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Study Question: What is the global variability in recurrent implantation failure (RIF) definition, investigation and therapy, currently offered to patients undergoing IVF?Sumamry Answer: Definitions, diagnostic investigations and treatments offered to RIF patients differ widely amongst assisted reproduction healthcare professionals and clinical guidelines on RIF are urgently needed.What Is Known Already: RIF affects around 10% of patients undergoing IVF worldwide. There is no consensus on the definition of RIF, its diagnostic investigations or the therapeutic options, which leads to inconsistencies in clinical practice.Study Design, Size, Duration: A cross-sectional study of clinicians and embryologists was conducted between May and June 2020. The survey included 43 questions aimed at understanding participants' background and their current practice with regards to defining, investigating and managing RIF. The questions were designed by the European Society of Human Reproduction and Embryology (ESHRE) Special Interest Group (SIG) on implantation and early pregnancy following three consensus meetings.Participants/materials, Setting, Methods: A total of 8579 ESHRE members from 6916 IVF centers were invited to participate using two global email calls based on their pre-specified interest in implantation and early pregnancy. SurveyMonkey and SPSS were used for data collection and analysis, respectively. Furthermore, differences were reported in the answers of European and non-European professionals, as well as between public and private settings and among clinicians clustered according to the average number of RIF patients treated per year.Main Results and the Role Of Chance: The final data set included 735 clinicians and 300 embryologist or IVF-biologists. The majority defines RIF based on the number of failed embryo transfers (ETs) with the most common threshold adopted being three ETs both fresh and frozen. More than two-thirds take lifestyle factors into account, mainly drugs, smoking and BMI. The highest consensus on which diagnostic investigations should be performed was reached for anatomical malformations and gynecological aspects focusing on hydrosalpinx, Asherman's syndrome, endometrial thickness and endometriosis. Concerning treatment of RIF patients, the highest consensus was reached for preconceptional therapies, including BMI adjustment, smoking and endometritis followed by therapies during IVF procedures.Limitations, Reasons For Caution: The response rate was relatively low, but comparable to other surveys.Wider Implications Of the Findings: A consensus on definition, diagnosis and treatment of RIF would help to reduce costly, time-consuming and poorly validated approaches.Study Funding/competing Interest(s): No external funding was used. B.T. received support from Bayer for Clinical trials concerning endometriosis and Ferring for clinical trials concerning ovarian stimulation. She received reimbursement for travel expenses from Astropharm, Ferring. Dr Kade and is a shareholder of Reprognostics. She is a board member of the Austrian Society for Obstetrics and Gynecology (OEGGG), the associate head of the 'Reproduktionsmedizinische Zentren Baden-Württemberg' (RZBW), a member of guideline group of the German Society for Obstetrics and Gynecology (DGGG) and an editorial board member of the following journals: American Journal of Reproductive Immunology (AJRI), Archives of Gynecology and Obstetrics. All the other authors declare no conflict of interest.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Competing Interests: Competing interests: None declared.

Study Question: Which clinical and embryological factors should be considered to apply double embryo transfer (DET) instead of elective single embryo transfer (eSET)?, Summary Answer: No clinical or embryological factor per se justifies a recommendation of DET instead of eSET in IVF/ICSI., What Is Known Already: DET is correlated with a higher rate of multiple pregnancy, leading to a subsequent increase in complications for both mother and babies. These complications include preterm birth, low birthweight, and other perinatal adverse outcomes. To mitigate the risks associated with multiple pregnancy, eSET is recommended by international and national professional organizations as the preferred approach in ART., Study Design, Size, Duration: The guideline was developed according to the structured methodology for development and update of ESHRE guidelines. Literature searches were performed in PUBMED/MEDLINE and Cochrane databases, and relevant papers published up to May 2023, written in English, were included. Live birth rate, cumulative live birth rate, and multiple pregnancy rate were considered as critical outcomes., Participants/materials, Setting, Methods: Based on the collected evidence, recommendations were discussed until a consensus was reached within the Guideline Development Group (GDG). A stakeholder review was organized after the guideline draft was finalized. The final version was approved by the GDG and the ESHRE Executive Committee., Main Results and the Role of Chance: The guideline provides 35 recommendations on the medical and non-medical risks associated with multiple pregnancies and on the clinical and embryological factors to be considered when deciding on the number of embryos to transfer. These recommendations include 25 evidence-based recommendations, of which 24 were formulated as strong recommendations and one as conditional, and 10 good practice points. Of the evidence-based recommendations, seven (28%) were supported by moderate-quality evidence. The remaining recommendations were supported by low (three recommendations; 12%), or very low-quality evidence (15 recommendations; 60%). Owing to the lack of evidence-based research, the guideline also clearly mentions recommendations for future studies., Limitations, Reasons for Caution: The guideline assessed different factors one by one based on existing evidence. However, in real life, clinicians' decisions are based on several prognostic factors related to each patient's case. Furthermore, the evidence from randomized controlled trials is too scarce to formulate high-quality evidence-based recommendations., Wider Implications of the Findings: The guideline provides health professionals with clear advice on best practice in the decision-making process during IVF/ICSI, based on the best evidence currently available, and recommendations on relevant information that should be communicated to patients. In addition, a list of research recommendations is provided to stimulate further studies in the field., Study Funding/competing Interest(s): The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, the literature searches, and the dissemination of the guideline. The guideline group members did not receive payment. DPB declared receiving honoraria for lectures from Merck, Ferring, and Gedeon Richter. She is a member of ESHRE EXCO, and the Mediterranean Society for reproductive medicine and the president of the Croatian Society for Gynaecological Endocrinology and Reproductive Medicine. CDG is the past Chair of the ESHRE EIM Consortium and a paid deputy member of the Editorial board of Human Reproduction. IR declared receiving reimbursement from ESHRE and EDCD for attending meetings. She holds an unpaid leadership role in OBBCSSR, ECDC Sohonet, and AER. KAR-W declared receiving grants for clinical researchers and funding provision to the institution from the Swedish Cancer Society (200170F), the Senior Clinical Investigator Award, Radiumhemmets Forskningsfonder (Dnr: 201313), Stockholm County Council FoU (FoUI-953912) and Karolinska Institutet (Dnr 2020-01963), NovoNordisk, Merck and Ferring Pharmaceuticals. She received consulting fees from the Swedish Ministry of Health and Welfare. She received honoraria from Roche, Pfizer, and Organon for chairmanship and lectures. She received support from Organon for attending meetings. She participated in advisory boards for Merck, Nordic countries, and Ferring. She declared receiving time-lapse equipment and grants with payment to institution for pre-clinical research from Merck pharmaceuticals and from Ferring. SS-R received research funding from Roche Diagnostics, Organon/MSD, Theramex, and Gedeo-Richter. He received consulting fees from Organon/MSD, Ferring Pharmaceuticals, and Merck Serono. He declared receiving honoraria for lectures from Ferring Pharmaceuticals, Besins, Organon/MSD, Theramex, and Gedeon Richter. He received support for attending Gedeon Richter meetings and participated in the Data Safety Monitoring Board of the T-TRANSPORT trial. He is the Deputy of ESHRE SQART special interest group. He holds stock options in IVI Lisboa and received equipment and other services from Roche Diagnostics and Ferring Pharmaceuticals. KT declared receiving payment for honoraria for giving lectures from Merck Serono and Organon. She is member of the safety advisory board of EDQM. She holds a leadership role in the ICCBBA board of directors. ZV received reimbursement from ESHRE for attending meetings. She also received research grants from ESHRE and Juhani Aaltonen Foundation. She is the coordinator of EHSRE SQART special interest group. The other authors have no conflicts of interest to declare., Disclaimer: This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgement to each individual presentation, nor variations based on locality and facility type. ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose (full disclaimer available at https://www.eshre.eu/Guidelines-and-Legal)., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Background: Endometrial receptivity has been the focus of continuous research for over eight decades; however, current clinical practice lacks an accurate test of endometrial receptivity to allow the prediction of successful pregnancy. We aimed to characterize the endometrial metabolomic profiles of women who suffered recurrent miscarriage using discovery metabolomics and to set the foundation for the development of an endometrial receptivity test., Methods: This was a prospective multicenter cohort study led by the Tommy's National Centre for Miscarriage Research in Birmingham. Endometrial biopsies were obtained during the window of implantation from 24 women aged 18-35 years, who were not pregnant and regularly menstruating, diagnosed with unexplained recurrent miscarriage. The metabolite composition and relative concentrations of samples were analyzed applying ultra-high performance liquid chromatography-mass spectrometry to investigate water-soluble and lipid metabolites., Results: Various metabolic perturbations are associated with observation of increased numbers of miscarriages. They relate to fatty acid metabolism including increased lipolysis and decreased medium chain fatty acid beta-oxidation, poorer mitochondrial health, and redox-active co-factors which are present at higher oxidative levels. Other metabolic perturbations are associated with observation of live birth following miscarriages. They relate to perturbed cholesterol-cholesterol sulphate metabolism, fatty acid metabolism including increased diacylglyceride lipolysis and decreased medium chain fatty acid beta-oxidation, and improved mitochondrial health., Conclusions: The present endometrial metabolomics discovery studies have implicated a small number of metabolic pathways and biological functions which are biologically important in miscarriage mechanisms.

Objective: To study the safety and feasibility of virtual consultations in reproductive medicine., Design: This was a descriptive cross-sectional study involving subfertile patients attending a video consultation between September 2021 and August 2022. Clinicians conducting virtual consultations during the same period responded to a parallel survey for healthcare professionals., Setting: University Hospital in Manchester, UK., Participants: Subfertile patients attending a virtual consultation. Healthcare professionals conducting virtual consultations., Intervention: The survey link was offered in 4,932 consultations. A total of 577 (11.69%) patients responded and 510 completed the questionnaire (88.3%)., Main Outcome Measures: Patient satisfaction measured as the percentage of patients preferring virtual to in person consultations., Results: The majority of the patients (475, 91.70%) had a positive experience with the video consultation and just under half of the patients (152, 48.65%) preferred a video consultation to an in person consultation due to cost and time savings. Most patients (375, 72.68%) felt safer and less exposed to COVID-19. When the risk of COVID-19 subsides, 242 patients (47%) would still prefer to attend video consultations, while 169 (32.82%) had no preference. Analysis of the responses from patients reporting a negative experience identified technical problems as a possible cause. The virtual consultations appeared to be suitable for patients with disabilities. The clinicians' survey identified potential legal and ethical concerns., Conclusion: Virtual consultations are a safe and feasible alternative to in person consultations for subfertile patients. This large cross-sectional study revealed a high rate of patient satisfaction. Appropriate patient selection accounting for IT literacy, English language understanding and preference is crucial for successful virtual consultations. Further consideration should be given to ethical and legal challenges of virtual consultations., Trial Registration: Research Registry, UIN 6912, https://www.researchregistry.com/browse-the-registry., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Premature ovarian insufficiency (POI) is a clinical syndrome resulting from loss of ovarian function before the age of 40. It is a state of hypergonadotropic hypogonadism, characterised by amenorrhoea or oligomenorrhoea, with low ovarian sex hormones (oestrogen deficiency) and elevated pituitary gonadotrophins. POI with primary amenorrhoea may occur as a result of chromosomal and genetic abnormalities, such as Turner syndrome, Fragile X, or autosomal gene defects; secondary amenorrhoea may be iatrogenic after the surgical removal of the ovaries, radiotherapy, or chemotherapy. Other causes include autoimmune diseases, viral infections, and environmental factors; in most cases, POI is idiopathic. Appropriate replacement of sex hormones in women with POI may facilitate the achievement of near normal uterine development. However, the optimal effective hormone therapy (HT) regimen to maximise the reproductive potential for women with POI remains unclear., Objectives: To investigate the effectiveness and safety of different hormonal regimens on uterine and endometrial development in women with POI., Search Methods: We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and two trials registers in September 2021. We also checked references of included studies, and contacted study authors to identify additional studies., Selection Criteria: We included randomised controlled trials (RCTs) investigating the effect of various hormonal preparations on the uterine development of women diagnosed with POI., Data Collection and Analysis: We used standard methodological procedures recommended by Cochrane. The primary review outcome was uterine volume; secondary outcomes were endometrial thickness, endometrial histology, uterine perfusion, reproductive outcomes, and any reported adverse events., Main Results: We included three studies (52 participants analysed in total) investigating the role of various hormonal preparations in three different contexts, which deemed meta-analysis unfeasible. We found very low-certainty evidence; the main limitation was very serious imprecision due to small sample size. Conjugated oral oestrogens versus transdermal 17ß-oestradiol We are uncertain of the effect of conjugated oral oestrogens compared to transdermal 17ß-oestradiol (mean difference (MD) -18.2 (mL), 95% confidence interval (CI) -23.18 to -13.22; 1 RCT, N = 12; very low-certainty evidence) on uterine volume, measured after 12 months of treatment. The study reported no other relevant outcomes (including adverse events). Low versus high 17ß-oestradiol dose We are uncertain of the effect of a lower dose of 17ß-oestradiol compared to a higher dose of 17ß-oestradiol on uterine volume after three or five years of treatment, or adverse events (1 RCT, N = 20; very low-certainty evidence). The study reported no other relevant outcomes. Oral versus vaginal administration of oestradiol and dydrogesterone We are uncertain of the effect of an oral or vaginal administration route on uterine volume and endometrial thickness after 14 or 21 days of administration (1 RCT, N = 20; very low-certainty evidence). The study reported no other relevant outcomes (including adverse events)., Authors' Conclusions: No clear conclusions can be drawn in this systematic review, due to the very low-certainty of the evidence. There is a need for pragmatic, well designed, randomised controlled trials, with adequate power to detect differences between various HT regimens on uterine growth, endometrial development, and pregnancy outcomes following the transfer of donated gametes or embryos in women diagnosed with POI., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Ovarian tissue cryopreservation involves freezing and storing of surgically retrieved ovarian tissue in liquid or vapour nitrogen below -190°C. The tissue can be thawed and transplanted back with the aim of restoring fertility or ovarian endocrine function. The techniques for human ovarian tissue freezing and transplantation have evolved over the last 20 years, particularly in the context of fertility preservation in pre-pubertal cancer patients. Fresh ovarian tissue transplantation, using an autograft or donor tissue, is a more recent development; it has the potential to preserve fertility and hormonal function in women who have their ovaries removed for benign gynaecological conditions. The techniques of ovarian tissue cryopreservation and transplantation have progressed rapidly since inception; however, the evidence on the success of this intervention is largely based on case reports and case series., Objective and Rationale: The aim of this study was to systematically review the current evidence by incorporating study-level and individual patient-level meta-analyses of women who received ovarian transplants, including frozen-thawed transplant, fresh or donor graft., Search Methods: The review protocol was registered with PROSPERO (CRD42018115233). A comprehensive literature search was performed using MEDLINE, EMBASE, CINAHL and Cochrane Central Register of Controlled Trials from database inception to October 2020. Authors were also contacted for individual patient data if relevant outcomes were not reported in the published manuscripts. Meta-analysis was performed using inverse-variance weighting to calculate summary estimates using a fixed-effects model., Outcomes: The review included 87 studies (735 women). Twenty studies reported on ≥5 cases of ovarian transplants and were included in the meta-analysis (568 women). Fertility outcomes included pregnancy, live birth and miscarriage rates, and endocrine outcomes included oestrogen, FSH and LH levels. The pooled rates were 37% (95% CI: 32-43%) for pregnancy, 28% (95% CI: 24-34%) for live birth and 37% (95% CI: 30-46%) for miscarriage following frozen ovarian tissue transplantation. Pooled mean for pre-transplant oestrogen was 101.6 pmol/l (95% CI: 47.9-155.3), which increased post-transplant to 522.4 pmol/l (95% CI: 315.4-729; mean difference: 228.24; 95% CI: 180.5-276). Pooled mean of pre-transplant FSH was 66.4 IU/l (95% CI: 52.8-84), which decreased post-transplant to 14.1 IU/l (95% CI: 10.9-17.3; mean difference 61.8; 95% CI: 57-66.6). The median time to return of FSH to a value <25 IU/l was 19 weeks (interquartile range: 15-26 weeks; range: 0.4-208 weeks). The median duration of graft function was 2.5 years (interquartile range: 1.4-3.4 years; range: 0.7-5 years). The analysis demonstrated that ovarian tissue cryopreservation and transplantation could restore reproductive and hormonal functions in women. Further studies with larger samples of well-characterized populations are required to define the optimal retrieval, cryopreservation and transplantation processes., Wider Implications: Ovarian tissue cryopreservation and transplantation may not only be effective in restoring fertility but also the return of reproductive endocrine function. Although this technology was developed as a fertility preservation option, it may have the scope to be considered for endocrine function preservation., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The removal of cumulus cells in a process called oocyte denudation is required in order to visualise, grade and manipulate the oocytes before injection. The objective of this study was to appraise critically the published randomised controlled trials (RCTs) comparing recombinant hyaluronidase with bovine hyaluronidase for oocyte denudation before intracytoplasmic sperm injection (ICSI). We performed a comprehensive literature search of the standard medical databases in order to identify the RCTs comparing oocyte denudation with recombinant hyaluronidase or bovine hyaluronidase before ICSI. Three RCTs involving 2445 oocytes collected from 200 women were analysed. There was substantial heterogeneity among the included RCTs. A meta-analysis from the available moderate to high quality trials found no statistical difference in terms of fertilisation rate, embryo quality and live birth rate between the use of recombinant or bovine hyaluronidase for oocyte denudation before ICSI.IMPACT STATEMENT What is already known on this subject? The removal of cumulus cells in a process called oocyte denudation is required in order to visualise, grade and manipulate the oocytes before injection. The long-established source of hyaluronidase has been represented by bovine testes, but concern has been raised regarding the possible negative effects over the fragile oocytes by mechanisms involving low enzyme purity, variable concentrations, trauma, prolonged exposure and integration of external DNA in the oocyte. Recombinant human hyaluronidase has been proposed as an alternative in order to counteract the possible negative effects of using animal derived products. What do the results of this study add? A meta-analysis from the available moderate to high quality trials found no statistical difference in fertilisation rate, embryo quality and live birth rate between the use of recombinant or bovine hyaluronidase for oocyte denudation before ICSI. What are the implications of these findings or clinical practice and/or further research? Future trials should be powered adequately in order to be able to identify the possible small differences between the study groups and they should be conducted according to the CONSORT guidelines as the absence of blinding for outcome assessors can induce detection bias.

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., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Miscarriage describes the spontaneous loss of pregnancy before the threshold of viability; the vast majority occur before 12 weeks of gestation. Miscarriage affects one in four couples and is the most common complication of pregnancy. Chromosomal abnormalities of the embryo are identified in ∼50% of first trimester miscarriages; aneuploidy accounts for 86% of these cases. The majority of trisomic miscarriages are of maternal origin with errors occurring during meiotic division of the oocytes. Chromosome segregation errors in oocytes may be sporadic events secondary to advancing maternal age; however, there is increasing evidence to suggest possible maternal germline contributions to this., Objective and Rationale: The objective of this review was to appraise critically the existing evidence relating to maternal germline factors associated with pregnancy loss secondary to embryo aneuploidy, identify limitations in the current evidence base and establish areas requiring further research., Search Methods: The initial literature search was performed in September 2019 and updated in January 2021 using the electronic databases OVID MEDLINE, EMBASE and the Cochrane Library. No time or language restrictions were applied to the searches and only primary research was included. Participants were women who had suffered pregnancy loss secondary to numerical chromosomal abnormalities of the embryo. Study identification and subsequent data extraction were performed by two authors independently. The Newcastle-Ottawa Scale was used to judge the quality of the included studies. The results were synthesized narratively., Outcomes: The literature search identified 2198 titles once duplicates were removed, of which 21 were eligible for inclusion in this systematic review. They reported on maternal germline factors having variable degrees of association with pregnancy loss of aneuploid origin. The Online Mendelian Inheritance in Man (OMIM) gene ontology database was used as a reference to establish the functional role currently attributed to the genes reported. The majority of the cases reported and included were secondary to the inheritance of maternal structural factors such as Robertsonian translocations, deletions and insertions. Germline factors with a plausible role in aneuploid pregnancy loss of maternal origin included skewed X-inactivation and CGG repeats in the fragile X mental retardation (FMR1) gene. Studies that reported the association of single gene mutations with aneuploid pregnancy loss were conflicting. Single gene mutations with an uncertain or no role in aneuploid pregnancy loss included mutations in synaptonemal complex protein 3 (SYCP3), mitotic polo-like kinase 4 (PLK4) and meiotic stromal antigen 3 (STAG3) spindle integrity variants and 5,10-methylenetetrahydrofolate reductase (MTHFR)., Wider Implications: Identifying maternal genetic factors associated with an increased risk of aneuploidy will expand our understanding of cell division, non-disjunction and miscarriage secondary to embryo aneuploidy. The candidate germline factors identified may be incorporated in a screening panel for women suffering miscarriage of aneuploidy aetiology to facilitate counselling for subsequent pregnancies., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To characterise the endometrial transcriptomic profiles of women who suffered recurrent miscarriage and to set the foundation for the development of an endometrial receptivity test that could predict the fate of subsequent pregnancies., Study Design: This was a prospective multicentre cohort study performed at the Tommy's National Centre for Miscarriage Research in Birmingham, Saint Mary's Hospital in Manchester and Royal Devon & Exeter Hospital, United Kingdom. The study was conducted between December 2017 and December 2019. Endometrial biopsies were obtained during the window of implantation from 24 women aged 18-35 years, who were not pregnant and regularly menstruating, diagnosed with unexplained recurrent miscarriage by standard investigations as per the ESHRE guidelines. Exclusion criteria included risk factors such as smoking, obesity or hyperprolactinemia. The RNA transcripts abundances were quantified using Kallisto. R packages tximport and DESeq2 were used to summarize count estimates at the gene level and to analyse the differential gene expression., Results: Women who suffered four or more miscarriages had 19 differently expressed genes after adjustment for multiple comparisons. They were related to biological processes such as immunity (HLA-DMA, CCR8, ALOX5), energy production (ATP12A), hormone secretion (CGA), adhesion (CHAD, ADGRF2, AQP5, TBCD, CTNND1, NKD2) and cell proliferation (NCCRP1). Based on 421 differently expressed genes, women who achieved a subsequent live birth displayed an enrichment of processes related to the regulation of cell structure and proliferation, and a depletion of processes related to immunity, trans-membrane transport and coagulation., Conclusions: Women in the extreme miscarriage cohort had a distinctive endometrial transcriptomic signature compared to women with low order miscarriages. There was a partial overlap with the transcriptome of asynchronous endometrium suggesting the endometrial factor to be a different entity in the context of recurrent miscarriage. Women who achieved a live birth in their subsequent pregnancy displayed an enrichment of genes related to the regulation of cell structure and proliferation, while women who suffered a subsequent miscarriage displayed an enrichment of genes related to immunity, trans-membrane transport and coagulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: More than 60,000 hysteroscopies are performed every year in the UK for common reasons such as heavy menstrual bleeding (HMB) or postmenopausal bleeding. A significant number of women requiring hysteroscopy receive oral anticoagulants and there is often a reluctance to perform these procedures due to bleeding concerns., Study Design: We are presenting the first proof of concept cohort of patients undergoing minor hysteroscopic procedures while on anticoagulant or antiplatelet medication. A variety of minor procedures such as cervical dilatation, targeted endometrial biopsies, Pipelle endometrial biopsies and insertion or removal of intrauterine contraceptive devices were performed alongside hysteroscopy., Results: Completion of planned procedures was feasible in all women due to minimal bleeding despite the ongoing anticoagulation or anti-platelet treatment., Conclusion: More research is needed to establish the safety of performing diagnostic and operative hysteroscopies without bridging or interrupting anticoagulation or antiplatelet treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest and nothing to disclose., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To assess the women's views in relation to the characteristics of an endometrial receptivity test in the context of recurrent miscarriage with an overarching aim to guide the development of a Target Product Profile (TPP) based on minimum acceptable ("worst-case") and ideal ("best-case") features., Study Design: This was a descriptive cross-sectional study involving a total of 131 women who answered questions related to the development of an endometrial receptivity test between December 2017 and May 2018. Women attending the recurrent miscarriage clinic at the Tommy's National Centre for Miscarriage Research in Birmingham, United Kingdom, were invited to participate. Referral criteria included two or more miscarriages irrespective of the timing in relation to successful pregnancies. The 'best-case' (ideal) and 'worst-case' (minimum acceptable) thresholds were arbitrary set to satisfy at least 80% and 40% of responders, respectively., Results: The ideal endometrial receptivity test should be indicated after two miscarriages to comply with the wish of 80.9% (106 women) of responders. It should be performed in a window of three to four days within the menstrual cycle (93.2%; 122 women) and results should be available within one to two days (87.7%; 115 women). Invasiveness of testing should not extend beyond a vaginal examination (85.4%; 112 women). Repeating the test should not be required more than twice (96.1%; 125 women) and the results should remain useful for at least six menstrual cycles (89.3%; 117 women). The importance score given for the endometrium was weakly associated with the willingness to pay for testing; however, there was no evidence to suggest this correlation was different from 0 (Kendall's tau = 0.1101765, z = 1.4327, p-value = 0.1519; Spearman's rho = 0.1268444, S = 327136, p-value = 0.1488)., Conclusions: Women understand the important role the endometrium plays for a successful pregnancy and they have specific views in relation to the indication, timing and invasiveness of testing, need for test repetition, validity of results and costs of testing., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Thyroid disease is the second most common endocrine disorder affecting women of reproductive age. Subclinical hypothyroidism is diagnosed by an elevated thyroid-stimulating hormone concentration with a normal concentration of free thyroxine hormone. Autoimmune thyroid disease (ATD) is diagnosed by the presence of thyroid autoantibodies, regardless of thyroid hormone levels. Thyroxine may be a useful treatment for subfertile women with these two specific types of thyroid disease for improving pregnancy outcomes during assisted reproduction., Objectives: To evaluate the efficacy and harms of levothyroxine replacement in subfertile women with subclinical hypothyroidism or with normal thyroid function and thyroid autoimmunity (euthyroid autoimmune thyroid disease, or euthyroid ATD) undergoing assisted reproduction., Search Methods: We searched the Cochrane Gynaecology and Fertility (CGF) Group specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trials registers together with reference checking and contact with study authors and experts in the field to identify studies. We searched for all published and unpublished randomised controlled trials (RCTs) comparing thyroxine with no treatment or placebo, without language restrictions, from inception to 8 April 2019, and in consultation with the Cochrane CGF Information Specialist., Selection Criteria: We included women undergoing assisted reproduction treatment, meaning both in vitro fertilisation and intracytoplasmic sperm injection, with a history of subfertility and with subclinical hypothyroidism or with euthyroid ATD. We excluded women with a previously known clinical hypothyroidism or already taking thyroxine or tri-iodothyronine. RCTs compared thyroxine (levothyroxine) with either placebo or no treatment., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane. Our primary review outcomes were live birth and adverse events of thyroxine; our secondary outcomes were clinical pregnancy, multiple pregnancy and miscarriage., Main Results: The review included four studies with 820 women. The included studies were of overall low risk of bias. Using GRADE methodology, we assessed the quality of evidence for the primary outcomes of this review to be very low- to low-quality evidence. Evidence was downgraded for imprecision as it was based on single, small trials with wide confidence intervals (CI). We were able to include data from three of the four included studies.In one study of women with both subclinical hypothyroidism and positive or negative anti-TPO antibodies (autoimmune disease), the evidence suggested that thyroxine replacement may have improved live birth rate (RR 2.13, 95% CI 1.07 to 4.21; 1 RCT, n = 64; low-quality evidence) and it may have led to similar miscarriage rates (RR 0.11, 95% CI 0.01 to 1.98; 1 RCT, n = 64; low-quality evidence). The evidence suggested that women with both subclinical hypothyroidism and positive or negative anti-TPO antibodies would have a 25% chance of a live birth with placebo or no treatment, and that the chance of a live birth in these women using thyroxine would be between 27% and 100%.In women with normal thyroid function and thyroid autoimmunity (euthyroid ATD), treatment with thyroxine replacement compared with placebo or no treatment may have led to similar live birth rates (risk ratio (RR) 1.04, 95% CI 0.83 to 1.29; 2 RCTs, number of participants (n) = 686; I 2 = 46%; low-quality evidence) and miscarriage rates (RR 0.83, 95% CI 0.47 to 1.46, 2 RCTs, n = 686, I 2 = 0%; low-quality evidence). The evidence suggested that women with normal thyroid function and thyroid autoimmunity would have a 31% chance of a live birth with placebo or no treatment, and that the chance of a live birth in these women using thyroxine would be between 26% and 40%.Adverse events were rarely reported. One RCT reported 0/32 in the thyroxine replacement group and 1/32 preterm births in the control group in women diagnosed with subclinical hypothyroidism and positive or negative anti-TPO antibodies. One RCT reported 21/300 preterm births in the thyroxine replacement group and 19/300 preterm births in the control group in women diagnosed with positive anti-TPO antibodies. None of the RCTs reported on other maternal pregnancy complications, foetal complications or adverse effects of thyroxine., Authors' Conclusions: We could draw no clear conclusions in this systematic review due to the very low to low quality of the evidence reported.

Background: Early reproductive failure is the most common complication of pregnancy with only 30% of conceptions reaching live birth. Establishing a successful pregnancy depends upon implantation, a complex process involving interactions between the endometrium and the blastocyst. It is estimated that embryos account for one-third of implantation failures, while suboptimal endometrial receptivity and altered embryo-endometrial dialogue are responsible for the remaining two-thirds. Endometrial receptivity has been the focus of extensive research for over 80 years, leading to an indepth understanding of the processes associated with embryo-endometrial cross-talk and implantation. However, little progress has been achieved to translate this understanding into clinically meaningful prognostic tests and treatments for suboptimal endometrial receptivity., Objective and Rationale: The objective of this systematic review was to examine the evidence from observational studies supporting the use of endometrial receptivity markers as prognostic factors for pregnancy outcome in women wishing to conceive, in order to aid clinicians in choosing the most useful marker in clinical practice and for informing further research., Search Methods: The review protocol was registered with PROSPERO (CRD42017077891). MEDLINE and Embase were searched for observational studies published from inception until 26 February 2018. We included studies that measured potential markers of endometrial receptivity prior to pregnancy attempts and reported the subsequent pregnancy outcomes. We performed association and accuracy analyses using clinical pregnancy as an outcome to reflect the presence of receptive endometrium. The Newcastle-Ottawa scale for observational studies was employed to assess the quality of the included studies., Outcomes: We included 163 studies (88 834 women) of moderate overall quality in the narrative synthesis, out of which 96 were included in the meta-analyses. Studies reported on various endometrial receptivity markers evaluated by ultrasound, endometrial biopsy, endometrial fluid aspirate and hysteroscopy in the context of natural conception, IUI and IVF. Associations were identified between clinical pregnancy and various endometrial receptivity markers (endometrial thickness, endometrial pattern, Doppler indices, endometrial wave-like activity and various molecules); however, their poor ability to predict clinical pregnancy prevents them from being used in clinical practice. Results from several modern molecular tests are promising and further data are awaited., Wider Implications: The post-test probabilities from our analyses may be used in clinical practice to manage couples' expectations during fertility treatments (IUI and IVF). Conventionally, endometrial receptivity is seen as a dichotomous outcome (present or absent), but we propose that various levels of endometrial receptivity exist within the window of implantation. For instance, different transcriptomic signatures could represent varying levels of endometrial receptivity, which can be linked to different pregnancy outcomes. Many studies reported the means of a particular biomarker in those who achieved a pregnancy compared with those who did not. However, extreme values of a biomarker (as opposite to the means) may have significant prognostic and diagnostic implications that are not captured in the means. Therefore, we suggest reporting the outcomes by categories of biomarker levels rather than reporting means of biomarker levels within clinical outcome groups., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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.

Background: Subfertility affects 15% of couples and represents the inability to conceive naturally following 12 months of regular unprotected sexual intercourse. Assisted reproduction refers to procedures involving the in vitro handling of both human gametes and represents a key option for many subfertile couples. Most women undergoing assisted reproduction treatment will reach the stage of embryo transfer (ET) but the proportion of embryos that successfully implant following ET has remained small since the mid-1990s. Human chorionic gonadotropin (hCG) is a hormone synthesised and released by the syncytiotrophoblast and has a fundamental role in embryo implantation and the early stages of pregnancy. Intrauterine administration of synthetic or natural hCG via an ET catheter during a mock procedure around the time of ET is a novel approach that has recently been suggested to improve the outcomes of assisted reproduction., Objectives: To investigate whether the intrauterine administration of hCG around the time of ET improves the clinical outcomes in subfertile women undergoing assisted reproduction., Search Methods: We performed a comprehensive literature search of the Cochrane Gynaecology and Fertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, PsycINFO, registers of ongoing trials andreference lists of all included studies and relevant reviews (from inception to 10 November 2015), in consultation with the Cochrane Gynaecology and Fertility Group Trials Search Co-ordinator., Selection Criteria: We included all randomised controlled trials (RCTs) evaluating intrauterine administration of hCG around the time of ET in this review irrespective of language and country of origin., Data Collection and Analysis: Two authors independently selected studies, assessed risk of bias, extracted data from studies and attempted to contact the authors where data were missing. We performed statistical analysis using Review Manager 5 in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. We assessed evidence quality using GRADE methods., Main Results: Twelve RCTs investigated the effect of intrauterine administration of hCG for 4038 subfertile women undergoing assisted reproduction. The intra-cavity hCG (IC-hCG) was administered in variable doses at different timings before the ET. The source of hCG was from the urine of pregnant women or from cell cultures using recombinant DNA technology.Most of the studies (9/12) 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 in the overall quality of the evidence were high risk of bias and serious imprecision.For the analyses of live birth and clinical pregnancy, there was considerable heterogeneity (I(2) greater than 75%) and we did not undertake a meta-analysis. Exploration for the sources of heterogeneity identified two key pre-specified variables as important determinants: stage of ET (cleavage versus blastocyst stage) and dose of IC-hCG (less than 500 international units (IU) versus 500 IU or greater). We then performed meta-analysis for these analyses within the subgroups defined by stage of embryo and dose of IC-hCG.There was an increase in live birth rate in the subgroup of women having cleavage-stage ETs with an IC-hCG dose of 500 IU or greater compared to women having cleavage-stage ETs with no IC-hCG (risk ratio (RR) 1.57, 95% confidence interval (CI) 1.32 to 1.87, three RCTs, n = 914, I(2) = 0%, moderate quality evidence). In a clinic with a live birth rate of 25% per cycle then the use of IC-hCG -500 IU or greater would be associated with a live birth rate that varies from 33% to 46%. We did not observe a significant effect on live birth in any of the other subgroups.The was an increase in clinical pregnancy rate in the subgroup of women having cleavage-stage ETs with an IC-hCG dose of 500 IU or greater compared to women having cleavage-stage ETs with no IC-hCG (RR 1.41, 95% CI 1.25 to 1.58, seven RCTs, n = 1414, I(2) = 0%, moderate quality evidence). We did not observe a significant effect on clinical pregnancy in either of the other subgroups.There was no evidence that miscarriage was influenced by intrauterine hCG administration (RR 1.09, 95% CI 0.83 to 1.43, seven RCTs, n = 3395, I(2) = 0%, very low quality evidence).Other complications reported in the included studies were ectopic pregnancy (three RCTs, n = 915, three events overall), heterotopic pregnancy (one RCT, n = 495, one event), intrauterine death (two RCTs, n = 978, 21 events) and triplets (one RCT, n = 48, three events). There was no evidence of a difference between the groups, but there were too few events to allow any conclusions to be drawn and the evidence was very low quality., Authors' Conclusions: The pregnancy outcome for cleavage-stage ETs using an IC-hCG dose of 500 IU or greater is promising. However, given the small size and the variable quality of the trials and the fact that the positive finding was from a subgroup analysis, the current evidence for IC-hCG treatment does not support its use in assisted reproduction cycles. A definitive large clinical trial with live birth as the primary outcome is recommended. There was no evidence that miscarriage was influenced by intrauterine hCG administration, irrespective of embryo stage at transfer or dose of IC-hCG. There were too few events to allow any conclusions to be drawn with regard to other complications.

The majority of patients undergoing in vitro fertilization (IVF) and intracytoplasmatic sperm injection (ICSI) treatment will reach the stage of embryo transfer (ET), but only a small proportion of transferred embryos implant. Bed rest following ET has been recommended as a way to prevent embryo expulsion by gravity. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) published prior to May 2014 reporting the effect of bed rest following ET, and irrespective of language, country of origin, blinding or sample size. Four RCTs, including 757 women met the inclusion criteria. Bed rest following ET did not improve clinical pregnancy and live birth rates, but reduced the implantation rate. The quality of the trials included was moderate because of attrition bias and possible reporting bias. The findings of this systematic review and meta-analysis are concordant with previously published literature and suggest that bed rest is not beneficial following ET. Moreover, it might negatively affect the outcome of IVF/ICSI cycles via stress/anxiety mechanisms.

Objective: To determine whether the modified Beckman-Coulter 2nd-generation (Gen II) antimüllerian hormone (AMH) assay (Gen IIm) provides more consistent results following storage at room temperature and on dilution than the original Gen II assay, to compare AMH results from the modified assay with those obtained from the original assay, and to assess the relationship between new AMH values and the antral follicle count (AFC)., Design: Cohort., Setting: Hospital fertility clinic., Patient(s): A total of 678 consecutive women (21-46 years old) investigated for subfertility., Intervention(s): None., Main Outcome Measure(s): AMH was measured by means of the Gen IIm assay protocol in women with known AFC. AMH values were obtained on a subset of serum samples by means of both original and modified assays., Result(s): Specimens analyzed by Gen IIm exhibited a proportional AMH response on dilution, and AMH values decreased by an average of 12.1% after 7 days at room temperature, in contrast to the steady increase seen with the use of the original Gen II assay. Gen IIm assay values were, on average, 51.4% higher than Gen II values. Population analysis suggested a conversion factor of 1.35 (95% CI 1.23-1.47) between the Gen IIm and historical data obtained for the Diagnostic Systems Laboratories AMH assay. The relationship between the Gen IIm AMH measurement and AFC was adequately represented by a linear function., Conclusion(s): The Gen IIm assay gave more reliable AMH results on sample dilution and storage than the original Gen II protocol. Findings obtained with the use of the original Gen II ELISA method should be treated with caution., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

We performed a systematic review of the randomized controlled trials (RCTs) reporting on the use of a peritoneal gas drain following gynecological laparoscopy. The standard medical databases were searched for studies published prior to with no restrictions for language, country of origin, blinding or sample size. We defined the primary endpoints: shoulder and total pain at 4-6, 24 and 48h following laparoscopy and secondary endpoints: women satisfaction, requirement of analgesia and antiemetics. The quality of the included RCTs was assessed by the guideline of the Cochrane Collaboration. Based on the data from 5 moderate quality RCTs we concluded that there is very little evidence of an overall benefit from using a peritoneal gas drain following gynecological laparoscopy The possible reduction of shoulder and total pain is not associated with a reduction in the requirement of analgesia and antiemetics when compared to the control group., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: The incidence of postoperative ileus (POI) after gynaecological surgery is 10-15% Chewing gum following general surgery improves outcomes, including early flatus, early bowel sounds, and shortening of hospitalisation periods. There is currently no guideline that supports the use of chewing gum after caesarean sections., Objectives: To systematically analyse the published randomised controlled trials regarding the effectiveness of chewing gum in preventing POI in women undergoing caesarean sections., Search Strategy: Systematic search of medical databases up to March 2013., Selection Criteria: Randomised controlled trials that reported the role of chewing gum in preventing POI in women undergoing caesarean sections., Data Collection and Analysis: Two authors independently identified the relevant studies for inclusion, extracted outcome-related data, and analysed it systematically using REVMAN(®). The combined outcome was expressed as an odds ratio and standardised mean difference., Main Results: Seven randomised controlled trials involving 1462 women (728 in the chewing gum group, 734 controls) were systematically analysed. There was significant heterogeneity (χ(2) = 29.02, df = 7; P < 0.0001; I(2) = 76%) among the included trials. Among women undergoing caesarean sections, chewing gum reduced the risk of POI (odds ratio 0.36; 95% confidence interval 0.19-0.69; z = 3.08; P < 0.002) but did not affect duration of hospitalisation (P = 0.32)., Conclusions: Chewing gum for 30-60 minutes at least three times a day appears to be effective in reducing the incidence and consequences of POI following caesarean sections., (© 2014 Royal College of Obstetricians and Gynaecologists.)

Objective: To appraise critically the published randomized controlled trials (RCTs) reporting on the effectiveness of cervical mucus removal before embryo transfer., Design: Systematic review and meta-analysis of RCTs., Setting: Assisted reproduction technology (ART) units., Patient(s): Women undergoing embryo transfer after in vitro fertilization/intracytoplasmic sperm injection (IVF-ICSI)., Intervention(s): Cervical mucus removal followed or not by cervical irrigation immediately before embryo transfer., Main Outcome Measure(s): Clinical pregnancy, implantation and live-birth rates., Result(s): Eight RCTs involving 1,715 women were systematically analyzed. There was substantial heterogeneity among the included trials. There was no statistically significant difference in terms of pregnancy, implantation, or live-birth rates., Conclusion(s): A meta-analysis from the available moderate to low quality trials provides very little evidence of an overall benefit of cervical mucus removal before embryo transfer for women undergoing IVF/ICSI. Due to problems of clinical diversity, statistical heterogeneity, and risk of bias, additional pragmatic multicenter RCTs are needed to evaluate the possible small benefit of cervical mucus removal before embryo transfer., (Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To appraise critically the published randomized controlled trials (RCTs) comparing carbon dioxide (CO2) with normal saline (NS) as distension medium for diagnostic hysteroscopy., Design: Systematic review and meta-analysis of RCTs., Setting: Outpatient and inpatient hysteroscopy clinics., Patient(s): Women undergoing diagnostic hysteroscopy., Refvention(s): CO2 or NS as distension medium for diagnostic hysteroscopy., Main Outcome Measure(s): Procedural and shoulder pain, side effects, satisfaction, quality of view, duration of procedure., Result(s): Ten RCTs involving 1,839 women (905 in the CO2 group, 934 in the NS group) were systematically analyzed. There was significant heterogeneity among the included trials. Compared with NS, CO2 was associated with greater procedural pain, more occurrences of shoulder pain and side effects, less satisfaction, less quality of view, and greater duration of procedure., Conclusion(s): A meta-analysis from the available moderate quality trials suggests that NS might be superior to CO2 for use in diagnostic hysteroscopy. Owing to problems of clinical diversity, statistical heterogeneity, and risk of bias, it is clear that additional pragmatic multicenter RCTs are needed to corroborate these findings before firm evidence-based guidelines can be given., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)