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Background: It is currently inconclusive whether different intracytoplasmic sperm injection (ICSI) timings post oocyte retrieval (POR) lead to altered chance of clinical pregnancy and live birth following in vitro fertilization (IVF) treatment. This study, therefore, aimed to synthesize literature-based evidence for better clinical guidance regarding ICSI practice. Methods: A systematic review and meta-analysis were performed according to PRISMA guidelines. Studies were searched for in PubMed, MEDLINE, EMBASE, and the Cochrane Library. Outcome endpoints included clinical pregnancy and live birth rates (LBRs). Results: A total of 605 records were retrieved in the initial search. After exclusion, 30 articles were included for further screening for eligibility. For meta-analysis, 1 prospective and 5 retrospective cohort studies were included for pooled analysis, from which clinical pregnancy rates (CPRs) were evaluated in 6 studies while LBRs were evaluated in 3 studies. CPRs were comparable when ICSI was performed at (a) [Formula: see text] hours POR (risk ratio or RR = 1.00, [Formula: see text] confidence interval [CI] 0.94–1.08) vs [Formula: see text] hours, (b) [Formula: see text] hours (RR = 1.01, [Formula: see text] CI 0.88–1.16) vs [Formula: see text] hours, (c) [Formula: see text] hours (RR = 0.99, [Formula: see text] CI 0.93–1.05) vs [Formula: see text] hours, (d) [Formula: see text] hours (RR = 0.98, [Formula: see text] CI 0.93–1.02) vs [Formula: see text] hours, and (e) [Formula: see text] hours (RR = 1.05, [Formula: see text] CI 0.90–1.23) vs [Formula: see text] hours. However, LBR was reduced when ICSI was performed [Formula: see text] hours POR vs [Formula: see text] hours (RR = 0.94, [Formula: see text] CI 0.89–0.99), but such reduction disappeared when comparing [Formula: see text] hours POR (RR = 1.09, [Formula: see text] CI 0.85–1.38) vs [Formula: see text] hours. Conclusions: CPRs remain comparable when ICSI is performed at a range of timings up to 6-hour POR. However, LBR may benefit slightly by scheduling ICSI between 5- and 6-hour POR.

Objective: This study aims to investigate the impact of slow embryo development on the subsequent live birth rate and birthweight outcomes following a fresh day 5 transfer. Study design: This retrospective multicenter cohort study included 1,213 consecutive patients undergoing autologous oocyte in vitro fertilization (IVF) treatment at four associated private clinics during 2016–2019. Only fresh single day 5 transfers were included for analysis. Results: No implantation was achieved by embryos that failed to reach the early blastocyst stage on day 5 ([Formula: see text]). After adjusting for potential confounding factors, multivariate logistic regression (expressed as adjusted odds ratio or aOR and [Formula: see text] confidence interval) showed a significantly reduced live birth rate in early blastocysts ([Formula: see text]) in reference to those at the expanding (aOR = 0.584, [Formula: see text], [Formula: see text], [Formula: see text]), expanded (aOR = 0.322, [Formula: see text], [Formula: see text], [Formula: see text]), or hatching/hatched stages (aOR = 0.255, [Formula: see text], [Formula: see text], [Formula: see text]). However, early blastocysts led to similar birthweights ([Formula: see text], [Formula: see text]) in comparison to those at the expanding ([Formula: see text], [Formula: see text], [Formula: see text]), expanded ([Formula: see text], [Formula: see text], [Formula: see text]), or hatching/hatched stages ([Formula: see text], [Formula: see text], [Formula: see text]). This was further confirmed by linear regression analysis using either birthweight or [Formula: see text] score (gestation-adjusted birthweight). Conclusion: Slow day 5 development is associated with reduced live birth rate when transferred fresh, however, subsequent birthweight is not impacted once pregnancy is initiated.

Background and Aims: The recent clinical application of time-lapse videography has enabled detection of abnormal cleavage (ABNC) in in vitro cultured human embryos and the quantification of their developmental speed. However, growing evidence has highlighted the inter-laboratory transferability issue when involving morphokinetics measures for embryo selection, as different culture conditions and patient profiles are known to alter embryo morphokinetics. Having originally reported several ABNC phenomena, our recent birth outcome data also implied a potential self-correction mechanism in ABNC affected embryos. In this abstract, we review the most up-to-date evidence in this field and highlight the elastic nature of embryo development. Method: Literature review. Results: In this abstract, data from both our group and others are analyzed from 2 different aspects. First, we discuss both embryo and patient factors that have been shown to alter embryo morphokinetics. We also share evidence supporting the ability of embryos to be elastic in morphokinetics without losing the ability to implant. We therefore stress that caution ought to be taken when applying morphokinetics based embryo selection, especially when such models were developed using an external dataset. Secondly, we present the various impacts of ABNC when it occurs at different developmental stages and with different number of occasions. We also present the live birth rates and neonatal outcomes of ABNC embryos that had successfully achieved blastulation. Based on that, we propose blastulation as a self-correction milestone, supported by time-lapse footage showing exclusion/extrusion of ABNC-affected cells. Conclusion: Human embryos demonstrate detectable developmental elasticity which may be related to their ability to stand physical and chemical stress during in vitro culture. Embryos affected by ABNC can self-correct at blastulation by excluding/extruding affected cells. However, the limits of such elasticity in human embryos before losing their viability remain unknown.

Background and Aims: Spontaneous collapsing (SC) is a relatively new viability biomarker of human blastocysts which is only detectable via time-lapse videography. However, the prognosis of affected blastocysts remains poorly understood, with systematic review and meta-analysis absent from literature. This study is the first to comprehensively evaluate the clinical prognosis of SC blastocysts, including ploidy status, pregnancy, live birth and miscarriage rates. Method: Systematic review and meta-analysis were performed according to PRISMA, with protocol registered with PROSPERO (CRD42022373749). Studies were searched for in PUBMED, EMBASE and the Cochrane Library on 10 October 2022, using key words relevant to “blastocyst collapse” and “Time-Lapse Imaging”. Data were summarised by risk ratios (RRs) and their 95% confidence intervals (CIs). All meta-analyses were performed with fixed-effect models using RevMan 5.4 Results: A total of 7 retrospective cohort studies were eventually included from 196 records identified through the initial search. The incidence of SC was 37.0% (2516/6801) amongst 7 studies (ranging from 17.4% to 56.2%). SC was associated with significantly lower clinical pregnancy rate (2 studies, n=736; RR=0.77, 95% CI=0.65-0.91; [Formula: see text]2=30%), ongoing pregnancy rate (4 studies, n=2147; RR=0.73, 95%CI=0.64-0.82; [Formula: see text]2=0%), live birth rate (2 studies, n=816; RR=0.78, 95%CI=0.65-0.94; [Formula: see text]2=56%), and reduced euploidy rate (3 studies, n=3569; RR=0.71, 95% CI=0.66-0.78; [Formula: see text]2 =69%). However, miscarriage rate was not significantly different between blastocysts with or without SC (4 studies, n=1358; RR=1.28, 95%CI=0.93-1.76; [Formula: see text]2=0%). Significant heterogeneity was detected between the studies included for evaluation of live birth rates ([Formula: see text]2=56%, P=0.13) and ploidy rates ([Formula: see text]2=69%, P=0.04). Further subgroup analysis according to (a) different definition of SC, (b) collapse occasions, and (c) whether the transferred blastocyst had been genetically tested; showed unchanged trends. Conclusion: Our results indicate strong negative implications following SC in human blastocysts. SC should be a recognised criterion for the deselection of blastocysts for intrauterine transfer.

Background: Low grade blastocyst (LGB) transfer results in varied live birth rates (5-39%). Only limited studies with small sample sizes (n=10-440) exist, due to LGB transfer being less desirable. Definitions of LGB and study designs are heterogenous, further confounding outcome interpretation. Aim: This study aimed to obtain sufficient LGB transfers to determine live birth rates, as well as allow subgroup analysis by blastocyst quality and maternal age. Method: This study was a multicentre, multinational retrospective cohort study across nine IVF clinics in China and New Zealand between 2012 to 2019. 6966 single blastocyst transfer cycles on days 5-7 (fresh and frozen) were collected; of these, 875 transfers were from LGBs (

Background: Recent time-lapse studies have investigated potential live birth prediction by pronuclei (PN) associated morphometric and morphokinetic measures. Whether there is gender associated difference in such measures is unknown. Aim: To determine if morphometric and morphokinetic profiles of PN vary between male and female zygotes. Method: This retrospective study included 94 consecutive autologous single day 5 transfers leading to a singleton live birth (43 males and 51 females) at Monash IVF Gold Coast between January 2019 and March 2020. Timing parameters included 2nd polar body extrusion (tPB2), sperm-originated PN (tSPNa) or oocyte-originated PN (tOPNa) appearance (differentiated by proximity to PB2) and PN fading (tPNF). Morphometrics were evaluated at 8 (stage 1), 4 (stage 2) and 0 hour before PNF (stage 3), measuring PN area (um2), PN juxtaposition, and nucleolar precursor bodies (NPB) arrangement. Results: Male zygotes had longer time intervals of tPB2_tSPNa than female (4.8±0.2 vs 4.2±0.1 h, p=0.044), but not tPB2_tOPNa and tPB2_tPNF. SPN increased in size from stage 1 through 2 to 3 (435.3±7.2, 506.7±8.0, and 556.3±8.9 um2, p=0.000) and OPN did similarly (399.0±6.1, 464.3±6.7, and 513.8±6.5 um2, p=0.000), with SPN being significantly larger than OPN at each stage (p[Formula: see text]0.05 respectively). However, their relative size difference (SPN-OPN) was similar between male and female zygotes at all 3 stages. More male than female zygotes reached central PN juxtaposition at stage 1 (76.7% vs 51.0%, p=0.010), stage 2 (97.7% vs 86.3%, p=0.048) and stage 3 (97.7% vs 86.3%, p=0.048). Furthermore, more OPN showed aligned NPBs than in SPN at stage 1 (44.7% vs 28.7%, p=0.023). No gender associated differences were detected in NPB alignment in either SPN or OPN (p[Formula: see text]0.05 for each comparison). Conclusion: Zygotes with different genders display different morphokinetic and morphometric features. Embryo selection using such parameters may lead to unbalanced sex ratio in the resulting offspring.

Background: Inter-operator variation in morphology-based embryo assessment is known to be an ongoing issue in in vitro fertilisation (IVF). This includes inconsistent annotation of embryo morphology and disagreement in the predictive weightings amongst different morphological features. Although currently underexplored, subjectivity reduction using statistical tools is considered clinically valuable, and is more affordable than newer approaches such as time-lapse imaging. Aim: This study aims to develop a robust numerical D5 embryo ranking system by incorporating several patient and embryo characteristics arising from routine static D5 assessment. Method: A total of 8866 autologous-oocyte single fresh D5 transfers performed at 14 Monash IVF clinics during 2012-2018 were retrospectively analyzed, with repeat cycles from the same patients excluded to avoid clustering effects. The dataset was randomly split into two subsets at 60:40 ratio, including one (n=5274) used for regression analysis and model development and the other (n=3592) for validation. Multiple logistic regression was performed to evaluate live birth prediction by several variables, expressed by odds ratio (OR) and 95% confidence interval (CI). A numerical ranking system was developed based on calculated weightings of contributing factors and subsequently tested using receiver operating characteristics (ROC) as expressed by area under the ROC curve (AUC). Results: All included variables were significantly predictive of live birth, including maternal age (OR=1.465, 1.364-1.574, P=0.000), assessment timing (OR=1.096, 1.020-1.177, P=0.012), embryo developmental stage (OR=1.341, 1.244-1.445, P=0.000) and morphological sore (OR=1.520, 1.392-1.661, P=0.000). Increments of resultant numerical ranking scores ([Formula: see text]3, 3-3.99, 4-4.99, and [Formula: see text]5) were associated with increasing live birth rates (9.4%, 27.2%, 43.6%, and 54.9%; respectively). ROC analysis indicated significantly predictive power of the numerical ranking system in both the development (AUC=0.690, 0.675-0.704, P=0.000) and validation (AUC=0.685, 0.667-0.703, P=0.000) subsets. Conclusion: A robust numerical model can be developed for D5 embryo selection, potentially leading to improved inter-operator subjectivity for embryo assessment.

Background: The combination of time-lapse imaging and artificial intelligence (AI) offers novel potential for embryo assessment by allowing a vast quantity of image data to be analysed via machine learning. Most algorithms developed to date have used neural networks which are uninterpretable (“black-box”) and cannot be understood by doctors, embryologists and patients, which raises ethical and epistemic concerns for embryo selection in a clinical setting. Aim: This study aims to discuss ethical and epistemic considerations surrounding clinical implementation of “black-box” based embryo selection algorithms. Method: A scoping review was performed by evaluating publications reporting “black-box” embryo selection algorithms. Potential ethical and epistemic issues were identified and discussed. Results: No randomised controlled trial was identified in the literature evaluating clinical effectiveness of “black-box” embryo selection algorithms. Several ethical and epistemic concerns were identified. Potential ethical issues included (1) lack of randomised controlled trials, (2) impact on the shared decision-making process in embryo selection between clinicians and patients, (3) misrepresentation of patient values due to hidden reasoning process in “black-box” algorithms, (4) social impacts if algorithm subsequently proven to be biased, and (5) unclear responsibility when algorithm makes obviously poor choices of embryos. Potential epistemic issues included (1) information asymmetries between algorithm developers and doctors, embryologists and patients; (2) risk of biased prediction due to data selection during training process; (3) inability to troubleshoot for data training purposes due to limited interpretability; and (4) the economics of buying into commercial proprietary add-ons. Conclusion: There are significant epistemic and ethical concerns with “black-box” embryo selection. No published randomised controlled trial is available to support its clinical implementation. AI embryo selection in general, however, is potentially useful but must be done carefully and transparently. Interpretable AI would be preferred alternative in causing fewer issues.

Background: There is currently no consensus regarding developmental cutoff for fresh transfer of slow developing day 5 embryos on. Literature is sparse regarding true prognosis of such embryos. Aim: To investigate live birth and birthweight outcomes of slow developing day 5 transferred embryos. Method: This retrospective multi-center study included 1213 consecutive autologous-oocyte single fresh day 5 transfers performed at 4 Monash IVF clinics during 2016-2019. Repeat cycles by same patients were excluded to avoid clustering effects. Live birth and birthweight were followed up in all pregnancies. Multiple regression was performed to investigate associations between slow day 5 development (defined as ≤ early blastocyst) and (a) live birth, (b) birthweight, and (c) gestation-adjusted birthweight (Z score) to account for gestational age and gender. Results were expressed as adjusted odds ratio (aOR) with 95% confidence interval (CI). Results: No implantation was achieved when day 5 embryo failed to reach early blastocyst stage (i.e. ≤morula, n=76). Live birth rate was significantly lower following transfer of early blastocysts (n=237, 16%), in comparison to expanding (n=329, 27%, P=0.001), expanded (n=392, 41%, P=0.000), and ≥hatching blastocysts (n=169, 44%, P=0.000). After adjusting for maternal age, hours post insemination at day 5 assessment, number of oocytes collected, number of 2PNs, and number of embryos frozen; multiple logistic regression showed a significantly reduced likelihood of live birth resulting from early blastocysts in reference to expanding (aOR=0.584, 0.371-0.917, P=0.020), expanded (aOR=0.322, 0.208-0.501, P=0.000), or ≥hatching stages (aOR=0.255, 0.147-0.443, P=0.000). However, early blastocysts resulting in live birth (n=39) did not alter birthweight or Z score in reference to expanding (n=90, P>0.05 respectively), expanded (n=160, P>0.05 respectively), or ≥hatching (n=75, P>0.05 respectively). Conclusion: There is no clinical value of fresh transferring day 5 embryos at ≤morula stage. Fresh early blastocysts lead to a reduced live birth rate but not birthweight outcomes.

Objective: Recent studies have investigated the impact of paternal age on the incidence of embryo aneuploidy using young oocyte donors to control for maternal age, with conflicting results observed. This study takes a different approach, looking at the parental source of embryo aneuploidy as detected by SNP array. The aim was to determine whether the incidence and type of paternal-origin aneuploidy would increase with advancing paternal age. Design: A retrospective study of PGT outcomes from 1541 embryos with trio SNP array linkage-based testing from 2012-2020 across three paternal age groups: 40yrs (n=315). The primary outcome was frequency of paternally derived aneuploidy in each age bracket. The secondary endpoint was comparison of the complex abnormality rate and the rates of specific trisomies and monosomies of paternal origin. Results: There was no association between advancing paternal age and prevalence of paternal-origin aneuploidy (40yrs: 17.1%). Moreover, no differences were found between age cohorts in the occurrence of paternal-origin trisomy and paternal-origin monosomy. However, the rate of paternally derived complex abnormal embryos appeared increased with advancing paternal age (40yrs: 4.4%) but did not reach statistical significance. Analysis of specific chromosomes showed the >40yrs cohort had a marked increase in rates of trisomy 4 (2.22% vs. 1.22% 40yrs) on the rate of paternally derived complex abnormalities, as well as increased rate of specific paternal-origin trisomies (4, 10, 12, 19).