Article Text

Modified sutureless and glue-free method versus conventional sutures for conjunctival autograft fixation in primary pterygium surgery: a systematic review and meta-analysis
  1. Faisal Aljahdali1,2,
  2. Waleed Khayyat1,
  3. Abdulelah T BinYamin3,
  4. Sultan A Al-Qahtani4,
  5. Mohammed D Alghamdi5,
  6. Ali Saleh Alsudais2,
  7. Husain A Alalgum2,
  8. Halah Bin Helayel6,
  9. Mohammed AlMutlak6
  1. 1King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
  2. 2College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
  3. 3Department of Ophthalmology, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia
  4. 4Department of Ophthalmology, King Abdulaziz University, Jeddah, Saudi Arabia
  5. 5Department of ophthalmology, Ohud hospital, Al Madinah, Saudi Arabia
  6. 6Anterior Segment Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
  1. Correspondence to Dr Faisal Aljahdali; faisalfahadaljahdali{at}gmail.com

Abstract

Background Pterygium is a common ocular surface disorder that requires surgical intervention for treatment. Conjunctival autografts are preferred over simple excision due to lower recurrence rates. This systematic review and meta-analysis compared the modified sutureless glue-free (MSGF) method with conventional sutures (CS) for conjunctival autograft fixation in primary pterygium surgery.

Methods A comprehensive search was conducted in MEDLINE, Embase, CENTRAL, Google Scholar and ClinicalTrials.gov for randomised controlled trials (RCTs) comparing MSGF and CS conjunctival autografts. Outcome measures included operation time, recurrence and postoperative complications. Standardised mean difference (SMD) and risk ratio (RR) were used for continuous and dichotomous outcomes, respectively.

Results 11 RCTs involving 833 participants were included. The analysis revealed that MSGF had a significantly shorter operation time compared with CS (SMD −3.704, 95% CI −5.122 to −2.287, p<0.001). CS was associated with a higher risk of foreign body sensation (RR 0.22, 95% CI 0.06 to 0.74, p=0.01). MSGF was associated with a higher risk of graft dehiscence (RR 9.01, 95% CI 2.74 to 29.68, p=0.000) and graft retraction (RR 2.37, 95% CI 1.17 to 4.77, p=0.02). No significant differences were found in recurrence, graft haemorrhage, granuloma, Dellen and conjunctival oedema.

Conclusion Using the MSGF technique in conjunctival autograft fixation for pterygium surgery reduces operation time by relying solely on the patient’s blood for fixation. However, it increases the risk of graft dehiscence and retraction. However, CS is linked to a higher likelihood of experiencing foreign body sensations. Understanding the learning curve and surgeon familiarity with novel techniques is crucial for optimising patient care and surgical outcomes, while individualised decision-making is necessary considering the advantages and disadvantages of each approach. Further research is warranted to minimise complications and optimise surgical outcomes.

  • Cornea
  • Ocular surface
  • Vision

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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WHAT IS ALREADY KNOWN ON THIS TOPIC

  • It is known that conjunctival autografts are preferred over simple excision due to lower recurrence rates in primary pterygium surgery.

WHAT THIS STUDY ADDS

  • We compare the efficacy of two different techniques for the fixation of the conjunctival autografts, which are modified sutureless glue-free and conventional sutures.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

  • We show that the new modified technique takes a shorter operation time compared with conventional sutures and how both techniques share similar recurrence rates.

  • We examine the importance of learning curves in adapting new surgical techniques.

Introduction

Pterygium is a common ocular disorder characterised by a wing-shaped fibrovascular growth from the conjunctiva onto the cornea, with nasal involvement being more common than temporal involvement.1 2 Chronic ultraviolet (UV) exposure is the primary risk factor, along with other factors such as smoking, low income, rural living, alcohol consumption, older age, male gender and outdoor occupations.3 4 The global prevalence of pterygium is approximately 12%.3 Indications for managing pterygium include vision impairment from induced astigmatism and pupillary axis involvement, chronic irritation and redness, corneal irregularities, concerns about malignancy and cosmetic purposes.5 6 Surgical removal of the pterygium is the only effective definitive treatment.6 Various surgical approaches are used in the management of pterygium, such as bare sclera resection,5 pterygium excision followed by mitomycin C application and pterygium excision with tissue graft (conjunctival autografting or amniotic membrane graft).6 However, high recurrence rates following successful excision remain problematic. Hence, pterygium surgery aims to excise the pterygium while also trying to prevent its recurrence.7 Currently, free limbal conjunctival autograft is the most popular method for preventing recurrence.7 Moreover, conjunctival autograft exhibits a lower recurrence rate, up to 15%, in comparison to bare sclera excision, which possesses a higher recurrence rate.7 Nonetheless, the recurrence rate may also vary based on other factors including the specific characteristics of the pterygium, patient-related factors and the surgical technique employed.4 7 The most preferred technique for securing autografts at the required site is suturing, but this comes with several possible complications, such as prolonged operating times, discomfort after surgery, oedema and inflammation, scarring, and granuloma development.8

Fibrin glue, autologous blood and cauterisation have been used in place of sutures for the fixation of conjunctival autografts to reduce the reaction to sutures and its associated complications, minimise the operating time and simplify the procedure.9 10 Fibrin glue is the most used substitute for sutures among them. It can decrease operative time and reduce postoperative complications, but it has some drawbacks, such as high cost, an increased risk of allergic reactions and the potential risk of transmission of blood-borne infections.11 12

Numerous randomised controlled trials (RCTs) have been conducted to compare modified sutureless and glue-free methods versus conventional sutures for conjunctival autograft fixation in primary pterygium surgery. These studies have shown that the modified graft fixation technique, which eliminates the need for sutures and the employment of adhesive agents, holds promise as a viable and efficient approach for primary pterygium surgeries. Furthermore, it offers certain advantages over the traditional suturing method, such as reduced surgical duration, enhanced graft stability and diminished postoperative discomfort.13–23 Hence, a meta-analysis is warranted to delineate a definitive conclusion. This systematic review and meta-analysis compare modified sutureless and glue-free methods vs conventional sutures.

Methods

This systematic review and meta-analysis were carried out following a pre-defined protocol registered with PROSPERO (CRD42023455769) and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis checklist (online supplemental file 3).

Eligibility criteria

The study included patients diagnosed with primary pterygium and aimed to compare the effectiveness of a modified sutureless and glue-free method with the conventional suturing technique. The primary outcomes of interest were operation time, recurrence rates and postoperative complications. To ensure the study’s clarity and validity, certain patient groups were excluded from participation. Specifically, individuals with pseudopterygium, double-head pterygium, a history of previous eye surgery, other ocular disorders, coagulopathies, ongoing anticoagulation therapy, or rheumatic immune-related diseases were not included in the study sample.

Search strategy

The systematic search encompassed the period from the databases’ inception up to (5 September 2023), which was performed on MEDLINE, Embase and the Cochrane Central Register of Controlled Trials without imposing constraints related to language or publication date. Furthermore, we conducted searches within a number of trial registries and search engines, including ClinicalTrials.gov and Google Scholar, to identify ongoing or recently completed trials. The search strategy involved using a combination of keywords to retrieve studies related to primary pterygium, including terms such as ‘primary pterygium’, ‘pterygium’, ‘pterygium surgery’, ‘pterygium excision’, ‘conjunctival autograft fixation’, ‘limbal conjunctival autografts’, ‘limbal conjunctival’, ‘conjunctival autograft’, ‘autograft’, ‘autograft fixation’, ‘conjunctival autografting’ and ‘autografting’. Additionally, terms representing modified sutureless and glue-free techniques compared with conventional sutures or sutured limbal conjunctival autografts were included, such as ‘modified sutureless and glue-free’, ‘modified sutureless’, ‘sutureless’, ‘glue-free’, ‘glue-free’ and ‘sutureless glue free’. The search terms incorporated additional terms associated with RCTs, randomised trials, clinical trials and trials in general to capture a wide range of relevant studies. In addition, a thorough review of the reference lists of the included RCTs was carried out to pinpoint potentially relevant RCTs that may have been inadvertently missed during the initial systematic search.

Study selection and data extraction

Two reviewers independently conducted eligibility screening for titles and abstracts, assessed full-text articles and extracted data from eligible trials. In case of any disagreements, consensus was reached, or a discussion with a third reviewer was initiated to resolve them.

Risk of the bias assessment

The risk of bias in the included randomised clinical trials was evaluated based on the Cochrane Collaboration’s tool for assessing the risk of bias. This tool is composed of seven items: random sequence generation, allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other possible causes of bias.24

Certainty of evidence

The Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria25 were employed to evaluate the quality of evidence for each outcome. The utilisation of the GRADE instrument, a technique recommended by Cochrane, allowed for the examination of evidence quality and the grading of recommendation strength in the studies included in the meta-analysis.26 To ensure the reliability and objectivity of the assessment process, two independent reviewers diligently conducted the certainty of evidence assessment using the GRADE criteria. In the event of any discrepancies or differences of opinion, a consensus was sought to resolve such matters. This assessment took into account various factors, including research design, consistency, directness, heterogeneity, precision, publication bias and other relevant features indicated in the papers encompassed in this systematic review. Subsequently, the quality of the evidence was categorised as high, moderate, low, or very low.25 26

Statistical analysis

Standardised mean difference (SMD) was used for meta-analysing the continuous data. The risk ratio (RR) with 95% CI was used for analysing binary variables. The fixed-effect model was used when homogeneity between the effect sizes was revealed. Paradoxically, the random-effects model was used once the statistical heterogeneity was established. Statistical heterogeneity was determined using the Higgins I2 statistic, at the value of >50%, and the Cochrane Q (χ2 test), at the value of p<0.10.27 Publication bias was revealed with the asymmetrical distribution of the included studies within the funnel plot along the middle line and based on Egger’s regression test (p value<0.10). The trim and fill method of Duval and Tweedie was executed to investigate the impact of publication bias on the overall significance level.28 Review Manager V.5.429 and Comprehensive Meta-Analysis V.3 software30 were used to analyse the data. The significant difference between sutureless and sutured techniques was revealed when the value of p<0.05.

Results

The flowchart of the study selection process for this review is depicted in figure 1. The initial literature search identified 40 articles, of which 5 duplicates were removed. After evaluating titles and abstracts, 22 articles were excluded, resulting in 13 articles that underwent full-text assessment. Ultimately, 11 RCTs met the eligibility criteria.13–23

Figure 1

The flowchart and study inclusion in this review. RCT, randomised controlled trial.

Demographic characteristics of the included studies

The meta-analysis included 11 articles, including 833 patients with primary pterygium.13–23 Of them, 394 and 439 patients were treated with sutureless and sutured techniques, respectively. Six articles included patients from India and one from Nepal, the Philippines, Egypt, Pakistan and China. All surgical procedures were performed under peribulbar anaesthesia; most patients had nasal pterygium. The average age of the included patients ranged from 36.86 to 60 years among the sutureless group and from 35.67 to 62 years among the sutured group. There were 398 men and 332 women. The most affected side, the right side, accounted for 129 and 169 cases among the sutureless and sutured groups, respectively. The average follow-up period ranged from 3 months to 24 months (online supplemental table 1).

Risk of bias of the included studies

All the included studies showed a low risk of random sequence generation bias. Apart from,Yan et al23 the included studies showed an unclear risk of allocation concealment bias. All the included studies showed a low risk of performance bias apart from Elwan.16 Four articles showed a low risk of detection bias,13 16 22 23 and all the included articles showed a low risk of attribution bias. All the included articles showed a low risk of reporting bias, and eight articles showed unclear risk of other sources of bias (figure 2).13 15 16 18 19 21–23

Figure 2

(A) Risk of bias graph. (B) Risk of bias summary: review authors’ judgements about.

Study endpoints

Operation time

A total of seven articles, involving 602 patients, examined the disparity in average operation time between the sutureless group and the sutured group.14–16 18 20 21 23 Pooling the data in the random-effects model (I2=96.9%, p<0.001) revealed a statistically significant shorter duration of surgery among patients treated with sutureless technique (SMD −3.704; 95% CI −5.122 to –2.287; p<0.001). Figure 3 provides a graphical representation of the results. The evidence supporting these findings is of moderate quality and is summarised in table 1.

Table 1

Grading of Recommendations Assessment, Development and Evaluation evidence profile

Figure 3

Forest plot of summary analysis of the standardised mean difference and 95% CI of the mean operation time (minutes) between the sutureless and sutured techniques. The size of the black squares is proportional to the statistical weight of each trial. The black diamond represents the pooled point estimate. The positioning of both diamonds and squares (along with 95% CIs) beyond the vertical line (unit value) suggests a significant outcome.

Recurrence

11 articles encompassing 833 patients diagnosed with primary pterygium were assessed to determine the likelihood of recurrence among patients who underwent either sutureless and sutured techniques.13–23 There were 19 recurrent cases among the sutureless group and 31 among the sutured group. Pooling the data in the random-effects model (I2=0%, p=0.90) revealed a risk ratio of 0.78 among patients with the sutureless technique with 95% CI ranging from 0.45 to 1.35 and a p value of 0.38. No publication bias was detected by the symmetrical distribution of studies along the middle line of the funnel plot and based on Egger’s regression test (Intercept=−0.74, p=0.26). The findings of the study are presented in figure 4 and online supplemental figure 1, which provide visual representations of the results. The evidence supporting these findings is of high quality and is summarised in table 1.

Figure 4

Forest plot of summary analysis of the risk ratio and 95% CI of the risk of recurrence between the sutureless and sutured techniques for primary pterygium. The size of the blue squares is proportional to the statistical weight of each trial. The black diamond represents the pooled point estimate. The positioning of both diamonds and squares (along with 95% CIs) beyond the vertical line (unit value) suggests a significant outcome.

Postoperative complications

Graft haemorrhage

Five studies involving a total of 374 patients diagnosed with primary pterygium examined the risk of graft haemorrhage in patients who underwent either sutureless or sutured techniques.13–15 18 22 There were 14 and 16 events of graft haemorrhage among the sutureless and sutured groups, respectively. In the random-effects model (I2=0%, p=0.88), both groups had a similar risk of graft haemorrhage (RR 0.88; 95% CI 0.45 to 1.72; p=0.70). The findings of the study are presented in online supplemental figure 2, which provides visual representations of the results. The evidence supporting these findings is of high quality and is summarised in table 1.

Granuloma

The risk of granuloma between sutureless and sutured primary pterygium excision techniques was assessed in nine articles, including 823 patients.13 14 16–18 20–23 The risk of granuloma among patients treated with the sutureless technique was 0.49, with 95% CI ranging from 0.19 to 1.25 and a probability value of 0.14 in the random-effects model (I2=0%, p=0.75). The findings of the study are presented in online supplemental figure 2, which provides visual representations of the results. The evidence supporting these findings is of moderate quality and is summarised in table 1.

Dellen

Three studies included 396 patients with primary pterygium and evaluated the risk of Dellen among patients treated with sutureless and sutured groups.13 16 17 Pooling the data in the random-effects model (I2=0%, p=0.89) revealed no statistically significant difference between the sutureless and sutured groups regarding the risk of Dellen (RR 0.54; 95% CI 0.11 to 2.74; p=0.45). The findings of the study are presented in online supplemental figure 4, which provides visual representations of the results. The evidence supporting these findings is of high quality and is summarised in table 1.

Graft retraction

The risk of graft retraction between the sutureless and sutured groups was evaluated among 486 patients with primary pterygium within five studies.13 15–17 22 In the random-effects model (I2=0%, p=0.90), patients treated with sutureless technique were 2.37 times more likely to develop graft retraction with a RR of 2.37 and 95% CI ranging from 1.17 to 4.77 with a p value of 0.02. The findings of the study are presented in online supplemental figure 5, which provides visual representations of the results. The evidence supporting these findings is of high quality and is summarised in table 1.

Graft dehiscence

Six studies evaluated the risk of graft dehiscence between the sutureless and sutured groups among 583 patients with primary pterygium.13 14 16 17 19 23 Patients treated with the sutureless technique were 9.01 times more at higher risk of graft dehiscence (RR 9.01; 95% CI 2.74 to 29.68; p=0.0003) in the random-effects model (I2=0%, p=0.97). The findings of the study are presented in online supplemental figure 6, which provides visual representations of the results. The evidence supporting these findings is of moderate quality and is summarised in table 1.

Conjunctival oedema

Eight articles included 684 patients with primary pterygium and evaluated the risk of conjunctival oedema between the sutureless and sutured groups.13–16 18 20–22 In the random-effects model (I2=54%, p=0.04), there was a similar risk of conjunctival oedema between the sutureless and sutured groups (RR 1.03; 95% CI 0.54 to 1.96; p=0.93). The findings of the study are presented in online supplemental figure 7, which provides visual representations of the results. The evidence supporting these findings is of moderate quality and is summarised in table 1.

Foreign body sensation

Two studies included 114 patients with primary pterygium and evaluated the risk of foreign body sensation among patients with sutureless and sutured techniques.14 15 There was a relatively higher risk of foreign body sensation among the sutured group (RR 0.22; 95% CI 0.06 to 0.74; p=0.01) in the random-effects model (I2=48%, p=0.17). The findings of the study are presented in online supplemental figure 8, which provides visual representations of the results. The evidence supporting these findings is of high quality and is summarised in table 1.

Discussion

This systematic review and meta-analysis of 11 RCTs, involving 833 participants, compared modified sutureless glue-free and conventional suture techniques for conjunctival autograft (CAG) fixation in primary pterygium surgery. The pooled estimate significantly shorter operation time using a sutureless glue-free than a conventional suture. All RCTs included studies in the analysis shared similar results.14–16 18 20 21 23 In the literature, the average duration of autograft fixation in pterygium surgery, where autologous blood coagulum is used, ranged from 12.0 to 24.8 min, which is relatively faster than fixating the autograft by sutures.12 21 31–34

Conjunctival autografting is the preferred and most effective approach to treating primary pterygium. Nevertheless, the primary obstacle in successfully removing a pterygium using CAG is the significant risk of recurrence and complications related to grafting.35 One of the complications associated with CAG fixation is graft dehiscence after pterygium excision. Graft dehiscence is usually noted in the early postoperative period and could be related to trauma or eye rubbing.21 This highlights the importance of instructing patients to wear protective eye shields and avoid eye rubbing within the first postoperative week. Another risk factor for dehiscence is the presence of the tenon capsule with the graft, so meticulous dissection is highly important.16 Six RCTs included in the analysis have compared the graft dehiscence between both groups. They reported 21 cases of graft dehiscence in the less glue-free group. None reported graft dehiscence incidence among the sutured group.13 14 16 17 19 23 Similarly, the forest plot of the analysis demonstrates that the patients undergoing suturesless glue-free are at higher risk of developing graft dehiscence patients undergoing conventional sutures for CAG fixation.

Using sutures for CAG fixation is a time-honoured technique and relatively straightforward for even inexperienced surgeons. However, despite its simplicity and practicality, one of the primary drawbacks of this method lies in the lengthy surgical procedure and the discomfort that patients may experience after surgery due to heightened inflammation and complications associated with sutures.21 35 36 It is important to note that comprehending the learning curve of surgeons and their familiarity with novel surgical techniques is of paramount importance. This understanding enables realistic expectations and facilitates the evaluation of surgical approaches. By acknowledging the progression of surgeons’ skills over time, healthcare providers can optimise patient care and enhance surgical outcomes, ultimately resulting in shorter operation durations. Notably, two RCTs evaluated the rate of developing foreign body sensations between both groups and showed a higher rate in the sutured group.14 15 Similarly, this analysis revealed that the sutured group was at higher risk of developing foreign body sensations than the sutures less glue-free group.

The risk of pterygium recurrence is six times lower when a conjunctival autograft is used compared with bare sclera resection.37 However, the method of graft fixation showed no significant difference in the risk of future recurrence in our analysis. Previous studies have shown that pterygium recurrence usually occurs within the first 6 months.38 All the studies included in this analysis examined the risk of recurrence but within different study periods (range: 6–24 months).

Graft or subconjunctival haemorrhage following pterygium surgery is expected to develop due to manipulation of the conjunctival and episcleral vessels. The analysis showed no difference in the occurrence of haemorrhage using either fixation technique. Similarly, no difference was found in regards to conjunctival oedema, although using interrupted sutures should allow more fluid to escape through the intervening spaces. Both conjunctival haemorrhage and oedema are transient events that will eventually resolve spontaneously within 2–6 weeks.14 39 Excessive oedema or chemosis may result in graft retraction. On the contrary to the risk of oedema, the analysis showed that patients treated with the sutureless technique were at higher risk of developing graft retraction compared with patients treated with the conventional suture technique. Graft retraction usually resolves conservatively. One case of graft retraction developed dehiscence and needed surgical correction.21

The risk of granuloma occurrence was almost three times higher in the suture group. However, this difference was not statistically significant. Pyogenic granuloma can form mostly in areas where the tenon is exposed. The presence of an elevated part of the graft can result in a dellen effect. Sutureless techniques provide even tension over the graft.33 Nonetheless, our analysis showed no difference between both fixation techniques in causing a dellen effect.

To the best of our knowledge, this is the first systematic review and meta-analysis comparing modified sutures less glue-free and conventional suture techniques for fixation of the conjunctival autograft in primary pterygium surgery. In our evaluation, we incorporated RCTs that possessed substantial evidence and encompassed a large number sample size. Also, the results of these RCTs showed a low rate of heterogeneity in outcomes. Furthermore, our review thoroughly analyses both techniques, covering a broad spectrum of outcomes.

We recognise that there are certain limitations in our review. First, there was heterogenicity among the studies we included regarding complications after the surgery. Second, long-term follow-up data is currently unavailable. Third, Additional data comparing the cost-effectiveness of both interventions is required. Lastly, even though 11 RCTs were included, the sample size available for this review is still considered relatively limited.

Conclusions

In conclusion, based on the findings of this systematic review and meta-analysis comparing the modified sutureless glue-free (MSGF) method with conventional sutures (CS) for conjunctival autograft fixation in primary pterygium surgery, it was observed that the MSGF technique is associated with a significantly longer operation time and an increased risk of graft dehiscence and retraction. These findings can potentially be attributed to variations in individual surgical experience, the learning curve and the surgeon’s familiarity with the new techniques adopted. Understanding the learning curve and familiarity of surgeons with novel surgical techniques is crucial for setting realistic expectations, evaluating surgical approaches, optimising patient care, enhancing surgical outcomes and potentially reducing operation durations. Conversely, CS was found to be linked with a higher risk of foreign body sensation. While no significant differences were noted in recurrence, graft haemorrhage, granuloma, Dellen and conjunctival oedema between the two techniques, it is crucial for surgeons to carefully consider the advantages and disadvantages of each approach. Therefore, individualised decision-making, considering patient characteristics, surgical expertise and available resources, is essential in primary pterygium surgery. Further research is needed to optimise surgical outcomes, minimise complications, and identify strategies to mitigate the drawbacks associated with both techniques.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

Ethics statements

Patient consent for publication

Ethics approval

Not applicable.

References

Supplementary material

Footnotes

  • Twitter @Alisud00

  • Contributors FA, MA and HBH conceived and designed the study. FA, WK, ATB, SAA, MDA, ASA and HAA collected and screened the data. FA, ASA and HAA acquired, analysed or interpreted the data. FA, MA and HBH drafted the manuscript. All authors critically revised the manuscript for important intellectual content. FA and ASA did the statistical analysis. MA obtained funding. FA and WK provided administrative, technical or material support. MA and HBH supervised the study. FA had full access to all the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. FA is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.