Recommendations from the 2024 Australian evidence-based guideline for unexplained infertility: ADAPTE process from the ESHRE evidence-based guideline on unexplained infertility.

INTRODUCTION: The 2024 Australian evidence-based guideline for unexplained infertility provides clinicians with evidence-based recommendations for the optimal diagnostic workup for infertile couples to establish the diagnosis of unexplained infertility and optimal therapeutic approach to treat couples diagnosed with unexplained infertility in the Australian health care setting. The guideline recommendations were adapted for the Australian context from the rigorous, comprehensive European Society of Human Reproduction and Embryology (ESHRE) 2023 Evidence-based guideline: unexplained infertility, using the ADAPTE process and have been approved by the Australian National Health and Medical Research Council. MAIN RECOMMENDATIONS: The guideline includes 40 evidence-based recommendations, 21 practice points and three research recommendations addressing: definition - defining infertility and frequency of intercourse, infertility and age, female and male factor infertility; diagnosis - ovulation, ovarian reserve, tubal factor, uterine factor, laparoscopy, cervical/vaginal factor, male factor, additional testing for systemic conditions; and treatment - expectant management, active treatment, mechanical-surgical procedures, alternative therapeutic approaches, quality of life. CHANGES IN ASSESSMENT AND MANAGEMENT RESULTING FROM THE GUIDELINE: This guideline refines the definition of unexplained infertility and addresses basic diagnostic procedures for infertility assessment not considered in previous guidelines on unexplained infertility. For therapeutic approaches, consideration of evidence quality, efficacy, safety and, in the Australian setting, feasibility, acceptability, cost, implementation and ultimately recommendation strength were integrated across multidisciplinary expertise and consumer perspectives in adapting recommendations to the Australian context by using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework, which had not been used in past guidelines on unexplained infertility to formulate recommendations. The Australian process also included an established data integrity check to ensure evidence could be trusted to guide practice. Practice points were added and expanded to consider the Australian setting. No evidence-based recommendations were underpinned by high quality evidence, with most having low or very low quality evidence. In this context, research recommendations were made including those for the Australian context. The full guideline and technical report are publicly available online and can be accessed at https://www.monash.edu/medicine/mchri/infertility and are supported by extensive translation resources, including the free patient ASKFertility mobile application (https://www.askfertility.org/).

Utility of culture and molecular methods using AllplexTM Bacterial Vaginosis Plus Assay (SeegeneⓇ) as a tool for endometriosis, infertility and recurrent pregnancy loss diagnosis.

Endometriosis, infertility, or recurrent pregnancy loss (RPL) are entities characterised by a decrease in Lactobacillus spp. and an increase in bacterial vaginosis-associated bacteria, (BVAV) according with 16S rRNA sequencing studies. However, the use of nucleic acid amplification tests (NAAT) as a tool for diagnosis algorithms is unknown. Seventy-four patients were included, with a median age of 36.5 years old (IQR: 34-39) including infertility (n=31), endometriosis (n=25), or RPL (n=18), for culturing and NAAT using the Allplex™ Bacterial Vaginosis Plus (ABVP) assay (SeegeneⓇ) with endometrial samples. The objective was determining the utility of ABVP assay for diagnosing the entities. Forty-six microorganisms were isolated from 31 out of 74 patients (41.9 %). Twenty-five endometrial samples (33.8 %) were positive for some targets included in the ABVP-assay, with median Ct value ∼37 (IQR: 31.3-37.1) and Qt value 1.43 Log10copies/reaction (IQR:1.1-2.6). For Lactobacillus species, sensitivity and specificity were 80 % and 84 %, respectively. Gardnerella vaginalis, 63.6 % and 95.7 %. No significant increase in BVAV was detected in any of the gynaecological entities. The ABVP and culture based algorithm did not show utility as a tool for endometriosis, infertility, or RPL diagnosis.

Clinical Applications of Assisted Oocyte Activation in Couples with Various Reproductive Problems: A Systematic Review.

ICSI may face fertilization failure, prompting the use of assisted oocyte activation (AOA) techniques. While AOA is implemented in infertility clinics, its target patients and definitive application remain uncertain. This systematic review adheres to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to assess reproductive outcomes in ICSI-AOA cycles compared to conventional ICSI and evaluate AOA effectiveness in various infertility disorders. A literature search encompassed PubMed, Web of Science, EMBASE, and Scopus databases until December 2023 for relevant English studies. Included studies compared ICSI-AOA with conventional ICSI in couples with prior fertilization failure, utilizing diverse AOA methods. Control groups consisted of sibling oocytes, previous cycles of the same couples, or couples undergoing conventional ICSI. Evaluated outcomes included fertilization, cleavage, embryo quality, implantation, pregnancy, and live birth rates. Article screening and data extraction were performed by two authors, with risk of bias assessed by another investigator. Out of 3088 initially identified articles, 30 studies were included, focusing on fertilization failure (n = 10), female infertility (n = 3), PLCζ defects (n = 4), poor sperm quality (n = 4), Globozoospermia (n = 4), and surgically retrieved sperm (n = 8). Most studies concluded that AOA could overcome fertilization failure, but success rates varied based on sperm-related or oocyte-related factors in ICSI-AOA cycles. Due to differences in patient inclusion criteria and sample sizes, most studies were not sufficiently similar for pooled analysis, limiting robust conclusions. There is insufficient evidence, particularly from randomized controlled trials (RCTs), to determine the efficacy or safety of ICSI-AOA as a treatment strategy. Registration number is PROSPERO, CRD42024551221.

Parity, infertility, age at first birth, and risk of atrial fibrillation: data from the HUNT study.

AIMS: Although parity, infertility, and age at first birth are important for later development of cardiovascular disease, research on their association with atrial fibrillation (AF) is limited. METHODS AND RESULTS: We linked data from the population-based HUNT study and the Medical Birth Registry of Norway (MBRN) and validated medical records from local hospitals. A total of 24 015 women aged 45 years or older were followed for verified incident AF. Parity and age at first birth were retrieved from the MBRN or from self-reported questionnaires in the HUNT study. A history of infertility was self-reported on the HUNT questionnaire. Cox proportional hazards models were used to calculate hazard ratios (HRs) for the multivariable-adjusted associations of parity, infertility, and age at first birth with risk of AF. During a median follow-up of 12.8 years, 1448 (6.0%) participants developed AF. Women with higher parity (four or more births vs. two births) were at 21% higher risk of AF [HR 1.21, 95% confidence interval (CI) 1.05-1.39]. A history of infertility was also associated with the risk of AF (HR 1.20, 95% CI 1.02-1.42). Among parous women, younger age at first birth (<20 vs. 20-29 years) was associated with a 20% higher risk of AF (HR 1.20, 95% CI 1.03-1.40). CONCLUSION: Women with four or more births, or a history of infertility, or younger age at first birth have approximately a 20% higher risk of AF among women over 45 years old.

A higher number of births and a younger age at first birth are associated with a higher risk of cardiovascular disease. However, there is limited evidence on the associations between parity, age at first birth, and atrial fibrillation (AF). Moreover, the association between infertility and AF remains largely unexplored. We investigated the association between parity, infertility, age at first birth, and AF in a population-based cohort from Norway (the HUNT study) among women over 45 years old. Our findings reveal that women with four or more births, or a history of infertility, or younger age at first birth have approximately a 20% higher risk of AF.

Local Government Initiatives: A Comprehensive Analysis of Infertility Diagnostic and Treatment Programs in Poland (2009-2020).

BACKGROUND Infertility is an increasingly significant public health problem. However, thanks to the achievements of modern medicine, it is possible to take steps to treat it. The objective of this study was to present data about programs for the diagnosis and treatment of infertility that were developed, implemented, and financed by local governments at all levels in Poland in 2009-2020. MATERIAL AND METHODS The study was conducted based on the analysis of existing data from the Minister of Health. We present data on infertility diagnostics and treatment programs, the number of programs in particular years, the number of programs implemented by individual levels of local governments, the number of people participating in the programs, and the total cost of the programs in EUR. RESULTS Programs aimed at diagnosing/treating infertility began to be implemented in 2012 (most were implemented in 2019 and 2020, 18 each). Twenty-three local governments of various levels, including 5 communes, 13 cities with poviat rights, 1 poviat, and 4 voivodeships, participated in the implementation of these programs. A total of 22 379 people were covered by infertility diagnosis and treatment programs in the years 2012-2020. The cost of all implemented programs was over EUR 10.7 million. CONCLUSIONS The legal situation in Poland caused the vast majority of infertile couples who wanted to have children to have to self-finance in vitro fertilization procedures. A small number of local governments undertook actions aimed at co-financing in vitro fertilization procedures.

Imprinting disorders in children conceived with assisted reproductive technology in Sweden.

OBJECTIVE: To assess whether the use of assisted reproductive technology (ART) therapy for conception is associated with imprinting disorders in children and the impact of parental factors related to infertility. DESIGN: A nationwide register-based cohort study. SETTING: Swedish national registers and nationwide quality IVF register. PATIENT(S): All liveborn singletons in Sweden (N = 2,084,127) between 1997 and 2017 with follow-up to December 31, 2018. INTERVENTION(S): The use of specific methods implemented in ART. MAIN OUTCOME MEASURE(S): The International Classification of Diseases version 10 was used to identify three distinct imprinting disorder groups: Beckwith-Wiedemann syndrome (BWS), Prader-Willi syndrome (PWS), and Silver-Russell syndrome (SRS), as well as central precocious puberty. The Cox model combined with inverse probability treatment weights was used to estimate the weighted hazard ratio (wHR) with a 95% confidence interval (CI), accounting for multiple confounders. RESULT(S): A total of 1,044 children were diagnosed with the disorders of interest, and 52 of them were conceived using ART therapy. The overall risk of being diagnosed with any of the studied imprinting disorders was elevated in children conceived using ART therapy compared with all other children (HR, 1.84; 95% CI, 1.38-2.45). After adjusting for parental background factors, the association was partially attenuated (wHR, 1.50; 95% CI, 0.97-2.32), but remained in the weighted comparison restricted to children of couples with known infertility (wHR, 1.52; 95% CI, 1.05-2.21). For the specific diagnoses of PWS/SRS, and BWS compared with children of couples with known infertility, children conceived with ART therapy showed a small excess risk, which could not be distinguished from the null (wHR, 1.56; 95% CI, 0.93-2.62 and 1.80; 95% CI, 0.99-3.28, respectively). Further subgroup analysis showed that the combined use of intracytoplasmic sperm injection and cryopreserved embryos was associated with a higher risk of both PWS/SRS (wHR, 4.60; 95% CI, 1.72-12.28) and BWS (wHR, 6.69; 95% CI, 2.09-21.45). The number of central precocious puberty cases in children conceived using ART therapy was too small (N = 3) to make any meaningful inference. CONCLUSION(S): The combined use of intracytoplasmic sperm injection and cryopreserved embryos was associated with small elevated risks of PWS/SRS, and BWS in children, independent of parental factors related to infertility.

In vitro fertilization and perinatal outcomes of patients with advanced maternal age after single frozen euploid embryo transfer: a propensity score-matched analysis of autologous and donor cycles.

OBJECTIVE: To evaluate in vitro fertilization (IVF) and perinatal outcomes of donor egg and autologous cycles in patients with advanced reproductive age after undergoing single frozen euploid embryo transfer. DESIGN: A multicenter, retrospective, cohort study. SETTING: University-affiliated and private IVF centers. PATIENT(S): Patients aged 39-46 years who underwent IVF with intracytoplasmic sperm injection and preimplantation genetic testing for aneuploidy using whole-chromosome sequencing with donor (n = 278) or autologous (n = 278) oocytes between October 2017 and October 2021. INTERVENTION(S): Single frozen euploid embryo transfer with donor or autologous euploid embryo. MAIN OUTCOME MEASURE(S): The main outcome measure was the live birth rate (LBR) after the first embryo transfer, calculated per embryo transfer. The secondary outcomes included the implantation rate, ectopic pregnancy rate, miscarriage rate, and gestational age and birth weight at the time of delivery. RESULT(S): Patients using donor or autologous oocytes had a similar likelihood of implantation (57.91% [51.87-63.78] vs. 57.19% [51.15-63.09]) and LBR (41.01% [95% confidence interval {CI}, 35.17-47.04] vs. 42.45% [95% CI, 36.56-48.49]). Furthermore, there were no significant differences in the ectopic pregnancy rate (0.72% [0.09-2.57] vs. 0.36% [0.01-1.99]), miscarriage rate (16.19% [12.06-21.05] vs. 14.39% [95% CI, 10.48-19.08]), gestational age (38.50 [38.08-38.92] vs. 39.16 [38.25-40.07] weeks), or birth weight of infants (2,982.25 [2,606.69-3,357.81] vs. 3,128.24 [2,962.30-3,294.17] kg). The univariate analysis showed no association between advanced maternal age and the LBR (relative risk, 1.03 [95% CI, 0.84-1.25]). Multivariate analysis using putative confounders for embryo competency found no associations with LBR (adjusted relative risk, 1.22 [95% CI, 0.75-1.98]). CONCLUSION(S): Patients with euploid blastocysts derived from donor or autologous oocytes did not reveal statistically significant differences in the LBR, implantation rate, ectopic pregnancy rate, miscarriage rate, duration of gestation, or infant birth weight. These findings suggest that age-related reproductive decline and/or poor IVF outcomes associated with women with advanced reproductive age undergoing IVF are heavily driven by embryonic aneuploidy.

Treating obesity and fertility in the era of glucagon-like peptide 1 receptor agonists.

The objective of this narrative review is to advocate for improved comprehensive care of patients with obesity and infertility. Persons with an increased body mass index have less successful reproductive outcomes, and recently, new medications to treat neuroendocrine hormone imbalances are producing meaningful weight loss akin to surgical interventions. For the first time, obesity is publicly being recognized as a disease. These medications contain the newest generation of glucagon-like peptide 1 receptor agonists and deserve our attention for several reasons: regardless of body mass index, many patients will be using them; it is necessary to understand the mode of action, side effects, and implications for anesthetic procedures and pregnancy; and it is important to evaluate when they could be used to improve health outcomes and/or access to fertility care.

Clinical outcomes of single blastocyst transfer with machine learning guided noninvasive chromosome screening grading system in infertile patients.

BACKGROUND: Prospective observational studies have demonstrated that the machine learning (ML) -guided noninvasive chromosome screening (NICS) grading system, which we called the noninvasive chromosome screening-artificial intelligence (NICS-AI) grading system, can be used embryo selection. The current prospective interventional clinical study was conducted to investigate whether this NICS-AI grading system can be used as a powerful tool for embryo selection. METHODS: Patients who visited our centre between October 2018 and December 2021 were recruited. Grade A and B embryos with a high probability of euploidy were transferred in the NICS group. The patients in the control group selected the embryos according to the traditional morphological grading. Finally, 90 patients in the NICS group and 161 patients in the control group were compared statistically for their clinical outcomes. RESULTS: In the NICS group, the clinical pregnancy rate (70.0% vs. 54.0%, p < 0.001), the ongoing pregnancy rate (58.9% vs. 44.7%, p = 0.001), and the live birth rate (56.7% vs. 42.9%, p = 0.001) were significantly higher than those of the control group. When the female was ≥ 35 years old, the clinical pregnancy rate (67.7% vs. 32.1%, p < 0.001), ongoing pregnancy rate (56.5% vs. 25.0%, p = 0.001), and live birth rate (54.8% vs. 25.0%, p = 0.001) in the NICS group were significantly higher than those of the control group. Regardless of whether the patients had a previous record of early spontaneous abortion or not, the live birth rate of the NICS group was higher than that of the control group (61.0% vs. 46.9%; 57.9% vs. 34.8%; 33.3% vs. 0%) but the differences were not statistically significant. CONCLUSIONS: NICS-AI was able to improve embryo utilisation rate, and the live birth rate, especially for those ≥ 35 years old, with transfer of Grade A embryos being preferred, followed by Grade B embryos. NICS-AI can be used as an effective tool for embryo selection in the future.

Effect of postthaw change in embryo score on single euploid embryo transfer success rates.

OBJECTIVE: To assess whether the change in embryo morphology from precryopreservation to postthaw is associated with the embryo transfer success rates in single euploid embryo transfer cycles. DESIGN: Retrospective cohort study. SETTING: Academic affiliated fertility clinic. PATIENT(S): Patients who underwent a single euploid embryo transfer cycle from September 2016 to April 2022 were included. A decision support tool was used to assign each embryo a reproductive potential score on the basis of the day of biopsy, expansion, and grade of trophectoderm and inner cell mass at the time of cryopreservation and after thaw. Embryos were divided into 4 groups: group 1 included embryos with the same score after thaw (reference); group 2 included those with a higher score; group 3 included those with a lower score; and group 4 included those that did not re-expand after thaw. INTERVENTION(S): No interventions administered. MAIN OUTCOME MEASURE(S): The primary outcome was the live birth rates (LBRs) per embryo transfer. The secondary outcomes included the chemical pregnancy, clinical pregnancy, and clinical pregnancy loss rates. Comparative statistics and univariate analyses were performed using the Kruskal-Wallis and χ2tests. Multivariate logistic regression fitted with generalized estimating equation was performed to compare the odds of live birth between groups. RESULT(S): A total of 7,750 embryo transfers performed for 4,613 patients met inclusion criteria: 5,331 in group 1; 486 in group 2; 1,726 in group 3; and 207 in group 4. In the univariate analysis, there was a statistically significant difference in the LBR between groups 1, 2, 3, and 4 (55.8% vs. 51.4%, 47.5%, and 26.6%). Logistic regression controlling for oocyte age, antimüllerian hormone, body mass index, endometrial thickness, year of embryo transfer, time from thaw to final grading, and embryo score before cryopreservation showed significantly lower odds of live birth when the embryo was downgraded (odds ratio [OR], 0.70; confidence interval [CI], 0.62-0.79) or did not re-expand (OR, 0.36; CI, 0.26-0.51) than those with no change in score. When controlling for all variables, there was a significant increase in the odds of live birth between embryos that had a higher score after thaw and those without a change (OR, 1.42; CI, 1.14-1.76). There was no significant difference in the clinical pregnancy loss rate among the 4 groups. CONCLUSION(S): The change in the quality of the embryo after thaw is an important factor in embryo transfer success. In an adjusted analysis, the chemical and clinical pregnancy rates and LBR per embryo transfer all significantly decrease in embryos that were downgraded or did not expand on the day of single euploid embryo transfer. Embryos that re-expand and have improved quality after thaw have the highest odds of live birth.

Patient interest in and clinician reservations on polygenic embryo screening: a qualitative study of stakeholder perspectives.

PURPOSE: We explored and compared perspectives of reproductive endocrinology and infertility specialists (REIs) and in vitro fertilization (IVF) patients regarding polygenic embryo screening (PES), a new type of preimplantation screening that estimates the genetic chances of developing polygenic conditions and traits in the future. METHODS: Qualitative thematic analysis of semi-structured interviews with US-based REIs and IVF patients. RESULTS: Clinicians and patients often held favorable views of screening embryos for physical or psychiatric conditions, though clinicians tended to temper their positive attitudes with specific caveats. Clinicians also expressed negative views about screening embryos for traits more frequently than patients, who generally held more positive views. Most clinicians were either unwilling to discuss or offer PES to patients or were willing to do so only under certain circumstances, while many patients expressed interest in PES. Both stakeholder groups envisioned multiple potential benefits or uses of PES and raised multiple potential, interrelated concerns about PES. CONCLUSION: A gap exists between clinician and patient attitudes toward PES; clinicians generally maintained reservations about such screening and patients indicated interest in it. Clinicians and patients sometimes imagined using PES to prepare for the birth of a predisposed or "affected" individual-a rationale that is often associated with prenatal testing. Many clinicians and patients held different attitudes depending on what is specifically screened, despite the sometimes blurry distinction between conditions and traits. Considerations raised by clinicians and patients may help guide professional societies in developing guidelines to navigate the uncertain terrain of PES.

Predictors of success after in vitro fertilization.

The last few decades have witnessed a rise in the global uptake of in vitro fertilization (IVF) treatment. To ensure optimal use of this technology, it is important for patients and clinicians to have access to tools that can provide accurate estimates of treatment success and understand the contribution of key clinical and laboratory parameters that influence the chance of conception after IVF treatment. The focus of this review was to identify key predictors of IVF treatment success and assess their impact in terms of live birth rates. We have identified 11 predictors that consistently feature in currently available prediction models, including age, duration of infertility, ethnicity, body mass index, antral follicle count, previous pregnancy history, cause of infertility, sperm parameters, number of oocytes collected, morphology of transferred embryos, and day of embryo transfer.