The increasing corpus of clinical studies using time-lapse imaging for embryo selection demonstrates considerable variation in study protocols and only limited-sized study cohorts. Outcome measures are based on implantation or clinical pregnancy; some predict blastulation from early cleavage-stage data, and few have evaluated live birth. Erroneously, most studies treat the embryos as independent variables and do not include patient or treatment variables in the statistical analyses. In this study, cohort size was 14,793 patients and 23,762 cycles. The incidence of live birth (n = 973 deliveries) after embryo selection by objective morphokinetic algorithms was compared with conventional embryology selection parameters (n = 6948 deliveries). A 19% increase in the incidence of live birth was observed when morphokinetic data were used to select embryos for the patient cohort aged younger than 38 years (OR 1.19 with 95% CI 1.06 to 1.34) using their own eggs, and an increase of 37% for oocyte recipients aged over 37 years (OR 1.370; 95% Cl 0.763 to 2.450). This is the largest study of the prospective use of time-lapse imaging algorithms in IVF reporting on live birth outcome, although the nature of purely a closed system versus standard incubation could not be assessed.
Louise Kellam studied at Leicester University, specializing in mammalian reproduction and development. Louise has held a senior position at CARE Fertility since its inception and has played a key role in embryology management. She is an experienced Clinical Embryologist, with published chapters in 'The Atlas of Time-Lapse Embryology'. KEY MESSAGEPerivitelline threads are observed during human zygote cleavage. Spanning the perivitelline space, they appear as the cytoplasmic membrane withdraws from the zona pellucida. They are observed in 56% of embryos, and are associated with fragmentation. We postulate that they have a role in the mechanics of cytokinesis and fragmentation.
Study question Are there any advantages in using High security tubes rather than High Security straws for conventional slow sperm freezing? Summary answer Freezing sperm in High Security tubes (HST) improved post-thaw recovery rate and motility, and also reduced processing and handling compared to High Security straws (HSS). What is known already The use of High Security freezing consumables (HSFC) in an IVF setting is a safe and effective way of eliminating concerns related to viral cross-contamination during storage. The lower diameter of HSS does make them susceptible to warming during handling. The HSFC used in this study is the only CE marked products that are made of resin, leak-proof and shatter-proof in all cryogenic temperatures even in LN2. No previous studies have compared the use of HST with HSS for conventional human sperm freezing. This study sets out to investigate the performance of HST compared to HSS. Study design, size, duration The study was designed as a controlled split-sample study with blind post-thaw analysis. Following the routine WHO analysis of 20 semen samples, the remainder of each of the samples was evenly divided and cryopreserved by conventional slow freezing in each of the two different HSFC. The freeze was conducted simultaneously by the same practitioner, employing the same freezing protocol and cryoprotectant. The pre-freeze and post-thaw concentration, total and progressive sperm motility were recorded. Participants/materials, setting, methods At one IVF clinic, semen samples with sperm density ≥15million/ml, ≥40% motility, ≥1.5ml were included. Cryoprotectant (SpermFreeze, Fertipro) was added dropwise to unprepared semen and kept at room temperature for 10 minutes before loading into HSFC (0.5ml CBS™HSS; CBS™HST). HSFC were heat-sealed (SYMS; SYMSIII sealers) and placed in vapour for 30 minutes before plunging into LN2. Samples were thawed by immersion in a 37Cº water bath for 5 minutes and analysed using WHO methods. Main results and the role of chance Paired-t test was used to compare the percentage motility between the different HSFC. All analysis was considered statistically significant when p < 0.01. We demonstrated that the sperm recovery rate (Percentage total motility post-thaw/ Percentage total motility pre-freeze) in HST was 66.63 ± 14.94 (mean ± standard deviation) compared to 40.80 ± 14.69 in HSS. In the HSS, the percentage post-thaw total motility was 19.99 ± 7.21 and the percentage post-thaw progressive motility was 12.26 ± 2.59. In the HST, the percentage post-thaw total motility was 32.57 ± 8.33 and the percentage post-thaw progressive motility was 23.08 ± 5.53. The overall improvement when using HST against HSS was 12.53 ± 5.69, 10.44 ± 5.29 for the total motility and the progressive motility respectively. Comments were recorded regarding the handling and the condition of the HSS and HST for each freeze event. Neither device displayed any leakage of LN2 or any explosion during the warming. The freezing process was easier and faster using HST rather than HSS. It was also noted that the entire sample can be recovered from the HST, unlike the HSS. Limitations, reasons for caution The study looked at sperm recovery in terms of motility only. DNA damage was not considered as a parameter of sperm quality. Also, fertilization, pregnancy rates, live birth rates and the use of poorer quality sperm samples have not been investigated. Wider implications of the findings: For conventional sperm freezing, the use of HST resulted in improved sperm motility and progression post-thaw, when compared to HSS. This finding supports the use of HST to improve the post thaw quality of sperm, benefitting patients with own frozen samples, recipients of donor sperm and donor sperm banks. Trial registration number Not applicable.
Study question Can incorporation of novel markers of morphology with known temporal events successfully rank embryos to enable prediction of propensity for live birth? Summary answer Incorporation of variables for trophectoderm and morula grading demonstrably enhanced the model to rank embryos in order of potential for live birth. What is known already Models built using morphokinetic markers of development are widely used to rank embryos within a cohort. Such models include defined temporal parameters which are closely related to morphological grade. However, morphological grading by an embryologist is subjective and is not strongly correlated to outcome. Combining with defined kinetic events has been suggested to improve prediction of outcome. Study design, size, duration Data from 6228 known live birth outcome embryos from 8 UK clinics between 2011 – 2018 were investigated using an exploratory approach to identify novel markers of development. Participants/materials, setting, methods Five significant variables were defined, a derivative of time to start of blastulation; a derivative of trophectoderm grade; a kinetic variable utilising t3, t4, t5 and t8; an interval variable of tB-tSB and a variable based on novel morula classification. To maximise the output, a proxy value was derived for missing datapoints. The model was built using logistical regression and validated using fivefold cross validation with the data split as 80% training and 20% test. Main results and the role of chance An algorithm was developed including the five significant variables identified with an AUC of 0.685 demonstrating reliable prediction of live birth. Without morphological variables, the AUC was 0.674 demonstrating the improvement in the prediction value by including the derivative of the trophectoderm and morula grade. This resulted in ten classes of algorithm scores, 1–10, giving a live birth rate from 2% to 46%, irrespective of patient variables, for chance of live birth. Limitations, reasons for caution Successful application of the algorithm is reliant on stringent quality assurance for maintenance of accurate annotation and grading, and may not be transferable between laboratories with different SOPs. Wider implications of the findings: The addition of a trophectoderm and morula grade in combination with morphokinetic parameters, increases the predictive value of the algorithm in relation to live birth outcome. Using proxy values allows maximization of data for model generation, and allows the model to be applied when missing values are present. Trial registration number Not applicable
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