Vitro Fertilization Research Articles

Ethical constraints and dilemmas in the provision of in-vitro fertilization treatment in Ghana: from the perspectives of experts

BackgroundInfertility presents both medical and public health challenges, with in vitro fertilization (IVF) emerging as a prominent solution, particularly when other alternatives are exhausted. However, IVF treatment raises significant ethical questions that have been under explored in the Ghanaian context. This study aimed to explore ethical constraints and dilemmas in the provision of in vitro fertilization (IVF) treatment in Ghana.MethodsA descriptive phenomenological qualitative design was employed. Purposive sampling techniques were used to recruit 12 participants including ART experts from three in vitro fertilization (IVF) centres, ethicists and a legal practitioner. In-depth face-to-face interviews guided by an open-ended interview guide were conducted. Thematic analysis of the interviews was performed to identify major themes.ResultsProviding IVF treatment in Ghana raises several ethical issues, including inequitable access due to high costs and limited availability, which favour wealthier individuals and leave marginalized populations with fewer options. There are significant ethical considerations in balancing the potential benefits of successful IVF treatment outcomes against the health risks and emotional tolls on patients. Decisions about the fate of surplus embryos present moral dilemmas, including whether to preserve, donate, or discard them. Differing personal beliefs about the moral status of the embryo further complicate the ethical landscape. Ensuring informed consent is challenging due to the complex medical, ethical, and emotional implications of IVF treatment, potentially leading to compromised consent. Additionally, there are ongoing risks of breaches in confidentiality, given the sensitive nature of reproductive health data and the importance of protecting patient privacy.ConclusionThis study revealed that several ethical dilemmas confront both healthcare providers and couples in the process of IVF. There is an urgent need for the development of clear and uniform regulations to govern the practice of IVF treatment in Ghana, with further attention given to mitigating financial barriers and enhancing support systems for couples considering IVF treatment.

Preimplantation Genetic Testing for Aneuploidy (PGT-A) in In-Vitro Fertilisation (IVF) Treatment: Study Protocol for Pilot Phase of a Randomised Controlled Trial.

Introduction: Poor outcomes following IVF treatments are speculated to be due to the transfer of aneuploid embryos that cannot be identified based on morphological evaluation alone. This leads to patients requiring numerous embryo transfers and, consequently, a prolonged time interval before live birth. Embryo selection following preimplantation genetic testing for aneuploidy (PGT-A) with next-generation sequencing (NGS) has been suggested as an intervention to shorten time to pregnancy in women undergoing in vitro fertilisation (IVF). Past studies assessing the clinical efficacy of PGT-A in improving clinical outcomes have been conflicting and the associated clinical pregnancy rates and live birth rates following the transfer of a mosaic embryos have yet to be determined. None of the existing studies solely included women of advanced reproductive age (ARA). The pilot study and proposed RCT will determine if, compared to morphological evaluation alone, the use of PGT-A through NGS is a more clinically effective, safer, and more cost-effective way to provide IVF treatment in women of advanced reproductive age. Method and Analysis: The proposed pilot study will aim to randomise 100 patients within a single-centre study to evaluate recruitment, randomisation, and adherence to study protocol and allocated trail arms by participating patients. The results of the pilot study will enable us to determine the sample size for a larger study to establish the effectiveness of PGT-A in ARA women. Ethics and Dissemination: The study (Integrated Research Application System Number 236067) received approval from the Health Research Authority and Health and Care Research Wales (HCRW) and the East Midlands-Leicester South Research Ethics Committee (20/EM/0290). The results will be made available to patients, the funders, the Reproductive Medicine societies, and other researchers. Trial registration: ClinicalTrials.gov Identifier: NCT05009745, n.

Diagnosing a genetic disease in a donor-conceived child: case report and discussion of the ethical, legal, and practical issues.

We describe the unexpected challenges pediatricians may experience when children conceived with assisted reproduction are diagnosed with a rare genetic condition. A local case series triggered a dialogue between many stakeholders with varied expertise. Indeed, diagnosing a genetic disease in a child conceived by embryo, egg, or sperm donation is becoming more common now that genetic testing and in vitro fertilization (IVF) are readily accessible. However, how and whether to share that information with other stakeholders in the gamete donation process has not been fully explored, and the clinical responsibilities of the treating clinician remain ill-defined. This work centers on a patient with a confirmed diagnosis of X-linked nephrogenic diabetes insipidus. Ultimately, we found the same AVPR2 mutation in two children from two families conceived by egg donation. It led to multigenerational cascade diagnoses in the family of the shared, anonymous egg donor. First, we review current genetic testing practices in gamete donation and third-party reproduction. Then, we provide an overview of relevant genomic, ethical, legal, and psychosocial considerations for sharing relevant genomic information. Finally, and to maximize the best interests of genetic relatives, we discuss how a pediatrician can play a role in the early disclosure of relevant clinical information to all stakeholders in the gamete donation process, starting with the fertility clinic. While these clinical cases are cast in a Canadian context, we submit that its important lessons generally apply to medical systems of nearly all developed countries, broadly defined.

Ensemble machine learning models for sperm quality evaluation concerning success rate of clinical pregnancy in assisted reproductive techniques

This study aimed to investigate the influence of various sperm quality characteristics, including morphology, motility, and count, on the success rates of clinical pregnancy achieved through assisted reproductive technologies (ART) such as in-vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), and intrauterine insemination (IUI). The secondary objective was to assess the impact of these sperm parameters on the clinical pregnancy rate that resulted in the detection of a fetal heartbeat during the 11th week of gestation, a crucial milestone in successful ART-derived pregnancies. The researchers employed a retrospective analysis, evaluating data from 734 couples undergoing IVF/ICSI and 1197 couples undergoing IUI across two infertility centers. Exclusion criteria included cases involving donated eggs or sperm, surrogate uteri, and infertile couples with combined male and female factors. Five ensemble machine-learning models were utilized to predict the clinical pregnancy success rates. The Random Forest (RF) model achieved the highest mean accuracy (0.72) and area under the curve (AUC) (0.80), outperforming the other models for both IVF/ICSI and IUI procedures. The Shapley Additive Explanations (SHAP) value analysis revealed that for IUI cycles, all three sperm parameters (morphology, motility, and count) had significant negative impacts on the prediction of clinical pregnancy success. In contrast, for IVF/ICSI cycles, sperm motility had a positive effect, while sperm morphology and count were negative factors. In cycles with 1 to 5 retrieved eggs, sperm motility, and count, they positively affected the clinical pregnancy rate. The study also identified cut-off values for sperm count, with 54 and 35 being the respective thresholds for IVF/ICSI and IUI. Additionally, a significant cut-off point 30 was found for the sperm morphology parameter across all procedures. This study underscores the immense potential of leveraging ensemble machine learning models with traditional sperm quality assessments. This integrated approach can elevate the precision and personalization of clinical decision-making in the field of assisted reproductive technologies, ultimately offering more hope and better outcomes for couples struggling with infertility.

Multi-omics PGT: re-evaluation of euploid blastocysts for implantation potential based on RNA sequencing.

In addition to chromosomal euploidy, can the transcriptome of blastocysts be used as a novel predictor of embryo implantation potential? This retrospective analysis showed that based on differentially expressed genes (DEGs) between euploid blastocysts which resulted and did not result in a clinical pregnancy, machine learning models could help improve implantation rates by blastocyst optimization. Embryo implantation is a multifaceted process, with implantation loss and pregnancy failure related not only to blastocyst euploidy but also to the intricate dialog between blastocyst and endometrium. Although in vitro studies have revealed the characteristics of trophectoderm (TE) differentiation in implanted blastocysts and the function of TE placentation at the implantation site, the precise molecular mechanisms of embryo implantation and their clinical application remain to be fully elucidated. This study involved 102 patients who underwent 111 cycles for preimplantation genetic testing for aneuploidies (PGT-A) between March 2022 and July 2023. The study included 412 blastocysts biopsied at Day 5 [D5] or Day 6 [D6] for patients who underwent PGT-A. The biopsy lysates were split and subjected to DNA and RNA sequencing (DNA- and RNA-seq). One part was used for PGT-A to detect DNA copy number variations, whereas the other part was assessed simultaneously by RNA-seq to determine the transcriptome characteristics. To validate the reliability and accuracy of RNA-seq obtained from this strategy, we initially analyzed the transcriptome of blastocysts with chromosomal aneuploidies. Subsequently, we compared the transcriptomic features of blastocysts with different rates of formation (D5 vs D6) and investigated the network of interactions between key blastulation genes and the receptive endometrium. Then to evaluate the implantation potential of euploid blastocysts, we identified DEGs between euploid blastocysts that resulted in clinical pregnancy (defined as the presence of a gestational sac detected by ultrasound after 5 weeks) and those that did not. These DEGs were then employed to construct a predictive model for optimizing blastocyst selection. The successful detection rate of PGT-A was remarkably high at 99.8%. The RNA data may infer aneuploidy for both trisomy and monosomy. Between the euploid blastocysts that formed on D5 and D6, 187 DEGs were predominantly involved in cell differentiation for embryonic placenta development, the PPAR signaling pathway, and the Notch signaling pathway. These D5/D6 DEGs also exhibited a functional dialog with the receptive phase endometrium-specific genes through protein-protein interaction networks, indicating that the embryo undergoes further differentiation for post-implantation development. Furthermore, a modeling strategy using 280 DEGs between blastocysts leading to successful clinical pregnancies or failing to produce clinical pregnancies was implemented to refine the euploid embryo optimization, achieving areas under the curves of 0.88, 0.71, and 0.84 for the random forest (RF), support vector machine, and linear discriminant analysis models, respectively. Finally, a retrospective analysis of 83 transferred euploid blastocysts using the RF model identified three types of euploid embryos with a decreasing trend in implantation potential. Notably, the implantation rate of the good group was significantly higher than that of the moderate group (88.6% vs 50.0% P = 0.001) and that of the moderate group was higher than that of the poor group (50.0% vs 20.8%, P = 0.035). The sample size was insufficient; thus, a prospective study is needed to verify the clinical effectiveness of the above model. Because we did not analyze blastocysts that led only to biochemical pregnancies but failed clinical pregnancies separately, our classification system still must be modified to screen these embryos. Transcriptomic analysis of blastocysts offers a novel approach for predicting embryo implantation potential, which can be utilized to optimize clinical embryo selection. The ranking system may be effective in reducing the times and costs involved in achieving a clinical pregnancy. This study was funded by the "Pioneer" and "Leading Goose" R&D Program of Zhejiang (No. 2023C03034), the National Natural Science Foundation of China (82101709), and the National Key Research and Development Program for Young Scientists of China (No. 2022YFC2702300). The authors state no competing interests. N/A.

Supplementation of spermidine enhances the quality of postovulatory aged porcine oocytes

BackgroundSpermidine (SPD) is an intermediate compound in the polyamine metabolism which takes critical part in a variety of cellular processes. In particular, it has been reported to exert anti-aging effects, suppress the age-related diseases, and extend lifespan across species. However, whether it has the favorable influence on the quality of postovulatory aged oocytes remains elusive.MethodsImmunostaining and fluorescence intensity measurement were used to evaluate the effects of postovulatory aging and SPD supplementation on the oocyte fragmentation, spindle/chromosome structure, actin polymerization, dynamics of cortical granules (CGs) and ovastacin, mitochondrial distribution and function, as well as autophagy levels. In addition, in vitro sperm binding assay and in vitro fertilization (IVF) experiment were applied to assess the impacts of postovulatory aging and SPD supplementation on the sperm binding ability and fertilization capacity of oocytes.ResultsHere, we showed that supplementation of SPD during postovulatory aging could relieve the deterioration of porcine oocytes. Specifically, we found that postovulatory aging impaired the oocyte quality by damaging the morphological integrity of oocytes, maintenance of spindle/chromosome structure, and dynamics of actin cytoskeleton. Postovulatory aging also weakened the sperm binding ability and fertilization capacity of oocytes by compromising the distribution pattern of CGs and their content ovastacin. Notably, supplementation of SPD attenuated these defects in postovulatory aged porcine oocytes via strengthening mitochondrial function, eliminating excessive reactive oxygen species (ROS), inhibiting apoptosis, and enhancing autophagy levels.ConclusionAltogether, our findings demonstrate that SPD supplementation is a feasible approach to ameliorate the quality of postovulatory aged oocytes, which can be potentially applied to the human assisted reproductive technology (ART) and in vitro production of animal embryos.

A review of artificial intelligence applications in in vitro fertilization.

The field of reproductive medicine has witnessed rapid advancements in artificial intelligence (AI) methods, which have significantly enhanced the efficiency of diagnosing and treating reproductive disorders. The integration of AI algorithms into the in vitro fertilization (IVF) has the potential to represent the next frontier in advancing personalized reproductive medicine and enhancing fertility outcomes for patients. The potential of AI lies in its ability to bring about a new era characterized by standardization, automation, and an improved success rate in IVF. At present, the utilization of AI in clinical practice is still in its early stages and faces numerous ethical, regulatory, and technical challenges that require attention. In this review, we present an overview of the latest advancements in various applications of AI in IVF, including follicular monitoring, oocyte assessment, embryo selection, and pregnancy outcome prediction. The aim is to reveal the current state of AI applications in the field of IVF, their limitations, and prospects for future development. Further studies, which involve the development of comprehensive models encompassing multiple functions and the conduct of large-scale randomized controlled trials, could potentially indicate the future direction of AI advancements in the field of IVF.

Altered metabolic profiles in male offspring conceived from intracytoplasmic sperm injection

BackgroundWhile most research has focused on the association between intracytoplasmic sperm injection (ICSI) and neurodevelopmental disorders in children, relatively little attention has been given to its metabolic effects. Previous studies have reported that low serum lipid levels are associated with mental health problems. Our objective was to analyze the impact of ICSI on metabolic alterations compared to their in vitro fertilization (IVF) counterparts in male offspring, as well as its interaction with paternal overweight/obesity.MethodsWe recruited families between January 2006 and December 2017 at the Center for Reproductive Medicine, Shandong University, China. Prospective data of offspring were obtained for body mass index (BMI), blood pressure, glucose, and lipid profile in their 0–11 years old. Linear mixed models were utilized to compute the mean difference and 95% confidence intervals (CI).ResultsA total of 14,196 offspring visits were identified. In offspring aged 4–11 years, ICSI-conceived offspring exhibited significantly lower fasting glucose z-scores, total cholesterol z-scores, and low-density lipoprotein cholesterol (LDL-C) z-scores compared with their IVF counterparts (fasting glucose z-score: adjusted mean difference: − 0.13, 95% CI: − 0.23 to − 0.03; total cholesterol z-score: adjusted mean difference: − 0.13, 95% CI: − 0.23 to − 0.02; LDL-C z-score: adjusted mean difference: − 0.12, 95% CI: − 0.22 to − 0.01). Paternal overweight/obesity significantly influenced the relationship between ICSI and metabolic changes in offspring. In offspring born from fathers with overweight/obesity, ICSI-conceived offspring displayed significantly lower fasting glucose and total cholesterol z-scores than their IVF controls (fasting glucose z-score: adjusted mean difference: − 0.20, 95% CI: − 0.32 to − 0.08; total cholesterol z-score: adjusted mean difference: − 0.15, 95% CI: − 0.27 to − 0.02). In offspring born to fathers with normal weight, ICSI-conceived offspring showed significantly lower systolic blood pressure z-scores compared to those conceived via the IVF procedures (adjusted mean difference: − 0.21, 95% CI: − 0.37 to − 0.05).ConclusionsThe findings of this study suggested that ICSI was associated with altered glucose and lipid profiles compared to their IVF controls, characterized by lower fasting glucose z-scores, total cholesterol z-scores, and LDL-C z-scores. Encouraging fathers to reduce their body weight could potentially improve the metabolic health of their ICSI-conceived children.

Factors affecting the outcomes of in vitro fertilization in women with endometriosis: Preliminary data from Vietnam

Objectives: This study aimed to assess the efficacy of in vitro fertilization (IVF) in patients with endometriosis and identify related factors that may influence treatment outcomes. Methods: This retrospective descriptive study was conducted between November 2018 and November 2022. The study group comprised individuals who were diagnosed with endometriosis (endometrioma and/or adenomyosis) indicated for in vitro fertilization. The control group (129 patients with 249 cycles), which included patients without endometriosis and had an equivalent mean age as the study group patients. Results: In the endometriosis group, the quantities of retrieved oocytes and Anti-Müllerian Hormone (AMH) were reduced compared to the control group. The overall dose of gonadotropin and the duration of ovarian stimulation were significantly higher than the control group. The endometriosis group exhibited a Metaphase II (MII) oocyte rate of 82.3% and an oocyte fertilization rate of 82.2%. However, in patients with endometriosis, the rates of implantation, clinical pregnancy, and ongoing pregnancy were significantly lower than in patients without endometriosis. Besides, the clinical pregnancy rate of women with endometriosis was remarkably higher in the groups with maternal age ⩽35 years, a ratio of Follicle-stimulating Hormone to Luteinizing Hormone (FSH/LH) ⩽1.5, and over 10 retrieved oocytes. Conclusion: Endometriosis was associated with a decreased rate of implantation, clinical pregnancy, and ongoing pregnancy after in vitro fertilization treatment compared with patients without endometriosis. In vitro fertilization outcomes in patients with endometriosis were influenced by maternal age ⩽35 years, FSH/LH ratio ⩽1.5, and number of retrieved oocytes over 10.

Inconsistent embryo selection across polygenic score methods.

Inconsistent embryo selection across polygenic score methods.

Multi-omics approach to reveal follicular metabolic changes and their effects on oocyte competence in PCOS patients.

Polycystic ovary syndrome (PCOS) is a common heterogeneous disorder linked with endocrine and metabolic disturbances. The underlying mechanism of PCOS, especially its effect on oocyte competence, remains unclear. The study aimed to identify abnormal follicular metabolic changes using a multi-omics approach in follicular fluid from PCOS patients and to determine their effects on oocyte competence. A total of 36 women with PCOS and 35 women without PCOS who underwent in vitro fertilization and embryo transfer were included in the study. Cumulus cells and follicular fluid samples were collected. Follicular fluid samples underwent metabolomic analysis, while cumulus cell clusters from the same patients were assessed using transcriptomic analysis. Clinical information of patients and assisted reproductive technology (ART) results were recorded. Transcriptomics and metabolomics were integrated to identify disrupted pathways, and receiver operation characteristics (ROC) analysis was conducted to identify potential diagnostic biomarkers for PCOS. Pearson correlation analysis was conducted to assess the relationship between metabolites in follicular fluid and oocyte competence (fertilization and early embryo development potential). Through multi-omics analysis, we identified aberrantly expressed pathways at both transcriptional and metabolic levels, such as the citrate cycle (TCA cycle), oxidative phosphorylation, the cAMP signaling pathway, the mTOR signaling pathway, and steroid hormone biosynthesis. Ten candidate metabolites were identified based on metabolic profiling data from these altered pathways. Phytic acid, succinic acid, 2'-deoxyinosine triphosphate, and 4-trimethylammoniobutanoic acid in the follicular fluid exhibited high specificity and sensitivity in distinguishing PCOS. Among these metabolites, L-arginine showed a negative correlation with the 2PN fertilization rate and cleavage rate, while estrone sulfate showed a negative correlation with the high-quality embryo rate in the in-vitro fertilization (IVF) cycle. We have conducted a preliminary study of a novel metabolic signature in women with PCOS using a multi-omics approach. The alterations in key metabolic pathways may enhance our understanding of the pathogenesis of PCOS.

DEEP LEARNING DEVELOPMENTAL MODEL FOR EMBRYO GRADING IN THAI POPULATION

In light of the growing challenges associated with infertility, an increasing number of researchers are resorting to assisted reproductive technologies such as In Vitro Fertilization (IVF). Embryo grading is a crucial step in the IVF process that requires embryologists’ expertise. However, their limited availability has led to the exploration of technological alternatives. This study aims to use deep learning for human embryo grading, with models specifically designed for the dataset in Thailand at Vajira Hospital. The process of IVF at Vajira Hospital presents its own set of challenges since its embryo classification extends beyond the Istanbul consensus. Furthermore, classes that occur infrequently are removed and classes with similarities are merged. We apply transfer learning to pretrained deep learning models like VGG19, VGG16, ResNet152, Resnet101, Xception, InceptionV3, and EfficientNet, to create a system capable of accurately classifying embryo quality scores. Experimental results from the embryo dataset collected from Vajira Hospital in Thailand demonstrate the proposed classifier’s accuracy, precision, recall, f1-score, and AUC superiority. This research contributes to the field of IVF in Thailand by potentially reducing human errors and addressing the demand for skilled embryologists.

The High Estradiol Environment after IVF Causes the Increased Risk of Glucose Metabolic Dysfunction in Offspring.

Assisted reproductive technology (ART) is associated with increased metabolic risks in offspring. The effect of high maternal estradiol (E2) levels during early pregnancy on the glucose metabolism of offspring remains unclear. To evaluate glucose metabolism in in vitro fertilization (IVF)-conceived children and assess whether high E2 exposure during early pregnancy is associated with metabolic alterations. This retrospective analysis included 500 singletons aged 3-10 years born after fresh embryo transfer (ET) (n=200), frozen ET (n=100), and natural conception (NC) (n=200) from a university hospital. Children underwent anthropometric measurements and examinations for fasting glucose, insulin, and lipid levels. A mouse model of high E2 exposure during early pregnancy was established to study glucose and insulin tolerance, and insulin secretion. Compared with NC, children born after fresh ET showed higher fasting glucose/insulin levels, increased insulin resistance, and higher incidence of impaired fasting glucose, which might be associated with a higher maternal E2 levels. Frozen ET showed intermediate results. In mice, offspring exposed to high E2 levels during gestation exhibited impaired glucose/insulin tolerance and defects in insulin secretion. High maternal E2 levels in early pregnancy are associated with altered glucose metabolism and increased metabolic risks in IVF-conceived children. Further studies are needed to elucidate the underlying mechanisms.

Fixed versus flexible gonadotropin releasing hormone antagonist protocol in women with polycystic ovary syndrome undergoing in vitro fertilization: An RCT.

Despite the extensive use of the gonadotropin-releasing hormone (GnRH) antagonist protocol in treating infertile women, particularly those with polycystic ovary syndrome (PCOS), there have not been sufficient evidence to compare the flexible and fixed variants in in vitro fertilization (IVF) cycles. This study aims to assess the treatment outcomes of flexible and fixed types of GnRH-antagonist protocol for IVF in women with PCOS. In this randomized clinical trial, 150 infertile women with PCOS, who were candidates for IVF, and referred to the Yazd Research and Clinical Center for Infertility, Yazd, Iran between October 2023 and February 2024 were included. Participants were divided into 2 groups (n = 75/each) based on the type of antagonist protocol (fixed or flexible). GnRH antagonist administration started on the 5 day of gonadotropin treatment in the fixed group. In the flexible group when there was at least one follicle 12-14 mm, GnRH antagonist was started. Finally, the number of metaphase II oocyte, the quality of embryos, the duration of the stimulation cycle, the dose of gonadotropin, the number of GnRH-antagonist, and the rate of ovarian hyperstimulation syndrome were evaluated. No statistically significant difference was observed in terms of cycle length and the total dose of gonadotropin between groups. Nevertheless, a notable distinction was observed in the total number of oocytes (17.84 vs. 15.5, p = 0.023) and mature oocytes (13.64 vs. 11.83, p = 0.019) in the flexible group compared to the fixed group. In conclusion, the IVF outcomes are more favorable in women with PCOS undergoing the flexible GnRH-antagonist protocol compared to the fixed protocol.

Correlation of adenomyosis features to live birth rates after the first IVF/ICSI treatment, when using the revised Morphological Uterus Sonographic Assessment group definitions.

Data regarding the impact of adenomyosis on the outcomes after invitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment are conflicting. Standardized diagnostic criteria are prerequisites for studying a potential association between adenomyosis and IVF/ICSI treatment outcomes. This study aims to examine the cumulative live birth rate (CLBR) after the first IVF/ICSI treatment in women with or without direct or indirect features of adenomyosis, using the revised Morphological Uterus Sonographic Assessment (MUSA) group definitions. This was a prospective cohort study of 1037 women aged 25-≤39 years, undergoing their first IVF/ICSI treatment between January 2019 and October 2022. The presence of MUSA features of adenomyosis was assessed prior to treatment start. The CLBR after the first IVF/ICSI treatment was 424/1037 (40.9%, 95% CI, 37.9-43.8) in the total cohort. Women with direct features of adenomyosis had lower CLBR, 25/102 (24.5%; 95% CI, 17.5-31.5) than women without, 399/935 (42.7%; 95% CI, 39.5-45.8), p < 0.001. The adjusted relative risk (aRR) for live birth for women with direct features of adenomyosis compared to women without was 0.62 (95% CI, 0.43-0.88), p = 0.007. Direct features were associated with a higher risk of miscarriage after frozen embryo transfer, aRR 2.88 (95% CI, 1.49-5.57), p = 0.002. Women with indirect features had a lower CLBR [50/188 (26.6%, 95% CI, 20.3-32.9)] than women without [399/935, (42.7%, 95% CI, 39.5-45.8)], aRR 0.58 (95% CI, 0.45-0.75), p < 0.001. For features located in the inner myometrium, the aRR for live birth was 0.29 (95% CI 0.11-0.74), p = 0.010 and for the outer myometrium 2.61 (95% CI 1.42-4.8), p = 0.002. An interrupted junctional zone was the single feature that impacted CLBR the most. The presence of direct or indirect MUSA features of adenomyosis correlates to reduced live birth rates in women undergoing their first IVF/ICSI treatment. Features located in the inner myometrium, particularly an interrupted junctional zone, reduced the chance of live birth the most, whereas location in the outer myometrium was associated with higher chances of live birth. Systematic ultrasound examinations should be considered for women scheduled for IVF/ICSI treatment, for adequate counseling on the chances of successful treatment.

Steady morphokinetic progression is an independent predictor of live birth: a descriptive reference for euploid embryos.

Can modelling the longitudinal morphokinetic pattern of euploid embryos during time-lapse monitoring (TLM) be helpful for selecting embryos with the highest live birth potential? Longitudinal reference ranges of morphokinetic development of euploid embryos have been identified, and embryos with steadier progression during TLM are associated with higher chances of live birth. TLM imaging is increasingly adopted by fertility clinics as an attempt to improve the ability of selecting embryos with the highest potential for implantation. Many markers of embryonic morphokinetics have been incorporated into decision algorithms for embryo (de)selection. However, longitudinal changes during this temporal process, and the impact of such changes on embryonic competence remain unknown. Aiming to model the reference ranges of morphokinetic development of euploid embryos and using it as a single longitudinal trajectory might provide an additive value to the blastocyst morphological grade in identifying highly competent embryos. This observational, retrospective cohort study was performed in a single IVF clinic between October 2017 and June 2021 and included only autologous single euploid frozen embryo transfers (seFET). Reference ranges were developed from [hours post-insemination (hpi)] of the standard morphokinetic parameters of euploid embryos assessed as tPB2, tPNa, tPNf, t2-t9, tSC, tM, tSB, and tB. Variance in morphokinetic patterns was measured and reported as morphokinetic variance score (MVS). Nuclear errors (micronucleation, binucleation, and multinucleation) were annotated when present in at least one blastomere at the two- or four-cell stages. The blastocyst grade of expansion, trophectoderm (TE), and inner cell mass (ICM) were assessed immediately before biopsy using Gardner's criteria. Pre-implantation genetic diagnosis for aneuploidy (PGT-A) was performed by next-generation sequencing. All euploid embryos were singly transferred in a frozen transferred cycle and outcomes were assessed as live birth, pregnancy loss, or not pregnant. Association of MVS with live birth was investigated with regression analyses. TLM data from 340 seFET blastocysts were included in the study, of which 189 (55.6%) resulted in a live birth. The median time for euploid embryos to reach blastulation was 109.9 hpi (95% CI: 98.8-121.0 hpi). The MVS was calculated from the variance in time taken for the embryo to reach all morphokinetic points and reflects the total morphokinetic variability it exhibits during its development. Embryos with more erratic kinetics, i.e. higher morphokinetic variance, had higher rates of pregnancy loss (P = 0.004) and no pregnancy (P < 0.001) compared to embryos with steadier morphokinetic patterns. In the multivariable analysis adjusting for ICM, TE grade, presence of nuclear errors, and time of blastulation, MVS was independently associated with live birth (odds ratio [OR]: 0.62, 95% CI: 0.46-0.84, P = 0.002) along with ICM quality. Live birth rate of embryos with the same ICM grading but different morphokinetic variance patterns differed significantly. Live birth rates of embryos exhibiting low MVS with ICM grades A, B, and C were 85%, 76%, and 67%, respectively. However, ICM grades A, B, and C embryos with high MVS had live birth rates of 65%, 48%, and 21% (P < 0.001). The addition of the MVS to embryo morphology score (ICM and TE grading) significantly improved the model's AUC value (0.67 vs 0.62, P = 0.015) and this finding persisted through repeat cross-validation (0.64 ± 0.08 vs 0.60 ± 0.07, P < 0.001). The exclusion of IVF cases limits, for now, the utility of the model to only ICSI-derived embryos. The utility of these reference ranges and the association of MVS with various clinical outcomes should be further investigated. We have developed reference ranges for morphokinetic development of euploid embryos and a marker for measuring total morphokinetic variability exhibited by developed blastocysts. Longitudinal assessment of embryonic morphokinetics rather than static time points may provide more insight about which embryos have higher live birth potential. The developed reference ranges and MVS show an association with live birth that is independent of known morphological factors and could emerge as a valuable tool in prioritizing embryos for transfer. This study received no external funding. The authors declare no conflicting interests. N/A.

Patient-Centric In Vitro Fertilization Prognostic Counseling Using Machine Learning for the Pragmatist.

Although in vitro fertilization (IVF) has become an extremely effective treatment option for infertility, there is significant underutilization of IVF by patients who could benefit from such treatment. In order for patients to choose to consider IVF treatment when appropriate, it is critical for them to be provided with an accurate, understandable IVF prognosis. Machine learning (ML) can meet the challenge of personalized prognostication based on data available prior to treatment. The development, validation, and deployment of ML prognostic models and related patient counseling report delivery require specialized human and platform expertise. This review article takes a pragmatic approach to review relevant reports of IVF prognostic models and draws from extensive experience meeting patients' and providers' needs with the development of data and model pipelines to implement validated ML models at scale, at the point-of-care. Requirements of using ML-based IVF prognostics at point-of-care will be considered alongside clinical ML implementation factors critical for success. Finally, we discuss health, social, and economic objectives that may be achieved by leveraging combined human expertise and ML prognostics to expand fertility care access and advance health and social good.

Survey of in vitro fertilization add-ons in Japan (Izanami project).

To identify any correlations between evidence levels, adoption rates, and additional costs of in vitro fertilization (IVF) add-ons. Online survey. The survey was conducted in 621 assisted reproductive technology-registered facilities that are members of the Japanese Society of Obstetrics and Gynecology from December 22, 2021, to February 13, 2022. The survey included details regarding the specific add-on modalities employed and their associated costs; inquiries pertained to the fertility healthcare infrastructure in Japan before the implementation of the National Health Insurance scheme. The correlation between the adoption rate and cost of IVF add-ons and their evidence levels were analyzed. The evidence level of the add-on treatments was classified into Green, Amber, and Red categories based on the United Kingdom's Human Fertilisation and Embryology Authority and Cochrane systematic reviews. A total of 438 eligible responses were analyzed, with clinics constituting 70.9% of the respondents' facilities. A total of 18 add-ons were assessed, and 96.5% (423/438) of facilities used at least one add-on. A positive correlation of the adoption rate and an inverse correlation of the cost with the evidence level of the IVF add-on treatment were observed (not significant). Outpatient clinics, defined as medical facilities with no beds, had a significantly higher adoption rate (Amber, 65.7%; Red, 52.0%) of add-ons than other facilities, regardless of the evidence rating, although the costs were similar across all site attributes. Accumulating evidence on the efficacy and safety of add-ons will lead to the development of medical care with a high-cost benefit, as an increase in the adoption rate and a decrease in cost are expected when limiting to medical care with a high level of evidence.

Additional Daily Intramuscular Progesterone for Luteal Phase Support does not Improve Live Birth Rates of Programmed Frozen-Thawed Embryo Transfer Cycles

This retrospective cohort study aims to investigate whether additional daily intramuscular progesterone (IMP) for luteal phase support improves live birth rates of programmed frozen-thawed embryo transfer (FET) cycles. The study was conducted at a tertiary level university hospital assisted reproductive technology (ART) center between January 2014 and Jan 2021. Six hundred four infertile patients with single-day 5-6 frozen-thawed blastocyst embryo transfer were enrolled in the study. All patients received either 8% micronized vaginal gel or vaginal progesterone capsules for luteal phase support. Intramuscular progesterone was added to vaginal progesterone depending on the in vitro fertilization (IVF) specialist’s choice. Luteal phase support (LPS) was started 6 days before transfer in frozen-thawed cycles and continued until the end of the first trimester. Cycles were compared depending on vaginal progesterone types (8% gel vs. capsule) and the presence of intramuscular progesterone. The primary outcome was the live birth rate. A total of 604 FET cycles were enrolled. Using 8% micronized progesterone or progesterone capsules did not change the live birth rates (24% vs. 25.9%). As the main result, intramuscular progesterone support with vaginal progesterone compared with only vaginal progesterone did not improve the live birth results (22% vs. 24%). In conclusion, this study demonstrated that routine IMP progesterone given in combination with vaginal progesterone does not improve ART outcomes. This combination may be beneficial in a selective population with a monitored luteal phase. Using any form of vaginal progesterone alone is adequate for LPS.

Comparative analysis of the bioaccumulation of bisphenol A in the blood serum and follicular fluid of women living in two areas with different environmental impacts.

Bisphenol A (BPA) is a common contaminant widely used in many industrial sectors. Because of its wide use and dispersion, it can be accumulated in living human bodies through both oral assumption and nondietary routes. BPA exhibits hormone-like properties, falling under the class of endocrine disruptors; therefore, it can alter relevant physiological functions. In particular, in women, it can affect folliculogenesis and therefore reproduction, contributing not only to infertility, but also to endometriosis and premature puberty. We conducted a multicenter study on 91 women undergoing a first in vitro fertilization (IVF) treatment in the Campania region (Southern Italy). We investigated the presence and concentration of BPA in serum and follicular fluids to assess the effects of airborne BPA contamination. The analysis was conducted on 32 women living in a low environmental impact (LEI) area, from the Sele Valley River and Cilento region, and 59 women living in a high environmental impact (HEI) area, the so-called "Land of Fires", a highly contaminated territory widely exposed to illegal waste practices. A higher average BPA content in both blood serum and follicular fluid was revealed in the HEI group when compared with the LEI group. In addition, we revealed higher average BPA content in blood serum than in folliclular fluid in the HEI area, with opposite average content in the two fluids in the LEI zone. In addition, our results also showed a lack of correlation between BPA content in follicular and serum fluids both in the overall population and in the HEI and LEI groups, with peculiar trends in different subsets of women. From our results, we revealed a heterogeneity in the distribution of BPA content between serum and follicular fluid. Further studies are needed to unravel the bioaccumulation mechanisms of BPA in highly polluted and nonpolluted areas.