Laparoscopic ovarian drilling for ovulation induction in women with anovulatory polycystic ovary syndrome

Esmée M Bordewijk; Ka Ying Bonnie Ng; Lidija Rakic; Ben Willem J Mol; Julie Brown; Tineke J Crawford; Madelon van Wely

doi:10.1002/14651858.CD001122.pub5

. 2020 Feb 11;2020(2):CD001122. doi: 10.1002/14651858.CD001122.pub5

Laparoscopic ovarian drilling for ovulation induction in women with anovulatory polycystic ovary syndrome

Esmée M Bordewijk ¹, Ka Ying Bonnie Ng ², Lidija Rakic ¹, Ben Willem J Mol ³, Julie Brown ⁴, Tineke J Crawford ⁵, Madelon van Wely ^1,^✉

Editor: Cochrane Gynaecology and Fertility Group

PMCID: PMC7013239 PMID: 32048270

Abstract

Background

Polycystic ovary syndrome (PCOS) is a common condition affecting 8% to 13% of reproductive‐aged women. In the past clomiphene citrate (CC) used to be the first‐line treatment in women with PCOS. Ovulation induction with letrozole should be the first‐line treatment according to new guidelines, but the use of letrozole is off‐label. Consequently, CC is still commonly used. Approximately 20% of women on CC do not ovulate. Women who are CC‐resistant can be treated with gonadotrophins or other medical ovulation‐induction agents. These medications are not always successful, can be time‐consuming and can cause adverse events like multiple pregnancies and cycle cancellation due to an excessive response. Laparoscopic ovarian drilling (LOD) is a surgical alternative to medical treatment. There are risks associated with surgery, such as complications from anaesthesia, infection, and adhesions.

Objectives

To evaluate the effectiveness and safety of LOD with or without medical ovulation induction compared with medical ovulation induction alone for women with anovulatory polycystic PCOS and CC‐resistance.

Search methods

We searched the Cochrane Gynaecology and Fertility Group (CGFG) trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trials registers up to 8 October 2019, together with reference checking and contact with study authors and experts in the field to identify additional studies.

Selection criteria

We included randomised controlled trials (RCTs) of women with anovulatory PCOS and CC resistance who underwent LOD with or without medical ovulation induction versus medical ovulation induction alone, LOD with assisted reproductive technologies (ART) versus ART, LOD with second‐look laparoscopy versus expectant management, or different techniques of LOD.

Data collection and analysis

Two review authors independently selected studies, assessed risks of bias, extracted data and evaluated the quality of the evidence using the GRADE method. The primary effectiveness outcome was live birth and the primary safety outcome was multiple pregnancy. Pregnancy, miscarriage, ovarian hyperstimulation syndrome (OHSS), ovulation, costs, and quality of life were secondary outcomes.

Main results

This updated review includes 38 trials (3326 women). The evidence was very low‐ to moderate‐quality; the main limitations were due to poor reporting of study methods, with downgrading for risks of bias (randomisation and allocation concealment) and lack of blinding.

Laparoscopic ovarian drilling with or without medical ovulation induction versus medical ovulation induction alone

Pooled results suggest LOD may decrease live birth slightly when compared with medical ovulation induction alone (odds ratio (OR) 0.71, 95% confidence interval (CI) 0.54 to 0.92; 9 studies, 1015 women; I² = 0%; low‐quality evidence). The evidence suggest that if the chance of live birth following medical ovulation induction alone is 42%, the chance following LOD would be between 28% and 40%. The sensitivity analysis restricted to only RCTs with low risk of selection bias suggested there is uncertainty whether there is a difference between the treatments (OR 0.90, 95% CI 0.59 to 1.36; 4 studies, 415 women; I² = 0%, low‐quality evidence). LOD probably reduces multiple pregnancy rates (Peto OR 0.34, 95% CI 0.18 to 0.66; 14 studies, 1161 women; I² = 2%; moderate‐quality evidence). This suggests that if we assume the risk of multiple pregnancy following medical ovulation induction is 5.0%, the risk following LOD would be between 0.9% and 3.4%.

Restricting to RCTs that followed women for six months after LOD and six cycles of ovulation induction only, the results for live birth were consistent with the main analysis.

There may be little or no difference between the treatments for the likelihood of a clinical pregnancy (OR 0.86, 95% CI 0.72 to 1.03; 21 studies, 2016 women; I² = 19%; low‐quality evidence). There is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage (OR 1.11, 95% CI 0.78 to 1.59; 19 studies, 1909 women; I² = 0%; low‐quality evidence). OHSS was a very rare event. LOD may reduce OHSS (Peto OR 0.25, 95% CI 0.07 to 0.91; 8 studies, 722 women; I² = 0%; low‐quality evidence).

Unilateral LOD versus bilateral LOD

Due to the small sample size, the quality of evidence is insufficient to justify a conclusion on live birth (OR 0.83, 95% CI 0.24 to 2.78; 1 study, 44 women; very low‐quality evidence).

There were no data available on multiple pregnancy.

The likelihood of a clinical pregnancy is uncertain between the treatments, due to the quality of the evidence and the large heterogeneity between the studies (OR 0.57, 95% CI 0.39 to 0.84; 7 studies, 470 women; I² = 60%, very low‐quality evidence). Due to the small sample size, the quality of evidence is not sufficient to justify a conclusion on miscarriage (OR 1.02, 95% CI 0.31 to 3.33; 2 studies, 131 women; I² = 0%; very low‐quality evidence).

Other comparisons

Due to lack of evidence and very low‐quality data there is uncertainty whether there is a difference for any of the following comparisons: LOD with IVF versus IVF, LOD with second‐look laparoscopy versus expectant management, monopolar versus bipolar LOD, and adjusted thermal dose versus fixed thermal dose.

Authors' conclusions

Laparoscopic ovarian drilling with and without medical ovulation induction may decrease the live birth rate in women with anovulatory PCOS and CC resistance compared with medical ovulation induction alone. But the sensitivity analysis restricted to only RCTs at low risk of selection bias suggests there is uncertainty whether there is a difference between the treatments, due to uncertainty around the estimate. Moderate‐quality evidence shows that LOD probably reduces the number of multiple pregnancy. Low‐quality evidence suggests that there may be little or no difference between the treatments for the likelihood of a clinical pregnancy, and there is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage. LOD may result in less OHSS.

The quality of evidence is insufficient to justify a conclusion on live birth, clinical pregnancy or miscarriage rate for the analysis of unilateral LOD versus bilateral LOD. There were no data available on multiple pregnancy.

Plain language summary

Laparoscopic application of heat or laser to the ovaries to cause ovulation in women with polycystic ovary syndrome who do not ovulate

Review question

Cochrane authors reviewed the evidence about the effect of a surgical procedure called laparoscopic ovarian drilling (LOD) compared with medical treatment to cause ovulation in women with polycystic ovary syndrome (PCOS) who do not ovulate. We also reviewed the effect of different LOD techniques.

Background

Women with PCOS have problems with ovulating and therefore may have difficulty becoming pregnant. In the past clomiphene citrate (CC) used to be the first‐line treatment in women with PCOS. Ovulation induction with letrozole should be the first‐line treatment according to new guidelines, but the use of letrozole is not officially approved. Consequently, clomiphene citrate is still commonly used. Approximately 20% of women on CC do not ovulate. When this occurs, we call it CC‐resistant PCOS. For women with CC‐resistant PCOS there are different medications available to induce ovulation, such as gonadotrophins, metformin or aromatase inhibitors, but these medications are not always successful and can cause adverse events like multiple pregnancies and cycle cancellation due to an excessive response. Another option for treatment is a surgical procedure called laparoscopic ovarian drilling (LOD). This involves applying heat or laser to the ovaries with a laparoscope (a camera) passed through a small cut, usually just below the belly button. This procedure is thought to improve the way the ovaries produce and respond to hormones, increasing the chance of ovulation. However, there are risks associated with surgery, such as complications from anaesthesia, infection, and adhesions. LOD is a surgical alternative to medical treatment, and this review aimed to determine its benefits and risks.

Study characteristics

In this updated review we included 38 controlled trials comparing LOD with medical ovulation induction or comparing different techniques of LOD. The evidence is current to October 2019

Key results

Our main analysis with low‐quality evidence shows that LOD with and without medical ovulation induction may decrease the live birth rate slightly in women with anovulatory PCOS and CC‐resistance compared with medical ovulation induction alone. Analysis including only the higher‐quality RCTs shows uncertainty about any difference between the treatments. The evidence suggests that if the chance of live birth following medical ovulation induction alone is 44%, the chance following LOD would be between 32% and 52%. Moderate‐quality evidence shows that LOD probably reduces the number of multiple pregnancies. The evidence suggests that if we assume the chance of a multiple pregnancy following medical ovulation induction alone to be 5.0%, the chance following LOD would be between 0.9% and 3.4%.

There may be little or no difference between the treatments for clinical pregnancy, and there is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage. Ovarian hyperstimulation syndrome (OHSS) may occur less often following LOD.

The quality of the evidence is not sufficient to justify a conclusion on live birth, clinical pregnancy or miscarriage for the analysis of unilateral LOD versus bilateral LOD.

The results of the primary outcomes for the other interventions were insufficient to enable us to draw any conclusions.

Quality of the evidence

The evidence was of very low to moderate quality. The main limitations in the evidence were poor reporting of study methods, the presence of bias introduced by the selection of individuals and variability in the results.

Summary of findings

Background

Description of the condition

Polycystic ovary syndrome (PCOS) is a common condition, affecting 8% to 13% of reproductive‐aged women. PCOS is commonly diagnosed with the Rotterdam PCOS diagnostic criteria (two of clinical or biochemical hyperandrogenism, ovulatory dysfunction, or polycystic ovaries on ultrasound (ESHRE 2018)). Problems in inducing ovulation are well recognised in women with PCOS. Surgical ovarian wedge resection by laparotomy was the first established treatment for women with anovulatory PCOS (Stein 1939), but was largely abandoned because of the risk of post‐surgical adhesion formation, which converted endocrinological subfertility to mechanical subfertility as a result of scarring (Adashi 1981; Buttram 1975). Wedge resection was replaced by medical ovulation induction (Franks 1985). In the past clomiphene citrate (CC) used to be the first‐line treatment in women with PCOS. According to new guidelines, ovulation induction with letrozole should be the first‐line treatment, but the use of letrozole is off‐label (ESHRE 2018). Ovulation induction with CC is not always successful, with approximately 20% of women described as 'clomiphene citrate‐resistant' (Imani 1998). CC resistance is defined as lack of ovulation with the use of CC. Women who are CC‐resistant can be treated with gonadotrophins, other medical ovulation induction agents or a surgical therapy using laparoscopic techniques known as laparoscopic ovarian drilling (LOD).

Description of the intervention

LOD was first described by Gjönnaess 1984. Both laparoscopic ovarian cautery and laser vaporisation using carbon dioxide (CO₂), argon or neodymium‐doped yttrium aluminium garnet (Nd:YAG; Nd:Y3Al5O12) crystal lasers have been used to create multiple perforations (approximately 10 holes per ovary) in the ovarian surface and stroma (inner area of the ovary). The procedure can be done on an outpatient basis with less trauma and fewer postoperative adhesions than with ovarian wedge resection. Uncontrolled observational studies claim that it is followed, at least temporarily, by a high rate of spontaneous postoperative ovulation and conception (Armar 1990; Armar 1993; Greenblatt 1987; Kovacs 1991), or that subsequent medical ovulation induction becomes easier (Farhi 1995).

How the intervention might work

The mechanism of action of LOD is thought to be similar to that of ovarian wedge resection. Both procedures may destroy ovarian androgen‐producing tissue and reduce the peripheral conversion of androgens to oestrogens (one of the many disturbances of endocrine physiology that occur in women with PCOS). A fall in the serum levels of androgens and luteinising hormone (LH) and an increase in follicle‐stimulating hormone (FSH) levels have been demonstrated after ovarian drilling (Armar 1990; Greenblatt 1987). The endocrine changes following the surgery are thought to convert the adverse androgen‐dominant intrafollicular environment to an oestrogenic one (Aakvaag 1985), and to restore the hormonal environment to normal by correcting disturbances of the ovarian‐pituitary feedback mechanism (Balen 1993). Thus, both local and systemic effects are thought to promote follicular recruitment, maturation and subsequent ovulation.

Why it is important to do this review

Women who are CC‐resistant can be treated with gonadotrophins or other medical ovulation‐induction agents. These medications are not always successful and can cause adverse events like multiple pregnancies and cycle cancellation due to an excessive response. Gonadotrophin therapy requires daily injections and the need for intensive monitoring with ultrasound which makes them expensive, inconvenient and time‐consuming (ESHRE 2018). LOD is a surgical alternative to medical treatment. There are risks associated with surgery, such as complications from anaesthesia, infection, and adhesions.There might be a small risk of reduced ovarian reserve or loss of ovarian function. Clarification of the role of LOD is needed, in comparison to other treatments, in infertile women with PCOS. This review aimed to determine its benefits, safety, and costs.

Objectives

To evaluate the effectiveness and safety of laparoscopic ovarian drilling (LOD) with or without medical ovulation induction compared with medical ovulation induction alone for women with anovulatory polycystic ovary syndrome (PCOS) and clomiphene citrate resistance.

Methods

Criteria for considering studies for this review

Types of studies

We include randomised controlled trials (RCTs), but exclude quasi‐randomised trials.

Types of participants

Women with anovulatory polycystic ovary syndrome (PCOS), diagnosed by the Rotterdam criteria for PCOS, who had been shown to be resistant to clomiphene (100 mg/day or more). Clomiphene resistance was defined as lack of proven ovulation with the use of clomiphene citrate (CC).

Types of interventions

Laparoscopic ovarian drilling (LOD) with or without medical ovulation induction versus medical ovulation induction alone, including all different types of medical ovulation induction and different time periods of follow‐up
LOD in women undergoing artificial reproductive technologies (ART) such as LOD plus in vitro fertilisation (IVF) versus IVF
LOD with second‐look laparoscopy versus LOD with expectant management
Techniques for LOD, including:

- LOD of one ovary (unilateral) versus LOD of both ovaries (bilateral)
- monopolar versus bipolar
- adjusted thermal dose versus fixed thermal dose
- laser versus diathermy

We excluded trials that only compared the number of punctures to each ovary, and echoscopic transvaginal hydrolaparoscopic ovarian surgery, since the Cochrane Review Zhang 2019 includes these studies.

Types of outcome measures

Primary outcomes

Live birth (defined as delivery of a live fetus after 20 completed weeks of gestation)
Multiple pregnancy

Secondary outcomes

Clinical pregnancy (defined as evidence of a gestational sac, confirmed by ultrasound)
Miscarriage
Ovarian hyperstimulation syndrome (OHSS)
Ovulation
Costs
Quality of life

Search methods for identification of studies

For the 2020 update we searched for all published and unpublished RCTs of LOD, without language restriction and in consultation with the Cochrane Gynaecology and Fertility Group (CGFG) Information Specialist.

Electronic searches

We searched the following databases for relevant trials:

The CGFG Specialised Register of Controlled Trials, searched 8 October 2019 (Procite platform) (Appendix 1);
Cochrane Central Register of Controlled Trials (CENTRAL); searched 8 October 2019 via the Cochrane Register of Studies Online (CSRO Web platform) (Appendix 2);
MEDLINE, searched from 1946 to 8 October 2019 (Ovid platform) (Appendix 3);
Embase, searched from 1980 to 8 October 2019 (Ovid platform) (Appendix 4);
PsycINFO, searched from 1806 to 8 October 2019 (Ovid platform) (Appendix 5);
Cumulative Index to Nursing and Allied Health Literature (CINAHL), searched from 1961 to 8 October 2019 (Ebsco platform) (Appendix 6).

We combined the MEDLINE search with the Cochrane highly sensitive search strategy for identifying randomised trials, which appears in the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1.0, Chapter 6, 6.4.11; Higgins 2011). We combined the Embase, PsycINFO, and CINAHL searches with trial filters developed by the Scottish Intercollegiate Guidelines Network (www.sign.ac.uk/search‐filters.html).

Other electronic sources of trials include the following:

Trial registers for ongoing and registered trials: www.clinicaltrials.gov (a service of the US National Institutes of Health) and www.who.int/trialsearch/Default.aspx (the World Health Organization International Trials Registry Platform search portal);
LILACS and other Spanish and Portuguese language databases (Latin American and Caribbean Health Science Information database (from 1982 ongoing)), found in the Virtual Health Library Regional Portal (VHL) pesquise.bvsalud.org/portal/.
PubMed and Google Scholar, for recent trials not yet indexed in the major databases.

Searching other resources

We handsearched the reference lists of relevant trials and systematic reviews retrieved by the search, and contacted experts in the field to obtain additional data. We also handsearched for relevant journals and conference abstracts that were not covered in the CGFG register, in liaison with the Information Specialist.

Data collection and analysis

Selection of studies

For the 2020 update, after an initial screen of titles and abstracts retrieved by the search, conducted by EB and LR, we retrieved the full texts of all the potentially eligible studies. Two review authors (EB and LR or JM and JB) then independently examined the full‐text articles for compliance with the inclusion criteria and to select eligible studies. We intended to contact study investigators if required, to clarify study eligibility. We resolved disagreements by discussion with a third review author (MW). We documented the 2020 update selection process with a PRISMA flow chart.

Data extraction and management

Two review authors (EB and LR or JB and BN) independently extracted data from eligible studies using a data extraction form, and resolving any disagreements by discussion with a third review author (MW). Data extraction included study characteristics and outcome data (see Characteristics of included studies tables). We reported studies with multiple publications under a single study ID with multiple references. We contacted study investigators for further data on methods and results, if required.

Assessment of risk of bias in included studies

Two review authors (EB and LR or BN and JB) independently assessed the included studies for risks of bias, using the Cochrane 'Risk of bias' assessment tool (Higgins 2017) to assess: selection (random sequence generation and allocation concealment); performance (blinding of participants and personnel); detection (blinding of outcome assessors); attrition (incomplete outcome data); reporting (selective reporting); and other potential bias. We resolved disagreements by discussion with a third review author (MW). We described all judgements fully and presented the conclusions in the 'Risk of bias' table, which we incorporated into the interpretation of review findings by means of sensitivity analyses.

Measures of treatment effect

For dichotomous data, we used the numbers of events in the control and intervention groups of each study and calculated Mantel‐Haenszel odds ratios (ORs) or Peto ORs. For continuous data (e.g. costs), if all studies reported exactly the same outcomes, we calculated mean differences (MDs) between treatment groups. If similar outcomes were reported on different scales we calculated the standardised mean difference (SMD). We treated ordinal data (e.g. quality‐of‐life scores) as continuous data. We present 95% confidence intervals (CIs) for all outcomes.

Unit of analysis issues

The primary analysis was by woman randomised. We counted multiple births as one live birth event. If data did not allow valid analysis (e.g. 'by cycle' data) we contacted the primary authors for data by woman randomised, and did not include the 'by cycle' data in the meta‐analyses. For cross‐over trials, we included only first‐phase data.

Dealing with missing data

We analysed the data on an intention‐to‐treat basis as far as possible (i.e. including all randomised participants in analysis, in the groups to which they were randomised). We tried to obtain missing data from the original trialists, by contacting the primary authors. We analysed only the available data, without imputation.

Assessment of heterogeneity

We considered whether 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. We took an I² measurement greater than 50% as an indication of substantial heterogeneity (Deeks 2017).

Assessment of reporting biases

In view of the difficulty of detecting and correcting for publication bias and other reporting biases, we aimed to minimise their potential impact by ensuring a comprehensive search for eligible studies and by being alert for duplication of data. 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), where 10 studies or more contributed to the analysis.

Data synthesis

If studies were sufficiently similar, we combined the data using a fixed‐effect model in the following comparisons:

LOD with or without medical ovulation induction versus medical ovulation induction alone
LOD in women undergoing IVF versus IVF
LOD with second‐look laparoscopy versus LOD with expectant management
Techniques for LOD, including:

- LOD of one ovary (unilateral) versus LOD of both ovaries (bilateral)
- monopolar versus bipolar
- fixed thermal dose versus adjusted thermal dose
- laser versus diathermy

We performed statistical analysis using Review Manager 5.3 (Review Manager 2014).

Subgroup analysis and investigation of heterogeneity

We conducted subgroup analyses for the different medical ovulation‐induction agents, to determine the separate evidence for:

clomiphene citrate (CC)
CC + metformin
CC + tamoxifen
CC + rosiglitazone
gonadotrophins
gonadotrophins (rFSH) + metformin
letrozole
letrozole + metformin
metformin

Sensitivity analysis

We conducted sensitivity analyses for the primary outcomes of live birth and multiple pregnancy, to determine whether the conclusions were robust to arbitrary decisions made about eligibility and analysis. These analyses included consideration of whether the review conclusions would have differed if:

Eligibility had been restricted to studies at low risk of bias (defined as studies at low risk of selection bias);
High levels of heterogeneity were present;
Follow‐up in the individual trials had lasted for at least six months or six cycles.

Overall quality of the body of evidence

We updated the 'Summary of findings' tables using GRADEpro and Cochrane methods (Gradepro GDT 2015; Schünemann 2017). Table 1 presents the overall quality of the body of evidence for the main review outcomes (live birth, multiple pregnancy, clinical pregnancy, miscarriage and OHSS) for the main review comparison (LOD with or without medical ovulation induction compared with medical ovulation induction alone). We produced an additional 'Summary of findings' table (Table 2) for the main review outcomes for one other important comparison: Unilateral LOD versus bilateral LOD. We evaluated the quality of the evidence using GRADE criteria: risk of bias, consistency of effect, imprecision, indirectness and publication bias. Two review authors (EB and LR), working independently, made judgements about the evidence quality (high, moderate, low or very low), resolving disagreements by discussion with a third review author (MW). The judgements were justified, documented, and incorporated into the reporting of results for each outcome.

Summary of findings for the main comparison. LOD with and without medical ovulation compared to medical ovulation induction alone.

Laparoscopic ovarian drilling with and without medical ovulation compared to medical ovulation induction alone
Patient or population: women with anovulatory PCOS and CC resistance  Setting: fertility clinics  Intervention: laparoscopic ovarian drilling with and without medical ovulation  Comparison: medical ovulation induction alone
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
Outcomes	Risk with medical ovulation induction alone	Risk with LOD ±medical ovulation	Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
Live birth	418 per 1000	338 per 1000  (279 to 398)	OR 0.71  (0.54 to 0.92)	1015  (9 RCTs)	⊕⊕⊝⊝  Low^a
Live birth (sensitivity analysis)	439 per 1000	413 per 1000 (316 to 516)	OR 0.90 (0.59 to 1.36)	415 (4 RCTs)	⊕⊕⊝⊝  Low^b,c
Multiple pregnancy	50 per 1000	18 per 1000  (9 to 34)	Peto OR 0.34  (0.18 to 0.66)	1161  (14 RCTs)	⊕⊕⊕⊝  Moderate^b
Clincial pregnancy	460 per 1000	423 per 1000  (380 to 467)	OR 0.86  (0.72 to 1.03)	2016  (21 RCTs)	⊕⊕⊝⊝  Low^a
Miscarriage	64 per 1000	71 per 1000  (51 to 99)	Peto OR 1.11  (0.78 to 1.59)	1909  (19 RCTs)	⊕⊕⊝⊝  Low^a
OHSS	23 per 1000	6 per 1000  (2 to 21)	Peto OR 0.25  (0.07 to 0.91)	722  (8 RCTs)	⊕⊕⊝⊝  Low^b,c
*The risk in the intervention group (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.

LOD of one ovary (unilateral) versus LOD of both ovaries (bilateral)
Patient or population: women with anovulatory PCOS and CC resistance  Setting: fertility clinics  Intervention: bilateral LOD  Comparison: unilateal LOD
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
Outcomes	Risk with Bilateral	Risk with Unilateral	Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
Live birth	409 per 1000	365 per 1000  (142 to 658)	OR 0.83  (0.24 to 2.78)	44  (1 RCT)	⊕⊝⊝⊝  Very low^a,b	‐
Multiple pregnancy	‐	‐	‐	‐	‐	No data were reported for this outcome.
Clinical pregnancy	464 per 1000	331 per 1000  (253 to 421)	OR 0.57  (0.39 to 0.84)	470  (7 RCTs)	⊕⊕⊝⊝  Low^a	‐
Miscarriage	91 per 1000	93 per 1000  (30 to 250)	Peto OR 1.02  (0.31 to 3.33)	131  (2 RCTs)	⊕⊝⊝⊝  Very low^a,b	‐
OHSS	‐	‐	‐	‐	‐	No data were reported for this outcome.
*The risk in the intervention group (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.

Study	LOD ± CC	Other treatment	P value
Palomba 2004	EUR 1050	Metformin ± CC EUR 50	< 0.05
Farquhar 2002	Total cost per patient NZD 2953 Chance of pregnancy 28% Cost per pregnancy NZD 10,938 Chance of live birth 14% Cost per live birth NZD 21,095	Gonadotrophin Total cost per woman NZD 5461 Chance of pregnancy 33% Cost per pregnancy NZD 16,549 Chance of live birth 19% Cost per live birth NZD 28,744	NS NS

Date	Event	Description
14 October 2019	New citation required but conclusions have not changed	The addition of new studies has not led to changes in our conclusion.
14 October 2019	New search has been performed	Added new studies: Darwish 2016; Elgafor 2013; El‐Sayed 2017; Giampaolino 2016; Ibrahim 2017; Liu 2015; Nasr 2013; Nasr 2015; Rezk 2016; Sorouri 2015; Yadav 2018; Zakherah 2011, and amendments to review text. Placed Abu Hashim 2010a and Abu Hashim 2011a to awaiting classification.

Date	Event	Description
20 March 2014	Amended	Correction of effect estimate (from RR to OR) for one outcome in comparison 1, and consequential amendments to review text.
6 August 2012	Feedback has been incorporated	Abu Hashim 2011a excluded in response to feedback
15 May 2012	New citation required but conclusions have not changed	There is insufficient evidence for the conclusions to this review to be changed.
15 May 2012	New search has been performed	This review was first published in 1998. Updates were published in 2001 and 2007. Nine trials were included in the 2007 version. In the current update an additional 16 studies have been added to the meta‐analysis: Abdellah 2011; Abu Hashim 2010; Abu Hashim 2011; Abu Hashim 2011b; Ashrafinia 2009; Amer 2009; Ghafarnegad 2010; Hamed 2010; Palomba 2004; Palomba 2010; Rimington 1997; Roy 2009; Roy 2010; Sharma 2006; Youssef 2007; Zakherah 2009; Zakherah 2010.
11 November 2008	Amended	Converted to new review format.
1 May 2007	New citation required and conclusions have changed	Substantive amendment

#	Query	Results
S38	S25 AND S37	126
S37	S26 OR S27 OR S28 OR S29 OR S30 OR S31 OR S32 OR S33 OR S34 OR S35 OR S36	1,350,648
S36	TX allocat* random*	10,967
S35	(MH "Quantitative Studies")	23,381
S34	(MH "Placebos")	11,451
S33	TX placebo*	59,249
S32	TX random* allocat*	10,967
S31	(MH "Random Assignment")	56,159
S30	TX randomi* control* trial*	176,191
S29	TX ( (singl* n1 blind) or (singl n1 mask) ) or TX ( (doubl n1 blind) or (doubl n1 mask) ) or TX ( (tripl n1 blind) or (tripl n1 mask) ) or TX ( (trebl n1 blind) or (trebl n1 mask*) )	1,030,772
S28	TX clinic* n1 trial*	251,547
S27	PT Clinical trial	86,654
S26	(MH "Clinical Trials+")	267,630
S25	S5 AND S24	556
S24	S6 OR S7 OR S8 OR 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 OR S23	814,589
S23	TX electrosurg*	1,359
S22	TX surg*	794,505
S21	TX photocoagulation	886
S20	TX laser	29,283
S19	TX laparoscop* N5 ovar*	544
S18	(MM "Laser Therapy+")	7,115
S17	TX thermocoagulation	141
S16	TX electrocoagulation	985
S15	TX electrocauter*	612
S14	TX drilling	1,560
S13	TX diathermy	676
S12	TX cystectomy	2,323
S11	(MM "Cystectomy")	869
S10	TX electrocautery	570
S9	TX cauter*	1,152
S8	(MM "Cautery+")	11,718
S7	(MM "Surgery, Laparoscopic+")	4,587
S6	(MM "Diathermy+") OR (MM "Electrocoagulation+")	13,284
S5	S1 OR S2 OR S3 OR S4	4,752
S4	TX polycystic ovar*	4,141
S3	TX stein leventhal syndrome	10
S2	TX PCOS or TX PCOD	2,578
S1	(MM "Polycystic Ovary Syndrome")	2,596

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth	9	1015	Odds Ratio (M‐H, Fixed, 95% CI)	0.71 [0.54, 0.92]
1.1 LOD versus CC + metformin	2	170	Odds Ratio (M‐H, Fixed, 95% CI)	0.59 [0.32, 1.09]
1.2 LOD versus CC + tamoxifen	1	150	Odds Ratio (M‐H, Fixed, 95% CI)	0.81 [0.42, 1.53]
1.3 LOD versus gonadotrophins	4	407	Odds Ratio (M‐H, Fixed, 95% CI)	0.87 [0.56, 1.36]
1.4 LOD versus letrozole	2	288	Odds Ratio (M‐H, Fixed, 95% CI)	0.55 [0.32, 0.92]
2 Multiple pregnancy	14	1161	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.34 [0.18, 0.66]
2.1 LOD versus clomiphene citrate	1	72	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 LOD versus CC + metformin	2	170	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.3 LOD versus CC + rosiglitazone	1	43	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.12 [0.21, 21.52]
2.4 LOD versus gonadotrophins	7	532	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.22 [0.10, 0.46]
2.5 LOD versus gonadotrophins (rFSH) + metformin	1	36	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.6 LOD versus letrozole	1	147	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.7 LOD versus metformin	1	161	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.32 [0.25, 6.94]
3 Clinical pregnancy	21	2016	Odds Ratio (M‐H, Fixed, 95% CI)	0.86 [0.72, 1.03]
3.1 LOD versus clomiphene citrate	1	72	Odds Ratio (M‐H, Fixed, 95% CI)	0.52 [0.19, 1.44]
3.2 LOD versus CC + metformin	2	170	Odds Ratio (M‐H, Fixed, 95% CI)	0.71 [0.39, 1.31]
3.3 LOD versus CC + tamoxifen	1	150	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.47, 1.71]
3.4 LOD versus CC + rosiglitazone	1	43	Odds Ratio (M‐H, Fixed, 95% CI)	0.75 [0.23, 2.50]
3.5 LOD versus gonadotrophins	9	760	Odds Ratio (M‐H, Fixed, 95% CI)	1.01 [0.74, 1.36]
3.6 LOD versus gonadotrophins (rFSH) + metformin	1	36	Odds Ratio (M‐H, Fixed, 95% CI)	0.21 [0.04, 1.00]
3.7 LOD versus letrozole	3	368	Odds Ratio (M‐H, Fixed, 95% CI)	0.65 [0.42, 1.01]
3.8 LOD versus letrozole + metformin	1	146	Odds Ratio (M‐H, Fixed, 95% CI)	0.83 [0.42, 1.65]
3.9 LOD versus metformin	2	271	Odds Ratio (M‐H, Fixed, 95% CI)	1.25 [0.75, 2.08]
4 Miscarriage	19	1909	Odds Ratio (M‐H, Fixed, 95% CI)	1.11 [0.78, 1.59]
4.1 LOD versus CC + metformin	2	170	Odds Ratio (M‐H, Fixed, 95% CI)	1.95 [0.69, 5.54]
4.2 LOD versus CC + tamoxifen	1	150	Odds Ratio (M‐H, Fixed, 95% CI)	1.71 [0.39, 7.45]
4.3 LOD versus CC + rosiglitazone	1	43	Odds Ratio (M‐H, Fixed, 95% CI)	1.05 [0.06, 17.95]
4.4 LOD versus gonadotrophins	8	725	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.49, 1.33]
4.5 LOD versus gonadotrophins (rFSH) + metformin	1	36	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.6 LOD versus letrozole	3	368	Odds Ratio (M‐H, Fixed, 95% CI)	1.86 [0.61, 5.67]
4.7 LOD versus letrozole + metformin	1	146	Odds Ratio (M‐H, Fixed, 95% CI)	0.74 [0.16, 3.43]
4.8 LOD versus metformin	2	271	Odds Ratio (M‐H, Fixed, 95% CI)	1.60 [0.53, 4.82]
5 OHSS	8	722	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.25 [0.07, 0.91]
5.1 LOD versus clomiphene citrate	1	72	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.14 [0.00, 6.82]
5.2 LOD versus CC + metformin	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.3 LOD versus CC + rosiglitazone	1	43	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.4 LOD versus gonadotrophins	5	446	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.12 [0.02, 0.64]
5.5 LOD versus letrozole	0	0	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.6 LOD versus metformin	1	161	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.31 [0.13, 13.44]
6 Ovulation	10	951	Odds Ratio (M‐H, Fixed, 95% CI)	0.96 [0.73, 1.28]
6.1 LOD versus clomiphene citrate	1	72	Odds Ratio (M‐H, Fixed, 95% CI)	0.7 [0.27, 1.83]
6.2 LOD versus CC + metformin	1	50	Odds Ratio (M‐H, Fixed, 95% CI)	1.0 [0.32, 3.10]
6.3 LOD versus CC + tamoxifen	1	150	Odds Ratio (M‐H, Fixed, 95% CI)	1.34 [0.56, 3.17]
6.4 LOD versus CC + rosiglitazone	1	43	Odds Ratio (M‐H, Fixed, 95% CI)	0.67 [0.13, 3.44]
6.5 LOD versus gonadotrophins	2	139	Odds Ratio (M‐H, Fixed, 95% CI)	0.66 [0.32, 1.36]
6.6 LOD versus letrozole	1	80	Odds Ratio (M‐H, Fixed, 95% CI)	0.58 [0.23, 1.46]
6.7 LOD versus letrozole + metformin	1	146	Odds Ratio (M‐H, Fixed, 95% CI)	0.95 [0.49, 1.81]
6.8 LOD versus metformin	2	271	Odds Ratio (M‐H, Fixed, 95% CI)	1.52 [0.86, 2.68]
7 Costs	3		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
7.1 LOD versus CC + metformin	1	50	Mean Difference (IV, Fixed, 95% CI)	3711.3 [3585.17, 3837.43]
7.2 LOD versus gonadotrophins only (short‐term)	2	203	Mean Difference (IV, Fixed, 95% CI)	‐1115.75 [‐1309.72, ‐921.77]
7.3 LOD versus gonadotrophins only (long‐term)	1	168	Mean Difference (IV, Fixed, 95% CI)	‐2235.0 [‐4433.16, ‐36.84]
8 Quality of Life (Health related quality of life: SF‐36)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
8.1 Physical functioning at 24 weeks	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.2 Social functioning at 24 weeks	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.3 Role limitations (physical) at 24 weeks	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.4 Role limitations (emotional) at 24 weeks	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.5 Mental health at 24 weeks	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.6 Vitality at 24 weeks	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.7 Pain at 24 weeks	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.8 General health at 24 weeks	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
9 Quality of life (Rotterdam Symptom Checklist at 24 weeks)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
9.1 Physical symptoms	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.2 Psychological distress	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.3 Activity level	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.4 Overall quality of life	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Quality of life (Depression scales (CES‐D) at 24 weeks)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.1 Gonadotrophins	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
11 Multiple pregnancy per pregnancy	14	577	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.34 [0.17, 0.66]
11.1 LOD versus clomiphene citrate	1	23	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
11.2 LOD versus CC + metformin	2	99	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
11.3 LOD versus CC + rosiglitazone	1	20	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.66 [0.24, 29.46]
11.4 LOD versus gonadotrophins	7	280	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.20 [0.09, 0.43]
11.5 LOD versus gonadotrophins (rFSH) + metformin	1	11	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
11.6 LOD versus letrozole	1	45	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
11.7 LOD versus metformin	1	99	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.42 [0.27, 7.53]
12 Miscarriage per pregnancy	19	900	Odds Ratio (M‐H, Fixed, 95% CI)	1.28 [0.88, 1.88]
12.1 LOD versus CC + metformin	2	120	Odds Ratio (M‐H, Fixed, 95% CI)	2.49 [0.86, 7.24]
12.2 LOD versus CC + tamoxifen	1	78	Odds Ratio (M‐H, Fixed, 95% CI)	1.87 [0.41, 8.43]
12.3 LOD versus CC + rosiglitazone	1	20	Odds Ratio (M‐H, Fixed, 95% CI)	1.25 [0.07, 23.26]
12.4 LOD versus gonadotrophins	8	373	Odds Ratio (M‐H, Fixed, 95% CI)	0.91 [0.53, 1.56]
12.5 LOD versus gonadotrophins (rFSH) + metformin	1	11	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
12.6 LOD versus letrozole	3	118	Odds Ratio (M‐H, Fixed, 95% CI)	2.75 [0.86, 8.79]
12.7 LOD versus letrozole + metformin	1	49	Odds Ratio (M‐H, Fixed, 95% CI)	0.83 [0.16, 4.15]
12.8 LOD versus metformin	2	131	Odds Ratio (M‐H, Fixed, 95% CI)	1.30 [0.41, 4.08]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Clinical pregnancy	1	Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Miscarriage	1	Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Ovulation	1	Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Miscarriage per pregnancy	1	Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clinical pregnancy	3	354	Odds Ratio (M‐H, Fixed, 95% CI)	0.94 [0.62, 1.44]
2 Ovulation	2	108	Odds Ratio (M‐H, Fixed, 95% CI)	0.33 [0.14, 0.76]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clinical pregnancy	2	195	Odds Ratio (M‐H, Fixed, 95% CI)	1.84 [1.04, 3.26]
2 Miscarriage	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Ovulation	2	195	Odds Ratio (M‐H, Fixed, 95% CI)	1.83 [1.01, 3.33]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Live birth	4	415	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.59, 1.36]
1.1 LOD versus gonadotrophins	2	218	Odds Ratio (M‐H, Fixed, 95% CI)	1.04 [0.59, 1.85]
1.2 LOD versus CC + metformin	1	50	Odds Ratio (M‐H, Fixed, 95% CI)	1.17 [0.39, 3.56]
1.3 LOD versus letrozole	1	147	Odds Ratio (M‐H, Fixed, 95% CI)	0.62 [0.30, 1.31]
2 Multiple pregnancy	6	522	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.18 [0.06, 0.57]
2.1 LOD versus CC + metformin	1	50	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 LOD versus gonadotrophins	3	253	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.18 [0.06, 0.57]
2.3 LOD versus letrozole	1	147	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.4 LOD versus clomiphene citrate	1	72	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]

Methods	Randomised controlled trial conducted in UK Timing: not stated.
Participants	21 women randomised (this may be a typographical error in the abstract). Mean age 27 and 28 years; mean duration of infertility was 5.0 versus 4.8 years and the mean BMI was 19 versus 17 kg/m² Included: women with clomiphene‐resistant PCOS (150 mg clomiphene) with chronic anovulation, and 5 were resistant to FSH ovulation induction
Interventions	Bilateral ovarian surgery by diathermy (n = 10), versus  Unilateral ovarian surgery (n = 11).  LOS was performed with a diathermy needle creating 4 punctures/ovary 12 months follow‐up
Outcomes	Pregnancy rate (by participant)
Notes	Conflict of interest: not stated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "allocated randomly"; no other details in conference abstract
Allocation concealment (selection bias)	Unclear risk	No details in conference abstract.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No evidence of blinding of researchers, participants
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No evidence of blinding of outcome assessors
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All participants appear to have been followed through the study and all those randomised were analysed
Selective reporting (reporting bias)	High risk	No live birth data
Other bias	High risk	Conference abstract only

Methods	Randomised trial conducted in UK fertility clinic Timing: March 2002 to March 2006
Participants	72 anovulatory women with PCOS. Mean age of women in LOD group 28.1 ± 4.3 years and in CC group 29.1 ± 4.8 years Inclusion: Women with anovulatory infertility with PCOS. Aged 18 to 39 years, BMI ≤ 32 kg/m², duration of infertility ≥ 1 year. At least 1 patent fallopian tube on hysterosalpingogram and normal semen analysis Exclusion: Inability to give informed consent, contra‐indication to clomiphene citrate or general anaesthetic. Any ovarian induction therapy in previous 6 months
Interventions	Laparoscopic ovarian diathermy: 4 punctures per ovary in both ovaries. CC was also given if there was no ovulation 6 ‐ 8 weeks after surgery (n = 36), versus CC daily dose increasing from 50 mg to 150 mg on days 2 to 6 of a menstrual period or after a progestogen withdrawal bleed using medroxyprogesterone acetate. Treatment for 6 cycles and then offered LOD (n = 36)
Outcomes	Ovulation, pregnancy (biochemical, cumulative), multiple pregnancies, live birth rate
Notes	Conflict of interest: not stated Supported by a grant from the University of Sheffield Clinical trial registration number: NCT00220545
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "...block randomisation method using a random number table .."
Allocation concealment (selection bias)	Low risk	Quote: "held centrally by a trial administrator" Comment: Appears to be central allocation
Blinding of participants and personnel (performance bias)   All outcomes	High risk	There was no blinding; once randomised the allocation was revealed to the investigator and the participant
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details
Incomplete outcome data (attrition bias)   All outcomes	Low risk	LOD: 3 conceived before LOD, 1 discontinued and 1 postponed. 33 /36 were analysed CC: 3 conceived before CC and 1 postponed treatment. 32 were analysed
Selective reporting (reporting bias)	Low risk	We found the registered protocol on ClinicalTrials.gov (NCT00220545). All the outcomes mentioned in the protocol were presented in the published report
Other bias	Low risk	No evidence of other risk of bias

Methods	Prospective randomised controlled trial conducted in UK (Middlesex Hospital, London) Timing: not stated
Participants	10 women randomised. Refractory PCO. Mean age (range) of the women was 29.5 (27 to 33) years and mean duration (range) of infertility was 5.6 years (4 to 8). Infertility work‐up consisted of tubal patency testing by laparoscopy, semen analysis, endocrinology. In one case the tubes were blocked, 2 had pelvic adhesions, 3 had severe oligospermia or azoospermia and underwent donor insemination. Mean BMI 23 kg/m²  Study duration and timing not stated.
Interventions	Bilateral ovarian surgery by diathermy (N=6), versus  Unilateral ovarian surgery (N=4)   LOD was performed with a diathermy needle creating 4 punctures/ovary, cooled with normal saline Follow‐up for 3 months
Outcomes	Pregnancy rate (by participant)  Ovulation rate (by participant)
Notes	Conflict of interest: not stated Definitions:  PCO: not defined.  Refractory PCO: failure to ovulate on 100 mg/day (duration not specified); some had also been treated previously with tamoxifen or gonadotrophins  Pregnancy: not defined  Ovulation: not defined
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details in paper
Allocation concealment (selection bias)	Unclear risk	No details in paper
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No evidence of blinding of researchers or participants
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Data reported from all 10 women
Selective reporting (reporting bias)	Unclear risk	We could not retrieve the original protocol. The outcomes mentioned in the Method section are presented in the Results section of the abstract. No live birth
Other bias	Low risk	No evidence of other risk of bias

Methods	Parallel randomised controlled trial. Multicentre (n = 25 centres) in The Netherlands Timing: February 1998 to October 2001
Participants	168 women randomised Time of randomisation: during diagnostic laparoscopy, after determining eligibility.  Invited to participate: 213 consecutive women. 45 excluded (27 refused, 3 too obese for surgery, 1 had language barrier, 5 became pregnant while awaiting laparoscopy, 9 excluded during diagnostic laparoscopy due to endometriosis (1), adhesions (5), tubal occlusion (2) or infeasibility of electrocautery (1)). Mean age 29 years, mean duration of infertility was 2.8 years and the mean BMI was 27 kg/m². Infertility was primary in 76% of women  Inclusion criteria: women with clomiphene‐resistant PCOS (150 mg clomiphene) with chronic anovulation  Exclusion criteria: women with tubal obstruction, other causes of infertility including severe male‐factor infertility, aged > 40 years
Interventions	Laparoscopic electrocautery of the ovaries strategy: each ovary was punctured 5 to 10 times depending on its size. If the woman ovulated in 6 subsequent cycles, no further treatment was given. If ovulatory cycles were not established 8 weeks after surgery or the woman became anovulatory again then clomiphene citrate was given in increasing doses. If the woman still remained anovulatory, rFSH was given in increasing, doses starting at 75 IU daily (n = 83)  versus  6 cycles of rFSH. Women were treated until 6 subsequent cycles were achieved within 6 months (n = 85)
Outcomes	Primary: ongoing pregnancy rate within 12 months, defined as a viable pregnancy of at least 12 weeks  Secondary: live birth, miscarriage, multiple pregnancy, cost‐related quality of life Followed up to 1 year
Notes	Analyses on an intention‐to‐treat basis  Powered to detect a 10% difference in ongoing pregnancy rate No conflict of interest Funding: Serono Benelux provided financial support for rFSH during the first eight months of the study when this drug was not funded by the health services. FvdV was supported by a grant from the Health Insurance Funds Council (OG 97/007), Amstelveen, Netherlands.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated block randomisation, stratified by centre
Allocation concealment (selection bias)	Low risk	Telephone call to central office
Blinding of participants and personnel (performance bias)   All outcomes	High risk	There was no evidence of blinding
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All women randomised were analysed in the primary study
Selective reporting (reporting bias)	Low risk	The original protocol was supplied by the authors. All the outcomes mentioned in the protocol were presented in the published report
Other bias	Low risk	No evidence of other risk of bias

Methods	Randomised trial conducted in Eygpt Timing: July 2007 to February 2010
Participants	156 women assessed for eligibility in fertility clinics and 147 randomised Mean age of women in the letrozole group was 23.9 ± 3.2 years and in the LOD group was 23.6 ± 3.2 years Inclusion: Women with clomiphene‐resistant PCOS, primary or secondary infertility because of anovulation and clomiphene resistance for at least 1 year, normal sperm analysis from partner, patent tubes as seen by hysterosalpingography or diagnostic laparoscopy Exclusion: Age < 20 or > 35 years, hormonal treatment within 3 months prior to study, hyperprolactinaemia, any other endocrine, hepatic or renal disorder, presence of an organic pelvic mass, history of abdominal surgery that might have caused pelvic factor infertility
Interventions	Letrozole 5 mg/day for 5 days starting on day 3 of menses for a maximum of 6 cycles (n = 74), versus LOD ‐ each ovary was punctured 4 to 6 times depending on the size of the ovary (n = 73) Follow‐up for 6 months
Outcomes	Endometrial thickness, biochemical pregnancy, clinical pregnancy, spontaneous abortion, ovulation rate
Notes	No conflict of interest Clinical trial registration number: not stated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "computer generated random numbers table"
Allocation concealment (selection bias)	Low risk	Quote: "achieved using serially numbered opaque envelopes that were only opened once the interventions were assigned"
Blinding of participants and personnel (performance bias)   All outcomes	High risk	There are no details of blinding in the paper. Blinding was unlikely to have occurred as the interventions were oral medication versus surgery.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	There are no details of outcome assessors being blinded
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	147 randomised; 4 in the letrozole group and 3 in the LOD dropped out of the trial, all for non‐compliance. Intention‐to‐treat analysis was not conducted
Selective reporting (reporting bias)	High risk	We could not retrieve the original protocol. Live birth rate was reported in the Results section and was not listed as an outcome in the Methods section of the paper. Adverse effects on the mother and congenital malformations were also addressed in the Discussion section of the paper but had not been reported in the results section
Other bias	Low risk	No evidence of other risk of bias

Methods	Prospective randomised trial conducted in Iran from March 2006 to February 2008
Participants	126 women attending a fertility clinic aged 15 to 45 years with a history of infertility for at least 1 year and 3 treatment cycles of clomiphene citrate with no response. Mean age of women in LOD group was 26.54 ± 4.72 years and in the metformin group was 25.13 ± 3.47 years Inclusion: Irregular menstruation, clinical and biochemical signs of hyperandrogenism, polycystic ovaries Exclusion: Diseases that would disturb clinical and hormonal responses, pregnancy during follow‐up, BMI > 30 or < 17
Interventions	LOD performed 4 times in each ovary (n = 63), versus Metformin 1500 g daily (n = 63) Follow‐up for 6 months
Outcomes	Menstrual regularity, hormonal levels, Ferriman‐Gallwey score
Notes	No conflict of interest We have contacted authors for obstetric outcomes Clinical trial registration number: not stated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details in paper
Allocation concealment (selection bias)	Low risk	Quote: "serially numbered opaque envelopes"
Blinding of participants and personnel (performance bias)   All outcomes	High risk	There was no evidence that participants or researchers were blinded
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All participants appear to have been followed through the study and all those randomised were analysed
Selective reporting (reporting bias)	Unclear risk	We could not retrieve the original protocol. All outcomes mentioned in the Method section are presented in the Results. There are no reproductive outcomes. Authors have been contacted.
Other bias	Low risk	No evidence of other risk of bias

Methods	Parallel randomised controlled trial conducted in Womens Health University Hospital, Eygpt Timing: June 2013 to November 2014
Participants	88 women randomised. 80 women analysed. Mean age of women in monopolar group was 25 ± 4.7 years and for the bipolar group was 24.8 ± 4.4 years Inclusion criteria: Clomiphene‐resistant PCOS (Rotterdam 2003) Exclusion criteria: Male‐factor infertility, tubal or peritoneal factor infertility and endometriosis. One or both tubes blocked. Pelvic adhesions
Interventions	Monopolar LOD: monopolar needle. 4 seconds with 40 W, 4 punctures to each ovary. Energy for each ovary 640 J (n = 45), versus Bipolar LOD: bipolar needle. 4 seconds with 40 W, 4 punctures to each ovary. Energy for each ovary 640 J (n = 43) Follow‐up for 6 months
Outcomes	Regularity of menstrual cycle, ovulation rate, pregnancy rate
Notes	No conflict of interest No funding Clinical trial registration number: not stated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "randomly assigned" "computerized random table"
Allocation concealment (selection bias)	Unclear risk	No details provided
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No details provided
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details provided
Incomplete outcome data (attrition bias)   All outcomes	Low risk	45 women allocated to monopolar group; 5 cases lost to follow‐up due to difficulty in travelling and follow‐up by own doctor 43 women allocated to bipolar group; 3 cases lost to follow‐up due to difficulty in travelling and follow‐up by own doctor
Selective reporting (reporting bias)	Unclear risk	We could not retrieve the original protocol. The outcomes mentioned in the Methods section are presented in the Results section
Other bias	Low risk	No evidence of other risk of bias

Methods	Parallel arm "randomized clinical study" conducted in Zagazig University Hospital, Egypt Timing: November 2015 to January 2017
Participants	100 women randomised (50 per group), 95 women analysed (48 in group 1 and 47 in group 2). Mean age: Group 1: 27.5 ± 4.25; Group 2: 28.03 ± 4.32 Inclusion criteria: Infertile women with clomiphene citrate‐resistant PCOS (150 mg/day for 5 days), aged between 25 and 35 years, infertility duration of ≤ 3 years, BMI < 30 kg/m² luteinising hormone ≥ 10 IU/ml or LH/FSH ratio ≥ 2, Free androgen index ≥ 4, normal semen analysis in the husband, normal oral glucose tolerance test Exclusion criteria: Hyper‐androgenic disorders such as late onset congenital adrenal hyperplasia, hyperprolactinaemia, thyroid diseases, Cushing's syndrome, androgen‐secreting tumours
Interventions	Unilateral laparoscopic ovarian surgery on the right side, using thermal dose adjusted according to ovarian volume (n = 50), versus Bilateral laparoscopic ovarian surgery using thermal dose adjusted to ovarian volume on both sides (n = 50) Follow‐up for 6 months
Outcomes	Menstrual cycle resumption, ovulation rate, cumulative pregnancy rate
Notes	Further information confirming methods requested from authors 2 August 2017 No conflict of interest Clinical trial registration number: not stated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was done using a computer
Allocation concealment (selection bias)	Unclear risk	No details in the paper
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No details in the paper but unlikely to have occurred
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details in the paper
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Unilateral LOD group: 2 participants excluded; 1 had a tubal disease which was identified during laparoscopy and 1 missed the follow‐up Bilateral LOD group: 3 participants excluded; 1 was excluded due to endometriosis which was diagnosed during laparoscopy, and 2 participants missed follow‐up
Selective reporting (reporting bias)	Unclear risk	We could not retrieve the original protocol. The outcomes mentioned in the Methods section are presented in the Results section
Other bias	Low risk	No evidence of other risk of bias

Methods	Randomised trial conducted in Fertility Plus, National Women's Hospital, New Zealand Timing: mid 1996 to late 1999
Participants	50 women randomised,3 cycles/participant, mean age 30 years, mean BMI 28 kg/m², mean length of infertility: 36 months in the LOD group and 29 months in the gonadotrophin group Included: women aged 20 to 38 years with clomiphene‐resistant PCOS (150 mg clomiphene for 5 days), BMI < 32 (for European women) and < 34 (for Polynesian women)  Excluded: Other known causes of infertility, including male‐factor infertility
Interventions	Bilateral ovarian drilling by diathermy, versus  3 cycles of gonadotrophins (HMG or rFSH)  Laparoscopic ovarian drilling was performed with a diathermy needle creating 10 punctures/ovary, cooled with normal saline Follow‐up for 6 months
Outcomes	Pregnancy rate 6 months after drilling or after 3 cycles of gonadotrophins (per participant), live birth, ovulation rate (per participant), costs
Notes	Analyses on an intention‐to‐treat basis.  Powered to detect a 10% difference in ongoing pregnancy rate.  Definitions  PCO: clinical (oligo‐ or amenorrhoea) + ovarian appearance on ultrasound (criteria by Adams 1986)  Refractory PCO: failure to conceive after 3 cycles of ovulation induction with clomiphene citrate (150 mg/day)  Pregnancy: positive HCG and fetal heart on ultrasound  Ovulation: disappearance of a leading follicle or appearance of a corpus luteum on ultrasound OR mid‐luteal phase serum progesterone > 20 mmol/l Conflict of interest: not stated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "computer generated sequences.."
Allocation concealment (selection bias)	Low risk	Quote: "sealed numbered opaque envelopes"
Blinding of participants and personnel (performance bias)   All outcomes	High risk	There was no evidence that researchers or participants were blinded
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details of blinding of outcome assessors
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No losses to follow‐up
Selective reporting (reporting bias)	Unclear risk	We could not retrieve the original protocol. All outcomes listed in Methods were reported in the Results
Other bias	Low risk	No evidence of other risk of bias

Methods	Randomised trial conducted in Iran Timing: not stated
Participants	100 infertile, clomiphene‐resistant women with PCOS
Interventions	Gonadotrophin (n = 50), versus Laparoscopic ovarian electrocautery (n = 50) Follow‐up for 4 months
Outcomes	Pregnancy, live birth
Notes	Conflict of interest: not stated Clinical trial registration number: not stated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "randomised". Awaiting further details in translation but numbers are equal in both groups so probably satisfactory
Allocation concealment (selection bias)	Unclear risk	No details
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No details
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All women accounted for at trial end and intention‐to‐treat data reported
Selective reporting (reporting bias)	Unclear risk	We could not retrieve the original protocol
Other bias	High risk	Only abstract available

Methods	Parallel randomised controlled trial, conducted in Department of Obstetrics and Gynaecology, University of Naples, Italy Timing: December 2009 to July 2015
Participants	246 women randomised, 201 analysed. Mean age of women in LOD group was 30.1 ± 7.5 years and in the THL group was 27.5 ± 6.8 years Inclusion criteria: Age 18 to 40 years, PCOS (Rotterdam 2003 criteria), clomiphene resistant Exclusion criteria: endocrine anomalies other than PCOS, any disease potentially responsible for ovarian adhesions, previous abdominal or pelvic surgery, presence of adhesions, fixed retroverted uterus, lateral displacement of the cervix, suspected pelvic tumour, vaginal infection, abnormalities at vaginal examination and transvaginal ultrasound, psychiatric disorder preventing ability to participate, obliteration of the Pouch of Douglas or inability to perform vaginal examination or any other contraindication to THL or laparoscopy
Interventions	Laparoscopic ovarian drilling: Unipolar needle electrode with a power setting of 40 W for 4 to 5 seconds set at 30 W per ovary. 3 ‐ 6 punctures per ovary (n = 123), versus Transvaginal hydrolaparoscopy ovarian drilling: Bipolar electrosurgical probe and 3 ‐ 6 points per ovary drilled at a power setting of 110 ‐ 130 W (n = 123) . At 6 months, all women offered follow‐up with THL and asked to monitor menstrual cycles for next 12 months for spontaneous pregnancy
Outcomes	Presence and type of adhesions, peri‐ and post‐operative complications, cumulative pregnancy rate, multiple pregnancy rate
Notes	Only overall cumulative pregnancy rate reported in the paper. We contacted the authors 25 October 2016 for additional data on pregnancy rate by group No conflict of interest Clinical trial registration number: not stated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "computer generated"
Allocation concealment (selection bias)	Low risk	Quote: "Allocation sequence was concealed from the researchers' 'sequentially numbered opaque, sealed and stapled envelope"
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No blinding of surgeons or participants
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Assessors of participants were blinded to allocation
Incomplete outcome data (attrition bias)   All outcomes	High risk	246 women were randomised. 19 women in the LOD group refused follow‐up with THL and therefore follow‐up was completed on 104 women. 26 women in the THL group refused follow‐up with THL and therefore follow‐up was completed on 97 women. Unclear if cumulative pregnancy rate is for all 246 women or only for those who had follow‐up with THL
Selective reporting (reporting bias)	High risk	We could not retrieve the original protocol. Data for cumulative pregnancy are given as an overall value and not by group. Pregnancy rate and multiple pregnancy rate are not prespecified as outcomes in the Methods
Other bias	Low risk	Groups were balanced at baseline

Methods	Randomised trial conducted in Turkey at the University of Hecettepi, Ankara, Turkey.  Time of randomisation: after initial laparoscopic ovarian drilling.  Timing: not stated
Participants	40 women randomised, clomiphene‐resistant PCOS patients (see definitions). Mean age (range) of the participants was 25.2 years (21 to 31) and mean duration of infertility was 4.4 years. 33 participants had primary and 7 had secondary infertility. Infertility work‐up consisted of semen analysis (normal in 36 participants and mildly oligo/asthenospermia in 4) and normal HSG. All women were anovulatory There were no clear inclusion or exclusion criteria specified
Interventions	2nd look laparoscopic adhesiolysis following ovarian laser drilling, versus  Ovarian laser drilling only  Ovarian laser drilling consisted of creating 20 to 25 holes/ovary using beam power of 50 W with the Nd:YAG laser followed by pelvic irrigation with Ringer lactate. Laparoscopic adhesiolysis with sharp or blunt dissection was done 3 to 4 weeks later
Outcomes	Pregnancy rate (by participant), ovulation rate (by participant), miscarriage rate (by pregnancy), multiple pregnancy rate (by pregnancy) Follow‐up for 6 months
Notes	Conflict of interest: not stated Definitions:  PCO: clinical (oligomenorrhoea, hirsutism, obesity) + LH/FSH ratio > 2 + elevated testosterone and/or androstenedione (not specified)  Clomiphene resistant: failure to ovulate on 200 mg/day for 5 days (duration not stated)  Pregnancy: ultrasound (not specified)  Ovulation: biphasic BBT + luteal serum progesterone > 3 ng/ml
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "table of random numbers"
Allocation concealment (selection bias)	Unclear risk	No details in paper
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No details in paper but blinding unlikely to have occurred
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details
Incomplete outcome data (attrition bias)   All outcomes	Low risk	40 women randomised, 1 refused second‐look laparoscopy
Selective reporting (reporting bias)	Unclear risk	We could not retrieve the original protocol. A priori outcomes in Methods section of paper were reported in Results section
Other bias	Low risk	No evidence of other risk of bias

Methods	Randomised trial conducted in Egypt Timing: May 2007 to September 2008
Participants	110 participants. The mean age of the women in the metformin group was 23.6 ± 2.6 years and in the LOD group was 24.3 ± 4.5 years Inclusion: Women with diagnosis of PCOS attending infertility clinic. Clomiphene resistance. Age 20 to 35 years. Patent fallopian tubes shown by hysterosalpingography, insulin resistance, normal semen analysis Exclusion: women < 20 years and > 35 years, received gonadotrophins or hormonal contraception in previous 3 months, having hyperprolactinaemia, or other endocrine, hepatic, or renal disorders, having organic pelvic mass, or previous abdominal surgery suggesting pelvic factor infertility
Interventions	850 mg metformin orally twice daily (n = 55), versus LOD using 4 to 8 punctures (n = 55) Follow‐up for 6 cycles/30 weeks
Outcomes	BMI, ovulation, pregnancy (biochemical, clinical), miscarriage, resuming regular cycles, glucose/insulin ratio
Notes	No conflict of interest Clinical trial registration number: not stated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "..computer generated random numbers tables" Comment: Satisfactory method.
Allocation concealment (selection bias)	Low risk	Quote: '..using serially numbered opaque envelopes" Comment: Satisfactory method
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	There were no details in the paper on blinding, but blinding unlikely due to differences in interventions
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details
Incomplete outcome data (attrition bias)   All outcomes	Low risk	There were 55 women allocated to each group and there were no losses to follow‐up or discontinuation of medication. All women were analysed
Selective reporting (reporting bias)	Unclear risk	We could not retrieve the original protocol. Report on adverse effects of treatment that were not prespecified as outcomes in the Methods section of the paper
Other bias	Low risk	No evidence of other risk of bias

Methods	Randomised prospective trial conducted in Turkey Timing: January 2000 to January 2004
Participants	Clomiphene‐resistant PCOS participants (see definitions). Mean age of LOMNT group was 26.3 ± 4.3 years and for gonadotrophin group 25.6 ± 4.08 years. All women had anovulatory infertility for > 1 year Exclusions: History of abdominopelvic surgery, systemic disease, proven or suspected pelvic inflammatory disease or ectopic pregnancy
Interventions	Bilateral ovarian drilling by diathermy (n = 17), versus  3 cycles of gonadotrophins (step up protocol) plus IUI (n = 18) Laparoscopic ovarian drilling was performed with a specially‐designed instrument which was then applied across the ovary and then squeezed Follow‐up for 6 months
Outcomes	Pregnancy rate by participant, multiple pregnancy rate and ovarian hyperstimulation rate, costs by treatment 8/17 who underwent ovarian drilling had second‐look laparoscopy for adhesion formation All women followed up for 6 months
Notes	Conflict of interest: not stated Definitions:  PCO: clinical (oligomenorrhoea, hirsutism, obesity) + LH/FSH ratio > 2 + elevated testosterone or androstenedione or both (not specified)  Clomiphene‐resistant: failure to ovulate on 200 mg/day for 5 days (duration not stated)  Pregnancy: ultrasound (not specified)  Ovulation: biphasic BBT + luteal serum progesterone > 3 ng/ml
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "computer generated random sequence"
Allocation concealment (selection bias)	Low risk	Quote: "sealed opaque envelopes"
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No details of blinding, which is unlikely to have occurred
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details provided.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	1 woman in the LOD group and 2 women in the gonadotrophin group were lost to follow‐up, but their data were included in the analysis
Selective reporting (reporting bias)	Unclear risk	We could not retrieve the original protocol. A priori outcomes stated in the Methods section of the paper were reported in the Results section
Other bias	Low risk	No evidence of other risk of bias

PERMALINK

Laparoscopic ovarian drilling for ovulation induction in women with anovulatory polycystic ovary syndrome

Esmée M Bordewijk

Ka Ying Bonnie Ng

Lidija Rakic

Ben Willem J Mol

Julie Brown

Tineke J Crawford

Madelon van Wely

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Overall quality of the body of evidence

Summary of findings for the main comparison. LOD with and without medical ovulation compared to medical ovulation induction alone.

Summary of findings 2. LOD of one ovary (unilateral) versus LOD of both ovaries (bilateral).

Results

Description of studies

Results of the search

1.

Included studies

Study design and setting

Participants

1. LOD with or without medical ovulation induction versus medical ovulation induction alone

2. LOD plus IVF versus IVF

3. LOD with second‐look laparoscopy versus LOD with expectant management

Techniques of ovarian drilling

4. Unilateral LOD versus bilateral LOD

Interventions

1. LOD with or without medical ovulation induction versus medical ovulation induction alone

2. LOD plus IVF versus IVF

3. LOD with second‐look laparoscopy versus LOD with expectant management

Techniques of LOD

Outcomes

1. Outcomes for LOD with or without medical ovulation induction versus medical ovulation induction alone

2. Outcomes for LOD plus IVF versus IVF

3. Outcomes for LOD with second‐look laparoscopy versus LOD with expectant management

4. Outcomes for techniques of LOD: unilateral versus bilateral

5. Outcomes for techniques of LOD: monopolar versus bilateral

6. Outcomes for techniques of LOD: adjusted thermal dose versus fixed thermal dose

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Methods	Randomised trial, cross‐over design, data available prior to cross‐over. Study conducted in Institute for Obstetrics and Gynaecology, University of Belgrade, Belgrade, Yugoslavia Timing: not stated.
Participants	56 participants randomised, 6 cycles/patient. Clomiphene‐resistant PCOS participants (high LH). Mean age, duration of infertility, infertility work‐up, mean BMI not stated
Interventions	Ovarian drilling with diathermy or laser vaporisation with CO₂ (n = 28), versus Gonadotrophins (FSH or hMG) for ovulation induction for 6 cycles. Number of drill holes per ovary is not stated. (n = 28) Follow‐up for 6 months
Outcomes	Pregnancy rate (by participant), miscarriage rate (by pregnancy), multiple pregnancy rate (by pregnancy)
Notes	Conflict of interest: not stated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No details in paper
Allocation concealment (selection bias)	Unclear risk	No details in paper
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No details of blinding, but unlikely to have occurred.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All participants appear to be included in the analysis
Selective reporting (reporting bias)	High risk	This is a conference abstract only. No full paper was identified
Other bias	High risk	Conference abstract

Methods	Parallel randomised controlled trial in university‐affiliated tertiary centre, Egypt Timing: Not stated
Participants	80 women randomised Mean age of unilateral drilling group was 28.4 ± 2.2 years and in bilateral group was 29.2 ± 1.9 years Inclusion criteria: Clomiphene‐resistant PCOS Exclusion criteria: No details
Interventions	Unilateral drilling (n = 40), versus Bilateral drilling (n = 40) 40 normally‐ovulating women were included as controls but not included in this review and were not randomised Follow‐up for 6 months
Outcomes	Serum anti‐Mullerian hormone at 6 months follow‐up
Notes	Conflict of interest: not stated Clinical trial registration number: not stated Conference abstract only
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "randomized" Comment: no other details
Allocation concealment (selection bias)	Unclear risk	No details
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No details
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	80 women randomised but not clear if all women were analysed at 6 months
Selective reporting (reporting bias)	High risk	Conference abstract that only reported on anti‐Mullerian hormone, which was not a prespecified outcome for this review
Other bias	High risk	States that groups were balanced at baseline but conference abstract only. No tables or P values identified

Methods	Randomised double‐blind study conducted in Italy Timing: October 2001 to December 2002
Participants	120 women; mean age of metformin group was 26.8 ± 2.2 and in LOD group 27.5 ± 2.4 years Inclusion: Overweight (BMI 25 ‐ 30 kg/m²) women with PCOS, clomiphene‐resistant Exclusion: Age < 22 or > 34 years; hypothyroidism, hyperprolactinaemia, Cushings syndrome, nonclassical congenital adrenal hyperplasia, and current or previous (within 6 months) use of oral contraceptives, glucocorticoids, antiandrogens, ovulation induction agents, antidiabetic or anti‐obesity drugs, or other hormonal drugs; neoplasms, metabolic, hepatic, or cardiovascular disorder or other concurrent medical illness; women who were intending to start a diet or a specific programme of physical activity; having organic pelvic disease, previous pelvic surgery, suspected peritoneal factor infertility , and tubal or male infertility
Interventions	Diagnostic laparoscopy followed by metformin cloridrate 850 mg twice daily. If anovulatory at 6 months clomiphene citrate 150 mg daily from Day 3 ‐ 7 (n = 60), versus LOD (3 to 6 punctures in each ovary depending on size of ovary) followed by multivitamins twice daily. If anovulatory at 6 months clomiphene citrate 150 mg daily from day 3 ‐7 (n = 60) Follow‐up for 6 months
Outcomes	Live birth, adverse events, menstrual cycle characteristics, ovulation rate, pregnancy, miscarriage, costs
Notes	Conflict of interest: not stated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The randomisation was carried out using online software to generate a random allocation sequence in double block as method of restriction"
Allocation concealment (selection bias)	Unclear risk	Quote: 'The random allocation sequence was concealed until the interventions were assigned" Comment: there were no further details in the paper
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Participants were blinded
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Outcome assessors were blinded
Incomplete outcome data (attrition bias)   All outcomes	Low risk	6 women in metformin group and 5 in the LOD group. Reasons given were evidence of minimal endometriosis by laparoscopy (4 in Group A and 2 from Group B) and non‐compliance (1 from each group). 1 woman from Group A and 2 from group B were excluded for weight loss observed in the first 3 months of the study
Selective reporting (reporting bias)	Unclear risk	The original protocol could not be retrieved. All outcomes cited in the Methods section were reported
Other bias	Low risk	No evidence of other risk of bias

Methods	Randomised trial conducted in Italy Timing: February 2003 to May 2004
Participants	50 participants Inclusion: Anovulatory, clomiphene‐resistant, with PCOS, seeking pregnancy Exclusion: < 18 or > 35 years, BMI > 35 kg/m², neoplastic, metabolic, endocrine, hepatic, renal , and cardiovascular disorders, or other concurrent medical illnesses; and current or previous use of any drug that affected hormone levels, metabolism or appetite. Organic or pelvic diseases, previous pelvic surgery, suspected peritoneal factor infertility/ subfertility, and tubal or male‐factor infertility or subfertility that was excluded by hysterosalpingogram and semen analysis. Wanting to start a diet or a specific programme of physical activity, cigarette smokers or alcoholic beverage abusers
Interventions	LOD followed by 6 cycles of observation (n = 25), versus Clomiphene citrate (incremental dose) plus metformin (850 mg increasing to 1700g daily) for 6 cycles (n = 25) Follow‐up for 6 months
Outcomes	Live birth, pregnancy rates, multiple pregnancy, miscarriage, ovulation rate, adverse events, compliance, cost
Notes	Conflict of interest: not stated Clinical trial registration number: NCT00558077 No funding
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "achieved using online software (www.randomization.it)"
Allocation concealment (selection bias)	Low risk	Concealed in sealed dark envelopes until the interventions were assigned
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No details but blinding unlikely due to differences in the interventions
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details provided
Incomplete outcome data (attrition bias)   All outcomes	Low risk	3 women (1 in the LOD group and 2 in the CC + metformin group) were lost to follow‐up because they missed a follow‐up visit
Selective reporting (reporting bias)	Low risk	We found the registered protocol on ClinicalTrials.gov (NCT00558077). All the outcomes mentioned in the protocol were presented in the published report
Other bias	Low risk	No evidence of other risk of bias

Methods	Parallel randomised controlled trial. Single centre, Department of Obstetrics and Gynaecology, Menoufia University Hospital, Egypt Timing: October 2014 to July 2015
Participants	108 women randomised. Mean age of women in unilateral ovarian drilling group was 29.7 ± 1.5 years and in bilateral ovarian drilling group was 29.8 ± 1.4 years Inclusion criteria: Clomiphene‐resistant PCOS (revised Rotterdam criteria); normal semen analysis for partner, normal uterine cavity, bilateral tubal patency Exclusion criteria: FSH > 15 IU/ml, medical disorders such as diabetes and hypertension, contraindications for laparoscopy, endocrine disorders, hyperprolactinaemia, thyroid disorder, Cushing syndrome, acromegaly, pelvic organ disease, abnormal semen analysis from partner
Interventions	Unilateral ovarian drilling of the larger ovary. Number of punctures was calculated as Np = 60 J/cm³/ 30 W x 4 seconds (n = 52), versus Bilateral ovarian drilling: 5 punctures per ovary at 30 W for 4 seconds. Each ovary received 600 J (n = 53) Follow‐up for 6 months
Outcomes	Ovulation rate, clinical pregnancy, ovarian reserve measures.
Notes	Clinical trial registration number: PACTR201405000757313 No conflict of interest
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "randomly assigned into two groups" "computer generated simple random tables"
Allocation concealment (selection bias)	Unclear risk	No details provided .
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No details provided .
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details provided .
Incomplete outcome data (attrition bias)   All outcomes	Low risk	108 women randomised.105 women analysed (2 lost in Unilateral group and 1 lost in Bilateral group ‐ reasons were loss to follow‐up)
Selective reporting (reporting bias)	Low risk	All prespecified outcomes were reported
Other bias	Low risk	Groups balanced at baseline. No other bias identified

Methods	Randomised prospective study conducted in a Fertility clinic in Wales, UK Timing: not stated
Participants	50 women, mean age in IVF group was 31 (95% CI 29.8 to 32.2) and for LOE + IVF the mean age was 31.8 (95% CI 30.3 to 33.2) Inclusion: Diagnosis of PCOS, requiring IVF for reasons other than anovulation, at least 1 previous unsuccessful ovarian stimulation cycle with gonadotrophins Exclusion: Aged > 40 years, history of > 2 miscarriages, severe male‐factor infertility
Interventions	IVF (n = 25), versus Ovarian electrocautery and IVF (grid of holes 10 mm apart) ovarian stimulation started 1 week after LOE (n = 25). Follow‐up for 1 cycle
Outcomes	Number of abandoned cycles, OHSS, pregnancy, miscarriage
Notes	Conflict of interest: not stated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Blocked method of randomisation.."
Allocation concealment (selection bias)	Unclear risk	No details in paper
Blinding of participants and personnel (performance bias)   All outcomes	High risk	There was no evidence of blinding of researchers or participants
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details provided
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All women randomised appear to be analysed
Selective reporting (reporting bias)	Unclear risk	We could not retrieve the original protocol. All outcomes listed in the Methods section were reported in the Results
Other bias	Low risk	No evidence of other risk of bias

Methods	Randomised prospective pilot study, conducted in India Timing: not stated
Participants	20 women with clomiphene‐resistant PCOS, patent tubes on hysterosalpingography and normal partner semen. Average age of unipolar group was 27.3 (range 21 to 32), and for the bipolar group was 25.5 (range 23 to 30) years No exclusion criteria detailed.
Interventions	Unipolar (n = 10), versus Bipolar ovarian drilling (n = 10) The average number of punctures across both groups was 14.85 per ovary Follow‐up for 3 months and if no evidence of ovulation then started on clomiphene citrate
Outcomes	Ovulation and pregnancy rate, androgen and biochemical measurements
Notes	Conflict of interest: not stated Clinical trial registration number: not stated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "randomly assigned by using computerized random table"
Allocation concealment (selection bias)	Unclear risk	No details in paper
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No evidence of blinding of researchers or participants
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details provided
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Although not stated it appears as though all women randomised were analysed
Selective reporting (reporting bias)	Unclear risk	We could not retrieve the original protocol. The outcomes listed in the Methods section were reported in the Results
Other bias	Low risk	No evidence of other risk of bias

Methods	Randomised trial, no method stated. Conducted at First Department of Obstetrics and Gynaecology, University of Milan and Gynaecology Unit, University of Pavia, Varese, Italy  Timing: May 1996 to April 1997
Participants	29 participants randomised, 6 cycles/participant. Clomiphene‐resistant PCO women (high LH). Mean age not stated  Duration of infertility 2 to 6.5 years, Infertility work‐up not stated, mean BMI not stated
Interventions	Ovarian drilling with diathermy (at least 20 drill holes per ovary), (N = 16) versus  Gonadotrophins (pure FSH with low‐dose step‐up protocol) (N = 13) for ovulation induction for 6 cycles Follow‐up for 6 months
Outcomes	Pregnancy rate (per participant), miscarriage rate (per pregnancy), multiple pregnancy rate (per pregnancy)
Notes	Interim results only ‐ further patients will be randomised and a later publication is expected Conflict of interest: not stated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated
Allocation concealment (selection bias)	Unclear risk	Unclear
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No blinding of participants or study personnel
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details provided
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Not stated
Selective reporting (reporting bias)	Unclear risk	We could not retrieve the original protocol
Other bias	Unclear risk	Interim details only

Methods	Randomized controlled prospective trial conducted in India Timing: January 2012 to May 2015
Participants	109 women randomised. The mean age of women was 26.23 ± 2.9 years in gonadotropin group and 26.11 ± 2.7 years in ovarian drilling group Inclusion criteria: chronic anovulation, polycystic ovaries diagnosed by transvaginal ultrasonography, clomiphene citrate‐resistant, shown by anovulation after taking 150 mg clomiphene citrate daily for 5 days for at least 3 cycles. Aged between 21 and 35 years. Exclusion criteria: severe male‐factor subfertility, other causes of infertility like tubal obstruction and extensive adhesion (endometriosis) stages III and IV according to the classification of the American Fertility Society Secondary exclusion criteria identified during diagnostic laparoscopy: tubal obstruction, extensive adhesion of the ovaries or fallopian tubes, and endometriosis stage III or IV
Interventions	Gonadotrophins (N = 44), versus LOD with CC or gonadotrophins (N = 45) (4 to 5 puncture sites, 40 W, monopolar needle) Follow‐up for 6 months
Outcomes	Ovulation rate, pregnancy rate, live birth, abortion, ectopic, multiple pregnancies
Notes	No conflict of interest No funding Clinical trial registration number: not stated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Randomly allocated2 Comment: no other details in the paper
Allocation concealment (selection bias)	Unclear risk	No details in the paper
Blinding of participants and personnel (performance bias)   All outcomes	High risk	There was no evidence that participants or researchers were blinded
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No details in the paper
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Out of 109 women, 8 were excluded after diagnostic laparoscopy because of the presence of endometriosis and adhesions. 12 women did not complete the study protocol
Selective reporting (reporting bias)	High risk	We could not retrieve the original protocol. The primary outcome in the Method section was ongoing pregnancy within 12 months. The primary outcome in the Result section was a positive urine pregnancy test after 3 and 6 cycles
Other bias	Unclear risk	Women with LOD received CC or gonadotrophins

Study	Reason for exclusion
Abdel Gadir 1990	Serial randomisation
Abu Hashim 2011b	Participants had CC failure (defined as failure to achieve pregnancy despite successful CC‐induced ovulation for 6 cycles) as opposed to CC resistance
Al‐Mizyen 2007	Randomisation was by cards numbered 1 to 20; even numbers allocated to one group and odd numbers to another group
Badawy 2009	Trial compared methods of drilling only
Foroozanfard 2010	Compared 5 to 10 punctures in each ovary
Franz 2016	Ineligible intervention: transabdominal versus transvaginal laparoscopic ovarian drilling
Gadir 1992	Serial method of randomisation
Greenblatt 1993	RCT comparing drilling by diathermy + Interceed to 1 ovary versus drilling only to the other ovary 1. Unit of randomisation: ovaries, not participants  2. Only outcome is adhesion formation at second‐look laparoscopy
Gürgan 1991	Use of concurrent controls
Heylen 1994	Use of concurrent controls
Kamel 2004	Compared re‐electrocautery with FSH
Kandil 2018	Compares transvaginal ovarian needle drilling with LOD
Keckstein 1990	Non‐randomised controlled trial comparing Nd:YAG laser drilling versus CO2 laser drilling Different duration of follow‐up between the 2 groups (8 versus 18 to 30 months)
Kocak 2006	Ineligible comparisons. LOD was compared with LOD + metformin
Lockwood 1995	Conference abstract only; lack of usable data; we were not able to obtain data after multiple attempts to contact the authors.
Malkawi 2005	Not an RCT
Muenstermann 2000	Randomisation used an 'alternate' allocation method
Nasr 2010	Both groups underwent LOD
Rath 2006	Quasi‐RCT
Roy 2018	Ineligible intervention: LOD by harmonic scalpel versus monopolar drilling needle
Salah 2013	Ineligible intervention: RCT comparing LOD under local anaesthetic versus general anaesthetic
Saravelos 1996	RCT comparing LOD + interceed to 1 ovary versus drilling only to the other ovary Outcome is adhesion formation at second‐look laparoscopy
Seyam 2018	Not an RCT; prospective controlled study
Sunj 2013	Not an RCT; quasi‐random allocation
Tabrizi 2005	RCT comparing 5 versus 10 versus 15 points electrocautery of the ovary
Vrbikova 1998	No interventions of interest
Wang 2015	Excluded due to article being retracted
Zeng 2012	Ineligible intervention: trial comparing needle puncture drainage with unipolar electrocoagulation drilling
Zhu 2010	This trial compared different numbers of coagulation points