Does flavoured dentifrice increase fluoride intake compared with regular toothpaste in children? A systematic review and meta-analysis

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1 DOI: /ipd REVIEW Does flavoured dentifrice increase fluoride intake compared with regular toothpaste in children? A systematic review and meta-analysis THIAGO ISIDRO VIEIRA 1, ADRIELLE MANGABEIRA 1,AD ILIS KALINA ALEXANDRIA 1, DANIELE MASTERSON T. P. FERREIRA 2, TATIANA KELLY DA SILVA FIDALGO 3, ANA MARIA GONDIM VALENCßA 4 & LUCIANNE COPLE MAIA 5 1 Department of Paediatric Dentistry and Orthodontics, School of Dentistry, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil, 2 Library of the Health Science Center, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil, 3 Department of Preventive and Community Dentistry, School of Dentistry, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil, 4 Department of Clinic and Social Dentistry, School of Dentistry, Universidade Federal da Paraıba, Paraıba, Brazil, and 5 Department of Paediatric Dentistry and Orthodontics, School of Dentistry, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil International Journal of Paediatric Dentistry 2018; 28: Background. Toothpaste manufacturers encourage through aggressive marketing strategies the overconsumption of fluoridated dentifrices. There are conflicting results regarding fluoride intake from toothpastes in children. Aim. The aim of this systematic review and meta-analysis was to determine whether dentifrice flavour increases fluoride ingestion by children. Design. We included clinical trials on children that evaluated the use of flavoured dentifrice FD vs regular dentifrice RD to identify the fluoride intake. An electronic search was performed in PubMed, Web of Science, Scopus, The Cochrane Library, LILACS/BBO, and grey literature followed by manual search. The methodological quality of the studies was assessed using the Cochrane Collaboration common scheme for bias and ROBINS-I tool. Data were analysed in subgroups such as low (G1) and ordinary (G2) fluoride concentrations of dentifrices. We carried out heterogeneity and sensitive analyses. Results. For G1, the fluoride intake from RD was significantly higher than from FD [standardised mean difference = 2.57 ( 3.26, 1.89), P < ]. For G2, the fluoride ingestion from RD was significantly higher than from FD [mean difference = 0.00 ( 0.00, 0.00), P = 0.02]. Conclusions. There is evidence to support the null hypothesis that flavouring from dentifrice does not increase fluoride intake in young children. Introduction There is strong evidence that toothbrushing with fluoride dentifrice is an efficient method for preventing dental caries in the permanent teeth of schoolchildren 1 3 and the same occurring in the primary teeth of pre-schoolchildren 4. Especially in young children, it is extremely important to balance the anticaries effect of fluoride dentifrice vs dental fluorosis Correspondence to: Lucianne Cople Maia, Departamento de Odontopediatria e Ortodontia, Universidade Federal do Rio de Janeiro, Rua Professor Rodolpho Paulo Rocco, 325, Ilha do Fund~ao, Rio de Janeiro/RJ, CEP: , Brazil. rorefa@terra.com.br occurrence. According to the available evidence, parental supervision during tooth brushing should be encouraged along with applying a pea-sized or smear amount of toothpaste and spitting out the excess rather than rinsing, maximising the benefits of tooth brushing and minimising the chance of fluorosis occurrence 5. Dental fluorosis is a systemic disorder that results in an enamel developmental disturbance that is associated with fluoride ingestion preceding tooth eruption. This condition is related to the fluoride amounts in the surrounding area of developing tooth, during the formation of enamel. Its severity and risk are closely related to amount of ingestion, developmental stage of the tooth, exposure time, 279

2 280 T. I. Vieira et al. body weight of the child, and fluoride bioavailability 6. An important risk factor for dental fluorosis is the fluoride dentifrice ingestion in early ages, since pre-schoolers, from 22 to 25 months, are more prone to develop this disturbance in anterior teeth with aesthetics commitment 7. Another aspect that should be pointed out is that fluoride toothpaste is not the only factor that can increase the prevalence of dental fluorosis; however, it is a challenge to accurately estimate the total fluoride intake from different sources available such as drinking water, foods and beverages, and other fluoride products 8. In relation to dentifrices, toothpaste manufacturers encourage through marketing strategies the overconsumption of fluoridated dentifrices. The literature points out aggressive marketing strategies targeting children. Of all the advertisements, 92.30% stated that the toothpastes were flavoured and 26.90% depicted a full swirl of toothpaste, directly contradicting dentists recommendations for young children. These authors also highlight some conflict between this marketing strategy and dentists recommendations. It is important to point out that the labels warn the consumer to use only a pea-sized amount, but the packaging of many types of toothpaste boasts the pictures of fruit with flavouring to match. This could stimulate consumption as if it were food 9. It was especially recommended that flavoured fluoridated dentifrices (such as bubble gum and fruit) for children not be used by preschoolers, because they might increase ingestion 10. A wide variety of toothpastes designed for children are however available, and many of them have added flavours to make them particularly attractive to children 11. Many of these flavours are attractive and present similar tasty of candies, and thus, they may induce children to use a large volume of dentifrice and also increase the time spent brushing 12,13. The literature has investigated fluoride intake from foods, drinks, toothpaste 14 18, and water 19. Regarding toothpastes, there are some conflicting results, however. While some studies have demonstrated higher fluoride ingestion from flavoured dentifrice 12,20 22, others have published contradictory results In this sense, the null hypothesis of this study is that flavoured dentifrice does not increase fluoride ingestion when compared with regular toothpaste. Therefore, these systematic review and meta-analysis were performed to answer the following focused question: Does flavoured dentifrice increase fluoride intake compared with regular toothpaste in children? According to the PICO strategy, clinical trials on children (P) that evaluated the use of flavoured dentifrice FD (I) vs regular dentifrice RD (C) in order to identify the fluoride intake (O) were included. Material and methods This systematic review was registered in PROS- PERO under the number CRD The authors also followed the recommendations of the PRISMA statement 26 and Maia and Antonio 27 guideline. Bibliographic sources and search strategy The current systematic review was based on seven electronic bibliographic data sources such as PubMed, Scopus, Web of Science, The Cochrane Library, Lilacs, and BBO. The grey literature was also searched through the SIGLE database. The search was carried out on 21 June Hand searches on the reference of the included papers were also performed. There was no date or language restriction. All references were imported into reference management online (EndNote Web; Thomson Reuters Inc., Philadelphia, PA, USA). Two authors performed the search independently (T.I.V. and A.M.) under the guidance of a librarian (D. M.). Any differences between the two reviewers were solved by consensus with a third senior reviewer. Medical Subject Headings (MeSH) terms and keywords were identified in the published papers. We applied the filters humans and child for the PubMed database and dentistry and article for the Scopus and Web of Science databases. The search strategy was appropriately modified for each database (Table 1).

3 Dentifrice flavour and fluoride intake 281 Table 1. Electronic database and search strategy. Database Search strategy PubMed #1 (toothpastes [mesh] OR toothpaste* [tiab] OR fluoride toothpaste* [tiab] OR fluoridated toothpaste* [tiab] OR dentifrices [mesh] OR dentifrice* [tiab] OR fluoride dentifrice* [tiab] OR fluoridated dentifrice* [tiab]) #1 AND #2 Web of Science and Scopus #1 (toothpaste OR toothpastes OR fluoride toothpaste OR fluoride toothpastes OR fluoridated toothpaste OR fluoridated toothpastes OR dentifrice OR dentifrices OR fluoride dentifrice OR fluoride dentifrices OR fluoridated dentifrice OR fluoridated dentifrices ) #2 (fluorides [mesh] OR fluoride* [tiab] OR fluorine [mesh] OR fluorine [tiab]) #2 (fluoride OR fluorides OR fluorine) #1 AND #2 The Cochrane Library #1 MeSH descriptor: [Toothpastes] explode all trees #9 MeSH descriptor: [Fluorides] explode all trees #2 toothpaste* #10 fluoride* #3 #1 or #2 #11 #9 or #10 #4 fluoride toothpaste* or fluoridated toothpaste* #12 MeSH descriptor: [Fluorine] explode all trees #5 MeSH descriptor: [Dentifrices] explode all trees #13 fluorine #6 dentifrice* or fluoride dentifrice* or fluoridated #14 #12 or #13 dentifrice* #7 #4 or #5 or #6 #15 #11 or #14 #8 #3 or #7 #16 #8 and #15 Lilacs and BBO #1 (tw:((mh:dentifrıcios OR mh:cremes dentais OR toothpastes OR toothpaste OR pastas de dientes OR cremes dentais OR fluoride toothpaste OR fluoride toothpastes OR fluoridated toothpaste OR fluoridated toothpastes OR creme dental fluoretado OR pasta de dientes con fluoruro OR dentifrice OR dentifrices))) #1 AND #2 SIGLE #1 (tw:((mh:dentifrıcios OR mh:cremes dentais OR toothpastes OR toothpaste OR pastas de dientes OR cremes dentais OR fluoride toothpaste OR fluoride toothpastes OR fluoridated toothpaste OR fluoridated toothpastes OR creme dental fluoretado OR pasta de dientes con fluoruro OR dentifrice OR dentifrices))) #1 AND #2 #2 (tw:((mh:fluor OR mh:fluoretos OR fluorides OR fluoride OR fluoretos OR fluoruros OR fluorine OR fluor))) #2 (tw:((mh:fluor OR mh:fluoretos OR fluorides OR fluoride OR fluoretos OR fluoruros OR fluorine OR fluor))) Criteria for inclusion/exclusion of papers Two investigators (T.I.V. and A.M.) screened all titles and abstracts and full-text manuscripts retrieved from the database searches and excluded irrelevant records. And in the case of any inconsistency, a third author (L.C.M.) was consulted. To be included in the review, a paper had to meet some criteria such as: (a) be a clinical trial in children; (b) determine the fluoride intake from flavoured dentifrices compared with regular dentifrice by recording the amount of fluoride ingested, resulting in estimated dose calculated as mg F/day kg of body weight. This measure was obtained by subtracting the amount of fluoride expectorated from the initial amount placed onto the toothbrush or determined by gas chromatography; (c) use a clinical convenience sample or random sample with no restrictions regarding settings. The exclusion criteria were the following: studies where the fluoride intake from flavoured dentifrices compared with regular dentifrice was not the outcome, manuscripts assessing specific subpopulations (mentally handicapped or disabled children), articles evaluating serum and urine fluoride levels,

4 282 T. I. Vieira et al. laboratories studies, in situ studies, animal studies, guidelines, letters, reviews of the literature, systematic reviews, and case reports. Data collection A data extraction spread sheet was developed, and data were collected independently by two researchers (T.I.V. and A.M.). For each selected manuscript, the following information was collected: author/country/publication year, study design, age, sample size, and outcome related to flavoured dentifrice compared with regular ones. Additionally, mean values and standard deviations from fluoride intake with the respective 95% confidence intervals were collected. The authors of primary studies were contacted in case of relevant data were missing. Quality assessment The quality assessment was conducted according to Cochrane Collaboration 28 for randomised clinical trials for bias and ROBINS-I tool for non-randomised clinical trials. 29 For Cochrane s risk of bias 28 assessments, the random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other sources of bias were considered. Studies were considered to be at low risk of bias if key domains (random sequence generation, allocation concealment, blinding of participants and personnel, and other source of bias) were judged adequate. When the study was judged as unclear in their key domains, we tried to contact authors to obtain more information and allow a definitive judgement of yes or no. If the final judgement was unclear for one or more key domains, studies were considered to be at unclear risk of bias. At least, studies were considered to be at high risk of bias if one or more key domain was considered inadequate. The following domains were considered to be evaluated through the ROBINS-I tool 29 : confounding, selection of participants into the study, classification of intervention, departures from intended interventions, missing data, measurements of outcomes, and selection of the reported result. For each domain, an outcome of low, moderate, serious, critical, and no information for risk of bias is recorded. The studies were considered at critical risk of bias if it was judged problematic enough to provide evidence on the interventions effect. The possible outcomes for each domain were recorded as low, moderate, serious, critical, and no information for risk of bias. An overall risk of bias judgement was determined through combination of the seven domains 29. Meta-analysis The meta-analysis was performed on the studies considered low and moderate/low risk of bias 28 through RevMan software. The following data were retrieved from each paper: mean concentration (standard deviation) of ingested fluoride and the number of subjects for each group. The random-effects model was used on studies that were not functionally equivalent in which the objective was to generalise the results from this meta-analysis and a fixed-effects model for the analysis of a small number (five or less) of studies 30. The mean difference was used to measure the absolute difference between the mean value in two different groups that used similar methodology, and standard mean difference was used when compared means between groups with different unit measurements 30. Thus, always when Bentley et al. (1999) 23 were included, we used standard mean difference as the authors used chromatography and the others studies ion-specific electrode. A subgroup assessment was conducted among the studies that evaluated fluoride intake comparing low ( ppm F) vs regular (1450 ppm F) fluoride concentration toothpastes (subgroup 1) and 1100 ppm F vs 1450 ppm F toothpastes (subgroup 2). The I 2 index was used to test the heterogeneity among the studies, and forest plots were generated for each comparison group of studies. Sensitivity analysis (leave-one-out assessment) was carried out to verify the influence of each study on global standardised mean differences. Publication bias evaluation was

5 Dentifrice flavour and fluoride intake 283 not conducted because the minimum number of studies for the implementation of this test ( 10) was not achieved. 28 Results All of the articles found (10,724) were exported to EndNote Web software â in database groups (1679 from PubMed, 1612 from Web of Science, 5651 from Scopus, 1552 from The Cochrane Library, 179 from LILACS, 46 from BBO, and five from SIGLE). All duplicates were removed and 9083 papers remained. Based on the exclusion criteria, we excluded 8973 articles. The main reasons were laboratory studies, in situ studies, animal studies, guidelines, letters, reviews of the literature, systematic reviews not related to dentifrice flavour, and case reports. One hundred and ten papers were assessed for eligibility, and of them, 103 were excluded because the outcome was not related to dentifrice flavour; they were letters to the editor and no response contact was achieved. After full-text reading, all seven studies 12,20 25 were included in the qualitative synthesis. From these studies, five 12,22 25 were included in the meta-analysis since Oliveira et al and Oliveira were removed due to overlapping sample. Figure 1 shows the flow diagram of the search and inclusion of manuscripts. Characteristics of the included studies regarding subjects, study design, data collection, and main results are detailed in Table 2. In relation to fluoride ingestion, three studies showed flavoured toothpaste did not increase fluoride intake by children when compared with ordinary dentifrice Four studies demonstrated that fluoride ingestion was higher in children whose toothpaste was flavoured than in those who used regular dentifrice 12, Toothpaste ingestion was assessed using an estimated dose calculated as mg F/ day kg of body weight in all studies reviewed 12,20 25.Onlyonestudy 23 determined the amount of fluoride from toothpaste by gas chromatography. Six studies determined the amount of fluoride from toothpaste using the fluoride ion-specific electrode coupled to a potentiometer 12,20 22,24,25. The studies risk of bias assessment is presented in Figure 2 and Table S1. One study 24 was evaluated for inner methodological risk of bias according to the Cochrane Collaboration 28, while the remaining retrieved studies 12,22,23,25 were assessed through ROBINS-I 29. No study had serious design flaws. The included studies (n = 5) were classified as having a low/moderate risk of bias. The forest plots containing the studies with low/moderate risk of bias were included (Fig. 3). A total of 36 children FD users and 35 RD users were included in the first subgroup. For G1, the fluoride intake from RD was significantly higher than from FD [standardised mean difference = 2.57 ( 3.26, 1.89), P < ]. The heterogeneity was 92% (I 2 ). A total of 181 FD users and 149 RD users were included in the second subgroup. For G2, the fluoride ingestion from RD was significantly higher than from FD [mean difference = 0.00 ( 0.00, 0.00), P = 0.02]. The heterogeneity was 98% (I 2 ). (Fig. 3). A sensitivity analysis was performed; however, it was not observed an important reduction in the heterogeneity (I 2 index ranged from 90% to 98%). In a leave-one-out sensitivity analysis, the results remained unchanged. Discussion Systematic reviews provide a summary of the evidence related to a specific question and are useful to unify and synthesis evidence, assisting in the guidance of future investigations 31. More specifically, a meta-analysis could provide an aggregation of data with a more accurate statistical power for each measure of interest 32.Some limitations of studies are however transported to the systematic reviews, such as publication and citation bias. Studies that present positive results, with statistical difference, are more prone to be published compared to inconclusive studies, as well as to be cited 28. The current systematic review and metaanalysis explored the potential effect of flavoured dentifrices on fluoride ingestion by children. The findings showed a significantly higher amount of fluoride ingested from RD compared with FD ( ppm F vs 1450 ppm F toothpastes). In the same way, a

6 284 T. I. Vieira et al. Fig. 1. Systematic review flow diagram.

7 Dentifrice flavour and fluoride intake 285 Table 2. Characteristics of the sample. Author Country/year Participants Range of age of participants Flavoured dentifrice Regular dentifrice Source of sample Sample size Source of sample (months) Sample size FD RD Fluoride intake (mg F ingested/day/kg of body weight) Age (months) FD mean SD (confidence interval) RD mean SD (confidence interval) P value Statistical analysis Lima et al. Teresina-Brazil/ Public kindergarten 50 Public kindergarten Student s t-test Oliveira et al. Montes Claros- Brazil/ Oliveira. Montes Claros- Brazil/ Moraes et al. Bauru-Brazil/ Oliveira et al. Belo Horizonte- Brazil/ Oliveira et al. Belo Horizonte- Brazil/ Four private and four public kindergartens Four private and four public kindergartens Public child care centre Group A (500 ppm F) 12 Two kindergartens located in regions with distinct socio-economic levels 78 Four private and four public kindergartens 197 Four private and Group B (1100 ppm F) 11 four public kindergartens Public child care centre 42 Two kindergartens located in regions with distinct socio-economic levels Mann Whitney <0.001 Wilcoxon ( ) ( ) ( ) Two schools 15 Two schools ( ) ( ) ( ) ( ) <0.001 ANOVA and Tukey < Paired t-test >0.05 Student s t-test Bentley et al. England-United Kingdom/ Community dental health programme 24 Community dental health programme ( ) ( ) <

8 286 T. I. Vieira et al. Fig. 2. Risk of bias summary containing authors judgements about each risk of bias of all included studies. (a) Cochrane Collaboration common scheme for bias; (b) ROBINS-I tool assessment: yellow ball indicates studies at moderate risk of bias, orange ball indicates no information, and green ball indicates studies at low risk of bias. significantly higher amount of fluoride ingested from RD compared with FD was observed when ordinary concentrations were used (for 1100 ppm F vs 1450 ppm F toothpastes). The current meta-analysis presented heterogeneity among studies in both subgroups. This finding could be explained by the ages of the studied population, sample size, variations in study length, and methodological issues. Additionally, the values of heterogeneity were not surprising, because fluoride ingestion is influenced by many variables, such as salivary flow rate and capacity for absorption and excretion of fluoride. Two studies 20,21 retrieved exhibited sample overlapping. Participant overlapping can introduce substantial biases if studies are inadvertently included more than once in a meta-analysis. For this reason, attention should also paid to identify any sample overlapping as well as duplicate publication 28. The studies included in the current meta-analysis were designed as clinical trials. Therefore, matching the controls for age, gender, and other variables may be sufficient for between-group comparisons. Three of the studies involved the same children using both flavoured and regular dentifrice 12,20,21. Moreover, if the model is adjusted by the same group of individuals receiving both treatments (experimental and control), selection bias can be minimised. With respect to the participants, the ages of the children enrolled in these studies 12,20 25 ranged from 9 to 48 months. Children from 20 to 30 months of age are the highest risk for dental fluorosis, especially in the permanent maxillary incisors. This period is characterised by the change between the end of the secretory stage and the beginning of the maturation stage of these teeth 7. It is relevant to highlight that the presence of flavour in toothpaste, especially toothpaste designed for children, does not necessarily imply an increased fluoride intake. The forest plots from the current review (Fig. 3) strengthen this theory. Flavours could stimulate children s regular toothbrushing acceptance with fluoride dentifrice, resulting in caries prevention. An unceasing challenge to the paediatric dentist is to assure that the preventive benefits of fluoride dentifrice are best achieved when risks of dental fluorosis are reduced 8,33. The data from low fluoride toothpastes and ordinary toothpastes included in the meta-analysis revealed that the presence of flavour did not increase fluoride intake. In other words, this result reinforces that the fluoride concentration in the toothpaste was the main factor of the amount of fluoride ingested, irrespective of the flavour itself. The effectiveness of fluoride toothpastes (>1000 ppm) in reducing dental caries and

9 Dentifrice flavour and fluoride intake 287 Fig. 3. (a) Forest plot of the fluoride intake from flavoured dentifrice and regular toothpaste ( ppm F vs 1450 ppm F toothpastes G1); (b) Forest plot of the fluoride intake from flavoured dentifrice and regular toothpaste (1100 ppm F vs 1450 ppm F toothpastes G2) minimising the risk of fluorosis is well documented in the literature. The findings of a systematic review that assessed the efficacy and safety of fluoride toothpaste used in children younger than 6 years showed that the use of less-than-a-pea-sized fluoride dentifrice should be encouraged regardless of age. 33 According to the selected studies in the metaanalysis, the ingested dose of F did not exceed the acceptable limit of 0.07 mg/d kg of body weight. This dose represents the critical point at which dental fluorosis can occur. Fluoride intake above 0.07 is associated with an increased risk of dental fluorosis 34. Another pertinent aspect is the fluoride guidelines related to toothpaste for young children. They generally recommend the use of a smear or pea-sized quantity of dentifrice. This could be achieved by applying the toothpaste transversally across the brush rather than along the length 6. Focused on children, the extrapolation of the present meta-analysis to overall practice should encourage tooth brushing performed under parental supervision; the child must be encouraged to expectorate the slurry and to do this soon after the meal because food interferes with fluoride absorption. The spitting response should be reinforced because when it is not well developed, ~40% of the toothpaste (systematic available fluoride) is ingested 35. The toothpaste manufacturers are aware that adding flavour makes the product particularly attractive to children 9,36. This industry has become concerned about the challenge faced by paediatric dentists of specially designed toothpastes without any fluoride or with low fluoride concentrations ( ppm F) and non-existent anticaries effects 4. On the other hand, other researchers have pointed out that the increased fluoride intake could be reduced by assuming measures or technologies related to regulate the quantity of toothpaste used during brushing by young children and to ensure that children under the age of 7 years are supervised when tooth brushing 36. On the basis of the inexistence of an anticaries effect of low-concentration dentifrices ( ppm F), the findings of our metaanalysis revealed an important point. When assessing the subgroup that compared 1100 ppm F vs 1450 ppm F toothpastes, the pooled data indicated that there was no increase in fluoride ingestion from flavoured dentifrice. Considering the results of the present meta-analysis, parents are encouraged to continue using regular dentifrice during toothbrushing, because it presents a higher fluoride concentration than flavoured dentifrice and its effect on dental caries reduction is solidified 1 3. Study points out that total

10 288 T. I. Vieira et al. soluble fluoride is indicated for measuring of fluoride intake, as intake may be overestimated when total fluoride is considered 25. The result however remains the same when only total soluble fluoride was used in the analysis (Fig. S1). The amount of bioavailable fluoride in dental cream is related to the type of fluoride salt and abrasive employed 37. Dentifrices containing calcium carbonate as abrasive are formulated using sodium monofluorophosphate while toothpastes presenting silicon dioxide (silica) are prepared with sodium fluoride 25. In the latter ones, all fluoride is chemically soluble while in the former ones, a lower degree of fluoride bioavailability is observed 37. According to the Cochrane Collaboration common scheme for bias and ROBINS-I tool, the studies demonstrated low/moderate risk of bias. There was not any methodological weakness that could lead to a biased interpretation of the results impairing the extrapolation of the findings. This study adds to the current knowledge of the relationship between flavoured toothpaste and fluoride intake. On the basis of the results of this systematic review and metaanalysis, the data indicate that there is evidence to support the null hypothesis that flavouring from dentifrice does not increase fluoride intake in young children. Why this paper is important to paediatric dentists This study is of particular interest for paediatric dentists, especially regarding the appropriate amount of toothpaste that should be used when counselling caregivers. Flavouring from dentifrice does not increase fluoride intake in young children. The amount of fluoride ingested is closely related to its fluoride concentration in the dentifrice. Acknowledgements This study was conducted during the doctoral stage of Thiago Isidro Vieira under the supervision of the Prof. Lucianne Cople Maia. This study was supported by the CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), CNPQ / and / / FAPERJ E-26/ /2014. Conflict of interest The authors declare no conflict of interest. Author s Contribution Dr. Vieira conceptualised and designed the study, collected data, drafted the initial manuscript, and approved the final manuscript as submitted. Dr. Mangabeira conceptualised the study, collected data, and critically reviewed and approved the final manuscript as submitted. Dr. Alexandria analysed data, and critically reviewed and approved the final manuscript as submitted. Dr. Ferreira critically reviewed the search strategy and bibliographic source and approved the final manuscript as submitted. Dr. Fidalgo conducted data analyses, reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr. Valencßa critically revised and approved the final manuscript as submitted. Dr. Maia designed the study, conducted the analysis, critically reviewed manuscript, and approved the final manuscript as submitted. References 1 Chaves SC, Vieira-da-Silva LM. Anticaries effectiveness of fluoride toothpaste: a meta-analysis. Rev Saude Publ 2002; 36: Marinho VC, Higgins JP, Sheiham A, Logan S. Fluoride toothpaste for preventing dental caries in children and adolescents. Cochrane Database Syst Rev 2003; 1: CD Twetman S, Axelsson S, Dahlgren H et al. Cariespreventive effect of fluoride toothpaste: a systematic review. Acta Odontol Scand 2003; 61: Santos APP, Nadanovsky P, Oliveira BH. A systematic review and meta-analysis of the effects of fluoride toothpastes on the prevention of dental caries in the primary dentition of preschool children. Community Dent Oral Epidemiol 2013; 41: Ellwood RP, Fejerskov O. Clinical use of fluoride. In: Fejerskov O, Kidd E (eds). Dental Caries, the Disease and Its Clinical Management. Copenhagen: Blackwell Munksgaard, 2003: Ellwood RP, Cury JA. How much toothpaste should a child under the age of 6 years use? Eur Arch Paediatr Dent 2009; 10: Evans RW, Stamm JW. An epidemiologic estimate of the critical period during which human maxillary central incisors are most susceptible to fluorosis. J Public Health Dent 1991; 51:

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12 290 T. I. Vieira et al. Supporting Information Additional Supporting Information may be found in the online version of this article: Fig. S1. Forest plot of the fluoride intake from flavoured dentifrice and regular toothpaste (1100 ppm F vs 1450 ppm F toothpastes) considering total soluble fluoride. Table S1. Risk of bias assessment of the studies.

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