Delineating the heterogeneity of embryo preimplantation development using automated and accurate morphokinetic annotation.

PURPOSE: Our objective was to design an automated deep learning model that extracts the morphokinetic events of embryos that were recorded by time-lapse incubators. Using automated annotation, we set out to characterize the temporal heterogeneity of preimplantation development across a large number of embryos. METHODS: To perform a retrospective study, we used a dataset of video files of 67,707 embryos from four IVF clinics. A convolutional neural network (CNN) model was trained to assess the developmental states that appear in single frames from 20,253 manually-annotated embryos. Probability-weighted superposition of multiple predicted states was permitted, thus accounting for visual uncertainties. Superimposed embryo states were collapsed onto discrete series of morphokinetic events via monotonic regression of whole-embryo profiles. Unsupervised K-means clustering was applied to define subpopulations of embryos of distinctive morphokinetic profiles. RESULTS: We perform automated assessment of single-frame embryo states with 97% accuracy and demonstrate whole-embryo morphokinetic annotation with R-square 0.994. High quality embryos that had been valid candidates for transfer were clustered into nine subpopulations, as characterized by distinctive developmental dynamics. Retrospective comparative analysis of transfer versus implantation rates reveals differences between embryo clusters as marked by poor synchronization of the third mitotic cell-cleavage cycle. CONCLUSIONS: By demonstrating fully automated, accurate, and standardized morphokinetic annotation of time-lapse embryo recordings from IVF clinics, we provide practical means to overcome current limitations that hinder the implementation of morphokinetic decision-support tools within clinical IVF settings due to inter-observer and intra-observer manual annotation variations and workload constrains. Furthermore, our work provides a platform to address embryo heterogeneity using dimensionality-reduced morphokinetic descriptions of preimplantation development.

Embryo classification beyond pregnancy: early prediction of first trimester miscarriage using machine learning.

PURPOSE: First trimester miscarriage is a major concern in IVF-ET treatments, accounting for one out of nine clinical pregnancies and for up to one out of three recognized pregnancies. To develop a machine learning classifier for predicting the risk of cleavage-stage embryos to undergo first trimester miscarriage based on time-lapse images of preimplantation development. METHODS: Retrospective study of a 4-year multi-center cohort of 391 women undergoing intra-cytoplasmatic sperm injection (ICSI) and fresh single or double embryo transfers. The study included embryos with positive indication of clinical implantation based on gestational sac visualization either with first trimester miscarriage or live-birth outcome. Miscarriage was determined based on negative fetal heartbeat indication during the first trimester. Data were recorded and obtained in hospital setting and research was performed in university setting. RESULTS: A minimal subset of six non-redundant morphodynamic features were screened that maintained high prediction capacity. Features that account for the distribution of the nucleolus precursor bodies within the small pronucleus and pronuclei dynamics were highly predictive of miscarriage outcome as evaluated using the SHapley Additive exPlanations (SHAP) methodology. Using this feature subset, XGBoost and random forest models were trained following a 100-fold Monte-Carlo cross validation scheme. Miscarriage was predicted with AUC 0.68 to 0.69. CONCLUSION: We report the development of a decision-support tool for identifying the embryos with high risk of miscarriage. Prioritizing embryos for transfer based on their predicted risk of miscarriage in combination with their predicted implantation potential is expected to improve live-birth rates and shorten time-to-pregnancy.

The effect of hyaluronic acid in embryo transfer media in donor oocyte cycles and autologous oocyte cycles: a systematic review and meta-analysis.

STUDY QUESTION: Does the addition of hyaluronic acid (HA) to embryo transfer medium improve pregnancy outcomes in both autologous and oocyte donation IVF cycles? SUMMARY ANSWER: The best available evidence indicates that the addition of HA to embryo transfer medium is clinically beneficial in cycles with autologous oocytes. WHAT IS KNOWN ALREADY: There is a known clinical benefit of HA addition to embryo transfer media but it is not known if HA affects donor and autologous oocyte cycles differently. STUDY DESIGN, SIZE, DURATION: A systematic review with meta-analysis was performed. The Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL via Cochrane Register of Studies Online (CRSO), MEDLINE, Embase and PsycINFO electronic databases (until 8 January 2020) were searched for randomized controlled trials (RCTs) examining the effect of HA in embryo transfer medium on pregnancy outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: RCTs with separate donor and autologous oocyte data that compared embryo transfer medium with functional HA concentrations (0.5 mg/ml) to those containing no or low HA concentrations (0.125 mg/ml) were included. Two review authors independently selected trials for inclusion, extracted data and assessed the included studies using the Cochrane risk of bias assessment tool. Pooled risk ratios and 95% CIs were calculated. A summary of findings table was generated using Grading of Recommendations, Assessment, Development and Evaluation criteria. Judgements about evidence quality were justified and incorporated into the reported results for each outcome. MAIN RESULTS AND THE ROLE OF CHANCE: Fifteen studies, totalling 4686 participants, were analysed. In autologous oocyte cycles, live birth increased from 32% to 39% when embryo transfer media contained functional HA concentrations (risk ratio (RR) 1.22, 95% CI 1.11-1.34; nine studies, 3215 participants, I2 = 39%, moderate-quality evidence (number needed to treat (NNT) 14). HA-enriched media increased clinical pregnancy and multiple pregnancy rates by 5% and 8%, respectively (RR 1.11, 95% CI 1.04-1.18; 13 studies, 4014 participants, I2 = 0%, moderate-quality evidence, NNT 21) and (RR 1.49, 95% CI 1.27-1.76; 5 studies, 2400 participants, I2 = 21%, moderate-quality evidence, number needed to harm 13). Conversely, in donor oocyte cycles, HA addition showed little effect on live birth and clinical pregnancy (RR 1.12 95% CI 0.86-1.44; two studies, 317 participants, I2 = 50%, low-quality evidence) and (RR 1.06, 95% CI 0.97-1.28; three studies, 351 participants, I2 = 23%, low-quality evidence). There was insufficient available information on multiple pregnancy in donor oocyte cycles and on total adverse effects in both groups to draw conclusions. LIMITATIONS, REASONS FOR CAUTION: There were limited studies with separate data on donor oocyte cycles and limited information on oocyte quality. Additionally, one-third of the included studies did not include the main outcome, live birth rate. WIDER IMPLICATIONS OF THE FINDINGS: There is a moderate level of evidence to suggest that functional HA concentration in embryo transfer medium increases clinical pregnancy, live birth and multiple pregnancy rates in IVF cycles using autologous oocytes. This effect was not seen in donor oocyte cycles, indicating either intrinsic differences between donor and autologous oocytes or lack of statistical power. The combination of HA addition to transfer media in cycles using autologous oocytes and a single embryo transfer policy might yield the best combination, with higher clinical pregnancy and live birth rates without increasing the chance of multiple pregnancies. STUDY FUNDING/COMPETING INTEREST(S): No financial assistance was received. The authors have no competing interests. REGISTRATION NUMBER: N/A.

Spontaneous in vitro hatching of the human blastocyst: the proteomics of initially hatching cells.

Spontaneous in vitro hatching of human blastocysts starts with the formation of a tunnel through the zona pellucida (ZP) by cellular projections of trophoblast cells. Our aim was to identify the proteins that are upregulated in these initially hatching cells as compared to trophectoderm (TE) cells from blastocysts that had not yet hatched. Forty seven women that underwent assisted reproduction treatment donated their ICSI-derived polyploid blastocysts for the study. In polyploid blastocysts that started spontaneous hatching, hatched clusters of cells were collected from the outer side of the ZP. Liquid chromatography mass spectrometry was applied to determine the proteins that were upregulated in these cells as compared to TE cells obtained from inside the ZP. Whole non-hatched polyploid blastocysts were used as controls. Overall 1245 proteins were identified in all samples. Forty nine proteins were significantly upregulated in hatching cells and 17 in the TE cells. There was minimal overlap between hatching and TE samples; only serine protease inhibitors (SERPINS) and lipocalin were detected in both samples. Myosin and actin were highly upregulated in the hatching cells as well as paraoxonase, N-acetylmuramoyl alanine amidase, and SERPINS clade A and galectin. In the TE cells, gamma butyrobetaine dioxygenase, lupus La protein, sialidase, lysosomal Pro-X carboxypeptidase, phospholipase b, and SERPINS clade B and A were among the most highly upregulated proteins. These findings may contribute to the basic knowledge of the molecular behavior of the specific cells that actively perforate the glycoprotein matrix of the ZP.

Hyaluronic acid in embryo transfer media for assisted reproductive technologies.

BACKGROUND: This is an update of a Cochrane Review first published in the Cochrane Library (2010, Issue 7). To increase the success rate of assisted reproductive technologies (ARTs), adherence compounds such as hyaluronic acid (HA) have been introduced into subfertility management. Adherence compounds are added to the embryo transfer medium to increase the likelihood of embryo implantation, with the potential for higher clinical pregnancy and live birth rates. OBJECTIVES: To determine whether adding adherence compounds to embryo transfer media could improve pregnancy outcomes, including improving live birth and decreasing miscarriage, in women undergoing assisted reproduction. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE, Embase, and PsycINFO electronic databases on 7 January 2020 for randomised controlled trials that examined the effects of adherence compounds in embryo transfer media on pregnancy outcomes. Furthermore, we communicated with experts in the field, searched trials registries, checked reference lists of relevant studies, and conference abstracts were handsearched. SELECTION CRITERIA: Only truly randomised controlled trials comparing embryo transfer media containing functional concentrations of adherence compounds to media with no or low adherence compound concentrations were included. DATA COLLECTION AND ANALYSIS: Two review authors selected trials for inclusion according to the above criteria, after which the same two review authors independently extracted data for subsequent analysis. Statistical analysis was performed according to the guidelines developed by Cochrane. We combined data to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I² statistic. We used GRADE methods to assess the overall quality of evidence for the main comparisons. MAIN RESULTS: We analysed 26 studies with a total of 6704 participants. Overall, the certainty of evidence was low to moderate: the main limitations were imprecision and/or heterogeneity. Compared to embryos transferred in media containing no or low (0.125 mg/mL) HA, the addition of functional (0.5 mg/mL) HA concentrations to the transfer media probably increases the live birth rate (RR 1.21, 95% CI 1.1 to 1.31; 10 RCTs, N = 4066; I² = 33%; moderate-quality evidence). This suggests that if the chance of live birth following no HA addition in media is assumed to be 33%, the chance following HA addition would be between 37% and 44%. The addition of HA may slightly decrease miscarriage rates (RR 0.82, 95% CI 0.67 to 1.00; 7 RCTs, N = 3091; I² = 66%; low-quality evidence). Nevertheless, when only studies with low risk of bias were included in the analysis, there was no conclusive evidence of a difference in miscarriage rates (RR 0.96, 95% CI 0.75 to 1.23; N = 2219; I² = 36%). Adding HA to transfer media probably results in an increase in both clinical pregnancy (RR 1.16, 95% CI 1.09 to 1.23; 17 studies, N = 5247; I² = 40%; moderate-quality evidence) and multiple pregnancy rates (RR 1.45, 95% CI 1.24 to 1.70; 7 studies, N = 3337; I² = 36%; moderate-quality evidence). We are uncertain of the effect of HA added to transfer media on the rate of total adverse events (RR 0.86, 95% CI 0.40 to 1.84; 3 studies, N = 1487; I² = 0%; low-quality evidence). AUTHORS' CONCLUSIONS: Moderate-quality evidence shows improved clinical pregnancy and live birth rates with the addition of HA as an adherence compound in embryo transfer media in ART. Low-quality evidence suggests that adding HA may slightly decrease miscarriage rates, but when only studies at low risk of bias were included in the analysis, the results were inconclusive. HA had no clear effect on the rate of total adverse events. The increase in multiple pregnancy rates may be due to combining an adherence compound and transferring more than one embryo. Further studies of adherence compounds with single embryo transfer need to be undertaken.

Is there a pre-retrieval serum human chorionic gonadotrophin (hCG) threshold level for prediction of subsequent retrieval outcomes and pregnancy in fresh ICSI cycles?

Modern ICSI (intracytoplasmic sperm injection) cycles' outcomes are difficult to predict. Whether human chorionic gonadotrophin (hCG) or luteinizing hormone (LH) serum levels 24 h prior to oocyte retrieval are correlated with retrieval and subsequent cycle results is unclear. An observational historic cohort study of 645 fresh ICSI cycles was conducted. After controlled oocyte stimulation, and 10-12 h after a self-administered trigger, serum levels of hCG (hCG trigger n = 563) and LH (GnRHa trigger n = 82) were measured. Correlations between pre-retrieval hormone levels and cycle results were assessed. No correlation (p > .12) was found between serum pre-retrieval hCG levels or LH levels (in GnRHa-triggered cycles) and total oocytes, M2, M1 + M2 or oocyte maturity rates (OMR) for any of the stimulation protocols. ROC (receiver operator curve) analysis for fertilization rates showed a possible cutoff for LH levels. Pregnancy rates (PR) were higher in rising hCG groups; a cutoff of 117 IU/L was associated with an increase in PR (30.9% to 45.6%) and a moderate sensitivity and specificity (60.6% and 55.0%). However, HCG was not predictive of pregnancy in a logistic regression model. We conclude that preretrieval hCG serum levels are not useful for pre-retrieval estimation of aspiration results but might have a role in prediction of pregnancy.

Worldwide live births following the transfer of chromosomally "Abnormal" embryos after PGT/A: results of a worldwide web-based survey.

PURPOSE: Preimplantation genetic testing for aneuploidy (PGT-A) has become increasingly controversial since normal euploid births have been reported following transfer of embryos diagnosed as "abnormal." There is an increasing trend in transferring "abnormal" embryos; but it is still unknown how many IVF centers transfer "abnormal" embryos and with what efficiency. METHODS: We performed a worldwide web-survey of IVF centers to elucidate PGT-A related practice patterns including transfer of human embryos found "abnormal" by PGT-A. Participating centers reflected in vitro fertilization (IVF) cycles in the USA, Canada, Europe, Asia, South America, and Africa. RESULTS: One hundred fifty-one IVF centers completed the survey; 125 (83%) reported utilization of PGT-A. Europe had the highest utilization (32.3%), followed by the USA and Canada combined at 29.1%. The leading indications for PGT-A were advanced maternal age (77%), followed by recurrent implantation failure (70%), unexplained pregnancy loss (65%), and sex determination (25%); 14% of respondents used PGT-A for all of their IVF cycles; 20% of IVF units reported transfers of chromosomally "abnormal" embryos, and 56% of these took place in the USA, followed by Asia in 20%. Remarkably, 106 (49.3%) cycles resulted in ongoing pregnancies (n = 50) or live births (n = 56). Miscarriages were rare (n = 20; 9.3%). CONCLUSIONS: The transfers of "abnormal" embryos by PGT-A offered robust pregnancy and live birth chances with low miscarriage rates. These data further strengthen the argument that PGT-A cannot reliably determine which embryos should or should not be transferred and leads to disposal of many normal embryos with excellent pregnancy potential.

Fertility preservation from the point of view of hematopoietic cell transplant specialists-a worldwide-web-based survey analysis.

With the increase in cancer survival, men and women have a chance to conceive children post-recovery. This study aims to better understand hematopoietic cell transplant (HCT) specialist practices and opinions related to fertility preservation for hematological malignancy patients. Survey requests were emailed to 586 European Society for Blood and Marrow Transplantation (EBMT) members. Respondents completed the mostly multiple-choice questionnaire on the IVF-Worldwide.com website. Results were reported as a percentage of respondents. Responses were submitted by 150 HCT specialists from 41 (of 195) countries worldwide. The survey showed that most HCT specialists (87%) are aware of and inform patients that chemotherapy, radiotherapy, and transplantation could harm fertility. Specialists referred 56% of their male patients to fertility preservation but only 36% of their female patients; many pre-pubertal or near post-menopausal patients were not referred. This indicates that barriers may be preventing specialists from referring patients for fertility preservation. Many HCT specialists do not know about or use international fertility preservation recommendations, indicating that new protocols for enhancing awareness are needed. Establishing a referral process protocol to reproductive specialists should be considered. When non-urgent treatment can be deferred for 10-20 days, patients can have a sufficient window to undergo certain fertility preservation procedures.

Oncofertility: insights from IVF specialists-a worldwide web-based survey analysis.

PURPOSE: This research sought to understand IVF-physicians' knowledge of, experience with, and attitudes toward fertility preservation for cancer patients. METHODS: A 35-question, self-report survey request was emailed to IVF providers who were registered on the IVF-Worldwide.com network (3826 clinics). Physicians submitted responses on the IVF-Worldwide.com website. Survey results were reported as a proportion of the responding clinics. RESULTS: Survey responses were completed by 321 (8.4%) globally distributed IVF clinics, representing 299,800 IVF cycles. Of these clinics, 86.6% (278) performed fertility preservation, treating approximately 6300 patients annually. However, 18.4% of the centers reported that patients sought advice independently, without an oncologist's referral. Ovarian tissue cryopreservation was performed by 37.7% of the clinics, yet 52.6% considered the procedure experimental. IVM was performed by 16.5% of responding clinics. A majority (63.6%) of the clinics selected treatment protocols based on each patient's malignancy. Most respondents (76.3%) disagreed that fertility preservation was not yet successful enough to make it an available option. However, 44.2% believed that pregnancy rates following oocyte cryopreservation could not be determined because not enough oocyte cryopreservation patients had completed embryo transfer. CONCLUSIONS: Most clinics performed fertility preservation, tailoring protocols to each patient's disease and condition. Almost 20% of patients sought advice independently, indicating that more effort is needed to encourage oncologists to refer patients. Most survey respondents believed that data was not yet available on either live birth outcomes or the best protocol for each disease. Therefore, long-term study must continue, with the establishment of interim milestones and an outcome-tracking registry.

Preimplantation genetic screening: results of a worldwide web-based survey.

Our objective was to evaluate and characterize the extent and patterns of worldwide usage of preimplantation genetic screening (PGS) among the assisted reproductive technique community. A prospective, web-based questionnaire with questions relating to practices of, and views on, PGS was directed to users and non-users of PGS. A total of 386 IVF units from 70 countries conducting 342,600 IVF cycles annually responded to the survey. A total of 77% of respondents routinely carry out PGS in their clinics for a variety of indications: advanced maternal age (27%), recurrent implantation failure (32%) and recurrent pregnancy loss (31%). Few (6%) offer PGS to all their patients. In most cycles (72%), trophectoderm biopsy is carried out and either array-comparative genomic hybridization (59%) or next-generation sequencing (16%) are used for genetic analysis. Only 30% of respondents regard PGS as clearly evidenced-based, and most (84%) believe that more randomized controlled trials are needed to support the use of PGS. Despite ongoing debate and lack of robust evidence, most respondents support the use of PGS, and believe that it may aid in transferring only euploid embryos, thereby reducing miscarriage rates and multiple pregnancies, increasing live birth rates and reducing the risk of aneuploid pregnancies and births.

Use of various gonadotropin and biosimilar formulations for in vitro fertilization cycles: results of a worldwide Web-based survey.

PURPOSE: The purpose of this study was to identify trends in gonadotropin therapy in patients undergoing in vitro fertilization (IVF) treatment worldwide. METHODS: Retrospective evaluation utilizing the results of a Web-based survey, IVF-Worldwide ( www.IVF-worldwide.com ) was performed. RESULTS: Three hundred fourteen centers performing a total of 218,300 annual IVF cycles were evaluated. Respondents representing 62.2% of cycles (n = 135,800) did not believe there was a difference between urinary and recombinant gonadotropins in terms of efficacy and live birth rate. Of the respondents, 67.3% (n = 146,800) reported no difference between recombinant and urinary formulations in terms of short-term safety and risk of ovarian hyperstimulation syndrome. In terms of long-term safety using human urinary gonadotropins, 50.6% (n = 110,400) of respondents believe there are potential long-term risks including prion disease. For 95.3% of units (n = 208,000), the clinician was the decision maker determining which specific gonadotropins are used for IVF. Of the units, 62.6% (n = 136,700) identified efficacy as the most important factor in deciding which gonadotropin to prescribe. While most (67.3%, n = 146,800) were aware of new biosimilar recombinant FSH products entering the market, 92% (n = 201,000) reported they would like more information. A fraction of respondents (25.6%, n = 55,900) reported having experience with these new products, and of these, 80.3% (n = 46,200) reported that they were similar in efficacy as previously used gonadotropins in a similar patient group. CONCLUSIONS: Respondents representing the majority of centers do not believe a difference exists between urinary and recombinant gonadotropins with respect to efficacy and live birth rates. While many are aware of new biosimilar recombinant FSH products entering the market, over 90% desire more information on these products.

Chromosomal mosaicism detected during preimplantation genetic screening: results of a worldwide Web-based survey.

Embryonic mosaicism, the presence of more than one distinct cell line within an embryo, has recently become the focus of growing attention and controversy in the context of preimplantation genetic screening (PGS). To evaluate the extent of mosaic aneuploidy in clinical practice and to gain insight on the practices and views regarding this issue, we conducted a survey using a prospective, 20-item Web-based questionnaire with questions related to practices and views regarding mosaicism in PGS. A total of 102 in vitro fertilization (IVF) units from 32 countries that performed 108,900 IVF cycles annually responded to the survey. More than half responded that embryonic mosaic aneuploidy is reported by the laboratory, but 31.9% stated that samples are reported as euploid or aneuploid only. If mosaic aneuploidy is reported, 46% stated that it was present in ≤10% of the embryos. More than two-thirds were of the opinion that next-generation sequencing is required to reliably detect mosaicism. Among centers performing PGS, 47.9% consider embryonic mosaicism when detected in >20% of the cells, and nearly two-thirds believe that mosaic aneuploid embryos should be stored for potential therapeutic use after extensive and appropriate counseling. In summary, mosaicism has always existed in preimplantation embryos, and new technologies can now detect its presence with higher resolution. More studies are needed before definite conclusions can be drawn.

Ratio between inner cell mass diameter and blastocyst diameter is correlated with successful pregnancy outcomes of single blastocyst transfers.

OBJECTIVE: To evaluate the ability to predict pregnancy outcomes of single-blastocyst transfers by measuring the ratio of inner cell mass (ICM) diameter to blastocyst diameter using time-lapse images. DESIGN: Retrospective cohort study. SETTING: University-affiliated medical center. PATIENT(S): One hundred twenty-seven women undergoing a total of 129 blastocyst transfers with intracytoplasmic sperm injection. INTERVENTION(S): Embryo monitoring by time-lapse microscopy. MAIN OUTCOME MEASURE(S): The ratio of ICM diameter to blastocyst diameter in single-blastocyst transfers and clinical pregnancy rates. RESULT(S): In phase I of the study, 63 women underwent 65 single blastocyst transfers that resulted in 25 pregnancies (40% of the women). The successfully implanted blastocysts had an average ICM/blastocyst diameter ratio of 0.487 ± 0.086, whereas the average ICM/blastocyst ratio of nonimplanted blastocysts was significantly lower (0.337 ± 0.086). The live-birth rate was 29% (18/63). In phase II, 64 single-blastocyst transfers were performed in 64 women. The ICM/blastocyst diameter ratio was measured, and blastocysts with the highest ratios were chosen for transfer. Forty-three women (67%) with an average ICM/blastocyst diameter ratio of 0.46 achieved pregnancy, and 36 of the 43 pregnancies (84%) resulted in the delivery of a healthy baby. In the 21 women (33%) who failed to achieve pregnancy, the average ICM/blastocyst ratio was 0.45. The resultant positive predictive value was 74%, and the negative predictive value was 70%. CONCLUSION(S): The ICM-to-blastocyst diameter ratio is a predictor of implantation and live birth in single-blastocyst transfers, offering a simple, noninterfering method to select blastocysts with high developmental capacity.

Minimizing the Risk of Infection and Bleeding at Trans-Vaginal Ultrasound-Guided Ovum Pick-up: Results of a Prospective Web-Based World-Wide Survey.

OBJECTIVE: The objective of this study was to identify clinical practices worldwide, which would help in recognizing women at risk of excessive bleeding or of developing pelvic infection following trans-vaginal ovum pick-up (TV-OPU), measures taken to minimize risks and their management. METHOD: A prospective, web-based questionnaire with distinct questions related to the practice of TV-OPU. RESULTS: A total of 155 units from 55 countries performing 97,200 IVF cycles annually responded to this web-based survey. A majority (65 %) responded that they would routinely carry out full blood count, while 35 % performed coagulation profile. Less than a third agreed screening women for vaginal infections. About a third used both sterile water and antiseptic to minimize ascending infection, and 52 % used antibiotics for prophylaxis. Doppler ultrasound was routinely used by 20 % of clinicians. 73 % of the clinicians preferred conservative management as their first line management for patients diagnosed with intra-abdominal bleeding. CONCLUSION: The study has identified a wide variation in the practices of minimizing infection and bleeding complications. The dearth of good quality evidence may be responsible for the lack of published guidelines, and therefore a lack of consensus on the optimum practice for minimizing the risk of infection and bleeding during TV-OPU.

Irregular cleavage of early preimplantation human embryos: characteristics of patients and pregnancy outcomes.

PURPOSE: This is a retrospective analysis of the morphokinetics, prevalence, and implantation potential of embryos with irregular first and second cleavages as identified by time-lapse microscopy. METHODS: The study included 253 women who underwent 387 assisted reproduction treatments with intracytoplasmic sperm injection (ICSI). Each patient was assigned to one of three groups based on embryo cleavage results. In group I, one to two embryos per cycle showed irregular cleavage; group II, at least three embryos with abnormal cleavage; and in group III (the control group), all embryos cleaved normally. The number of embryos that cleaved from 1 to ≥3 cells or from 2 to ≥5 cells for each patient was recorded. Their prevalence and association with women's characteristics and pregnancy outcome were evaluated. RESULTS: The prevalence of irregular cleavage was 15.6 % among 1772 ICSI embryos. In 101 cycles, 1-2 embryos per cycle showed irregular cleavage (group I). In 32 cycles, at least 3 embryos showed abnormal cleavage (group II). In 254 cycles, all embryos cleaved normally (group III). The average age of the women in group II was significantly lower in comparison with groups I and III (32.5 ± 4.2 vs. 35.1 ± 4.9 and 35.5 ± 5.1, respectively, p < 0.02). In comparison of groups I and II, the odds ratio for ≥3 embryos with irregular cleavage in women younger than 35 was 3.48 (95 % CI, 1.28 to 9.46). Embryos with irregular cleavage were transferred in 16 women. Three live births were achieved following the transfer of single blastocysts derived from embryos with irregular cleavage from two to five cells. CONCLUSIONS: Early embryos with irregular cleavage are significantly more prevalent in younger women. When these embryos develop to the blastocyst stage, they may have normal implantation potential, leading to the birth of healthy babies.

Use of anti-mullerian hormone for testing ovarian reserve: a survey of 796 infertility clinics worldwide.

PURPOSE: The aim of this study is to assess how anti-mullerian hormone (AMH) is used worldwide to test ovarian reserve and guide in vitro fertilization (IVF) cycle management. METHODS: An internet-based survey was sent electronically to registered IVF providers within the IVF-Worldwide.com network. This survey consisted of nine questions which assessed the clinics' use of AMH. The questionnaire was completed online through the IVF-Worldwide.com website, and quality assurance tools were used to verify that only one survey was completed per clinical IVF center. Results are reported as the proportion of IVF cycles represented by a particular answer choice. RESULTS: Survey responses were completed from 796 globally distributed IVF clinics, representing 593,200 IVF cycles worldwide. Sixty percent of the respondent-IVF cycles reported to use AMH as a first line test, and 54 % reported it as the best test for evaluating ovarian reserve. Eighty-nine percent reported that AMH results were extremely relevant or relevant to clinical practice. However in contrast, for predicting live birth rate, 81 % reported age as the best predictor. CONCLUSIONS: AMH is currently considered a first line test for evaluating ovarian reserve and is considered relevant to clinical practice by the majority of IVF providers.

Measurement of antral follicle count in patients undergoing in vitro fertilization treatment: results of a worldwide web-based survey.

PURPOSE: The purpose of the present study was to identify trends in the therapeutic approaches used to measure antral follicle count (AFC) in patients undergoing in vitro fertilization (IVF) treatment worldwide. METHODS: A retrospective evaluation utilizing the results of a web-based survey, IVF-Worldwide ( www.IVF-Worldwide.com ), was performed. RESULTS: Responses from 796 centers representing 593,200 cycles were evaluated. The majority of respondents (71.2 %) considered antral follicle count as a mandatory part of their practice with most (69.0 %) measuring AFC in the follicular phase. Most respondents (89.7 %) reported that they would modify the IVF stimulation protocol based on the AFC. There was considerable variation regarding a limit for the number of antral follicles required to initiate an IVF cycle with 46.1 % designating three antral follicles as their limit, 39.9 % selecting either four or five follicles as their limit, and 14.0 % reporting a higher cutoff criteria. With respect to antral follicle size, 61.5 % included follicles ranging between 2 and 10 mm in the AFC. When asked to identify the best predictor of ovarian hyper-response during IVF cycles, AFC was selected most frequently (49.4 %), followed by anti-Mullerian hormone level (42.7 %). Age was selected as the best predictor of ongoing pregnancy rate in 81.7 % of respondents. CONCLUSIONS: While a large proportion of respondents utilized AFC as part of their daily practice and modified IVF protocol based on the measurement, the majority did not consider AFC as the best predictor of ongoing pregnancy rate.

Medroxyprogesterone acetate is an effective oral alternative for preventing premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization.

OBJECTIVE: To investigate the use of medroxyprogesterone acetate (MPA) to prevent LH surge during controlled ovarian hyperstimulation (COH) and to compare cycle characteristics and pregnancy outcomes in subsequently frozen-thawed ET (FET) cycles. DESIGN: A prospective controlled study. SETTING: Tertiary-care academic medical center. PATIENT(S): Three hundred patients undergoing IVF/intracytoplasmic sperm injection treatment. INTERVENTION(S): In the study group, hMG and MPA were administered simultaneously beginning on cycle day 3. Ovulation was induced with a GnRH agonist or cotriggered by a GnRH agonist and hCG when dominant follicles matured. A short protocol was used in the control group. Viable embryos were cryopreserved for later transfer in both protocols. MAIN OUTCOME MEASURE(S): The primary outcome measure was the number of oocytes retrieved. Secondary outcomes included the number of mature oocytes, the incidence of premature LH surge, and clinical pregnancy outcomes from FETs. RESULT(S): The number of oocytes retrieved in the study group was similar to those in the controls (9.9 ± 6.7 vs. 9.0 ± 6.0), and higher doses of hMG were administered. In the study group, LH suppression persisted during ovarian stimulation, and the incidence of premature LH surge was 0.7% (1/150). No statistically significant differences were found in the clinical pregnancy rates (47.8% vs. 43.3%), implantation rates (31.9% vs. 27.7%), and live-birth rates (42.6% vs. 35.5%) in the study group and controls. CONCLUSION(S): The results show that MPA is an effective oral alternative for the prevention of premature LH surge in woman undergoing COH. This finding will help establish a new regimen for ovarian stimulation in combination with embryo cryopreservation. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR-ONRC-14004419.

How to define, diagnose and treat poor responders? Responses from a worldwide survey of IVF clinics.

Poor responders represent a significant percentage of couples treated in IVF units (10-24%), but the standard definition of poor responders remains uncertain and consequently optimal treatment options remain subjective and not evidence-based. In an attempt to provide uniformity on the definition, diagnosis and treatment of poor responders, a worldwide survey was conducted asking IVF professionals a set of questions on this complex topic. The survey was posted on www.IVF-worldwide.com, the largest and most comprehensive IVF-focused website for physicians and embryologists. A total of 196 centres replied, forming a panel of IVF units with a median of 400 cycles per year. The present study shows that the definition of poor responders is still subjective, and many practices do not use evidence-based treatment for this category of patients. Our hope is that by leveraging the great potential of the internet, future studies may provide immediate large-scale sampling to standardize both poor responder definition and treatment options.

Comparison of live-birth defects after luteal-phase ovarian stimulation vs. conventional ovarian stimulation for in vitro fertilization and vitrified embryo transfer cycles.

OBJECTIVE: To assess live-birth defects after a luteal-phase ovarian-stimulation regimen (LPS) for in vitro fertilization (IVF) and vitrified embryo transfer (ET) cycles. DESIGN: Retrospective cohort study. SETTING: Tertiary-care academic medical center. PATIENT(S): Infants who were born between January 1, 2013 and May 1, 2014 from IVF with intracytoplasmic sperm injection (ICSI) treatments (n = 2,060) after either LPS (n = 587), the standard gonadotropin-releasing hormone-agonist (GnRH-a) short protocol (n = 1,257), or mild ovarian stimulation (n = 216). INTERVENTION(S): The three ovarian-stimulation protocols described and assisted reproductive technology (ART) treatment (IVF or ICSI, and vitrified ET) in ordinary practice. MAIN OUTCOME MEASURE(S): The main measures were: gestational age, birth weight and length, multiple delivery, early neonatal mortality, and birth defects. Associations were assessed using logistic regression by adjusting for confounding factors. RESULT(S): The final sample included 2,060 live-born infants, corresponding to 1,622 frozen-thawed (FET) cycles, which led to: 587 live-born infants from LPS (458 FET cycles); 1,257 live-born infants from the short protocol (984 FET cycles); and 216 live-born infants from mild ovarian stimulation (180 FET cycles). Birth characteristics regarding gestational age, birth weight and length, multiple delivery, and early neonatal death were comparable in all groups. The incidence of live-birth defects among the LPS group (1.02%) and the short GnRH-a protocol group (0.64%) was slightly higher than in the mild ovarian-stimulation group (0.46%). However, none of these differences reached statistical significance. For congenital malformations, the risk significantly increased for the infertility-duration factor and multiple births; the adjusted odds ratios were 1.161 (95% confidence interval [CI]: 1.009-1.335) and 3.899 (95% CI: 1.179-12.896), respectively. No associations were found between congenital birth defects and various ovarian-stimulation regimens, maternal age, body mass index, parity, insemination method, or infant gender. CONCLUSION(S): To date, the data do not indicate an elevated rate of abnormality at birth after LPS, but further study with larger populations is needed to confirm these results. However, infertility itself poses a risk factor for congenital malformation. A higher likelihood of birth defects in multiple births may lead couples to favor elective, single ET; couples undertaking ART should be made aware of the known increased birth defects associated with a twin birth.