Study selection
A total of 1033 citations were initially identified after an electronic database search (1032 articles) and a manual search (1 article). The selection process was presented as a flow diagram (Fig. 1). Ultimately, 22 articles of the 17 latest studies were included (Tables 1a-b and 2), of which 9 articles were related to 4 different series of studies and 1 article compared infiltration and sealing to the control group individually [23-28, 42-57].
Characteristics of the included studies
The data from included studies were summarised in Tables 1 and 2. All of the studies were split-mouth RCTs. A total of 830 patients (ranging from 4.6 to 45 years old) were enrolled in 17 clinical trials. There were 2124 non-cavitated proximal lesions in the trials. A total of 5 studies were included that assessed lesions in the primary dentition [27, 42, 45-48], and 12 studies assessed lesions in the permanent dentition [23-26, 28, 43, 44, 49-57]. The interventions included resin infiltration (11 studies) [42-48, 50-57] and sealant (7 studies) [23-28, 49, 50]. The follow-up duration ranged from 6 to 84 months. In terms of caries risk levels, 2 studies reported high risk [25, 55, 56], 4 studies reported moderate to high risk [42, 43, 46, 48, 49], 1 study reported low to moderate risk [47], 1 study reported low or moderate risk [57], 2 studies reported low or high risk [45, 51], 3 studies reported mixed risk levels [27, 50, 52-54] and 4 studies did not report caries risk in the articles [23, 24, 26, 28, 44]. Five caries risk statuses were included in the subgroup analysis: low [51, 57], low to moderate [47], moderate [57], moderate to high [42, 43, 46, 48, 49] and high [25, 51, 55, 56]. All of the trials used radiographic lesion progression as the primary outcome. Methods for evaluating lesion progression included independent reading of radiographs, pairwise reading of radiographs and DSR. For data analysis, the most sensitive outcome was recorded if two or more evaluation methods were used in a study (outcomes obtained by DSR>pairwise reading>independent reading).
Risk of bias within studies
The risk of bias within studies was summarised in Figs. 2 and 3. Except for 3 studies with unclear risk for randomisation process due to unbalanced distribution of lesions at baseline [49, 52-54, 57], the remaining studies all had a low risk of bias [23-26, 28, 42-51]. Eight studies had some concerns due to deviations from intended interventions [26, 28, 44, 46, 47, 49-51] while 8 studies have high risk [23-25, 27, 43, 45, 52-54, 57] and 1 study has low risk [55, 56]. All of the studies had low risk for bias due to missing outcome data, measurement of the outcomes and selection of the reported results.
Heterogeneity assessment
For clinical heterogeneity, sealing and infiltration were two types of invention treatments enrolled as micro-invasive treatments. For non-invasive treatments, it differed across studies. Five studies had placebo treatments, while flossing, fluoride application and dietary advice were also set as comparators. Further, in different studies, these comparators were not combined totally and consistently. Independent reading, pairwise reading, and DSR were used as outcome assessments and varied in studies. In addition, results of bias due to deviations from intended interventions turned out to be due to inconsistency in methodological assessments. No statistical heterogeneity was found between studies (τ2=0).
Meta-regression analysis
The meta-regression analysis results revealed that different research durations (ranging from 6 to 84 months) did not influence caries progression (P>|t|: 0.620, 95% CI: -0.143 to 0.233). Thus, we chose caries progression at the longest follow-up times for continuous RCTs, similar to previous reviews [3, 13, 30].
Efficacy of infiltration and sealing for non-cavitated proximal caries
Seventeen RCTs were enrolled to assess the efficacy of infiltration and sealing for non-cavitated proximal caries. A random-effects model was used even though there was no significant statistical heterogeneity between studies (τ2 = 0.00, Fig. 4). The overall intervention effects of infiltration and sealing were significantly different from the intervention effects of the control treatment (OR = 0.23, 95% CI: 0.18 to 0.30). We analysed the two different measures (infiltration and sealing) using subgroup analysis, and we found that both invention measures reduced the odds of lesion progression compared with the control group (infiltration vs non-invasive treatments: OR = 0.21, 95% CI: 0.15 to 0.30; sealing vs placebo: OR = 0.27, 95% CI: 0.18 to 0.42).
Seventeen RCTs were related to infiltration and sealing of primary dentition or permanent dentition. There was no significant statistical heterogeneity of the included RCTs (τ2 = 0.00, Fig. 5). Non-cavitated proximal lesions were reduced when measures were undertaken in the primary dentition and permanent dentition (primary dentition: OR = 0.30, 95% CI: 0.20 to 0.45; permanent dentition: OR = 0.20, 95% CI: 0.14 to 0.28, Fig. 5).
Nine RCTs were analysed for the efficacy of infiltration and sealing at different caries risk levels (Tables 1a-b). There was no significant statistical heterogeneity among the nine RCTs (τ2 = 0.00, Fig. 6). The overall effects of infiltration and sealing were significantly different from the overall effects of control treatment (OR = 0.20, 95% CI: 0.14 to 0.28). For patients with different caries risk levels, there were significant differences between micro-invasive treatments and non-invasive treatments (low risk: OR = 0.24, 95% CI: 0.08 to 0.72; low to moderate risk: OR=0.38, 95% CI: 0.18 to 0.81; moderate to high risk: OR = 0.17, 95% CI: 0.10 to 0.29; and high risk: OR=0.14, 95% CI: 0.07 to 0.28) except for moderate risk: (OR = 0.32, 95% CI: 0.01 to 8.27). Seven RCTs were related to infiltration at different caries risk levels. There was no significant statistical heterogeneity among the seven RCTs (τ2 = 0.00, Fig. 7). In contrast to patients with moderate caries risk (OR = 0.32, 95% CI: 0.01 to 8.27), significant differences in the progression rate were found among patients who were treated with infiltration and non-invasive treatments (low risk: OR = 0.24, 95% CI: 0.08 to 0.72; low to moderate risk: OR = 0.38, 95% CI: 0.18 to 0.81; moderate to high risk: OR = 0.20, 95% CI: 0.10 to 0.39; and high risk: OR = 0.14, 95% CI: 0.05 to 0.37). Two RCTs were related to sealing across different caries risk levels. Due to insufficient patient information in terms of caries risk levels in the sealing group, no subgroup analysis was conducted.
Publication bias
For this meta-analysis, publication bias was not evaluated due to insufficient studies (fewer than 10) with clinical and methodological homogeneity.
Quality of evidence
Based on this study, infiltration or sealing arrested progression in 283 lesions per 1000 treated lesions. Infiltration arrested progression in 275 lesions per 1000 treated lesions. Sealing arrested progression in 288 lesions per 1000 treated lesions. It was downgraded one level mainly owing to a high risk of bias in half of the included studies. All of the evidence was graded as moderate (Appendix 2).