The Cochrane Oral Health Group's Trials Register, Cochrane Central Register of Controlled Trials, Medline, Embase, BIOSIS, Dissertation Abstracts and LILACS/BBO databases were searched. Also, reference lists from relevant articles and five journals (Community Dentistry and Oral Epidemiology, Caries Research, Journal of Dental Research, British Dental Journal, Journal of Public Health Dentistry) were searched by hand, and experts in the field of preventive dentistry and oral epidemiology contacted. Studies [randomised controlled trials (RCT), quasi-RCT, cohort studies, case-control studies and cross-sectional surveys] were selected if they had included children under the age of 6 years when topical fluorides were administered, and in which fluoride toothpastes, mouthrinses, gels, foams, paint-on solutions and varnishes were compared with an alternative fluoride treatment, placebo or no intervention group. Data from all selected studies were extracted by two review authors. Risk ratios (RR) for controlled, prospective studies and odds ratios (OR) for case-control studies or cross-sectional surveys were extracted or calculated. Where both adjusted and unadjusted risk ratios or OR were presented, the adjusted value was included in the meta-analysis. From 3573 identified papers, 25 studies were included: two RCT, one cohort study, six case-control studies and 16 cross-sectional surveys. Only one RCT was judged to be at low risk of bias. The other RCT and all observational studies were judged to be at moderate to high risk of bias. Studies were included in four intervention/ exposure comparisons. A statistically significant reduction in fluorosis was found if brushing of a child's teeth with fluoride toothpaste commenced after the age of 12 months [OR, 0.70; random-effects 95% confidence interval (CI) for topical fluoride, 0.57-0.88; data from observational studies]. Inconsistent but statistically significant associations were found between occurrence of fluorosis and starting use of fluoride toothpaste/ toothbrushing before or after the age of 24 months (data from observational studies). From the RCT, use of higher concentrations of fluoride was associated with an increased risk of fluorosis. No significant association between the frequency of toothbrushing or the amount of fluoride toothpaste used and fluorosis was found. There should be a balanced consideration of the benefits of topical fluorides in caries prevention and the risk of the development of fluorosis. Most of the available evidence focuses on mild fluorosis. There is weak unreliable evidence that starting the use of fluoride toothpaste in children aged <12 months may be associated with an increased risk of fluorosis. The evidence if use begins between the age of 12 and 24 months is equivocal. If the risk of fluorosis is of concern, the fluoride level of toothpaste for young children (under 6 years of age) is recommended to be lower than 1000 parts per million (ppm). More evidence from studies with low risk of bias is needed. Future trials assessing the effectiveness of different types of topical fluorides (including toothpastes, gels, varnishes and mouthrinses) or different concentrations or both should ensure that they include an adequate followup period in order to collect data on potential fluorosis. As it is unethical to propose RCT to assess fluorosis itself, further observational studies will necessarily be undertaken in this area. Attention does, however, need to be given to the choice of study design, bearing in mind that prospective, controlled studies will be less susceptible to bias than retrospective and/ or uncontrolled studies.
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