Interventions for undescended testes in children(protocol)

Transcription

1 Cochrane Database of Systematic Reviews Interventions for undescended testes in children(protocol) Deshpande AV, Michail P, Smith GH Deshpande AV, Michail P, Smith GH. Interventions for undescended testes in children. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD DOI: / CD Interventions for undescended testes in children(protocol) Copyright 2014 The Cochrane Collaboration. Published by John Wiley& Sons, Ltd.

2 T A B L E O F C O N T E N T S HEADER ABSTRACT BACKGROUND OBJECTIVES METHODS ACKNOWLEDGEMENTS REFERENCES APPENDICES CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST i

3 [Intervention Protocol] Interventions for undescended testes in children Aniruddh V Deshpande 1, Peter Michail 2, Grahame H Smith 3 1 School of Medicine and Public Health, University of Newcastle, Newcastle, Australia. 2 School of Medicine and Public Health, University of Newcastle, Newcastle, Australia. 3 Department of Urology, The Children s Hospital at Westmead, Westmead, Australia Contact address: Aniruddh V Deshpande, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia. deshpande.aniruddh@gmail.com. deshpande.aniruddh@gmail.com. Editorial group: Cochrane Kidney and Transplant Group. Publication status and date: New, published in Issue 2, Citation: Deshpande AV, Michail P, Smith GH. Interventions for undescended testes in children. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD DOI: / CD A B S T R A C T This is the protocol for a review and there is no abstract. The objectives are as follows: This review aims to look at the benefits and harms of interventions for undescended testes in children performed in order to facilitate placement of the testis or testes in a scrotal position without subsequent atrophy. B A C K G R O U N D Description of the condition Undescended testes is a common problem in boys and is defined as failure of testis to reach a scrotal position (Acerini 2009).The prevalence of undescended testes at birth has been reported to be 9% to 30% in preterm males and 4% to 5% of full-term males (Acerini 2009; Hutson 2007). The undescended testes can be found in any location along the line of descent of testis (e.g. lower pole of the kidney to the superficial inguinal pouch). Depending on the severity of the maldescent, undescended testes are commonly discussed as palpable or impalpable. Palpable undescended testes are located in the superficial inguinal pouch or in the inguinal canal. Impalpable undescended testes may be in the inguinal canal or in the abdomen proximal to the deep inguinal ring. It has been estimated that only about 20% of undescended testes are at the deep inguinal ring or proximal to that. If left untreated, testis in an undescended location is prone to possible complications like histological changes leading to subfertility, increased risk of malignancy, trauma and torsion (Hutson 2007). Prompt recognition and treatment of undescended testes has been recommended in order to optimise long term testicular function since progressive damage to germ cells has been convincingly proven beyond the age of two years (Ong 2005). Description of the intervention Treatment of undescended testes is aimed at relocating the affected testis in its anatomically appropriate scrotal position in a timely manner to prevent the sequelae and complications including subfertility and testicular cancer (Hutson 2007; Pettersson 2007). The current standard treatment for undescended testes is surgical (orchiopexy). In recent literature, an increase in both the incidence of undescended testes and surgical correction for the same has been reported (Acerini 2009; Mandat 1992). The increase in the incidence is likely to be due an increased awareness and hence an increase in detection during the first year of life (Acerini 2009). Surgical correction of undescended testes is thus one of the commonest interventions to be performed in children. Various 1

4 surgical techniques are currently practiced (Aycan 2006; Cortesi 1976; Esposito 2003; Jallouli 2009; Park 2010). The comparative efficacy of these techniques has not been evaluated using metaanalytic techniques. In addition, hormonal therapy is also used for stimulating testicular descent (Jallouli 2009; Zivkovic 2006; Zucchini 1996). Surgical treatment (orchiopexy) Surgical correction of undescended testes was first performed in 1877 by Annandale (Fischer 2005). The surgical technique was further refined through the contributions of Schuller, Bevan and Lattimer (Park 2010). The basic principles underpinning orchiopexy include separation of the processus vaginalis from the cord structures, achieving adequate cord length and anchoring the testis in a subdartos pouch within the scrotum. A success rate of 90% has been reported for this technique for all undescended testes except the high abdominal ones (Park 2010). Fowler and Stephens described a technique of dividing the testicular vessels in order to enable testes with short vessels to be brought down to the scrotum (Fowler 1959). This technique relies on the development of collateral circulation through the cremasteric artery and the artery to the vas deferens. The success of this procedure was reported to be about 70%, failure was due to an ischaemic loss of the testis. This procedure is now done as a two-stage procedure with some improvement in the testicular survival (Elyas 2010). In the 1970s, laparoscopy was first used to locate the impalpable testis (Cortesi 1976). The use of laparoscopy has had a significant impact on the management of the high intra-abdominal testis (Gatti 2007) and lead to a resurgence in the popularity of the Fowler-Stephens orchiopexy both as a single-stage and a two-stage procedure. Hormonal therapy Human chorionic gonadotropin (HCG), human menopausal gonadotropin, and gonadotropin releasing hormone (GnRH) analogue have been reported to effect the descent of testis in a child with undescended testis (Aycan 2006; Dixon 2007; Esposito 2003; Giannopoulos 2001). If hormonal therapy is used, it is typically commenced in the neonatal period (Dixon 2007) but has also been reported to induce descent at a later age (Esposito 2003).The reported success rates are as high as 60% (Aycan 2006; Giannopoulos 2001) when a combination of HCG and luteinising hormone releasing hormone (LH) have been used whereas success rates between 25% to 35% have been reported by others (Esposito 2003). A 20% response was noted in bilateral undescended testes (Dixon 2007). Beneficial effects of hormonal therapy on the contralateral testis have also been reported (Zivkovic 2006). On the other hand, a high incidence of side effects has also been reported (Cortes 2000; Thorsson 2007). There has been an ongoing debate over the optimal age of intervention for undescended testes (Hutson 2007; Ong 2005; Thorup 2009). Some authors believe that early surgical correction (between three and six months) prevents histological changes which could reduce fertility or increase malignancy risk (Hutson 2007), while others believe that correction up to two years of age prevents long-term complications (Thorup 2009). Traditionally, surgical interventions have been delayed beyond six months due to a higher incidence of complications of orchiopexy in early infancy How the intervention might work The aim of interventions in children with undescended testes is to achieve a viable testis in a scrotal position at an optimal age. Germ cell development is an active process that continues till about four years after birth (Ong 2005). It is known that testes in an undescended location are prone to progressive histological damage resulting in a possible decrease in the germ cells (Ong 2005). Maturation of neonatal gonocytes into spermatogonia is an active process that extends to up to four years of age (Ong 2005). Timely relocation of the testis in a scrotal position can halt further damage to the germ cells (Tasian 2009; Thorup 2009). A 2% risk/month of severe germ cell loss and 1% risk/month of Leydig cell depletion for each month a testis remains undescended, and a 50% greater risk of germ cell depletion in nonpalpable testes has been reported, thus emphasising the need for early relocation of an undescended testis (Tasian 2009). At the same time, early relocation of undescended testes appeared to have no effect on the risk of malignancy or sperm extraction (Pike 1986; Wiser 2009). Surgery is currently recommended before the age of two years (Hutson 2007; Thorup 2009) and this is believed to decrease the chance of impact on germ cell maturation. Hormonal therapy is commenced in the newborn period to induce testicular descent (Dixon 2007). Hormonal therapy has also been used after surgical correction since it may have beneficial effects on germ cell maturation in the operated as well as the contralateral testis (Zivkovic 2006). Why it is important to do this review In reported literature, hormonal therapy and surgical correction have been used with varying successes (Ong 2005; Park 2010). Hormonal therapy has also been used as an adjunct to surgical correction (Jallouli 2009; Zivkovic 2006). The precise role of either modality (surgical and hormonal) of therapy needs to be clarified on the backdrop of the possible benefits and harms. Overall, robust comparisons between hormonal therapy and surgical correction, between various surgical approaches and between different recommended ages of correction will provide useful information for clinicians and policy makers to tailor the clinical practice and also design future research studies. 2

5 O B J E C T I V E S This review aims to look at the benefits and harms of interventions for undescended testes in children performed in order to facilitate placement of the testis or testes in a scrotal position without subsequent atrophy. M E T H O D S Criteria for considering studies for this review Types of studies All randomised controlled trials (RCTs), and quasi-rcts (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) that are comparing an intervention for undescended testes with another intervention or no treatment or comparing early versus late intervention. We will include studies looking at both surgical and medical treatment. We will also compare types of surgical interventions with each other. Types of participants We will include studies of children undergoing surgery or hormonal therapy for children up to 16 years with undescended testes. been completely descended) is being made with increasing frequency in recent years (Tasian 2010). The precise aetiology remains unclear. We have chosen to exclude the ascending testes from this review due to the underlying differences in the age of diagnoses, pathogenetic mechanisms and outcomes of treatment. Orchiopexy beyond childhood Trapped testes resulting from prior inguinal surgery Types of outcome measures Primary outcomes 1. Presence of testis in a scrotal position without atrophy 2. Testicular growth (measured in comparison to the unaffected contralateral side). The size of the affected testis is often smaller than the normally descended peer. Testicular volume is an approximate indicator of underlying spermatogenesis and hence catch up growth following intervention can be compared as a surrogate outcome of improvement in spermatogenesis in the affected testis. 3. Histology i) Histological fertility index. The histological fertility index is defined as the number of Ad spermatogonia per tubule. Ad (dark) spermatogonia seen on testicular biopsy obtained at the time of surgery are an indicator of defective germ cell maturation 4. Sperm counts or paternity rates. This will only be relevant if the study includes a long follow-up into late adolescence or adulthood. Types of interventions 1. Orchiopexy versus no treatment 2. Hormonal therapy versus no treatment 3. Orchiopexy versus hormonal therapy 4. Open orchiopexy versus laparoscopic orchiopexy 5. Single-stage orchiopexy versus two-stage orchiopexy 6. All types of testicular fixation 7. Adjuvant hormonal therapy versus no treatment (in combination with orchiopexy). Expected procedures include inguinal orchiopexy, scrotal Bianchi orchiopexy, single-stage Fowler-Stephen s orchiopexy (open or laparoscopic), two-stage Fowler-Stephen orchiopexy (open or laparoscopic) and laparoscopic orchiopexy. Hormonal therapy for undescended testes will include primary treatment with HCG or GnRH analogues. Studies may also include hormonal therapy used as an adjuvant to surgical interventions. We will exclude studies if they include the following (only). Re-do surgery for failed orchiopexy Orchiopexy or testicular fixation for retractile testes Orchiopexy or testicular fixation for ascending testes (acquired undescended testes). The diagnosis of ascending testes (i.e. testes in an undescended location after being noted to have Secondary outcomes 1. Complications of intervention: wound infection, testicular atrophy, other surgical complications, side effects of hormones 2. Effects on contralateral testis 3. Need to redo intervention. This will not include multiple doses of hormones if the regime has been explicitly pre stated in the protocol 4. Compare outcomes of intervention on palpable versus impalpable testes, only if data is available 5. Satisfaction scores (parents or children) 6. Other fertility indices: Inhibin B, FSH and LH Search methods for identification of studies Electronic searches We will search the following databases from inception using search terms developed through contact with the Cochrane Renal Group s Trials Search Co-ordinator. 3

6 1. Cochrane Register of Controlled Trials (CENTRAL) via TheCochraneLibrary.com 2. MEDLINE (OvidSP) 3. EMBASE (OvidSP) 4. BIOSIS Previews 5. International Clinical Trials Register (ICTRP) Search Portal 6. ClinicalTrials.gov. We will use search filters for retrieving RCTs in MEDLINE and EMBASE as listed in Chapter 6 of the Cochrane Handbook of Systematic Reviews of Interventions (Lefebvre 2011). See Appendix 1 for search terms used in strategies for this review. Searching other resources 1. Reference lists of paediatric surgery and paediatric urology textbooks, clinical practice guidelines, review articles and relevant studies. 2. Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies. Data collection and analysis Selection of studies The search strategy described will be used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts will be screened independently by two authors, who will discard studies that are not applicable; however, studies and reviews that might include relevant data or information on studies will be retained initially. Two authors will independently assess retrieved abstracts and, if necessary, the full text of these studies to determine which studies satisfy the inclusion criteria. A third author will be consulted to resolve any disagreement that arises between the two authors. Data extraction and management Data extraction will be carried out independently by two authors using standard data extraction forms. Studies reported in non- English language journals will be translated before assessment. Where more than one publication of one study exists, reports will be grouped together and the publication with the most complete data will be used in the analyses. Where relevant outcomes are only published in earlier versions, these data will be used. Any discrepancy between published versions will be highlighted. Assessment of risk of bias in included studies The following items will be independently assessed by two authors using the risk of bias assessment tool (Higgins 2011) (see Appendix 2). Was there adequate sequence generation (selection bias)? Was allocation adequately concealed (selection bias)? Was knowledge of the allocated interventions adequately prevented during the study (detection bias)? Participants and personnel Outcome assessors Were incomplete outcome data adequately addressed (attrition bias)? Are reports of the study free of suggestion of selective outcome reporting (reporting bias)? Was the study apparently free of other problems that could put it at a risk of bias? Measures of treatment effect For dichotomous outcomes (successful versus unsuccessful surgery, need for re-do surgery) results will be expressed as risk ratio (RR) with 95% confidence intervals (CI). We anticipate the misclassification of the categorical pretreatment characteristics as well as the outcomes to be a non-differential type and hence likely to shift the point estimate towards the null. Where continuous scales of measurement are used to assess the effects of treatment (testicular size, histological fertility index), the mean difference (MD) will be used, or the standardised mean difference (SMD) if different scales have been used. Unit of analysis issues We will only include RCTs with a parallel group design in our review. The unit of analysis in our review is an undescended testis. Cluster randomisation (where individuals are randomised in groups) and cross-over studies are unlikely to be used to investigate the role of any single therapy for undescended testes and it is anticipated that the majority of studies will be parallel group RCTs. Dealing with missing data Any further information required from the original author will be requested by written correspondence (e.g. ing or writing to corresponding author) and any relevant information obtained in this manner will be included in the review. Evaluation of important numerical data such as screened, randomised patients as well as intention-to-treat (ITT), as-treated and per-protocol (PP) population will be carefully performed. Attrition rates, for example drop-outs, losses to follow-up and withdrawals will be investigated. Issues of missing data and imputation methods (e.g. lastobservation-carried-forward (LOCF)) will be critically appraised (Higgins 2011). 4

7 Assessment of heterogeneity Heterogeneity will be analysed using a Chi² test on N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2003). I² values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity. Assessment of reporting biases If possible, funnel plots will be used to assess for the potential existence of small study bias (Higgins 2011). Data synthesis Data will be pooled using the random-effects model but the fixedeffect model will also be used to ensure robustness of the model chosen and susceptibility to outliers. Subgroup analysis and investigation of heterogeneity Subgroup analysis will be used to explore possible sources of heterogeneity. Heterogeneity among participants could be related to the pretreatment location of the undescended testis or the age of the child at the time of the intervention. For example, the outcomes of intra-abdominal testes may be different (less efficacy) as compared to the testes located outside the superficial inguinal ring. Heterogeneity in treatments could be related to the type of surgical procedure used or the dose of the hormone used to effect descent. Adverse effects will be tabulated and assessed with descriptive techniques, as they are likely to be different for the various interventions used. Where possible, the risk difference with 95% CI will be calculated for each adverse effect, either compared to no treatment or to another agent. Sensitivity analysis We will perform sensitivity analyses in order to explore the influence of the following factors on effect size. Repeating the analysis excluding unpublished studies Repeating the analysis taking account of risk of bias, as specified above Repeating the analysis excluding any very long or large studies to establish how much they dominate the results Repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), country. A C K N O W L E D G E M E N T S We would like to thank the referees for their feedback and advice during the preparation of this protocol. R E F E R E N C E S Additional references Acerini 2009 Acerini CL, Miles HL, Dunger DB, Ong KK, Hughes IA. The descriptive epidemiology of congenital and acquired cryptorchidism in a UK infant cohort. Archives of Disease in Childhood 2009;94(11): [MEDLINE: ] Aycan 2006 Aycan Z, Ustunsalih-Inan Y, Cetinkaya E, Vidinlisan S, Ornek A. Evaluation of low-dose hcg treatment for cryptorchidism. Turkish Journal of Pediatrics 2006;48(3): [MEDLINE: ] Cortes 2000 Cortes D, Thorup J, Visfeldt J. Hormonal treatment may harm the germ cells in 1 to 3-year-old boys with cryptorchidism. Journal of Urology 2000;163(4): [MEDLINE: ] Cortesi 1976 Cortesi N, Ferrari P, Zambarda E, Manenti A, Baldini A, Morano FP. Diagnosis of bilateral abdominal cryptorchidism by laparoscopy. Endoscopy 1976;8(1):33 4. [MEDLINE: 16743] Dixon 2007 Dixon J, Wallace AM, O Toole S, Ahmed SF. Prolonged human chorionic gonadotrophin stimulation as a tool for investigating and managing undescended testes. Clinical Endocrinology 2007;67(6): [MEDLINE: ] Elyas 2010 Elyas R, Guerra LA, Pike J, DeCarli C, Betolli M, Bass J, et al. Is staging beneficial for Fowler-Stephens orchiopexy? A systematic review. Journal of Urology 2010;183(5): [MEDLINE: ] Esposito 2003 Esposito C, De Lucia A, Palmieri A, Centonze A, Damiano R, Savanelli A, et al. Comparison of five different hormonal treatment protocols for children with cryptorchidism. Scandinavian Journal of Urology & Nephrology 2003;37(3): [PUBMED: ] Fischer 2005 Fischer MC, Milen MT, Bloom DA. Thomas Annandale and the first report of successful orchiopexy. Journal of Urology 2005;174(1):37 9. [MEDLINE: ] Fowler 1959 Fowler R, Stephens FD. The role of testicular vascular 5

8 anatomy in the salvage of high undescended testes. Australian & New Zealand Journal of Surgery 1959;29: [MEDLINE: ] Gatti 2007 Gatti JM, Ostlie DJ. The use of laparoscopy in the management of nonpalpable undescended testes. Current Opinion in Pediatrics 2007;19(3): [MEDLINE: ] Giannopoulos 2001 Giannopoulos MF, Vlachakis IG, Charissis GC. 13 Years experience with the combined hormonal therapy of cryptorchidism. Hormone Research 2001;55(1):33 7. [MEDLINE: ] Higgins 2003 Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327 (7414): [MEDLINE: ] Higgins 2011 Higgins JP, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version [updated March 2011]. The Cochrane Collaboration, Available from Hutson 2007 Hutson JM, Clarke MC. Current management of the undescended testicle. Seminars in Pediatric Surgery 2007;16 (1): [MEDLINE: ] Jallouli 2009 Jallouli M, Rebai T, Abid N, Bendhaou M, Kassis M, Mhiri R. Neoadjuvant gonadotropin-releasing hormone therapy before surgery and effect on fertility index in unilateral undescended testes: a prospective randomized trial. Urology 2009;73(6): [MEDLINE: ] Lefebvre 2011 Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JP, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version [updated March 2011]. The Cochrane Collaboration, Available from Mandat 1992 Mandat K, Swietochowski A, Wieczorkiewicz B, Gubala M. Increase in the number of operations for undescended testis. Wiadomosci Lekarskie 1992;45(7-8): [MEDLINE: ] Ong 2005 Ong C, Hasthorpe S, Hutson JM. Germ cell development in the descended and cryptorchid testis and the effects of hormonal manipulation. Pediatric Surgery International 2005;21(4): [MEDLINE: ] Park 2010 Park K, Choi H. An evolution of orchiopexy: historical aspect. Korean Journal of Urology 2010;51(3): [EMBASE: ] Pettersson 2007 Pettersson A, Richiardi L, Nordenskjold A, Kaijser M, Akre O. Age at surgery for undescended testis and risk of testicular cancer. New England Journal of Medicine 2007; 356(18): [MEDLINE: ] Pike 1986 Pike MC, Chilvers C, Peckham MJ. Effect of age at orchidopexy on risk of testicular cancer. Lancet 1986;1 (8492): [MEDLINE: ] Tasian 2009 Tasian GE, Hittelman AB, Kim GE, DiSandro MJ, Baskin LS. Age at orchiopexy and testis palpability predict germ and Leydig cell loss: clinical predictors of adverse histological features of cryptorchidism. Journal of Urology 2009;182(2): [MEDLINE: ] Tasian 2010 Tasian GE, Zaid H, Cabana MD, Baskin LS. Proximal hypospadias and risk of acquired cryptorchidism. Journal of Urology 2010;184(2): [MEDLINE: ] Thorsson 2007 Thorsson AV, Christiansen P, Ritzen M. Efficacy and safety of hormonal treatment of cryptorchidism: current state of the art. Acta Paediatrica 2007;96(5): [MEDLINE: ] Thorup 2009 Thorup J, Cortes D. Surgical treatment and follow up on undescended testis. Pediatric Endocrinology Reviews 2009;7 (1): [PUBMED: ] Wiser 2009 Wiser A, Raviv G, Weissenberg R, Elizur SE, Levron J, Machtinger R, et al. Does age at orchidopexy impact on the results of testicular sperm extraction?. Reproductive Biomedicine Online 2009;19(6): [MEDLINE: ] Zivkovic 2006 Zivkovic D, Bica DG, Hadziselimovic F. Effects of hormonal treatment on the contralateral descended testis in unilateral cryptorchidism. Journal of Pediatric Urology 2006; 2(5): [EMBASE: ] Zucchini 1996 Zucchini S, Cacciari E. Medical therapy of cryptorchidism. Pediatria Medica e Chirurgica 1996;18(5 Suppl):35 6. [MEDLINE: ] Indicates the major publication for the study 6

9 A P P E N D I C E S Appendix 1. Electronic search strategies Database CENTRAL MEDLINE EMBASE Search terms 1. Cryptorchidism:ti,ab,kw 2. cryptorchism:ti,ab,kw 3. (undescended next (test*s or testicle*)):ti,ab,kw 4. (ectopic next (test*s or testicle*)):ti,ab,kw 5. (maldescended next (test*s or testicle*)):ti,ab,kw 6. (impalpable next (test*s or testicle*)):ti,ab,kw 7. testicular maldescent :ti,ab,kw 8. maldescensus testis :ti,ab,kw 9. (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8) 1. Cryptorchidism/ 2. cryptorchidism.tw. 3. cryptorchism.tw. 4. (undescended adj (test#s or testicle*)).tw. 5. (ectopic adj (test#s or testicle*)).tw. 6. (maldescended adj (test#s or testicle*)).tw. 7. (impalpable adj (test#s or testicle*)).tw. 8. testicular maldescent.tw. 9. maldescensus testis.tw. 10. or/ Cryptorchism/ 2. Ectopic Testis/ 3. cryptorchidism.tw. 4. cryptorchism.tw. 5. (undescended adj (test#s or testicle*)).tw. 6. (ectopic adj (test#s or testicle*)).tw. 7. (maldescended adj (test#s or testicle*)).tw. 8. (impalpable adj (test#s or testicle*)).tw. 9. testicular maldescent.tw. 10. maldescensus testis.tw. 11. or/1-10 7

10 Appendix 2. Risk of bias assessment tool Potential source of bias Random sequence generation Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence Assessment criteria Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random) High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention Unclear: Insufficient information about the sequence generation process to permit judgement Allocation concealment Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web-based, and pharmacy-controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes) High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or nonopaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure Unclear: Randomisation stated but no information on method used is available Blinding of participants and personnel Performance bias due to knowledge of the allocated interventions by participants and personnel during the study Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding Unclear: Insufficient information to permit judgement 8

11 (Continued) Blinding of outcome assessment Detection bias due to knowledge of the allocated interventions by outcome assessors Incomplete outcome data Attrition bias due to amount, nature or handling of incomplete outcome data Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding Unclear: Insufficient information to permit judgement Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; as-treated analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation Unclear: Insufficient information to permit judgement Selective reporting Reporting bias due to selective outcome reporting Low risk of bias: The study protocol is available and all of the study s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon) 9

12 (Continued) High risk of bias: Not all of the study s pre-specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified; one or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a metaanalysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study Unclear: Insufficient information to permit judgement Other bias Bias due to problems not covered elsewhere in the table Low risk of bias: The study appears to be free of other sources of bias. High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data-dependent process (including a formal-stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias C O N T R I B U T I O N S O F A U T H O R S 1. Draft the protocol: AD, GS, PM 2. Study selection: AD, GS, PM 3. Extract data from studies: AD, GS, PM 4. Enter data into RevMan: AD, GS, PM 5. Carry out the analysis: AD 6. Interpret the analysis: AD, GS, PM 7. Draft the final review: AD, GS, PM 8. Disagreement resolution: AD, GS, PM 9. Update the review: AD 10

13 D E C L A R A T I O N S O F None known. I N T E R E S T 11