Aromatase inhibitors (letrozole) for ovulation induction in infertile women with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 5% to 20% of women worldwide and often leads to anovulatory infertility. Aromatase inhibitors (AIs) are a class of drugs that were introduced for ovulation induction in 2001. Since about 2001 clinical trials have reached differing conclusions as to whether the AI, letrozole, is at least as effective as the first-line treatment clomiphene citrate (CC), a selective oestrogen receptor modulator (SERM). OBJECTIVES: To evaluate the effectiveness and safety of AIs (letrozole) (with or without adjuncts) compared to SERMs (with or without adjuncts) for infertile women with anovulatory PCOS for ovulation induction followed by timed intercourse or intrauterine insemination. SEARCH METHODS: We searched the following sources, from their inception to 4 November 2021, to identify relevant randomised controlled trials (RCTs): the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase and PsycINFO. We also checked reference lists of relevant trials, searched the trial registers and contacted experts in the field for any additional trials. We did not restrict the searches by language or publication status. SELECTION CRITERIA: We included all RCTs of AIs used alone or with other medical therapies for ovulation induction in women of reproductive age with anovulatory PCOS. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted the data and assessed risks of bias using RoB 1. We pooled trials where appropriate using a fixed-effect model to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for most outcomes, and risk differences (RDs) for ovarian hyperstimulation syndrome (OHSS). The primary outcomes were live birth rate and OHSS rate. Secondary outcomes were clinical pregnancy, miscarriage and multiple pregnancy rates. We assessed the certainty of the evidence for each comparison using GRADE methods. MAIN RESULTS: This is a substantive update of a previous review; of six previously included trials, we excluded four from this update and moved two to 'awaiting classification' due to concerns about validity of trial data. We included five additional trials for this update that now includes a total of 41 RCTs (6522 women). The AI, letrozole, was used in all trials. Letrozole compared to SERMs with or without adjuncts followed by timed intercourse Live birth rates were higher with letrozole (with or without adjuncts) compared to SERMs followed by timed intercourse (OR 1.72, 95% CI 1.40 to 2.11; I2 = 0%; number needed to treat for an additional beneficial outcome (NNTB) = 10; 11 trials, 2060 participants; high-certainty evidence). This suggests that in women with a 20% chance of live birth using SERMs, the live birth rate in women using letrozole with or without adjuncts would be 27% to 35%. There is high-certainty evidence that OHSS rates are similar with letrozole or SERMs (0.5% in both arms: risk difference (RD) -0.00, 95% CI -0.01 to 0.01; I2 = 0%; 10 trials, 1848 participants; high-certainty evidence). There is evidence for a higher pregnancy rate in favour of letrozole (OR 1.69, 95% CI 1.45 to 1.98; I2 = 0%; NNTB = 10; 23 trials, 3321 participants; high-certainty evidence). This suggests that in women with a 24% chance of clinical pregnancy using SERMs, the clinical pregnancy rate in women using letrozole with or without adjuncts would be 32% to 39%. There is little or no difference between treatment groups in the rate of miscarriage per pregnancy (25% with SERMs versus 24% with letrozole: OR 0.94, 95% CI 0.66 to 1.32; I2 = 0%; 15 trials, 736 participants; high-certainty evidence) and multiple pregnancy rate (2.2% with SERMs versus 1.6% with letrozole: OR 0.74, 95% CI 0.42 to 1.32; I2 = 0%; 14 trials, 2247 participants; high-certainty evidence). However, a funnel plot showed mild asymmetry, indicating that some trials in favour of SERMs might be missing.  Letrozole compared to laparoscopic ovarian drilling (LOD) One trial reported very low-certainty evidence that live birth rates may be higher with letrozole compared to LOD (OR 2.07, 95% CI 0.99 to 4.32; 1 trial, 141 participants; very low-certainty evidence). This suggests that in women with a 22% chance of live birth using LOD with or without adjuncts, the live birth rate in women using letrozole with or without adjuncts would be 24% to 47%. No trial reported OHSS rates. Due to the low-certainty evidence we are uncertain if letrozole improves pregnancy rates compared to LOD (OR 1.47, 95% CI 0.95 to 2.28; I² = 0%; 3 trials, 367 participants; low-certainty evidence). This suggests that in women with a 29% chance of clinical pregnancy using LOD with or without adjuncts, the clinical pregnancy rate in women using letrozole with or without adjuncts would be 28% to 45%. There seems to be no evidence of a difference in miscarriage rates per pregnancy comparing letrozole to LOD (OR 0.65, 95% CI 0.22 to 1.92; I² = 0%; 3 trials, 122 participants; low-certainty evidence). This also applies to multiple pregnancies (OR 3.00, 95% CI 0.12 to 74.90; 1 trial, 141 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: Letrozole appears to improve live birth rates and pregnancy rates in infertile women with anovulatory PCOS, compared to SERMs, when used for ovulation induction, followed by intercourse. There is high-certainty evidence that OHSS rates are similar with letrozole or SERMs. There was high-certainty evidence of no difference in miscarriage rate and multiple pregnancy rate. We are uncertain if letrozole increases live birth rates compared to LOD. In this update, we added good quality trials and removed trials with concerns over data validity, thereby upgrading the certainty of the evidence base.

Interventions for heavy menstrual bleeding; overview of Cochrane reviews and network meta-analysis.

BACKGROUND: Heavy menstrual bleeding (HMB) is excessive menstrual blood loss that interferes with women's quality of life, regardless of the absolute amount of bleeding. It is a very common condition in women of reproductive age, affecting 2 to 5 of every 10 women. Diverse treatments, either medical (hormonal or non-hormonal) or surgical, are currently available for HMB, with different effectiveness, acceptability, costs and side effects. The best treatment will depend on the woman's age, her intention to become pregnant, the presence of other symptoms, and her personal views and preferences. OBJECTIVES: To identify, systematically assess and summarise all evidence from studies included in Cochrane Reviews on treatment for heavy menstrual bleeding (HMB), using reviews with comparable participants and outcomes; and to present a ranking of the first- and second-line treatments for HMB. METHODS: We searched for published Cochrane Reviews of HMB interventions in the Cochrane Database of Systematic Reviews. The primary outcomes were menstrual bleeding and satisfaction. Secondary outcomes included quality of life, adverse events and the requirement of further treatment. Two review authors independently selected the systematic reviews, extracted data and assessed quality, resolving disagreements by discussion. We assessed review quality using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) 2 tool and evaluated the certainty of the evidence for each outcome using GRADE methods. We grouped the interventions into first- and second-line treatments, considering participant characteristics (desire for future pregnancy, failure of previous treatment, candidacy for surgery). First-line treatments included medical interventions, and second-line treatments included both the levonorgestrel-releasing intrauterine system (LNG-IUS) and surgical treatments; thus the LNG-IUS is included in both groups. We developed different networks for first- and second-line treatments. We performed network meta-analyses of all outcomes, except for quality of life, where we performed pairwise meta-analyses. We reported the mean rank, the network estimates for mean difference (MD) or odds ratio (OR), with 95% confidence intervals (CIs), and the certainty of evidence (moderate, low or very low certainty). We also analysed different endometrial ablation and resection techniques separately from the main network: transcervical endometrial resection (TCRE) with or without rollerball, other resectoscopic endometrial ablation (REA), microwave non-resectoscopic endometrial ablation (NREA), hydrothermal ablation NREA, bipolar NREA, balloon NREA and other NREA. MAIN RESULTS: We included nine systematic reviews published in the Cochrane Library up to July 2021. We updated the reviews that were over two years old. In July 2020, we started the overview with no new reviews about the topic. The included medical interventions were: non-steroidal anti-inflammatory drugs (NSAIDs), antifibrinolytics (tranexamic acid), combined oral contraceptives (COC), combined vaginal ring (CVR), long-cycle and luteal oral progestogens, LNG-IUS, ethamsylate and danazol (included to provide indirect evidence), which were compared to placebo. Surgical interventions were: open (abdominal), minimally invasive (vaginal or laparoscopic) and unspecified (or surgeon's choice of route of) hysterectomy, REA, NREA, unspecified endometrial ablation (EA) and LNG-IUS. We grouped the interventions as follows. First-line treatments Evidence from 26 studies with 1770 participants suggests that LNG-IUS results in a large reduction of menstrual blood loss (MBL; mean rank 2.4, MD -105.71 mL/cycle, 95% CI -201.10 to -10.33; low certainty evidence); antifibrinolytics probably reduce MBL (mean rank 3.7, MD -80.32 mL/cycle, 95% CI -127.67 to -32.98; moderate certainty evidence); long-cycle progestogen reduces MBL (mean rank 4.1, MD -76.93 mL/cycle, 95% CI -153.82 to -0.05; low certainty evidence), and NSAIDs slightly reduce MBL (mean rank 6.4, MD -40.67 mL/cycle, -84.61 to 3.27; low certainty evidence; reference comparator mean rank 8.9). We are uncertain of the true effect of the remaining interventions and the sensitivity analysis for reduction of MBL, as the evidence was rated as very low certainty. We are uncertain of the true effect of any intervention (very low certainty evidence) on the perception of improvement and satisfaction. Second-line treatments Bleeding reduction is related to the type of hysterectomy (total or supracervical/subtotal), not the route, so we combined all routes of hysterectomy for bleeding outcomes. We assessed the reduction of MBL without imputed data (11 trials, 1790 participants) and with imputed data (15 trials, 2241 participants). Evidence without imputed data suggests that hysterectomy (mean rank 1.2, OR 25.71, 95% CI 1.50 to 439.96; low certainty evidence) and REA (mean rank 2.8, OR 2.70, 95% CI 1.29 to 5.66; low certainty evidence) result in a large reduction of MBL, and NREA probably results in a large reduction of MBL (mean rank 2.0, OR 3.32, 95% CI 1.53 to 7.23; moderate certainty evidence). Evidence with imputed data suggests hysterectomy results in a large reduction of MBL (mean rank 1.0, OR 14.31, 95% CI 2.99 to 68.56; low certainty evidence), and NREA probably results in a large reduction of MBL (mean rank 2.2, OR 2.87, 95% CI 1.29 to 6.05; moderate certainty evidence). We are uncertain of the true effect for REA (very low certainty evidence). We are uncertain of the effect on amenorrhoea (very low certainty evidence). Evidence from 27 trials with 4284 participants suggests that minimally invasive hysterectomy results in a large increase in satisfaction (mean rank 1.3, OR 7.96, 95% CI 3.33 to 19.03; low certainty evidence), and NREA also increases satisfaction (mean rank 3.6, OR 1.59, 95% CI 1.09 to 2.33; low certainty evidence), but we are uncertain of the true effect of the remaining interventions (very low certainty evidence). AUTHORS' CONCLUSIONS: Evidence suggests LNG-IUS is the best first-line treatment for reducing menstrual blood loss (MBL); antifibrinolytics are probably the second best, and long-cycle progestogens are likely the third best. We cannot make conclusions about the effect of first-line treatments on perception of improvement and satisfaction, as evidence was rated as very low certainty. For second-line treatments, evidence suggests hysterectomy is the best treatment for reducing bleeding, followed by REA and NREA. We are uncertain of the effect on amenorrhoea, as evidence was rated as very low certainty. Minimally invasive hysterectomy may result in a large increase in satisfaction, and NREA also increases satisfaction, but we are uncertain of the true effect of the remaining second-line interventions, as evidence was rated as very low certainty.

GM-CSF (granulocyte macrophage colony-stimulating factor) supplementation in culture media for women undergoing assisted reproduction.

BACKGROUND: GM-CSF (granulocyte macrophage colony-stimulating factor) is a growth factor that is used to supplement culture media in an effort to improve clinical outcomes for those undergoing assisted reproduction. It is worth noting that the use of GM-CSF-supplemented culture media often adds a further cost to the price of an in vitro fertilisation (IVF) cycle. The purpose of this review was to assess the available evidence from randomised controlled trials (RCTs) on the effectiveness and safety of GM-CSF-supplemented culture media. OBJECTIVES: To assess the effectiveness and safety of GM-CSF-supplemented human embryo culture media versus culture media not supplemented with GM-CSF, in women or couples undergoing assisted reproduction. SEARCH METHODS: We used standard methodology recommended by Cochrane. We searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE, Embase, CINAHL, LILACS, DARE, OpenGrey, PubMed, Google Scholar, and two trials registers on 15 October 2019, checked references of relevant papers and communicated with experts in the field. SELECTION CRITERIA: We included RCTs comparing GM-CSF (including G-CSF (granulocyte colony-stimulating factor))-supplemented embryo culture media versus any other non-GM-CSF-supplemented embryo culture media (control) in women undergoing assisted reproduction. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary review outcomes were live birth and miscarriage rate. The secondary outcomes were clinical pregnancy, multiple gestation, preterm birth, birth defects, aneuploidy, and stillbirth rates. We assessed the quality of the evidence using GRADE methodology. We undertook one comparison, GM-CSF-supplemented culture media versus culture media not supplemented with GM-CSF, for those undergoing assisted reproduction. MAIN RESULTS: We included five studies, the data for three of which (1532 participants) were meta-analysed. We are uncertain whether GM-CSF-supplemented culture media makes any difference to the live-birth rate when compared to using conventional culture media not supplemented with GM-CSF (odds ratio (OR) 1.19, 95% confidence interval (CI) 0.93 to 1.52, 2 RCTs, N = 1432, I2 = 69%, low-quality evidence). The evidence suggests that if the rate of live birth associated with conventional culture media not supplemented with GM-CSF was 22%, the rate with the use of GM-CSF-supplemented culture media would be between 21% and 30%. We are uncertain whether GM-CSF-supplemented culture media makes any difference to the miscarriage rate when compared to using conventional culture media not supplemented with GM-CSF (OR 0.75, 95% CI 0.41 to 1.36, 2 RCTs, N = 1432, I2 = 0%, low-quality evidence). This evidence suggests that if the miscarriage rate associated with conventional culture media not supplemented with GM-CSF was 4%, the rate with the use of GM-CSF-supplemented culture media would be between 2% and 5%. Furthermore, we are uncertain whether GM-CSF-supplemented culture media makes any difference to the following outcomes: clinical pregnancy (OR 1.16, 95% CI 0.93 to 1.45, 3 RCTs, N = 1532 women, I2 = 67%, low-quality evidence); multiple gestation (OR 1.24, 95% CI 0.73 to 2.10, 2 RCTs, N = 1432, I2 = 35%, very low-quality evidence); preterm birth (OR 1.20, 95% CI 0.70 to 2.04, 2 RCTs, N = 1432, I2 = 76%, very low-quality evidence); birth defects (OR 1.33, 95% CI 0.59 to 3.01, I2 = 0%, 2 RCTs, N = 1432, low-quality evidence); and aneuploidy (OR 0.34, 95% CI 0.03 to 3.26, I2 = 0%, 2 RCTs, N = 1432, low-quality evidence). We were unable to undertake analysis of stillbirth, as there were no events in either arm of the two studies that assessed this outcome. AUTHORS' CONCLUSIONS: Due to the very low to low quality of the evidence, we cannot be certain whether GM-CSF is any more or less effective than culture media not supplemented with GM-CSF for clinical outcomes that reflect effectiveness and safety. It is important that independent information on the available evidence is made accessible to those considering using GM-CSF-supplemented culture media. The claims from marketing information that GM-CSF has a positive effect on pregnancy rates are not supported by the available evidence presented here; further well-designed, properly powered RCTs are needed to lend certainty to the evidence.

Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is an important cause of ill health in premenopausal women. Although surgery is often used as a treatment, a range of medical therapies are also available. Non-steroidal anti-inflammatory drugs (NSAIDs) reduce prostaglandin levels, which are elevated in women with excessive menstrual bleeding and also may have a beneficial effect on dysmenorrhoea. OBJECTIVES: To determine the effectiveness, safety and tolerability of NSAIDs in achieving a reduction in menstrual blood loss (MBL) in women of reproductive years with HMB. SEARCH METHODS: We searched, in April 2019, the Cochrane Gynaecology and Fertility specialised register, Cochrane Central Register of Studies Online (CENTRAL CRSO), MEDLINE, Embase, PsycINFO, the clinical trial registries and reference lists of articles. SELECTION CRITERIA: The inclusion criteria were randomised comparisons of individual NSAIDs or combined with other medical therapy with each other, placebo or other medical treatments in women with regular heavy periods measured either objectively or subjectively and with no pathological or iatrogenic (treatment-induced) causes for their HMB. DATA COLLECTION AND ANALYSIS: We identified 19 randomised controlled trials (RCTs) (759 women) that fulfilled the inclusion criteria for this review and two review authors independently extracted data. We estimated odds ratios (ORs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes from the data of nine trials. We described in data tables the results of the remaining seven cross-over trials with data unsuitable for pooling, one trial with skewed data, and one trial with missing variances. One trial had no data available for analysis. MAIN RESULTS: As a group, NSAIDs were more effective than placebo at reducing HMB but less effective than tranexamic acid, danazol or the levonorgestrel-releasing intrauterine system (LNG IUS). Treatment with danazol caused a shorter duration of menstruation and more adverse events than NSAIDs, but this did not appear to affect the acceptability of treatment, based on trials from 1980 to 1990. However, currently danazol is not a usual or recommended treatment for HMB. There was no clear evidence of difference between NSAIDs and the other treatments (oral luteal progestogen, ethamsylate, an older progesterone-releasing intrauterine system and the oral contraceptive pill (OCP), but most studies were underpowered. There was no evidence of a difference between the individual NSAIDs (naproxen and mefenamic acid) in reducing HMB. The evidence quality ranged from low to moderate, the main limitations being risk of bias and imprecision. AUTHORS' CONCLUSIONS: NSAIDs reduce HMB when compared with placebo, but are less effective than tranexamic acid, danazol or LNG IUS. However, adverse events are more severe with danazol therapy. In the limited number of small studies suitable for evaluation, there was no clear evidence of a difference in efficacy between NSAIDs and other medical treatments such as oral luteal progestogen, ethamsylate, OCP or the older progesterone-releasing intrauterine system.

Endometrial resection and ablation versus hysterectomy for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is an important cause of ill health in women of reproductive age, causing them physical problems, social disruption and reducing their quality of life. Medical therapy has traditionally been first-line therapy. Surgical treatment of HMB often follows failed or ineffective medical therapy. The definitive treatment is hysterectomy, but this is a major surgical procedure with significant physical and emotional complications, as well as social and economic costs. Less invasive surgical techniques, such as endometrial resection and ablation, have been developed with the purpose of improving menstrual symptoms by removing or ablating the entire thickness of the endometrium. OBJECTIVES: To compare the effectiveness, acceptability and safety of techniques of endometrial destruction by any means versus hysterectomy by any means for the treatment of heavy menstrual bleeding. SEARCH METHODS: Electronic searches for relevant randomised controlled trials (RCTs) targeted-but were not limited to-the following: the Cochrane Gynaecology and Fertility Group's specialised register, CENTRAL via the Cochrane Register of Studies Online (CRSO), MEDLINE, Embase, PsycINFO, and the ongoing trial registries. We made attempts to identify trials by examining citation lists of review articles and guidelines and by performing handsearching. Searches were performed in 1999, 2007, 2008, 2013 and on 10 December 2018. SELECTION CRITERIA: Any RCTs that compared techniques of endometrial resection or ablation (by any means) with hysterectomy (by any technique) for the treatment of heavy menstrual bleeding in premenopausal women. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted data and assessed trials for risk of bias. MAIN RESULTS: We identified nine RCTs that fulfilled our inclusion criteria for this review. For two trials, the review authors identified multiple publications that assessed different outcomes at different postoperative time points for the same women. No included trials used third generation techniques.Clinical measures of improved bleeding symptoms and satisfaction rates were observed in women who had undergone hysterectomy compared to endometrial ablation. A slightly lower proportion of women who underwent endometrial ablation perceived improvement in bleeding symptoms at one year (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.85 to 0.93; 4 studies, 650 women, I² = 31%; low-quality evidence), at two years (RR 0.92, 95% CI 0.86 to 0.99; 2 studies, 292 women, I² = 53%) and at four years (RR 0.93, 95% CI 0.88 to 0.99; 2 studies, 237 women, I² = 79%). Women in the endometrial ablation group also showed improvement in pictorial blood loss assessment chart compared to their baseline (PBAC) score at one year (MD 24.40, 95% CI 16.01 to 32.79; 1 study, 68 women; moderate-quality evidence) and at two years (MD 44.00, 95% CI 36.09 to 51.91; 1 study, 68 women). Repeat surgery resulting from failure of the initial treatment was more likely to be needed after endometrial ablation than after hysterectomy at one year (RR 16.17, 95% CI 5.53 to 47.24; 927 women; 7 studies; I2 = 0%), at two years (RR 34.06, 95% CI 9.86 to 117.65; 930 women; 6 studies; I2 = 0%), at three years (RR 22.90, 95% CI 1.42 to 370.26; 172 women; 1 study) and at four years (RR 36.32, 95% CI 5.09 to 259.21;197 women; 1 study). The satisfaction rate was lower amongst those who had endometrial ablation at two years after surgery (RR 0.87, 95% CI 0.80 to 0.95; 4 studies, 567 women, I² = 0%; moderate-quality evidence), and no evidence of clear difference was reported between post-treatment satisfaction rates in groups at other follow-up times (1 and 4 years).Most adverse events, both major and minor, were more likely after hysterectomy during hospital stay. Women who had an endometrial ablation were less likely to experience sepsis (RR 0.19, 95% CI 0.12 to 0.31; participants = 621; studies = 4; I2 = 62%), blood transfusion (RR 0.20, 95% CI 0.07 to 0.59; 791 women; 5 studies; I2 = 0%), pyrexia (RR 0.17, 95% CI 0.09 to 0.35; 605 women; 3 studies; I2 = 66%), vault haematoma (RR 0.11, 95% CI 0.04 to 0.34; 858 women; 5 studies; I2 = 0%) and wound haematoma (RR 0.03, 95% CI 0.00 to 0.53; 202 women; 1 study) before hospital discharge. After discharge from hospital, the only difference that was reported for this group was a higher rate of infection (RR 0.27, 95% CI 0.13 to 0.58; 172 women; 1 study).Recovery time was shorter in the endometrial ablation group, considering hospital stay, time to return to normal activities and time to return to work; we did not, however, pool these data owing to high heterogeneity. Some outcomes (such as a woman's perception of bleeding and proportion of women requiring further surgery for HMB), generated a low GRADE score, suggesting that further research in these areas is likely to change the estimates. AUTHORS' CONCLUSIONS: Endometrial resection and ablation offers an alternative to hysterectomy as a surgical treatment for heavy menstrual bleeding. Both procedures are effective, and satisfaction rates are high. Although hysterectomy offers permanent and immediate relief from heavy menstrual bleeding, it is associated with a longer operating time and recovery period. Hysterectomy also has higher rates of postoperative complications such as sepsis, blood transfusion and haematoma (vault and wound). The initial cost of endometrial destruction is lower than that of hysterectomy but, because retreatment is often necessary, the cost difference narrows over time.

Endometrial resection and ablation techniques for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is a significant health problem in premenopausal women; it can reduce their quality of life and can cause social disruption and physical problems such as iron deficiency anaemia. First-line treatment has traditionally consisted of medical therapy (hormonal and non-hormonal), but this is not always successful in reducing menstrual bleeding to acceptable levels. Hysterectomy is a definitive treatment, but it is more costly and carries some risk. Endometrial ablation may be an alternative to hysterectomy that preserves the uterus. Many techniques have been developed to 'ablate' (remove) the lining of the endometrium. First-generation techniques require visualisation of the uterus with a hysteroscope during the procedure; although it is safe, this procedure requires specific technical skills. Newer techniques for endometrial ablation (second- and third-generation techniques) have been developed that are quicker than previous approaches because they do not require hysteroscopic visualisation during the procedure. OBJECTIVES: To compare the efficacy, safety, and acceptability of endometrial destruction techniques to reduce heavy menstrual bleeding (HMB) in premenopausal women. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, CINAHL, and PsycInfo (from inception to May 2018). We also searched trials registers, other sources of unpublished or grey literature, and reference lists of retrieved studies, and we made contact with experts in the field and with pharmaceutical companies that manufacture ablation devices. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing different endometrial ablation or resection techniques for women reporting HMB without known uterine pathology, other than fibroids outside the uterine cavity and smaller than 3 centimetres, were eligible. Outcomes included improvement in HMB and in quality of life, patient satisfaction, operative outcomes, complications, and the need for further surgery, including hysterectomy. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed trials for risk of bias, and extracted data. We contacted study authors for clarification of methods or for additional data. We assessed adverse events only if they were separately measured in the included trials. We undertook comparisons with individual techniques as well as an overall comparison of first- and second-generation ablation methods. MAIN RESULTS: We included in this update 28 studies (4287 women) with sample sizes ranging from 20 to 372. Most studies had low risk of bias for randomisation, attrition, and selective reporting. Less than half of these studies had adequate allocation concealment, and most were unblinded. Using GRADE, we determined that the quality of evidence ranged from moderate to very low. We downgraded evidence for risk of bias, imprecision, and inconsistency.Overall comparison of second-generation versus first-generation (i.e. gold standard hysteroscopic ablative) techniques revealed no evidence of differences in amenorrhoea at 1 year and 2 to 5 years' follow-up (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.78 to 1.27; 12 studies; 2145 women; I² = 77%; and RR 1.16, 95% CI 0.78 to 1.72; 672 women; 4 studies; I² = 80%; very low-quality evidence) and showed subjective improvement at 1 year follow-up based on a Pictorial Blood Assessment Chart (PBAC) (< 75 or acceptable improvement) (RR 1.03, 95% CI 0.98 to 1.09; 5 studies; 1282 women; I² = 0%; and RR 1.12, 95% CI 0.97 to 1.28; 236 women; 1 study; low-quality evidence). Study results showed no difference in patient satisfaction between second- and first-generation techniques at 1 year follow-up (RR 1.01, 95% CI 0.98 to 1.04; 11 studies; 1750 women; I² = 36%; low-quality evidence) nor at 2 to 5 years' follow-up (RR 1.02, 95% CI 0.93 to 1.13; 672 women; 4 studies; I² = 81%).Compared with first-generation techniques, second-generation endometrial ablation techniques were associated with shorter operating times (mean difference (MD) -13.52 minutes, 95% CI -16.90 to -10.13; 9 studies; 1822 women; low-quality evidence) and more often were performed under local rather than general anaesthesia (RR 2.8, 95% CI 1.8 to 4.4; 6 studies; 1434 women; low-quality evidence).We are uncertain whether perforation rates differed between second- and first-generation techniques (RR 0.32, 95% CI 0.10 to 1.01; 1885 women; 8 studies; I² = 0%).Trials reported little or no difference between second- and first-generation techniques in requirement for additional surgery (ablation or hysterectomy) at 1 year follow-up (RR 0.72, 95% CI 0.41 to 1.26; 6 studies: 935 women; low-quality evidence). At 5 years, results showed probably little or no difference between groups in the requirement for hysterectomy (RR 0.85, 95% CI 0.59 to 1.22; 4 studies; 758 women; moderate-quality evidence). AUTHORS' CONCLUSIONS: Approaches to endometrial ablation have evolved from first-generation techniques to newer second- and third-generation approaches. Current evidence suggests that compared to first-generation techniques (endometrial laser ablation, transcervical resection of the endometrium, rollerball endometrial ablation), second-generation approaches (thermal balloon endometrial ablation, microwave endometrial ablation, hydrothermal ablation, bipolar radiofrequency endometrial ablation, endometrial cryotherapy) are of equivalent efficacy for heavy menstrual bleeding, with comparable rates of amenorrhoea and improvement on the PBAC. Second-generation techniques are associated with shorter operating times and are performed more often under local rather than general anaesthesia. It is uncertain whether perforation rates differed between second- and first-generation techniques. Evidence was insufficient to show which second-generation approaches were superior to others and to reveal the efficacy and safety of third-generation approaches versus first- and second-generation techniques.

Inositol for subfertile women with polycystic ovary syndrome.

BACKGROUND: Subfertile women are highly motivated to try different adjunctive therapies to have a baby, and the widespread perception is that dietary supplements such as myo-inositol (MI) and D-chiro-insoitol (DCI) are associated with only benefit, and not with harm. Many fertility clinicians currently prescribe MI for subfertile women with polycystic ovary syndrome (PCOS) as pre-treatment to in vitro fertilisation (IVF) or for ovulation induction; however no high-quality evidence is available to support this practice. This review assessed the evidence for the effectiveness of inositol in subfertile women with a diagnosis of PCOS. OBJECTIVES: To evaluate the effectiveness and safety of oral supplementation of inositol for reproductive outcomes among subfertile women with PCOS who are trying to conceive. SEARCH METHODS: We searched the following databases (to July 2018): Cochrane Gynaecology and Fertility Group (CGFG) Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and AMED. We also checked reference lists and searched the clinical trials registries. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared any type, dose, or combination of oral inositol versus placebo, no treatment/standard treatment, or treatment with another antioxidant, or with a fertility agent, or with another type of inositol, among subfertile women with PCOS. DATA COLLECTION AND ANALYSIS: Two review authors independently selected eligible studies, extracted data, and assessed risk of bias. The primary outcomes were live birth and adverse effects; secondary outcomes included clinical pregnancy rates and ovulation rates. We pooled studies using a fixed-effect model, and we calculated odds ratios (ORs) with 95% confidence intervals (CIs). We assessed the overall quality of the evidence by applying GRADE criteria. MAIN RESULTS: We included 13 trials involving 1472 subfertile women with PCOS who were receiving myo-inositol as pre-treatment to IVF (11 trials), or during ovulation induction (two trials). These studies compared MI versus placebo, no treatment/standard, melatonin, metformin, clomiphene citrate, or DCI. The evidence was of 'low' to 'very low' quality. The main limitations were serious risk of bias due to poor reporting of methods, inconsistency, and lack of reporting of clinically relevant outcomes such as live birth and adverse events.We are uncertain whether MI improves live birth rates when compared to standard treatment among women undergoing IVF (OR 2.42, 95% CI 0.75 to 7.83; P = 0.14; 2 RCTs; 84 women; I² = 0%). Very low-quality evidence suggests that for subfertile women with PCOS undergoing pre-treatment to IVF who have an expected live birth rate of 12%, the rate among women using MI would be between 9% and 51%.We are uncertain whether MI may be associated with a decrease in miscarriage rate when compared to standard treatment (OR 0.40, 95% CI 0.19 to 0.86; P = 0.02; 4 RCTs; 535 women; I² = 66%; very low-quality evidence). This suggests that among subfertile women with PCOS with an expected miscarriage rate of 9% who are undergoing pre-treatment to IVF, the rate among women using MI would be between 2% and 8%; however this meta-analysis is based primarily on one study, which reported an unusually high miscarriage rate in the control group, and this has resulted in very high heterogeneity. When we removed this trial from the sensitivity analysis, we no longer saw the effect, and we noted no conclusive differences between MI and standard treatment.Low-quality evidence suggests that MI may be associated with little or no difference in multiple pregnancy rates when compared with standard treatment (OR 1.04, 95% CI 0.63 to 1.71; P = 0.89; 2 RCTs; 425 women). This suggests that among subfertile women with PCOS who are undergoing pre-treatment to IVF, with an expected multiple pregnancy rate of 18%, the rate among women using inositol would be between 12% and 27%.We are uncertain whether MI may be associated with an increased clinical pregnancy rate when compared to standard treatment (OR 1.27, 95% CI 0.87 to 1.85; P = 0.22; 4 RCTs; 535 women; I² = 0%; very low-quality evidence). This suggests that among subfertile women with PCOS who are undergoing pre-treatment to IVF, with an expected clinical pregnancy rate of 26%, the rate among women using MI would be between 24% and 40%. Ovulation rates were not reported for this comparison.Other comparisons included only one trial in each, so for the comparisons MI versus antioxidant, MI versus an insulin-sensitising agent, MI versus an ovulation induction agent, and MI versus another DCI, meta-analysis was not possible.No pooled evidence was available for women with PCOS undergoing ovulation induction, as only single trials performed comparison of the insulin-sensitising agent and the ovulation induction agent. AUTHORS' CONCLUSIONS: In light of available evidence of very low quality, we are uncertain whether MI improves live birth rate or clinical pregnancy rate in subfertile women with PCOS undergoing IVF pre-treatment taking MI compared to standard treatment. We are also uncertain whether MI decreases miscarriage rates or multiple pregnancy rates for these same women taking MI compared to standard treatment. No pooled evidence is available for use of MI versus placebo, another antioxidant, insulin-sensitising agents, ovulation induction agents, or another type of inositol for women with PCOS undergoing pre-treatment to IVF. No pooled evidence is available for use of MI in women undergoing ovulation induction.

Aromatase inhibitors (letrozole) for subfertile women with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 4% to 8% of women worldwide and often leads to anovulatory subfertility. Aromatase inhibitors (AIs) are a class of drugs that were introduced for ovulation induction in 2001. Since about 2001 clinical trials have reached differing conclusions as to whether the AI letrozole is at least as effective as the first-line treatment clomiphene citrate (CC). OBJECTIVES: To evaluate the effectiveness and safety of aromatase inhibitors for subfertile women with anovulatory PCOS for ovulation induction followed by timed intercourse or intrauterine insemination (IUI). SEARCH METHODS: We searched the following sources from inception to November 2017 to identify relevant randomised controlled trials (RCTs): the Cochrane Gynaecology and Fertility Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO, Pubmed, LILACS, Web of Knowledge, the World Health Organization (WHO) clinical trials register and Clinicaltrials.gov. We also searched the references of relevant articles. We did not restrict the searches by language or publication status. SELECTION CRITERIA: We included all RCTs of AIs used alone or with other medical therapies for ovulation induction in women of reproductive age with anovulatory PCOS. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted the data and assessed risks of bias. We pooled studies where appropriate using a fixed-effect model to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for most outcomes, and risk differences (RDs) for ovarian hyperstimulation syndrome (OHSS). The primary outcomes were live birth and OHSS. Secondary outcomes were clinical pregnancy, miscarriage and multiple pregnancy. We assessed the quality of the evidence for each comparison using GRADE methods. MAIN RESULTS: This is a substantive update of a previous review. We identified 16 additional studies for the 2018 update. We include 42 RCTs (7935 women). The aromatase inhibitor letrozole was used in all studies.Letrozole compared to clomiphene citrate (CC) with or without adjuncts followed by timed intercourseLive birth rates were higher with letrozole (with or without adjuncts) compared to clomiphene citrate (with our without adjuncts) followed by timed intercourse (OR 1.68, 95% CI 1.42 to 1.99; 2954 participants; 13 studies; I2 = 0%; number needed to treat for an additional beneficial outcome (NNTB) = 10; moderate-quality evidence). There is high-quality evidence that OHSS rates are similar with letrozole or clomiphene citrate (0.5% in both arms: risk difference (RD) -0.00, 95% CI -0.01 to 0.00; 2536 participants; 12 studies; I2 = 0%; high-quality evidence). There is evidence for a higher pregnancy rate in favour of letrozole (OR 1.56, 95% CI 1.37 to 1.78; 4629 participants; 25 studies; I2 = 1%; NNTB = 10; moderate-quality evidence). There is little or no difference between treatment groups in the rate of miscarriage by pregnancy (20% with CC versus 19% with letrozole; OR 0.94, 95% CI 0.70 to 1.26; 1210 participants; 18 studies; I2 = 0%; high-quality evidence) and multiple pregnancy rate (1.7% with CC versus 1.3% with letrozole; OR 0.69, 95% CI 0.41 to 1.16; 3579 participants; 17 studies; I2 = 0%; high-quality evidence). However, a funnel plot showed mild asymmetry, indicating that some studies in favour of clomiphene might be missing.Letrozole compared to laparoscopic ovarian drillingThere is low-quality evidence that live birth rates are similar with letrozole or laparoscopic ovarian drilling (OR 1.38, 95% CI 0.95 to 2.02; 548 participants; 3 studies; I2 = 23%; low-quality evidence). There is insufficient evidence for a difference in OHSS rates (RD 0.00, 95% CI -0.01 to 0.01; 260 participants; 1 study; low-quality evidence). There is low-quality evidence that pregnancy rates are similar (OR 1.28, 95% CI 0.94 to 1.74; 774 participants; 5 studies; I2 = 0%; moderate-quality evidence). There is insufficient evidence for a difference in miscarriage rate by pregnancy (OR 0.66, 95% CI 0.30 to 1.43; 240 participants; 5 studies; I2 = 0%; moderate-quality evidence), or multiple pregnancies (OR 3.00, 95% CI 0.12 to 74.90; 548 participants; 3 studies; I2 = 0%; low-quality evidence).Additional comparisons were made for Letrozole versus placebo, Selective oestrogen receptor modulators (SERMS) followed by intrauterine insemination (IUI), follicle stimulating hormone (FSH), Anastrozole, as well as dosage and administration protocols. There is insufficient evidence for a difference in either group of treatment due to a limited number of studies. Hence more research is necessary. AUTHORS' CONCLUSIONS: Letrozole appears to improve live birth and pregnancy rates in subfertile women with anovulatory polycystic ovary syndrome, compared to clomiphene citrate. There is high-quality evidence that OHSS rates are similar with letrozole or clomiphene citrate. There is high-quality evidence of no difference in miscarriage rates or multiple pregnancy rates. There is low-quality evidence of no difference in live birth and pregnancy rates between letrozole and laparoscopic ovarian drilling, although there were few relevant studies. For the 2018 update, we added good-quality trials, upgrading the quality of the evidence.

Oral contraceptive pill, progestogen or oestrogen pretreatment for ovarian stimulation protocols for women undergoing assisted reproductive techniques.

BACKGROUND: Among subfertile women undergoing assisted reproductive technology (ART), hormone pills given before ovarian stimulation may improve outcomes. OBJECTIVES: To determine whether pretreatment with the combined oral contraceptive pill (COCP) or with a progestogen or oestrogen alone in ovarian stimulation protocols affects outcomes in subfertile couples undergoing ART. SEARCH METHODS: We searched the following databases from inception to January 2017: Cochrane Gynaecology and Fertility Group Specialised Register, The Cochrane Central Register Studies Online, MEDLINE, Embase, CINAHL and PsycINFO. We also searched the reference lists of relevant articles and registers of ongoing trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) of hormonal pretreatment in women undergoing ART. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary review outcomes were live birth or ongoing pregnancy and pregnancy loss. MAIN RESULTS: We included 29 RCTs (4701 women) of pretreatment with COCPs, progestogens or oestrogens versus no pretreatment or alternative pretreatments, in gonadotrophin-releasing hormone (GnRH) agonist or antagonist cycles. Overall, evidence quality ranged from very low to moderate. The main limitations were risk of bias and imprecision. Most studies did not describe their methods in adequate detail. Combined oral contraceptive pill versus no pretreatmentWith antagonist cycles in both groups the rate of live birth or ongoing pregnancy was lower in the pretreatment group (OR 0.74, 95% CI 0.58 to 0.95; 6 RCTs; 1335 women; I2 = 0%; moderate quality evidence). There was insufficient evidence to determine whether the groups differed in rates of pregnancy loss (OR 1.36, 95% CI 0.82 to 2.26; 5 RCTs; 868 women; I2 = 0%; moderate quality evidence), multiple pregnancy (OR 2.21, 95% CI 0.53 to 9.26; 2 RCTs; 125 women; I2 = 0%; low quality evidence), ovarian hyperstimulation syndrome (OHSS; OR 0.98, 95% CI 0.28 to 3.40; 2 RCTs; 642 women; I2 = 0%, low quality evidence), or ovarian cyst formation (OR 0.47, 95% CI 0.08 to 2.75; 1 RCT; 64 women; very low quality evidence).In COCP plus antagonist cycles versus no pretreatment in agonist cycles, there was insufficient evidence to determine whether the groups differed in rates of live birth or ongoing pregnancy (OR 0.89, 95% CI 0.64 to 1.25; 4 RCTs; 724 women; I2 = 0%; moderate quality evidence), multiple pregnancy (OR 1.36, 95% CI 0.85 to 2.19; 4 RCTs; 546 women; I2 = 0%; moderate quality evidence), or OHSS (OR 0.63, 95% CI 0.20 to 1.96; 2 RCTs; 290 women, I2 = 0%), but there were fewer pregnancy losses in the pretreatment group (OR 0.40, 95% CI 0.22 to 0.72; 5 RCTs; 780 women; I2 = 0%; moderate quality evidence). There were no data suitable for analysis on ovarian cyst formation.One small study comparing COCP versus no pretreatment in agonist cycles showed no clear difference between the groups for any of the reported outcomes. Progestogen versus no pretreatmentAll studies used the same protocol (antagonist, agonist or gonadotrophins) in both groups. There was insufficient evidence to determine any differences in rates of live birth or ongoing pregnancy (agonist: OR 1.35, 95% CI 0.69 to 2.65; 2 RCTs; 222 women; I2 = 24%; low quality evidence; antagonist: OR 0.67, 95% CI 0.18 to 2.54; 1 RCT; 47 women; low quality evidence; gonadotrophins: OR 0.63, 95% CI 0.09 to 4.23; 1 RCT; 42 women; very low quality evidence), pregnancy loss (agonist: OR 2.26, 95% CI 0.67 to 7.55; 2 RCTs; 222 women; I2 = 0%; low quality evidence; antagonist: OR 0.36, 95% CI 0.06 to 2.09; 1 RCT; 47 women; low quality evidence; gonadotrophins: OR 1.00, 95% CI 0.06 to 17.12; 1 RCT; 42 women; very low quality evidence) or multiple pregnancy (agonist: no data available; antagonist: OR 1.05, 95% CI 0.06 to 17.76; 1 RCT; 47 women; low quality evidence; gonadotrophins: no data available). Three studies, all using agonist cycles, reported ovarian cyst formation: rates were lower in the pretreatment group (OR 0.16, 95% CI 0.08 to 0.32; 374 women; I2 = 1%; moderate quality evidence). There were no data on OHSS. Oestrogen versus no pretreatmentIn antagonist or agonist cycles, there was insufficient evidence to determine whether the groups differed in rates of live birth or ongoing pregnancy (antagonist versus antagonist: OR 0.79, 95% CI 0.53 to 1.17; 2 RCTs; 502 women; I2 = 0%; low quality evidence; antagonist versus agonist: OR 0.88, 95% CI 0.51 to 1.50; 2 RCTs; 242 women; I2 = 0%; very low quality evidence), pregnancy loss (antagonist versus antagonist: OR 0.16, 95% CI 0.02 to 1.47; 1 RCT; 49 women; very low quality evidence; antagonist versus agonist: OR 1.59, 95% CI 0.62 to 4.06; 1 RCT; 220 women; very low quality evidence), multiple pregnancy (antagonist versus antagonist: no data available; antagonist versus agonist: OR 2.24, 95% CI 0.09 to 53.59; 1 RCT; 22 women; very low quality evidence) or OHSS (antagonist versus antagonist: no data available; antagonist versus agonist: OR 1.54, 95% CI 0.25 to 9.42; 1 RCT; 220 women). Ovarian cyst formation was not reported. Head-to-head comparisonsCOCP was compared with progestogen (1 RCT, 44 women), and with oestrogen (2 RCTs, 146 women), and progestogen was compared with oestrogen (1 RCT, 48 women), with an antagonist cycle in both groups. COCP in an agonist cycle was compared with oestrogen in an antagonist cycle (1 RCT, 25 women). Data were scant but there was no clear evidence that any of the groups differed in rates of live birth or ongoing pregnancy, pregnancy loss or other adverse events. AUTHORS' CONCLUSIONS: Among women undergoing ovarian stimulation in antagonist protocols, COCP pretreatment was associated with a lower rate of live birth or ongoing pregnancy than no pretreatment. There was insufficient evidence to determine whether rates of live birth or ongoing pregnancy were influenced by pretreatment with progestogens or oestrogens, or by COCP pretreatment using other stimulation protocols. Findings on adverse events were inconclusive, except that progesterone pretreatment may reduce the risk of ovarian cysts in agonist cycles, and COCP in antagonist cycles may reduce the risk of pregnancy loss compared with no pretreatment in agonist cycles.

Interventions for the prevention of OHSS in ART cycles: an overview of Cochrane reviews.

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) in assisted reproductive technology (ART) cycles is a treatment-induced disease that has an estimated prevalence of 20% to 33% in its mild form and 3% to 8% in its moderate or severe form. These numbers might even be higher for high-risk women such as those with polycystic ovaries or a high oocyte yield from ovum pickup. OBJECTIVES: The objective of this overview is to identify and summarise all evidence from Cochrane systematic reviews on interventions for prevention or treatment of moderate, severe and overall OHSS in couples with subfertility who are undergoing ART cycles. METHODS: Published Cochrane systematic reviews reporting on moderate, severe or overall OHSS as an outcome in ART cycles were eligible for inclusion in this overview. We also identified Cochrane submitted protocols and title registrations for future inclusion in the overview. The evidence is current to 12 December 2016. We identified reviews, protocols and titles by searching the Cochrane Gynaecology and Fertility Group Database of Systematic Reviews and Archie (the Cochrane information management system) in July 2016 on the effectiveness of interventions for outcomes of moderate, severe and overall OHSS. We undertook in duplicate selection of systematic reviews, data extraction and quality assessment. We used the AMSTAR (Assessing the Methodological Quality of Systematic Reviews) tool to assess the quality of included reviews, and we used GRADE methods to assess the quality of the evidence for each outcome. We summarised the characteristics of included reviews in the text and in additional tables. MAIN RESULTS: We included a total of 27 reviews in this overview. The reviews were generally of high quality according to AMSTAR ratings, and included studies provided evidence that ranged from very low to high in quality. Ten reviews had not been updated in the past three years. Seven reviews described interventions that provided a beneficial effect in reducing OHSS rates, and we categorised one additional review as 'promising'. Of the effective interventions, all except one had no detrimental effect on pregnancy outcomes. Evidence of at least moderate quality indicates that clinicians should consider the following interventions in ART cycles to reduce OHSS rates.• Metformin treatment before and during an ART cycle for women with PCOS (moderate-quality evidence).• Gonadotrophin-releasing hormone (GnRH) antagonist protocol in ART cycles (moderate-quality evidence).• GnRH agonist (GnRHa) trigger in donor oocyte or 'freeze-all' programmes (moderate-quality evidence). Evidence of low or very low quality suggests that clinicians should consider the following interventions in ART cycles to reduce OHSS rates.• Clomiphene citrate for controlled ovarian stimulation in ART cycles (low-quality evidence).• Cabergoline around the time of human chorionic gonadotrophin (hCG) administration or oocyte pickup in ART cycles (low-quality evidence).• Intravenous fluids (plasma expanders) around the time of hCG administration or oocyte pickup in ART cycles (very low-quality evidence).• Progesterone for luteal phase support in ART cycles (low-quality evidence).• Coasting (withholding gonadotrophins) - a promising intervention that needs to be researched further for reduction of OHSS.On the basis of this overview, we must conclude that evidence is currently insufficient to support the widespread practice of embryo cryopreservation. AUTHORS' CONCLUSIONS: Currently, 27 reviews in the Cochrane Library were conducted to report on or to try to report on OHSS in ART cycles. We identified four review protocols but no new registered titles that can potentially be included in this overview in the future. This overview provides the most up-to-date evidence on prevention of OHSS in ART cycles from all currently published Cochrane reviews on ART. Clinicians can use the evidence summarised in this overview to choose the best treatment regimen for individual patients - a regimen that not only reduces the chance of developing OHSS but does not compromise other outcomes such as pregnancy or live birth rate. Review results, however, are limited by the lack of recent primary studies or updated reviews. Furthermore, this overview can be used by policymakers in developing local and regional protocols or guidelines and can reveal knowledge gaps for future research.

Long-term hormone therapy for perimenopausal and postmenopausal women.

BACKGROUND: Hormone therapy (HT) is widely provided for control of menopausal symptoms and has been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women. This is an updated version of a Cochrane review first published in 2005. OBJECTIVES: To assess effects of long-term HT (at least 1 year's duration) on mortality, cardiovascular outcomes, cancer, gallbladder disease, fracture and cognition in perimenopausal and postmenopausal women during and after cessation of treatment. SEARCH METHODS: We searched the following databases to September 2016: Cochrane Gynaecology and Fertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and PsycINFO. We searched the registers of ongoing trials and reference lists provided in previous studies and systematic reviews. SELECTION CRITERIA: We included randomised double-blinded studies of HT versus placebo, taken for at least 1 year by perimenopausal or postmenopausal women. HT included oestrogens, with or without progestogens, via the oral, transdermal, subcutaneous or intranasal route. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias and extracted data. We calculated risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data, along with 95% confidence intervals (CIs). We assessed the quality of the evidence by using GRADE methods. MAIN RESULTS: We included 22 studies involving 43,637 women. We derived nearly 70% of the data from two well-conducted studies (HERS 1998; WHI 1998). Most participants were postmenopausal American women with at least some degree of comorbidity, and mean participant age in most studies was over 60 years. None of the studies focused on perimenopausal women.In relatively healthy postmenopausal women (i.e. generally fit, without overt disease), combined continuous HT increased the risk of a coronary event (after 1 year's use: from 2 per 1000 to between 3 and 7 per 1000), venous thromboembolism (after 1 year's use: from 2 per 1000 to between 4 and 11 per 1000), stroke (after 3 years' use: from 6 per 1000 to between 6 and 12 per 1000), breast cancer (after 5.6 years' use: from 19 per 1000 to between 20 and 30 per 1000), gallbladder disease (after 5.6 years' use: from 27 per 1000 to between 38 and 60 per 1000) and death from lung cancer (after 5.6 years' use plus 2.4 years' additional follow-up: from 5 per 1000 to between 6 and 13 per 1000).Oestrogen-only HT increased the risk of venous thromboembolism (after 1 to 2 years' use: from 2 per 1000 to 2 to 10 per 1000; after 7 years' use: from 16 per 1000 to 16 to 28 per 1000), stroke (after 7 years' use: from 24 per 1000 to between 25 and 40 per 1000) and gallbladder disease (after 7 years' use: from 27 per 1000 to between 38 and 60 per 1000) but reduced the risk of breast cancer (after 7 years' use: from 25 per 1000 to between 15 and 25 per 1000) and clinical fracture (after 7 years' use: from 141 per 1000 to between 92 and 113 per 1000) and did not increase the risk of coronary events at any follow-up time.Women over 65 years of age who were relatively healthy and taking continuous combined HT showed an increase in the incidence of dementia (after 4 years' use: from 9 per 1000 to 11 to 30 per 1000). Among women with cardiovascular disease, use of combined continuous HT significantly increased the risk of venous thromboembolism (at 1 year's use: from 3 per 1000 to between 3 and 29 per 1000). Women taking HT had a significantly decreased incidence of fracture with long-term use.Risk of fracture was the only outcome for which strong evidence showed clinical benefit derived from HT (after 5.6 years' use of combined HT: from 111 per 1000 to between 79 and 96 per 1000; after 7.1 years' use of oestrogen-only HT: from 141 per 1000 to between 92 and 113 per 1000). Researchers found no strong evidence that HT has a clinically meaningful impact on the incidence of colorectal cancer.One trial analysed subgroups of 2839 relatively healthy women 50 to 59 years of age who were taking combined continuous HT and 1637 who were taking oestrogen-only HT versus similar-sized placebo groups. The only significantly increased risk reported was for venous thromboembolism in women taking combined continuous HT: Their absolute risk remained low, at less than 1/500. However, other differences in risk cannot be excluded, as this study was not designed to have the power to detect differences between groups of women within 10 years of menopause.For most studies, risk of bias was low in most domains. The overall quality of evidence for the main comparisons was moderate. The main limitation in the quality of evidence was that only about 30% of women were 50 to 59 years old at baseline, which is the age at which women are most likely to consider HT for vasomotor symptoms. AUTHORS' CONCLUSIONS: Women with intolerable menopausal symptoms may wish to weigh the benefits of symptom relief against the small absolute risk of harm arising from short-term use of low-dose HT, provided they do not have specific contraindications. HT may be unsuitable for some women, including those at increased risk of cardiovascular disease, increased risk of thromboembolic disease (such as those with obesity or a history of venous thrombosis) or increased risk of some types of cancer (such as breast cancer, in women with a uterus). The risk of endometrial cancer among women with a uterus taking oestrogen-only HT is well documented.HT is not indicated for primary or secondary prevention of cardiovascular disease or dementia, nor for prevention of deterioration of cognitive function in postmenopausal women. Although HT is considered effective for the prevention of postmenopausal osteoporosis, it is generally recommended as an option only for women at significant risk for whom non-oestrogen therapies are unsuitable. Data are insufficient for assessment of the risk of long-term HT use in perimenopausal women and in postmenopausal women younger than 50 years of age.

Clomiphene and other antioestrogens for ovulation induction in polycystic ovarian syndrome.

BACKGROUND: Subfertility due to anovulation is a common problem in women. First-line oral treatment is with antioestrogens such as clomiphene citrate, but resistance may be apparent with clomiphene. Alternative and adjunctive treatments have been used including tamoxifen, dexamethasone, and bromocriptine. The effectiveness of these is to be determined. OBJECTIVES: To determine the relative effectiveness of antioestrogen agents including clomiphene alone or in combination with other medical therapies in women with subfertility associated with anovulation, possibly caused by polycystic ovarian syndrome. SEARCH METHODS: We conducted a search of the Cochrane Gynaecology and Fertility Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO, and CINAHL (all from inception to August 2016) to identify relevant randomised controlled trials (RCTs). We searched the United Kingdom National Institute for Clinical Excellence (NICE) guidelines and the references of relevant reviews and RCTs. We also searched the clinical trial registries for ongoing trials (inception until August 2016). SELECTION CRITERIA: We considered RCTs comparing oral antioestrogen agents for ovulation induction (alone or in conjunction with medical therapies) in anovulatory subfertility. We excluded insulin-sensitising agents, aromatase inhibitors, and hyperprolactinaemic infertility. DATA COLLECTION AND ANALYSIS: Two review authors independently performed data extraction and quality assessment. The primary outcome was live birth; secondary outcomes were pregnancy, ovulation, miscarriage, multiple pregnancy, ovarian hyperstimulation syndrome, and adverse effects. MAIN RESULTS: This is a substantive update of a previous review. We identified an additional 13 studies in the 2016 update. The review now includes 28 RCTs (3377 women) and five RCTs awaiting classification. Five of the 28 included trials reported live birth/ongoing pregnancy. Secondary outcomes were poorly reported.The quality of the evidence ranged from low to very low. The primary reasons for downgrading the evidence were imprecision and risk of bias associated with poor reporting. Antioestrogen versus placebo Live birth rate, miscarriage rate, multiple pregnancy rate, and ovarian hyperstimulation syndrome (OHSS)No data were reported for these outcomes. Clinical pregnancy rateClomiphene citrate was associated with an increased chance of a clinical pregnancy compared with placebo, though the size of the benefit was very uncertain (odds ratio (OR) 5.91, 95% confidence interval (CI) 1.77 to 19.68; 3 studies; 133 women; low-quality evidence). If the chance of a clinical pregnancy was 5% in the placebo group, then between 8% and 50% of women would have a clinical pregnancy in the clomiphene group. Clomiphene citrate versus tamoxifen Live birth rateThere was no clear evidence of a difference in the chance of a live birth between the clomiphene citrate and tamoxifen groups (OR 1.24, 95% CI 0.59 to 2.62; 2 studies; 195 women; low-quality evidence). If 20% of women in the tamoxifen group had a live birth, then between 13% and 40% of women in the clomiphene citrate group would have a live birth. Miscarriage rateThere was no clear evidence of a difference in the chance of a miscarriage between the clomiphene citrate and tamoxifen groups (OR 1.81, 95% CI 0.80 to 4.12; 4 studies; 653 women; low-quality evidence). If 3% of women in the tamoxifen group had a miscarriage, then between 2% and 10% in the clomiphene citrate group would have a miscarriage. Clinical pregnancy rateThere was no clear evidence of a difference in the chance of a clinical pregnancy between the clomiphene citrate and tamoxifen groups (OR 1.30, 95% CI 0.92 to 1.85; 5 studies; 757 women; I2 = 69%; low-quality evidence). If 22% of women in the tamoxifen group had a clinical pregnancy, then between 21% and 35% in the clomiphene citrate group would have a clinical pregnancy. Multiple pregnancy rate There was insufficient evidence of a difference in the chance of a multiple pregnancy between the clomiphene citrate group (OR 2.34, 95% CI 0.34 to 16.04; 3 studies; 567 women; very low-quality evidence). If 0% of women in the tamoxifen group had a multiple pregnancy, then between 0% and 0.5% of women in the clomiphene group would have a multiple pregnancy. OHSSThere were no instances of OHSS in either the clomiphene citrate or the tamoxifen group reported from three studies. Clomiphene citrate with tamoxifen versus tamoxifen alone Clinical pregnancy rateThere was insufficient evidence to determine whether there was a difference between groups (OR 3.32, 95% CI 0.12 to 91.60; 1 study; 20 women; very low-quality evidence). No data were reported for the other outcomes. Other comparisons of interestLimited evidence suggested that compared with a gonadotropin, clomiphene citrate was associated with a reduced chance of a pregnancy, ongoing pregnancy, or live birth, with no clear evidence of a difference in multiple pregnancy rates.The comparison of clomiphene citrate plus medical adjunct versus clomiphene alone was limited by the number of trials reporting the comparison and poor reporting of clinical outcomes relevant to this systematic review and by the number of adjuncts reported (ketoconazole, bromocriptine, dexamethasone, combined oral contraceptive, human chorionic gonadotropin, hormone supplementation). The addition of dexamethasone or combined oral contraceptive suggested a possible benefit in pregnancy outcomes, but findings were very uncertain and further research is required to confirm this.There was limited evidence suggesting that a 10-day regimen of clomiphene citrate improves pregnancy outcomes compared with a 5-day regimen. Data for early versus late regimens of clomiphene citrate were insufficient to be able to make a judgement on differences for pregnancy outcomes. AUTHORS' CONCLUSIONS: We found evidence suggesting that clomiphene citrate improves the chance of a clinical pregnancy compared with placebo, but may reduce the chance of live birth or ongoing pregnancy when compared with a gonadotropin. Due to low event rates, we advise caution interpreting these data.The comparison of clomiphene citrate plus medical adjunctive versus clomiphene alone was limited by the number of trials reporting the comparison. The evidence was very low quality and no firm conclusions could be drawn, but very limited evidence suggested a benefit from adjunctive dexamethasone or combined oral contraceptives. Low-quality evidence suggested that a 10-day regimen of clomiphene citrate improves pregnancy rates compared with a 5-day regimen, but further research is required.

Combination of the non-invasive tests for the diagnosis of endometriosis.

BACKGROUND: About 10% of women of reproductive age suffer from endometriosis, a costly chronic disease causing pelvic pain and subfertility. Laparoscopy is the gold standard diagnostic test for endometriosis, but is expensive and carries surgical risks. Currently, there are no non-invasive tests available in clinical practice to accurately diagnose endometriosis. This review assessed the diagnostic accuracy of combinations of different non-invasive testing modalities for endometriosis and provided a summary of all the reviews in the non-invasive tests for endometriosis series. OBJECTIVES: To estimate the diagnostic accuracy of any combination of non-invasive tests for the diagnosis of pelvic endometriosis (peritoneal and/or ovarian or deep infiltrating) compared to surgical diagnosis as a reference standard. The combined tests were evaluated as replacement tests for diagnostic surgery and triage tests to assist decision-making to undertake diagnostic surgery for endometriosis. SEARCH METHODS: We did not restrict the searches to particular study designs, language or publication dates. We searched CENTRAL to July 2015, MEDLINE and EMBASE to May 2015, as well as the following databases to April 2015: CINAHL, PsycINFO, Web of Science, LILACS, OAIster, TRIP, ClinicalTrials.gov, DARE and PubMed. SELECTION CRITERIA: We considered published, peer-reviewed, randomised controlled or cross-sectional studies of any size, including prospectively collected samples from any population of women of reproductive age suspected of having one or more of the following target conditions: ovarian, peritoneal or deep infiltrating endometriosis (DIE). We included studies comparing the diagnostic test accuracy of a combination of several testing modalities with the findings of surgical visualisation of endometriotic lesions. DATA COLLECTION AND ANALYSIS: Three review authors independently collected and performed a quality assessment of the data from each study by using the QUADAS-2 tool. For each test, the data were classified as positive or negative for the surgical detection of endometriosis and sensitivity and specificity estimates were calculated. The bivariate model was planned to obtain pooled estimates of sensitivity and specificity whenever sufficient data were available. The predetermined criteria for a clinically useful test to replace diagnostic surgery were a sensitivity of 0.94 and a specificity of 0.79 to detect endometriosis. We set the criteria for triage tests at a sensitivity of 0.95 and above and a specificity of 0.50 and above, which 'rules out' the diagnosis with high accuracy if there is a negative test result (SnOUT test), or a sensitivity of 0.50 and above and a specificity of 0.95 and above, which 'rules in' the diagnosis with high accuracy if there is a positive result (SpIN test). MAIN RESULTS: Eleven eligible studies included 1339 participants. All the studies were of poor methodological quality. Seven studies evaluated pelvic endometriosis, one study considered DIE and/or ovarian endometrioma, two studies differentiated endometrioma from other ovarian cysts and one study addressed mapping DIE at specific anatomical sites. Fifteen different diagnostic combinations were assessed, including blood, urinary or endometrial biomarkers, transvaginal ultrasound (TVUS) and clinical history or examination. We did not pool estimates of sensitivity and specificity, as each study analysed independent combinations of the non-invasive tests.Tests that met the criteria for a replacement test were: a combination of serum IL-6 (cut-off >15.4 pg/ml) and endometrial PGP 9.5 for pelvic endometriosis (sensitivity 1.00 (95% confidence interval (CI) 0.91 to 1.00), specificity 0.93 (95% CI, 0.80, 0.98) and the combination of vaginal examination and transvaginal ultrasound (TVUS) for rectal endometriosis (sensitivity 0.96 (95% CI 0.86 to 0.99), specificity 0.98 (95% CI 0.94 to 1.00)). Tests that met the criteria for SpIN triage tests for pelvic endometriosis were: 1. a multiplication of urine vitamin-D-binding protein (VDBP) and serum CA-125 (cut-off >2755) (sensitivity 0.74 (95% CI 0.60 to 0.84), specificity 0.97 (95% CI 0.86 to 1.00)) and 2. a combination of history (length of menses), serum CA-125 (cut-off >35 U/ml) and endometrial leukocytes (sensitivity 0.61 (95% CI 0.54 to 0.69), specificity 0.95 (95% CI 0.91 to 0.98)). For endometrioma, the following combinations qualified as SpIN test: 1. TVUS and either serum CA-125 (cut-off ≥25 U/ml) or CA 19.9 (cut-off ≥12 U/ml) (sensitivity 0.79 (95% CI 0.64 to 0.91), specificity 0.97 (95% CI 0.91 to 1.00)); 2. TVUS and serum CA 19.9 (cut-off ≥12 U/ml) (sensitivity 0.54 (95% CI 0.37 to 0.70), specificity 0.97 (95% CI 0.91 to 1.0)); 3-4. TVUS and serum CA-125 (cut-off ≥20 U/ml or cut-off ≥25 U/ml) (sensitivity 0.69 (95% CI 0.49 to 0.85), specificity 0.96 (95% CI 0.88 to 0.99)); 5. TVUS and serum CA-125 (cut-off ≥35 U/ml) (sensitivity 0.52 (95% CI 0.33 to 0.71), specificity 0.97 (95% CI 0.90 to 1.00)). A combination of vaginal examination and TVUS reached the threshold for a SpIN test for obliterated pouch of Douglas (sensitivity 0.87 (95% CI 0.69 to 0.96), specificity 0.98 (95% CI 0.95 to 1.00)), vaginal wall endometriosis (sensitivity 0.82 (95% CI 0.60 to 0.95), specificity 0.99 (95% CI 0.97 to 1.0)) and rectovaginal septum endometriosis (sensitivity 0.88 (95% CI 0.47 to 1.00), specificity 0.99 (95% CI 0.96 to 1.00)).All the tests were evaluated in individual studies and displayed wide CIs. Due to the heterogeneity and high risk of bias of the included studies, the clinical utility of the studied combination diagnostic tests for endometriosis remains unclear. AUTHORS' CONCLUSIONS: None of the biomarkers evaluated in this review could be evaluated in a meaningful way and there was insufficient or poor-quality evidence. Laparoscopy remains the gold standard for the diagnosis of endometriosis and using any non-invasive tests should only be undertaken in a research setting.

Endometrial injury for pregnancy following sexual intercourse or intrauterine insemination.

BACKGROUND: Intentional endometrial injury is currently being proposed as a technique to improve the probability of pregnancy in women undergoing assisted reproductive technologies (ART) such as in vitro fertilisation (IVF). Endometrial injury is often performed by pipelle biopsy or a similar technique, and is a common, simple, gynaecological procedure that has an established safety profile. However, it is also known to be associated with a moderate degree of discomfort/pain and requires an additional pelvic examination. The effectiveness of this procedure outside of ART, in women or couples attempting to conceive via sexual intercourse or with low complexity fertility treatments such as intrauterine insemination (IUI) and ovulation induction (OI), remains unclear. OBJECTIVES: To evaluate the effectiveness and safety of intentional endometrial injury in subfertile women and couples attempting to conceive through sexual intercourse or intrauterine insemination (IUI). SEARCH METHODS: We searched the Cochrane Gyanecology and Fertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS, DARE, ISI Web of Knowledge and ClinicalTrials.gov; as well as reference lists of relevant reviews and included studies. We performed the searches from inception to 31 October 2015. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that evaluated any kind of intentional endometrial injury in women planning to undergo IUI or attempting to conceive spontaneously (with or without OI) compared to no intervention, a mock intervention or intentional endometrial injury performed at a different time or to a higher/lower degree. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted data and assessed trial quality using GRADE methodology. The primary outcomes were live birth/ongoing pregnancy and pain experienced during the procedure. Secondary outcomes were clinical pregnancy, miscarriage, ectopic pregnancy, multiple pregnancy and bleeding secondary to the procedure. We combined data to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I(2) statistic. MAIN RESULTS: Nine trials, which included a total of 1512 women, met the inclusion criteria of this Cochrane review. Most of these studies included women with unexplained infertility. In seven studies the women were undergoing IUI and in two studies the women were trying to conceive from sexual intercourse. Eight trials compared intentional endometrial injury with no injury/placebo procedure; of these two trials also compared intentional endometrial injury in the cycle prior to IUI with intentional endometrial injury in the IUI cycle. One trial compared higher vs. lower degree of intentional endometrial injury. Intentional endometrial injury vs. either no intervention or a sham procedureWe are uncertain whether endometrial injury improves live birth/ongoing pregnancy as the quality of the evidence has been assessed as very low (risk ratio (RR) 2.22, 95% confidence interval (CI) 1.56 to 3.15; six RCTs, 950 participants; I² statistic = 0%, very low quality evidence). When we restricted the analysis to only studies at low risk of bias the effect was imprecise and the evidence remained of very low quality (RR 2.64, 95% CI 1.03 to 6.82; one RCT, 105 participants; very low quality evidence). Endometrial injury may improve clinical pregnancy rates however the evidence is of low quality (RR 1.98, 95% CI 1.51 to 2.58; eight RCTs, 1180 participants; I² statistic = 0%, low quality evidence).The average pain experienced by participants undergoing endometrial injury was 6/10 on a zero-10 visual analogue scale (VAS)(standard deviation = 1.5). However, only one study reported this outcome. Higher vs. lower degree of intentional endometrial injuryWhen we compared hysteroscopy with endometrial injury to hysteroscopy alone, there was no evidence of a difference in ongoing pregnancy rate (RR 1.29, 95% CI 0.71 to 2.35; one RCT, 332 participants; low quality evidence) or clinical pregnancy rate (RR 1.15, 95% CI 0.66 to 2.01; one RCT, 332 participants, low quality evidence). This study did not report the primary outcome of pain during the procedure. Timing of intentional endometrial injuryWhen endometrial injury was performed in the cycle prior to IUI compared to the same cycle as the IUI, there was no evidence of a difference in ongoing pregnancy rate (RR 0.65, 95% CI 0.37 to 1.16, one RCT, 176 participants; very low quality evidence) or clinical pregnancy rate (RR 0.82, 95% CI 0.50 to 1.36; two RCTs, 276 participants; very low quality evidence). Neither of these studies reported the primary outcome of pain during the procedure.In all three comparisons there was no evidence of an effect on miscarriage, ectopic pregnancy or multiple pregnancy. No studies reported bleeding secondary to the procedure. AUTHORS' CONCLUSIONS: It is uncertain whether endometrial injury improves the probability of pregnancy and live birth/ongoing pregnancy in women undergoing IUI or attempting to conceive via sexual intercourse. The pooled results should be interpreted with caution as we graded the quality of the evidence as either low or very low. The main reasons we downgraded the quality of the evidence were most included studies were at a high risk of bias and had an overall low level of precision. Further well-conducted RCTs that recruit large numbers of participants and minimise internal bias are required to confirm or refute these findings.

High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with early poor prognosis breast cancer.

BACKGROUND: Overall survival rates are disappointing for women with early poor prognosis breast cancer. Autologous transplantation of bone marrow or peripheral stem cells (in which the woman is both donor and recipient) has been considered a promising technique because it permits use of much higher doses of chemotherapy. OBJECTIVES: To compare the effectiveness and safety of high-dose chemotherapy and autograft (either autologous bone marrow or stem cell transplantation) with conventional chemotherapy for women with early poor prognosis breast cancer. SEARCH METHODS: We searched the Cochrane Breast Cancer Group Specialised Register, MEDLINE (1966 to October 2015), EMBASE (1980 to October 2015), the World Health Organization's International Clinical Trials Registry Search Platform, and ClinicalTrials.gov on the 21 October 2015. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing high-dose chemotherapy and autograft (bone marrow transplant or stem cell rescue) versus chemotherapy without autograft for women with early poor prognosis breast cancer. DATA COLLECTION AND ANALYSIS: Two review authors selected RCTs, independently extracted data and assessed risks of bias. We combined data using a Mantel-Haenszel fixed-effect model to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs). We assessed the quality of the evidence using GRADE methods. Outcomes were survival rates, toxicity and quality of life. MAIN RESULTS: We included 14 RCTs of 5600 women randomised to receive high-dose chemotherapy and autograft (bone marrow transplant or stem cell rescue) versus chemotherapy without autograft for women with early poor prognosis breast cancer. The studies were at low risk of bias in most areas.There is high-quality evidence that high-dose chemotherapy does not increase the likelihood of overall survival at any stage of follow-up (at three years: RR 1.02, 95% CI 0.95 to 1.10, 3 RCTs, 795 women, I² = 56%; at five years: RR 1.00, 95% CI 0.96 to 1.04, 9 RCTs, 3948 women, I² = 0%; at six years: RR 0.94, 95% CI 0.81 to 1.08, 1 RCT, 511 women; at eight years: RR1.17, 95% CI 0.95 to 1.43, 1 RCT, 344 women; at 12 years: RR 1.18, 95% CI 0.99 to 1.42, 1 RCT, 382 women).There is high-quality evidence that high-dose chemotherapy improves the likelihood of event-free survival at three years (RR 1.19, 95% CI 1.06 to 1.34, 3 RCTs, 795 women, I² = 56%) but this effect was no longer apparent at longer duration of follow-up (at five years: RR 1.04, 95% CI 0.99 to 1.09, 9 RCTs, 3948 women, I² = 14%; at six years RR 1.04, 95% CI 0.87 to 1.24, 1 RCT, 511 women; at eight years: RR 1.27, 95% CI 0.99 to 1.64, 1 RCT, 344 women; at 12 years: RR 1.18, 95% CI 0.95 to 1.45, 1 RCT, 382 women).Treatment-related deaths were much more frequent in the high-dose arm (RR 7.97, 95% CI 3.99 to 15.92, 14 RCTs, 5600 women, I² = 12%, high-quality evidence) and non-fatal morbidity was also more common and more severe in the high-dose group. There was little or no difference between the groups in the incidence of second cancers at four to nine years' median follow-up (RR 1.25, 95% CI 0.90 to 1.73, 7 RCTs, 3423 women, I² = 0%, high-quality evidence). Women in the high-dose group reported significantly worse quality-of-life scores immediately after treatment, but there were few statistically significant differences between the groups by one year.The primary studies were at low risk of bias in most areas, and the evidence was assessed using GRADE methods and rated as high quality for all comparisons. AUTHORS' CONCLUSIONS: There is high-quality evidence of increased treatment-related mortality and little or no increase in survival by using high-dose chemotherapy with autograft for women with early poor prognosis breast cancer.

Blood biomarkers for the non-invasive diagnosis of endometriosis.

BACKGROUND: About 10% of reproductive-aged women suffer from endometriosis, a costly chronic disease causing pelvic pain and subfertility. Laparoscopy is the gold standard diagnostic test for endometriosis, but is expensive and carries surgical risks. Currently, there are no non-invasive or minimally invasive tests available in clinical practice to accurately diagnose endometriosis. Although other reviews have assessed the ability of blood tests to diagnose endometriosis, this is the first review to use Cochrane methods, providing an update on the rapidly expanding literature in this field. OBJECTIVES: To evaluate blood biomarkers as replacement tests for diagnostic surgery and as triage tests to inform decisions on surgery for endometriosis. Specific objectives include:1. To provide summary estimates of the diagnostic accuracy of blood biomarkers for the diagnosis of peritoneal, ovarian and deep infiltrating pelvic endometriosis, compared to surgical diagnosis as a reference standard.2. To assess the diagnostic utility of biomarkers that could differentiate ovarian endometrioma from other ovarian masses. SEARCH METHODS: We did not restrict the searches to particular study designs, language or publication dates. We searched CENTRAL to July 2015, MEDLINE and EMBASE to May 2015, as well as these databases to 20 April 2015: CINAHL, PsycINFO, Web of Science, LILACS, OAIster, TRIP, ClinicalTrials.gov, DARE and PubMed. SELECTION CRITERIA: We considered published, peer-reviewed, randomised controlled or cross-sectional studies of any size, including prospectively collected samples from any population of reproductive-aged women suspected of having one or more of the following target conditions: ovarian, peritoneal or deep infiltrating endometriosis (DIE). We included studies comparing the diagnostic test accuracy of one or more blood biomarkers with the findings of surgical visualisation of endometriotic lesions. DATA COLLECTION AND ANALYSIS: Two authors independently collected and performed a quality assessment of data from each study. For each diagnostic test, we classified the data as positive or negative for the surgical detection of endometriosis, and we calculated sensitivity and specificity estimates. We used the bivariate model to obtain pooled estimates of sensitivity and specificity whenever sufficient datasets were available. The predetermined criteria for a clinically useful blood test to replace diagnostic surgery were a sensitivity of 0.94 and a specificity of 0.79 to detect endometriosis. We set the criteria for triage tests at a sensitivity of ≥ 0.95 and a specificity of ≥ 0.50, which 'rules out' the diagnosis with high accuracy if there is a negative test result (SnOUT test), or a sensitivity of ≥ 0.50 and a specificity of ≥ 0.95, which 'rules in' the diagnosis with high accuracy if there is a positive result (SpIN test). MAIN RESULTS: We included 141 studies that involved 15,141 participants and evaluated 122 blood biomarkers. All the studies were of poor methodological quality. Studies evaluated the blood biomarkers either in a specific phase of the menstrual cycle or irrespective of the cycle phase, and they tested for them in serum, plasma or whole blood. Included women were a selected population with a high frequency of endometriosis (10% to 85%), in which surgery was indicated for endometriosis, infertility work-up or ovarian mass. Seventy studies evaluated the diagnostic performance of 47 blood biomarkers for endometriosis (44 single-marker tests and 30 combined tests of two to six blood biomarkers). These were angiogenesis/growth factors, apoptosis markers, cell adhesion molecules, high-throughput markers, hormonal markers, immune system/inflammatory markers, oxidative stress markers, microRNAs, tumour markers and other proteins. Most of these biomarkers were assessed in small individual studies, often using different cut-off thresholds, and we could only perform meta-analyses on the data sets for anti-endometrial antibodies, interleukin-6 (IL-6), cancer antigen-19.9 (CA-19.9) and CA-125. Diagnostic estimates varied significantly between studies for each of these biomarkers, and CA-125 was the only marker with sufficient data to reliably assess sources of heterogeneity.The mean sensitivities and specificities of anti-endometrial antibodies (4 studies, 759 women) were 0.81 (95% confidence interval (CI) 0.76 to 0.87) and 0.75 (95% CI 0.46 to 1.00). For IL-6, with a cut-off value of > 1.90 to 2.00 pg/ml (3 studies, 309 women), sensitivity was 0.63 (95% CI 0.52 to 0.75) and specificity was 0.69 (95% CI 0.57 to 0.82). For CA-19.9, with a cut-off value of > 37.0 IU/ml (3 studies, 330 women), sensitivity was 0.36 (95% CI 0.26 to 0.45) and specificity was 0.87 (95% CI 0.75 to 0.99).Studies assessed CA-125 at different thresholds, demonstrating the following mean sensitivities and specificities: for cut-off > 10.0 to 14.7 U/ml: 0.70 (95% CI 0.63 to 0.77) and 0.64 (95% CI 0.47 to 0.82); for cut-off > 16.0 to 17.6 U/ml: 0.56 (95% CI 0.24, 0.88) and 0.91 (95% CI 0.75, 1.00); for cut-off > 20.0 U/ml: 0.67 (95% CI 0.50 to 0.85) and 0.69 (95% CI 0.58 to 0.80); for cut-off > 25.0 to 26.0 U/ml: 0.73 (95% CI 0.67 to 0.79) and 0.70 (95% CI 0.63 to 0.77); for cut-off > 30.0 to 33.0 U/ml: 0.62 (95% CI 0.45 to 0.79) and 0.76 (95% CI 0.53 to 1.00); and for cut-off > 35.0 to 36.0 U/ml: 0.40 (95% CI 0.32 to 0.49) and 0.91 (95% CI 0.88 to 0.94).We could not statistically evaluate other biomarkers meaningfully, including biomarkers that were assessed for their ability to differentiate endometrioma from other benign ovarian cysts.Eighty-two studies evaluated 97 biomarkers that did not differentiate women with endometriosis from disease-free controls. Of these, 22 biomarkers demonstrated conflicting results, with some studies showing differential expression and others no evidence of a difference between the endometriosis and control groups. AUTHORS' CONCLUSIONS: Of the biomarkers that were subjected to meta-analysis, none consistently met the criteria for a replacement or triage diagnostic test. A subset of blood biomarkers could prove useful either for detecting pelvic endometriosis or for differentiating ovarian endometrioma from other benign ovarian masses, but there was insufficient evidence to draw meaningful conclusions. Overall, none of the biomarkers displayed enough accuracy to be used clinically outside a research setting. We also identified blood biomarkers that demonstrated no diagnostic value in endometriosis and recommend focusing research resources on evaluating other more clinically useful biomarkers.

Pipelle for Pregnancy (PIP): study protocols for three randomised controlled trials.

BACKGROUND: The success rate of infertility treatments remains modest. Endometrial injury has been suggested as an intervention to increase the probability of pregnancy in women undergoing assisted reproductive technologies such as in vitro fertilisation (IVF). The majority of studies and systematic reviews have reported that endometrial injury improves the outcomes of IVF, intrauterine insemination and natural conception; however, the size and quality of the studies are poor. The low quality of the available evidence questions the presence of any real beneficial effect, and the applicability of the intervention in different populations remains unclear. METHODS/DESIGN: The PIP trials are three multi-centre, randomised controlled trials designed to test three separate hypotheses: whether endometrial injury increases the probability of live birth in women or couples 1) who are undergoing autologous embryo transfer as part of an IVF cycle (PIP-IVF), 2) with unexplained infertility who are attempting to conceive naturally (PIP-UE) and 3) with subfertility related to polycystic ovarian syndrome (PCOS) who are on ovulation induction medication and attempting to conceive (PIP-PCOS). Participants will be randomised to either undergo endometrial injury by endometrial pipelle biopsy or to: • no intervention (PIP-IVF), or • a sham procedure (PIP-PCOS and PIP-UE). In PIP-IVF, endometrial injury will be carried out between day three of the cycle prior to the IVF cycle, and day three of the IVF cycle. In PIP-UE and PIP-PCOS, endometrial injury or a sham procedure will be undertaken between days 1-12 of a menstrual cycle or ovulation induction cycle respectively. Participants in PIP-UE and PIP-PCOS will then be followed for three cycles during which time they will attempt to conceive from sexual intercourse. To ensure allocation concealment, randomisation will be carried out using a web-based system or sequentially numbered, opaque, sealed envelopes. The primary outcome is live birth. Secondary outcomes include ongoing pregnancy, clinical pregnancy and miscarriage. The required sample sizes for the PIP studies have been estimated at 840 (PIP-IVF), 350 (PIP-UE) and 280 (PIP-PCOS). Primary analysis will be as per intention-to-treat principles. DISCUSSION: The PIP trials are designed to address the gaps in the utility of endometrial scratching as a treatment for subfertility in three different populations. If the beneficial effect of this intervention can be confirmed in these settings, endometrial scratching will provide a cost-effective method for helping women and couples to conceive. TRIAL REGISTRATIONS: PIP-IVF ACTRN12614000626662 registered 13/6/2014; PIP-PCOS ACTRN12614000657628 registered 24/6/2014; PIP-UE ACTRN12614000656639 registered 24/6/2014. The trials are ongoing.