Abstract
Objective
This clinical trial aimed to compare the caries-preventive effect of annual application of 38% silver diamine fluoride solution (SDF) with 5% sodium fluoride varnish (FV) to the anterior primary teeth of children. The hypothesis was that SDF was superior to FV at 1 year. Secondary objectives were to determine the child's cooperation and the parent's satisfaction and assess adverse effects.
Method
We recruited 688 3- to 4-year-old children and randomly allocated them to receive SDF or FV (positive control) on their 6 upper anterior teeth. Tooth-surface status was recorded using the decayed, missing, and filled surfaces index. A trained observer rated the child's cooperation as “totally cooperative” or “not totally cooperative.” We used a questionnaire to determine the parent's satisfaction as “satisfied,” “neutral,” or “dissatisfied.” Adverse effects (yes/no) were evaluated 1 day and about 1 year after treatment.
Results
Of the children, 434 (SDF, n = 209; FV, n = 225) completed the trial. The mean new decayed tooth surfaces developed for SDF and FV groups were 0.4 ± 1.5 and 0.4 ± 1.3, respectively (P = .65). Child's cooperation for SDF and FV therapy was 71% (244/344) and 70% (241/344), respectively (P = .89). Parent's satisfaction for SDF and FV therapy was 71% (148/209) and 69% (155/225), respectively (P = .29). Adverse effects were found neither at 1 day nor at about 1 year after treatment for either treatment arm.
Conclusions
SDF is not superior to FV for caries prevention in primary upper anterior teeth at 1-year follow-up. Child's cooperation and parent's satisfaction were similarly high with SDF and FV therapy at 1-year follow-up. Neither short-term nor long-term adverse effects were observed. This study is registered at ClinicalTrials.gov (NCT04399369).
Key words: Caries, Children, Silver diamine fluoride, Prevention, Early childhood, Oral health
Introduction
Early childhood caries is a global oral disease affecting more than 530 million children worldwide.1 The prevalence of early childhood caries was reported to be 70% to 90% in Southeast Asian countries in 2006 to 2015.2 In Hong Kong, a 2021 survey found that more than half of 5-year-old children experienced untreated early childhood caries.3 Early childhood caries may progress rapidly into the dental pulp and cause pain and infection. Moreover, chewing, nutrition absorption, physical and cognitive development, and oral health quality of life are negatively affected.4 Conventional dental treatment is largely surgical. It often requires young children to be treated under general anaesthesia, which entails risks. However, affordability, accessibility, and availability of the conventional care is inequitable in most countries. Simple, inexpensive, alternative treatments are necessary to address the high prevalence and inequity.
Clinical trials have shown that silver diamine fluoride (SDF) arrests caries lesions in young children.5,6 SDF is commonly available as a 38% solution containing approximately 255,000 ppm silver and 44,800 ppm fluoride ions.7 Silver is antimicrobial and inhibits cariogenic biofilm. Fluoride promotes remineralisation and inhibits the demineralisation of teeth. Incidental findings have suggested that SDF exerted a preventive effect on sound teeth when it was applied only on the carious lesions.5,6 SDF at 38% has the highest fluoride concentration amongst the available fluoride agents,7 approximately double that of most fluoride varnishes (FVs).8 In addition, SDF, but not FV, contains silver, which has strong antibacterial properties against cariogenic biofilm.9 Although FV has been the standard of care for caries prevention,10 SDF may be superior to FV in caries prevention. No trial has directly investigated the caries-preventive effect of SDF applied in the sound primary teeth. Thus, the primary objective of this study was to assess the preventive effect of a single SDF application. We tested the hypothesis that SDF was superior to an active control. Secondary objectives were to determine the child's cooperation and parent's satisfaction and to assess short- and long-term adverse effects on young children.
Methods
This report follows the Consolidated Standards of Reporting Trials (CONSORT) 2010 checklist.11
Trial design
This is a triple-blind, active-controlled, parallel-assigned randomised clinical trial with 1:1 allocation to 2 arms. The local Institutional Review Board (UW-20-397) approved the study. It is registered at ClinicalTrials.gov (NCT04399369).
Important change in the method
Because the new cases of COVID-19 in Hong Kong were surging during the trial in 2020, only one of the nine kindergartens allowed the one-day follow-up examination. The parents of the children in the other eight kindergartens were asked to examine the child's upper anterior teeth and surrounding soft tissue for adverse effects, which could include gingival irritation, swelling, or bleaching. They could take and send a photo via their mobile phone to the dentist for consultation if they had any questions.
Participants, settings, and location
This trial recruited healthy 3- to 4-year-old children with parental consent. Children with significant systemic diseases or who were taking regular medication such as methylphenidate were excluded. The setting was a kindergarten classroom in Hong Kong, where the water supply was fluoridated at a level of 0.5 ppm. The Water Supplies Department monitors the fluoride level and the government set up a Drinking Water Safety Advisory Committee to advise on fluoride level and drinking water safety issues.12 The first participating child was recruited and examined on September 16, 2020, and the last child was evaluated on April 30, 2022.
Questionnaire
A validated parental questionnaire was used to collect the child's oral health–related behaviours, including bottle-feeding, snack intake, and toothbrushing habits at baseline.6,13 Another parental questionnaire was used to collect parent's satisfaction at 1-year follow-up.
Clinical examination
One trained dentist performed the baseline, 1-day, and 1-year examinations. Caries experience was evaluated with the decayed, missing, and filled teeth (dmft) index, and the tooth surface status of the 6 upper anterior teeth with the decayed, missing, and filled surfaces (dmfs) index.5,14 Decayed surface was diagnosed at cavitation level according to the criteria the World Health Organization recommends.15 Child's oral hygiene was assessed using the Visible Plaque Index.16 The assistant randomly selected 10% of the children in each kindergarten visit for duplicate examination to assess intra-examiner reliability of the assessment of caries experience.
Interventions
The treatment arms were SDF and FV. The SDF group received 38% SDF solution (Advantage Arrest, Elevate Oral Care), and the FV group received 5% sodium FV (Duraphat Varnish, Colgate-Palmolive) following a trained examiner's baseline examination. An independent operator applied SDF or FV according to the group assignment. Each tooth surface (sound or decayed) of the 6 upper anterior teeth received one fluoride application with a microbrush applicator. The dentist took good care to minimise direct contact of FV and SDF with the gingivae in fluoride application. Our laboratory study showed that the amounts of SDF and FV applied per application were 5.60 mg (0.25 mg F) and 21.46 mg (0.49 mg F), respectively.17 The children refrained from eating or drinking for 30 minutes after the fluoride application.
Outcomes
The primary outcome is caries incidence at 1-year follow-up. Caries incidence was calculated based on the number of decayed surfaces developed (sound to decayed surface) in the 6 upper anterior teeth.
The secondary outcomes were the child's cooperation, parent's satisfaction, and adverse effects. A trained research assistant rated the child's cooperation with treatment using a dichotomised behavior rating scale (totally cooperative/not totally cooperative) adapted from the Venham's 6-point Behavior Rating Scale.18 A self-administered parental questionnaire was used to collect parent's satisfaction (satisfied, neutral, or dissatisfied) at the 1-year follow-up. The trained examiner evaluated adverse effects (yes/no) 1 day and about 1 year after treatment. The adverse effects included but were not limited to gum irritation, swelling, or bleaching. The trial was conducted in the midst of the COVID-19 pandemic; changes in the evaluation of the 1-day adverse effects were detailed in the above subsection of “Important change in the method.”
Sample size calculation
The data used for sample size calculation in this superiority trial were drawn from a clinical trial on preschool children.5 We estimated that the mean numbers of new decayed surfaces developed after 1 year in the SDF and FV groups would be 0.47 (SD = 0.87) and 0.70 (SD = 0.84), respectively. We set the difference in preventive effects at 33%, the statistical power at 0.90, the type I error at 0.05, and the loss to follow-up at 15%. This trial required 688 children at baseline to test the primary hypothesis. With reference to our pilot study, the power to test the secondary hypotheses on the child's cooperation (SDF 0.7 vs FV 0.8) and the parent's satisfaction (SDF 0.8 vs FV 0.9) was 0.86 and 0.96, respectively.
Randomisation: sequence generation, concealment, and implementation
An independent researcher generated the allocation sequences of the 2 strata and sealed the numbers in opaque envelopes. A field assistant conducted the treatment allocation. The trial used a stratified block randomisation method with a block size of 8. After baseline examination, the assistant assigned the children according to their caries experience (dmft) into 2 strata (without caries experience [dmft = 0] and with caries experience [dmft > 0]).
Blinding
The examiner, the children, and their parents did not know the intervention allocation.
Statistical methods
The analysis was performed using SPSS version 28.0 (IBM Corp.). For patient-level data, 2-sample t tests (or Mann– Whitney U test if data did not follow a normal distribution) were conducted to compare the mean dmft and mean number of newly developed decayed surfaces between the groups. For surface-level data, generalised estimating equations (GEE) for binary data with logit link function and exchangeable correlation were used to investigate the relationship between the intervention and incidence of decayed surfaces adjusted for possible clustering of tooth surfaces within the same child. The baseline caries score (dmft) was included to explore the adjusted effect of the intervention groups. Chi-square tests were performed to investigate the differences between groups in the distribution of the child's cooperation and parent's satisfaction. Descriptive statistics were used to report the 1-day and 1-year adverse effects. The statistical significance level was set at .05 for 2-sided tests.
Results
A total of 688 children (344 per group) from 9 kindergartens were recruited. Table 1 shows the groups’ mean (SD) dmft, mean (SD) dmfs for 6 upper anterior teeth, and mean (SD) Visible Plaque Index scores. No statistical significance between the SDF and FV groups were found for any of the variables. There was also no significant difference between the baseline parameters of the study participants who remained in the study and those who dropped out except for toothbrushing habits (Supplemental Table 1). Cohen's kappa values for measuring caries activity and caries experience were at least 0.90 in all examinations.
Table 1.
Demographic data and oral health-related behaviour of the children at baseline examination (n = 688).
| Intervention |
|||
|---|---|---|---|
| Variables | 38% SDF | 5% FV | P value |
| No. of participant children | 344 | 344 | |
| Sex, No. (%) | .76+ | ||
| Boys | 171 (50%) | 174 (51%) | |
| Girls | 173 (50%) | 170 (49%) | |
| Children's caries experience, No. (%) | .85+ | ||
| Yes (dmft > 0) | 68 (20%) | 66 (19%) | |
| No (dmft = 0) | 276 (80%) | 278 (81%) | |
| Mean dmft | 0.8 ± 2.0 | 0.7 ± 2.1 | .73* |
| Mean decayed surface of upper anterior teeth | 0.7 ± 1.9 | 0.6 ± 1.8 | .48* |
| Visible plaque index (%) | 35 ± 19 | 32 ± 19 | .58^ |
| Toothbrushing habit, No. (%) | .79+ | ||
| Once or fewer daily | 117 (34%) | 120 (35%) | |
| Twice or more daily | 227 (66%) | 224 (65%) | |
| Sugary snack intake, No, (%) | .17+ | ||
| Once or fewer daily | 210 (61%) | 227 (66%) | |
| Twice or more daily | 134 (39%) | 117 (34%) | |
| Bottle-fed before going to bed, No. (%) | .55+ | ||
| Yes | 138 (40%) | 131 (38%) | |
| No | 206 (60%) | 213 (62%) | |
Mann–Whitney U test.
Student t test.
Chi-square test.
dmft, decayed, missing, and filled teeth; SDF, silver diamine fluoride; FV, sodium fluoride varnish.
The Figure presents the CONSORT flow diagram. A total of 688 children from 9 kindergartens were recruited at baseline, and 434 children completed the trial. Because of the COVID-19 pandemic, 2 of the 9 kindergartens, with a total of 192 children (96 per group), withdrew before one-year follow-up examination. Their withdrawal accounted for the majority of children lost to follow-up (192/254, 76%). The dropout rate after 1 year was 39% (135/344) in the SDF group and 35% (119/344) in the FV group (P = .21). There was no significant difference in the baseline dmft or baseline decayed surface of upper anterior teeth between the children who completed the study and those who were lost to follow-up (P > .05).
Figure.
Consort flow diagram.
Caries-preventive effects
Table 2 shows the study's outcomes. Mean (SD) new decayed surface of the 6 upper anterior teeth after 1 year in the SDF and FV groups were 0.4 (1.5) and 0.4 (1.3), respectively (P = .65). The 2 groups had no significant difference in caries increment after 1 year (SDF, 26.8%; FV, 24.9%; P = .65). The multivariable GEE analysis found no significant difference in the incidence of new decayed surface between groups (P = .96). The clustering effect at the patient level (intraclass correlation coefficient) on the incidence of new decayed surfaces was 0.05. There was no difference in the incidence of new decayed surfaces between the 2 groups after adjusting for the baseline dmft (P = .62). The chance of having a new decayed surface after 1 year for a child with baseline caries experience (dmft > 0) was higher (P < .01; odds ratio, 1.25; 95% CI, 1.17–1.33) compared to those without caries experience (dmft = 0).
Table 2.
Outcomes of SDF and FV therapy on upper anterior teeth.
| Outcomes measure | SDF | FV | P value |
|---|---|---|---|
| Primary outcome | |||
| Caries incidence | |||
| Mean new decayed surface (n = 434 children) | 0.4 ± 1.5 (n = 209) | 0.4 ± 1.3 (n = 225) | .65* |
| Odds ratio (95% CI) of decayed surface incidence (n = 10,071 tooth surfaces in total) | 0.99 (0.59–1.64) (n = 4880) | 1 (reference) (n = 5191) | .96# |
| Odds ratio (95% CI) of decayed surface incidence (n = 10,071 tooth surfaces, adjusted for baseline dmft) | 1.15 (0.66–2.00) (n = 4880) | 1 (reference) (n = 5191) | .62# |
| Secondary outcomes | |||
| Child's cooperation (n = 688 children), No. (%) | .89+ | ||
| Children who were “totally cooperative” | 244 (71%) | 241 (70%) | |
| Children who were “not totally cooperative” | 100 (29%) | 103 (30%) | |
| Parent's satisfaction (n = 434 parents), No. (%) | .29+ | ||
| Parents who were “satisfied” | 148 (71%) | 155 (69%) | |
| Parents who were “neutral” | 59 (28%) | 70 (31%) | |
| Parents who were “dissatisfied” | 2 (1%) | 0 (0) | |
| Short-term adverse effect (n = 688 children) | |||
| 1-day adverse effect, yes/no | 0/344 | 0/344 | |
| Long-term adverse effect (n = 434 children) | |||
| 1-year adverse effect, yes/no | 0/209 | 0/225 | |
Generalised estimating equations model for binary data with logit link function and exchangeable correlation.
Mann–Whitney U test.
Chi-square test.
SDF, silver diamine fluoride; FV, sodium fluoride varnish.
Child's cooperation and parent's satisfaction
The 244 (of 344, 71%) children in the SDF group and the 241 (of 344, 70%) children in the FV group were rated totally cooperative with the operator to the fluoride therapy (P = .89). Of the parents, 148 (of 209; 71%) were satisfied with SDF treatment and 155 (of 225; 69%) were satisfied with FV treatment (P = .29).
Short-term and long-term adverse effects
No short-term (1-day) adverse effects of SDF or FV therapy were found either through the clinical examination of 78 children or from the parents’ reports of 610 children. Similarly, no long-term (1-year) adverse effects were found after SDF or FV treatment on examination of 434 children.
Discussion
The choice of study design and the implementation of this clinical trial was conducted whilst Hong Kong was enforcing its long-lasting strict dynamic “zero infection” COVID-19 strategy to halt the spread of the COVID-19. Because it is as yet unclear from available literature whether reapplying SDF is necessary to maintain the preventative effect of the first application,19 and because multiple dental visits to kindergarten is nonsensical in the midst of the COVID-19 pandemic, this clinical study chose annual SDF application.
This 1-year study is the only reported clinical trial of a single SDF treatment on sound teeth for caries prevention. Researchers employed single, biannual, or more frequent SDF applications in their study design. Horst and Heima performed a review and found no significant difference in the outcomes between once- or twice-per-year application in children with a high caries rate.19 This trial used a single annual FV treatment as the positive control.8 FV varnish is the standard of care for caries prevention.8,10 A Cochrane Review concluded that FV reduces caries experience (dmft) of primary teeth by about 37%.20 Our previous 2-year clinical trial using water as a placebo control showed that SDF and FV had similar efficacy in preventing fissure caries of primary molars.21 This 1-year study did not have a placebo because of ethical considerations.
Consistent with our previous findings, this study's results also showed no difference in the caries preventive effect between SDF and FV on upper anterior teeth. An ex vivo study showed that an application of Duraphat FV was effective in preventing demineralisation of sound enamel.22 The results imply that SDF is as effective as FV is in preventing early childhood caries on upper anterior teeth, which are the teeth that commonly develop early childhood caries in young children. Our previous study found the amount of fluoride of an application of FV was double that of 38% SDF.23 We estimated that SDF delivered an average of 4.75 mg F vs 9.31 mg F from FV to a child in this study. Although the risk of dental fluorosis of both SDF and FV therapies is very low, SDF may be a better choice than FV is for very young children, for children who require more frequent application, or for situations in which parents are concerned about fluoride toxicity.
Although the kindergarten welcomed us to provide baseline examination and fluoride therapy for the children's benefit, only a single kindergarten with 78 children permitted the 1-day follow-up examination. Parents were asked to perform the 1-day follow-up examination at home. The examination is less accurate at home compared to in kindergarten and is one of this study's limitations. Another limitation of this trial is the different assessment methods between the 1-day and 1-year follow-up. There were no complaints from parents at either follow-up. We found no adverse effects or concerns, including gingival irritation from either treatment.
Two kindergartens did not allow the 1-year examination, and their withdrawal accounted for the majority (76%) of loss to follow-up. Because the type of loss is essentially missing at random, we could handle the missing data in a way that was unbiased and statistically valid. We set a high statistical power at 0.9 to generate a large sample size of 688 children for the trial. The number of children completing this trial (434) is not far from required number of children (436) if we set the statistical power at 0.8, which most researchers generally accept.24 Therefore, the conclusion drawn from this trial is acceptable, although the loss to follow-up is greater compared with our previous clinical trials.5,6,13
Venham's Behavior Rating Scale is a measure of uncooperative behaviour developed to assess children's responses to dental stress. The results showed that the majority of the children in both groups were totally cooperative. The finding confirms our previous study results, which found high levels of positive and cooperative behaviour of Hong Kong kindergarten children.25 The dichotomised rating scale provided a high interexaminer agreement between the research assistant and an experienced paediatric dentist in calibration. In addition, we found that the dichotomised behaviour rating scale was simpler and more direct than the Venham's Behavior Rating Scale was.
SDF has a metallic taste, whereas FV is flavoured. Nevertheless, we found no differences and a high rate of child's cooperation. A previous study reported that children's experience and perception of the medication mainly influenced their rejection of or compliance with medication.26 We believe that cooperation with the SDF therapy is related to the child's perception and experience of fluoride therapy delivered. We attribute the high level of child's cooperation to teacher support and encouragement from other students. To enhance the child's cooperation with fluoride therapy for caries prevention, clinicians can provide SDF therapy in kindergarten.
We used a self-administered questionnaire to rate the parent's satisfaction. The questionnaire survey was quick, low-cost, and practical to collect responses. Moreover, the researcher could not influence the parents’ responses. We found no difference and high satisfaction with both SDF and FV. However, we have developed good relationships with kindergarten teachers and parents, which could affect parent's satisfaction with the fluoride therapies. In this study, we found that more than two-thirds of the parents were satisfied with SDF therapy. SDF therapy is affordable and requires a simple armamentarium and minimal support. In 2021, the WHO included SDF as an efficacious, safe, and cost‐effective medicine for meeting the most important needs in a health system for adults and children.27
Conclusions
This 12-month randomised clinical trial found that a single application of 38% SDF was not superior to FV for caries prevention in primary upper anterior teeth. Child's cooperation and parent's satisfaction were similarly high in SDF and FV therapy. Neither short-term nor long-term adverse effects were observed.
Author contributions
Faith Miaomiao Zheng: drafting the article or revising it critically for important intellectual content and analysis and interpretation of data. Iliana Gehui Yan: analysis and interpretation of data. Duangporn Duangthip: analysis and interpretation of data. Edward Chin Man Lo: final approval of the version to be submitted. Sherry Shiqian Gao: the conception and design of the study, acquisition of data, and final approval of the version to be submitted. Chun Hung Chu: the conception and design of the study, final approval of the version to be submitted, and funding acquisition.
Conflict of interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This research is funded by the General Research Fund (number: 17100019) of the University Grant Council, Hong Kong. The authors thank Ms Samantha Li for her statistical advice. They also thank the kindergarten teachers, the children, and their parents for their support in this study.
Footnotes
Supplementary material associated with this article can be found in the online version at doi:10.1016/j.identj.2022.12.005.
Contributor Information
Sherry Shiqian Gao, Email: sherrysgao@xmu.edu.cn.
Chun Hung Chu, Email: chchu@hku.hk.
Appendix. Supplementary materials
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