When to randomize patients in a randomized controlled trial?

The timing of randomization should be considered carefully in the context of each trial because it has implications for the particular research question answered. In most instances, randomization should be delayed until as close as practically possible to the moment of intervention. In some cases, early randomization may offer certain advantages, but trialists should balance these, including any administrative complexity or inconvenience, against the risk of avoidable protocol violations and avoidable drop out.

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.

Posthumous conception in Australia - legal and ethical considerations.

Posthumous conception, the ability to conceive a child after the death of one partner, is increasingly prevalent due to advances in Artificial Reproduction Technology (ART). This paper considers the complexities surrounding the practice in Australia, focusing primarily on the ethical and legal dimensions. It observes that state-based regulations in Australia create disparities in accessibility: some states prohibit the procedure without the deceased's written consent, while others permit it based on guidelines or lack explicit prohibitions. Addressing the juxtaposition of Will Theory and Interest Theory, it emphasises the ongoing debate on whether rights, particularly reproductive autonomy, outlive a person's demise. Finally, the paper highlights an evident inconsistency in Australian legislation and promotes a uniform approach across states.

Providers' attitudes towards payment to egg donors: an international survey.

The research question 'How do fertility professionals worldwide perceive the issue of payment for egg donation and does this view change under different circumstances?' was addressed. A worldwide online survey was conducted between January and March 2023, focusing on the views of fertility providers concerning egg donor payments. From the 3,790 IVF-Worldwide.com members invited, 532 (14%) from 88 countries responded. The majority of participants, primarily from Europe (38.9%) and Asia (20.1%), were fertility specialists, embryologists, and fertility nurses. Most (60.3%) favoured regulated donor compensation, with only 13% advocating for unrestricted amounts. Compensation opposition (22.4%) was often rooted in concerns about donors' best interests. When considering egg donation from low-resource to high-resource countries, 38.5% were opposed. When asked about compensating women who underwent elective, non-medical egg freezing should they choose to donate their unused oocytes, most responders supported it to some degree, with only 28.4% opposing any compensation. The survey revealed that a significant majority of fertility professionals worldwide are supportive of some form of compensation for egg donors. However, perspectives diverge depending on the specific scenario and the country of practice.

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.

Live birth rates in day 5 fresh versus vitrified single blastocyst transfer cycles: A cross-sectional analysis.

Background: The use of frozen embryo transfers (FET) in assisted reproduction has increased worldwide. Controlled ovarian hyperstimulation in a fresh transfer may impair endometrial-embryo synchronicity. However, there is conflicting evidence on live birth rates (LBR) and clinical pregnancy rates (CPR). Objective: To compare LBRs and CPRs between single autologous day 5 fresh vs. vitrified blastocyst transfer cycles, to investigate the impact of controlled ovarian hyperstimulation on embryo-endometrium asynchrony. Materials and Methods: A large cross-sectional analysis of 6002 embryo transfers (ET) comprised 3774 fresh and 2228 FET cycles from 2016 to 2019. Multivariate and subgroup analysis were performed for high responders ( > 20 oocytes). Results: Univariate analysis showed no difference in LBR (28.3% vs. 27.4%, p = 0.43) and CPR (32.2% vs. 30.9%, p = 0.30); however, multivariate analysis demonstrated significantly lower LBR (OR 0.864, p = 0.046, 95% CI 0.749-0.997) and CPR (OR 0.852, p = 0.024, 95% CI 0.742-0.979) in FET compared to fresh ETs. Younger participant age, previous in vitro fertilization pregnancy, advanced blastocyst expansion, higher trophectoderm quality, and lower cumulative number of ETs all improved the odds of LBR and CPR. Conventional in vitro fertilization, rather than intracytoplasmic sperm injection, improved CPR but not LBR. Body mass index affected neither LBR nor CPR. In the subgroup, multivariate analysis of high responders showed no difference in LBR or CPR. Conclusion: This study demonstrates relatively higher LBR and CPR of nearly 14% for fresh ETs compared to FETs, in multivariate analysis. A universal freeze-all strategy, without appropriate indication, may lead to suboptimal outcomes. In high responders, freeze-all cycles may be beneficial, as outcomes appear similar.

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.

Barriers to reproductive treatments in Australia.

BACKGROUND: Most couples in Australia want to have children but some might not attain their reproductive goals, experiencing involuntary childlessness or not reaching their desired family size. There is increased focus on helping couples achieve their reproductive goals. Identifying existing barriers, such as those related to social and societal factors, access to treatment and treatment success, is crucial to optimising outcomes. OBJECTIVE: This article discusses existing barriers to reproduction to help general practitioners (GPs) raise the topic of future fertility with patients, care for those presenting with fertility concerns and support those undergoing fertility treatment. DISCUSSION: Recognition of the impact of barriers such as age to achieving reproductive goals remains the highest priority for GPs. This will help them to broach this topic with patients, carry out a timely evaluation or provide referral, as well as discuss opportunities such as elective egg freezing. Other barriers can be mitigated by educating patients, informing them about available resources and supporting those undergoing fertility treatment as part of a multidisciplinary reproductive team.

How do IVF patients interpret claims about fertility treatments? A randomised survey experiment.

Trials evaluating the efficacy of IVF and various treatment options often focus on upstream outcome measures, improvements which may not translate into clinical outcome improvements. A cross-sectional online survey was distributed globally among IVF patients. Respondents were randomised to view one of 16 statements about a hypothetical IVF treatment option called 'FertiSure', stated to improve one of four upstream outcomes. Statements varied in whether they contained information stating that FertiSure was not proven to improve live-birth rates and about potential risks. Many patients inferred that improvements in upstream outcomes would result in improvements in the probability of live-birth. Nearly 80% of respondents were willing to use FertiSure. Respondents told that FertiSure was not proven to improve live-birth rates and were less willing to use FertiSure. More respondents agreed that FertiSure may pose a risk to patients when they were told this was the case. However, this did not affect their willingness to use FertiSure. Interestingly, 34% of respondents believed FertiSure would not improve the probability of live-birth but were still willing to use it. These results have implications for IVF clinic websites and information about treatment options which may not routinely contain statements about the limited evidence-base and possible risks.

Elective egg freezing: State of the ART.

BACKGROUND: Women are having children later in life, and the risk and prevalence of involuntary childlessness is thus increasing. Oocyte storage is widely available and increasingly used for elective (non-medical) indications by women trying to safeguard future fertility. There is controversy, however, regarding who should consider oocyte freezing, at what age and how many oocytes should be frozen. OBJECTIVE: The aim of this article is to provide an update on the practical management of non-medical oocyte freezing, including patient counselling and selection. DISCUSSION: The latest studies indicate that younger women are less likely to return to use their frozen oocytes, while a live birth is far less likely to result from oocytes frozen at an older age. While not guaranteeing a future pregnancy, oocyte cryopreservation is also associated with a substantial financial burden and uncommon but serious complications. Therefore, patient selection, appropriate counselling and maintenance of realistic expectations are crucial for this new technology to be used with the greatest positive impact.

Novel embryo selection strategies-finding the right balance.

The use of novel technologies in the selection of embryos during in vitro fertilisation (IVF) has the potential to improve the chances of pregnancy and birth of a healthy child. However, it is important to be aware of the potential risks and unintended consequences that may arise from the premature implementation of these technologies. This article discusses the ethical considerations surrounding the use of novel embryo selection technologies in IVF, including the growing uptake of genetic testing and others, and argues that prioritising embryos for transfer using these technologies is acceptable, but discarding embryos based on unproven advances is not. Several historical examples are provided, which demonstrate possible harms, where the overall chance of pregnancy may have been reduced, and some patients may have missed out on biological parenthood altogether. We emphasise the need for caution and a balanced approach to ensure that the benefits of these technologies outweigh any potential harm. We also highlight the primacy of patients' autonomy in reproductive decision-making, especially when information gained by utilising novel technologies is imprecise.

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.

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.

POMMS: Pre-operative misoprostol in myomectomy surgery: A randomised controlled pilot study.

OBJECTIVE: To assess the effect of pre-operative sublingual misoprostol on intra-operative blood loss in abdominal myomectomy as compared to placebo. STUDY DESIGN: Double-blind randomised controlled pilot study. A single tertiary Gynaecology Unit in Melbourne, Australia. Women ≥ 18 years old undergoing laparoscopic or open myomectomy. Women undergoing laparoscopic or open myomectomy for symptomatic uterine leiomyomas were randomised to pre-operative sublingual 400mcg misoprostol or placebo. Intra-operative blood loss was measured via accurate record keeping of the post-operative volume in the suction canister and weighed packs, minus any irrigation fluid used. RESULTS: Intraoperative blood loss in the misoprostol treatment group was 306 ml ± 281 ml, compared to 325 ± 352 ml in the placebo group; P = 0.83. Fibroid volume was a consistent predictor of intra-operative blood loss. For each 1 ml increase in fibroid volume there is an increase in blood loss by 0.26 ml (95 % CI: 0.07 - 0.46). CONCLUSIONS: In this study, we found that there was no significant difference in blood loss between women who received and did not receive sublingual misoprostol before abdominal myomectomy. This is an exploratory study laying the foundation for further randomised clinical trials.

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.