Blastocyst quality and reproductive and perinatal outcomes: a multinational multicentre observational study.

STUDY QUESTION: Does the transfer of single low-grade blastocysts result in acceptable reproductive and perinatal outcomes compared to the transfer of single good-grade blastocysts? SUMMARY ANSWER: The transfer of single low-grade blastocysts resulted in a reduced live birth rate of around 30% (14% for very low-grade blastocysts) compared to 44% for single good-grade blastocysts, but does not lead to more adverse perinatal outcomes. WHAT IS KNOWN ALREADY: It is known that low-grade blastocysts can result in live births. However, the current studies are limited by relatively small sample sizes and single-centre designs. Furthermore, evidence on perinatal outcomes after transferring low-grade blastocysts is limited. STUDY DESIGN, SIZE, DURATION: We conducted a multi-centre, multi-national retrospective cohort study of 10 018 women undergoing 10 964 single blastocyst transfer cycles between 2009 and 2020 from 14 clinics across Australia, China, and New Zealand. PARTICIPANTS/MATERIALS, SETTING, METHODS: Blastocysts were graded individually based on assessment of the morphology and development of the inner cell mass (ICM) and trophectoderm (TE), and were grouped into three quality categories: good- (AB, AB, or BA), moderate- (BB), and low-grade (grade C for ICM or TE) blastocysts. CC blastocysts were individually grouped as very low-grade blastocysts. Logistic regression with generalized estimating equation was used to analyse the association between blastocyst quality and live birth as well as other reproductive outcomes. Binomial, multinomial logistic, or linear regression was used to investigate the association between blastocyst quality and perinatal outcomes. Odds ratio (OR), adjusted OR (aOR), adjusted regression coefficient, and their 95% CIs are presented. Statistical significance was set at P < 0.05. MAIN RESULTS AND THE ROLE OF CHANCE: There were 4386 good-grade blastocysts, 3735 moderate-grade blastocysts, and 2843 low-grade blastocysts were included in the analysis, for which the live birth rates were 44.4%, 38.6%, and 30.2%, respectively. Compared to good-grade blastocysts, the live birth rate of low-grade blastocysts was significantly lower (aOR of 0.48 (0.41-0.55)). Very low-grade blastocysts were associated with an even lower live birth rate (aOR 0.30 (0.18-0.52)) and their absolute live birth rate was 13.7%. There were 4132 singleton live births included in the analysis of perinatal outcomes. Compared with good-grade blastocysts, low-grade blastocysts had comparable preterm birth rates (<37 weeks, aOR 1.00 (0.65-1.54)), birthweight Z-scores (adjusted regression coefficient 0.02 (0.09-0.14)), and rates of very low birth weight (<1500 g, aOR 0.84 (0.22-3.25)), low birth weight (1500-2500 g, aOR 0.96 (0.56-1.65)), high birth weight (>4500 g, aOR 0.93 (0.37-2.32)), small for gestational age (aOR 1.63 (0.91-2.93)), and large for gestational age (aOR 1.28 (0.97-1.70)). LIMITATIONS, REASONS FOR CAUTION: Due to the nature of the retrospective design, residual confounding could not be excluded. In addition, the number of events for some perinatal outcomes was small. Between-operator and between-laboratory variations in blastocyst assessment were difficult to control. WIDER IMPLICATIONS OF THE FINDINGS: Patients undergoing IVF should be informed that low-grade blastocysts result in a lower live birth rate, however they do not increase the risk of adverse perinatal outcomes. Further research should focus on the criteria for embryos that should not be transferred and on the follow-up of long-term outcomes of offspring. STUDY FUNDING/COMPETING INTEREST(S): H.Z. is supported by a Monash Research Scholarship. B.W.J.M. is supported by a NHMRC Investigator grant (GNT1176437). R.W. is supported by an NHMRC Emerging Leadership Investigator grant (2009767). B.W.J.M. reports consultancy, travel support, and research funding from Merck. The other authors do not have competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

What happens to abnormally fertilized embryos? A scoping review.

A dearth of evidence exists on embryos derived from oocytes without two pronuclei (2PN) or 'normal fertilization', i.e. embryos arising from non-pronuclear oocytes (0PN), mono-pronuclear oocytes (1PN) and tri-pronuclear oocytes (3PN). We searched the published literature on non-2PN oocytes and their clinical outcomes using a two-part collection strategy of relevant articles. A total of 33 articles were deemed eligible for the scoping review. A significant difference exists between potential development of oocytes with an abnormal number of pronuclei and those with 2PN in most studies; the abnormal pronuclei oocytes occur rarely and significant attrition occurs between day 1 and day 6, with corresponding reduction in chromosome integrity and clinical utility. Most recent studies describe outcomes of blastocysts derived from non-2PN oocytes, rather than cleavage stage embryo transfers. Compared with 2PN oocytes, blastocyst rates are lower in 1PN oocytes (68.3 versus 32.2%), with larger 1PN oocytes having better developmental potential compared with their smaller counterparts. Blastocysts from 1PN oocytes seem to have a slightly reduced implantation potential compared with those from 2PN blastocysts (33.3% versus 35.9%), with a reduced ongoing pregnancy rate (27.3% versus 28.1%). Live birth rates were only reported in 13 of the included studies. The comparators varied between studies, with live birth rates provided ranging from 0-66.7%, with two case reports (100%); this is a clear indication of the variability in practices and the significant heterogeneity of studies. A distinct lack of evidence exists on non-2PN oocytes; however, it seems that most abnormally fertilized oocytes that are non-viable will developmentally arrest in culture, and those that are viable can form viable pregnancies. Concerns remain about the outcome of pregnancies arising from the use of abnormally fertilized oocytes. Coupled with appropriate outcome measures, abnormally fertilized oocytes hold the potential to increase the pool of embryos eligible for transfer.

Impact of a postpartum care rehabilitation program to prevent postpartum depression at a secondary municipal hospital in Qingdao China: a cross-sectional study.

BACKGROUND: The emerging postpartum rehabilitation (PPR) program in Chinese hospitals characterized by applying ongoing medical care through traditional cultural practices shows a protective effect in early puerperium in China. This study explores the benefit of PPR program practices to postpartum depression (PPD) and the influencing factors for PPD among Chinese women during the first postnatal six weeks. METHODS: The cross-sectional study included 403 participants and was conducted in a Secondary Municipal Hospital in Qingdao, China, from 01 to 2018 to 31 December 2021. Information on this PPR program was collected during the six-weeks postpartum consultation, including the Edinburgh postnatal depression scale (EPDS) scores, the measurement results for diastasis recti abdominis, and the international physical activity questionnaire (long form) (IPAQ-L) scores. Logistic regression models were used to examine the effect of the PPR program on PPD among the local population. The secondary aim of this study was to investigate possible influencing factors for PPD, such as coronavirus disease 2019 (COVID-19), physical exercises, etc. RESULTS: PPR program has shown a positive effect in preventing PPD (p < 0.001) and diastasis recti prevalence (p < 0.001) during the six-weeks postnatal control in Qingdao, China. Better post-pregnancy weight reduction (p = 0.04) and higher metabolic equivalent of task (MET) value (p < 0.001) were noticed in the non-PPR group. Furthermore, lower PPD risk was associated with factors such as longer relationship duration years (2-5 years) (p = 0.04) and exercising one to three times a week (p = 0.01). A higher PPD risk was related to factors such as urinary incontinence during the postpartum period (p = 0.04) and subjective insomnia (p < 0.001). No significant effect was shown between COVID-19 and the EPDS score in this study (p = 0.50). CONCLUSION: Our results suggested that the PPR program provided protection against PPD and diastasis recti during the first six weeks after delivery. Urinary incontinence and subjective insomnia were the main risk factors for PPD, while longer relationship duration years and exercising one to three times a week gave protective effects to PPD. This study emphasized that a comprehensive ongoing medical care program, such as the PPR program, effectively improves women's mental and physical health in the early postpartum in China.

Data solidarity for machine learning for embryo selection: a call for the creation of an open access repository of embryo data.

The last decade has seen an explosion of machine learning applications in healthcare, with mixed and sometimes harmful results despite much promise and associated hype. A significant reason for the reversal in the reported benefit of these applications is the premature implementation of machine learning algorithms in clinical practice. This paper argues the critical need for 'data solidarity' for machine learning for embryo selection. A recent Lancet and Financial Times commission defined data solidarity as 'an approach to the collection, use, and sharing of health data and data for health that safeguards individual human rights while building a culture of data justice and equity, and ensuring that the value of data is harnessed for public good' (Kickbusch et al., 2021).

Should we look for a low-grade threshold for blastocyst transfer? A scoping review.

Embryo quality is a key determinant of the success of IVF. Although the focus has been on selecting the best embryo for transfer, the classification of low-grade blastocysts (LGB) in existing scoring systems has received less attention. This is worrisome; embryo freezing allows optimal use of all created embryos, thus maximizing the cumulative live birth rate, which is arguably the most important outcome for infertile couples. A PubMed search was conducted in August 2020, using '((('poor-quality' OR 'poor quality') OR ('low-grade' OR 'low grade')) AND ('embryo' OR 'blastocyst')) AND ('pregnancy' OR 'live birth')'. This scoping review shows that LGB have similar euploidy and pregnancy success rates after implantation and have no adverse effects on pregnancy or perinatal outcomes. Evidence for pregnancy outcomes is lacking for different grades of LGB, with most studies clustering all LQB as one to compare with optimal blastocysts.

Generating translatable evidence to improve patient care: the contribution of human factors.

Generating translatable evidence to improve patient care has proved challenging in reproductive medicine, with many 'add-on' treatments in routine assisted conception clinical practice that have not been reliably tested. This has consequences for patient care; specifically, IVF pregnancy rates have not improved. A change of culture is required in our profession, from indiscriminately applying the latest 'add-on' to large-scale participation in generating reliable translatable evidence.

Between-laboratory reproducibility of time-lapse embryo selection using qualitative and quantitative parameters: a systematic review and meta-analysis.

PURPOSE: To investigate the between-laboratory reproducibility of embryo selection/deselection effectiveness using qualitative and quantitative time-lapse parameters. METHODS: A systematic search was performed on MEDLINE, EMBASE, and the Cochrane Library (up to February 2020) without restriction on date, language, document type, and publication status. Measuring outcomes included implantation, blastulation, good-quality blastocyst formation, and euploid blastocyst. RESULTS: We detected 6 retrospective cohort studies externally validating the first clinical time-lapse model (Meseguer) emphasizing quantitative parameters, of which 3 (including one involving 2 independent centers) were included for the pooled analysis. Receiver operating characteristics analysis showed reduced predictive power of the model when either including or not including sister clinic validation. Fifteen cohort studies evaluating qualitative parameters were included for meta-analysis, and the mean Newcastle-Ottawa Scale was 5.3. Overall, meta-analysis showed significantly adverse association between the presence of ≥ 1 cleavage abnormalities and embryo implantation rates (11 studies, n = 7266; RR = 0.39[0.28, 0.55]95% CI; I2 = 57%). Further analysis showed adverse impacts of direct cleavage (7 studies, n = 7065; RR = 0.28 [0.15, 0.54] 95% CI; I2 = 46%), reverse cleavage (2 studies, n = 3622; RR = 0.16 [0.03, 0.75] 95% CI; I2 = 0%), chaotic cleavage (2 studies, n = 3643; RR = 0.11 [0.02, 0.69] 95% CI; I2 = 24%), and multinucleation (5 studies, n = 2576; RR = 0.59 [0.50, 0.69] 95% CI; I2 = 0%), but not the < 6 intercellular contact points at the 4-cell stage (1 study, n = 185; RR = 0.17 [0.02, 1.15] 95% CI). CONCLUSIONS: Qualitative time-lapse parameters are reliably associated with embryo developmental potential among laboratories, whereas the reproducibility of time-lapse embryo selection model that emphasizes quantitative parameters may be compromised when externally applied.

Interpretable, not black-box, artificial intelligence should be used for embryo selection.

Artificial intelligence (AI) techniques are starting to be used in IVF, in particular for selecting which embryos to transfer to the woman. AI has the potential to process complex data sets, to be better at identifying subtle but important patterns, and to be more objective than humans when evaluating embryos. However, a current review of the literature shows much work is still needed before AI can be ethically implemented for this purpose. No randomized controlled trials (RCTs) have been published, and the efficacy studies which exist demonstrate that algorithms can broadly differentiate well between 'good-' and 'poor-' quality embryos but not necessarily between embryos of similar quality, which is the actual clinical need. Almost universally, the AI models were opaque ('black-box') in that at least some part of the process was uninterpretable. This gives rise to a number of epistemic and ethical concerns, including problems with trust, the possibility of using algorithms that generalize poorly to different populations, adverse economic implications for IVF clinics, potential misrepresentation of patient values, broader societal implications, a responsibility gap in the case of poor selection choices and introduction of a more paternalistic decision-making process. Use of interpretable models, which are constrained so that a human can easily understand and explain them, could overcome these concerns. The contribution of AI to IVF is potentially significant, but we recommend that AI models used in this field should be interpretable, and rigorously evaluated with RCTs before implementation. We also recommend long-term follow-up of children born after AI for embryo selection, regulatory oversight for implementation, and public availability of data and code to enable research teams to independently reproduce and validate existing models.

Time-lapse videography for embryo selection/de-selection: a bright future or fading star?

The recent clinical introduction of time-lapse videography into in vitro fertilization laboratories has offered a novel opportunity for embryologists to explore improved methods for embryo selection. While the concept of uninterrupted culture of embryos provided by such systems is welcomed, the current evidence does not support its full application in routine clinical practice. The issue of whether or not algorithms for embryo selection can be extrapolated between laboratories, which may represent a major hurdle to its wide application, is currently gaining increasing attention amongst embryologists worldwide. In this commentary issues identified in time-lapse embryo selection/de-selection algorithms, such as quantitative versus qualitative parameters, are discussed alongside the reference start point for the timing system, and types of datasets used for developing and validating time-lapse algorithms. Considering these factors, alternative future research directions which could potentially solve current issues are proposed.

Identifying real differences in live birth rates between HMG and rFSH in IVF.

Fertility treatment strives for the delivery of a healthy live birth. Human menopausal gonadotrophin (HMG) and recombinant FSH (rFSH) are the two types of gonadotrophin currently used for ovarian stimulation in assisted reproduction treatments. Although both HMG and rFSH have been shown to be effective, a number of studies have examined whether a potential difference in clinical benefit or outcome exists between treatments. Unlike rFSH preparations, HMG contains both FSH and LH activity (in the form of LH and human chorionic gonadotrophin, which are short- and long-acting, respectively). The beneficial effect of exogenous LH activity has been investigated in the Menotrophin versus Recombinant FSH in-vitro Fertilisation Trial (MERiT), which revealed differences in embryo quality and endometrial receptivity between rFSH and highly purified HMG. Current evidence suggests that HMG provides significantly higher live birth rates than rFSH in women undergoing ovarian stimulation for in-vitro fertilization/intracytoplasmic sperm injection cycles using long gonadotrophin-releasing hormone agonist protocol. Further studies will continue to provide data with which to expand these findings and optimize the chances of achieving a live birth following assisted reproduction treatment.

Ultrasound-guided hydrosalpinx aspiration during oocyte collection improves pregnancy outcome in IVF: a randomized controlled trial.

BACKGROUND: Hydrosalpinges have adverse effects on IVF outcomes. Salpingectomy is effective in improving outcomes, but it is not always practical or safe. Ultrasound-guided aspiration of hydrosalpinges at oocyte collection is an option for those who develop hydrosalpinges during controlled ovarian stimulation; however, there is no randomized evidence to show whether this practice is effective. METHODS: Between October 1999 and June 2003, consenting women of age

Urinary hMG versus recombinant FSH for controlled ovarian hyperstimulation following an agonist long down-regulation protocol in IVF or ICSI treatment: a systematic review and meta-analysis.

BACKGROUND: Since the most recent Cochrane review on hMG versus rFSH for controlled ovarian hyperstimulation following a long down-regulation protocol, several new trials have emerged. METHODS: We conducted a systematic review and meta-analysis of randomized trials comparing the effectiveness of hMG versus rFSH following a long down-regulation protocol in IVF-ICSI cycles, on the primary outcome of live birth per woman randomized, as well as several other secondary outcomes. Searches were conducted in MEDLINE, EMBASE, Science Direct, Cochrane Library and databases of abstracts (last search January 2007). RESULTS: Seven randomized trials, consisting of a total of 2159 randomized women, were identified. A meta-analysis of these trials showed a significant increase in live birth rate with hMG when compared with rFSH (relative risk, RR = 1.18, 95% CI: 1.02-1.38, P = 0.03). The heterogeneity test was non-significant (P = 0.97), suggesting that there was no statistical inconsistency between the seven studies. The pooled risk difference (RD) for the outcome of live birth rate was 4% (95% CI: 1-7%) for these study populations. There was an increase in clinical pregnancy rates with hMG when compared with rFSH (RR = 1.17, 95% CI 1.03-1.34). No significant differences were noted for gonadotrophin use, spontaneous abortion, multiple pregnancy, cancellation and ovarian hyperstimulation syndrome rates. CONCLUSIONS: For the populations in the randomized trials, hMG was associated with a pooled 4% increase in live birth rate when compared with rFSH in IVF-ICSI treatment following a long down-regulation protocol.

Coordinated transcriptional regulation patterns associated with infertility phenotypes in men.

INTRODUCTION: Microarray gene-expression profiling is a powerful tool for global analysis of the transcriptional consequences of disease phenotypes. Understanding the genetic correlates of particular pathological states is important for more accurate diagnosis and screening of patients, and thus for suggesting appropriate avenues of treatment. As yet, there has been little research describing gene-expression profiling of infertile and subfertile men, and thus the underlying transcriptional events involved in loss of spermatogenesis remain unclear. Here we present the results of an initial screen of 33 patients with differing spermatogenic phenotypes. METHODS: Oligonucleotide array expression profiling was performed on testis biopsies for 33 patients presenting for testicular sperm extraction. Significantly regulated genes were selected using a mixed model analysis of variance. Principle components analysis and hierarchical clustering were used to interpret the resulting dataset with reference to the patient history, clinical findings and histological composition of the biopsies. RESULTS: Striking patterns of coordinated gene expression were found. The most significant contains multiple germ cell-specific genes and corresponds to the degree of successful spermatogenesis in each patient, whereas a second pattern corresponds to inflammatory activity within the testis. Smaller-scale patterns were also observed, relating to unique features of the individual biopsies.

Efficacy and safety of Ding-Kun-Dan for female infertility patients with predicted poor ovarian response undergoing in vitro fertilization/intracytoplasmic sperm injection: study protocol for a randomized controlled trial.

BACKGROUND: Women undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) who have a predicted poor ovarian response (POR) present a challenge for reproductive medicine specialists. Traditional Chinese medicine (TCM) is commonly used in China for such patients, in the belief that it will improve the ovarian response and ultimately increase pregnancy rates. However, there is a lack of high-quality evidence about the effect of TCM on improving ovarian response in such patients. The purpose of this study is to evaluate ongoing viable pregnancy rate at 12 weeks' gestation and related indicators of ovarian response in fertile women who have a predicted poor ovarian response having immediate versus delayed IVF/ICSI after 3 months of Ding-Kun-Dan (DKD) pre-treatment. METHODS/DESIGN: This study is a multicenter, randomized controlled, parallel-group, phase III, superiority clinical trial. Two hundred and seventy-eight eligible female infertility patients with POR will be included in the study and randomly allocated into an immediate treatment group and a DKD group in a 1:1 ratio. Both groups will receive IVF or ICSI as a standard treatment while in the DKD group, a commercially available Chinese medicine, DKD, will be administrated for 3 months before the IVF/ICSI cycle starts. The primary outcome of the study is the ongoing pregnancy rate at 12 weeks' gestation. The secondary outcomes include total gonadotropin dosage, duration of stimulation, estradiol (E2) and progesterone (P) levels on human chorionic gonadotropin (hCG) trigger day, cycle cancellation rate, number of oocytes retrieved, high-quality embryo rate, biochemical pregnancy rate, the change of serum anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), and E2 levels and all side effects, safety outcomes, and any adverse events. The protocol was approved by the Ethics Committee of the First Teaching Hospital of Tianjin university of TCM (approval no. TYLL2017[K] 004). DISCUSSION: IVF/ICSI is increasingly used to treat couples desiring a baby. Many of these women will have poor ovarian function. In China, DKD is commonly used for these patients prior to undergoing IVF/ICSI. There is no effective treatment for poor ovarian response in Western medicine currently. It is important, therefore, to undertake this randomized control trial to determine whether DKD is effective or not. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ID: ChiCTR-IOR-17011697 . Registered on 19 June 2017.

The apoptotic profile of human cumulus cells changes with patient age and after exposure to sperm but not in relation to oocyte maturity.

OBJECTIVE: To determine the expression of apoptosis-associated molecules on cumulus cells removed from individual oocytes of different maturity, inseminated oocytes and to investigate the possibility of an age-dependent expression. DESIGN: Analysis of apoptosis in cumulus cells isolated from oocytes of different stages of maturity. SETTING: Assisted reproductive technology program of the Birmingham Women's Hospital, Birmingham, UK. PATIENT(S): Patients undergoing intracytoplasmic sperm injection or IVF cycles. MAIN OUTCOME MEASURE(S): Percentage of positive cumulus cells when assessed for nuclear DNA damage using the terminal deoxyuridine nucleotide end-labeling assay or stained with antibodies [Fas, Fas ligand, the antiapoptotic protein Bcl-xl, and the RNA-binding protein (TIAR)]. RESULT(S): Cumulus cells collected from mature oocytes showed no significant difference in the percentage of apoptotic markers compared to those recovered from immature oocytes, whereas those from patients >/=38 years differed significantly. When cumulus cells were exposed to sperm the levels of apoptotic markers altered significantly from those not exposed to sperm. CONCLUSION(S): The results show that the cumulus cells of human oocytes are equipped with a mechanism to undergo apoptosis and that patient age and the exposure of cumulus cells to sperm can alter their profiles of apoptotic markers.

Use of the egg-share model to investigate the paternal influence on fertilization and embryo development after in vitro fertilization and intracytoplasmic sperm injection.

OBJECTIVE: To investigate whether sperm from different males can influence fertilization and embryo development. DESIGN: To use an egg-sharing model, in which the eggs from one woman are shared between herself and a recipient, and different spermatozoa are used to fertilize the eggs. SETTING: Assisted Conception Unit, Birmingham Women's Hospital, Edgbaston, United Kingdom. PATIENT(S): Infertile women undergoing egg sharing. INTERVENTION(S): In vitro fertilization (IVF). MAIN OUTCOME MEASURE(S): Fertilization rates and the mean day 2 or 3 embryo score (cell number X grade) were examined for egg-sharing pairs. A comparison was also made for pairs in which intracytoplasmic sperm injection (ICSI) and IVF was used as the insemination method. A paired samples t-test was used to compare the sharer and recipient results. RESULT(S): Pregnancy rates did not differ between sharer and recipient couples. Interestingly, when comparing fertilization, there was a significant difference (P<.05) in favor of IVF over ICSI. When comparing embryo development between egg-sharing pairs, we found that approximately 30% of patients showed a difference in mean embryo score of >or= 5 in all embryo development and 14% in the quality of embryos available for transfer. CONCLUSION(S): We showed that the egg-sharing model is a successful alternative for the treatment of women who required donated eggs. More important, the egg-sharing model shows that, in a certain percentage of couples, differences in early embryo development are paternally influenced.

Functional genomics in reproductive medicine.

The British Fertility Society organised a workshop on Functional Genomics in Reproductive Medicine at the University of Birmingham on 13-14 September 2001. The primary aim was to inform delegates about the power of the technology that has been made available after completion of the sequencing of the human genome, and to stimulate debate about using functional genomics to address both clinical and scientific questions in reproductive medicine. Three specific areas were addressed: proteomics, gene expression and bioinformatics. Although the sophistication and plethora of techniques available were obvious, major limitations in the technology were also discussed. The future promises to be very challenging indeed.

Modification of the coaxial technique for selective salpingography with measurement of tubal perfusion pressures.

This article describes the use of the fallopotorque catheter system for transcervical selective salpingography and tubal catheterization under fluoroscopic guidance for the diagnosis and treatment of obstruction of the proximal Fallopian tube. The technique of tubal perfusion pressure assessment during the procedure, using the same catheter system, is also described. The relative advantages of this method of selective salpingography and tubal catheterization are then discussed in the background of previously described techniques.