Menstrual Tampons Are Reliable and Acceptable Tools to Self-Collect Vaginal Microbiome Samples.

Many women report embarrassment as the cause for their avoidance of routine gynaecological screening appointments. Methods of self-collection of bio samples would perhaps encourage women to participate in routine screening programs. The vaginal microbiome plays a key role in women's health and reproductive function. Microbial disturbances can result in the loss of lactobacillus dominance, also known as dysbiosis, associated with an increased risk of contracting sexually transmitted infections (STIs), pregnancy complications and infertility. Our primary aim was to determine if vaginal microbiome screening results are comparable between two methods for self-collected sample acquisition: tampons and lower vaginal swabs (LVSs). Secondary aims included the assessment of the effect of pre-analytic storage on the data (to streamline processing), the prevalence of dysbiosis and the acceptability of the tampons to the participants. Statistical analysis revealed no significant difference in the microbiome data, from tampons versus LVSs or fresh versus frozen samples. The prevalence of dysbiosis in this population of healthy volunteers was 42.9%. The questionnaire data revealed that 52.4% of volunteers use tampons every period, and the majority of volunteers rated the tampons as 5 on a 1-5 Likert scale regarding their perceived comfort using tampons. All (100%) of volunteers were happy to provide a tampon as a sample for testing. The findings from this study show that tampons and LVSs were comparable when analysing the vaginal microbiome, with potential superiority of the tampon with regard to patient acceptability. Self-collection of vaginal secretions for gynaecological screening using tampons warrants further research as this could change the screening landscape, ensuring wider participation and increasing efficacy.

Histological 3D reconstruction and in vivo lineage tracing of the human endometrium.

Regular menstrual shedding and repair of the endometrial functionalis is unique to humans and higher-order primates. The current consensus postulates endometrial glands to have a single-tubular architecture, where multi-potential stem cells reside in the blind-ending glandular-bases. Utilising fixed samples from patients, we have studied the three-dimensional (3D) micro-architecture of the human endometrium. We demonstrate that some non-branching, single, vertical functionalis glands originate from a complex horizontally interconnecting network of basalis glands. The existence of a multipotent endometrial epithelial stem cell capable of regenerating the entire complement of glandular lineages was demonstrated by in vivo lineage tracing, using naturally occurring somatic mitochondrial DNA mutations as clonal markers. Vertical tracking of mutated clones showed that at least one stem-cell population resides in the basalis glands. These novel findings provide insight into the efficient and scar-less regenerative potential of the human endometrium. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Anterior Gradient Protein 3 and S100 Calcium-Binding Protein P Levels in Different Endometrial Epithelial Compartments May Play an Important Role in Recurrent Pregnancy Failure.

Recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL) are distressing conditions without effective treatments. The luminal epithelium (LE) is integral in determining receptivity of the endometrium, whereas functionalis glands and stroma aid in nurturing early embryo development. Calcium signalling pathways are known to be of vital importance to embryo implantation and pregnancy establishment, and anterior gradient protein 3 (AGR3) and S100 calcium-binding protein P (S100P) are involved with these pathways. We initially examined 20 full-thickness endometrial biopsies from premenopausal women across the menstrual cycle to characterize levels of AGR3 protein in each endometrial sub-region at the cellular level. A further 53 endometrial pipelle biopsies collected in the window of implantation were subsequently assessed to determine differential endometrial AGR3 and S100P levels relevant to RIF (n = 13) and RPL (n = 10) in comparison with parous women (n = 30) using immunohistochemistry. Significantly higher AGR3 and S100P immunostaining was observed in ciliated cells of the LE of women with recurrent reproductive failure compared with parous women, suggesting aberrant subcellular location-associated pathophysiology for these conditions. The nuclear localisation of S100P may allow transcriptional regulatory function, which is necessary for implantation of a viable pregnancy. Further work is thus warranted to assess their utility as diagnostic/therapeutic targets.

Babies in occiput posterior position are significantly more likely to require an emergency cesarean birth compared with babies in occiput transverse position in the second stage of labor: A prospective observational study.

INTRODUCTION: Malposition complicates 2-13% of births at delivery, leading to increased obstetric interventions (cesarean section and instrumental delivery) and higher rates of adverse fetal and maternal outcomes. Limited data are available regarding the likely rates of obstetric intervention and subsequent neonatal and maternal outcomes of births with babies in persistent occiput posterior position vs those in persistent occiput transverse position. The UK Audit and Research trainee Collaborative in Obstetrics and Gynecology (UK-ARCOG) network set out to collect data prospectively at delivery on final mode of delivery and immediate outcomes. MATERIAL AND METHODS: The UK-ARCOG network collected data on all births with malposition of the fetal head complicating the second stage of labor (n = 838) (occiput posterior/occiput transverse) requiring rotational vaginal operative birth or emergency cesarean to expedite delivery across 66 participating UK National Health Service maternity units over a 1-month period. The outcomes considered were the need for emergency cesarean section without a trial of instrumental delivery, success of the first method of delivery employed in achieving a vaginal delivery and neonatal/maternal outcomes. RESULTS: Obstetricians regarded assistance with an operative vaginal delivery method to be unsafe in 15% of babies in occiput posterior position and 6.1% of babies in occiput transverse position, and they were delivered by primary emergency cesarean section. When vaginal delivery was deemed safe (defined as attempted assisted vaginal rotational delivery), the first instrument attempted was successful in 74.4% of occiput posterior babies and 79.3% of occiput transverse babies. CONCLUSIONS: Our data facilitates decision making by obstetricians to increase safety of assisted rotational operative delivery of a malpositioned baby at initial assessment and in counseling women. Until data from a well-designed randomized controlled trial of instrumental delivery vs emergency cesarean section are available, this manuscript provides contemporaneous national data from a high resource setting within a structured training program, to assist the selection of an appropriate instrument/method for the delivery of a malpositioned baby.

Endometrial Stem Cell Markers: Current Concepts and Unresolved Questions.

The human endometrium is a highly regenerative organ undergoing over 400 cycles of shedding and regeneration over a woman's lifetime. Menstrual shedding and the subsequent repair of the functional layer of the endometrium is a process unique to humans and higher-order primates. This massive regenerative capacity is thought to have a stem cell basis, with human endometrial stromal stem cells having already been extensively studied. Studies on endometrial epithelial stem cells are sparse, and the current belief is that the endometrial epithelial stem cells reside in the terminal ends of the basalis glands at the endometrial/myometrial interface. Since almost all endometrial pathologies are thought to originate from aberrations in stem cells that regularly regenerate the functionalis layer, expansion of our current understanding of stem cells is necessary in order for curative treatment strategies to be developed. This review critically appraises the postulated markers in order to identify endometrial stem cells. It also examines the current evidence supporting the existence of epithelial stem cells in the human endometrium that are likely to be involved both in glandular regeneration and in the pathogenesis of endometrial proliferative diseases such as endometriosis and endometrial cancer.

Does advanced operative obstetrics still have a place in contemporary practice?

PURPOSE OF REVIEW: This article reviews recent significant contributions to the literature concerning advanced operative obstetric procedures used for rotational vaginal deliveries and their alternative, primary caesarean section. RECENT FINDINGS: Rising caesarean section rates are a global concern. Caesarean section in the second stage of labour is associated with high rates of maternal and fetal morbidity. Rotational vaginal deliveries may reduce the caesarean section rate without additional adverse effects on maternal and fetal outcomes. A recent national trainees' survey highlighted that training in the management of operative birth in the second stage of labour, especially when there is malposition of the fetal head, is a priority. SUMMARY: There is a need for evidence-based guidelines, including standardized documentation of these advanced procedures. Training strategies for junior practitioners to acquire these skills and for experienced practitioners to maintain and disseminate their skills should be prioritized. The safety of rotational delivery methods versus primary caesarean section is likely to prove difficult to assess directly, in the context of a randomized controlled trial, but may be approximated via a national prospective audit.

Endometrial compaction to predict pregnancy outcomes in patients undergoing assisted reproductive technologies: a systematic review and meta-analysis.

STUDY QUESTION: Does endometrial compaction (EC) help predict pregnancy outcomes in those undergoing ART? SUMMARY ANSWER: EC is associated with a significantly higher clinical pregnancy rate (CPR) and ongoing pregnancy rate (OPR), but this does not translate to live birth rate (LBR). WHAT IS KNOWN ALREADY: EC describes the progesterone-induced decrease in endometrial thickness, which may be observed following the end of the proliferative phase, prior to embryo transfer. EC is proposed as a non-invasive tool to help predict pregnancy outcome in those undergoing ART, however, published data is conflicting. STUDY DESIGN SIZE DURATION: A literature search was carried out by two independent authors using PubMed, Cochrane Library, MEDLINE, Embase, Science Direct, Scopus, and Web of Science from inception of databases to May 2023. All peer-reviewed studies reporting EC and pregnancy outcomes in patients undergoing IVF/ICSI treatment were included. PARTICIPANTS/MATERIALS SETTING METHODS: The primary outcome is LBR. Secondary outcomes included other pregnancy metrics (positive pregnancy test (PPT), CPR, OPR, miscarriage rate (MR)) and rate of EC. Comparative meta-analyses comparing EC and no EC were conducted for each outcome using a random-effects model if I 2 > 50%. The Mantel-Haenszel method was applied for pooling dichotomous data. Results are presented as odds ratios (OR) with 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: Out of 4030 screened articles, 21 cohort studies were included in the final analysis (n = 27 857). No significant difference was found between LBR in the EC versus the no EC group (OR 0.95; 95% CI 0.87-1.04). OPR was significantly higher within the EC group (OR 1.61; 95% CI 1.09-2.38), particularly when EC ≥ 15% compared to no EC (OR 3.52; 95% CI 2.36-5.23). CPR was inconsistently defined across the studies, affecting the findings. When defined as a viable intrauterine pregnancy <12 weeks, the EC group had significantly higher CPR than no EC (OR 1.83; 95% CI 1.15-2.92). No significant differences were found between EC and no EC for PPT (OR 1.54; 95% CI 0.97-2.45) or MR (OR 1.06; 95% CI 0.92-1.56). The pooled weighted incidence of EC across all studies was 32% (95% CI 26-38%). LIMITATIONS REASONS FOR CAUTION: Heterogeneity due to differences between reported pregnancy outcomes, definition of EC, method of ultrasound, and cycle protocol may account for the lack of translation between CPR/OPR and LBR findings; thus, all pooled data should be viewed with an element of caution. WIDER IMPLICATIONS OF THE FINDINGS: In this dataset, the significantly higher CPR/OPR with EC does not translate to LBR. Although stratification of women according to EC cannot currently be recommended in clinical practice, a large and well-designed clinical trial to rigorously assess EC as a non-invasive predictor of a successful pregnancy is warranted. We urge for consistent outcome reporting to be mandated for ART trials so that data can be pooled, compared, and concluded on. STUDY FUNDING/COMPETING INTERESTS: H.A. was supported by the Hewitt Fertility Centre. S.G.P. and J.W. were supported by the Liverpool University Hospital NHS Foundation Trust. D.K.H. was supported by a Wellbeing of Women project grant (RG2137) and MRC clinical research training fellowship (MR/V007238/1). N.T. was supported by the National Institute for Health and Care Research. D.K.H. had received honoraria for consultancy for Theramex and has received payment for presentations from Theramex and Gideon Richter. The remaining authors have no conflicts of interest to report. REGISTRATION NUMBER: PROSPERO CRD42022378464.

Diagnostic utility of clinicodemographic, biochemical and metabolite variables to identify viable pregnancies in a symptomatic cohort during early gestation.

A significant number of pregnancies are lost in the first trimester and 1-2% are ectopic pregnancies (EPs). Early pregnancy loss in general can cause significant morbidity with bleeding or infection, while EPs are the leading cause of maternal mortality in the first trimester. Symptoms of pregnancy loss and EP are very similar (including pain and bleeding); however, these symptoms are also common in live normally sited pregnancies (LNSP). To date, no biomarkers have been identified to differentiate LNSP from pregnancies that will not progress beyond early gestation (non-viable or EPs), defined together as combined adverse outcomes (CAO). In this study, we present a novel machine learning pipeline to create prediction models that identify a composite biomarker to differentiate LNSP from CAO in symptomatic women. This prospective cohort study included 370 participants. A single blood sample was prospectively collected from participants on first emergency presentation prior to final clinical diagnosis of pregnancy outcome: LNSP, miscarriage, pregnancy of unknown location (PUL) or tubal EP (tEP). Miscarriage, PUL and tEP were grouped together into a CAO group. Human chorionic gonadotrophin ß (ß-hCG) and progesterone concentrations were measured in plasma. Serum samples were subjected to untargeted metabolomic profiling. The cohort was randomly split into train and validation data sets, with the train data set subjected to variable selection. Nine metabolite signals were identified as key discriminators of LNSP versus CAO. Random forest models were constructed using stable metabolite signals alone, or in combination with plasma hormone concentrations and demographic data. When comparing LNSP with CAO, a model with stable metabolite signals only demonstrated a modest predictive accuracy (0.68), which was comparable to a model of ß-hCG and progesterone (0.71). The best model for LNSP prediction comprised stable metabolite signals and hormone concentrations (accuracy = 0.79). In conclusion, serum metabolite levels and biochemical markers from a single blood sample possess modest predictive utility in differentiating LNSP from CAO pregnancies upon first presentation, which is improved by variable selection and combination using machine learning. A diagnostic test to confirm LNSP and thus exclude pregnancies affecting maternal morbidity and potentially life-threatening outcomes would be invaluable in emergency situations.

Four-dimensional ultrasound guided embryo transfers improve live birth rates when compared to the clinical touch technique: a randomised controlled trial.

Most aspects of in-vitro fertilisation (IVF) have changed dramatically since introduction, but embryo transfer (ET) technique remains largely unaltered. We aimed to determine whether four-dimensional ultrasound guided embryo transfers (4D UGET) could improve pregnancy rates when compared with clinical touch technique (CTT). This was a single centre open labelled randomised controlled trial in a tertiary fertility centre in the UK. 320 women were randomised on the day of single ET. The primary outcome was clinical pregnancy rate (CPR), secondary outcomes included live birth rate (LBR), biochemical pregnancy rate (BPR), miscarriage, pregnancy of unknown location (PUL) and ectopic pregnancy. 4D-UGET resulted in significantly higher CPR [50% vs 36% p = 0.02, OR 1.78 (1.12-2.84)] and LBR [41% vs 28%, p = 0.02, OR 1.77 (1.09-2.87)] when compared to CTT technique. Miscarriage (p = 0.49), PUL (p = 0.14) and ectopic pregnancy (p = 0.96) were similar between the two groups. LBR, from this trial, are significantly higher than the current UK average (41% vs 24%). 4D UGET allows for superior imaging of the uterine cavity, whilst tailoring the embryo deposition point specifically to the patient. Further RCTs are required to determine if these results can be replicated in other units and whether 4D UGET is superior to 2D UGET.

Implantation in the lower half of the uterine cavity and decreased trophoblastic thickness can predict subsequent miscarriage: a prospective cohort study.

Abstract: Embryo implantation is vital for successful conception but remains to be fully understood. Trophoblast invasion is key for implantation, with anchorage and depth of placentation determined by its extent. There is a dearth of synchronous information regarding IVF, implantation site, and trophoblastic thickness (TT). Our aim was to determine whether pregnancy implantation site and TT, had an impact on outcomes of IVF pregnancies. This prospective observational study was undertaken at a tertiary referral UK fertility unit over 14 months, collecting data on implantation site and TT from three-dimensional (3D) images of the uterus following early pregnancy scan. Of the 300 women recruited, 277 (92%) had live births, 20 (7%) miscarried, 2 (0.7%) had stillbirths, and 1 (0.3%) had a termination. Significantly more pregnancies that resulted in miscarriage (7/20, 35%) were located in the lower uterine cavity when compared to ongoing pregnancies (15/277, 5%) (P < 0.01). TT was significantly higher in ongoing pregnancies when compared with those who miscarried (7.2 mm vs 5.5 mm; P < 0.01). Implantation in the lower half of the uterine cavity and decreased TT are significantly associated with an increased rate of miscarriage. Identification of those at risk should prompt increased monitoring with the aim of supporting these pregnancies. Lay summary: Implantation of an embryo in the womb is vital for a successful pregnancy. We wanted to find out whether findings on an ultrasound scan in early pregnancy had an impact on outcomes of IVF pregnancies. Three hundred women were recruited to the study, 277 (92%) had live births and unfortunately 20 (7%) had a miscarriage, 2 (0.7%) had stillbirths, and 1 (0.3%) had a termination. Many more of the pregnancies that miscarried implanted in the lower part of the womb. The thickness of the infiltration of the pregnancy into the womb was significantly higher in the ongoing pregnancies. We concluded that implantation in the lower half of the womb and reduced infiltration of the pregnancy seen on scan are associated with an increased rate of miscarriage. We propose that when we identify those at risk, we should increase monitoring, with the aim of supporting these pregnancies.

Feasibility of a RCT of techniques for managing an impacted fetal head during emergency caesarean section: the MIDAS scoping study.

Background: Second-stage caesarean sections, of which there are around 34,000 per year in the UK, have greater maternal and perinatal morbidity than those in the first stage. The fetal head is often deeply impacted in the maternal pelvis, and extraction can be difficult. Numerous techniques are reported, but the superiority of one over another is contentious and there is no national guidance. Objective: To determine the feasibility of a randomised trial of different techniques for managing an impacted fetal head during emergency caesarean. Design: A scoping study with five work packages: (1) national surveys to determine current practice and acceptability of research in this area, and a qualitative study to determine acceptability to women who have experienced a second-stage caesarean; (2) a national prospective observational study to determine incidence and rate of complications; (3) a Delphi survey and consensus meeting on choice of techniques and outcomes for a trial; (4) the design of a trial; and (5) a national survey and qualitative study to determine acceptability of the proposed trial. Setting: Secondary care. Participants: Health-care professionals, pregnant women, women who have had a second-stage caesarean, and parents. Results: Most (244/279, 87%) health-care professionals believe that a trial in this area would help guide their practice, and 90% (252/279) would be willing to participate in such a trial. Thirty-eight per cent (98/259) of parents reported that they would take part. Women varied in which technique they thought was most acceptable. Our observational study found that impacted head is common (occurring in 16% of second-stage caesareans) and leads to both maternal (41%) and neonatal (3.5%) complications. It is most often treated by an assistant pushing the head up vaginally. We designed a randomised clinical trial comparing the fetal pillow with the vaginal push technique. The vast majority of health-care professionals, 83% of midwives and 88% of obstetricians, would be willing to participate in the trial proposed, and 37% of parents reported that they would take part. Our qualitative study found that most participants thought the trial would be feasible and acceptable. Limitations: Our survey is subject to the limitation that, although responses refer to contemporaneous real cases, they are self-reported by the surgeon and collected after the event. Willingness to participate in a hypothetical trial may not translate into recruitment to a real trial. Conclusions: We proposed a trial to compare a new device, the fetal pillow, with a long-established procedure, the vaginal push technique. Such a trial would be widely supported by health-care professionals. We recommend that it be powered to test an effect on important short term maternal and baby outcomes which would require 754 participants per group. Despite the well-known difference between intent and action, this would be feasible within the UK. Future work: We recommend a randomised controlled trial of two techniques for managing an impacted fetal head with an in-built internal pilot phase and alongside economic and qualitative substudies. Study registration: This study is registered as Research Registry 4942. 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. 27, No. 6. See the NIHR Journals Library website for further project information.

Text: One-quarter of UK pregnant women have a caesarean section. Most of these procedures are straightforward, but in a small number of cases unexpected complications can make the birth difficult. One complication, an impacted fetal head, may happen when caesarean sections are done in the second 'pushing' stage of labour. If the baby's head is low and wedged in the woman's pelvis, lifting it can be difficult, which can result in damage to the mother's womb and vagina, and to her baby. Occasionally, babies die. There are different techniques doctors and midwives can use to make these births easier, but there is uncertainty around which is best. To plan a trial to test these techniques, we needed to know how often impacted head happens, what techniques are used to manage it and whether or not research is acceptable to parents and health-care professionals. We surveyed doctors and midwives to find out which techniques they use and what training they need. We surveyed parents and pregnant women and interviewed women who had experienced a second-stage caesarean. We collected information from UK hospitals to find out how common this is and the impact on women and babies. We found out the following. List: • Around 7% of caesareans take place in second stage, and impacted fetal head occurs in 16% of these births. List: • One-third of women would consent to take part in a trial, if the complication happened to them. List: • Nearly all midwives and doctors thought that this research was important and would be willing to take part. Text: Using all of the information we collected, we designed a clinical trial. We wanted to compare two techniques for managing an impacted fetal head. The first is the vaginal push technique, where the doctor or midwife puts their hand into the mother's vagina to push her baby's head up, and the second is the fetal pillow, a device inserted into the mother's vagina before the operation starts to dislodge the baby's head upwards.

The Role of Endometrial Stem/Progenitor Cells in Recurrent Reproductive Failure.

Recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL), collectively referred to as recurrent reproductive failure (RRF), are both challenging conditions with many unanswered questions relating to causes and management options. Both conditions are proposed to be related to an aberrant endometrial microenvironment, with different proposed aetiologies related to a restrictive or permissive endometrium for an invading embryo. The impressive regenerative capacity of the human endometrium has been well-established and has led to the isolation and characterisation of several subtypes of endometrial stem/progenitor cells (eSPCs). eSPCs are known to be involved in the pathogenesis of endometrium-related disorders (such as endometriosis) and have been proposed to be implicated in the pathogenesis of RRF. This review appraises the current knowledge of eSPCs, and their involvement in RRF, highlighting the considerable unknown aspects in this field, and providing avenues for future research to facilitate much-needed advances in the diagnosis and management of millions of women suffering with RRF.

Managing an impacted fetal head at caesarean section: a UK survey of healthcare professionals and parents.

OBJECTIVE(S): To understand current practice, expertise and training requirements for management of an impacted fetal head (IFH) at caesarean section (CS) in the UK, and whether a clinical trial of techniques to manage an IFH is acceptable. STUDY DESIGN: Five hundred and thirty-eight online surveys were completed by obstetricians (n = 206), obstetric anaesthetists (n = 38), midwives (n = 35) and parents (n = 259). Data was collected on incidences of CS and IFH, current use of techniques, and acceptability of a clinical trial to manage an IFH from health care professionals. Information on incidences of CS and recollection of an IFH, acceptability of techniques, and likelihood of taking part in a clinical trial were sought from parents. RESULTS: The most common technique used by obstetricians (84%) and midwives (69%) was the 'push technique'. Eighty-seven percent of health care professionals would be willing to participate in a clinical trial, with 89% confirming that results would guide their clinical practice. Most parents expressed reluctance regarding participation in a clinical trial during labour (62%), due to preferring a doctor to adopt the technique they felt most comfortable with (63%). CONCLUSION(S): Given the lack of national guidance on appropriate techniques, no formal training, and no consensus on best practice for the management of an IFH during emergency CS, it is perhaps not surprising that the majority of heath care professionals would be willing to participate in a clinical trial, where results will guide their clinical practice. The future development of clinical trials, involving relevant stakeholders in the design of such trials, is crucial to improve upon the guidance and training provided to staff who may encounter an IFH.

Altered endometrial oestrogen-responsiveness and recurrent reproductive failure.

Abstract: Recurrent reproductive failure (RRF) encompasses recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL). These highly prevalent, distressing conditions have many unanswered questions regarding aetiology and management. Oestrogen receptor beta (ERß) is the predominant oestrogen receptor expressed in the vascular endothelium of the endometrium during the window of implantation (WOI). The establishment of normal endometrial receptivity is integrally associated with progesterone receptor (PR). Therefore, we aimed to investigate whether women with RRF have clinical, type-specific endometrial aberrations of ERß, PR and Ki-67 expression during the WOI. Thirty-eight endometrial biopsies were collected; 29 RRF (10 RIF, 9 recurrent loss of early pregnancy (RLEP) and 10 recurrent fetal loss (RFL)) and 9 fertile controls (FC). Within RIF, RLEP and RFL groups, the perivascular compartment showed significantly lower levels of ERß vs FC (P = 0.02, P = 0.03 and P = 0.01, respectively). Vascular endothelium also displayed significantly lower levels of ERß within RIF and RFL cohorts vs FC (P = 0.03 and P = 0.003). The expression of Ki-67 was significantly lower within vascular endothelium of all RRF; RIF (P = 0.02), RLEP (P = 0.02) and RFL (P <0.01). PR was significantly reduced (P <0.001) in the perivascular area of women with RIF. These findings provide novel insights into biological correlates of clinical subtypes of RRF. The endometrium of women with RRF display significantly altered levels of ERß, PR and Ki-67 during the WOI, furthering our understanding of the defective endometrial phenotype of women suffering from RRF, with possible impaired glandular function, angiogenesis and decidualisation. Lay summary: Recurrent reproductive failure (RRF) refers to a group of devastating conditions with many unanswered questions regarding their causes and treatment options. The lining of the womb, the endometrium, is primed and suitable for successful embryo implantation for a short time during the menstrual cycle; the window of implantation (WOI). Oestrogen is a key hormone that plays an important role in regulating the endometrium and its effects are exerted via two oestrogen receptor subtypes. Oestrogen receptor beta (ERß) is the main oestrogen receptor present during the WOI. Progesterone receptor allows the other main hormone, progesterone, to influence the endometrial activity and Ki-67 reflects the proliferative activity of the cells within the endometrium. We investigated the expression of these markers in endometrial samples collected from women with RRF and proven fertility. We found that the endometrium of women with RRF has significantly lower levels of ERß and Ki-67 during the WOI, possibly leading to unsuccessful pregnancies.

Novel microarchitecture of human endometrial glands: implications in endometrial regeneration and pathologies.

BACKGROUND: Human endometrium remains a poorly understood tissue of the female reproductive tract. The superficial endometrial functionalis, the site of embryo implantation, is repeatedly shed with menstruation, and the stem cell-rich deeper basalis is postulated to be responsible for the regeneration of the functionalis. Two recent manuscripts have demonstrated the 3D architecture of endometrial glands. These manuscripts have challenged and replaced the prevailing concept that these glands end in blind pouches in the basalis layer that contain stem cells in crypts, as in the intestinal mucosa, providing a new paradigm for endometrial glandular anatomy. This necessitates re-evaluation of the available evidence on human endometrial regeneration in both health and disease in the context of this previously unknown endometrial glandular arrangement. OBJECTIVE AND RATIONALE: The aim of this review is to determine if the recently discovered glandular arrangement provides plausible explanations for previously unanswered questions related to human endometrial biology. Specifically, it will focus on re-appraising the theories related to endometrial regeneration, location of stem/progenitor cells and endometrial pathologies in the context of this recently unravelled endometrial glandular organization. SEARCH METHODS: An extensive literature search was conducted from inception to April 2021 using multiple databases, including PubMed/Web of Science/EMBASE/Scopus, to select studies using keywords applied to endometrial glandular anatomy and regeneration, and the references included in selected publications were also screened. All relevant publications were included. OUTCOMES: The human endometrial glands have a unique and complex architecture; branched basalis glands proceed in a horizontal course adjacent to the myometrium, as opposed to the non-branching, vertically coiled functionalis glands, which run parallel to each other as is observed in intestinal crypts. This complex network of mycelium-like, interconnected basalis glands is demonstrated to contain endometrial epithelial stem cells giving rise to single, non-branching functionalis glands. Several previous studies that have tried to confirm the existence of epithelial stem cells have used methodologies that prevent sampling of the stem cell-rich basalis. More recent findings have provided insight into the efficient regeneration of the human endometrium, which is preferentially evolved in humans and menstruating upper-order primates. WIDER IMPLICATIONS: The unique physiological organization of the human endometrial glandular element, its relevance to stem cell activity and scarless endometrial regeneration will inform reproductive biologists and clinicians to direct their future research to determine disease-specific alterations in glandular anatomy in a variety of endometrial pathological conditions.

Habitual physical activity levels in women attending the one stop infertility clinic: A prospective cross-sectional observational study.

Optimisation of lifestyle factors such as smoking and alcohol are encouraged to improve fecundability rates in the fertility setting. Currently, routine fertility consultations do not involve counselling or imparting advice regarding habitual physical activity (PA) and/or structured exercise, despite data showing that vigorous PA can be associated with delayed time to pregnancy. Therefore, this study aimed to determine habitual PA in a sample of women attending the one stop infertility (OSI) clinic. 250 women attending a large tertiary level NHS fertility unit prospectively anonymously completed a questionnaire over a period of 9 months. Participant's (mean age 34±5years, mean BMI 29±7kg/m2) habitual PA levels varied from vigorous exercise on ≥5 days/week (8%, n=17), to no moderate or high intensity activities across the whole week (66%, n=29). The majority of women reported no structured exercise (72%, n=179). No association was identified between any domain of PA and BMI, age, alcohol units, regular periods, or time spent trying to conceive (P > 0.05). Participant's habitual PA levels varied widely and no association between any domain of PA and background of the women was identified. No existing evidence and/or guidelines to explicitly inform women attempting to conceive regarding recommended PA levels are available, despite PA being a modifiable, affordable, and feasible lifestyle choice with the possible potential to improve fertility. A large-scale, clinical trial assessing effects of PA on fecundability is warranted to gain insights into the potential of this lifestyle factor to improve fertility outcomes and to explore the underlying biological mechanisms involved.

Mental health impact on Black, Asian and Minority Ethnic populations with preterm birth: A systematic review and meta-analysis.

BACKGROUND: Preterm birth (PTB) is one of the main causes of neonatal deaths globally, with approximately 15 million infants are born preterm. Women from the Black, Asian, and Minority Ethnic (BAME) populations maybe at higher risk of PTB, therefore, the mental health impact on mothers experiencing a PTB is particularly important, within the BAME populations. AIM: To determine the prevalence of mental health conditions among BAME women with PTB as well as the methods of mental health assessments used to characterise the mental health outcomes. METHODS: A systematic methodology was developed and published as a protocol in PROSPERO (CRD42020210863). Multiple databases were used to extract relevant data. I 2 and Egger's tests were used to detect the heterogeneity and publication bias. A trim and fill method was used to demonstrate the influence of publication bias and the credibility of conclusions. RESULTS: Thirty-nine studies met the eligibility criteria from a possible 3526. The prevalence rates of depression among PTB-BAME mothers were significantly higher than full-term mothers with a standardized mean difference of 1.5 and a 95% confidence interval (CI) 29%-74%. The subgroup analysis indicated depressive symptoms to be time sensitive. Women within the very PTB category demonstrated a significantly higher prevalence of depression than those categorised as non-very PTB. The prevalence rates of anxiety and stress among PTB-BAME mothers were significantly higher than in full-term mothers (odds ratio of 88% and 60% with a CI of 42%-149% and 24%-106%, respectively). CONCLUSION: BAME women with PTB suffer with mental health conditions. Many studies did not report on specific mental health outcomes for BAME populations. Therefore, the impact of PTB is not accurately represented in this population, and thus could negatively influence the quality of maternity services they receive.

Premenopausal Women With a Diagnosis of Endometriosis Have a Significantly Higher Prevalence of a Diagnosis or Symptoms Suggestive of Restless Leg Syndrome: A Prospective Cross-Sectional Questionnaire Study.

Background: Endometriosis and restless leg syndrome (RLS) are both chronic conditions that can negatively affect a woman's quality of life. A higher prevalence of RLS is seen in women and particularly in those who are pregnant, suggesting a possible ovarian hormonal influence. Endometriosis is a common (affecting 1 in 10 women) estrogen driven gynecological condition, and the prevalence of RLS in women with symptoms or a diagnosis of endometriosis is unknown. Methods: A prospective, cross-sectional, observational self-completed questionnaire study was distributed to 650 pre-menopausal women attending the gynecological department at Liverpool Women`s Hospital over a period of 4 months. 584 questionnaires were returned and 465 completed questionnaires were included in the final dataset. Data on RLS-associated (The International Restless Leg Syndrome Study Group rating scale) and endometriosis-associated (modified-British Society of Gynaecological Endoscopists pelvic pain questionnaire) symptoms were collected. Results: Women who reported a prior surgical diagnosis of endometriosis had a greater risk of having a prior formal diagnosis of RLS (OR 4.82, 95% CI 1.66,14.02) and suffering RLS symptoms (OR 2.13, 95% CI 1.34-3.39) compared with those without a diagnosis. When women with either a formal surgical diagnosis or symptoms associated with endometriosis were grouped together, they also have a significantly increased risk of having either a formal diagnosis or symptoms suggestive of RLS (OR 2.49, 95% CI 1.30, 3.64). In women suffering with endometriosis-associated symptoms, the cumulative endometriosis-associated symptom scores demonstrated a modest positive correlation with RLS severity scores (r=0.42 95% CI 0.25 to 0.57). Conclusions: This is the first study highlighting an association between the symptoms relevant to the two chronic conditions RLS and endometriosis, showing that women with a reported prior surgical diagnosis or symptoms suggestive of endometriosis have a significantly higher prevalence of a prior formal diagnosis or symptoms suggestive of RLS. This data will help in facilitating the discovery of novel therapeutic targets relevant to both conditions. The simultaneous treatment of these conditions could potentially lead to improvement in the overall quality of life for these women.

Do women with HIV/AIDS on anti-retroviral therapy have a lower incidence of symptoms associated with menstrual dysfunction?

BACKGROUND: Symptoms associated with menstruation and endometriosis are common amongst women of reproductive ages and the pathogenesis of these illnesses is postulated to be associated with aberrations in endometrial regeneration, immune response and in endometrial stem cell function. Highly active antiretroviral therapy (HAART) has been shown to enhance events seen in biological aging of tissues, with HIV/AIDS patients enduring the premature appearance of illnesses associated with stem-cell aging. Considering the intricate relationship between dysregulation of stem cell function, in both HAART therapy and in menstrual disorders/endometriosis, we sought to examine the prevalence of menstrual related symptoms (MRS) associated with endometriosis in women on HIV/AIDS therapy. METHODS: A menstrual related symptoms (MRS) questionnaire adapted from the British Society of Gynaecological Endoscopists (BSGE) pelvic pain questionnaire, which has been used in both clinical and research setting, was completed by 100 women living with HIV (WLWH) attending a specialist HIV clinic and by 100 women without a diagnosis of HIV attending the Sexual Health clinic (WWH). HIV related demographic details, including results from recent blood tests, were also recorded prospectively from the WLWH. RESULTS: WLWH were slightly older (37.7 vs. 34.8 years, P = 0.01); with higher BMI (28.9 vs. 24.8, P < 0.001); and were likely to be parous (85% vs. 54% P < 0.001) and non-Caucasian (79% vs 18%) compared with WWH. Most women in both groups had regular periods (77.9% vs. 74.7%), and WLWH were more likely to have a shorter duration of bleeding compared with WWH (81.4% vs 69.3% P = 0.05). However, WLWH were more likely to suffer with pre-menstrual tension compared with WWH (60.8% vs 50.6% P = 0.01). CONCLUSION: Our data suggests that WLWH, despite being older and of higher BMI, have a shorter duration of menstrual bleeding, and we hypothesise that this may possibly be due to the (beneficial) side effects of some HAART components. Further research is needed to explore the effect of HAART on MRS to determine if these therapies could be used in the future as a fertility retaining treatment for MRSs/endometriosis.

National Survey Highlights the Urgent Need for Standardisation of Embryo Transfer Techniques in the UK.

Embryo transfer (ET) is one of the vital steps in the in vitro fertilisation (IVF) process, yet there is wide variation in ET technique throughout the UK, without a nationally approved standardised approach. The aim of this study was to gain contemporaneous information regarding the current clinical ET practice in the UK. METHOD: A 38-question electronic survey was distributed to the 79 UK Human Fertilisation and Embryology Authority (HFEA) registered clinics performing ETs. RESULTS: In total, 59% (47/79) of units responded, 83% (39/47) performing ultrasound-guided transfers, with 42% (20/47) of units using a tenaculum; 22% (10/45) would proceed with transfer regardless of fluid in the endometrial cavity. In 91% (43/47) of units, embryos were deposited in the upper/middle portion of the uterine cavity, but interpretation of this area ranged from 0.5 to >2 cm from the fundus, with 68% (32/47) allowing patients to mobilise immediately after transfer. In 60% (27/45) of clinics, success rates were based on clinical pregnancy rates (CPR). CONCLUSION: Within the UK there is a wide range of variability in ET techniques, with >70% of discordance in survey-responses between clinics. Whilst there are areas of good practice, some disadvantageous techniques continue to persist. This survey emphasises the importance of developing a standardised, evidence-based approach to improve ET success rates.