Ear mould for congenital auricular deformities: a protocol for systematic review and meta-analysis

Background: Congenital auricle deformities (CADs) not only affect the appearance, but may also result in social inferiority or diculties, inuence the hearing and mental health of the children. Although some studies have pointed out CADs have a natural improvement trend, there is still a lack of high-quality research to demonstrate the degree of that. Therefore, related studies agree that early treatment are necessary. Ear mold correction is currently main non-surgical treatment for CADs, but the existing research often involves a small sample size, and the research conclusions are inconsistent. More importantly, there is still no systematic review on ear mold correction for CADs. This study aims to systematically evaluate the effectiveness and safety of ear mold correction for CADs, so as to provide an evidence base for further research. Methods: The study has been designed according to the Preferred Reporting program for Systems Evaluation and Meta-analysis Protocol (PRISMA-P). We will search electronic literature databases of PubMed, Embase, Cochrane Library, Web of science, CBM, CNKI, Wanfang and VIP from their initiative to 1 June 2020 for interventional studies on ear mould for children with CADs. The study selection, data extraction and quality assessment will be performed by two authors. Meta-analysis will be conducted on primary outcome effectiveness rate of physician assessment and secondary outcomes of effectiveness rate of parents’ assessment, effectiveness score, hearing assessment, and adverse reactions using relative ratio or mean difference and their 95% condence intervals. The heterogeneity of the included studies will be tested using Chi square test and I 2 , and random-effects model will be used when signicant heterogeneity was found, otherwise, xed-effects model will be used. Sensitivity analysis will be performed using trials with high quality and using alternative [1]models (xed-effects or random effects model). Publication bias will be tested using funnel plot and Egger’s test. Discussion: This study will be the rst to systematically evaluate the effectiveness and safety of ear mold correction for CADs, to provide evidence base for clinical guideline making, clinical decision and future research. synthesis of evidence of ear mold correction for CADs, which will provide basis for clinical guideline making, clinical decision and further empirical research.

1 June 2020 for interventional studies on ear mould for children with CADs. The study selection, data extraction and quality assessment will be performed by two authors. Meta-analysis will be conducted on primary outcome effectiveness rate of physician assessment and secondary outcomes of effectiveness rate of parents' assessment, effectiveness score, hearing assessment, and adverse reactions using relative ratio or mean difference and their 95% con dence intervals. The heterogeneity of the included studies will be tested using Chi square test and I 2 , and random-effects model will be used when signi cant heterogeneity was found, otherwise, xed-effects model will be used. Sensitivity analysis will be performed using trials with high quality and using alternative [1]models ( xed-effects or random effects model). Publication bias will be tested using funnel plot and Egger's test.
Discussion: This study will be the rst to systematically evaluate the effectiveness and safety of ear mold correction for CADs, to provide evidence base for clinical guideline making, clinical decision and future research.

Background
Congenital auricle deformities (CADs) are common among neonates. Tan ST, Leonardi and Eun Woo JE et al. [1][2][3] have all described their de nitions, generally thinking that it had a complete organizational structure, but with morphological abnormalities. Due to the lack of a uni ed de nition and diagnostic criteria, previous studies found that the incidence of CADs in Japan, China, and the United States was 55.20%, 43.46%, and 25.00%, respectively [4][5][6]. CADs not only affect the appearance, but may also result in social inferiority or di culties, in uence the hearing and mental health of the children [7]. Although Matsuo K et al. [8] in Japan found that different types of CADs have the tendency of natural improvement, there is still a lack of high-quality studies to demonstrate the degree of natural improvement. Therefore, it is suggested that treatment and correction should be carried out as early as possible [9][10][11].
The treatments of CADs includes surgical and non-surgical treatments. The former is mainly performed at the age of 6, and its effect is closely related to the type, severity and operation mode of the deformities [12][13][14]. In addition, surgery, as an invasive method, can bring complications such as suture extrusion, hematoma, wound depravation and skin necrosis, and at the same time, it is expensive and imposes a greater economic burden on families and society [15][16].
Non-surgical correction of CADs has been increasingly used since its rst introduced by Matsuo et al. [8] and Kurozumi et al. [17] in the 1980s, initially by splint and later evolved to ear (ear mold) orthotics. This method is non-invasive, simple, effective and has achieved good results at the beginning of its use, which has been unanimously recognized by the academic circle [18]. It has been reported that the clinical effect on early non-surgical correction for CADs is signi cant [19][20]. Therefore, it has been popularized successively in Japan, European and American countries, and different types of ear orthotics have appeared one after another In 2009, van Wijk MP et al. [21] reviewed the non-surgical treatment for CADs, and concluded that the clinical effect on early non-surgical correction for CADs by earmold was signi cant. However, only the splint correction was included in this review, and its data source was limited to Pubmed. Existing studies of ear mould for CADs often involved a small sample size, and there is still controversy on the effectiveness, safety, intervention time, and intervention duration of ear mould correction for CADs [22][23]. To our best knowledge, no systematic evaluation of ear mould for CADs has been made. Therefore, this study aims to systematically evaluate the effectiveness and safety of the ear model correction for CADs.

Research design and methodology
The review has been registered in the PROSPERO International Systematic Review Prospective Register (ID:CRD42020190982). This protocol has been prepared in accordance with the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) statement, as provided in Additional le.

Eligibility criteria
The inclusion and exclusion criteria for this systematic review were formulated following the PICOS principle: 1. Participants: children who was diagnosed as congenital CADs.
2. Interventions: ear mould correction for children with CADs.
3. Control: surgical treatment, other non-surgical treatment, placebo, no intervention, or before after comparison.
Only publications using English and Chinese will be included as we lack of resources to review research in other languages.

Search strategy
We will search the following databases: PubMed, Embase, Cochrane Library, CBM, CNKI, Wanfang and VIP, Web of science from their initiative to 1 june 2020. Key words and MeSH will be used including: congenital ear/auricular abnormalities, deformity, malformation, non-surgical treatment, ear mould/mold, Earwell. Reference lists of included studies will also be scanned for eligible studies. Preliminary Pubmed search strategy is showed in Table 1.

Outcome measures
The effectiveness rate according to physician assessment will be the main outcome. The following secondary outcomes will be considered: (1) Effectiveness rate according to parents'assessment. (2) Hearing assessment. (3) Adverse reactions including: redness or swelling of the skin, dermatitis, allergy, eczema, local infection, tissue necrosis, ear mould loss, recurrence of CAD, or other unexpected mild or severe adverse reactions.

Study selection
The two authors (JCH, YQM) will jointly lter the headings and abstracts of all checked records, and fulltext search will be conducted on the quali ed records screened, then these full-texts will be reviewed by using the above eligibility/exclusion criteria. Any differences arising will be resolved by a separate author's decision (LZ, KZ). Comprehensive information extraction of eligible articles will be carried out. The consistency between the evaluators will be evaluated using the kappa value [24].

Data extraction
The data will be independently extracted by two authors (JCH, YQM). Any disagreement will be resolved by discussion until consensus is reached or by consulting a third senior reviewer. The following data will be extracted: author, year of publication, language, study design, participants characteristics (gender, age, type of congenital deafness shape deformity sample size), intervention characteristics (start time, duration), control characteristics, and outcomes.

Risk of bias (quality) assessment
The risk bias of the included studies will be independently assessed by two authors (JCH, YQM), and the controversial opinions will be resolved after discussion with a senior author (LZ, KZ). The following dimensions of bias will be assessed according to the Cochrane Collaboration Bias Risk Assessment Tool [25]: selection bias, implementation bias, measurement bias, follow-up bias, reporting bias, and other biases of the included studies. The quality of evidence for each outcome will be appraised using the Grading of Recommendations Assessment Development and Evaluation (GRADE) approach. RevMan will be used to make a bias risk map or a screenshot of the bias risk to describe the risk of bias.

Data synthesis
Heterogeneity between included studies will be examined using I 2 and Chi square test. Fixed-effects model will be used when there is no substantial heterogeneity (I 2 <50%, P>0.05), otherwise, random-effects model will used [26]. For binary outcomes, such as the effectiveness rate according to physician assessment or parents' assessment, adverse events, relative ratio and risk difference and their 95% con dence intervals (CI) will be estimated. For continuous outcomes, such as improvement score, mean difference with 95% CI will be estimated. Publication bias will be tested using funnel plot and Egger's test.

Subgroup analysis and sensitivity analysis
Age, timing of intervention, duration of follow-up and race of the subjects will be classi ed and grouped, and the combined effects of each subgroup will be estiamted and compared, respectively. Sensitivity analysis will be performed using trials with high quality (low risk of bias) and using alternative models ( xed-effects or random effects model).

Discussion
The mechanism of non-surgical correction for CADs is that the newborn body contains a large amount of maternal estrogen, and the hormone reaches an obvious peak within 72 h after birth, which increases the concentration of hyaluronic acid in cartilage, thus increasing the ductility and plasticity of cartilage [27][28]. After that, the estrogen concentration gradually decreases and gradually returns to the normal level at 6 weeks after birth, and the plasticity and ductility of cartilage also decreases [29][30][31]. For this reason, the researchers emphasize early ear mold correction. However, researchers and medical professionals have no uni ed opinion on the timing and duration of ear mold correction. In addition, there is still a lack of systematic evaluation on ear mode correction for CADs. This study will be the rst systematic synthesis of evidence of ear mold correction for CADs, which will provide basis for clinical guideline making, clinical decision and further empirical research.

Authors'contributions
Conceived the study: LZ, YJF; study design: KZ, LZ, MY, PY, LHZ, JCH; will perform the study: JCH, KZ, LZ, LHZ ; will collect and manage the data: JCH, KZ, LHZ; will perform the statistical analysis: JCH, KZ, LHZ; wrote the draft: JCH, KZ, LZ, YJF, MY. All authors contribute to the revision and approved the nal manuscript.