Sarah Lensen

Endometrial scratching for subfertility: everyone's doing it

STUDY QUESTION What proportion of clinicians across Australia, New Zealand and the UK are currently offering or recommending endometrial scratching for subfertility? SUMMARY ANSWER Eighty-three percent of clinicians responding to this survey are recommending endometrial scratching to women undergoing IVF. WHAT IS KNOWN ALREADY Endometrial scratching is currently being proposed as a technique to increase the probability of implantation in women undergoing IVF. While trial results provide evidence in favour of this procedure, there remains some uncertainty about both the extent of any beneficial effect and the subgroups of women most likely to benefit. STUDY DESIGN, SIZE, DURATION Cross-sectional survey with responses from a total of 143 public and private fertility care providers surveyed between August and October 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS An online survey was distributed to all 189 fertility clinics across Australia, New Zealand and the UK. All clinicians, nurses and embryologists were eligible to take part. One hundred and forty-three of the 152 responses received were eligible for inclusion, with multiple responses per clinic in 33 cases. At least one response was received from 68 clinics (36% response rate per clinic). MAIN RESULTS AND THE ROLE OF CHANCE This survey found that 83% of clinicians commend endometrial scratching prior to IVF. Of these, 92% recommend endometrial scratching to women with recurrent implantation failure (RIF) and 6% recommend it to all women having IVF. Most respondents (73%) agreed that the procedure is beneficial in women with RIF undergoing IVF and disagreed (53%) that the procedure is beneficial for women undergoing their first IVF cycle. The most common timeframe for performing endometrial scratching is the luteal phase of the cycle prior to the IVF cycle. Additionally, only 4% of clinicians recommend endometrial scratching to women undergoing intrauterine insemination or trying to conceive naturally. LIMITATIONS, REASONS FOR CAUTION Fertility care providers who recommend endometrial scratching may be more likely to respond to the survey and this could exaggerate the use of the procedure reported here. WIDER IMPLICATIONS OF THE FINDINGS This study was conducted across three countries and may be generalizable to similar settings. While this procedure already appears to be offered by the majority of respondents, the results of further studies in this area may further refine or expand the context in which this procedure is beneficial. STUDY FUNDING/COMPETING INTERESTS No funding or competing interests. TRIAL REGISTRATION NUMBER N/A.

There were large discrepancies in risk of bias tool judgments when a randomized controlled trial appeared in more than one systematic review

OBJECTIVES To assess the consistency in risk of bias (RoB) judgments across Cochrane reviews for studies appearing in more than one Cochrane review in the field of subfertility. STUDY DESIGN AND SETTING We retrieved any study that had been used more than once in systematic reviews present on the Cochrane Database of Systematic Reviews in the area of subfertility. We then retrieved the recorded RoB assessments for these studies and looked at the consistency of judgments made between different authoring teams on the same trials. RESULTS From the 156 bias judgments that were completed by at least two separate groups of authors, 45% of these judgments differed. For the domains of random sequence generation and incomplete outcome data, there was reasonably high level of agreement (71% and 79%, respectively). However, for the domain of blinding, agreement was reached in only 35% of cases. CONCLUSION This assessment of how consistently the RoB is being applied in Cochrane reviews has shown that, especially in some domains, there are large discrepancies in how RoB is being evaluated. Further work needs to be undertaken to improve the application of this tool.

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.

Incidence, risk factors and perinatal outcomes for placenta accreta in Australia and New Zealand: a case–control study

Objective Estimate the incidence of placenta accreta and describe risk factors, clinical practice and perinatal outcomes. Design Case–control study. Setting Sites in Australia and New Zealand with at least 50 births per year. Participants Cases were women giving birth (≥20 weeks or fetus ≥400 g) who were diagnosed with placenta accreta by antenatal imaging, at operation or by pathology specimens between 2010 and 2012. Controls were two births immediately prior to a case. A total of 295 cases were included and 570 controls. Methods Data were collected using the Australasian Maternity Outcomes Surveillance System. Primary and secondary outcome measures Incidence, risk factors (eg, prior caesarean section (CS), maternal age) and clinical outcomes of placenta accreta (eg CS, hysterectomy and death). Results The incidence of placenta accreta was 44.2/100 000 women giving birth (95% CI 39.4 to 49.5); however, this may overestimated due to the case definition used. In primiparous women, an increased odds of placenta accreta was observed in older women (adjusted OR (AOR) women≥40 vs <30: 19.1, 95% CI 4.6 to 80.3) and current multiple birth (AOR: 6.1, 95% CI 1.1 to 34.1). In multiparous women, independent risk factors were prior CS (AOR ≥2 prior sections vs 0: 13.8, 95% CI 7.4 to 26.1) and current placenta praevia (AOR: 36.3, 95% CI 14.0 to 93.7). There were two maternal deaths (case fatality rate 0.7%). Women with placenta accreta were more likely to have a caesarean section (AOR: 4.6, 95% CI 2.7 to 7.6) to be admitted to the intensive care unit (ICU)/high dependency unit (AOR: 46.1, 95% CI 22.3 to 95.4) and to have a hysterectomy (AOR: 209.0, 95% CI 19.9 to 875.0). Babies born to women with placenta accreta were more likely to be preterm, be admitted to neonatal ICU and require resuscitation.

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

BackgroundThe 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/designThe 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 couples1) 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) and3) 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.DiscussionThe 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 registrationsPIP-IVF ACTRN12614000626662 registered 13/6/2014; PIP-PCOS ACTRN12614000657628 registered 24/6/2014; PIP-UE ACTRN12614000656639 registered 24/6/2014. The trials are ongoing.

Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing IVF/ICSI

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: This review has two objectives. These are: to assess the comparative effectiveness (pregnancy and live birth) and safety (ovarian hyperstimulation syndrome) in women undergoing in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI): of different doses of gonadotropin in women subgrouped by their expected response to stimulation, as defined by at least one ovarian reserve test (ORT) measure (do women with low, moderate or high anticipated response to ovarian stimulation, based on an ORT, benefit from a modified gonadotropin dose?); and of individualisation of gonadotropin dose using ORT, as compared to dose selection without ORT, or to an alternative individualised dosing algorithm using ORT (does using ORT to individualise gonadotropin dose improve IVF/ICSI outcomes, and is there evidence to suggest one algorithm is better than another?).

BMI Trumps Age in Decision for Endometrial Biopsy: Cohort Study of Symptomatic Premenopausal Women

The most common reason for referral to a gynecologist is abnormal uterine bleeding (AUB). Heavy or irregular vaginal bleeding often leads to an invasive diagnostic test such as endometrial biopsy or hysteroscopy. Data from 1 large study showed that, in premenopausal women with AUB referred for endometrial biopsy, the prevalence of complex endometrial hyperplasia or cancer was 3.0%. Women with complex hyperplasia are at risk for progression to endometrial cancer (EC). Recognized risk factors for EC include age, obesity, nulliparity, infertility, and late-onset menopause. An association between obesity and EC has been demonstrated in several systematic reviews. American and Canadian clinical guidelines recommend that women with AUB with risk factors have an endometrial biopsy to exclude hyperplasia or cancer. The majority of EC occurs in postmenopausal women and it is not widely recognized that obesity in young, symptomatic, premenopausal women is a significant risk factor for endometrial hyperplasia and cancer. The aim of this retrospective cohort study was to investigate the association of body mass index (BMI) and endometrial complex hyperplasia or cancer in premenopausal women with AUB who had an endometrial biopsy. The study was designed to test the hypothesis that obese premenopausal womenwould be more likely to have complex hyperplasia or cancer than normal weight women. Criteria used to categorize BMI were as follows: normal, 18.5–24.9 kg/m; overweight, 25–29.9 kg/m; Health, Inc. All rights reserved. 596 Obstetrical and Gynecological Survey obese, ≥30 kg/m. The study was conducted at a single large urban secondary womens health service in New Zealand between 2008 and 2014. The study population was composed of 916 premenopausal women referred for AUB who had a endometrial biopsy. The primary study outcome was histologic diagnosis of complex endometrial hyperplasia (with or without atypia) or EC. Multivariable analyses using logistic regression were used to adjust for covariables including obesity, age, anemia, nulliparity, menstrual history, and diabetes. The primary variable of interest, obesity, was measured around the time of the biopsy. Of the 840 womenwith sufficient tissue for diagnosis, 41 (4.9%) had complex endometrial hyperplasia or cancer. Multivariable analyses adjusted for covariables showed that obese women were 4 times more likely than normal weight women of having complex hyperplasia or cancer; the adjusted odds ratio (aOR) was 4.00, with a 95% confidence interval (CI) of 1.36 to 11.74. There was no increased risk among overweight women. Nulliparity and anemia were also significant risk factors (aOR, 3.08; 95% CI, 1.43–6.64 and aOR, 2.23; 95% CI, 1.14–4.35, respectively). Age, diabetes, and menstrual history were not significant risk factors. These data show that obesity is an important risk factor for complex endometrial hyperplasia or cancer in premenopausal women with AUBwho undergo endometrial biopsy. Age may be an important risk factor for EC in perimenopausal and postmenopausal women but not in premenopausal women. The authors suggest that BMI instead of age be used as the primary deciding factor to further investigate AUB in premenopausal women with an invasive test. Guidelines could be updated to suggest that endometrial biopsy be performed in obese women or other risk factors such as nulliparity or anemia.