Ultrastructural cilia defects in multi-ciliated uterine glandular epithelial cells from women with reproductive failure.

In brief: The causes of subfertility and recurrent pregnancy loss are often unclear. This study shows that endometrial gland cilia from women with subfertility have ultrastructural defects. Abstract: Endometrial glands secrete products into the endometrium and are necessary for embryo implantation and successful pregnancy. However, structural and functional abnormalities in endometrial gland cilia from women with reproductive failure remain poorly understood. This was a cross-sectional study where endometrial biopsies were collected at days 19-23 of the menstrual cycle from women with unexplained recurrent pregnancy loss (n = 15), unexplained subfertility (n = 11) or from egg donor control participants (n = 10). Endometrial gland cilia ultrastructure was imaged by transmission electron microscopy and cilia defects assessed by an electron-microscopist from a national primary ciliary dyskinesia diagnostic centre. Endometrial glands were isolated, and the cilia beat frequency recorded by high speed video. Subfertile women have proportionately lower ultrastructurally normal cilia (P < 0.05); higher frequency of absent dynamin arms (P < 0.01) or inner arm defects (P < 0.01) and lower cilia beat frequency (P < 0.05). The mechanisms underlying these obversions have yet to be determined. Recent studies have identified cilia related gene expression changes associated with reproductive failure and this study adds to the growing body of literature revealing structural and functional changes. The observation that cilia defects occurred at a higher frequency in endometrial glands of subfertile women raises the question of its mechanistic role in implantation.

Decrease in peripheral natural killer cell level during early pregnancy predicts live birth among women with unexplained recurrent pregnancy loss: a prospective cohort study.

BACKGROUND: Previous studies have suggested that trophoblast cells inhibit the proliferation of peripheral natural killer cells and that the level of peripheral natural killer cells decrease in the middle and late pregnancy stage among healthy women. The change in peripheral natural killer cell level during early pregnancy and the relationship between the change in peripheral natural killer cell level and pregnancy outcomes among women with unexplained recurrent pregnancy loss have not been sufficiently explored. OBJECTIVE: This study aimed to characterize the level of prepregnancy peripheral natural killer cells in comparison with those in early pregnancy among women with unexplained recurrent pregnancy loss and to determine if the change in the level of peripheral natural killer cells from prepregnancy to early pregnancy can predict pregnancy outcomes. STUDY DESIGN: In this prospective cohort study, 1758 women with recurrent pregnancy loss were recruited between January 2017 and December 2021 among whom 252 women with unexplained recurrent pregnancy loss had prepregnancy and early pregnancy (4-6 weeks gestation) peripheral natural killer cell measurements. These 252 women were divided into 2 groups, namely those with a lower gestational peripheral natural killer cell level (group 1) when compared with prepregnancy levels and those who did not (group 2). The respective outcomes of these groups in terms of live birth and pregnancy loss were comparatively analyzed using chi-square and Student's t tests. Candidate factors that could influence live birth were selected using the Akaike information criterion. The participates were then randomly divided into training and testing groups. A multivariable logistic regression analysis was performed and a nomogram was created to assess the possibility of live birth. The predictive accuracy was determined by the area under the receiver operating characteristic curve and validated by plotting the predicted probabilities and the observed probabilities. A Hosmer-Lemeshow test was used to assess the goodness of fit. RESULTS: When early gestational peripheral natural killer cell levels were compared with prepregnancy peripheral natural killer cell levels, 61.5% (154) of women had a comparatively lower early-gestational peripheral natural killer cell level and 38.9% (98) of women had an increase or no change in the peripheral natural killer cell level. The live birth rate in group 1 was 89.0% (137/154), which was significantly higher than the rate of 49.0% (48/98) in group 2 (P<.001). A decrease in the peripheral natural killer cell level (odds ratio, 1.36; 95% confidence interval, 1.22-1.55; P<.001) and the anti-Muellerian hormone level (odds ratio, 1.41; 95% confidence interval, 1.14-1.81; P=.003) were important predicting factors for a higher live birth rate. Female body mass index (odds ratio, 0.97; 95% confidence interval, 0.82-1.15; P=.763) and parity (odds ratio, 1.61; 95% confidence interval, 0.71-4.12; P=.287) also were predicting factors. Furthermore, the area under the receiver operating characteristic curve of the model to diagnose of live birth was 0.853 with a sensitivity of 81.6% and a specificity of 78.0% using the training data set. And the Hosmer-Lemeshow test showed that the model was a good fit (p=6.068). CONCLUSION: We report a comparative decrease in the peripheral natural killer cell levels in early gestation when compared with prepregnancy cell levels in more than 60% of women with unexplained recurrent pregnancy loss at 4 to 6 weeks of gestation. When compared with prepregnancy peripheral natural killer cell levels, a decrease in the peripheral natural killer cell level during early pregnancy might be a useful predictor of the live birth rate among women with unexplained recurrent pregnancy loss.

Elective freezing of embryos versus fresh embryo transfer in IVF: a multicentre randomized controlled trial in the UK (E-Freeze).

STUDY QUESTION: Does a policy of elective freezing of embryos, followed by frozen embryo transfer result in a higher healthy baby rate, after first embryo transfer, when compared with the current policy of transferring fresh embryos? SUMMARY ANSWER: This study, although limited by sample size, provides no evidence to support the adoption of a routine policy of elective freeze in preference to fresh embryo transfer in order to improve IVF effectiveness in obtaining a healthy baby. WHAT IS KNOWN ALREADY: The policy of freezing all embryos followed by frozen embryo transfer is associated with a higher live birth rate for high responders but a similar/lower live birth after first embryo transfer and cumulative live birth rate for normal responders. Frozen embryo transfer is associated with a lower risk of ovarian hyperstimulation syndrome (OHSS), preterm delivery and low birthweight babies but a higher risk of large babies and pre-eclampsia. There is also uncertainty about long-term outcomes, hence shifting to a policy of elective freezing for all remains controversial given the delay in treatment and extra costs involved in freezing all embryos. STUDY DESIGN, SIZE, DURATION: A pragmatic two-arm parallel randomized controlled trial (E-Freeze) was conducted across 18 clinics in the UK from 2016 to 2019. A total of 619 couples were randomized (309 to elective freeze/310 to fresh). The primary outcome was a healthy baby after first embryo transfer (term, singleton live birth with appropriate weight for gestation); secondary outcomes included OHSS, live birth, clinical pregnancy, pregnancy complications and cost-effectiveness. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples undergoing their first, second or third cycle of IVF/ICSI treatment, with at least three good quality embryos on Day 3 where the female partner was ≥18 and <42 years of age were eligible. Those using donor gametes, undergoing preimplantation genetic testing or planning to freeze all their embryos were excluded. IVF/ICSI treatment was carried out according to local protocols. Women were followed up for pregnancy outcome after first embryo transfer following randomization. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 619 couples randomized, 307 and 309 couples in the elective freeze and fresh transfer arms, respectively, were included in the primary analysis. There was no evidence of a statistically significant difference in outcomes in the elective freeze group compared to the fresh embryo transfer group: healthy baby rate {20.3% (62/307) versus 24.4% (75/309); risk ratio (RR), 95% CI: 0.84, 0.62 to 1.15}; OHSS (3.6% versus 8.1%; RR, 99% CI: 0.44, 0.15 to 1.30); live birth rate (28.3% versus 34.3%; RR, 99% CI 0.83, 0.65 to 1.06); and miscarriage (14.3% versus 12.9%; RR, 99% CI: 1.09, 0.72 to 1.66). Adherence to allocation was poor in the elective freeze group. The elective freeze approach was more costly and was unlikely to be cost-effective in a UK National Health Service context. LIMITATIONS, REASONS FOR CAUTION: We have only reported on first embryo transfer after randomization; data on the cumulative live birth rate requires further follow-up. Planned target sample size was not obtained and the non-adherence to allocation rate was high among couples in the elective freeze arm owing to patient preference for fresh embryo transfer, but an analysis which took non-adherence into account showed similar results. WIDER IMPLICATIONS OF THE FINDINGS: Results from the E-Freeze trial do not lend support to the policy of electively freezing all for everyone, taking both efficacy, safety and costs considerations into account. This method should only be adopted if there is a definite clinical indication. STUDY FUNDING/COMPETING INTEREST(S): NIHR Health Technology Assessment programme (13/115/82). This research was funded by the National Institute for Health Research (NIHR) (NIHR unique award identifier) using UK aid from the UK Government to support global health research. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the UK Department of Health and Social Care. J.L.B., C.C., E.J., P.H., J.J.K., L.L. and G.S. report receipt of funding from NIHR, during the conduct of the study. J.L.B., E.J., P.H., K.S. and L.L. report receipt of funding from NIHR, during the conduct of the study and outside the submitted work. A.M. reports grants from NIHR personal fees from Merck Serono, personal fees for lectures from Merck Serono, Ferring and Cooks outside the submitted work; travel/meeting support from Ferring and Pharmasure and participation in a Ferring advisory board. S.B. reports receipt of royalties and licenses from Cambridge University Press, a board membership role for NHS Grampian and other financial or non-financial interests related to his roles as Editor-in-Chief of Human Reproduction Open and Editor and Contributing Author of Reproductive Medicine for the MRCOG, Cambridge University Press. D.B. reports grants from NIHR, during the conduct of the study; grants from European Commission, grants from Diabetes UK, grants from NIHR, grants from ESHRE, grants from MRC, outside the submitted work. Y.C. reports speaker fees from Merck Serono, and advisory board role for Merck Serono and shares in Complete Fertility. P.H. reports membership of the HTA Commissioning Committee. E.J. reports membership of the NHS England and NIHR Partnership Programme, membership of five Data Monitoring Committees (Chair of two), membership of six Trial Steering Committees (Chair of four), membership of the Northern Ireland Clinical Trials Unit Advisory Group and Chair of the board of Oxford Brain Health Clinical Trials Unit. R.M. reports consulting fees from Gedeon Richter, honorarium from Merck, support fees for attendance at educational events and conferences for Merck, Ferring, Bessins and Gedeon Richter, payments for participation on a Merck Safety or Advisory Board, Chair of the British Fertility Society and payments for an advisory role to the Human Fertilisation and Embryology Authority. G.S. reports travel and accommodation fees for attendance at a health economic advisory board from Merck KGaA, Darmstadt, Germany. N.R.-F. reports shares in Nurture Fertility. Other authors' competing interests: none declared. TRIAL REGISTRATION NUMBER: ISRCTN: 61225414. TRIAL REGISTRATION DATE: 29 December 2015. DATE OF FIRST PATIENT'S ENROLMENT: 16 February 2016.

Follicular flushing during oocyte retrieval in assisted reproductive techniques.

BACKGROUND: Follicular aspiration under transvaginal ultrasound guidance is routinely performed as part of assisted reproductive technology (ART) to retrieve oocytes for in vitro fertilisation (IVF). The process involves aspiration of the follicular fluid followed by the introduction of flush, typically culture media, back into the follicle followed by re-aspiration. However, there is a degree of controversy as to whether this intervention yields a larger number of oocytes and is hence associated with greater potential for pregnancy than aspiration only. OBJECTIVES: To assess the safety and efficacy of follicular flushing as compared with aspiration only performed in women undergoing ART. SEARCH METHODS: We searched the following electronic databases up to 13 July 2021: the Cochrane Gynaecology and Fertility Specialised Register of Controlled Trials, CENTRAL (containing output from two trial registries and CINAHL), MEDLINE, Embase, and PsycINFO. We also searched LILACS, Google Scholar, and Epistemonikos. We reviewed the reference lists of relevant papers and contacted experts in the field to identify further relevant studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared follicular aspiration and flushing with aspiration alone in women undergoing ART using their own gametes. Primary outcomes were live birth rate and miscarriage rate per woman randomised. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies identified by search against the inclusion criteria, extracted data, and assessed risk of bias. A third review author was consulted if required. We contacted study authors as needed. We analysed dichotomous outcomes using Mantel-Haenszel odds ratios (ORs), 95% confidence intervals (CIs), and a fixed-effect model, and we analysed continuous outcomes using mean differences (MDs) between groups presented with 95% CIs. We examined the heterogeneity of studies via the I2 statistic. We assessed the certainty of evidence using the GRADE approach. MAIN RESULTS: We included 15 studies with a total of 1643 women. Fourteen studies reported outcomes per woman randomised, and one study reported outcomes per ovary. No studies were at low risk of bias across all domains; the main limitation was lack of blinding. The certainty of the evidence ranged from moderate to very low, and was downgraded for risk of bias, imprecision, and inconsistency. We are uncertain of the effect of follicular flushing on live birth rate compared to aspiration alone (OR 0.93, 95% CI 0.59 to 1.46; 4 RCTs; n = 467; I2 = 0%; moderate-certainty evidence). This suggests that with a live birth rate of approximately 30% with aspiration alone, the equivalent live birth rate with follicular flushing lies between 20% and 39%.  We are uncertain of the effect of follicular flushing on miscarriage rate compared to aspiration alone (OR 1.98, 95% CI 0.18 to 22.22; 1 RCT; n = 164; low-certainty evidence). This suggests that with a miscarriage rate of approximately 1% with aspiration alone, the equivalent miscarriage rate with follicular flushing lies between 0% and 22%. We are uncertain of the effect of follicular flushing on oocyte yield (MD -0.47 oocytes, 95% CI -0.72 to -0.22; 9 RCTs; n = 1239; I2 = 61%; very low-certainty evidence); total number of embryos (MD -0.10 embryos, 95% CI -0.34 to 0.15; 2 RCTs; n = 160; I2 = 58%; low-certainty evidence); and clinical pregnancy rate (OR 1.12, 95% CI 0.85 to 1.51; 7 RCTs; n = 939; I2 = 46%; low-certainty evidence). The duration of the retrieval process may be longer with flushing (MD 175.44 seconds, 95% CI 152.57 to 198.30; 7 RCTs; n = 785; I2 = 87%; low-certainty evidence). It was not possible to perform a meta-analysis for adverse events, although individual studies reported on outcomes ranging from depression and anxiety to pain and pelvic organ injury. AUTHORS' CONCLUSIONS: The effect of follicular flushing on both live birth and miscarriage rates compared with aspiration alone is uncertain. Although the evidence does not permit any firm conclusions on the impact of follicular flushing on oocyte yield, total number of embryos, number of cryopreserved embryos, or clinical pregnancy rate, it may be that the procedure itself takes longer than aspiration alone. The evidence was insufficient to permit any firm conclusions with respect to adverse events or safety.

Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The anti-progesterone drug mifepristone and the prostaglandin misoprostol can be used to treat missed miscarriage. However, it is unclear whether a combination of mifepristone and misoprostol is more effective than administering misoprostol alone. We investigated whether treatment with mifepristone plus misoprostol would result in a higher rate of completion of missed miscarriage compared with misoprostol alone. METHODS: MifeMiso was a multicentre, double-blind, placebo-controlled, randomised trial in 28 UK hospitals. Women were eligible for enrolment if they were aged 16 years and older, diagnosed with a missed miscarriage by pelvic ultrasound scan in the first 14 weeks of pregnancy, chose to have medical management of miscarriage, and were willing and able to give informed consent. Participants were randomly assigned (1:1) to a single dose of oral mifepristone 200 mg or an oral placebo tablet, both followed by a single dose of vaginal, oral, or sublingual misoprostol 800 µg 2 days later. Randomisation was managed via a secure web-based randomisation program, with minimisation to balance study group assignments according to maternal age (<30 years vs ≥30 years), body-mass index (<35 kg/m2vs ≥35 kg/m2), previous parity (nulliparous women vs parous women), gestational age (<70 days vs ≥70 days), amount of bleeding (Pictorial Blood Assessment Chart score; ≤2 vs ≥3), and randomising centre. Participants, clinicians, pharmacists, trial nurses, and midwives were masked to study group assignment throughout the trial. The primary outcome was failure to spontaneously pass the gestational sac within 7 days after random assignment. Primary analyses were done according to intention-to-treat principles. The trial is registered with the ISRCTN registry, ISRCTN17405024. FINDINGS: Between Oct 3, 2017, and July 22, 2019, 2595 women were identified as being eligible for the MifeMiso trial. 711 women were randomly assigned to receive either mifepristone and misoprostol (357 women) or placebo and misoprostol (354 women). 696 (98%) of 711 women had available data for the primary outcome. 59 (17%) of 348 women in the mifepristone plus misoprostol group did not pass the gestational sac spontaneously within 7 days versus 82 (24%) of 348 women in the placebo plus misoprostol group (risk ratio [RR] 0·73, 95% CI 0·54-0·99; p=0·043). 62 (17%) of 355 women in the mifepristone plus misoprostol group required surgical intervention to complete the miscarriage versus 87 (25%) of 353 women in the placebo plus misoprostol group (0·71, 0·53-0·95; p=0·021). We found no difference in incidence of adverse events between the study groups. INTERPRETATION: Treatment with mifepristone plus misoprostol was more effective than misoprostol alone in the management of missed miscarriage. Women with missed miscarriage should be offered mifepristone pretreatment before misoprostol to increase the chance of successful miscarriage management, while reducing the need for miscarriage surgery. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.

A randomised controlled trial to assess the clinical effectiveness and safety of the endometrial scratch procedure prior to first-time IVF, with or without ICSI.

STUDY QUESTION: What is the clinical-effectiveness and safety of the endometrial scratch (ES) procedure compared to no ES, prior to usual first time in vitro fertilisation (IVF) treatment? SUMMARY ANSWER: ES was safe but did not improve pregnancy outcomes when performed in the mid-luteal phase prior to the first IVF cycle, with or without intracytoplasmic sperm injection (ICSI). WHAT IS KNOWN ALREADY: ES is an 'add-on' treatment that is available to women undergoing a first cycle of IVF, with or without ICSI, despite a lack of evidence to support its use. STUDY DESIGN, SIZE, DURATION: This pragmatic, superiority, open-label, multi-centre, parallel-group randomised controlled trial involving 1048 women assessed the clinical effectiveness and safety of the ES procedure prior to first time IVF, with or without ICSI, between July 2016 and October 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants aged 18-37 years undergoing their first cycle of IVF, with or without ICSI, were recruited from 16 UK fertility clinics and randomised (1:1) by a web-based system with restricted access rights that concealed allocation. Stratified block randomisation was used to allocate participants to TAU or ES in the mid-luteal phase followed by usual IVF with or without ICSI treatment. The primary outcome was live birth after completing 24 weeks gestation within 10.5 months of egg collection. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 1048 women randomised to TAU (n = 525) and ES (n = 523) were available for intention to treat analysis. In the ES group, 453 (86.6%) received the ES procedure. IVF, with or without ICSI, was received in 494 (94.1%) and 497 (95.0%) of ES and TAU participants respectively. Live birth rate was 37.1% (195/525) in the TAU and 38.6% (202/523) in the ES: an unadjusted absolute difference of 1.5% (95% CI -4.4% to 7.4%, P = 0.621). There were no statistical differences in secondary outcomes. Adverse events were comparable across groups. LIMITATIONS, REASONS FOR CAUTION: A sham ES procedure was not undertaken in the control group, however, we do not believe this would have influenced the results as objective fertility outcomes were used. WIDER IMPLICATIONS OF THE FINDINGS: This is the largest trial that is adequately powered to assess the impact of ES on women undergoing their first cycle of IVF. ES was safe, but did not significantly improve pregnancy outcomes when performed in the mid-luteal phase prior to the first IVF or ICSI cycle. We recommend that ES is not undertaken in this population. STUDY FUNDING/COMPETING INTEREST(S): Funded by the National Institute of Health Research. Stephen Walters is an National Institute for Health Research (NIHR) Senior Investigator (2018 to present) and was a member of the following during the project: National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Clinical Trials and Evaluation Committee (2011-2017), NIHR HTA Commissioning Strategy Group (2012 to 2017); NIHR Programme Grants for Applied Research Committee (2020 to present); NIHR Pre doctoral Fellowship Committee (2019 to present). Dr. Martins da Silva reports grants from AstraZeneca, during the conduct of the study; and is Associate editor of Human Reproduction and Editorial Board member of Reproduction and Fertility. Dr. Bhide reports grants from Bart's Charity and grants and non-financial support from Pharmasure Pharmaceuticals outside the submitted work. TRIAL REGISTRATION NUMBER: ISRCTN number: ISRCTN23800982. TRIAL REGISTRATION DATE: 31 May 2016. DATE OF FIRST PATIENT'S ENROLMENT: 04 July 2016.

Smartphone-based lifestyle coaching modifies behaviours in women with subfertility or recurrent miscarriage: a randomized controlled trial.

RESEARCH QUESTION: Is an online lifestyle coaching platform more effective at modifying periconceptional behaviours than standard advice offered by the UK National Health Service (NHS)? DESIGN: Women with subfertility or recurrent miscarriage were recruited to a two-centre randomized controlled trial. They were randomized to either the online lifestyle coaching platform Smarter Pregnancy (intervention) or periconceptional advice provided by NHS websites (control). Participants completed a lifestyle questionnaire at baseline, 6, 12, 18 and 24 weeks, and the results were used to tailor lifestyle coaching in the intervention group. At baseline, 12 and 24 weeks, composite risk scores (CRS) were calculated. A lower CRS corresponds to a healthier lifestyle. RESULTS: Of the 400 women recruited, 262 women were randomized (131 in each arm). At 12 weeks, a reduction in CRS (includes risk score for intake of folic acid, vegetables and fruits, smoking and alcohol) was observed in the intervention versus control arms. After correcting for baseline, the difference in the CRS between intervention and control was -0.47 (95% CI -0.97 to 0.02) at 12 weeks and -0.32 (95% CI -0.82 to 0.15) at 24 weeks. A statistically significant reduction in lifestyle risk scores was found in women with a body mass index (BMI) of 25 kg/m2 or above compared with those with a BMI below 25kg/m2. The odds of being pregnant at 24 weeks was increased in the intervention versus control (OR 2.83, 95% CI 0.35 to 57.76). CONCLUSIONS: The Smarter Pregnancy coaching platform is more effective in delivering lifestyle advice and modulating behaviours to support women with a history of subfertility or recurrent miscarriage than standard online NHS advice.

Clinical adhesion score (CLAS): development of a novel clinical score for adhesion-related complications in abdominal and pelvic surgery.

BACKGROUND: Adhesions are a major cause of long-term postsurgical complications in abdominal and pelvic surgery. Existing adhesion scores primarily measure morphological characteristics of adhesions that do not necessarily correlate with morbidity. The aim of this study was to develop a clinical adhesion score (CLAS) measuring overall clinical morbidity of adhesion-related complications in abdominal and pelvic surgery. METHODS: An international Delphi study was performed to identify relevant score items for adhesion-related complications, including small bowel obstruction, female infertility, chronic abdominal or pelvic pain, and difficulties at reoperation. The CLAS includes clinical outcomes, related to morbidity of adhesions, and weight factors, to correct the outcome scores for the likelihood that symptoms are truly caused by adhesions. In a pilot study, two independent researchers retrospectively scored the CLAS in 51 patients to evaluate inter-observer reliability, by calculating the Intraclass correlation coefficient. During a feasibility assessment, we evaluated whether the CLAS completely covered different clinical scenarios of adhesion-related morbidity. RESULTS: Three Delphi rounds were performed. 43 experts agreed to participate, 38(88%) completed the first round, and 32 (74%) the third round. Consensus was reached on 83.4% of items. Inter-observer reliability for the CLAS was 0.95 (95% CI 0.91-0.97). During feasibility assessment, six items were included. As a result, the CLAS includes 22 outcomes and 23 weight factors. CONCLUSION: The CLAS represents a promising scoring system to measure and monitor the clinical morbidity of adhesion-related complications. Further studies are needed to confirm its utility in clinical practice.

Levonorgestrel-releasing intrauterine device (LNG-IUD) for symptomatic endometriosis following surgery.

BACKGROUND: Endometriosis is a condition characterised by the presence of ectopic deposits of endometrial-like tissue outside the uterus, usually in the pelvis. The impact of laparoscopic treatment on overall pain is uncertain and a significant proportion of women will require further surgery. Therefore, adjuvant medical therapies following surgery, such as the levonorgestrel-releasing intrauterine device (LNG-IUD), have been considered to reduce recurrence of symptoms.  OBJECTIVES: To determine the effectiveness and safety of post-operative LNG-IUD in women with symptomatic endometriosis. SEARCH METHODS: We searched the following databases from inception to January 2021: The Specialised Register of the Cochrane Gynaecology and Fertility Group, CENTRAL (which now includes records from two trial registries), MEDLINE, Embase, PsycINFO, LILACS and Epistemonikos. We handsearched citation lists of relevant publications, review articles, abstracts of scientific meetings and included studies. We contacted experts in the field for information about any additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing women undergoing surgical treatment of endometriosis with uterine preservation who were assigned to LNG-IUD insertion, versus control conditions including expectant management, post-operative insertion of placebo (inert intrauterine device), or other medical treatment such as gonadotrophin-releasing hormone agonist (GnRH-a) drugs. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, and extracted data to allow for an intention-to-treat analysis. For dichotomous data, we calculated the risk ratio (RR) and 95% confidence interval (CI) using the Mantel-Haenszel fixed-effect method. For continuous data, we calculated the mean difference (MD) and 95% CI using the inverse variance fixed-effect method. MAIN RESULTS: Four RCTs were included, with a total of 157 women. Two studies are ongoing. The GRADE certainty of evidence was very low to low. The certainty of evidence was graded down primarily for serious risk of bias and imprecision. LNG-IUD versus expectant management Overall pain: No studies reported on the primary outcome of overall pain. Dysmenorrhoea: We are uncertain whether LNG-IUD improves dysmenorrhoea at 12 months. Data on this outcome were reported on by two RCTs; meta-analysis was not possible (RCT 1: delta of median visual analogue scale (VAS) 81 versus 50, P = 0.006, n = 55; RCT 2: fall in VAS by 50 (35 to 65) versus 30 (25 to 40), P = 0.021, n = 40; low-certainty evidence). Quality of life: We are uncertain whether LNG-IUD improves quality of life at 12 months. One trial demonstrated a change in total quality of life score with postoperative LNG-IUD from baseline (mean 61.2 (standard deviation (SD) 14.8) to 12 months (mean 70.3 (SD 16.2) compared to expectant management (baseline 55.1 (SD 17.0) to 57.0 (SD 33.2) at 12 months) (n = 55, P = 0.014, very low-certainty evidence). Patient satisfaction: Two studies found higher rates of satisfaction with LNG-IUD compared to expectant management; however, combining the studies in meta-analysis was not possible (n = 95, very low-certainty evidence). One study found 75% (15/20) of those given post-operative LNG-IUD were "satisfied" or "very satisfied", compared to 50% (10/20) of those in the expectant management group (RR 1.5, 95% CI 0.90-2.49, 1 RCT, n=40, very low-certainty evidence). The second study found that fewer were "very satisfied" in the expectant management group when compared to LNG, but there were no data to include in a meta-analysis.  Adverse events: One study found a significantly higher proportion of women reporting melasma (n = 55, P = 0.015, very low-certainty evidence) and bloating (n = 55, P = 0.021, very low-certainty evidence) following post-operative LNG-IUD. There were no differences in other reported adverse events, such as weight gain, acne, and headaches.  LNG-IUD versus GnRH-a Overall pain: No studies reported on the primary outcome of overall pain. Chronic pelvic pain: We are uncertain whether LNG-IUD improves chronic pelvic pain at 12 months when compared to GnRH-a (VAS pain scale) (MD -2.0, 95% CI -20.2 to 16.2, 1 RCT, n = 40, very low-certainty evidence). Dysmenorrhoea: We are uncertain whether LNG-IUD improves dysmenorrhoea at six months when compared to GnRH-a (measured as a reduction in VAS pain score) (MD 1.70, 95%.CI -0.14 to 3.54, 1 RCT, n = 18, very low-certainty evidence). Adverse events: One study suggested that vasomotor symptoms were the most common adverse events reported with patients receiving GnRH-a, and irregular bleeding in those receiving LNG-IUD (n = 40, very low-certainty evidence) AUTHORS' CONCLUSIONS: Post-operative LNG-IUD is widely used to reduce endometriosis-related pain and to improve operative outcomes. This review demonstrates that there is no high-quality evidence to support this practice. This review highlights the need for further studies with large sample sizes to assess the effectiveness of post-operative adjuvant hormonal IUD on the core endometriosis outcomes (overall pain, most troublesome symptom, and quality of life).

Surgical interventions for the management of chronic pelvic pain in women.

BACKGROUND: Chronic pelvic pain (CPP) is a common gynaecological condition accounting for 20% of all gynaecological referrals. There are wide ranges of causes with overlapping symptomatology, therefore the management of the condition is a formidable challenge for clinicians. The aetiology of CPP is heterogeneous and in many cases, no clear diagnosis can be reached. It is in this scenario that the label of chronic pelvic pain syndrome (CPPS) can be applied. We defined women with CPPS as having a minimum duration of pain of at least 6 months, including with a diagnosis of pelvic congestion syndrome, but excluding pain caused by a condition such as endometriosis. Many surgical interventions have been tried in isolation or in conjunction with non-surgical interventions in the management with variable results. Surgical interventions are invasive and carry operative risks. Surgical interventions must be evaluated for their effectiveness prior to their prevalent use in the management of women with CPPS. OBJECTIVES: To review the effectiveness and safety of surgical interventions in the management of women with CPPS. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group (CGF) Specialised Register of Controlled Trials, CENTRAL, MEDLINE, Embase and PsycINFO, on 23 April 2021 for any randomised controlled trials (RCT) for surgical interventions in women with CPPS. We also searched the citation lists of relevant publications, two trial registries, relevant journals, abstracts, conference proceedings and several key grey literature sources. SELECTION CRITERIA: RCTs with women who had CPPS. The review authors were prepared to consider studies of any surgical intervention used for the management of CPPS. Outcome measures were pain rating scales, adverse events, psychological outcomes, quality of life (QoL) measures and requirement for analgesia. DATA COLLECTION AND ANALYSIS: Two review authors independently evaluated studies for inclusion and extracted data using the forms designed according to Cochrane guidelines. For each included trial, we collected information regarding the method of randomisation, allocation concealment, blinding, data reporting and analyses. We reported pooled results as mean difference (MDs) or odds ratios (OR) and 95% confidence interval (CI) by the Mantel-Haenszel method. If similar outcomes were reported on different scales, we calculated the standardised mean difference (SMD). We applied GRADE criteria to judge the overall certainty of the evidence. MAIN RESULTS: Four studies met our inclusion criteria involving 216 women with CPP and no identifiable cause. Adhesiolysis compared to no surgery or diagnostic laparoscopy We are uncertain of the effect of adhesiolysis on pelvic pain scores postoperatively at three months (MD -7.3, 95% CI -29.9 to 15.3; 1 study, 43 participants; low-certainty evidence), six months (MD -14.3, 95% CI -35.9 to 7.3; 1 study, 43 participants; low-certainty evidence) and 12 months postsurgery (MD 0.00, 95% CI -4.60; 1 study, 43 participants; very low-certainty evidence). Adhesiolysis may improve both the emotional wellbeing (MD 24.90, 95% CI 7.92 to 41.88; 1 study, 43 participants; low-certainty evidence) and social support (MD 23.90, 95% CI -1.77 to 49.57; 1 study, 43 participants; low-certainty evidence) components of the Endometriosis Health Profile-30, and both the emotional component (MD 32.30, 95% CI 13.16 to 51.44; 1 study, 43 participants; low-certainty evidence) and the physical component of the 12-item Short Form (MD 22.90, 95% CI 10.97 to 34.83; 1 study, 43 participants; low-certainty evidence) when compared to diagnostic laparoscopy. We are uncertain of the safety of adhesiolysis compared to comparator groups due to low-certainty evidence and lack of structured adverse event reporting. No studies reported on psychological outcomes or requirements for analgesia. Laparoscopic uterosacral ligament ablation or resection compared to diagnostic laparoscopy/other treatment We are uncertain of the effect of laparoscopic uterosacral ligament/nerve ablation (LUNA) or resection compared to other treatments postoperatively at three months (OR 1.26, 95% CI 0.40 to 3.93; 1 study, 51 participants; low-certainty evidence) and six months (MD -2.10, 95% CI -4.38 to 0.18; 1 study, 74 participants; very low-certainty evidence). At 12 months post-surgery, we are uncertain of the effect of LUNA on the rate of successful treatment compared to diagnostic laparoscopy. One study of 56 participants found no difference in the effect of LUNA on non-cyclical pain (P = 0.854) or dyspareunia (P = 0.41); however, there was a difference favouring LUNA on dysmenorrhea (P = 0.045) and dyschezia (P = 0.05). We are also uncertain of the effect of LUNA compared to vaginal uterosacral ligament resection on pelvic pain at 12 months (MD 2.00, 95% CI 0.47 to 3.53; 1 study, 74 participants; very low-certainty evidence). We are uncertain of the safety of LUNA or resection compared to comparator groups due to the lack of structured adverse event reporting. Women undergoing LUNA may require more analgesia postoperatively than those undergoing other treatments (P < 0.001; 1 study, 74 participants). No studies reported psychological outcomes or QoL. AUTHORS' CONCLUSIONS: We are uncertain about the benefit of adhesiolysis or LUNA in management of pain in women with CPPS based on the current literature. There may be a QoL benefit to adhesiolysis in improving both emotional wellbeing and social support, as measured by the validated QoL tools. It was not possible to synthesis evidence on adverse events as these were only reported narratively in some studies, in which none were observed. With the inadequate objective assessment of adverse events, especially long-term adverse events, associated with adhesiolysis or LUNA for CPPS, there is currently little to support these interventions for CPPS.

Is sleep deficit associated with infertility and recurrent pregnancy losses? Results from a prospective cohort study.

INTRODUCTION: Biological rhythms, the innate cycle of changes in the body's physiological functions, are circadian if they have a 24-hour period. It is known that sleep is a key feature of human circadian rhythm but the relation between sleep and female fertility is largely unknown. This paucity of research is surprising given that circadian rhythms are paramount to human physiology and sleep is related to major female reproductive events. This study was designed to investigate whether there is a difference between the sleep and activity parameters of women with poor reproductive outcome compared with healthy, fertile parous women (comparator group) using subjective (questionnaires) and objective (actigraphy and light exposure) measures. MATERIAL AND METHODS: A prospective cohort study in a tertiary in vitro fertilization referral center in the UK; composed of three study groups: women diagnosed with recurrent implantation failure, women with recurrent miscarriage (RM) and a comparison group (fertile women without endometrial pathology). Comparison women were selected gynecology patients without endometrial disease (ie perineal complaints or altruistic egg donors). Primary outcome was differences in objective length of sleep in each of the participant groups using actigraphy. Secondary outcomes were subjective sleep quality and quantity, using participant questionnaires, light exposure, and the feasibility of machine learning in activity-pattern interpretation. RESULTS: Women with recurrent implantation failure slept daily on average for 7 hours 35 minutes (± 57 min), 53 minutes less than the comparison group (P = .03), although quality of their objective sleep, and quantity of their subjective sleep, were not significantly different. Women with recurrent miscarriage slept less that the comparison women (36 minutes less/night) but more than women with recurrent implantation failure (17 minutes more/night). No difference in light exposure was found between recurrent miscarriage and the recurrent implantation failure and comparison groups. CONCLUSIONS: This study demonstrates an objective observation of sleep time reduction in women with subfertility, although it is not yet clear if this association is casual. Given our increased understanding of the internal body clock and circadian rhythm on fertility, our observation warrants further investigation.

Effective support following recurrent pregnancy loss: a randomized controlled feasibility and acceptability study.

RESEARCH QUESTION: Is it feasible to perform a future definitive trial to determine the effectiveness of the positive reappraisal coping intervention (PRCI) in improving the psychological well-being of women with recurrent pregnancy loss (RPL) during the early stages of a new pregnancy? DESIGN: This mixed method study aimed to establish the feasibility of conducting a multicentre randomized controlled trial (RCT) to definitively test the effects of the PRCI on the psychological well-being of women with RPL. Participants (n = 75) were recruited to the study and at the point of a positive pregnancy test, 47 were randomized into two study groups. The intervention group received the PRCI and weekly questionnaire assessment (Hospital Anxiety and Depression Scale and Weekly Record Keeping Form [WRK]) to monitor psychological well-being; the control group received the same questionnaires. Nested within the RCT was a qualitative process evaluation (QPE) exploring participants' subjective experience of study methods and the intervention. The study was conducted over a two-year period between 2014 and 2016. RESULTS: This study successfully gathered knowledge about the feasibility aspects of conducting a future multicentre definitive study to determine the effects of the PRCI on the psychological well-being of women with RPL. Participants were receptive to its use and the intervention appeared to convey benefits with no apparent downside. CONCLUSIONS: The study concluded that a definitive RCT of the PRCI is possible and that the model of care already has the potential to be made more widely available as a safe, low-cost, convenient and easily deliverable intervention to provide much-needed support to a vulnerable patient population.

Surgical treatment of fibroids for subfertility.

BACKGROUND: Fibroids are the most common benign tumours of the female genital tract and are associated with numerous clinical problems including a possible negative impact on fertility. In women requesting preservation of fertility, fibroids can be surgically removed (myomectomy) by laparotomy, laparoscopically or hysteroscopically depending on the size, site and type of fibroid. Myomectomy is however a procedure that is not without risk and can result in serious complications. It is therefore essential to determine whether such a procedure can result in an improvement in fertility and, if so, to then determine the ideal surgical approach. OBJECTIVES: To examine the effect of myomectomy on fertility outcomes and to compare different surgical approaches. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group (CGFG) Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, Epistemonikos database, World Health Organization (WHO) International Clinical Trials Registry Platform search portal, Database of Abstracts of Reviews of Effects (DARE), LILACS, conference abstracts on the ISI Web of Knowledge, OpenSigle for grey literature from Europe, and reference list of relevant papers. The final search was in February 2019. SELECTION CRITERIA: Randomised controlled trials (RCTs) examining the effect of myomectomy compared to no intervention or where different surgical approaches are compared regarding the effect on fertility outcomes in a group of infertile women suffering from uterine fibroids. DATA COLLECTION AND ANALYSIS: Data collection and analysis were conducted in accordance with the procedure suggested in the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: This review included four RCTs with 442 participants. The evidence was very low-quality with the main limitations being due to serious imprecision, inconsistency and indirectness. Myomectomy versus no intervention One study examined the effect of myomectomy compared to no intervention on reproductive outcomes. We are uncertain whether myomectomy improves clinical pregnancy rate for intramural (odds ratio (OR) 1.88, 95% confidence interval (CI) 0.57 to 6.14; 45 participants; one study; very low-quality evidence), submucous (OR 2.04, 95% CI 0.62 to 6.66; 52 participants; one study; very low-quality evidence), intramural/subserous (OR 2.00, 95% CI 0.40 to 10.09; 31 participants; one study; very low-quality evidence) or intramural/submucous fibroids (OR 3.24, 95% CI 0.72 to 14.57; 42 participants; one study; very low-quality evidence). Similarly, we are uncertain whether myomectomy reduces miscarriage rate for intramural fibroids (OR 1.33, 95% CI 0.26 to 6.78; 45 participants; one study; very low-quality evidence), submucous fibroids (OR 1.27, 95% CI 0.27 to 5.97; 52 participants; one study; very low-quality evidence), intramural/subserous fibroids (OR 0.80, 95% CI 0.10 to 6.54; 31 participants; one study; very low-quality evidence) or intramural/submucous fibroids (OR 2.00, 95% CI 0.32 to 12.33; 42 participants; one study; very low-quality evidence). This study did not report on live birth, preterm delivery, ongoing pregnancy or caesarean section rate. Laparoscopic myomectomy versus myomectomy by laparotomy or mini-laparotomy Two studies compared laparoscopic myomectomy to myomectomy at laparotomy or mini-laparotomy. We are uncertain whether laparoscopic myomectomy compared to laparotomy or mini-laparotomy improves live birth rate (OR 0.80, 95% CI 0.42 to 1.50; 177 participants; two studies; I2 = 0%; very low-quality evidence), preterm delivery rate (OR 0.70, 95% CI 0.11 to 4.29; participants = 177; two studies; I2 = 0%, very low-quality evidence), clinical pregnancy rate (OR 0.96, 95% CI 0.52 to 1.78; 177 participants; two studies; I2 = 0%, very low-quality evidence), ongoing pregnancy rate (OR 1.61, 95% CI 0.26 to 10.04; 115 participants; one study; very low-quality evidence), miscarriage rate (OR 1.25, 95% CI 0.40 to 3.89; participants = 177; two studies; I2 = 0%, very low-quality evidence), or caesarean section rate (OR 0.69, 95% CI 0.34 to 1.39; participants = 177; two studies; I2 = 21%, very low-quality evidence). Monopolar resectoscope versus bipolar resectoscope One study evaluated the use of two electrosurgical systems during hysteroscopic myomectomy. We are uncertain whether bipolar resectoscope use compared to monopolar resectoscope use improves live birth/ongoing pregnancy rate (OR 0.86, 95% CI 0.30 to 2.50; 68 participants; one study, very low-quality evidence), clinical pregnancy rate (OR 0.88, 95% CI 0.33 to 2.36; 68 participants; one study; very low-quality evidence), or miscarriage rate (OR 1.00, 95% CI 0.19 to 5.34; participants = 68; one study; very low-quality evidence). This study did not report on preterm delivery or caesarean section rate. AUTHORS' CONCLUSIONS: There is limited evidence to determine the role of myomectomy for infertility in women with fibroids as only one trial compared myomectomy with no myomectomy. If the decision is made to have a myomectomy, the current evidence does not indicate a superior method (laparoscopy, laparotomy or different electrosurgical systems) to improve rates of live birth, preterm delivery, clinical pregnancy, ongoing pregnancy, miscarriage, or caesarean section. Furthermore, the existing evidence needs to be viewed with caution due to the small number of events, minimal number of studies and very low-quality evidence.

Genetic diagnosis of subfertility: the impact of meiosis and maternal effects.

During reproductive age, approximately one in seven couples are confronted with fertility problems. While the aetiology is diverse, including infections, metabolic diseases, hormonal imbalances and iatrogenic effects, it is becoming increasingly clear that genetic factors have a significant contribution. Due to the complex nature of infertility that often hints at a multifactorial cause, the search for potentially causal gene mutations in idiopathic infertile couples has remained difficult. Idiopathic infertility patients with a suspicion of an underlying genetic cause can be expected to have mutations in genes that do not readily affect general health but are only essential in certain processes connected to fertility. In this review, we specifically focus on genes involved in meiosis and maternal-effect processes, which are of critical importance for reproduction and initial embryonic development. We give an overview of genes that have already been linked to infertility in human, as well as good candidates which have been described in other organisms. Finally, we propose a phenotypic range in which we expect an optimal diagnostic yield of a meiotic/maternal-effect gene panel.

A Randomized Trial of Progesterone in Women with Recurrent Miscarriages.

BACKGROUND: Progesterone is essential for the maintenance of pregnancy. However, whether progesterone supplementation in the first trimester of pregnancy would increase the rate of live births among women with a history of unexplained recurrent miscarriages is uncertain. METHODS: We conducted a multicenter, double-blind, placebo-controlled, randomized trial to investigate whether treatment with progesterone would increase the rates of live births and newborn survival among women with unexplained recurrent miscarriage. We randomly assigned women with recurrent miscarriages to receive twice-daily vaginal suppositories containing either 400 mg of micronized progesterone or matched placebo from a time soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) through 12 weeks of gestation. The primary outcome was live birth after 24 weeks of gestation. RESULTS: A total of 1568 women were assessed for eligibility, and 836 of these women who conceived naturally within 1 year and remained willing to participate in the trial were randomly assigned to receive either progesterone (404 women) or placebo (432 women). The follow-up rate for the primary outcome was 98.8% (826 of 836 women). In an intention-to-treat analysis, the rate of live births was 65.8% (262 of 398 women) in the progesterone group and 63.3% (271 of 428 women) in the placebo group (relative rate, 1.04; 95% confidence interval [CI], 0.94 to 1.15; rate difference, 2.5 percentage points; 95% CI, -4.0 to 9.0). There were no significant between-group differences in the rate of adverse events. CONCLUSIONS: Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with a history of unexplained recurrent miscarriages. (Funded by the United Kingdom National Institute of Health Research; PROMISE Current Controlled Trials number, ISRCTN92644181.).

A randomised controlled trial of a personalised lifestyle coaching application in modifying periconceptional behaviours in women suffering from reproductive failures (iPLAN trial).

BACKGROUND: Lifestyle, in particular obesity and smoking has significant impacts on fertility and an important focus for the treatment of reproductive failures is the optimisation of periconceptional lifestyle behaviours. The preimplantation intrauterine environment within the uterus is also key for embryo development and early programming. Although the benefits a healthy periconceptional lifestyle are well described, there remains a paucity of data demonstrating the efficacy of interventions designed to optimise preconceptional lifestyle behaviours and choices. METHODS: This study is a prospective randomised controlled trial which aims to address the question of whether an online personalised lifestyle coaching application is an effective means of delivering periconceptional advice in women suffering from reproductive failures. Women suffering from subfertility or recurrent miscarriages attending the outpatient clinic will be randomised into either the intervention arm (personalised online lifestyle coaching application) or the control arm (standard periconceptional advice including information from NHS websites). Both groups will be asked to complete a validated lifestyle questionnaire at baseline, and 6, 12, 18 and 24 weeks after randomisation. The primary outcome is the composite dietary and lifestyle risk score at 12 weeks. The secondary outcomes will include compliance with the program, proportion achieving spontaneous conception during the study period and the dietary and lifestyle risk score at 24 weeks. DISCUSSION: With this study, we aim to clarify whether a personalised online based lifestyle coaching application is more effective at improving behaviours than standard advice offered by National Health Service (NHS) resources. A personalised lifestyle coaching application may represent an empowering and cost effective means of delivering periconceptional advice in women with subfertility or recurrent miscarriages. TRIAL REGISTRATION: The iPLAN trial was retrospectively registered ( ISRCTN 89523555 ).

Are pelvic adhesions associated with pain, physical, emotional and functional characteristics of women presenting with chronic pelvic pain? A cluster analysis.

BACKGROUND: Chronic pelvic pain is a debilitating condition. It is unknown if there is a clinical phenotype for adhesive disorders. This study aimed to determine if the presence or absence, nature, severity and extent of adhesions correlated with demographic and patient reported clinical characteristics of women presenting with CPP. METHODS: Women undergoing a laparoscopy for the investigation of chronic pelvic pain were recruited prospectively; their pain and phenotypic characteristics were entered into a hierarchical cluster analysis. The groups with differing baseline clinical and operative characteristics in terms of adhesions involvement were analyzed. RESULTS: Sixty two women were recruited where 37 had adhesions. A low correlation was found between women's reported current pain scores and that of most severe (r = 0.34) or average pain experienced (r = 0.44) in the last 6 months. Three main groups of women with CPP were identified: Cluster 1 (n = 35) had moderate severity of pain, with poor average and present pain intensity; Cluster 2 (n = 14) had a long duration of symptoms/diagnosis, the worst current pain and worst physical, emotional and social functions; Cluster 3 (n = 11) had the shortest duration of pain and showed the best evidence of coping with low (good) physical, social and emotional scores. This cluster also had the highest proportion of women with adhesions (82%) compared to 51% in Cluster 1 and 71% in Cluster 2. CONCLUSIONS: In this study, we found that there is little or no correlation between patient-reported pain, physical, emotional and functional characteristics scores with the presence or absence of intra-abdominal/pelvic adhesions found during investigative laparoscopy. Most women who had adhesions had the lowest reported current pain scores.

Abnormal uterine bleeding.

Introduction: It is not uncommon for a woman to suffer from abnormal uterine bleeding (AUB) or heavy menstrual bleeding (HMB) at some point during her lifetime. Once pathology is excluded, in practice, management needs to be individualised, taking into account the improvement of the woman's symptoms and quality of life. Sources of data: Peer-reviewed journals, governmental and professional society publications. Areas of agreement: There is now agreement on a structured, universal approach to the diagnosis of AUB, with the aide memoirs PALM (polyps, adenomyosis, leiomyoma, malignancy) and COEIN (coagulopathies, ovulatory dysfunction, endometrial, iatrogenic, not otherwise classified). Once malignancy and significant pelvic pathology have been ruled out, medical treatment is an effective first-line therapeutic option, with surgery, including endometrial ablation and hysterectomy, offered when medical management has failed to resolve symptoms and fertility is no longer desired. Areas of controversy: There remains controversy around the management of the types and subtypes of adenomyosis and leiomyoma, and understanding their impact on clinical reproductive outcomes. Areas currently under development: Standardised assessment tools for measuring outcomes of AUB are being developed. Areas timely for developing research: Novel diagnostic and monitoring tools should be developed to help stratify treatment for women with AUB, particularly relating to 'unclassified' and 'endometrial' causes.

Ovarian surgery for symptom relief in women with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine condition, affecting approximately one in 10 women. PCOS is defined by two of three features: oligo- or anovulation, clinical or biochemical hyperandrogenism or both, or polycystic ovaries.Women with PCOS can have a wide range of health problems, including infrequent and irregular periods, unwanted hair growth and acne, and subnormal fertility. Long-term health concerns include an increased risk of heart disease, diabetes and the development of precancerous disease of the womb. OBJECTIVES: To assess the effectiveness and harms of ovarian surgery as a treatment for symptomatic relief of hirsutism, acne and menstrual irregularity in PCOS. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group specialized register, CENTRAL, MEDLINE, Embase and PsycINFO (from inception to 17 October 2016). We handsearched citation lists, registers of ongoing trials and conference proceedings. SELECTION CRITERIA: We included randomized controlled trials (RCTs) of women undergoing ovarian drilling in comparison to no treatment, medical treatment, or other forms of surgical treatment for the symptoms of PCOS. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary outcome measures were improvement in menstrual regularity and androgenic symptoms of PCOS (hirsutism, acne); the secondary outcome measures included harms, change of body mass index (BMI), waist circumference, androgen levels, metabolic measures and quality of life. We assessed the quality of the evidence using GRADE methods. MAIN RESULTS: We included 22 RCTs (2278 women analyzed) of participants with PCOS and symptoms of acne, hirsutism or irregular menstrual cycles, all of which included laparoscopic ovarian drilling (LOD) as an intervention.Two studies reported their funding source (Farquhar 2002 - supported in part by the Auckland Medical Research Foundation; Sarouri 2015 - the authors thank the Vice Chancellor for Research of Guilan University of Medical Sciences for funding this project).The quality of the evidence ranged from very low to moderate quality. The main limitations were imprecision associated with the low number of studies, inconsistency and risk of bias associated with the inability to blind participants. There were too few studies to assess risk of publication bias. Menstrual RegularityTwo studies compared LOD versus metformin (n=226) but no conclusions could be drawn with regard to menstrual regularity, as their findings were inconsistent and they were unsuitable for pooling. There appeared to be little or no difference in the rate of women reporting improvement in menstrual regularity when LOD was compared with medical treatment including metformin + clomiphene (OR 1.02, 95% CI 0.64 to 1.64, 2 studies, 332 women, I2 = 13%, low-quality evidence), letrozole (OR 1.08, 95% CI 0.64 to 1.84, 1 study, 260 women, low-quality evidence), or metformin + letrozole (OR 0.95, 95% CI 0.49 to 1.81, 1 study, 146 women, low-quality evidence). However, one study reported that LOD was superior to gonadotrophin (OR 19.2, 95% CI 3.17 to 116.45, 1 study, 35 women, very low-quality evidence).There appeared to be little or no difference in the rate of women reporting improvement in menstrual regularity when bilateral unipolar LOD was compared to unilateral LOD (OR 1.51, 95% CI 0.62 to 3.71, 2 studies, 104 women, I2 = 0%, moderate-quality evidence), transvaginal ultrasound-guided LOD (OR 1.23, 95% CI 0.64 to 2.37, 1 study, 147 women, low-quality evidence), LOD using adjusted thermal dose in accordance with the ovarian volume (OR 0.42, 95% CI 0.16 to 1.14, 1 study, 115 women, low-quality evidence) or bipolar LOD (OR 1.00, 95% CI 0.05 to 18.57, 1 study, 18 women, low-quality evidence).Four to five punctures per ovary may improve the rate of women reporting menstrual regularity compared with two or fewer (OR 16.04, 95% CI 4.19 to 61.34, 2 studies, 73 women, I2 = 0%, low-quality evidence). Androgenic SymptomsThere was probably little or no difference in improvement in androgenic symptoms when LOD was compared to metformin (OR 1.00, 95% CI 0.42 to 2.37, 1 study, 126 women, moderate-quality evidence) or gonadotrophins; acne (OR 3.20, 95% CI 0.33 to 30.94, 1 study, 25 women, low-quality evidence), hirsutism (OR 2.31, 95% CI 0.22 to 23.89, 1 study, 25 women, low-quality evidence).There appeared to be little or no difference in improvement of androgenic symptoms when LOD was compared to transvaginal ultrasound-guided LOD, with respect to hirsutism (OR 1.09, 95% CI 0.30 to 3.91, 1 study, 39 women, low-quality evidence) or acne (OR 0.84, 95% CI 0.20 to 3.50, 1 study, 31 women, low-quality evidence). HarmsLOD was associated with fewer gastrointestinal side effects than metformin plus clomiphene (OR 0.05, 95% CI 0.01 to 0.36, 2 studies, 332 women, I2 = 0%, moderate-quality evidence). One study suggested little or no difference in rates of ovarian hyperstimulation syndrome between LOD and gonadotrophins (OR 0.08, 95% CI 0.00 to 1.61, 1 study, 33 women, low-quality evidence).There were fewer adhesions with transvaginal hydrolaparoscopy compared to LOD (OR 0.10, 95% CI 0.05 to 0.18, 1 study, 246 women, moderate-quality evidence). There appeared to be little or no difference in adhesions when variable energy LOD was compared with standard LOD (OR 0.96, 95% CI 0.32 to 2.88, 1 study, 64 women, low-quality evidence). Another study (44 women) reported that none of the women who returned for surgery following either traditional or unilateral LOD were found to have adhesions. AUTHORS' CONCLUSIONS: There was no clear evidence that LOD improves menstrual regularity or the androgenic symptoms of PCOS, compared to most of the medical treatments used in the included studies. LOD was associated with fewer gastrointestinal side effects compared to metformin and clomiphene.There was also no clear evidence of different effectiveness between types of LOD, except that LOD with four to five punctures per ovary may be more effective than two or fewer punctures. There was little evidence comparing LOD with different types of surgery, although one study concluded that transvaginal hydrolaparoscopy had a lower risk of adhesions than LOD.There was evidence from one small study of benefit from LOD compared to gonadotrophins for menstrual regulation. However, gonadotrophins are seldom used for this indication.