Development of an IVF prediction model for donor oocytes: a retrospective analysis of 10 877 embryo transfers.

STUDY QUESTION: Can we develop a prediction model for the chance of a live birth following the transfer of an embryo created using donated oocytes? SUMMARY ANSWER: Three primary models that included patient, past treatment, and cycle characteristics were developed using Australian data to predict the chance of a live birth following the transfer of an embryo created using donated oocytes; these models were well-calibrated to the population studied, achieved reasonable predictive power and generalizability when tested on New Zealand data. WHAT IS KNOWN ALREADY: Nearly 9% of ART embryo transfer cycles performed globally use embryos created using donated oocytes. This percentage rises to one-quarter and one-half in same-sex couples and women aged over 45 years, respectively. STUDY DESIGN, SIZE, DURATION: This study uses population-based Australian clinical registry data comprising 9384 embryo transfer cycles that occurred between 2015 and 2021 for model development, with an external validation cohort of 1493 New Zealand embryo transfer cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: Three prediction models were compared that incorporated patient characteristics, but differed in whether they considered use of prior autologous treatment factors and current treatment parameters. We internally validated the models on Australian data using grouped cross-validation and reported several measures of model discrimination and calibration. Variable importance was measured through calculating the change in predictive performance that resulted from variable permutation. The best-performing model was externally validated on data from New Zealand. MAIN RESULTS AND THE ROLE OF CHANCE: The best-performing model had an internal validation AUC-ROC of 0.60 and Brier score of 0.20, and external validation AUC-ROC of 0.61 and Brier score of 0.23. While these results indicate ∼15% less discriminatory ability compared to models assessed on an autologous cohort from the same population the performance of the models was clearly statistically significantly better than random, demonstrated generalizability, and was well-calibrated to the population studied. The most important variables for predicting the chance of a live birth were the oocyte donor age, the number of prior oocyte recipient embryo transfer cycles, whether the transferred embryo was cleavage or blastocyst stage and oocyte recipient age. Of lesser importance were the oocyte-recipient parity, whether donor or partner sperm was used, the number of prior autologous embryo transfer cycles and the number of embryos transferred. LIMITATIONS, REASONS FOR CAUTION: The models had relatively weak discrimination suggesting further features need to be added to improve their predictive power. Variation in donor oocyte cohorts across countries due to differences such as whether anonymous and compensated donation are allowed may necessitate the models be recalibrated prior to application in non-Australian cohorts. WIDER IMPLICATIONS OF THE FINDINGS: These results confirm the well-established importance of oocyte age and ART treatment history as the key prognostic factors in predicting treatment outcomes. One of the developed models has been incorporated into a consumer-facing website (YourIVFSuccess.com.au/Estimator) to allow patients to obtain personalized estimates of their chance of success using donor oocytes. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Australian government as part of the Medical Research Future Fund (MRFF) Emerging Priorities and Consumer Driven Research initiative: EPCD000007. L.R. declares personal consulting fees from Abbott and Merck, lecture fees from Abbott, receipt of an educational grant from Merck, past presidency of the Fertility Society of Australia & New Zealand and World Endometriosis Society and being a minor shareholder in Monash IVF Group (ASX:MVF). G.M.C. declares receipt of Australian government grant funding for the research study and the development and maintenance of the YourIVFSuccess website. O.F., J.N., and A.P. report no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Progesterone-modified natural cycle preparation for frozen embryo transfer.

RESEARCH QUESTION: Is there any difference in clinical outcomes between the progesterone-modified natural cycle (P4mNC) and hormone replacement therapy (HRT) endometrial preparation protocols after single euploid blastocyst frozen embryo transfer (FET) cycles? DESIGN: A retrospective cohort study was performed at a single, private, high-volume fertility centre. Patients who underwent single euploid blastocyst FET between January 2017 and December 2019 were included. A total of 1933 FET cycles were reviewed, and 723 FET cycles from 548 patients met the inclusion criteria. Two groups were compared according to endometrial preparation: 327 P4mNC-FET and 396 HRT-FET cycles. The primary outcome was the live birth rate. The secondary outcomes included the clinical pregnancy rate and the miscarriage rate. RESULTS: There were no differences in the clinical pregnancy rate (50.2% versus 47.0%, P = 0.688), miscarriage rate (9.8% versus 14.5%, P = 0.115) and live birth rate (45.0% versus 39.6%, P = 0.331) between the P4mNC-FET and HRT-FET groups after covariate adjustments. CONCLUSIONS: There were no differences in the clinical outcomes between the P4mNC-FET and HRT-FET cycles. These results indicate that P4mNC-FET cycles produce clinical outcomes comparable to those of more traditional HRT-FET while allowing greater flexibility in the timing of embryo transfer.

Assessing obstetric outcomes: A systematic review and meta-analysis comparing fresh, artificial, and natural thaw embryo transfer cycles.

BACKGROUND: The increasing utilisation of in vitro fertilisation (IVF) has prompted significant interest in determining the optimal endometrial environment to increase pregnancy rates and minimise the obstetric complications associated with various embryo transfer strategies. AIMS: To determine which cycle is associated with increased obstetric complications: fresh embryo transfer (FreshET), natural thaw (NatThawET) or artificial thaw (ArtThawET). Outcomes of interest included: hypertensive disorders of pregnancy (HDP), gestational diabetes (GD), pre-term birth (PTB), post-partum haemorrhage (PPH) and large for gestational age (LGA). MATERIALS AND METHODS: A comprehensive search of MEDLINE, EMBASE, CENTRAL, and PUBMED was conducted from 1947 to May 17, 2022. Two independent reviewers carried out the screening, and data extraction for the following comparisons: ArtThawET vs NatThawET, ArtThawET vs FreshET, and NatThawET vs FreshET. Meta-analysis was conducted using a fixed-effect Mantel-Haenszel model. The quality of the studies was assessed using GRADEpro. RESULTS: A total of 23 studies were included in this review. ArtThawET was associated with a significantly increased odds of HDP (odds ratio (OR) 1.76, confidence interval (CI) 1.66-1.86), PTB (OR 1.18, CI 1.13-1.23), PPH (OR 2.61, CI 2.3-2.97) and LGA (OR 1.11, CI 1.07-1.15), compared to NatThawET. ArtThawET was also associated with increased odds of HDP (OR 2.13, CI 1.89-2.4), PPH (OR 3.52, CI 3.06-4.04) and LGA (OR 2.12, CI 1.77-2.56), compared to FreshET. Furthermore, NatThawET demonstrated increased odds of HDP (OR 1.20, CI 1.11-1.29), PPH (OR 1.25, CI 1.14-1.38) and LGA (OR 1.85, CI 1.66-2.07) compared to FreshET. CONCLUSION: When clinically feasible, ArtThawET should be avoided as a first-line option for IVF to reduce the risk of obstetric complications. An adequately powered, multicentre randomised controlled trial is necessary to confirm these findings and investigate the underlying pathophysiology.

Controlled ovarian hyperstimulation in breast cancer patients: Does oestrogen receptor status make a difference?

BACKGROUND: The presence of different breast cancer receptor status may impact ovarian stimulation outcomes. AIM: To study the association between oestrogen receptor (ER) status in breast cancer patients and fertility preservation outcomes in a major tertiary referral centre. MATERIALS AND METHODS: Women who underwent fertility preservation following the diagnosis of breast cancer from 2008 to 2018 were included in the study. Patient age, ovarian stimulation parameters and laboratory outcomes were recorded and compared between the ER positive and negative groups. The primary outcome was total number of oocytes frozen. Secondary outcomes included total number of oocytes collected, mature oocytes, and embryos frozen. RESULTS: The women included in the study (n = 214) were analysed in the following groups based on their fertility preservation method: oocyte freezing (n = 131), embryo freezing (n = 70), and both embryo and oocyte freezing (n = 13). There was an increase in the mean (but not mature) number of oocytes frozen (12.4 and 9.2, P-value = 0.03) favouring the ER positive group, even though the women in this group were older (35.0 and 33.4, P-value of 0.03). There is no difference in the starting follicle-stimulating hormone dose, duration of stimulation, mature oocytes collected, and embryos frozen in both groups. CONCLUSION: Patients with ER positive breast cancer may have more positive ovarian stimulation outcomes.

The ovarian hyperstimulation that truly matters: Admissions, severity and prevention strategies.

INTRODUCTION: Ovarian hyperstimulation syndrome (OHSS) is a common but serious complication of in vitro fertilisation. Despite available strategies to reduce OHSS incidence, a small proportion of patients will develop the clinically significant disease with substantial morbidity. Efforts toward better understanding and the prevention of severe disease are required to improve patient outcomes. AIMS: The aims are to: (1) formulate clinically relevant OHSS classification for inpatient settings and data collection/reporting; (2) estimate OHSS prevalence requiring hospital admission in Victoria; and (3) determine the extent of OHSS preventability with clinical strategies. MATERIALS AND METHODS: This retrospective cohort study included all OHSS admissions in a tertiary referral centre, January 2016-December 2021, which included approximately 40% of all cases of hospitalisation for OHSS in the State of Victoria. Patient characteristics, treatment regimes, fertility treatment outcomes, timing classification, and clinical markers of disease severity were studied. Patients were classified as having mild, moderate, or severe OHSS with a novel inpatient classification system. RESULTS: Of 199 OHSS cases presenting to the tertiary institution, 107 were classified as moderate/severe, with no significant difference between age, body mass index, length of stimulation and follicle number between mild/moderate and severe groups. There were more cases of early hyperstimulation (137) compared to late (62) presentation, of which 53% were severe. The average length of stay overall was 3.1 days, and 5.2 days for severe presentations. In 15% of severe cases, an agonist trigger was used. CONCLUSIONS: The overall prevalence of OHSS requiring hospital admission appears to be low (approximately 0.6% of all stimulated cycles). Established risk factors may not accurately predict clinically relevant OHSS risk. Further monitoring, clinician and patient education are required to minimise the risk of significant OHSS that results in hospital admissions.

Modelling futility in the setting of fertility treatment.

When is a fertility treatment futile? This question has great practical importance, given the role futility plays in ethical, legal and clinical discussions. Here, we outline a novel method of determining futility for IVF treatments. Our approach is distinctive for considering the economic value attached to the intended aim of IVF treatments, i.e. the birth of a child, rather than just the effects on prospective parents and the health system in general. We draw on the commonly used metric, quality-adjusted life years (QALYs), to attach a monetary value to new lives created through IVF. We then define futility as treatments in which the chance of achieving a live birth is so low that IVF is no longer a cost-effective intervention given the economic value of new births. This model indicates that IVF treatments in which the chance of a live birth are <0.3% are futile. This suggests IVF becomes futile when women are aged between 47 and 49 years of age. This is notable older than ages currently considered as futile in an Australian context (∼45). In the UK, government subsidized treatment with the couple's own gametes stops at the age of 42, while privately funded treatments are self-regulated by individual providers. In most European countries and the USA, the 'age of futility' is likewise managed by clinical consensus.

Polygenic risk score for embryo selection-not ready for prime time.

Numerous chronic diseases have a substantial hereditary component. Recent advances in human genetics have allowed the extent of this to be quantified via genome-wide association studies, producing polygenic risk scores (PRS), which can then be applied to individuals to estimate their risk of developing a disease in question. This technology has recently been applied to embryo selection in the setting of IVF and preimplantation genetic testing, with limited data to support its utility. Furthermore, there are concerns that the inherent limitations of PRS makes it ill-suited for use as a screening test in this setting. There are also serious ethical and moral questions associated with this technology that are yet to be addressed. We conclude that further research and ethical reflection are required before embryo selection based on PRS is offered to patients outside of the research setting.

Serum progesterone concentration on the day of embryo transfer in stimulated cycles does not correlate with reproductive outcomes.

RESEARCH QUESTION: Is the live birth rate (LBR) in fresh embryo transfer IVF cycles affected by serum progesterone concentration on the day of embryo transfer? DESIGN: A single-centre retrospective analysis of prospectively collected data from women who underwent IVF or intracytoplasmic sperm injection between July 2019 and July 2020, and had a fresh day 5 single embryo transfer. Overall, 825 first and second stimulation cycles were included. Patients underwent a gonadotrophin-releasing hormone antagonist protocol with human chorionic gonadotrophin (HCG) trigger, and received vaginal-only luteal phase support. The study population was an everyday patient cohort, treated with the unit's usual stimulation protocols. The correlation between serum progesterone concentrations on the day of embryo transfer and the incidence of positive HCG, clinical pregnancy and live birth were examined. Patients were divided into four groups based on serum progesterone concentrations (<150, 150-250, 251-400 and >400 nmol/l). The data were further interrogated using additional progesterone cut-offs. RESULTS: There was no concentration of progesterone below or above which the chance of pregnancy was reduced. The chance of live birth following a blastocyst transfer was no different across the four groups (29.8, 26.6, 32.7 and 31.5%, respectively, P = 0.55). There was no negative association between progesterone and chance of pregnancy when other progesterone thresholds were applied. Estimates were adjusted for confounding factors such as maternal age. CONCLUSION: Serum progesterone concentration on the day of fresh embryo transfer does not correlate with the LBR.

Timing of progesterone luteal support in natural cryopreserved embryo transfer cycles: back to basics.

Moderate quality evidence suggests that the administration of progesterone luteal phase support (LPS) is beneficial in natural and modified (HCG-triggered) natural frozen embryo transfer (FET) cycles. No comparative studies examining the optimal timing of progesterone LPS administration in natural FET cycles have been conducted, and the common practice differs greatly between clinics worldwide. In the absence of clinical trials, we aimed to provide a scheme for progesterone supplementation in an attempt to mimic its natural secretion by the corpus luteum. On the basis of early studies of ovulation physiology, we suggest that progesterone luteal support administration in natural FET cycles should start 36 h after the onset of the LH surge when measured in a morning serum test, or 36 h after the administration of HCG for triggering final follicular maturation. Blastocyst transfer should be carried out after 5 full days of progesterone supplementation. Randomized clinical trials are required to confirm these recommendations.

Neonatal and clinical outcomes after transfer of a mosaic embryo identified by preimplantation genetic testing for aneuploidies.

RESEARCH QUESTION: Do clinical and neonatal outcomes differ between mosaic embryo transfers (MET) and euploid embryo transfers (EET)? DESIGN: This retrospective cohort study compared the implantation rate, live birth rate (LBR) and miscarriage rate between 513 euploid embryos and 118 mosaic embryos (72 whole chromosome mosaic [WCM], 40 segmental mosaic and six complex mosaic). Blastocysts were analysed using preimplantation genetic testing for aneuploidies with next-generation sequencing, followed by a single vitrified-warmed embryo transfer. Trophectoderm biopsies were classified as mosaic if they had 20-80% abnormal cells. RESULTS: Overall, EET resulted in a significantly higher implantation rate (47.0%) and LBR (40.7%) than MET (implantation rate 39.0%, P = 0.005; LBR 28.8%, P = 0.008) and WCM embryos (implantation rate 37.5%, P = 0.01; LBR 22.2%, P = 0.007) after covariate adjustment. Segmental mosaic embryos had an implantation rate (47.5%) and LBR (45.0%) comparable to those of euploid embryos. Mosaic embryos with a high percentage of aneuploid cells (≥60%) showed a significantly lower LBR (10.5% versus 40.7%, P = 0.03) than euploid embryos after covariate adjustment, with three of the five implantations of mosaic embryos resulting in miscarriage. Neonatal outcomes did not differ significantly between the mosaic and euploid groups. Of the 34 women with a live birth after MET, 13 had a prenatal or postnatal genetic testing result, and no abnormalities were found. CONCLUSIONS: Mosaic embryos were associated with a lower LBR, while segmental mosaic embryos had similar clinical outcomes to euploid embryos. Mosaic embryos with a high aneuploidy percentage (≥60%) should be assigned a low transfer priority. Neonatal outcomes did not differ significantly between the euploid and mosaic groups.

A survey study of endometrial receptivity tests and immunological treatments in in vitro fertilisation (IVF).

BACKGROUND: Suboptimal endometrial receptivity is a key factor behind in vitro fertilisation (IVF) implantation failure. Direct clinical tests of the endometrium of natural killer (NK) cells and endometrial receptivity analysis (ERA) are controversial. AIMS: To examine the current practice of endometrial receptivity tests (NK cells and ERA) and immunological treatments (corticosteroids, anticoagulants, antiplatelets, intravenous immunoglobulin, Intralipid, other) among fertility specialists in Australia and New Zealand. METHODS: A prospective 23-item web-based survey was distributed by email via the Fertility Society of Australia and New Zealand, between August and October 2020. Data were collected and analysed using Qualtrics. RESULTS: Of 238 fertility specialists, 90 completed the survey (response rate 37.8%). ERA (48/90, 53.3%) was most commonly ordered, followed by uterine NK (uNK) (36/90, 40.0%) and peripheral blood NK (pNK) (12/90, 13.3%). For all tests, the most common indication was recurrent implantation failure (RIF) (41/48, 22/36, 6/12; 85.4%, 61.1%, and 50.0%, respectively for ERA, uNK and pNK). Of those that did not offer these tests, the main reason cited was insufficient evidence (30/42, 47/54, 68/78; 71.4%, 87.0%, and 87.0%). A third of specialists offered empirical immunological treatment for RIF (30/90, 33.3%): anticoagulants (28/30, 93.3%), antiplatelets (27/30, 90.0%), and corticosteroids (25/30; 83.3%). The majority of specialists (56/90, 62.2%) stated they had refused a patient request for endometrial testing or treatment. CONCLUSIONS: Tests for presumed endometrial receptivity pathology are often used in Australia and New Zealand. Immunological treatments for RIF are commonly employed empirically, without strong evidence of their effectiveness or safety. Further studies should focus on education and clinical adherence to evidence-based guidelines.

An algorithm to personalise the diagnosis of recurrent implantation failure based on theoretical cumulative implantation rate.

Recurrent implantation failure (RIF) is an imprecisely defined disorder lacking a robust scientific basis. The incomplete understanding of RIF provides significant diagnostic and therapeutic challenges, and a better understanding of the underlying issues is necessary to improve outcomes. We propose a novel concept termed 'Theoretical Cumulative Implantation Rate', the calculation of which is based on objective data, to define whether a patient should be diagnosed with RIF. An updated definition to assist with patient counselling and planning research studies, which is more precise and standardised, is well overdue.

Experience with transplantation of human cryopreserved ovarian tissue to a sub-peritoneal abdominal site.

STUDY QUESTION: Is a sub-peritoneal abdominal site a suitable site for cryopreserved ovarian tissue transplantation? SUMMARY ANSWER: Live births have resulted from oocytes aspirated from follicles within cryopreserved ovarian tissue transplanted in a sub-peritoneal abdominal site with similar outcomes observed in terms of number of mature oocytes recovered and embryo development from tissue transplanted to sub-peritoneal abdominal, ovarian, and pelvic sites in our clinic. WHAT IS KNOWN ALREADY: Over 130 live births have been reported from cryopreservation of ovarian tissue and subsequent transplantation. In the majority of these, tissue was transplanted onto the remaining ovary. Although grafting to a non-ovarian, non-pelvic, sub-peritoneal abdominal site has resulted in births, it has been suggested that compromised outcomes may be expected from a non-pelvic site. STUDY DESIGN, SIZE, DURATION: The aim of the study was to assess the outcome from cryopreserved ovarian tissue transplanted to a site out of the pelvic area; a sub-peritoneal abdominal site. These outcomes were compared to transplantation to the ovary and peritoneal pelvic area in a cohort of 17 fertility preservation women where the individual sites of follicle aspiration were known and subsequent outcomes tracked. Ovarian tissue was slow frozen using the cryoprotectants propanediol and sucrose (n = 16 women) or using dimethyl sulfoxide and sucrose (n = 1 woman). Tissue was kept at 4°C overnight prior to freezing for 1 case. Tissue was thawed appropriately and prepared on 6.0 vicryl sutures for transplantation. Tissue was placed laparoscopically into a sub-peritoneal abdominal site, a pelvic side wall peritoneal pocket and the ovary. PARTICIPANTS/MATERIALS, SETTING, METHODS: Following resumption of cycling, gonadotrophin stimulation commenced with FSH, LH and antagonist and a trigger was given when one follicle was >13 mm in diameter. Abdominal follicles were aspirated under ultrasound guidance trans-abdominally; ovarian and pelvic follicles were aspirated trans-vaginally. Due to an inability to differentiate pelvic from ovarian follicles at the time of ultrasound-guided oocyte retrieval, both were classified as ovarian on the side where both were present. However, on the side, where no ovary was present, outcomes from pelvic follicles were reported. MAIN RESULTS AND THE ROLE OF CHANCE: Average time lapse between ovarian tissue harvest and graft was 6 years. Resumption of cycling occurred on average 4.2 months post first graft, regardless of graft site. Mean follicle diameter on the day of oocyte aspiration was 14 mm for all sites. Aspiration failed to retrieve an oocyte in 30% (36/120) of abdominal follicles which was similar to the other sites; ovarian 24% (21/87), pelvic 32% (31/97). A similar proportion of retrieved oocytes was mature from all sites (67% (50/75) abdominal, 68% (42/62) ovarian, 59% (34/58) pelvic). The proportion of embryos which developed on Day 2 from those fertilized was also similar in all groups (90% (34/38) abdominal, 76% (22/29) ovarian, 96% (22/23) pelvic). To our knowledge, this is the first report of outcomes from cryopreserved ovarian tissue transplanted to a sub-peritoneal abdominal site and the subsequent comparison to outcomes from the ovary and a sub-peritoneal pelvic graft, within the same cohort of patients, where tissue was slow frozen predominantly with the cryoprotectant propanediol and sucrose. LIMITATIONS, REASONS FOR CAUTION: The study reports outcomes from a small number of women following ovarian tissue transplantation. Follicle density is an estimate only and the amount of tissue grafted varied between patients. WIDER IMPLICATIONS OF THE FINDINGS: The demonstration of successful outcomes from cryopreserved ovarian tissue grafted to a sub-peritoneal abdominal site has significant implications for the management of women in which grafting to pelvic sites is contraindicated although it appears to be important to trigger follicle maturation at a lower than normal follicular diameter. The relative ease of oocyte retrieval at the sub-peritoneal abdominal site also has positive implications for the introduction of this approach into clinical practice. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was used. All authors have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Social egg freezing and donation: waste not, want not.

The trend towards postponement of childbearing has seen increasing numbers of women turning towards oocyte banking for anticipated gamete exhaustion (AGE banking), which offers a realistic chance of achieving genetically connected offspring. However, there are concerns around the use of this technology, including social/ethical implications, low rate of utilisation and its cost-effectiveness. The same societal trends have also resulted in an increased demand and unmet need for donor oocytes, with many women choosing to travel overseas for treatment. This has its own inherent social, medical, financial and psychological sequelae. We propose a possible pathway to address these dual realities. The donation of oocytes originally stored in the context of AGE banking, with appropriate compensatory mechanisms, would ameliorate AGE banking concerns, while simultaneously improving the supply of donor oocytes. This proposed arrangement will result in tangible benefits for prospective donors, recipients and society at large.

Sexual function in reproductive-aged women following radiotherapy: a cross sectional study.

Background While female sexual dysfunction post-radiation therapy has been previously described, much of the literature is focused on older, often postmenopausal, women; and neglects the experiences of younger populations. Our study aims to describe the changes in sexual functioning following radiotherapy among women of a reproductive age. Methods A cross-sectional survey was conducted on reproductive-aged women post-radiation therapy. Information on sexual frequency, pleasure, discomfort and habit was collected and compared to responses from healthy women of comparable ages. Results Reproductive-aged women post-radiotherapy experienced decreased pleasure, more discomfort and had less sexual activity than healthy controls. However, sexual habit was comparable. Conclusions Our findings illustrated that most domains of sexual function are negatively affected in our study population. Understanding the sexual sequelae of radiation therapy may help guide clinicians in counselling their patients and planning their future needs.

Ovarian tissue grafting: Lessons learnt from our experience with 55 grafts.

Purpose: Uncertainties remain regarding the clinical efficacy of ovarian tissue cryopreservation and grafting. We report a retrospective analysis of reproductive outcomes and lessons learnt following 55 ovarian tissue transplant procedures at our center from 2006 to 2019. Methods: We analyzed variables related to graft success such as tissue volume, follicular density, total follicular volume, and age on the duration of graft function. Results: Follicular density and total follicular volume correlate positively with duration of graft function. All clinical pregnancies in our cohort occurred in women who were aged 35 or less at the time of ovarian tissue cryopreservation. Conclusion: Graft success, as determined by eventual pregnancy and the longevity of graft function, may be impacted by factors including age at cryopreservation, follicular density, and total follicular volume.

Do serum progesterone levels on day of embryo transfer influence pregnancy outcomes in artificial frozen-thaw cycles?

PURPOSE: The purpose of this study is to investigate whether progesterone (P4) levels on the day of frozen-thawed embryo transfer (FET) to a hormonally prepared endometrium correlate with pregnancy outcomes. METHODS: This is a large retrospective cohort analysis comprising of N = 2010 FETs. In these cycles, P4 levels on the day of transfer were assessed in relation to pregnancy outcomes. A threshold of 10 ng/mL was used to simulate currently accepted levels for physiological corpus luteal function. Biochemical pregnancy, clinical pregnancy, and live birth rates were compared between those with P4 levels above and below this threshold. Analyses using transfer day P4 thresholds of 5 ng/mL and 20 ng/mL were then completed to see if these could create further prognostic power. RESULTS: When comparing FET outcomes in relation to P4 levels < 10 ng/mL and ≥ 10 ng/mL, we observed no differences in biochemical pregnancy rates (39.53% vs. 40.98%, p = 0.52), clinical pregnancy rates (20.82 vs. 22.78, p = 0.30), and live birth rates (14.25 vs. 16.21 p = 0.23). In patients whose P4 met the threshold of 20 ng/mL, there was similarly no statistically significant improvement in pregnancy outcomes. While there was no difference for biochemical or clinical pregnancy rates, a statistically significant improvement in live birth rates was observed for those with a transfer day P4 level ≥ 5 ng/mL. CONCLUSIONS: We demonstrated that P4 levels at or above 10 ng/mL on the day of FET do not confer a statistically significant improvement in pregnancy outcomes. P4 below 5 ng/mg was associated with lower live birth rates suggesting that there is a threshold below which it is difficult to salvage FET cycles.

Is it possible to apply trial outcomes to a real-world population? A novel approach to External Validity Analysis.

BACKGROUND: Translation of findings from randomised controlled trials (RCT), the foundation of evidence-based medicine, into clinical practice requires an understanding of relationships between patient characteristics, treatment practices and outcomes. We propose a novel technique, External Validity Analysis (EVA), to evaluate applicability of findings from a large RCT, comparing baseline characteristics, interventions and outcomes between the RCT and a large clinical database. AIM: To perform EVA of the findings of a randomised controlled trial (ESTHER-1) to a population in an Australian clinic setting. To demonstrate this method, we evaluated the discordance in first cycle follicle-stimulating hormone (FSH) exposure and outcomes between the two populations, to inform clinical practice. MATERIALS AND METHODS: In this retrospective, descriptive analysis, we compared practices and outcomes between the follitropin alfa 'conventional' dosing arm of the ESTHER-1 trial and a selected comparable clinic subpopulation of patients who underwent controlled ovarian stimulation using FSH. RESULTS: Mean FSH exposure was 34% higher in the clinic subpopulation than in the trial subpopulation, resulting in higher average ovarian response without improving the likelihood of clinical pregnancy or live birth. CONCLUSIONS: EVA allowed for the comparison of a trial population with a selected clinic population with similar characteristics. With respect to FSH consumption, this analysis revealed higher exposure to FSH in the clinic setting without a corresponding benefit. The comparison reveals population differences as well as the potential to improve clinical outcomes through a reappraisal of current practices and objectives in gonadotropin dose selection.

Comparing pregnancy outcomes between natural cycles and artificial cycles following frozen-thaw embryo transfers.

BACKGROUND: Frozen embryo transfer (FET) is increasing in prevalence. In contrast to the amount of research performed on the actual cryopreservation procedure, there are limited data with respect to optimal endometrial preparation in FET cycles. Increasingly artificial cycle (AC) preparation is being adopted over the natural cycle (NC) to facilitate greater access to FET. However, there remains a paucity of data comparing pregnancy outcomes between these two commonly used cycle types. AIMS: To examine the efficacy of AC vs NC following FET, by comparing pregnancy outcomes including biochemical, clinical and live birth rates, along with miscarriage rates. MATERIALS AND METHOD: This is a large single-centre retrospective analysis, examining a standardised data set from January 2015 to July 2018. It included 3030 cycles (NC = 2033, AC = 997). Main outcomes were biochemical pregnancy (beta-human chorionic gonadotropin > 5 IU), ultrasound-diagnosed clinical pregnancy, and live births. Using the χ2 test, the above pregnancy outcomes were compared between AC and NC. A multivariate logistic regression, controlling for factors such as age, embryo quality, and day of blastocyst freeze was further utilised to assess for confounding variables. RESULTS: No difference was observed between biochemical pregnancy rates (NC = 39.45% vs AC = 37.71%, P = 0.357); statistically significant differences were observed between clinical pregnancy (30.84% vs 26.08%, P = 0.007), and live birth rates (24.40% vs 18.86% P = 0.001). Multivariate analysis confirmed that NC produces superior pregnancy outcomes when controlling for confounding variables. CONCLUSION: This analysis demonstrates the non-inferiority of NC thaw compared to AC, on continuing pregnancy rates. Taken together with patient acceptability and possibly increased obstetric risks with AC, these findings support the use of NC when medically possible.

Use of intracytoplasmic sperm injection (ICSI) in normospermic men may result in lower clinical pregnancy and live birth rates.

BACKGROUND: While intracytoplasmic sperm injection (ICSI) was developed for overcoming male infertility, it is increasingly being used for non-male factor indications, without consensus regarding the safety and efficacy of this approach. AIMS: To determine whether ICSI offers any benefit compared to standard in vitro fertilisation (IVF), in the setting of normal semen parameters. MATERIALS AND METHODS: Retrospective analysis of reproductive outcomes in 3363 stimulated cycles (IVF = 1661; ICSI = 1702), in patients treated between 2009-2015, was performed. Selected couples had no male factor infertility. Couples with abnormal semen parameters (based on WHO 2010 guidelines), presence of anti-sperm antibodies and low oocyte yield of ≤4 oocytes, were excluded. The outcomes analysed included: (1) fertilisation rate (FR); (2) clinical pregnancy rate (CPR); and (3) live birth rate (LBR), by method of fertilisation used (IVF vs ICSI) and controlling for significant confounders. RESULTS: FR, CPR and LBR were significantly higher in the IVF group compared with ICSI (67.1% vs 62.3%, 23.06% vs 16.8%, 17.22% vs 13.2%, respectively). Pregnancy rate with ICSI was approximately 30% lower than with IVF, even when controlling for significant factors such as day of embryo transfer and number of embryos transferred. This translates to one less pregnancy in every 15 cycles where ICSI was used without clear indication. CONCLUSIONS: Our data suggest that ICSI may be detrimental to clinical outcomes and contributes to the wider understanding of use of ICSI in normospermic men.