Protocol and Registration

The study protocol was registered on PROSPERO (CRD42020168673). The report of this systematic review followed the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement.¹⁰

Eligibility Criteria

A PICOS (population, intervention, comparison, outcomes, study design) question was established as an inclusion criterion:

• Population (P): subjects of any gender without restriction of ethnicity or age, undergoing RME (orthopedic or surgical).

• Intervention (I): use of adjunctive interventions that included: laser irradiation, osteoperforation, pulsed electromagnetic waves, intermittent resonance vibration, pharmacological methods, or novel materials described by authors.

• Comparison (C): control group of subjects without the use of adjunctive interventions.

• Outcomes (O): the effectiveness of interventions was assessed using the following parameters: primary: stimulation of bone regeneration/healing; secondary: improvement in skeletal/dentoalveolar measurements, enhancement of the midpalatal sutural opening, decreased periodontal side effects (such as buccal alveolar bone thickness, bone loss, gingival recession), and greater stability.

• Study design (S): randomized clinical trial (RCT), quasirandomized clinical trial, or non-randomized clinical trial. The exclusion criteria were: case reports, animal and in vitro studies, descriptions of clinical technique, studies with orthodontic/orthopedic approaches performed concomitant with RME, studies that evaluated distraction osteogenesis, and studies evaluating individuals with craniofacial deformities, syndromes, or cleft lip/palates.

Information Sources and Search Strategy

Electronic searches in MEDLINE (via PubMed), Web of Science, Cochrane Library, Scopus and LILACS were conducted up to June 2020. Google Scholar was investigated to partially access the gray literature. The Controlled Trials Database of clinical trials (http://www.controlled-trials.com) and the Clinical Trials: U.S. National Institutes of Health (http://www.clinicaltrials.gov) were consulted to check for possible ongoing studies. Finally, manual searches in the reference list of the included articles were also carried out. There was no restriction of language, year, or status of publication for inclusion.

Detailed search strategies were developed for each database based on the search strategy developed for MEDLINE, and subsequently adapted for the other databases (Appendix).

Study Selection

In the first phase, two reviewers (LGS, LSM) independently and in duplicate screened the titles/abstracts of the references. Those that met the eligibility criteria were included. References with insufficient information in the title/abstract for a decision on inclusion or exclusion were retrieved for full-text evaluation. In the second phase, the full-texts were accessed and those studies that met the eligibility criteria were included. Agreement between reviewers was measured using the kappa index. In both phases, differences were resolved by consensus.

Data Extraction and Items Extracted

A standardized table was used to extract the following data: authors, year of publication, study design, characteristics of participants, description of groups and interventions, details of evaluations, and main findings. Data were compared for accuracy, and any discrepancy was resolved through reexamination of the original study.

Assessment of Bias Risk Within Studies

The risk of bias in RCT was assessed using the revised Cochrane risk-of-bias tool for randomized trials-2,¹¹ which includes the following domains: randomization processes; deviations from intended interventions; missing outcome data; measurement of outcome; and selective outcome reporting. After answering the signaling questions for each domain following the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions 6.0 (https://training.cochrane.org/handbook), each source of bias was graded as: “low” risk, “some concerns,” or “high” risk of bias.

Evaluation of the Level Evidence (Risk of Bias Across Studies)

The level of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation Pro software (GRADEpro Guideline Development Tool, available online at gradepro.org).¹² For each outcome examined, the GRADE assesses the number of studies included, the study designs, risk of bias, inconsistency, indirectness, imprecision, and other considerations (such as publication bias). Based on this assessment, the certainty of the evaluation of the outcome could be very low, low, moderate, or high quality.

Summary Measurements

Measurements were based on continuous data (millimeters or degrees) and nominal/ordinal data from clinical indices, dental casts, radiographs, or cone-beam computed tomography (CBCT).

Synthesis of Results

Data collected were synthetized in a descriptive table. A meta-analysis was planned if there was relative homogeneity among included studies.

Study Selection

The search strategy yielded a total of 2334 studies (Figure 1). After the removal of duplicates and application of the eligibility criteria, 19 studies were considered for full-text evaluation. Among them, 13 were excluded, and the reasons are provided in Table 1. Good agreement between the reviewers was found (Kappa index, 0.75). At the end of the eligibility phase, only six studies were included in this systematic review.

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Table 1.  List of Studies Excluded With Reasons After Full Text Evaluation

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Study Characteristics

Table 2 provides the descriptive characteristics of the included studies. All studies were RCT, and one⁹ used a non-parallel design (split-mouth). Concerning population items, a total of 63 individuals participated in the intervention group and 54 individuals were controls in studies with parallel design. A total of 18 individuals were enrolled in the split-mouth study.⁹ The mean age of participants at baseline ranged from 8⁸ to 17¹³ years. In one study,¹⁴ only the age range of the individuals included was reported. Four studies^9,13–15 reported the diagnosis of transverse maxillary deficiency as an inclusion criterion, while two^8,16 studies only cited the need for RME.

Table 2.  Summary of Study Characteristics and Results of the Included Studies^a

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Regarding the adjunctive interventions evaluated by the included studies, one study¹³ performed osteoperforations produced by the erbium-doped yttrium aluminium garnet (Erbium-YAG) laser along the region of the midpalatal suture. Three studies^8,15,16 carried out the application of low-level laser therapy (LLLT) around the midpalatal suture adjunctive to the orthopedic RME, and one study¹⁴ applied the laser after surgically assisted RME. Finally, one study⁹ used platelet-rich plasma (PRP) injected in the buccal alveolar mucosa along the roots of the anchoring teeth (first molars and first premolars).

All studies used the hyrax expander, with different activation protocols as described in Table 2. The mean time of posttreatment evaluation varied substantially and ranged from 75⁸ to 210¹⁴ days.

Risk of Bias Within Studies

The methodological appraisal of the included studies is reported in Figure 2. Overall, one study⁹ was judged to be “low” risk of bias for all domains. Three studies^8,14,16 were graded as having “some concerns” regarding bias arising from the randomization processes domain due to not reporting any information about allocation concealment. In addition, one study¹⁶ did not provide information regarding the blinding of the evaluator. Two studies were graded as overall “high” risk of bias. The first study¹⁵ carried out the randomization of the participants after the RME procedure, generating bias in randomization, in addition to dropping out of half of the participants in one of the groups, generating attrition bias. The second study¹³ failed to provide information about the randomization process and blinding outcome evaluators.

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Results of Individual Studies

Owing to a significant amount of population, clinical, methodological, and statistical heterogeneity, meta-analysis was not justifiable. Identified sources of heterogeneity were: distinct survey methods, different parameters to identify similar outcomes, studies with population undergoing orthopedic and surgical RME, and the different follow-up durations. Thus, a descriptive comparison was reported (Table 2).

As far as the pattern of changes in the midpalatal suture were concerned, three studies reported^8,15,16 that application of low-level laser in the suture region associated with orthopedic RME stimulated the suture opening or healing pattern. Improvement in the opening of the midpalatal suture was reported¹⁶ during the screw activation phase, with a significant decrease of 2.3-fold (P = .049) in bone density compared to the control group. During the retention phase, three studies reported^8,15,16 significant rates of stimulation of bone healing. The highest rate was a 3.5-fold (P = .017) acceleration after approximately 3 months.¹⁶ A study¹⁵ that used CBCT scans found similar values of bone repair in the suture region in the irradiated group after 4 months of retention (P < .005). Regarding the areas of the suture that had accelerated healing with the use of LLLT, the anterior superior (P = .008) and posterior (P = .001) margins of the suture in the laser group seemed to be the most sensitive to respond to the laser stimulus.⁸

Similar to the orthopedic RME, the application of LLLT adjunctive to surgically assisted RME¹⁴ in eight sessions at intervals of 48 hours after surgery led to a progressive increase in the rate of bone healing in the region of the midpalatal anterior suture compared to the control group, ranging from +10.6% in the first month to +26.3% after 7 months (P < .001). In addition, it was found that the mean rate of bone remineralization in patients in the control group after 7 months was similar to the average values found between the second and third months of patients who underwent laser application.

A high risk of bias study¹³ evaluated the application of Erbium-YAG laser to create osteoperforations in the suture region in subjects with maxillary atresia undergoing orthopedic RME. The outcomes evaluated were skeletal and dentoalveolar measurements, and the intervention group achieved more skeletal increase in lateronasal width (+2.19 mm, P < .001), maxillomandibular width (+3.94 mm, P < .001), maxillary width (+2.98 mm, P < .001) compared with the control group at the end of the expansion phase. After 3 months of retention follow-up, relapse was similar between the groups.

Regarding the methods to minimize the periodontal side effects of RME, a low risk of bias study⁹ evaluating the effectiveness of injection of PRP on the periodontal tissue found no significant differences (P > .05) in vertical bone loss (mean difference ranged from -0.08 mm to 0.2 mm) and buccal bone thickness (mean difference ranged from -0.15 to 0.85 mm) in anchorage teeth in patients after conventional RME when compared to patients in the group with injections with PRP. A higher prevalence of dehiscence (3.5%) was found in the intervention group for all supporting teeth.

Assessment of the Certainty of Evidence

The certainty of evidence was evaluated according to the GRADE approach (Table 3). Reasons for downgrading the evidence are detailed there. The level of certainty for the bone regeneration outcome was graded as moderate while, for the outcomes suture opening and reduction of periodontal side effects, levels of certainty were low. For the outcomes skeletal/dentoalveolar measurements, the certainty was graded as very low.

Table 2.  Extended

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Table 3.  GRADE Evidence Profile About Outcomes of Adjunctive Interventions With RME^a

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Summary of Evidence

This review systematically assessed the available evidence for the effectiveness and safety of adjunctive interventions in patients undergoing RME under the main aspect: bone healing in the suture region. In addition, the outcomes stimulation of suture opening, improvement of skeletal changes, and reduction of periodontal side effects were evaluated.

The results of this systematic review consistently suggested, with a moderate level of certainty, that interventions with LLLT were effective to increase bone mineralization in the midpalatal suture in children and adolescents after orthopedic RME. Likewise, the rate of bone remineralization in patients undergoing LLLT after surgical maxillary expansion seemed to be accelerated a few months compared to patients without laser intervention.¹⁴ The hypothesis is that the laser acted at the molecular level, stimulating osteoblastic activity.^17,18 A possible useful clinical interpretation of this result may be the prevention of relapse and the reduction of retention time by the local application of LLLT. Notwithstanding, at this time, it is not possible to draw conclusions about this with the current literature.

Current knowledge comparing different RME appliances indicated that no expander appeared to be superior when it came to opening the midpalatal suture, including bone-borne appliances.¹⁹ An important finding reported by this review was the facilitated and improved opening of the suture with the application of LLLT. Despite the low level of evidence, this outcome may represent some clinical benefits, such as the increased orthopedic effects and the arch perimeter of the therapy,³ a reduction in the loss in thickness and height of the buccal alveolar bone, and the frequency of dehiscence and fenestrations. Nevertheless, it is important to mention that the studies that used LLLT did not investigate the outcomes that are believed to have clinical importance.

The effectiveness of osteoperforations to improve skeletal changes in late adolescents and young adults undergoing RME was investigated using the Erbium-YAG laser. This method aimed to decrease sutural interdigitation to enable significant transverse skeletal changes in non-growing individuals through orthopedic maxillary expansion. The results indicated significant gains in the measures of maxillary width. However, it is important to note that in addition to the high risk of bias reported in the study¹³ that evaluated this intervention, the method was invasive and repeated over 3 months. In view of the possible need to repeat the procedure, further studies are needed evaluating outcomes such as acceptance among patients, pain/discomfort, and possible postoperative complications to make this intervention clinically realistic as an alternative to surgically assisted RME.

PRP used as adjunct to RME failed to produce any healing effect in periodontal tissue. Nevertheless, the evaluation was limited to post-retention, without assessing long-term changes and possible subsequent healing. The potential effect of periodontal regeneration caused by growth factors seemed to be more apparent after a few months.²⁰ Therefore, long-term studies are recommended to indicate the effectiveness of this therapy.

Two previous reviews^21,22 were conducted evaluating the effects of LLLT associated with RME regarding bone regeneration. However, those reviews did not consider the effect on dentoalveolar/skeletal measures, suture opening and periodontal health, as well as other adjuvant interventions were not considered. In one of them,²² the search was restricted to the English language, which probably limited the inclusion of potential studies, and the other review included results of animal studies.²¹ Additionally, no analysis of level of certainty supporting the conclusions was considered, which decreased confidence of the recommendations.

Limitations

A quantitative analysis was not feasible given the heterogeneity among the included studies. Fundamental questions such as survey methods and units of measurement used, stage of growth at the beginning of treatment, post-treatment follow-up, and the protocols for the application of the interventions used varied substantially and were a source of heterogeneity.

A qualitative review presents significant drawbacks in comparison to mathematical synthesis, since it becomes quite challenging to weigh the data coming from individual studies. The use of the GRADE tool should have taken this into consideration. A possible selection bias was avoided by extensive searches across multiple electronic databases and accessing partial gray literature without language or publication status restrictions.

This review included individuals without restriction of age or degree of maxillary transverse deficiency. These items may influence the effects of RME. Generally, the opening of the midpalatal suture becomes progressively more difficult as patients grow older.²³ Finally, several adjunctive interventions were investigated and some methods had only one study to be analyzed. This impacted the level of evidence certainty of some outcomes.

Implications for Practice and Research

The use of the LLLT is effective as an adjunct tool to facilitate the opening of the suture during the activation of the screw, and accelerates bone healing after orthopedic and surgical RME. It is important to emphasize that the clinical impact of these results still needs to be better elucidated. Osteoperforation along the midpalatal suture appears to increase the transverse skeletal gains of the maxilla in late adolescents and young adults. Nevertheless, the use of this intervention must be done carefully in clinical practice due to limited evidence.

There was great variation in the survey method used by the included studies to assess changes in the midpalatal suture. For this outcome, three-dimensional assessment using low-dose computed tomography can be considered more favorable.²⁴

Some RCTs failed to provide details on the sample size, sample randomization/allocation, blinding outcome assessor, and statistician. There is a need for well-designed and reported clinical trials following guidelines such as CONSORT (Consolidated Standards of Reporting Trials)²⁵ to increase the certainty of evidence about the proposed adjunctive methods to boost the benefits of RME. It is important that future studies assess the clinical significance of the improvement in opening of the suture (such as changes in the maxillary width and less periodontal side effects) and the stimulation of bone regeneration (such as the relapse rate and the possibility of reducing retention time). The clinical meaning of these variables is more relevant and may be a determining factor for RME therapy success.