Current In Vitro Fertilization Research Articles

Artificial intelligence system for outcome evaluations of human in vitro fertilization-derived embryos.

In vitro fertilization (IVF) has emerged as a transformative solution for infertility. However, achieving favorable live-birth outcomes remains challenging. Current clinical IVF practices in IVF involve the collection of heterogeneous embryo data through diverse methods, including static images and temporal videos. However, traditional embryo selection methods, primarily reliant on visual inspection of morphology, exhibit variability and are contingent on the experience of practitioners. Therefore, an automated system that can evaluate heterogeneous embryo data to predict the final outcomes of live births is highly desirable. We employed artificial intelligence (AI) for embryo morphological grading, blastocyst embryo selection, aneuploidy prediction, and final live-birth outcome prediction. We developed and validated the AI models using multitask learning for embryo morphological assessment, including pronucleus type on day 1 and the number of blastomeres, asymmetry, and fragmentation of blastomeres on day 3, using 19,201 embryo photographs from 8271 patients. A neural network was trained on embryo and clinical metadata to identify good-quality embryos for implantation on days or day 5, and predict live-birth outcomes. Additionally, a 3D convolutional neural network was trained on 418 time-lapse videos of preimplantation genetic testing (PGT)-based ploidy outcomes for aneuploidy prediction and consequent live-birth outcomes. These two approaches enabled us to automatically assess the implantation potential. By combining embryo and maternal metrics in an ensemble AI model, we evaluated live-birth outcomes in a prospective cohort that achieved higher accuracy than experienced embryologists (46.1% vs. 30.7% on day 3, 55.0% vs. 40.7% on day 5). Our results demonstrate the potential for AI-based selection of embryos based on characteristics beyond the observational abilities of human clinicians (area under the curve: 0.769, 95% confidence interval: 0.709-0.820). These findings could potentially provide a noninvasive, high-throughput, and low-cost screening tool to facilitate embryo selection and achieve better outcomes. Our study underscores the AI model's ability to provide interpretable evidence for clinicians in assisted reproduction, highlighting its potential as a noninvasive, efficient, and cost-effective tool for improved embryo selection and enhanced IVF outcomes. The convergence of cutting-edge technology and reproductive medicine has opened new avenues for addressing infertility challenges and optimizing IVF success rates.

Unravelling the role of HAS2, GREM1, and PTGS2 gene expression in cumulus cells: implications for human oocyte development competency - a systematic review and integrated bioinformatic analysis.

The leading indicator for successful outcomes in in-vitro fertilization (IVF) is the quality of gametes in oocytes and sperm. Thus, advanced research aims to highlight the parameter in assessing these qualities - DNA fragmentation in sperm and oocyte development capacity (ODC) via evaluation of microenvironments involving its maturation process. Regarding oocytes, most evidence reveals the role of cumulus cells as non-invasive methods in assessing their development competency, mainly via gene expression evaluation. Our review aims to consolidate the evidence of GDF-9 derivatives, the HAS2, GREM1, and PTGS2 gene expression in cumulus cells used as ODC markers in relevant publications and tailored to current IVF outcomes. In addition to that, we also added the bioinformatic analysis in our review to strengthen the evidence aiming for a better understanding of the pathways and cluster of the genes of interest - HAS2, GREM1, and PTGS2 in cumulus cell level. Otherwise, the current non-invasive method can be used in exploring various causes of infertility that may affect these gene expressions at the cumulus cell level. Nevertheless, this method can also be used in assessing the ODC in various cohorts of women or as an improvement of markers following targeted tools or procedures by evaluating the advancement of these gene expressions following the targeted intervention.

Advances in microfluidic technology for sperm screening and in vitro fertilization.

About 18% of reproductive-age adults worldwide are affected by infertility. In vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) are widely used assisted reproductive technologies (ARTs) aimed at improving clinical outcomes. Efficient and noninvasive selection and isolation of highly motile sperm with intact DNA are essential for the success of IVF and ICSI and can potentially impact the therapeutic efficacy and the health of the offspring. Compared to traditional methods, microfluidic technology offers significant advantages such as low sample consumption, high efficiency, minimal damage, high integration, similar microenvironment, and high automation, providing a new platform for ARTs. Here, we review the current situation of microfluidic technology in the field of sperm motility screening and evaluation and IVF research. First, we focus on the working principle, structural design, and screening results of sperm selection microfluidic platforms. We then highlight how the multiple steps of the IVF process can be facilitated and integrated into a microfluidic chip, including oocyte capture, sperm collection and isolation, sperm sorting, fertilization, and embryo culture. Ultimately, we summarize how microfluidics can complement and optimize current sperm sorting and IVF protocols, and challenges and possible solutions are discussed.

WNT Co-Receptor LRP6 Is Critical for Zygotic Genome Activation and Embryonic Developmental Potential by Interacting with Oviductal Paracrine Ligand WNT2.

Mammalian preimplantation development depends on the interaction between embryonic autocrine and maternal paracrine signaling. Despite the robust independence of preimplantation embryos, oviductal factors are thought to be critical to pregnancy success. However, how oviductal factors regulate embryonic development and the underlying mechanism remain unknown. In the present study, focusing on WNT signaling, which has been reported to be essential for developmental reprogramming after fertilization, we analyzed the receptor-ligand repertoire of preimplantation embryonic WNT signaling, and identified that the WNT co-receptor LRP6 is necessary for early cleavage and has a prolonged effect on preimplantation development. LRP6 inhibition significantly impeded zygotic genome activation and disrupted relevant epigenetic reprogramming. Focusing on the potential oviductal WNT ligands, we found WNT2 as the candidate interacting with embryonic LRP6. More importantly, we found that WNT2 supplementation in culture medium significantly promoted zygotic genome activation (ZGA) and improved blastocyst formation and quality following in vitro fertilization (IVF). In addition, WNT2 supplementation significantly improved implantation rate and pregnancy outcomes following embryo transfer. Collectively, our findings not only provide novel insight into how maternal factors regulate preimplantation development through maternal-embryonic communication, but they also propose a promising strategy for improving current IVF systems.

The Health Services Legal Problems of In Vitro Fertilization (IVF) Program Patients in Indonesia

Introduction to The Problem: Every married couple expects children that the Constitution guarantees. However, the difficulty of having a child tends to be a problem in maintaining married life. Some couples decide to have a child by undergoing In Vitro Fertilization (IVF) Program. The arising problems are on how the current regulation of the IVF program and how to fulfil the rights of IVF program patients from consumer protection law. Purpose/Objective Study: This article focus on the problem of health services for IVF program patients based on the values of justice on the ground of consumer protection law in Indonesia. Design/Methodology/Approach: This study is socio-legal research. However, to support the validity of research, an empirical approach is critical to do-furthermore, where data obtained through interviews based on the researcher’s own experience. Findings: IVF program agreement between the IVF clinic and patients is a law based on Article 1338 of the Indonesian Civil Code. Even so, the research validation was still carried out with the support of an empirical approach. The results of this research are that the current IVF program has not been able to protect its patients’ rights. Patients’ position tends to be weak compared to the clinic or IVF hospital; the concept of the IVF program implementation agreement does not protect patient rights. In the future, attempts to protect IVF patients’ rights need an integrated and comprehensive regulation from the philosophical, juridical, and sociological basis to its practical implementation. Paper Type: Research Article

Predicting the chance on live birth per cycle at each step of the IVF journey: external validation and update of the van Loendersloot multivariable prognostic model

ObjectiveTo study the performance of the ‘van Loendersloot’ prognostic model for our clinic’s in vitro fertilisation (IVF) in its original version, the refitted version and in an adapted version replacing...

IVF-on-a-Chip: Recent Advances in Microfluidics Technology for In Vitro Fertilization.

In vitro fertilization (IVF) has been one of the most exciting modern medical technologies. It has transformed the landscape of human infertility treatment. However, current IVF procedures still provide limited accessibility and affordability to most infertile couples because of the multiple cumbersome processes and heavy dependence on technically skilled personnel. Microfluidics technology offers unique opportunities to automate IVF procedures, reduce stress imposed upon gametes and embryos, and minimize the operator-to-operator variability. This article describes the rapidly evolving state of the application of microfluidics technology in the field of IVF, summarizes the diverse angles of how microfluidics has been complementing or transforming current IVF protocols, and discusses the challenges that motivate continued innovation in this field.

Double-edged sword of gonadotropin-releasing hormone (GnRH): A novel role of GnRH in the multiple beneficial functions of endometrial stem cells

Gonadotropin-releasing hormone (GnRH) stimulates the synthesis and release of gonadotropins, which induce estrogen production and subsequent ovulation. Therefore, long-term GnRH exposure to regulate ovarian hyperstimulation is recognized as the gold standard for most in vitro fertilization (IVF) strategies. However, one of the most disappointing aspects of current IVF technology is relatively low rate (between 35 and 50%) of positive pregnancy outcomes, and the major reason for this high cancellation rate has not yet been revealed. Previous studies have demonstrated that resident stem cell deficiency limits the cyclic regenerative capacity of the endometrium and subsequently increases pregnancy failure rates. Therefore, we hypothesized that long-term GnRH exposure directly damages endometrial stem cells and consequently negatively affects pregnancy outcomes in GnRH-based IVF. In addition to their well-known roles in regulating the hypothalamus-pituitary-gonadal axis, GnRH and its receptors also localize in the extra-hypothalamic endometrium, suggesting a possible non-canonical role in endometrial stem cells. Consistent with our hypothesis, we show for the first time that GnRH suppresses the multiple beneficial functions of endometrial stem cells via the PI3K/Akt signaling pathway in vitro and in vivo. To the best of our knowledge, this is the first study to focus on the direct effects of GnRH on the regenerative potential of stem cells, and the findings will facilitate the development of more promising IVF strategies.

Effect of semen preparation technique and its incubation on sperm quality in the Moroccan population.

In in vitro fertilisation (IVF), sperm preparation as critical part and influencing the sperm quality is especially dependent on the chosen technique itself and incubation parameters including temperature and CO2. In this study, we compared firstly density-gradient centrifugation technique (DGC) to the adapted DGC using the sperm pellet of 80% fraction (DGC/80P) in order to improve the sperm yield. Secondly, this study led to evaluate different sperm incubation conditions based on temperature effect (room temperature (RT=23°C) versus 35°C) and in the other hand, with or without 5% CO2 during 24hrs. Based on evaluating sperm conventional parameters and the DNA damage using TUNEL assay, our result showed that DGC/80P increased sperm quality compared to DGC with 25% of improvement. For temperature incubation effect after 24hrs, 35°C increased the DNA damage and decreased the sperm quality while RT could improve sperm motility by 38%. Moreover, the sperm incubation with 5% CO2 after 24hrs realised a negative impact on sperm parameters and its DNA damage. Indeed, for current IVF practice, a good sperm quality can be maintained for several hours at room temperature, while the sperm preparation is processed using the DGC/80P without CO2.

Human embryo mosaicism: did we drop the ball on chromosomal testing?

There are newly recognized challenges presented by the occurrence of mosaicism in the context of trophectoderm (TE) biopsy for pre-implantation genetic screening (PGS) in in vitro fertilization (IVF) embryos. Chromosomal mosaicism, known to be significantly higher in IVF embryos than in later prenatal samples, may contribute to errors in diagnosis. In particular, PGS may result in discarding embryos diagnosed as aneuploid but in which the inner cell mass may be completely or mainly euploid, thus representing a false positive diagnosis. Although less likely, some embryos diagnosed as euploid could be mosaic and contain some aneuploid cells, possibly impacting their implantation potential. The ability of current diagnostic techniques to detect mosaicism is limited by the number and location of TE cells in the biopsy and by the methodology used for chromosomal assessment. The clinical consequences of mosaicism are dependent on the chromosome(s) involved, the developmental stage at which the mosaicism evolved, and whether TE biopsy accurately reflects the status of the inner cell mass that forms the fetus. Consequently, in patients with no euploid embryos identified on PGS, it may be appropriate to consider the transfer of diagnosed aneuploid embryos if the TE biopsy result is a non-viable chromosomal monosomy or triploidy that could not result in a birth. It should be acknowledged in consent forms that mosaicism has the potential to impact test results and that its detection may be below the resolution of the genetic tests being used. This concept represents a major shift in current IVF practice and ought to be considered given the data, or lack thereof, of the impact of mosaicism on IVF/PGS outcomes.

The Use of Mitochondrial Replacement in IVF: A Call for Expansion

The Use of Mitochondrial Replacement in IVF: A Call for Expansion

Day 4 Biopsy Improves Pregnancy Outcome Comparing to Day 3 Biopsy in Preimplantation Genetic Screening

Aim: Preimplantation genetic screening (PGS) is a routine procedure performed in many in vitro fertilization (IVF) clinics. Embryo biopsy is an invasive procedure, and it has long been recognised that this procedure can affect the subsequent growth and development of the embryo. Materials and methods: In total, 38 cycles from 31 couples were included in this study. Day 3 biopsy was performed on 126 embryos of 18 patients; 20 patients chose day 4 biopsy with 150 embryos tested. All specimens were screened on a 24-chromosome comparative genomic hybridization (CGH) array. Results: Of the embryos subjected to day 3 and day 4 biopsies, 22.2% (28/126) and 28.7% (43/150) were normal, demonstrating that our biopsy system has no obvious detrimental effect on compaction. Embryos were transferred on the mornings of day 4 and day 5. Compared with day 3 biopsy (4/13; 30.8%), the day 4 biopsy (7/16; 43.8%) procedure provides an improved pregnancy rate with embryo transfer in current IVF cycle. Conclusions: We suggest that biopsy performance on day 4, to obtain genetic materials without compromising embryo viability, shows promise for successful PGS in IVF.

Kisspeptin: a novel physiological trigger for oocyte maturation in in-vitro fertilisation treatment

BackgroundAlthough in-vitro fertilisation (IVF) treatment allows infertile couples to conceive, it can result in a potentially life-threatening condition termed the ovarian hyperstimulation syndrome (OHSS). The major cause of OHSS is use of human chorionic gonadotropin (hCG) in current IVF protocols for initiating oocyte maturation. The development of a more physiological stimulus for oocyte maturation would avoid this dangerous side-effect and thus improve safety of IVF treatment. Kisspeptin is a recently identified hypothalamic hormone that acutely and potently increases endogenous secretion of luteinising hormone in a gonadotropin-releasing hormone (GnRH)-dependent manner. We aimed to investigate whether kisspeptin can induce oocyte maturation in IVF treatment. MethodsIn this single-centre prospective clinical trial at Hammersmith Hospital, London, women were recruited with the following inclusion criteria: age 18–35 years, body mass index less than 30 kg/m2, serum anti-Mullerian hormone 10–40 pmol/L, and no more than one previous IVF cycle. They underwent a recombinant follicle stimulating hormone plus GnRH antagonist IVF protocol with a single subcutaneous injection of kisspeptin. A control group was not recruited for ethical reasons. Primary outcome was production of mature oocytes (metaphase II oocytes) after egg collection. Participants and doctors giving IVF treatment were masked to the dose of kisspeptin administered. Women were independently randomised by the study statistician, initially to the lowest tier of kisspeptin doses (1·6 or 3·2 nmol/kg, n=2–3 per dose) and then as per protocol to a higher tier of doses (6·4 or 12·8 nmol/kg, n=21 per dose). Oocyte retrieval was done 36 h after kisspeptin injection. After intracytoplasmic sperm injection (ICSI) one or two embryos were transferred to the woman and pregnancy testing done 12 days later. Clinical pregnancy was confirmed on ultrasound scan at 6 weeks of gestation. Multiple means were compared by use of one-way ANOVA with post-hoc Bonferroni correction. Proportions were compared by χ2 test. All data were analysed on an intention-to-treat basis. Women gave written informed consent. The study received approval from the Hammersmith and Queen Charlottes Research Ethics Committee (application number 10/H0707/2) and the Medicines and Healthcare Products Regulatory Agency. The trial is registered with ClinicalTrials.gov, number NCT01667406. FindingsUp to Sept 1, 2013, 47 women completed the study protocol. All doses of kisspeptin resulted in a mean 9·0-fold (SD 7·5) increase in luteinising hormone release 12 h after injection. Oocyte maturation was observed at all doses of kisspeptin. 45 women (96%) had oocyte maturation (mean number of metaphase II oocytes 7·9, SD 4·1). Embryogenesis occurred in 43 women (91%) after treatment with kisspeptin (mean number of zygotes 5·7, SD 3·5). Complete pregnancy data are awaited, but up to Sept 1, 2013, 16 (36%) of 44 women had a positive pregnancy test at 12 days post embryo transfer and ten (23%) had clinical pregnancy confirmed on ultrasound examination at 6 weeks of gestation. Clinical follow-up during pregnancy is continuing, but already the first participant to have received kisspeptin to induce oocyte maturation gave birth to a healthy baby boy in May, 2013. No adverse events were noted at any time during the study. InterpretationThe results of this study suggest, for the first time, to our knowledge, that kisspeptin induces oocyte maturation in women undergoing IVF treatment. Kisspeptin might therefore offer a novel therapeutic option for fertility treatment. This small pilot study provides proof of concept that kisspeptin can stimulate oocyte maturation in women undergoing IVF treatment. Further work is now underway in a larger number of patients to determine the optimum protocol for kisspeptin administration to induce oocyte maturation in a population at high risk of OHSS. FundingUK Medical Research Council, National Institute for Health Research.

Influence of Acupuncture on the Outcomes of in Vitro Fertilisation When Embryo Implantation Has Failed: A Prospective Randomised Controlled Clinical Trial

To evaluate the effectiveness of acupuncture and moxibustion as an adjuvant treatment in women undergoing in vitro fertilisation (IVF) when embryo implantation has failed. A prospective, randomised controlled clinical trial was conducted with 84 infertile patients who had had at least two unsuccessful attempts of IVF. The patients were randomised in three groups: control (n=28), sham (n=28) and acupuncture (n=28). The sample size was calculated by assuming a pregnancy rate of 10% when embryo implantation had failed. The pregnancy rates of the current IVF cycle were evaluated by measurement of blood β human chorionic gonadotrophin (βhCG) and subsequent transvaginal ultrasound. Acupuncture was performed on the first and seventh day of ovulation induction, on the day before ovarian puncture and on the day after embryo transfer. In the acupuncture group, patients were treated with moxibustion at nine acupuncture points (BL18, BL22, BL23, BL52, CV3, CV4, CV5, CV7, GV4) and needling at 12 points. In the sham group needles were inserted in eight areas that did not correspond to known acupuncture points. The clinical pregnancy rate in the acupuncture group was significantly higher than that in the control and sham groups (35.7% vs 7.1% vs 10.7%; p=0.0169). In this study, acupuncture and moxibustion increased pregnancy rates when used as an adjuvant treatment in women undergoing IVF, when embryo implantation had failed.

Effects of different embryo development media on hCG and progesterone release by JEG-3 and BeWo cells

Summary Current in vitro fertilisation (IVF) practice requires synchronisation between the environment of cultured oocytes and embryos and the surroundings to what they would have been exposed to in vivo. Commercial, sequential media follow this requirement but their exact composition is not available. We have compared two widely used IVF culture media systems using the two choriocarcinoma cell lines JEG-3 and BeWo. The two hormones hCG and progesterone were determined in the culture supernatants as endpoints. In both cell lines, but in a more pronounced way in JEG-3, progesterone rather than hCG production was stimulated, and a higher hormone release was observed in the fertilisation than in the cleavage media. Differences between manufacturers were small and did not favour one system over the other. We conclude that both sequential media systems can be equally well used in current IVF laboratory practice.

A protocol for rat in vitro fertilization during conventional laboratory working hours

In vitro fertilization (IVF) is a valuable technique for the propagation of experimental animals. IVF has typically been used in mice to rapidly expand breeding colonies and create large numbers of embryos. However, applications of IVF in rat breeding experiments have stalled due to the inconvenient laboratory work schedules imposed by current IVF protocols for this species. Here, we developed a new rat IVF protocol that consists of experimental steps performed during common laboratory working hours. Our protocol can be completed within 12h by shortening the period of sperm capacitation from 5 to 1h and the fertilization time from 10 to 8h in human tubal fluid (HTF) medium. This new protocol generated an excellent birth rate and was applicable not only to closed colony rat strains, such as Wistar, Long-Evans, and Sprague-Dawley (SD), but also to the inbred Lewis strain. Moreover, Wistar and Long-Evans embryos prepared by this protocol were successfully frozen by vitrification and later successfully thawed and resuscitated. This protocol is practical and can be easily adopted by laboratory workers.

Money in—babies out: assessing the long-term economic impact of IVF-conceived children

We welcome Ms Smajdor’s critique into our investigations of expected future tax gains to the state from children conceived by in vitro fertilisation (IVF).1 To better inform the JME readership,...

Too old for IVF: are we discriminating against older women?

In vitro fertilization (IVF) in women of advanced age (>42 years) represents only 5%, a comparatively minute part, of the national IVF experience in the United States (US). In view of evolving population dynamics, it, however, also represents proportionally a rather quickly expanding patient need. Because of access restrictions at many IVF programs, this market does not live up to its potential. As best demonstrated by the 2004 US National Summary and Fertility Clinic Report, which for the first time reported pregnancies and births above age 45 year, IVF in women of advanced reproductive age represents a cutting edge area of interest for improving current IVF outcomes. Access to IVF should, therefore, not be withheld based on female age and/or baseline FSH levels. Instead, a definition of acceptable minimal pregnancy and life birth rates could be used to define the limits of offered access to IVF, independent of age and/or baseline FSH levels.

In vitro fertilization, GIFT and related technologies--hope in a test tube.

In vitro fertilization (IVF) is demanding, expensive and inefficient. Nevertheless, tens of thousands of couples have undertaken the procedure because of their intense desire to have a biological child. Modifications of the current IVF process--simplification of ovulation induction and prediction of successful cycles; use of ultrasound instead of laparoscopy for egg retrieval; freezing of excess embryos for later replacement; and the substitution of GIFT (gamete intra-fallopian transfer) for IVF when it is indicated--may increase its acceptability to couples and improve success rates. Meanwhile, IVF has had tremendous impact on our understanding of fertility and should help physicians in their approach to infertility in the future. It has also ushered in a new era of genetic engineering whose potential we have not yet begun to realize.