Laparoscopic surgery for endometriosis
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.
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.
PICOs
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.
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.
Authors' conclusions
Summary of findings
| Laparoscopic treatment versus diagnostic laparoscopy for endometriosis | ||||||
| Population: Women with mild to moderate endometriosis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Diagnostic laparoscopy | Laparoscopic ablation or excision | |||||
| Overall pain better or improved at 6 month follow‐up | 321 per 1000 | 756 per 1000 | OR 6.58 (3.31 to 13.10 ) | 171 | ⊕⊕⊕⊝ | Assessed in trials of women seeking pain relief for endometriosis |
| Overall pain better or improved at 12 month follow‐up | 214 per 1000 | 732 per 1000 | OR 10.00 (3.21 to 31.17 ) | 69 | ⊕⊕⊕⊝ LOW2 | Assessed in trials of women seeking pain relief for endometriosis |
| Live birth or ongoing pregnancy | 179 per 1000 | 297 per 1000 | OR 1.94 (1.20 to 3.16) | 382 | ⊕⊕⊕⊝ | Assessed in trials of subfertile women |
| Clinical pregnancy | 186 per 1000 | 302 per 1000 | OR 1.89 (1.25 to 2.86 ) | 528 | ⊕⊕⊕⊝ | Assessed in trials of subfertile women |
| Miscarriage (per pregnancy) | 190 per 1000 | 181 per 1000 | OR 0.94 (0.35 to 2.54) | 112 | ⊕⊕⊕⊝ | Assessed in trials of subfertile women |
| 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 | |||||
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1None 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 3One study does not describe methods in detail, as it is only published as an abstract 4Most of the data apply to ongoing pregnancy. Of 92 events in this comparison, only 12 were live birth. 5Two studies do not adequately describe randomisation methods; one study at high risk of attrition bias 6The larger study (n=100) does not include fetal losses after 20 weeks | ||||||
| Laparoscopic surgery versus diagnostic laparoscopy and medical therapy for pain related to endometriosis | ||||||
| Population: Women with mild to moderate endometriosis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Diagnostic laparoscopy plus medical therapy | Laparoscopic surgery | |||||
| Number of women pain free at 12 months | 167 per 1000 | 530 per 1000 | OR 5.63 (1.18 to 26.85) | 35 | ⊕⊕⊝⊝ | |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Only conference abstract available: randomisation methods not fully described, unclear whether blinded; small study, n = 35 | ||||||
| Laparoscopic ablation versus laparoscopic excision for pain related to endometriosis | ||||
| Population: Women with mild to moderate endometriosis | ||||
| Outcomes | Illustrative comparative risks (95% CI) | No of Participants | Quality of the evidence | Comments |
| Laparoscopic ablation versus laparoscopic excision | ||||
| Reduction in overall pain score at 12 month follow‐up | The mean reduction in overall pain score at 12 months was the same in both groups (1.22 lower to 1.22 higher on a VAS 0 to 10 pain scale) | 103 | ⊕⊕⊝⊝ | |
| CI: Confidence interval | ||||
| GRADE Working Group grades of evidence | ||||
| 1High risk of attrition bias 2Imprecision compatible with a clinically relevant difference between the groups, or with no difference | ||||
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 dysmenorrhoea (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 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:
-
excision of peritoneal deposits utilising any technique including sharp dissection, electro‐excision, Argon Neutral Plasma Energy or laser energy;
-
ablation of peritoneal deposits utilising any technique including electrocautery or Argon Neutral Plasma Energy;
-
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.
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).
Electronic searches
We searched the following electronic databases, trial registers and websites (from inception to July 2013):
-
Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of controlled trials (Appendix 1);
-
Cochrane Central Register of Controlled Trials (CENTRAL) (Appendix 2);
-
EMBASE (Appendix 3);
-
MEDLINE (Appendix 4);
-
PsycINFO (Appendix 5);
-
CINAHL (Appendix 6).
Other electronic searches we performed included the following.
-
Trial registers for ongoing and registered trials: http://clinicaltrials.gov/ct2/home and http://www.who.int/trialsearch/Default.aspx (Appendix 7).
-
Citation indexes: http://scientific.thomson.com/products/sci.
-
Conference abstracts in the Web of Knowledge: http://wokinfo.com.
-
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.
-
PubMed: http://www.ncbi.nlm.nih.gov/pubmed/.
-
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.
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.
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.
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.
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.
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. 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 meta‐analysis 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).
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
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
Where data were available, we planned subgroup analyses to determine the separate evidence within the following subgroups.
-
Severity of disease.
-
Surgical technique to excise peritoneal deposits.
-
Surgical technique to ablate peritoneal deposits.
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:
-
eligibility was restricted to studies without high risk of bias;
-
a random‐effects model was adopted;
-
alternative imputation strategies were implemented;
-
the summary effect measure was relative risk;
-
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).
Study flow diagram.
Included studies
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).
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.
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 (Abbott 2004, Healey 2010, Wright 2005) reported dyspareunia
-
2/10 RCTs (Abbott 2004, Healey 2010) reported dyschezia
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
Live birth or ongoing pregnancy rate
-
2/10 RCTs reported live birth (Gad 2012) or ongoing pregnancy (Marcoux 1997)
Secondary outcome
-
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.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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.
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; 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.
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
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.
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.
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
A. Pelvic pain
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
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
i. Pain scores (six and 12 months)
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 0.94, 95% CI 0.35 to 2.54, 2 RCTs, 112 participants) (Analysis 1.16).
4. Adverse events
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.
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 laparoscopy and GnRHa with add‐back therapy (Lalchandani 2005).
Primary outcomes
1. Overall pain
i. Pain free (12 months)
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).
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
No RCTs reported this outcome.
Secondary outcomes
No RCTs reported these outcomes.
3. Laparoscopic ablation compared with laparoscopic excision of endometriosis
Two studies made this comparison (Healey 2010; Wright 2005).
Primary outcomes
1. Overall pain
i. Pain scores (12 months)
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.
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
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 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
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.
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 considering 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. 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 follow‐up, 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 Table for the main comparison; summary of findings Table 2; summary of findings Table 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 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.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Forest plot of comparison: 1 Laparoscopic treatment versus diagnostic laparoscopy, outcome: 1.3 Overall pain better or improved (12 months).
Forest plot of comparison: 1 Laparoscopic treatment versus diagnostic laparoscopy, outcome: 1.6 Live birth or ongoing pregnancy.
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).
Forest plot of comparison: 3 Laparoscopic ablation versus laparoscopic excision, outcome: 3.1 Overall pain scores (reduction in VAS at 12 months).
Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 1 Overall pain better or improved (3 months).
Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 2 Overall pain better or improved (6 months).
Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 3 Overall pain better or improved (12 months).
Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 4 Overall pain scores (6 months).
Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 5 Overall pain scores (12 months).
Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 6 Live birth or ongoing pregnancy.
Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 7 Pelvic pain scores (6 months).
Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 8 Pelvic pain scores (12 months).
Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 9 Dysmenorrhoea pain scores (6 months).
Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 10 Dysmenorrhea pain scores (12 months).
Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 11 Dyspareunia pain scores (6 months).
Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 12 Dyspareunia pain scores (12 months).
Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 13 Dyschezia pain scores (6 months).
Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 14 Dyschezia pain scores (12 months).
Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 15 Clinical pregnancy.
Comparison 1 Laparoscopic treatment versus diagnostic laparoscopy, Outcome 16 Miscarriage per pregnancy.
Comparison 2 Laparoscopic versus diagnostic laparoscopy and medical therapy, Outcome 1 Ablation vrs. diagnostic laparoscopy and GnRHa (& add back therapy).
Comparison 3 Laparoscopic ablation versus laparoscopic excision, Outcome 1 Overall pain scores (reduction in VAS at 12 months).
Comparison 3 Laparoscopic ablation versus laparoscopic excision, Outcome 2 Pelvic pain scores (12 months).
Comparison 3 Laparoscopic ablation versus laparoscopic excision, Outcome 3 Dyspareunia pain scores (12 months).
Comparison 3 Laparoscopic ablation versus laparoscopic excision, Outcome 4 Dyschezia pain scores (12 months).
| Laparoscopic treatment versus diagnostic laparoscopy for endometriosis | ||||||
| Population: Women with mild to moderate endometriosis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Diagnostic laparoscopy | Laparoscopic ablation or excision | |||||
| Overall pain better or improved at 6 month follow‐up | 321 per 1000 | 756 per 1000 | OR 6.58 (3.31 to 13.10 ) | 171 | ⊕⊕⊕⊝ | Assessed in trials of women seeking pain relief for endometriosis |
| Overall pain better or improved at 12 month follow‐up | 214 per 1000 | 732 per 1000 | OR 10.00 (3.21 to 31.17 ) | 69 | ⊕⊕⊕⊝ LOW2 | Assessed in trials of women seeking pain relief for endometriosis |
| Live birth or ongoing pregnancy | 179 per 1000 | 297 per 1000 | OR 1.94 (1.20 to 3.16) | 382 | ⊕⊕⊕⊝ | Assessed in trials of subfertile women |
| Clinical pregnancy | 186 per 1000 | 302 per 1000 | OR 1.89 (1.25 to 2.86 ) | 528 | ⊕⊕⊕⊝ | Assessed in trials of subfertile women |
| Miscarriage (per pregnancy) | 190 per 1000 | 181 per 1000 | OR 0.94 (0.35 to 2.54) | 112 | ⊕⊕⊕⊝ | Assessed in trials of subfertile women |
| 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 | |||||
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1None 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 3One study does not describe methods in detail, as it is only published as an abstract 4Most of the data apply to ongoing pregnancy. Of 92 events in this comparison, only 12 were live birth. 5Two studies do not adequately describe randomisation methods; one study at high risk of attrition bias 6The larger study (n=100) does not include fetal losses after 20 weeks | ||||||
| Laparoscopic surgery versus diagnostic laparoscopy and medical therapy for pain related to endometriosis | ||||||
| Population: Women with mild to moderate endometriosis | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Diagnostic laparoscopy plus medical therapy | Laparoscopic surgery | |||||
| Number of women pain free at 12 months | 167 per 1000 | 530 per 1000 | OR 5.63 (1.18 to 26.85) | 35 | ⊕⊕⊝⊝ | |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Only conference abstract available: randomisation methods not fully described, unclear whether blinded; small study, n = 35 | ||||||
| Laparoscopic ablation versus laparoscopic excision for pain related to endometriosis | ||||
| Population: Women with mild to moderate endometriosis | ||||
| Outcomes | Illustrative comparative risks (95% CI) | No of Participants | Quality of the evidence | Comments |
| Laparoscopic ablation versus laparoscopic excision | ||||
| Reduction in overall pain score at 12 month follow‐up | The mean reduction in overall pain score at 12 months was the same in both groups (1.22 lower to 1.22 higher on a VAS 0 to 10 pain scale) | 103 | ⊕⊕⊝⊝ | |
| CI: Confidence interval | ||||
| GRADE Working Group grades of evidence | ||||
| 1High risk of attrition bias 2Imprecision compatible with a clinically relevant difference between the groups, or with no difference | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Overall pain better or improved (3 months) Show forest plot | 1 | 63 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.37 [0.51, 3.70] |
| 1.1 Ablation & uterine nerve transection vrs. diagnostic laparoscopy | 1 | 63 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.37 [0.51, 3.70] |
| 2 Overall pain better or improved (6 months) Show forest plot | 3 | 171 | Odds Ratio (M‐H, Fixed, 95% CI) | 6.58 [3.31, 13.10] |
| 2.1 Ablation or excision vrs. diagnostic laparoscopy | 1 | 69 | Odds Ratio (M‐H, Fixed, 95% CI) | 6.48 [2.14, 19.56] |
| 2.2 Excision vrs. diagnostic laparoscopy | 1 | 39 | Odds Ratio (M‐H, Fixed, 95% CI) | 8.67 [2.01, 37.38] |
| 2.3 Ablation & uterine nerve transection vrs. diagnostic laparoscopy | 1 | 63 | Odds Ratio (M‐H, Fixed, 95% CI) | 5.71 [1.89, 17.25] |
| 3 Overall pain better or improved (12 months) Show forest plot | 1 | 69 | Odds Ratio (M‐H, Fixed, 95% CI) | 10.0 [3.21, 31.17] |
| 3.1 Ablation or excision vrs. diagnostic laparoscopy | 1 | 69 | Odds Ratio (M‐H, Fixed, 95% CI) | 10.0 [3.21, 31.17] |
| 4 Overall pain scores (6 months) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 4.1 Excision vrs. diagnostic laparoscopy | 1 | 16 | Mean Difference (IV, Fixed, 95% CI) | 0.90 [0.31, 1.49] |
| 5 Overall pain scores (12 months) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 5.1 Excision vrs. diagnostic laparoscopy | 1 | 16 | Mean Difference (IV, Fixed, 95% CI) | 1.65 [1.11, 2.19] |
| 6 Live birth or ongoing pregnancy Show forest plot | 2 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 6.1 Ablation or excision vrs. diagnostic laparoscopy | 2 | 382 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.94 [1.20, 3.16] |
| 7 Pelvic pain scores (6 months) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 7.1 Excision vrs. diagnostic laparoscopy | 1 | 39 | Mean Difference (IV, Fixed, 95% CI) | ‐5.10 [‐16.64, 6.44] |
| 8 Pelvic pain scores (12 months) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 8.1 Excision vrs. diagnostic laparoscopy | 1 | 39 | Mean Difference (IV, Fixed, 95% CI) | 7.0 [‐1.27, 15.27] |
| 9 Dysmenorrhoea pain scores (6 months) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 9.1 Excision vrs. diagnostic laparoscopy | 1 | 39 | Mean Difference (IV, Fixed, 95% CI) | 2.40 [‐6.18, 10.98] |
| 10 Dysmenorrhea pain scores (12 months) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 10.1 Excision vrs. diagnostic laparoscopy | 1 | 39 | Mean Difference (IV, Fixed, 95% CI) | ‐9.5 [‐20.58, 1.58] |
| 11 Dyspareunia pain scores (6 months) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 11.1 Excision vrs. diagnostic laparoscopy | 1 | 39 | Mean Difference (IV, Fixed, 95% CI) | 6.30 [‐8.18, 20.78] |
| 12 Dyspareunia pain scores (12 months) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 12.1 Excision vrs. diagnostic laparoscopy | 1 | 39 | Mean Difference (IV, Fixed, 95% CI) | 6.10 [‐7.48, 19.68] |
| 13 Dyschezia pain scores (6 months) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 13.1 Excision vrs. diagnostic laparoscopy | 1 | 39 | Mean Difference (IV, Fixed, 95% CI) | ‐9.2 [‐24.41, 6.01] |
| 14 Dyschezia pain scores (12 months) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 14.1 Excision vrs. diagnostic laparoscopy | 1 | 39 | Mean Difference (IV, Fixed, 95% CI) | ‐3.60 [‐19.61, 12.41] |
| 15 Clinical pregnancy Show forest plot | 3 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 15.1 Ablation or excision vrs. diagnostic laparoscopy | 3 | 528 | Odds Ratio (M‐H, Fixed, 95% CI) | 1.89 [1.25, 2.86] |
| 16 Miscarriage per pregnancy Show forest plot | 2 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 16.1 Ablation or excision vrs. diagnostic laparoscopy | 2 | 112 | Odds Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.35, 2.54] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Ablation vrs. diagnostic laparoscopy and GnRHa (& add back therapy) Show forest plot | 1 | Odds Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 1.1 Overall pain described as "Pain free" (12 months) | 1 | 35 | Odds Ratio (M‐H, Fixed, 95% CI) | 5.63 [1.18, 26.85] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Overall pain scores (reduction in VAS at 12 months) Show forest plot | 1 | 103 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [‐1.22, 1.22] |
| 2 Pelvic pain scores (12 months) Show forest plot | 1 | 103 | Mean Difference (IV, Fixed, 95% CI) | 0.10 [‐1.10, 1.30] |
| 3 Dyspareunia pain scores (12 months) Show forest plot | 1 | 103 | Mean Difference (IV, Fixed, 95% CI) | ‐1.3 [‐2.89, 0.29] |
| 4 Dyschezia pain scores (12 months) Show forest plot | 1 | 103 | Mean Difference (IV, Fixed, 95% CI) | ‐1.1 [‐2.37, 0.17] |
