Laparoscopic surgery for endometriosis.

Laparoscopic surgery for endometriosis (Review) Duffy JMN, Arambage K, Correa FJS, Olive D, Farquhar C, Garry R, Barlow DH, Jacobson TZ

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2014, Issue 4 http://www.thecochranelibrary.com

Laparoscopic surgery for endometriosis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 1 Overall pain better or improved (3 months). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.2. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 2 Overall pain better or improved (6 months). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.3. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 3 Overall pain better or improved (12 months). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.4. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 4 Overall pain scores (6 months). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.5. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 5 Overall pain scores (12 months). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.6. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 6 Live birth or ongoing pregnancy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.7. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 7 Pelvic pain scores (6 months). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.8. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 8 Pelvic pain scores (12 months). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.9. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 9 Dysmenorrhoea pain scores (6 months). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.10. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 10 Dysmenorrhea pain scores (12 months). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.11. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 11 Dyspareunia pain scores (6 months). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.12. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 12 Dyspareunia pain scores (12 months). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.13. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 13 Dyschezia pain scores (6 months). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.14. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 14 Dyschezia pain scores (12 months). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.15. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 15 Clinical pregnancy. Laparoscopic surgery for endometriosis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Analysis 1.16. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 16 Miscarriage per pregnancy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.1. Comparison 2 Laparoscopic versus diagnostic laparoscopy and medical therapy, Outcome 1 Ablation vrs. diagnostic laparoscopy and GnRHa (& add back therapy). . . . . . . . . . . . . . . . . . . Analysis 3.1. Comparison 3 Laparoscopic ablation versus laparoscopic excision, Outcome 1 Overall pain scores (reduction in VAS at 12 months). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 3.2. Comparison 3 Laparoscopic ablation versus laparoscopic excision, Outcome 2 Pelvic pain scores (12 months). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 3.3. Comparison 3 Laparoscopic ablation versus laparoscopic excision, Outcome 3 Dyspareunia pain scores (12 months). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 3.4. Comparison 3 Laparoscopic ablation versus laparoscopic excision, Outcome 4 Dyschezia pain scores (12 months). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


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[Intervention Review]

Laparoscopic surgery for endometriosis James MN Duffy1 , Kirana Arambage2 , Frederico JS Correa3 , David Olive4 , Cindy Farquhar5 , Ray Garry6 , David H Barlow7 , Tal Z Jacobson8 1 Women’s Health Research Unit,

Blizard Institute of Cell and Molecular Science, London, UK. 2 Women’s Centre, John Radcliffe Hospital, Oxford University Hospitals, Oxford, UK. 3 Department of Medicine, Catholic University of Brasília, Brasilia, Brazil. 4 Wisconsin Fertility Institute, Middleton, Wisconsin, USA. 5 Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand. 6 Gynaecological Surgery, University of Teeside and South Cleveland Hospital, Middlesbrough, Guisborough, UK. 7 Hamad Medical Corporation, Qatar, Qatar. 8 Department of Obstetrics and Gynaecology, Mater Mother’s Hospital, Brisbane, Australia Contact address: James MN Duffy, Women’s Health Research Unit, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, 58 Turner Street, London, Greater London, E1 2AB, UK. [email protected]. Editorial group: Cochrane Menstrual Disorders and Subfertility Group. Publication status and date: New, published in Issue 4, 2014. Review content assessed as up-to-date: 31 July 2013. Citation: Duffy JMN, Arambage K, Correa FJS, Olive D, Farquhar C, Garry R, Barlow DH, Jacobson TZ. Laparoscopic surgery for endometriosis. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD011031. DOI: 10.1002/14651858.CD011031.pub2. Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background Endometriosis is the presence of endometrial glands or stroma in sites other than the uterine cavity and is associated with pain and subfertility. Surgical interventions aim to remove visible areas of endometriosis and restore the anatomy. Objectives To assess the effectiveness and safety of laparoscopic surgery in the treatment of painful symptoms and subfertility associated with endometriosis. Search methods This review has drawn on the search strategy developed by the Cochrane Menstrual Disorders and Subfertility Group including searching CENTRAL, MEDLINE, EMBASE, PsycINFO, and trial registries from inception to July 2013. Selection criteria Randomised controlled trials (RCTs) were selected in which the effectiveness and safety of laparoscopic surgery used to treat pain or subfertility associated with endometriosis was compared with any other laparoscopic or robotic intervention, holistic or medical treatment or diagnostic laparoscopy only. Data collection and analysis Selection of studies, assessment of trial quality and extraction of relevant data were performed independently by two review authors with disagreements resolved by a third review author. The quality of evidence was evaluated using GRADE methods. Laparoscopic surgery for endometriosis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Main results Ten RCTs were included in the review. The studies randomised 973 participants experiencing pain or subfertility associated with endometriosis. Five RCTs compared laparoscopic ablation or excision versus diagnostic laparoscopy only. Two RCTs compared laparoscopic excision versus diagnostic laparoscopy only. Two RCTs compared laparoscopic excision versus ablation. One RCT compared laparoscopic ablation versus diagnostic laparoscopy and injectable gonadotropin-releasing hormone analogue (GnRHa) (goserelin) with add-back therapy. Common limitations in the primary studies included lack of clearly-described blinding, failure to fully describe methods of randomisation and allocation concealment, and risk of attrition bias. Laparoscopic surgery was associated with decreased overall pain (measured as ‘pain better or improved’) compared with diagnostic laparoscopy, both at six months (odds ratio (OR) 6.58, 95% CI 3.31 to 13.10, 3 RCTs, 171 participants, I2 = 0%, moderate quality evidence) and at 12 months (OR 10.00, 95% CI 3.21 to 31.17, 1 RCT, 69 participants, low quality evidence). Compared with diagnostic laparoscopy, laparoscopic surgery was also associated with an increased live birth or ongoing pregnancy rate (OR 1.94, 95% CI 1.20 to 3.16, P = 0.007, 2 RCTs, 382 participants, I2 = 0%, moderate quality evidence) and increased clinical pregnancy rate (OR 1.89, 95% CI 1.25 to 2.86, P = 0.003, 3 RCTs, 528 participants, I2 = 0%, moderate quality evidence). Two studies collected data on adverse events (including infection, vascular and visceral injury and conversion to laparotomy) and reported no events in either arm. Other studies did not report this outcome. The similar effect of laparoscopic surgery and diagnostic laparotomy on the rate of miscarriage per pregnancy was imprecise (OR 0.94, 95% CI 0.35 to 2.54, 2 studies, 112 women, moderate quality evidence). When laparoscopic ablation was compared with diagnostic laparoscopy plus medical therapy (GnRHa plus add-back therapy), more women in the ablation group reported that they were pain free at 12 months (OR 5.63, 95% CI 1.18 to 26.85, 1 RCT, 35 participants, low quality evidence). The difference between laparoscopic ablation and laparoscopic excision in the proportion of women reporting overall pain relief at 12 months on a VAS 0 to 10 pain scale was 0 (95% CI -1.22 to 1.22, P = 1.00, 1 RCT, 103 participants, low quality evidence). Authors’ conclusions There is moderate quality evidence that laparoscopic surgery to treat mild and moderate endometriosis reduces overall pain and increases live birth or ongoing pregnancy rates. There is low quality evidence that laparoscopic excision and ablation were similarly effective in relieving pain, although there was only one relevant study. More research is needed considering severe endometriosis, different types of pain associated with endometriosis (for example dysmenorrhoea (pain with menstruation)) and comparing laparoscopic interventions with holistic and medical interventions. There was insufficient evidence on adverse events to allow any conclusions to be drawn regarding safety.

PLAIN LANGUAGE SUMMARY Laparoscopic surgery for pain and subfertility associated with endometriosis Background Endometriosis is the presence in inappropriate sites of tissue that normally lines the uterus. It can cause pain and subfertility. Different treatments for endometriosis are available, one of which is laparoscopic (’key hole’) surgery, performed to remove visible areas of endometriosis. Cochrane review authors assessed the evidence on the use of laparoscopic surgery to treat pain and fertility problems in women with endometriosis. Laparoscopic surgical techniques include ablation, which means destruction of a lesion (for example by burning), and excision, which means cutting a lesion out. Study characteristics We included 10 randomised controlled trials (involving 973 participants). They were conducted in Australia, Canada, Egypt, Iran and the United Kingdom. Most compared laparoscopic ablation or excision versus diagnostic laparoscopy only. Four of the 10 studies reported their source of funding. The evidence was current to July 2013. Key results We found that laparoscopic surgery may be of benefit in treating overall pain and subfertility associated with mild to moderate endometriosis. Laparoscopic excision and ablation were similarly effective in relieving pain, although this result came from a single study. There was insufficient evidence on adverse events to allow any conclusions to be drawn regarding safety. Laparoscopic surgery for endometriosis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Quality of the evidence The quality of the evidence was moderate with regard to the effectiveness of laparoscopic surgery. Additional studies are needed in this field, and these should report adverse events as an outcome.


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S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Laparoscopic treatment versus diagnostic laparoscopy for endometriosis Population: Women with mild to moderate endometriosis Settings: Any setting Intervention: Laparoscopic ablation or excision Comparison: Diagnostic laparoscopy Outcomes

Illustrative comparative risks* (95% CI)

Assumed risk

Corresponding risk

Diagnostic laparoscopy

Laparoscopic ablation or excision

Relative effect (95% CI)

No of Participants (studies)

Quality of the evidence (GRADE)

Comments

Overall pain better or im- 321 per 1000 proved at 6 month followup

756 per 1000 (610 to 861)

OR 6.58 (3.31 to 13.10 ) 171 (3 Studies)

⊕⊕⊕ MODERATE 1

Assessed in trials of women seeking pain relief for endometriosis

Overall pain better or im- 214 per 1000 proved at 12 month follow-up

732 per 1000 (467 to 895)

OR 10.00 (3.21 to 31.17 69 ) (1 Study)

⊕⊕⊕ LOW2

Assessed in trials of women seeking pain relief for endometriosis

Live birth or ongoing 179 per 1000 pregnancy

297 per 1000 (207 to 408)

OR 1.94 (1.20 to 3.16)

382 (2 Studies)

⊕⊕⊕ MODERATE 3,4

Assessed in trials of subfertile women

Clinical pregnancy

186 per 1000

302 per 1000 (223 to 396)

OR 1.89 (1.25 to 2.86 )

528 (3 Studies)

⊕⊕⊕ MODERATE 5


Miscarriage (per preg- 190 per 1000 nancy)

181 per 1000 (76 to 374)

OR 0.94 (0.35 to 2.54)

112 (2 Studies)

⊕⊕⊕ MODERATE 3,6


Adverse events

Most studies did not report adverse events as an outcome and so there was insufficient evidence to reach a conclusion on the relative safety of these interventions

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*The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; OR: Odds ratio GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 None

of studies blinded participants, only one fully described methods of randomisation and allocation concealment 2 Only conference abstract available: randomisation methods not fully described, high risk of attrition bias, unclear whether blinded; small study, n=69 3 One study does not describe methods in detail, as it is only published as an abstract 4 Most of the data apply to ongoing pregnancy. Of 92 events in this comparison, only 12 were live birth. 5 Two studies do not adequately describe randomisation methods; one study at high risk of attrition bias 6 The larger study (n=100) does not include fetal losses after 20 weeks

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BACKGROUND

Description of the condition Endometriosis is the presence of endometrial glands or stroma in sites other than the uterine cavity, such as the ovaries, fallopian tubes and the pelvis. Despite extensive basic and clinical research the exact pathogenesis of the disease remains controversial. Possible mechanisms include induction, in situ development and transplantation (Giudice 2012; Ridley 1968). Transplantation describes the process of endometrial cells transported along the fallopian tubes (retrograde menstruation) and through blood borne or lymphatic spread from the uterus to another location inside the body. Other theories exist including the induction theory, which hypothesises that combinations of hormonal, immunological and genetic factors combine to induce endometrial differentiation in undifferentiated cells; also in situ development, which hypothesises the development of endometriosis from embryological remnants of structures which contribute to the uterine cavity. Endometriosis is a common condition. A few studies have reported the prevalence (frequency of diagnosis among women in a given period of time) with no studies reporting the incidence (frequency of diagnosis among women without a previous diagnosis of endometriosis in a given period of time). The reported prevalence rate is between 3% and 6% in women aged 15 to 44 years (Giudice 2012; Eskenazi 1997; Houston 1988; Mahmood 1991; Missmer 2003; Strathy 1982; Vigano 2004). Differences in the reported prevalence of endometriosis may reflect the different inclusion criteria for each study, the indications for surgery and the attention paid by surgeons in identifying endometriosis. No studies have been conducted on representative samples of the general population. Endometriosis can be suspected based on a careful history and physical examination performed by an experienced gynaecologist. Unfortunately peritoneal endometriosis cannot be identified by any imaging modality. It is possible to diagnose the presence of deep infiltrating endometriosis involving the bladder, rectum and ovaries by transvaginal or endoanal ultrasound. Magnetic resonance imaging can visualise deep infiltrating endometriosis but it is relatively expensive and may not always be available. The gold standard test is to diagnose endometriosis with direct biopsy at laparoscopy establishing a histological diagnosis. The revised American Society for Reproductive Medicine classification (rASRM) provides a numerical score of severity based on visual findings at laparoscopy (American Society for Reproductive Medicine, 1997). Unfortunately the value of all staging systems including rASRM is limited by the diversity of the disease and the wide variations in reported symptoms (Kurata 1993; Vercellini 1996). Pain is universally recognised as the primary complaint of women with endometriosis. Endometriosis is a variable condition exemplified by the nature and severity of the pain experienced (Giudice 2004). Women can experience a wide range of pain including dys-

menorrhoea (pain with menstruation), pelvic pain (pain not related to menstruation) and dyspareunia (pain with intercourse). Women with endometriosis may present with pain related to the gastrointestinal tract and bladder, pain referred to distant sites as well as nerve entrapment and neuropathic pain. This variability reflects the diverse mechanisms responsible for the sensation of pain. Relatively little is known about the mechanisms which trigger the sensations of pain in endometriosis (Howard 2009). Endometriosis lesions contain high numbers of sensory and autonomic nerve fibres which provide a route for painful stimuli. Endometriosis has features of an inflammatory process that stimulates a wide range of immune and inflammatory cells. These immune cells secrete immune modulators, which can stimulate the sensation of pain. Subfertility is associated with endometriosis, with studies reporting 30% to 50% of women with endometriosis being subfertile (Practice Committee ASRM, 2012). A cause and effect relationship between endometriosis and subfertility has not been established (Giudice 2012). Severe endometriosis adversely affects fertility by virtue of the distortion or obliteration of functional anatomy alone. However, the role of minimal to moderate endometriosis in subfertility remains controversial. It has been hypothesised that a combination of deregulation of biomarkers responsible for endometrial receptivity including endometrial progesterone resistance, increased cell proliferation and decreased cell apoptosis results in subfertility (Giudice 2012). With no intervention 50% of women with mild endometriosis will conceive, only 25% with moderate endometriosis will conceive, and unfortunately only a few with severe disease will conceive (Practice Committee ASRM, 2012).

Description of the intervention Conservative, holistic and medical interventions exist for the management of endometriosis. Several Cochrane reviews have been published evaluating holistic interventions including acupuncture (Zhu 2011), medical interventions including analgesics (Allen 2009), Chinese herbal medicines (Flower 2012), modulators of the inflammatory and immune systems (Lu 2012; Lu 2013), ovarian suppression (Brown 2010; Brown 2013; Davis 2007; Hughes 2007; Selak 2007), intrauterine devices (Abou-Setta 2013), and surgical interventions with medical interventons which act as adjuvants to surgery (Yap 2004). Unfortunately hormonal medical interventions provide contraception and therefore are not appropriate for women seeking treatment for subfertility. A review that summarises all Cochrane reviews concerning all interventions for endometriosis is currently being prepared (Brown 2012). Surgical interventions may be performed robotically, laparoscopically (key hole) or as an open (laparotomy) procedure. Within high resource settings, a laparoscopic approach is now considered routine for the diagnosis and removal of endometriosis as it offers several advantages when compared to open procedures including decreased recovery time and cost (Ahmad 2012; Somigliana


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2009). Laparoscopic surgery aims to destroy or remove all visible endometriotic lesions and repair the damage to organs and other sites caused by endometriosis, which restores the normal anatomy. Laparoscopic excision of peritoneal deposits of endometriosis may be accomplished utilising different techniques including sharp dissection, electro-excision or Argon Neutral Plasma Energy. Electrocautery or Argon Neutral Plasma Energy may be utilised to ablate peritoneal deposits of endometriosis. With appropriate expertise and setting, a laparoscopic approach can manage moderate to severe endometriosis. Severe endometriosis involving the bowel, rectum and bladder may require a multidisciplinary team involving gynaecologists, general surgeons and urologists, requiring significant expertise. The removal of moderate to severe endometriosis may result in significant complications caused by damaging important organs and structures. In addition, the destruction of the nerve pathways thought to be responsible for carrying pain fibres (uterine nerve ablation and presacral neurectomy) aims to reduce pain associated with endometriosis. The role of laparoscopic surgery for the treatment of subfertility associated with endometriosis remains controversial (Vercellini 2009). It is debated whether artificial reproductive technology (for example in vitro fertilisation) should be considered instead of surgery to achieve conception (Berlanda 2013). A diagnostic laparoscopy is a procedure to view the internal organs for signs of endometriosis in order to make a firm diagnosis. It does not involve removal of the lesions.

How the intervention might work Laparoscopic surgery aims to treat the structural causes of pain and subfertility associated with endometriosis by restoring the normal anatomy by destroying or removing all visible endometriotic lesions and repairing damaged organs and other sites (Berlanda 2013). Eliminating endometriotic lesions and restoring normal anatomy may not reverse the inflammatory and bio-molecular changes which result in persisting pain, or the deregulation of biomarkers of endometrial receptivity which contributes to subfertility including endometrial progesterone resistance, increased cell proliferation and decreased cell apoptosis.

Why it is important to do this review This review assesses and summarises the current evidence comparing laparoscopic surgical interventions methods with other treatment modalities, as well as comparing the efficacy of different laparoscopic techniques in the treatment of pelvic pain and subfertility associated with endometriosis. With such a wide variety of different conservative, medical and surgical interventions available, the comparisons within the review should assist women with endometriosis and their clinicians in choosing management plans with a better knowledge of the current evidence. The review serves

to highlight the current limitations in the literature and to highlight the need for further research.

OBJECTIVES To assess the effectiveness and safety of laparoscopic surgery in the treatment of painful symptoms and subfertility associated with endometriosis.

METHODS

Criteria for considering studies for this review

Types of studies Published and unpublished randomised controlled trials (RCTs) were eligible for inclusion. We excluded non-randomised and quasi-randomised trials as they are associated with a high risk of bias. Types of participants Women with endometriosis confirmed with a visual diagnosis at diagnostic or operative laparoscopy. Types of interventions Trials were included if they compared any laparoscopic intervention with another laparoscopic or robotic intervention, holistic or medical intervention, or diagnostic laparoscopy. Specific laparoscopic or robotic procedures of the surgical interventions assessed included: 1. excision of peritoneal deposits utilising any technique including sharp dissection, electro-excision, Argon Neutral Plasma Energy or laser energy; 2. ablation of peritoneal deposits utilising any technique including electrocautery or Argon Neutral Plasma Energy; 3. treatment of moderate and severe endometriosis utilising any technique including mucosal skinning, nodulectomy, full thickness disc resection or segmental resection. Types of outcome measures

Primary outcomes

The primary outcome depended upon the primary symptom being treated.


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1. Overall pain: self reported pain relief using dichotomous (better or improved versus not better or improved) or continuous measures (e.g. visual analogue scale (VAS) pain scores). 2. Live birth (defined as delivery of a live fetus after 20 completed weeks of gestation) or ongoing pregnancy (defined as evidence of ongoing pregnancy after 20 completed weeks of gestation). Secondary outcomes

1. Specific types of pain: self reported pain relief using dichotomous (better or improved versus not better or improved) or continuous measures (pain scores): 1.1 pelvic pain; 1.2 dysmenorrhoea; 1.3 dyspareunia; 1.4 dyschezia. 2. Clinical pregnancy, defined as evidence of a gestational sac confirmed with transvaginal or abdominal ultrasound. 3. Miscarriage, defined as pregnancy loss before 20 completed weeks of gestation. 4. Adverse events: 4.1 mortality; 4.2 vascular injury (major and abdominal wall vessels); 4.3 visceral injury (bladder including ureters or bowel injury); 4.4 solid organ injury (uterus); 4.5 conversion to laparotomy; 4.6 infection (intra-abdominal, urinary, wound); 4.7 venous thromboembolism. Peer reviewers suggested that quality of life would be a useful outcome, and this will be included as an outcome in updates of this review.

Search methods for identification of studies We searched for all published and unpublished RCTs, without language restriction and in consultation with the Menstrual Disorders and Subfertility Group (MDSG) Trials Search Co-ordinator (Mrs Marian Showell).

1. Trial registers for ongoing and registered trials: http:// clinicaltrials.gov/ct2/home and http://www.who.int/trialsearch/ Default.aspx (Appendix 7). 2. Citation indexes: http://scientific.thomson.com/products/ sci. 3. Conference abstracts in the Web of Knowledge: http:// wokinfo.com. 4. LILACS database for trials from the Portuguese and Spanish-speaking world: http://bases.bireme.br/cgibin/ wxislind.exe/iah/online/?IsisScript=iah/iah.xis&base=LILACS& lang=i&form=F. 5. PubMed: http://www.ncbi.nlm.nih.gov/pubmed/. 6. OpenGrey database: http://opengrey.eu/ and Google for grey literature.

Searching other resources We handsearched reference lists of articles retrieved by the search and contacted experts in the field to obtain additional data. In addition, we handsearched relevant journals and conference abstracts that are not covered in the MDSG register, in liaison with the Trials Search Co-ordinator.

Data collection and analysis

Selection of studies After an initial screen of the titles and abstracts retrieved by the search, conducted by KA and SF, the full texts of all potentially eligible studies were retrieved. Two review authors (KA and SF) independently examined these full text articles for compliance with the inclusion criteria and selected studies eligible for inclusion in the review. We corresponded with study investigators, as required, to clarify study eligibility or to seek further data where necessary. Disagreements as to study eligibility were resolved by discussion or by a third review author (JD). The selection process has been documented with a ’PRISMA’ flow chart.

Electronic searches We searched the following electronic databases, trial registers and websites (from inception to July 2013): 1. Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of controlled trials (Appendix 1); 2. Cochrane Central Register of Controlled Trials (CENTRAL) (Appendix 2); 3. EMBASE (Appendix 3); 4. MEDLINE (Appendix 4); 5. PsycINFO (Appendix 5); 6. CINAHL (Appendix 6). Other electronic searches we performed included the following.

Data extraction and management Two review authors independently extracted the data from eligible studies using a data extraction form designed and pilot-tested by the authors (KA, SF, FC). Any disagreements were resolved by discussion or by a third review author (JD). Data extracted included study characteristics and outcome data. Where studies had multiple publications, the main trial report was used as the reference and additional details were derived from the secondary papers. We corresponded with study investigators for further data on methods and results, as required.


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Assessment of risk of bias in included studies Two out of three possible review authors (KA, SF, FC) independently assessed the included studies for risk of bias using the Cochrane risk of bias assessment tool in the Cochrane Handbook for Systematic Reviews of Interventions (www.cochranehandbook.org) to assess: allocation (random sequence generation and allocation concealment); blinding of participants and personnel, blinding of outcome assessors; incomplete outcome data; selective reporting; and other bias. Disagreements were resolved by discussion or by a third review author (JD). We described all the judgements fully and presented the conclusions in the ’Risk of bias’ table. The risk of bias was incorporated into the interpretation of review findings by means of sensitivity analyses. We took care to search for within trial selective reporting, such as trials failing to report obvious outcomes or reporting them in insufficient detail to allow inclusion. We sought published protocols and compared the outcomes between the protocol and the final published study.

Live births were assumed not to have occurred in participants without a reported outcome. For other outcomes, only the available data were analysed. We planned that any imputation undertaken would be subjected to sensitivity analysis (see below). When studies reported sufficient detail to calculate mean differences but no information on associated standard deviations (SD), we calculated a change from baseline standard deviation using a correlation coefficient and performed a sensitivity analysis inputting different values of Corr (0.2, 0.5 and 0.8), see the Cochrane Handbook for Systematic Reviews of Interventions section 16.1.3.2 (Higgins 2011). Assessment of heterogeneity We considered whether the clinical and methodological characteristics of the included studies were sufficiently similar for metaanalysis to provide a clinically meaningful summary. We assessed statistical heterogeneity by the I2 statistic. An I2 value greater than 50% was taken to indicate substantial heterogeneity (Higgins 2011).

Measures of treatment effect For dichotomous data (for example live birth rates), we used the numbers of events in the control and intervention groups of each study and calculated Mantel-Haenszel odds ratios (ORs). For continuous data (for example pain), we reported mean differences (MD) between the groups using change from baseline pain scores. If similar outcomes had been reported on different scales for the same outcome we planned to calculate the standardised mean difference (SMD). We planned to reverse the direction of effect of individual studies, if required, to ensure consistency across trials. We presented 95% confidence intervals (CI) for all outcomes. Where the data to calculate ORs or SMDs were not available, we utilised the most detailed numerical data available that facilitated similar analyses of included studies (for example test statistics, P values). We compared the magnitude and direction of effect reported by studies with how they are presented in the review, taking account of legitimate differences.

Assessment of reporting biases Reporting biases arise when the dissemination of research findings is influenced by the nature and direction of results. Some types of reporting bias (for example publication bias, multiple publication bias, language bias) reduce the likelihood that all studies eligible for a review will be retrieved. If all eligible studies are not retrieved, the review may be biased. In view of the difficulty of detecting and correcting for publication bias and other reporting biases, the authors aimed to minimise their potential impact by ensuring a comprehensive search for eligible studies and by being alert for duplication of data. If there were 10 or more studies in an analysis, we used a funnel plot to explore the possibility of small study effects (a tendency for estimates of the intervention effect to be more beneficial in smaller studies). Data synthesis

Unit of analysis issues The primary analysis was per woman randomised; per pregnancy data were included for some outcomes (for example miscarriage). Data that did not allow valid analysis were briefly summarised and were not included in the meta-analysis. Multiple live births (for example twins or triplets) were counted as one live birth event.

When studies were sufficiently similar, we combined the data using a fixed effect model. An increase in the odds of a particular outcome, which may be beneficial (for example live birth) or detrimental (for example adverse effects), is displayed graphically in the meta-analysis to the right of the centre-line and a decrease in the odds of an outcome to the left of the centre-line. Subgroup analysis and investigation of heterogeneity

Dealing with missing data These data were analysed on an intention-to-treat basis, as far as possible, and attempts were made to obtain missing data from the original trialists. Where these were unobtainable, imputation of individual values was undertaken for the primary outcomes only.

Where data were available, we planned subgroup analyses to determine the separate evidence within the following subgroups. 1. Severity of disease. 2. Surgical technique to excise peritoneal deposits. 3. Surgical technique to ablate peritoneal deposits.


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If we detected substantial heterogeneity, we planned to explore possible explanations in sensitivity analyses. We planned to take any statistical heterogeneity into account when interpreting the results, especially when there was any variation in the direction of effect. Sensitivity analysis We conducted sensitivity analyses for the primary outcomes to determine whether the conclusions were robust to arbitrary decisions made regarding the eligibility and analysis. This analyses included consideration of whether the review conclusions would have differed if: 1. eligibility was restricted to studies without high risk of bias; 2. a random-effects model was adopted; 3. alternative imputation strategies were implemented; 4. the summary effect measure was relative risk; 5. the outcome of live birth or ongoing pregnancy was restricted to live birth only. Summary of findings table We prepared a ’Summary of findings’ table using Guideline Development Tool software (http://www.guidelinedevelopment.org/ ). This table evaluated the overall quality of the body of evidence for the primary review outcomes (improvement in pain and live birth), for clinical pregnancy, and for the outcomes of miscarriage

and other adverse events using GRADE criteria (study limitations (that is risk of bias), consistency of effect, imprecision, indirectness and publication bias). We restricted the selection of outcomes for the summary of findings tables to time points that have the most clinical relevance. Judgements about evidence quality (high, moderate or low) have been justified, documented, and incorporated into reporting of results for each outcome.

RESULTS

Description of studies

Results of the search The search retrieved 1838 articles. Fifteen studies (21 references) were potentially eligible and were retrieved in full text. Ten studies (15 references) met our inclusion criteria. Four studies (five references) were excluded and one study is ongoing. Please see the study tables: Characteristics of included studies, Characteristics of ongoing studies and Characteristics of excluded studies. Please see the PRISMA flow chart (Figure 1).


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Figure 1. Study flow diagram.


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Included studies

• 3/10 RCTs (Abbott 2004, Healey 2010, Wright 2005) reported dyspareunia • 2/10 RCTs (Abbott 2004, Healey 2010) reported dyschezia

Study design and setting Ten parallel design randomised controlled trials (RCTs) were included in the review. Six RCTs were conducted in a single centre (Abbott 2004; Healey 2010; Jarrell 2005; Moini 2012; Sutton 1994; Wright 2005) and three RCTs were conducted in multiple centres (Gad 2012; Lalchandani 2005; Marcoux 1997) . The trials were conducted in Australia (Healey 2010), Canada (Jarrell 2005; Marcoux 1997), Egypt (Gad 2012), Iran (Moini 2012) and United Kingdom (Abbott 2004; Lalchandani 2005; Sutton 1994; Wright 2005). The study setting was unclear in one RCT report (Tutunaru 2006).

VAS scales reported by individual studies • Abbott 2004: scores were presented as a range from 0 to 100 • Healey 2010: pain severity was measured by use of a VAS made up of a 0 to 10 cm line marked with ‘no pain’ at the left end and ‘worst imaginable pain’ at the right end. The VAS lines were measured to the nearest millimetre. Scores were presented as a range from 0 to 10 • Jarrell 2005: no detailed description • Lalchandani 2005: no detailed description • Wright 2005: ranked ordinal scale of 1 to 5

Participants The studies randomised 973 participants experiencing pain ( Abbott 2004; Healey 2010; Jarrell 2005; Lalchandani 2005; Tutunaru 2006; Sutton 1994; Wright 2005) or subfertility (Gad 2012; Marcoux 1997; Moini 2012) associated with endometriosis.

Live birth or ongoing pregnancy rate • 2/10 RCTs reported live birth (Gad 2012) or ongoing pregnancy (Marcoux 1997)

Secondary outcome Interventions • 5/10 RCTs (Gad 2012; Marcoux 1997; Moini 2012; Tutunaru 2006; Sutton 1994) compared laparoscopic ablation or excision with diagnostic laparoscopy only; 2/5 RCTs (Marcoux 1997; Sutton 1994) performed adhesiolysis • 2/10 RCTs (Abbott 2004; Jarrell 2005) compared laparoscopic excision with diagnostic laparoscopy only • 1/10 RCTs (Wright 2005) compared laparoscopic ablation and uterine nerve transection with diagnostic laparoscopy only • 2/10 RCTs (Healey 2010; Wright 2005) compared laparoscopic excision with ablation • 1/10 RCTs (Lalchandani 2005) compared laparoscopic ablation with diagnostic laparoscopy and injectable GnRHa (goserelin) with add-back therapy Primary outcome

Pain (measured by VAS) • 4/10 RCTs (Healey 2010, Jarrell 2005, Lalchandani 2005, Wright 2005) reported overall pain • 2/10 RCT (Healey 2010, Wright 2005) reported pelvic pain • 3/10 RCTs (Abbott 2004, Healey 2010, Wright 2005) reported dysmenorrhoea

• 3/10 RCTs (Gad 2012; Marcoux 1997; Moini 2012) reported clinical pregnancy rate • 2/10 RCTs (Gad 2012; Marcoux 1997) reported miscarriage rate • 4/10 RCTs reported adverse events without a detailed definition (Lalchandani 2005; Marcoux 1997) and specifically vascular injury (Moini 2012), visceral injury (Moini 2012), solid organ injury (Abbott 2004), conversion to laparotomy (Abbott 2004) and infection (Abbott 2004; Moini 2012) Excluded studies Three studies (five references) were excluded from the review for the following reasons. • 1/3 RCTs (Parazzini 1999) assessed a medical adjuvant (typtorelin). • 1/3 RCTs (Soysal 2001) included participants with no definitive diagnosis of endometriosis or not presenting with symptoms of pain or subfertility. • 1/3 RCTs (Darai 2010) compared a laparoscopic procedure with an open procedure for severe endometriosis.

Risk of bias in included studies Please refer to Characteristics of included studies, Figure 2 and Figure 3.


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Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.


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Figure 3. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.


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Allocation Five RCTs (Abbott 2004; Healey 2010; Jarrell 2005; Marcoux 1997; Sutton 1994) were at low risk of selection bias related to sequence generation as they used computer randomisation. The other five RCTs (Gad 2012; Lalchandani 2005; Moini 2012; Tutunaru 2006; Wright 2005) did not describe the method used. Six RCTs were at low risk of selection bias related to allocation concealment as they used appropriate methods (Abbott 2004; Healey 2010; Jarrell 2005; Marcoux 1997; Moini 2012; Wright 2005). The other four RCTs (Gad 2012; Lalchandani 2005; Tutunaru 2006; Sutton 1994) did not describe the method used and were at unclear risk of selection bias related to allocation concealment.

Blinding We considered that blinding of participants and outcome observers would influence the subjective primary outcome of pain. It would not be possible to blind the personnel involved in surgical interventions. However, it would be possible to blind participants and outcome assessors where one laparoscopic intervention was compared to another (Abbott 2004; Healey 2010; Jarrell 2005; Lalchandani 2005; Marcoux 1997; Tutunaru 2006; Sutton 1994; Wright 2005). Four RCTs (Abbott 2004; Healey 2010; Jarrell 2005; Sutton 1994) blinded both participants and outcome assessors and so were at low risk of performance and detection bias. Four RCTs (Lalchandani 2005; Marcoux 1997; Tutunaru 2006; Wright 2005) did not state whether participants and outcome assessors were blinded and so were at high risk of performance and detection bias. We did not consider that blinding was likely to influence the findings for the remaining primary (live birth rate) or secondary (clinical pregnancy rate, miscarriage rate or adverse events) outcomes. Two RCTs (Healey 2010; Moini 2012) blinded participants and were deemed at low risk of performance bias. A single RCT (Healey 2010) blinded outcome assessors and was deemed at low risk of detection bias. Two RCTs (Gad 2012; Marcoux 1997) did not state whether participants and outcome assessors were blinded and so were deemed at unclear risk of performance and detection bias.

Tutunaru 2006) were considered to be at high risk of attrition bias because their combined losses to follow-up and exclusion rate was over 20%. The reported dropout rates for these RCTs were 46/ 178 (26%) (Healey 2010), 15/29 (16%) (Jarrell 2005), and 24/ 146 (16%) (Moini 2012). The exclusion rate was 29/178 (16%) (Healey 2010) and 36/146 (24%) (Moini 2012). Tutunaru 2006 did not report its losses to follow up or exclusions and so was considered to be at an unclear risk of attrition bias.

Selective reporting Protocols were available for 2/10 RCTs (Abbott 2004; Moini 2012) and these reported the prespecified outcomes. However Abbott 2004 did not report adverse events and Moini 2012 did not report live birth rate, so both were rated as at unclear risk of selective reporting. Among seven RCTs where protocols were not available, five RCTs (Healey 2010; Jarrell 2005; Marcoux 1997; Sutton 1994; Wright 2005) reported outcomes that were pre-stated in the methods section. However, Marcoux 1997 did not report live birth rate and was deemed at unclear risk of reporting bias. Gad 2012 and Tutunaru 2006 were conference abstracts so the full methods and results were not described; moreover, adverse events were not reported. We therefore considered these at unclear risk of reporting bias. Lalchandani 2005 stated that the “analysis of pain scores and success rates of the two treatment modalities will be discussed in a second paper”, which was not subsequently published; moreover this study did not report adverse events. It was rated as at unclear risk of reporting bias. In summary, as all studies either failed to report adverse events or (in the case of fertility studies) failed to report live births, they were rated as at unclear risk of selective reporting.

Other potential sources of bias No studies reported substantial baseline differences in prognostic factors between the treatment and control groups. We found no other potential sources of bias within the included studies.

Incomplete outcome data A total of 4/10 RCTs (Abbott 2004; Gad 2012; Lalchandani 2005; Wright 2005) studies reported no exclusions or participants lost to follow-up. Marcoux 1997 reported a loss to follow-up rate of 21/ 348 (6%) and exclusion rate of 28/348 (8%) and Sutton 1994 reported a loss to follow-up rate of 3/74 (4%) and exclusion rate of 11/74 (15%) balanced between the intervention and control groups and were judged to be at unclear risk of attrition bias. Four RCTs (Healey 2010; Jarrell 2005; Moini 2012;

Effects of interventions See: Summary of findings for the main comparison Laparoscopic surgery versus diagnostic laparoscopy for pain or subfertility related to endometriosis; Summary of findings 2 Laparoscopic versus diagnostic laparoscopy and medical therapy for pain related to endometriosis; Summary of findings 3 Laparoscopic ablation versus laparoscopic excision for pain related to endometriosis


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1. Laparoscopic treatment of endometriosis compared with diagnostic laparoscopy

Seven studies compared laparoscopic ablation or excision versus diagnostic laparoscopy only (Abbott 2004; Gad 2012; Jarrell 2005; Marcoux 1997; Moini 2012; Sutton 1994; Tutunaru 2006).

Primary outcomes

1. Overall pain

i. Pain better or improved (three, six and 12 months) Laparoscopic ablation was not associated with decreased overall pain (measured as ‘pain better or improved’) at 3 months compared to diagnostic laparoscopy only (OR 1.37, 95% CI 0.51 to 3.70, P = 0.53, 1 RCT, (Sutton 1994), 63 participants, moderate quality

evidence) (Analysis 1.1). Sensitivity analysis or subgroup analysis was not possible. Laparoscopic ablation or excision was associated with decreased overall pain (measured as ‘pain better or improved’) at 6 months compared to diagnostic laparoscopy only (OR 6.58, 95% CI 3.31 to 13.10, P = 0.00001, 3 RCTs (Abbott 2004; Sutton 1994; Tutunaru 2006), 171 participants, I2 = 0%, moderate quality evidence) (Analysis 1.2). Sensitivity analysis excluding a poor quality RCT (Tutunaru 2006) and a RCT which deployed uterine nerve transection in the treatment group (Sutton 1994) did not affect the statistical significance of the main analysis for this outcome. Subgroup analysis investigating the different laparoscopic techniques deployed to remove endometriosis deposits demonstrated no statistically significant differences. Laparoscopic ablation or excision was associated with decreased overall pain (measured as ‘pain better or improved’) at 12 months compared to diagnostic laparoscopy only (OR 10.00, 95% CI 3.21 to 31.17, P = 0.001, 1 RCT (Tutunaru 2006), 69 participants, low quality evidence) (Analysis 1.3; Figure 4). No subgroup analysis or sensitivity analysis was possible.

Figure 4. Forest plot of comparison: 1 Laparoscopic treatment versus diagnostic laparoscopy, outcome: 1.3 Overall pain better or improved (12 months).

ii. Pain scores (six and 12 months) Laparoscopic excision was associated with decreased overall pain scores compared to diagnostic laparoscopy only at 6 months (MD on 0 to 100 VAS 0.90, 95% CI 0.31 to 1.49, P = 0.003, 1 RCT, 16 participants, low quality evidence) and at 12 months (MD 1.65, 95% CI 1.11 to 2.19, P = 0.00001, 1 RCT, 16 participants, low quality evidence) (Jarrell 2005; Analysis 1.4; Analysis 1.5). Sensitivity analysis was undertaken by trying different values of Corr (0.2, 0.5, 0.8), which did not alter the overall effect. No subgroup analysis was possible.

2. Live birth or ongoing pregnancy

Laparoscopic ablation or excision was associated with an increased live birth or ongoing pregnancy rate compared to diagnostic laparoscopy only (OR 1.94, 95% CI 1.20 to 3.16, P = 0.007, 2 RCTs (Gad 2012; Marcoux 1997), 382 participants, I2 = 0%, moderate quality evidence) (Analysis 1.6; Figure 5). Sensitivity analysis excluding poor quality studies (Gad 2012) did not affect the statistical significance of the main analysis for this outcome.


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Figure 5. Forest plot of comparison: 1 Laparoscopic treatment versus diagnostic laparoscopy, outcome: 1.6 Live birth or ongoing pregnancy.

When the analysis was restricted to the study reporting live birth (Gad 2012) rather than the much larger study which reported ongoing pregnancy over 20 weeks (Marcoux 1997), the findings were no longer significant. This was probably due to lack of statistical power. No subgroup analysis was possible. Secondary outcomes

1. Pain

i. Pain scores (six and 12 months) Laparoscopic excision was not associated with decreased dyspareunia at 6 and 12 months compared to diagnostic laparoscopy only (MD on 0 to100 VAS 6.30, 95% CI -8.18 to 20.78, P = 0.39; SMD 6.10, 95% CI -7.48 to 19.68, P = 0.38, 1 RCT (Abbott 2004), 39 participants) (Analysis 1.11; Analysis 1.12). Sensitivity analysis was undertaken by trying different values of Corr (0.2, 0.5, 0.8), which did not alter the overall effect. No subgroup analysis was possible. D. Dyschezia

A. Pelvic pain i. Pain scores (six and 12 months) i. Pain scores (six and 12 months) Laparoscopic excision was not associated with decreased pelvic pain at 6 or 12 months compared to diagnostic laparoscopy only (MD on 0 to 100 VAS -5.10, 95% CI -16.64 to 6.44, P = 0.39; MD on 0 to 100 VAS 7.00, 95% CI -1.27 to 15.27, P = 0.10, 1 RCT (Abbott 2004), 39 participants) (Analysis 1.7; Analysis 1.8). Sensitivity analysis was undertaken by trying different values of Corr (0.2, 0.5, 0.8), which did not alter the overall effect. No subgroup analysis was possible. B. Dysmenorrhoea

i. Pain scores (six and 12 months) Laparoscopic excision was not associated with decreased dysmenorrhoea at 6 and 12 months compared to diagnostic laparoscopy only (MD on 0 to 100 VAS 2.40, 95% CI -6.18 to 10.98, P = 0.58; SMD -9.50, 95% CI -20.58 to 1.58, P = 0.09, 1 RCT (Abbott 2004), 39 participants) (Analysis 1.9; Analysis 1.10). Sensitivity analysis was undertaken by trying different values of Corr (0.2, 0.5, 0.8), which did not alter the overall effect. No subgroup analysis was possible. C. Dyspareunia

Laparoscopic excision was not associated with decreased dyschezia at 6 and 12 months compared to diagnostic laparoscopy only (MD on 0 to100 VAS -9.20, 95% CI - 24.41 to 6.01, P = 0.24; SMD -3.60, 95% CI -19.61 to 12.41, P = 0.66, 1 RCT (Abbott 2004), 39 participants) (Analysis 1.13; Analysis 1.14). Sensitivity analysis was undertaken by trying different values of Corr (0.2, 0.5, 0.8), which did not alter the overall effect. No subgroup analysis was possible. 2. Clinical pregnancy rate Laparoscopic ablation or excision was associated with an increased clinical pregnancy rate compared to diagnostic laparoscopy only (OR 1.89, 95% CI 1.25 to 2.86, P = 0.003, 3 RCTs (Gad 2012; Marcoux 1997; Moini 2012), 528 participants, I2 = 0%) (Analysis 1.15). Sensitivity analysis excluding poor quality studies (Gad 2012; Moini 2012) did not affect the statistical significance of the main analysis for this outcome. No subgroup analysis was possible. 3. Miscarriage rate When laparoscopic ablation or excision was compared to diagnostic laparoscopy only there was no difference between them in the pre-pregnancy miscarriage rate (defined as early fetal loss) (OR


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0.94, 95% CI 0.35 to 2.54, 2 RCTs, 112 participants) (Analysis 1.16).

paroscopy and GnRHa with add-back therapy (Lalchandani 2005).

4. Adverse events

Primary outcomes

Infection, vascular injury, and visceral injury were reported by Moini 2012 and conversion to laparotomy was reported by Marcoux 1997; no events occurred. Mortality, solid organ injury and venous thromboembolism were not reported by any of the included studies.

1. Overall pain

i. Pain free (12 months) 2. Laparoscopic treatment of endometriosis compared with diagnostic laparoscopy and medical treatment for pain

One study made this comparison. It compared laparoscopic ablation of endometriotic lesions compared with diagnostic la-

Laparoscopic ablation was associated with decreased overall pain at 12 months compared to diagnostic laparoscopy and GnRHa with add-back therapy (measured as ’pain free at 12 months’) (OR 5.63, 95% CI 1.18 to 26.85, 1 RCT, 35 participants, low quality evidence) (Analysis 2.1; Figure 6).

Figure 6. Forest plot of comparison: 2 Laparoscopic versus diagnostic laparoscopy and medical therapy, outcome: 2.1 Ablation versus diagnostic laparoscopy and GnRHa (and add-back therapy).

2. Live birth

Primary outcomes

No RCTs reported this outcome. 1. Overall pain Secondary outcomes No RCTs reported these outcomes.

i. Pain scores (12 months)

3. Laparoscopic ablation compared with laparoscopic excision of endometriosis

Laparoscopic ablation was not associated with decreased overall pain at 12 months compared to laparoscopic excision (MD on 0 to 10 VAS 0.00, 95% CI -1.22 to 1.22, P = 1.00, 1 RCT (Healey 2010), 103 participants, moderate quality evidence) (Analysis 3.1; Figure 7). No subgroup or sensitivity analysis was possible.

Two studies made this comparison (Healey 2010; Wright 2005).


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Figure 7. Forest plot of comparison: 3 Laparoscopic ablation versus laparoscopic excision, outcome: 3.1 Overall pain scores (reduction in VAS at 12 months).

Wright and colleagues (Wright 2005) compared ablation with excision for pelvic pain associated with mild endometriosis and reported good symptom relief at six months for the majority of participants irrespective of the treatment modality. Their data could not be included in the meta-analysis as the participants completed a ranked ordinal scale. 2. Live birth

i. Pain scores (12 months) Laparoscopic ablation was not associated with decreased dyspareunia at 12 months compared to laparoscopic excision (MD on 0 to 10 VAS -1.30, 95% CI -2.89 to 0.29, P = 0.87 1 RCT (Healey 2010), 103 participants, moderate quality evidence) (Analysis 3.3). No subgroup or sensitivity analysis was possible. D. Dyschezia

No RCTs reported this outcome. Secondary outcomes

1. Pain A. Pelvic pain

i. Pain scores (12 months) Laparoscopic ablation was not associated with decreased pelvic pain at 12 months compared to laparoscopic excision (MD on 0 to 10 VAS 0.10, 95% CI -1.10 to 1.30, P = 0.87 1 RCT (Healey 2010), 103 participants, moderate quality evidence) (Analysis 3.2). No subgroup or sensitivity analysis was possible. B. Dysmenorrhoea No RCTs were identified reporting this outcome. C. Dyspareunia

i. Pain scores (12 months) Laparoscopic ablation was not associated with decreased dyschezia at 12 months compared to laparoscopic excision (MD on 0 to 10 VAS -1.10, 95% CI -2.37 to 0.17, P = 0.09, 1 RCT (Healey 2010), 103 participants, moderate quality evidence) (Analysis 3.4). No subgroup or sensitivity analysis was possible.

2. Clinical pregnancy rate; 3. Miscarriage rate; 4. Adverse events No RCTs were identified reporting these outcomes.

Publication bias We were unable to construct a funnel plot to assess publication bias because there were insufficient studies reporting the same comparison.


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A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]

Laparoscopic surgery versus diagnostic laparoscopy and medical therapy for pain related to endometriosis Population: Women with mild to moderate endometriosis Settings: Any setting Intervention: Laparoscopic surgery Comparison: Diagnostic laparoscopy plus medical therapy (GNRHa plus add back therapy) Outcomes

Illustrative comparative risks* (95% CI)

Assumed risk

Relative effect (95% CI)

No of Participants (studies)


OR 5.63 (1.18 to 26.85)

35 (1 study)

⊕⊕

LOW 1

Comments

Corresponding risk

Diagnostic laparoscopy Laparoscopic surgery plus medical therapy Number of women pain 167 per 1000 free at 12 months

530 per 1000 (191 to 843)

*The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Only

conference abstract available: randomisation methods not fully described, unclear whether blinded; small study, n = 35

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Laparoscopic ablation versus laparoscopic excision for pain related to endometriosis Population: Women with mild to moderate endometriosis Settings: Any setting Intervention: Laparoscopic ablation Comparison: Laparoscopic excision Outcomes

Illustrative comparative No of Participants risks (95% CI) (studies)


Comments

Laparoscopic ablation versus laparoscopic excision Reduction in overall pain The mean reduction in 103 score at 12 month follow- overall pain score at 12 (1 study) up months was the same in both groups (1.22 lower to 1.22 higher on a VAS 0 to 10 pain scale)

⊕⊕

LOW 1,2

CI: Confidence interval GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 High

risk of attrition bias compatible with a clinically relevant difference between the groups, or with no difference

2 Imprecision

DISCUSSION Summary of main results Laparoscopic surgery (ablation or excision) reduces overall pain associated with minimal and moderate endometriosis. Laparoscopic surgery reduces overall pain at six months and 12 months when compared to diagnostic laparoscopy only. In several studies (Marcoux 1997; Sutton 1994) laparoscopic adhesiolysis was utilised in addition to ablation and excision. The degree of reduction in overall pain is likely to be of clinical as well as statistical significance and is notable at six months, by which time any placebo effect relating to the procedure will be minimised. When consid-

ering the different types of pain, including pelvic pain, dysmenorrhoea, dyspareunia, and dyschezia, there is insufficient evidence to determine which pain type responds best to laparoscopic surgery. There is also no evidence of a difference when laparoscopic ablation is compared with laparoscopic excision with regard to the outcomes of overall pain, pelvic pain, dyspareunia and dyschezia. Laparoscopic coagulation therapy is more beneficial than diagnostic laparoscopy and treatment with a gonadotropin-releasing hormone analogue (GnRHa) and add-back therapy in terms of reducing overall pain at 12 months. Laparoscopic treatment of minimal and moderate endometriosis improves the pregnancy and live birth rates in couples with otherwise unexplained infertility.


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None of the studies were of sufficient power to assess safety and although no complications were reported this does not allow any conclusions to be drawn regarding safety. The ’Summary of findings’ table summarises the main outcomes.

Overall completeness and applicability of evidence The evidence for each comparison was limited. Only one study (Gad 2012) reported live birth and evidence on adverse events was lacking. There were only a few women diagnosed with pain associated with severe endometriosis included in the meta-analysis and therefore any conclusions regarding treatment of severe endometriosis should be made with caution. Most researchers in this area have found it difficult to consider a randomised trial for severe endometriosis due to the associated pain symptoms and need for intervention. This is an area that could be explored by comparing the efficacy of different laparoscopic techniques or medical interventions. No trials were included with participants experiencing subfertility associated with severe endometriosis. The management of subfertility associated with severe endometriosis is complex and referral to a centre with the necessary expertise is strongly recommended. This an area that could be explored further by comparing different surgical interventions with other treatments including in vitro fertilisation (IVF). Endometriosis is considered a chronic condition and unfortunately the included RCTs had follow-up durations ranging from three to 18 months. Observational studies have reported a high reoccurrence and re-intervention rate following surgical intervention over a three to five year follow-up period following surgical intervention (Abbott 2003). No conclusions can be made with regards to the efficacy of interventions assessed within this review in the longer term. Future research should ensure adequate followup, with a suggested time period of five years. We do not currently have published RCTs available which consider the effectiveness and safety of laparoscopic surgery compared to holistic or medical interventions for pain associated with endometriosis. There are many clinical trials of holistic or medical interventions which indicate that they can relieve pain but these are usually comparisons of alternative regimes rather than comparisons against laparoscopic surgery. In this review, laparoscopic ablation was associated with decreased overall pain at 12 months compared to diagnostic laparoscopy and GnRHa with add-back therapy in the Lalchandani 2003 study. This result needs to be interpreted with caution as the full article has not been published and this information was only available in an abstract from a conference proceeding.

Quality of the evidence

Unfortunately there were few studies for each comparison and meta-analysis could rarely be performed. When performed, the heterogeneity in the analyses was low. Using GRADE methods of assessment, the quality of the evidence for effectiveness outcomes was moderate or low for most comparisons, denoting that further research is likely or very likely (respectively) to have an important impact on our confidence in the estimate of effect and may change the estimate. Reasons for downgrading the quality of the evidence included risk of bias in the primary studies (for example lack of clearly-described blinding, failure to fully describe methods of randomisation and allocation concealment, and risk of attrition bias) and imprecision due to small sample sizes. Evidence on miscarriage was of moderate quality. There was insufficient evidence to reach any conclusions on other adverse outcomes (Summary of findings for the main comparison; Summary of findings 2; Summary of findings 3)

Potential biases in the review process In order to prevent bias in the review process, the search was guided and developed by the Cochrane Menstrual Disorders and Subfertility Group. No limitations such as a publication type, language, or date restrictions were applied. The study selection, ’Risk of bias’ assessment, and data collection were conducted independently by two review authors. Any disagreement was resolved by discussion with a third review author. The main bias remains the issue of multiple comparisons and small number of trials, making extrapolation difficult. There was a lack of consistency in the outcome measures used in trials, which led to difficulties in combining data in a suitable meta-analysis and thus made it difficult to draw clinically relevant conclusions. The conflicts of interests for all review authors have been stated and are limited to academic activities.

Agreements and disagreements with other studies or reviews Several national and international organisations have produced guidelines concerning the management of pain associated with endometriosis. Examples include The Society of Obstetricians and Gynaecologists of Canada, which recommends that surgery for pain associated with endometriosis should be reserved for those in whom medical treatment has failed (Leyland 2010). The Royal College of Obstetricians and Gynaecologists states “ablation of endometriotic lesions reduces endometriosis to associated pain compared with diagnostic laparoscopy” and “endometriosis associated pain can be reduced by removing the entire lesions in severe and deeply infiltrating disease” (RCOG 2008). Several published observational studies have reported an improvement in pain, including pelvic pain, dysmenorrhoea, dyspareunia and dyschezia associated with endometriosis following laparoscopic surgery. This systematic review has been unable to draw any conclusions with


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regards to the efficacy of laparoscopic surgery in treating the subtypes of pain associated with endometriosis. However, there was often a need for re-intervention for pain which was not always associated with endometriosis (Giudice 2004). Abbott and colleagues reported a surgical re-intervention rate of 36% and an endometriosis recurrence rate of 22%, confirmed with a histological diagnosis within a five year post-excisional follow-up period (Garry 2000, Abbott 2003). Another study reported a recurrence rate of 24% for dysmenorrhoea and 23% chronic pelvic pain during a three year follow-up (Vercellini 2006). National and international organisations have produced guidelines concerning the management of subfertile women with endometriosis. The American Society for Reproductive Medicine recommends expectant management of subfertility associated with mild to moderate endometriosis in women aged 35 years or younger. For women 35 years of age or older, they recommend considering intrauterine insemination, IVF or laparoscopic treatment (Practice Committee ASRM, 2012). The Society of Obstetricians and Gynaecologists of Canada recommends laparoscopic treatment of subfertility associated with minimal or mild endometriosis and states “the effect on fertility of surgical treatment of deeply infiltrating endometriosis is controversial” (Leyland 2010). The European Society of Human Reproduction and Embryology states “There is insufficient evidence available to determine whether surgical excision of moderate to severe endometriosis enhances pregnancy rates. IVF is appropriate treatment especially if there are coexisting causes of infertility and/or other treatments have failed, but IVF pregnancy rates are lower in women with endometriosis than in those with tubal infertility. The management of severe/ deeply infiltrating endometriosis is complex and referral to a centre with the necessary expertise is strongly recommended.” (Kennedy 2005). The limited evidence base and the slow evolution of the evidence is highlighted in National Institute for Health and Care Excellence (NICE) guidance, which advocates for laparoscopic treatment of minimal and mild endometriosis and discourages medical therapy in minimal and mild endometriosis, alone or as a surgical adjuvant (NICE 2013). Adamson and colleagues have published an analysis of all uncontrolled studies concerning the efficacy of surgery for subfertility associated with endometriosis. Based on the results of a meta-analysis of uncontrolled studies, surgical intervention to treat subfertility associated with endometriosis was estimated to produce pregnancy rates that were 38% (95% CI 28 to 48) higher in the surgical group when compared to the control non-surgical treatment group (Adamson 1994). However, these uncontrolled studies fail to take into account the potential for spontaneous pregnancy in untreated patients and cannot be used to assess the effectiveness of treatment. Many subfertile women eventually conceive without surgical or medical interventions. A recent review of the literature with regard to the efficacy of surgery for subfertility associated with endometriosis concluded that the enhancement of pregnancy rates seems lower than previously suggested by Adamson and colleagues and is closer to a 10% to 25%

increase, although this estimate is largely based on the results of observational or non-randomised trials (Vercellini 2009). This systematic review supports the use of laparoscopic treatment of minimal and moderate endometriosis in improving the pregnancy and live birth rates in couples with otherwise unexplained infertility.

AUTHORS’ CONCLUSIONS Implications for practice There is moderate quality evidence that laparoscopic surgery reduces pain and subfertility due to mild to moderate endometriosis when compared to diagnostic laparoscopy alone. There is low quality evidence that laparoscopic excision and ablation are similarly effective in relieving pain, though there was only one relevant study. It is not possible to draw conclusions with regards to the treatment of severe endometriosis, the types of pain which respond best to laparoscopic treatment, which specific laparoscopic surgical intervention is most effective, or whether other holistic or medical treatment modalities are more effective than laparoscopic surgery. No conclusions can be made with regards to adverse events. Practitioners offering laparoscopic surgery for endometriosis should be appropriately trained in the use of these techniques. Careful patient selection, adequate surgical experience and appropriate equipment are very important in ensuring that these techniques are usefully applied. All decisions regarding management of pain and subfertility associated with endometriosis should be made after detailed discussion with the patient of the options available.

Implications for research There are very few trials in this area and further trials are required focusing on different laparoscopic techniques, pain types and severities of endometriosis. Further research is required comparing laparoscopic interventions with holistic and medical interventions. Trials should be of high methodological quality, adequately powered for the primary outcome, and with five year follow-up, which reflects the chronic nature of pain associated with endometriosis.

ACKNOWLEDGEMENTS We would like to thank the members of the Cochrane Menstrual Disorders and Subfertility Review Group based in Auckland, New Zealand, who assisted us with this review. We would like to thank the National Institute of Health Research, UK, which provided funding to complete this review. We thank also Dr Sophie Fincher for assisting with study selection and drafting of the background section.


23

REFERENCES

References to studies included in this review Abbott 2004 {published data only (unpublished sought but not used)} Abbott J, Hawe J, Hunter D, Holmes M, Finn P, Garry R. Laparoscopic excision of endometriosis: a randomised, placebo-controlled trial. Fertility and Sterility 2004;82: 878–84. Gad 2012 {published data only (unpublished sought but not used)} ∗ Gad M, Badroui M. Evidence-based therapy for infertility associated with early stage endometriosis. International Journal of Gynaecology and Obstetrics 2012;S531-S867: S548. Healey 2010 {published data only (unpublished sought but not used)} Healey M, Ang W C, Cheng C. Surgical treatment of endometriosis: a prospective randomised double-blinded trial comparing excision and ablation. Fertility and Sterility 2010;94:2536–40. Jarrell 2005 {published data only (unpublished sought but not used)} Jarrell J, Mohindra R, Ross S, Taenzer P, Brant R. Laparoscopy and reported pain among patients with endometriosis. Journal of Obstetrics and Gynaecology Canada 2005;27:477–85. Lalchandani 2005 {published data only (unpublished sought but not used)} Lalchandani S, Baxter A, Phillips K. A prospective randomised comparison of laparoscopic treatment and treatment with gonadotrophin releasing hormone analogue in patients with mild to moderate endometriosis. International Journal of Obstetrics and Gynecology 2003;83: 48. ∗ Lalchandani S, Baxter A, Phillips K. Is helium thermal coagulator therapy for the treatment of women with minimal to moderate endometriosis cost-effective? A prospective randomised controlled trial. Gynaecological Surgery 2005;2:255–8. Marcoux 1997 {published data only (unpublished sought but not used)} Berube S, Marcoux S, Langevin M, Maheux R. Fecundity of infertile women with minimal or mild endometriosis and women with unexplained infertility. Fertility and Sterility 1998;69(6):1035–41. Marcoux S, Maheux R, Berube S. Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. New England Journal of Medicine 1997;337:217–22. Moini 2012 {published data only (unpublished sought but not used)} Moini A. Comparison of laparoscopic surgery with no treatment in infertile women with endometriosis (Main ID: IRCT201012311952N2). WHO International Clinical Trials Registry Platform 2008. Moini A, Bahar L, Ashrafinia M, Eslami B, Hosseini R, Ashrafinia N. Fertility outcome after operative laparoscopy versus no treatment in infertile women with minimal or mild endometriosis. International Journal of Fertility and Sterility 2012;5(4):235–40.

Sutton 1994 {published data only} Sutton C J, Ewen S P, Whitelaw N, Haines P. Prospective, randomised, double-blind, controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal, mild, and moderate endometriosis. Fertility and Sterility 1994;62:696–700. Sutton CJ, Pooley AS, Ewen SP, Haines P. Follow-up report on a randomised controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal to moderate endometriosis. Fertility and Sterility 1997;68: 1070–4. Whitelaw NL, Haines P, Ewen S, Sutton C. Assessing the efficacy of laser laparoscopy in the treatment of endometriosis. Journal of Obstetrics and Gynaecology 1993; 13:486. Tutunaru 2006 {published data only (unpublished sought but not used)} Tutunaru D, Vladareanu R, Dumitrascu MC, Alexandru B. Placebo effect of diagnostic laparoscopy alone in mild endometriosis. Journal of Gynaecology and Obstetrics 2006; 2:144. Wright 2005 {published data only (unpublished sought but not used)} Wright J, Lotfallah H, Jones K, Lovell D. A randomised trial of excision versus ablation for mild endometriosis. Fertility and Sterility 2005;83:1830–6.

References to studies excluded from this review Darai 2010 {published data only (unpublished sought but not used)} Darai E, Dubernard G, Coutant C, Frey C, Rouzier R, Ballester M. Randomized trial of laparoscopically assisted versus open colorectal resection for endometriosis: morbidity, symptoms, quality of life, and fertility. Annals of Surgery 2010;251:1018–23. Daraii E, Lesieur B, Dubemand G, Rouzier R, Bazot M, Ballester M. Fertility after colorectal resection for endometriosis:results of a prospective study comparing laparoscopy with open surgery. Fertility and Sterility 2011; 95(6):1903–8. Daraï E. Laparoscopy Versus Laparotomy for Colorectal Endometriosis (Identifier: NCT00939861). ClinicalTrials.gov 2009. Parazzini 1999 {published data only} Parazzini F. Ablation of lesions or no treatment in minimalmild endometriosis in infertile women: a randomised trial. Gruppo Italiano per lo Studio dell’Endometriosi. Human Reproduction 1999;14:1332–4. Soysal 2001 {published data only} Soysal M, Soysal S, Vicdan K. Laparoscopically assisted definitive treatment of severe endometriosis. International Journal of Gynaecology and Obstetrics 2001;72:191–2.

References to ongoing studies


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Soto 2012 {unpublished data only} Soto E. Laparoscopy vs. Robotic Surgery for Endometriosis (LAROSE): a Prospective Randomized Controlled Trial (NCT01556204). ClinicalTrials.gov 2012.

Additional references Abbott 2003 Abbott JA, Hawe J, Clayton RD, Garry R. The effects and effectiveness of laparoscopic excision of endometriosis: a prospective study with 2-5 year follow-up. Human Reproduction 2003;18:1922–7. Abou-Setta 2013 Abou-Setta AM, Houston B, Al-Inany HG, Farquhar C. Levonorgestrel-releasing intrauterine device (LNG-IUD) for symptomatic endometriosis following surgery. Cochrane Database of Systematic Reviews 2013;1:CD005072. Adamson 1994 Adamson GD, Pasta DJ. Surgical treatment of endometriosis-associated infertility: meta-analysis compared with survival analysis. American Journal of Obstetrics and Gynecology 1994;171:1488-504; discussion 1504-5. Ahmad 2012 Ahmad G, O’Flynn H, Duffy JM, Phillips K, Watson A. Laparoscopic entry techniques. Cochrane Database of Systematic Reviews 2012;2:CD006583. Allen 2009 Allen C, Hopewell S, Prentice A, Gregory D. Nonsteroidal anti-inflammatory drugs for pain in women with endometriosis. Cochrane Database of Systematic Reviews 2009:CD004753. American Society for Reproductive Medicine, 1997 Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertility and Sterility 1997;67(5):817–21. Berlanda 2013 Berlanda N, Vercellini P, Somigliana E, Frattaruolo MP, Buggio L, Gattei U. Role of surgery in endometriosisassociated subfertility. Seminars in Reproductive Medicine 2013;31:133–43. Brown 2010 Brown J, Pan A, Hart RJ. Gonadotrophin-releasing hormone analogues for pain associated with endometriosis. Cochrane Database of Systematic Reviews 2010:CD008475. Brown 2012 Brown J, Farquhar C, Dias S. Endometriosis: an overview of Cochrane Reviews. Cochrane Database of Systematic Reviews 2012, Issue 1. [DOI: 10.1002/14651858.CD009590] Brown 2013 Brown J, Kives S, Akhtar M. Progestagens and antiprogestagens for pain associated with endometriosis. Cochrane Database of Systematic Reviews 2012, Issue 3. [DOI: 10.1002/14651858.CD002122.pub2] Davis 2007 Davis L, Kennedy SS, Moore J, Prentice A. Modern combined oral contraceptives for pain associated with

endometriosis. Cochrane Database of Systematic Reviews 2007:CD001019. Eskenazi 1997 Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstetrics and Gynecology Clinics of North America 1997;24: 235–58. Flower 2012 Flower A, Liu JP, Lewith G, Little P, Li Q. Chinese herbal medicine for endometriosis. Cochrane Database of Systematic Reviews 2012;5:CD006568. Garry 2000 Garry R, Clayton R, Hawe J. The effect of endometriosis and its radical laparoscopic excision on quality of life indicators. BJOG 2000;107:44–54. Giudice 2004 Giudice LC, Kao LC. Endometriosis. Lancet 2004;364: 1789–99. Giudice 2012 Giudice L, Evers JLH, Healy DL. Endometriosis: science and practice. Oxford: Wiley-Blackwell, 2012. Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane–handbook.org. Houston 1988 Houston DE, Noller KL, Melton LJ 3rd, Selwyn BJ. The epidemiology of pelvic endometriosis. Clinical Obstetrics and Gynecology 1988;31:787–800. Howard 2009 Howard FM. Endometriosis and mechanisms of pelvic pain. Journal of Minimally Invasive Gynecology 2009;16:540–50. Hughes 2007 Hughes E, Brown J, Collins JJ, Farquhar C, Fedorkow DM, Vandekerckhove P. Ovulation suppression for endometriosis. Cochrane Database of Systematic Reviews 2007:CD000155. Kennedy 2005 Kennedy S, Bergqvist A, Chapron C, D’Hooghe T, Dunselman G, Greb R, et al.ESHRE guideline for the diagnosis and treatment of endometriosis. Human Reproduction 2005;20:2698–704. Kurata 1993 Kurata S, Ishimaru T, Masuzaki H, Yamabe T. Relationship between the prognosis of conception and the location of pelvic involvement in endometriosis: significance of the TOP (tube, ovary, peritoneum) classification. Asia-Oceania Journal of Obstetrics and Gynaecolpgy 1993;19:391–9. Leyland 2010 Leyland N, Casper R, Laberge P, Singh SS, SOGC. Endometriosis: diagnosis and management. Journal of Obstetrics and Gynaecology Canada 2010;32:S1–32.


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Lu 2012 Lu D, Song H, Li Y, Clarke J, Shi G. Pentoxifylline for endometriosis. Cochrane Database of Systematic Reviews 2012;1:CD007677. Lu 2013 Lu D, Song H, Shi G. Anti-TNF-alpha treatment for pelvic pain associated with endometriosis. Cochrane Database of Systematic Reviews 2013;3:CD008088. Mahmood 1991 Mahmood TA, Templeton A. Prevalence and genesis of endometriosis. Human Reproduction 1991;6:544–9. Missmer 2003 Missmer SA, Cramer DW. The epidemiology of endometriosis. Obstetrics and Gynecology Clinics of North America 2003;30:1-19, vii. NICE 2013 National Institute for Health and Care Excellence. Assessment and treatment for people with fertility problems. 2013. Practice Committee ASRM, 2012 Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility: a committee opinion. Fertility and Sterility 2012;98(3): 591–8. RCOG 2008 Royal College of Obstetricians and Gynaecologists. The investigation and management of endometriosis. Green-top guideline no. 24 2008:1–14. Ridley 1968 Ridley J. The histogenesis of endometriosis. Obstetrical & Gynecological Survey 1968;23:1–35. Selak 2007 Selak V, Farquhar C, Prentice A, Singla A. Danazol for pelvic pain associated with endometriosis. Cochrane Database of Systematic Reviews 2007:CD000068. Somigliana 2009 Somigliana E, Vigano P, Barbara G, Vercellini P. Treatment of endometriosis-related pain: options and outcomes. Frontiers in Bioscience 2009;1:455–65. Strathy 1982 Strathy JH, Molgaard CA, Coulam CB, Melton LJ 3rd. Endometriosis and infertility: a laparoscopic study of endometriosis among fertile and infertile women. Fertility and Sterility 1982;38:667–72. Vercellini 1996 Vercellini P, Trespidi L, De Giorgi O, Cortesi I, Parazzini F, Crosignani PG. Endometriosis and pelvic pain: relation to disease stage and localization. Fertility and Sterility 1996; 65:299–304.

Vercellini 2006 Vercellini P, Fedele L, Aimi G, De Giorgi O, Consonni D, Crosignani PG. Reproductive performance, pain recurrence and disease relapse after conservative surgical treatment for endometriosis: the predictive value of the current classification system. Human Reproduction 2006; 21:2679–85. Vercellini 2009 Vercellini P, Somigliana E, Vigano P, Abbiati A, Barbara G, Crosignani PG. Surgery for endometriosis-associated infertility: a pragmatic approach. Human Reproduction 2009;24:254–69. Vigano 2004 Vigano P, Parazzini F, Somigliana E, Vercellini P. Endometriosis: epidemiology and aetiological factors. Best Practice & Research. Clinical Obstetrics & Gynaecology 2004; 18:177–200. Yap 2004 Yap C, Furness S, Farquhar C. Pre and post operative medical therapy for endometriosis surgery. Cochrane Database of Systematic Reviews 2004:CD003678. Zhu 2011 Zhu X, Hamilton KD, McNicol ED. Acupuncture for pain in endometriosis. Cochrane Database Syst Rev 2011: CD007864.

References to other published versions of this review Jacobson 2001 Jacobson TZ, Barlow DH, Garry R, Koninckx P. Laparoscopic surgery for pelvic pain associated with endometriosis. Cochrane Database of Systematic Reviews 2001:CD001300. Jacobson 2002 Jacobson TZ, Barlow DH, Koninckx PR, Olive D, Farquhar C. Laparoscopic surgery for subfertility associated with endometriosis. Cochrane Database of Systematic Reviews 2002:CD001398. Jacobson 2009 Jacobson TZ, Duffy JM, Barlow D, Koninckx PR, Garry R. Laparoscopic surgery for pelvic pain associated with endometriosis. Cochrane Database of Systematic Reviews 2009:CD001300. Jacobson 2010 Jacobson TZ, Duffy JM, Barlow D, Farquhar C, Koninckx PR, Olive D. Laparoscopic surgery for subfertility associated with endometriosis. Cochrane Database of Systematic Reviews 2010:CD001398. ∗ Indicates the major publication for the study


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CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID] Abbott 2004 Methods

Design Comment: Parallel to design randomised controlled trial Quote: “...randomised, placebo to controlled trial...” Setting Comment: Single centre in the United Kingdom Quote: ”Women for the study were recruited from the outpatient department of The James Cook University Hospital in Middlesbrough, United Kingdom.” Follow-up Duration: 12 months but only 6 month follow-up data could be included in the metaanalysis Quote: “All of the above measures were re administered immediately before the second surgery at 6 months, and on follow to up at 12 months after the first surgery.”

Participants

Inclusion criteria Comment: Indication for intervention: Pain Severity of Disease: rAFS Stage 1 to 4 Quote: “Inclusion criteria were clinical symptoms and signs suggestive of endometriosis, such as dysmenorrhoea, non to menstrual pelvic pain, dyspareunia or dyschezia, and pelvic abnormality on examination, in association with histologic evidence of endometriosis at the time of surgery.” Exclusion criteria Quote: “Women were excluded if they had suspected gynaecologic malignancy or its precursors, current or chronic pelvic inflammatory disease, or became pregnant preoperatively.”

Interventions

Treatment Group 1 Comment: Laparoscopic excision and histological diagnosis Quote: “In the immediate surgery group (ISG), women had excision of endometriosis by laparoscopy performed at surgery. Histologic diagnosis of endometriosis was confirmed. “ Treatment Group 2 Comment: Diagnostic laparoscopy only, Laparoscopic excision was performed 6 months later Quote: “In the delayed surgery group (DSG), women had a staging laparoscopy performed at the time of surgery 1, with note made of revised American Fertility Society score, and a detailed laparoscopic assessment of endometriosis.”

Outcomes

Primary outcomes Pain: Reported with participants completing a visual analogue scale prior to surgery and 6 months after surgery Live birth rate: Not applicable Secondary outcomes Clinical pregnancy rate: Not applicable


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Abbott 2004

(Continued)

Miscarriage rate: Not applicable Adverse events: Reported solid organ and vascular injury and conversion to laparotomy Quote: “There were two complications in the ISG; one patient had disease of the posterior cervix that required a laparotomy to repair, and a second patient had a two unit blood transfusion postoperatively for symptomatic surgical anaemia.” Power Comment: Power calculation performed and information to repeat the calculation was presented Quote: “Sample size calculations were based on the assumption that there would be a 50% reduction in pain after excision of endometriosis and that a 22% placebo response to surgery would be reported. Based on these factors, 40 women were required in the study (Epi Info 6; CDC Epidemiology Office, Atlanta, GA). Significance was set at the 5% level. To allow for a 20% rate due to dropout or exclusion for a diagnosis other than endometriosis, 50 women were sought for the study.” Notes

Publication: Journal article Corresponding author was contacted for clarification of data but no response was received

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk bias)

Comment: Computer to generated randomisation Quote: “Randomization was by computer to generated randomisation blocks in balanced groups of 10.”

Allocation concealment (selection bias)

Low risk

Comment: Third to party allocation Quote: “...concealment achieved by third to party allocation to one of two groups”

Blinding of participants and personnel Low risk (performance bias) All outcomes

Comment: Blinding of participants only Quote: “Medical and nursing staff not involved with the research team undertook pre-intervention and postoperative care. The operative notes were kept within the operating suite and could be accessed in case of emergency. Separate notes accompanied the patient to the recovery areas and postoperative care ward. No information was given to staff responsible for postoperative care, to the patient, to the patient’s family, or to general practitioners regarding the exact procedure that had been performed. Surgeons and other staff present during the surgical procedure did not interact with the patients postoperatively, to minimize potential influence.”


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Abbott 2004

(Continued)

Blinding of outcome assessment (detection Low risk bias) All outcomes

Comment: Blinding of outcome assessors and participants Quote: See ‘Blinding of participants and personnel’

Incomplete outcome data (attrition bias) All outcomes

Low risk

Follow-up Entered the study: 29 participants Lost to follow-up: 0 (0%) participant Exclusions: none Intetion-to-treat analysis Intention-to-treat principle was used for all analyses Quote: “All analyses were two to tailed and undertaken by intention to treat.”

Selective reporting (reporting bias)

Unclear risk

Published protcol Comment: Protocol was available all outcomes were reported, however adverse events were not reported. Adverse events were not reported

Other bias

Low risk

Included patient characteristics Comment: no evidence of a differences in baseline patient characteristics Quote: “There were no significant differences between the groups at baseline for any demographic parameter, pain or quality of life measure, or previous treatment for endometriosis.” Funding source Not detailed Ethical approval Comment: Ehitcal approval obtained Quote: “Approval for the study was obtained from the institution’s ethics committee.” Other sources No other biases were evident


29

Gad 2012 Methods

Design Comment: Parallel to design randomised controlled trial Quote: “A randomised prospective clinical trial.” Setting Comment: Multicentre trial in Egypt Quote: “Gynaecology Endoscopic Units in El Menoufia University Hospital and Infertility clinic at a private hospital.” Follow-up Duration: 18 months follow-up or up to 20 weeks of pregnancy Quote: “Follow to up data were collected for 18 months after laparoscopy or up to 20 weeks of pregnancy.”

Participants

Inclusion criteria Comment: Indication for intervention: Subfertility Severity of Disease: rAFS Stage 1 or 2 Quote: “The study included 41 infertile women with laparoscopically confirmed endometriosis, stage I or II of the revised AFS classification.” Exclusion criteria Comment: Not stated

Interventions

Treatment Group 1 Comment: Laparsocopic ablation or resection Treatment Group 2 Comment: Diagnostic laparoscopy only Quote: “Twenty women were randomly allocated to resection or ablation of visible endometriosis during laparoscopy (Group I), and Twenty to one Women to diagnostic laparoscopy only (Group II).”

Outcomes

Primary outcomes Pain: Not applicable Live birth rate: Reported and defined as “20 weeks of pregnancy” Secondary outcomes Clincial pregnancy rate: Reported but not defined. All pregnancies resulted in pregnancies of 20 weeks duration Miscarriage rate: Reported but not defined Adverse events: Not reported Quote: “By the end of the study, a total of 19/41 women (46.3%) conceived and no abortion occurred.” Power Comment: No power calculation performed was presented in the study report

Notes

Publication: Conference abstract Corresponding author was contacted for clarification of data but no response was received

Risk of bias Bias




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Gad 2012

(Continued)

Random sequence generation (selection Unclear risk bias)

Comment: Method of sequence generation not stated Quote: “Twenty women were randomly allocated to resection or ablation of visible endometriosis during laparoscopy (Group I), and Twenty-one Women to diagnostic laparoscopy only (Group II).”


Comment: Method of allocation concealment not stated

Unclear risk

Blinding of participants and personnel High risk (performance bias) All outcomes

Comment: Did not report blinding of participants

Blinding of outcome assessment (detection High risk bias) All outcomes

Comment: Did not report blinding of outcome assessors


Low risk

Follow-up Entered the study: 41 participants Lost to follow-up: no participants Exclusions: no participants Intention-to-treat analysis Intention-to-treat principle was not reported


Unclear risk

Comment Protocol was not available but outcomes in methods and results are similar. Conference abstract so full description of methods and results not available. Adverse events were not reported

Other bias

Low risk

Included patient characteristics Comment: No statistical differences between intervention and control group participants Quote: “The base line distribution of subjects was similar in the two groups” Funding Comment: Not stated Ethical approval Comment: Not stated Other sources No other biases were evident from the trial report


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Healey 2010 Methods

Design Comment: Parallel to design randomised controlled trial Quote: “This study was a prospective randomised double to blinded trial aiming to assess for superiority between two laparoscopic treatments of endometriosis.” Setting Comment: Single centre in Australia. Quote: “The site of this study was a university teaching hospital.” Follow-up Duration: 12 months Quote: “The null hypothesis was that there was no evidence of a difference in overall pain visual analogue scale scores between the two treatment groups at 1 year after operation.”

Participants

Inclusion criteria Comment: Indication for intervention: Pain Severity of disease: rAFS Stage 1 and 2 Quote: “Subjects were women recruited from an outpatient setting with pain symptoms suggestive of endometriosis (dysmenorrhoea, deep dyspareunia, or cyclic pelvic pain) who had been booked for an operative laparoscopy. Recruitment occurred between July 2001 and September 2007. To be included subjects had to provide informed consent, speak English, not be using or planning to use continuous hormonal therapy, and be > 18 years of age. At laparoscopy each recruited subject’s pelvis and abdomen were assessed for the presence of visible endometriosis.” Exclusion criteria Quote: “Subjects were excluded if there was no obvious endometriosis or there was obvious endometriosis involving the muscle levels of bowel, bladder, or ureter.”

Interventions

Treatment Group 1 Comment: Laparoscopic ablation or excision Treatment Group 2 Comment: Diagnositc laparoscopy only. Quote: “Treatment of all recognized endometriosis then was performed by a trainee gynaecologist while supervised and assisted by the consultant gynaecologist with expertise in the chosen treatment method [ablation or excision].”

Outcomes

Primary outcomes Pain: Reported with participants completing a visual analogue scale prior to surgery and 3, 6, 9, and 12 months after surgery Live birth rate: Not applicable Secondary outcomes Clincial pregnancy rate: Not applicable Miscarriage rate: Not applicable Adverse events: Not reported Quote: “The null hypothesis was that there was no evidence of a difference in overall pain visual analogue scale scores between the two treatment groups at 1 year after operation. A questionnaire assessing pain types and severity was completed by subjects before surgery and then every 3 months for a year. Pain severity was measured by use of VASs made up of a 10 cm line marked with “no pain” at the left end and “worst imaginable pain” at the right end. The VAS lines were measured to the nearest millimetre. Scores were presented


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Healey 2010

(Continued)

as a range from 0 to 10.” Power Comment: Power calculation performed and information to repeat the calculation was presented Quote: “The power calculation assumed a base reduction in overall pain VAS score of 3. 7 (estimated from the reduction in mean VAS pain score at 6 months in Sutton’s study in 1994); a clinically significant difference between groups being a change of VAS score of 1.0; an SD of 2.0; and a power of 80% and alpha value of 5%. The calculated sample size was N=49 in each group. To allow for wastage a sample size of 120 (60 in each group) was chosen. Because an interim analysis demonstrated a subject loss of 35% at 1 year, the sample size was increased to 180 to compensate.” Notes


Risk of bias Bias




Comment: Computer random number generator Quote: “Randomization of subjects occurred intra to operatively at the time of surgery once endometriosis was diagnosed visually and after evaluation of the pelvis confirmed no involvement of rectal, ureteric, or bladder muscle. Treatment randomisation was performed with use of a computer random number generator.”


Comment: Consecutively numbered opaque envelopes Quote: “Treatment randomisation was performed with use of a computer random number generator, and the results were placed in consecutively numbered opaque envelopes.”

Low risk


Comment: Blinding of participants only Quote: “Both the subjects and the medical staff performing follow to up care were blinded to the type of treatment.”


Comment: Blinding of outcome assessors Quote: See above ‘Blinding of participants and personnel’


33

Healey 2010

(Continued)


High risk

Follow-up Entered the study: 178 participants Lost to follow-up: 46 participants Exclusions: 29 participants Intention-to-treat analysis Comment: Intention-to-treat principle was deployed Quote: “The remainder were included as this was an “intention to treat” study (ablation N = 85 and excision N = 85).”


Unclear risk

Comment: Protocol was not available all outcomes referred to within the methods were reported. Adverse events were not reported

Other bias

Low risk

Included patient characteristics Commet: No statistical differences between intervention and control group participants Quote: “no evidence of a differences were found when demographic factors and preintervention operation VAS pain scores were compared between subjects included at the 12 to month analysis and those excluded.” Funding Not stated Ethical approval Ethical approval sort Quote: “This study was approved by the Research and Ethics Committees of the Royal Women’s Hospital, Melbourne.” Other sources No other biases were evident from the trial report


34

Jarrell 2005 Methods

Design Comment: Parallel design randomised controlled trial Quote: “placebo controlled randomised trial” Setting Comment: Single centre in Canada Follow-up Duration: 12 months Quote: “At completion of a 1 year follow to up period”

Participants

Inclusion criteria Comment: Indication for intervention: Pain Severity of disease: rAFS Stage 1 to 3 Quote: “The inclusion criteria were severe pelvic pain requiring investigation, premenopausal state, and no evidence of pregnancy. We entered women into the study at the time of laparoscopy if the clinical impression was that of endometriosis.” Exclusion criteria Quote: “Exclusion criteria were severe ancillary medical disease, endometriosis that was too expensive to resect at laparoscopy, and symptoms requiring urgent intervention.”

Interventions

Treatment Group 1 Comment: Laparoscopic excision and biopsy Treatment Group 2 Comment: Diagnostic laparoscopy and biopsy Quote: “Women allocated to the excision group had a biopsy of their endometriosis followed by complete excision. Control patients only had a biopsy.”

Outcomes

Primary outcomes Pain: Reported with participants completing a 1 month pain diary consisting of visual analogue scales prior to surgery and at 3, 6, 9, and 12 months after surgery Live birth rate: Not applicable Secondary outcomes Clincial pregnancy rate: Not applicable Miscarriage rate: Not applicable Adverse events: Not reported Quote: “Women who entered the study completed pain diaries, using Visuals Analogue Scales daily for 1 month at baseline and then daily for 1 month at 3 month intervals for the next year. The visual analogues scales were designed to aggregate pain in various parts of the body including the chest, back, abdomen, pelvis, and thighs.” Power Comment: Power calculation performed and information to repeat the calculation was presented Quote: “We determined the desired sample size in a preliminary pilot study. A meaningful outcome was determined to be a 50% reduction in pain. With a 65% improvement in the treatment group and a 35% improvement in the control group, we required 42 women per group for an alpha of 0.05 and a beta of 0.80. We predicated a potential 20% loss of women, leaving a required total of 100 women (50 per group).”


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Jarrell 2005

(Continued)

Notes


Risk of bias Bias




Comment: Computer generated randomisation Quote: “We used computer generated randomisation to allocate women to the control or excision group. Randomisation in blocks of 5 subjects were stratified for severity based on the presence or absence of previous pelvic surgery for endometriosis.”


Comment: Opaque, sealed envelopes Quote: “Cards indicating allocation were kept in opaque envelopes in the operating groom and opened at the time of laparoscopy.”

Low risk


Comment: Blinding of participants only Quote: “Operating room staff members were aware of the allocation, but all remaining staff were blinded. All patients had 3 incisions, to avoid breaches in the integrity of the trial, and a biopsy of a representative portion of the disease. Women who participated in the trial were transferred back to the care of their referring physician and were seen as required postoperatively. They remained blinded to the identify of their procedure for 1 year, and the referring physician did not have access to the operative record in the clinic chart.“


Comment: Blinding of outcome assessors Quote: See ‘Blinding of participants and personnel’


Follow-up Entered the study: 29 participants Lost to follow-up: 15 (52%) participants Exclusions: 0 participants Intention-to-treat analysis Comment: Intention-to-treat analysis was reported within the study

High risk


36

Jarrell 2005

(Continued)


Unclear risk


Other bias

Low risk

Included patient characteristics Comment: No statistical differences between intervention and control group participants Quote: “The groups were similar in gravidity, parity, preoperative pain scores, and ASRM scores at surgery.” Source of funding Comment: Source of funding detailed within the report Quote: “This project was funded by a grant from the Alberta Heritage Foundation for Medical Research” Ethical approval Comment: Ehtical approval sort Quote: “The University of Calgary Ethics Committee approved the study.” Other sources: No other biases were evident from the trial report

Lalchandani 2005 Methods

Design Comment: Parallel design randomised controlled trial Quote: “A prospective randomised controlled trial.” Setting Comment: Likely multicentre trial in the UK Follow-up Duration: 12 months Quote: “All women were given visual analogue pain scores preoperatively and 3, 6, and 12 months postoperatively.”

Participants

Inclusion criteria Comment: Indication for intervention: Pain Severity of disease: rAFS Stage 1 to 2 Quote: “All women presenting to the gynaecology outpatient clinic with a history of pelvic pain, dysmenorrhoea, dyspareunia, and dyschezia suggestive of endometriosis or who had previously been diagnosed as having the disease were asked to enter the trial.” Exclusion criteria Quote: “All women who were less than 16 years of age, pregnant, or subfertile were excluded from the study.”


37

Lalchandani 2005

(Continued)

Interventions

Treatment Group 1 Comment: Laparoscopic ablation (helium thermal coagulator therapy) Treatment Group 2 Comment: Diagnostic laparoscopy and Gonadotrophin-releasing hormone analogue (injectable Goserelin) with add to back therapy (tibolone) Quote: “Randomisation into either HTC or GnRH to a therapy was done at the time of diagnostic laparoscopy.”

Outcomes

Primary outcomes Pain: Reported with participants completing a visual analogue scale prior to surgery and 3, 6, and 12 months after surgery Live birth rate: Not applicable Secondary outcomes Clincial pregnancy rate: Not applicable Miscarriage rate: Not applicable Adverse events: Reported but not defined Quote: “All women were given visual analogue pain scores preoperatively and 3, 6, and 12 months postoperatively, and their symptoms were taken into consideration... There were no surgical complications reported in this series.” Power Comment: Power calculation performed but information to repeat the calculation was not presented Quote: “Power studies were performed prior to the study, and 25 patients were required in each arm.”

Notes

Publication: Journal article (x1) and conference abstract (x1) Corresponding author was contacted for clarification of data but no response was received

Risk of bias Bias




Comment: Unclear method of random sequence generation Quote: “Randomisation into either HTC or GnRH to a therapy was done at the time of diagnostic laparoscopy.”



Unclear risk


Comment: Did not report blinding of personnel




38

Lalchandani 2005

(Continued)


Low risk

Follow-up Entered the study: 35 participants Lost to follow-up: 0 participants Exclusions: 0 participants Intention-to-treat analysis Comment: Intention-to-treat analysis was not reported within the study


Unclear risk

Comment: Protocol was not available. Incomplete data reporting Quote: “Analysis of the pain scores and of the success rates of the two treatment modalities will be discussed in our second paper comparing the effectiveness of medical versus surgical treatment”. Not published (Aug, 2013). Adverse events were not reported

Other bias

Low risk

Included patient characteristics Comment: no evidence of a differences in participant characteristics Funding Comment: Not stated Ethical approval Comment: Ethical approval obtained Other sources No other biases were evident from the trial report

Marcoux 1997 Methods

Design Comment: Parallel design randomised controlled trial Quote: “Randomized, controlled multi to centre trial” Setting Comment: Multicentre trial in Canada Quote: “25 hospitals in Canada.” Follow-up Duration: 9 months or until 20 weeks of pregnancy Quote: “The women were followed for 36 weeks or, for those who became pregnant during that interval, for up to 20 weeks of pregnancy.”

Participants

Inclusion criteria Comment: Indication for intervention: Subfertility Severity of disease: rAFS Stage 1 to 2 Quote: “The eligibility criteria to be met before the laparoscopy were the following: age between 20 and 39 years; infertility (at least 12 consecutive months of unprotected inter-


39

Marcoux 1997

(Continued)

course in unsuccessful attempts to become pregnant); normal ovulatory cycles; partner’s semen sample containing at least 20 million motile spermatozoa; no previous surgical treatment for endometriosis; no medical treatment for endometriosis in the previous 9 months; no ovulatory drug therapy or intrauterine insemination with partner’s sperm in the previous month; no other medical or surgical treatment for infertility in the previous 3 months; no previous oophorectomy or salpingectomy; no history of pelvic inflammatory disease; and no severe pelvic pain precluding expectant management.” Exclusion criteria Quote: “Women with adhesions precluding adequate visualization of a tube or ovary were ineligible for the study, as were women in whom the laparoscopic tubal patency test revealed complete obstruction of one or both tubes, unless hysterosalpingography in the previous year had indicated that both tubes were patent.” Interventions

Treatment Group 1 Comment: Laparoscopic ablation or excision Treatment Group 2 Comment: Diagnostic laparoscopic only Quote: “The laparoscopic surgical treatment involved the destruction or removal of all visible endometriotic implants and the lysis of adhesions. The choice of instruments was left to the surgeon. The implants were destroyed by cautery only (78 %), laser only (19 %), or a combination (3 %). “In the diagnostic to laparoscopy group, removal of implants and adhesiolysis were not allowed.”

Outcomes

Primary outcomes Pain: Not applicable Live birth rate: Reported defined as “intrauterine pregnancy that was carried beyond 20 weeks” Secondary outcomes Clincial pregnancy rate: Reported defined as “all the women who became pregnant had ultrasonography” Miscarriage rate: Reported but not defined. Quote: “Three fetal losses were due to ectopic pregnancies (two in the laparoscopic to surgery group and one in the diagnostic to laparoscopy group).” Adverse events: Reported but not defined. Quote: “intraoperative and postoperative complications” Power Comment: Power calculation performed and information to repeat the calculation was presented Quote: ”We ascertained that 330 women were required for us to detect a 15% difference in the primary end point (a=0.05, b=0.20, two to tailed test) if the expected probability in the control group was between 15% and 30%.“

Notes

Publication: Journal article (x2) Corresponding author was contacted for clarification of data but no response was received

Risk of bias Bias




40

Marcoux 1997

(Continued)


Comment: Method of sequence generation was computer generated random number tables Quote: “Stratified randomisation according to hospital, balanced for every two to six assignments. Allocation by telephone call to central randomisation service while the patient was anaesthetised. Women were informed which group they had been randomised to following the surgery and were not blinded during the follow to up period. ”


Comment: Method of allocation concealment was by a telephone call to central randomisation service while the patient was anaesthetised Quote: ”A surgical assistant called the centralized randomisation service while the patient was still anaesthetised.”

Low risk


Comment: Did not report blinding of personnel




Unclear risk

Follow-up Entered the study: 348 participants Lost to follow-up: 21 (6%) participants Exclusions: 28 (8%) participants Intention-to-treat analysis Comment: Intention-to-treat analysis was not reported within the study


Unclear risk

Comment: Protocol was not available but outcomes in methods and results are similar. Did not report birth rate

Other bias

Low risk

Included patient characteristics Comment: No statistical differences between intervention and control group participants Quote: “The baseline characteristics of the women are shown in Table 1. Twelve women (3.5%) - seven in the laparoscopic to surgery


41

Marcoux 1997

(Continued)

group and five in the diagnostic to laparoscopy group - had a previous diagnosis of endometriosis. Tubal patency was documented during the laparoscopy in 99 % and 98 % of the women in the laparoscopic surgery group and the diagnostic to laparoscopy group, respectively, and by previous hysterosalpingography in the remainder. The proportion of women whose status at the end of the 36 to week follow to up was confirmed by a pregnancy test (67 %) did not differ between the two groups. ” Ethical approval Comment: Ethical approval sort Quote: “The study protocol was approved by the appropriate review committee at each hospital, and all the women gave written consent before the laparoscopy was performed.” Source of funding Comment: Source of funding stated Quote: “Supported by a grant from the Medical Research Council of Canada. Dr. Marcoux holds a National Health Research Scholarship from Health Canada.” Other sources No other biases were evident from the trial report

Moini 2012 Methods

Design Comment: Parallel to design randomised controlled trial Quote: ”..randomised controlled trial...“ Setting Comment: Single centre in Tehran Quote: “Gynaecological Outpatient Clinic of Arash Hospital between April 2008 and March 2009.” Follow-up Duration: 9 months follow-up

Participants

Inclusion criteria Comment: Indication for intervention: Subfertility Severity of Disease: rAFS score 1 or 2 Quote: “Inclusion criteria were: age between 20 to 32 years, unexplained infertility more than 1 year, normal semen analysis, normal ovulatory cycles (menstrual interval 24 to 35 days and biphasic basal temperature), normal hormonal assay [thyroid stimulating


42

Moini 2012

(Continued)

hormone (TSH), follicle to stimulating hormone (FSH), prolactin (PRL)] and normal hysterosalpingography.” Exclusion criteria Quote: “Women who met the following criteria were excluded from our study: surgical history for infertility or endometriosis, oophorectomy, salpingectomymy, history of pelvic inflammatory disease (PID) and those who received any treatment for endometriosis during the previous 3 months.” Interventions

Treatment Group 1 Comment: Laparoscopic ablation or excision Treatment Group 2 Comment: Diagnositic laparoscopy only Quote: ”Operative laparoscopy patients underwent ablation to remove any visible endometrial implants. During surgery, the surgeon chose the type of procedure. The removal was done by bipolar cauterization. In difficult anatomical positions, implants were cauterized with the fulguration method without complete resection.”

Outcomes

Primary outcomes Pain: Not applicable Live birth rate: Not reported Secondary outcomes Clincial pregnancy rate: Reported and defined as “visualization [at ultrasound] of an embryo with cardiac activity at 6 to 7 weeks of pregnancy” Miscarriage rate: Not reported Adverse events: Reported but not comprehensively defined. Quote: “Complications during or post to surgery, such as: intestinal injury, slight tear of the tubal serosa, vascular trauma, infection of wounds, hematomas, and urinary tract infection” Power Comment: Power calculation performed and information to repeat the calculation was presented Quote: “Based on the results of Marcoux et al. (6), we estimated the rate of pregnancy in the surgical group as 15% and the diagnostic group, 35%. Thus, we calculated that 73 patients would be required in each group to detect differences in pregnancy rate with a power of 90% and α=0.05 by Epi Info (www.cdc.gov/epiinfo/).”

Notes

Publication: Journal article and trial registration Corresponding author was contacted for clarification of data but no response was received

Risk of bias Bias




Support for judgement Comment: Method not stated Quote: “After confirmation of minimal or mild endometriosis by diagnostic laparoscopy in all patients, eligible women were randomly assigned to surgery or diagnostic laparoscopy only.”

43

Moini 2012

(Continued)


Low risk

Comment: Consecutively numbered, opaque sealed envelopes Quote: “After confirmation of minimal or mild endometriosis by diagnostic laparoscopy in all patients, eligible women were randomly assigned to surgery or diagnostic laparoscopy only using consecutively numbered, opaque sealed envelopes by a surgical assistant while the patient was still anaesthetised.”


Comment: Blinding of participants only




High risk

Follow-up Entered the study: 146 participants Lost to follow-up: 24 (16%) participants Exclusions: 36 (24%) participants Intention-to-treat analysis Comment: Intention to treat analysis was not reported within the study


Unclear risk

Comment: Protocol was available and outcomes were reported. Did not report live birth rate

Other bias

Low risk

Included patient characteristics Comment: No statistical differences between intervention and control group participants Quote: “Age, body mass index (BMI) and duration of infertility were statistically similar in both groups (p>0.05).” Ethical approval Comment: Ethical approval sort Quote: “The Ethics Institutional Review Board of Tehran University of Medical Sciences approved the study and informed consent was obtained from all participants after counselling regarding the potential risks of laparoscopy.” Source of funding Comment: Source of funding stated Quote: “This study was supported by a


44

Moini 2012

(Continued)

grant aid from Tehran University of Medical Sciences.” Other sources Comment: No other biases were evident from the trial report

Sutton 1994 Methods

Design Comment: Parallel to design randomised controlled trial Quote: “Prospective, randomised, double to blind, controlled trial...” Setting Comment: Single centre, UK Follow-up Duration: Six months Quote: “After the six month follow to up visit, the randomisation code was broken...”

Participants

Inclusion criteria Comment: Indication for intervention: Pain Severity of Disease: rAFS score 1 to 3 Quote: “To be included in the study women were neither pregnant or lactating, were between 18 and 45 years of age, and had not received any treatment (medical or surgical) for endometriosis in the previous 6 months.” Exclusion criteria Comment: Not stated

Interventions

Treatment Group 1 Comment: Laparoscopic ablation (Laser) and uterine nerve transection Quote: ”Laser treatment included vaporisation of all visible endometriosis implants, adhesiolysis, and uterine nerve transection with the CO2 laser...“ Treatment Group 2 Comment: Diagnositic laparoscopy only Quote: ”No treatment intervention was carried out in the women allocated to expectant management...”

Outcomes

Primary outcomes Pain: VAS (10cm linear scale) measuring dysmenorrhoea, dyspareunia, and pelvic pain at 3 and 6 months after surgery Live birth rate: Not applicable Secondary outcomes Clincial pregnancy rate: Not applicable Miscarriage rate: Not applicable Adverse events: Not reported Power Comment: No reference to a power calculation

Notes Laparoscopic surgery for endometriosis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

45

Sutton 1994

(Continued)

Risk of bias Bias




Comment: Computer generated randomisation Quote: “At the time of laparoscopy, treatment was allocated randomly (computer to generated randomisation sequence)...”



Unclear risk


Comment: Blinding of participants only Quote: “Patients were not informed of which treatment they had been allocated to...”


Comment: Blinding of outcome assessors Quote: “...an independent observer (research nurse) who was unaware of the treatment that they had been allocated to...”


Unclear risk

Follow-up Entered the study: 74 participants Lost to follow up: 3 (4%) participants Exclusions: 11 (15%) participants Intention-to-treat analysis Comment: Intention-to-treat analysis was not reported within the study


Unclear risk

Comment: Protocol was available and outcomes were reported. Outcome outlined in the methods were reported in the results section. Adverse events were not reported

Other bias

Low risk

Included patient characteristics Comment: No statistical differences between intervention and control group participants Quote: “The patient characteristics in both groups were not significantly different.” Ethical approval Comment: Ethical approval sort Source of funding Comment: Source of funding stated Quote: “Suppoted by Birthright Research Grant, RCOG and Laserscope, Cwmbran,


46

Sutton 1994

(Continued)

UK.” Other sources Comment: No other biases were evident from the trial report

Tutunaru 2006 Methods

Design Comment: Parallel design randomised controlled trial Quote: “Prospective, single blind, randomised, group controlled trial.” Setting Comment: Not stated Follow to up Duration: 12 months Quote: “Post-operative follow to up for one year”.

Participants

Inclusion criteria Comment: Indication for intervention: Pain Severity of Disease: rAFS stage 1 Quote: “Patients in reproductive age, with endometriotic implants discovered by laparoscopy done because of dysmenorrhoea, who have signed informed consent.” Exclusion criteria Quote: “Severe adhesions, prior abdominal surgery, unwilling to comply with the study. ”

Interventions

Treatment Group 1 Comment: Laparoscopic excision or ablation Treatment Group 2 Comment: Diagnostic laparoscopy

Outcomes

Primary outcomes Pain: Core questionnaires completed prior to surgery and 6 and 12 months following surgery Live birth rate: Not applicable Secondary outcomes Clincial pregnancy rate: Not applicable Miscarriage rate: Not applicable Adverse events: Not reported Quote: “Core questionnaire with 30 items and five pain scales: pain, control and powerlessness, emotional well to being, social support, self to image.” Power Comment: Power calculation was not presented in the report

Notes

Publication: Conference abstract Corresponding author was contacted for clarification of data but no response was received

Risk of bias Laparoscopic surgery for endometriosis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

47

Tutunaru 2006

(Continued)

Bias




Comment: Method not stated Quote: “...69 patients were randomly divided in two groups...”


Comment: No reference to allocation concealment

Unclear risk


Comment: Did not report the blinding of participants




High risk

Follow-up Entered the study: 69 participants Lost to follow up: Not reported Exclusions: Not reported Intention-to-treat analysis Comment: Intention-to-treat analysis was not reported within the study


Unclear risk

Comment: Protocol was not available and outcomes in the methods were reported. Conference abstract so full description of methods and results not available. Adverse events were not reported

Other bias

Low risk

Included patient characteristics Comment: Not stated Ethical approval Comment: Not stated Source of funding Comment: Not stated Other sources Conference abstract so full description of methods and results not available No other biases were evident from the trial report


48

Wright 2005 Methods

Design Comment: Parallel to design randomised controlled trial Quote: “A randomised study of excision or ablation for mild endometriosis, participants and investigators alike blinded to the treatment modality at the follow to up visit.” Setting Comment: Single centre in the UK Quote: “District general hospital with a specialist pelvic pain clinic in the United Kingdom.” Follow-up Duration: 6 months Quote: “At laparoscopy they were randomly assigned to excision or ablation of any endometriotic lesions, and the questionnaire was repeated at 6 months.”

Participants

Inclusion criteria Comment: Indication for intervention: Pain Severity of disease: rAFS 1 Quote: “After agreement by the local research ethics committee, women with a presumptive diagnosis of endometriosis were recruited from a specialist pelvic pain clinic on the grounds of a history of dysmenorrhoea, pelvic pain, backache, dyspareunia, or dyschezia in the absence of any physical signs such as ovarian cysts or uterosacral nodularity that would point to a diagnosis of more advanced disease. A routine laparoscopy was performed; if endometriosis was diagnosed and staged as “mild” (stage 1 to 2 on the revised AFS scale), they were randomised by means of opening a consecutively numbered envelope to receive either ablation or excision of all the identified lesions.” Exclusion criteria Quote: “Women who had infiltrating and nodular disease were excluded from the trial on the grounds that electrocoagulation was not an appropriate form of treatment for these lesions.”

Interventions

Treatment Group 1 Comment: Laparoscopic ablation Treatment Group 2 Comment: Laparoscopic excision Quote: “In the ablation group, the endometriosis was ablated using monopolar diathermy at a coagulation current of 50 watts. The closed end of a pair of 3 to mm monopolar laparoscopic scissors was used. Coagulation continued until the peritoneum was destroyed and an escar could be seen. All visible lesions were coagulated. Excision was carried out using 3 to mm monopolar diathermy scissors with a combination of 90 watts pure cut and 50 watts coagulation; the majority of the surgery was performed in cutting mode.”

Outcomes

Primary outcomes Pain: Reported with participants completing a questionnaire rating their symptoms on a ranked ordinal scale completed prior to surgery and 6 months following surgery Live birth rate: Not applicable Secondary outcomes Clincial pregnancy rate: Not applicable Miscarriage rate: Not applicable Adverse events: Not reported


49

Wright 2005

(Continued)

Quote: “The participants were asked to complete a questionnaire rating their symptoms on a ranked ordinal scale of 1 to 5, a technique that is well recognized as a tool for measuring pain in endometriosis. Signs were assessed by asking the patient to rate the amount of discomfort during palpation.” Power Comment: Power calculation was described within the report Notes


Risk of bias Bias




Comment: Unclear method of sequence allocation Quote: “A routine laparoscopy was performed; if endometriosis was diagnosed and staged as “mild” (stage 1 to 2 on the revised AFS scale), they were randomised by means of opening a consecutively numbered envelope to receive either ablation or excision of all the identified lesions. Randomization was in blocks of 10 to ensure an equal number in each group.”


High risk

Comment: Consecutively numbered envelope Quote: “Opening a consecutively numbered envelope to receive either ablation or excision of all the identified lesions.“


Comment: Did not report the blinding of personnel


Comment: Did not report the blinding of outcome assessors


Follow-up Entered the study: 24 participants Lost to follow up: 0 participants Exclusions: 0 participants Intention-to-treat analysis Comment: Intention-to-treat analysis was not reported within the study

Low risk


50

Wright 2005

(Continued)


Unclear risk


Other bias

Unclear risk

Included patient characteristics Comment: Not reported Ethical approval Comment: Ethical approval sort Quote: “After agreement by the local research ethics committee” Source of funding Comment: Not reported Other sources No other biases were evident from the trial report

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Darai 2010

Comment: Compared a laparoscopic approach with an open procedure Quote: “Randomized Trial of Laparoscopically Assisted Versus Open Colorectal Resection for Endometriosis.”

Parazzini 1999

Comment: Medical adjuvant used Quote: “The protocol allowed after surgery the use of a medical treatment (tryptorelin 3.75 mg slow release every 28 days for 3 months) according to the physician’s judgement.”

Soysal 2001

Comment: No definitive diagnosis of endometriosis or presenting symptom of pain Quote: “Patients with known or suspected endometriosis causing pelvic pain and/or mass with no interest in further childbearing were considered eligible for entrance to the study.”

Characteristics of ongoing studies [ordered by study ID] Soto 2012 Trial name or title

Laparoscopy vs. Robotic Surgery for Endometriosis (LAROSE): a Prospective Randomized Controlled Trial

Methods

Parallel design, randomised, single-blinded controlled trial

Participants

Women 18 years of age or greater who are-intervention undergo laparoscopic treatment of presumed endometriosis, as determined clinically by the operating surgeon


51

Soto 2012

(Continued)

Interventions

Experimental: robotic surgery da Vinci Surgical System. Active comparator: laparoscopy

Outcomes

Primary outcome measures: operative time Secondary outcome measures: pain, activity assessment

Starting date

March 2012, Anticipated end date: December 2014

Contact information

Enrique Soto, The Cleaveland Clinic, USA

Notes

ClinicalTrials.gov Identifier: NCT01556204


52

DATA AND ANALYSES

Comparison 1. Laparoscopic treatment versus diagnostic laparoscopy

Outcome or subgroup title 1 Overall pain better or improved (3 months) 1.1 Ablation & uterine nerve transection vrs. diagnostic laparoscopy 2 Overall pain better or improved (6 months) 2.1 Ablation or excision vrs. diagnostic laparoscopy 2.2 Excision vrs. diagnostic laparoscopy 2.3 Ablation & uterine nerve transection vrs. diagnostic laparoscopy 3 Overall pain better or improved (12 months) 3.1 Ablation or excision vrs. diagnostic laparoscopy 4 Overall pain scores (6 months) 4.1 Excision vrs. diagnostic laparoscopy 5 Overall pain scores (12 months) 5.1 Excision vrs. diagnostic laparoscopy 6 Live birth or ongoing pregnancy 6.1 Ablation or excision vrs. diagnostic laparoscopy 7 Pelvic pain scores (6 months) 7.1 Excision vrs. diagnostic laparoscopy 8 Pelvic pain scores (12 months) 8.1 Excision vrs. diagnostic laparoscopy 9 Dysmenorrhoea pain scores (6 months) 9.1 Excision vrs. diagnostic laparoscopy 10 Dysmenorrhea pain scores (12 months) 10.1 Excision vrs. diagnostic laparoscopy

No. of studies

No. of participants

1

63

Odds Ratio (M-H, Fixed, 95% CI)

1.37 [0.51, 3.70]

1

63


1.37 [0.51, 3.70]

3

171


6.58 [3.31, 13.10]

1

69


6.48 [2.14, 19.56]

1

39


8.67 [2.01, 37.38]

1

63


5.71 [1.89, 17.25]

1

69


10.0 [3.21, 31.17]

1

69


10.0 [3.21, 31.17]

1 1

16

Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)

Subtotals only 0.90 [0.31, 1.49]

1 1

16



2 2

382

Odds Ratio (M-H, Fixed, 95% CI) Odds Ratio (M-H, Fixed, 95% CI)


1 1

39


Subtotals only -5.10 [-16.64, 6.44]

1 1

39


Subtotals only 7.0 [-1.27, 15.27]

Mean Difference (IV, Fixed, 95% CI)

Subtotals only


2.40 [-6.18, 10.98]


Subtotals only


-9.5 [-20.58, 1.58]

1 1

39

1 1

39

Statistical method


Effect size

53

11 Dyspareunia pain scores (6 months) 11.1 Excision vrs. diagnostic laparoscopy 12 Dyspareunia pain scores (12 months) 12.1 Excision vrs. diagnostic laparoscopy 13 Dyschezia pain scores (6 months) 13.1 Excision vrs. diagnostic laparoscopy 14 Dyschezia pain scores (12 months) 14.1 Excision vrs. diagnostic laparoscopy 15 Clinical pregnancy 15.1 Ablation or excision vrs. diagnostic laparoscopy 16 Miscarriage per pregnancy 16.1 Ablation or excision vrs. diagnostic laparoscopy

1 1

39

1 1

39

1 1

39

1


Subtotals only


6.30 [-8.18, 20.78]


Subtotals only


6.10 [-7.48, 19.68]


Subtotals only


-9.2 [-24.41, 6.01]


Subtotals only

1

39


3 3

528


-3.60 [-19.61, 12. 41] Subtotals only 1.89 [1.25, 2.86]

2 2

112



Comparison 2. Laparoscopic versus diagnostic laparoscopy and medical therapy

Outcome or subgroup title 1 Ablation vrs. diagnostic laparoscopy and GnRHa (& add back therapy) 1.1 Overall pain described as ”Pain free” (12 months)

No. of studies

No. of participants

1

1

35

Statistical method

Effect size


Subtotals only


5.63 [1.18, 26.85]

Comparison 3. Laparoscopic ablation versus laparoscopic excision

Outcome or subgroup title 1 Overall pain scores (reduction in VAS at 12 months) 2 Pelvic pain scores (12 months) 3 Dyspareunia pain scores (12 months) 4 Dyschezia pain scores (12 months)

No. of studies

No. of participants

1

103


0.0 [-1.22, 1.22]

1 1

103 103


0.10 [-1.10, 1.30] -1.3 [-2.89, 0.29]

1

103


-1.1 [-2.37, 0.17]

Statistical method


Effect size

54

Analysis 1.1. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 1 Overall pain better or improved (3 months). Review:

Laparoscopic surgery for endometriosis

Comparison: 1 Laparoscopic treatment versus diagnostic laparoscopy Outcome: 1 Overall pain better or improved (3 months)

Study or subgroup

Surgery

Diagnostic

Odds Ratio

n/N

n/N

M-H,Fixed,95% CI

Weight

Odds Ratio M-H,Fixed,95% CI

1 Ablation % uterine nerve transection vrs. diagnostic laparoscopy Sutton 1994

Total (95% CI)

18/32

15/31

100.0 %

1.37 [ 0.51, 3.70 ]

32

31

100.0 %

1.37 [ 0.51, 3.70 ]

Total events: 18 (Surgery), 15 (Diagnostic) Heterogeneity: not applicable Test for overall effect: Z = 0.62 (P = 0.53) Test for subgroup differences: Not applicable

0.01

0.1

Favours diagnostic

1

10

100

Favours surgery


55




Study or subgroup

Surgery

Diagnostic

Odds Ratio

n/N

n/N

M-H,Fixed,95% CI

Weight


1 Ablation or excision vrs. diagnostic laparoscopy Tutunaru 2006

Subtotal (95% CI)

34/41

12/28

38.5 %

6.48 [ 2.14, 19.56 ]

41

28

38.5 %

6.48 [ 2.14, 19.56 ]

16/20

6/19

19.4 %

8.67 [ 2.01, 37.38 ]

20

19

19.4 %

8.67 [ 2.01, 37.38 ]

Total events: 34 (Surgery), 12 (Diagnostic) Heterogeneity: not applicable Test for overall effect: Z = 3.31 (P = 0.00093) 2 Excision vrs. diagnostic laparoscopy Abbott 2004

Subtotal (95% CI)

Total events: 16 (Surgery), 6 (Diagnostic) Heterogeneity: not applicable Test for overall effect: Z = 2.90 (P = 0.0038) 3 Ablation % uterine nerve transection vrs. diagnostic laparoscopy Sutton 1994

Subtotal (95% CI)

20/32

7/31

42.1 %

5.71 [ 1.89, 17.25 ]

32

31

42.1 %

5.71 [ 1.89, 17.25 ]

78

100.0 %

6.58 [ 3.31, 13.10 ]

Total events: 20 (Surgery), 7 (Diagnostic) Heterogeneity: not applicable Test for overall effect: Z = 3.09 (P = 0.0020)

Total (95% CI)

93

Total events: 70 (Surgery), 25 (Diagnostic) Heterogeneity: Chi2 = 0.20, df = 2 (P = 0.90); I2 =0.0% Test for overall effect: Z = 5.36 (P < 0.00001) Test for subgroup differences: Chi2 = 0.20, df = 2 (P = 0.90), I2 =0.0%

0.01

0.1

Favours diagnostic

1

10

100

Favours surgery


56




Study or subgroup

Surgery

Diagnostic

Odds Ratio

n/N

n/N

M-H,Fixed,95% CI

Weight


1 Ablation or excision vrs. diagnostic laparoscopy Tutunaru 2006

Total (95% CI)

30/41

6/28

100.0 %

10.00 [ 3.21, 31.17 ]

41

28

100.0 %

10.00 [ 3.21, 31.17 ]

Total events: 30 (Surgery), 6 (Diagnostic) Heterogeneity: not applicable Test for overall effect: Z = 3.97 (P = 0.000072) Test for subgroup differences: Not applicable

0.01

0.1

Favours diagnostic

1

10

100

Favours surgery

Analysis 1.4. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 4 Overall pain scores (6 months). Review:


Comparison: 1 Laparoscopic treatment versus diagnostic laparoscopy Outcome: 4 Overall pain scores (6 months)

Study or subgroup

Surgery N

Mean Difference

Diagnostic Mean(SD)

N

Mean(SD)

1.9 (0.5)

9

1 (0.7)

Weight

IV,Fixed,95% CI

Mean Difference IV,Fixed,95% CI

1 Excision vrs. diagnostic laparoscopy Jarrell 2005

Subtotal (95% CI)

7

7

9

100.0 %

0.90 [ 0.31, 1.49 ]

100.0 %

0.90 [ 0.31, 1.49 ]

Heterogeneity: not applicable Test for overall effect: Z = 3.00 (P = 0.0027)

-2

-1

Favours surgery


0

1

2

Favours diagnostic

57

Analysis 1.5. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 5 Overall pain scores (12 months). Review:


Comparison: 1 Laparoscopic treatment versus diagnostic laparoscopy Outcome: 5 Overall pain scores (12 months)

Study or subgroup

Surgery N

Mean Difference

Diagnostic Mean(SD)

N

Mean(SD)

2.6 (0.5)

9

0.95 (0.6)

Weight

IV,Fixed,95% CI


1 Excision vrs. diagnostic laparoscopy Jarrell 2005

Subtotal (95% CI)

7

7

9

100.0 %

1.65 [ 1.11, 2.19 ]

100.0 %

1.65 [ 1.11, 2.19 ]

Heterogeneity: not applicable Test for overall effect: Z = 6.00 (P < 0.00001)

-2

-1

Favours diagnostic


0

1

2

Favours surgery

58

Analysis 1.6. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 6 Live birth or ongoing pregnancy. Review:


Comparison: 1 Laparoscopic treatment versus diagnostic laparoscopy Outcome: 6 Live birth or ongoing pregnancy

Study or subgroup

Ablation or excision


Odds Ratio

n/N

n/N

M-H,Fixed,95% CI

7/20

5/21

13.3 %

1.72 [ 0.44, 6.72 ]

50/172

29/169

86.7 %

1.98 [ 1.18, 3.32 ]

192

190

100.0 %

1.94 [ 1.20, 3.16 ]

Weight


1 Ablation or excision vrs. diagnostic laparoscopy Gad 2012 Marcoux 1997

Subtotal (95% CI)

Total events: 57 (Ablation or excision), 34 (Diagnostic laparoscopy) Heterogeneity: Chi2 = 0.03, df = 1 (P = 0.85); I2 =0.0% Test for overall effect: Z = 2.69 (P = 0.0071)

0.001 0.01 0.1

1

10 100 1000

Increased by diagnostic

Increased by surgery

Analysis 1.7. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 7 Pelvic pain scores (6 months). Review:


Comparison: 1 Laparoscopic treatment versus diagnostic laparoscopy Outcome: 7 Pelvic pain scores (6 months)

Study or subgroup

Surgery

Mean Difference

Diagnostic

N

Mean(SD)

N

Mean(SD)

18.8 (17.6)

19

23.9 (19.1)

Weight

IV,Fixed,95% CI


1 Excision vrs. diagnostic laparoscopy Abbott 2004

Subtotal (95% CI)

20

20

19

100.0 %

-5.10 [ -16.64, 6.44 ]

100.0 %

-5.10 [ -16.64, 6.44 ]


-20

-10

Favours diagnostic


0

10

20

Favours surgery

59

Analysis 1.8. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 8 Pelvic pain scores (12 months). Review:


Comparison: 1 Laparoscopic treatment versus diagnostic laparoscopy Outcome: 8 Pelvic pain scores (12 months)

Study or subgroup

Surgery N

Mean Difference

Diagnostic Mean(SD)

N

Mean(SD)

45.7 (7.46)

19

38.7 (16.9)

Weight

IV,Fixed,95% CI



Subtotal (95% CI)

20

20

19

100.0 %

7.00 [ -1.27, 15.27 ]

100.0 %

7.00 [ -1.27, 15.27 ]


-10

-5

Favours diagnostic


0

5

10

Favours surgery

60

Analysis 1.9. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 9 Dysmenorrhoea pain scores (6 months). Review:


Comparison: 1 Laparoscopic treatment versus diagnostic laparoscopy Outcome: 9 Dysmenorrhoea pain scores (6 months)

Study or subgroup

Surgery

Mean Difference

Diagnostic

N

Mean(SD)

N

Mean(SD)

26 (8.5)

19

23.6 (17.2)

Weight

IV,Fixed,95% CI



20

Subtotal (95% CI)

20

19

100.0 %

2.40 [ -6.18, 10.98 ]

100.0 %

2.40 [ -6.18, 10.98 ]


-20

-10

0

Favours diagnostic

10

20

Favours surgery

Analysis 1.10. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 10 Dysmenorrhea pain scores (12 months). Review:


Comparison: 1 Laparoscopic treatment versus diagnostic laparoscopy Outcome: 10 Dysmenorrhea pain scores (12 months)

Study or subgroup

Surgery N

Mean Difference

Diagnostic Mean(SD)

N

Mean(SD)

48.9 (11.8)

19

58.4 (21.8)

Weight

IV,Fixed,95% CI



Subtotal (95% CI)

20

20

19

100.0 %

-9.50 [ -20.58, 1.58 ]

100.0 %

-9.50 [ -20.58, 1.58 ]


-50

-25

Favours diagnostic


0

25

50

Favours surgery

61

Analysis 1.11. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 11 Dyspareunia pain scores (6 months). Review:


Comparison: 1 Laparoscopic treatment versus diagnostic laparoscopy Outcome: 11 Dyspareunia pain scores (6 months)

Study or subgroup

Surgery N

Mean Difference

Diagnostic Mean(SD)

N

Mean(SD)

16.8 (22.8)

19

10.5 (23.3)

Weight

IV,Fixed,95% CI



20

Subtotal (95% CI)

20

19

100.0 %

6.30 [ -8.18, 20.78 ]

100.0 %

6.30 [ -8.18, 20.78 ]


-100

-50

0

Favours diagnostic

50

100

Favours surgery

Analysis 1.12. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 12 Dyspareunia pain scores (12 months). Review:


Comparison: 1 Laparoscopic treatment versus diagnostic laparoscopy Outcome: 12 Dyspareunia pain scores (12 months)

Study or subgroup

Surgery N

Mean Difference

Diagnostic Mean(SD)

N

Mean(SD)

43.1 (20.9)

19

37 (22.3)

Weight

IV,Fixed,95% CI



Subtotal (95% CI)

20

20

19

100.0 %

6.10 [ -7.48, 19.68 ]

100.0 %

6.10 [ -7.48, 19.68 ]


-20

-10

Favours diagnostic


0

10

20

Favours surgery

62

Analysis 1.13. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 13 Dyschezia pain scores (6 months). Review:


Comparison: 1 Laparoscopic treatment versus diagnostic laparoscopy Outcome: 13 Dyschezia pain scores (6 months)

Study or subgroup

Surgery

Mean Difference

Diagnostic

N

Mean(SD)

N

Mean(SD)

19.5 (23.5)

19

28.7 (24.9)

Weight

IV,Fixed,95% CI



20

Subtotal (95% CI)

20

19

100.0 %

-9.20 [ -24.41, 6.01 ]

100.0 %

-9.20 [ -24.41, 6.01 ]


-100

-50

0

Favours diagnostic

50

100

Favours surgery

Analysis 1.14. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 14 Dyschezia pain scores (12 months). Review:


Comparison: 1 Laparoscopic treatment versus diagnostic laparoscopy Outcome: 14 Dyschezia pain scores (12 months)

Study or subgroup

Surgery

Mean Difference

Diagnostic

N

Mean(SD)

N

Mean(SD)

14.5 (26.3)

19

18.1 (24.7)

Weight

IV,Fixed,95% CI



Subtotal (95% CI)

20

20

19

100.0 %

-3.60 [ -19.61, 12.41 ]

100.0 %

-3.60 [ -19.61, 12.41 ]


-100

-50

Favours diagnostic


0

50

100

Favours surgery

63

Analysis 1.15. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 15 Clinical pregnancy. Review:


Comparison: 1 Laparoscopic treatment versus diagnostic laparoscopy Outcome: 15 Clinical pregnancy

Study or subgroup



Odds Ratio

n/N

n/N

M-H,Fixed,95% CI

7/20

5/21

9.6 %

1.72 [ 0.44, 6.72 ]

63/172

37/169

71.8 %

2.06 [ 1.28, 3.33 ]

9/73

7/73

18.6 %

1.33 [ 0.47, 3.77 ]

265

263

100.0 %

1.89 [ 1.25, 2.86 ]

Weight


1 Ablation or excision vrs. diagnostic laparoscopy Gad 2012 Marcoux 1997 Moini 2012

Subtotal (95% CI)

Total events: 79 (Ablation or excision), 49 (Diagnostic laparoscopy) Heterogeneity: Chi2 = 0.59, df = 2 (P = 0.75); I2 =0.0% Test for overall effect: Z = 3.02 (P = 0.0025)

0.001 0.01 0.1

1



10 100 1000 Increased by surgery

64

Analysis 1.16. Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 16 Miscarriage per pregnancy. Review:


Comparison: 1 Laparoscopic treatment versus diagnostic laparoscopy Outcome: 16 Miscarriage per pregnancy

Study or subgroup



Odds Ratio

n/N

n/N

M-H,Fixed,95% CI

0/7

0/5

13/63

8/37

100.0 %

0.94 [ 0.35, 2.54 ]

70

42

100.0 %

0.94 [ 0.35, 2.54 ]

Weight


1 Ablation or excision vrs. diagnostic laparoscopy Gad 2012 Marcoux 1997

Subtotal (95% CI)

Not estimable

Total events: 13 (Ablation or excision), 8 (Diagnostic laparoscopy) Heterogeneity: not applicable Test for overall effect: Z = 0.12 (P = 0.91)

0.001 0.01 0.1

1



10 100 1000 Increased by surgery

65

Analysis 2.1. Comparison 2 Laparoscopic versus diagnostic laparoscopy and medical therapy, Outcome 1 Ablation vrs. diagnostic laparoscopy and GnRHa (& add back therapy). Review:


Comparison: 2 Laparoscopic versus diagnostic laparoscopy and medical therapy Outcome: 1 Ablation vrs. diagnostic laparoscopy and GnRHa (% add back therapy)

Study or subgroup

Ablation

Diag Lap % Med Tx

Odds Ratio

n/N

n/N

M-H,Fixed,95% CI

Weight


1 Overall pain described as ”Pain free” (12 months) Lalchandani 2005

9/17

3/18

100.0 %

5.63 [ 1.18, 26.85 ]

Subtotal (95% CI)

17

18

100.0 %

5.63 [ 1.18, 26.85 ]

Total events: 9 (Ablation), 3 (Diag Lap % Med Tx) Heterogeneity: not applicable Test for overall effect: Z = 2.17 (P = 0.030) Test for subgroup differences: Not applicable

0.002

0.1

Favours Diag Lap % Med Tx

1

10

500

Favours Ablation

Analysis 3.1. Comparison 3 Laparoscopic ablation versus laparoscopic excision, Outcome 1 Overall pain scores (reduction in VAS at 12 months). Review:


Comparison: 3 Laparoscopic ablation versus laparoscopic excision Outcome: 1 Overall pain scores (reduction in VAS at 12 months)

Study or subgroup

Ablation

Healey 2010

Total (95% CI)

Mean Difference

Excision

N

Mean(SD)

N

Mean(SD)

49

2.9 (2.9)

54

2.9 (3.4)

49

Weight

IV,Fixed,95% CI


54

100.0 %

0.0 [ -1.22, 1.22 ]

100.0 %

0.0 [ -1.22, 1.22 ]

Heterogeneity: not applicable Test for overall effect: Z = 0.0 (P = 1.0) Test for subgroup differences: Not applicable

-4

-2

Favours excision


0

2

4

Favours ablation

66

Analysis 3.2. Comparison 3 Laparoscopic ablation versus laparoscopic excision, Outcome 2 Pelvic pain scores (12 months). Review:


Comparison: 3 Laparoscopic ablation versus laparoscopic excision Outcome: 2 Pelvic pain scores (12 months)

Study or subgroup

Ablation

Healey 2010

Total (95% CI)

Mean Difference

Excision

N

Mean(SD)

N

Mean(SD)

49

2.7 (2.7)

54

2.6 (3.5)

49

Weight

Mean Difference

100.0 %

0.10 [ -1.10, 1.30 ]

100.0 %

0.10 [ -1.10, 1.30 ]

IV,Fixed,95% CI

IV,Fixed,95% CI

54


-4

-2

0

Favours excision

2

4

Favours ablation

Analysis 3.3. Comparison 3 Laparoscopic ablation versus laparoscopic excision, Outcome 3 Dyspareunia pain scores (12 months). Review:


Comparison: 3 Laparoscopic ablation versus laparoscopic excision Outcome: 3 Dyspareunia pain scores (12 months)

Study or subgroup

Ablation

Healey 2010

Total (95% CI)

Mean Difference

Excision

N

Mean(SD)

N

Mean(SD)

49

1.8 (4.1)

54

3.1 (4.1)

49

Weight

IV,Fixed,95% CI


54

100.0 %

-1.30 [ -2.89, 0.29 ]

100.0 %

-1.30 [ -2.89, 0.29 ]


-10

-5

Favours excision


0

5

10

Favours ablation

67

Analysis 3.4. Comparison 3 Laparoscopic ablation versus laparoscopic excision, Outcome 4 Dyschezia pain scores (12 months). Review:


Comparison: 3 Laparoscopic ablation versus laparoscopic excision Outcome: 4 Dyschezia pain scores (12 months)

Study or subgroup

Ablation

Healey 2010

Total (95% CI)

Mean Difference

Excision

N

Mean(SD)

N

Mean(SD)

49

0.7 (3.1)

54

1.8 (3.5)

49

Weight

Mean Difference

100.0 %

-1.10 [ -2.37, 0.17 ]

100.0 %

-1.10 [ -2.37, 0.17 ]

IV,Fixed,95% CI

IV,Fixed,95% CI

54


-4

-2

Favours excision

0

2

4

Favours ablation

APPENDICES Appendix 1. MDSG Specialised Register of controlled trials search strategy Keywords CONTAINS “laparoscopic procedure” or “laparoscopic surgery” or “laparoscopic surgical treatment” or “laparoscopic techniques” or “laparoscopic treatment” or “laparoscopy” or “*Surgical-Procedures,-Laparoscopic” or “minor gynecological surgery ” or “laparoscopic procedure” or “laparoscopic surgery” or “laparoscopic surgical treatment” or “laparoscopic techniques” or “laparoscopic treatment” or “laparoscopy” or “*Surgical-Procedures,-Laparoscopic” or “minor gynecological surgery ” or “laparoscopic uterine nerve ablation”or “Laparoscopic” or “laparoscopic excision” or Title CONTAINS “laparoscopic procedure” or “laparoscopic surgery” or “laparoscopic surgical treatment” or “laparoscopic techniques” or “laparoscopic treatment” or “laparoscopy” or “laparoscopic procedure” or “laparoscopic surgery” or “laparoscopic surgical treatment” or “laparoscopic techniques” or “laparoscopic treatment” or “laparoscopy” or “laparoscopic uterine nerve ablation”or “Laparoscopic” or“laparoscopic excision” AND Keywords CONTAINS “*Endometriosis” or “Endometriosis-Symptoms” or “endometriosis scores” or “endometriosis-outcome” or “adenomyosis” or “pelvic pain” or “chronic pelvic pain” or“dyschezia” or“dysmenorrhea” or “dysmenorrhoea”or “dyspareunia” or “endometriosis” or Title CONTAINS “*Endometriosis” or “Endometriosis-Symptoms” or “endometriosis scores” or “endometriosis-outcome” or “adenomyosis” or “pelvic pain” or “chronic pelvic pain”or “dyschezia” or“dysmenorrhea” or “dysmenorrhoea” or“dyspareunia” or “endometriosis”


68

Appendix 2. CENTRAL search strategy 1 exp Laparoscopy/ (3174) 2 Laparoscop$.ti,ab,sh. (5137) 3 celioscop$.tw. (10) 4 peritoneoscop$.tw. (13) 5 exp Surgical Procedures, Minimally Invasive/ (16359) 6 Lasers/ (470) 7 exp Diathermy/ (664) 8 LUNA.tw. (16) 9 presacral neurectom$.tw. (9) 10 (minimal$ adj5 surg$).tw. (533) 11 laser$.tw. (7007) 12 diathermy.tw. (328) 13 plasmajet.tw. (2) 14 plasma jet.tw. (0) 15 excision.tw. (1501) 16 microlaparoscop$.tw. (23) 17 minilaparoscop$.tw. (27) 18 exp Robotics/ (217) 19 exp Surgery, Computer-Assisted/ (299) 20 Computer-Assisted Surg$.tw. (42) 21 da vinci.tw. (20) 22 (keyhole adj3 surg$).tw. (2) 23 Robot$.tw. (367) 24 remote surg$.tw. (2) 25 microsurg$.tw. (265) 26 minimally invasive.tw. (827) 27 (ablation or ablative).tw. (1979) 28 or/1-27 (29590) 29 exp Endometriosis/ (442) 30 endometrio$.tw. (823) 31 dyschezia.tw. (9) 32 dyspareunia.tw. (195) 33 or/29-32 (999) 34 28 and 33 (357)

Appendix 3. EMBASE search strategy 1 exp Laparoscopy/ (97264) 2 Laparoscop$.tw. (111905) 3 celioscop$.tw. (571) 4 peritoneoscop$.tw. (804) 5 exp minimally invasive surgery/ (24033) 6 exp laser/ (83949) 7 exp diathermy/ (4643) 8 Diathermy.tw. (2722) 9 LUNA.tw. (898) 10 presacral neurectom$.tw. (102) 11 laser$.tw. (179899) 12 plasmajet.tw. (32) 13 plasma jet.tw. (107) 14 microlaparoscop$.tw. (178) Laparoscopic surgery for endometriosis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

69

15 minilaparoscop$.tw. (191) 16 exp robotics/ (21358) 17 exp computer assisted surgery/ (6533) 18 Computer-Assisted Surg$.tw. (911) 19 da vinci.tw. (2655) 20 (keyhole adj3 surg$).tw. (118) 21 Robot$.tw. (24984) 22 remote surg$.tw. (106) 23 microsurg$.tw. (21971) 24 uterine nerve ablation$.tw. (35) 25 minimally invasive.tw. (45892) 26 (ablation or ablative).tw. (80369) 27 exp hand assisted laparoscopy/ (276) 28 or/1-27 (479984) 29 exp endometriosis/ (24399) 30 endometrio$.tw. (26930) 31 dyschezia.tw. (270) 32 dyspareunia.tw. (3776) 33 or/29-32 (35300) 34 28 and 33 (8151) 35 Clinical Trial/ (890473) 36 Randomized Controlled Trial/ (361695) 37 exp randomization/ (64120) 38 Single Blind Procedure/ (18620) 39 Double Blind Procedure/ (119085) 40 Crossover Procedure/ (39166) 41 Placebo/ (230446) 42 Randomi?ed controlled trial$.tw. (97388) 43 Rct.tw. (13204) 44 random allocation.tw. (1315) 45 randomly allocated.tw. (20067) 46 allocated randomly.tw. (1942) 47 (allocated adj2 random).tw. (739) 48 Single blind$.tw. (14163) 49 Double blind$.tw. (142276) 50 ((treble or triple) adj blind$).tw. (342) 51 placebo$.tw. (198421) 52 prospective study/ (257096) 53 or/35-52 (1395671) 54 case study/ (22803) 55 case report.tw. (257728) 56 abstract report/ or letter/ (895512) 57 or/54-56 (1170523) 58 53 not 57 (1358179) 59 34 and 58 (1223)


70

Appendix 4. MEDLINE search strategy 1 exp Laparoscopy/ (68564) 2 Laparoscop$.ti,ab,sh. (91589) 3 celioscop$.tw. (547) 4 peritoneoscop$.tw. (708) 5 exp Surgical Procedures, Minimally Invasive/ (366376) 6 Lasers/ (31294) 7 exp Diathermy/ (11649) 8 LUNA.tw. (603) 9 presacral neurectom$.tw. (91) 10 (minimal$ adj5 surg$).tw. (14777) 11 laser$.tw. (183571) 12 diathermy.tw. (2497) 13 plasmajet.tw. (9) 14 plasma jet.tw. (119) 15 excision.tw. (87688) 16 microlaparoscop$.tw. (142) 17 minilaparoscop$.tw. (158) 18 exp Robotics/ (13272) 19 exp Surgery, Computer-Assisted/ (9380) 20 Computer-Assisted Surg$.tw. (796) 21 da vinci.tw. (1645) 22 (keyhole adj3 surg$).tw. (93) 23 Robot$.tw. (17427) 24 remote surg$.tw. (91) 25 microsurg$.tw. (18631) 26 minimally invasive.tw. (34272) 27 (ablation or ablative).tw. (62551) 28 or/1-27 (756661) 29 exp Endometriosis/ (16815) 30 endometrio$.tw. (20621) 31 dyschezia.tw. (163) 32 dyspareunia.tw. (2475) 33 or/29-32 (26130) 34 28 and 33 (5804) 35 randomized controlled trial.pt. (391739) 36 controlled clinical trial.pt. (90142) 37 randomized.ab. (308700) 38 randomised.ab. (67948) 39 placebo.tw. (169272) 40 clinical trials as topic.sh. (175823) 41 randomly.ab. (218284) 42 trial.ti. (133119) 43 (crossover or cross-over or cross over).tw. (63483) 44 or/35-43 (985984) 45 exp animals/ not humans.sh. (4067794) 46 44 not 45 (911244) 47 34 and 46 (500)


71

Appendix 5. PsycINFO search strategy 1 exp Surgery/ (40177) 2 Laparoscop$.tw. (277) 3 uterine nerve ablation$.tw. (0) 4 LUNA.tw. (72) 5 presacral neurectom$.tw. (0) 6 (minimal$ adj5 surg$).tw. (107) 7 laser$.tw. (2111) 8 diathermy.tw. (27) 9 exp Robotics/ (3119) 10 Computer-Assisted Surg$.tw. (4) 11 Robot$.tw. (4388) 12 (minimal$ adj2 invasi$).tw. (290) 13 microsurg$.tw. (154) 14 (ablation or ablative).tw. (3141) 15 or/1-14 (49940) 16 exp Gynecological Disorders/ (1406) 17 endometrio$.tw. (160) 18 dyschezia.tw. (5) 19 dyspareunia.tw. (435) 20 or/16-19 (1926) 21 15 and 20 (110) 22 random.tw. (39269) 23 control.tw. (305265) 24 double-blind.tw. (17466) 25 clinical trials/ (7148) 26 placebo/ (3636) 27 exp Treatment/ (562140) 28 or/22-27 (858345) 29 21 and 28 (103)

Appendix 6. CINAHL

Query

Results

S44

S29 AND S43

113

S43

S30 OR S31 or S32 or S33 OR S34 OR S35 OR S36 OR S37 Display OR S38 OR S39 OR S40 OR S41 OR S42

S42

TX allocat* random*

Display

S41

(MH “Quantitative Studies”)

Display

S40

(MH “Placebos”)

Display

S39

TX placebo*

Display


72

(Continued)

S38

TX random* allocat*

Display

S37

(MH “Random Assignment”)

Display

S36

TX randomi* control* trial*

Display

S35

TX ( (singl* n1 blind*) or (singl* n1 mask*) ) or TX ( (doubl* Display n1 blind*) or (doubl* n1 mask*) ) or TX ( (tripl* n1 blind*) or (tripl* n1 mask*) ) or TX ( (trebl* n1 blind*) or (trebl* n1 mask*) )

S34

TX ( (trebl* n1 blind*) or (trebl* n1 mask*) )

Display

S33

TX ( (trebl* n1 blind*) or (trebl* n1 mask*) )

Display

S32

TX clinic* n1 trial*

Display

S31

PT Clinical trial

Display

S30

(MH “Clinical Trials+”)

Display

S29

S23 AND S28

570

S28

S24 OR S25 OR S26 OR S27

2,762

S27

TX dyspareunia

657

S26

TX dyschezia

12

S25

TX endometrio*

2,162

S24

(MM “Endometriosis”)

1,303

S23

S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR 54,000 S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22

S22

TX microsurg*

2,115

S21

TX minimally invasive

10,102

S20

TX remote surg*

96

S19

TX Robot*

4,993

S18

TX keyhole Surg*

44


73

(Continued)

S17

TX unmanned surg*

0

S16

TX da vinci

239

S15

TX Computer-Assisted Surg*

282

S14

(MH “Robotics”)

4,025

S13

TX minilaparoscop*

25

S12

TX microlaparoscop*

20

S11

TX ablation or TX ablative

12,159

S10

(MH “Diathermy”) OR (MH “Electrocoagulation”)

689

S9

TX presacral neurectom*

9

S8

TX LUNA

728

S7

TX laser*

14,385

S6

(MM “Lasers”) OR (MM “Laser Therapy”)

5,673

S5

(MM “Minimally Invasive Procedures”)

2,690

S4

TX peritoneoscop*

57

S3

TX celioscop*

1

S2

TX Laparoscop*

14,502

S1

(MM “Laparoscopy”) OR (MH “Surgery, Laparoscopic+”)

Appendix 7. Trials registers search strategy Laparoscopic surgery and Gynaecological surgery Endometriosis


74

CONTRIBUTIONS OF AUTHORS JD: Took the lead in writing the protocol and review, was involved in selecting trials for inclusion, performed independent data extraction and quality assessment of the included trials, and was responsible for statistical analysis and interpretation of the data. KA: was involved in developing the protocol, and for the full review selected trials for inclusion, performed independent data extraction and quality assessment of the included trials and assisted with writing up. FC: was involved in selecting trials for inclusion, performed independent data extraction, quality assessment of the included trials, and provided clinical expertise to the discussion. DO: commented on drafts of the protocol and review, and added clinical expertise to the discussion. CF: commented on drafts of the protocol and review, and provided clinical expertise to the discussion. RG: commented on drafts of the protocol and review, and added clinical expertise to the discussion. DB: commented on drafts of the protocol and review, and added clinical expertise to the discussion. TZ: took the lead in writing the protocol, commented on drafts of the protocol and review, added clinical expertise to the discussion, and takes overall reasonability for the review.

DECLARATIONS OF INTEREST KA: 1. Trainee representative and council member, British Society of Gynaecological Endoscopy (www.BSGE.org.uk). 2. Received BSGE travel grant and MSc bursary 2013 JD: 1. Received travel and subsistence expenses from the European Society of Gynaecological Endoscopy to a facilitate a pre-congress meeting ’How to write a paper’ (Paris 2012 and Berlin 2013). 2. Involved in a project to create core outcome sets for endometriosis in collaboration with the Core Outcomes Sets in Women’s Health (CROWN) Intiative (www.crown to initaitve.org) and Core Meaures in Effectiveness Trails (COMET) Intiative (http:// www.comet to initiative.org). DB, FC, RG, CF, DO, TJ: No conflicts of interests.

SOURCES OF SUPPORT


75

Internal sources • None, Not specified.

External sources • National Insitute of Health Research, UK. £5,000

DIFFERENCES BETWEEN PROTOCOL AND REVIEW The protocol stated pain would be measured by the “mean difference or standard mean pain difference by a pain scale at different time intervals or as specified in the individual study”. On further consideration the review authors decided to include both continuous and dichotomous measures of pain. For the primary subfertility outcome, the authors decided to combine live birth and ongoing pregnancy after 20 weeks gestation, and to assess the effect of combining these outcomes by conducting a sensitivity analysis including only studies reporting live birth.

NOTES This review has combined two existing reviews: ’Laparoscopic surgery for pelvic pain associated with endometriosis’ and ’Laparoscopic surgery for subfertility associated with endometriosis’ (Jacobson 2009; Jacobson 2010). We have expanded the interventions assessed to include both laparoscopic and robotic approaches. The primary outcome of pain has been further expanded to include relevant pain types associated with endometriosis, for example dysmenorrhoea. We have updated the outcome definitions in line with Cochrane guidelines. We have included three new RCTs (Gad 2012; Healey 2010; Moini 2012) and excluded a previously included RCT because of their use of medical adjuvants (Parazzini 1999).


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Employing laparoscopic surgery for endometriosis.

Laparoscopic surgery for subfertility related to endometriosis: a meta-analysis.

Laparoscopic "Successful" Excision of Deep Endometriosis: A Fertility-enhancing Surgery.

Laparoscopic treatment of deep infiltrating endometriosis: results of the combined laparoscopic gynecologic and colorectal surgery.

Multidisciplinary laparoscopic treatment for bowel endometriosis.

Does ovarian suspension following laparoscopic surgery for endometriosis reduce postoperative adhesions? An RCT.

Reply: Criticizing the effect of ovarian suspension on adhesions in laparoscopic surgery for endometriosis.

Endometriosis Fertility Index for Predicting Pregnancy after Endometriosis Surgery.

Surgery versus pharmacological treatment for endometriosis.

Laparoscopic segmental resection of the sigmoid colon for endometriosis.

Laparoscopic management of moderate: Severe endometriosis.

[Experience with multidisciplinary laparoscopic surgery in patients with deep infiltrating colorectal endometriosis].

A case of clear cell adenocarcinoma arising from endometriosis of the rectum treated by laparoscopic surgery.

Laparoscopic surgery for radiation enteritis.

Laparoscopic Surgery for Focal Adenomyosis.

Laparoscopic surgery for colon cancer.

Surgery: green light given for laparoscopic surgery for rectal cancer.

[Pictures balance for optimal surgical management of pelvic endometriosis. Imaging and surgery of endometriosis].

Association of history of surgery for endometriosis with severity of deeply infiltrating endometriosis.

Laparoscopic surgery.

Is nerve-sparing surgery suitable for deeply infiltrating endometriosis?

Open abdominal surgery: a risk factor for future laparoscopic surgery?

FOR: Robotic surgery has no advantages over conventional laparoscopic surgery.

Single-incision laparoscopic surgery for intersigmoid hernia.