Attitudes, knowledge and practice regarding the anti-müllerian hormone test among general practitioners and reproductive specialists: A cross-sectional study.

OBJECTIVE: To describe clinicians' attitudes, knowledge and practice relating to the anti-müllerian hormone (AMH) test. DESIGN: Cross-sectional nationwide survey. SETTING: Australia. POPULATION OR SAMPLE: A total of 362 general practitioners (GPs), gynaecologists and reproductive specialists. METHODS: Clinicians were recruited through relevant professional organisations, with data collected from May 2021 to April 2022. MAIN OUTCOME MEASURES: Clinicians' attitudes, knowledge and practice relating to the AMH test, measured using multiple choice, Likert scales and open-ended items. RESULTS: Fifteen percent of GPs (n = 27) and 40% of gynaecologists and other specialists (n = 73) order at least one AMH test per month. Specialists reported raising the idea of testing most of the time, whereas GPs reported that patient request was more common. Half of clinicians lacked confidence interpreting (n = 182, 51%) and explaining (n = 173, 48%) an AMH result to their patients. Five percent (n = 19) believed the test was moderately/very useful in predicting natural conception/birth and 22% (n = 82) believed the same for predicting premature menopause, despite evidence that the test cannot reliably predict either. Forty percent (n = 144) had previously ordered the test to help with reproductive planning and 21% (n = 75) to provide reassurance about fertility. CONCLUSIONS: Clinicians reported use of AMH testing in clinical circumstances not supported by the evidence. With the proliferation of direct-to-consumer testing, efforts to support clinicians in the judicious use of testing and effectively navigating patient requests are needed.

Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI).

BACKGROUND: During a stimulated cycle of in vitro fertilisation or intracytoplasmic sperm injection (IVF/ICSI), women receive daily doses of gonadotropin follicle-stimulating hormone (FSH) to induce multifollicular development in the ovaries. A normal response to stimulation (e.g. retrieval of 5 to 15 oocytes) is considered desirable. Generally, the number of eggs retrieved is associated with the dose of FSH. Both hyper-response and poor response are associated with an increased chance of cycle cancellation. In hyper-response, this is due to increased risk of ovarian hyperstimulation syndrome (OHSS), while poor response cycles are cancelled because the quantity and quality of oocytes is expected to be low. Clinicians often individualise the FSH dose using patient characteristics predictive of ovarian response. Traditionally, this meant women's age, but increasingly, clinicians use various ovarian reserve tests (ORTs). These include basal FSH (bFSH), antral follicle count (AFC), and anti-Müllerian hormone (AMH). It is unclear whether individualising FSH dose improves clinical outcomes. This review updates the 2018 version. OBJECTIVES: To assess the effects of individualised gonadotropin dose selection using markers of ovarian reserve in women undergoing IVF/ICSI. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL, MEDLINE, Embase, and two trial registers in February 2023. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared (a) different doses of FSH in women with a defined ORT profile (i.e. predicted low, normal, or high responders based on AMH, AFC, and/or bFSH) or (b) an individualised dosing strategy (based on at least one ORT measure) versus uniform dosing or a different individualised dosing algorithm. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. Primary outcomes were live birth/ongoing pregnancy and severe OHSS. MAIN RESULTS: We included 26 studies, involving 8520 women (6 new studies added to 20 studies included in the previous version). We treated RCTs with multiple comparisons as separate trials for the purpose of this review. Meta-analysis was limited due to clinical heterogeneity. Evidence certainty ranged from very low to low, with the main limitations being imprecision and risk of bias associated with lack of blinding. Direct dose comparisons according to predicted response in women Due to differences in dose comparisons, caution is required when interpreting the RCTs in predicted low responders. All evidence was low or very low certainty. Effect estimates were very imprecise, and increased FSH dosing may or may not have an impact on rates of live birth/ongoing pregnancy, OHSS, and clinical pregnancy. Similarly, in predicted normal responders (10 studies, 4 comparisons), higher doses may or may not impact the probability of live birth/ongoing pregnancy (e.g. 200 versus 100 international units (IU): odds ratio (OR) 0.88, 95% confidence interval (CI) 0.57 to 1.36; I2 = 0%; 2 studies, 522 women) or clinical pregnancy. Results were imprecise, and a small benefit or harm remains possible. There were too few events for the OHSS outcome to enable inferences. In predicted high responders, lower doses may or may not affect live birth/ongoing pregnancy (OR 0.98, 95% CI 0.66 to 1.46; 1 study, 521 women), severe OHSS, and clinical pregnancy. It is also unclear whether lower doses reduce moderate or severe OHSS (Peto OR 2.31, 95% CI 0.80 to 6.67; 1 study, 521 participants). ORT-algorithm studies Eight trials compared an ORT-based algorithm to a non-ORT control group. It is unclear whether live birth/ongoing pregnancy and clinical pregnancy are increased using an ORT-based algorithm (live birth/ongoing pregnancy: OR 1.12, 95% CI 0.98 to 1.29; I2 = 30%; 7 studies, 4400 women; clinical pregnancy: OR 1.04, 95% CI 0.91 to 1.18; I2 = 18%; 7 studies, 4400 women; low-certainty evidence). However, ORT algorithms may reduce moderate or severe OHSS (Peto OR 0.60, 95% CI 0.42 to 0.84; I2 = 0%; 7 studies, 4400 women; low-certainty evidence). There was insufficient evidence to determine whether the groups differed in rates of severe OHSS (Peto OR 0.74, 95% CI 0.42 to 1.28; I2 = 0%; 5 studies, 2724 women; low-certainty evidence). Our findings suggest that if the chance of live birth with a standard starting dose is 25%, the chance with ORT-based dosing would be between 25% and 31%. If the chance of moderate or severe OHSS with a standard starting dose is 5%, the chance with ORT-based dosing would be between 2% and 5%. These results should be treated cautiously due to heterogeneity in the algorithms: some algorithms appear to be more effective than others. AUTHORS' CONCLUSIONS: We did not find that tailoring the FSH dose in any particular ORT population (low, normal, high ORT) affected live birth/ongoing pregnancy rates, but we could not rule out differences, due to sample size limitations. Low-certainty evidence suggests that it is unclear if ORT-based individualisation leads to an increase in live birth/ongoing pregnancy rates compared to a policy of giving all women 150 IU. The confidence interval is consistent with an increase of up to around six percentage points with ORT-based dosing (e.g. from 25% to 31%) or a very small decrease (< 1%). A difference of this magnitude could be important to many women. It is unclear if this is driven by improved outcomes in a particular subgroup. Further, ORT algorithms reduced the incidence of OHSS compared to standard dosing of 150 IU. However, the size of the effect is also unclear. The included studies were heterogeneous in design, which limited the interpretation of pooled estimates. It is likely that different ORT algorithms differ in their effectiveness. Current evidence does not provide a clear justification for adjusting the dose of 150 IU in poor or normal responders, especially as increased dose is associated with greater total FSH dose and cost. It is unclear whether a decreased dose in predicted high responders reduces OHSS, although this would appear to be the most likely explanation for the results.

The most impactful endometriosis symptom: An international, cross-sectional, two-round survey study.

INTRODUCTION: There is considerable variation in the types of symptoms experienced by people living with endometriosis, and it is unclear which symptoms impact people the most. This study aimed to identify the specific symptoms that are "most impactful" to people living with the condition. MATERIAL AND METHODS: Two sequential online surveys were conducted. Women aged over 18 years with a diagnosis of endometriosis were eligible to participate. Participants first provided a free-text list of all the endometriosis symptoms they experienced (Survey 1, Australian only). Responses were condensed into a shorter list by grouping symptom types and selecting the top 20 most common and most impactful. Survey 2 (international) participants reviewed the list and selected all that they had experienced in the last 3 months, nominated one as their single "most impactful symptom", and rated its impact on one of five randomized scale types. RESULTS: Survey 1 and Survey 2 had 195 and 983 responses, respectively. The mean age of respondents was 30.8 ± 7.9 years. There were 275 separate symptom descriptions from Survey 1, which were condensed into 104 groups, of which 25 met criteria for inclusion in Survey 2. The most commonly experienced symptoms were abdominal pain (93% of respondents), bloating (92%), and fatigue (90%), and the symptoms nominated as causing the most impact were pelvic pain (20%), abdominal pain (15%), and cramps (7%). Nearly everyone (99.7%) in Survey 2 reported experiencing at least one pain symptom. The symptoms that generated the highest impact scores were infertility (99.8/100), irregular menstrual cycles (95.3/100), and constipation (92/100). The average impact score was 87.5/100. CONCLUSIONS: There was substantial variation in the symptom selected as causing the most impact, and the level of impact was high. A focus on measuring the "most impactful symptom" in future research may enable us to better capture and measure the true symptom experience.

The "most bothersome symptom" construct: A qualitative study of Australians living with endometriosis.

INTRODUCTION: "Improvement in the most bothersome symptom" was recently selected as a core outcome for endometriosis intervention trials. This study aimed to explore the applicability of the construct of "symptom bother" in representing the lived experiences of people with endometriosis. MATERIAL AND METHODS: Semi-structured interviews were conducted to understand the meaning of "symptom bother" and related constructs. Eighteen interviews were conducted: 14 among people with a surgical diagnosis of endometriosis who were recruited from the community, and four with people who were recruited from a private gynecology clinic who had either a confirmed diagnosis or a high suspicion of the disease. All interviews were audio recorded, transcribed verbatim, and analyzed thematically. RESULTS: Three primary themes were identified: (1) endometriosis symptoms and priorities vary with time and context, (2) endometriosis symptoms impair normal daily functioning, (3) endometriosis symptoms are more than just a "bother." The concept of "bother" to describe endometriosis symptoms did not resonate with most participants. Whilst "bother" was familiar language, it did not encompass the broader implications of living with endometriosis. Participants felt "bother" implied emotional distress, lacking a full understanding of the consequences of the disease. Instead, "symptom impact" was endorsed, allowing participants to quantify and objectively assess their symptoms, free from negative connotations. CONCLUSIONS: This was the first qualitative study to explore "symptom bother" among people living with endometriosis. Instead of "bother," "impact" was widely endorsed as a suitable construct. This term more appropriately captured the broad ways in which endometriosis symptoms impair daily functioning.

Community awareness and use of anti-Müllerian hormone testing in Australia: a population survey of women.

STUDY QUESTION: What is the anti-Mullerian hormone (AMH) test usage, awareness, and perceived reasons for testing in a representative community sample of women in Australia? SUMMARY ANSWER: : Among women aged 18-55 years, 13% had heard about AMH testing and 7% had had an AMH test, with the top three reasons for testing including due to infertility investigations (51%), considering pregnancy and wanting to understand their chances (19%) or to find out if a medical condition had affected fertility (11%). WHAT IS KNOWN ALREADY: The growing availability of direct-to-consumer AMH testing has raised concerns about overuse, however as most AMH tests are paid for privately by consumers, data on test usage is not publicly available. STUDY DESIGN, SIZE, DURATION: National cross-sectional survey of 1773 women, conducted in January 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Females aged 18-55 years were recruited from the representative 'Life in Australia' probability-based population panel and completed the survey online or by telephone. Main outcome measures included if and how participants had heard about AMH testing, whether they had ever had an AMH test, main reason for testing and test access. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 2423 women who were invited 1773 responded (73% response rate). Of these, 229 (13%) had heard about AMH testing and 124 (7%) had had an AMH test. Testing rates were highest among those currently aged 35-39 years (14%) and associated with educational attainment. Almost all accessed the test through their general practitioner or fertility specialist. Reasons for testing were: part of an infertility investigation (51%), considering pregnancy and wanting to understand chances of conceiving (19%), finding out if a medical condition had affected fertility (11%), curiosity (9%), considering egg freezing (5%), and considering delaying pregnancy (2%). LIMITATIONS, REASONS FOR CAUTION: Although the sample was large and mostly representative, it was over-represented by people holding a university degree and under-represented by people aged 18-24, however, we used weighted data where possible to account for this. All data were self-reported so there is a risk of recall bias. The number of survey items was also restricted, so the type of counselling women received prior to testing, reasons for declining an AMH test or test timing were not measured. WIDER IMPLICATIONS OF THE FINDINGS: Whilst most women reported having an AMH test for appropriate reasons, about one third had it for reasons not supported by evidence. Public and clinician education about the lack of utility of AMH testing for women not undergoing infertility treatment is needed. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by a National Health and Medical Research Council (NHMRC) Centre for Research Excellence grant (1104136) and Program grant (1113532). T.C. is supported by an NHMRC Emerging Leader Research Fellowship (2009419). B.W.M. reports research funding, consultancy and travel support from Merck. D.L. is the Medical Director of City Fertility NSW and reports consultancy for Organon, Ferring, Besins and Merck. The authors have no other competing interests. TRIAL REGISTRATION NUMBER: N/A.

A Randomized Trial of Endometrial Scratching before In Vitro Fertilization.

BACKGROUND: Endometrial scratching (with the use of a pipelle biopsy) is a technique proposed to facilitate embryo implantation and increase the probability of pregnancy in women undergoing in vitro fertilization (IVF). METHODS: We conducted a pragmatic, multicenter, open-label, randomized, controlled trial. Eligible women were undergoing IVF (fresh-embryo or frozen-embryo transfer), with no recent exposure to disruptive intrauterine instrumentation (e.g., hysteroscopy). Participants were randomly assigned in a 1:1 ratio to either endometrial scratching (by pipelle biopsy between day 3 of the cycle preceding the embryo-transfer cycle and day 3 of the embryo-transfer cycle) or no intervention. The primary outcome was live birth. RESULTS: A total of 1364 women underwent randomization. The frequency of live birth was 180 of 690 women (26.1%) in the endometrial-scratch group and 176 of 674 women (26.1%) in the control group (adjusted odds ratio, 1.00; 95% confidence interval, 0.78 to 1.27). There were no significant between-group differences in the rates of ongoing pregnancy, clinical pregnancy, multiple pregnancy, ectopic pregnancy, or miscarriage. The median score for pain from endometrial scratching (on a scale of 0 to 10, with higher scores indicating worse pain) was 3.5 (interquartile range, 1.9 to 6.0). CONCLUSIONS: Endometrial scratching did not result in a higher rate of live birth than no intervention among women undergoing IVF. (Funded by the University of Auckland and others; PIP Australian New Zealand Clinical Trials Registry number, ACTRN12614000626662 .).

A randomized trial of endometrial scratching in women with PCOS undergoing ovulation induction cycles.

RESEARCH QUESTION: Does endometrial scratching improve the chance of a live birth in women with polycystic ovary syndrome (PCOS) undergoing ovulation induction and trying to conceive? DESIGN: An international, multicentre, randomized, sham-controlled trial across six fertility clinics in three countries (New Zealand, UK and Brazil). Women with a diagnosis of PCOS who were planning to commence ovulation induction cycles (at least three cycles) in order to conceive were randomly assigned to receive the pipelle (scratch) procedure or a sham (placebo) procedure in the first cycle of ovulation induction. Women kept a diary of ovulation induction and sexual intercourse timing over three consecutive cycles and pregnancies were followed up to live birth. Primary outcome was live birth and secondary outcomes were clinical pregnancy, ongoing pregnancy, multiple pregnancy, adverse pregnancy outcomes, neonatal outcomes, bleeding following procedure and pain score following procedure. RESULTS: A total of 117 women were randomized; 58 to the scratch group and 59 to the sham group. Live birth occurred in 11 (19%) women in the scratch group and 14 (24%) in the sham group (odds ratio 0.76, 95% confidence interval [CI] 0.30-1.92). Secondary outcomes were similar in each group. Significantly higher pain scores were reported in the scratch group (adjusted mean difference 3.2, 95% CI 2.5-3.9) when measured on a visual analogue scale. CONCLUSION: No difference was detected in live birth rate for women with PCOS who received an endometrial scratch when trying to conceive using ovulation induction; however, uncertainty remains due to the small sample size in this study.

Endometrial injury for pregnancy following sexual intercourse or intrauterine insemination.

BACKGROUND: Intentional endometrial injury is 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 and is a common gynaecological procedure with established safety. However, it causes 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 intrauterine insemination (IUI), remains unclear. OBJECTIVES: To assess the effectiveness and safety of intentional endometrial injury performed in infertile women or couples attempting to conceive through sexual intercourse or intrauterine insemination (IUI). SEARCH METHODS: The Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, LILACS, ISI Web of Knowledge, and clinical trial registries were searched from inception to 21 May 2020, as were conference abstracts and reference lists of relevant reviews and included studies. 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 ovarian stimulation (OS)) compared to no intervention, a mock intervention, or intentional endometrial injury performed at a different time. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. Primary outcomes were live birth/ongoing pregnancy and pain experienced during the procedure. Due to high risk of bias associated with many of the studies, primary analyses of all review outcomes were restricted to studies at low risk of bias. Sensitivity analysis including all studies was then performed. MAIN RESULTS: We included 22 RCTs (3703 women). Most of these studies included women with unexplained infertility. Intentional endometrial injury versus either no intervention or a sham procedure The primary analysis was restricted to studies at low risk of bias, which left only one study included. We are uncertain whether endometrial injury has an effect on the probability of live birth, as only one study is included in the analysis and the confidence interval is wide (risk ratio (RR) 1.11, 95% confidence interval (CI) 0.78 to 1.59; 1 RCT, 210 participants). Evidence suggests that if the chance of live birth with no intervention/a sham procedure is assumed to be 34%, then the chance with endometrial injury would be 27% to 55%. When all studies were included in the sensitivity analysis, we were uncertain whether endometrial injury improves live birth/ongoing pregnancy, as the evidence was of very low quality (RR 1.71, 95% CI 1.32 to 2.21; 8 RCTs, 1522 participants; I² = 16%). Evidence suggests that if the chance of live birth/ongoing pregnancy with no intervention/a sham procedure is assumed to be 13%, then the chance with endometrial injury would be 17% to 28%. A narrative synthesis conducted for the other primary outcome of pain during the procedure included studies measuring pain on a zero-to-ten visual analogue scale (VAS) or grading pain as mild/moderate/severe, and showed that most often mild to moderate pain was reported (6 RCTs, 911 participants; very low-quality evidence). Timing of intentional endometrial injury Four trials compared endometrial injury performed in the cycle before IUI to that performed in the same cycle as IUI. None of these studies reported the primary outcomes of live birth/ongoing pregnancy and pain during the procedure. One study compared endometrial injury in the early follicular phase (EFP; Day 2 to 4) to endometrial injury in the late follicular phase (LFP; Day 7 to 9), both in the same cycle as IUI. The primary outcome live birth/ongoing pregnancy was not reported, but the study did report the other primary outcome of pain during the procedure assessed by a zero-to-ten VAS. The average pain score was 3.67 (standard deviation (SD) 0.7) when endometrial injury was performed in the EFP and 3.84 (SD 0.96) when endometrial injury was performed in the LFP. The mean difference was -0.17, suggesting that on average, women undergoing endometrial injury in the EFP scored 0.17 points lower on the VAS as compared to women undergoing endometrial injury in the LFP (95% CI -0.48 to 0.14; 1 RCT, 110 participants; very low-quality evidence). AUTHORS' CONCLUSIONS: Evidence is insufficient to show whether there is a difference in live birth/ongoing pregnancy between endometrial injury and no intervention/a sham procedure in women undergoing IUI or attempting to conceive via sexual intercourse. The pooled results should be interpreted with caution, as the evidence was of low to very low quality due to high risk of bias present in most included studies and an overall low level of precision. Furthermore, studies investigating the effect of timing of endometrial injury did not report the outcome live birth/ongoing pregnancy; therefore no conclusions could be drawn for this outcome. Further well-conducted RCTs that recruit large numbers of participants and minimise bias are required to confirm or refute these findings. Current evidence is insufficient to support routine use of endometrial injury in women undergoing IUI or attempting to conceive via sexual intercourse.

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.

Surveys of clinician and patient attitudes to an add-on for in vitro fertilisation.

BACKGROUND: Add-ons at the time of in vitro fertilisation (IVF) have become commonplace, despite a general lack of evidence that they are effective and safe. The 'Colorado Protocol' is a commonly used add-on consisting of aspirin, steroid and an antibiotic. Before commencing planning for a clinical trial evaluating the Colorado Protocol, researchers and funders need evidence that the Colorado Protocol is being prescribed, and to be assured that sufficient numbers of participants can be recruited for a clinical trial. AIMS: To survey fertility clinicians and patients on attitudes toward use of add-ons during IVF, willingness of patients to be randomly assigned to an add-on trial treatment or placebo, and what would be the clinically meaningful outcomes, using the Colorado Protocol as a test case. MATERIALS AND METHODS: Two online surveys were conducted: clinicians from fertility clinics across the United Kingdom, Australia, and New Zealand; and patients from Auckland-based clinics and NZ patient support groups. RESULTS: Of 58 clinicians, 44 (75%) had recommended an add-on within the preceding year. Thirty-nine (67%) clinicians were aware of the Colorado Protocol, with 17 (29%) having recommended it within the preceding year. Of the 289 patients, 80% indicated willingness to take trial medications during IVF, and 68% were willing to be randomly assigned to the placebo arm of a trial. The median perceived minimum clinically important difference in live births in both samples was 5%. CONCLUSIONS: A future trial of this add-on in IVF would be supported by patients in the context of the New Zealand fertility healthcare system.

Endometrial injury in women undergoing in vitro fertilisation (IVF).

BACKGROUND: Implantation of an embryo within the endometrial cavity is a critical step in the process of in vitro fertilisation (IVF). Previous research has suggested that endometrial injury (also known as endometrial scratching), defined as intentional damage to the endometrium, can increase the chance of pregnancy in women undergoing IVF. OBJECTIVES: To assess the effectiveness and safety of endometrial injury performed before embryo transfer in women undergoing in vitro fertilisation (IVF) including intracytoplasmic sperm injection (ICSI) and frozen embryo transfer. SEARCH METHODS: In June 2020 we searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, LILACS, DARE and two trial registries. We also checked the reference sections of relevant studies and contacted experts in the field for any additional trials. SELECTION CRITERIA: Randomised controlled trials comparing intentional endometrial injury before embryo transfer in women undergoing IVF, versus no intervention or a sham procedure. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. Two independent review authors screened studies, evaluated risk of bias and assessed the certainty of the evidence by using GRADE (Grading of Recommendation, Assessment, Development and Evaluation) criteria. We contacted and corresponded with study investigators as required. Due to the high risk of bias associated with many of the studies, the primary analyses of all review outcomes were restricted to studies at a low risk of bias for selection bias and other bias. Sensitivity analysis was then performed including all studies. The primary review outcomes were live birth and miscarriage. MAIN RESULTS: Endometrial injury versus control (no procedure or a sham procedure) A total of 37 studies (8786 women) were included in this comparison. Most studies performed endometrial injury by pipelle biopsy in the luteal phase of the cycle before the IVF cycle. The primary analysis was restricted to studies at low risk of bias, and included eight studies. The effect of endometrial injury on live birth is unclear as the result is consistent with no effect, or a small reduction, or an improvement (odds ratio (OR) 1.12, 95% confidence interval (CI) 0.98 to 1.28; participants = 4402; studies = 8; I2 = 15%, moderate-certainty evidence). This suggests that if the chance of live birth with IVF is usually 27%, then the chance when using endometrial injury would be somewhere between < 27% and 32%. Similarly, the effect of endometrial injury on clinical pregnancy is unclear (OR 1.08, 95% CI 0.95 to 1.23; participants = 4402; studies = 8; I2 = 0%, moderate-certainty evidence). This suggests that if the chance of clinical pregnancy from IVF is normally 32%, then the chance when using endometrial injury before IVF is between 31% and 37%. When all studies were included in the sensitivity analysis, we were unable to conduct meta-analysis for the outcomes of live birth and clinical pregnancy due to high risk of bias and statistical heterogeneity. Endometrial injury probably results in little to no difference in chance of miscarriage (OR 0.88, 95% CI 0.68 to 1.13; participants = 4402; studies = 8; I2 = 0%, moderate-certainty evidence), and this result was similar in the sensitivity analysis that included all studies. The result suggests that if the chance of miscarriage with IVF is usually 6.0%, then when using endometrial injury it would be somewhere between 4.2% and 6.8%. Endometrial injury was associated with mild to moderate pain (approximately 4 out of 10), and was generally associated with some minimal bleeding. The evidence was downgraded for imprecision due to wide confidence intervals and therefore all primary analyses were graded as moderate certainty. Higher versus lower degree of injury Only one small study was included in this comparison (participants = 129), which compared endometrial injury using two different instruments in the cycle prior to the IVF cycle: a pipelle catheter and a Shepard catheter. This trial was excluded from the primary analysis due to risk of bias. In the sensitivity analysis, all outcomes reported for this study were graded as very-low certainty due to risk of bias, and as such we were not able to interpret the study results. AUTHORS' CONCLUSIONS: The effect of endometrial injury on live birth and clinical pregnancy among women undergoing IVF is unclear. The results of the meta-analyses are consistent with an increased chance, no effect and a small reduction in these outcomes. We are therefore uncertain whether endometrial injury improves the chance of live birth or clinical pregnancy in women undergoing IVF. Endometrial injury does not appear to affect the chance of miscarriage. It is a somewhat painful procedure associated with a small amount of bleeding. In conclusion, current evidence does not support the routine use of endometrial injury for women undergoing IVF.

Endometrial injury for pregnancy following sexual intercourse or intrauterine insemination.

BACKGROUND: Intentional endometrial injury is 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 and is a common gynaecological procedure with established safety. However, it causes 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 intrauterine insemination (IUI), remains unclear. OBJECTIVES: To assess the effectiveness and safety of intentional endometrial injury performed in infertile women or couples attempting to conceive through sexual intercourse or intrauterine insemination (IUI). SEARCH METHODS: The Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, LILACS, ISI Web of Knowledge, and clinical trial registries were searched from inception to 21 May 2020, as were conference abstracts and reference lists of relevant reviews and included studies. 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 ovarian stimulation (OS)) 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: We used standard methodological procedures recommended by Cochrane. Primary outcomes were live birth/ongoing pregnancy and pain experienced during the procedure. Due to high risk of bias associated with many of the studies, primary analyses of all review outcomes were restricted to studies at low risk of bias. Sensitivity analysis including all studies was then performed. MAIN RESULTS: We included 23 RCTs (4035 women). Most of these studies included women with unexplained infertility. Intentional endometrial injury versus either no intervention or a sham procedure The primary analysis was restricted to studies at low risk of bias, which left only one study included. We are uncertain whether endometrial injury has an effect on the probability of live birth, as only one study is included in the analysis and the confidence interval is wide (risk ratio (RR) 1.11, 95% confidence interval (CI) 0.78 to 1.59; 1 RCT, 210 participants). Evidence suggests that if the chance of live birth with no intervention/a sham procedure is assumed to be 34%, then the chance with endometrial injury would be 27% to 55%. When all studies were included in the sensitivity analysis, we were uncertain whether endometrial injury improves live birth/ongoing pregnancy, as the evidence was of very low quality (RR 1.71, 95% CI 1.32 to 2.21; 8 RCTs, 1522 participants; I² = 16%). Evidence suggests that if the chance of live birth/ongoing pregnancy with no intervention/a sham procedure is assumed to be 13%, then the chance with endometrial injury would be 17% to 28%. A narrative synthesis conducted for the other primary outcome of pain during the procedure included studies measuring pain on a zero-to-ten visual analogue scale (VAS) or grading pain as mild/moderate/severe, and showed that most often mild to moderate pain was reported (6 RCTs, 911 participants; very low-quality evidence). Higher versus lower degree of intentional endometrial injury Evidence was insufficient to show whether there is a difference in ongoing pregnancy rates (RR 1.29, 95% CI 0.71 to 2.35; 1 RCT, 332 participants; low-quality evidence) between hysteroscopy with endometrial injury and hysteroscopy alone. Evidence suggests that if the chance of ongoing pregnancy with hysteroscopy alone is 10%, then the chance with hysteroscopy with endometrial injury would be 7% to 24%. This study did not report the primary outcomes of live birth and pain during the procedure. Timing of intentional endometrial injury Four trials compared endometrial injury performed in the cycle before IUI to that performed in the same cycle as IUI. None of these studies reported the primary outcomes of live birth/ongoing pregnancy and pain during the procedure. One study compared endometrial injury in the early follicular phase (EFP; Day 2 to 4) to endometrial injury in the late follicular phase (LFP; Day 7 to 9), both in the same cycle as IUI. The primary outcome live birth/ongoing pregnancy was not reported, but the study did report the other primary outcome of pain during the procedure assessed by a zero-to-ten VAS. The average pain score was 3.67 (standard deviation (SD) 0.7) when endometrial injury was performed in the EFP and 3.84 (SD 0.96) when endometrial injury was performed in the LFP. The mean difference was -0.17, suggesting that on average, women undergoing endometrial injury in the EFP scored 0.17 points lower on the VAS as compared to women undergoing endometrial injury in the LFP (95% CI -0.48 to 0.14; 1 RCT, 110 participants; very low-quality evidence). AUTHORS' CONCLUSIONS: Evidence is insufficient to show whether there is a difference in live birth/ongoing pregnancy between endometrial injury and no intervention/a sham procedure in women undergoing IUI or attempting to conceive via sexual intercourse. The pooled results should be interpreted with caution, as the evidence was of low to very low quality due to high risk of bias present in most included studies and an overall low level of precision. Furthermore, studies investigating the effect of timing of endometrial injury did not report the outcome live birth/ongoing pregnancy; therefore no conclusions could be drawn for this outcome. Further well-conducted RCTs that recruit large numbers of participants and minimise bias are required to confirm or refute these findings. Current evidence is insufficient to support routine use of endometrial injury in women undergoing IUI or attempting to conceive via sexual intercourse.

IVF add-ons in Australia and New Zealand: A systematic assessment of IVF clinic websites.

BACKGROUND: In vitro fertilisation (IVF) 'add-ons' are extra (non-essential) procedures, techniques or medicines, which usually claim to increase the chance of a successful IVF outcome. Use of IVF add-ons is believed to be widespread in many settings; however, information about add-on availability in Australasia is lacking. AIMS: To understand which add-ons are advertised on Australasian IVF clinic websites, and what is the evidence for their benefit. MATERIALS AND METHODS: A systematic assessment of website content was undertaken between December 2019-April 2020, capturing IVF add-ons advertised, including costs, claims of benefit, statements of risk or limitations, and evidence of effectiveness for improving live birth and pregnancy. A literature review assessed the strength and quality of evidence for each add-on. RESULTS: Of the 40 included IVF clinics websites, 31 (78%) listed one or more IVF add-ons. A total of 21 different add-ons or add-on groups were identified, the most common being preimplantation genetic testing for aneuploidies (offered by 63% of clinics), time-lapse systems (33%) and assisted hatching (28%). In most cases (77%), descriptions of the IVF add-ons were accompanied by claims of benefit. Most claims (90%) were not quantified and very few referenced scientific publications to support the claims (9.8%). None of the add-ons were supported by high-quality evidence of benefit for pregnancy or live birth rates. The cost of IVF add-ons varied from $0 to $3700 (AUD/NZD). CONCLUSIONS: There is widespread advertising of add-ons on IVF clinic websites, which report benefits for add-ons that are not supported by high-quality evidence.

Intrauterine insemination with ovarian stimulation versus expectant management for unexplained infertility (TUI): a pragmatic, open-label, randomised, controlled, two-centre trial.

BACKGROUND: Women with unexplained infertility are often offered intrauterine insemination (IUI) with ovarian stimulation as an alternative to in-vitro fertilisation (IVF). However, little evidence exists that IUI is an effective treatment. In 2013, the UK National Institute for Health and Care Excellence recommended that IUI should not be routinely offered for couples with unexplained infertility. METHODS: For this pragmatic, open-label, randomised, controlled, two-centre study, we enrolled women attending two fertility clinics in New Zealand with unexplained infertility and an unfavourable prognosis of natural conception. Participants were randomly assigned (1:1) using a computer-generated randomisation sequence, prepared by an independent statistician, to either three cycles of IUI with ovarian stimulation (with either oral clomifene citrate [50-150 mg, days 2-6] or oral letrozole [2·5-7·5 mg, days 2-6], with choice of ovarian stimulation made by the clinic) or three cycles of expectant management (couples advised to be sexually active around the likely time of ovulation and provided with a diary to record the first day of each menstrual cycle and dates of sexual activity) in blocks of four, six, and ten, without stratification. The participating couple and the clinicians were informed of treatment allocation. The primary outcome was cumulative livebirth rate in the intention-to-treat population. The safety analyses were done in the intention-to-treat population. This study was prospectively registered with the Australian and New Zealand Clinical Trials Register, number ACTRN12612001025820. FINDINGS: Between March 12, 2013, and May 12, 2016, we randomly assigned 101 women to IUI with ovarian stimulation and 100 to expectant management, all of whom were included in the primary efficacy analysis and safety analyses. Women assigned to IUI had a higher cumulative livebirth rate than women assigned to expectant management (31 [31%] livebirths among 101 women vs nine [9%] livebirths among 100 women; risk ratio [RR] 3·41, 95% CI 1·71-6·79; p=0·0003). Of 31 livebirths in the IUI group, 23 resulted from IUI cycles and eight were conceived without assistance before or between IUI cycles. Of nine livebirths in the expectant management group, one patient was pregnant from IUI with ovarian stimulation at study entry and one had received off-protocol treatment (IVF). Two sets of twins were born, both in the IUI group (one from a cancelled cycle for over-response). INTERPRETATION: IUI with ovarian stimulation is a safe and effective treatment for women with unexplained infertility and an unfavourable prognosis for natural conception. FUNDING: Auckland Medical Research Foundation, Evelyn Bond Fund of Auckland District Health Board, Mercia Barnes Trust of Royal Australian and New Zealand College of Obstetricians and Gynaecologists, Maurice and Phyllis Paykel Trust, and The Nurture Foundation for Reproductive Research.

Randomised controlled trials evaluating endometrial scratching: assessment of methodological issues.

STUDY QUESTION: Do randomised controlled trials (RCTs) evaluating endometrial scratching suffer from methodological issues including insufficient trial registration, statistical errors or irreproducibility, randomisation errors or miscellaneous issues? SUMMARY ANSWER: The majority of RCTs investigating endometrial scratching have methodological issues. WHAT IS KNOWN ALREADY: A large number of small RCTs investigating the effectiveness of endometrial scratching prior to in vitro fertilisation (IVF) and intrauterine insemination (IUI)/intercourse have reported favourable findings. Subsequently, systematic reviews incorporating these RCTs yielded meta-analyses in favour of endometrial scratching. Endometrial scratching has been widely adopted by infertility specialists around the world. Recently, an international RCT including 1364 women reported no benefit from endometrial scratching before IVF. STUDY DESIGN, SIZE, DURATION: We evaluated several methodological issues of RCTs investigating the effectiveness of endometrial scratching prior to IVF and IUI/intercourse. We identified 25 RCTs for IVF and 12 RCTs for IUI/intercourse with full-text publication. PARTICIPANTS/MATERIALS, SETTING, METHODS: We assessed the RCTs on the following criteria: adequacy of trial registration, statistical issues (description of statistical methods and reproducibility of univariable statistical analysis), excessive similarity or difference in baseline characteristics that is not compatible with chance (Monte Carlo simulations and Kolmogorov-Smirnov test) and miscellaneous methodological issues. MAIN RESULTS AND THE ROLE OF CHANCE: Of 25 RCTs evaluating endometrial scratching prior to IVF, only eight (32%) had adequate trial registration. In total, 10 (40%) RCTs had issues regarding statistical methods. Nine (69%, 13 applicable) RCTs had at least one inconsistency between reported and reproduced univariable statistical analysis for categorical baseline/intermediate characteristics. Statistical results of at least one outcome were not reproducible in 14 (74%, 19 applicable) RCTs. Only two (8%) RCTs had none of the above issues. Suggested by the simulations, these RCTs did not significantly violate the null hypothesis that the baseline characteristics were the results of a properly conducted randomisation process (P = 0.4395).Of 12 IUI/intercourse RCTs, only 2 (17%) had adequate trial registration. In total, five (42%) studies had issues of statistical methods. Inconsistency between reported and reproduced univariable analysis for baseline/intermediate categorical variable(s) was found in four (57%, 7 applicable) RCTs. Statistical analysis was not reproducible for at least one outcome in eight (80%, 10 applicable) studies. All RCTs had at least one of the above issues. These RCTs were inconsistent with the null hypothesis that their baseline characteristics were the results of proper randomised allocation (P = 1.659*10-7). LIMITATIONS, REASONS FOR CAUTION: We were unable to assess RCTs which were not published as full-text papers. We could not analyse individual participant data to investigate possible reasons for statistical inconsistencies. The method to infer the likelihood of proper random sampling rests on assumptions including independent baseline characteristics, simple randomisation and no publication bias. WIDER IMPLICATIONS OF THE FINDINGS: The methodological issues common to RCTs evaluating endometrial scratching may have biased the results of the trials. Further development and validation of these novel methods may be helpful for the critical appraisal of RCTs. STUDY FUNDING/COMPETING INTEREST(S): No external funding was sought to support this work. B.W.M. is supported by a National Health Medical Research Council (NHMRC) Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck and Guerbet. D.W. is supported by a grant from the Paracelsus Medical University Salzburg, Austria (PMU Research Fund-PMU FFF Number: L-18/02/006-WET) and by Drs Haackert Foundation, Germany. S.L. is an author of a trial included in this study, an author of an included systematic review and a Cochrane editor. All other authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI).

BACKGROUND: During a cycle of in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI), women receive daily doses of gonadotropin follicle-stimulating hormone (FSH) to induce multifollicular development in the ovaries. Generally, the dose of FSH is associated with the number of eggs retrieved. A normal response to stimulation is often considered desirable, for example the retrieval of 5 to 15 oocytes. Both poor and hyper-response are associated with increased chance of cycle cancellation. Hyper-response is also associated with increased risk of ovarian hyperstimulation syndrome (OHSS). Clinicians often individualise the FSH dose using patient characteristics predictive of ovarian response such as age. More recently, clinicians have begun using ovarian reserve tests (ORTs) to predict ovarian response based on the measurement of various biomarkers, including basal FSH (bFSH), antral follicle count (AFC), and anti-Müllerian hormone (AMH). It is unclear whether individualising FSH dose based on these markers improves clinical outcomes. OBJECTIVES: To assess the effects of individualised gonadotropin dose selection using markers of ovarian reserve in women undergoing IVF/ICSI. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register, Cochrane Central Register of Studies Online, MEDLINE, Embase, CINAHL, LILACS, DARE, ISI Web of Knowledge, ClinicalTrials.gov, and the World Health Organisation International Trials Registry Platform search portal from inception to 27th July 2017. We checked the reference lists of relevant reviews and included studies. SELECTION CRITERIA: We included trials that compared different doses of FSH in women with a defined ORT profile (i.e. predicted low, normal or high responders based on AMH, AFC, and/or bFSH) and trials that compared an individualised dosing strategy (based on at least one ORT measure) versus uniform dosing or a different individualised dosing algorithm. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. Primary outcomes were live birth/ongoing pregnancy and severe OHSS. Secondary outcomes included clinical pregnancy, moderate or severe OHSS, multiple pregnancy, oocyte yield, cycle cancellations, and total dose and duration of FSH administration. MAIN RESULTS: We included 20 trials (N = 6088); however, we treated those trials with multiple comparisons as separate trials for the purpose of this review. Meta-analysis was limited due to clinical heterogeneity. Evidence quality ranged from very low to moderate. The main limitations were imprecision and risk of bias associated with lack of blinding.Direct dose comparisons in women according to predicted responseAll evidence was low or very low quality.Due to differences in dose comparisons, caution is warranted in interpreting the findings of five small trials assessing predicted low responders. The effect estimates were very imprecise, and increased FSH dosing may or may not have an impact on rates of live birth/ongoing pregnancy, OHSS, and clinical pregnancy.Similarly, in predicted normal responders (nine studies, three comparisons), higher doses may or may not impact the probability of live birth/ongoing pregnancy (e.g. 200 versus 100 international units: OR 0.88, 95% CI 0.57 to 1.36; N = 522; 2 studies; I2 = 0%) or clinical pregnancy. Results were imprecise, and a small benefit or harm remains possible. There were too few events for the outcome of OHSS to enable any inferences.In predicted high responders, lower doses may or may not have an impact on rates of live birth/ongoing pregnancy (OR 0.98, 95% CI 0.66 to 1.46; N = 521; 1 study), OHSS, and clinical pregnancy. However, lower doses probably reduce the likelihood of moderate or severe OHSS (Peto OR 2.31, 95% CI 0.80 to 6.67; N = 521; 1 study).ORT-algorithm studiesFour trials compared an ORT-based algorithm to a non-ORT control group. Rates of live birth/ongoing pregnancy and clinical pregnancy did not appear to differ by more than a few percentage points (respectively: OR 1.04, 95% CI 0.88 to 1.23; N = 2823, 4 studies; I2 = 34%; OR 0.96, 95% CI 0.82 to 1.13, 4 studies, I2=0%, moderate-quality evidence). However, ORT algorithms probably reduce the likelihood of moderate or severe OHSS (Peto OR 0.58, 95% CI 0.34 to 1.00; N = 2823; 4 studies; I2 = 0%, low quality evidence). There was insufficient evidence to determine whether the groups differed in rates of severe OHSS (Peto OR 0.54, 95% CI 0.14 to 1.99; N = 1494; 3 studies; I2 = 0%, low quality evidence). Our findings suggest that if the chance of live birth with a standard dose is 26%, the chance with ORT-based dosing would be between 24% and 30%. If the chance of moderate or severe OHSS with a standard dose is 2.5%, the chance with ORT-based dosing would be between 0.8% and 2.5%. These results should be treated cautiously due to heterogeneity in the study designs. AUTHORS' CONCLUSIONS: We did not find that tailoring the FSH dose in any particular ORT population (low, normal, high ORT), influenced rates of live birth/ongoing pregnancy but we could not rule out differences, due to sample size limitations. In predicted high responders, lower doses of FSH seemed to reduce the overall incidence of moderate and severe OHSS. Moderate-quality evidence suggests that ORT-based individualisation produces similar live birth/ongoing pregnancy rates to a policy of giving all women 150 IU. However, in all cases the confidence intervals are consistent with an increase or decrease in the rate of around five percentage points with ORT-based dosing (e.g. from 25% to 20% or 30%). Although small, a difference of this magnitude could be important to many women. Further, ORT algorithms reduced the incidence of OHSS compared to standard dosing of 150 IU, probably by facilitating dose reductions in women with a predicted high response. However, the size of the effect is unclear. The included studies were heterogeneous in design, which limited the interpretation of pooled estimates, and many of the included studies had a serious risk of bias.Current evidence does not provide a clear justification for adjusting the standard dose of 150 IU in the case of poor or normal responders, especially as increased dose is generally associated with greater total FSH dose and therefore greater cost. However, a decreased dose in predicted high responders may reduce OHSS.

Body mass index trumps age in decision for endometrial biopsy: cohort study of symptomatic premenopausal women.

BACKGROUND: Clinical guidelines recommend that women with abnormal uterine bleeding with risk factors have an endometrial biopsy to exclude hyperplasia or cancer. Given the majority of endometrial cancer occurs in postmenopausal women, it has not been widely recognized that obesity is a significant risk factor for endometrial hyperplasia and cancer in young, symptomatic, premenopausal women. OBJECTIVE: We sought to evaluate the effect of body mass index on risk of endometrial hyperplasia or cancer in premenopausal women with abnormal uterine bleeding. STUDY DESIGN: This was a retrospective cohort study in a single large urban secondary women's health service. Participants were 916 premenopausal women referred for abnormal uterine bleeding of any cause and had an endometrial biopsy from 2008 through 2014. The primary outcome was complex endometrial hyperplasia (with or without atypia) or endometrial cancer. RESULTS: Almost 5% of participants had complex endometrial hyperplasia or cancer. After adjusting for clinical and demographic factors, women with a measured body mass index ≥30 kg/m2 were 4 times more likely to develop complex hyperplasia or cancer (95% confidence interval, 1.36-11.74). Other risk factors were nulliparity (adjusted odds ratio, 3.08; 95% confidence interval, 1.43-6.64) and anemia (adjusted odds ratio, 2.23; 95% confidence interval, 1.14-4.35). Age, diabetes, and menstrual history were not significant. CONCLUSION: Obesity is an important risk factor for complex endometrial hyperplasia or cancer in premenopausal women with abnormal uterine bleeding who had an endometrial biopsy in a secondary gynecology service. As over half of women with the outcome in this study were age <45 years, deciding to biopsy primarily based on age, as currently recommended in national guidelines, potentially misses many cases or delays diagnosis. Body mass index should be the first stratification in the decision to perform endometrial biopsy and/or to refer secondary gynecology services.

Obesity and endometrial hyperplasia and cancer in premenopausal women: A systematic review.

OBJECTIVE: To systematically review the literature on the association between obesity and endometrial hyperplasia or cancer in premenopausal women. DATA SOURCES: We searched the bibliographic databases MEDLINE, EMBASE, PubMed, and CINAHL (inception to May 5, 2015), and checked reference lists of included studies and systematic reviews. STUDY ELIGIBILITY CRITERIA: Studies of more than 50 women with endometrial pathology diagnosed during premenopause that reported on obesity as a risk factor were eligible. STUDY APPRAISAL AND SYNTHESIS METHODS: Study identification and data extraction were independently performed by 2 authors. Where possible, data were pooled in a generic inverse variance forest plot. Heterogeneity was reported using the I(2) statistic. RESULTS: Nine case-control studies of moderate quality were included. Quantitative analysis of 5 studies showed a dose-response relationship of body mass index and increased risk of endometrial cancer. For studies of women with body mass index of ≥25, the pooled odds ratio was 3.85 (95% confidence interval 2.53-5.84); body mass index of ≥30 was 5.25 (4.00-6.90); and body mass index of ≥40 was 19.79 (11.18-35.03). CONCLUSION: Body mass index is a consistent and leading risk factor for endometrial complex hyperplasia or cancer in premenopausal women. Body mass index should be considered when deciding to assess the endometrium in symptomatic premenopausal women.