Community Dent Oral Epidemiol 2001; 29: 399411 Printed in Denmark .

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Systematic review

A systematic review of selected caries prevention and management methods

Bader JD, Shugars DA, Bonito AJ. A systematic review of selected caries prevention and management methods. Community Dent Oral Epidemiol 2001; 29: 399 411. C Munksgaard, 2001 Abstract A systematic review of the periodic scientic literature was undertaken to determine the strength of the evidence for the efcacy of professional caries preventive methods applied to high risk individuals, and the efcacy of professionally applied methods to arrest or reverse non-cavitated carious lesions. An initial search identied 1435 articles, of which 27 were eventually included in the review. Among the 22 studies addressing the prevention of carious lesions in caries-active or high risk individuals, the strength of the evidence was judged to be fair for uoride varnishes and insufcient for all other methods. Among the seven studies addressing the management of non-cavitated carious lesions, the strength of the evidence for efcacy was judged to be insufcient for all methods. The results do not indicate that the preventive and management methods reviewed are not efcacious; rather, they demonstrate that not enough is known to determine the efcacy of the methods. Suggestions for strengthening the limited evidence base involve the following: i) increasing the number of studies that examine prevention among high risk individuals and non-surgical management of non-cavitated lesions, ii) including a wider variety of subject ages, iii) targeting aspects of the efcacy questions not yet addressed, iv) strengthening research methods employed in the studies, and v) reporting methods and outcomes more completely.

James D. Bader1,2, Daniel A. Shugars1 and Arthur J. Bonito3

Operative Dentistry, School of Dentistry and Sheps Center for Health Services Research, University of North Carolina, Chapel Hill NC; 3Research Triangle Institute, Research Triangle Park, NC, USA
2 1

Key words: dental caries, prevention; tooth remineralization; cariostatic agents; uoride supplements; uorides, topical; chlorhexidine; xylitol; pit and ssure sealants Jim Bader, Sheps Center CB.7590, University of North Carolina, Chapel Hill NC 27599, USA Tel: 1 919 966 5727 Fax: 1 919 966 3811 e-mail: jim_bader/unc.edu Submitted 5 January 2001; accepted 28 February 2001

Dental caries is a chronic infectious disease that produces lesions experienced by more than twothirds of all children and more than 90% of all dentate adults in the US (1, 2). Despite being nearly universal, the disease displays a wide range of severity both in children and adults in terms of the number of tooth surfaces that are decayed and/or lled (1, 2). This uneven distribution of lesions has prompted calls for attention to the provision of caries management and prevention procedures appropriate to each individuals current disease burden, stage of carious lesions and risk for development of future lesions. In particular, attention to caries risk assessment (38) and remineralization of initial lesions (810) has been urged. Application of specic preventive treatment pro-

tocols or interventions based on assessment of current caries activity and/or level of risk for the development of carious lesions is a concept for which there has been increasing support within the dental profession. A JADA supplement prepared by the American Dental Associations Council on Access, Prevention, and Interprofessional Relations recommended the basic approach in 1995 (6). By 1998, virtually all US dental schools included lecture and clinical content on caries risk assessment and management, and more than a third mandated completion of one of more formal risk assessment/management procedures as a requirement for graduation (11). The majority of discussions urging the adoption of risk-based approaches for the management and

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prevention of dental caries do not discuss the potential efcacy of specic interventions for preventive treatment. Typically, the discussion is focused on classifying individuals risk, with the assumption being made that once the classication is made, appropriate preventive therapy will follow (7), which presumably will prove to be efcacious. The JADA supplement does list several types of procedures considered appropriate for children and adults in low, moderate and high caries risk categories, but offers no guidance for combining procedures into specic preventive interventions or estimates of efcacy (5). It is likely that the infrequent appearance of specic treatment recommendations and efcacy estimates for children and adults by risk category in the recent literature is due at least in part to a lack of knowledge of the efcacy of preventive interventions among individuals with specic caries risk classications. Most caries prevention studies are clinical or community trials with child populations selected by age or school year. Often studies are conducted among particular study populations because they reect one or more high caries risk indicators, such as lower socioeconomic status, but selection of individual study participants based on one or more individual caries risk indicators is less common. Hence, there is comparatively little information available describing the efcacy of caries management and prevention interventions among high risk individuals. Recent discussions of caries management have also stressed dentists opportunities for remineralization of initial caries lesions (8, 10, 11) but, again, these exhortations are generally not accompanied by descriptions of specic interventions or information about the efcacy of professional remineralization therapy. This information, too, may be quite scarce. Caries trials often have excluded initial lesions because of difculties they pose for both reliable detection and analysis of caries increments. There is a need to assess what is known about the efcacy of professional remineralization strategies and caries prevention interventions in cariesactive or high caries risk children and adults. Remineralization is now commonly suggested as an appropriate, if not essential, step prior to surgical intervention for non-cavitated lesions and, as noted, intensive prevention based on an assessment of high caries risk is becoming a de facto standard of practice. Yet the evidence supporting these procedures is not well-dened. This paper reports the ndings of a rigorous systematic review of the

relevant scientic literature on two focused questions important to dentists caries prevention and management efforts prevention in high-risk individuals and management of non-cavitated lesions. The review was conducted under the auspices of the Research Triangle Institute-University of North Carolina Evidence-based Practice Center, sponsored by the Agency for Healthcare Research and Quality (AHRQ) and supported by the National Institute for Dental and Craniofacial Research (NIDCR). It was intended to anchor portions of the March 2001 Consensus Development Conference on Diagnosis and Management of Dental Caries through Life. Selection of the questions to which the review was directed was guided by the Steering Committee for the Consensus Development Conference.

Methods
We developed our review methods with the help of a Technical Expert Advisory Group (see Acknowledgments). We addressed two questions involving the professional prevention and management of dental caries. The rst question asked What are the efcacies of the professional methods available for reducing the incidence of new coronal carious lesions in primary and permanent teeth among individuals who are deemed to be caries-active or at high caries risk? The second question, which was not restricted to high risk individuals, asked What are the efcacies of the non-surgical methods available for stopping or reversing the progression of a non-cavitated coronal lesion in a primary or permanent tooth? To address the two questions, we conducted a detailed search of the relevant English language literature from 1966 to October of 1999 using MEDLINE, EMBASE and the Cochrane controlled trials register. We did not pursue reports in the gray literature, dened as theses, dissertations, product reports and unpublished studies. We did hand search the most fruitful journals from 1998 to the end of 1999 to accommodate for the lag in MEDLINE postings. The search focused on dental caries preventive or management methods, using keywords for methods (uorides, topical; uoride supplements; pit and ssure sealants; health education, dental; dental prophylaxis; oral hygiene; dental plaque; chlorhexidine; xylitol; cariostatic agents) and study design, in addition to the disease key words. Our initial search of MEDLINE plus hand searching identied 1435 citations, with 43 additional citations identied through EMBASE.

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We applied several inclusion and exclusion criteria to the reports identied in our literature search. For both questions we limited studies to in vivo designs involving human subjects, excluding in situ and in vitro studies. We excluded all studies without concurrent control groups (nil, placebo, or active), but did not require any particular method of subject selection or assignment as an inclusion criterion. Because the question addressed only professional methods, we included reports involving preventive or management interventions requiring professional application or prescription, or interventions likely to be undertaken only upon the recommendation of a dentist. We specically excluded only dentifrice studies where dentifrice use was not a part of a larger intervention. Because we expected some ndings to be subgroup analyses, we did not establish a minimum sample size. For the question involving the efcacy of preventive interventions in caries-active or high risk groups, we excluded studies where such classications were not made on an individual basis. We accepted caries-active or high caries risk classications based on any combination of decayed, lled and/or missing primary and/or permanent surface or tooth scores. We also included all studies where risk was established through microbiological testing. In no instances were studies excluded due to the criterion value established for classication as caries-active or high caries risk. We excluded studies where outcomes were not expressed in terms of numbers of decayed and lled, or decayed, missing and lled surfaces or teeth. For the question involving management of noncavitated lesions, we included all studies where the lesions examined were identied as initial, incipient or non-cavitated. Because we were interested specically in the fate of these lesions, we excluded studies where the lesion was not the unit of observation and analysis. We also excluded studies where the outcome was not expressed or could not be calculated from the data provided as the percent of lesions identied at baseline that progressed. We applied the inclusion and exclusion criteria by examining titles, abstracts and, where necessary, full papers for the 1478 studies identied in the searches through dual independent reviews. The two reviewers agreed on inclusion status for 97% of the reports, with discussion leading to consensus where disagreement occurred. We included 22 studies of the efcacy of caries preventive methods

in caries-active/high risk individuals. We included ve studies of the management of non-cavitated carious lesions. Two more studies were separately identied later, and added to the review. In addition, we separately identied for inclusion six studies evaluating preventive methods in patients who had received radiotherapy for head and neck neoplasms, a special high-risk group, and seven studies evaluating preventive methods in patients with orthodontic bands or brackets, another unique high-risk group. We felt that these studies should be included in the review but not combined with the main group of studies due to substantial differences in oral environments and study methods. We abstracted data (single abstraction, subsequent independent review) from the studies, achieving a 100% agreement rates on results, and 88% for other study descriptors. We also computed a quality score for each included study using a quality rating form covering several elements of internal validity. The items and proportion of the overall score weight they represented addressed duration (15%), sample size (15%), study type (10%), blinding (10%), examiner reliability (10%), baseline assessments of differences among groups (5%), loss to follow-up (5%), previous/concurrent prevention exposure (5%), intention-to-treat analyses (5%), criteria for non-cavitated lesions (caries management study only) or proportion of population designated as high-risk (prevention study only) (5%) and reviewers subjective assessment of both internal (7.5%) and external validity (7.5%) of the study. For these latter two items, reviewers were directed to consider whether one or more threats to internal validity were present, and whether the results could be generalized beyond small, very specic populations. For most studies, quality scores could range from 0 to 20, although for some studies not all items were appropriate, and maxima of 18 and 19 were used. All scores were rescaled to a 0100 scale. We did not exclude any study based on its quality score; rather, we judged the overall strength of the evidence for efcacy based on the consistency of effects across studies, sample size, magnitude of effects and quality of the available studies. The categories for overall strength of the evidence were: O Good: Data are sufcient for evaluating efcacy. The sample size is substantial, the data are consistent and the ndings indicate that the intervention is clearly superior to the placebo/usual care alternative.

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Experimental groupa 0.04% Fr*1/day 2.2%Fv*2/year 0.7%Fv*2/year 2.2%Fv/4*year 0.2%FeAlFr*4/year 1.23%APFg*2/year 1.1%Fv*3/year 1%AFr*2/year 0.1%Fv*2/year 1%CHXg*prn 1%CHXg*4/year 1%CHXg*prn 0.05%CHXr*sp CHXv*3 in 8 months CHXv*2/year CHXv*2/year 1%CHX/Fr*1/day 1%CHXg*prn OS 1%CHXg*prnFt&Fg 0.05%CHX/0.04F/Sr*sp 0.05%CHX/0.04Fr*sp 1%CHX/0.2%Fr *2/year 1%CHXv0.1%Fv* 5% Kg*2 OS *prn Xylitol gum*3/day high risk protocol 0.9% alum rinse*1/day sugar-free gum*3/day placebo nil nil no protocol placebo nil 31 24 36 24 12 36 months months months months months months (29) (350) (66) (246) (163) (1256) nil nil nil nil nil nil 0.1%Fv*2/year 24 months (76) 36 months (17) 12 months (25) 33 months (116) 33 months (118) 36 months (106) 36 months (219) 30.4/28.01 nr/nr 94/921 nr/nr nr/nr 0/07 2.0/1.76 nr/nr 0/08 6.8/6.52 13.8/14*79 4.7/4.51 nr/nr nil placebo nil nil nil placebo placebo 22 months (31) 36 months (69) 24 months (100) 33 months (116) 24 months (9) 30 months (47) 30 months (115) 9.8/9*92 nr/nr 26.8/22.92 nr/nr 0/0 nr/nr nr/nr 2.6/3.5 2.5/4.52 3.1/6.3 3.4/3.51 33%/44% 1.8/2.75 2.4/2.25 2.9/5.1 3.9/20.81 0.2/1.7 3.5/3.81 2.5/3.81 0.6/0.7 3.8/3.0 1.8/3.51 0.1/0.5 1.7/3.5 2.2/2.6 1.6/2.0 8.3/9.31 placebo nil nil nil nil placebo 2.3%Fv*3/year placebo nil 24 36 36 24 24 24 36 60 24 months months months months months months months months months (72) (134) (140) (92) (97) (431) (249) (91) (303) 29.2/28.01 9.1/8.61 8.6/8.71 24.3/22.92 25.1/22.92 0.59/0.741 8.5/8*/91 0.6/0.73 nr/nr 4.3/5.1 4.3/6.1 4.4/4.9 5.9/6.3 5.5/6.3 2.9/3.2 4.2/4.2 1.5/2.0 1.7/2.34 15%/ns/2.5 30%/s/1.6 11%/ns/5.4 7%/ns/4.3 13%/ns/2.5 9%/s/6.7 0%/ns/ 24%/nr/10.2 25%/s/3.5 26%/ns/2.0 44%/nr/1.5 52%/s/0.6 3%/ns/6.9 25%/ns/ 33%/s/2.8 9%/ns/ 43%/s/0.9 81%/s/0.2 89%/s/0.7 8%/ns/9.2 34%/ns/2.1 13%/ns/33.5 26%/ns/ 45%/nr/1.6 88%/nr/4.4 55%/s/1.4 13%/ns/5.9 23%/ns/2.2 11%/s/3.0 Comparison group Duration (nal n) Baseline cariesb Increment exp./comp. % Reduction/ sig./NNTc Quality scored 60 50 50 55 55 80 55 60 50 40 60 55 70 25 55 55 60 45 45 70 70 40 65 40 65 70 60 65 65

Table 1. Trials evaluating the efcacy of preventive interventions in caries-active or high caries risk individuals

Bader et al.

Source (Ref.)

Fluoride studies Louma et al. (1978) (12) Sepp et al. (1982) (13) Sepp et al. (1982 (13) Lindquist et al. (1989) (14) Lindquist et al. (1989) (14) Olivier et al. (1992) (15) Sepp et al. (1994) (16) Brambilla et al. (1994) (17) Petersson et al. (1998) (18)

Chlorhexidine studies Lundstrom & Krasse (1987) (19) Gisselsson et al. (1988) (20) Lindquist et al. (1989) (14) Spets-Happonen et al. (1991) (21) Bratthall et al. (1995) (22)e Fennis-le et al. (1998) (23) Fennis-le et al. (1998) (23)

Combination studies Louma et al. (1978) (12) Zickert et al. (1982) (24) Rask et al. (1988) (25) Spets-Happonen et al. (1991) (21) Spets-Happonen et al. (1991) (21) Tenovuo et al. (1992) (26)f Petersson et al. (1998) (27)

Studies of other agents Loesche et al. (1977) (28) Sheykholeslam & Houpt (1978) (29) Isokangas et al. (1987) (30) Sepp et al. (1991) (31)g Kelber et al. (1996) (32) Beiswanger et al. (1998) (33)

Intervention abbreviations: Fr, sodium uoride rinse. Fv, uoride varnish. FeAlFr, ferric aluminum uoride rinse. APFg, acidulated phosphouoride gel. Afr, amine uoride rinse. CHXg, chlorhexidine gel. CHXr, chlorhexidine rinse. OS, occlusal sealant. Ft, uoride, topical. Fg, uoride gel. F/Sr, sodium uoride/strontium rinse. Kg, kanamycin gel. Prn, as needed. Sp, special protocol. b Caries measures: 1DMFS. 2DFS. 3DMFT. 4dfs proximal surfaces only. 5DFS on molar occlusal surfaces. 6DFS proximal surfaces only. 7dft. 8DFT on 1st molars only. 9DFS without occlusal component. c NNT, number needed to treat. d Quality score is based on a scale of 0 to 100. e Split mouth design, caries increment reported as a percent of at risk sites (molar occlusal ssures) at baseline. f Intervention applied to mothers of infants, effects measured in the infants. g Intervention consisted of protocol issued to dentists for patients classied at high caries risk.

Systematic review of selected caries prevention methods

O Fair: Data are sufcient for evaluating efcacy. The sample size is adequate, but the data show some inconsistencies in outcomes between intervention and placebo/usual care groups such that efcacy is not clearly established. O Poor: Data are sufcient for evaluating efcacy. The sample size is sufcient, but the data show that the intervention is no more efcacious than placebo or usual care. O Insufcient: Data are insufcient for assessing the efcacy of the intervention, due to limited numbers of studies, limited sample sizes and/or poor quality. The overall strength of the evidence ratings was assigned by consensus of the three authors. No formal weighting scheme was employed in making these judgments, and the preceding criteria were not elaborated.

Results
Management of caries-active/high risk individuals
Table 1 summarizes results of the 22 studies reporting 29 evaluations of preventive interventions among caries-active or high caries risk subjects. The interventions are shown in four groups, those based on uorides, chlorhexidine, combinations involving chlorhexidine and uoride or sealants, and other agents. Fluorides Nine evaluations reported in seven studies examined the efcacy of uorides for the prevention of carious lesions. All of the studies involved children as subjects; one study examined effects on primary teeth (18). The percent reductions ranged from 7 to 30% among the eight interventions where comparisons were made to placebo or no treatment. However, only three of these reductions were statistically signicant. Five of the interventions involved the use of uoride varnish. Ignoring the study that compared a half-strength formulation against the full-strength version (16), two of the remaining four evaluations showed signicant effects, one each on primary and permanent teeth (13, 18). The number needed to treat (NNT) values for the uoride varnish interventions ranged from 1.6 to 5.4. This statistic, the number of individuals who must receive the preventive intervention if one decayed surface in one individual is to be prevented in 1 year, combines percent reduction information with the caries incidence rate

among the study population, offering some insight into the practicality of the prevention method. Of the other uoride-based interventions, which included sodium, amine and ferric aluminum uoride rinses and acidulated phosphate uoride (APF) gel, only APF gel provided a statistically signicant reduction in dental caries (15). We judged the evidence for efcacy to be fair for uoride varnishes and insufcient for other uoridebased methods, based primarily on small numbers of studies of any type of intervention upon which to determine efcacy. Chlorhexidine Six studies reported seven evaluations of chlorhexidine gel, rinse and varnish preventive interventions. All of the studies were conducted among children, all evaluating efcacy on permanent teeth. Percent reductions ranged from 9 to 52%, although only two of the reductions, one gel and one rinse, were statistically signicant (14, 23), and one was untested (20). A variety of concentrations, vehicles and administration patterns were employed, so that the evidence for any particular intervention technique is limited. Chlorhexidine gel was usually applied at the beginning of the study, and again whenever microbiological testing showed an increase in mutans streptococci, while chlorhexidine varnish was applied at set intervals. We judged the evidence for efcacy to be insufcient but suggestive of efcacy for all forms of chlorhexidine, due to both the small number of studies of any particular type of intervention and the ability of those studies to demonstrate statistically signicant reductions in lesions. For example, the three studies of gels were similar in design, and yielded percent reductions from 26 to 52%, with NNTs ranging from 0.6 to 2.0, yet only one of the studies reported the effect to be statistically signicant. Combinations Six studies reported seven interventions consisting of combined application of chlorhexidine and other preventive agents. This group of studies was quite varied in terms of the strategies employed, even though in all but one instance the other agent was some form of uoride. Two of ve chlorhexidine/uoride rinses evaluated showed percent reductions of 34 and 43% with NNTs of 2.0 and 0.9 (12, 21), but only one of these results was statistically signicantly (12). The other three studies were not signicant, and presented a mixed pattern of results. A chlorhexidine/ uoride rinse with added strontium was ineffective (21), as was a rinse administered to mothers of infants with the effects determined in the infants

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Experimental treatmenta Comparison treatment placebo dye placebo dye 20 months (24) 20 months (25) 12 months (27) 12 months (19) 12 months (28) 0.12/2.511 0.04/2.511 0.27/0.352 0.02/0.352 0.81/1.122 Monthly caries Duration nal n incrementb exp./comp. %Reduction/ signicanceb 95%/s 98%/s 177%/s 94%/ns 28%/nr Quality scorec 26 26 05 05 21 1% Fg*1/day disclosing dye 1% Fg*1/day disclosing dye sucrose restriction 1% CHX/Fs*1/wk then 0.2% CHX/0.05% Fr*1/day 0.2% CHX/0.05% Fr*1/day 0.2% Fg*1/wkCaP/Fr 2/day then CaP/Fr *1/dayFg*2/year 0.4% SnFg*1/day 0.4% SnFg*1/day 12 months (125) 12 months (125) 12 months (37) 6 months (23) 0.06/0.062 0.13/0.443 0.44/0.361 0.01/0.031 0%/ns 70%/s 22%/ns 67%/ns 37 37 42 26 1.23% APF*1/wk then 0.05% Fr*1/day 1.23% APF*1/wk then 0.05% Fr*1/day 02% Fg*1/wk 0.05%Fr*2/day then 0.05% Fr*1/day 1.1% Fg*1/day then 0.04% Fg*1/day 1.1% Fg1*day then 0.04% Fg*1/day 0.4% Fg w/Xylitol *1/day 1.1% Fg*1/day 1.2% APF*1/day Then 0.4% Fg w/xylitol*1/day slow release F

Bader et al.

Table 2. Trials evaluating the efcacy of preventive intervention among individuals receiving radiotherapy

Source (Ref.)

Dreizer et al. (1977) (34) Dreizer et al. (1977) (34)

Katz (1982) (35)

Katz (1982) (35)

Makkonen et al. (1986) (36)

Al-Joburi et al. (1991) (37)

Al-Joburi et al. (1991) (37)

Spak et al. (1994) (38)

Meyerowitz & Watson (1998) (39)

Intervention abbreviations: Fg, sodium uoride gel. CHX/Fs, chlorhexidine/sodium uoride solution. APF, acidulated phosphouoride solution. Fr, sodium uoride rinse. Fg, sodium uoride gel. SnFg, stannous uoride gel. b Caries measures: 1DMFS/month. 2DFS/month. 3RCI/month. c Results of statistical testing: s, signicant. ns, not signicant. nr, not reported. d Quality score is based on a scale of 0 to 100.

Systematic review of selected caries prevention methods

Intervention abbreviations: APFr, acidulated phosphouoride rinse. CHXr, chlorhexidine rinse. Fr, sodium uoride rinse, Fd, uoride dentifrice. SnFg, stannous uoride gel. TiFt, titanium tetrauoride topical, Fv, uoride varnish. b Outcome measures: 1% of sites with demineralization. 2No. of initial lesions/subject. 3mean lesion depth. c Results of statistical testing: s, signicant. ns, not signicant. nr, not reported. d Quality score is based on a scale of 0 to 100. e Only areas under orthodontic bands included in study. Bands removed for plaque removal only in experimental group.

(26). When a combination rinse was compared to uoride alone, the uoride rinse group had an insignicantly smaller increment of disease on proximal surfaces of primary teeth (27). A combination of chlorhexidine rinse and occlusal sealants showed an 82% reduction in caries increment and a low NNT of 0.2 in a small study of 17 individuals (24). Finally, in the only study of the management of caries-active and high risk individuals conducted in adults, a combination of a chlorhexidine gel plus sodium uoride topical applications and home gels provided an 89% reduction in caries increment with an NNT of 0.7 (25). We judged the evidence for efcacy of any given combination treatment to be insufcient, again due both to limited evaluation of any one intervention and variability in outcomes, but we found this evidence generally suggestive of efcacy for combined treatment approaches. Other agents Six studies reported evaluations of other agents, including an antibiotic, occlusal sealants, an alum rinse, distribution of a high risk protocol to treating dentists, and two studies of the effects of gum. Only the two gum studies showed signicant effects. One study examined the effects of a xylitol gum (30), and the other of a sugar-free gum containing sorbitol, mannitol and aspartane (33). Both experimental interventions were conducted among 1113-year-old children and compared to no gum groups. They returned percent reductions of 55 and 11% and NNTs of 1.4 and 3.0, respectively. An evaluation of occlusal sealants returned an 88% reduction, but a NNT of 4.4 due to low caries incidence (29). No statistical evaluation was reported. We judged the evidence to be insufcient for any of these agents, none of which was represented by more than one study, although we found the evidence for the efcacy of gum-based interventions to be suggestive. Prevention in radiotherapy patients Table 2 summarizes six studies reporting nine interventions evaluated among patients receiving head and neck radiotherapy. These studies generally evaluated daily uoride or chlorhexidine interventions against alternative uoride interventions in a limited number of subjects. The two interventions tested against placebos showed signicant reductions of 95% and 98% (34). Adding calcium phosphate to a standard uoride regimen did not result in a signicant reduction (36), and brushing with a stannous uoride gel was not more effective on coronal surfaces, but signicantly more effective on root surfaces than a sodium uoride gel (37). A

Quality scored %Reduction/ signicancec Outcomeb exp./comp. Table 3. Trials evaluating the efcacy of preventive interventions on orthodontically banded teeth Comparison treatment Experimental treatmenta Source (Ref.) Duration nal n

Hirscheld (1978) (40) Lundstrom et al. (1980 (41) Lundstrom et al. (1980) (41) Lundstrom et al. (1980) (41) Holmen et al. (1988) (42)e Holmen et al. (1988) (42)e Boyd (1993) (43) Boyd (1993) (43) Buyukyilmaz et al. (1994) (44) Ullsfoss et al. (1994) (45) Ogaard et al. (1996) (46)

APFr*1/day prophylaxis 0.2% CHXr*18/year prophylaxis* 18/year 0.2%CHXr*18/year plaque removal w/cotton pellet plaque removal w/prophylaxis 0.05% Fr*1/day1100 ppm Fd 0.4%SnFg*2/day1100 ppm Fd 1% TiFt 5%Fv 0.05% Fr*1/day0.2% CHXr*2/day

nil placebo rinse placebo rinse placebo rinse nil nil nil nil nil nil 0.05% Fr*1/day

20 months (120) 24 months (30) 24 months (30) 24 months (30) 5 weeks (14) 5 weeks (14) 26 months (58) 26 months (56) 4 weeks (nr)3 4 weeks (12)3 4 weeks (29)3

15%/32%1 0.1/2.12 0.7/2.12 1.8/2.1 0%/100%1 0%/100%1 10.1/14.42 4.1/14.42 26m/41m 80m/152m 8m/26m

53%/s 95%/nr 67%/nr 15%/nr 100%/nr 100%/nr 30%/s 72%/s 37%/s 48%/s 69%/s

30 50 50 50 15 15 45 45 10 15 25

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Intervention abbreviations: APFs, acidulated phosphouoride solution, no conc. reported. SnFs, stannous uoride solution. ASN, ammoniacal silver nitrate, no conc. reported. Fr, sodium uoride rinse. Fs, sodium uoride solution. Fv, uoride varnish. OS, occlusal sealant. b Results of statistical testing: 1signicant, 2not signicant, 3not reported. c Quality score is based on a scale of 0 to 100. d Subjects rinsed 1/week for 3 weeks, and repeated the pattern once at 3 months.

Table 4. Trials evaluating the efcacy of non-surgical treatment for non-cavitated carious lesions

Hyde (1973) (47) APFs*1 Hyde (1973) (47) 8% SnFs*1 Hyde (1973) (47) ASN*1 Forsman (1974) (48) 0.025% Fr*1/week Hollender & Koch (1976) (49) 0.5% Fr*2/month Bruun et al. (1985) (50) ?% Fv (FluorPro.) *2/year de Liefde (1987) (51) 2% Fs*1/week (6 weeks)d Modeer et al. (1984) (52) 5% Fv*4/year0.2%Fr*2/month Heller et al. (1995) (53) OS

combination of daily chlorhexidine/sodium uoride rinses returned a non-signicant 94% reduction in caries in a small study with eight subjects in the experimental group (35). When this regimen was supplemented with sodium uoride gels and rinse treatments for the rst 4 weeks of the regimen, a signicant 177% reduction was found among 16 experimental subjects (35). We judged the evidence for efcacy for both uorides and chlorhexidine to be fair among individuals receiving head and neck radiotherapy. Prevention on orthodontically banded teeth Table 3 summarizes the seven studies reporting 11 evaluations of preventive interventions conducted on teeth with orthodontic bands. The studies were of two general types, short-term studies where banded teeth were extracted after 45 weeks to measure depth of demineralization, and longer-term studies evaluating the number of lesions or the percent of sites that became demineralized. In the short-term studies, titanium tetrauoride solution, sodium uoride varnish, plaque removal by swabbing and by prophylaxis, and a combination of a sodium uoride and chlorhexidine rinse all resulted in signicant reductions in mean depth of demineralization (4446) or percent of sites with demineralization (42). Among longer-term evaluations, uoride-based interventions (APF rinse, sodium uoride rinse, stannous uoride gel) all resulted in signicant reductions in percent of demineralized sites (40), or number of initial lesions per subject (43). Finally, in a study with no statistical testing of the effects, prophylaxis with and without chlorhexidine rinsing returned 95% and 67% reductions in numbers of lesions per subject (41). Overall, these studies suggest that a variety of preventive interventions may well reduce demineralization and hence carious lesions among individuals with orthodontically banded teeth. However, we judged the evidence for efcacy to be insufcient for any given method due to the small sample sizes, generally low quality scores and small number of studies per method.

Quality scorec % Reversal/signicancec comp.b comp.b exp. Experimental treatmenta exp. % Progression Duration (nal n) Comparison treatment

placebo placebo placebo 0.2% Fr*1/week placebo 0.2%Fr*2/month 2%Fs*2/year 0.2% Fr nil

24 months (192) 24 months (189) 24 months (196) 24 months (200) 36 months (900) 36 months (125) 2236 months (871) 36 months (518) 60 months (436)

51% 67% 69% 30% 24% 50% 33% 60% 11%

82%1 82%1 82%1 23%3 16%3 44%3 36%2 61%3 52%1

nr nr nr 9% 25% 0% nr 7% nr

nr nr nr 3%3 32%3 0% nr 7%3 nr

60 60 60 70 55 70 40 65 45

Management of non-cavitated carious lesions

Table 4 summarizes the results of the search for studies evaluating methods for the management of non-cavitated lesions. Unlike the studies on orthodontically banded teeth, criteria for these studies required the presence of a non-cavitated smooth surface or pit and ssure lesion at baseline. Only seven studies, which described nine evaluations, were found, all on permanent teeth in children. In

Source (Ref.)

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one study, three different solutions (APF, stannous uoride, silver nitrate) each applied once to exposed mesial proximal surfaces of rst molars all showed statistically signicant reductions in the proportion of lesions that progressed (47). However, biweekly in-school rinsing with sodium uoride solution was ineffective in preventing progression of lesions on facial surfaces (49). Weekly application of a sodium uoride solution for 3 weeks, with the pattern repeated at 3 months, was ineffective on occlusal surfaces (51). Fluoride varnish every 3 months combined with sodium uoride rinses twice per month was ineffective on posterior proximal surfaces (52). Two studies with active controls showed no difference between two concentrations of weekly uoride rinses (48) and biannual uoride varnish and uoride rinses twice each month (50). Occlusal sealants did show a signicant reduction in progression (53). These studies varied in terms of comparison groups, with placebos used in two studies, uoride rinses in four, and no treatment in another. They also varied in the criteria used to identify non-cavitated lesions, with three studies using visual criteria (49, 51, 53), and four employing radiographic criteria (47, 48, 50, 52). We judged the evidence for efcacy of any given method for arresting or reversing the progression of non-cavitated carious lesions to be insufcient for any specic type of intervention due to the small number of studies and the lack of statistical testing in most studies.

Discussion
Limitations in the evidence base
The literature on the management of dental caries in individuals considered to be caries-active or at high risk for carious lesions has several limitations. The principal shortcomings are the number of available studies for any given intervention, the variety of experimental protocols among any set of studies, the lack of studies including adult subjects and root surfaces, the meager number of studies examining effects on primary teeth, the identication of caries-active and at risk subjects, and several study design issues. For any given intervention, the number of available studies is small. Most preventive protocols have been tested in general populations, with few investigations limiting their samples to individuals with elevated caries experience or with known risk factors for caries. The lack of a focus on such cariesactive individuals is understandable because inter-

est in targeting preventive procedures at the individual level has grown only within the past decade. Nevertheless, the small number of available studies limits conclusions that can be drawn about the efcacy of any specic preventive approach among caries-active/high risk individuals. Our ability of draw conclusions about any specic preventive approach is further limited by the variation in experimental protocols. For example, uoride varnish was one of the few interventions for which we were able to rate the evidence at a level other than incomplete. Yet, among ve uoride varnish studies, three different concentrations of two different varnishes were evaluated using three different application frequencies. Comparison groups in these ve studies received three different types of treatment, and both experimental and comparison subjects received ve different patterns of additional community and individual preventive procedures during the course of the trials. The literature focuses almost exclusively on children and, among children, on permanent teeth. Only two studies of primary teeth are included in the literature, and only one of adults. The efcacy of preventive approaches on root caries among caries-active individuals is examined only in one study of radiotherapy patients. The generalizability to adults of the outcomes among children is unknown, particularly in populations with relatively high incidence rates for carious lesions. Similarly, the extent of generalizability of the results to primary teeth is unknown. The variation in the methods for identication of caries-active subjects (not shown in Table 1) reects the developmental nature of the literature on risk assessment methods for dental caries. Several approaches were employed. All enjoy some support from the literature on risk factors for dental caries, but none have been validated. The two principal methods for selecting subjects were based on mutans streptococci levels and previous or current caries experience. One study used both to form two separate post-hoc analytical groups (23). The proportions of the entire sample population included were 15% and 36%, respectively, and the outcomes of the analysis were markedly different, a signicant 33% reduction in 30-month caries incidence and a 9% increase, respectively. This observation heightens our general concern about the comparability of outcomes among subjects selected using differing criteria for caries activity. The quality scores for the studies included in the review ranged from 25 to 80, with a mean of 57.

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Bader et al.

Quality scores reected limitations in less than half of the studies with respect to subject blinding, small sample sizes, high or unreported loss to follow-up, and insufcient information or selectivity about identication of caries-active subjects. More frequent problems occurred in terms of analytical design, examiner reliability and the raters subjective assessment of internal validity. Finally, most studies did not report compliance estimates for subjects in the study, which was not a component of the quality score. The principal limitation of the literature on the management of non-cavitated carious lesions is the small number of studies. Seven comparative studies might offer sufcient evidence even if most aspects of the study designs were similar or identical. When subjects, tooth surfaces, lesion criteria, progression criteria, experimental intervention and comparison group intervention all vary across studies, it is impossible to reach any conclusions concerning the efcacy of any single method. When the results of any seven studies display as much variation in efcacy determinations as the seven included in this analysis, generalizations about the merits of the entire approach of stopping and reversing non-cavitated lesions are also not possible. The most problematic aspect among the studies included in the review was the lack of standardized criteria for initially identifying non-cavitated lesions and for assessing their progression. It is not at all clear that the lesions included in these seven studies were equivalent in terms of their depth of penetration or their activity status, and for the lesions identied initially using radiographs, whether they were in fact non-cavitated. The quality scores for the seven studies of the management of non-cavitated lesions were generally in the middle or upper part of the range of possible scores. Most of the studies did not report intra- and, when appropriate, inter-examiner reliabilities. All studies employed analyses that included only those subjects with nal exams. The loss to follow-up was either over 15% per year or unreported in four studies. Three studies did not describe other preventive dental exposures, either individual or community-based. External generalizability was judged to be limited in four studies, and internal validity was a concern in ve. Conversely, ve of the seven studies reported appropriate blinding and also indicated that, baseline assessments of treatment group equality were performed. The duration of all but one study was

2 years or more and all but one included 50 or more lesions in the smallest analysis group. None of the studies reported a power analysis, however, and four did not analyze their results statistically.

Recommendations for future research

At the most general level, additional clinical studies examining outcomes of management strategies for non-cavitated lesions and for caries-active/high caries risk patients are clearly needed. Clinicians are just beginning to evaluate carious lesions longitudinally and to delay surgical intervention until lesions are well advanced. The delay permits a period of time over which to evaluate whether a lesion is progressing or is inactive, necessitates a second evaluation that may lead to correction of initial false positive diagnoses, and offers an opportunity for non-surgical treatment to arrest or reverse progression if it is occurring. Without such treatments with proven efcacy, an important rationale for minimizing immediate surgical intervention is weakened. The same situation exists for management of caries-active patients. Clinicians are beginning to appreciate the role that risk assessment can play in the management of their patients, but again, in the absence of efcacious treatments, much of the attractiveness of risk assessment will be lost. The simplistic goal of acquiring more studies may be an inefcient solution to the problem of determining the efcacy of current methods for management of non-cavitated lesions and cariesactive individuals. For example, although there were four times as many studies reviewed for the caries-active question as for the non-cavitated lesion question, the additional studies contributed to the resolution of only one efcacy question. Investigators must be encouraged to contribute studies that ll identied gaps, build upon existing ndings and use methods that facilitate comparison across studies. The crazy quilt of intervention protocols and study designs we found in our review of studies involving caries-active/high caries risk individuals suggests that without such a scheme, much of the research effort expended on a topic will not be very useful in basic determinations of efcacy. Gap lling research and comparability could be encouraged by more emphasis by sponsors on the expectation that proposals include thorough reviews of all relevant existing studies, together with explanations of how the proposed ndings can be compared with and how they will complement the results of these studies. Compara-

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bility could also be improved through editorial review criteria that encourage rather more complete reporting of study methods and results than has been the norm in many dental trials. At a minimum, adherence to the CONSORT criteria (54) should be expected by editors as a guide for providing information about study procedures. In addition, to facilitate comparisons of caries studies, more complete descriptive information about community and individual preventive dentistry exposures is needed. Comparison group regimens for future research on preventive interventions for non-cavitated lesions should be designed so that the evaluation of the experimental intervention will describe its efcacy compared to the most commonly used alternative non-surgical treatment. Similarly, studies of preventive interventions for caries-active/high risk individuals should compare efcacy with the most common alternative preventive intervention. In both instances, the most common alternative is doing nothing unusual for the lesion or the individual, which is translated into usual care. Because usual care is seldom the same between studies, or even for all group members within a study, investigators should, at a minimum, document the professional preventive care received by each member of the comparison group. Controlling the care received by all subjects is an alternative approach, but one that could add to the cost of doing the research. In addition to specic treatment received by members of the comparison group, some of the reviewed studies indicated that experimental and comparison groups were exposed to other professional and/or community preventive dentistry regimens. Again, such exposure should be documented at the individual level. These exposures together with those accruing through participation in the comparison group should be included as covariates in the analyses. What is important is that the efcacy of the experimental intervention be evaluated under conditions that are easily generalizable to dental practice, and where all possible threats to internal validity are known, reported and, if possible, controlled. These recommendations are nothing more than an appeal to execute well-designed studies. Attention to the preceding issues, as well as to sample sizes and needed power, regimen compliance, attrition and examiner reliability would all represent needed strengthening of this literature. There is an opportunity to increase the amount of information available about management of

both non-cavitated lesions and caries-active individuals through secondary analyses of existing data. Since almost all trials of preventive agents include baseline caries assessments, secondary analyses of outcomes stratied by baseline caries prevalence are theoretically possible. Some studies may also have collected information describing other risk factors for caries, which could be used in such stratied analyses. Similarly, an unknown number of trials include initial, or D1, lesions in the examination criteria. Analyses of the fate of such lesions identied at baseline could be readily accomplished and would add to our very limited store of knowledge. Finally, the methods used to establish individuals high risk status should receive some scrutiny. As noted, criteria for high risk varied widely across the studies. In one study, the effectiveness of the preventive intervention differed with different high risk criteria. Identication of standardized, valid criteria and/or validation of criteria in individual studies through use of both high risk and low risk control groups would strengthen evaluations of efcacy among high risk individuals.

Acknowledgments
This study was developed by the RTI/UNC Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality (Contract No. 290-97-0011), Rockville, MD. We acknowledge the capable assistance of Jacqueline Besteman, EPC Program Ofces, Tina Murray, Task Order Ofcer, and Isabel Garcia, National Institute of Dental and Craniofacial Research liaison with AHRQ, for the task. We thank the Technical Expert Advisory Committee members, Craig Amundson, Ken Anusavice, Brian Burt, John Featherstone, David Pendrys, Nigel Pitts and Jane Weintraub and our consultants, Jan Clarkson, Amid Ismail, Gary Rozier and Alex White for their helpful comments throughout the review process. We acknowledge and thank Elizabeth Treasure for identifying additional studies for inclusion in the review. Finally, we thank Kathy Lohr and Jessica Nelson at RTI and Anne Jackman, Lynn Whitner, Donna Curasi, Sally Mauriello, Teg Hughes and Jessica Lee at UNC for their invaluable assistance with the project. Further information pertaining to the systematic review is available from the authors or from the AHRQ website: www.ahrq.gov

Disclaimer
The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an ofcial position of the Agency for

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Healthcare Research and Quality or the U.S. Department of Health and Human Services.

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