Treatment of dental and orthodontic complications in thalassaemia

Abstract

Background

Thalassaemia is a quantitative abnormality of haemoglobin caused by mutations in genes controlling production of alpha or beta globins. Abnormally unpaired globin chains cause haemolytic anaemia by causing membrane damage and cell death within organ systems and destruction of erythroid precursors in the bone marrow. The life‐long management of the general health effects of thalassaemia in affected individuals is a highly challenging issue in and of itself; and failure to deal with dental and orthodontic complications in people with thalassaemia exacerbates the public health, financial and personal burden posed by the condition. There exists a lack of evidence‐based guidelines for care‐seekers and providers to best deal with such dental and orthodontic complications in thalassaemia, which this review seeks to address.

Objectives

The main objective of this review was to assess different methods to treat dental and orthodontic complications in people with thalassaemia.

Search methods

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We searched the reference lists of relevant articles and reviews.

Date of last search: 01 August 2019.

We also searched nine online databases (PubMed, Google Scholar, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Literature in the Health Sciences in Latin America and the Caribbean database, African Index Medicus, Index Medicus for South East Asia Region, Index Medicus for the Eastern Mediterranean Region, Indexing of Indian Medical Journals). We searched the reference lists of relevant articles and reviews and contacted haematologists, experts in fields of dentistry, organizations, pharmaceutical companies and researchers working in this field.

Date of last search: 22 July 2019.

Selection criteria

We searched for published or unpublished randomised controlled trials for treatment of dental and orthodontic complications in individuals diagnosed with thalassaemia, irrespective of phenotype, severity, age, gender and ethnic origin.

Data collection and analysis

Two review authors independently screened 35,202 titles from search results. We identified four unique randomised controlled trials, of which one seemed potentially relevant. Based on closer inspection, the trial was found not to be eligible for inclusion.

Main results

We did not find any relevant trials for inclusion in the review.

Authors' conclusions

We were unable to draw any conclusions due to the lack of available data and trials. This review highlights the need for conducting and appropriate reporting, of high‐quality randomised controlled trials investigating the effectiveness of various treatment modalities for dental and orthodontic complications in people with thalassaemia.

Plain language summary

Treatment of dental and orthodontic problems in thalassaemia

Review question

We reviewed the evidence about how best to treat dental and orthodontic problems in people with thalassaemia.

Background

Red blood cells make an oxygen‐carrying pigment known as haemoglobin. In thalassaemia the haemoglobin is not normal, due to defects (mutations) in two specific types of genes, leading to the classification of alpha (α) or beta (β) thalassaemias. About 5% of the world population are carriers of the mutation that causes the α‐globin gene to only function partially or not at all, for the β‐globin gene the carrier rate is about 1.5%, and millions more are being identified each year. Both forms of thalassaemia are mainly found in the belt of countries stretching from sub‐Saharan Africa, through the Mediterranean region and the Middle East, to South and South‐East Asia. Currently, due to people moving from country to country, these disorders are now also found in many other parts of the world.

When people inherit two copies of the mutated gene, the defective haemoglobin in the red blood cells does not release oxygen normally into the body, resulting in the symptoms of thalassaemia. These defective cells build up in the body's organs and bone marrow cells, causing both tissue damage and cell death. This leads to anaemia, which is a decrease in red blood cells. The lack of oxygen due to anaemia can stop organs from working normally, so, depending on severity of the condition, blood transfusions are often needed to correct the drop in red blood cells. The body tries to compensate for this anaemia naturally by increasing the number of formative red blood cells which causes expansion of the bone marrow spaces. In the skull, cheekbones and jawbones, this expanding bone marrow leads to abnormal bony swellings, which results in jaw deformity and teeth not being in their correct position (known as malocclusion). Difficulties with speech, eating and appearance result from severe changes to the face and jaw. These visible features can cause distress in people with thalassaemia and have a negative impact on their quality of life.

Since people with thalassaemia inevitably have to focus on dealing with the serious impact of anaemia on their general health to survive and on managing complications related to its long‐term treatment, they may neglect other dental problems like tooth decay, gum disease, infections, etc. As a result ordinary dental infections can become more severe and require advanced treatment. Before starting any kind of dental treatment in people with thalassaemia, practitioners need to consider both the underlying condition and the effects of the resulting anaemia or its treatment. Dental treatment may be particularly risky in people with thalassaemia who have had their spleen removed, which can make them more prone to infections.

Given the significant effects of dental and orthodontic problems on the lives of people with thalassaemia, it is important to find the best way to treat them effectively. However, due to a lack of information in scientific literature, there are no guidelines to suggest the best treatment plan. Therefore, we aimed to search for any evidence for treating dental and orthodontic complications in people with thalassaemia and make it available to healthcare providers as well as people with this condition.

Search date

The evidence is current to: 22 July 2019.

Trial characteristics

We screened the titles of 35,202 references, but none of them were found to be suitable for inclusion in our review.

Key results

There need to be high‐quality randomised controlled trials (trials where different treatments are compared and people are chosen for one or the other treatment by chance) investigating different treatment options for dental and orthodontic complications in people with thalassaemia.

Background

For an explanation of clinical terms, please refer to the glossary (Appendix 1).

Description of the condition

Haemoglobinopathies are a group of Mendelian recessive conditions, in which the structure and synthesis of haemoglobin is defective; this results in chronic anaemia when found in the homozygous or compound heterozygous states. The two major subgroups are sickle cell disease and the thalassaemia syndromes. The most common inherited disorder of haemoglobin is alpha (α)‐thalassaemia, with around 5% of the world’s population being carriers and approximately one million individuals being affected with the various α‐thalassaemia syndromes worldwide (Taher 2013). Beta (β)‐thalassaemia is also highly prevalent, with 80 to 90 million people reported to be carriers across the world (1.5% of the global population) with approximately half of these originating from South‐East Asia (Taher 2013). Annually at least 56,000 individuals are affected by thalassaemia, including at least 30,000 who need regular transfusions to survive and 5500 who die perinatally due to transfusion‐dependent α‐thalassaemia (Modell 2008). Haemoglobin disorders, such as the thalassaemias, have lost their regional specificity and are now a global concern (Weatherall 2010). While they occur primarily in the belt of countries stretching from sub‐Saharan Africa, through the Mediterranean region and the Middle East, to South and South‐East Asia, with global movement of populations, these disorders are no longer localized and now they are also found in many other parts of the world (Taher 2013).

Thalassaemia is a quantitative abnormality of haemoglobin and is caused by mutations which result in reduced production of either α or non‐α chains. In the α‐thalassaemias the disruption of one or both alleles on chromosome 16 results in reduced or absent production of α‐globin chains. Deletions of the α‐genes are the most common mutations causing α‐thalassaemia. The deletion of one of the four α‐globin genes results in a clinically asymptomatic silent carrier state; the deletion of two α‐globin genes results in mild anaemia or α‐thalassaemia minor; the deletion of three α‐globin genes causes mild to moderate chronic haemolytic anaemia (known as haemoglobin H disease); and the deletion of all four α‐globin genes results in hydrops fetalis, a condition which if untreated in utero results in an in‐utero death or the death of the infant shortly after birth. In the β‐thalassaemias, mutations in the genes controlling β‐chain production on chromosome number 11, cause no (β⁰) or reduced (β⁺) β‐chain production leading to four clinical syndromes:

• β‐thalassaemia minor (one affected gene) with mild, microcytic, hypochromic anaemia;

• β‐thalassaemia major (homozygous or compound heterozygous state) with severe anaemia leading to dependence on transfusions;

• β‐thalassaemia intermedia where symptoms of severity vary between major and heterozygote β‐thalassaemia; or

• a silent carrier state, with no clinical manifestation of the disease in spite of genetic changes being present (Colledge 2010; Park 2012; Rodak 2012).

Transfusion dependence is another method used to differentiate the various thalassaemia phenotypes and their severity is divided into two categories: transfusion‐dependent thalassemia (TDT) (where lifelong regular blood transfusions are required for survival, e.g. in β‐thalassaemia) and non‐transfusion‐dependent thalassemia (NTDT) (individuals do not require such lifelong regular blood transfusions to survive, although they may require occasional or even frequent transfusions in certain clinical settings and for defined periods of time). The term NTDT includes some β‐thalassaemia intermedia, haemoglobin E/β‐thalassaemia (mild and moderate forms) and α‐thalassaemia intermedia (haemoglobin H disease) (Taher 2013).

The unpaired globin chains produced in the thalassaemias are insoluble and incapable of releasing oxygen normally. These unpaired chains accumulate and precipitate into almost every organ system and also in erythroid precursors in the bone marrow, causing membrane damage and cell death which results in ineffective erythropoesis. Chronic anaemia causes increased gastrointestinal absorption of iron causing systemic complications such as cardiac failure and multiple endocrine abnormalities (Park 2012; Rodak 2012).

In poorer countries, improved hygiene, nutrition and public health services contribute to reduced levels of infant and childhood mortality, which means more infants with haemoglobinopathies including thalassaemia are surviving and presenting for treatment later in life (Weatherall 2001). Thalassaemia being a life‐threatening disorder, managing the systemic condition alone becomes the priority for the individual. This in turn results in health issues which are non‐life‐threatening and chronic in nature, such as dental problems, potentially being neglected both by the affected individuals and non‐oral health care providers. However, the continued neglect of minor oral health issues may lead to worsening of the underlying medical condition, precipitate serious complications and require advanced or complex treatment strategies for dental or orthodontic conditions which can be avoided with early detection and treatment (Drew 1997; Ricerca 2009). For instance, increased erythroid hyperplasia or extramedullary hematopoiesis over the years worsens malocclusion, hence early diagnosis and management of orofacial deformities is critical. Routine blood transfusions, essential for survival, can cause higher iron deposition in the gingiva and teeth resulting in discoloured teeth. People with thalassaemia who have undergone a splenectomy also have high risks for infection due to bacteraemia following dental procedures (AlDallal 2016; Capellini 2014; Einy 2016).

In people with thalassaemia, the pathogenesis, range and treatment of dental and orthodontic problems acquire different dimensions. The term 'dental complications' refers to all oral infections, diseases and conditions affecting the teeth, jaws, orofacial region and associated structures, such as dental caries, periodontal disease, odontogenic infections, osteomyelitis, cellulitis etc. Common dental complications occurring in people with thalassaemia include pallor of the gingiva and mucous membranes, caries, infections, pain and swelling of parotid glands, atrophic candidiasis, discolouration of teeth, reduction in tooth size and dental arch dimensions, delay in development and eruption of dentition and short root size, cortical erosion and trabecular enlargement (Capellini 2014; Goldfarb 1983; Hattab 1999; Hattab 2001; Mehdizadeh 2008; Poyton 1968; Van Dis 1986).

The term 'orthodontic complications' includes craniofacial deformities, jaw abnormalities, malocclusion or any other condition necessitating orthodontic and its adjunctive treatment procedures including orthognathic surgery. Commonly seen orthodontic complications are Class II malocclusion, flaring and spacing of maxillary anterior teeth, increased overjet and open‐bite. Consequent to the increased iron absorption in thalassaemia, compensatory erythroid hyperplasia, which occurs in facial and cranial bones, gives rise to appearances variously termed as "facies thalassaemica", or "Cooley's facies". The appearance is characterized by craniofacial features such as prominent frontal and parietal bones, a depressed bridge of the nose, protruding cheekbones and canting of eyes (Drew 1997; Hattab 2012). These craniofacial manifestations and deformities lead to speech, eating and emotional difficulties. The severity of anaemia, age, the duration of clinical symptoms, timing of therapeutic blood transfusion and splenectomy are said to have an impact on these deformities (Drew 1997; Logothetis 1971).

The visible features described above can cause distress in people with thalassaemia. Moreover, in people with chronic conditions like thalassaemia, the life‐long management of the condition may also generate symptoms of anxiety and depression depending on the perceived impact of the condition on functioning, the intensity of the medical regimen, and the individual's ability to control the condition. In people with thalassaemia increased symptoms of both anxiety and depression were associated with poorer functional health and well‐being (Capellini 2014; Mednick 2010). In this context, the maintenance of good oral health is very important, since oral health status affects the psychological aspects of Oral Health Related Quality of Life (OHRQoL) more than functional aspects (Motallebnejad 2014).

Description of the intervention

In people with thalassaemia, any treatment recommended as part of routine dental and orthodontic care needs to be augmented with procedures or modified to accommodate their specific needs. Early and conservative management of dental caries is recommended to prevent disease progression and resultant complications, including those arising from complex treatment such as endodontic therapy. If tooth extractions or minor surgeries are undertaken, prophylactic antibiotic coverage is recommended to prevent the development of osteonecrosis of the jaw, as well as the use of appropriate surgical management techniques (AlDallal 2016; Akintoye 2012; Barasch 2011; Hellstein 2011).

The orthodontic treatment of facial deformity and malocclusion in people with thalassaemia improves their appearance, occlusion, function and oral health (Zahrowski 2009). Functional appliances and extra‐oral appliances are used from a younger age to correct the dentofacial deformity (Einy 2016). Hypertransfusion or even therapeutic transfusion have also been suggested to decrease the severity of craniofacial deformity in growing children (Drew 1997; Habibzadeh 2005; Kaplan 1964; Logothetis 1971; Park 2012; Saxon 1998). Hypertransfusion refers to transfusion regimens instituted early after diagnosis which are intended to prevent clinical symptoms caused by anaemia and are aimed at maintaining a trough Hb of 10 g/dL in order to promote normal growth and development through childhood until the second decade of life. Furthermore, low doses of radiation and administration of myelosuppressive agents, such as hydroxyurea, are suggested to restrict post‐operative medullary expansion and thus prevent the recurrence of facial deformity (Drew 1997; Habibzadeh 2005; Park 2012; Saxon 1998).

How the intervention might work

The principle for dental treatment in individuals with thalassaemia is to tailor the treatment plan, keeping in mind their general health as well as the possible impact of the dental procedures on their pre‐existing systemic condition (AlDallal 2016; Capellini 2014). A conservative approach and early intervention for managing dental caries may help to arrest disease in its early stages and eliminate the need for complex treatment like root canal therapy or tooth extractions. This is more important in individuals receiving bisphosphonate therapy to treat thalassaemia‐related bone loss, which contraindicates the extraction of teeth due to the elevated risk of osteonecrosis (Akintoye 2012; Terpos 2010). However, if extractions or minor surgeries are unavoidable, prophylactic antibiotic coverage is recommended before carrying out the treatment. This is to prevent infections secondary to bacteraemia caused by the invasive dental procedures in susceptible and immunocompromised individuals with thalassaemia (AlDallal 2016; Akintoye 2012; Barasch 2011; Capellini 2014; Hellstein 2011).

Early diagnosis and orthodontic treatment help to intercept and correct craniofacial deformities, thus rehabilitating occlusion and restoring function. Orthodontic treatment using fixed or removable appliances corrects the malocclusion by moving teeth through alveolar bone. However, thinning of cortical bone may hasten tooth movement in this population, so the orthodontist must closely monitor tooth movements at shorter intervals, both clinically and radiographically, and use lighter forces than usual (Capellini 2014; Einy 2016). Hypertransfusion, or therapeutic transfusion, reduces reactive medullary hyperplasia, thus helping to arrest or reduce the severity of craniofacial deformity in growing children (Drew 1997; Habibzadeh 2005; Kaplan 1964; Logothetis 1971; Park 2012; Saxon 1998). In advanced stages, thalassaemia‐induced facial deformity necessitates surgery (Drew 1997; Park 2012). Surgical interventions may often necessitate blood transfusions, a definitive determination of which should always be made in consultation with haematologists and be based on the type of thalassaemia and haemoglobin levels (Drew 1997; Taher 2013). Correction of haemoglobinopathy‐related deformities through surgical procedures (e.g. maxillary anterior segmental osteotomy, vertical maxillary reduction, resection and re‐contouring of the maxilla) removes the excessively proliferated marrow and disfigured bony structure and re‐establishes normal naso‐maxillary architecture, shape, transverse, sagittal and vertical maxillary dimensions. Thus, restoring form and function in the craniofacial area. Partial or complete prosthesis may also be used to cover up extreme facial deformities, if surgery is not feasible (Drew 1997; Park 2012).

Why it is important to do this review

There is a lack of evidence‐based clinical guidelines and research data regarding dental treatment of people with haemoglobinopathies. Even the comprehensive guidelines by the Thalassemia International Foundation (TIF) fail to include guidance on managing oral health complications in people with thalassaemia (Taher 2013). Conseqently dental healthcare practitioners lack the necessary information, awareness and training, which may lead them to refuse to treat with thalassaemia due to fear of trans‐ and post‐operative complications.

Managing the serious forms of thalassaemia over an individual's lifetime is extremely expensive and can be compounded by having to deal with infections and complications secondary to inadequate or inappropriate dental care (Weatherall 2001). It is a challenge to public health resources and the expertise of the medical community to provide long‐term, comprehensive healthcare to these people, leading to this issue being labelled as an "emerging global health burden". Developing effective, accurate and timely treatment modalities for dental and orthodontic complications in people with thalassaemia will not only help in controlling the costs of treatment over a lifetime, but also significantly improve their quality of life (Weatherall 2001). With all these factors in mind, we aim to identify clinically‐proven treatment strategies to provide the best dental and orthodontic care for people with thalassaemia.

Objectives

The main objective of this review was to assess different methods to treat dental and orthodontic complications in people with thalassaemia.

The term 'dental complications' is used to represent all oral infections, diseases and conditions affecting the teeth, jaws, orofacial region and associated structures, such as dental caries, periodontal disease, odontogenic infections, osteomyelitis, cellulitis, etc. Under 'orthodontic complications' we will include craniofacial deformities, jaw abnormalities, malocclusion or any other condition necessitating orthodontic and its adjunctive treatment procedures including orthognathic surgery.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) and quasi‐RCTs were eligible for inclusion.

Cross‐over trials were not eligible given that the severity of condition may change with a preceding treatment, meaning no washout period would be of sufficient length to ensure that interventions are comparable.

Types of participants

All children and adults diagnosed with thalassaemia, irrespective of phenotype, severity, age, gender and ethnic origin.

Types of interventions

One or more of the following interventions compared with either placebo, no treatment or an alternative treatment for managing dental and orthodontic complications.

1. Different types of orthodontic appliances (e.g. fixed, removable, functional, orthopedic, etc.)

2. Application of light forces, non‐extraction mechanics and modification of treatment according to bone and systemic conditions during orthodontic therapy

3. Techniques to manage craniofacial deformity (e.g. surgical procedures, maintaining haemoglobin levels with early and regular transfusions, prostheses, radiation, administration of myelosuppressive agents such as hydroxyurea, etc.)

4. Techniques for caries management (e.g. minimally invasive techniques (such as remineralization), arresting active lesions and restorations with minimal cavity design, and invasive techniques (such as root canal treatment, etc.))

5. Prophylactic antibiotics (e.g. penicillins, amoxicillin, etc.) during treatment of dental complications

6. Management of dental pain using analgesics (e.g. non‐steroidal anti‐inflammatory drugs (NSAIDs), etc.) and alternative techniques (e.g. acupressure, relaxation, reiki, etc.)

Types of outcome measures

Primary outcomes

1. Resolution or reduction in the severity of malocclusion (as measured by class of malocclusion, cephalometric analysis, malocclusion indices, etc.)

2. Resolution or reduction in severity of any other dental complication (dental caries, periodontal disease, cysts, tumours, etc., as reported by relevant measures)

3. Adverse events consequent to treatment (e.g. worsening of systemic condition, impairment or loss of oral function, root resorption, nerve damage or bone loss, etc.)

Secondary outcomes

1. Resolution or reduction in the severity of pain (as measured by visual analogue scale, dichotomy scale or Likert scale for pain assessment, etc.)

2. Occurence of systemic infections consequent to dental treatment under antibiotic prophylaxis

3. Quality of life (physical and social function, ability to fulfil roles, life satisfaction) as measured using a validated scoring system (e.g. Health Status Survey Short Form (SF‐36), the Profile of Mood Status (POMS), Child Health Questionnaire‐Parent Report Form, etc.)

4. Effects on professional and academic functions (e.g. loss or change of job, number of days off work or school)

Search methods for identification of studies

We searched for all relevant published and unpublished trials without restrictions on language, year or publication status.

Electronic searches

We searched for relevant trials from the Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register using the term: dental AND (thalassaemia OR haemoglobinopathies general).

The Haemoglobinopathies Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of the Cochrane Library) and weekly searches of MEDLINE. Unpublished work is identified by searching the abstract books of five major conferences: the European Haematology Association conference; the American Society of Hematology conference; the British Society for Haematology Annual Scientific Meeting; the Caribbean Health Research Council Meetings; and the National Sickle Cell Disease Program Annual Meeting. For full details of all searching activities for the register, please see the relevant section of the Cochrane Cystic Fibrosis and Genetic Disorders Group website.

Date of latest search: 01 August 2009.

We also searched the following databases and trial registers for relevant trials:

• PubMed (www.ncbi.nlm.nih.gov/pubmed; 1946 to present);

• CllinicalTrials.gov (www.clinicaltrials.gov);

• World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch);

• Google Scholar (scholar.google.co.uk/);

• LILACS (Latin America and the Caribbean Health Science Information database; lilacs.bvsalud.org/en/; 1982 to present);

• AIM African Index Medicus (indexmedicus.afro.who.int/);

• Index Medicus for South East Asia Region (http://imsear.searo.who.int/simple‐search);

• Index Medicus for the Eastern Mediterranean Region (applications.emro.who.int/library/Databases/wxis.exe/Library/Databases/iah/?IsisScript=iah/iah.xis&lang=I&base=imemr);

• Indexing of Indian Medical Journals (indmed.nic.in/indmed.html).

Date of latest search: 22 July 2019.

The website of Indexing of Indian Medical Journals (indmed.nic.in/indmed.html) could not be reached, message received from latest search was "indmed.nic.in’s server IP address could not be found". Queries to resolve this issue by emailing the concerned people have until now been unanswered. Hence we were not able to update search results from this particular database beyond what we obtained from our search on 16th February 2018.

Full search strategies are available in the appendices (Appendix 2).

Searching other resources

We aimed to check the bibliographies of included trials and any relevant systematic reviews identified for further references to relevant trials. We contacted haematologists, experts in different fields of dentistry, organizations and researchers working in this field. We also contacted pharmaceutical companies for information on unpublished and ongoing trials.

Data collection and analysis

Selection of studies

Two review authors (PM, RC) independently assessed for inclusion all the potential trials identified by the searches. We settled any disagreements which we could not resolve through discussion by consulting a third review author (ABL). We did not identify any trials for inclusion in this version of the review; if we include trials in the future, we will follow the methods described in our published protocol (Mulimani 2018).

Data extraction and management

We will design a form to record extracted data including trial design, setting, participant characteristics, intervention details and outcome data. For eligible trials, two review authors (PM, PK) will extract the data independently. We will resolve discrepancies through discussion or, if required, by consulting a third or fourth review author (ABL, LK). We will enter the data into the Review Manager software and check for accuracy (RevMan 2014).

Assessment of risk of bias in included studies

Two review authors (PM, ABL) will independently assess the risk of bias for the included trials using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions(Higgins 2011). We will resolve any disagreements by discussion or by involving a third review author (LK).

1. Random sequence generation (checking for possible selection bias)

For each included trial, we will describe the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups. We assessed the method as:

• low risk of bias (any truly random process, e.g. random number table; computer random number generator);

• high risk of bias (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number);

• unclear risk of bias.

2. Allocation concealment (checking for possible selection bias)

For each included trial, we will describe the method used to conceal the allocation to interventions prior to assignment and assess whether this allocation could have been foreseen in advance of, or during recruitment, or changed after assignment. We assessed the methods as:

• low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

• high risk of bias (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);

• unclear risk of bias.

3. Blinding

3.1. of participants and personnel (checking for possible performance bias)

For each included trial, we will describe the methods used, if any, to blind participants and personnel from knowledge of which intervention a participant received. We would consider that trials are at low risk of bias if they were blinded, or if we judged that the lack of blinding would be unlikely to affect results. We assessed blinding separately for different outcomes or classes of outcomes. We assessed the methods as:

• low, high or unclear risk of bias for participants;

• low, high or unclear risk of bias for personnel.

3.2. of outcome assessment (checking for possible detection bias)

For each included trial, we will describe the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We assessed blinding separately for different outcomes or classes of outcomes. We assessed methods used to blind outcome assessment as:

• low risk of bias;

• high risk of bias;

• unclear risk of bias.

4. Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

For each included trial and for each outcome or class of outcomes, we will describe the completeness of data including attrition and exclusions from the analysis. We were to state whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported, or could be supplied by the trial authors, we would have re‐included missing data in the analyses which we would have undertaken. We assessed methods as:

• low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);

• high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation);

• unclear risk of bias.

We will use a cut‐off point of 20% to assess the level of missing data as adequate for different outcomes.

5. Selective reporting (checking for reporting bias)

For each included trial, we will describe how we investigated the possibility of selective outcome reporting bias and what we found. We assessed the methods as:

• low risk of bias (where it is clear that all of the trial's pre‐specified outcomes and all expected outcomes of interest to the review have been reported);

• high risk of bias (where not all the trial's pre‐specified outcomes have been reported; one or more reported primary outcomes were not pre‐specified; outcomes of interest are reported incompletely and so cannot be used; trial fails to include results of a key outcome that would have been expected to have been reported);

• unclear risk of bias.

6. Other bias (checking for bias due to problems not covered by (1) to (5) above)

For each included trial, we will describe any important concerns we have about other possible sources of bias. We will assess whether each trial was free of other problems that could put it at risk of bias:

• low risk of other bias;

• high risk of other bias;

• unclear whether there is risk of other bias.

7. Overall risk of bias

We will make explicit judgements about whether trials are at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). With reference to the individual points listed above, we will assess the likely magnitude and direction of the bias and whether we consider it as likely to impact the findings. We will explore the impact of the level of bias through undertaking sensitivity analyses

Measures of treatment effect

Dichotomous data

For dichotomous data (such as a dichotomy scale for pain assessment, systemic infections after treatment for dental complications under antibiotic prophylaxis, adverse events consequent to treatment, malocclusion indices, DMFT index, radiographic changes, quality of life and economic effects) we will present results as a summary risk ratio (RR) with 95% confidence intervals (CIs).

Continuous data

For continuous data (such as changes in cephalometric analysis or the visual analogue scale or the Likert scale for pain assessment) we will use the mean difference (MD) and 95% CIs (if outcomes are measured in the same way across trials). We will use the standardised mean difference (SMD) to combine trials that measure the same outcome, but use different units of measurement.

We will calculate the events occurring more than once per person as the number of counts and treated in the same way as continuous outcome data. We intend to present the MD and compare the difference in the mean number of events (standardised to a unit time period) experienced by participants in the intervention group compared with participants in the control group (Deeks 2011).

Unit of analysis issues

Cross‐over trials are not eligible for inclusion because the severity of condition may have changed with the preceding treatment procedure, and even a washout period of appropriate length would not be able to ensure that effectiveness of interventions can be comparable under such different circumstances.

We aim to include cluster‐randomised trials in the analyses along with individually randomised trials. We will adjust their sample sizes by methods using an estimate of the intracluster correlation co‐efficient (ICC) derived from the trial (if possible), or from another source. If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variations in the ICC. If we identify both cluster‐randomised trials and individually randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both types of trial if there is little heterogeneity between the trial designs and the interaction between the effect of intervention and the choice of randomisation unit is unlikely. We also intend to acknowledge heterogeneity in the randomisation unit and perform a separate meta‐analysis. Therefore, we will perform the meta‐analysis in two parts.

Dealing with missing data

For included trials, we intend to note levels of attrition. We also plan to explore the impact of including trials with high levels of missing data in the overall assessment of treatment effect by using a sensitivity analysis (see below). For all outcomes, we will carry out analyses (as far as possible) on an intention‐to‐treat basis, i.e. we will attempt to include all participants randomised to each group in the analyses, and analyse all participants in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial will be the number randomised minus any participants whose outcomes are known to be missing. We will also perform sensitivity analyses to assess how sensitive results are to reasonable changes in the assumptions that we make.

Assessment of heterogeneity

We will assess clinical heterogeneity by considering any differences in design or participant characteristics of included trials and by visually examining forest plots for clear differences in results.

We will assess statistical heterogeneity in each meta‐analysis using the Tau² (T²), I² and Chi² statistics. For the interpretation of the I² values, we intend to use the following guidelines (Higgins 2011):

• 0% to 40%: might not be important;
 • 30% to 60%: may represent moderate heterogeneity;
 • 50% to 90%: may represent substantial heterogeneity;
 • 75% to 100%: considerable heterogeneity.

We will regard heterogeneity as substantial if the I² statistic is greater than 50% and either the T² is greater than zero, or there is a low P value (less than 0.10) in the Chi² test for heterogeneity.

Assessment of reporting biases

If there are at least 10 trials in any meta‐analysis, we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually and if this suggests there is asymmetry, we will perform exploratory analyses to investigate this as detailed in the Cochrane Handbook for Systematic Reviews of Interventions (Sterne 2011).

Data synthesis

We will carry out statistical analysis using the Review Manager software (RevMan 2014). We will use a fixed‐effect meta‐analysis for combining data where it is reasonable to assume that trials are estimating the same underlying treatment effect, i.e. where trials are examining the same intervention, and the trial populations and methods are judged sufficiently similar. If there is clinical heterogeneity sufficient to expect that the underlying treatment effects will differ between trials, or if substantial statistical heterogeneity (as defined above) is detected and an average treatment effect across trials is still considered clinically meaningful, we intend to use a random‐effects meta‐analysis to produce an overall summary. We will treat the random‐effects summary as the average range of possible treatment effects and we aim to discuss the clinical implications of treatment effects differing between trials. If the average treatment effect is not clinically meaningful, we will not combine trials. If we use a random‐effects analysis, we will present the results as the average treatment effect with 95% CIs and the estimates of T² and I².

Subgroup analysis and investigation of heterogeneity

If we identify substantial heterogeneity (as defined above), we plan to investigate it using subgroup analyses. We will consider whether an overall summary is meaningful, and if so we will use a random‐effects analysis to produce it. We intend to carry out the following subgroup analyses:

• different types of thalassaemia;

• different ages ‐ paediatric (up to 18 years of age) versus adult (18 years and over);

• severity of anaemia (mild, moderate, severe).

We will assess subgroup differences using interaction tests available within the Review Manager software (RevMan 2014). We will report the results of the subgroup analyses quoting the Chi² statistic and P value, and the interaction test I² value.

Sensitivity analysis

For future updates if we include more trials, we will perform sensitivity analyses for aspects of the review that might affect the results; e.g. where there is a risk of bias associated with the quality of some of the included trials. We will undertake analysis of the primary outcome separately for trials with a low risk of bias and a high or unknown risk of bias for allocation concealment. We will explore the impact of including trials with high levels of missing data in the overall assessment of treatment effect and also to assess how sensitive results are to reasonable changes in the assumptions that are made on missing data by using a sensitivity analysis. We will carry out a sensitivity analysis to explore the effects of random‐effects analyses for outcomes with statistical heterogeneity. We will also conduct sensitivity analyses to investigate the effect of variations in any ICCs we have used.

Summary of findings table

We intended to create a separate 'Summary of finding' table for each comparison using the outcomes listed below.

1. Change in class of malocclusion

2. Reduction of DMFT index

3. Number of systemic infections after treatment for dental complications under antibiotic prophylaxis

4. Any other adverse events consequent to treatment

We would use the five GRADE considerations (trial limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of a body of evidence as it related to the studies which contribute data to the meta‐analyses for the prespecified outcomes. We would use methods and recommendations described in section 8.5 and chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions using GRADEpro software (Higgins 2011; Schünemann 2011). We would have justified all decisions to downgrade or upgrade the quality of trials using footnotes and we made comments to aid the reader's understanding of the review where necessary.

Results

Description of studies

Results of the search

We screened 35,202 titles from search results of eight databases, of which five randomised controlled trials (RCTs) were identified. Two of them were duplicates, hence we had four unique RCTs and only one among them was identified as potentially eligible for inclusion (Figure 1). Only the abstract of this RCT recorded on the trial registries was available and authors did not respond to requests to provide full‐text. Based on the information in the abstract alone, we excluded the trial.

1.

PRISMA Study Flow diagram.

Included studies

None of the trials found were suitable for inclusion.

Excluded studies

After screening search results, only one RCT was found eligible for full‐text retrieval (NCT03311243). Based on information available from the abstract (since authors did not provide full‐text on request), this trial was excluded. It was a parallel design, triple‐blinded RCT with 52 participants, which was conducted at King Saud University, Saudi Arabia. It aimed to assess the level of systemic pro‐inflammatory markers, in response to local non‐surgical periodontal therapy consisting of scaling, root planing, chlorhexidine mouthwash and tooth‐brushing instructions in individuals having chronic periodontitis. The primary outcome measure the investigators intended to report were systemic pro‐inflammatory cytokines like Interleukin‐6 (IL‐6) and tumor necrosis factor (TNF‐alpha) in a time‐frame of six weeks. However, the two groups with chronic periodontitis consisted of one group with beta‐thalassaemia and another group was of systemically healthy demographically matched controls. Since our review aims to compare different treatment strategies in individuals with thalassaemia and not with healthy controls, we decided to exclude this study.

Risk of bias in included studies

No RCTs were eligible for inclusion in this Cochrane Review.

Effects of interventions

Effects of interventions could not be assessed since, no RCTs were eligible for inclusion.

Discussion

Summary of main results

No RCTs were eligible for inclusion in this Cochrane Review.

Overall completeness and applicability of evidence

No RCTs were eligible for inclusion in this Cochrane Review.

Quality of the evidence

No RCTs were eligible for inclusion in this Cochrane Review.

Potential biases in the review process

We conducted our review with meticulous care, based on the peer‐reviewed and pre‐approved exhaustive methodology laid out in the protocol to eliminate arbitrariness or bias. To strengthen the quality of evidence generated we chose to include only RCTs and eliminated other study designs which are less methodologically rigorous and prone to bias.

We searched the literature extensively for this Cochrane Review without language or date restrictions. We contacted experts and pharmaceutical companies to seek unpublished, unregistered, ongoing trials. Appropriate inclusion and exclusion criteria were strictly applied to filter out the trials which truly addressed the review question. Steps in the review such as screening and selection of trials were carried out independently by review authors and any disagreements were clarified through consensus.

Nothwithstanding the thoroughness of the search, there still exists the risk that we may have inadvertently missed including relevant trials in our review. However, we believe that the efforts made through our review reflect the best possible status of available evidence for treatment of dental and orthodontic complications in thalassaemia. The current status is that, there are no appropriately designed, executed and reported RCTs to investigate treatment modalities for dental and orthodontic problems in individuals with thalassaemia to aid in clinical practice and application.

Agreements and disagreements with other studies or reviews

Most of the evidence on this topic consists of case‐reports, prevalence, cross‐sectional and observational studies ‐ most of them on clinical features and manifestation of the condition and few on treatment modalities. Neither RCTs nor comprehensive reviews were available for comparison. Moreover, even if they had been available, by virtue of the absence trials included in our review, we would still be unable to present the agreements or disagreements of our review with other studies or reviews.

Authors' conclusions

Implications for practice.

Due to absence of trials eligible for inclusion, we are unable to offer any implications for practice.

Implications for research.

This Cochrane Review has identified the need for well‐designed, adequately powered, properly executed and reported RCTs to assess the effectiveness of treatments for dental and orthodontic complications in people with thalassaemia.

Appendices

Appendix 1. Glossary of terms

Term	Explanation
atrophic candidiasis	infection of the mucous membranes of the mouth by a fungus of the genus Candida, characterized by appearance of red areas on the tongue, buccal mucosa and palate
cellular hyperplasia	pertaining to an abnormal increase in the number of cells in an organ or a tissue with consequent enlargement
cephalometric	relating to dental and skeletal relationships in the head
craniofacial	related to both the face and cranium
dentition	the natural teeth, as considered collectively, in the dental arch; may be deciduous, permanent, or mixed
erythroid marrow	a highly cellular blood‐cell producing connective tissue filling the central cavities and spongy ends of bones
gingivitis	inflammation of the gingiva as a response to bacterial plaque on adjacent teeth
malocclusion	any deviation from a physiologically acceptable contact of opposing dentitions
maxillary	relating to the maxilla, or upper jaw
maxillary anterior segmental osteotomy	surgical cutting of the front part of the maxilla
medullary hyperplasia	hyperplasia of the bone marrow
microcytic	abnormally small cell
myelosuppressive	causing suppression of the bone marrow's production of blood cells and platelets
odontogenic	containing or arising from tissues related to the teeth and associated structures
orofacial	relating to the mouth and face
osteomyelitis	inflammation of the bone marrow and adjacent bone
osteonecrosis	death of a bone or part of a bone, either atraumatic or posttraumatic
overjet	the horizontal overlap of the upper teeth over the lower teeth
parietal bones	the two bones in the human skull which form the sides and roof of the skull
prophylaxis / prophylactic	prevention / to prevent

Appendix 2. Electronic search strategies

Database/Resource	Type of Search	Search terms
PubMed (www.ncbi.nlm.nih.gov/pubmed) 1946 to present	Advanced	#1 randomized controlled trial [pt] #2 controlled clinical trial [pt] #3 randomized [tiab] #4 placebo [tiab] #5 drug therapy [sh] #6 randomly [tiab] #7 trial [tiab] #8 groups [tiab] #9 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 #10 animals [mh] NOT humans [mh] #11 #9 NOT #10 #12 (thalassemia OR thalassaemia) AND (mouth OR dental OR teeth OR tooth OR orthodontic OR craniofacial OR malocclusion OR orthognathic OR jaw OR orofacial OR facies OR periodontal OR odontogenic OR gingiva OR caries OR root OR roots OR candidiasis OR dentition OR incisor OR incisors OR overjet OR bite) #13 #11 AND #12 NOTE: Lines #1‐ #11 is the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity‐maximizing version (2008 revision); PubMed format
ClinicalTrials.gov (provided by US National Library of Medicine) (www.clinicaltrials.gov)	Advanced	SEARCH 1 CONDITION OR DISEASE: Thalassemia OR thalassaemia OTHER TERMS: dental OR teeth OR tooth OR orthodontic OR craniofacial OR malocclusion OR orthognathic OR jaw OR orofacial OR facies OR periodontal OR odontogenic OR gingiva OR caries OR root OR roots OR candidiasis OR dentition STUDY TYPE: Interventional Studies (Clinical Trials)
		SEARCH 2 CONDITION OR DISEASE: Thalassemia OR thalassaemia OTHER TERMS: incisor OR incisors OR overjet OR bite STUDY TYPE: Interventional Studies (Clinical Trials)
World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch)	Advanced	TITLE: mouth OR dental OR teeth OR tooth OR orthodontic OR craniofacial OR malocclusion OR orthognathic OR jaw OR orofacial OR facies OR periodontal OR odontogenic OR gingiva OR caries OR root OR roots OR candidiasis OR dentition OR incisor OR incisors OR overjet OR bite CONDITION: Thalassemia OR thalassaemia RECRUITMENT STATUS: All
Google Scholar (scholar.google.co.uk/)	Basic	SEARCH 1. allintitle: thalassemia mouth OR dental OR teeth OR tooth OR orthodontic OR craniofacial OR malocclusion OR orthognathic OR jaw OR orofacial OR facies OR periodontal OR odontogenic OR gingiva OR caries OR root OR roots OR candidiasis
		SEARCH 2. allintitle: thalassaemia mouth OR dental OR teeth OR tooth OR orthodontic OR craniofacial OR malocclusion OR orthognathic OR jaw OR orofacial OR facies OR periodontal OR odontogenic OR gingiva OR caries OR root OR roots OR candidiasis
LILACS ( Literature in the Health Sciences in Latin America and the Caribbean) http://bases.bireme.br/cgi‐bin/wxislind.exe/iah/online/?IsisScript=iah/iah.xis&base=LILACS&lang=i&form=A	Advanced	LINE 1: Thalassemia OR Thalassaemia [AND] LINE 2: mouth OR dental OR teeth OR tooth OR orthodontic OR craniofacial OR malocclusion OR orthognathic OR jaw OR orofacial OR facies OR periodontal OR odontogenic OR gingiva OR caries OR root OR roots OR candidiasis OR dentition OR incisor OR incisors OR overjet OR bite
IMEMR (Index Medicus for the Eastern Mediterranean Region) http://applications.emro.who.int/library/Databases/wxis.exe/Library/Databases/iah/?IsisScript=iah/iah.xis&lang=I&base=imemr	Advanced	Thalassemia OR Thalassaemia
African Index Medicus http://indexmedicus.afro.who.int/aim/opac_css/?database=biblo	Basic	Thalassemia Thalassaemia
IMSEAR (Index Medicus for South East Asia Region) http://imsear.searo.who.int/simple‐search	Basic	Thalassemia Thalassaemia dental
IndMED (Indexing of Indian Medical Journals) http://indmed.nic.in/indmed.html	Simple	Thalassemia OR Thalassaemia

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
NCT03311243	Trial compared the effectiveness of non‐surgical plaque control measures for treating chronic periodontitis, in 2 groups ‐ β‐thalassaemia and healthy controls. Since our review aims to compare different interventions between 2 groups of people with thalassaemia, this trial was not suitable for inclusion.

Contributions of authors

Conceiving the protocol: PM, LK

Designing the protocol: PM, LK, ABL

Coordinating the protocol: PM

Designing search strategies: PM, LK

Writing the protocol: PM, ABL, LK, RC, PK

Providing general advice on the protocol: PM, ABL, LK, RC, PK

Sources of support

Internal sources

• No sources of support supplied

External sources

• National Institute for Health Research, UK.

  This systematic review was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Cochrane Cystic Fibrosis and Genetic Disorders Group.

Declarations of interest

All authors declare they have no known potential conflicts of interest.

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