Upper Airway Changes in Diverse Orthodontic Looms: A Systematic Review and Meta-Analysis

: Upper airway assessment is particularly important in the daily work of orthodontists, because of its close connection with the development of craniofacial structures and with other pathologies such as Obstructive Sleep Apnea Syndrome (OSAS). Three-dimensional cone-beam computed tomography images provide a more reliable and comprehensive tool for airway assessment and volumetric measurements. However, the association between upper airway dimensions and skeletal malocclusion is unclear. Therefore, the current systematic review evaluates the effects of different surgical movements on the upper airway. Materials and Methods: Medline (PubMed, OVID Medline, and EBSCO), Cochrane Library (Cochrane Review and Trails), Web of Knowledge (social science, and conference abstracts), Embase (European studies, pharmacological literature, and conference abstracts), CINAHL (nursing and allied health), PsycInfo (psychology and psychiatry), SCOPUS (conference abstracts, and scientiﬁc web pages), and ERIC (education) databases were searched. Two authors independently performed the literature search, selection, quality assessment, and data extraction. Inclusion criteria encompassed computed tomography evaluations of the upper airway spaces with retrospective, prospective, and randomised clinical trial study designs. To grade the methodological quality of the included studies a GRADE risk of bias tool was used. Results and conclusion: In total, 29 studies were included. Among these, 17 studies had a low risk of bias, whereas 10 studies had a moderate risk of bias. A meta-analysis was performed with the mean differences using a ﬁxed-effects model. Heterogeneity was assessed with the Q-test and the I 2 index. The meta-analysis revealed signiﬁcant ( p ≤ 0.001, 95% conﬁdence interval) increases in upper airway volume after rapid maxillary expansion and surgical advancement for the correction of Class II.


Introduction
The human upper airway could be defined as the airway space extending from the nose's nares and the mouth's stoma down to the cricoid cartilage in the larynx.The nasal and oral cavities merge in the area known as the pharynx, which is divided anatomically into three sections: the nasopharynx, oropharynx, and hypopharynx.
The shape and dimensions of the upper airway passages influence the volume of air passing through them.The close anatomical relationship between the upper airway and the craniofacial and dental structures dictates their influence on each other.The normal growth and development of craniofacial structures depend on a patent airway and nasal breathing.
Orthodontists have long been interested in airway analysis because of the airway's potential importance to the normal development of the craniofacial region as well as its involvement in the diagnosis and treatment of mouth breathing and sleep disorders.Clinicians need to evaluate the upper airway objectively and identify the normal and abnormal anatomical boundaries and dimensions.Although two-dimensional lateral cephalograms have been used for decades to evaluate the airway's shape, size, position, and relationship with other anatomical structures, they lack the information to illustrate the anatomically complex airway structure in three dimensions.Lateral cephalograms could be used as an initial screening method for airway evaluation, but three-dimensional conebeam computed tomography (CBCT) images provide a more reliable and comprehensive tool for airway assessment and volumetric measurements.The findings of snoring and interrupted sleep together with diagnostic images obtained during the dental examination can provide indications of possible airway disorders and support the need for referral to a medical specialist referral.
Nasal obstruction and its inseparable companion, "mouth breathing," have been assumed to affect dentofacial growth in the current literature.Although some researchers have found no association between the adequacy of the airway and dentofacial morphology [1].It seems to be a consensus that the oropharyngeal (OP) and nasopharyngeal structures play roles in the development of the dentofacial complex [2].
The etiology of malocclusions is believed to be multifactorial, and it could be considered erroneous to associate malocclusions with only breathing mode.Because the airway is assumed to play a role in dentofacial development, several studies have attempted to correlate patients with normal naso-respiratory functions with different malocclusions and airway dimensions.
Despite this, the relationship between upper airway dimensions and skeletal malocclusion remains controversial.Some studies have shown no effect on the airway after orthodontic treatment [3], whereas others have reported a change in the airway [4].The controversy regarding these outcomes might be related to the heterogeneity in the included articles, types of malocclusions, and imaging methods.
In addition, there has been no meta-analysis published in the literature that has compared changes in the airway dimensions resulting from different types of orthodontic treatment by using cone-beam computed tomography (CBCT), a 3D imaging technique, and only one single meta-analysis that included a small number of studies [5].Previous systematic reviews [5][6][7][8] have investigated this subject based on data from only twodimensional images.
Therefore, the present meta-analysis focused only on studies that used computed tomography (CT) for airway evaluation, particularly CBCT.Through a meta-analysis, this study aims to assemble scientific evidence related to the effects of orthodontic treatment modalities on airway space.

Materials and Methods
The systematic review is constructed in accordance with the Preferred Reporting Items for Systematic Reviews and Metanalyses standards of quality for the planning, conducting, and reporting of systematic reviews and meta-analyses [9].A search protocol was specified in advance and registered at PROSPERO (International Prospective Register of Systematic Reviews ID CRD42020180936).
To better outline the study, the participants, interventions, control and outcomes (PICO) format was followed (Table A1).

Search Strategy for the Identification of Studies
We performed a database search that included Medline (PubMed, OVID Medline, and EBSCO), Cochrane Library (Cochrane Review, Trails), Web of Knowledge (social science, and conference abstracts), Embase (European studies, pharmacological literature, and conference abstracts), CINAHL (nursing and allied health), PsycInfo (psychology and psychiatry), SCOPUS (conference abstracts, and scientific web pages), and ERIC (education).We used a specific search strategy with the following focused key terms: (airway OR oropharyngeal OR pharyngeal) AND ((orthodontic AND extraction) OR (Orthodontic AND Expansion)) OR ((Orthodontic AND ORTHOGNATHIC SURGERY)) OR ((Orthodontic AND Non-Extraction)) OR ((Orthodontic AND Distalization)) OR ((Orthodontic AND Expansion)) OR ((Orthodontic AND Cleft)) OR ((Orthodontic AND Functional Appliance)) OR ((Orthodontic AND Headgear)) OR ((Orthodontic AND Surgery)) OR (Orthodontic AND functionalization) OR (Orthodontic AND instrumentation) OR (Orthodontic AND surgical procedures) OR (Orthodontic AND oropharynx).
A gray literature search was performed using the following databases: Google Scholar, National Library of Medicine, and Social Science Research for Thesis.In addition, we searched four key orthodontic journals (Angle Orthodontics, American Journal of Orthodontics and Dentofacial Orthopedics, Journal of Clinical Orthodontics, and European Journal of Orthodontics) using their table of contents for relevant articles.The article search was performed up to November 2021.

Study Selection Procedure
Two authors independently reviewed all studies.Titles and abstracts were first screened to exclude irrelevant articles.Full texts of the remaining studies were further evaluated on the basis of preset selection criteria.Discrepancies between the two reviewers were addressed by a discussion with a third author.Final decisions were made after a consensus was reached.The selection of articles for inclusion in this review was based on the following criteria: human clinical trials with a prospective or retrospective design children or adult patients submitted to orthodontic treatment measurement of OP airway via CT before and after treatment and articles in English.The exclusion criteria were case reports, review articles, editorials, or opinions, and patients with a syndromic cleft.

Data Extraction
Data were extracted independently by two reviewers, using a specially designed data extraction form.The following data were extracted: author, year of publication, country, age, sample size, study design, type of orthodontic intervention, methodology, mean results, and outcome.

Risk of Bias Assessment
The risk of bias assessment of the included studies was performed using the GRADE tool [10].We developed a checklist for evaluating meta-analyses of RCTs for the purpose of informing a GRADE assessment.The checklist covers the main determinants for each of the five factors (risk of bias, inconsistency, indirectness, imprecision, and publication bias) that can lead to a downgrading of quality in the GRADE system.Table A2 summarised the domains used to determine the risk of bias using standardized criteria, the included studies were further classified for each domain as low risk, moderate risk, serious risk, and critical risk of bias.The experiments were comparable to well-performed randomised controlled trials, and the domain in question was considered to have a low risk of bias.The experiments that could not be compared with well-performed randomised studies but were sound within the domain of a nonrandomized trial were considered to have a moderate bias.Studies containing certain significant problems were classified as being at serious risk of bias.A critical risk of bias was classified as studies that were too problematic to provide any useful evidence on the effect of the intervention or that did not provide any information on the basis of the included of the 29 studies, 9 studies had a low risk of bias, 2 studies had a high risk of bias, and 18 studies had a moderate risk of bias.

Meta-Analysis
RevMan 5.3 analysis software (http://ims.cochrane.org/revman(accessed on 11 January 2022)) was used for conducting the meta-analysis (Cochrane Collaboration, Copenhagen, Denmark).Data related to the Mean Difference (MD) from various studies were estimated using the inverse-variance method.Two-sided 95% confidence intervals (95% CIs) were computed by using the fixed-effect model.The proportion of variability that attributes for heterogeneity was assessed via Cochran's Q-statistic and I 2 statistics.A fixed-effects model was used when heterogeneity was low (I 2 < 50%) and, when I 2 was >50%, a random-effects model was used.Funnel plots were employed for the detection of publication bias, and bias is revealed if the plots are asymmetrical.A value of p < 0.05 was considered statistically significant.Sensitivity analysis was performed to evaluate the robustness of the meta-analysis by removing outliers from the analyses with publication bias.

Results
After screening the titles and abstracts of 102 unique papers, 66 potentially eligible articles were selected.Two researchers independently reviewed each title and abstract, and the obtained information was compared.Inter-examiner disagreements were resolved in a consensus meeting.Of the 66 potentially eligible articles, 37 were excluded.These articles were excluded for the following reasons: non-3D (n = 27) and systematic review and review articles (n = 15) (Figure 1).

Included Studies
A total of 29 articles were identified for inclusion in this review (Table A3).This systematic review was based on prospective and retrospective cross-sectional studies and controlled clinical trials.

Study Characteristics
Of the 29 included studies, 10 studies were performed in the United States, 5 were performed in China, 2 studies were published in each Australia, Brazil, Italy, and Turkey.Other studies were performed in Egypt, Korea, Minneapolis, Singapore, South Korea, and India.Among the included 29 studies in this review, 20 studies were retrospective studies, 6 studies were prospective studies and the remaining studies were controlled clinical studies, longitudinal study and Quasi-experimental study.

Clinical Characteristics
A total of 1012 patients were included in the study, with sample sizes ranging from 8 to 83.Female patients were dominant in this review.The majority of the included studies demonstrated the Class III malocclusion type of malocclusion (n = 9) followed by Class II malocclusion (n = 7) and Class I malocclusion (n = 9).Out of 29 studies included in this review, 27 studies were used CBCT for the assessment of airways.

Included Studies
A total of 29 articles were identified for inclusion in this review (Table A3).This systematic review was based on prospective and retrospective cross-sectional studies and controlled clinical trials.Five studies report the Meta analysis for expansion with protraction between the experimental and control group.The pooled analysis showed a significant effect on expansion with protraction between the experiment and control group (MD = 0.78, CI-0.29,1.28;Chi 2 = 9.01;I 2 = 56%, p = 0.002 < 0.05).Heterogeneity between the five studies is medium (I 2 = 56%).Test for overall effect: Z = 3.12 (p = 0.002) (Figures 2 and 3).
review, 27 studies were used CBCT for the assessment of airways.

Expansion with Protraction
Five studies report the Meta analysis for expansion with protraction between the experimental and control group.The pooled analysis showed a significant effect on expansion with protraction between the experiment and control group (MD = 0.78, CI-0.29,1.28;Chi2 = 9.01; I2 = 56%, p = 0.002 < 0.05).Heterogeneity between the five studies is medium (I2 = 56%).Test for overall effect: Z = 3.12 (p = 0.002) (Figures 2 and 3).malocclusion (n = 7) and Class I malocclusion (n = 9).Out of 29 studies included in this review, 27 studies were used CBCT for the assessment of airways.

Expansion with Protraction
Five studies report the Meta analysis for expansion with protraction between the experimental and control group.The pooled analysis showed a significant effect on expansion with protraction between the experiment and control group (MD = 0.78, CI-0.29,1.28;Chi2 = 9.01; I2 = 56%, p = 0.002 < 0.05).Heterogeneity between the five studies is medium (I2 = 56%).Test for overall effect: Z = 3.12 (p = 0.002) (Figures 2 and 3).

Functional Appliance
Three studies report the Meta analysis for functional appliance between the experiment and control group.The pooled analysis showed a significant effect on functional appliance between the experiment and the control group (MD = 2.54, CI 1.17,3.90;Chi 2 = 10.27;I 2 = 81%, p = 0.0003).Heterogeneity between the three studies is high (I 2 = 81%).Test  Three studies report the Meta analysis for functional appliance between the experiment and control group.The pooled analysis showed a significant effect on functional appliance between the experiment and the control group (MD = 2.54, CI 1.17,3.90;Chi 2 = 10.27;I 2 = 81%, p = 0.0003).Heterogeneity between the three studies is high (I 2 = 81%).Test for overall effect: Z = 3.64 (p = 0.0003) (Figures 8 and 9).

Functional Appliance
Three studies report the Meta analysis for functional appliance between the experiment and control group.The pooled analysis showed a significant effect on functional appliance between the experiment and the control group (MD = 2.54, CI 1.17,3.90;Chi 2 = 10.27;I 2 = 81%, p = 0.0003).Heterogeneity between the three studies is high (I 2 = 81%).Test for overall effect: Z = 3.64 (p = 0.0003) (Figures 8 and 9).

Maxillary Expansion
Eight studies report the Meta analysis for maxillary expansion between the experiment and control group.The pooled analysis showed a significant effect on maxillary

Functional Appliance
Three studies report the Meta analysis for functional appliance between the experiment and control group.The pooled analysis showed a significant effect on functional appliance between the experiment and the control group (MD = 2.54, CI 1.17,3.90;Chi 2 = 10.27;I 2 = 81%, p = 0.0003).Heterogeneity between the three studies is high (I 2 = 81%).Test for overall effect: Z = 3.64 (p = 0.0003) (Figures 8 and 9).

Maxillary Expansion
Eight studies report the Meta analysis for maxillary expansion between the experiment and control group.The pooled analysis showed a significant effect on maxillary

Maxillary Expansion
Eight studies report the Meta analysis for maxillary expansion between the experiment and control group.The pooled analysis showed a significant effect on maxillary expansion between the experiment and control group (MD = −1.94,CI −2.44, −1.43; Chi 2 = 588.08;I 2 = 99%, p < 0.0001).Heterogeneity between the eight studies is high (I 2 = 99%).Test for overall effect: Z = 7.47 (p = 0.0001) (Figures 10 and 11).

Discussion
Respiratory function has a considerable influence on the development of the craniofacial complex, and the upper airway assessment has been an important concern for the orthodontist while performing different modalities of the management of dental and skeletal malocclusion [2].Controversies exist regarding the influence of orthodontic treatment on the upper airway; hence we undertook this systematic review.Twenty-seven studies were found to be appropriate for inclusion in this review, and the methodological quality of most of the studies was acceptable which permitted quantitative synthesis.The effects on the airway were assessed with orthopaedic protraction, rapid maxillary expansion, myofunctional appliances, fixed orthodontic therapy with extraction, and orthognathic surgery for correction of skeletal Class II and Class III malocclusion.
Randomised controlled trials provide the highest level of evidence.However, wellconducted observational studies also contribute meaningful evidence to the existing scientific knowledge, especially when randomised clinical trials are unethical or unfeasible [16].Because there were not enough randomised studies that evaluated the airway after different modalities of orthodontic treatment, prospective, and retrospective observational studies were also included in this review.
Airway dimensions are assessed by various means including lateral cephalograms, and CBCT.Although the pharyngeal airway is a 3-D structure.Conventional lateral

Discussion
Respiratory function has a considerable influence on the development of the craniofacial complex, and the upper airway assessment has been an important concern for the orthodontist while performing different modalities of the management of dental and skeletal malocclusion [2].Controversies exist regarding the influence of orthodontic treatment on the upper airway; hence we undertook this systematic review.Twenty-seven studies were found to be appropriate for inclusion in this review, and the methodological quality of most of the studies was acceptable which permitted quantitative synthesis.The effects on the airway were assessed with orthopaedic protraction, rapid maxillary expansion, myofunctional appliances, fixed orthodontic therapy with extraction, and orthognathic surgery for correction of skeletal Class II and Class III malocclusion.
Randomised controlled trials provide the highest level of evidence.However, wellconducted observational studies also contribute meaningful evidence to the existing scientific knowledge, especially when randomised clinical trials are unethical or unfeasible [16].Because there were not enough randomised studies that evaluated the airway after different modalities of orthodontic treatment, prospective, and retrospective observational studies were also included in this review.
Airway dimensions are assessed by various means including lateral cephalograms, and CBCT.Although the pharyngeal airway is a 3-D structure.Conventional lateral cephalography provides only the sagittal and vertical dimensions and thus has limited value for an accurate assessment.The transverse dimension of the airway has been found to be variable for a similar area of the nasopharyngeal airway, which raises concerns over the conclusions drawn from the lateral head film [17].Thus, it would be more accurate to provide a 3-D analysis of the airway assessment and this review included studies evaluating the 3-D volume of the airway after the use of various orthodontic treatment approaches.
Rapid maxillary expansion, introduced in the 19th century, is routinely performed for the correction of posterior crossbite and the creation of space to relieve crowding.This technique is now believed to be helpful for additional purposes, such as reduction of nocturnal enuresis [18], improvement of impaired nasal respiration [19], and relief from obstructive sleep apnoea [20].This review identified eight studies that assessed the impact of rapid palatal expansion on the airway where all of them were found to have significant improvements except for the study by El et al. [4] and Abdalla et al. [21].The combined analysis showed a significant improvement in the upper airway, which is similar to the findings reported by Buck et al. [22] in their 2017 systematic review.The mean age of the patient was higher in the studies by Kim et al. [15] and Li et al. [23] and those authors used implant-supported maxillary expansion in contrast to other studies in which tooth-supported expanders were used in adolescents.
For managing skeletal class III malocclusion, retrognathic maxilla expansion in combination with protraction is indicated for growth modulation.This modality has recently received increased attention as several studies have suggested improvement in the airway dimension facilitating the management of obstructive sleep apnoea [15,20,24].Separation of the midpalatal suture decreases the resistance of the circummaxillary sutures and subsequent protraction initiates the cellular response resulting in the forward and downward movement of the maxillary complex [25].This review included five observational studies that assessed the effect of maxillary expansion and protraction on the airway.All of the studies were retrospective except the study by Fu et al. [26] which had a prospective study design.Fu et al. [26] and Alrejaye et al. [3] enrolled cleft patients, whereas noncleft subjects were evaluated in the other studies.The pharyngeal anatomy of cleft patients was found to be different from the noncleft children and there was a varying effect of skeletal protraction among the cleft patients as compared with non-cleft patients [27].Only the study by Fu et al. [26] showed a significant increase in the pharyngeal airway volume after expansion and protraction, however, this difference was insignificant when combined with the data from other studies.In contrast, the systematic review by Lee et al. [5] found a significant increase in the upper airway after rapid maxillary expansion and protraction with nonsignificant changes in the lower airway when assessed on two-dimensional lateral cephalogram.
The extraction of one or more teeth is frequently indicated in contemporary orthodontics for the management of various dentoskeletal problems.Premolars are most often extracted for crowding correction and retraction of anteriors which can result in a considerable number of changes in the hard and soft tissues of the dentofacial region [28].Distal movement of the incisors could lead to the encroachment of space with posterior displacement of the tongue narrowing the upper airway.In this review, we identified Five observational studies that assessed the upper airway after the extraction of premolars and the retraction of anteriors.All the studies were retrospective and compared airway changes after orthodontic treatment in patients with and without extraction of at least two premolars.Studies by Stefanovic et al. [29] and Valiathan et al. [30] included adolescent patients, whereas the other three studies included adult patients (>18 years).During the period of active craniofacial growth (i.e., 8 to 18 years of age), the length and volume of the airways increase.Thus, in adolescents' treatment effect, if any, can be compensated by the growth of tissues surrounding the airway in adolescents [31].In this review, none of the included studies reported a significant volumetric change in the upper airway, and the results of the pooled analysis were inconclusive.The hyoid bone was displaced backward and downward with a large incisor retraction [32] and the evidence varies on its effect on the airway [33,34].Only the study by Zhang et al. [12] reported a change in the position of the hyoid bone in which the displacement was not statistically significant.
A posteriorly positioned mandible is commonly associated with obstructive sleep apnoea [35] and its advancement is believed to facilitate an increase in the upper airway volume which mitigates the apnoea [36].Functional appliances enhance the growth of the mandible by repositioning it anteriorly, however, recent evidence suggests that the advancement consists of dentoalveolar changes with only minimal skeletal changes [37,38].We identified three studies measuring the volumetric changes in the airway after functional appliances in growing Class II patients with mandibular retrusion.Among all the studies, airway volume immediately after the treatment was compared with the pretreatment values, we conclude the effects on long-term changes could not explore the effect on long-term changes.The studies varied in the type of appliances used: Oliveira et al. [39] used Herbst appliance, Temani et al. [40] studied on Forsus, and Alhammadi et al. [41] compared removable twin block and Forsus with the control group.All studies reported a significant improvement in the upper airway except for the Forsus group in the study by Alhammadi et al. [41] in which insignificant changes were noticed.The pooled analysis revealed an insignificant increase in the airway volume which is in contrast with the result of the meta-analysis by Xiang et al. [42], who found a significant increase in the airway dimension at the OP region as measured with a cephalogram.In the systematic review by Kannan et al. [43] in which most of the included studies used lateral cephalogram, the use of twin block induced significant changes in the airway volume at the nasopharynx, and hypopharynx, however, no such improvement was observed with the Herbst.
A retrognathic maxilla and mandible can compromise the upper airway volume and are associated with obstructive sleep apnoea [35,44,45].Orthognathic surgery involves the manipulation of the jawbones in which their position is changed from the surrounding craniofacial structures.This may cause morphological alteration of the airway resulting in further respiratory complications such as obstructive sleep apnea.However, there is conflicting evidence on the effects of this surgery on the airway [46,47].This review identified six studies, three each for skeletal Class II and Class III malocclusion treated by means of orthognathic surgery.Da Silva Machado et al. [48] found an overall increase in the upper airway after bimaxillary surgery in Class III which contradicts the findings by Gandedkar et al. [49] who noticed a decrease in the oropharynx volume without any change in the STOP-BANG score.The pooled analysis showed a significant decrease in the upper airway after orthognathic surgery for skeletal Class III malocclusion.All included studies for surgical Class II correction found a significant increase in the airway volume.Similarly, in their systematic reviews, Christovam et al. [50] Hernando et al. [51] found significant improvement in the airway dimensions after maxillomandibular advancement.
This systematic review differs from the past reviews in which two-dimensional cephalography was used to assess 3-D airways.In addition, CBCT measures the transverse dimension and evaluates the volume rather than the area.However, there are also some technical issues with the CBCT with regard to quantifying the airway volume.Most of the included studies captured the CBCT images in an upright position with the Frankfort Horizontal (FH) plane parallel to the ground [13,21,22] or the head in the natural head position [4,12,22].Only the study by Li et al. [23] considered CBCT in a supine position with the FH plane perpendicular to the ground.The dimension of the upper airway is sensitive to the body position [52], and the volume at the supine position is important because obstructive sleep apnoea occurs only during sleep.Although CBCT provides a clear picture of the hard and soft tissues at a single point in time, it does not provide any information on the muscle tone or susceptibility of collapse.Hence, the use of CBCT alone is not valuable for the diagnosis of obstructive sleep apnoea [10].
Most of the studies in this review consisted of adolescent participants.It is well known that the pharyngeal airway continues its growth along with the other craniofacial structures until 18 years of age, and future growth of the airway can compensate for any change resulting from the treatment.Furthermore, a shorter duration of follow-up cannot give a clear picture of the result in the long term which is most important for the patient and clinician.In addition, assessment of the respiratory functions and sleep quality would have more clinical applicability.The inclusion of randomised trials with large samples and a longer duration of follow-up would yield a better quality of evidence.
Was allocation concealment used (i.e., no potential for selection bias)?
Was there blinding of participants and personnel (i.e., no potential for performance bias)?

M H H M M H L L M H M H H L H L H L M H M H M H M M L H H
Was there blinding of outcome assessment (i.e., no potential for detection bias)?
Were more than (80%) a of participants enrolled in trials included in the analysis?(i.e., no potential attrition bias) Were data reported consistently for the outcome of interest (i.e., no potential selective reporting)?(no potential reporting bias) No other biases reported?(no potential of other bias)

H M M L H H H H M H M H H M H M H L M L H H H M M L H L Imprecision
Was the confidence interval for the pooled estimate not consistent with benefit and harm?
What was the magnitude of the median sample size?
Authors did not apply restrictions to study selection on the basis of language?
There was no industry influence on studies included in the review?
There was no evidence of funnel plot asymmetry?
There was no discrepancy in findings between published and upublished trials?

Figure 2 .
Figure 2. Forest plot for expansion with protraction between experiment and control.

Figure 3 .
Figure 3. Funnel plot for expansion with protraction between experiment and control.

Figure 2 .
Figure 2. Forest plot for expansion with protraction between experiment and control.

Figure 2 .
Figure 2. Forest plot for expansion with protraction between experiment and control.

Figure 3 .
Figure 3. Funnel plot for expansion with protraction between experiment and control.Figure 3. Funnel plot for expansion with protraction between experiment and control.

Figure 3 .
Figure 3. Funnel plot for expansion with protraction between experiment and control.Figure 3. Funnel plot for expansion with protraction between experiment and control.

Figure 4 .
Figure 4. Forest plot for clear aligner between before and after treatment.

Figure 4 .
Figure 4. Forest plot for clear aligner between before and after treatment.

Figure 4 .
Figure 4. Forest plot for clear aligner between before and after treatment.

Figure 5 .
Figure 5. Funnel plot for clear aligner between before and after treatment.

Figure 6 .
Figure 6.Forest plot for extraction and non-extraction.

Figure 5 .
Figure 5. Funnel plot for clear aligner between before and after treatment.

Figure 4 .
Figure 4. Forest plot for clear aligner between before and after treatment.

Figure 5 .
Figure 5. Funnel plot for clear aligner between before and after treatment.

Figure 6 .
Figure 6.Forest plot for extraction and non-extraction.Figure 6. Forest plot for extraction and non-extraction.

Figure 7 .
Figure 7. Funnel plot for extraction and non-extraction.

Figure 7 .
Figure 7. Funnel plot for extraction and non-extraction.

Figure 8 .
Figure 8. Forest plot for functional appliance between experiment and control.

Figure 9 .
Figure 9. Funnel plot for functional appliance between experiment and control.

Figure 8 .
Figure 8. Forest plot for functional appliance between experiment and control.

Figure 7 .
Figure 7. Funnel plot for extraction and non-extraction.

Figure 8 .
Figure 8. Forest plot for functional appliance between experiment and control.

Figure 9 .
Figure 9. Funnel plot for functional appliance between experiment and control.

Figure 9 .
Figure 9. Funnel plot for functional appliance between experiment and control.

Figure 10 .
Figure 10.Forest plot for maxillary expansion between experiment and control.Figure 10.Forest plot for maxillary expansion between experiment and control.

Figure 10 .
Figure 10.Forest plot for maxillary expansion between experiment and control.Figure 10.Forest plot for maxillary expansion between experiment and control.

Figure 10 .
Figure 10.Forest plot for maxillary expansion between experiment and control.

Figure 11 .
Figure 11.Funnel plot for maxillary expansion between experiment and control.3.4.6.Surgery Class III Three studies report the Meta analysis for surgery class III between the pre-and postsurgical group.The pooled analysis showed a significant effect on surgery class III between the pre-and post-surgical group (MD = 3.45, CI 2.54, 4.35; Chi 2 = 7.60;I 2 = 74%, p < 0.0001).Heterogeneity between the three studies is high (I 2 = 74%).Test for overall effect: Z = 7.48 (p = 0.0001) (Figures 12 and 13). ).

Figure 12 .
Figure 12.Forest plot for Surgery class III between pre and post surgery.

Figure 11 .
Figure 11.Funnel plot for maxillary expansion between experiment and control.3.4.6.Surgery Class III Three studies report the Meta analysis for surgery class III between the pre-and post-surgical group.The pooled analysis showed a significant effect on surgery class III between the pre-and post-surgical group (MD = 3.45, CI 2.54, 4.35; Chi 2 = 7.60;I 2 = 74%, p < 0.0001).Heterogeneity between the three studies is high (I 2 = 74%).Test for overall effect: Z = 7.48 (p = 0.0001) (Figures 12 and 13). ).

Figure 10 .
Figure 10.Forest plot for maxillary expansion between experiment and control.

Figure 11 .
Figure 11.Funnel plot for maxillary expansion between experiment and control.3.4.6.Surgery Class III Three studies report the Meta analysis for surgery class III between the pre-and postsurgical group.The pooled analysis showed a significant effect on surgery class III between the pre-and post-surgical group (MD = 3.45, CI 2.54, 4.35; Chi 2 = 7.60;I 2 = 74%, p < 0.0001).Heterogeneity between the three studies is high (I 2 = 74%).Test for overall effect: Z = 7.48 (p = 0.0001) (Figures 12 and 13). ).

Figure 12 .
Figure 12.Forest plot for Surgery class III between pre and post surgery.Figure 12. Forest plot for Surgery class III between pre and post surgery.

Figure 12 .
Figure 12.Forest plot for Surgery class III between pre and post surgery.Figure 12. Forest plot for Surgery class III between pre and post surgery.

23 Figure 13 .
Figure 13.Funnel plot for Surgery class III between pre and post surgery.

Figure 13 .
Figure 13.Funnel plot for Surgery class III between pre and post surgery.

Figure 13 .
Figure 13.Funnel plot for Surgery class III between pre and post surgery.

Figure 14 .
Figure 14.Forest plot for extraction and non-extraction after removing the studies lies outside the funnel.

Figure 15 .
Figure 15.Funnel plot for extraction and non-extraction after removing the studies lies outside the funnel.

Figure 14 .
Figure 14.Forest plot for extraction and non-extraction after removing the studies lies outside the funnel.

Figure 13 .
Figure 13.Funnel plot for Surgery class III between pre and post surgery.

Figure 14 .
Figure 14.Forest plot for extraction and non-extraction after removing the studies lies outside the funnel.

Figure 15 .
Figure 15.Funnel plot for extraction and non-extraction after removing the studies lies outside the funnel.

Figure 15 .
Figure 15.Funnel plot for extraction and non-extraction after removing the studies lies outside the funnel.

Figure 16 .
Figure 16.Forest plot for maxillary expansion between experiment and control after removing the studies lies outside the funnel.

Figure 16 .
Figure 16.Forest plot for maxillary expansion between experiment and control after removing the studies lies outside the funnel.

Figure 16 .
Figure 16.Forest plot for maxillary expansion between experiment and control after removing the studies lies outside the funnel.

Figure 17 .
Figure 17.Funnel plot for maxillary expansion between experiment and control after removing the studies lies outside the funnel.

Figure 17 .
Figure 17.Funnel plot for maxillary expansion between experiment and control after removing the studies lies outside the funnel.
)? H M L M H L L L L M M L M L M L M L L M L M L H L H L H L Was the test for heterogeneity statistically significant (p < 0.1)?L M M M L M M L L M L M L M L M L M L M L M L H L H L H L Indirectness Were the populations in included studies applicable to the target population?L M M M M L M L L H H H H M L L M M L M M L M L H L H L H Were the interventions in included studies applicable to target intervention?L L H H H H M L L M L L M L M L L M L M M M L H L H L H L Was the included outcome not a surrogate outcome?H L M H H M L L H M H H M H H L H L H H L H L H L H L L H Was the outcome timeframe sufficient?M M M H L L L H L M L L M L L M M L L M L M L L L M L M L Were the conclusions based on direct comparisons?H H H L HWas the outcome a common event?(e.g., occurs more than 1/100) aM L M H M L M L H H H H L H L L L M L M L M L M L L M M MWas there no evidence of serious harm associated with treatment?M L M H L L L L L M L M L M M M M L M H H L H L H H H L H Publication bias Did the authors conduct a comprehensive search?L M H M M L M L M L M L M L M L M L L M L M L M L M L M MDid the authors search for grey literature?

Table A2 .
Risk of bias assessment of the inlcuded studies.