Ultrasound‐guided transvaginal ovarian needle drilling for clomiphene‐resistant polycystic ovarian syndrome in subfertile women

Abstract

Background

Ovulatory disturbance is a key diagnostic feature of polycystic ovarian syndrome (PCOS), leading to infertility and correspondingly heavy disease burden. Many therapeutic strategies have been used to induce ovulation for women with PCOS who are infertile. Ultrasound‐guided transvaginal ovarian needle drilling (UTND) is a novel surgical method used to induce ovulation for women with clomiphene‐resistant PCOS at the outpatient clinic. 

Objectives

To evaluate the efficacy and safety of UTND for subfertile women with clomiphene‐resistant PCOS.

Search methods

We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, and other databases to December 2020. We checked conference abstracts, reference lists, and clinical trials registries. We also contacted experts and specialists in the field for any additional trials .

Selection criteria

We planned to include randomised controlled trials comparing UTND to laparoscopic ovarian drilling, and UTND combined with gonadotropins to gonadotropins, in women of reproductive age with clomiphene‐resistant PCOS and infertility.

Data collection and analysis

Two review authors independently screened the trials identified by the search for inclusion, assessed methodological quality and risk of bias, and extracted data. The primary outcomes were live birth rate and incidence of surgical complications (bleeding and infection). Secondary outcomes included pregnancy rate, ovulation rate, and ovarian hyperstimulation syndrome. We planned to calculate odds ratios with 95% confidence intervals for dichotomous data. We would assess overall quality of the evidence by applying the GRADE criteria.

Main results

We did not identify any trials for inclusion in the review. We were unable to assess the benefit or harm of applying UTND for women with clomiphene‐resistant PCOS, as no studies could be included in the current review. We moved the previously included trials to studies awaiting classification due to concerns regarding methodology.

Authors' conclusions

Since we did not identify any studies for inclusion, we were unable to assess the benefit or harm of applying UTND for women with clomiphene‐resistant PCOS.

Plain language summary

Ultrasound‐guided transvaginal ovarian needle drilling for clomiphene‐resistant polycystic ovarian syndrome in subfertile women

Review question

We looked at whether women who have clomiphene‐resistant polycystic ovarian syndrome (PCOS) would benefit from applying ultrasound‐guided transvaginal ovarian needle drilling (UTND) to induce ovulation.

Background

Clomiphene citrate is one of the first‐line treatments used to induce ovulation (release of an egg from the ovary) in women with PCOS (a hormonal disorder common in women of child‐bearing age). However, 15% to 40% of women with PCOS do not ovulate after clomiphene administration (known as clomiphene resistance). Ultrasound‐guided transvaginal ovarian needle drilling (puncturing an ovary under the guidance of images created by an ultrasound probe inserted into the vagina) is used in women with clomiphene‐resistant PCOS to assist releasing a dominant follicle (ovulation). Also, gonadotropins (injectable hormonal medicines) may be offered as a treatment option to induce ovulation in women with clomiphene‐resistant PCOS.

It has been suggested that compared to laparoscopic (where small incisions are made in the pelvis and a tiny camera is used to view the ovaries) ovarian drilling, UTND may decrease the risk of surgical complications. Nevertheless, most of the studies of UTND have limitations in study quality. We did not identify any studies for inclusion. The safety and effectiveness of UTND are still uncertain.

Search date

We searched for studies published up to December 2020.

Study characteristics

No studies could be included for analysis. We placed three previously included studies in the awaiting classification category due to uncertainties regarding study methods.

Key results

We were unable to assess the benefit or harm of applying UTND for women with clomiphene‐resistant PCOS, as no studies could be included in the current review.

Quality of the evidence

No studies could be included for quality evaluation.

Background

Description of the condition

Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age (from 18 to 44 years) (Bozdag 2016; March 2010). The main characteristics of PCOS are oligo‐ovulation or anovulation (chronic failure or absence of ovulation), hyperandrogenism (excessive secretion of androgens), and polycystic ovary morphology (profile features described as 20 follicles or more whose diameter are 2 mm to 9 mm in each ovary with or without an ovarian volume more than 10 mL) identified under ultrasonography (ESHRE/ASRM 2004; Teede 2018; Trivax 2007). The aetiology and pathogenesis (causes and mechanisms) of PCOS remain unclear, but they are considered to be related to a combination of genetic and environmental influences (Diamanti‐Kandarakis 2006; Huang 2007; Norman 2007). Common clinical symptoms of PCOS include menstrual irregularities, infertility (inability to conceive), hirsutism (excessive hair growth), acne, obesity, depression, and anxiety (the psychological disorders that affect the woman's mood changes, physical functions, and social interactions) (Barnard 2007; Lane 2006; Teede 2010).

About 8% to 13% of women of reproductive age are affected by PCOS (Bozdag 2016); however, up to 70% of affected women remain undiagnosed (March 2010). PCOS is the major cause of anovulatory infertility (Franks 1995; Seow 2008), and induces a high risk of both pregnancy‐related and neonatal complications (Boomsma 2006; Boomsma 2008; Legro 2007). PCOS is also associated with an increased prevalence of type 2 diabetes mellitus (Kakoly 2018; Ollila 2017), metabolic syndrome (a combination of metabolic disorders that increase the risk of developing cardiovascular disease and diabetes) (Carmina 2006; Sam 2005), and cardiovascular disease (Wild 2010). Moreover, PCOS may lead to endometrial hyperplasia (benign proliferation of the endometrium, which usually leads to irregular menstrual cycles) and endometrial cancer (Barry 2014; Cheung 2001; Dockerty 1957; Gutman 2007; Lobo 2000).

PCOS results in heavy economic burdens (Azziz 2005), and furthermore has negative effects on health‐related quality of life, which is affected by anxiety, poor body image, low self‐esteem, delayed diagnosis, depressive symptoms, and inadequate education and information provision by health professionals (Böttcher 2018; Deeks 2011). Meanwhile, PCOS is a major cause of psychological morbidity, as the prevalence and severity of depressive and anxiety symptoms are increased in PCOS (Cesta 2016; Cooney 2017; Jones 2008).

Description of the intervention

Ovulatory disturbance is a key diagnostic feature of PCOS, leading to infertility. Many therapeutic strategies have been used to restore ovulation in women with PCOS who are infertile (Balen 2016; Teede 2018). Excess weight can exacerbate infertility, response to infertility treatment, and pregnancy health; hence prevention of weight gain and lifestyle interventions for weight loss are recommended for women with PCOS as basic treatments (Balen 2016; Domecq 2013; Teede 2018; Thomson 2010). First‐line treatment to induce ovulation (using artificial techniques to stimulate follicle development and rupture, to release the ovum) is either clomiphene citrate or letrozole (Balen 2016; Teede 2018). The second‐line intervention is either exogenous (produced outside the body) gonadotropins or laparoscopic ovarian drilling (LOD). The third‐line strategy is in vitro fertilisation with embryo transfer (ESHRE/ASRM 2008).

Clomiphene citrate is an economical and convenient intervention to induce ovulation in women with PCOS. However, clomiphene resistance and failure has been documented, and there is a noted discrepancy between good ovulation rates and lower pregnancy rates, which is due to the antioestrogenic effects of clomiphene citrate on the endometrium and cervical mucous (ESHRE/ASRM 2008; Palomba 2009). About 15% to 40% of women with PCOS are resistant to clomiphene (absence of ovulation after clomiphene administration at doses of 100 mg/day to 150 mg/day for at least three cycles) (Brown 2016; Palomba 2009). Clomiphene plus metformin can significantly increase the pregnancy and ovulation rates of women with PCOS, especially in clomiphene‐resistant women (Brown 2016; Creanga 2008; Morley 2017).

Letrozole is an aromatase inhibitor, which catalyses the conversion of androgens to oestrogens, increases secretion of follicle‐stimulating hormone (FSH), then stimulates ovarian follicle development and maturation. It was originally used to improve pregnancy rates and limit adverse effects, especially with clomiphene resistance and failure (Casper 2003; Legro 2014). However, letrozole has adverse effects including gastrointestinal disturbances, hot flushes, headache, and back pain (Legro 2014).

Gonadotropins or LOD may be considered if a woman does not respond well to the above interventions and is still infertile because of anovulation. Gonadotropins require daily injections and intensive monitoring with ultrasound; are more expensive than LOD (Farquhar 2004); and their use increases the risk of serious ovarian hyperstimulation syndrome (OHSS, a complication of ovulation induction expressed as ovarian enlargement and symptoms of acute fluid shift out of the intravascular space such as ascites (excessive fluid in the abdomen), hydrothorax (excessive fluid in the thorax or chest), and anasarca (generalised pitting oedema), and multiple gestation (two or more foetuses in a pregnancy)) (Norman 2007). Cochrane Reviews have indicated that LOD has a reduced risk of multiple pregnancies compared with gonadotropins (Bordewijk 2020; Farquhar 2012), but it still has two main potential complications. These are periadnexal adhesion (around the fallopian tubes and ovaries) and premature ovarian failure (the symptom of amenorrhoea before age 40 years and associated with serum FSH concentration more than 40 IU/L) (Seow 2008). In addition, intraoperative and postoperative risks of LOD are higher in women who are overweight and obese.

Ultrasound‐guided transvaginal ovarian needle drilling (UTND) is a novel surgical method used to induce ovulation. A long, sharp needle is used to puncture each ovary from different angles in order to assist the dominant follicle to release an ovum to the cavitas pelvis and to aspirate all visible small follicles, under the guidance of ultrasound (Badawy 2009; Kandil 2018; Atwa 2020). Compared to LOD, UTND may reduce the risk of surgical complications because it does not cause any peripheral thermal damage to the ovary or the ovary stroma. UTND could enhance pregnancy rates whilst reducing the risk of complications and lowering costs, and could be conducted in the outpatient clinic. The two main UTND treatment strategies are UTND alone (Badawy 2009; Kandil 2018), or combined with drug ovulation induction (Chen 2004; Atwa 2020; Ma 2007; Qing 2005; Tang 2007; Zhou 2006).

How the intervention might work

The mechanism of UTND is not well understood, but it might be similar to ovarian wedge resection and LOD. Ovary puncture and aspiration of follicular fluid through UTND reduces intraovarian androgen and other steroids rapidly and directly because both ovarian stromal and follicular tissues of women with PCOS produce much more androgen, and their follicular fluid contains a high concentration of androgen (McNatty 1980). Serum androgen and luteinising hormone levels also decrease remarkably after UTND (Atwa 2020). The decrease of androgens leads to lower peripheral conversion of androgen to oestrogen and hence restores feedback to the hypothalamus and pituitary, resulting in appropriate gonadotropin secretion and increased FSH levels. All of the above, and the rupture of thickened ovarian surface induced by ovary puncture, facilitate follicular development and ovulation (Hendriks 2007).

Why it is important to do this review

UTND is a novel treatment for women with clomiphene‐resistant PCOS and may be an attractive surgical treatment for subfertile women with clomiphene‐resistant PCOS. More studies on UTND have been done in recent years (Badawy 2009; Jing 2008; Kandil 2018; Atwa 2020; Liang 2008; Liu 2015; Qi 2015; Tang 2008; Zhu 2003); however, most of these studies appear to have limitations in their study methodology. As the safety and efficacy of UTND may still be uncertain, a systematic review was warranted.

Objectives

To evaluate the efficacy and safety of UTND for subfertile women with clomiphene‐resistant PCOS.

Methods

Criteria for considering studies for this review

Types of studies

We planned to include randomised controlled trials (RCTs) of UTND for subfertile women with clomiphene‐resistant PCOS. We planned to include only first‐phase data from cross‐over trials, because UTND might have lasting effects that would be carried over into the second phase of the trial. We also excluded quasi‐ and pseudo‐RCTs. Any RCTs with unclear methodology would not be included until the methodology has been clarified.

Types of participants

We included women of reproductive age (from 18 to 44 years) with clomiphene‐resistant PCOS and infertility (duration of infertility one year or longer). According to the Rotterdam Consensus (2003), the diagnostic criteria of PCOS are: oligo‐ovulation or anovulation, clinical or biochemical signs of hyperandrogenism, and polycystic ovaries (by gynaecological ultrasound); two of these three criteria were required with the exclusion of other endocrine disorders (such as congenital adrenal hyperplasias, androgen‐secreting tumours, Cushing's syndrome) (ESHRE/ASRM 2004). Two review authors (JZ, LK) independently evaluated the diagnostic criteria of PCOS to judge if they were in accordance with the Rotterdam criteria.

However, there was no consensus on the definition of clomiphene resistance in the literature, which meant that women were resistant to different dosages of clomiphene (50 mg to 150 mg per day, five days per cycle). We excluded women with both clomiphene and gonadotropin resistance because gonadotropins may be applied as an important co‐intervention with UTND.

We excluded trials including infertile women with both PCOS and other causes of infertility if the proportion of women with PCOS was less than 90%, or was unclear.

Types of interventions

Experimental interventions included UTND and UTND combined with drug ovulation induction (such as clomiphene, insulin‐sensitising drugs, aromatase inhibitors, and gonadotropins). Comparison interventions included LOD (with or without drug ovulation induction) and gonadotropins. We included the following interventions in both experimental and comparison groups without any restrictions:

• UTND (with or without drug ovulation induction) versus LOD (with or without drug ovulation induction);

• UTND (with or without gonadotropins) versus gonadotropins.

We excluded trials including UTND in both the experimental and comparison groups and studies including intrauterine injection only in the intervention group (Wang 2004), and studies including clomiphene for ovulation induction only in the comparison group (Xiao 2011).

Types of outcome measures

Primary outcomes

• Live birth rate (per woman): the percentage of women who gave birth to a living baby.

• Incidence of surgical complications (per woman, bleeding or infection).

Secondary outcomes

• Pregnancy rate (per woman): the percentage of women who achieved a pregnancy (confirmed by serum human chorionic gonadotropin (hCG) and ultrasound).

• Ovulation rate (per woman): the percentage of women who achieved ovulation confirmed by ultrasound or increased serum progesterone (greater than 5 ng/mL).

• Incidence of OHSS (per woman).

• Miscarriage rate (per woman): the percentage of women who had a miscarriage before 20 weeks' gestation.

• Multiple pregnancy rate (per woman).

• Premature delivery rate (per woman): the percentage of women who delivered between 20 and 37 weeks' gestation.

• Costs: the total costs of treatment (per woman).

Search methods for identification of studies

We searched for all RCTs of UTND for subfertile women with clomiphene‐resistant PCOS using the following resources with the help of Cochrane Gynaecology and Fertility Group Information Specialist Marian Showell. We applied no language or date restrictions.

Electronic searches

We searched the following electronic databases without any limitations:

• Cochrane Gynaecology and Fertility Group (CGF) Specialised Register of Controlled Trials, ProCite platform; searched 21 December 2020 (Appendix 1);

• CENTRAL, via the Cochrane Register of Studies Online (CRSO), web platform; searched 21 December 2020 (Appendix 2);

• MEDLINE, Ovid platform; searched from 1946 to 20 December 2020 (Appendix 3);

• Embase, Ovid platform; searched from 1980 to 20 December 2020 (Appendix 4);

• Chinese National Knowledge Infrastructure (CNKI), including China Academic Journal Network Publishing Database (CAJD), web platform; searched from 1915 to 29 March 2021 (for this database and all other Chinese databases listed below see Appendix 5);

• China Doctoral Dissertations Full‐text Database (CDFD) , web platform; searched from 1984 to 29 March 2021;

• China Master's Theses Full‐text Database (CMFD), web platform; searched from 1984 to 29 March 2021;

• China Proceedings of Conference Full‐text Database (CPCD), web platform; searched from 1953 to 29 March 2021;

• China Core Newspapers Full‐text Database (CCND), web platform; searched from 2000 to 29 March 2021;

• Chinese Book Full‐text Database (CBFD) and China Yearbook Full‐text Database (CYBD), web platform; searched from 1949 to 29 March 2021;

• VIP, web platform, searched from 1984 to 29 March 2021;

• Chinese Medical Association (CMA) Digital Periodicals of Wanfang, web platform; searched from 1990 to 29 March 2021.

The detailed search strategies listed in the appendices were translated into Chinese when we searched the Chinese databases.

Searching other resources

We also searched the following additional sources.

• We handsearched the reference lists of included studies, relevant reviews, and systematic reviews, as well as appropriate journals and textbooks to locate potentially eligible studies.

• We searched the following international trial registries for ongoing trials on 29 March 2021:

  • ClinicalTrials.gov, a service of the US National Institutes of Health (clinicaltrials.gov/); and

  • World Health Organization International Clinical Trials Registry Platform (ICTRP) (trialsearch.who.int/).

• We checked the conference abstracts from the 2018 European Society of Human Reproduction and Embryology (ESHRE) (academic.oup.com/humrep/article/33/suppl_1/i1/5046210) and the 2020 36th Virtual Annual Meeting of ESHRE. All other ESHRE conference abstracts were included in the CGF specialised register. 

• We contacted experts in the field to enquire as to any additional studies.

Data collection and analysis

Selection of studies

After the initial screen of titles and abstracts retrieved by the search, we retrieved the full texts of eligible studies for further assessment. Two review authors (JZ, LK) independently examined the full text of the trials reported as randomised. If the random allocations of the selected trials were not explicitly described according to the noted criteria (Appendix 6), one review author (JZ) attempted to contact the trial authors by e‐mail to confirm whether the methods of random allocation were correct. Any disagreements were resolved by discussion or by consultation with a third review author (LX). We documented the selection process in a PRISMA flow chart.

Data extraction and management

Two review authors (JZ, LK) independently extracted the following study characteristics using a data extraction form designed according to Cochrane guidelines. We (JZ, LK, LX) resolved any discrepancies by discussion. One review author (JZ) attempted to correspond with study investigators by e‐mail to obtain further data on methods or results, but without reply. When studies had multiple publications, the review authors collated multiple reports of the same study so that each study, rather than each report, was the unit of interest in review; such studies would have a single study ID with multiple references.

Study characteristics

• Method of randomisation

• Concealment of allocation

• Blinding

• Study design: type of study (single‐centre or multicentre study)

• Timing and location of the study

• Duration of follow‐up

• Number of women recruited, excluded, randomised, and analysed

• Analysis: power calculation, if intention‐to‐treat (ITT) analysis was performed or not

• Source of funding

Participant characteristics

• Diagnostic criteria of PCOS

• Inclusion criteria

• Exclusion criteria

• Definition of clomiphene resistance

• Baseline characteristics: previously administered treatment, age, body mass index, duration of infertility, hormonal profiles, and clinical manifestations

Interventions

• Total number of intervention groups

• Description of all experimental and comparison interventions

• Dose regimen and duration of gonadotropins

• Co‐interventions

Outcomes

• Types of outcomes (as described in Types of outcome measures) reported in the original trials

• Definitions of outcomes

• Methods of outcome measurement

• Time points of outcome measurement

The excluded studies that initially seemed to meet inclusion criteria and the reasons for their exclusion are briefly listed in the Characteristics of excluded studies section.

Assessment of risk of bias in included studies

Two review authors (JZ, LX) were to independently assess risk of bias of the included studies using Cochrane's risk of bias tool. The following six domains are evaluated in the tool: selection bias (random sequence generation and allocation concealment); performance bias (blinding of participants and personnel); detection bias (blinding of outcome assessors); attrition bias (incomplete outcome data); reporting bias (selective reporting); and other bias. Each domain is graded as low risk of bias, high risk of bias, or unclear risk of bias (see Appendix 6) (Higgins 2011). Any disagreements would have been resolved by consensus. We planned to describe all judgements fully and present our conclusions in risk of bias tables. We planned to describe the data in detail and facilitate the interpretation of the reliability of the results. We would take care to search for within‐trial selective reporting, that is trials failing to report obvious outcomes or reporting them in insufficient detail. We planned to search for published protocols and compare the outcomes specified in the protocol versus those reported in the final published study.

Measures of treatment effect

For dichotomous data (e.g. live birth rates, pregnancy rate), we planned to use the numbers of events in the control and intervention groups of each study to calculate Mantel‐Haenszel odds ratios (ORs) or (where events are very rare) Peto ORs with 95% confidence intervals (CI). For continuous data (e.g. costs), if all studies reported exactly the same outcomes, we would calculate mean difference (MD) and 95% CIs between treatment groups. If studies reported similar outcomes on different scales, we would calculate the standardised mean difference (SMD) with 95% CIs. We planned to use ITT analysis to measure the treatment effect.

Unit of analysis issues

If RCTs with non‐standard designs are available in the future, such as those with multiple treatment groups or cluster‐randomised trials, we will assess for potential unit of analysis error. Data that do not allow valid analysis (e.g. 'per cycle' data) will be briefly summarised in an Additional table and will not be meta‐analysed. We will count multiple births as one live birth event. Only first‐phase data from cross‐over trials will be included.

Dealing with missing data

We planned to describe for each included study and each outcome the completeness of data, including attrition and exclusions from the analysis. We planned to state whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. In the case of sufficient available information, we would include missing data in the analyses undertaken.

We planned to analyse the data on an ITT basis to the greatest degree possible. We planned to undertake imputation of individual values for live birth rate, pregnancy rate, and ovulation rate. We would assume that live births, pregnancies, and ovulation do not occur in women without a reported outcome. We planned to subject any imputation undertaken to sensitivity analysis.

Assessment of heterogeneity

We planned to evaluate clinical heterogeneity by examining the variability in participant factors (e.g. baseline characteristics and diagnostic criteria of PCOS), interventions (e.g. therapeutic strategies, co‐intervention, and time of treatment), and the outcomes studied (e.g. definition, format, and time points of measurement). We planned to assess methodological heterogeneity based on differences in the design factors of trials (e.g. randomisation methods). Clinical and methodological heterogeneity lead to statistical heterogeneity, which is simply referred to as heterogeneity. We will evaluate statistical heterogeneity if more studies are assessed in future updates of this review. We planned to use two methods for identifying heterogeneity: the Chi² test (P value) and the I² statistic. A low P value (less than 0.10) qualitatively indicates heterogeneity of intervention effects. The I² statistic quantitatively estimates the heterogeneity across studies: an I² greater than 50% is indicative of substantial heterogeneity (Higgins 2021). If there is no evidence of substantial or considerable heterogeneity, we will consider meta‐analysis to be appropriate.

Assessment of reporting biases

In view of the difficulty in detecting and correcting for publication bias and other reporting biases, the review authors aimed to minimise their potential impact by ensuring a comprehensive search for eligible studies and by staying alert for duplication of data. We planned to assess potential publication bias using a funnel plot or other corrective analytical methods (Egger 1997). We planned to evaluate selective reporting by comparing the protocol to the published article (Higgins 2021). As possible sources of asymmetry of funnel plots include publication bias and other biases (Higgins 2021), the visual inspection of the funnel plot may be misleading, and we would not place excessive emphasis on it (Lau 2006).

Data synthesis

We planned to use Review Manager 5 to analyse the data (Review Manager 2020).

Subgroup analysis and investigation of heterogeneity

We planned to perform the following subgroup analyses to investigate the possible sources of heterogeneity.

• Different experimental interventions: two operation methods of UTND:

  • one used a long, sharp needle to puncture each ovary from different angles to assist the dominant follicle to release ova to the cavitas pelvis and to aspirate all other visible small follicles, under the guidance of ultrasound; and

  • the other used a long, sharp needle to puncture each ovary from different angles to aspirate all visible follicles under the guidance of ultrasound.

• Different comparison interventions: gonadotropins (for three cycles or fewer, more than three cycles, and six cycles or fewer; used or not).

• Different duration of research: six months or less, or more than six months.

• Different co‐interventions: UTND versus LOD, with or without gonadotropin.

Sensitivity analysis

We planned that if we identified at least three studies, we would conduct sensitivity analyses for the outcomes live birth, pregnancy, and ovulation to determine whether our conclusions were robust to different decisions made regarding eligibility and analysis. These analyses include consideration of whether review conclusions would differ if we restrict:

• eligibility to studies at low risk of bias (studies with low risk of bias in the domains of random sequence generation and allocation concealment);

• analyses to studies without imputed data.

Summary of findings and assessment of the certainty of the evidence

We planned to assess the certainty of the evidence using the GRADE approach (Schünemann 2013). This relates to the seven main outcomes (live birth, incidence of surgical complications, pregnancy rate, ovulation rate, incidence of OHSS, miscarriage rate, and multiple pregnancy rate) for the main comparisons.

Results

Description of studies

Results of the search

Our search conducted in December 2020 identified 960 citations, 800 in English and 160 in Chinese. We screened 960 records after excluding duplications. Of these 960 studies, 913 studies were excluded for the reasons of non‐PCOS, non‐RCT, non‐UTND, or duplications after abstract screening. We retrieved 47 full texts for further evaluation, 41 of which were excluded (see Characteristics of excluded studies). We moved three studies with inadequate randomisation to studies awaiting classification (Chen 2010; Hu 2013; Li 2002). We placed Badawy 2009 and Kandil 2018 in awaiting assessment while we wait for further information regarding the studies.  We assessed Atwa 2020 as awaiting classification as well due to a discrepancy in the presented results (see Characteristics of studies awaiting classification). We documented the study selection process in a PRISMA flow diagram (Figure 1).

1.

Study flow diagram.

Abbreviations: PCOS: polycystic ovarian syndrome; RCT: randomised controlled trial; UTND: ultrasound‐guided transvaginal ovarian needle drilling.

Included studies

We included no studies in the updated review.

Excluded studies

We excluded 41 studies for the reasons summarised in the Characteristics of excluded studies section. In total, we excluded 18 studies for including women with PCOS without clomiphene resistance; two studies for including women with PCOS with both clomiphene and gonadotropin resistance (Dai 2013; Li 2007); seven studies that were non‐RCTs, of which three had inadequate randomisation methods (Chen 2010; Hu 2013; Li 2002); eight studies for applying UTND to both study arms; four studies for not applying UTND; one study for application of intrauterine insemination in the UTND group only (Wang 2004); and one study for application of clomiphene to the comparison group only (Xiao 2011).

Risk of bias in included studies

We did not include any studies for bias evaluation.

Allocation

We did not include any studies for bias evaluation.

Blinding

We did not include any studies for bias evaluation.

Incomplete outcome data

We did not include any studies for bias evaluation.

Selective reporting

We did not include any studies for bias evaluation.

Other potential sources of bias

We did not include any studies for bias evaluation.

Effects of interventions

We did not identify any studies for inclusion in the review. The efficacy of UTND in inducing ovulation as compared to LOD or gonadotropins is unclear.

Discussion

Summary of main results

We did not include any studies in the current review. Due to lack of data, we were unable to assess the benefit or harm of applying UTND for women with clomiphene‐resistant PCOS.

Overall completeness and applicability of evidence

No studies were included. No suitable evidence regarding the efficacy of UTND could be assessed.

Quality of the evidence

No definitive evidence could be included and assessed in current review. The quality of studies relating to the role of UTND in inducing ovulation for women with PCOS is limited by the poor reporting of methods.

Potential biases in the review process

We believe that we have identified all relevant studies. However, our attempts at contact with the primary authors of studies awaiting assessment were unsuccessful. We will make further attempts at contact in future. Subjective judgements are involved in the assessment of the methodology. This potential limitation is minimised by following the procedures in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021), with review authors independently assessing studies and resolving any disagreements through discussion, or if required by involving a third review author in the decision.

Agreements and disagreements with other studies or reviews

There is no other systematic review on UTND for subfertile women with PCOS. Future well‐designed RCTs with large sample sizes and good reporting are warranted. 

Authors' conclusions

Implications for practice.

Since we did not identify any studies for inclusion, we were unable to assess the benefit or harm of applying ultrasound‐guided transvaginal ovarian needle drilling (UTND) for women with clomiphene‐resistant polycystic ovarian syndrome (PCOS).

Implications for research.

There is no suitable evidence available on the safety and efficacy of UTND compared with laparoscopic ovarian drilling. Large, well‐designed RCTs on the efficacy of UTND combined with gonadotropins versus gonadotropins alone are warranted. Long‐term obstetrical outcomes such as live birth, preterm delivery, and adverse effects are lacking in most studies. Participants with different and specific body mass indexes should be studied to locate the efficacy of UTND on obese and non‐obese women with PCOS. The influence of insulin‐sensitising drugs on the efficacy of UTND should also be explored. Long‐term obstetric outcomes and postoperative adverse effects should be followed up and reported. Randomised controlled trials should be carefully reported and detailed for quality evaluation. Details on methods of randomisation, allocation concealment, and blinding should be clearly reported.

What's new

Date	Event	Description
15 August 2021	New citation required and conclusions have changed	We identified no new studies.
15 June 2021	New search has been performed	We updated the review. We identified no new studies. We moved all previously included studies with unclear methodology to studies awaiting classification.

History

Protocol first published: Issue 7, 2010
Review first published: Issue 7, 2019

Date	Event	Description
30 July 2020	Amended	We amended the review. We moved two initially included studies to studies awaiting classification whilst we await further information (Badawy 2009; Kandil 2018). We amended the following parts of the review accordingly. Abstract Plain language summary Results Discussion Authors' conclusions PRISMA flow diagram
17 September 2010	Amended	Minor edits made.

Appendices

Appendix 1. Cochrane Gynaecology and Fertility Group (CGF) Specialised Register search strategy

ProCite platform

Searched 21 December 2020

Keywords CONTAINS "polycystic ovary syndrome" or "polycystic ovary morphology" or "PCOS" or Title CONTAINS "polycystic ovary syndrome" or "polycystic ovary morphology" or "PCOS"

AND

 Keywords CONTAINS "ovarian drilling" or "needle insertion" or "transvaginal" or "transvaginal ultrasound" or Title CONTAINS "ovarian drilling" or "needle insertion" or "transvaginal" or "transvaginal ultrasound"

(110 records)

Appendix 2. CENTRAL via the Cochrane Register of Studies Online (CRSO) search strategy

Web platform

Searched 21 December 2020

#1    MESH DESCRIPTOR Polycystic Ovary Syndrome EXPLODE ALL TREES    1505
#2    (polycystic adj5 ovar*):TI,AB,KY    3666
#3    (PCOS or PCO or PCOD):TI,AB,KY    3607
#4    (stein‐leventhal or leventhal):TI,AB,KY    63
#5    #1 OR #2 OR #3 OR #4    4607
#6    MESH DESCRIPTOR Ultrasonography, Interventional EXPLODE ALL TREES    1960
#7    (ultrasound guided):TI,AB,KY    6501
#8    (needle drill*):TI,AB,KY    6
#9    UTND:TI,AB,KY    2
#10    (ovar* adj2 drill*):TI,AB,KY    110
#11    (follicl* adj2 puncture*):TI,AB,KY    20
#12    (follicl* adj2 drill):TI,AB,KY    0
#13    (follicl* adj2 aspirat*):TI,AB,KY    79
#14    (transvagina* adj2 ovar*):TI,AB,KY    27
#15    (punctur* adj2 ovar*):TI,AB,KY    10
#16    #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15    7671
#17    #5 AND #16    127

Appendix 3. MEDLINE search strategy

Ovid platform

Searched from 1946 to 21 December 2020

1     exp Polycystic Ovary Syndrome/ (14721)
2     (polycystic adj5 ovar$).tw. (17367)
3     (PCOS or PCO).tw. (16057)
4     PCOD.tw. (296)
5     (stein‐leventhal or leventhal).tw. (730)
6     PCOM.tw. (266)
7     or/1‐6 (24340)
8     exp Ultrasonography, Interventional/ (26022)
9     ultrasound guided.tw. (23682)
10     needle drill*.tw. (11)
11     UTND.tw. (7)
12     (follicl$ adj2 puncture*).tw. (179)
13     (follicl$ adj2 drill$).tw. (1)
14     (ovar$ adj2 drill$).tw. (276)
15     (follicl$ adj2 aspirat$).tw. (741)
16     (transvagina$ adj2 ovar*).tw. (142)
17     or/8‐16 (43103)
18     randomized controlled trial.pt. (519221)
19     controlled clinical trial.pt. (93971)
20     randomized.ab. (503677)
21     randomised.ab. (100621)
22     placebo.tw. (219642)
23     clinical trials as topic.sh. (193978)
24     randomly.ab. (347562)
25     trial.ti. (231540)
26     (crossover or cross‐over or cross over).tw. (87339)
27     or/18‐26 (1403882)
28     exp animals/ not humans.sh. (4767460)
29     27 not 28 (1293289)
30     7 and 17 and 29 (80)

Appendix 4. Embase search strategy

Ovid platform

Searched from 1980 to 21 December 2020

1     exp ovary polycystic disease/ (27795)
2     (polycystic adj5 ovar$).tw. (24113)
3     (PCOS or PCO).tw. (21722)
4     (stein‐leventhal or leventhal).tw. (319)
5     PCOD.tw. (414)
6     or/1‐5 (35301)
7     exp ultrasound therapy/ (16694)
8     ultrasound guided.tw. (38026)
9     needle drill$.tw. (7)
10     UTND.tw. (8)
11     (follicl$ adj2 puncture$).tw. (223)
12     (follicl$ adj2 drill$).tw. (1)
13     (ovar$ adj2 drill$).tw. (477)
14     (follicl$ adj2 aspirat$).tw. (1020)
15     (transvagina$ adj2 ovar*).tw. (196)
16     or/7‐15 (55887)
17     6 and 16 (580)
18     Clinical Trial/ (985037)
19     Randomized Controlled Trial/ (632469)
20     exp randomization/ (89465)
21     Single Blind Procedure/ (41215)
22     Double Blind Procedure/ (176426)
23     Crossover Procedure/ (65338)
24     Placebo/ (346455)
25     Randomi?ed controlled trial$.tw. (245455)
26     Rct.tw. (39829)
27     random allocation.tw. (2115)
28     randomly.tw. (458927)
29     randomly allocated.tw. (36975)
30     allocated randomly.tw. (2609)
31     (allocated adj2 random).tw. (832)
32     Single blind$.tw. (25836)
33     Double blind$.tw. (208858)
34     ((treble or triple) adj blind$).tw. (1248)
35     placebo$.tw. (312836)
36     prospective study/ (647719)
37     or/18‐36 (2532402)
38     case study/ (74356)
39     case report.tw. (422256)
40     abstract report/ or letter/ (1134161)
41     or/38‐40 (1619490)
42     37 not 41 (2476404)
43     (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) (6124757)
44     42 not 43 (2306055)
45     17 and 44 (191)

Appendix 5. CNKI search strategy

Web platform

Searched 21 March 2021

1) polycystic ovary syndrome

2) polycystic ovary

3) Polycystic Ovary Disease

4) or/1‐3

5) follicle puncture

6) follicle drilling

7) follicle aspiration

8) or/5‐7

9) random*

10) 4 and 8 and 9

49 hits

The same search strategy were used in the VIP database (5 hits), Chinese Medical Association (CMA) Digital Periodicals of Wanfang database (2 hits).

Appendix 6. Criteria for judging risk of bias in the risk of bias assessment tool

• Random sequence generation (possible selection bias; biased allocation to the intervention due to inadequate generation of a randomised sequence). Criteria included:

• low risk of bias (e.g. random number table; computer random number generator);

• high risk of bias (e.g. quasi‐randomised); such studies would have been excluded from the current review;

• unclear risk of bias (e.g. studies providing insufficient information or not describing the methods used for randomisation).

• Allocation concealment (possible selection bias; biased allocation to interventions due to inadequate concealment of allocations before assignment). Criteria included:

• low risk of bias (e.g. sequentially numbered, sealed, opaque envelopes, telephone, or central randomisation);

• high risk of bias (e.g. open allocation, unsealed envelopes, date of birth, medical record number);

• unclear risk of bias (e.g. no description of how allocation was concealed, insufficient information provided).

• Blinding of participants and personnel (possible performance bias due to knowledge of the allocated interventions by participants and personnel during the study) and blinding of outcome assessors (possible detection bias due to knowledge of the allocated interventions by outcome assessors). We will assess studies as at low risk of bias if they are blinded, or if we judge that lack of blinding would have been unlikely to have affected the study results. Lack of blinding of outcome assessors is unlikely to introduce performance or detection bias with objective outcomes such as live birth, pregnancy, miscarriage, and multiple pregnancy; however, lack of blinding may influence subjective outcomes such as abdominal pain and menstruation resume. Criteria for participants and personnel included:

• low risk of bias, if study authors reported no blinding of personnel or outcome assessment, and the review authors judged that the outcome was unlikely to have been affected by lack of blinding; or if the study was blinded, and it was unlikely that the blinding could have been broken;

• high risk of bias, if study authors reported no blinding, and the outcome was likely to have been influenced by lack of blinding, or if  blinding was likely to have been broken;

• unclear risk of bias, if study authors provided insufficient information, or if the study did not address this outcome.

• Incomplete outcome data (possible attrition bias due to the quantity, nature, and handling of incomplete outcome data). Criteria included:

• low risk of bias (e.g. no missing outcome data, missing outcome data balanced across groups, missing data imputed by appropriate methods);

• high risk of bias (e.g. the reason for missing outcome data was likely to be related to the true outcome with either an imbalance in numbers or reasons for missing data across intervention groups; 'as treated' analysis was done with substantial departure of the intervention received from that assigned at randomisation);

• unclear risk of bias (e.g. insufficient reporting of attrition to permit judgement of low or high risk, no reasons given for missing data).

• Selective reporting (possible reporting bias). We will attempt to find protocols of the included studies and to compare outcomes between the protocol and the final published study to assess within‐trial selective reporting. Criteria included:

• low risk of bias, when it was clear that all of the study's prespecified outcomes and all expected outcomes of interest to the review were reported, and evidence suggested that the trial was registered;

• high risk of bias, when not all of the study's prespecified outcomes were reported, one or more reported primary outcomes were not prespecified, or outcomes of interest were reported incompletely and so could not be entered into a meta‐analysis; or when the study failed to report the results of a key outcome that would have been expected to have been reported;

• unclear risk of bias, when insufficient information was available to permit a judgement of high or low risk.

• Other bias (possible bias due to problems not previously described). Criteria included:

• low risk of bias, when the study appeared free of any other source of bias;

• high risk of bias, when a specific study design was used or when a study was fraudulent;

• unclear risk of bias, when the study authors provided insufficient information.

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
An 2007	Participants were women with PCOS, but without clomiphene‐resistance.
Bao 2011	Non‐randomised controlled trial (case‐control study)
Branigan 2006	Treatments were different methods of UTND (punctured all visible follicles vs punctured follicles containing oocytes).
Chen 2005	Treatments were UTND with or without hMG stimulation before the procedure.
Chen 2008	Participants were women with PCOS, but without clomiphene‐resistance.
Chen 2010	Non‐randomised controlled trial
Dai 2013	Participants were women with both clomiphene‐ and gonadotropin‐resistant PCOS.
De Geyter 1996	Non‐randomised controlled trial of UTND
Deng 2015	Participants were women with PCOS, but without clomiphene‐resistance. Treatments were UTND with or without Chinese herbal medicine.
Gao 2008	Participants were women with PCOS, but without clomiphene‐resistance.
He 2014	Participants were women with PCOS, but without clomiphene‐resistance.
Hu 2011	Participants were women with PCOS, but without clomiphene‐resistance.
Hu 2013	Non‐randomised controlled trial. Participants were women with PCOS, but without clomiphene‐resistance.
Li 2002	Non‐randomised controlled trial. Participants were women with PCOS, but without clomiphene‐resistance.
Li 2007	Participants were women with both clomiphene‐ and gonadotropin‐resistant PCOS.
Liang 2008	Treatments were UTND combined with Chinese herbal medicine combined with medical ovulation induction vs UTND combined with medical ovulation induction.
Liao 2012	Treatments were UTND with or without clomiphene ovulation induction before the procedure.
Liu 2010	Treatments were UTND combined with clomiphene, with or without ethinyloestradiol 35 μg and cyproterone acetate 2 mg (Diane‐35) and metformin.
Liu 2011	Participants were women with PCOS, but without clomiphene‐resistance.
Liu 2012	Treatments were hMG stimulation before UTND vs no hMG stimulation before UTND.
Liu 2014	Participants were women with PCOS, but without clomiphene‐resistance.
Liu 2015	Treatments were UTND combined with medical ovulation induction, with or without acupuncture.
Liu 2016	Participants were women with PCOS, but without clomiphene‐resistance. Treatments were UTND vs ethinyloestradiol 35 μg and cyproterone acetate 2 mg (Diane‐35).
Qi 2016	Participants were women with PCOS, but without clomiphene‐resistance.
Shen 2011	Participants were women with PCOS, but without clomiphene‐resistance. Treatments were different follicular puncture timings of UTND.
Wang 2004	Intrauterine injection was applied only in the UTND group.
Wang 2010	Participants were women with PCOS, but without clomiphene‐resistance. Treatments were different puncture timings of UTND combined with medical ovulation induction.
Wang 2012	Treatments were ovarian coagulation drilling guided by transvaginal ultrasound or laparoscopy.
Wang 2015	Participants were women with PCOS, but without clomiphene‐resistance.
Xiao 2011	Clomiphene for ovulation induction was used only in the comparison group.
Xu 2008	Treatments were UTND combined with metformin vs UTND.
Xu 2009	Participants were women with PCOS, but without clomiphene‐resistance.
Xu 2014	Participants were women with PCOS, but without clomiphene‐resistance.
Yi 2017	Participants were women with PCOS, but without clomiphene‐resistance. Treatments were UTND combined with hCG vs ethinyloestradiol 35 μg and cyproterone acetate 2 mg (Diane‐35).
Ying 2017	Non‐randomised controlled trial (case‐control study). Participants were women with both PCOS and OHSS.
Zeng 2012	Ovary puncture was guided by laparoscopy, but not ultrasound.
Zhang 2011	Participants were women with PCOS, but without clomiphene‐resistance. Treatments were UTND combined with Chinese herbal medicine and medical ovulation induction vs UTND combined with medical ovulation induction.
Zhou 2011	Participants were women with PCOS, but without clomiphene‐resistance.
Zhu 2006	Non‐randomised controlled trial (before‐and‐after study)
Zhu 2009	4 treatment groups of different laser doses of transvaginal ultrasound‐guided ovarian interstitial laser coagulation
Zhu 2010	4 treatment groups of different laser doses of transvaginal ultrasound‐guided ovarian interstitial laser coagulation

hMG, human menopausal gonadotropin; OHSS, ovarian hyperstimulation syndrome; PCOS, polycystic ovarian syndrome; UTND, ultrasound‐guided transvaginal ovarian needle drilling.

Characteristics of studies awaiting classification [ordered by study ID]

Atwa 2020.

Methods	Study design: single‐centre 2‐arm randomised controlled trial Study grouping: parallel group
Participants	Women of reproductive age (18 to 40 years) with clomiphene citrate‐resistant PCOS with either primary or secondary infertility
Interventions	Group 1: transvaginal needle ovarian puncture prior to aromatase inhibitors (letrozole 2.5 mg twice daily from day 2 of the cycle and for 5 days) and FSH administered with 75 IU daily from cycle day 3 and maintained for up to the 14th day of the cycle.  Group 2: aromatase inhibitors (letrozole 2.5 mg twice daily from day 2 of the cycle and for 5 days) and FSH administered with 75 IU daily from cycle day 3 and maintained for up to the 14th day of the cycle.
Outcomes	Ovulation rate, pregnancy rate, LH, FSH, testosterone, number and size of the dominant follicles and the percentage of completed cycles with monofollicular development, endometrial thickness, percentage of cancelled cycles
Notes	Clomiphene resistance, meaning that women were previously treated with CC 150 mg daily for 5 days per cycle, for 2 to 3 cycles, with persistent anovulation or ovulation with very thin endometrium < 5 mm at the time of hCG administration. There were inconsistencies in the manuscript, such as incorrect P values in Table 1 and discrepancies between results in Table 3 and the text. We have contacted authors, but have not heard back. Study moved to awaiting classification whilst we await further information.

Badawy 2009.

Methods	Study design: single‐centre 2‐arm randomised controlled trial Study grouping: parallel group
Participants	Women with clomiphene‐resistant PCOS (n = 163) Baseline characteristics: age (18 to 32 years), BMI (28.2 to 29.3 kg/m2), duration of infertility, hormonal profiles, clinical manifestations, and ultrasound findings of PCOS had no significant differences between groups. Inclusion criteria: women with clomiphene‐resistant PCOS (2003 Rotterdam criteria), partner's semen analysis normal, fallopian tubal patency proved by hysterosalpingography, normal serum PRL, TSH, and 17‐OH‐P. Exclusion criteria: none reported. Other outcomes reported in the paper: serum FSH, LH, LH/FSH, and free T levels on day 3 of the next menses after the procedure, resumption of normal menstruation, hirsutism, acne, ovulation, pregnancy, complications of procedure, duration of procedure. Notes: clomiphene resistance was defined as failure to ovulate or ovulation with thin endometrium (< 5 mm) after 2 to 3 cycles of stimulation with clomiphene (100 mg/day, 5 days per cycle).
Interventions	Intervention: UTND (n = 82, using a 16‐gauge, 35‐centimetre long, sharp needle, each ovary punctured from different angles with 3 to 6 punctures with aspiration of all visible small follicles) Control: LOD (n = 81, using a monopolar electrosurgical probe, 3 to 6 punctures for each ovary, 30 watts for 5 seconds for each penetration, 4 mm in diameter, and 5 to 7 mm in depth)
Outcomes	Complication Outcome type: adverse event, intraoperative or postoperative Direction: lower was better Pregnancy Outcome type: dichotomous outcome Note: pregnancy confirmed by the absence of menstruation with positive serum hCG test Ovulation Outcome type: dichotomous outcome Reporting: fully reported Unit of measure: per woman Direction: higher was better Data value: endpoint Note: ovulation was confirmed by the luteal serum progesterone (> 5 ng/mL)
Notes	E‐mailed study author regarding risk of bias and live birth rate, but received no reply. Study moved to awaiting classification whilst we await further information.

Chen 2004.

Methods	Study design: single‐centre 2‐arm randomised controlled trial; no information regarding randomisation method Study grouping: parallel group
Participants	Women with clomiphene‐resistant PCOS (n = 60) Baseline characteristics: age (25 to 35 years), BMI not reported Inclusion criteria: women with clomiphene‐resistant PCOS, infertile > 2 years, partner's semen analysis normal, normal uterine cavity, bilateral fallopian tubal patency identified by hysterosalpingography Exclusion criteria: none reported Other outcomes reported in the paper: serum FSH, LH, A2, and T levels measured on day 2 of the next menses after the procedure. Notes: clomiphene resistance was defined as failure to ovulate after 3 cycles of stimulation with clomiphene 150 mg/day for 5 days per cycle.
Interventions	Intervention: UTND (n = 30, 3rd to 7th days after menstruation, using a 16‐gauge long, sharp needle, each ovary was punctured from different angles and aspirated of all visible small follicles) Control: LOD (n = 30, 3rd to 7th days after menstruation, using a bipolar electrocoagulation, 8 to 15 coagulations per ovary, 2 seconds per coagulation, 4 mA 50 MHz 220 V) Co‐interventions: If ovulation did not occur during the 2 months after procedure, clomiphene or hMG could be used, then hCG (10,000 IU) would be injected when the dominant follicle reached 18 mm.
Outcomes	Pregnancy rate Outcome type: dichotomous outcome Ovulation Outcome type: dichotomous outcome Unit of measure: per woman Direction: higher was better Data value: endpoint Notes: confirmed by ultrasonograph or basal body temperature Miscarriage rate Outcome type: dichotomous outcome Unit of measure: per woman Direction: lower was better
Notes	Baseline comparability between the groups was not reported. No information regarding randomisation or allocation. Lack of telephone number or e‐mail address precluded author contact. Study moved to awaiting classification.

Kandil 2018.

Methods	Study design: single‐centre 2‐arm randomised controlled trial Study grouping: parallel group
Participants	Women with clomiphene‐resistant PCOS (n = 250) Baseline characteristics: no significant difference groups regarding demographic data (mean age 28.3 to 28.8 years, mean BMI 27.9 to 28.1 kg/m2, duration of infertility), basal hormonal profile (AMH, FSH, and LH), ovary volume. Inclusion criteria: women with clomiphene‐resistant PCOS (2003 Rotterdam criteria), partner's semen analysis normal, normal uterine cavity, bilateral tubal patency proved by hysterosalpingography. Exclusion criteria: high basal FSH > 15 mIU/mL, endocrine disorders such as hyperprolactinaemia (PRL > 22 ng/dL), thyroid disorders, Cushing's syndrome or acromegaly, comorbidities such as diabetes mellitus or hypertension, contraindications for laparoscopy, or organic pelvic disease (e.g. myomas, adnexal mass, or endometriosis), partner's semen abnormalities (e.g. severe oligospermia). Other outcomes reported in the paper: AFC and AMH measured at 3 and 6 months if pregnancy did not occur. Notes: clomiphene resistance was defined as failure to ovulate after 3 to 6 cycles of stimulation with clomiphene 150 mg/day for 5 days per cycle.
Interventions	Intervention: UTND (n = 125, using a 16‐gauge, 35‐centimetre long, sharp needle, each ovary punctured from different angles with 3 to 6 punctures with aspiration of all visible small follicles) Control: LOD (n = 125, using a monopolar electrosurgical needle, 5 punctures per ovary, 30 W for 4 seconds per puncture, 600 J for each ovary)
Outcomes	Clinical pregnancy rate Outcome type: dichotomous outcome Notes: confirmed by the absence of menstruation with positive serum hCG test; recorded during 1st to 3rd month and 4th to 6th month after the procedure Ovulation Outcome type: dichotomous outcome Unit of measure: per woman Direction: higher was better Data value: endpoint Notes: serial follow‐up ultrasonography and confirmed by mid‐luteal serum progesterone (> 10 ng/mL)
Notes	E‐mailed author to determine the overall impact of interventions for the whole 6 months and for information on blinding, but received no reply. Calculated sample size and 110 women were required in each group to have 80% power at the 5% significance level. Study moved to awaiting classification whilst we await further information.

Ma 2007.

Methods	Study design: single‐centre 2‐arm randomised controlled trial; no information regarding randomisation method Study grouping: parallel group
Participants	Women with clomiphene‐resistant PCOS (n = 74) Baseline characteristics: aged 22 to 36 years, BMI not reported, duration of infertility 2 to 10 years Inclusion criteria: women with clomiphene‐resistant PCOS (2003 Rotterdam criteria) Exclusion criteria: other endocrinological disease, male infertility, fallopian tubal or uterine cavity abnormality Other outcomes reported in the paper: AFC, usage amount of hMG per cycle, serum FSH, LH, PRL, E2, and T levels measured on day 2 of the next menses after the procedure Notes: clomiphene resistance was defined as failure to ovulate after > 3 cycles of stimulation with clomiphene 150 mg/day for 5 days per cycle
Interventions	Intervention: UTND combined with drug ovulation induction (n = 37) hMG (75 to 150 IU/day, from day 5 of menses), hCG (10,000 IU, injected when the dominant follicle reached 9 to 10 mm), UTND (each ovary was punctured and aspirated all visible small follicles at 36 hours after hCG injection), drug ovulation induction (as the control group, from the next menses after UTND) Control: Drug ovulation induction (n = 37) Drug ovulation induction ≤ 6 cycles (hMG with 75 to 150 IU/day, from day 5 of menses; hCG with 5000 to 10,000 IU when dominant follicles reached 16 to 18 mm) Co‐intervention: Oral contraceptive pill (desogestrel 150 μg + ethinyloestradiol 30 μg; 21 days per cycle in women with oligoamenorrhoea)
Outcomes	Incidence of OHSS Outcome type: adverse effect Direction: lower was better Pregnancy rate Outcome type: dichotomous outcome Unit of measure: per woman Direction: higher was better Data value: endpoint Multiple pregnancy rate Outcome type: adverse effect Direction: lower was better
Notes	Baseline comparability between the groups was not reported. We e‐mailed the study author regarding risk of bias and live birth rate, but the e‐mail was returned undeliverable. No information regarding randomisation or allocation Study moved to awaiting classification whilst we await further information.

Qi 2015.

Methods	Study design: single‐centre 2‐arm randomised controlled trial; no information regarding randomisation method Study grouping: parallel group
Participants	Women with clomiphene‐resistant PCOS (n = 92) Baseline characteristics: aged 22 to 35 years, BMI (without data), duration of infertility 1 to 8 years, no difference between groups Inclusion criteria: women with clomiphene‐resistant PCOS (2003 Rotterdam criteria), partner's semen analysis normal, with unilateral tubal patency at least Exclusion criteria: other organ disease Other outcomes reported in the paper: number of days of hMG stimulation, quantity of hMG units used, number of cycle cancellations Notes: clomiphene resistance was defined as failure to ovulate after > 3 cycles of stimulation with clomiphene 50 to 150 mg per day, 5 days per cycle
Interventions	Intervention: UTND combined with drug ovulation induction (n = 46) UTND (on the 3rd cycle of menses induced by ethinyloestradiol 35 μg and cyproterone acetate 2 mg (Diane‐35), using a 17‐gauge needle, each ovary was punctured from different angles and aspirated of all visible small follicles), drug ovulation induction for 1 cycle being the same as control group Control: Drug ovulation induction (n = 46) hMG injected from day 5 of menses (75 IU, every other day), hCG (10,000 IU) injected when the follicle reached 18 mm, progesterone was used for 15 days after ovulation (100 mg, twice daily), oestradiol valerate would be added if the thickness of endometrium was < 7 mm (2 mg/day, until pregnancy confirmation) Co‐intervention: Pretreated with ethinyloestradiol 35 μg and cyproterone acetate 2 mg (Diane‐35; 1 pill per day, 21 days per cycle, 3 months) and metformin (500 mg, twice daily, 3 months)
Outcomes	Incidence of OHSS Pregnancy rate Ovulation rate Miscarriage rate Multiple pregnancy rate
Notes	Duration of follow‐up not reported. No information regarding randomisation or allocation Lack of e‐mail or telephone number precluded author contact. Study moved to awaiting classification.

17‐OH‐P, 17 hydroxyprogesterone; AFC, antral follicle count; AMH, anti‐müllerian hormone; A₂, androstenedione; BMI, body mass index; CC, clomiphene; E₂, estradiol; FSH, follicle stimulating hormone; hCG, human chorionic gonadotropin; hMG, human menopausal gonadotropin; LOD, laparoscopic ovarian drilling; LH, luteinising hormone; OHSS, ovarian hyperstimulation syndrome; PCOS, polycystic ovarian syndrome; PRL, prolactin; T, testosterone; TSH, thyroid stimulating hormone; UTND, ultrasound‐guided transvaginal ovarian needle drilling;

Differences between protocol and review

We updated the Background section.

We moved the studies with unclear methodology to studies awaiting classification (Characteristics of studies awaiting classification).

We did not search ISI Web of Science Database, Chinese Biomedical Literature Database, PsycINFO, and Virtual Health Library Regional Portal (VHL). We handsearched the conference abstracts from the 2018 and 2020 European Society of Human Reproduction and Embryology (ESHRE).

Linglingli Kong joined the author team.

Contributions of authors

JZ: searched for and assessed studies for eligibility, performed data extraction and analysis, wrote and updated the review.

LT: designed and wrote the protocol, searched for trials.

LK: searched for and assessed studies for eligibility, extracted data, evaluated the quality of trials, updated the review.

TW: provided advice on review methodology.

LX: evaluated the quality of trials and risk of bias, revised the review.

XP: revised the review to conform to the English language.

GL: provided advice on statistical methods.

Sources of support

Internal sources

• West China Second University Hospital, Sichuan University, China

• Chinese Cochrane Center, West China Hospital, Sichuan University, China

External sources

• No sources of support provided

Declarations of interest

JZ: none.

LT: none.

LK: none.

TW: none.

LX: none.

XP: none

GL: none

New search for studies and content updated (conclusions changed)