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Limited research has been published comparing PIEZO-ICSI with conventional ICSI. While positive effects have been documented in improving fertilization and degeneration, the outcomes in patients with previous poor results from conventional ICSI remain unclear. It is hypothesized that these patients may benefit the most from this form of insemination.This retrospective paired within-patient cohort study investigated patients (n=72) undertaking PIEZO-ICSI after a previous conventional ICSI cycle resulted in poor outcomes (including low fertilization (50%), high degeneration (15%), and/or poor embryo development and utilization). Patients required at least five oocytes collected in both cycles and a period of less than 2 years between the cycles. The outcomes of both cycles were compared in respect to fertilization, degeneration, embryo utilization, and pregnancy rates. Further analyses were applied to patients38 and ≥38 years of age, with50% or ≥50% fertilization with conventional ICSI and with20% or ≥20% utilization with conventional ICSI.PIEZO-ICSI resulted in significantly higher fertilization (61.9% vs 45.3%, P0.0001) and lower degeneration (7.7% vs 18.2%, P=0.0001) when compared to the conventional ICSI cycles. The greatest benefit was seen in patients who had less than 50% fertilization or20% utilization in their conventional ICSI cycle, with improvements in fertilization and degeneration rates resulting in a significantly higher number of embryos utilized (frozen or transferred) per cycle.PIEZO-ICSI improved fertilization, degeneration, and utilization rates in patients with previous poor outcomes from conventional ICSI. The number of embryos available for use per cycle was also increased. Further significant improvements were achieved in patients who exhibited poor fertilization (50%) or low utilization (20%) from conventional ICSI.

Turner syndrome (TS), a common chromosomal abnormality affecting females, is associated with partial or complete loss of the second sex chromosome. Although the classic karyotype is 45, X, the detection of mosaic TS is increasing. TS is a multi-system disorder with significant endocrine, cardiovascular and reproductive impacts. Accelerated ovarian follicular loss leads to primary amenorrhoea or premature ovarian insufficiency and infertility. Early diagnosis and counselling regarding hormone replacement therapy and future reproductive capacity, including fertility preservation, are essential to improve reproductive outcomes. Pubertal induction or estrogen replacement is usually required to optimise long-term health outcomes; however, initiation may be delayed due to delayed diagnosis. Spontaneous pregnancy occurs in a small number of women; however, many require donor oocytes and assisted reproductive technology to achieve a pregnancy. Pregnancy is a high risk especially when associated with congenital heart disease. Prepregnancy counselling by the multidisciplinary team (MDT) to identify contraindications and optimise pre-existing health issues is essential. Pregnancy management should be led by a maternal-fetal medicine unit with input from the MDT. This review examines reproductive health outcomes in women with TS and how best to manage them to reduce health risks and improve maternal and neonatal outcomes.

Background Intraperitoneal local anaesthetic has shown benefit in operative laparoscopy; however, no randomised controlled trial has been reported with patients having diagnostic laparoscopy. Aims To determine the effect of intraperitoneal ropivacaine on post-operative analgesic requirements, pain, nausea scores and recovery following gynaecological diagnostic laparoscopy and hysteroscopy. Materials and methods Randomised double-blind placebo-controlled trial. Well women aged 18-50 years, undergoing day case hysteroscopy and diagnostic laparoscopy for gynaecological indications were randomised to 20 mL of 150 mg intraperitoneal ropivacaine diluted in saline, or 20 mL normal saline instillation (placebo) at the end of the procedure. Women were followed up until eight hours post-discharge. Results Slower than anticipated recruitment meant that the study was finished before the sample size of 100 patients was achieved. Fifty-nine patients were included for analysis. Thirty-one patients were randomised to ropivacaine and 28 patients to control. Sixty-one percent of patients in both arms required opioid medication in recovery. The total median equivalent morphine dose was significantly higher in the patients randomised to control (11.7 mg) vs ropivacaine (6.7 mg), P = 0.03. Time to discharge was 20 min faster in patients randomised to ropivacaine, but this finding did not reach significance. Overall pain and nausea scores in the first eight hours showed no significant differences. Conclusion There was significantly reduced opioid use in recovery when using intraperitoneal ropivacaine compared to placebo, in this randomised placebo-controlled trial on women undergoing day case diagnostic laparoscopy and hysteroscopy.

STUDY QUESTIONDoes the naturally menstruating spiny mouse go through menopause?SUMMARY ANSWEROur study is the first to show a natural and gradual menopausal transition in a rodent.WHAT IS KNOWN ALREADYAge-related depletion of the human ovarian reserve (OvR) leads to menopause, the permanent cessation of menstruation and reproduction. Current rodent models of menopause are inappropriate for inferences of the human condition, as reproductive senescence is abrupt or induced through ovariectomy. The spiny mouse is the only confirmed rodent with a naturally occurring menstrual cycle.STUDY DESIGN, SIZE, DURATIONHistological assessment of virgin spiny mice occurred in females aged 6 months (n = 14), 1 year (n = 7), 2 years (n = 13), 3 years (n = 9) and 4 years (n = 9). Endocrinology was assessed in a further 9 females per age group. Five animals per group were used for ovarian stereology with additional ovaries collected at prenatal Day 35 (n = 3), day of birth (n = 5), postnatal Days 35 (n = 5) and 100 (n = 5) and 15 months (n = 5).PARTICIPANTS/MATERIALS, SETTING, METHODSMorphological changes in the reproductive system were examined using hematoxylin and eosin stains. Proliferating cell nuclear antigen immunohistochemistry assessed endometrial proliferation and sex steroids estradiol and testosterone were assayed using commercial ELISA kits.MAIN RESULTS AND THE ROLE OF CHANCEThe proportion of females actively cycling was 86% at 6 months, 71% at 1 year, 69% at 2 years, 56% at 3 years and 44% at 4 years. Uterine and ovarian weights declined steadily from 1 year in all groups and corresponded with loss of uterine proliferation (P LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONThis is a descriptive study in a novel research rodent whereby reagents validated for use in the spiny mouse were limited.WIDER IMPLICATIONS OF THE FINDINGSThe gradual, rather than sudden, menopausal transition suggests that the spiny mouse is a more appropriate perimenopausal model than the current rodent models in which to examine the neuroendocrine pathways that encompass all hormonal interactions in the hypothalamic–pituitary–gonadal axis. The logistic, ethical and economic advantages of such a model may reduce our reliance on primates in menopause research and enable more thorough and invasive investigation than is possible in humans.STUDY FUNDING/COMPETING INTEREST(S)Hudson Institute is supported by the Victorian State Government Operational Infrastructure Scheme. The authors declare no competing interests.

Background: Ectopic pregnancy remains the most common cause of early pregnancy mortality, with management options differing according to clinical presentation and investigations. This audit aims to investigate the indications for medical and surgical management of ectopic pregnancy at a tertiary hospital network, in order to assess variances in practice and adherence to local hospital protocols. Methods: A retrospective audit of the management of women with a diagnosis of ectopic pregnancy was performed over 12 months from July 2018 to June 2019, at three hospitals in the largest healthcare network in Victoria, Australia. Information collected included patient demographics, risk factors for ectopic pregnancy, pathology and radiology results, documented indication for surgery, and any complications of treatment. A subgroup analysis of data was done to investigate changes and deficiency in management of ectopic pregnancy compared to local hospital protocol. Results: Over a 12-month period, 138 women were diagnosed with an ectopic pregnancy, of which 99 (72%) received surgical management and 39 (28%) received medical management. Four women within the medical group were excluded from analysis, one due to loss of follow-up and three patients who were diagnosed with nontubal ectopic pregnancies. About 94% (33/35) of women who received methotrexate were within hospital guidelines for medical management and 91% (32/35) were successfully managed without surgery. All women who received surgical management underwent a salpingectomy and 97% (96/99) had clear indications documented for surgery within local protocol. Conclusion: Overall, the majority of women with ectopic pregnancy were treated according to local guidelines. Expectant management and the option of salpingostomy as a surgical alternative could be considered in the local guidelines. The dissemination of this clinical audit data is aimed at continuing clinical governance and improvements in outcomes.

STUDY QUESTIONDoes female ageing have a negative effect on the DNA repair capacity of oocytes fertilised by spermatozoa with controlled levels of DNA damage?SUMMARY ANSWERCompared to oocytes from younger females, oocytes from older females have a reduced capacity to repair damaged DNA introduced by spermatozoa.WHAT IS KNOWN ALREADYThe reproductive lifespan in women declines with age predominantly due to poor oocyte quality. This leads to decreased reproductive outcomes for older women undergoing assisted reproductive technology (ART) treatments, compared to young women. Ageing and oocyte quality have been clearly associated with aneuploidy, but the range of factors that influence this change in oocyte quality with age remains unclear. The DNA repair activity prior to embryonic genomic activation is considered to be of maternal origin, with maternal transcripts and proteins controlling DNA integrity. With increasing maternal age, the number of mRNAs stored in oocytes decreases. This could result in diminished efficiency of DNA repair and/or negative effects on embryo development, especially in the presence of DNA damage.STUDY DESIGN, SIZE, DURATIONOocytes from two age groups of 30 super-ovulated female mice (young: 5–8 weeks old, n = 15; old: 42–45 weeks old, n = 15) were inseminated with sperm from five males with three different controlled DNA damage levels; control: ≤10%, 1 Gray (Gy): 11–30%, and 30 Gy: >30%. Inseminated oocytes (young: 125, old: 78) were assessed for the formation of zygotes (per oocyte) and blastocysts (per zygote). Five replicates of five germinal vesicles (GVs) and five MII oocytes from each age group were analysed for gene expression. The DNA damage response (DDR) was assessed in a minimum of three IVF replicates in control and 1 Gy zygotes and two-cell embryos using γH2AX labelling.PARTICIPANTS/MATERIALS, SETTING, METHODSSwim-up sperm samples from the cauda epididymidis of C57BL6 mice were divided into control (no irradiation) and 1- and 30-Gy groups. Treated spermatozoa were irradiated at 1 and 30 Gy, respectively, using a linear accelerator Varian 21iX. Following irradiation, samples were used for DNA damage assessment (Halomax) and for insemination. Presumed zygotes were cultured in a time-lapse incubator (MIRI, ESCO). Gene expression of 91 DNA repair genes was assessed using the Fluidigm Biomark HD system. The DNA damage response in zygotes (6–8 h post-fertilisation) and two-cell embryos (22–24 h post-fertilisation) was assessed by immunocytochemical analysis of γH2AX using confocal microscopy (Olympus FV1200) and 3D volumetric analysis using IMARIS software.MAIN RESULTS AND THE ROLE OF CHANCEThe average sperm DNA damage for the three groups was statistically different (control: 6.1%, 1 Gy: 16.1%, 30 Gy: 53.1%, P LARGE-SCALE DATAN/ALIMITATIONS, REASONS FOR CAUTIONIonising radiation was used only for experimental purposes, aiming at controlled levels of sperm DNA damage; however, it can also damage spermatozoa proteins. The female age groups selected in mice were intended to model effects in young and old women, but clinical studies are required to demonstrate a similar effect.WIDER IMPLICATIONS OF THE FINDINGSFertilisation can occur with sperm populations with medium and high DNA damage, but subsequent embryo growth is affected to a greater extent with aging females, supporting the theory that oocyte DNA repair capacity decreases with age. Assessment of the oocyte DNA repair capacity may be a useful diagnostic tool for infertile couples.STUDY FUNDING/COMPETING INTEREST(S)Funded by the Education Program in Reproduction and Development, Department of Obstetrics and Gynaecology, Monash University. None of the authors has any conflict of interest to report.

Importance Preimplantation genetic testing for aneuploidy (PGT-A) has undergone many technical developments over recent years, including changes in biopsy timings, methodology, and genetic analysis techniques. The evidence surrounding the efficaciousness of PGT-A is sporadic and inconsistent; as such, significant doubt and concern remain regarding its widespread implementation. Objective This review seeks to describe the historical development of PGT-A and to analyze and summarize the current published literature. Conclusions At times during its infancy, PGT-A failed to display conclusive improvements in results; with newer technologies, PGT-A appears to yield superior outcomes, including reductions in miscarriages and multiple gestations. Clinicians and patients should assess the use of PGT-A on a case-by-case basis, with laboratories encouraged to utilize blastocyst biopsy and next-generation sequencing when conducting PGT-A. Further studies providing cumulative live birth rates and time to live birth are required if PGT-A is to be proven as producing superior outcomes. Relevance PGT-A has the potential ability to impact in vitro fertilization success rates, and as it is increasingly adopted worldwide, it is crucial that clinicians are aware of the evidence for its continued use.

Refereed/Peer-reviewed Purpose: To determine if 5mM calcium chloride dihydrate supplementation of the Polyvinylpyrrolidone (PVP) media at the time of ICSI (ICSI-Ca) improves fertilization, utilization, and clinical pregnancy rates compared to ICSI alone, particularly in patients with a history of low fertilization ( 6 cycles, and patients with ≤ 5 inseminated oocytes. Results: Calcium supplementation significantly increased both fertilization (28.8% ICSI vs 49.7% ICSI-Ca, P

Uterine Fibroids, or leiomyomata, affect millions of women world-wide, with a high incidence of 75% within women of reproductive age. In ~30% of patients, uterine fibroids cause menorrhagia, or heavy menstrual bleeding, and more than half of the patients experience symptoms such as heavy menstrual bleeding, pelvic pain, or infertility. Treatment is symptomatic with limited options including hysterectomy as the most radical solution. The genetic foundations of uterine fibroid growth have been traced to somatic driver mutations (MED12, HMGA2, FH−/−, and COL4A5-A6). These also lead to downstream expression of angiogenic factors including IGF-1 and IGF-2, as opposed to the VEGF-driven mechanism found in the angiogenesis of hypoxic tumors. The resulting vasculature supplying the fibroid with nutrients and oxygen is highly irregular. Of particular interest is the formation of a pseudocapsule around intramural fibroids, a unique structure within tumor angiogenesis. These aberrations in vascular architecture and network could explain the heavy menstrual bleeding observed. However, other theories have been proposed such as venous trunks, or venous lakes caused by the blocking of normal blood flow by uterine fibroids, or the increased local action of vasoactive growth factors. Here, we review and discuss the evidence for the various hypotheses proposed.

Background Maternal immunisation is an essential public health intervention aimed at improving the health outcomes for pregnant women and providing protection to the newborn. Despite international recommendations, safety and efficacy data for the intervention, and often a fully funded program, uptake of vaccines in pregnancy remain suboptimal. One possible explanation for this includes limited access to vaccination services at the point of antenatal care. The aim of this study is to evaluate the change in vaccine coverage among pregnant women following implementation of a modified model of delivery aimed at improving access at the point of antenatal care, including an economic evaluation. Methods This prospective multi-centre study, using action research design, across six maternity services in Victoria, Australia, evaluated the implementation of a co-designed vaccine delivery model (either a pharmacy led model, midwife led model or primary care led model) supported by provider education. The main outcome measure was influenza and pertussis vaccine uptake during pregnancy and the incremental cost of the new model (compared to existing models) and the cost-effectiveness of the new model at each participating health service. Results Influenza vaccine coverage in 2019 increased between 50 and 196% from baseline. All services reduced their average cost per immunisation under the new platforms due to efficiencies achieved in the delivery of maternal immunisations. This cost saving ranged from $9 to $71. Conclusion Our study demonstrated that there is no ‘one size fits all’ model of vaccine delivery. Future successful strategies to improve maternal vaccine coverage at other maternity services should be site specific, multifaceted, targeted at the existing barriers to maternal vaccine uptake, and heavily involve local stakeholders in the design and implementation of these strategies. The cost-effectiveness analysis indicates that an increase in maternal influenza immunisation uptake can be achieved at a relatively modest cost through amendment of maternal immunisation platforms.

What is the impact of the response to COVID-19 on the management of fertility treatments and clinical practice around the world?Fertility clinic associates around the world were approached. They completed an online survey containing 33 questions focused on the country's response to the COVID-19 pandemic. Known fertility clinic associates that were contacted comprised scientific directors, medical directors and laboratory managers.There were 43 individual country responses from Asia (13), Africa (3), Europe (17), North America (3), Oceania (2) and South America (5). In nine countries, clinics followed their government body recommendations, in 22 countries there was a combination of recommendations, in 3 countries changes were made by clinic initiative, and 9 countries did not specify. In 34 countries IVF/intracytoplasmic sperm injection (ICSI) and frozen embryo transfer (FET) treatments had an average delay of 56 days (IVF/ICSI) (minimum 0, maximum 160) and 57 days (FET) (minimum 0, maximum 166 days). During the shutdown, the number of freeze-all cycles increased in 22 countries. Only 23 countries reported patients having to undergo a SARS-CoV-2 test, and 20 countries did not report any COVID-19 testing in their clinic. Additional support counselling was offered in 28 countries, partner restrictions at clinics were reported in 41 countries and time between patients' appointments was increased in 39 countries.The implications of COVID-19 mitigation measures proved the need for government societies to introduce a set protocol that includes requirements such as increased patient counselling and additional guidelines for prioritizing couples who need care most urgently.

Background There is interest in longer term outcomes in IVF-conceived offspring compared with those conceived naturally. So far, the findings have been conflicting. The Australian Early Developmental Consensus (AEDC) assesses children in their first year of primary school across five domains. Methods To compare school entry outcomes in IVF-conceived children with naturally conceived controls, we undertook a statewide data linkage study, with perinatal data (2005-2014) linked to data from IVF providers in Victoria and the AEDC. Our approach to analysis included: complete case analysis, multiple imputation of missing data, consideration of clustering (siblings) and inverse probability weighted modeling to adjust for covariates. Our primary outcome was an AEDC score indicative of developmental vulnerability in two or more domains. We adjusted for confounders: child’s age at assessment, sex, highest level of maternal education, maternal age, parity, SEIFA (Socio-Economic Indexes for Areas) quintile, language background other than English, and Aboriginal and Torres Strait Islander (ATSI) status. Results The linked dataset comprised 163,418 children, including 4,441 IVF-conceived children. The IVF-conceived population had older, more highly educated mothers who lived in more affluent areas and were less likely to be from non-English speaking backgrounds or identify as ATSI. IVF-conceived children were less likely to be developmentally vulnerable, in both unadjusted (RR 0.59, 95%CI:0.52-0.67, p Conclusions IVF-conceived were less likely to be developmentally vulnerable in their first year of schooling, compared with peers conceived naturally.

Background Melatonin is a potent oxygen scavenger and is capable of altering blood flow in various vascular beds. Aims We aimed to determine the effect of melatonin on ovarian vascular indices during ovarian stimulation for in vitro fertilisation (IVF). Materials and methods This is a pilot double-blind placebo-controlled randomised trial. Sixty-nine women (mean age 35.8 ± 4.3 years) undergoing their first cycle of IVF were randomised to receive either placebo, 2, 4 or 8 mg of melatonin, twice a day. Each participant underwent a transvaginal ultrasound at days 6-10 assessing follicular number and size. The vascularisation index (VI), flow index (FI) and vascularisation-flow index (VFI) were measured. These indices were then correlated with embryological outcomes. Informed consent was obtained from participants. This trial was registered with the Australia New Zealand Clinical Trials Registry (ACTRN12613001317785). Results The number of follicles did not differ between groups (P = 0.4). There were no differences in the VI (P = 0.4), FI (P = 0.1) or VFI (P = 0.3) in the right ovary or the FI (P = 0.3) or VFI (P = 0.3) in the left ovary between groups. When comparing placebo to any dose of melatonin, there were no differences in any measured parameter. While there was correlation between the number of follicles on ultrasound and all measured embryological outcomes, there was no correlation between ovarian vascular indices and these important clinical outcomes. Conclusions Melatonin does not appear to change ovarian vascular indices during ovarian stimulation. In addition, such vascular indices cannot predict the number or quality of oocytes or embryos obtained in an IVF cycle. These findings require confirmation in future larger studies.

Hysteroscopy is one of the most frequent procedures that a gynecologist will perform over their career. It is also one of the safest procedures. Operative hysteroscopy has an increased risk profile due to the nature of the surgery. The following review will address the issue of gas embolism in hysteroscopy. This review will look at the evidence regarding the likely causation, rates, and potential methods of minimizing risk to patients as well as treatment options available should this complication arise.

To assess the effect of oral complementary and alternative medicine (CAM) on the oocyte, embryo and pregnancy rate in first-cycle in vitro fertilisation (IVF).A prospective cohort study using the International CAM Questionnaire, reviewing patient IVF outcomes. Local ethics approval was obtained.Over 18 months (October 2015 to April 2017) 25 patients were prospectively recruited, with 52% (n = 13) using herbal or dietary supplements, including Chinese medicine, fish oil, liver 'detox', co-enzyme Q10, spirulina, probiotics and maca root. Comparing users to non-users, there was no statistical difference in age, body mass index, primary infertility, gravidity or parity. Total follicle-stimulating hormone dose was equivalent (2760 vs 2451 IU, P = 0.60), but there was a significant difference in maximum oestradiol response (4134 vs 8335, P = 0.045), on univariate analysis alone. While no difference was found in the number of follicles11 mm (7.5 vs 11.5, P = 0.80), or eggs collected (8.0 vs 12.5, P = 0.91), there was a lower number of eggs fertilised in users (3.0 vs 4.0, P = 0.046). There was no difference in the chemical or clinical pregnancy rate.This small study demonstrates a high use of oral CAM in first-cycle IVF patients, with a wide range of types. There appears to be a lower fertilisation rate in the women who used oral CAMs. It is unclear whether this is a negative effect of the CAM or selection bias. This concern about confounders supports the need for further research into unregulated herbal medicine on IVF outcomes, given that so many women are using these substances.

Objective To study whether endometrial epithelial podocalyxin (PCX) inhibits implantation of human embryos in vitro and in patients undergoing in vitro fertilization (IVF). Design We have recently identified PCX as a key negative regulator of endometrial epithelial receptivity. Podocalyxin is expressed in all epithelial cells in the nonreceptive endometrium, but is selectively downregulated in the luminal epithelium (LE) for receptivity. In the current study, we first investigated whether high levels of PCX in Ishikawa monolayer inhibit attachment and/or penetration of human blastocysts in in vitro models. We then examined PCX by immunohistochemistry in putative receptive endometrial tissues biopsied from 81 IVF patients who underwent frozen embryo transfer in the next natural cycle and retrospectively analyzed the association between PCX staining in LE and clinical pregnancy as a proxy of successful implantation. Setting RMIT University, Australia; Vrije Universiteit Brussel, Belgium. Patient(s) In vitro fertilization patients undergoing frozen/thawed embryo transfer. Intervention(s) N/A. Main Outcome Measure(s) Endometrial epithelial PCX inhibits implantation of human embryos in vitro and in IVF patients. Result(s) High levels of PCX in Ishikawa monolayer significantly inhibited blastocyst attachment and penetration. Among the 81 putative receptive tissues, 73% were negative, but 27% were heterogeneously positive for PCX in LE. The clinical pregnancy rate was 53% in those with a PCX-negative LE but only 18% in those with a PCX-positive LE. If LE was positive for PCX, the odds ratio of no clinical pregnancy was 4.95 (95% Confidence interval, 1.48–14.63). Conclusion(s) Podocalyxin inhibits embryo implantation. Assessment of PCX may aid the evaluation and optimization of endometrial receptivity in fertility treatment.

STUDY QUESTION Does the presence of adenomyosis in women treated with IVF alter IVF outcomes? SUMMARY ANSWER Adenomyosis does not significantly alter IVF outcomes when adjusted for confounding factors including maternal age and smoking status. WHAT IS KNOWN ALREADY Studies evaluating adenomyosis and its impact on infertility, particularly when focusing on IVF, remain controversial. Many studies report that adenomyosis has a detrimental effect on IVF outcomes, however age is strongly related with both the prevalence of adenomyosis and worse reproductive outcomes. STUDY DESIGN, SIZE, DURATION A prospective cohort study of women undergoing 4002 IVF cycles who had undergone a screening ultrasound assessing features of adenomyosis from 1 January 2016 to 31 March 2018 at a multi-site private fertility clinic. Of these women, 1228 fulfilled the inclusion criteria and commenced an IVF cycle, with a subset of 715 women undergoing an embryo transfer (ET). Women were defined as having adenomyosis if there was sonographic evidence of adenomyosis on ultrasound as per the Morphological Uterus Sonographic Assessment criteria, and were then compared to women without. PARTICIPANTS/MATERIALS, SETTING, METHODS All women at a private multi-site IVF clinic who underwent a standardised ultrasound to identify features of adenomyosis and also commenced an IVF cycle were assessed for their outcomes. These included clinical pregnancy (defined as the presence of a gestational sac on ultrasound at 7 weeks’ gestation), clinical pregnancy loss, number of cancelled cycles, number of useful embryos for transfer or freezing and live birth rates. As a secondary aim, initiated stimulation cycles and those that had an ET were analysed separately to determine when an effect of adenomyosis on IVF might occur: during stimulation or transfer. MAIN RESULTS AND THE ROLE OF CHANCE When adjusting for confounders, women with and without sonographic features of adenomyosis had no significant differences in most of their IVF outcomes including live birth rates. LIMITATIONS, REASONS FOR CAUTION Adenomyosis had a detrimental impact on IVF outcomes prior to adjusting for confounding factors. No allowance was made for the possibility that confounding factors may merely reduce the effect size of adenomyosis on IVF outcomes. Second, despite a power calculation, the study was underpowered as not all fresh cycles led to an ET. WIDER IMPLICATIONS OF THE FINDINGS This is one of the largest studies to evaluate adenomyosis and IVF outcomes, while also importantly adjusting for confounding factors. The results suggest that adenomyosis does not have the detrimental impact on IVF that has previously been suggested, possibly reducing the importance of screening for and treating this entity. STUDY FUNDING/COMPETING INTEREST(S) The study received no external funding. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER ACTRN12617000796381.

Pain following laparoscopic surgery remains a neglected healthcare issue. Virtual reality-mediated therapy’s (VRT) analgesic potential could address this. However, its effect in this setting remains unexplored. We aimed to establish the feasibility and safety of VRT as an adjunct analgesic following gynaecological laparoscopy and explore differences between active distraction and passive meditation content. 35 women were enrolled into an open crossover pilot and randomised to either intervention group 1 (active then passive content) or intervention group 2 (passive then active content) following surgery. VRT was administered in two 10-min segments with a 10-min washout period in between. Pain scores, opioid requirements and side effects were recorded before and after each segment whilst questionnaires evaluated acceptability. We observed a significant reduction in pain over time for the entire study population (F = 8.63, p

BackgroundVirtual reality is increasingly being utilized by clinicians to facilitate analgesia and anxiolysis within an inpatient setting. There is however, a lack of a clinically relevant review to guide its use for this purpose.ObjectiveTo systematically review the current evidence for the efficacy of virtual reality as an analgesic in the management of acute pain and anxiolysis in an inpatient setting.MethodsA comprehensive search was conducted up to and including January 2019 on PubMed, Ovid Medline, EMBASE, and Cochrane Database of Systematic reviews according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Search terms included virtual reality, vr, and pain. Primary articles with a focus on acute pain in the clinical setting were considered for the review. Primary outcome measures included degree of analgesia afforded by virtual reality therapy, degree of anxiolysis afforded by virtual reality therapy, effect of virtual reality on physiological parameters, side effects precipitated by virtual reality, virtual reality content type, and type of equipment utilized.ResultsEighteen studies were deemed eligible for inclusion in this systematic review; 67% (12/18) of studies demonstrated significant reductions in pain with the utilization of virtual reality; 44% (8/18) of studies assessed the effects of virtual reality on procedural anxiety, with 50% (4/8) of these demonstrating significant reductions; 28% (5/18) of studies screened for side effects with incidence rates of 0.5% to 8%; 39% (7/18) of studies evaluated the effects of virtual reality on autonomic arousal as a biomarker of pain, with 29% (2/7) demonstrating significant changes; 100% (18/18) of studies utilized a head mounted display to deliver virtual reality therapy, with 50% being in active form (participants interacting with the environment) and 50% being in passive form (participants observing the content only).ConclusionsAvailable evidence suggests that virtual reality therapy can be applied to facilitate analgesia for acute pain in a variety of inpatient settings. Its effects, however, are likely to vary by patient population and indication. This highlights the need for individualized pilot testing of virtual reality therapy’s effects for each specific clinical use case rather than generalizing its use for the broad indication of facilitating analgesia. In addition, virtual reality therapy has the added potential of concurrently providing procedural anxiolysis, thereby improving patient experience and cooperation, while being associated with a low incidence of side effects (nausea, vomiting, eye strain, and dizziness). Furthermore, findings indicated a head mounted display should be utilized to deliver virtual reality therapy in a clinical setting with a slight preference for active over passive virtual reality for analgesia. There, however, appears to be insufficient evidence to substantiate the effect of virtual reality on autonomic arousal, and this should be considered at best to be for investigational uses, at present.

The uterine junctional zone represents the juncture between endometrium and myometrium. The junctional zone is hormonally dependent and displays continuous peristaltic activity throughout the menstrual cycle in the nonpregnant state which is concerned with sperm transport and embryo implantation. Peristalsis may be observed using various invasive and noninvasive modalities, of which ultrasound is the most readily applied in the clinical setting. Women with pelvic pathology display alterations in uterine peristalsis which may contribute to infertility. Characterization of peristalsis in infertility subgroups, the development of a subjective peristalsis tool, and the application of potential therapeutics to an assisted reproductive treatment setting are the subject of ongoing investigation. Meta-analysis indicates a potential role for oxytocin antagonist in the improvement of fertility treatments.

PURPOSE: Oocyte quality and reproductive outcome are negatively affected by advanced maternal age, ovarian stimulation and method of oocyte maturation during assisted reproduction; however, the mechanisms responsible for these associations are not fully understood. The aim of this study was to compare the effects of ageing, ovarian stimulation and in-vitro maturation on the relative levels of transcript abundance of genes associated with DNA repair during the transition of germinal vesicle (GV) to metaphase II (MII) stages of oocyte development. METHODS: The relative levels of transcript abundance of 90 DNA repair-associated genes was compared in GV-stage and MII-stage oocytes from unstimulated and hormone-stimulated ovaries from young (5–8-week-old) and old (42–45-week-old) C57BL6 mice. Ovarian stimulation was conducted using pregnant mare serum gonadotropin (PMSG) or anti-inhibin serum (AIS). DNA damage response was quantified by immunolabeling of the phosphorylated histone variant H2AX (γH2AX). RESULTS: The relative transcript abundance in DNA repair genes was significantly lower in MII oocytes compared to GV oocytes in young unstimulated and PMSG stimulated but was higher in AIS-stimulated mice. Interestingly, an increase in the relative level of transcript abundance of DNA repair genes was observed in MII oocytes from older mice in unstimulated, PMSG-stimulated and AIS-stimulated mice. Decreased γH2AX levels were found in both GV oocytes (82.9%) and MII oocytes (37.5%) during ageing in both ovarian stimulation types used (PMSG/AIS; p < 0.05). CONCLUSIONS: In conclusion, DNA repair relative levels of transcript abundance are altered by maternal age and the method of ovarian stimulation during the GV-MII transition in oocytes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10815-020-01981-6) contains supplementary material, which is available to authorized users.

STUDY QUESTION How is endometrial epithelial receptivity, particularly adhesiveness, regulated at the luminal epithelial surface for embryo implantation in the human? SUMMARY ANSWER Podocalyxin (PCX), a transmembrane protein, was identified as a key negative regulator of endometrial epithelial receptivity; specific downregulation of PCX in the luminal epithelium in the mid-secretory phase, likely mediated by progesterone, may act as a critical step in converting endometrial surface from a non-receptive to an implantation-permitting state. WHAT IS KNOWN ALREADY The human endometrium must undergo major molecular and cellular changes to transform from a non-receptive to a receptive state to accommodate embryo implantation. However, the fundamental mechanisms governing receptivity, particularly at the luminal surface where the embryo first interacts with, are not well understood. A widely held view is that upregulation of adhesion-promoting molecules is important, but the details are not well characterized. STUDY DESIGN, SIZE, DURATION This study first aimed to identify novel adhesion-related membrane proteins with potential roles in receptivity in primary human endometrial epithelial cells (HEECs). Further experiments were then conducted to determine candidates’ in vivo expression pattern in the human endometrium across the menstrual cycle, regulation by progesterone using cell culture, and functional importance in receptivity using in vitro human embryo attachment and invasion models. PARTICIPANTS/MATERIALS, SETTING, METHODS Primary HEECs (n = 9) were isolated from the proliferative phase endometrial tissue, combined into three pools, subjected to plasma membrane protein enrichment by ultracentrifugation followed by proteomics analysis, which led to the discovery of PCX as a novel candidate of interest. Immunohistochemical analysis determined the in vivo expression pattern and cellular localization of PCX in the human endometrium across the menstrual cycle (n = 23). To investigate whether PCX is regulated by progesterone, the master driver of endometrial differentiation, primary HEECs were treated in culture with estradiol and progesterone and analyzed by RT-PCR (n = 5) and western blot (n = 4). To demonstrate that PCX acts as a negative regulator of receptivity, PCX was overexpressed in Ishikawa cells (a receptive line) and the impact on receptivity was determined using in vitro attachment (n = 3–5) and invasion models (n = 4–6), in which an Ishikawa monolayer mimicked the endometrial surface and primary human trophoblast spheroids mimicked embryos. Mann–Whitney U-test and ANOVA analyses established statistical significance at *P ≤ 0.05 and **P ≤ 0.01. MAIN RESULTS AND THE ROLE OF CHANCE PCX was expressed on the apical surface of all epithelial and endothelial cells in the non-receptive endometrium, but selectively downregulated in the luminal epithelium from the mid-secretory phase coinciding with the establishment of receptivity. Progesterone was confirmed to be able to suppress PCX in primary HEECs, suggesting this hormone likely mediates the downregulation of luminal PCX in vivo for receptivity. Overexpression of PCX in Ishikawa monolayer inhibited not only the attachment but also the penetration of human embryo surrogates, demonstrating that PCX acts as an important negative regulator of epithelial receptivity for implantation. LIMITATIONS, REASONS FOR CAUTION Primary HEECs isolated from the human endometrial tissue contained a mixture of luminal and glandular epithelial cells, as further purification into subtypes was not possible due to the lack of specific markers. Future study would need to investigate how progesterone differentially regulates PCX in endometrial epithelial subtypes. In addition, this study used primary human trophoblast spheroids as human embryo mimics and Ishikawa as endometrial epithelial cells in functional models, future studies with human blastocysts and primary epithelial cells would further validate the findings. WIDER IMPLICATIONS OF THE FINDINGS The findings of this study add important new knowledge to the understanding of human endometrial remodeling for receptivity. The identification of PCX as a negative regulator of epithelial receptivity and the knowledge that its specific downregulation in the luminal epithelium coincides with receptivity development may provide new avenues to assess endometrial receptivity and individualize endometrial preparation protocols in assisted reproductive technology (ART). The study also discovered PCX as progesterone target in HEECs, identifying a potentially useful functional biomarker to monitor progesterone action, such as in the optimization of progesterone type/dose/route of administration for luteal support. STUDY FUNDING/COMPETING INTEREST(S) Study funding was obtained from ESHRE, Monash IVF and NHMRC. LR reports potential conflict of interests (received grants from Ferring Australia; personal fees from Monash IVF Group and Ferring Australia; and non-financial support from Merck Serono, MSD, and Guerbet outside the submitted work. LR is also a minority shareholder and the Group Medical Director for Monash IVF Group, a provider of fertility preservation services). The remaining authors have no potential conflict of interest to declare. TRIAL REGISTRATION NUMBER NA.

BACKGROUND Virtual reality is increasingly being utilized by clinicians to facilitate analgesia and anxiolysis within an inpatient setting. There is however, a lack of a clinically relevant review to guide its use for this purpose. OBJECTIVE To systematically review the current evidence for the efficacy of virtual reality as an analgesic in the management of acute pain and anxiolysis in an inpatient setting. METHODS A comprehensive search was conducted up to and including January 2019 on PubMed, Ovid Medline, EMBASE, and Cochrane Database of Systematic reviews according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Search terms included virtual reality, vr, and pain. Primary articles with a focus on acute pain in the clinical setting were considered for the review. Primary outcome measures included degree of analgesia afforded by virtual reality therapy, degree of anxiolysis afforded by virtual reality therapy, effect of virtual reality on physiological parameters, side effects precipitated by virtual reality, virtual reality content type, and type of equipment utilized. RESULTS Eighteen studies were deemed eligible for inclusion in this systematic review; 67% (12/18) of studies demonstrated significant reductions in pain with the utilization of virtual reality; 44% (8/18) of studies assessed the effects of virtual reality on procedural anxiety, with 50% (4/8) of these demonstrating significant reductions; 28% (5/18) of studies screened for side effects with incidence rates of 0.5% to 8%; 39% (7/18) of studies evaluated the effects of virtual reality on autonomic arousal as a biomarker of pain, with 29% (2/7) demonstrating significant changes; 100% (18/18) of studies utilized a head mounted display to deliver virtual reality therapy, with 50% being in active form (participants interacting with the environment) and 50% being in passive form (participants observing the content only). CONCLUSIONS Available evidence suggests that virtual reality therapy can be applied to facilitate analgesia for acute pain in a variety of inpatient settings. Its effects, however, are likely to vary by patient population and indication. This highlights the need for individualized pilot testing of virtual reality therapy’s effects for each specific clinical use case rather than generalizing its use for the broad indication of facilitating analgesia. In addition, virtual reality therapy has the added potential of concurrently providing procedural anxiolysis, thereby improving patient experience and cooperation, while being associated with a low incidence of side effects (nausea, vomiting, eye strain, and dizziness). Furthermore, findings indicated a head mounted display should be utilized to deliver virtual reality therapy in a clinical setting with a slight preference for active over passive virtual reality for analgesia. There, however, appears to be insufficient evidence to substantiate the effect of virtual reality on autonomic arousal, and this should be considered at best to be for investigational uses, at present.

Background: Uterine peristalsis occurs in the endometrial–myometrial junctional zone. It is involved in sperm transport and embryo implantation in spontaneous and in vitro fertilization (IVF) cycles. We investigated the reproducibility of transvaginal assessment of peristalsis and endometrial combined thickness (ECT) as a surrogate marker for contraction frequency and directionality. Methods: We studied 74 women undergoing IVF between 2015 and 2018. On day 9 of stimulation, participants had a transvaginal ultrasound to assess follicular development and ECT. Women proceeding to fresh embryo transfer had an ultrasound preprocedure. A videoclip was analyzed for frequency (total contractions per minute) and directionality of contractions (cervical to fundal [CF] and fundal to cervical [FC]). Anonymized images were reviewed on three separate occasions by a single observer. Intraclass correlation (ICC with 95% CI) and Bland–Altman plots were constructed to assess intraobserver agreement. Secondary analysis was performed to assess peristalsis with ECT and pregnancy rates. Results: Between the first and second observations, there was suboptimal correlation between visual assessment of contraction frequency and directionality (ICC–total 0.67 (0.43–0.80) p < 0.001, ICC–CF 0.62 (0.35–0.78), p < 0.001, ICC–FC 0.74 (0.55–0.85), p < 0.001. Correlation for both frequency and directionality significantly improved between second and third viewing (ICC–total 0.97 (0.95–0.98), p < 0.001, ICC–CF 0.84 (0.73–0.91), p < 0.001, ICC–FC 0.89 (0.81–0.94), p < 0.001). Good agreement was seen on Bland–Altman plots with narrower limits of agreement on second and third viewing. Median ECT was 10 mm (interquartile range [IQR] 8–12 mm). Women with ECT [Formula: see text] 10 mm versus Conclusion: Uterine peristalsis is a reproducible observation displaying a learning curve to achieve excellent agreement. Endometrial thickness [Formula: see text]10 mm was associated with increased contraction frequency. There was no association between contraction frequency and/or directionality and clinical pregnancy rates.

The endometrium lines a women's uterus becoming receptive, and allowing embryo implantation to occur, for just a few days during the post-ovulatory mid-secretory phase of each menstrual cycle. We investigated whether concentrations of proposed receptivity biomarkers (VEGF, IL8, FGF2, CSF3 sFlt-1, sGP130 and PlGF) secreted by the endometrium into the uterine cavity and forming the microenvironment for embryo implantation is altered among a population of age-matched women with unexplained (idiopathic) infertility compared to fertile women during the receptive mid-secretory phase (n = 16 fertile, 18 infertile) and the prior pre-receptive early secretory phase (n = 19 fertile, 18 infertile) of their cycle. In the mid-secretory cohort significantly elevated concentrations of five biomarkers; PlGF (p = 0.001), IL8 (p = 0.004), sGP130 (p = 0.009), sFlt-1 (p = 0.021), and CSF3 (p = 0.029) was present in uterine fluid of infertile women during the mid-secretory phase, but only CSF3 was significantly elevated in the pre-receptive early secretory phase (p = 0.006). In vitro studies of glycosylated and non-glycosylated forms of CSF3 at representative fertile (20 ng/mL) and infertile (70 ng/mL) effects on endometrium and embryo behaviour were performed. Non-glycosylated CSF3 at fertile concentrations significantly (p 0.001) elevated endometrial epithelial cell proliferation however chronic treatment or elevated (infertile) concentrations of CSF3 in glycosylated form abrogated the positive effects. Both forms of CSF3 increased trophoblast cell invasion (p 0.001) regardless of concentration. Mouse embryo outgrowth was significantly (p 0.01) increased at fertile but not at infertile concentrations. The study confirmed potential utility of five biomarkers of endometrial receptivity for future application in the mid-secretory phase while highlighting CSF3 is elevated in the earlier pre-receptive phase. Our data provides evidence that CSF3 acts on both human endometrium and embryo in a manner that is concentration and glycosylation dependent.

The regenerative, proliferative phase of a woman's menstrual cycle is a critical period which lays the foundation for the subsequent, receptive secretory phase. Although endometrial glands and their secretions are essential for embryo implantation and survival, the proliferative phase, when these glands form, has been rarely examined. We hypothesized that alterations in the secreted proteome of the endometrium of idiopathic infertile women would reflect a disturbance in proliferative phase endometrial regeneration. Our aim was to compare the proteomic profile of proliferative phase uterine fluid from fertile (n = 9) and idiopathic infertile (n = 10) women. Proteins with ≥2-fold change (P < 0.05) were considered significantly altered between fertile and infertile groups. Immunohistochemistry examined the endometrial localization of identified proteins. Western immunoblotting defined the forms of extracellular matrix protein 1 (ECM1) in uterine lavage fluid. Proteomic analysis identified four proteins significantly downregulated in infertile women compared to fertile women, including secreted frizzled-related protein 4 (SFRP4), CD44, and ECM1: two proteins were upregulated. Seven proteins were unique to the fertile group and six (including isoaspartyl peptidase/L-asparaginase [ASRGL1]) were unique to the infertile group. Identified proteins were classified into biological processes of tissue regeneration and regulatory processes. ASRGL1, SFRP4, and ECM1 localized to glandular epithelium and stroma, cluster of differentiation 44 (CD44) to stroma and immune cells. ECM1 was present in two main molecular weight forms in uterine fluid. Our results indicate a disturbance in endometrial development during the proliferative phase among infertile women, providing insights into human endometrial development and potential therapeutic targets for infertility.Summary SentenceProteomic analysis of proliferative phase uterine fluid in both fertile and infertile women showed significant differences in the secreted proteins including ECM1 which was further studied for its cellular location and hormonal regulation.

There is a lack of consensus on the optimal dose and form of progesterone supplementation during frozen-thawed embryo transfer with hormone replacement therapy.We aim to identify the serum progesterone concentration on day 16 most likely to result in positive pregnancy outcomes.We undertook a retrospective study of 4582 women who underwent frozen embryo transfer with hormone replacement therapy, or natural frozen embryo transfer, over 14 years at a multi-site private in vitro fertilisation clinic. Embryos were 3-5 days of age at time of transfer. We extracted data on serum progesterone concentrations and outcomes, as well as dose and form of progesterone supplementation, from patient and pharmacy records.Increased live birth rates for frozen embryo transfer with hormone replacement therapy were seen with day 16 serum progesterone concentrations50 nmol/L (26.4% vs 11.3% for50 nmol/L; adjusted odds ratio (OR) 3.14 (95% CI 2.21-4.48)). Similarly, a decreased pregnancy loss rate was seen in this group (14.3% vs 32.6% for ≤50 nmol/L; adjusted OR 0.26 (95% CI 0.12-0.58)). There was a positive correlation between live births and the number of progesterone doses per day (r = 0.119, P = 0.026) and day 16 progesterone concentrations (r = 0.128, P = 0.011).Improved pregnancy outcomes are seen with day 16 serum progesterone concentrations50 nmol/L. There is a statistically significant correlation between live births, number of progesterone doses per day and day 16 serum progesterone concentrations in this study.

Background Some past studies have suggested a link between autism spectrum disorder (ASD) and testosterone related cancers. This study explored androgen-related cancer in mothers of children with and without parent-reported ASD in a prospective Australian population based sample. Methods Odds of self-reported breast, uterine and cervical cancer in mothers of children with and without parent-reported ASD in the Longitudinal Study of Australian Children. This prospective population based study contains two cohorts of children recruited at birth or 4 years of age. Results Of 324 children with parent-reported ASD and 6,948 without, there were no significantly increased odds for children with ASD and mother breast (AOR 1.20 [95 % CI .50, 2.87]), uterine (AOR .92 [95 % CI .05, 15.78]), cervical (AOR 1.23 [95% CI .46, 3.25]) or all cancers (AOR 1.13 [95% CI .58, 2.21]). Conclusions This study found no evidence to support an increased or decreased androgen related cancer risk in mothers of children with parent-reported ASD.

External cephalic version (ECV) is associated with a moderate degree of pain. Virtual reality (VR) is a technology that has shown promise in offering procedural analgesia. We undertook a clinical pilot to assess the viability of VR to reduce pain during ECV. In an open randomised controlled trial (RCT), we randomised 50 women to either VR or standard care each (25 per group). Women receiving VR were administered VR content (Skylights) via a headset. Pre- and post-procedural measures of pain, anxiety, device experience and vital signs were measured. There were no significant differences between groups (VR/no VR) in pain scores (60.68 vs 49.76; p = 0.2), ECV success rates (80% vs 76%; p = 0.7) or anxiety levels. The women receiving VR had a significantly higher anticipation of pain pre-procedurally (70.0 vs 50.0; p = 0.03). 20 (80%) of the VR women indicated that they would use VR again and 22 (88%) indicated they would recommend it to a friend having ECV. There were no significant differences between groups for side effects encountered or changes in vital signs. We have shown that using VR during ECV is feasible and appears safe. Our results inform the design of future RCTs.

Research question Does the quality of transferred embryos have an impact on the rate of congenital malformations in IVF/intracytoplasmic sperm injection (ICSI)-conceived babies? Design Retrospective cohort study involving 6637 pregnancies of ≥20 weeks' gestation from women undergoing embryo transfer with a single Day 5 embryo at a private multisite IVF clinic between 2005 and 2015. Embryos were classified as good quality (n = 5537) or poor quality (n = 1100) based on an internal grading system of morphological parameters; malformation rates were compared. Results In pregnancies proceeding to delivery (≥20 weeks' gestation), poor quality embryos were associated with increased odds of at least one anomaly (adjusted odds ratio [OR] 1.33, 95% confidence interval [CI] 1.03–1.71), major anomalies (adjusted OR 1.42, 95% CI 1.05–1.91), musculoskeletal anomalies (adjusted OR 2.09, 95% CI 1.35–3.22), particularly talipes (adjusted OR 2.88, 95% CI 1.33–6.25), and the International Classification of Diseases (ICD) classification ‘Other congenital malformations' (adjusted OR 2.34, 95% CI 1.13–4.34). Furthermore, for pregnancies ≥9 weeks' gestation, poor embryos had more than double the odds of chromosomal anomalies than good embryos (adjusted OR 2.33, 95% CI 1.30–4.18, P = 0.005). Conclusions This is the first study to compare the rates of individual congenital malformations for good and poor quality embryos. It provides insight into potential risks of transferring poor quality embryos. In pregnancies ≥20 weeks' gestation, poor quality Day 5 embryos are associated with major malformations, at least one anomaly, musculoskeletal anomalies, talipes and the ICD classification ‘Other congenital malformations'. In pregnancies ≥9 weeks' gestation, poor quality Day 5 embryos are associated with chromosomal anomalies.

Women are surviving cancer in greater numbers. For this population, fertility becomes an important issue to be discussed before treatment to ensure maximal chances of fertility after treatment completion. Options for fertility preservation include egg or embryo freezing, ovarian tissue freezing, as well as gonadotropin releasing hormone analogs. The option for each individual patient will depend on the type of cancer, its aggressiveness and the time before treatment needs to commence, the type of treatment, the health of the patient, and whether the patient has a male partner.