Description of the condition
Orofacial cleft (OC) can be defined as the non-fusion of the facial structures that occurs between 5 and 10 weeks of gestation. The overall prevalence of OCs is about 1 per 500-700 of live births. This rate varies considerably across different ethnic groups and geographical regions (WHO 2012). OCs are, therefore, one of the most common congenital anomalies, with a higher birth prevalence than neural tube defects or Down's syndrome.
Although unique causal factors remain unknown, it is currently widely accepted that OCs are of multifactorial aetiology, with genetic predisposition and environmental influence playing a role (Hayes 2002). While no strong risk factors have been identified, maternal cigarette smoking (Chung 2000), alcohol consumption (Romitti 1999; Romitti 2007; Shaw 1999), anti-epileptic drugs (Hecht 1989; Hecht 1990) or corticosteroids administered topically or systematically (Czeizel 1997) have shown an association with increased incidence of various subtypes of clefts. Inadequate maternal nutrition during pregnancy, and lower socioeconomic status, have also been suspected as conducive to occurrence of oral clefts (Shaw 1995; Wong 1999). Influence of a genetic defect is obvious in some syndromic forms of orofacial clefts. For example, in the van der Woude syndrome that manifests with cleft lip and/or palate and lower lip pits, a deletion in chromosome 1q32-q41 or in a second chromosomal locus at 1p34 has been linked to this disturbance, but the exact mechanism of influence of this mutation on craniofacial development is uncertain (Oberoi 2005). In non-syndromic clefts, however, the understanding of multi-gene and gene-environmental interactions in the development of the cleft is incomplete (Mossey 2007).
Treatment of OCs is prolonged and delivered usually by organized multidisciplinary teams. The cleft patient is typically treated from birth until adulthood or even after it. Despite the fact that a great volume of research concerning treatment strategies of OCs has been undertaken, there is still much debate concerning the best treatment protocol. This was highlighted in the 1996 to 2000 Eurocleft project, where substantial differences between the registered centres were found. 201 participating teams practiced 194 different protocols for one cleft subtype (Shaw 2001).
Furthermore, residual deformities or functional disturbances or both are frequently seen in adult patients with a repaired cleft. The extent of residual deformities is various and depends on the cleft subtype. In a relatively homogeneous category (cleft lip and palate), the resulting growth disturbances range from increased interocular width to a general retrusion of the midface relative to the cranial base. In fact, maxillary retrusion/hypoplasia can be a common clinical problem because up to approximately 45% of patients with cleft lip and palate may develop a severe maxillary hypoplasia, which cannot be treated alone with orthodontics but requires complex orthognathic surgical procedures (Mølsted 2005; Scolozzi 2008).
The aim of the orthognathic operation is to achieve an aesthetic and functional result by a displacement of the maxilla that will correct the pathological condition in all three planes of space (vertical, horizontal, and transversal), which, in turn, is associated with the patient’s psychological adjustment. This displacement of the maxilla, however, could influence other parameters, such as the velopharyngeal function and speech ability. There are two widely used types of orthognathic procedures: conventional orthognathic surgery and distraction osteogenesis.
Description of the intervention
The conventional orthognathic surgery for correction of maxillary retrusion/hypoplasia is a Le Fort I osteotomy. The word 'osteotomy' designates the division, or excision of bone. The bony segment is cut, adapted, and repositioned to correct a dentofacial deformity. It is held in the correct position (fixed) with the aid of wires or rigid fixation plates. Over the past decades, Le Fort I with rigid fixation has become a standard approach.
Distraction osteogenesis is the surgical process of correction of skeletal deformity utilizing bone lengthening by gradual mechanical distraction. It was first introduced in orthopaedics by Codivilla in 1905 but it was further developed and popularised by Ilizarov in the 1950s (Ilizarov 1989). Following the favourable outcomes of distraction osteogenesis in orthopaedics, it was first used in orthognathic surgery in 1992 (McCarthy 1992). Since then, distraction osteogenesis has been accepted as an effective method for the treatment of various craniofacial anomalies ranging from cleft lip and palate to craniosynostosis, to hemifacial microsomia and transverse discrepancies (Iannetti 2004).
How the intervention might work
In patients with OCs, Le Fort I surgery can be performed as a single-piece or multi-piece osteotomy. The former is carried out if there is adequate alveolar continuity achieved after a successful bone graft, whereas the latter is performed in circumstances where a notable residual alveolar defect with a substantial dental gap and oronasal fistulae is present. Also, in cases where additional expansion of the maxillary arch is needed, segmentalization of the maxilla may be required during Le Fort I surgery (Phillips 2012). Irrespective of the type of Le Fort I surgery (single- or multi-piece), the goal is to displace the maxilla forward to obtain adequate occlusion, good support for the nose and upper lip, and close fistulae, if present.
Distraction osteogenesis consists of several phases. After attachment of the distracting device and the bone cuts, latency phase ensues. In this 5 to 7-day period after the initial bone cuts the callus forms. In the next phase (activation), bony in-growth is induced by distraction of the callus. This phase lasts from a few to more than 15 days, depending on the required change. Once the desired bone length has been attained, the distraction device remains in situ. It acts as a rigid skeletal fixation device until maturation of the new bone is accomplished. This phase is termed as a consolidation period. Distraction osteogenesis is suggested to be equivalent, or even superior, alternative to conventional orthognathic surgery for patients who have a midface deficiency associated with cleft lip and palate (Shaw 2002).
Why it is important to do this review
Distraction osteogenesis and orthognathic surgery have been both widely used in cleft surgery. However, there is uncertainty as to which is the optimal corrective method.
In 2001, McCarthy et al reported the first 11 years of experimental and clinical experience with mandibular distraction osteogenesis (McCarthy 2001) indicating that distraction osteogenesis of the craniofacial skeleton produced favourable results. However, Shaw et al published a critical appraisal of 88 studies on distraction osteogenesis published from 1995 to 2000 (Shaw 2002). Almost all publications were retrospective, with short-term evaluation of small numbers of patients taken from heterogeneous patient populations without any controls.
On the other hand, it was advocated that the outcome of the orthognathic surgery might not be as stable as distraction osteogenesis. Saltaji et al found in a systematic review on maxillary advancement with conventional orthognathic surgery in patients with cleft lip and palate, that maxilla suffers a moderate relapse in the horizontal plane and a higher relapse in the vertical plane (Saltaji 2012a). Moreover, another systematic review of the same author that was published recently came to the conclusion that maxillary advancement with distraction osteogenesis has good stability in cleft patients with moderate and severe maxillary hypoplasia (Saltaji 2012b).
Taking into account that most evidence regarding the relative value of distraction osteogenesis and orthognathic surgery is of low quality, and that systematic reviews already published focused either solely on maxillary advancement or did not directly compare distraction osteogenesis and orthognathic surgery, there is an urgent need to identify the best available evidence and to conclude which of the two: distraction osteogenesis or orthognathic surgery, is a better treatment alternative for patients with OC in need of surgical correction.
To provide evidence regarding the effects and long-term results of maxillary distraction osteogenesis compared to orthognathic surgery for the treatment of hypoplastic maxilla in patients with cleft lip and palate. The following aspects will be considered: soft and hard tissue changes, surgical stability/relapse, speech outcomes, velopharyngeal function, psychological adjustment and clinical morbidities.
Criteria for considering studies for this review
Types of studies
Only randomised controlled trials (RCTs) will be considered in this review.
Types of participants
Adolescents or adults, 15 years of age or older, with an established diagnosis of complete cleft lip and alveolar process, complete unilateral cleft lip and palate, and complete bilateral cleft lip and palate (involving the alveolar process).
Participants with associated syndromic conditions, atypical (i.e. midline, etc.) clefts or unclear diagnosis regarding the type of cleft will be excluded.
Types of interventions
Surgical procedures, namely maxillary distraction osteogenesis or orthognathic surgery (conventional Le Fort I maxillary osteotomy), against each other to correct cleft lip and palate maxillary hypoplasia.
Types of outcome measures
- Midfacial soft and hard tissue changes, assessed with lateral cephalometric radiography and/or photographic archives and their superimposition, when applicable. Transversal maxillary changes will be assessed with anteroposterior cephalometric radiography or digital cast models of the occlusion, when available.
- Surgical relapse/stability, assessed with lateral cephalographs taken at different postoperative times.
- Perceptual speech assessment i.e. articulation, resonance (hypernasality and hyponasality), and nasal emission using video or any other form of voice recording device, conducted by a professional speech-language therapist.
- Instrumental assessment of velopharyngeal function. Nasoendoscopy or videonasopharyngoscopy or videofluoroscopy to assess the velopharyngeal gap size at rest and closure.
- Assessment of self esteem and psychological adjustment of the patients by any validated and internationally accepted questionnaires.
- Any other adverse effects or clinical morbidities, such as mucosal infection, sinusitis, transection of vessels, etc. will be evaluated and reported.
Search methods for identification of studies
For the identification of studies included or considered for this review, detailed search strategies will be developed for each database searched. These will be based on the search strategy developed for MEDLINE but revised appropriately for each database to take account of differences in controlled vocabulary and syntax rules.
The subject search will use a combination of controlled vocabulary and free text terms based on the search strategy for searching MEDLINE (Appendix 1).
We will search the following electronic databases:
- The Cochrane Oral Health Group's Trials Register (whole database)
- The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, current issue)
- MEDLINE via OVID (1946 to present) (Appendix 1)
- EMBASE via OVID (1980 to present)
- LILACS via BIREME Virtual Health Library (1982 to present)
- The WHO International Trials Registry Platform (whole database) (http://www.who.int/ictrp/en/)
- Web of Knowledge Conference Proceedings (1990 to present).
The search will attempt to identify all relevant studies irrespective of language. Non-English papers will be translated. There will be no restrictions on the date of publication.
Searching other resources
The following journals have been identified as being important to be handsearched for this review. Where these have not already been searched as part of the Cochrane Journal Handsearching Programme, the journals will be handsearched by the review authors:
- Cleft Palate and Craniofacial Journal (2003 to present)
- International Journal of Oral and Maxillofacial Surgery (2003 to present)
- Plastic and Reconstructive Surgery (2005 to present)
- Journal of Oral and Maxillofacial Surgery (2009 to present)
- British Journal of Oral and Maxillofacial Surgery (2005 to present)
- Journal of Cranio-Maxillofacial Surgery (2005 to present).
The reference lists of all eligible trials will be checked for additional studies.
Data collection and analysis
Selection of studies
Two review authors will examine the titles and abstracts of the search results independently and in duplicate to remove irrelevant reports. The full text of potentially relevant reports will be retrieved, and multiple reports of the same study will be linked together. After that, two review authors will independently and in duplicate assess the full text reports for eligibility by using defined criteria. Disagreements will be resolved by discussion between the two review authors or by the involvement of another review author as an arbiter. A record of all decisions on study identification will be kept. The review authors will not be blinded to author(s), institution or site of publication. If additional information is required, the corresponding author of the trial will be contacted and the study will be categorised as awaiting assessment.
Data extraction and management
Two review authors will perform data extraction independently and in duplicate using a data collection form. A calibration exercise will take place with the first two randomised controlled trials found. Disagreements will be resolved by discussion or the involvement of an arbiter. Data collection forms will be used to record information on participants, methods, interventions and results. The following data will be collected on a customised data collection form.
- Date that the study was conducted.
- Year of publication.
- Journal name, title of the manuscript and corresponding author.
- Where the study was conducted (which country and setting), funding, number of centres.
- Inclusion and exclusion criteria, number of patients recruited, number of patients randomised to each group, number of patients withdrawn, numbers evaluated.
- Method of surgical treatment, duration of treatment, details of surgical devices (e.g. type of distractor) that were used.
- Duration of follow-up.
- Sample size and whether a sample size calculation was performed.
- Age of participants and the number of male and female participants per study group.
- Primary and secondary outcomes, numbers of patients included in the outcome evaluation, times measured.
Assessment of risk of bias in included studies
This will be conducted using the recommended approach for assessing the risk of bias in studies included in Cochrane reviews (Higgins 2011). A two-part tool, addressing the six specific domains (namely sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other bias). Each domain includes one or more specific entries in a 'Risk of bias' table. Within each study, the first part of the tool involves describing what was reported to have happened in the study. The second part of the tool involves assigning a judgement relating to the risk of bias for that entry. This is achieved by assigning a judgement of low risk of bias, high risk of bias, or unclear risk of bias.
The domains of sequence generation, allocation concealment, incomplete outcome data and selective outcome reporting are each addressed in the tool by a single entry for each study. For blinding two entries will be used because assessments need to be made separately for a) patients and b) outcome assessor. Where the patients self assess the outcomes to the trial, this will be noted. The final domain (other bias) will be assessed as a single entry for studies as a whole.
The risk of bias assessment will be undertaken independently and in duplicate by two review authors as part of the data extraction process. Disagreements will be resolved by discussion or the involvement of an arbiter.
After taking into account the additional information provided by the authors of the trials, studies will be grouped into the following categories.
- Low risk of bias (plausible bias unlikely to seriously alter the results) for all key domains.
- Unclear risk of bias (plausible bias that raises some doubt about the results) if one or more key domains were assessed as unclear.
- High risk of bias (plausible bias that seriously weakens confidence in the results) if one or more key domains were assessed to be at high risk of bias.
A 'Risk of bias' table will be completed for each included study. The results will also be presented graphically.
Measures of treatment effect
For continuous outcomes (such as midfacial soft and hard tissue changes, velopharyngeal function), mean differences and standard deviations will be used to summarise the data for each trial.
For dichotomous outcomes the estimate of treatment effect of an intervention will be expressed as risk ratios together with 95% confidence intervals.
Unit of analysis issues
In most cases, the unit of analysis will be the patient. In addition, a unit of analysis issue may arise due to the measurement of outcomes at several time points. If this is the case, the most common endpoint(s) and a separate analysis for each time point will be used, where applicable.
Dealing with missing data
Where data are missing from the published report of a trial, the author(s) will be contacted in order to obtain the data and clarify any uncertainty. The analysis will generally include only the available data (ignoring missing data), however, methods for estimating missing standard deviations in section 7.7.3 of the Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0 (Higgins 2011) will be used. Otherwise it is not intended to undertake any imputations nor to use statistical methods to allow for missing data.
Assessment of heterogeneity
Heterogeneity will be assessed by inspection of the point estimates and confidence intervals on the forest plots. The variation in treatment effects will be assessed by means of Cochran's test for heterogeneity and quantified by the I
Assessment of reporting biases
If there are sufficient numbers of trials (more than 10) in any meta-analysis, publication bias will be assessed according to the recommendations on testing for funnel plot asymmetry (Egger 1997) as described in section 10.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If asymmetry is identified, possible causes will be examined.
A meta-analysis will only be conducted if there are studies of similar comparisons reporting the same outcome measures. Risk ratios will be combined for dichotomous data, and mean differences for continuous data, using a random-effects model provided there are more than three studies in the meta-analysis.
Subgroup analysis and investigation of heterogeneity
Clinical heterogeneity will be assessed by examining the differences in outcomes between various cleft subtypes, genders, and treatment centres. Providing there are sufficient studies of each intervention and outcome, we plan a priori to conduct subgroup analyses for different sex and centre.
Provided there are sufficient studies for each outcome and intervention, sensitivity analysis will be undertaken based on the overall risk of bias (low risk versus high or unclear risk of bias).
Presentation of main results
A 'Summary of findings' table will be developed for the primary outcomes of this review using GRADEpro software. The quality of the body of evidence will be assessed with reference to the overall risk of bias of the included studies, the directness of the evidence, the inconsistency of the results, the precision of the estimates, the risk of publication bias, the magnitude of the effect and whether or not there is evidence of a dose response. The quality of the body of evidence for each of the primary outcomes will be categorised as high, moderate, low or very low.
We would like to acknowledge the assistance of Anne Littlewood (Trials Search Co-ordinator, Cochrane Oral Health Group) in developing the search strategy.
Appendix 1. MEDLINE (OVID) search strategy
1. Cleft lip/
2. Cleft palate/
3. Mouth abnormalities/
4. exp Velopharyngeal insufficiency/
5. (cleft$ adj5 (palat$ or lip$ or maxilla$ or oral or orofacial or alveolar)).mp.
6. (harelip$ or "hare lip$" or hare-lip$).mp.
7. (hypoplas$ and maxilla$).mp.
8. (maxilla$ adj5 (defect$ or abnorm$ or malform$)).mp.
9. (alveolar$ adj5 (defect$ or abnorm$ or malform$)).mp.
10. (palate$ adj5 (defect$ or abnorm$ or malform$)).mp.
11. (lip$ adj5 (defect$ or abnorm$ or malform$)).mp.
12. (UCLP or CLP).ti,ab.
13. (velopharyngeal adj5 (dysfunction$ or insufficien$ or incompet$)).mp.
14. (palatopharyngeal adj5 (dysfunction$ or insufficien$ or incompet$)).mp.
16. Distraction osteogenesis/
17. (distract$ adj5 osteogene$).mp.
19. (maxilla adj5 distract$).mp.
21. Orthognathic surgical procedures/
22. Orthognathic surgery/
23. Le Fort Osteotomy/
24. (orthognathic adj5 surg$).mp.
25. (convention$ adj5 osteotom$).mp.
26. "le fort".mp.
28. (maxilla$ adj5 (surg$ or osteotom$ or reposition$ or re-position$ or section$ or advanc$)).mp.
29. (cleft and (surg$ or osteotom$)).mp.
30. (mandib$ and (setback$ or set-back$ or "set back$" or surger$ or surgical$)).mp.
32. 20 and 31
33. 15 and 32
Contributions of authors
- Dimitrios Kloukos will be responsible for designing, co-ordinating and updating the review.
- Dimitrios Kloukos and Piotr Fudalej will be responsible for screening search results, screening retrieved papers against inclusion criteria, extracting data from papers, and data collection for the review.
- Dimitrios Kloukos, Piotr Fudalej and Patrick Sequeira-Byron will be responsible for appraising the quality of papers and for data analysis.
- All review authors will contribute to analysis and interpretation of the data, and to writing the review.
Declarations of interest
None known. The participating review authors declare that there is no financial conflict of interest and that they do not have any associations with industry regarding the subject of this review.
Sources of support
- No sources of support supplied
- Cochrane Oral Health Group Global Alliance, UK.All reviews in the Cochrane Oral Health Group are supported by Global Alliance member organizations (British Orthodontic Society, UK; British Society of Paediatric Dentistry, UK; National Center for Dental Hygiene Research & Practice, USA and New York University College of Dentistry, USA) providing funding for the editorial process (http://ohg.cochrane.org/).
- National Institute for Health Research (NIHR), UK.All reviews in the Cochrane Oral Health Group are supported by NIHR Systematic Reviews Programme infrastructure funding.