Endometrial scratching in women undergoing IVF/ICSI: an individual participant data meta-analysis.

BACKGROUND: In IVF/ICSI treatment, the process of embryo implantation is the success rate-limiting step. Endometrial scratching has been suggested to improve this process, but it is unclear if this procedure increases the chance of implantation and live birth (LB) and, if so, for whom, and how the scratch should be performed. OBJECTIVE AND RATIONALE: This individual participant data meta-analysis (IPD-MA) aims to answer the question of whether endometrial scratching in women undergoing IVF/ICSI influences the chance of a LB, and whether this effect is different in specific subgroups of women. After its incidental discovery in 2000, endometrial scratching has been suggested to improve embryo implantation. Numerous randomized controlled trials (RCTs) have been conducted, showing contradicting results. Conventional meta-analyses were limited by high within- and between-study heterogeneity, small study samples, and a high risk of bias for many of the trials. Also, the data integrity of several trials have been questioned. Thus, despite numerous RCTs and a multitude of conventional meta-analyses, no conclusion on the clinical effectiveness of endometrial scratching could be drawn. An IPD-MA approach is able to overcome many of these problems because it allows for increased uniformity of outcome definitions, can filter out studies with data integrity concerns, enables a more precise estimation of the true treatment effect thanks to adjustment for participant characteristics and not having to make the assumptions necessary in conventional meta-analyses, and because it allows for subgroup analysis. SEARCH METHODS: A systematic literature search identified RCTs on endometrial scratching in women undergoing IVF/ICSI. Authors of eligible studies were invited to share original data for this IPD-MA. Studies were assessed for risk of bias (RoB) and integrity checks were performed. The primary outcome was LB, with a one-stage intention to treat (ITT) as the primary analysis. Secondary analyses included as treated (AT), and the subset of women that underwent an embryo transfer (AT+ET). Treatment-covariate interaction for specific participant characteristics was analyzed in AT+ET. OUTCOMES: Out of 37 published and 15 unpublished RCTs (7690 participants), 15 RCTs (14 published, one unpublished) shared data. After data integrity checks, we included 13 RCTs (12 published, one unpublished) representing 4112 participants. RoB was evaluated as 'low' for 10/13 RCTs. The one-stage ITT analysis for scratch versus no scratch/sham showed an improvement of LB rates (odds ratio (OR) 1.29 [95% CI 1.02-1.64]). AT, AT+ET, and low-RoB-sensitivity analyses yielded similar results (OR 1.22 [95% CI 0.96-1.54]; OR 1.25 [95% CI 0.99-1.57]; OR 1.26 [95% CI 1.03-1.55], respectively). Treatment-covariate interaction analysis showed no evidence of interaction with age, number of previous failed embryo transfers, treatment type, or infertility cause. WIDER IMPLICATIONS: This is the first meta-analysis based on IPD of more than 4000 participants, and it demonstrates that endometrial scratching may improve LB rates in women undergoing IVF/ICSI. Subgroup analysis for age, number of previous failed embryo transfers, treatment type, and infertility cause could not identify subgroups in which endometrial scratching performed better or worse. The timing of endometrial scratching may play a role in its effectiveness. The use of endometrial scratching in clinical practice should be considered with caution, meaning that patients should be properly counseled on the level of evidence and the uncertainties.

Transfer of thawed frozen embryo versus fresh embryo to improve the healthy baby rate in women undergoing IVF: the E-Freeze RCT.

BACKGROUND: Freezing all embryos, followed by thawing and transferring them into the uterine cavity at a later stage (freeze-all), instead of fresh-embryo transfer may lead to improved pregnancy rates and fewer complications during in vitro fertilisation and pregnancies resulting from it. OBJECTIVE: We aimed to evaluate if a policy of freeze-all results in a higher healthy baby rate than the current policy of transferring fresh embryos. DESIGN: This was a pragmatic, multicentre, two-arm, parallel-group, non-blinded, randomised controlled trial. SETTING: Eighteen in vitro fertilisation clinics across the UK participated from February 2016 to April 2019. PARTICIPANTS: Couples undergoing their first, second or third cycle of in vitro fertilisation treatment in which the female partner was aged < 42 years. INTERVENTIONS: If at least three good-quality embryos were present on day 3 of embryo development, couples were randomly allocated to either freeze-all (intervention) or fresh-embryo transfer (control). OUTCOMES: The primary outcome was a healthy baby, defined as a live, singleton baby born at term, with an appropriate weight for their gestation. Secondary outcomes included ovarian hyperstimulation, live birth and clinical pregnancy rates, complications of pregnancy and childbirth, health economic outcome, and State-Trait Anxiety Inventory scores. RESULTS: A total of 1578 couples were consented and 619 couples were randomised. Most non-randomisations were because of the non-availability of at least three good-quality embryos (n = 476). Of the couples randomised, 117 (19%) did not adhere to the allocated intervention. The rate of non-adherence was higher in the freeze-all arm, with the leading reason being patient choice. The intention-to-treat analysis showed a healthy baby rate of 20.3% in the freeze-all arm and 24.4% in the fresh-embryo transfer arm (risk ratio 0.84, 95% confidence interval 0.62 to 1.15). Similar results were obtained using complier-average causal effect analysis (risk ratio 0.77, 95% confidence interval 0.44 to 1.10), per-protocol analysis (risk ratio 0.87, 95% confidence interval 0.59 to 1.26) and as-treated analysis (risk ratio 0.91, 95% confidence interval 0.64 to 1.29). The risk of ovarian hyperstimulation was 3.6% in the freeze-all arm and 8.1% in the fresh-embryo transfer arm (risk ratio 0.44, 99% confidence interval 0.15 to 1.30). There were no statistically significant differences between the freeze-all and the fresh-embryo transfer arms in the live birth rates (28.3% vs. 34.3%; risk ratio 0.83, 99% confidence interval 0.65 to 1.06) and clinical pregnancy rates (33.9% vs. 40.1%; risk ratio 0.85, 99% confidence interval 0.65 to 1.11). There was no statistically significant difference in anxiety scores for male participants (mean difference 0.1, 99% confidence interval -2.4 to 2.6) and female participants (mean difference 0.0, 99% confidence interval -2.2 to 2.2) between the arms. The economic analysis showed that freeze-all had a low probability of being cost-effective in terms of the incremental cost per healthy baby and incremental cost per live birth. LIMITATIONS: We were unable to reach the original planned sample size of 1086 and the rate of non-adherence to the allocated intervention was much higher than expected. CONCLUSION: When efficacy, safety and costs are considered, freeze-all is not better than fresh-embryo transfer. TRIAL REGISTRATION: This trial is registered as ISRCTN61225414. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 25. See the NIHR Journals Library website for further project information.

During in vitro fertilisation, eggs and sperm are mixed in a laboratory to create embryos. An embryo is placed in the womb 2­5 days later (fresh-embryo transfer) and the remaining embryos are frozen for future use. Initial research suggested that freezing all embryos followed by thawing and replacing them a few weeks later could improve treatment safety and success. Although these data were promising, the data came from small studies and were not enough to change practice and policy. We conducted a large, multicentre, clinical trial to evaluate the two strategies: fresh-embryo transfer compared with later transfer of frozen embryos. We also compared the costs of both strategies during in vitro fertilisation treatment, pregnancy and delivery. This study was conducted across 18 clinics in the UK from 2016 to 2019, and 619 couples participated. Couples were allocated to one of two strategies: immediate fresh-embryo transfer or freezing of all embryos followed later by transfer of frozen embryo. The study's aim was to find out which type of embryo transfer gave participants a higher chance of having a healthy baby. We found that freezing all embryos followed by frozen-embryo transfer did not lead to a higher chance of having a healthy baby. There were no differences between strategies in the number of live births, the miscarriage rate or the number of pregnancy complications. Fresh-embryo transfer was less costly from both a health-care and a patient perspective. A routine strategy of freezing all embryos is not justified given that there was no increase in success rates but there were extra costs and delays to embryo transfer.

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

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

Oxytocin antagonists for assisted reproduction.

BACKGROUND: Embryo transfer (ET) is a crucial step of in vitro fertilisation (IVF) treatment, and involves placing the embryo(s) in the woman's uterus. There is a negative association between endometrial wave-like activity (contractile activities) at the time of ET and clinical pregnancy, but no specific treatment is currently used in clinical practice to counteract their effects. Oxytocin is a hormone produced by the hypothalamus and released by the posterior pituitary. Its main role involves generating uterine contractions during and after childbirth. Atosiban is the best known oxytocin antagonist (and is also a vasopressin antagonist), and it is commonly used to delay premature labour by halting uterine contractions. Other oxytocin antagonists include barusiban, nolasiban, epelsiban, and retosiban. Administration of oxytocin antagonists around the time of ET has been proposed as a means to reduce uterine contractions that may interfere with embryo implantation. The intervention involves administering the medication before, during, or after the ET (or a combination). OBJECTIVES: To evaluate the effectiveness and safety of oxytocin antagonists around the time of ET in women undergoing assisted reproduction. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and two trials registers in March 2021; and checked references and contacted study authors and experts in the field to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of the use of oxytocin antagonists for women undergoing ET, compared with the non-use of this intervention, the use of placebo, or the use of another similar drug. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. Primary review outcomes were live birth and miscarriage; secondary outcomes were clinical pregnancy and other adverse events. MAIN RESULTS: We included nine studies (including one comprising three separate trials, 3733 women analysed in total) investigating the role of three different oxytocin antagonists administered intravenously (atosiban), subcutaneously (barusiban), or orally (nolasiban). We found very low- to high-certainty evidence: the main limitations were serious risk of bias due to poor reporting of study methods, and serious or very serious imprecision. Intravenous atosiban versus normal saline or no intervention We are uncertain of the effect of intravenous atosiban on live birth rate (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.88 to 1.24; 1 RCT, N = 800; low-certainty evidence). In a clinic with a live birth rate of 38% per cycle, the use of intravenous atosiban would be associated with a live birth rate ranging from 33.4% to 47.1%. We are uncertain whether intravenous atosiban influences miscarriage rate (RR 1.08, 95% CI 0.75 to 1.56; 5 RCTs, N = 1424; I² = 0%; very low-certainty evidence). In a clinic with a miscarriage rate of 7.2% per cycle, the use of intravenous atosiban would be associated with a miscarriage rate ranging from 5.4% to 11.2%. Intravenous atosiban may increase clinical pregnancy rate (RR 1.50, 95% CI 1.18 to 1.89; 7 RCTs, N = 1646; I² = 69%; low-certainty evidence), and we are uncertain whether multiple or ectopic pregnancy and other complication rates were influenced by the use of intravenous atosiban (very low-certainty evidence). Subcutaneous barusiban versus placebo One study investigated barusiban, but did not report on live birth or miscarriage. We are uncertain whether subcutaneous barusiban influences clinical pregnancy rate (RR 0.96, 95% CI 0.69 to 1.35; 1 RCT, N = 255; very low-certainty evidence). Trialists reported more mild to moderate injection site reactions with barusiban than with placebo, but there was no difference in severe reactions. They reported no serious drug reactions; and comparable neonatal outcome between groups. Oral nolasiban versus placebo Nolasiban does not increase live birth rate (RR 1.13, 95% CI 0.99 to 1.28; 3 RCTs, N = 1832; I² = 0%; high-certainty evidence). In a clinic with a live birth rate of 33% per cycle, the use of oral nolasiban would be associated with a live birth rate ranging from 32.7% to 42.2%. We are uncertain of the effect of oral nolasiban on miscarriage rate (RR 1.45, 95% CI 0.73 to 2.88; 3 RCTs, N = 1832; I² = 0%; low-certainty evidence). In a clinic with a miscarriage rate of 1.5% per cycle, the use of oral nolasiban would be associated with a miscarriage rate ranging from 1.1% to 4.3%. Oral nolasiban improves clinical pregnancy rate (RR 1.15, 95% CI 1.02 to 1.30; 3 RCTs, N = 1832; I² = 0%; high-certainty evidence), and probably does not increase multiple or ectopic pregnancy, or other complication rates (moderate-certainty evidence). AUTHORS' CONCLUSIONS: We are uncertain whether intravenous atosiban improves pregnancy outcomes for women undergoing assisted reproductive technology. This conclusion is based on currently available data from seven RCTs, which provided very low- to low-certainty evidence across studies. We could draw no clear conclusions about subcutaneous barusiban, based on limited data from one RCT. Further large well-designed RCTs reporting on live births and adverse clinical outcomes are still required to clarify the exact role of atosiban and barusiban before ET. Oral nolasiban appears to improve clinical pregnancy rate but not live birth rate, with an uncertain effect on miscarriage and adverse events. This conclusion is based on a phased study comprising three trials that provided low- to high-certainty evidence. Further large, well-designed RCTs, reporting on live births and adverse clinical outcomes, should focus on identifying the subgroups of women who are likely to benefit from this intervention.

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.

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

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

Suboptimal mid-luteal progesterone concentrations are associated with aberrant endometrial gene expression, potentially resulting in implantation failure.

RESEARCH QUESTION: What is the difference in endometrial transcriptomics between women with normal and with low mid-luteal progesterone during the implantation window? DESIGN: An endometrial biopsy and serum progesterone concentration were taken from participants during the mid-luteal phase (LH+7 to LH+9). A total of 12 participants were recruited and categorized into two groups based on their progesterone concentrations: normal progesterone (>15 ng/ml, n = 6) and low progesterone (<15 ng/ml, n = 6). Global endometrial gene expression between the two groups was compared by microarray techniques. Principal component analysis was used to display the gene's expression pattern. Pathway and gene ontology enrichment analysis were performed to determine the biological mechanism of progesterone on the endometrium. RESULTS: Several key genes related to endometrial receptivity were found to be regulated by progesterone. With regard to gene ontology and pathway analysis, progesterone was shown to be mainly involved in structure morphogenesis predominantly during a process of decidualization, extracellular matrix-receptor interaction and cell adhesion. Distinct differences were observed in the transcriptomic profiles between the two groups, indicating potential impairment of endometrial receptivity in women with suboptimal progesterone concentrations. There was a relatively similar pattern of gene expression between endometrial samples with progesterone concentrations approximately 10 ng/ml and >15 ng/ml. Thus, a progesterone concentration of between 10 and 15 ng/ml appears to be sufficient to induce endometrial receptivity. CONCLUSIONS: Abnormally low progesterone below the threshold of 10-15 ng/ml during the implantation window results in aberrant endometrial gene expression that may affect implantation potential.

The Prevalence of Thyroid Dysfunction and Autoimmunity in Women With History of Miscarriage or Subfertility.

OBJECTIVE: To describe the prevalence of and factors associated with different thyroid dysfunction phenotypes in women who are asymptomatic preconception. DESIGN: Observational cohort study. SETTING: A total of 49 hospitals across the United Kingdom between 2011 and 2016. PARTICIPANTS: Women aged 16 to 41years with history of miscarriage or subfertility trying for a pregnancy. METHODS: Prevalences and 95% confidence intervals (CIs) were estimated using the binomial exact method. Multivariate logistic regression analyses were conducted to identify risk factors for thyroid disease. INTERVENTION: None. MAIN OUTCOME MEASURE: Rates of thyroid dysfunction. RESULTS: Thyroid function and thyroid peroxidase antibody (TPOAb) data were available for 19213 and 19237 women, respectively. The prevalence of abnormal thyroid function was 4.8% (95% CI, 4.5-5.1); euthyroidism was defined as levels of thyroid-stimulating hormone (TSH) of 0.44 to 4.50 mIU/L and free thyroxine (fT4) of 10 to 21 pmol/L. Overt hypothyroidism (TSH > 4.50 mIU/L, fT4 < 10 pmol/L) was present in 0.2% of women (95% CI, 0.1-0.3) and overt hyperthyroidism (TSH < 0.44 mIU/L, fT4 > 21 pmol/L) was present in 0.3% (95% CI, 0.2-0.3). The prevalence of subclinical hypothyroidism (SCH) using an upper TSH concentration of 4.50 mIU/L was 2.4% (95% CI, 2.1-2.6). Lowering the upper TSH to 2.50 mIU/L resulted in higher rates of SCH, 19.9% (95% CI, 19.3-20.5). Multiple regression analyses showed increased odds of SCH (TSH > 4.50 mIU/L) with body mass index (BMI) ≥ 35.0 kg/m2 (adjusted odds ratio [aOR] 1.71; 95% CI, 1.13-2.57; P = 0.01) and Asian ethnicity (aOR 1.76; 95% CI, 1.31-2.37; P < 0.001), and increased odds of SCH (TSH ≥ 2.50 mIU/L) with subfertility (aOR 1.16; 95% CI, 1.04-1.29; P = 0.008). TPOAb positivity was prevalent in 9.5% of women (95% CI, 9.1-9.9). CONCLUSIONS: The prevalence of undiagnosed overt thyroid disease is low. SCH and TPOAb are common, particularly in women with higher BMI or of Asian ethnicity. A TSH cutoff of 2.50 mIU/L to define SCH results in a significant proportion of women potentially requiring levothyroxine treatment.

Men, chronic illness and healthwork: accounts from male partners of women with endometriosis.

Currently dominant in medical discourse, the concept of self-management sees the responsibility for health and illness shift from the state to the individual. However, while this emphasis on individual responsibility and management has burgeoned, the role and status of partners and other family members in the management of chronic illness remains under-theorised. While self-management privileges individual responsibility for the management of chronic illness, the role of partners remains unclear. This paper utilises data from a study of heterosexual couples' experiences of living with the chronic gynaecological condition endometriosis to explore how male partners engage in its day-to-day management. In all, 22 couples participated in in-depth, semi-structured interviews with each partner interviewed separately (n = 44). Data were analysed thematically and dyadically, informed by an interpretivist relational approach. The paper utilises the concept of healthwork to describe the illness work, everyday life work, biographical work and emotion work men engaged in. The paper demonstrates how the conceptual value of healthwork is enhanced by incorporating an analysis of the emotional effort required in managing chronic illness. The paper illustrates the value of investigating the role of partners in managing chronic illness to provide a fuller account of the distributed and relational nature of healthwork.

Regular (ICSI) versus ultra-high magnification (IMSI) sperm selection for assisted reproduction.

BACKGROUND: Subfertility is a condition found in up to 15% of couples of reproductive age. Gamete micromanipulation, such as intracytoplasmic sperm injection (ICSI), is very useful for treating couples with compromised sperm parameters. An alternative method of sperm selection has been described; the spermatozoa are selected under high magnification (over 6000x) and used for ICSI. This technique, named intracytoplasmic morphologically selected sperm injection (IMSI), has a theoretical potential to improve reproductive outcomes among couples undergoing assisted reproduction techniques (ART). However, our previous version of this Cochrane Review was unable to find evidence that supported this possible beneficial effect. This is an update of Teixeira 2013. OBJECTIVES: To identify, appraise, and summarise the available evidence regarding efficacy and safety of IMSI compared to ICSI in couples undergoing ART. SEARCH METHODS: We searched for randomised controlled trials (RCTs) in these electronic databases: the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, LILACS, and in these trial registers: ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. We also handsearched the reference lists of included studies and similar reviews. We performed the last electronic search on 18 November 2019. SELECTION CRITERIA: We only considered RCTs that compared ICSI and IMSI; we did not include quasi-randomised trials. We considered studies that permitted the inclusion of the same participant more than once (cross-over or per cycle trials) only if data regarding the first treatment of each participant were available. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, data extraction, and assessment of the risk of bias and quality of the evidence; we solved disagreements by consulting a third review author. We corresponded with study investigators to resolve any queries, as required. MAIN RESULTS: The updated search retrieved 535 records; we included 13 parallel-designed RCTs comparing IMSI and ICSI (four studies were added since the previous version), comprising 2775 couples (IMSI = 1256; ICSI = 1519). We are uncertain if IMSI improves live birth rates (risk ratio (RR) 1.11, 95% confidence interval (CI) 0.89 to 1.39; 5 studies, 929 couples; I² = 1%), miscarriage rates per couple (RR 1.07, 95% CI 0.78 to 1.48; 10 studies, 2297 couples; I² = 0%, very-low quality evidence), and miscarriage rate per pregnancy (RR 0.90, 95% CI 0.68 to 1.20; 10 studies, 783 couples; I² = 0%, very-low quality evidence). We are uncertain if IMSI improves clinical pregnancy rates (RR 1.23, 95% CI 1.11 to 1.37; 13 studies, 2775 couples; I² = 47%, very-low quality evidence). None of the included studies reported congenital abnormalities. We judged the evidence for all outcomes to be of very low-quality. We downgraded the quality of the evidence due to limitations of the included studies (risk of bias), inconsistency of results, and a strong indication of publication bias. AUTHORS' CONCLUSIONS: The current evidence from randomised controlled trials does not support or refute the clinical use of intracytoplasmic sperm injection (intracytoplasmic morphologically selected sperm injection (IMSI). We are very uncertain of the chances of having a live birth and of the risk of having a miscarriage. We found very low-quality evidence that IMSI may increase chances of a clinical pregnancy, which means that we are still very uncertain about any real difference. We did not find any trials reporting on the risk of congenital abnormalities. Well-designed and sufficiently powered trials are still required.

Conducting dyadic, relational research about endometriosis: A reflexive account of methods, ethics and data analysis.

Despite a growing literature on the value of relational data in studies of social phenomena, individuals still commonly constitute the basic unit of analysis in qualitative research. Methodological aspects of interviewing couples, particularly interviewing partners separately, and of conducting dyadic analysis have received scant attention. This article describes the experience of conducting separate interviews with both partners in 22 heterosexual couples (n = 44) in a study of the impact of the gynaecological condition endometriosis. In order to advance current methodological thinking regarding interviewing couples, we describe the dyadic, relational approach employed in designing the study and our specific method of dyadic analysis. We argue that utilising separate interviews with dyadic analysis rather than conducting joint interviews, while not without its ethical, practical and analytical challenges, offers considerable methodological benefits. Such an approach allows a unique relational insight into the impact of chronic illness on couples and how they navigate chronic illness by illuminating both shared and individual interpretations, experiences, understandings and meanings.

Study protocol: E-freeze - freezing of embryos in assisted conception: a randomised controlled trial evaluating the clinical and cost effectiveness of a policy of freezing embryos followed by thawed frozen embryo transfer compared with a policy of fresh embryo transfer, in women undergoing in vitro fertilisation.

BACKGROUND: Infertility affects one in seven couples; many of these need in vitro fertilisation (IVF). IVF involves external hormones to stimulate a woman's ovaries to produce eggs which are harvested surgically. Embryos, created in the laboratory by mixing eggs with sperm, are grown in culture for a few days before being replaced within the uterus (fresh embryo transfer). Spare embryos are usually frozen with a view to transfer at a later point in time - especially if the initial fresh transfer does not result in a pregnancy. Despite improvements in technology, IVF success rates remain low with an overall live birth rate of 25-30% per treatment. Additionally, there are concerns about health outcomes for mothers and babies conceived through IVF, particularly after fresh embryo transfer, including maternal ovarian hyperstimulation syndrome (OHSS) and preterm delivery. It is believed that high levels of hormones during ovarian stimulation could create a relatively hostile environment for embryo implantation whilst increasing the risk of OHSS. It has been suggested that freezing all embryos with the intention of thawing and replacing them within the uterus at a later stage (thawed frozen embryo transfer) instead of fresh embryo transfer, may lead to improved pregnancy rates and fewer complications. We aim to compare the clinical and cost effectiveness of fresh and thawed frozen embryo transfer, with the primary aim of identifying any difference in the chance of having a healthy baby. METHODS: E-Freeze is a pragmatic, multicentre two-arm parallel group randomised controlled trial where women aged ≥18 and < 42 years, with at least three good quality embryos are randomly allocated to receive either a fresh or thawed frozen embryo transfer. The primary outcome is a healthy baby, defined as a term, singleton, live birth with appropriate weight for gestation. Cost effectiveness will be calculated from a healthcare and societal perspective. DISCUSSION: E-Freeze will determine the relative benefits of fresh and thawed frozen embryo transfer in terms of improving the chance of having a healthy baby. The results of this pragmatic study have the potential to be directly transferred to clinical practice. TRIAL REGISTRATION: ISRCTN registry: ISRCTN61225414 . Date assigned 29/12/2015.

Evaluation of progestogen supplementation for luteal phase support in fresh in vitro fertilization cycles.

OBJECTIVE: To evaluate the effectiveness of progestogen supplementation in improving clinical pregnancy rates in women undergoing fresh IVF cycles and to compare different routes, start times, durations, and estrogen coadministration regimen. DESIGN: Comprehensive systematic review and meta-analysis. SETTING: University. PATIENT(S): Women undergoing fresh IVF cycles who did and did not receive progestogen supplementation. INTERVENTION(S): Summary odds ratios (ORs) were calculated by binomial logistic regression. MAIN OUTCOME MEASURE(S): Clinical pregnancy rates. RESULT(S): Eighty-two articles (26,726 women) were included. Clinical pregnancy rates were increased by IM (OR = 4.57), vaginal (OR = 3.34), SC (OR = 3.36), or oral (OR = 2.57) progestogen supplementation versus no treatment. The greatest benefit was observed when progestogens were supplemented IM versus vaginally (OR = 1.37). The optimal time to commence administration was between oocyte retrieval and ET (OR = 1.31), with oocyte retrieval +1 day being most beneficial. Coadministration of estrogen had no benefit (OR = 1.33), whether progestogens were coadministered vaginally or IM. Clinical pregnancy rates were equivalent when progestogen supplementation was ceased after ≤3 weeks or continued for up to 12 weeks (OR = 1.06). CONCLUSION(S): This broad-ranging meta-analysis highlights the need to reevaluate current clinical practice. The use of progestogens in fresh IVF cycles is substantially beneficial to clinical pregnancy. Critically, the use of IM progestogens should not be dismissed, as it yielded the greatest clinical pregnancy rates. Pregnancy success was impacted by initiation of therapy, with 1 day after oocyte retrieval being optimal. There is little evidence to support coadministration of estrogen or prolonging progestogen treatment beyond 3 weeks.

Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception.

BACKGROUND: Thyroid peroxidase antibodies are associated with an increased risk of miscarriage and preterm birth, even when thyroid function is normal. Small trials indicate that the use of levothyroxine could reduce the incidence of such adverse outcomes. METHODS: We conducted a double-blind, placebo-controlled trial to investigate whether levothyroxine treatment would increase live-birth rates among euthyroid women who had thyroid peroxidase antibodies and a history of miscarriage or infertility. A total of 19,585 women from 49 hospitals in the United Kingdom underwent testing for thyroid peroxidase antibodies and thyroid function. We randomly assigned 952 women to receive either 50 µg once daily of levothyroxine (476 women) or placebo (476 women) before conception through the end of pregnancy. The primary outcome was live birth after at least 34 weeks of gestation. RESULTS: The follow-up rate for the primary outcome was 98.7% (940 of 952 women). A total of 266 of 470 women in the levothyroxine group (56.6%) and 274 of 470 women in the placebo group (58.3%) became pregnant. The live-birth rate was 37.4% (176 of 470 women) in the levothyroxine group and 37.9% (178 of 470 women) in the placebo group (relative risk, 0.97; 95% confidence interval [CI], 0.83 to 1.14, P = 0.74; absolute difference, -0.4 percentage points; 95% CI, -6.6 to 5.8). There were no significant between-group differences in other pregnancy outcomes, including pregnancy loss or preterm birth, or in neonatal outcomes. Serious adverse events occurred in 5.9% of women in the levothyroxine group and 3.8% in the placebo group (P = 0.14). CONCLUSIONS: The use of levothyroxine in euthyroid women with thyroid peroxidase antibodies did not result in a higher rate of live births than placebo. (Funded by the United Kingdom National Institute for Health Research; TABLET Current Controlled Trials number, ISRCTN15948785.).

Intrauterine administration of human chorionic gonadotropin (hCG) for subfertile women undergoing assisted reproduction.

BACKGROUND: Most women undergoing assisted reproduction treatment will reach the stage of embryo transfer (ET), but the proportion of embryos that can be successfully implanted after ET has remained small since the mid-1990s. Human chorionic gonadotropin (hCG) is a hormone that is synthesised and released by the syncytiotrophoblast and has a fundamental role in embryo implantation and the early stages of pregnancy. Intrauterine administration of hCG via ET catheter during a mock procedure around the time of ET is a novel approach that has been suggested to improve the outcomes of assisted reproduction. OBJECTIVES: To investigate whether intrauterine (intracavity) administration of hCG (IC-hCG) around the time of ET improves clinical outcomes in subfertile women undergoing assisted reproduction. SEARCH METHODS: We performed searches on 9 January 2018 using Cochrane methods. SELECTION CRITERIA: We looked for randomised controlled trials (RCTs) evaluating IC-hCG around the time of ET, irrespective of language and country of origin. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias, extracted data from studies, and attempted to contact study authors when data were missing. We performed statistical analysis using Review Manager 5. We assessed evidence quality using GRADE methods. Primary outcomes were live birth and miscarriage; secondary outcomes were clinical pregnancy rate and complications. MAIN RESULTS: Seventeen RCTs investigated the effects of IC-hCG administration for 4751 subfertile women undergoing assisted reproduction. IC-hCG was administered in variable doses at different times before the ET. hCG was obtained from the urine of pregnant women or from cell cultures using recombinant DNA technology.Most studies (12/17) were at high risk of bias in at least one of the seven domains assessed. Common problems were unclear reporting of study methods and lack of blinding. The main limitations for evidence quality were high risk of bias and serious imprecision.For analyses of live birth and clinical pregnancy, there was considerable heterogeneity (I² > 75%) and therefore we present subgroups for dosage and stage of ET. Exploration for sources of heterogeneity revealed two key prespecified variables as important determinants: stage of ET (cleavage vs blastocyst stage) and dose of IC-hCG (< 500 international units (IU) vs ≥ 500 IU). We performed meta-analyses within subgroups defined by stage of embryo and dose of IC-hCG.Live birth rates among women having cleavage-stage ET with an IC-hCG dose < 500 IU compared to women having cleavage-stage ET without IC-hCG showed no benefit of the intervention and would be consistent with no substantive difference or disadvantage of indeterminate magnitude (risk ratio (RR) 0.76, 95% confidence interval (CI) 0.58 to 1.01; one RCT; 280 participants; I² = 0%; very low-quality evidence). In a clinic with a live birth rate of 49% per cycle, use of IC-hCG < 500 IU would be associated with a live birth rate ranging from 28% to 50%.Results show an increase in live birth rate in the subgroup of women undergoing cleavage-stage ET with an IC-hCG dose ≥ 500 IU compared to women having cleavage-stage ET without IC-hCG (RR 1.57, 95% CI 1.32 to 1.87; three RCTs; 914 participants; I² = 0%; moderate-quality evidence). At a clinic with a live birth rate of 27% per cycle, use of IC-hCG ≥ 500 IU would be associated with a live birth rate ranging from 36% to 51%.Results show no substantive differences in live birth among women having blastocyst-stage ET with an IC-hCG dose ≥ 500 IU compared to women having blastocyst-stage ET without IC-hCG (RR 0.92, 95% CI 0.80 to 1.04; two RCTs; 1666 participants; I² = 0%; moderate-quality evidence). At a clinic with a live birth rate of 36% per cycle, use of IC-hCG ≥ 500 IU would be associated with a live birth rate ranging from 29% to 38%.Evidence for clinical pregnancy among women having cleavage-stage ET with an IC-hCG dose < 500 IU showed no benefit of the intervention and would be consistent with no substantive difference or disadvantage of indeterminate magnitude (RR 0.88, 95% CI 0.70 to 1.10; one RCT; 280 participants; I² = 0%; very low-quality evidence).Results show an increase in clinical pregnancy rate in the subgroup of women having cleavage-stage ET with an IC-hCG dose ≥ 500 IU compared to women having cleavage-stage ET without IC-hCG (RR 1.49, 95% CI 1.32 to 1.68; 12 RCTs; 2186 participants; I² = 18%; moderate-quality evidence).Results show no substantive differences in clinical pregnancy among women having blastocyst-stage ET with an IC-hCG dose ≥ 500 IU (RR 0.99, 95% CI 0.85 to 1.15; four RCTs; 2091 participants; I² = 42%; moderate-quality evidence) compared to women having blastocyst-stage ET with no IC-hCG.No RCTs investigated blastocyst-stage ET with an IC-hCG dose < 500 IU.We are uncertain whether miscarriage was influenced by intrauterine hCG administration (RR 1.04, 95% CI 0.81 to 1.35; 11 RCTs; 3927 participants; I² = 0%; very low-quality evidence).Reported complications were ectopic pregnancy (four RCTs; 1073 participants; four events overall), heterotopic pregnancy (one RCT; 495 participants; one event), intrauterine death (three RCTs; 1078 participants; 22 events), and triplets (one RCT; 48 participants; three events). Events were few, and very low-quality evidence was insufficient to permit conclusions to be drawn. AUTHORS' CONCLUSIONS: There is moderate quality evidence that women undergoing cleavage-stage transfer using an IC-hCG dose ≥ 500 IU have an improved live birth rate. There is insufficient evidence for IC-hCG treatment for blastocyst transfer. There should be further trials with live birth as the primary outcome to identify the groups of women who would benefit the most from this intervention. There was no evidence that miscarriage was reduced following IC-hCG administration, irrespective of embryo stage at transfer or dose of IC-hCG. Events were too few to allow conclusions to be drawn with regard to other complications.

Serum concentrations of Ang-2 and Flt-1 may be predictive of pregnancy outcome in women with pregnancies of uncertain viability: a phase I exploratory prognostic factor study.

The aim of this study was to determine whether serum concentrations of Ang-1, Ang-2, Flt-1, IL-15 and/or TRAIL can be used to predict outcome in women with pregnancies of uncertain viability (PUVs). Women presenting to the Early Pregnancy Unit at the Queen's Medical Centre in Nottingham between 17.06.14 and 01.09.15 were prospectively recruited. Serum concentrations of Ang-1, Ang-2, Flt-1, IL-15 and TRAIL were measured in women with PUVs. Women were followed-up according to departmental protocols until viability was determined. Biomarker concentrations were correlated with pregnancy outcome. Ninety-four PUVs were studied, of which 61 (64.9%) were subsequently proven to be viable. There were statistically significant (p < .01), linear (p-valuetrend <.01) associations between Ang-2 and Flt-1 concentrations and pregnancy viability such that women with lower concentrations were significantly more likely to have viable pregnancies than women with higher concentrations. In conclusion, Ang-2 and Flt-1 may be useful in predicting outcome in women with PUVs. Impact statement What is already known on this subject: Predicting outcome in women with pregnancies of uncertain viability (PUVs) is challenging. There is currently no accurate and reliable method. All PUVs need to be followed-up until a definitive diagnosis of either a viable or non-viable pregnancy can be made. This takes time, utilises limited resources and generates significant anxiety. Recent studies have demonstrated serum concentrations of Ang-1, Ang-2, Flt-1, IL-15 and TRAIL in viable pregnancies are significantly different to those in non-viable or ectopic pregnancies. What the results of this study add: The results from this prospective study of 94 women with PUVs suggest that serum concentrations of Ang-2 and Flt-1 may be able to predict pregnancy viability in cases of uncertainty. Women with PUVs and low concentrations of Ang-2 or Flt-1 are significantly more likely to have viable pregnancies than women with high concentrations. What the implications are of these findings for clinical practice and/or further research: Evidence from multiple studies is necessary to appreciate the discriminating ability of these prognostic factors. Rapid clinical adoption in the absence of such evidence may lead to wasted resources. If our findings are confirmed, however, these biomarkers, either alone or as part of a prognostic model, may be capable of accurately predicting pregnancy outcome in cases of uncertainty. This would reduce the strain on limited resources and alleviate anxiety for women.

Efficacy of Dehydroepiandrosterone (DHEA) to overcome the effect of ovarian ageing (DITTO): A proof of principle double blinded randomized placebo controlled trial.

OBJECTIVE: To evaluate the effect of DHEA supplementation on In-Vitro Fertilisation (IVF) outcome as assessed by ovarian response, oocyte developmental competence and live birth rates in women predicted to have poor ovarian reserve (OR). The feasibility of conducting a large trial is also assessed by evaluating the recruitment rates and compliance of the recruited participants with DHEA/placebo intake and follow-up rates. STUDY DESIGN: A single centre, double blinded, placebo controlled, randomized trial was performed over two years with 60 women undergoing in-vitro fertilisation (IVF). Subjects were randomized, based on a computer-generated pseudo-random code to receive either DHEA or placebo with both capsules having similar colour, size and appearance. 60 women with poor OR based on antral follicle count or anti-Mullerian hormone thresholds undergoing IVF were recruited. They were randomised to receive DHEA 75mg/day or placebo for at-least 12 weeks before starting ovarian stimulation. They had long protocol using hMG 300 IU/day. Data analysed by "intention to treat". Ovarian response, live birth rates and molecular markers of oocyte quality were compared between the study and control groups. RESULTS: The recruitment rate was 39% (60/154). A total of 52 participants (27 versus 25 in the study and placebo groups) were included in the final analysis after excluding eight. While the mean (standard deviation) DHEA levels were similar at recruitment (9.4 (5) versus 7.5 (2.4) ng/ml; P=0.1), the DHEA levels at pre-stimulation were higher in the study group than in the controls (16.3 (5.8) versus 11.1 (4.5) ng/ml; P<0.01). The number (median, range) of oocytes retrieved (4, 0-18 versus 4, 0-15 respectively; P=0.54) and live birth rates (7/27, 26% versus 8/25, 32% respectively; RR (95% CI): 0.74 (0.22-2.48) and mRNA expression of developmental biomarkers in granulosa and cumulus cells were similar between the groups. CONCLUSION: Pre-treatment DHEA supplementation, albeit statistical power in this study is low, did not improve the response to controlled ovarian hyperstimulation or oocyte quality or live birth rates during IVF treatment with long protocol in women predicted to have poor OR.

Priorities for research in miscarriage: a priority setting partnership between people affected by miscarriage and professionals following the James Lind Alliance methodology.

OBJECTIVES: To identify and prioritise important research questions for miscarriage. DESIGN: A priority setting partnership using prospective surveys and consensus meetings following methods advocated by the James Lind Alliance. SETTING: UK. PARTICIPANTS: Women and those affected by miscarriage working alongside healthcare professionals. RESULTS: In the initial survey, 1093 participants (932 women who have experienced miscarriage, 8 partners, 17 family members, friends or colleagues, 104 healthcare professionals and eight charitable organisations) submitted 3279 questions. A review of existing literature identified a further 64. Non-questions were removed, and the remaining questions were categorised and summarised into 58 questions. In an interim electronic survey, 2122 respondents chose their top 10 priorities from the 58 summary questions. The 25 highest ranked in the survey were prioritised at a final face-to-face workshop. In summary, the top 10 priorities were ranked as follows: research into preventative treatment, emotional aspects in general, investigation, relevance of pre-existing medical conditions, emotional support as a treatment, importance of lifestyle factors, importance of genetic and chromosomal causes, preconception tests, investigation after different numbers of miscarriage and male causal factors. CONCLUSIONS: These results should be the focus of future miscarriage research. Presently, studies are being conducted to address the top priority; however, many other priorities, especially psychological and emotional support, are less well researched areas. We hope our results will encourage both researchers and funders to focus on these priorities.