Prevalence and Associated Risk Factors with Unawareness of Folic Acid Benefits Prior to Pregnancy: Results From Canadian Community Health Survey.

Recent national studies on awareness of folic acid (FA) prior to pregnancy among Canadian women are lacking. Using the 2017-2018 Canadian Community Health Survey, we aimed to estimate prevalence and risk factors associated with Canadian women who reported they were unaware of the benefits of FA supplementation before pregnancy. Prevalence of unawareness of FA was 22.1%. Lower education, lack of a health care provider, low household income, and an immigrant background were associated with greater odds of unawareness of the benefits of FA supplementation. Persistent associations with measures of social disadvantage and social determinants of health emphasize the need for new targeted public health campaigns.

Building Healthy Babies: A Mixed-Methods Needs Assessment for a Pre-Conception Program in Ontario.

OBJECTIVES: The objective of this study was to gather Ontario clinicians' and public members' views on the design of a pre-conception patient education program. METHODS: In this mixed-methods study, online surveys comprised of rank order, multiple choice, and short answer questions were completed by clinicians and public members. Semi-structured focus groups consisting of 2-6 participants each were then held via videoconference. Demographic variables and survey responses were analyzed quantitatively using descriptive and summary statistics. Descriptive thematic qualitative analysis using the constant comparative method of grounded theory was completed on each transcript to generate themes. RESULTS: A total of 168 public members and 43 clinicians in Ontario completed surveys, while 11 clinicians and 11 public members participated in the focus groups. A pre-conception program in Ontario was felt to be important. An individual appointment with a primary care provider was the favoured program format per survey responses, whereas a virtual format with an interactive component was preferred among focus group participants. Important topics to include were pre-conception health (infertility, genetic screening, folic acid), prenatal and postpartum counselling (diet, activity, substance use, prenatal care, postpartum course), and medical optimization in pregnancy (high-risk medical conditions, medications, mental health). Both groups emphasized the need to consider accommodations for marginalized populations and various cultures and languages. CONCLUSION: A standardized pre-conception patient education program is felt to be of high value by Ontario clinicians and public members. A pre-conception program may help improve obstetrical outcomes and decrease rates of major congenital anomalies in Ontario.

Is a day 7 blastocyst predictive of the reproductive potential of sibling day 5 and day 6 blastocysts?

PURPOSE: To explore if a day 7 blastocyst is predictive of the reproductive potential of sibling day 5 or day 6 blastocysts? METHODS: Retrospective cohort of autologous frozen embryo transfers (FET), February 2019 to April 2022. Cycles divided into groups 1 to 5, according to the day of embryo cryopreservation and the presence of a day 7 blastocyst sibling within the cohort: group 1/group 2-day 5 blastocyst without/with a day 7 sibling, group 3/group 4-day 6 blastocyst without/with a day 7 sibling, group 5-day 7 blastocyst. Clinical, ongoing pregnancy and miscarriage rates, cycle, and patient characteristics are reported. Multivariable generalized estimating equations (GEE) logistic regression analysis accounts for confounders and assesses the effect of a sibling day 7 blastocyst on ongoing pregnancy rates of day 5 or day 6 blastocyst FETs. RESULTS: Ongoing pregnancy rates are 38.4%, 59.5%, 30.8%, 32.7%, and 4.4% in groups 1-5, respectively. When correcting for maternal age, number of oocytes retrieved and discarded per cohort, and ploidy, embryos cryopreserved on either day 6 or day 7 have reduced odds of ongoing pregnancy after FET compared to day 5 blastocysts (OR = 0.76, IQR [0.61-0.95], p-value = 0.01). However, the presence of a day 7 sibling does not significantly affect odds of ongoing pregnancy of day 5 or day 6 blastocysts compared to the same-day blastocyst without a day 7 sibling (p-value = 0.20 and 0.46, respectively). This finding is consistent within both the Preimplantation Genetic Testing for Aneuploidy (PGT-A) unscreened and screened (euploid) embryo subgroups. CONCLUSIONS: Day of embryo cryopreservation significantly affects ongoing pregnancy rates. However, day 7 embryos within a cohort do not affect the reproductive potential of sibling day 5 and day 6 blastocysts, suggesting that slow embryo development is an embryo-specific trait.

Maternal Placental Growth Factor (PlGF) levels, sonographic placental parameters, and outcomes of IVF pregnancies with and without embryo trophectoderm biopsy.

PURPOSE: In vitro fertilization (IVF) is associated with abnormal trophoblast invasion and resultant decreased levels of circulating placental biomarkers such as placental growth factor (PlGF). Our objective was to evaluate maternal serum levels of second/third trimester PlGF, sonographic placental parameters, and clinical outcomes among IVF frozen embryo transfer (FET) pregnancies with and without embryo trophectoderm biopsy. METHODS: This was a retrospective study of pregnant patients who conceived using a single frozen embryo transfer (FET) and gave birth between 30 January 2018 and 31 May 2021. We compared PlGF levels, sonographic placental parameters, and clinical outcomes between FET with biopsy and FET without biopsy groups. RESULTS: The median PlGF level was 614.5 pg/mL (IQR 406-1020) for FET pregnancies with biopsy, and 717.0 pg/mL (IQR 552-1215) for FET pregnancies without biopsy. The adjusted mean difference was 190.9 pg/mL lower in the FET biopsy group (95% CI, -410.6, 28.8; p = 0.088). There were no statistically significant differences in placental parameters or clinical pregnancy outcomes. CONCLUSION: This exploratory study demonstrated a possible trend toward lower maternal serum PlGF in the pregnancies conceived with FET using a biopsied embryo. Further investigation is warranted into the potential placental health effects of trophectoderm biopsy.

The effect of the Ontario Fertility Program on IVF utilization and outcomes in women of advanced reproductive age.

RESEARCH QUESTION: Are the demographics and clinical outcomes similar for patients aged ≥40 but <43 years seeking IVF in Ontario, Canada, before and after implementation of the Ontario Fertility Program (OFP), which supports public funding of IVF up to age 43? DESIGN: Retrospective database review using the Canadian Assisted Reproductive Technologies Registry Plus (CARTR Plus) and Better Outcomes Registry & Network (BORN) Ontario databases. Cycles from women who underwent autologous IVF and who were aged ≥40 and <43 years were analysed during a 2-year period prior to (2014-2015) and after (2016-2017) introduction of publicly funded IVF through the OFP. RESULTS: There was an almost doubling of treatment cycles in women aged 40-42 in Ontario after the OFP launch. Clinical pregnancy rate per cycle start (17.0% versus 13.3%, P < 0.001) and cumulative clinical pregnancy rate per stimulation cycle (20.5% versus 16.8%, P < 0.001) were statistically higher in women before OFP implementation. While cumulative live birth rate per cycle start was statistically lower after funding was introduced (12.5% versus 10.5%, P = 0.027), the clinical importance of this difference appears small. Outcomes were above the 10% live birth per cycle threshold recommended by the Advisory Process for Infertility Services panel, commissioned by the Ministry of Health, to determine access to publicly funded IVF. CONCLUSIONS: Use of IVF in women over age 40 doubled with access to OFP funding; however, eligibility criteria based on age still meet the target of achieving a cumulative live birth rate of at least 10%.

Patients' and providers' perspectives on non-urgent egg freezing decision-making: a thematic analysis.

BACKGROUND: The decision to undergo non-urgent egg freezing (EF) is complex for patients and providers supporting them. Though prior studies have explored patient perspectives, no study has also included the separate perspectives of providers. METHODS: This qualitative study involved semi-structured individual interviews exploring the decision to undergo EF. Participants included patients considering EF at one academic fertility clinic and providers who counsel patients about EF from across Canada. Data analysis was accomplished using thematic analysis. Data saturation was met after interviewing 13 providers and 12 patients. FINDINGS: Four themes were identified and explored, illuminating ways in which patients and providers navigate decision-making around EF: (1) patients viewed EF as a 'back-up plan' for delaying the decision about whether to have children, while providers were hesitant to present EF in this way given the uncertainty of success; (2) providers viewed ovarian reserve testing as essential while patients believed it unnecessarily complicated the decision; (3) patients and providers cited a need for change in broader societal attitudes regarding EF since social stigma was a significant barrier to decision-making; and (4) commonality and peer support were desired by patients to assist in their decision, although some providers were hesitant to recommend this to patients. CONCLUSIONS: In conclusion, the decision to undergo EF is complex and individual patient values play a significant role. In some areas, there is disconnect between providers and patients in their views on how to navigate EF decision-making, and these should be addressed in discussions between providers and patients to improve shared decision-making.

Patients' and providers' perspectives on the decision to undergo non-urgent egg freezing: a needs assessment.

BACKGROUND: Previous research has demonstrated that patients have difficulty with the decision to undergo non-urgent egg freezing (EF). This study aimed to investigate the decisional difficulties and possible decisional support mechanisms for patients considering EF, and for their providers. METHODS: This qualitative study involved a needs assessment via individual interviews. Participants included patients considering EF at one academic fertility clinic and providers from across Canada who counsel patients considering EF. 25 participants were included (13 providers and 12 patients). The interview guide was developed according to the Ottawa Decision Support Framework. Interviews were transcribed, and transcripts analyzed for themes and concepts using NVIVO 12. FINDINGS: Multiple factors contributing to decisional difficulty were identified, including: (1) multiple reproductive options available with differing views from patients/providers regarding their importance; (2) a decision typically made under the pressure of reproductive aging; (3) uncertainty surrounding the technology/inadequate outcome data; (4) the financial burden of EF; (5) inherent uncertainty relating to potential decision regret; and (6) differing perceptions between patients/providers regarding the role providers should play in the decision. Additionally, potential sources of decisional support were identified, including provision of basic information before and/or during initial consultation, followed by an opportunity during or after initial consultation for clarifying information and helping with value judgements. Individualized counselling based on patient values, adequate follow-up, psychosocial counselling, and peer support were also emphasized. CONCLUSIONS: More decisional support for women considering EF is needed. Suggestions include a patient decision aid in conjunction with modified healthcare provider counselling, support and follow up.

Deep learning analysis of endometrial histology as a promising tool to predict the chance of pregnancy after frozen embryo transfers.

PURPOSE: Endometrial histology on hematoxylin and eosin (H&E)-stained preparations provides information associated with receptivity. However, traditional histological examination by Noyes' dating method is of limited value as it is prone to subjectivity and is not well correlated with fertility status or pregnancy outcome. This study aims to mitigate the weaknesses of Noyes' dating by analyzing endometrial histology through deep learning (DL) algorithm to predict the chance of pregnancy. METHODS: Endometrial biopsies were taken during the window of receptivity from healthy volunteers in natural menstrual cycles (group A) and infertile patients undergoing mock artificial cycles (group B). H&E staining was performed followed by whole slide image scanning for DL analysis. RESULTS: In a proof-of-concept trial to differentiate group A (n=24) vs. B (n=37), a DL-based binary classifier was trained, cross-validated, and achieved 100% for accuracy. Patients in group B underwent subsequent frozen-thawed embryo transfers (FETs) and were further categorized into "pregnant (n=15)" or "non-pregnant (n=18)" sub-groups based on the outcomes. In the following trial to predict pregnancy outcome in group B, the DL-based binary classifier yielded 77.8% for accuracy. Its performance was further validated by an accuracy of 75% in a "held-out" test set where patients had euploid embryo transfers. Furthermore, the DL model identified histo-characteristics including stromal edema, glandular secretion, and endometrial vascularity as important features related to pregnancy prediction. CONCLUSIONS: DL-based endometrial histology analysis demonstrated its feasibility and robustness in pregnancy prediction for patients undergoing FETs, indicating its value as a prognostic tool in fertility treatment.

Endometrial laminin subunit beta-3 expression associates with reproductive outcome in patients with repeated implantation failure.

PURPOSE: Endometrial laminin subunit beta-3 (LAMB3) is a candidate gene whose expression distinguishes the endometrial window of receptivity (WOR) in human. This study aims to examine endometrial LAMB3 levels in patients with repeated implantation failure (RIF), in order to assess the ability of LAMB3 to predict pregnancy outcome. METHODS: Endometrial biopsies were taken during the WOR from 21 healthy volunteers in natural menstrual cycles and from 50 RIF patients in mock cycles prior to frozen embryo transfer (FET) cycles. Immunohistochemistry (IHC) staining of LAMB3 was performed, and the H-score was correlated with the pregnancy outcome in subsequent FETs. RESULTS: In healthy volunteers, endometrial LAMB3 was demonstrated to be highly expressed during the WOR with the staining exclusively in the cytoplasm of the epithelial cells. In a discovery set of RIF patients, the LAMB3 expression level was found to be significantly higher in those who conceived compared to those who did not in subsequent FETs. A receiving operator characteristic (ROC) analysis revealed an area under the curve (AUC) of 0.7818 (95% confidence interval 59.92-96.44%) with an H-score cutoff of 4.129 to differentiate cases with positive or negative pregnancy outcomes. This cutoff achieved an accuracy of 75% in pregnancy prediction in a following validation set of RIF patients, in which the pregnancy rate in subsequent FETs was three-fold higher when the mock cycle LAMB3 H-score was ≥ 4.129 compared to < 4.129. CONCLUSIONS: IHC measurement of endometrial LAMB3 expression could be a promising prognostic method to predict pregnancy outcome for RIF patients undergoing FETs.

Safety and Assisted Reproductive Technology Outcomes of Hysteroscopic Tubal Microinserts Versus Laparoscopic Proximal Tubal Occlusion or Salpingectomy for Hydrosalpinges Treatment.

OBJECTIVE: This study sought to answer the following question: What are the complications and assisted reproductive technology outcomes among women with hydrosalpinges managed by hysteroscopic microinsert tubal occlusion compared with women with hydrosalpinges managed by laparoscopic proximal tubal occlusion or salpingectomy? METHODS: This was a retrospective cohort study conducted from January 2009 to December 2014 at two academic, tertiary care, in vitro fertilization centres in Toronto, Ontario. All patients (n = 52) who underwent hysteroscopic tubal occlusion for hydrosalpinges were identified. Patients who proceeded with embryo transfer cycles after hysteroscopic microinsert (n = 33) were further age matched to a cohort of patients who underwent embryo transfer after laparoscopic proximal tubal occlusion or salpingectomy (n = 33). Main outcome measures were clinical pregnancy rate per patient and per embryo transfer cycle. RESULTS: Among 33 patients, there were 39 fresh and 37 frozen embryo transfer cycles in the hysteroscopic group (group A); among 33 patients in the laparoscopic group (group B), there were 42 fresh and 29 frozen embryo transfer cycles. The cumulative clinical pregnancy rate in group A and group B was similar (66.7% vs. 69.7%, respectively; P = 0.8). The clinical pregnancy rate per embryo transfer cycle was also similar in both groups (28.9% in group A vs. 32.4% in group B; P = 0.6). There were two incidents of ectopic pregnancy in the laparoscopic group and no ectopic pregnancy in the hysteroscopic group. There were three major complications: tubo-ovarian abscess, distal migration of the coil after microinsert placement, and an acute abdomen following the hysteroscopic procedure. CONCLUSION: Pregnancy outcomes after hysteroscopic placement of a microinsert for hydrosalpinx management before embryo transfer were comparable to those following laparoscopic proximal tubal occlusion or salpingectomy. However, caution is advised regarding microinsert placement for hydrosalpinges before proceeding with assisted reproductive technology.

Expanding Urgent Oncofertility Services for Reproductive Age Women Remote from a Tertiary Level Fertility Centre by Use of Telemedicine and an On-site Nurse Navigator.

The objective of this study was to examine a 1-year pilot program aimed at increasing access to fertility preservation (FP) information and services for reproductive-age women newly diagnosed with cancer at a centre geographically remote from a tertiary fertility clinic. An oncofertility nurse navigator (ONN) position was created within the regional cancer centre with the goals of (1) improving local physician knowledge of FP and FP services and (2) improving patient access to FP counselling and services. The ONN identified all women diagnosed with cancer requiring treatment that could impact their fertility and discussed FP options with them and their physicians. As part of a comprehensive program aimed at facilitating access to FP services, the ONN arranged consultations with fertility specialists via telemedicine and coordinated satellite cycle monitoring with a local gynaecologist in order to minimize travel. Patients were surveyed about their reproductive plans, decision-making around FP and experiences with the program. Physicians were surveyed about their engagement with FP services, barriers to FP access and satisfaction with the program. Twenty-two women were eligible for FP during the year-long pilot program. All participated in the study. The most common diagnoses were breast and cervical cancer. At the time of diagnosis, 36.4% of women had no biological children and 68.2% did not desire (more) children. Four women had an FP consultation, and two proceeded with oocyte or embryo cryopreservation. At the end of the pilot program, more physician respondents often or always discussed FP with their patients, stated they frequently refer for FP consultations and stated their patients could obtain FP services in a timely fashion. An ONN within a cancer centre remote from tertiary fertility care can enable access to FP services with minimal need for travel by using local gynaecologic expertise and telemedicine.

Progesterone, progesterone/estradiol and ART outcomes in day-5 transfer cycles.

The objective of this study was to assess the effects of elevated luteal-phase progesterone levels (PE) and high progesterone/estradiol ratio ('P/E2' ratio) on IVF outcomes, exclusively in GnRH-antagonist cycles with day-5 embryo transfer. PE was not found to have a significant effect on implantation or clinical pregnancy rate (CPR) (OR 0.56, 95% CI 0.25-1.25, p = .16). Elevated 'P/E2' ratio (≥0.55) on trigger day was associated with a poorer response to stimulation and lower clinical pregnancy rates (OR 0.58, 95% CI 0.34-1.00, p = .05). Patients with PE and low 'P/E2' ratio yielded significantly more oocytes than patients with PE and high 'P/E2' ratio. The mean implantation rate per patient decreased by 60% in the group with PE and high 'P/E2' ratio in comparison to the group with PE and low 'P/E2' ratio (17.9%±36.6 vs. 45.5%±47.2, p = .06), although no statistical significance was observed. The detrimental effect of PE may be mitigated by culturing embryos to day-5 before embryo transfer. Combined assessment of serum progesterone and 'P/E2' ratio may predict pregnancy outcome better than progesterone levels alone.

Unexplained Infertility and Undiagnosed Celiac Disease: Study of a Multiethnic Canadian Population.

OBJECTIVE: The aims of this study were to examine the prevalence of Celiac disease (CD) in Canadian women with unexplained infertility versus women with an identifiable cause of infertility and to assess the sensitivity of the point-of-care Biocard Celiac Test Kit versus standard serum serologic testing. METHODS: In this prospective cohort study, women aged 18 to 44 who were evaluated for infertility between February 2010 and May 2012 at a tertiary academic care fertility clinic in Toronto, ON, were invited to participate. They were categorized as having unexplained infertility (Cases) or infertility secondary to a known cause (Controls). Women on a gluten-free diet or previously diagnosed with CD were excluded. Outcome measures were the Celiac Questionnaire, serum testing for tissue transglutaminase IgA antibody (anti-tTG IgA), serum IgA levels, and Biocard Celiac Test Kit. RESULTS: Of 685 women approached, 1.2% (4/326) with unexplained infertility and 1.1% (4/359) with an identifiable infertility cause were newly found to have CD. Biocard testing revealed the same results as standard serologic IgA and anti-tTG IgA testing. CONCLUSION: CD was not more common in women with unexplained infertility than those with an identifiable cause of infertility. These results do not support the routine screening of Canadian women with infertility for CD.

Oocyte cryopreservation in Canada: a survey of Canadian ART clinics.

OBJECTIVE: To determine the status of oocyte cryopreservation in Canadian assisted reproductive technology (ART) clinics. METHODS: An online survey was sent to the medical directors of all Canadian ART clinics between December 2010 and February 2011. The survey included questions about the availability of, the indications for, and the elements of consent for oocyte cryopreservation. Clinics were also asked whether they offered social egg freezing. RESULTS: Twenty of the 28 Canadian ART clinics (71.4%) participated in this survey, and 16 (80%) of those clinics offered oocyte cryopreservation. Forty-five percent of the clinics offered elective oocyte cryopreservation (social egg freezing) for healthy women seeking to prolong fertility. Although most clinics counselled patients that oocyte cryopreservation is experimental, most clinics (87.5%) did not perform the procedure under a protocol approved by a research ethics board. The majority of clinics included most of the essential elements of informed consent during their counselling process. Most clinics that offered social egg freezing performed the procedure for women up to the age of 42, although some clinics did not offer the procedure for women under the age of 35 (28.6%) or over the age of 38 (42.9%). CONCLUSION: More than one half of Canadian ART clinics are offering oocyte cryopreservation, although not all clinics offer social egg freezing for healthy women to prolong fertility. Most clinics described the technique as experimental, and the majority included most of the elements of informed consent in their counselling process.

Fertility preservation practices among Ontario oncologists.

This study explores the attitudes, knowledge, and referring behaviors in fertility preservation among Ontario physicians providing adult cancer care. Ontario physicians with specialties in medical oncology, radiation oncology, gynaecologic oncology, and urology were invited to complete a 48-item questionnaire. A total of 152 questionnaires were available for analysis with a response rate of 23.7%. Seventy-four percent of the physicians indicated that they rarely or never modified cancer treatment due to concern about future fertility. Differences were found in fertility preservation knowledge among respondents in different medical specialties (p < 0.01) and clinical settings (p < 0.05). The frequency of initiating a referral was strongly associated with knowing where to refer patients (p < 0.001). The odds of knowing where to refer cancer patients was higher for physicians who work in a teaching hospital (p < 0.01) and a cancer centre (p < 0.01) compared with those who primarily work in a community setting. About 45% did not know where to refer female patients, and 69.7% rarely ever made a fertility preservation consultation referral for their female patients. The majority of respondents had positive attitudes despite their lack of current knowledge in cryopreservation services and fertility preservation options through assisted reproductive technologies. Our findings provide further insights of the relevance of considering physicians' medical backgrounds and practice settings when designing training modules to raise their awareness in fertility preservation issues.

Anti-mullerian hormone (AMH) reference values in the CALIPER cohort of healthy community children and adolescents.

The assessment of anti-mullerian hormone (AMH) pre- and post-gonadotoxic treatment helps define reproductive potential in young female adults facing cancer treatment. Normative childhood AMH levels are not well defined. Our objective was to help establish accurate pediatric reference intervals (RIs) for which AMH can be used to assess AMH in pediatric/adolescent survivors. Healthy female volunteers aged 6-<19 years were recruited from the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort. 300 serum samples were analyzed for AMH using an automated assay. Basic demographics and menstrual cycle data on the subjects were recorded at time of sample collection. Serum AMH distribution and RIs (2.5th and 97.5th percentiles) were established in four age groups. One recommended RI (0.98-7.84 ng/mL) was established for females aged 6-<19 years after outlier removal. Females 6-<9 years demonstrated significantly lower mean AMH concentration than did females 9-<12 years (Mean ± SD: 3.18 ± 1.62 and 4.16 ± 2.55 ng/mL, respectively), who in turn demonstrated significantly higher AMH concentrations than those aged 12-<15 years (Mean ± SD: 3.75 ± 1.61 ng/mL). Statistical differences are unlikely to be clinically meaningful. Menstrual status and ethnicity did not significantly impact AMH concentrations (p = 0.787 and p = 0.0965, respectively). This is the largest series of its kind using a contemporary, automated, single-batched AMH assay in a healthy pediatric female cohort. In conjunction with future data points and longitudinal data, the RI established may be a useful adjunct to reproductive health counselling delivered to pediatric cancer patients requiring fertility damaging therapies.

Cargo small non-coding RNAs of extracellular vesicles isolated from uterine fluid associate with endometrial receptivity and implantation success.

OBJECTIVE: To optimize a method of isolating extracellular vesicles (EVs) from uterine fluid and to characterize small non-coding RNAs (sncRNAs) from the EVs, with the goal of identifying novel receptivity-associated biomarkers. DESIGN: Longitudinal study comparing sncRNA expression profiles from endometrial EVs. SETTING: University-affiliated, hospital-based fertility clinic. PATIENT(S): Healthy volunteers with no history of infertility (Group A) and women receiving controlled ovarian stimulation (COS)-in vitro fertilization treatment (Group B). INTERVENTIONS(S): In Group A, EVs were isolated from uterine fluid obtained on luteinizing hormone (LH)+2 and LH+7 in one natural menstrual cycle. In Group B, EVs were isolated from uterine fluid obtained on human chorionic gonadotropin (hCG)+2 and hCG+7 in one COS cycle. RNAs extracted from EVs were profiled using next-generation sequencing. MAIN OUTCOME MEASURE(S): Differential EV-sncRNAs between LH+2 and LH+7 (Group A), between hCG+2 and hCG+7 (Group B), and between pregnant and nonpregnant in vitro fertilization cycles (Group B). RESULT(S): Ultracentrifugation was validated as the most efficient method to isolate EVs from uterine fluid. We identified 12 endometrial EV-sncRNAs (11 microRNAs and 1 piwi-interacting RNA) as receptivity-associated transcripts conserved in both natural and COS cycles. These sncRNAs were associated strongly with biological functions related to immune response, extracellular matrix, and cell junction. Within COS cycles, we also identified a group of EV-sncRNAs that exhibited differential expression in patients who conceived versus those who did not, with hsa-miR-362-3p most robustly overexpressed in the nonpregnant patients. CONCLUSION(S): This study is the first to profile comprehensively sncRNAs in endometrial EVs from uterine fluid and identify sncRNA biomarkers of endometrial receptivity and implantation success.

Comparing endometrial receptivity array to histologic dating of the endometrium in women with a history of implantation failure.

For patients with recurrent implantation failure in IVF, histologic or transcriptomic testing of the endometrium during the mid-secretory phase is often considered. Histological dating of endometrial biopsies (Noyes criteria) can determine if endometrial morphology is consistent with the period of receptivity. Alternatively, endometrial tissue can be sent for a commercial Endometrial Receptivity Array (ERA) test which characterizes the gene expression of the endometrium using a panel of 238 genes that have been implicated in endometrial receptivity. This study aimed to compare the two tests to assess their concordance and to examine the ability of the ERA to successfully predict implantation and pregnancy in a subsequent personalized embryo transfer. A retrospective review was done of 97 patients with a history of implantation failure who underwent an ERA, 35 of whom had histologic dating on the same sample. ERA and histology were classified as 'concordant' when samples were receptive by both tests or non-receptive by both tests. The ERA result was then used to personalize the embryo transfer day, and pregnancy rates from the first subsequent frozen transfer cycle were analyzed. The results indicated that there is poor concordance between ERA and histological dating with only 40.0% agreement and a kappa (95%CI) = -0.18 (-0.50, 0.14). According to the ERA, 48.5% of biopsies were receptive, 47.4% were non-receptive and 2.01% were insufficient tissue for analysis. The clinical pregnancy rate in patients shown to be receptive by ERA was 26.7% and non-receptive was 22.5% following the subsequent personalized ET (p = 0.66). This study concludes that there is a high degree of discordance between histological dating of the endometrium and molecular analysis by ERA. There was no evidence of clinical benefit when embryo transfer was personalized according to ERA in patients with a history of implantation failure.