## Background

Cleft lip and/or palate is the most common congenital orofacial deformity, affecting 1/800 births [1]. Primary or anterior clefts involve the lip, more or less the nostril, and the alveolar bone posteriorly. They can be unilateral or bilateral. Secondary or posterior clefts start at the soft palate and continue forward towards the hard palate [2]. Clefts can affect different structures such as bones, soft tissues and teeth, affecting eating, speaking, breathing, or hearing. It also affects facial esthetics, which has important psychological and social implications for children [3].

A thorough review of the literature has shown that cleft patients have lower levels of oral hygiene (OH) and dental health (DH) than other children, combined with higher levels of tooth caries on both temporary and permanent teeth and poorer periodontal health [4–17]. The incidence of dental caries is correlated with the severity of the cleft, bilateral cases, and patients with alveolar bone clefts. These three situations are associated with higher rates of dental caries [7, 18, 19]. Moreover, if the prevalence of carious lesions decreases in the general population, it remains stable in cleft patients [20]. The lower level of OH could be explained by several factors. First, cleft patients and parents may focus on surgical reconstruction, and dental care seems to be of secondary importance. Secondly, the anatomy of the cleft, scar tissue, and malocclusion may prevent patients from achieving a satisfactory level of OH [9–21]. In addition, some patients may find it difficult to access appropriate dental care from practitioners who are competent to treat cleft patients in remote areas or due to financial constraints [21]. Without proper instructions, patients may be afraid of soft tissue damage or bleeding from gingival inflammation [20–22]. Ahluwalia et al. reported higher levels of bacteria associated with tooth caries, such as *Lactobacillus* and *Streptococcus* mutans, in cleft patients compared to non-cleft children. In addition, sugar levels were higher in cleft patients, which could be explained by a longer oral clearance time, as cleft patients keep food in their mouths longer before swallowing [20].

The level of OH is a key element in deciding the appropriate strategy for managing the gap of the missing maxillary lateral incisor due to its agenesis or extraction. The gap can either be maintained, requiring an associated prosthetic solution such as a dental implant or bridge, or it can be closed orthodontically, bringing the canine mesially adjacent to the central incisor [11, 23, 24]. In a recent retrospective study of 212 cleft patients, Quenel et al. showed better functional and esthetic results with prosthetic replacement in cleft patients with a unilateral missing lateral incisor [25]. Prosthetic replacement required from an early age a higher level of OH; indeed,

it implies a longer orthodontic treatment; OH is also a key element in the choosing of the prothetic replacement and on its esthetics result [25]. A systematic review investigating specific dental care to improve OH in cleft patients concluded that there is a need for increased conventional dental treatment and follow-up in this population. However, few studies offered a preventive approach or new strategies to facilitate OH in cleft patients (26).

Clefts are a malformation affecting many tissues and aspect of a children life; in order to take proper care of those children, it seems important to resort to a multidisciplinary team. Cleft patients in the Pays de la Loire region of France are treated at the tertiary cleft center at the University Hospital of Nantes (CCMR MAFACE). A multidisciplinary team, including surgeons, speech therapists, gynecologists, orthodontists, geneticists, pediatricians, and psychologists, aims to provide comprehensive care from pre- or post-natal diagnosis until early adulthood and the end of growth.

The literature has highlighted the need for personalized and reinforced follow-up for cleft patients [26]; therefore, with this study, we aim to assess the impact of a reinforced dental program on OH and DH for cleft patients at the Nantes Cleft Centre.

## Methods/design

### Study design

This prospective, controlled, randomized study aims to evaluate the impact of an enhanced personal dental program on OH and DH in cleft patients at the Nantes Cleft Centre using DMF and Silness and Loe index. Data will be collected through practitioner observation, using the subject's medical records and questionnaires.

### Setting of the study

Recruitment will take place at the Nantes Hospital, in the Maxillofacial and Dental Department and its tertiary cleft center. Each enrolled patient will be randomly assigned to the control group or test group. The allocation process is generated by the investigator after consent and clinical examination thanks to an algorithm on the eCRF. The allocation is revealed by the computer once the clinical examination is done. The framework of this trial is superiority.

For the *control* group, patients and their parents will be given the usual basics OH instructions by the maxillofacial surgeons or the orthodontists during the yearly follow-up. If dental care is needed, patients will be encouraged to contact their own dentist.

Patients in the *test* group will have a 30–45 min dental consultation added to the annual follow-up visit, during which OH and dietary instructions will be given, dental prophylaxis will be provided, and a professional
fluoride treatment will be applied. If necessary, dental care will be provided during the same appointment or will be scheduled at the Nantes Hospital Pediatric Dentistry Department. In addition, patients will be contacted by telemedicine every 2 months to reinforce motivation, and an additional dental appointment will be made at 6 months for dental prophylaxis, application of professional fluoride treatment, and caries treatment. A summary of these different stages is provided in Fig. 1. Dental treatment will be carried out in the Maxillofacial and Dental Department; if necessary, equimolar mixture of oxygen and nitrous oxide (ENOMO) or general anesthesia (OR) will be available, depending on the patient's level of cooperation.

Patients in both groups will be scored for caries on day 1, year 1, and 1 year after the end of the study. All dental treatment and assessment of OH levels (DMF index and gingival index [27–29]) or carious lesion management for the test group will be performed by 2 dentists. The DMF index is the sum of the decayed teeth, field teeth, and missing teeth based divided by the total number of teeth

for permanent and temporary teeth. Prior to the study, the two dentists will be trained in the assessment of OH (DMF index and gingival index) in order to calibrate the assessment method. Intra- and interrater reliability will be determined by weighted kappa scores using a random sample of oral photographs and radiographs from the series.

### Objectives and criteria of judgment

The primary objective of this study is to assess the impact of an enhanced dental program with close follow-up of cleft patients on their OH status. The primary outcome is the evolution of the decayed, missing, filled teeth index (DMFT/DMFT) for both temporary and permanent teeth. It will be measured at 1 year.

Secondary objectives are to assess:

- The impact of the enhanced dental program on the gingival status of cleft patients

- The preferential localization of caries

<table><caption>Fig. 1 SPIRIT. X test O control</caption><thead><tr><th></th><th>Enrolment</th><th>Allocation</th><th></th><th></th><th colspan="4">Close-out</th><th></th><th></th></tr><tr><th>TIMEPOINT**</th><th>-t<sub>1</sub></th><th>0</th><th>t<sub>1</sub></th><th>M<sub>2</sub></th><th>M<sub>4</sub></th><th>M<sub>6</sub></th><th>M<sub>8</sub></th><th>M<sub>10</sub></th><th>Y<sub>1</sub></th><th>Y<sub>2</sub></th></tr></thead><tbody><tr><td>ENROLMENT:</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Eligibility screen</td><td>X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Informed consent</td><td></td><td>X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Allocation</td><td></td><td>X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Randomisation</td><td></td><td>X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>INTERVENTIONS:</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Test group (dental care-dental prophylaxis OH and dietary instructions)</td><td></td><td></td><td>X</td><td></td><td>X</td><td></td><td></td><td>X</td><td></td><td></td></tr><tr><td>Control group</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>ASSESSMENTS:</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>DMF index</td><td></td><td></td><td>XO</td><td></td><td>X</td><td></td><td></td><td>XO</td><td>XO</td><td></td></tr><tr><td>Silness and Loë index</td><td></td><td></td><td>XO</td><td></td><td>X</td><td></td><td></td><td>XO</td><td>XO</td><td></td></tr><tr><td>Datas for secondary outcomes</td><td></td><td></td><td>XO</td><td></td><td>X</td><td></td><td></td><td>XO</td><td>XO</td><td></td></tr></tbody></table>
- The influence of orthodontic appliances, syndromes, and other cleft-related conditions such as malocclusion, oral-nasal fistulas, dental anomalies, sweet drugs, or drugs causing hyposialia on caries

- THE influence of family dietary and hygiene habits on OH and its evolution during follow-up

- The satisfaction of patients and their parents with the dental care provided

- The accessibility (geographic and appointment availability) of dental care for cleft patients

- The financial implications of this protocol

The evaluation criteria will be based on data collected during the clinical examination, such as the DMF index and Silness and Loe's index, and on medical records. Parents and patients will also be asked to complete a questionnaire to assess their satisfaction. Finally, the financial impact of this study will be assessed through a comparative analysis of costs and benefits.

## Patient recruitment-participants

Patients will be recruited by the primary investigator at their annual follow-up visit according to the following inclusion criteria:

- Age between 3 and 15 years

- Patients with syndromic or non-syndromic cleft lip and/or palate treated at the Department of Maxillofacial Surgery, Nantes University Hospital

- Translation assistance for non-French speakers

The exclusion criteria are:

- Patients without health insurance

- Not registered with the French social security system

- Refusal to participate in the study

Each patient attending their annual follow-up appointment with their maxillofacial surgeon will be offered the opportunity to participate in the study. If the patient meets all the inclusion criteria, the dentist will ask the child and his/her parents or legal guardian if he/she wishes to participate in the study. Clear and appropriate verbal and written information about the study (objectives, scientific interest, and practical procedures) is given. The dentist obtains the patient's verbal consent (and that of at least one parent or legal guardian) without delay. The lack of delay is due to the design of the study, which has been approved by an ethic Committee for the Protection of Persons (CPP). Enrolment will start immediately after oral consent.

The number of subjects required has been calculated using two studies with the same primary outcome [17, 20]. It was fifty-four patients for the whole study, i.e., twenty-seven patients in the test and control groups. The 1st article used was by Ahluwalia et al.: with the results of Table 1 and the data from DFM index 2.38 ± 0.28 vs 0.62 ± 0.17, the number of patients required would be 54 (27 per arm). The 2nd paper was by Hazza'a et al.: with DFMT data 4.28 ± 4.19 vs. 1.66 ± 1.44, the number of patients required would also be 54 (27 per arm).

It seems relevant to consider a 10% loss of follow-up in each arm and therefore adjust the number of patients to be included in the study: we will end up with thirty patients per arm, i.e., sixty patients in total (27 × 1.10 = 29.7).

## Consent for participation

At enrolment, patients and their parents or legal guardians will receive an information leaflet for their age group. The investigator will record in the patient's medical record that the patient and parents have been verbally informed, have received the information leaflet, and have given verbal consent to participate in the research. At least one parent of all children, regardless of the age of the child, must be informed and consent.

## Calendar

<table><thead><tr><th></th><th>Control group</th><th>Test group</th></tr></thead><tbody><tr><td>D0</td><td>Annual surgical follow-up and orthodontics appointments<br>Referred to the dentist if needed<br>Dental check-up:<br>- DMFT/dmft<br>- Gingival index</td><td>Dental consultation:<br>DMFT/dmft<br>Gingival index<br>Verbal and written explanation for OH and its importance, appropriate brushing technic is taught, and fluoride toothpaste dispensed<br>Dietetic recommendations<br>Tooth scaling<br>Dental treatment if needed<br>Fluoride coating</td></tr><tr><td>M 2- M 4- M 8- M 10</td><td>-</td><td>Telehealth:<br>Answering patient or parents' questions<br>Questions about the frequency and supervision of toothbrushing<br>Reminder about OH and dietetic recommendations</td></tr></tbody></table>
<table><thead><tr><th></th><th>Control group</th><th>Test group</th></tr></thead><tbody><tr><td>M6</td><td>-</td><td>Dental consultation: DMFT/dmft<br>Gingival index<br>Verbal and written explanation for OH and its importance, appropriate brushing technic is taught, and fluoride toothpaste dispensed<br>Dietetic recommendations<br>Tooth scaling<br>Dental treatment if needed<br>Fluoride varnish</td></tr><tr><td>Y 1</td><td>Annual surgical follow-up and orthodontics appointments<br>Referred to the dentist<br>Dental check-up:<br>- DMFT/dmft<br>- Gingival index</td><td>Dental consultation: DMFT/dmft<br>Gingival index<br>Verbal and written explanation for OH and its importance, appropriate brushing technic is taught, and fluoride toothpaste dispensed<br>Dietetic recommendations<br>Tooth scaling<br>Dental treatment if needed<br>Fluoride varnish<br>Satisfaction questionnaire for patients and parents<br>about the dental program and the impact on their habits</td></tr><tr><td>1 Y after end of study</td><td>Annual surgical follow-up and orthodontics appointments<br>Referred to the dentist<br>Dental check-up:<br>- DMFT/dmft<br>- Gingival index</td><td>Annual surgical follow-up and orthodontics appointments<br>Explanation for OH and its importance<br>Referred to the dentist<br>Dental check-up: DMFT/dmft<br>Gingival index</td></tr></tbody></table>

## Variables and data measurement

Data for the analysis will be collected by the dentist during patient enrolment thanks to an electronic case report form (eCRF) on a secured website; all data will be entered electronically. This may be done at a core coordinating center or at the participating site where the data originated. Original study forms will be entered and kept on file at the participating site. Only authorized personnel can have access to the data. Data integrity will be enforced through a variety of mechanisms. Referential data rules, valid values, range checks, and consistency checks against data already stored in the database will be supported. Additional errors will be detected by

programs designed to detect missing data or specific errors in the data. These errors will be summarized along with detailed descriptions for each specific problem in data query reports. The rest of the data collection for the test group will take place during the dentist's appointment for both the primary and secondary objectives. Data will be collected for both groups on day 1, year 1, and 1 year after the end of the study. For the test group, additional data will be collected at 2, 4, 6, 8, and 10 months.

The data monitoring committee is a part of the clinical research department of Nantes's Hospital; it is a structure dedicated to applied human research (clinical research); it is independent from the sponsor and competing interests. It monitors trial conduct and safety, assesses risks and benefits, and makes recommendations to protect the participants of clinical trials. All study-related information will be stored securely at the study site. All participant information will be stored in locked file cabinets in areas with limited access.

The primary investigator will have access to the final trial dataset.

## Statistical analysis

At the end of the study, before the statistical analysis, a data review will take place with the principal investigator, the project manager, the data manager, and anyone closely involved in the study. The aim is to have an overview of the conduct of the study, the problems encountered, and any deviations from the protocol.

A description of the data will be carried out; the quantitative variables will be described by the mean, the standard deviation, and the 1st, 2nd, and 3rd quartiles. The qualitative variables will be described by their respective numbers and percentages.

The analysis of the primary endpoint, the comparison of the difference in progression between enrolment and 2 years for each patient between the two groups, will be examined using Student's t-test. A sensitivity analysis adjusted for known confounders may be performed by linear regression. An additional sensitivity analysis is performed by comparing the values at enrolment with the values at 6 months and 1 year.

Missing data will be treated with multiple amputation, and non-adherence to the protocol will be treated in intention to treat.

## Data monitoring

Through our web-based electronic case report form, the data coordinating center has daily visual cross-validation of the data for complex errors and regular on-site monitoring; the quality and completeness of the data will be reflective of the state of the art in clinical trials. The
monitors will review the source documents as needed, to determine whether the data reported in the web-based system are complete and accurate.

## Ethics statement

This non-interventional study has been declared to the French Data Protection Authority (CNIL) and received a favorable opinion from the French National Committee for the Protection of Individuals. It has also been registered at ClinicalTrials.gov (NCT05867862).

## Discussion

This is a single-center study. Patient recruitment for this study will be simple. In fact, out of the 309 patients aged between 3 and 15 currently treated at the Nantes Cleft Centre, we need sixty patients to reach the required number of subjects.

In the event that our results show a difference, the enhanced dental program would become standard practice at the Nantes Cleft Center and could inspire other cleft centers to improve the quality of care. On a local level, the additional procedures and appointments would lead us to reorganize the unit and offer a day clinic to combine the numerous consultations for the comfort of the patients and their parents.

If our protocol shows a significant improvement in OH and DH for cleft patients, the aim would be to generalize this experiment for all children with this malformation followed in the tertiary center.

On a local level, this would contribute to better oral health care for patients and optimize their care by reducing intermediaries and facilitating access to dental care. Finally, this long-term initiative would lead us to reorganize the unit and offer a day clinic to consolidate the many consultations for the patients' and parents' convenience. Children already benefit from a consultation with a surgeon, speech therapist, psychologist, geneticist, and orthodontist. An extension of this specialized dental care for children with clefts could also be envisaged for adults treated at the tertiary center, since adults also face therapeutic difficulties and wandering for dental treatment related to their clefts due to the complexity and multidisciplinary required (maxillofacial surgeon, dental surgeon, prosthetist, orthodontist).

At a national level, the success of this study would make it possible to consider extending this protocol to other tertiary centers. This would require the mobilization of centers with joint maxillo-facial/orthodontic teams. A multicenter study representative of French dental practices in a tertiary cleft center could be considered.

Version: 8th date 2023 May 05; inclusion started in July and will probably be done in March.

## Abbreviations

CCMR Centre de Compétences de Maladie Rare (Competence Center for Rare Diseases)

CPP Comité de Protection des Personnes (Committee for the Protection of Individuals)

DH Dental health

EMONO Equimolar mixture of oxygen and nitrous oxide

OH Oral hygiene

OR Operating room

## Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s13063-024-08507-w.

Supplementary Material 1.

Supplementary Material 2.

## Acknowledgements

Thanks to Dr. Pierre Keribin for his help in this work.

## Protocol amendment

Any modifications to the protocol which may impact on the conduct of the study, potential benefit of the patient or may affect patient safety, including changes of study objectives, study design, patient population, sample sizes, study procedures, or significant administrative aspects will require a formal amendment to the protocol.

## Ancillary and post-trial care

There is no ancillary treatment or compensation for any patients harmed during the trial.

## Authors' contributions

All authors read and approved the final manuscript. TP, CB, and PC conceived the study. TP, CB, and PC set up this study and will contribute to the smooth running of the study. TP and CB bring their expertise in pediatric odontology to the analysis of results. PC and JL bring their expertise in maxilla-facial surgery to the analysis of results. AG, RC, TP, and CB wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors made substantial contributions to the conception and design of the study. The result will be published once the study has ended.

## Funding

This project received the financial support from the French Institute of Research in Odontology (IFRO) of the amount of 10.000€ as part of the 2022 national call for tenders.

It also received funding from the local Scientific Committee of the Faculty of Dental Surgery in Nantes for the amount of 5.000€ as part of the 2021 call for tenders.

## Availability of data and materials

Not applicable.

## Declarations

### Ethics approval and consent to participate

The protocol was approved by a national ethical committee (Comité de Protection des Personnes/Committee for the Protection of Individuals) under the number 23.00520.000272. All patients will be provided written information, before giving informed consent to participate.

### Consent for publication

Not applicable.

### Competing interests

The authors declare that they have no competing interests.
Author details

¹INSERM, Regenerative Medicine and Skeleton, RMeS, CHU Nantes, Nantes Université, UMR 1229, Nantes 44000, France. ²Department of Maxilla-Facial Surgery and Stomatology, CHU Nantes, Nantes University, Nantes 44000, France. ³Université Polytechnique Hauts-de-France, LARSH, CHU Nantes, Nantes University, Valenciennes 59313, France.

Received: 13 February 2024 Accepted: 24 September 2024

Published online: 09 January 2025

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