Bibliografia

European Journal of Orthodontics, 2016

Lloyd M. Buck, Oyku Dalci, M. Ali Darendeliler, Spyridon N. Papageorgiou,and Alexandra K. Papadopoulou

INTRODUCTION

Rationale

Maxillary expansion as an orthodontic treatment modality has been reported since the 1860s (1). Rapid Maxillary Expansion (RME) aims to resolve maxillary transverse deficiencies, correct posterior dental crossbites, create arch space for relief of crowding, prevent maxillary canine impaction, and reduce nocturnal enuresis (2–4). Separation of the maxillary halves extends directly to the nasal cav- ity through lateral separation of the nasal walls and lowering of the palatal vault (5). Reported benefits to the upper airway include improving allergic rhinitis, asthma, and recurrent ear or nasal infec- tions (6). Many researchers have suggested that RME is a success- ful means of increasing the nasal permeability and reducing airway resistance, based on both objective and subjective evidence (7, 8). Reduced airway resistance reduces negative pressure during venti- lation, with promising results of RME shown in the treatment of paediatric sleep disordered breathing, including obstructive sleep apnoea (9). The effects on more distant structures include stretch- ing of the tensor palatine muscles by the expanding maxilla with subsequent improvement in drainage of the Eustachian tubes, aiding in reducing otitis media and conductive hearing loss (10). Enlarged palatal space may also allow for an improved tongue posture, which could facilitate increased airway space in the oropharynx (11).

Decreased airflow can be observed in various parts of the upper air- ways. In cases of considerable obstruction to the nasal airflow, the res- piratory pattern can shift towards mouth breathing, although breathing mode cannot be robustly predicted by nasal resistance data alone (8). On the other side, some researchers suggest that reduced nasal volumes are associated with mouth breathing (12). The interrelationship between respiratory obstruction, malocclusion, and facial growth continues to be debated after nearly a century of controversy (13). Interest in this subject has been rekindled in the past decades, based on the possible role of craniofacial morphology, and especially the shape/dimension of the upper airways, on obstructive sleep apnoea (14).

Many studies have assessed linear transverse dental and skeletal changes produced by maxillary expansion, but these changes do not necessarily reflect airway dimension changes (15, 16). Previous reports indicate that maxillary expansion is associated with an increase in nasal width, cross-sectional area, and volume (5, 17, 18). Subjective improvement in nasal breathing has also been considered as a concomitant result (7, 8). However, evidence on the changes induced by RME on upper airway volumes further from the nasal cavity, particularly the pharynx, is still inconclusive.

Accurate quantification of RME-induced changes at the upper airways has been a challenge. Linear measurements as performed on cephalograms cannot accurately express the upper airways (19). On the other side, the dimensional accuracy of both conventional com- puted tomography (CT) and cone-beam CT (CBCT) in quantifying the volume of the upper airway has long been verified (14, 20) with small method error, even though imaging reproducibility of dynamic regions has been suggested to be inconsistent (21). Although CBCT can offer reduced cost and radiation exposure to the patient com- pared to traditional CT, the latter shows reduced image noise, improved contrast resolution and accuracy to distinguish between soft tissues and air spaces over the former (22).

Acoustic rhinometry (AR), developed by Hilberg (23) can be used to objectively evaluate the nasal anatomy based on the reflec- tion of sound waves within the nasal cavity. Measurements are then processed to calculate nasal cavity area, volume, and resistance (15). Use of a decongestant is common to produce readings that are minimally influenced by the highly dynamic nasal mucosal tissues (24). Although AR has been shown to have good agreement with magnetic resonance imaging and CT in the anterior nasal cavity up to 6 cm from the nostrils (25), it may over-estimate cross-sectional areas in the posterior portion of the nasal cavity and pharynx, due to partial contribution of the maxillary sinuses (26).

Objectives

A previous systematic review (27) reported on the subject, however, only studies up to 2010 were included, no meta-analysis was per- formed, and the quality of overall evidence was not assessed with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (28). The aim of this study was to summarize in systematic manner evidence on upper airway volume changes induced by RME based on clinical studies in growing patients.

MATERIALS AND METHODS

Protocol and registration

The protocol of the present systematic review was based a priori on Cochrane Handbook for Systematic reviews of Interventions 5.1.0. (29). This systematic review follows the PRISMA statement (30), its extension for abstracts (31), and was not registered.

Information sources and search

Systematic search of major electronic databases was conducted covering publications in English from inception of each database through 1 February 2016. Electronic searches were performed in MEDLINE  via  Ovid  (1965  to  1  February  2016), PREMEDLINE

(all available), Old MEDLINE (1946–65), Embase (1947 to 1 February 2016), and Cochrane Central Register of Controlled Trials (CENTRAL). Unpublished literature was searched electronically through ClinicalTrials.gov (www.clinicaltrials.gov) and ISRCTN reg- istry (http://www.isrctn.com/) using the terms ‘expansion’, ‘airway’, and ‘volume’ without any limitations to publication date. Additional hand searching of reference lists of relevant articles, grey literature in Google Scholar, and correspondence with experts in the field was conducted for location of any additional studies. The search keywords and strategy were developed in consultation with a senior health sci- ences librarian and the search was performed independently by two authors (LB and OD). Exact search strategies for MEDLINE via Ovid and Embase are shown in Supplementary Tables 1 and 2, respectively.

Eligibility criteria

The eligibility criteria of included studies were determined a priori (Supplementary Table 3) with the scope of evaluating RME-induced volumetric changes in any region of the upper airway, made with any diagnostic modality. Eligible studies should report both baseline and post-expansion data. In order to minimize the confounding factor of relapse on the immediate volumetric airway changes, it was decided to include only time-points either immediately following the active expan- sion period or immediately after the retention period (to a maximum of 8 months of retention). Data from follow-up records taken after further non-retained periods, after a subsequent orthodontic treatment phase or at long-term reviews, were not used in order to avoid confounding. Only studies on growing patients (using the cut-off age of 18 years) were included, as skeletal changes produced by RME in this period are more consistent. Due to the scarcity of existing studies, we included randomized and non-randomized controlled clinical trials and non-ran- domized cohort clinical studies that included at least 8 patients.

Study selection and data collextions

Study selection and data collection were conducted by two independ- ent blinded authors (LB and OD), with discrepancies being resolved by discussion with the last author (AKP). Title and abstract screening was performed blinded (32) by these two authors by grading studies as ‘yes’, ‘no’, or ‘maybe’ based on the information provided by the title and abstract. Full text was located for all articles graded with ‘ yes’ or ‘maybe’, as well as studies where no abstract was available, or the information available was inconclusive in reaching a decision. The inclusion and exclusion criteria were rigorously applied to the full-text articles and where questions remained, efforts were made to contact the authors of the study.

Data collection was performed from the same two blinded authors using a customized data extraction form (Supplementary Table 4). The primary outcome measure sought was volumetric changes in any region of the upper airway. The upper airway was defined as includ- ing the nose, nasal passages, paranasal sinuses, oral cavity, pharynx (nasopharynx, oropharynx, hypopharynx) (33) and the portion of the larynx above the vocal cords (34). Information related to the study samples including sample size, age, gender, as well as patient selection criteria were recorded. Details of the type of RME device utilized as well as specifics of the expansion protocol, timing, turning frequency, amount of activation, and retention were retrieved from all included studies. The modality and technique used to quantify the airway vol- ume, as well as the exact time-points that these were recorded were extracted. Measurements were accepted from three specific time-points only, defined as: T1, immediately prior to insertion of RME appliance; T2, immediately at completion of the active expansion phase; and T3, immediately at completion of the retention phase (maximum 8 months).

Risk of bias within individual studies

The Cochrane Collaboration’s risk of bias tool (35) was used to assess the internal validity of included randomized controlled tri- als. The methodological adequacy of included non-randomized trials was assessed with a customized tool that was developed especially for this systematic review based on various appraisal tools (includ- ing the Newcastle–Ottawa scale) and empirical evidence of bias in orthodontic clinical research (Supplementary Table 5) (36–42). The developed checklist comprised 15 individual questions pertaining to four domains: study design, study conduct, statistical analysis, and conclusions, with a maximum score of 25. Studies were graded descriptively as having overall high (score > 20), moderate (20 ≤ score ≤ 13) or low (score < 13) methodological adequacy. However, specific domain questions were also used to determine the strength of the evidence, when drawing conclusions from the final data.

Summary measures

The primary outcome of this systematic review was the overall upper air- way volume, as this is the most clinically relevant outcome for the patient. As mentioned above, results from all diagnostic modalities (including AR, CT, etc.) were included, but were analyzed separately. All results were calculated as increment final (post-expansion or post-retention) minus initial (pre-expansion) upper airway volume. As many studies reported on the volume of various parts of the upper airway, we pooled for each study the total airway volume that was reported. As a secondary outcome, we adopted the changes in the volume of each upper airway volume separately and we calculated the RME-induced change likewise. For both primary and secondary outcomes, main emphasis was given on the results of controlled clinical trials, as these have greater internal valid- ity. Results of uncontrolled cohort studies were also reported in order to provide a quantitative overview of the effects of RME on upper airway volume, but were interpreted with caution.

Data synthesis

As the effects of RME were expected to vary among the included studies according to the different treatment protocols, RME appli- ances, patient characteristics, airway regions, and measurements techniques, a random-effects model according to DerSimonian and Laird (43) was judged appropriate to encompass this variability (44). For all meta-analyses, the mean differences and the associated 95 per cent confidence intervals (CIs) were calculated. Forest plots were constructed to depict the meta-analysis results and were augmented with contours denoting the magnitude of the observed effects.

Between-trial heterogeneity was quantified with the I2 statistic, defined as the proportion of total variability in the results explained by heterogeneity, and not chance (45). The 95 per cent uncertainty inter- vals (similar to CIs) around the I2 were calculated using the non-central χ2 approximation of Q (46). Ninety-five per cent predictive intervals were calculated for meta-analyses of three trials or more, as they incor- porate existing heterogeneity and provide a range of possible effects for a future clinical setting, which makes them crucial for the interpreta- tion of random-effects meta-analyses (47). All analyses were performed using Stata SE 10.0 (StataCorp, College Station, Texas, USA). Statistical significance was set at a two-sided α of 5 per cent, except for test of heterogeneity, where α was set at 10 per cent, due to low power (48).

The overall quality of evidence (confidence in effect estimates) for the primary outcome was rated using the GRADE approach (28). The GRADE assessment was based on evidence solely from con- trolled clinical bias, and not from uncontrolled cohort studies, as the latter are more prone to bias. The minimal clinical important, large, and very large effects were conventionally defined (49).

Risk of bias across studies and additional analyses

In meta-analyses of at least five studies, possible sources of heteroge- neity were planned a priori to be sought through pre-specified mixed- effects subgroup analyses and random-effects meta-regression with the Knapp and Hartung (50) adjustment according to appliance and patient characteristics. If at least 10 studies were included in a meta- analysis, reporting biases (including the possibility of publication bias) were assessed using contour-enhanced funnel plots (51) and Egger’s linear regression test (52). Sensitivity analyses were planned to be conducted for meta-analyses of at least 10 studies to assess their robustness according to the study design, the improvement of the GRADE classification, and signs of reporting bias.

RESULTS

Study selection

The initial literature search strategy yielded a total of 494 results, while five additional studies were identified from the manual search update (Supplementary Table 6). After duplicate removal and initial screening, another 44 studies were excluded after careful application of the eligi- bility criteria to their full texts, leaving a total 22 papers (15–17, 53–71) (20 unique studies) included in the qualitative synthesis (Figure 1). In two instances, two studies pertaining to the same trial were grouped together (55, 57, 69, 71). A complete list of included and excluded stud- ies with reasons can be found in Supplementary Table 7. From these, a total of 17 papers (15 unique studies) were included in the quantitative synthesis, as five studies did not adequately report outcome data.

Study characteristics

The characteristics of the 20 studies included in this systematic review are given in Supplementary Tables 8–10. As far as study design is con- cerned, one was a randomized controlled clinical trial (53), two were prospective controlled clinical trials (17, 62), and the remaining 17 were cohort studies [2 retrospective (56, 60) and 15 prospective (15, 16, 54, 55, 57–59, 61, 63–68, 70) in nature]. Data were collected for a total of 483 treated subjects and 55 controls (median of 20 treated and 20 control patients per study). Samples were mixed for size, gen- der and age of participants (Supplementary Table 8). Mean initial age of treated patients ranged from 7.5–14.5 years with an average of 11.9 years. Inclusion criteria varied; however, all involved patients that had transverse maxillary deficiency. In addition, posterior cross- bites were compulsory in 10 studies (15, 16, 55, 57, 59–62, 66) and optional in two studies (54, 58). The level of skeletal maturation of patients prior to expansion treatment was determined by using the cervical vertebral maturation index in three studies (58, 63, 64) or hand-wrist radiographs in one study (64). Separation of the maxil- lary halves by RME was verified, either by radiographic film (15) or recorded as clinical observation of midline diastema formation (64). The expansion appliance used in the studies included banded RME in 9 studies (53–56, 58–60, 64, 65), bonded RME in 10 studies (15, 16, 57, 58, 61–66), while a study compared banded, bonded and Haas-style RME appliance groups (64). The cast cup design was used in a study (67) and two studies did not clearly describe type of appliance used (68, 70). Duration of active expansion varied between studies, representing varied needs of the individual patients. Reported total expansion distances at the screw ranged from 2.7–10.0 mm. While the expansion protocol was well defined in most studies, it was not reported in three of them (57, 58, 65). Retention techniques varied, with keeping the expander in place passively for some period being the most commonly used practice in 12 studies (15, 17, 53–55, 60, 62–64, 66, 68, 70), four studies did to outline a retention scheme at all (59, 61, 65, 67), while the rest of the studies provided inadequate information (16, 56–58).

The volume of seven upper airway regions was evaluated in the included studies: nasal cavity, anterior nasal cavity, maxillary sinus, nasopharyngeal, oropharyngeal, hypopharyngeal, and palatal vol- ume. Within the nasal cavity, measurements by both AR and CT were considered. Nasal volume measures by AR were considered with decongestant or without decongestant (also known as basal condition).

All studies recorded baseline volume measurements immediately prior to commencement of RME (T1), five studies (59, 65, 67, 68,70) assessed these volumes again immediately after active expansion (T2) and 15 did so after the retention period (T3). The modalities used to quantify airway volume included AR in 6 studies (15–17, 53, 62, 64), CBCT in 8 studies (54, 55, 57–59, 67, 68, 70), CT in 6 studies (16, 56, 60, 61, 63, 65), surface laser scanning in one study (60), and photogrammetry in one study (66).

Figure 1. Flow diagram for the identification and selection of studies. RME, rapid maxillary expansion.

Risk of bias within studies

The risk of bias assessment for all included randomized and non- randomized trials is given in Tables 1 and 2, respectively. The inter- examiner consensus was that the risk of bias was high for all included studies. Most common biases observed were selection bias, sampling bias (due to differing inclusion/exclusion criteria), inexistent or problematic randomization, and allocation concealment. Blinding of treatment providers and patients was not feasible, as RME use was obvious, while only one randomized trial (58) attempted blinding during outcome assessment. Performance bias due to differences in care between groups was not deemed to be substantial within indi- vidual studies.

Results of individual studies, synthesis of results, and risk of bias across studies

The results of all included studies and the various upper airways volumes that were measured are listed in Supplementary Tables 9 and 10, respectively.

Total airway volume

The results of data synthesis regarding the primary outcome of total airway volume can be seen in Table 3. As, however, no controlled clinical trials were available, results are based solely on cohort stud- ies of only treated patients and therefore should be interpreted with caution as a quantitative overview of the RME-induced changes  on the upper airway. As far as total airway volume is concerned, patients treated with RME showed a significant increase both post- expansion (5 studies; increase from baseline: 1218.3 mm3; 95 per cent CI: 702.0–1734.6 mm3), which did not seem to considerably diminish after the retention period (11 studies; increase from base- line: 1143.9 mm3; 95 per cent CI: 696.9–1590.9 mm3) (Figure 2).

Table 1. Risk of bias of the included randomized clinical trial

Airway volumes of the various regions

As far as changes in the various upper airway regions are con- cerned, the results of data synthesis are given in Tables 4 and 5 and Supplementary Table 12.

The effect of RME on the nasal airway volume could be assessed both from controlled clinical studies and cohort studies of treated patients. As far as controlled studies using AR are concerned, RME was associated with a statistically significant increase in the nasal volume compared to untreated patients both after expansion and after the retention period (Table 4). Additionally, this increase was consistent in both basal and decongested conditions of the nasal cav- ity. Assessment of the results with the GRADE approach indicated that the quality of evidence for this increase was ‘very low’, due to the nature of the included studies and serious methodological limita- tions (Table 5).

Additionally, based on cohort studies of treated patients RME was associated with increased nasal cavity volume measured by CT, AR in the basal condition, and AR in the decongested condi- tion, although this was statistically significantly only for the latter. Additionally, this increase seemed to diminish slightly from post- expansion (increase of 69.0 mm3) to post-retention (25.8 mm3), although remaining statistically significant.

Furthermore, RME was associated with an increase in the CT-measured volume of the velopharynx (1201.2 mm3 post-reten- tion), the nasopharynx (662.3 mm3 post-expansion; 396.7 mm3 post-retention), the oropharynx (390.4 mm3 post-expansion;

70.7 mm3 post-retention), and the hypopharynx (170.0 mm3 post-retention). However, most of these volumes were not statis- tically significantly increased from baseline, presumably due to the limited number of contributing studies, their small samples, and the resulting low statistical power. In any case, caution is warranted in the interpretation of these findings, as no control groups were included to factor out the normal growth of the upper airways.

Additional analyses

Due to the limited number of studies in the meta-analyses, subgroup analyses could be performed only for two outcomes: the total air- way volume and the total nasal cavity volume, both measured post- retention with CT (Supplementary Table 13). No significant effect on the RME-induced volume increase could be found for patient age, patient sex, and appliance design.

As far as the assessment of reporting biases (including the possi- bility of publication bias is concerned) only one meta-analysis with at least 10 studies was included, assessing the total airway volume post- retention with CT. As can be seen in the contour-enhanced funnel plot (Figure 3) and the results of Egger’s test, no considerable indications of reporting biases could be found (Supplementary Table 13).

Finally, although various sensitivity analyses were initially planned, these could not be robustly performed, due to the small number and the characteristics of the included studies. The only sensitivity analysis that could be performed was the assessment of difference in the effects between prospective and retrospective stud- ies. Prospective studies tended to report considerably smaller total volume increases after RME compared to retrospective studies (dif- ference = −560.9 mm3; 95 per cent CI = −2139.5 to 1017.8 mm3), although this difference was not statistically significant (P = 0.442).

DISCUSSION

Summary of evidence

This systematic review summarized evidence on the effect of RME on the upper airway volume from clinical studies in humans. However, the results have to be considered with caution, due to the limited number of existing studies and serious methodological issues in their conduct.

In a previous systematic review, Baratieri et al. (27) investigated the long-term effects of RME on airway dimensions and functions. The authors included studies reporting 2D linear measurements from X-rays, nasal volume and minimal cross-sectional areas from CBCTs and AR and functional parameters such as nasal airway resistance and airflow as measured with rhinomanometry. They con- cluded that moderate evidence exists as to improvement of nasal breathing after RME in growing patients and these results are sta- ble for at least 11 months after treatment. However, in the present systematic review, we expanded the selection criteria in studies that not only evaluated volumetric changes in the nasal cavity but also in all upper airway areas. Moreover, studies reporting results after a retention period of more than 8months were excluded from our study in an attempt to reduce the effect of growth and evaluate the net result of RME.

The main finding of the present review was that RME is associ- ated with an increase in the total volume of the upper airway as well as the volume of the various regions of the upper airway. This increase seemed to be consistent to the various measurement modali- ties used in the studies and slightly diminished during the retention period. Although the type of expander appliance used varied amongst studies, no considerable differences were found based on appliance design. Additionally, some inconsistency existed across studies with regards to the definition of airway region borders. International consensus on region limits does not currently exist, particularly the landmarks or planes used to demarcate the junction of the nasal cavity and nasopharynx and between regions of the pharynx. This can lead to discrepancies between studies referring to similar airway spaces, although this has a smaller effect on the primary outcome of this review, which was the total airway volume. Also, various study designs were included, which have been shown to be associated with different extents of bias (41, 42), and this might explain part of the observed variability in the results.

When considering the nasal cavity volume, very low-quality evidence according to the GRADE approach indicates that RME is associated with a modest but consistent increase in volume measured by AR (Table 5). This is seen in both basal and decongested con- ditions, while uncontrolled CT-based evidence from cohort studies seems to back up this notion (Supplementary Table 12).

Table 2. Risk of bias assessment of the included non-randomized studies.

Table 3. Results of meta-analyses regarding the main outcome (total airway volume in mm3) only in treated groups. AR, acoustic rhinom- etry; CI, confidence interval; CT, computed tomography.

Figure 2. Contour-enhanced forest plot for the meta-analysis of the primary outcome (post-pre total airway volume change in mm3) in the patients treated with rapid maxillary expansion. Contours indicate increasing effect magnitude from the middle line-of-no-effect outwards (±2000.0, ±4000.0, ±8000.0 mm3 used as cut-offs to indicate moderate, large, and very large effects, respectively). Studies to the right indicate that the upper airway volume was increased compared to baseline. CI, confidence interval; NR, not reported; RME, rapid maxillary expansion.

Table 4. Results of meta-analyses on total nasal cavity volume in mm3 from studies with untreated controls (change in treated pa- tients minus change in untreated patients)*. AR, acoustic rhinom- etry; CI, confidence interval; MD, mean difference.

*I2 with its associated 95% intervals and 95% predictive intervals could not be calculated.

Amongst AR studies, initial subject age seemed to possibly correlate with the magnitude of the effect size, with younger initial age producing larger effect sizes. This descriptive trend was demonstrated in both decongested and non-decongested groups. Explanation is likely due to the reduced resistance in the bony sutures. Thus, nasal cavity vol- ume increase might be more pronounced in growing young subjects. Additionally, RME appears to increase the volume of the anterior nasal cavity based on CT measurements. The implications of dimen- sional increases in this zone are important, as it represents the region of greatest nasal airflow-resistance in most people (72) and a number of authors attribute improvements in nasal breathing to nasal valve enlargement (11).

There is much debate over the validity of CT and CBCT volumet- ric analysis in the measurement of function airway spaces. Topical contrast agents have been suggested to improve accuracy in defining soft tissue surfaces (73), an alternative that was not used in any of the included studies. Only a few studies that use CBCT for airway volume calculation describe using any form of standardization of patient positioning and protocol during image capture. This is par- ticularly relevant in the retrospective studies where airway standard- ization at capture would be unlikely to have occurred, unless future airway assessments were foreseen at the time. Vertical position in conjunction with a neck-brace and apparatus to orient natural head posture among other standards of breathing, swallowing and occlu- sion has been incorporated in order to obtain data with minimized variation (54). It has been shown that airway dimensions change according to head posture (74) and these changes were attributed to gravity acting on the relaxed soft palate, tongue and hyoid bone positions. More precisely, anteroposterior dimensions at the level of the velopharynx and sagittal cross-sectional areas of both velophar- ynx and oropharynx were decreased in response to body position change from upright to supine when measured in lateral cephalo- grams (75), indicating another factor that might increase heterogene- ity amongst studies.

Table 5. Summary of findings table according to the GRADE approach for the primary outcome results from studies with untreated con- trol group. Patients: patients with posterior crossbite or an anteriorly constricted maxillary arch in need of maxillary expansion. Settings: university clinic (Turkey). Intervention: conventional of fan-type rapid maxillary expansion. Comparison: patients with ideal occlusion that did not receive any treatment. AR, acoustic rhinometry; CI, confidence interval; GRADE, Grading of Recommendations Assessment, Devel- opment and Evaluation; MD, mean difference; RME, rapid maxillary expansion.

*GRADE starts from “low”, due to the inclusion of non-randomized studies. Downgraded further by one point for high risk of bias.

Figure 3. Contour-enhanced funnel plots for the assessment of reporting biases (including small-study effects and the possibility of publication bias).

Additionally, pharyngeal airway space (PAS) dimensions are closely related to both sagittal and vertical skeletal pattern. When CBCT reconstructions were used to evaluate linearly and volu- metrically the dimensions of PAS in children with different growth patterns, it was found that as the SNB angle was decreasing, linear measurements of PAS at the level of the uvula, uvula tip, mandibular line and back of the tongue also decreased. This trend was also con- sistent in regards to airway volume, airway area and minimum axial area. Further investigation on the effect of vertical facial type on PAS revealed that the hyperdivergent growth pattern was associated with reduced linear values at the level of the uvula tip. Conclusively, dimensions were significantly reduced in hyperdivergent patients with retrognathic mandibles (76). In the present systematic review, included studies did not provide information on grouping patients according to initial anteroposterior or vertical relationships. As airway dimensions differ according to the skeletal pattern, an addi- tional confounding factor at the baseline of the included studies increases heterogeneity of the sample and possibly creates individual variations in patients’ airway response to RME.

The ethical questions raised regarding the use of a control group relate to withholding RME treatment from a group of patients who are at an appropriate age for it for the purpose of acting as a control and to radiation exposure. Depending on the settings, full CBCT images of the head can produce dosages from 68–368 µSv (77). Keeping in mind the stochastic nature of the effect of ionizing radia- tion (78, 79), it might not be appropriate to subject a control group to multiple radiation exposures in relatively close succession.

Although cross-sectional area and respiratory indices were not considered in this review, the implication of increases in volume in the airway is the potential for improvements in compromised func- tional respiratory features. Further research in this area is required in order to provide better evidence on the normal growth changes in volumetric parameters during the growth period and possible respiratory effects that may occur from them. Given technological advancements in diagnostics and accuracy, it is hoped that care- ful attention to experimental design and conduct will allow for future results of sufficient strength to answer these questions more definitively.

As far as the generalizability/applicability of results is concerned, the results of this review might be applicable to the average growing patient with transverse maxillary constriction, as the eligibility cri- teria used for study selection were broad and most included studies were conducted in pragmatic conditions. As a random-effects model was used for the meta-analysis, the 95 per cent prediction intervals should be used for interpretation; these incorporate existing hetero- geneity and provide the range of possible effects of RME on airway volume. However, caution should be exerted during the interpreta- tion of the results, due to the high risk of bias and the fact that subgroup analyses could not be adequately used to describe the ideal candidates for RME.

Strengths and limitations

The strengths of this systematic review include the extensive litera- ture search, the duplicate and blinded review procedures, and the assessment of the quality of evidence with the GRADE approach. All procedures of the qualitative synthesis were conducted under the guidelines of the Cochrane Handbook (29) and the PRISMA statement (30), while attempts were made to minimize bias dur- ing quantitative synthesis (80), and no signs of reporting bias were identified.

The main shortcoming of this systematic review is the limited number of existing studies, most of which are non-randomized studies with serious methodological limitations. Additionally, most existing studies do not have a control group to reduce the con- founding effect of normal growth. As the aim of this review was   to determine the immediate effect of RME on airway volume, it was assumed that within the short experimental period of up to    8 months of the included studies the degree of growth effects occur- ring would be small. The dimensions of children’s airways between 6 and 15 years increase at a normal rate of 0.032 cm2/year (81), implying that the volume increase found in the present study can- not be attributed to growth alone. However, this cannot be com- pletely ruled out and future well-designed prospective controlled studies are needed to confirm this finding. Additionally, it was not possible to correlate overall the volumetric changes observed with the amount of RME activation because complete data on amount and appliance type was not provided by all studies. Finally, while sources of heterogeneity and robustness of the results were planned to be checked with subgroup and sensitivity analyses, respectively, most of these analyses could not be performed. The clinical hetero- geneity at the level of assessed appliances, expansion protocols, cho- sen outcomes, and measurement methods is evident and precludes any robust clinical suggestions on the effect of RME on upper air- way volume.

CONCLUSIONS

Evidence from existing controlled and uncontrolled clinical studies indicates that RME in growing patients with transversal maxillary constriction might be associated with a short-term increase in the total upper airway volume and most of the separate airway volumes. However, the results should be interpreted with caution, due to the small number of included trials and serious methodological issues, which might affect the risk of bias. Future well-conducted prospec- tive controlled clinical studies on growing patients are needed in order to recommend the use of RME to increase the upper airway volume in an evidence-based and predictable way.

SUPPLEMENTARY MATERIAL

Supplementary material is available at European Journal of Orthodontics online.

ACKNOWLEDGEMENTS

The authors would like to thank Professor Carla Evans for providing raw data of the Oliveira De Felippe et al. 2008 study, Associate Professor Oral Sökücü for providing clarifications on no sample overlapping within their different stud- ies, Dr Lam Cheng and Dr Jessica Li for translating articles written in Chinese language and Lajos Bordas (librarian) at the Faculty of Dentistry, for assistance and guidance with the online databases and developing the search strategies.

CONFLICT OF INTEREST

None declared.

REFERENCES

1. Angell, E.H. (1860) Treatment of irregularity of the permanent or adult teeth. Dental Cosmos, 1, 540–544.
2. Bishara, E. and Staley, R.N. (1987) Maxillary expansion: clinical impli- cations. American Journal of Orthodontics and Dentofacial Orthopedics, 91, 3–14.
3. Haas, J. (1961) Rapid expansion of the maxillary dental arch and nasal cavity by opening the midpalatal suture. The Angle Orthodontist, 31, 73–90.
4. Baccetti, , Leonardi, M. and Armi, P. (2008) A randomized clinical study of two interceptive approaches to palatally displaced canines. European Journal of Orthodontics, 30, 381–385.
5. Derichsweiler, (1953) The disjunction of the midpalatal suture. Trans- actions of the European Orthodontic Society, 29, 257–265.
6. Gray, P. (1987) Rapid maxillary expansion and impaired nasal respira- tion. Ear, Nose, and Throat Journal, 66, 248–251.
7. White, C., Woodside, D.G. and Cole, P. (1989) The effect of rapid maxil- lary expansion on nasal airway resistance. Journal of Otolaryngology, 18, 137–143.
8. Hartgerink, V., Vig, P.S. and Abbott, D.W. (1987) The effect of rapid maxillary expansion on nasal airway resistance. American Journal of Orthodontics and Dentofacial Orthopedics, 92, 381–389.
9. Pirelli, , Saponara, M. and Attanasio G. (2005) Obstructive Sleep Apnoea Syndrome (OSAS) and rhino-tubaric disfunction in children: therapeutic effects of RME therapy. Progress in Orthodontics, 6, 48–61.
10. Taşpinar,, Uçüncü, H. and Bishara, S.E. (2003) Rapid maxillary expan- sion and conductive hearing loss. The Angle orthodontist, 73, 669–673.
11. Koudstaal, M.J., Poort, L.J., van der Wal, G., Wolvius, E.B., Prahl- Andersen, B. and Schulten, A.J. (2005) Surgically assisted rapid maxillary expansion (SARME): a review of the literature. International Journal of Oral and Maxillofacial Surgery, 34, 709–714.
12. Zavras, A.I., White, G.E., Rich, A. and Jackson, A.C. (1994) Acoustic rhi- nometry in the evaluation of children with nasal or oral respiration. The Journal of Clinical Pediatric Dentistry, 18, 203–210.
13. Vig, W. (1998) Nasal obstruction and facial growth: the strength of evidence for clinical assumptions. American Journal of Orthodontics and Dentofacial Orthopedics, 113, 603–611.
14. Guijarro-Martínez, R. and Swennen, G.R. (2011) Cone-beam computer- ized tomography imaging and analysis of the upper airway: a systematic review of the International Journal of Oral and Maxillofacial Surgery, 40, 1227–1237.
15. Babacan, H., Sokucu, , Doruk, C. and Ay, S. (2006) Rapid maxillary expansion and surgically assisted rapid maxillary expansion effects on nasal volume. The Angle Orthodontist, 76, 66–71.
16. Doruk, C., Sökücü, , Biçakçi, A.A., Yilmaz, U. and Taş, F. (2007) Com- parison of nasal volume changes during rapid maxillary expansion using acoustic rhinometry and computed tomography. European Journal of Orthodontics, 29, 251–255.
17. Cappellette, , Jr, Cruz, O.L., Carlini, D., Weckx, L.L. and Pignatari,S.S. (2008) Evaluation of nasal capacity before and after rapid maxillary expansion. American Journal of Rhinology, 22, 74–77.
18. Kanomi, R., Deguchi, , Kakuno, E., Takano-Yamamoto, T. and Roberts,W.E. (2013) CBCT of skeletal changes following rapid maxillary expan- sion to increase arch-length with a development-dependent bonded or banded appliance. The Angle Orthodontist, 83, 851–857.
19. Lenza, M.G., Lenza, M.M., Dalstra, M., Melsen, B. and Cattaneo, M. (2010) An analysis of different approaches to the assessment of upper air- way morphology: a CBCT study. Orthodontics and Craniofacial Research, 13, 96–105.
20. Weissheimer, , Menezes, L.M., Sameshima, G.T., Enciso, R., Pham, J. and Grauer, D. (2012) Imaging software accuracy for 3-dimensional analy- sis of the upper airway. American Journal of Orthodontics and Dentofa- cial Orthopedics, 142, 801–813.
21. Aboudara, , Nielsen, I., Huang, J.C., Maki, K., Miller, A.J. and Hatcher,(2009) Comparison of airway space with conventional lateral headfilms and 3-dimensional reconstruction from cone-beam computed tomogra- phy. American Journal of Orthodontics and Dentofacial Orthopedics, 135, 468–479.
22. Liang,X. et et al. (2010) A comparative evaluation of Cone Beam Com- puted Tomography (CBCT) and Multi-Slice CT (MSCT) Part I. On subjec- tive image quality. European Journal of Radiology, 75, 265–269.
23. Hilberg, , Jackson, A.C., Swift, D.L. and Pedersen, O.F. (1989) Acous- tic rhinometry: evaluation of nasal cavity geometry by acoustic reflection. Journal of Applied Physiology, 66, 295–303.
24. Wight, R.G. and Cochrane, (1990) A comparison of the effects of two commonly used vasoconstrictors on nasal mucosal blood flow and nasal airflow. Acta Oto-Laryngologica, 109, 137–141.
25. Terheyden, H., Maune, S., Mertens, J. and Hilberg, (2000) Acoustic rhinometry: validation by three-dimensionally reconstructed computer tomographic scans. Journal of Applied Physiology, 89, 1013–1021.
26. Hilberg, and Pedersen, O.F. (1996) Acoustic rhinometry: influence of paranasal sinuses. Journal of Applied Physiology, 80, 1589–1594.
27. Baratieri, C., Alves, M., Jr, de Souza, M.M., de Souza Araújo, T. and Maia, L.C. (2011) Does rapid maxillary expansion have long-term effects on airway dimensions and breathing? American Journal of Orthodontics and Dentofacial Orthopedics, 140, 146–156.
28. Guyatt, G.H., Oxman, A.D., Schünemann, H.J., Tugwell, and Knottnerus, A. (2011) GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. Journal of Clinical Epidemiology, 64, 380–382.
29. Higgins, P.T. and Green, S. (eds) (2011) Cohrane handbook for system- atic reviews and intervensions. Version 5.1.0, updated March 2011, The Cochrane Collaboration. www.cochrane-handbook.org (10 May 2015, date last accessed).
30. Liberati,A., et al.et al. (2009) The PRISMA statement for reporting sys- tematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Journal of Clinical Epidemiol- ogy, 62, e1–e34.
31. Beller, M., et al.et al.; PRISMA for Abstracts Group (2013) PRISMA for Abstracts: reporting systematic reviews in journal and conference abstracts. PLOS Medicine, 10, e1001419.
32. Jørgensen, W., Hilden, J. and Gøtzsche, P.C. (2006) Cochrane reviews compared with industry supported meta-analyses and other meta-analyses of the same drugs: systematic review. British Medical Journal, 333, 782.
33. Morris, I.R. (1988) Functional anatomy of the upper airway. Emergency Medicine Clinics of North America, 6, 639–669.
34. Pohunek, (2004) Development, structure and function of the upper air- ways. Paediatric Respiratory Reviews, 5, 2–8.
35. Higgins,J.P., et et al.; Cochrane Bias Methods Group, Cochrane Statisti- cal Methods Group (2011) The Cochrane Collaboration’s tool for assess- ing risk of bias in randomised trials. British Medical Journal, 343, d5928.
36. NIH (2014) Quality assessment tool for before-after (pre-post) studies with no control group. http://www.nhlbi.nih.gov/health-pro/guidelines/ in-develop/cardiovascular-risk-reduction/tools/before-after February 2016 (date last accessed).
37. National Institute of Health and Clinical Excellence (2006) Methods for the Development of NICE Public Health Guidance. NICE,
38. Wells, A., Shea, B., O’Connell, D., Robertson, J., Peterson, J., Welch, V., Losos, M. and Tugwell, P. The Newcastle-Ottawa Scale (NOS) for assess- ing quality of nonrandomised studies in meta-analyses. http://www.ohri. ca/programs/clinical_epidemiology/oxford.asp February 2016 (date last accessed).
39. Stroup, F., Berlin, J.A., Morton, S.C., Olkin, I., Williamson, G.D., Ren- nie, D., Moher, D., Becker, B.J., Sipe, T.A. and Thacker, S.B. (2000) Meta- analysis of observational studies in epidemiology: a proposal for report- ing. The Journal of the American Medical Association, 283, 2008–2012.
40. Papageorgiou, N., Kloukos, D., Petridis, H., and Pandis, N. (2015) Pub- lication of statistically significant research findings in prosthodontics & implant dentistry in the context of other dental specialties. Journal of Den- tistry, 43, 1195–1202.
41. Papageorgiou, S.N., Xavier, M., Cobourne, M.T. (2015) Basic study design influences the results of orthodontic clinical investigations. Journal of Clinical Epidemiology, 68, 1512–1522.
42. Papageorgiou, S.N., Koretsi, and Jäger, A. Bias from historical control groups used in orthodontic research: a meta-epidemiological study. Euro- pean Journal of Orthodontics, Apr 29. pii: cjw035. [Epub ahead of print].
43. DerSimonian, R. and Laird, N. (1986) Meta-analysis in clinical Controlled Clinical Trials, 7, 177–188.
44. Papageorgiou, N. (2014) Meta-analysis for orthodontists: part I–how to choose effect measure and statistical model. Journal of Orthodontics, 41, 317–326.
45. Higgins, P. and Thompson, S.G. (2002) Quantifying heterogeneity in a meta-analysis. Statistics in Medicine, 21, 1539–1558.
46. Ioannidis, P., Patsopoulos, N.A. and Evangelou, E. (2007) Uncertainty in het- erogeneity estimates in meta-analyses. British Medical Journal, 335, 914–916.
47. Higgins, P., Thompson, S.G. and Spiegelhalter, D.J. (2009) A re-evalua- tion of random-effects meta-analysis. Journal of the Royal Statistical Soci- ety. Series A, (Statistics in Society), 172, 137–159.
48. Ioannidis, P. (2008) Interpretation of tests of heterogeneity and bias in meta-analysis. Journal of Evaluation in Clinical Practice, 14, 951–957.
49. Norman, G.R., Sloan, J.A. and Wyrwich, W. (2003) Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation. Medical Care, 41, 582–592.
50. Knapp, G. and Hartung, J. (2003) Improved tests for a random effects meta-regression with a single covariate. Statistics in Medicine, 22, 2693–2710.
51. Song, , Khan, K.S., Dinnes, J. and Sutton, A.J. (2002) Asymmetric funnel plots and publication bias in meta-analyses of diagnostic accuracy. Inter- national Journal of Epidemiology, 31, 88–95.
52. Egger, , Davey Smith, G., Schneide, M. and Minder, C. (1997) Bias in meta-analysis detected by a simple, graphical test. British Medical Journal, 315, 629–634.
53. Kabalan, , Gordon, J., Heo, G. and Lagravère, M.O. (2015) Nasal air- way changes in bone-borne and tooth-borne rapid maxillary expansion treatments. International Orthodontics, 13, 1–15.
54. Zeng, J. and Gao, X. (2013) A prospective CBCT study of upper airway changes after rapid maxillary expansion. International Journal of Pediatric Otorhinolaryngology, 77, 1805–1810.
55. Chang, , Koenig, L.J., Pruszynski, J.E., Bradley, T.G., Bosio, J.A. and Liu, D. (2013) Dimensional changes of upper airway after rapid maxillary expansion: a prospective cone-beam computed tomography study. Ameri- can Journal of Orthodontics and Dentofacial Orthopedics, 143, 462–470.
56. Smith, , Ghoneima, A., Stewart, K., Liu, S., Eckert, G., Halum, S. and Kula, K. (2012) Three-dimensional computed tomography analysis of air- way volume changes after rapid maxillary expansion. American Journal of Orthodontics and Dentofacial Orthopedics, 141, 618–626.
57. Ribeiro, N., de Paiva, J.B., Rino-Neto, J., Illipronti-Filho, E., Trivino, T. and Fantini, S.M. (2012) Upper airway expansion after rapid maxillary expansion evaluated with cone beam computed tomography. The Angle Orthodontist, 82, 458–463.
58. Pangrazio-Kulbersh, , Wine, P., Haughey, M., Pajtas, B. and Kaczynski, (2012) Cone beam computed tomography evaluation of changes in the naso-maxillary complex associated with two types of maxillary expand- ers. The Angle Orthodontist, 82, 448–457.
59. Darsey, M., English, J.D., Kau, C.H., Ellis, R.K. and Akyalcin, S. (2012) Does hyrax expansion therapy affect maxillary sinus volume? A cone- beam computed tomography report. Imaging Science in Dentistry, 42, 83–88.
60. Cordasco, , Nucera, R., Fastuca, R., Matarese, G., Lindauer, S.J., Leone, P., Manzo, P. and Martina, R. (2012) Effects of orthopedic maxillary expansion on nasal cavity size in growing subjects: a low dose computer tomography clinical trial. International Journal of Pediatric Otorhinolar- yngology, 76, 1547–1551.
61. Görgülü, S., Gokce, S.M., Olmez, H., Sagdic, and Ors, F. (2011) Nasal cavity volume changes after rapid maxillary expansion in adolescents eval- uated with 3-dimensional simulation and modeling programs. American Journal of Orthodontics and Dentofacial Orthopedics, 140, 633–640.
62. Sökücü, , Doruk, C. and Uysal, O.I. (2010) Comparison of the effects of RME and fan-type RME on nasal airway by using acoustic rhinometry. The Angle Orthodontist, 80, 870–875.
63. Haralambidis, A., Ari-Demirkaya, A., Acar, , Kücükkeleş, N., Ateş, M. and Ozkaya, S. (2009) Morphologic changes of the nasal cavity induced by rapid maxillary expansion: a study on 3-dimensional computed tomography models. American Journal of Orthodontics and Dentofacial Orthopedics, 136, 815–821.
64. Oliveira De Felippe, L., Da Silveira, A.C., Viana, G., Kusnoto, B., Smith, and Evans, C.A. (2008) Relationship between rapid maxillary expan- sion and nasal cavity size and airway resistance: short- and long-term effects. American Journal of Orthodontics and Dentofacial Orthopedics, 134, 370–382.
65. Palaisa, J., Ngan, , Martin, C. and Razmus, T. (2007) Use of conven- tional tomography to evaluate changes in the nasal cavity with rapid palatal expansion. American Journal of Orthodontics and Dentofacial Orthopedics, 132, 458–466.
66. Marini, I., Bonetti, G.A., Achilli, and Salemi, G. (2007) A photogram- metric technique for the analysis of palatal three-dimensional changes during rapid maxillary expansion. European Journal of Orthodontics, 29, 26–30.
67. Almuzian, M., Ju, X., Almukhtar, A., Ayoub, A., Al-Muzian, L. and McDonald, P. (2016) Does rapid maxillary expansion affect naso- pharyngeal airway? A prospective Cone Beam Computerised Tomography (CBCT) based study. Surgeon, Jan 27. pii: S1479-666X(15)00125-0. doi: 10.1016/j.surge.2015.12.006. [Epub ahead of print].
68. Azaredo, (2014) Mestrado en Odontologia. Area de Concentracao: orthodontia and Ortopedia facial. Avaliacao tridimensional das vias aer- eas oropharyngeal em pacientes com e sem fissural labio-palatal submeti- dos a expansao maxilar. Pontificia Universidade Catolica Do Rio Grande Do Sul, Facultade de Odontologia, Porto Alegre, Brazil.
69. Chang, H. (2011) Effects of rapid maxillary expansion on upper airway; a 3 dimensional cephalometric analysis. Master’s thesis, Marquette Uni- versity.
70. Li, L., Qi, S., Wang, , Ren, S. and Ban, J. (2015) Cone-beam CT evalu- ation of nasomaxillary complex and upper airway following rapid maxil- lary expansion. Chinese Journal of Stomatology, 50, 403–407.
71. Ribeiro, N.C. (2011) Assessment of upper airway before and after rapid maxillary expansion using cone beam computed tomography. Disserta- tion, Universidade de São Paulo, Faculdade de Odontologia.
72. Proctor, F. and Andersen, I.H.P. (1982) The Nose, Upper Airway Physi- ology and the Atmospheric Environment. Elsevier Biomedical Press, Amsterdam, The Netherlands.
73. Alsufyani, N.A., Noga, M.L., Finlay, H. and Major, P.W. (2013) Topi- cal contrast agents to improve soft-tissue contrast in the upper airway using cone beam CT: a pilot study. Dento Maxillo Facial Radiology, 42, 20130022.
74. Alsufyani, N.A., Al-Saleh, M.A. and Major, W. (2013) CBCT assessment of upper airway changes and treatment outcomes of obstructive sleep apnoea: a systematic review. Sleep and Breathing, 17, 911–923.
75. Tsuiki, , Almeida, F.R., Bhalla, P.S., Lowe, A.A. and Fleetham, J.A. (2003) Supine-dependent changes in upper airway size in awake obstructive sleep apnea patients. Sleep and Breathing, 7, 43–50.
76. Alves, M., Jr, Franzotti, E.S., Baratieri, C., Nunes, L.K., Nojima, L.I. and Ruellas, A.S. (2012) Evaluation of pharyngeal airway space amongst dif- ferent skeletal International Journal of Oral and Maxillofacial Surgery, 41, 814–819.
77. Pauwels,R., et al.et al.; SEDENTEXCT Project Consortium (2012) Effec- tive dose range for dental cone beam computed tomography scanners. European Journal of Radiology, 81, 267–271.
78. Halazonetis, J. (2012) Cone-beam computed tomography is not the imag- ing technique of choice for comprehensive orthodontic assessment. Ameri- can Journal of Orthodontics and Dentofacial Orthopedics, 141, 403–411.
79. Ludlow, J.B. (2009) Dose and risk in dental diagnostic imaging: with emphasis on dosimetry of Korean Journal of Oral and Maxillofa- cial Radiology, 39, 175–184.
80. Papageorgiou, N. (2014) Meta-analysis for orthodontists: Part II–Is all that glitters gold? Journal of Orthodontics, 41, 327–336.
81. Warren, D.W., Hairfield, W.M. and Dalston, E.T. (1990) Effect of age on nasal cross-sectional area and respiratory mode in children. Laryngoscope, 100, 89–93.