 1997), but increase the risk of fluorosis, which is related to both, the amount ingested and the fluoride concentration. Chronic ingestion of fluoride from toothpaste in children is common (Bentley 1999; Rojas‐Sanchez 1999) and despite the large variation in the amount swallowed, the younger children are, the more likely they are to swallow larger amounts, which often represent a substantial part of the total daily fluoride intake and can be enough to cause fluorosis (Levy 1994; Lewis 1996). Although the amount of fluoride ingested beyond which fluorosis may occur is not known accurately, a threshold of 0.05 to 0.07 mgF/kg body weight has been suggested (Burt 1992). A child‐sized toothbrush covered with a full strip of toothpaste holds approximately 0.75 to 1.0 g of toothpaste, and each gram of fluoride toothpaste, contains approximately 1.0 mg of fluoride; children aged less than 6 years may swallow an estimated 0.3 g of toothpaste per brushing (0.3 mg of fluoride) and can inadvertently swallow as much as 0.8 g (Levy 1994). As a result, it is generally recommended that children under 6 years of age should be supervised when brushing their teeth, and that no more than a pea‐sized amount, approximately 5 mm, should be used. The frequency of toothpaste use and the rinsing method after toothbrushing would be other factors influencing the effectiveness of fluoride toothpastes (and also their safety). Brushing twice a day or more, or rinsing less thoroughly, or not rinsing at all would confer greater caries reductions than brushing once a day or less, or rinsing with larger volumes of water after toothbrushing (Chesters 1992; O'Mullane 1997; Chestnutt 1998; Ashley 1999). A formal investigation of these aspects should help to clarify the optimal level of fluoride toothpaste needed to achieve caries prevention while limiting objectionable enamel fluorosis.

Although acute toxicity is extremely rare, young children are particularly at risk of ingesting toxic doses of fluoride from a standard toothpaste tube of 125 g, generally containing 1100 ppm F (1.1 mgF/g paste). As the probable toxic dose (PTD) is around 5 mgF/kg body weight (Whitford 1992), the accidental swallowing of one‐third of a toothpaste tube (45 g) or two‐thirds of it (90 g) is potentially life‐threatening for a 1‐year‐old (10 kg) or for a 5 to 6‐year‐old (20 kg) respectively (Ellwood 1998). For this reason it is recommended that a fluoride toothpaste tube should be kept out of the reach of young children.

More than 100 clinical trials conducted in many areas of the world since the 1940s, and summarised in several narrative reviews since the 1950s, have investigated the caries‐reducing effect of fluoride toothpastes in children. In the late 1970s, the acceptance of fluoride toothpastes as effective caries inhibiting agents had become so well established that clinical trials in many developed countries had to be benchmarked against standard fluoride toothpastes, as it was considered unethical to withdraw their benefit from a study group. Thus, the effectiveness of new forms and concentrations of fluoride toothpastes has not been so extensively investigated in placebo‐controlled trials in children with the lower levels of dental caries prevalence prevailing in many countries.

In the last 20 years, guidelines for caries clinical trials have changed (FDI 1982; CDT‐ADA 1988; ICW‐CCT 2002) in recognition of the fact that with the decline in caries prevalence and the need, for ethical reasons, to use a positive control instead of a placebo in fluoride toothpaste trials, differences between treatments had become smaller in both absolute and percentage terms. In order to overcome this problem of small group differences, study design approaches have been modified. The most important general strategies have focused on increasing sample size and power, reducing measurement error and conducting studies with high risk subjects, mainly defined on the basis of initial caries scores.

To date, there are two published meta‐analyses investigating the comparative efficacy of the two commercially available fluoride toothpaste compounds used most commonly nowadays: sodium fluoride (NaF) and sodium monofluorophosphate (SMFP) (Johnson 1993; Stamm 1995), a question that is not addressed in the present review. There is, however, no systematic quantitative investigation assessing the overall effectiveness and safety of fluoride toothpastes in comparison to placebo and examining formally the main factors that may influence their effectiveness.

Objectives

(1) To determine the effectiveness and safety of fluoride toothpaste in preventing dental caries in the child/adolescent population.   (2) To examine whether the effect of fluoride toothpaste is influenced by the initial level of caries severity.  (3) To examine whether the effect of fluoride toothpaste is influenced by the background exposure to fluoride in water (or salt), or reported fluoride sources other than the study option.  (4) To examine whether the effect of fluoride toothpaste 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 toothpaste is compared concurrently to placebo toothpaste 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 toothpastes only, using any of the following fluoride agents combined or not in the formulation: sodium fluoride (NaF), sodium monofluorophosphate (SMFP), stannous fluoride (SnF2), acidulated phosphate fluoride (APF), amine fluoride (AmF). These may be formulated with any compatible abrasive system and are considered at any fluoride concentration (ppm F), frequency of use, amount or duration of application, and with any technique of toothbrushing or post‐brushing procedure. The control group is placebo (non‐fluoride toothpaste) which makes the following as the relevant comparison: Fluoride toothpaste compared with placebo toothpaste.  Studies where the intervention consisted of any other active agent(s) or caries preventive measure(s) (e.g. chlorhexidine agent, other fluoride‐based procedures, oral hygiene procedures, sealants, xylitol chewing gums, glass ionomers) used in addition to fluoride toothpaste 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); 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: toothpaste, 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 (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 toothpastes 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. Nine fluoride toothpaste manufacturers were contacted (October 2000) and information on any unpublished trials requested: Colgate‐Palmolive, Unilever/Gibbs, Gaba AG, Smithkline Beecham, Procter and Gamble, Oral‐B, Bristol‐Myers Co, Warner‐Lambert, Synthelabo.

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 OLDMEDLINE 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 toothpaste intervention; or the trial compared fluoride toothpaste exclusively to no treatment, instead of fluoride‐free toothpaste).

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. However, in future updates all reports will be data extracted and quality assessed in duplicate. Checking of interobserver reliability was limited to validity assessments. 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. Provision was made to exclude data where agreement could not be reached but this situation did not occur. 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 (rinsing with water), 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 radiolographical), and approaches to account or not for reversals in caries increment adopted (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. 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.

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 imputed through linear regression of log(standard deviation)s on log(mean caries) increments. This is a suitable approach for caries prevention studies since, as they follow an approximate Poisson distribution, caries increments are closely related 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 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 outcome) 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. If meta‐analyses using standardised mean differences yielded materially similar results to those using prevented fractions, we would also present these within MetaView. Deciduous and permanent teeth would be 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 toothpastes differs according to the baseline levels of caries severity; (2) the effect of fluoride toothpastes differs according to exposure to other fluoride sources (in water, etc); and (3) the effect of fluoride toothpastes differs according to concentration of fluoride. The association of these factors with estimated effects (D(M)FS PFs) were examined by performing random effects meta‐regression 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 reported 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, and were grouped into two categories: one for studies which were based on samples not using/not reporting background use of fluorides and which were from non‐fluoridated areas (clearly non‐exposed), and another for studies based on samples using fluorides or studies in fluoridated communities, or both. 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. When background use or not of fluoride toothpaste (again, only for studies where the intervention was tested under supervision at school and no supply of any toothpaste had been provided for home use) 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 use' have not been categorised, but a 'total intensity of application per year' covariate was produced by multiplying frequency of application (per year) by concentration of toothpaste applied (in ppm F). Concentrations in multiple arm studies were averaged over fluoride toothpaste groups prior to this calculation. Frequency of use of once a day (365 times a year) was assumed when it was not precisely reported in studies of supervised use of fluoride toothpaste at school (where participants were provided with appropriate toothpastes for home use) or in studies of 'unsupervised' home use of fluoride toothpaste (even if it was reported that instructions to brush more than once a day were given); frequency of 200 times (days) a year was assumed when it was not precisely reported in studies of supervised use of fluoride toothpaste at school (where children were provided with non‐fluoride toothpastes for home use or not provided with any toothpaste for home use).

Further potential sources of heterogeneity were investigated by metaregression. These 'post hoc' analyses are clearly identified and the results should be treated with caution. These include assessment of the effect of toothpaste application mode', classified as either self‐applied under supervision (at school/institution) or as unsupervised use (at home).

Sensitivity analyses were performed using a random‐effects model for combining trials.

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 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 would be shown in the analyses tables.

Results

Description of studies

Search results

Searching the core database in Reference Manager retrieved 2600 records from MEDLINE, EMBASE, BIOSIS, SCISEARCH, SSCISEARCH, CINAHL, ERIC, ISTP and DISSERTATION ABSTRACTS. The specific search used was: 'dentifrice*' or 'fluoride dentifrice*' or 'toothpaste*' or 'toothbrush*' or 'tooth brush*' or 'acidulated fluorophosphate*' or 'acidulated phosphate fluoride*' or 'fluorophosphate*' or 'amine fluoride*' or 'sodium fluoride*' or 'stannous fluoride*' as keywords, combined with 'dentifrice' or 'toothpaste' or 'tooth paste' or 'paste' or 'toothbrush' or 'tooth brush' or 'brush' in titles, notes and all other fields. 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, 3566 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 toothpaste trials performed without a randomised controlled trial (RCT) filter produced 1005 records, and the search performed in the Cochrane Oral Health Group's Trials Register produced 244 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 99 additional records for inspection. One of the nine manufacturers of fluoride toothpastes 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 299 records were considered potentially eligible, and sought for further assessment.

Selection of studies

Two hundred and ninety‐nine (299) reports were sought for detailed assessment for inclusion, of which 10 full‐text reports could not be obtained (most of these were incomplete references to unpublished studies conducted decades ago by toothpaste manufacturers). One hundred and ten (110) reports were considered immediately irrelevant for this review (largely as a result of the type of interventions compared with, or used in addition to fluoride toothpaste, including head to head studies without a placebo group). Thus, 118 studies (179 reports) are considered/cited in this review. These comprise 120 reports relating to 74 included studies, 49 reports relating to 36 excluded studies, and 10 reports relating to eight studies waiting assessment: either because they require translation (three reports in Polish of two studies, two reports/studies in Japanese, one report/study in German), or because translations and/or attempted contact with the authors have not ascertained whether all inclusion criteria have been met (two reports, one in French and another in Dutch, of one study), or because additional information could not be obtained yet for two studies in abstract form. There were no reports of ongoing studies.

Thirty non‐English reports (19 studies) are listed either under excluded or included studies. Three of these (three studies) 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; four reports/studies were included based on an English publication related to the same study; and one report of an excluded study had other publications that did not require translation. There remained 22 non‐English reports that have been fully assessed (12 studies): 14 in German (by a German translator, with the contact reviewer), three in French (by a French translator, with the reviewer), one in Russian (by a Russian translator, with the reviewer), one in Czech (by a Czech translator, with the reviewer), one in Japanese (by a Japanese translator, with the reviewer), and two in Italian (by the contact reviewer).

Excluded studies

SeeCharacteristics of excluded studies table for the description of reasons for rejecting each study.

The thirty‐six studies in this section were excluded for a variety of reasons. One study was clearly not randomised/quasi‐randomised. One study randomised two clusters, each to one of the two groups compared. Six studies did not mention or indicate random/quasi‐random allocation nor blind outcome assessment. Six studies did not mention random or quasi‐random allocation (but used/indicated blind outcome assessment), and two other studies did not state/indicate blind outcome assessment (but indicated random allocation); the attempt to contact the author(s) of these studies was unsuccessful and they were excluded.

Ten studies had other active agents or other fluoride‐based interventions in addition to fluoride toothpaste. Three of these also did not state/indicate blind outcome assessment; another had only two clusters (one as each group); and another included participants older than those considered in this review.

Two studies included institutionalised children with specific health problems. One of these also included young adults. Eight studies included participants older than 16 years old. One of these did not mention blind outcome assessment; three others did not mention or indicate random/quasi‐random allocation; and another did not mention or indicate random/quasi‐random allocation nor blind outcome assessment.

Included studies

SeeCharacteristics of included studies table for details of each study.

There are 74 trials included. The studies by Forsman 1974; Hargreaves 1973; Marthaler 1970; Zacherl 1970; Held 1968; Marthaler 1965; Torell 1965 and one of the three studies by Koch 1967 have been treated as two (or more) independent trials each, since the results for two (or more) age groups and/or study sites in these studies have been reported separately as distinct studies. There were also completely distinct studies published as such in the same year by the same author: Zacherl 1972/Zacherl 1972a; Koch 1967a/Koch 1967b/Koch 1967c; and Slack 1967/Slack 1967a. All 120 reports were published between 1955 and 1996. The seventy‐four trials were conducted between 1954 and 1994: three in the 1950s, 41 in the 1960s, 28 in the 1970s, one in the 1980s, and one in the 1990s. Twenty‐four trials were conducted in USA, 20 in UK, nine in Sweden, six in Switzerland, five in France, three in Australia, two in Canada, and one in each of the following countries: Denmark, Norway, FRG, Italy, and Israel. Thirty‐five studies had more than one publication, 12 of these had four or more published reports each. Fifty‐five studies acknowledged assistance (product provision, etc) and/or financial support from fluoride toothpaste manufacturers. Of a total of twenty‐two studies whose authors were sent request letters for unpublished information, replies related to four studies were obtained.

Design and methods

Twenty‐two studies had more than one fluoride toothpaste treatment group compared to a control (multi‐treatment studies) and among these, two trials had two treatment groups and two placebo control groups. Ten trials used a factorial design to investigate the effects of multiple topical fluoride interventions. All trials used a placebo or non‐fluoride toothpaste control group. The study duration (indicated by the total length of follow up as well as the treatment duration) ranged from 1 to 7 years among included trials: seven lasted 4 years or more, 36 lasted 3 years, 27 lasted around 2 years, and the remaining four lasted 1/1.5 years. Studies were generally large with only nine allocating less than 100 children to relevant study groups. The total number of children participating in the 74 trials (given by the sample analysed at the end of the trial period) was 45,073, and ranged from 32 in the smallest trial to 2008 in the largest trial (average of 609 participants per trial). With the exception of five trials, where participants were in orphanages/institutions, participants were recruited from school settings.

Participants

All included trials reported that the participants were aged 16 or less at the start, with similar numbers from both sexes (where these data were reported); the exceptions were Ran 1991, who included male participants only in the study, and the two trials of Slack 1967; Slack 1967a that included only females. The ages of the children at the start of the trials ranged from 5 to 16 years; at least 49 trials included children who were 12, at least four trials included children younger than 6 years of age (5 year‐olds) and 18 trials included children who were 5 or 6 (in which deciduous teeth caries increment data could have been reported). Decayed, (missing) and filled surfaces (D(M)FS) data at baseline were reported in all but five studies, and ranged from 0.97 to 17.4 (this includes the study by Cahen 1982, where data for the control group only were available); only baseline data for deciduous tooth surface (dfs) were reported in one of the studies by Hargreaves 1973 (although it did not report caries increment data for the deciduous dentition). Where information on 'background exposure to other fluoride sources' was available/obtained, 11 studies were conducted in fluoridated communities (water fluoridation in six, low salt fluoridation in five), and 49 in low/non‐fluoridated areas; generalised use of other fluoride programmes (rinsing) was reported in only two of these. For the two trials where the intervention was tested under supervision at school and no supply of any toothpaste had been provided for home use, data on general use of fluoride toothpaste at home could not be obtained for one trial (Ran 1991) and was assumed based on study location and year started for the other (Koch 1967c). Thus, some form of fluoride exposure could be considered for 13 trials, and no exposure for 46; this information was not available for 15 trials.

Interventions

Fifty‐six of the included trials reported unsupervised (ad libitum) use of toothpaste at home, and in the remaining trials toothpaste was used under supervision either at school (13 trials, 11 of which reported provision of enough toothpaste for ad libitum home use) or institution (five trials). Toothpaste was administered using a toothbrush in all trials. A variety of fluoride agents were tested, including stannous fluoride (SnF2) in 29 trials, sodium monofluorophosphate (SMFP) in 27 trials, sodium fluoride (NaF) in 14 trials, amine fluoride (AmF) in eight trials, acidulated phosphate fluoride (APF) in five trials, and mixed agents in five trials (SMFP‐NaF in three, NaF‐SnF2 in two); these were formulated with various abrasive systems (see table). The fluoride concentrations used in a toothpaste ranged from 250 ppm F to 2500 ppm F (SMFP‐NaF); but the 1000/1100 ppm F toothpaste concentration was tested in at least 56 trials (the two studies which did not report these data are likely to have used this fluoride concentration). Ten studies investigated toothpaste with fluoride levels of 1250/1500 ppm F, and five studies investigated toothpaste with fluoride levels less than 1000 ppm F (250 ppm F was tested in three studies and 500 ppm F was also tested in three studies but one of the studies tested both concentrations). Six studies tested toothpaste with fluoride levels above 1500 ppm F (2400/2500 ppm F).

The brushing frequency did not vary greatly among studies, with only 12 studies among the 74 reporting other than daily frequencies (this was assumed when data were not reported): a frequency of less than once a day in five studies where supervised toothbrushing at school was performed, and a frequency of twice a day or more in seven studies (five of which were also studies where supervised brushing was performed). Data on the amount of toothpaste used and the duration of toothbrushing were reported in very few studies (amount reported either in 'gr' or in 'cm' dispensed over the brush). As regards the performance of some form of oral rinsing after toothbrushing, this was reported in two studies in the UK only (where toothpaste use was supervised at school) and was said to have been 'instructed' in three studies in Sweden (where toothpaste use was not supervised), but there were no reports specifying the method used for post‐brushing rinse (e.g. with or without a beaker); as long as performed with water (if with a fluoride solution the trial would have been excluded), the post‐brushing rinsing was considered by the reviewers as part of the method of toothpaste use and not as a separate intervention on its own.

Outcome measures

All but three of the 74 included trials reported caries increment data: 71 trials reported caries increment at the tooth surface level (D(M)FS), but d(e/m)fs/d was not reported in any of these, and 53 trials reported caries increment at the tooth level (D(M)FT). With regard to the components of the DMFS index used, 49 trials reported DMFS data, 33 reported DFS data, and one trial reported DS data only (DFS data were chosen over DMFS data in 12 of the trials). With regard to the types of teeth/surfaces assessed, results based on all tooth surface types were reported in all 71 trials that reported caries increment data, but results have also been reported separately for first molars, anterior/posterior teeth, approximal surfaces, occlusal and other surface types in many trials (see table). Thirty‐three trials presented D(M)FS data at more than one follow‐up time; follow up of 3 years was the most common (reported in 44 trials). In three trials, assessments of D(M)FS increments were also made during a post‐intervention follow‐up period.

Clinical (73 trials) and radiographic (65 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, in which case CA was assumed, 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. The five studies of Marthaler used partial recording as opposed to the full‐mouth recording used in all others.

Other dental caries data reported: caries incidence/attack rate (13 trials, including one trial reporting caries rate in the deciduous dentition), caries progression (five trials, four of which reporting the Extrapolated Carious Surface Increment Index (ECSI)), proportion of children developing new caries (six trials), proportion of children not remaining caries‐free (two trials), proportion of teeth developing new caries and failures, carious teeth, over time (one trial), proportion of caries‐free teeth/surfaces which developed caries (two trials).

Data on adverse effects were (partially or fully) reported in 12 trials: stain score (three trials), proportion of children with tooth staining (seven trials), proportion of children who complained of tooth staining (one trial), oral soft tissues lesions (three trials, none of which with complete or useable data, and with the following statement in all three: "no lesions attributable to product use were noted"). Fluorosis data have not been reported in any of the trials.

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, inter‐rater 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).

In general, studies included essential features of clinical trials: randomised groups, double‐blind designs and placebo controls. Nevertheless, there were differences in their methodological quality (using the reported information and additional information obtained from a few investigators).

Allocation concealment

Eleven of the trials which described the randomisation process or whose investigators provided further information in answer to our enquiry could be coded A (e.g. adequate concealment of allocation). Fifty‐six included trials were described as randomised but provided no description of the allocation process and were coded B. Seven trials were quasi‐randomised and coded C.

Blinding

Blind outcome assessment and use of placebo (double‐blinding, score A) was described in all but two trials where blind outcome assessment was unclear but indicated (score C), and these were placebo‐controlled trials. In three trials the fluoride‐free toothpaste used as control was not a true placebo (flavour and/or colour somewhat different from test toothpastes). Single‐blinding (blind dental caries assessment but no placebo used) was not described in any trial.

Follow up and withdrawals

All the participants included in the final analysis/present at the end of each study, as a proportion of all the participants present at start in all studies was 72% (38,868 analysed out of 53,710 randomised), excluding the 13 studies with no data on participants randomised to relevant groups. Drop‐out rates could be obtained from all but one of the 74 included studies. There was considerable variation in drop‐out rates ranging from 4% at 2 years to 66% at 3 years. A common reason for attrition was that participants were not available for follow‐up examination at the end of the study; exclusions based on presence in all follow‐up examinations were reported in 26 trials, and exclusions based on compliance were reported in three trials. Other reasons for exclusions (when given) included change of residence, and characteristics of participants also used as eligibility criteria before randomisation (e.g. starting use of orthodontic bands). A few trials reported the numbers excluded according to reason for attrition, but only two trials reported this by study arm.

Others

Type of randomisation: stratified randomisation was used in the majority of trials (but only one described use of blocking).  Unit of randomisation/analysis: none of the trials reported the use of cluster randomisation. Individuals were allocated to study arms in all trials, and each participant's caries increment, over a period of time was used as the unit of analysis (as the units of recording, the tooth or surface, are not independent within a given subject).  Baseline comparisons and handling of any differences: two trials did not report any baseline data, four of the trials described as 'balanced' (for which randomisation may have produced nearly exact balance) did not report the actual values for the baseline characteristic 'initial caries levels' (D(M)FS/T). 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 adjustment mentioned to have resulted in trivial differences in effect estimates. In three of the smallest trials by Held 1968, imbalances were most pronounced.  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 clearly described (see 'Notes' in the Characteristics of included studies table for methodological features assessed).

Effects of interventions

Effect of fluoride toothpaste on dental caries increment

The effects of fluoride tooothpastes on dental caries increment (as measured by the DMF index) were reported in a variety of different 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 toothpastes on caries increment as measured by the dmf index in deciduous teeth/surfaces could not be produced for this review, as there was no study contributing data. However, there was a single trial reporting caries incidence rate data for deciduous teeth, the results of which are described below.

Three included studies (Homan 1969; Powell 1981; Slack 1964) had no (caries increment) 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 16 of the 71 studies which contributed data (Abrams 1980; Dolles 1980; Fogels 1979; Forsman 1974; Forsman 1974a; Hargreaves 1973; Hargreaves 1973a; Hargreaves 1973b; Held 1968; Held 1968a; Held 1968b; James 1977; Kinkel 1972; Muhler 1955; Ran 1991; Segal 1967). 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 10 of the 53 trials reporting D(M)FT data (Abrams 1980; Fogels 1979; Hargreaves 1973; Hargreaves 1973a; Hargreaves 1973b; Held 1968; Held 1968a; Held 1968b; Muhler 1955).

We have decided to exclude the trial of Ran 1991 from all analyses because the control DMFS increment was very small (0.2) in this trial, resulting in a poor estimate of PF.

(1) Effect on tooth surfaces: D(M)FS PF

For all 70 trials combined, the D(M)FS PF pooled estimate was 0.24 (95% confidence interval (CI), 0.21 to 0.28; P < 0.0001), suggesting a substantial benefit from the use of fluoride toothpaste. The CIs are relatively narrow, but substantial heterogeneity in results could be observed graphically and statistically (Q = 489.89 on 69 degrees of freedom, P < 0.0001).

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 toothpaste (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).

1. Meta‐analyses of prevented fractions.

Analysis	Number of studies	RE estimate	95% CI	Meta‐analysis P‐value	Heterogeneity test
D(M)FS ‐ all studies	70	24%	21% to 28%	P < 0.0001	Q = 489.89 (69 df); P < 0.0001
D(M)FT ‐ all studies	53	23%	19% to 28%	P < 0.0001	Q = 541.04 (52 df); P < 0.0001

Characteristic	Number of studies	Slope estimate	95% CI	Slope interpretation	P‐value
Mean baseline caries	67	0.7%	(0.07% to 1.3%)	Increase in PF per unit increase in mean baseline caries	0.03
Fluoridated water	56	3.2%	(‐4% to 11%)	Higher PF in presence of water fluoridation	0.4
Background fluorides	56	0.6%	(‐6% to 8%)	Higher PF in presence of any background fluoride	0.9
Concentration of fluoride	69	8.3%	(1% to 16%)	Increase in PF per 1000 ppm F	0.03
Frequency of toothbrushing	70	14%	(6% to 22%)	Increase in PF moving from once to twice a day	< 0.0001
Intensity (freq times conc)	69	5.9%	(3.0% to 8.9%)	Increase in PF equivalent to doubling from once to twice a day and increasing by 1000 ppmF	< 0.0001
Mode of use	70	‐11%	(‐18% to ‐4%)	Lower PF with unsupervised toothbrushing	0.03
Allocation concealment	70	3.2%	(‐7% to 13%)	Higher PF with poorly concealed allocation	0.5
Drop out	70	2.6%	(0.2% to 5%)	Increase in PF per 10 drop outs	0.04
Length of follow up	70	0.8%	(‐4.2% to 5.7%)	Increase in PF per extra year of follow up	0.8
SMFP vs NaF (indirect comparison)	32	‐ 2.6%	(‐11.8% to 6.5%)	PF lower among SMFP trials	0.6
AmF vs NaF (indirect comparison)	15	3.2%	(‐11.0% to 17.3%)	PF higher among AmF trials	0.7
SnF2 vs NaF (indirect comparison)	29	‐4.8%	(14.1% to 4.5%)	PF lower among SnF2 trials	0.3

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 (70 trials)			Other data	No numeric data
2 D(M)FT increment (prevented fraction) ‐ nearest to 3 years (53 trials)			Other data	No numeric data
3 D(M)FS increment (SMD) ‐ nearest to 3 years (70 trials)	70	42300	Std. Mean Difference (IV, Random, 95% CI)	‐0.31 [‐0.35, ‐0.27]
4 D(M)FT increment (SMD) ‐ nearest to 3 years (53 trials)	53	32371	Std. Mean Difference (IV, Random, 95% CI)	‐0.28 [‐0.33, ‐0.23]
5 Developing one or more new caries (6 trials)	7	2878	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.80, 1.04]
6 Acquiring extrinsic tooth staining (5 trials)	5	3948	Risk Difference (M‐H, Random, 95% CI)	0.24 [0.19, 0.30]

D(M)FS increment (prevented fraction) ‐ nearest to 3 years (70 trials)
Study	Prevented fraction	95% c.i.
Abrams 1980	12%	(4% to 21%)
Andlaw 1975	21%	(12% to 30%)
Ashley 1977	21%	(9% to 33%)
Blinkhorn 1983	26%	(13% to 40%)
Brudevold 1966	21%	(12% to 30%)
Buhe 1984	22%	(16% to 27%)
Cahen 1982	13%	(6% to 20%)
Di Maggio 1980	61%	(55% to 68%)
Dolles 1980	17%	(‐48% to 81%)
Fanning 1968	21%	(15% to 27%)
Fogels 1979	18%	(11% to 25%)
Forsman 1974	10%	(‐9% to 29%)
Forsman 1974a	8%	(‐9% to 25%)
Gish 1966	26%	(13% to 40%)
Glass 1978	28%	(11% to 44%)
Glass 1983	26%	(12% to 39%)
Hanachowicz 1984	27%	(19% to 34%)
Hargreaves 1973	25%	(11% to 39%)
Hargreaves 1973a	28%	(15% to 42%)
Hargreaves 1973b	23%	(12% to 34%)
Held 1968	80%	(71% to 90%)
Held 1968a	31%	(‐5% to 68%)
Held 1968b	‐9%	(‐74% to 56%)
Hodge 1980	18%	(8% to 27%)
Horowitz 1966	17%	(7% to 27%)
Howat 1978	26%	(14% to 37%)
Jackson 1967	12%	(4% to 20%)
James 1967	18%	(5% to 31%)
James 1977	31%	(24% to 37%)
Kinkel 1972	37%	(26% to 49%)
Kleber 1996	‐4%	(‐54% to 46%)
Koch 1967	40%	(27% to 54%)
Koch 1967a	48%	(39% to 58%)
Koch 1967b	38%	(19% to 58%)
Koch 1967c	11%	(‐6% to 28%)
Lind 1974	32%	(23% to 40%)
Mainwaring 1978	16%	(7% to 25%)
Mainwaring 1983	19%	(10% to 29%)
Marthaler 1965	31%	(20% to 42%)
Marthaler 1965a	26%	(5% to 47%)
Marthaler 1970	22%	(‐1% to 44%)
Marthaler 1970a	35%	(6% to 64%)
Marthaler 1974	33%	(11% to 55%)
Mergele 1968	13%	(1% to 26%)
Muhler 1955	36%	(19% to 53%)
Muhler 1970	29%	(14% to 44%)
Murray 1980	30%	(21% to 39%)
Naylor 1967	14%	(7% to 21%)
Naylor 1979	22%	(14% to 31%)
Peterson 1967	17%	(9% to 25%)
Peterson 1979	10%	(‐7% to 27%)
Reed 1973	12%	(1% to 23%)
Reed 1975	30%	(15% to 45%)
Ringelberg 1979	18%	(1% to 35%)
Rule 1984	29%	(20% to 37%)
Segal 1967	19%	(5% to 34%)
Slack 1967	1%	(‐14% to 15%)
Slack 1967a	5%	(‐7% to 17%)
Slack 1971	17%	(9% to 24%)
Thomas 1966	30%	(17% to 44%)
Torell 1965	20%	(11% to 29%)
Torell 1965a	6%	(‐5% to 18%)
Torell 1965b	15%	(5% to 26%)
Weisenstein 1972	11%	(‐3% to 25%)
Zacherl 1970	40%	(32% to 49%)
Zacherl 1970a	43%	(37% to 50%)
Zacherl 1972	22%	(11% to 34%)
Zacherl 1972a	23%	(12% to 35%)
Zacherl 1973	30%	(10% to 49%)
Zacherl 1981	32%	(20% to 44%

Methods	Stratified random allocation; double‐blind (A); placebo‐controlled; 48% drop out after 3 years (study duration = 3 years). Reasons for high drop out described: change of residence, absenteeism, non‐adherence to study protocol; no differential group losses.
Participants	1141 children analysed at 3 years (available at final examination).  Age range at start: 5‐12 years. Surfaces affected at start: 3.2 DFS. Background exposure to fluoride: none reported.  Year study began: in/before 1976.  Location: USA.
Interventions	FT (2 groups) versus PL   (both SnF2 groups = 1000 ppm F). Home use/unsupervised, daily frequency assumed.  Abrasive system: silica gel in one SnF2 and placebo toothpaste, Ca pyrophosphate in the other SnF2 toothpaste.
Outcomes	3yNetDFS increment ‐ (E+U) (CA)cl+(ER)xr.  Reported at 1, 2 and 3 years follow ups. DMFT.  DMFS.  DFT.  MD‐DFS.  DFT rate.  DFS rate.
Notes	Participants randomised (N = 2210).  Baseline characteristics (DFS) 'balanced' .  Clinical (VT) caries assessment by two examiners, diagnostic threshold = CA. Radiographic assessment (postBW) by two examiners; diagnostic threshold = ER. State of tooth eruption included = E/U. Intra‐ and inter‐examiner reproducibility of clinical caries diagnosis (DFS) assessed annually by duplicate examination of 10% random sample (% of times diagnosis replicated in all 3 examinations ranged 42‐97% and 77‐ 92% for both examiners and for each respectively).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Random allocation; double‐blind (A); placebo‐controlled; 16% drop out (for both study groups combined) after 2 years (study duration = 2 years). Main reason for attrition described: left institution; any differential group losses not assessable.
Participants	42 children analysed at 2 years (available at final examination).  Age range at start: 11‐12 years. Surfaces affected at start: 11.7 DMFS.  Background exposure to fluoride: data not obtained for fluoridation status of site.  Year study began: in/before 1977.  Location: Italy.
Interventions	FT versus PL   (SMFP‐NaF group = 2500 ppm F). Institution use/supervised, three times a day.  Abrasive system: not clearly specified.
Outcomes	2yDMFS increment ‐ cl.  Reported at 1 and 2 years follow ups. DMFT.
Notes	Participants randomised (N = 50).  Baseline characteristics (DMFS, DMFT) 'balanced'.  Clinical caries assessment by two examiners; diagnostic threshold NR; state of tooth eruption included NR. Diagnostic errors NR.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Quasi‐random allocation; double‐blind (A); placebo‐controlled; 4% drop out after 3 years (study duration = 3 years). Reasons for attrition NR; exclusions based on presence in all follow‐up examinations; any differential group losses not assessable.
Participants	303 children analysed at 3 years (present for all examinations).  Age at start: 6 years.  Surfaces affected at start: 13.9 dfs (data for deciduous dentition only).  Background exposure to fluoride: none reported.  Year study began: 1968.  Location: UK.
Interventions	FT versus PL   (SMFP group = 2400 ppm F). Home use/unsupervised, daily frequency assumed.  Abrasive system: Al oxide trihydrate.
Outcomes	1‐3yNetDFS increment ‐ (E+U)(CA)cl+(ER)xr.  Reported at 3 years follow up. DFT.  DMFS.  DMFT.  ECSI.
Notes	Participants randomised (N = 316); numbers by group NR.  Baseline characteristics (age, tar, dfs, dmfs, dft, dmft, ecsi) 'balanced' (no DFS data at start).  Clinical (VT) caries assessment by two examiners; diagnostic threshold = CA; radiographic assessment (2 postBW) by two examiners; diagnostic threshold = ER. State of tooth eruption included = E/U. Diagnostic errors NR.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	High risk	C ‐ Inadequate

Methods	Stratified random allocation***; double‐blind (A); placebo‐controlled; 19% drop out after 3 years (study duration = 3 years + 2 years post‐intervention period). Natural losses; no differential group losses.
Participants	124 children analysed at 3 years (present for entire trial period).  Age range at start: 8‐10 years (average = 9).  Surfaces affected at start: 11.3 DFS.   Background exposure to fluoride: none reported.  Year study began: 1962.  Location: Sweden.
Interventions	FT versus PL   (NaF group = 1000 ppm F). School use/supervised, daily, 1g applied for 2 min (non‐fluoride toothpaste provided to all for home use).   Abrasive system: methacrylate polymer (acrylic).
Outcomes	3yDFS increment ‐ cl(CA)(E).  Reported at 1 and 3 years follow ups (and 2 years post‐treatment). DFT.  O‐DFS.  MD‐DFS.  BL‐DFS.  Annual CAR.  Secondary caries.
Notes	Participants randomised (N = 153).  Baseline characteristics (DFS, DFT, SAR) 'balanced'.  Clinical (VT) caries assessment by one examiner; diagnostic threshold = CA; radiographic assessment (2 postBW) used as an aid but not reported; state of tooth eruption included = E.  Intra‐examiner reproducibility checks for DFS in 10% sample (icc over 0.98); reversals very small in both groups and equally common.  *** Allocation concealment considered adequate by consensus.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Methods	Random allocation; double‐blind (A);  placebo‐controlled; 43% drop out (for all study groups combined) after 3 years (study duration = 7 years). Exclusions based on variation in toothpaste provision and presence in follow‐up examinations; any differential group losses not assessable.
Participants	269 children analysed at 3 years (present for all examinations).  Age range at start: 6‐9 years (average = 8).  Surfaces affected at start: 3.3 DMFS.  Background exposure to fluoride: salt (suboptimal).  Year study began: 1958.  Location: Switzerland.
Interventions	FT versus PL   (AmF group = 1250 ppm F). Home use/unsupervised, daily frequency assumed.  Abrasive system: IMP.
Outcomes	3yNetDFS increment ‐ (CA)cl+(DR)xr.  Reported at 1.5, 3, 5 and 7 years follow ups. postMD‐DFS.   antMD‐DFS.  BL‐DFS.  O‐DFS.  DMFT.  FT.  FS.  MT.
Notes	Participants randomised (numbers for relevant groups NR).  Baseline characteristics (age, DMFS, DMFT) 'balanced' (DFS baseline data NR).  Clinical (V) caries assessment by one examiner; diagnostic threshold = CA and NCA; state of tooth eruption included NR. Radiographic assessment (2 postBW) by one examiner; diagnostic threshold = DR and ER; partial recording. Diagnostic errors NR.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Methods	Random allocation; indication of blind caries assessment (C); placebo‐controlled; 18% drop out (for all study groups combined) after 3 years (study duration = 3 years). Exclusions based on use of orthodontic bands and presence in all follow‐up examinations; any differential group losses not assessable.
Participants	100 children analysed at 3 years (present for all examinations).  Age range at start: 6‐7 years (average = 7).  Surfaces affected at start: 1 DMFS.  Background exposure to fluoride: salt (suboptimal).  Year study began: 1966.  Location: Switzerland.
Interventions	FT versus PL   (AmF group = 1250 ppm F). Home use/unsupervised, twice/three times a day/680 times a year estimated.  Abrasive system: IMP.
Outcomes	3yNetDFS increment ‐ (CA)cl+(DR)xr.  Reported at 1 and 3 years follow ups. 1stmPF‐DFS.   1stmMD‐DFS.
Notes	Participants randomised (numbers for relevant groups NR).  Baseline characteristics (age, DMFS, 1stmDMFS) 'balanced' (DFS baseline data NR).  Clinical (V) caries assessment by two examiners; diagnostic threshold = CA and NCA; state of tooth eruption included NR. Radiographic assessment (2 postBW) by two examiners; diagnostic threshold = DR and ER; partial recording. "Sufficient agreement of the two examiners known from earlier work".
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Methods	Random allocation; double‐blind ('A'); placebo‐controlled; 33% drop‐out rate after 3 years (study duration = 3 years). Main reasons for drop out: moved away, left school, away on examination day, disliked toothpaste taste, brown staining of teeth; no differential group losses.
Participants	1110 children analysed at 3 years (available at final examination).  Age range at start: 11‐12 years. Surfaces affected at start: 11.6 DMFS.   Background exposure to fluoride: none reported.  Year study began: 1965.  Location: UK.
Interventions	FT (3 groups) versus 'PL'   (Both SnF2 groups = 1000 ppm F, APF group = 1000 ppm F). Home use/unsupervised, daily frequency assumed.  Abrasive system: IMP in one SnF2 toothpaste and in APF toothpaste, dicalcium pyrophosphate in another SnF2 toothpaste; control toothpaste abrasive NR.
Outcomes	3yCrudeDMFS increment ‐ (CA)cl+(ER)xr.  Reported at 3 years follow up.
Notes	Participants randomised (N = 1665).  Baseline characteristics (age, gender, DMFS, previous F toothpaste use) 'balanced'.  Clinical (VT) caries assessment by one examiner; diagnostic threshold = CA; state of tooth eruption included = NR. Radiographic assessment (2 postBW) by one examiner; diagnostic threshold = ER. Consistency of clinical diagnosis revealed by 10% sample checks at each examination.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Study	Reason for exclusion
Antia 1974	Random or quasi‐random allocation not stated.
Axelsson 1976	Additional fluoride‐based intervention associated to fluoride toothpaste. Blind outcome assessment not stated.
Bibby 1945	Random or quasi‐random allocation not stated or indicated. Blind outcome assessment not stated or indicated.
Bixler 1962	Group of participants more than 16 years old selected. Random or quasi‐random allocation not stated.
Bixler 1966	Group of young adults selected.
Bixler 1966a	Additional fluoride‐based intervention associated to fluoride toothpaste. Group of participants more than 16 years old selected. Blind outcome assessment not stated.
Downer 1976	Additional fluoride‐based intervention associated to fluoride toothpaste.
Ennever 1980	Random or quasi‐random allocation not stated or indicated.
Finn 1963	Medically compromised group of institutionalised children selected.
Gish 1965	Additional fluoride‐based intervention associated to fluoride toothpaste. Blind outcome assessment not stated.
Gutherz 1968	Random or quasi‐random allocation not stated or indicated. Blind outcome assessment not stated or indicated.
Halikis 1966	Random or quasi‐random allocation not stated or indicated.
Hill 1959	Random or quasi‐random allocation not stated or indicated. Blind outcome assessment not stated or indicated.
Jiraskova 1965	Random or quasi‐random allocation not stated or indicated. Blind outcome assessment not stated or indicated.
Jordan 1959	Only two clusters (schools), each randomised to one of the two interventions compared.
Kunzel 1977	Additional fluoride‐based intervention associated to fluoride toothpaste.
Lehnhoff 1966	Participants more than 16 years old selected.
Lu 1985	Additional active agent associated to fluoride in toothpaste.
Luoma 1978	Additional fluoride‐based intervention associated to fluoride toothpaste.
Mergele 1968a	Medically compromised group of institutionalised young adults and children selected.
Moller 1968	Additional active agent associated to fluoride in test toothpaste.
Muhler 1955a	Random or quasi‐random allocation not stated.
Muhler 1957	Random or quasi‐random allocation not stated.
Muhler 1958	Participants more than 16 years old selected. Random or quasi‐random allocation not stated.
Muhler 1960	Participants more than 16 years old selected. Random or quasi‐random allocation not stated. Blind outcome assessment not stated.
Muhler 1962	Participants more than 16 years old selected.
Niwa 1975	Random or quasi‐random allocation not stated or indicated. Blind outcome assessment not stated or indicated.
Onisi 1970	Random or quasi‐random allocation not stated or indicated. Blind outcome assessment not stated or indicated.
Onisi 1974	Additional active agent associated to fluoride in toothpaste. Only two clusters (villages), each assigned to one of the two interventions compared.
Patz 1970	Participants more than 16 years old selected. Blind outcome assessment not stated.
Peffley 1960	Participants more than 16 years old selected. Random or quasi‐random allocation not stated. Blind outcome assessment not stated.
Piccione 1979	Blind outcome assessment not stated or indicated.
Riethe 1975	Blind outcome assessment not stated or indicated.
Stookey 1975	Random or quasi‐random allocation not stated.
Wrinkler 1953	Random or quasi‐random allocation clearly not used (non‐random concurrent control: by matching procedure).
Zickert 1982	Additional fluoride‐based intervention associated to fluoride toothpaste.

PERMALINK

Fluoride toothpastes for preventing dental caries in children and adolescents

Valeria CC Marinho

Julian Higgins

Stuart Logan

Aubrey Sheiham (deceased)

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Background

Fluoride toothpastes (dentifrices)

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Search methods for identification of studies

Electronic searching

Up to 1998

From 1999 to 2001

Reference searching

Full‐text searching

Personal contact

Data collection and analysis

Identification of reports produced by the searches

Selection of studies

Data extraction

Quality assessment

Data analyses

Handling of missing main outcome data

Handling of results of studies (main outcome) with more than one treatment arm

Choice of measure of effect and meta‐analyses of main outcome

Assessment of heterogeneity and investigation of reasons for heterogeneity

Investigation of publication and other biases

Measures of effect and meta‐analysis of other outcomes

Results

Description of studies

Search results

Selection of studies

Excluded studies

Included studies

Design and methods

Participants

Interventions

Outcome measures

Risk of bias in included studies

Allocation concealment

Blinding

Follow up and withdrawals

Others

Effects of interventions

Effect of fluoride toothpaste on dental caries increment

(1) Effect on tooth surfaces: D(M)FS PF

1. Meta‐analyses of prevented fractions.

Metaregression and sensitivity analyses: D(M)FS PF

2. Random‐effects metaregression analyses of prevented fractions: D(M)FS.

Funnel plot and test for funnel plot asymmetry: D(M)FS PF

(2) Effect on whole teeth: D(M)FT PF

(3) Alternative treatment effect measure: Standardised mean difference (SMD)

Effect on deciduous dentition: df‐rate PF (results from one trial)

Effect of fluoride toothpaste on other outcomes

Proportion of children developing new caries

Proportion of children with tooth staining

Discussion

Authors' conclusions

Implications for practice.

Implications for research.

What's new

History

Notes

Acknowledgements

Appendices