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Research Question: How does the intracrine action of progestagens, oestrogens, androgens and corticosteroids affect endometrial tissue progression and function?, Design: In this prospective observational study, 76 patients (<50 years old, no uterine pathologies and at least one failed IVF cycle) undergoing endometrial biopsy collection for endometrial evaluation between 2018 and 2021 were included. The concentrations of 11 steroid metabolites (cortisone, cortisol, progesterone, oestrone, 2-methoxyestrone, oestradiol, oestriol, testosterone, androstenedione, 17α-hydroxyprogesterone and 17-hydroxypregnenolone) were measured by ultra-performance liquid chromatography-tandem mass spectrometry in the endometrial tissue samples collected during the mid-secretory phase. Endometrial dating and reproductive outcomes (relative to the next good-quality fresh or frozen embryo transfer after the biopsy) were analysed in relation to endometrial steroid concentrations using Barnard's test; correlations between metabolite concentrations were measured by Pearson's correlation co-efficient., Results: Endometrial cortisol concentrations increased with age, whereas oestrone and 17α-hydroxyprogesterone concentrations had inverse relationships with body mass index (all P < 0.05). No statistically significant differences were found in age or body mass index related to endometrial progression and reproductive outcomes. Low endometrial progesterone (<40.07 μg/g), along with high endometrial cortisol (>2.18 ng/g) and testosterone concentrations (≥0.52 ng/g), were mainly associated with out-of-phase endometria. Although low oestrone (<21.27 ng/g) and high androstenedione endometrial concentrations (≥1.35 ng/g) impaired reproductive success, low oestradiol (<1.15 ng/g) endometrial concentrations favoured conception (all P < 0.05)., Conclusions: In addition to progesterone and oestrogens, other steroid hormones are involved in intracrine signalling, and are probably necessary for acquiring adequate endometrial competence and supporting conception., (Copyright © 2024 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Research Question: Does the COVID-19 vaccination affect endometrial receptivity after single euploid embryo transfer, measured by sustained implantation rate?, Design: A retrospective cohort study analysing two groups of single euploid embryo transfers using own oocytes: one historical cohort of 3272 transfers 1 year before the pandemic; and one comprising 890 transfers in women previously vaccinated with mRNA vaccines against severe acute respiratory syndrome coronavirus 2. The main outcomes were clinical pregnancy rate (CPR) and sustained implantation rate (SIR) per embryo transfer. These outcomes were compared between non-vaccinated and vaccinated women, and women who had received one and two doses. Lastly, vaccinated women were divided into quartiles according to the time from last dose to embryo transfer., Results: Similar CPR and SIR were found between non-vaccinated and vaccinated women, and the odds ratio for both outcomes was not statistically significant after being controlled for potential confounders (OR 0.937, 95% CI 0.695 to 1.265 and OR 0.910, 95% CI 0.648 to 1.227 respectively). Within the vaccinated group, women who had received one or two doses also had similar outcomes. In addition, no differences were found according to the time interval from vaccination to embryo transfer., Conclusion: The administration of mRNA vaccines against COVID-19 had no effect on endometrial receptivity and embryo implantation, regardless of the number of doses and time interval from vaccination to embryo transfer. The potential negative effect of the vaccine on endometrial receptivity and reproductive outcomes is reassuring for patients in the process of undergoing assisted reproductive treatment., (Copyright © 2022 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

IVF techniques have changed over time with the aim of improving clinical results. Today, embryology is facing a change common to most areas of medicine, the introduction of automation. The use of automated systems in the IVF laboratory is already happening, for example, with electronic witnessing and the ranking of embryos according to their implantation potential. It is expected that in the near future, various systems in the IVF laboratory will be automated. In this way, gamete manipulation would cease to be manual and embryo culture and selection would be performed by means of microfluidics and artificial intelligence. Therefore, the tasks of the embryologist will inevitably be reduced. However, new functions related to data capture, management and analysis will emerge, along with other research skills and increased communication with other professionals and patients., (Copyright © 2021. Published by Elsevier Ltd.)

The main goal of assisted reproductive technology (ART) is to achieve a healthy singleton live birth after the transfer of one embryo. A major objective of IVF scientists has always been to use adequate criteria for selecting the embryo for transfer according to its implantation potential. Indeed, embryo quality is usually assessed by evaluating visual morphology, which relies on the removal of the embryo from the incubator and might include inter- and intra-evaluator variation among embryologists. Recently, an advancement in embryo culture has taken place with the introduction of a new type of incubator with an integrated time-lapse monitoring system, which enables embryologists to analyse the dynamic events of embryo development from fertilization to blastocyst formation. This novel practice is rapidly growing and has been used in many IVF centres worldwide. Therefore, the main aim of this review is to present the benefits of time-lapse monitoring in a modern embryology laboratory; in particular, we discuss blastocyst collapse and morphometric blastocyst assessment, and analyse their association with embryo viability and implantation potential. In addition, we highlight preliminary studies involving artificial intelligence and machine learning models as non-invasive markers of clinical pregnancy., (Copyright © 2021 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Research Question: Which pre-vitrification parameters are the most predictive of survival and live birth in vitrified-warmed blastocyst transfer cycles?, Design: A retrospective study including 11,936 warmed blastocysts. Pre-vitrification morphological parameters analysed for blastocysts included day of vitrification; blastocyst expansion degree; trophoectoderm grade (A, B and C); and inner cell mass grade (A, B and C). Univariate and multivariate generalized estimating equations models were used to analyse survival, clinical pregnancy and live birth rate. A stepwise regression analysis was conducted to select and classify by order which outcomes were the most predictive., Results: The odds of survival increased almost twice for blastocysts with lower expansion degree (OR 1.92; 95% CI 1.37 to 2.69; P < 0.001) and by about 50% for blastocysts vitrified on day 5 (OR 1.56; 95% CI 1.27 to 1.89; P < 0.001). Multivariate generalized estimating equations model showed that trophectoderm grade followed by the day of vitrification were the most significant predictors of live birth. The odds of live birth increased nearly three times for blastocysts with trophectoderm graded as A compared with those with trophectoderm graded as C (OR 2.85; 95% CI 2.48 to 3.27; P < 0.001), and double for blastocysts vitrified on day 5 compared with those vitrified on day 6 (OR 2.22; 95% CI 1.97 to 2.49; P < 0.001). The odds of live birth also increased in higher expansion degree blastocysts., Conclusions: Blastocysts vitrified on day 5 and those with higher trophoectoderm grade should be given priority when warming., (Copyright © 2021 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Research Question: The study aimed to develop an artificial intelligence model based on artificial neural networks (ANNs) to predict the likelihood of achieving a live birth using the proteomic profile of spent culture media and blastocyst morphology., Design: This retrospective cohort study included 212 patients who underwent single blastocyst transfer at IVI Valencia. A single image of each of 186 embryos was studied, and the protein profile was analysed in 81 samples of spent embryo culture medium from patients included in the preimplantation genetic testing programme. The information extracted from the analyses was used as input data for the ANN. The multilayer perceptron and the back-propagation learning method were used to train the ANN. Finally, predictive power was measured using the area under the curve (AUC) of the receiver operating characteristic curve., Results: Three ANN architectures classified most of the embryos correctly as leading (LB+) or not leading (LB-) to a live birth: 100.0% for ANN1 (morphological variables and two proteins), 85.7% for ANN2 (morphological variables and seven proteins), and 83.3% for ANN3 (morphological variables and 25 proteins). The artificial intelligence model using information extracted from blastocyst image analysis and concentrations of interleukin-6 and matrix metalloproteinase-1 was able to predict live birth with an AUC of 1.0., Conclusions: The model proposed in this preliminary report may provide a promising tool to select the embryo most likely to lead to a live birth in a euploid cohort. The accuracy of prediction demonstrated by this software may improve the efficacy of an assisted reproduction treatment by reducing the number of transfers per patient. Prospective studies are, however, needed., (Copyright © 2020 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Research Question: Is embryo selection by Dana (automatic software for embryo evaluation) associated with a higher implantation rate in IVF treatments?, Design: A three-phase study for Dana system's validation: creation of a data-cloud of known implantation data (KID) embryos from 1676 transferred embryos; embryo evaluation by Dana considering manual annotations and embryo development videos (389 transferred embryos); and validation of Dana automatic selection, without embryologist's intervention (147 transferred embryos); RESULTS: The implantation rate of the 1021 KID embryos from phase 1 served to set four grades of embryos referring to implantation rate: A = 34%, B = 25%, C = 24%, and D = 19%. Phase 2: a classification ranking according to the unit average distance (UAD) and implantation potential was established: top (UAD ≤0.50), high (UAD = 0.51-0.66), medium (UAD = 0.67-1.03) and low (UAD >1.03). Pregnancy rates were 59%, 46%, 36% and 28%, respectively (P < 0.001). Phase 3: embryos were automatically categorized according to Dana's classification ranking. Most implanted embryos were found in groups top, high and medium (UAD ≤1.03), whereas the implantation rate in group low (UAD >1.03) was significantly lower: 46% versus 25%, respectively (P = 0.037). The twin gestation rate was higher when number of top embryos (UAD ≤0.5) transferred were two (52%) versus one (25%) (P < 0.001)., Conclusions: Embryo selection based on Dana ranking increases the success of IVF treatments at least in oocyte donation programmes. The multicentre nature of the study supports its applicability at different clinics, standardizing the embryo development's interpretation. Dana's innovation is that the system increases its accuracy as the database grows., (Copyright © 2020 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Fertility societies worldwide responded to the COVID-19 pandemic by recommending that fertility clinics close, or sharply reduce, the clinical operation, leading to a shift in the management of IVF laboratories in three phases: shutdown preparation; maintenance during shutdown; and restart. Each of these phases carries distinct risks that need identification and mitigation, forcing laboratory managers to rethink and adapt their procedures in response to the pandemic. The sudden and unprecedented nature of the pandemic forced laboratory managers from around the world to base decisions on opinion and experience when evidence-based response options were unavailable. These perspectives on pandemic response were presented during a virtual international symposium on COVID-19, held on 3 April 2020, and organized by the London Laboratory Managers' Group. Laboratory managers from seven different countries at different stages of the pandemic (China, Italy, Spain, France, UK, Brazil and Australia) presented their personal experiences to a select audience of experienced laboratory managers from 19 different countries. The intention of this paper is to collect the learnings and considerations from this group of laboratory managers who collaborated to share personal experiences to contribute to the debate surrounding what constitutes good IVF laboratory practice in extraordinary circumstances, such as the COVID-19 pandemic., (Copyright © 2020 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Research Question: Does the presence of dysmorphisms affect post-warming survival and embryo development in vitrified autologous oocytes?, Design: A retrospective study comparing post-warming survival, fertilization and embryo development between morphologically normal (n = 269) and dysmorphic oocytes (n = 147)., Results: The survival rate was 81.4% in the morphologically normal oocytes and 87.1% in the dysmorphic oocyte group (OR 1.53; 95% CI 0.86 to 2.72). The fertilization rate was 69.9 versus 66.4% (OR 0.85; 95% CI 0.53 to 1.36), the proportion of good-quality embryos on day 3 was 30.3% versus 32.0% (OR 1.08; 95% CI 0.59 to 1.97) and the blastocyst formation rate was 54.5% versus 60.5% (OR 1.27; 95% CI 0.60 to 2.72) for the morphologically normal and the dysmorphic oocytes group, respectively. No statistical differences were found when the number and type of dysmorphism were analysed., Conclusion: Oocyte dysmorphisms did not seem to affect survival, fertilization and embryo development in vitrified autologous oocytes, and yielded comparable results to the morphologically normal oocytes., (Copyright © 2019 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Infertility affects over 70 million couples globally. Access to, and interest in, assisted reproductive technologies is growing worldwide, with more couples seeking medical intervention to conceive, in particular by IVF. Despite numerous advances in IVF techniques since its first success in 1978, almost half of the patients treated remain childless. The multifactorial nature of IVF treatment means that success is dependent on many variables. Therefore, it is important to examine how each variable can be optimized to achieve the best possible outcomes for patients. The current approach to IVF is fragmented, with various protocols in use. A systematic approach to establishing optimum best practices may improve IVF success and live birth rates. Our vision of the future is that technological advancements in the laboratory setting are standardized and universally adopted to enable a gold standard of care. Implementation of best practices for laboratory procedures will enable clinicians to generate high-quality gametes, and to produce and identify gametes and embryos of maximum viability and implantation potential, which should contribute to improving take-home healthy baby rates., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The morphology of fertilization events has been related to successful implantation by subjective criteria (pronuclei score, pronuclei symmetry and position). This work first described these events by time-lapse technology and then compared the timings of fertilization events (second polar body extrusion, first and second pronuclei appearance, abuttal and fading) in implanted versus nonimplanted embryos in a 2-year cohort retrospective study. A total of 1448 transferred embryos from 842 patients undergoing intracytoplasmic sperm injection with oocyte donation were monitored, 212 embryos from treatments where the number of gestational sacs matched the number of transferred embryos and 687 embryos from treatments no biochemical pregnancy was achieved. The timings at which second polar body extrusion (3.3-10.6 h), pronuclear fading (22.2-25.9 h) and length of S-phase (5.7-13.8 h) occurred were linked successfully to embryo implantation. The other parameters were apparently not related, as determined by image acquisition and time-lapse analysis., (Copyright © 2013 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Because of the different intrinsic characteristics of the classic IVF and intracytoplasmic sperm injection (ICSI) techniques, the timing of zygote development can be influenced by the method of fertilization. However, there is no information about the relevance of the insemination procedure on embryo-quality parameters as measured through their developmental dynamics. The aim of this work was to determine if the insemination technique, IVF or ICSI, influences embryo developmental kinetics by examining 1203 embryos from 178 couples undergoing oocyte donation with IVF or ICSI. Using time-lapse information, this work calculated several developmental kinetic variables, from pronuclear fading (PNF) to expanded blastocyst, and also the proportion of optimal embryos in a best time range with a predicted higher implantation potential. Embryo development after ICSI was slightly faster than after IVF; however, when PNF, rather than time of insemination, was established as t0, the differences between the two procedures disappeared. The percentage of optimal embryos showed a trend towards higher values in IVF-derived embryos; however, the difference was not statistically significant. With these results and through the time-lapse monitoring system, it is concluded that it is the fertilization method which determines embryo developmental kinetics if insemination time is used as the starting point. A key step in assisted reproduction is the assessment of oocyte and embryo viability to determine the embryo(s) most likely to implant. Current embryo assessment strategies in clinical settings largely rely on embryo morphology and cleavage rates, and although these systems have been successful in improving pregnancy rates, their precision is far from ideal as they are based on visual information. In contrast, automated image analysis may add objectivity to the process of embryo selection and consequently, lead to an improvement in the implantation rates. Timing of zygote development can be influenced by the method of fertilization or by in-vitro culture conditions, so it has been suggested that the fertilization procedure influences the length of time elapsed between fertilization and the first cleavage. In this report, we show the results from using a time-lapse monitoring system to determine the timing of key events during embryo development both in IVF and ICSI. Due to the different intrinsic characteristics of the classic IVF and ICSI techniques, the selection of a critical time point is essential so as to maximize the differences between the two methods. For that reason, we searched for evidence in the data obtained from the image analysis for a link connecting embryo cleavage and the fertilization technique and also to find whether the kinetic of development derived from classic IVF or ICSI is also related to a predicted higher implantation., (Copyright © 2013. Published by Elsevier Ltd.)

During follicular growth, the follicle is exposed to an almost ever-changing composition of isoforms of FSH and LH, which causes a number of different and divergent biological effects. Through a time-lapse system, embryo kinetics were examined following the use of FSH only (recombinant FSH, rFSH) and gonadotrophins containing LH activity (human menopausal gonadotrophin, HMG, and FSH+HMG) in oocyte donors. No significant differences were seen between the three groups (for rFSH, HMG and rFSH+HMG, t2 was 27.8h, 27.9h and 27.5h respectively). Moreover, although embryos obtained with rFSH showed an increase in the proportions of optimal timings of development, the differences observed were not significant, as shown by the percentages of embryos inside/outside these kinetic variables. In contrast, for gonadotrophin dosage and oestradiol concentration, this study observed differences in embryo development kinetics for some of the variables evaluated, which allowed the description of an optimal range of gonadotrophin dosage and oestradiol concentration. However, these kinetic differences did not translate into important distinctions in the proportion of optimal embryos with a higher implantation potential., (Copyright © 2012 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Noninvasive markers of embryo quality are being sought to improve IVF success. The present study aimed to discover possible associations between embryo division kinetics in the cleavage stage, the subsequent ability of human embryos to reach the blastocyst stage and the resulting blastocyst morphology. A retrospective cohort study analysed 834 embryos from 165 oocyte donation couples using a time-lapse monitoring system that allowed the recording of the exact timings for key events related to embryo development. Timing parameters were categorized into four quartiles. The probability of an embryo developing to a blastocyst was linked to a strict chronology of development. To further evaluate the relationships between these morphokinetic parameters and subsequent blastocyst formation, the ensuing blastocyst morphology was compared with a viability score based on a hierarchical classification of the cleavage-stage morphokinetic parameters. It is concluded that the kinetics of early embryo development and the potential for human embryos to develop to the blastocyst stage on day 5 are closely related and that time-lapse-based evaluation of the exact timing of early events in embryo development is a promising tool for the prediction of blastocyst formation and quality according to the proposed model., (Copyright © 2012 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Basic sperm analysis is limited as a method of estimating pregnancy. This study’s objective was use of microarray technology to differentiate the gene expressions of spermatozoa that achieved pregnancy in an intracytoplasmic sperm injection (ICSI)cycle in an oocyte donation programme with those that did not achieve pregnancy. A study of nested cases and controls was designed to evaluate fresh and frozen spermatozoa from infertile males undergoing ICSI with donor oocytes. The global genome expression of pooled samples from each group (achieving pregnancy versus those that didn’t, from fresh or frozen spermatozoa)was compared using microarray analysis. The level of expression of some of the transcripts from fresh spermatozoa was shown to differ for those that achieved pregnancy versus those that didn’t. Additionally, exclusively expressed transcripts were identified for both outcome groups. Analysis of frozen spermatozoa didn’t reveal differential expression, but exclusively expressed transcripts were detected. Lists of the transcripts were systematically analysed using different databases in order to provide information about them and their relationship with male fertility. The results revealed profound differences between the expression profiles of spermatozoa that resulted in pregnancy versus those that didn’t. These differences may explain ICSI failure associated with male factor infertility., (Copyright © 2010 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Semen analysis, as stated by the World Health Organization, is the only accepted tool to assess male fertility. However its predictive value to assess male capacity to initiate a pregnancy is limited. With the introduction of IVF (especially via intracytoplasmic sperm injection), infertility caused by diminished sperm production is frequently solved, but knowledge of sperm physiology remains very poor. Moreover, a percentage of males with apparently normal semen are unable to impregnate healthy women. Therefore, improvements in the diagnostic tools to assess male fertility potential are necessary. The aim of this review is to describe sperm molecular factors implicated in male fertility, demonstrated by their role in sperm physiology, the molecular differences found between fertile and infertile males, or by their influence on the results obtained in assisted reproduction treatments in terms of embryo quality and pregnancy achievement. From a search and objective evaluation of the currently available evidence, it is concluded that there is no unique factor able to predict male fertility, but several molecular factors are involved in sperm function and can potentially be considered as fertility markers. In this context, a complex molecular tool designed to analyse a battery of parameters seems to be necessary.

There has been an increasing tendency to delay parenthood in developed countries in recent years, and there is not enough information available regarding the effect of this on fertility. The aim of this work was to determine the role of paternal age on the outcome of assisted reproduction. A retrospective study was designed comprising a total of 2204 intrauterine insemination (IUI) cycles, 1286 IVF cycles and 1412 IVF cycles with donated oocytes during the period 2000 to 2006. Male mean age was 34.3 years (range 25-56) for IUI, 34.8 years (range 19-62) for IVF and 41.10 years (range 25-71) for ovum donation cycles. Statistics revealed no differences regarding pregnancy and miscarriage rates when the results were compared among age groups. In standard IVF and ovum donation cycles there was no clear association between embryo quality and paternal age. There was no significant relationship between male age and implantation rate. So far this is the largest study concerning the relevance of male age in assisted reproduction. As confirmed by the present data, the effect of the age of the male in the range studied is irrelevant. This finding contributes to the information that can be provided to infertile couples.