Obstetrics and Gynaecology - Research Publications
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ItemPolygenic risk score for embryo selection-not ready for prime time(OXFORD UNIV PRESS, 2022-09-30)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.
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ItemApplying plastic surgery principles to ovarian tissue transplantation(AME PUBLISHING COMPANY, 2021-07)Ovarian tissue cryopreservation (OTC) and transplantation is an innovative procedure increasingly utilized to help preserve fertility after gonadotoxic treatments especially in cancer patients. Approximately 30% of autotransplanted patients are able to achieve live birth, typically with the help of in-vitro fertilization. Numerous techniques and grafting sites have been described to continue to increase this figure. In the field of plastic surgery, tissue grafting has been successful performed for thousands of years and knowledge in this area has been significantly refined. A qualitative review of the literature using PubMed, Cochrane, SCOPUS and Medline databases was performed to look for articles relating to ovarian tissue transplantation (OTT) and comparisons made to plastic surgery tissue grafting. Many parallels were found between the principles of grafting in plastic surgery and the principles of OTT, including pre-operative patient optimization, suitable donor site selection, tissue harvest and preparation, graft site choice, immobilization of the graft and post-operative care. Consideration of the benefits and risks of using orthotopic versus heterotopic recipient sites is also highly important with regards to graft take, morbidity and ease of access of oocyte collection. We believe that ongoing discussion between disciplines can have the potential to improve knowledge, surgical techniques and patient outcomes.
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ItemUse of intracytoplasmic sperm injection (ICSI) in normospermic men may result in lower clinical pregnancy and live birth rates(WILEY, 2019-10)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.
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ItemComparing pregnancy outcomes between natural cycles and artificial cycles following frozen-thaw embryo transfers(Wiley, 2020-10)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.
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ItemIs it possible to apply trial outcomes to a real-world population? A novel approach to External Validity Analysis(WILEY, 2020-04)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.
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ItemNo Preview AvailableHow common is add-on use and how do patients decide whether to use them? A national survey of IVF patients(OXFORD UNIV PRESS, 2021-07)STUDY QUESTION: What is the prevalence and pattern of IVF add-on use in Australia? SUMMARY ANSWER: Among women having IVF in the last 3 years, 82% had used one or more IVF add-on, most commonly acupuncture, preimplantation genetic testing for aneuploidy and Chinese herbal medicine. WHAT IS KNOWN ALREADY: IVF add-ons are procedures, techniques or medicines which may be considered nonessential to IVF, but usually used in attempts to improve the probability of conception and live birth. The use of IVF add-ons is believed to be widespread; however, there is little information about the prevalence and patterns of use in different settings. STUDY DESIGN, SIZE, DURATION: An online survey was distributed via social media to women in Australia who had undergone IVF since 2017. Women were excluded if they were gestational surrogates, used a surrogate, or underwent ovarian stimulation for oocyte donation or elective oocyte cryopreservation only. The survey was open from 21 June to 14 July 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Survey questions included demographics, IVF and medical history, and use of IVF add-ons including details of the type of add-on, costs and information sources used. Participants were also asked about the relative importance of evidence regarding safety and effectiveness, factors considered in decision-making and decision regret. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1590 eligible responses were analysed. Overall, 82% of women had used one or more add-ons and these usually incurred an additional cost (72%). Around half (54%) had learned about add-ons from their fertility specialist, and most reported that the decision to use add-ons was equally shared with the specialist. Women placed a high level of importance on scientific evidence for safety and efficacy, and half (49%) assumed that add-ons were known to be safe. Most women experienced some regret at the decision to use IVF add-ons (66%), and this was more severe among women whose IVF was unsuccessful (83%) and who believed that the specialist had a larger contribution to the decision to use add-ons (75%). LIMITATIONS, REASONS FOR CAUTION: This retrospective survey relied on patient recall. Some aspects were particularly prone to bias such as contributions to decision-making. This approach to capturing IVF add-on use may yield different results to data collected directly from IVF clinics or from fertility specialists. WIDER IMPLICATIONS OF THE FINDINGS: There is a very high prevalence of IVF add-on use in Australia which may be generalisable to other settings with similar models of IVF provision. Although women placed high importance on scientific evidence to support add-ons, most add-ons do not have robust evidence of safety and effectiveness. This suggests that IVF patients are not adequately informed about the risks and benefits of IVF add-ons, or are not aware of the paucity of evidence to support their use. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by a McKenzie Postdoctoral Fellowship Grant (University of Melbourne), a Department of Obstetrics and Gynaecology Innovation Grant (University of Melbourne) and an NHMRC Investigator Grant (APP1195189). A.P. declares that he provides fertility services at Melbourne IVF (part of Virtus Health). J.W. reports grants from Wellcome Trust, during the conduct of the study, and that publishing benefits his career. The remaining authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.
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ItemA double-blinded, randomized, placebo-controlled trial assessing the effects of nifedipine on embryo transfer: Study protocol(LIPPINCOTT WILLIAMS & WILKINS, 2017-12)INTRODUCTION: Implantation failure is the main factor affecting the success rate of in vitro fertilization (IVF) procedures. Studies have reported that uterine contractions (UCs) at the time of embryo transfer (ET) were inversely related to implantation and pregnancy rate, hence reducing the success of IVF treatment. Various pharmacological agents, with the exception of calcium channel blocker (CCB), have been investigated to reduce UC. In this regard, we are presenting a proposal for a double-blind randomized placebo-controlled trial. The trial aims to determine whether nifedipine, a CCB with potent smooth muscle relaxing activity and an excellent safety profile, can improve the outcome of ET. METHODS AND ANALYSES: We will recruit 100 infertile women into one of 2 groups: placebo (n = 50) and nifedipine 20 mg (n = 50). Study participants will be admitted 30 minutes prior to ET and given either tablet after their baseline vital signs have been recorded. They will then undergo ET and be observed for adverse events for another 30 minutes post-ET. The primary outcome will be implantation rate and clinical pregnancy rate. Secondary outcomes include adverse events, miscarriage and pregnancy, and neonatal outcomes. Resulting data will then be analyzed using t test, Chi-square test, and multivariate test to compare outcomes between the 2 groups for any statistical significance. This protocol has been designed in accordance with the SPIRIT 2013 Guidelines.
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ItemImplications of the introduction of new criteria for the diagnosis of gestational diabetes: a health outcome and cost of care analysis(BMJ PUBLISHING GROUP, 2019-06)OBJECTIVE: To identify effects on health outcomes from implementing new criteria diagnosing gestational diabetes mellitus(GDM) and to analyse costs-of-care associated with this change. DESIGN: Quasi-experimental study comparing data from the calendar year before (2014) and after (2016) the change. SETTING: Single, tertiary-level, university-affiliated, maternity hospital. PARTICIPANTS: All women giving birth in the hospital, excluding those with pre-existing diabetes or multiple pregnancy. MAIN OUTCOME MEASURES: Primary outcomes were caesarean section, birth weight >90th percentile for gestation, hypertensive disorder of pregnancy and preterm birth less than 37 weeks. A number of secondary outcomes reported to be associated with GDM were also analysed.Care packages were derived for those without GDM, diet-controlled GDM and GDM requiring insulin. The institutional Business Reporting Unit data for average occasions of service, pharmacy schedule for the costs of consumables and medications, and Medicare Benefits Schedule ultrasound services were used for costing each package. All costs were estimated in figures from the end of 2016 negating the need to adjust for Consumer Price Index increases. RESULTS: There was an increase in annual incidence of GDM of 74% without overall improvements in primary health outcomes. This incurred a net cost increase of AUD$560 093. Babies of women with GDM had lower rates of neonatal hypoglycaemia and special care nursery admissions after the change, suggesting a milder spectrum of disease. CONCLUSION: New criteria for the diagnosis of GDM have increased the incidence of GDM and the overall cost of GDM care. Without obvious changes in short-term outcomes, validation over other systems of diagnosis may require longer term studies in cohorts using universal screening and treatment under these criteria.
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ItemA survey study of endometrial receptivity tests and immunological treatments in in vitro fertilisation (IVF)(WILEY, 2022-04)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.