Non-Invasive Methods and the Use of Infiltrating Resins for the Control of Caries Progression in Deciduous Teeth: A Systematic Review and Meta-Analysis

Non-invasive


Introduction
The current scenario regarding the diagnosis and treatment of caries lesions has been supported by the early detection and control of caries disease [1].Translational research has combined basic and applied areas supporting evidence-based dentistry [2].This has been especially important in poor regions, where resources are limited, with recent research helping identify best health practices [3].During childhood, untreated dental caries in deciduous teeth affects around 500 million children, thus, being the most prevalent chronic disease in this age group [3,4].
Caries have a complex etiology of a multifactorial nature and dependent biofilm -sucrose [5], considered a chronic-cumulative disease shaped by social and behavioral factors [6,7].Global reports demonstrate that the reduction in caries prevalence has been overestimated [8,9], especially in young children, whose incidence of early childhood caries has been linked to a public health problem worldwide [9][10][11][12].The effort to control the progression of incipient proximal caries is mandatory to avoid the circle of treatment and re-treatment, known as the 'death spiral of restorations' [13].
From this point of view, preventive and minimal intervention protocols have been proposed as an option for caries control.However, methods focused on a single or few risk factors tend to fail due to the etiological complexity of caries [11][12].Strategies such as diet control, flossing, and fluoride application are closely related to good practices in health education.However, these strategies require time, resources, and patient adherence to treatment [13].In this context, micro-invasive approaches have been gaining prominence as they depend not on the patient's behavior [9][10][11][12][13].Resin infiltration plays a prominent role and can be used up to 1/3 of the outer dentin, avoiding restorative treatment, especially on permanent teeth [11,12,14].Nevertheless, there is still a scientific gap in primary teeth, and it is necessary to evaluate the scientific evidence provided by the most recent clinical trials to verify its broad clinical recommendation.
In a recent systematic review [15], it was found that infiltrative resins can reduce the progression of caries in permanent teeth.Still, the evidence remains to be determined as to the effectiveness of this approach in primary teeth.Data on the efficacy of infiltrative resins in primary teeth are not robust in the literature, and when they are presented in meta-analysis [16], they are clustered with data from permanent teeth, which makes their interpretation and decision-making difficult.This situation emphasizes the need to conduct the present systematic review focused only on deciduous teeth.
In this regard, the present systematic literature review aims to analyze the following leading question -What is the best strategy to control the progression of incipient caries lesions in primary teeth: non-invasive treatments (diet control, biofilm control, and fluoride control) or their use combined with resins infiltration.

Protocol and Registration
The systematic review protocol was developed and registered on PROSPERO under protocol nº CRD 42021250816 and followed PRISMA's (Preferred Reporting Items for Systematic Reviews and Meta-Analyzes) [17] to guide to report this review and the Cochrane Handbook of Systematic Reviews for conducting systematic reviews of in vitro studies [18].The aim of this is to guide to report of studies.

Eligibility Criteria
This systematic review was based on the following guiding PICOS (P -incipient caries in primary teeth;

Inclusion Criteria
To properly refine the research, some inclusion criteria were defined: to have full text published, which answered the PICOS question, and clinical trials that involved incipient carious lesion (1/2 of the enamel or 1/3 of the outer dentin) in primary teeth.There were no language restrictions or period of publication.

Exclusion Criteria
Editorials, guidelines, letters, abstracts of conferences, theses, and dissertations were excluded.

Search Strategy
Keywords (MeSH and/or words) and Boolean operators were used to ensure a broader search for the subsequent analysis of the inclusion criteria.The following terms were appropriately combined and modified for each platform: "Child; Children; resin infiltrant; fluoride varnish; incipient caries; primary teeth; progression; caries development; clinical trial.The search was independently carried out by two researchers (H.C.R.A. and G.H.P.O.), and disagreements were resolved by consensus.The detailed research strategy for each platform can be consulted in the Supplementary file (Table 1).

Study Selection
In the first stage, two independent researchers performed the reading of titles and abstracts (H.C.R.A. and G.H.P.O).Duplicated studies and those that did not meet the inclusion criteria were discarded.The studies that met the inclusion criteria were selected for full reading, resulting in the selection of the articles included in this synthesis.During the searches, two other reviewers resolved disagreements (V.E.S.J. and M.V.H.).

Data Extraction
One author (H.C.R.A.) collected the information, another author (G.H.P.O.) reviewed the results, and a consensus meeting with two other authors (V.E.S.J. and M.V.H.) confirmed the data extracted.The qualitative data collected were as follows: authors, year of publication, type of study, country, sample, intervention, comparison, previous analysis of caries risk, dental surface, assessment time, outcomes, caries progression analysis method, main results, relative risk, therapeutic effect (absolute risk reduction: ARR) and preventive fraction.The preventive fraction was estimated by analyzing the occurrence of caries lesion progression in the experimental group and the control group.The formula used to obtain the calculation of the preventive fraction was PF = (Xc -Xe)/Xc, where "X" is the occurrence of caries lesion progression in each group [19].

Risk of Bias
The quality assessment of each manuscript was carried out through the Cochrane risk of bias tool (RoB 2) [18], which assesses the risk of bias taking into account the following domains: domain 1-Risk of bias arising from the randomization process; domain 2 -Risk of bias due to deviations from the intended interventions (effect of intervention assignment); domain 3 -Missing outcome data; domain 4 -Risk of bias when measuring the outcome; domain 5 -Risk of bias in the selection of the reported result.After analyzing these five domains, each study's overall risk of bias was verified.

Certainty of Evidence
The combined quality of the studies was evaluated through the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) [20] criteria system to identify any limitations, inconsistencies, indirect evidence, inaccuracies, and other relevant considerations.Through this analysis, it is possible to classify the certainty of evidence as high, moderate, low, and very low and identify the level of importance of the evidence.Only studies considered at low risk of bias or classified as having some considerations were included in this analysis.GRADE Working Group certainty of evidence: high certainty: very confident that the true effect lies close to that of the estimate of the effect.Moderate certainty: moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: confidence in the effect estimate is limited: the true effect may differ substantially from the estimate of the effect.Very low certainty: very little confidence in the effect estimate: the true effect is likely to differ substantially from the effect estimate.GRADE suggests a nine-point scale to judge the importance of evidence.The upper end of the scale, 7 to 9, identifies outcomes of critical importance.Ratings of 4 to 6 represent important outcomes but are not crucial to decision-making.Ratings of 1 to 3 are items of limited significance to decision-making.The chi-square test was applied to assess heterogeneity, with a p-value below the 10% level (p < 0.1) was considered indicative of significant heterogeneity [21].The I2 test for homogeneity was performed to quantify the extent of heterogeneity.Studies with some considerations or low risk of general bias, analyzed by ROB2, could be considered for inclusion in the meta-analysis.Random effects meta-analyses were conducted as they were considered appropriate better to approximate the expected variations in the trial environments.

Data Synthesis and Meta-analysis
Treatment effects were calculated using the relative risk (RR) for lesion progression, along with the associated 95% confidence intervals (95% CI).

Research Data
A total of 440 potentially eligible articles were found in the databases selected.Following the analysis of titles and abstracts, 46 duplicated articles were identified, which were promptly excluded.For the removal of duplicates, the endnote program was used.Out of the 394 previously eligible articles, 377 did not meet the specific objective of the present systematic review, with the remaining 17 manuscripts being analyzed thoroughly.
Subsequently, nine studies were discarded due to the following reasons: a) Adult patient or permanent teeth: (n=08); b) Different control group: (n=01).Therefore, eight studies were selected to be included in this systematic review.The references included in these eight studies (n=237) were also analyzed, though no additional manuscript was integrated into the present study (Figure 1).  1.
Table1.Individual characteristics of the studies selected for the risk of bias analysis.The certainty and importance of evidence were also analyzed in conjunction with the GRADE system.Therefore, the existence of severe inconsistencies and risks of bias was verified, as shown in Table 3.Among the issues verified were the small sample size, the need for a clearer description in the clinical trial registration of all studies, and the significant loss of samples in one of the studies.Through this assessment, it was possible to identify the certainty of available evidence on the analyzed outcome as moderate.The importance of this outcome was rated critical, i.e., there is a clear recommendation regarding the addition of infiltrating resins in non-invasive treatments to control caries lesions in primary teeth.⨁⨁⨁◯ MODERATE CRITICAL GRADE Working Group grades of Evidence; High Certainty: we are very confident that the true effect lies close to that of the estimate of the effect; Moderate Certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; Low Certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect; Very Low Certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of Effect; CI: Confidence Interval; RR: Risk Ratio; a No intention-to-treat analysis was performed; b There is a lack of clear descriptions in the clinical trial registration of all studies; c All studies report small sample; d There are sample losses due to tooth exfoliation, but it does not reach critical levels in most studies.Only in the 2-year analysis by Bagher et al., Sample loss is significant.

Meta-analyses
Six studies were included in this meta-analysis [8,11,12,[25][26][27].Two studies [23,24] were not included in the meta-analysis because they have a high risk of bias so as not to generate a confounding variable in the meta-analysis results.As for the study by Bagher et al. [26], only data referring to the initial 12 months of the research were considered, due to the high rate of losses in the 24-month interval, as referred above.The synthesis consisted of comparisons of non-invasive methods associated or not with the use of infiltrating resins for the control of caries progression in deciduous teeth.The outcomes were obtained based on the analysis of caries lesion progression using radiograph pairs.In the follow-up period of 12 months -2 years, there was a 51% risk of caries progression in the proximal surfaces in the control group, in which there was no use of infiltrating resins (0.51 [0.40-0.65])(Figure 2).No statistically significant heterogeneity was detected in the studies, with the I 2 =0 demonstrating that the studies in statistical results are homogeneous and that there was no variability.

Discussion
According to the results from the present systematic review, resin infiltration associated with noninvasive approaches is effective in arresting dental caries progression in primary teeth with incipient caries lesions (1/2 of the enamel or 1/3 of outer dentin) when compared to non-invasive methods alone, in deciduous teeth.Moreover, it is important to observe that no statistical heterogeneity was observed among the studies inserted (I 2 =%; p=0.55), enabling to cluster the data and carry out a metanalysis of such, corroborating the findings from this revision, thus suggesting the application of resin infiltration as a preferred treatment to avoid the progression of approximal caries.
Nevertheless, this conclusion should be interpreted with caution due to the qualitative (methodological) heterogeneity between the studies, namely regarding follow-up times [12,[23][24][25], the application of different caries detection criteria (ICDAS and radiograph) [22,25,26], as well as the adoption of several methods for an individual's caries risk assessment (Nyvad criteria and Caries Risk Analysis Instrument) [11,12,25,27].It is worth pointing out that the sample size in some studies [8,23] can reduce the magnitude and, consequently, the assurance of the evidence presented [28].
Caries is a sucrose biofilm-dependent oral disease with a solid multifactorial influence [29].Due to the anatomic characteristics of deciduous teeth, namely lower enamel and dentin thickness, higher permeability of these tissues, lower hardness and resistance, and greater volume of the pulp chamber, these teeth are more susceptible to dental caries, especially on proximal surfaces [30].These are possibly the reasons which hamper the carrying out of randomized clinical trials, as a result of the rapid progression of the disease, often leading to premature teeth loss [27].In addition, the lack of follow-up monitoring in the studies included in this review was due to the exfoliation of deciduous teeth [26].Therefore, an intent-to-treat analysis is inappropriate as it underestimates the results.It is of vital importance that preventive strategies based on scientific evidence should be established prematurely, aiming at reducing the risk of dental caries in early childhood, as emphasized in the Bangkok Declaration [31].It is also noteworthy that there are data on infiltrative resin for permanent teeth, and another systematic review [16], with meta-analysis, simultaneously evaluates deciduous and permanent teeth.Thus, the novelty of this review is to focus only on primary teeth.
Non-invasive treatments, namely the use of dental floss, have limited scientific findings, which prevent demonstrating the benefits of their use in preventing and reducing caries progression in deciduous teeth [28].
Nevertheless, these treatments are highly recommended as a good dental hygiene practice during childhood [32].In treating interproximal caries, resin infiltration was developed based on the highest penetrating and infiltrating power in the body of the lesion [33] compared to regular adhesive systems [30,34].Resin infiltration is a technique characterized by its rapid penetration, low viscosity, lower contact angle with the enamel, and higher surface tension [35].It is essential to point out that this technique requires greater patient cooperation, as anesthesia or the use of rotary instruments is not required, with the procedure being carried out in a single session, preserving the healthy tooth structure and paralyzing incipient caries lesions [36].
In some studies, the progression of dental caries was assessed through conventional X-rays, as the examiners did not have adequate calibration when carrying out radiograph techniques [11,[23][24][25].This can lead to positioning errors, misdiagnoses, and overtreatment [37].Others used a bitewing image with silicone material to standardize the radiographic technique [12,27].It is essential to point out that most of these studies only used radiographic parameters to assess caries lesions [11,12,23,26,27], hindering the interpretation of the results, as clinical data is essential to analyze caries progression [34].
The vast majority of the clinical trials inserted in the present review used the split-mouth design in the assessment [8,11,12,23,26,27], which is considered inappropriate due to the overlap of effects and difficulty in capturing the sample.In addition, this can limit the study's external validity [38].Therefore, parallel-arm designs are considered the "gold standard" as they are suitable to assess the outcomes considered in the present study.Besides the sample loss due to exfoliation [11,26,27], which was significant in the work carried out by Bagher et al. [26], loss due to other reasons was also observed, namely the lack of cooperation in x-ray exams [25], besides the change of address and/or loss of contact with the parents or guardians [11,27].Nonetheless, these did not compromise the results of the studies.
The qualitative evidence of this revision was assessed using the GRADE framework, which categorizes the evidence of the studies into four levels: high, moderate, low, and very low [39].The studies included were classified as moderate, thus, the true effect is close to the estimate.However, all studies presented serious inconsistencies due to the small sample size [8,11,12,23,24,26,27].The imprecision was not classified as serious, despite the significant sample loss.Nonetheless, for the purposes of the present metanalysis, only the first year analyzed in the study carried out by Bagher et al. [26] was considered, overcoming the effect of imprecision.
The present systematic review was carried out using a robust, reproducible, and detailed methodology, including the analysis of the evidence available on the use of resin infiltration in deciduous teeth through a wide range of search engines.A clear update of the data referring to the use of this material in deciduous teeth was observed, as well as the assessment of its effectiveness when combined with other prevention measures.The data of the present metanalysis consider this, establishing that resin infiltration is effective when controlling caries lesions.
However, the following limitations must be considered, namely inappropriate study design; lack of a direct comparison between resin infiltration and another micro-invasive dental material.Moreover, the effectiveness analysis was teeth-based, which minimizes the global effect and may lead to confusion due to the loss of teeth due to exfoliation or the assessment of the results using the mouth-split technique.
New studies need to be better designed and conducted in order to establish the same clinical diagnostic criteria.For example, ICDAS, as well as individualized locator instruments, need to be employed to obtain clear parameters and avoid false positives and/or negatives regarding caries progression.In particular, digital radiographs seem more suitable for this purpose due to the lower subjectivity of the software used.

Conclusion
The use of infiltrating resin to control incipient caries lesions in primary teeth (1/2 of the enamel or 1/3 of the outer dentin), when combined with non-invasive caries prevention methods, was promising and more effective than non-invasive measures used alone for the 1-year follow-up period.
Pesqui.Bras.Odontopediatria Clín.Integr.2023; 23:e220028 I -resin infiltration; or resin infiltration plus control of diet; resin infiltration plus use of fluorides; resin infiltration plus biofilm control (Flossing or oral hygiene); C -non-invasive treatments (diet control, biofilm control, and fluoride control); O -proximal caries progression; S -Clinical Trial) question: What is the best strategy to control the progression of incipient caries lesions in primary teeth: non-invasive treatments (control of diet, use of fluorides and biofilm control) or their use combined with resins infiltration?The eligible studies were identified on PubMed, Scopus, Lilacs, Open Grey, Science Direct, Web of Science, and Central Cochrane databases.
Study heterogeneity was assessed by evaluating individual study settings, inclusion and exclusion criteria, treatment methods, and data collection methods.Statistical heterogeneity was examined by visual inspection of Confidence Intervals (CIs) for estimated treatment effects on forest plots.

Figure 1 .
Figure 1.Flowchart showing the research steps and selection analysis adopted for the systematic review.

Figure 2 .
Figure 2. Random effects meta-analysis of lesion progression for experimental and control groups at 12 months-2 years.

Table 3 . The research steps and selection analysis were adopted for the systematic review. Question:
Resin Infiltrat with or without another non-invasive method [test] compared to Caries control methods [control] for progression of caries in primary teeth [problem] Setting: