These two questions were debated at length during two conferences organized in the 1990s to review the use of fluoride in caries prevention.^7–9 The goal of this systematic review is to present and critique the evidence as well as to update the information presented at previous conferences.

Does the use of fluoride supplements in children aged zero to 16 years prevent dental caries?

	METHODS AND MATERIALS

TOP ABSTRACT METHODS AND MATERIALS RESULTS DISCUSSION CONCLUSION REFERENCES

 
Search strategy: effectiveness of fluoride supplements We searched four databases for relevant studies about the effectiveness of fluoride supplements: MEDLINE (January 1966–June 2006), the Cochrane Central Register of Controlled Trials (January 1941–second quarter 2006), OVID All EBM Reviews (January 1991–June 2006), and EMBASE (1974–2006). We conducted the searches using the OVID search engine and a structured search filter that was developed on the basis of the filters used by the National Institutes of Health Consensus Development Conference on Diagnosis and Management of Dental Caries Throughout Life¹⁰ and the Cochrane Collaboration Oral Health Group’s systematic review of topical fluorides.¹¹ The filter used in this review captured all key studies that the review team identified before beginning the search. The search filter is available from the authors upon request.

The search of the databases yielded 988 citations. We imported the titles and abstracts to ENDNOTE (Thomson-ISI Research Software, Philadelphia). Of the 988 articles, we eliminated from the database 77 that were duplicates. Of the remaining 911 reports, 826 did not meet the inclusion criteria based upon our review of the titles and abstracts. Our review of the full reports of the remaining 85 articles identified 20 reports of clinical trials (12 unique clinical trials), nine cohort studies, 22 cross-sectional studies and eight retrospective studies. Of the remaining 26 articles, seven were reviews; four were of systemic fluorides other than supplements; five did not have a control group; one included only elderly adults; two were of the fluoride distribution in enamel, dentin or saliva; two focused on the caries experience of the children but not the use of supplements; three were written in languages other than English; and two involved dental fluorosis and use of supplements but did not include data regarding dental caries. (We included one of the two studies in the fluorosis-supplement review but not the other, because it did not measure the exposure to fluoride during the first six years of life.) For the first question, we focused the review on the analysis of findings from clinical or community-based trials because these studies were more appropriate than those of other designs.

We reviewed the articles cited in the 20 reports of clinical trials (12 separate trials in total) to locate additional studies that the search filter did not identify. We reviewed the proceedings of workshops on the use of fluorides in caries prevention that were held in 1990⁷ and 1994,² as well as papers cited in a previous review published in 1994.¹² These additional searches revealed no additional clinical trials that met the inclusion criteria used in this review.

With the aid of a research assistant, we conducted the review of titles and abstracts. When we identified differences among the reviewers during selection of studies or extraction of data, we resolved them by consensus, using the following inclusion and exclusion criteria.

Inclusion criteria We used the following criteria to select relevant studies for the first question:

– The study design is longitudinal and includes experimental (intervention) and control (comparison) groups.

– The intervention focused only on fluoride supplements (tablet, lozenges or drops) with or without toothbrushing at home with fluoridated dentifrice. The "control" group was not exposed to any source of systemic fluoride.

– Reports of the included studies are available in English.

Exclusion criteria We excluded studies if they

– evaluated other systemic fluoride sources (water, salt or milk);

– used nonrandomized designs (case-control, cohort, reviews, cross-sectional).

The included studies evaluated fluorosis in children who consumed fluoride in water or from other sources during the first six years of life.

Search strategy: dental fluorosis We conducted the search for evidence to answer the second question using the same search terms used in a previous systematic review.¹³ That previous review included cross-sectional, case-control or cohort studies that presented sufficient data for a meta-analysis of the risk of developing fluorosis in children who ingested fluoride supplements. The included studies evaluated fluorosis in children who consumed fluoride in water or from other sources during the first six years of life. For this update, we identified seven studies.^14–20 Of those, we excluded a well-designed longitudinal study conducted in Iowa¹⁹ because the independent contribution of fluoride supplements to the risk of fluorosis could not be ascertained. We excluded another study by Morgan and colleagues²⁰ because relevant data regarding use of fluoride supplements were not reported.

Quality assessment As unmasked reviewers, we independently conducted the quality assessment of the included studies relevant to the first question, following the methods reported in the Cochrane Handbook of Systematic Reviews (Section 6.7).²¹ Additionally, we evaluated the training and reliability of examiners and reasons for participants’ withdrawals. We rated studies that met all the criteria as having low potential for bias. We rated studies that reported their randomization scheme and had withdrawal rates of 30 percent or higher as having moderate potential for bias, and studies that did not meet these criteria as having high potential for bias.

Synthesis of findings We present only qualitative analyses of the evidence in this review because of the heterogeneity of subjects, outcomes and duration of follow-up. We have reported the means, standard deviations, risk measures and significance levels when the information was available in the original reports.

	RESULTS

TOP ABSTRACT METHODS AND MATERIALS RESULTS DISCUSSION CONCLUSION REFERENCES

 
Fluoride supplements and dental caries. Tables 1 and 2 (page 1462) describe the characteristics of the included 20 reports of the trials.^22–41 Eleven reports of seven trials provided results of tests of dosage of fluoride supplements in children with age ranges similar to those recommended by the ADA schedule (Table 1). The findings from these studies are as follows.

Children aged 3 to 6 years A trial reported by Petersson and colleagues³⁷ evaluated the efficacy of twice-daily chewing of fluoride tablets (0.25 mg/day) for two years by children aged 3 years. The children who used fluoride supplements did not have significantly different mean decayed and filled primary tooth surface (dfs) increments when compared with the children in the control group.

The children enrolled in the retrospective study by Mann and colleagues³⁸ were between the ages of 4 and 5 years or 6.5 and 7.5 years at the time of the baseline examination. The children had received drops containing 0.25 mg fluoride once a day when they were aged 6 months to 3 years; 0.5 mg fluoride drops once per day between the ages of 3 and 5 years, and 0.75 mg fluoride drops once per day between the ages of 5 and 8 years. After 3 years of age, the children in the test group exhibited a 43 percent reduction in the mean decayed, extracted owing to caries and filled primary teeth (deft) increment compared with that in children in the control group (P < .05). This highly biased study did not find statistically significant caries reduction in permanent teeth.

Children older than 6 years We included eight reports of four trials that evaluated the effectiveness of fluoride supplements in school-aged children according to the ADA recommendations. DePaola and Lax²⁵ evaluated the effectiveness of fluoride tablets used daily during the school year versus placebo tablets. The children chewed and ingested the tablets. This study was the first to provide data regarding the highly significant reduction in dental caries experience (mean decayed and filled surfaces [DFS] increment) in permanent teeth that erupted during the study. These teeth experienced a 53 percent lower mean DFS increment when compared with similar teeth in the control group (P = .01). Overall, the fluoride tablet program reduced the caries increment by 20 to 23 percent in two years (P < .05). Allmark and colleagues³⁶ reported a 61 percent reduction in mean DFS scores in children in the United Kingdom who ingested one 2.2-mg sodium fluoride tablet per school day for six years compared with children who did not use daily supplements (P < .001).

We included eight reports of four trials that evaluated the effectiveness of fluoride supplements in school-aged children.

Findings from a long-term trial in the United States in which the same children were examined at intervals 2.5, 4.7, 6.0 and 7.5 years after the start of a fluoride tablet program showed significant reductions at each follow-up period.^29,31,32,34 Chewing a fluoride tablet during school days significantly reduced caries incidence and severity. The effectiveness of the fluoride tablets increased with time and ranged from 6.2 percent after 2.5 years to 24.0 percent (P = .03) after 7.5 years of use in early-erupting permanent teeth. In teeth erupting during the study, the reduction ranged from 36.5 percent after 2.5 years to 45.9 percent (P < .01) after 7.5 years. Driscoll and colleagues³⁵ also found a 15.0 percent caries reduction (P = .39) in early-erupting permanent teeth and a 38.6 percent reduction in late-erupting permanent teeth (P = .01) four years after discontinuation of the program.

In Scotland, Stephen and Campbell³³ reported a significant reduction of 70.5 percent (P < .001) in mean decayed, missing and filled surface (DMFS) scores of first permanent molars in children who chewed and swallowed a fluoride tablet once a day during school days between the ages of 5.5 to 5.6 years and 8.5 to 8.7 years.

Additional findings One of the first studies evaluating fluoride supplements with added vitamins was conducted in Indiana. The investigators found that children who started supplementation between birth and 3 years, following a regimen that provided higher dosage than the 1994 ADA recommendations, had a significantly lower mean number of decayed, extracted because of caries and filled (defs) surfaces of primary teeth than did children who received only vitamin supplements (P < .001) (Table 2).²³ This finding was confirmed by findings of another study that also was conducted in Indiana.²⁸ Fluoride tablets significantly reduced caries in permanent teeth after daily use for four to 5.5 years. ^24,26

The study by Leverett and colleagues³⁹ evaluated the use of fluoride tablets by expectant mothers starting from the fourth month of pregnancy until delivery (Table 2). After birth, the children received fluoride drops daily until they reached 3 years of age. Children in the comparison group, whose mothers did not receive fluoride supplements during pregnancy, also received fluoride drops after birth. Hence, the design allows only for comparison of prenatal fluoride use in an environment in which fluoride supplements are used starting after birth. The study concluded that prenatal fluoride supplements had no benefits.

Findings from a 1971 study (potentially highly biased, according to the criteria in Table 3) conducted in Stockholm, Sweden, revealed a reduction in dental caries among children who received vitamin drops containing 0.5 mg fluoride starting at the age of 2 to 3 weeks until the age of 6 years²⁷ (Table 2). In 2005, investigators in another study involving 12-year-old Swedish children with high caries levels⁴¹ found in a five-year period that the children who chewed and ingested fluoride lozenges did not have significantly different caries experience from that of children who received topical applications of fluoride varnish, or from that of children who received oral health education, or from that of children who participated in individualized oral hygiene programs.

Children with fluorosis had lower odds of having caries in the primary and permanent dentitions than did children who did not have fluorosis.

Quality of the included studies of the effectiveness of fluoride supplements Seven of the 12 trials (15 reports) suffered from high rates of participant withdrawal^{23,24,26–32,34–36,38,40–41} (Table 3). We rated five trials^{22,25,33,37,39} as being moderately biased. The large proportions of children who withdrew from using the fluoride supplements in the included studies increased the potential for bias.

Fluoride supplements and fluorosis On the basis of a systematic review of studies evaluating the association between the use of fluoride supplements and dental fluorosis, Ismail and Bendekar¹³ reported in 1999 that the odds ratio of dental fluorosis in nonfluoridated communities was estimated to be about 2.5 among children who used fluoride supplements during the first six years of life.

In this review, we have used the same search strategy to update these findings. We identified seven additional studies, of which we included five. The additional studies^14–18 (Table 4, page 1466) confirmed the positive association between the use of fluoride supplements and dental fluorosis. (Fluorosis was measured by means of several indexes.^42–44) The odds ratio of dental fluorosis increased by 84 percent (95 percent confidence interval [CI] of the odds ratio = 1.4–2.5) for each year of use of fluoride supplements between the ages of younger than 6 months and 7 years.¹⁴ The study by Hiller and colleagues¹⁵ found that use of fluoride supplements during the first two years of life increased the prevalence of fluorosis compared with children who did not use supplements. Pendrys and Katz¹⁷ reported that the odds ratio of fluorosis was 10.3 (95 percent CI = 1.9–61.6) in children who used fluoride supplements during the first two years of life. Bottenberg and colleagues¹⁸ found that the use of fluoride supplements and fluoridated toothpaste was associated with a slight increase in the risk of developing fluorosis. Children with fluorosis had lower odds of having caries in the primary and permanent dentitions than did children who did not have fluorosis (P < .01).¹⁸

	DISCUSSION

TOP ABSTRACT METHODS AND MATERIALS RESULTS DISCUSSION CONCLUSION REFERENCES

Fluoride supplementation and dental caries While we found that the quality of the research conducted to evaluate the association between the use of fluoride supplements and dental caries was low, we noted sufficient evidence to raise questions that the dental community should address. The evidence supports the effectiveness of fluoride tablets in preventing caries when used in school-aged children (primarily providing a topical effect).

During the first three years of life, however, there is only limited evidence regarding the effectiveness of fluoride supplements in preventing caries; we included only one such study in our review.⁴⁰ The investigators in that study used the recommended fluoride supplementation in subjects from younger than 6 months to younger than 3 years, and the findings showed significant reductions in caries. However, the study lost a high number of participants to withdrawal and therefore is potentially highly biased. Findings from the study by Leverett and colleagues,³⁹ in which expectant mothers used fluoride supplements from the fourth month of pregnancy until delivery and their children used the supplements until reaching the age of 3 years, showed no caries-preventive benefit. The researchers who conducted this clinical trial, which was performed in the 1990s, concluded that fluoride supplements were of limited additional benefit in an environment in which caries incidence is low and fluoridated dentifrices are used regularly at home.

Regarding children aged 3 years to younger than 6 years, there is inconsistent and weak evidence regarding the effectiveness of supplements on primary teeth and permanent teeth. However, in school-aged children, the evidence is consistent regarding the use of fluoride supplements.^{22,26,30,32–37} Children who chewed and swallowed 1-mg fluoride tablets daily on school days had significantly lower caries experience than did other children who did not use fluoride supplements. It is interesting to note that fluoride tablets, when chewed and swallowed, had significant preventive benefit for teeth that erupted during the studies.^{29,31–32,34–35} However, the majority of these studies were conducted at a time when fluoridated dentifrices were not used widely. The researcher who conducted one more recent study⁴¹ that focused on schoolchildren aged 12 years with high caries experience found that the daily use of fluoride supplements for five years was not effective in reducing caries.

Fluoride supplements and fluorosis Consistent evidence exists that use of fluoride supplements during the first years of life is associated with an increased risk of fluorosis. The use of supplements during the first three years of life increased the risk of developing fluorosis. There was evidence that the first year of life was the most important period for development of fluorosis.¹⁹ Pendrys¹⁶ and Pendrys and Katz¹⁷ reached similar conclusions.

It is unfortunate that there is no method of measuring fluorosis that assesses the trade-off between esthetic acceptability and the risk of developing caries. Recently, Do and Spencer⁴⁵ found that children who had mild fluorosis had quality-of-life scores higher than those of children who had caries or more advanced fluorosis. This research should be expanded to define the societal tolerance level and perceptions of fluorosis and caries. Evidence, not our professional perceptions, should guide us to decide what is acceptable by society. Research to quantify the social impact of fluorosis is lacking in the United States. It is our opinion that the increasing prevalence of fluorosis, even in its mildest forms, in the United States⁴⁶ should not be dismissed; rather, the dental community should develop programs to reduce children’s multiple exposures to fluoride products during the first three years of life. We believe that dentists should dismiss the misconception that there is a balance between caries and fluorosis, because patients can accrue the benefits of topical fluorides without developing fluorosis and without systemic intake.⁴⁷

Quality of the studies evaluating the effectiveness of fluoride supplements One consistent finding among the majority of the studies on fluoride supplements is the subjects’ low rates of compliance. The high rates at which participants withdrew from these studies overall raise a concern about the utility of advocating for this preventive regimen, which requires daily commitment from caregivers.

Like most recent dental or medical systematic reviews, our review also demonstrated that the majority of the studies were highly biased. Our major concern regarding the studies we reviewed is the high rate of subjects’ withdrawal, as well as the lack of a clear definition of allocation concealment and of how the children were examined and followed up. One of our concerns about the studies that involved schoolchildren and in which the schools were randomized into different study groups is the potential bias of the examiners. Additionally, none of the investigators analyzed their data with the schools as the unit of analysis.

	CONCLUSION

TOP ABSTRACT METHODS AND MATERIALS RESULTS DISCUSSION CONCLUSION REFERENCES

 
Fluoride supplements have been recommended for preventing caries for more than three decades. In this systematic review, we found that the evidence supporting the effectiveness of supplements in caries prevention in primary teeth is weak. In permanent teeth, the daily use of supplements prevents dental caries. The use of supplements during the first six years of life, and especially during the first three years, is associated with a significant increase in fluorosis.