Tratamiento con clorhexidina para la prevención de la caries dental en niños y adolescentes
Resumen
Antecedentes
La caries dental es una enfermedad frecuente que es prevenible mediante la reducción de la ingesta dietética de azúcares libres y el uso de productos tópicos con fluoruro de sodio. Un agente antibacteriano conocido como clorhexidina también puede ayudar a prevenir la caries. Hay varias preparaciones con clorhexidina que se utilizan sin prescripción y se administran profesionalmente, en diversas formulaciones y concentraciones. Aunque las revisiones anteriores han concluido que algunas formulaciones de clorhexidina pueden ser eficaces en los niños para inhibir la progresión de la caries establecida, actualmente hay falta de pruebas que respalden o rechacen un efecto beneficioso de su uso para prevenir la caries dental.
Objetivos
Evaluar los efectos de los productos orales que contienen clorhexidina (dentífricos, enjuagues bucales, barnices, geles, chicles y esprays) sobre la prevención de la caries dental en niños y adolescentes.
Métodos de búsqueda
Se hicieron búsquedas electrónicas en el registro de ensayos del Grupo Cochrane de Salud Oral (Cochrane Oral Health Group) (25 febrero 2015), Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL; 2014, número 12), MEDLINE vía OVID (1946 hasta el 25 febrero 2015), EMBASE vía OVID (1980 hasta el 25 febrero 2015) y en CINAHL vía EBSCO (1937 hasta el 25 febrero 2015). Se hicieron búsquedas manuales en varias revistas sin aplicar restricciones de idioma en la búsqueda. Después de retirar las citas duplicadas, las búsquedas electrónicas recuperaron 1075 referencias de estudios.
Criterios de selección
Se incluyeron los ensayos controlados aleatorios (ECA) de grupos paralelos que compararon los efectos preventivos de la caries de los geles, dentífricos, barnices, enjuagues bucales, chicles o esprays de clorhexidina entre sí, placebo o ninguna intervención en niños y adolescentes. Se excluyeron los ensayos con intervenciones combinadas de clorhexidina y fluoruro o las comparaciones entre intervenciones con clorhexidina y fluoruro.
Obtención y análisis de los datos
Dos autores de la revisión extrajeron de forma independiente los datos de los ensayos y evaluaron el riesgo de sesgo. Los desacuerdos se resolvieron mediante consenso. Cuando fue necesario, se estableció contacto con los autores de los ensayos para obtener aclaraciones o información adicional de los estudios. El número de estudios incluidos apropiados para el metanálisis fue limitado debido a la diversidad clínica de los estudios incluidos con respecto a la edad, la composición de la intervención y la variación en las medidas de resultado y el seguimiento. Cuando no fue posible realizar el metanálisis, se decidió presentar una síntesis narrativa de los resultados.
Resultados principales
Se incluyeron ocho ECA que evaluaron los efectos de los barnices de clorhexidina (concentración 1%, 10% o 40%) y el gel de clorhexidina (0,12%) en los dientes primarios o permanentes, o ambos, de niños desde el nacimiento a los 15 años de edad al comienzo del estudio. Los estudios asignaron al azar a 2876 participantes, de los que se evaluaron 2276 (79%). Seis estudios se consideraron con riesgo alto de sesgo general y dos estudios con riesgo incierto de sesgo general. La evaluación del seguimiento varió de seis a 36 meses.
Seis ensayos compararon el barniz de clorhexidina con placebo o ningún tratamiento. Fue posible agrupar los datos de dos ensayos en la dentición permanente (un estudio utilizó clorhexidina al 10% y el otro al 40%). Lo anterior dio lugar a un aumento del DMFS en el grupo de barniz de 0,53 (intervalo de confianza [IC] del 95%: ‐0,47 a 1,53; dos ensayos, 690 participantes; pruebas de muy baja calidad). Solamente un ensayo (barniz de clorhexidina en concentración al 10%) proporcionó datos utilizables para los niveles elevados de estreptococos mutans cuatro con CR 0,93 (IC del 95%: 0,80 a 1,07; 496 participantes; pruebas de muy baja calidad). Un ensayo midió los efectos adversos (por ejemplo, úlceras o tinción de los dientes) e informó que no hubo; otro ensayo informó que no se observaron efectos secundarios del tratamiento. Ningún ensayo informó sobre el dolor, la calidad de vida, la satisfacción del paciente o los costes.
Dos ensayos compararon el gel de clorhexidina (concentración al 0,12%) con ningún tratamiento en la dentición primaria. La presencia de nuevas caries produjo un intervalo de confianza del 95% compatible con un aumento o una disminución de la incidencia de la caries (CR 1,00; IC del 95%: 0,36 a 2,77; 487 participantes; pruebas de muy baja calidad). De manera similar, los datos de los efectos del gel de clorhexidina sobre la prevalencia de estreptococos mutans no fueron concluyentes (CR 1,26; IC del 95%: 0,95 a 1,66; dos ensayos, 490 participantes; pruebas de muy baja calidad). Ambos ensayos midieron los efectos adversos, pero no observaron que ocurrieran. Ninguno de estos ensayos informó otros resultados secundarios como las medidas de dolor, la calidad de vida, la satisfacción de los pacientes o los costes directos e indirectos de las intervenciones.
Conclusiones de los autores
Se encontraron pocas pruebas de los ocho ensayos sobre barnices y geles incluidos en la presente revisión que apoyaran o rechazaran la afirmación de que la clorhexidina es más eficaz que el placebo o ningún tratamiento para la prevención de la caries o la reducción de los niveles de estreptococos mutans en niños y adolescentes. No hubo ensayos sobre otros productos que contienen clorhexidina como los esprays, los dentífricos, los chicles o los enjuagues bucales. Se necesitan estudios de investigación de alta calidad adicionales, en particular que evalúen los efectos sobre la dentición primaria y permanente y que utilicen otros productos orales que contienen clorhexidina.
PICO
Resumen en términos sencillos
Tratamiento antiséptico (clorhexidina) para la prevención de la caries dental en niños y jóvenes
Pregunta de la revisión
Esta revisión examinó la efectividad de los barnices y los geles que contenían clorhexidina para prevenir la caries dental en niños y jóvenes.
Antecedentes
La caries dental es una enfermedad muy frecuente que con el transcurso del tiempo destruye la superficie del diente. Se ha calculado que afecta hasta el 80% de las personas en los países de ingresos altos y, a pesar de ser prevenible mediante la higiene bucodental y medidas alimentarias y la administración de agentes como el fluoruro que reducen el riesgo de caries, es probable que aún sea un problema, especialmente en los países de bajos ingresos. La caries dental puede dar lugar a dolor e infección y en los niños pequeños, puede requerir tratamiento en el hospital bajo anestesia general. Además de causar ansiedad y dolor, puede provocar que el niño o el joven se ausente de la escuela y que sus padres o cuidadores tengan que perder horas de trabajo, con posibles pérdidas de ingresos y costes extra. La prevención de la caries dental es más sencilla y posiblemente más barata que esperar hasta que ocurra y luego necesite un tratamiento amplio.
La caries dental es en gran parte prevenible y hay varias cosas que pueden ayudar: el lavado de dientes con una crema dental fluorada dos veces al día, la reducción de la cantidad y el número de veces que se ingiere azúcar en el día y tomar agua que contenga fluoruro (embotellada o del grifo, según donde se viva).
La caries dental ocurre cuando ciertos tipos de bacterias (gérmenes) en la boca, como el Streptococcus mutans, producen ácidos a partir del azúcar que se ingiere, que disuelve el esmalte duro que recubre los dientes. El tratamiento antiséptico químico clorhexidina es muy exitoso para destruir estas bacterias y se puede utilizar con seguridad en el domicilio en forma de gel, espray, chicle, dentífrico o enjuague bucal. Alternativamente, un dentista puede aplicar la clorhexidina como un barniz a la superficie de los dientes.
Características de los estudios
Las pruebas de esta revisión, realizada a través del Grupo Cochrane de Salud Oral (Cochrane Oral Health Group), se actualizaron hasta el 25 de febrero de 2015. Se encontraron ocho estudios adecuados para su inclusión en esta revisión. En los estudios participaron 2876 niños desde el nacimiento hasta los 15 años de edad con riesgo moderado a alto de caries dental. Seis de los estudios consideraron los efectos de la aplicación por los profesionales dentales de diferentes concentraciones de barnices de clorhexidina a los dientes de los niños pequeños, los dientes permanentes o ambos tipos de dientes en niños y adolescentes. Los otros dos estudios consideraron los efectos del gel de clorhexidina aplicado por los padres en los dientes de los niños pequeños. No hubo estudios que examinaran otros productos que contienen clorhexidina como esprays, dentífricos, chicles o enjuagues bucales.
Resultados clave
Los resultados no proporcionaron pruebas de que el barniz o el gel de clorhexidina reduzcan la caries dental o las bacterias que promueven la caries dental. Los estudios no evaluaron otros resultados como el dolor, la calidad de vida, la satisfacción de los pacientes o los costos directos e indirectos de las intervenciones. Cuatro estudios midieron los efectos secundarios y no encontraron que ocurrieran.
Calidad de la evidencia
Debido a la falta de estudios adecuados y a la preocupación por el posible sesgo de los estudios incluidos, las pruebas son de muy baja calidad. Como resultado, no es posible concluir si la clorhexidina es eficaz para prevenir la caries dental en los niños o adolescentes, comparada con placebo (un sustituto inactivo para la clorhexidina) o ningún tratamiento. Se necesitan estudios de investigación futuros sobre la administración de clorhexidina para prevenir la caries dental, que deberían considerar los dientes primarios y permanentes y evaluar otros productos que contienen clorhexidina que se pueden utilizar en el domicilio como los dentífricos o los enjuagues bucales.
Authors' conclusions
Summary of findings
| Chlorhexidine varnish compared with placebo for the prevention of dental caries in children and adolescents | ||||||
| Patient or population: children and adolescents Settings: school, nursery or dental clinic Intervention: chlorhexidine varnish Comparison: placebo | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Chlorhexidine | |||||
| Caries in the primary teeth (24‐months follow‐up) | Two trials with unit of analysis problem. Data imputations indicated no evidence to claim or refute a benefit | |||||
| Caries in permanent dentition (DMFS) (30 to 36 months) Higher values indicate greater caries | The mean increment in the control group was 5.821 | The increment in the intervention groups was | ‐ | 690 (2) | ⊕⊝⊝⊝ | Chlorhexidine varnish concentration 10% varnish and 40% varnish. A further three trials provided some unusable data but indicted no evidence to claim or refute a benefit3 |
| Elevated mutans streptococci levels ≥4 with caries screen (6 to 36 months) | 620 per 10004 | 577 per 1000 | RR 0.93 (0.80 to 1.07) | 496 (1) | ⊕⊝⊝⊝ | Chlorhexidine concentration 10% varnish Two other studies reported unusable data but indicated no evidence to claim or refute a benefit6 |
| Adverse events | One study reported no adverse events for ulcers or tooth staining. One study stated “side‐effects due to the CHX treatment were not noted" | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. In the two trials that assessed this outcome, the DMFS increment in the control groups was 5.25 and 6.39, mean 5.82. This value was considered to be a moderate caries increment. 2. We downgraded the quality of the evidence due to risk of bias (high and unclear risk of bias overall) and inconsistency. 3. Conclusions reflected in remaining 3 studies (high risk of bias) with 6‐ to 24‐months follow‐up and chlorhexidine concentrations of 1% and 10%, reporting caries outcomes in permanent dentition that could not be pooled in a meta‐analysis. 4. In the single trial that assessed this outcome as presence or absence of high mutans streptococci levels, the prevalence of high mutans streptococci in the placebo varnish group was 62%. 5. We downgraded the quality of the evidence due to risk of bias (unclear risk of bias overall), imprecision and inconsistency. Mutans streptococci outcomes were reported as mean mutans streptococci levels or presence or absence of high mutans streptococci. 6. Equivocal results reported in 2 other studies (high risk of bias) with 6‐ to 24‐months follow‐up and chlorhexidine concentrations of 1% and 10%, which could not be pooled in a meta‐analysis. | ||||||
| Chlorhexidine gel compared with no treatment for prevention of caries in children and adolescents | ||||||
| Patient or population: children and adolescents Settings: all Intervention: chlorhexidine gel Comparison: no treatment | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No treatment | Chlorhexidine | |||||
| Presence of new caries in the primary teeth (24‐months follow‐up) | 16 per 10001 | 16 per 1000 (6 to 45) | RR 1.00 (0.36 to 2.77) | 487 (2) | ⊕⊝⊝⊝2 | Chlorhexidine concentration 0.12% gel |
| 70 per 1000 | 70 per 1000 (25 to 194) | |||||
| Mutans streptococci prevalence (24‐months follow‐up) | 180 per 10003 | 227 (171 to 299 | RR 1.26 (0.95 to 1.66) | 490 (2) | ⊕⊝⊝⊝4 | Chlorhexidine concentration 0.12% gel |
| 466 per 10003 | 587 per 1000 | |||||
| Adverse events (24‐months follow‐up) | Both studies reported there were no adverse events | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. Two trials assessed this outcome; the reported risk of caries in the control group was 1.6% and 6.9%. 2. We downgraded the quality of the evidence due to risk of bias (we assessed both studies to be at high risk of bias overall), imprecision of the estimate due to low numbers of events in both the control and intervention groups, and indirectness (infants administered very low daily concentration). 3. Two trials assessed this outcome; the reported risk of mutans streptococci in the control group was 46.6% and 18.1%. 4. We downgraded the quality of the evidence due to risk of bias (we assessed both studies to be at high risk of bias overall), imprecision, and indirectness. | ||||||
Background
Dental caries (tooth decay) is one of the most common diseases afflicting mankind and has been estimated to affect up to 80% of people in high‐income countries (Chadwick 2001). Dental caries is eminently preventable through a combination of oral hygiene and dietary measures and the use of anticariogenic agents, for example, water fluoridation or the use of fluoride‐containing toothpaste. Yet, notwithstanding an increased awareness of the array of preventive measures that are available, it is likely that dental caries will remain a common disease for the foreseeable future, with the prevalence being greatest in many of the low‐income countries (Yee 2002).
Description of the condition
Dental caries is a multifactorial disease in which the fermentation of food sugars by acidogenic bacteria, such as Streptococcus mutans (S. mutans), in the biofilm (dental plaque) causes localised demineralisation of tooth surfaces that can ultimately lead to cavity formation. Microbiological shifts within this biofilm can be triggered by such changes as an alteration in salivary flow or an increase in sugar consumption (Marsh 2006; Moynihan 2014; Selwitz 2007). The caries process progressively destroys and undermines tooth tissue, causing parts of the tooth to cavitate, which may eventually lead to cusp fracture under loading. Affected teeth can become painful when the lesion advances into the pulp (nerve) tissue, and if the infection passes further through the tooth, it can lead to a dental abscess. Dental caries can also have a negative impact on a child's health, particularly if the toothache is associated with a restricted dietary intake and the further possibility of impaired growth and reduced body weight (Sheiham 2006).
The prevalence and severity of caries are strongly associated with social deprivation, and as such is a concern of particular relevance to children (Sheiham 2005). In addition to causing human suffering, caries also result in a substantial financial burden that increases with recurrence of the disease process (Yee 2002). Emergency visits for dental treatment and hospitalisation can have a significant effect on a child's educational development, as well as the economy because of time lost from work by either parents or carers (Ratnayake 2005; Shepherd 1999).
Description of the intervention
Chlorhexidine gluconate is a cationic bis‐biguanide with a broad spectrum of antibacterial activity. It has been used as an antiplaque rinse for many years (Löe 1972), and its bacteriostatic and bactericidal effects on Streptococcus mutans are now well recognised (Matthijs 2002).
A number of over‐the‐counter and professionally administered chlorhexidine‐based preparations are available in a variety of formulations and a range of strengths. These include toothpastes (0.4%); mouthrinses in either alcohol‐based (ethanol) or non‐alcoholic formulations (0.12% and 0.2%); gels (1%) (Emilson 1994); thymol‐containing varnishes (1%, 10%, 20% and 35%) (Rodrigues 2008); chewing gums; and sprays (0.2%). Preparations can be administered by a dental healthcare professional (that is varnishes) or are self applied with or without supervision in the form of mouthrinses, gels and toothpastes and with wide variation in frequency of application or usage.
How the intervention might work
As dental caries is a plaque‐mediated disease, interventions based on chlorhexidine that have been shown to be effective in the growth suppression of plaque‐resident bacteria, in particular Streptococcus mutans, could form part of a strategy for the prevention of dental caries (Caufield 2001; Twetman 1998; Twetman 2004).
Although several mechanisms have been proposed, it is now widely accepted that the antimicrobial properties of chlorhexidine are directed principally at bacterial cell membrane disruption (Ribeiro 2007). In low concentrations, chlorhexidine affects the metabolic activity of bacteria and is bacteriostatic, while in high concentrations it acts as a bactericide by initiating irreversible precipitation of cellular content.
The effectiveness of any intervention may also be influenced by the nature of its formulation or mode of its application (Luoma 1992). Thus, whilst most of these formulations are likely to be equally capable of suppressing mutans streptococci on smooth enamel or proximal surfaces, the effects of chlorhexidine varnishes are likely to be longer lasting and therefore potentially more effective in pits and fissures than with the equivalent rinse or gel applications (Zhang 2007).
Why it is important to do this review
As dental caries affects an increasing number of children in many countries, its impact as a major public health issue should not be underestimated. Pain, distress, tooth loss and impaired function and growth are some of the most important sequelae.
Although laboratory studies have shown that chlorhexidine can result in reductions in the numbers of Streptococcus mutans bacteria (Järvinen 1993), dental caries is a complex process, involving other plaque species and salivary and dietary factors. Changes in the plaque ecosystem and recolonisation of tooth surfaces over time could influence the ability of chlorhexidine to prevent caries in vivo (Autio‐Gold 2008). Thus before any recommendations can be made, clinical, in‐vivo evidence is required on the effect of chlorhexidine on caries prevention.
Additionally, there is uncertainty about which formulation of oral product may provide the best mode of chlorhexidine delivery for caries prevention. Reports have claimed that chlorhexidine varnishes achieve the most persistent reduction in Streptococcus mutans, followed by gels and mouthrinses (Löe 1972), but there is still a degree of uncertainty on the comparative effectiveness of these agents (Ribeiro 2007).
Adverse effects associated with continuous usage of chlorhexidine preparations are well documented, the most common ones being temporary staining of teeth and discolouration of the tongue. Mucosal soreness and desquamation, bitter taste and temporary taste disturbances and an increase in calculus formation are also frequently reported. There are also increasing reports of immediate hypersensitivity to chlorhexidine, of the type that may result in life‐threatening anaphylaxis (Krishna 2014).
In view of the uncertainties surrounding the caries‐preventive and adverse effects of chlorhexidine‐based agents in children and adolescents, there was a need for an up‐to‐date systematic review.
Objectives
To assess the effects of chlorhexidine‐containing oral products (toothpastes, mouthrinses, varnishes, gels, gums and sprays) on the prevention of dental caries in children and adolescents.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) comparing the effects of chlorhexidine‐containing oral products with no treatment or placebo on dental caries, and comparing the effects of one chlorhexidine‐containing oral product with another. We revised our initial stipulation in the protocol that only studies reporting a treatment period of longer than one year were eligible for inclusion. Studies with a treatment period of less than one year were eligible for inclusion provided that administration of the intervention occurred at least once over that time period and that outcomes were measured at the end of the study period. To be included in the review, studies must have used explicit criteria for diagnosing dental caries, to include one or more of the following: standard visual and tactile examination with or without a supplementary radiograph or fibre‐optic transillumination.
We did not include RCTs of a split‐mouth design. The possibility of significant contamination with chlorhexidine of other sites cannot be ruled out (irrespective of the adhesiveness of the material to the tooth surface in the first hours after application).
Types of participants
Children and adolescents below the age of 18 years at the start of the study, with either mixed, permanent or primary dentition, irrespective of caries level or category of risk, socioeconomic status, health status or geographical location. We excluded studies involving participants undergoing fixed or removable orthodontic treatment.
Types of interventions
Chlorhexidine‐containing oral products such as gels, toothpastes, varnishes, mouthrinses, chewing gums and sprays compared to placebo or to no intervention (which can include routine dental care). Direct comparisons of different chlorhexidine interventions and comparisons of different concentrations of individual interventions and frequencies of application (single or multiple) were also eligible for inclusion. We excluded studies reporting only on combined interventions of chlorhexidine and fluoride, and/or comparisons between chlorhexidine and fluoride interventions.
Types of outcome measures
We have listed primary and secondary outcome measures below. These were not part of the inclusion criteria for studies in the review. We recorded the magnitude and variability of estimates of effect (for example, mean caries increment (standard deviation)).
Primary outcomes
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Caries increment at the dentine level measured by change from baseline (or final measurement where caries increment was not reported) in the decayed, (missing) and filled surface/teeth (D(M)FS/T) index in all permanent teeth or molar teeth, and d(m)fs/t for primary teeth, erupted at the start and erupting over the course of the study (following Marinho 2004). Caries incidence could also be expressed as the number of children developing caries over the course of the study. The time point of interest was at final follow‐up examination.
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Mutans streptococci bacteria, measured as a dichotomous outcome: either its presence or absence, or high or low levels.
Secondary outcomes
Secondary outcomes included measures of pain, quality of life or participant satisfaction. We also considered direct costs of interventions and any indirect costs related to materials and lost time from school or work as a result of attendance for treatment if reported. We noted any reported adverse effects related to any clinically diagnosed reactions to any of the interventions; those of specific interest included tooth staining/discolouration, soft tissue damage, hypersensitivity reactions, nausea and vomiting.
Search methods for identification of studies
Electronic searches
We developed detailed search strategies for each database we searched to identify studies to consider for this review. We based these on the search strategy developed for MEDLINE (Appendix 3), but revised appropriately for each database.
We searched the following databases:
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Cochrane Oral Health Group Trials Register (searched 25 February 2015) (Appendix 1)
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Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 12) (Appendix 2)
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MEDLINE via OVID (1946 to 25 February 2015) (Appendix 3)
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EMBASE via OVID (1980 to 25 February 2015) (Appendix 4)
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CINAHL via EBSCO (1937 to 25 February 2015) (Appendix 5)
For the MEDLINE search, we ran the subject search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity maximising version (2009 revision) as referenced in Section 6.4.11.1 and detailed in box 6.4.c of theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
We searched the US National Institutes of Health Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform (ICTRP) http://apps.who.int/trialsearch/ (until 25 February 2015) for any registered or ongoing studies (see Appendix 6).
Searching other resources
We examined the reference lists of relevant articles and attempted to contact the investigators of included studies by e‐mail to ask for details of additional published and unpublished trials and any missing trial details. We handsearched the following journals recommended by the Cochrane Oral Health Group:
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Caries Research (2003 to January 2014)
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Community Dentistry and Oral Epidemiology (January 2014)
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Journal of Dental Research (2003 to January 2014)
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Journal of Dentistry for Children (2002 to January 2014)
We attempted to contact the manufacturers of several of the relevant chlorhexidine‐based products for information about any unpublished studies, but this proved unsuccessful. It appears that the manufacturers of some of these products are no longer actively promoting their use for the prevention of dental caries in children.
We placed no language restrictions on included studies and arranged to translate any studies that were not in the English language.
Data collection and analysis
Selection of studies
Two review authors independently assessed the abstracts of records retrieved from the searches. We obtained full copies of all relevant and potentially relevant studies, including those that appeared to meet the inclusion criteria and those for which there were insufficient data in the title and abstract to make a clear decision. The two review authors independently assessed the full‐text papers and resolved any disagreements on the eligibility of included studies through discussion and consensus, or if necessary by involving a third party. We excluded all records not meeting the eligibility requirements and noted the reasons for their exclusion in the Characteristics of excluded studies section of the review.
Data extraction and management
Two review authors independently and in duplicate extracted data. Disagreements were resolved by consulting with a third review author. We entered study details into the Characteristics of included studies table in RevMan 5 and collected outcome data using a piloted data extraction form designed for this review (RevMan 2014).
We extracted the following details of study reports:
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Study characteristics: study design, country and setting, number of centres, recruitment period, funding source
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Participants: inclusion and exclusion criteria, number randomised and evaluated in each trial
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Intervention: (a) type and form of product; (b) concentration, dose and frequency; (c) duration of intervention and follow‐up
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Comparator: (a) type and form of product (b) concentration, dose and frequency; (c) duration of intervention and follow‐up
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Outcomes: primary and secondary outcomes (see Types of outcome measures) to include: diagnostic methods for caries assessment, measures of caries increment and any adverse effects
We entered study details into Characteristics of included studies tables and outcome data into additional tables or forest plots in Review Manager (RevMan) (RevMan 2014).
Assessment of risk of bias in included studies
Two review authors carried out the 'Risk of bias' assessments independently and in duplicate by following the domain‐based evaluation described in Chapter 8 of theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We compared the assessments and discussed any inconsistencies, resolving them through consensus. We assessed each included study as at low risk of bias, unclear risk of bias or high risk of bias for the following domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, completeness of outcome data, selective reporting and other sources of bias.
For this systematic review we assessed risk of bias according to the following criteria:
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Sequence generation: We will assess the use of a random number table, use of a computerised system, central randomisation, randomisation by an independent service using minimisation technique, random permuted block allocation as low risk of bias. If the paper merely states randomised or randomly allocated with no further information, we will assess this domain as unclear risk of bias.
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Allocation concealment: We will assess centralised allocation including access by telephone call or fax or pharmacy‐controlled randomisation, sequentially numbered, sealed, opaque envelopes as low risk of bias. If allocation concealment is not stated, we will assess this domain as unclear risk of bias.
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Blinding of participants and personnel: If blinding was not stated, we will assess this domain as unclear risk of bias.
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Blinding of outcome assessment: If blinding was not stated, we will assess this domain as unclear risk of bias. Where studies were described as double blind, we assumed that both participants and outcome assessors were blinded.
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Incomplete outcome data: We considered outcome data complete if all participants randomised were included in the analysis of the outcome(s). We assessed trials where 80% or more of those randomised were evaluated, where reasons for attrition or withdrawal were described for each group, and where both numbers and reasons were similar in each group, as being at low risk of bias due to incomplete outcome assessment. Where levels of attrition postrandomisation were greater than 20%, or reasons were not given for exclusions from each group, or where rates and reasons were different for each group, we assessed the risk of bias as unclear or high due to incomplete outcome data.
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Selective outcome reporting: We assessed a trial as being at low risk of bias due to selective outcome reporting if the outcomes described in the methods section were systematically reported in the results section. Where outcomes were omitted or where the outcomes were not fully reported, we assessed this domain as high risk of bias.
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Other bias: Sources of other potential bias included imbalance in potentially important prognostic factors between the groups at baseline (high risk of bias) or commercial funding of the trial (unclear risk of bias).
We categorised risk of bias in any included studies according to the following:
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Low risk of bias (plausible bias unlikely to seriously alter the results).
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Unclear risk of bias (plausible bias that raises some doubt about the results) if we assessed one or more domains as unclear.
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High risk of bias (plausible bias that seriously weakens confidence in the results) if we assessed one or more domains as high risk of bias.
Measures of treatment effect
For the primary outcome of caries increment at the dentine level measured by change from baseline (or final value where caries increment was not reported) in the decayed, (missing) and filled surface/teeth (D(M)FS/T) in permanent teeth, and d(m)fs/t for primary teeth, the effect measure was the difference in means (standardised difference in means where the same outcome was measured using different scales). The same effect measure was used for levels of mutans streptococci expressed on a continuous scale.
For dichotomous data, or for continuous data that was reported as dichotomised data, the effect measure used was the risk ratio (RR). All effect measures were accompanied by 95% confidence intervals (CI).
Unit of analysis issues
Cluster‐randomised trials, that is groups of individuals randomised to intervention or control, were identified in the searches and were checked for unit‐of‐analysis errors based on the advice provided in Section 16.3.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Where a unit‐of‐analysis error existed, and re‐analysis was not possible, we reported point estimates alone (no CIs or P values). Where re‐analysis was possible, we used intraclass correlation coefficient values (0, 0.05, 0.1, 0.2) to calculate the appropriate design effect and adjust the standard error of the effect estimate accordingly.
Dealing with missing data
Where possible, we attempted to contact authors of the included studies to obtain any missing trial details and data. We did not carry out imputations for missing data.
Assessment of heterogeneity
We assessed clinical heterogeneity by examining the similarity across the studies of the summary participant characteristics, the interventions and the outcomes as specified in the criteria for included studies section of this review. Clinical diversity between the studies meant that opportunities for pooling of the extracted data were limited. Where pooling was indicated, we assessed statistical heterogeneity using the Chi2 test and I2 statistic to quantify the percentage of the variability in effect estimates that was due to heterogeneity rather than sampling error (Higgins 2011).
Assessment of reporting biases
If we had identified a sufficient number of trials for inclusion in this review, we would have assessed publication bias according to the recommendations on testing for funnel plot asymmetry described in Section 10.4.3.1 of the Cochrane Handbook for Systematic Reviews of Interventions (Egger 1997; Higgins 2011). If we had identified asymmetry, we would have assessed for other possible causes and explored these further in the discussion if appropriate.
Data synthesis
Where sufficiently homogeneous data to inform a clinically important question were available, we performed a quantitative meta‐analysis using RevMan (RevMan 2014). We used the fixed‐effect model to pool effect estimates where only a small number of studies were identified per comparison and heterogeneity was low. We calculated a pooled estimate of effect together with the corresponding 95% CI. In future updates where data are not limited, we will use a random‐effects model provided it is appropriate to pool the data (as assessed by clinical and statistical heterogeneity).
Subgroup analysis and investigation of heterogeneity
If we had included a sufficient number of studies in this review and identified statistical heterogeneity between the studies, we had planned to evaluate the caries preventive effects of the interventions for the following factors:
-
Caries risk at baseline
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Modes of administration of chlorhexidine‐containing products (toothpastes, mouthrinses, varnishes, gels, gums and sprays)
Due to a lack of suitable data from the included studies we were unable to do a subgroup analysis, but we will consider carrying this out if further data are available from studies included in future updates of this review.
Sensitivity analysis
We did not carry out a sensitivity analysis in this review for the reasons mentioned previously. For future updates, if there are sufficient included studies, we plan to conduct sensitivity analyses to assess the robustness of our review results by repeating the analysis with the following adjustments: exclusion of studies with unclear or inadequate allocation concealment, unclear or inadequate blinding of outcomes assessment and unclear or inadequate completeness of follow‐up.
Summary of findings and assessing the quality of the evidence
We developed a 'Summary of findings' table for each comparison and for the main outcomes of this review following GRADE methods and using GRADEpro software (GRADE 2004). We assessed the quality of the body of evidence regarding the overall risk of bias of the included studies, the directness of the evidence, the inconsistency of the results, the precision of the estimates and the risk of publication bias. We categorised the quality of the body of evidence of each of the main outcomes for each comparison as high, moderate, low or very low.
Results
Description of studies
See Characteristics of included studies and Characteristics of excluded studies.
Results of the search
Electronic searches retrieved 1762 records, which reduced to 1075 after de‐duplication. After examination of the titles and abstracts of these references, we discarded all of those that did not match our inclusion criteria and were clearly ineligible. We obtained full‐text copies of the remaining 45 studies for further evaluation. Of this number, we found eight studies (reported in 12 publications) eligible for inclusion and excluded 33 studies. Handsearching of journals and reference lists of review articles did not yield any additional articles. We searched the World Health Organization International Clinical Trials Registry Platform (ICTRP) and the ClinicalTrials.gov databases up to February 2015 but identified no ongoing trials. We have illustrated the study flow in a PRISMA diagram, see Figure 1.
Our electronic searches also retrieved citations for two studies that none of the previous systematic reviews had identified (Bretz 1997; Nordling 1999). Through e‐mail we were able to reach the principal investigator in Bretz 1997,who clarified some of the study details that were missing from this report. This investigator also provided us with an additional published version of the study, which we had not identified in any of our searches. The citation for Nordling 1999 consisted of a conference proceedings abstract; there were no further references to this study in the literature. We contacted the principal investigator, who indicated that the full study had never been published but provided us with an electronic copy of the complete report. As this was in the Swedish language, we arranged for the translation of the report prior to further assessment.
Results of searching for studies for inclusion in the review
Included studies
This review included eight RCTs (Baca 200X; Bretz 1997; De Soet 2002; Du 2006; Forgie 2000; Nordling 1999; Plonka 2013; Pukallus 2013), published between 1997 and 2013, that randomised 2876 children and provided data for 2276. We have provided details of the included studies in the Characteristics of included studies table. None of the included studies comprehensively addressed all of the primary and secondary outcomes specified in the protocol for this review.
Design
Six RCTs had a parallel design and randomisation at the individual level (Bretz 1997; De Soet 2002; Forgie 2000; Nordling 1999; Plonka 2013; Pukallus 2013). Two studies used randomisation at the cluster level (school class) with a parallel design (Baca 200X; Du 2006), justifying this as a mechanism to minimise contamination of the outcome between the intervention and comparator arms of the study. However, as these studies were analysed without taking into account the clustering of pupils within a class, it is likely that the precision of the effect estimate in these studies will be too narrow.
Setting
Three studies were principally carried out in school settings in Spain, China and Scotland (Baca 200X; Du 2006; Forgie 2000, respectively). The settings for the other trials were an orphanage in Rio de Janeiro in Brazil (Bretz 1997), a district polyclinic in Sweden (Nordling 1999), a youth dental care centre in Surinam, South America (De Soet 2002) and in the family home in Australia (Plonka 2013; Pukallus 2013).
The providers of treatment in the studies were either university dental hospital or dental care centre staff or parents, and the assessors of outcomes were the investigators and healthcare providers. The provider of treatment was unclear in Nordling 1999 and Bretz 1997. Treatment was delivered by a dentist in the Baca 200X and Du 2006 studies, by a dental nurse in De Soet 2002, a dental therapist or hygienist in Forgie 2000 and by a parent in Plonka 2013 and Pukallus 2013.
The shortest period of follow‐up was 6 months (Bretz 1997); the longest was 36 months (Forgie 2000). Four studies followed up participants for 24 months (Baca 200X; Du 2006; Nordling 1999; Plonka 2013; Pukallus 2013) and one study followed up participants for 30 months (De Soet 2002).
Characteristics of the participants
Children from birth to 15 years with a moderate to high risk for caries participated in the included studies. The total sample size comprised 2876 children and adolescents with a comparable gender distribution in each of the studies aside from Bretz 1997, in which only females participated. Four of the included studies evaluated caries in the permanent dentition only (Bretz 1997; De Soet 2002; Forgie 2000; Nordling 1999); one study evaluated caries in both the primary and permanent dentition (Baca 200X); and three studies evaluated caries in the primary dentition alone (Du 2006; Plonka 2013; Pukallus 2013).
Baseline caries levels varied in the included studies. Two studies in children up to two years started before the eruption of any teeth, therefore there were no baseline caries (Plonka 2013; Pukallus 2013). For the two studies with participants aged four to seven years, the baseline caries level was comparable: the mean decayed and filled surfaces (dfs) was 3.48 in the untreated group and 4.40 in the active intervention group (Baca 200X); baseline mean decayed, missing or filled molar surfaces (dmfs‐molar) was 2.6 in the placebo group and 2.8 in the active intervention group (Du 2006). Four studies included older children, ranging in age from 10 to 15 years. Where baseline caries was reported as decayed, missing and filled teeth/surfaces, participants were classified as "moderately caries active", with a mean decayed, missing or filled surfaces (DMFS) of 3.83 from clinical exam alone, at the D3 threshold (De Soet 2002), and "high caries risk", with a mean DMFS of 6.64 in the placebo varnish group and 7.26 in the active varnish group from clinical exam and bitewing radiographs, also at the D3 threshold (Forgie 2000). The baseline data were incompletely reported in the remaining two studies with older participants (Bretz 1997; Nordling 1999).
The participants in two of the studies had access to continuing dental care either through the community dental services (Forgie 2000) or from the dental nurse at the dental care centre (De Soet 2002). However, whilst considerable dental treatment was provided in the first year for the participants in Forgie 2000, the investigators in De Soet 2002 indicated that not all children were able to access restorative treatment during the first year. The participants in Nordling 1999 received routine restorative treatment and prophylaxis. Although Bretz 1997 did not report the accessibility to ongoing dental care, the investigators indicated that not all of the participants had existing carious lesions restored during the study period. No organised oral healthcare programmes for preschool children were available in three studies (Du 2006; Plonka 2013; Pukallus 2013), and one further study reported that the children received no preventive treatment before or during the study period (Baca 200X).
Characteristics of the interventions
The active interventions in the trials consisted of concentrations (1%, 10%, 40%) of chlorhexidine varnish, each with a different application regimen, and one formulation of chlorhexidine gel at a concentration of 0.12%. Four studies used placebo varnish as a comparator; the other four studies used a comparator group of no treatment (Baca 200X; Bretz 1997; Plonka 2013; Pukallus 2013).
0.12% concentration gel
In the studies by Plonka 2013 and Pukallus 2013, parents of infants in the treatment group were instructed to apply a pea‐sized amount of the chlorhexidine gel onto a clean index finger and smear it onto the child's teeth after the evening toothbrushing with 0.304% fluoride toothpaste.
1% concentration varnish
In the study by Baca 200X, a thin coat of chlorhexidine varnish (1% chlorhexidine, 1% thymol) was professionally applied to all teeth during the first week and every 3 months until the end of the study at 24 months. In the study by Nordling 1999, six coatings of chlorhexidine varnish (1% chlorhexidine, 1% thymol) were professionally applied every four months over two years.
10% concentration varnish‐sealant
In the study by Bretz 1997, a 10% formulation of chlorhexidine varnish‐sealant was professionally applied once or twice (with an interval of a week between) at the start of the study and at the three‐month recall appointment (though frequency of application was varied according to S. mutans levels). In a later study of longer duration, the same intervention was professionally applied every week for a month and then at 3‐ and 6‐month intervals until the study's completion at 36 months (a maximum of 12 repeat applications) (Forgie 2000).
40% concentration varnish
In the study by De Soet 2002, chlorhexidine varnish was professionally applied as a 40% concentration every six months. In Du 2006, a chlorhexidine varnish of 40% chlorhexidine acetate in a sandarac resin was applied at the start of the study and every six months thereafter.
Oral instructions following professional application of the active interventions and placebo varied between studies. In Baca 200X, participants were discouraged from eating or drinking for three hours and were not allowed to brush their teeth for the first day or use dental floss for one week. In De Soet 2002, toothbrushing to remove the varnish was allowed after 10 minutes, whereas in Forgie 2000 participants were discouraged from any tooth cleaning for 24 hours and advised to refrain from flossing for 3 days. The participants in Nordling 1999 were instructed to avoid eating for three hours and to refrain from toothbrushing until the following day, whereas in Bretz 1997 participants were permitted to continue routine oral hygiene measures.
Characteristics of the outcome measures
All of the studies carried out clinical assessments of dental caries. Caries was measured using continuous measures as decayed and filled teeth/decayed and filled surfaces (DFT/DFS) on first permanent molars (Baca 200X), as decayed, missing and filled permanent teeth (DMFT) (Forgie 2000), as decayed, missing and filled primary molar surfaces (dmfs‐molar) (Du 2006) or as percentage of surfaces that were sound, decayed, restored or had white‐spot lesions (Bretz 1997). Plonka 2013 and Pukallus 2013 used dichotomous presence or absence of caries increment, as well as the mean number of carious teeth in each group. The only data provided in Nordling 1999 was that a "caries assessment" was carried out.
There was variability between the studies' assessment of dental caries, that is the time intervals between assessments, and whether these were solely clinical with a mirror and probe (Baca 200X; De Soet 2002; Du 2006; Pukallus 2013) or were supplemented by radiographs (Nordling 1999) or fibre‐optic transillumination and radiographs (Forgie 2000). Bretz 1997 did not provide the method of examination, and Plonka 2013 was not explicit about method.
Five studies also reported microbiological outcomes of mutans streptococci levels (Bretz 1997; De Soet 2002; Forgie 2000; Plonka 2013; Pukallus 2013). Salivary mutans streptococci levels were determined by classifying the number of colony forming units (cfu) per ml of saliva, in De Soet 2002, or per dip‐slide, in Bretz 1997, into categories ranging from 0 to greater than 105 cfu, in De Soet 2002, and 0 to greater than 106 cfu, in Bretz 1997. One study dichotomised the mutans streptococci levels as high or low, using a threshold of 250,000 cfu per ml of saliva (Forgie 2000), and two studies dichotomised the mutans streptococci outcome as presence or absence in saliva (Plonka 2013; Pukallus 2013).
Four studies reported that no adverse events were observed (De Soet 2002; Du 2006; Plonka 2013; Pukallus 2013); none of the other four studies reported that they had measured the occurrence of adverse events.
None of the included studies reported outcome measures of pain, quality of life, participant satisfaction or costs.
Excluded studies
We have listed all of the studies that were excluded from this review and the reasons for their exclusion in the 'Characteristics of excluded studies' table.
Risk of bias in included studies
We assessed six studies as at high risk of bias overall, resulting from a judgement of high risk of bias for at least one domain. We judged the remaining studies as at unclear risk of bias overall ( Du 2006 ; Forgie 2000). Concealment of the allocation sequence and blinding of outcome assessors are key domains in the assessment of risk of bias; none of the studies provided sufficient detail to enable the assessment of allocation concealment, and in five studies we assessed blinding of outcome assessors as low risk of bias.
For further details, see the 'Risk of bias' graph in Figure 2 and 'Risk of bias' summary in Figure 3.
'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies
'Risk of bias' summary: review authors' judgements about each domain for each included study
Allocation
Method of randomisation
In four studies the method of randomisation to treatment or control groups was stated clearly: "randomly divided the children into two groups, based on the class they attended, by drawing a card from a bag" (Du 2006); by drawing colour‐coded sticks from an opaque bag (Plonka 2013; Pukallus 2013); or using a computer‐generated random number sequence (Bretz 1997, with additional details following request to authors). In the other four studies the methods used to randomise participants were not clearly described: the participants "were assigned randomly to an experimental group and a control group" (De Soet 2002); "randomised into one of four groups" with stratification prior to randomisation by gender, baseline caries experience, and history of eczema (Forgie 2000); "divided into two groups by randomisation, computer printouts with the children in birth order were used as input" (Nordling 1999 as translated); two classes in five schools were selected and the classes in each school were randomly allocated (Baca 200X). We judged the risk of bias as unclear in these four studies where was insufficient information reported about the method used to generate the randomisation sequence to permit judgement.
Allocation concealment
Due to inadequate reporting, indicated by uncertainty as to whether adequate measures had been taken to ensure that the investigators were unaware of the upcoming treatment or control assignment, we were not able to make a judgement of low or high risk of bias for this domain in seven of the studies (Baca 200X; Bretz 1997; De Soet 2002; Du 2006; Forgie 2000; Plonka 2013; Pukallus 2013). In the remaining study (Nordling 1999), the "code was locked in the department's safety deposit box," and thus we gave a judgement of low risk of bias for this domain.
Blinding
In one study (Baca 200X), neither the outcome assessor nor the participants were blinded, and so we judged the study to be at high risk of bias for both these domains. We judged three studies to be at low risk of bias for both domains (De Soet 2002; Du 2006; Forgie 2000), as they explicitly reported the blinding of participants using a placebo comparator and assessors were blinded to group allocation.
We judged Nordling 1999, a placebo‐controlled trial, as being at low risk of bias for blinding of participants, while we judged Bretz 1997, with a no‐treatment comparator, as at high risk of bias. Neither of these studies mentioned the blinding of outcome assessors, so we gave a judgement of unclear risk of bias for this domain. We assessed Plonka 2013 and Pukallus 2013 as at high risk of performance bias due to use of a no‐treatment comparator, but at low risk of detection bias, as clinical outcome assessment was blinded.
Incomplete outcome data
We assessed attrition bias as low where there was small loss to follow‐up, balanced across groups, in De Soet 2002; Forgie 2000; Plonka 2013, and unclear where loss to follow‐up was low for reasons not likely to be related to the outcome, but where there was insufficient supporting information on loss to attrition to enable a judgement to be made (Baca 200X; Du 2006). Where reported overall losses to follow‐up were large (Nordling 1999: 28% attrition over 24 months, described by the investigators as "unexpectedly large"; Bretz 1997: 26.5% over 6 months; Pukallus 2013: 40% over 24 months), we judged such studies to be at high risk of bias.
Selective reporting
Although the study protocols were unavailable for all of the included studies, based on information presented in the methods sections of each of the reports, we have concluded that the investigators appear to have reported on all of their stated objectives and fully reported the expected outcomes of relevance to this systematic review in five studies (Baca 200X; Du 2006; Forgie 2000; Plonka 2013; Pukallus 2013). We judged risk of bias from selective reporting as high where the expected outcome measure of mean DFT/DFS was either not reported (Bretz 1997 presented results as percentage of sound, decayed, restored surfaces and white‐spot lesions) or inadequately reported (Nordling 1999 reported no standard deviations for caries outcome; De Soet 2002 reported no numerical estimates of levels of mutans streptococci and variability, presenting this information in graphs only).
Other potential sources of bias
The investigators in two of the trials reported receiving funding from the manufacturers of one of the chlorhexidine varnishes ( De Soet 2002 ; Forgie 2000 ). Although no details were provided regarding the extent, if any, of the sponsors' involvement in the conduct of the trial or the analysis of data, we found no evidence suggesting this funding might bias the results, and so we judged these studies as unclear on this domain. Similarly, the principal investigator in Bretz 1997 confirmed in an e‐mail that "the study was supported by a grant from Somcana International Canada", but provided no further details. In Nordling 1999, the manufacturer supplied the active and placebo varnishes, but we found no evidence in the report to suggest that this might present a potential source of bias. However, there was substantial baseline imbalance in caries levels in this study, which we consequently judged as at high risk of bias. No other potential sources of bias were reported in the four remaining studies (Baca 200X; Du 2006; Plonka 2013; Pukallus 2013).
Effects of interventions
See: Summary of findings for the main comparison Summary of findings ‐ chlorhexidine varnish; Summary of findings 2 Summary of findings ‐ chlorhexidine gel
Chlorhexidine varnish compared with no treatment or placebo
Six studies, two at unclear risk of bias and four at high risk of bias, compared chlorhexidine varnish with no treatment or placebo, and evaluated 1786 children. Two studies involving 471 children reported on this comparison in the primary dentition (Baca 200X at high risk of bias, and Du 2006 at unclear risk of bias); five studies involving 1232 children reported effects on the permanent dentition (Baca 200X; Bretz 1997; De Soet 2002; Forgie 2000; Nordling 1999). Due to the wide variation in chlorhexidine concentration used in the studies and variation in outcome measures and length of follow‐up, we were unable to pool many of the studies.
Primary outcome: caries
Primary dentition
Data for the two studies reporting caries in the primary dentition are presented in Table 1. When we re‐analysed the cluster‐randomised studies using a range of intraclass correlation coefficients to take into account the clustering, we found no statistically significant difference in mean d(m)fs/t‐molar increment between the groups (Baca 200X; Du 2006).
| Study ID | Intervention(s) and comparator | Outcome | Summary Intervention | Summary Comparator | Comment |
| Cervitec (1% chlorhexidine, 1% thymol) varnish applied 4 x year (n = 86) No treatment (n = 95) | Mean dft‐molar increment (24 months) Mean dfs‐molar increment (24 months) | Varnish 0.97 (SD 1.45) Varnish 2.21 (SD 2.96) | No treatment 0.94 (SD 1.50) No treatment 2.54 (SD 3.40) | Authors report "..the incidence of caries lesions at 24 months showed no significant differences between the 2 groups... Among the children who were caries free at the onset of the study, those in the varnish group showed a significantly lower incidence of caries lesions in teeth (P < .05) and on surfaces (P < .05) of primary molars at 24 months compared with those in the control group. On the other hand, among the children with dft > 0 at baseline, there were no statistically significant differences between the varnish and control groups." Statistical analysis did not take into account the cluster randomisation by school class. Inflation of the standard error of the effect estimate through a design effect with ICCs of 0.05, 0.1 and 0.2 would lead to the same conclusions as those reported | |
| 40% w/w chlorhexidine acetate in a sandarac resin applied 2 x year (n = 155) Placebo alcohol solution of sandarac resin (n = 135) | Mean dmfs‐molar increment (24 months) | Varnish 1.0 (SD 2.49) | Placebo 1.6 (SD 2.32) | Authors report "The mean caries increment of the primary molars was 1.0 dmfs‐molar in the test‐group children and 1.6 dmfs‐molar in the placebo group. The difference of 0.6 tooth surfaces...was statistically significant (p = 0.036)." Statistical analysis did not take into account the cluster randomisation by school class. Inflation of the standard error of the effect estimate through a design effect with ICCs of 0.05, 0.1 and 0.2 resulted in a non‐statistically significant result. ICC 0 MD ‐0.6 (95% CI ‐1.16 to ‐0.04) ICC 0.05 MD ‐0.6 (95% CI ‐1.71 to 0.51) ICC 0.1 MD ‐0.6 (95% CI ‐2.27 to 1.07) ICC 0.2 MD ‐0.6 (95% CI ‐3.38 to 2.18) | |
| Curasept (0.12%) chlorhexidine gel applied 1 x daily (n = 61) No treatment (n = 58) | Caries incidence (24 months) | Gel 3/61 | No treatment 4/58 | Authors report "These differences were not statistically significant (p = 0.7)." RR 0.71 (95% CI 0.17 to 3.05) | |
| Curasept (0.12%) chlorhexidine gel applied 1 x daily (n = 180) No treatment (n = 188) | Caries incidence (24 months) | Gel 4/180 | No treatment 3/188 | Authors report "The differences were not statistically significant (p = 0.66)." RR 1.39 (95% CI 0.32 to 6.14) |
CI: confidence interval
dfs‐molar: decayed and filled molar surfaces (primary)
dft‐molar: decayed and filled molar teeth (primary)
dmfs‐molar: decayed, missing and filled molar surfaces (primary)
ICC: intraclass correlation coefficient
MD: mean difference
RR: risk ratio
SD: standard deviation
Permanent dentition
Two studies evaluated the effects of 1% chlorhexidine with 1% thymol varnish. One study compared this to no treatment (Baca 200X), and one study compared this to placebo (Nordling 1999) (Table 2). Children ranged in age from 6 to 15 years, and the studies were carried out in an educational setting. We have presented the results from the 723 children analysed in Table 2. Both studies reported on caries increment. When we re‐analysed the cluster‐randomised study using a range of intraclass correlation coefficients to take into account the clustering (Baca 200X), we found no statistically significant difference in mean DFT/S‐molar (decayed or filled molar teeth or surfaces) increment between the chlorhexidine and no‐treatment groups. In the Nordling 1999 study, the mean DFS increment was slightly higher in the placebo group (1.9) than in the varnish group (1.8), but we were unable to analyse further due to the lack of standard deviations reported.
| Study ID | Intervention(s) and comparator | Outcome | Summary intervention | Summary comparator | Comment |
| Cervitec (1% chlorhexidine, 1% thymol) varnish applied 4 x year (n = 86) No treatment (n = 95) | Mean DFT increment (24 months) Mean DFS increment (24 months) | Varnish 0.88 (SD 1.25) Varnish 0.95 (SD 1.38) | No treatment 1.30 (SD 1.50) No treatment 1.85 (SD 2.27) | Authors report "There was a significant difference in the increase in caries on surfaces at 24 months between the two groups.... However, when we consider the teeth (DFT index), although the increment was smaller in the varnish group (0.88) versus controls (1.30), the difference did not reach statistical significance." Statistical analysis did not take into account the cluster randomisation by school class. Inflation of the standard error of the effect estimate through a design effect with ICCs of 0.05, 0.1 and 0.2 resulted in a non‐statistically significant result for both outcomes. ICC 0 MD ‐0.42 (95% CI ‐0.82 to ‐0.02) ICC 0.05 MD ‐0.42 (95% CI ‐1.17 to 0.33) ICC 0.1 MD ‐0.42 (95% CI ‐1.51 to 0.67) ICC 0.2 MD ‐0.42 (95% CI ‐2.20 to 1.36) ICC 0 MD ‐0.9 (95% CI ‐1.45 to ‐0.35) ICC 0.05 MD ‐0.9 (95% CI ‐1.92 to 0.12) ICC 0.1 MD ‐0.9 (95% CI ‐2.40 to 0.60) ICC 0.2 MD ‐0.9 (95% CI ‐3.34 to 2.18) | |
| Cervitec (1% chlorhexidine, 1% thymol) varnish applied 3 x year (n = 271) | Mean DFS increment (24 months) | Varnish 1.8 (no SD reported) | Placebo 1.9 (no SD reported) | No re‐analysis possible due to incomplete reporting | |
| Chlorzoin 10% chlorhexidine applied after 3 months (n = 43) No treatment (n = 40) | Mean % of sound surfaces (6 months) | Varnish 114.3 (SD 12.4) | No treatment 116.3 (SD 11.8) | Caries data presented as " dental decay parameters" i.e. % of sound, decayed, restored surfaces only. The trial reported that for all participants "...treatment groups were not predictors of dental decay parameters after 6 months" and for those participants treated as instructed at baseline examination "No significant differences on dental decay parameters were found between T and C groups at the 6 month examination". | |
| Chlorzoin 10% chlorhexidine applied 4 x year (n = 222) Placebo (n = 274) | Mean DMFS increment (36 months) | Varnish 6.83 (SD 6.17) | Placebo 6.39 (SD 6.41) | Authors reported "...the clinical trial failed to reject the null hypothesis of no difference in caries‐reducing efficacy between active and placebo chlorhexidine varnishes." (MD 0.44, 95% CI ‐0.67 to 1.55) | |
| 40% chlorhexidine varnish (EC40®) applied 2 x year (n = 99) Placebo: neutral gel without chlorhexidine (n = 95) | DMFS (30 months) | Varnish 6.16 (SD 10.01) | Placebo 5.25 (SD 6.03) | Authors reported "...no significant effect of CHX treatment on DMFS (p > 0.5)." (MD 0.91, 95% CI ‐1.40 to 3.22) |
CHX: chlorhexidine
CI: confidence interval
DFS: decayed and filled surfaces
DFT: decayed and filled teeth
DMFS: decayed, missing and filled surfaces
ICC: intraclass correlation coefficient
MD: mean difference
SD: standard deviation
One study evaluated the effects of 40% chlorhexidine compared with placebo in children aged 13 to 14 years, in a dental clinic (De Soet 2002). We have presented the results from the 194 children analysed in Table 2. The study reported no statistically significant caries preventive effect of 40% chlorhexidine varnish compared to placebo.
Two studies evaluated the effects of 10% chlorhexidine compared with no treatment or placebo (Bretz 1997; Forgie 2000, respectively), in children aged 10 to 15 years in a residential and school setting. We have presented the caries results from the 579 children analysed in Table 2. The Bretz 1997 study presented the caries data as "dental decay parameters". The authors reported no statistically significant differences in dental decay at six‐month follow‐up. In the Forgie 2000 study, the mean difference in DMFS increment between the chlorhexidine varnish and placebo groups was 0.44 (95% CI ‐0.67 to 1.55). On this basis, we were unable to exclude the possibility that 10% chlorhexidine varnish has no caries preventive effect.
Pooling data from two of the studies with the caries increment outcome of DMFS at 30 (De Soet 2002) or 36 months (Forgie 2000) follow‐up indicated an imprecise result of no appreciable difference between the chlorhexidine and placebo groups (mean difference 0.53, 95% CI ‐0.47 to 1.53; 690 participants; Analysis 1.1).
Primary outcome: mutans streptococci
Three studies reported on mutans streptococci (Bretz 1997; De Soet 2002; Forgie 2000; Table 3). A statistically significant difference in mutans streptococci levels was observed at 6 months in favour of chlorhexidine (Bretz 1997; Forgie 2000), but this finding was not replicated at longer follow‐up of 12, 24 and 36 months (Forgie 2000) (Analysis 1.2). De Soet 2002 also measured mutans streptococci, but did not fully report numerical estimates of mutans streptococci levels at the end of the study period and intermediate measurements, just "no significant differences between the two treatment groups" (Table 3).
| Study ID | Intervention(s) and comparator | Outcome | Summary intervention | Summary comparator | Comment |
| Chlorzoin 10% chlorhexidine applied after 3 months (n = 43) No treatment (n = 40) | Mean MS (6 months) | Varnish 2.9 (SD 1.5) | No treatment 4.1 (SD 1.3) | Authors report "After 6 months the C group exhibited significantly higher levels of the mutans streptococci when compared to the T group." (MD ‐1.20, 95% CI ‐1.80 to ‐0.60) | |
| Chlorzoin 10% chlorhexidine applied 4 x year (n = 222) Placebo (n = 274) | Number of participants with elevated MS levels Cariescreen® ≥ 4 (high) (36 months) | Varnish 129/224 | Placebo 169/272 | Authors report that Chlorzoin varnish "was not able to ensure continually low MS levels" following an initial benefit in favour of the active intervention observed at 3 and 6 months. This was not maintained at longer follow‐up at 12, 24 and 36 months. At 36 months there was no evidence of lower MS levels in the active varnish group (RR 0.93, 95% CI 0.80 to 1.07) | |
| 40% chlorhexidine varnish (EC40®) applied 2 x year (n = 99) Placebo: neutral gel without chlorhexidine (n = 95) | MS (30 months) | Not reported | Not reported | Numerical estimates of MS levels at the end of the study and intermediate data collection points not presented. Authors report "...no significant differences between the two treatment groups on these microbiological measures (p < 0.2)" |
CI: confidence interval
MD: mean difference
MS: mutans streptococci
RR: risk ratio
Secondary outcomes
No studies reported on pain, quality of life, patient satisfaction or costs. One study reported on adverse events: no adverse events such as ulceration or other mucosal lesions or tooth staining were observed during the course of the study (Du 2006). De Soet 2002 reported that “side‐effects due to the CHX treatment were not noted".
We judged the quality of the evidence for the outcomes of caries and mutans streptococci to be very low (summary of findings Table for the main comparison).
Chlorhexidine gel compared with no treatment or placebo
Two studies, both at high risk of bias, compared chlorhexidine gel with no treatment (Plonka 2013; Pukallus 2013), randomising 490 children.
Primary outcome: caries
Primary dentition
Both studies reported the incidence of caries (Plonka 2013; Pukallus 2013), the pooled best estimate of effect being 1.00 (RR 1.00, 95% CI 0.36 to 2.77; Analysis 2.1) at 24 months. On the basis of these analyses, we were unable to exclude the possibility that chlorhexidine gel has no caries preventive effect.
Primary outcome: mutans streptococci
Both studies reported on the levels of mutans streptococci (Plonka 2013; Pukallus 2013) (Table 4). The pooled best estimate of effect was 1.26 (RR 1.26, 95% CI 0.95 to 1.66; Analysis 2.2) at 24 months. On the basis of this analysis, we were unable to exclude the possibility that chlorhexidine gel has no effect on the presence or absence of mutans streptococci.
| Study ID | Intervention(s) and comparator | Outcome | Summary Intervention | Summary Comparator | Comment |
| Curasept (0.12%) chlorhexidine gel applied 1 x daily (n = 61) No treatment (n = 58) | MS prevalence (24 months) | Gel 28/61 | No treatment 27/58 | Authors report "Percentages of children with MS present were not significantly different between CHX and controls (P = 0.2)" RR 0.99 (95% CI 0.67 to 1.45) | |
| Curasept (0.12%) chlorhexidine gel applied 1 x daily (n = 180) No treatment (n = 188) | MS prevalence (24 months) | Gel 49/183 | No treatment 34/188 | Authors report "No statistically significant differences were present, however, at later ages." P = 0.05 RR 1.48 (95% CI 1.01 to 2.18) |
CHX: chlorhexidine
CI: confidence interval
MS: mutans streptococci
RR: risk ratio
SD: standard deviation
Secondary outcomes
Neither study reported on pain, quality of life, patient satisfaction or costs; however, both studies reported on adverse events: no adverse events such as ulceration or other mucosal lesions or tooth staining were observed during the course of the studies (Plonka 2013; Pukallus 2013).
We judged the quality of the evidence for the outcomes of caries and mutans streptococci to be very low (summary of findings Table for the main comparison).
Discussion
Summary of main results
Eight studies met the inclusion criteria for this review, all evaluating the effects of chlorhexidine varnishes or gels on the primary or permanent teeth of children and adolescents. We assessed the quality of the body of evidence with reference to the risk of bias of the included studies, the directness of the evidence, the consistency of the results (heterogeneity), the precision of the effect estimates and the risk of publication bias (GRADE 2004). We have provided a summary of this quality assessment in the 'Summary of findings' tables, separately for chlorhexidine varnish (summary of findings Table for the main comparison) and chlorhexidine gel (summary of findings Table 2) dentitions. We assessed the body of evidence for both as very low quality.
We evaluated three separate concentrations (1%, 10%, and 40%) and formulations of chlorhexidine varnish in six studies, each with a different application regimen. We evaluated one concentration (0.12%) of chlorhexidine gel in two studies.
In the permanent dentition, pooled estimates were possible for the effects of 40% and 10% chlorhexidine varnish on caries increment and 10% chlorhexidine varnish on mutans streptococci levels. We judged the quality of this body of evidence to be very low. The 95% confidence limits for the pooled effect sizes were compatible with both an increase or a decrease in caries.
Pooled estimates from two studies were possible for the effects of 0.12% chlorhexidine gel in the primary dentition on caries incidence and mutans streptococci levels. We judged the quality of this body of evidence to be very low. The 95% confidence limits were compatible with both an increase or a decrease in both caries and mutans streptococci levels.
Due to variation in the measurement of outcomes and incomplete or inadequate reporting, we were unable to pool much of the data.
It was not possible to pool the data on the outcome 'caries' from the following comparisons:
-
40% chlorhexidine varnish against placebo in the primary dentition (Du 2006)
-
1% chlorhexidine and 1% thymol varnish against no treatment in both the primary and permanent dentitions (Baca 200X)
-
1% chlorhexidine and 1% thymol varnish against placebo in the permanent dentition (Nordling 1999)
-
10% chlorhexidine varnish against no treatment in the permanent dentition (Bretz 1997)
It was not possible to pool the data on the outcome 'mutans streptococci' from the following comparisons:
-
10% chlorhexidine varnish against no treatment in the permanent dentition (Bretz 1997)
-
40% chlorhexidine varnish against placebo in the permanent dentition (De Soet 2002)
When we carried out re‐analysis to take into account the effect of clustering in the cluster‐randomised trials (Baca 200X; Du 2006), we found uncertainty surrounding the effect estimates, with the 95% confidence intervals including both the possibility of benefit and harm at the longest follow‐up point of the study. Of the above five studies, we judged four to be at high risk of bias and one to be at unclear risk of bias.
We found some evidence from two of the studies that using chlorhexidine‐containing varnishes according to the manufacturers' recommended protocols resulted in early reductions in mutans streptococci levels at 3 and 6 months in the permanent dentition, but this effect was not sustained at longer periods of follow‐up at 12, 24 and 36 months. It should also be noted that mutans streptococci levels is a proxy outcome, and that it is unclear how reductions would translate into any effect on caries prevention, due to the effects of other cariogenic oral bacteria (for example Lactobacillus species), recolonisation from reservoirs or retention sites that were not affected by the chlorhexidine or the possibility of the development of resistance to chlorhexidine over time.
Four studies reported on adverse events (De Soet 2002; Du 2006; Plonka 2013; Pukallus 2013); none were recorded over a period of 24 or 30 months. No studies reported on the other secondary outcomes of pain, quality of life, patient satisfaction, or direct or indirect costs.
After evaluation of the available evidence, it has not been possible to either claim or refute a benefit of chlorhexidine varnishes or gels for the prevention of caries in the primary or permanent dentitions.
Overall completeness and applicability of evidence
We found no studies that assessed chlorhexidine‐based mouthrinses, toothpastes, chewing gums or sprays for the prevention of dental caries in children and adolescents. All available RCTs evaluated the effects of chlorhexidine varnishes or gels.
Due to the different formulations of chlorhexidine products used, the variation in measurement of outcomes, and the incomplete reporting of outcome data, it was not possible to pool the results of many of the studies that we included in this review. Individual studies were typically small in size and at high or unclear risk of bias.
Of particular concern is that four of the eight included studies did not report adverse events. Known adverse effects of chlorhexidine include staining of the teeth and tongue, mucosal soreness and desquamation, temporary taste disturbances, parotid gland swelling and hypersensitivity (including anaphylaxis) (BNF 2015; Krishna 2014). Although rare, there have been cases of death due to anaphylaxis associated with chlorhexidine, therefore it is extremely important that the body of evidence addresses both benefits and risks of any intervention. As no eligible studies addressed patient satisfaction, pain, quality of life, or direct or indirect costs of the intervention, the evidence is incomplete regarding these outcomes.
Only three studies gave an indication of the population exposure to fluoride. Two studies reported the level of fluoride in the water supply, and one study stated that the use of fluoride toothpaste in the area was uncommon. Lack of information on contextual factors limits the external validity of the evidence base.
Quality of the evidence
The evidence that we have evaluated does not permit us to draw any conclusions regarding the effects of chlorhexidine varnish or gel on the prevention of dental caries. Neither the pooled estimates nor the estimates from the individual studies produced statistically significant effect sizes. We judged the overall quality of the evidence to be very low, meaning that we are very uncertain about any estimates of effect (GRADE 2004).
Of the eight studies included in this review, we judged six to be at high risk of bias and two to be at unclear risk of bias. For the studies at high risk of bias, the most common issue was with blinding of participants and personnel (performance bias). Incomplete outcome data (attrition bias) and selective reporting (reporting bias) were the next most common reasons for judging studies to be at high risk of bias. For example, although the studies included sizeable numbers of children, five of the eight studies did not consistently and fully report losses to follow‐up, leading to the possibility of attrition bias. Furthermore, of the two studies at unclear risk of bias, unclear reporting of allocation concealment (selection bias) was common to both studies. In addition to this risk of bias, we downgraded the quality of the evidence due to imprecision (low numbers of events), inconsistency, and indirectness of the studies to the review question.
Potential biases in the review process
As two of the included studies (Bretz 1997; Nordling 1999), which were unpublished and retrieved in our comprehensive electronic searches, were not cited in any previous systematic reviews, the existence of other unpublished studies and the possibility of publication bias cannot be ruled out.
Agreements and disagreements with other studies or reviews
The most recent previous systematic review on the topic of chlorhexidine varnish for preventing dental caries in children and adolescents also concluded that the evidence “is inconclusive" (James 2010). This review included 12 trials with inclusion criteria that were different than this Cochrane review in that studies of a split‐mouth design or with fluoride therapies as a comparator were eligible for inclusion.
An earlier literature review (that is not a systematic review) on “the use of chlorhexidine for caries prevention” concluded that "chlorhexidine rinses should not be recommended for use in caries prevention due to a current lack of evidence” and that the evidence on the effectiveness of chlorhexidine gels and varnishes was "suggestive but incomplete" (Autio‐Gold 2008). As a literature review and not a systematic review of randomised clinical trials, the inclusion and exclusion criteria were not strictly defined, and the authors also considered studies using chlorhexidine‐fluoride combinations as the intervention.
A systematic review by Zhang 2006a of the caries‐inhibiting effect of chlorhexidine varnishes on the permanent dentition of children, adolescents and young adults included 10 studies, several of which we excluded from our Cochrane review because they used split‐mouth design (Bratthall 1995; Haukali 2003; Joharji 2001; Zhang 2006), or the participants included children receiving orthodontic treatment (Madlena 2000), or concomitant fluoride applications were made (Fennis‐le 1998). The authors “tentatively conclude[ed] that CHX varnish has a moderate caries inhibiting effect when applied every 3‐4 months”, but that this effect is diminished around “two years after the last application”.
Another (non‐systematic) review found 20 studies addressing caries outcomes in children and adolescents (and two studies investigating maternal chlorhexidine application to reduce caries in infants) (Twetman 2004). The authors included trials with the outcomes of root caries, white‐spot lesions and mother‐child transmission of S. mutans and intervention protocols utilising fluoride and split‐mouth designs. This review also found the evidence to be inconclusive for the use of “chlorhexidine varnishes for caries prevention in risk groups”.
A review by Anderson 2003 concluded that the "literature remains mixed on the success of chlorhexidine for the reduction of dental caries whilst its performance as an antimicrobial against streptococcus mutans is more consistent and favorable".
This Cochrane systematic review is thus in agreement with most of the previous reviews conducted on the effect of chlorhexidine products for the prevention of caries in children and adolescents, in that the evidence is incomplete and no conclusions can be drawn from the existing evidence base.
Results of searching for studies for inclusion in the review
'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies
'Risk of bias' summary: review authors' judgements about each domain for each included study
Comparison 1 Chlorhexidine varnish versus placebo/no treatment, Outcome 1 Decayed, missing and filled surfaces/teeth (30 & 36 months, 40% & 10% CHX) ‐ permanent dentition.
Comparison 1 Chlorhexidine varnish versus placebo/no treatment, Outcome 2 Mutans streptococci prevalence (36 months, 10% CHX) ‐ permanent dentition.
Comparison 2 Chlorhexidine gel versus no treatment, Outcome 1 Caries incidence dmft (24 months, 0.12% CHX gel) ‐ primary dentition.
Comparison 2 Chlorhexidine gel versus no treatment, Outcome 2 Mutans streptococci prevalence (24 months, 0.12% CHX gel) ‐ primary dentition.
| Core elements | Issues to consider | Status of research for this review |
| Evidence | What is the current state of evidence? | A systematic review that identified eight RCTs matching the eligibility criteria, but were incompletely reported, had significant losses to follow‐up, and were assessed as at unclear or high risk of bias |
| Population | Diagnosis, disease stage, comorbidity, risk factor, sex, age, ethnic group, specific inclusion or exclusion criteria, clinical setting |
EXCLUDED
|
| Intervention | Type, frequency, dose, duration, prognostic | Chlorhexidine‐containing products:
Administration minimum once over a period of 1 year EXCLUDED
Compliance to be recorded |
| Comparison | Type, frequency, dose, duration, prognostic factor |
EXCLUDED
Compliance to be recorded |
| Outcome | Which clinical or patient‐related outcomes will the researcher need to measure, improve, influence or accomplish? | Dental caries (coronal) MS reductions in levels |
| Time Stamp | Date of literature search or recommendation | 14 January 2014 |
| Study Type | What is the most appropriate study design to address the proposed question? | RCT Blindness: Patients, carers, trialists, outcome assessors blind Setting for administration: home or dental hospital/clinic Setting for clinical outcome assessment: in dental hospital/clinic with appropriate length of follow‐up |
| (D(M)FS/T: decayed, missing and filled surfaces or teeth (permanent) | ||
| Chlorhexidine varnish compared with placebo for the prevention of dental caries in children and adolescents | ||||||
| Patient or population: children and adolescents Settings: school, nursery or dental clinic Intervention: chlorhexidine varnish Comparison: placebo | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Chlorhexidine | |||||
| Caries in the primary teeth (24‐months follow‐up) | Two trials with unit of analysis problem. Data imputations indicated no evidence to claim or refute a benefit | |||||
| Caries in permanent dentition (DMFS) (30 to 36 months) Higher values indicate greater caries | The mean increment in the control group was 5.821 | The increment in the intervention groups was | ‐ | 690 (2) | ⊕⊝⊝⊝ | Chlorhexidine varnish concentration 10% varnish and 40% varnish. A further three trials provided some unusable data but indicted no evidence to claim or refute a benefit3 |
| Elevated mutans streptococci levels ≥4 with caries screen (6 to 36 months) | 620 per 10004 | 577 per 1000 | RR 0.93 (0.80 to 1.07) | 496 (1) | ⊕⊝⊝⊝ | Chlorhexidine concentration 10% varnish Two other studies reported unusable data but indicated no evidence to claim or refute a benefit6 |
| Adverse events | One study reported no adverse events for ulcers or tooth staining. One study stated “side‐effects due to the CHX treatment were not noted" | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. In the two trials that assessed this outcome, the DMFS increment in the control groups was 5.25 and 6.39, mean 5.82. This value was considered to be a moderate caries increment. 2. We downgraded the quality of the evidence due to risk of bias (high and unclear risk of bias overall) and inconsistency. 3. Conclusions reflected in remaining 3 studies (high risk of bias) with 6‐ to 24‐months follow‐up and chlorhexidine concentrations of 1% and 10%, reporting caries outcomes in permanent dentition that could not be pooled in a meta‐analysis. 4. In the single trial that assessed this outcome as presence or absence of high mutans streptococci levels, the prevalence of high mutans streptococci in the placebo varnish group was 62%. 5. We downgraded the quality of the evidence due to risk of bias (unclear risk of bias overall), imprecision and inconsistency. Mutans streptococci outcomes were reported as mean mutans streptococci levels or presence or absence of high mutans streptococci. 6. Equivocal results reported in 2 other studies (high risk of bias) with 6‐ to 24‐months follow‐up and chlorhexidine concentrations of 1% and 10%, which could not be pooled in a meta‐analysis. | ||||||
| Chlorhexidine gel compared with no treatment for prevention of caries in children and adolescents | ||||||
| Patient or population: children and adolescents Settings: all Intervention: chlorhexidine gel Comparison: no treatment | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| No treatment | Chlorhexidine | |||||
| Presence of new caries in the primary teeth (24‐months follow‐up) | 16 per 10001 | 16 per 1000 (6 to 45) | RR 1.00 (0.36 to 2.77) | 487 (2) | ⊕⊝⊝⊝2 | Chlorhexidine concentration 0.12% gel |
| 70 per 1000 | 70 per 1000 (25 to 194) | |||||
| Mutans streptococci prevalence (24‐months follow‐up) | 180 per 10003 | 227 (171 to 299 | RR 1.26 (0.95 to 1.66) | 490 (2) | ⊕⊝⊝⊝4 | Chlorhexidine concentration 0.12% gel |
| 466 per 10003 | 587 per 1000 | |||||
| Adverse events (24‐months follow‐up) | Both studies reported there were no adverse events | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. Two trials assessed this outcome; the reported risk of caries in the control group was 1.6% and 6.9%. 2. We downgraded the quality of the evidence due to risk of bias (we assessed both studies to be at high risk of bias overall), imprecision of the estimate due to low numbers of events in both the control and intervention groups, and indirectness (infants administered very low daily concentration). 3. Two trials assessed this outcome; the reported risk of mutans streptococci in the control group was 46.6% and 18.1%. 4. We downgraded the quality of the evidence due to risk of bias (we assessed both studies to be at high risk of bias overall), imprecision, and indirectness. | ||||||
| Study ID | Intervention(s) and comparator | Outcome | Summary Intervention | Summary Comparator | Comment |
| Cervitec (1% chlorhexidine, 1% thymol) varnish applied 4 x year (n = 86) No treatment (n = 95) | Mean dft‐molar increment (24 months) Mean dfs‐molar increment (24 months) | Varnish 0.97 (SD 1.45) Varnish 2.21 (SD 2.96) | No treatment 0.94 (SD 1.50) No treatment 2.54 (SD 3.40) | Authors report "..the incidence of caries lesions at 24 months showed no significant differences between the 2 groups... Among the children who were caries free at the onset of the study, those in the varnish group showed a significantly lower incidence of caries lesions in teeth (P < .05) and on surfaces (P < .05) of primary molars at 24 months compared with those in the control group. On the other hand, among the children with dft > 0 at baseline, there were no statistically significant differences between the varnish and control groups." Statistical analysis did not take into account the cluster randomisation by school class. Inflation of the standard error of the effect estimate through a design effect with ICCs of 0.05, 0.1 and 0.2 would lead to the same conclusions as those reported | |
| 40% w/w chlorhexidine acetate in a sandarac resin applied 2 x year (n = 155) Placebo alcohol solution of sandarac resin (n = 135) | Mean dmfs‐molar increment (24 months) | Varnish 1.0 (SD 2.49) | Placebo 1.6 (SD 2.32) | Authors report "The mean caries increment of the primary molars was 1.0 dmfs‐molar in the test‐group children and 1.6 dmfs‐molar in the placebo group. The difference of 0.6 tooth surfaces...was statistically significant (p = 0.036)." Statistical analysis did not take into account the cluster randomisation by school class. Inflation of the standard error of the effect estimate through a design effect with ICCs of 0.05, 0.1 and 0.2 resulted in a non‐statistically significant result. ICC 0 MD ‐0.6 (95% CI ‐1.16 to ‐0.04) ICC 0.05 MD ‐0.6 (95% CI ‐1.71 to 0.51) ICC 0.1 MD ‐0.6 (95% CI ‐2.27 to 1.07) ICC 0.2 MD ‐0.6 (95% CI ‐3.38 to 2.18) | |
| Curasept (0.12%) chlorhexidine gel applied 1 x daily (n = 61) No treatment (n = 58) | Caries incidence (24 months) | Gel 3/61 | No treatment 4/58 | Authors report "These differences were not statistically significant (p = 0.7)." RR 0.71 (95% CI 0.17 to 3.05) | |
| Curasept (0.12%) chlorhexidine gel applied 1 x daily (n = 180) No treatment (n = 188) | Caries incidence (24 months) | Gel 4/180 | No treatment 3/188 | Authors report "The differences were not statistically significant (p = 0.66)." RR 1.39 (95% CI 0.32 to 6.14) | |
| CI: confidence interval | |||||
| Study ID | Intervention(s) and comparator | Outcome | Summary intervention | Summary comparator | Comment |
| Cervitec (1% chlorhexidine, 1% thymol) varnish applied 4 x year (n = 86) No treatment (n = 95) | Mean DFT increment (24 months) Mean DFS increment (24 months) | Varnish 0.88 (SD 1.25) Varnish 0.95 (SD 1.38) | No treatment 1.30 (SD 1.50) No treatment 1.85 (SD 2.27) | Authors report "There was a significant difference in the increase in caries on surfaces at 24 months between the two groups.... However, when we consider the teeth (DFT index), although the increment was smaller in the varnish group (0.88) versus controls (1.30), the difference did not reach statistical significance." Statistical analysis did not take into account the cluster randomisation by school class. Inflation of the standard error of the effect estimate through a design effect with ICCs of 0.05, 0.1 and 0.2 resulted in a non‐statistically significant result for both outcomes. ICC 0 MD ‐0.42 (95% CI ‐0.82 to ‐0.02) ICC 0.05 MD ‐0.42 (95% CI ‐1.17 to 0.33) ICC 0.1 MD ‐0.42 (95% CI ‐1.51 to 0.67) ICC 0.2 MD ‐0.42 (95% CI ‐2.20 to 1.36) ICC 0 MD ‐0.9 (95% CI ‐1.45 to ‐0.35) ICC 0.05 MD ‐0.9 (95% CI ‐1.92 to 0.12) ICC 0.1 MD ‐0.9 (95% CI ‐2.40 to 0.60) ICC 0.2 MD ‐0.9 (95% CI ‐3.34 to 2.18) | |
| Cervitec (1% chlorhexidine, 1% thymol) varnish applied 3 x year (n = 271) | Mean DFS increment (24 months) | Varnish 1.8 (no SD reported) | Placebo 1.9 (no SD reported) | No re‐analysis possible due to incomplete reporting | |
| Chlorzoin 10% chlorhexidine applied after 3 months (n = 43) No treatment (n = 40) | Mean % of sound surfaces (6 months) | Varnish 114.3 (SD 12.4) | No treatment 116.3 (SD 11.8) | Caries data presented as " dental decay parameters" i.e. % of sound, decayed, restored surfaces only. The trial reported that for all participants "...treatment groups were not predictors of dental decay parameters after 6 months" and for those participants treated as instructed at baseline examination "No significant differences on dental decay parameters were found between T and C groups at the 6 month examination". | |
| Chlorzoin 10% chlorhexidine applied 4 x year (n = 222) Placebo (n = 274) | Mean DMFS increment (36 months) | Varnish 6.83 (SD 6.17) | Placebo 6.39 (SD 6.41) | Authors reported "...the clinical trial failed to reject the null hypothesis of no difference in caries‐reducing efficacy between active and placebo chlorhexidine varnishes." (MD 0.44, 95% CI ‐0.67 to 1.55) | |
| 40% chlorhexidine varnish (EC40®) applied 2 x year (n = 99) Placebo: neutral gel without chlorhexidine (n = 95) | DMFS (30 months) | Varnish 6.16 (SD 10.01) | Placebo 5.25 (SD 6.03) | Authors reported "...no significant effect of CHX treatment on DMFS (p > 0.5)." (MD 0.91, 95% CI ‐1.40 to 3.22) | |
| CHX: chlorhexidine | |||||
| Study ID | Intervention(s) and comparator | Outcome | Summary intervention | Summary comparator | Comment |
| Chlorzoin 10% chlorhexidine applied after 3 months (n = 43) No treatment (n = 40) | Mean MS (6 months) | Varnish 2.9 (SD 1.5) | No treatment 4.1 (SD 1.3) | Authors report "After 6 months the C group exhibited significantly higher levels of the mutans streptococci when compared to the T group." (MD ‐1.20, 95% CI ‐1.80 to ‐0.60) | |
| Chlorzoin 10% chlorhexidine applied 4 x year (n = 222) Placebo (n = 274) | Number of participants with elevated MS levels Cariescreen® ≥ 4 (high) (36 months) | Varnish 129/224 | Placebo 169/272 | Authors report that Chlorzoin varnish "was not able to ensure continually low MS levels" following an initial benefit in favour of the active intervention observed at 3 and 6 months. This was not maintained at longer follow‐up at 12, 24 and 36 months. At 36 months there was no evidence of lower MS levels in the active varnish group (RR 0.93, 95% CI 0.80 to 1.07) | |
| 40% chlorhexidine varnish (EC40®) applied 2 x year (n = 99) Placebo: neutral gel without chlorhexidine (n = 95) | MS (30 months) | Not reported | Not reported | Numerical estimates of MS levels at the end of the study and intermediate data collection points not presented. Authors report "...no significant differences between the two treatment groups on these microbiological measures (p < 0.2)" | |
| CI: confidence interval | |||||
| Study ID | Intervention(s) and comparator | Outcome | Summary Intervention | Summary Comparator | Comment |
| Curasept (0.12%) chlorhexidine gel applied 1 x daily (n = 61) No treatment (n = 58) | MS prevalence (24 months) | Gel 28/61 | No treatment 27/58 | Authors report "Percentages of children with MS present were not significantly different between CHX and controls (P = 0.2)" RR 0.99 (95% CI 0.67 to 1.45) | |
| Curasept (0.12%) chlorhexidine gel applied 1 x daily (n = 180) No treatment (n = 188) | MS prevalence (24 months) | Gel 49/183 | No treatment 34/188 | Authors report "No statistically significant differences were present, however, at later ages." P = 0.05 RR 1.48 (95% CI 1.01 to 2.18) | |
| CHX: chlorhexidine | |||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Decayed, missing and filled surfaces/teeth (30 & 36 months, 40% & 10% CHX) ‐ permanent dentition Show forest plot | 2 | 690 | Mean Difference (IV, Fixed, 95% CI) | 0.53 [‐0.47, 1.53] |
| 2 Mutans streptococci prevalence (36 months, 10% CHX) ‐ permanent dentition Show forest plot | 1 | 496 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.80, 1.07] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Caries incidence dmft (24 months, 0.12% CHX gel) ‐ primary dentition Show forest plot | 2 | 487 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.36, 2.77] |
| 2 Mutans streptococci prevalence (24 months, 0.12% CHX gel) ‐ primary dentition Show forest plot | 2 | 490 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.26 [0.95, 1.66] |
