Blastocyst formation is similar in obese and normal weight women: a morphokinetic study.

STUDY QUESTION: Does the embryo cleavage pattern and rate of blastocyst formation differ between normal weight and obese women undergoing IVF? SUMMARY ANSWER: Embryo morphokinetic development, final blastocyst formation rate and blastocyst morphology do not differ between obese and normal weight women. WHAT IS KNOWN ALREADY: Female obesity has been related to impaired IVF outcomes. Although the mechanisms responsible for this detrimental effect are thought to include impaired oocyte and embryo quality and reduced endometrial receptivity, they are yet to be confirmed. Embryo quality has been commonly assessed using static morphological criteria. Only three studies have analysed the progress of embryos up to the blastocyst stage in women with elevated BMI, but they have used small samples of patients or have obtained contradictory results. STUDY DESIGN, SIZE, DURATION: This retrospective, cohort study, was performed from January 2016 to May 2020. A total of 3316 ICSI cycles from 2822 women were included, of which 1251 cycles were part of a preimplantation genetic testing programme. In total, 17 848 embryos were analysed. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study reports on the IVF cycles of infertile women, with a known BMI, who underwent ICSI and whose embryos were grown until the fifth/sixth day of development in a time-lapse system. Patients were grouped as follows. Underweight was defined as a BMI <18.5 kg/m2; normal weight was a BMI of 18.5-24.9 kg/m2; overweight was a BMI of 25-29.9 kg/m2; and obesity was a BMI of ≥30 kg/m2. Embryo development was assessed on an external computer with analysis software. MAIN RESULTS AND THE ROLE OF CHANCE: Despite an initial slower pattern of embryo development, the blastocyst formation rate on day 5 or on day 5 plus day 6 did not differ in obese women with respect to the other three BMI groups. Moreover, based on the evaluation of inner cell mass and the trophectoderm on both days of blastocyst development, embryo quality was similar across the BMI groups, as were the pattern of development and arrest up to blastocyst formation and the distribution of the categories of full, expanded and hatching blastocysts. LIMITATIONS, REASONS FOR CAUTION: Limitations include the retrospective analysis of data, the use of BMI as the only parameter to define normal/abnormal female body weight, and the lack of complete information about clinical outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Blastocyst formation and embryo morphokinetics are not affected by female obesity, and the poorer IVF outcomes described for such women are probably due to deficient endometrial receptivity. The role of endometrial progesterone exposure on the day of embryo transfer should be analysed in future studies as a possible determining factor. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used and there are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

An artificial intelligence model based on the proteomic profile of euploid embryos and blastocyst morphology: a preliminary study.

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.

Assessment of embryo implantation potential with a cloud-based automatic software.

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.

Novel and conventional embryo parameters as input data for artificial neural networks: an artificial intelligence model applied for prediction of the implantation potential.

OBJECTIVE: To describe novel embryo features capable of predicting implantation potential as input data for an artificial neural network (ANN) model. DESIGN: Retrospective cohort study. SETTING: University-affiliated private IVF center. PATIENT(S): This study included 637 patients from the oocyte donation program who underwent single-blastocyst transfer during two consecutive years. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The research was divided into two phases. Phase 1 consisted of the description and analysis of the following embryo features in implanted and nonimplanted embryos: distance and speed of pronuclear migration, blastocyst expanded diameter, inner cell mass area, and trophectoderm cell cycle length. Phase 2 consisted of the development of an ANN algorithm for implantation prediction. Results were obtained for four models fed with different input data. The predictive power was measured with the use of the area under the receiver operating characteristic curve (AUC). RESULT(S): Out of the five novel described parameters, blastocyst expanded diameter and trophectoderm cell cycle length had statistically different values in implanted and nonimplanted embryos. After the ANN models were trained and validated using fivefold cross-validation, they were capable of predicting implantation on testing data with AUCs of 0.64 for ANN1 (conventional morphokinetics), 0.73 for ANN2 (novel morphodynamics), 0.77 for ANN3 (conventional morphokinetics + novel morphodynamics), and 0.68 for ANN4 (discriminatory variables from statistical test). CONCLUSION(S): The novel proposed embryo features affect the implantation potential, and their combination with conventional morphokinetic parameters is effective as input data for a predictive model based on artificial intelligence.

Preimplantation genetic testing for aneuploidy in patients with partial X monosomy using their own oocytes: is this a suitable indication?

OBJECTIVE: To describe the outcome of preimplantation genetic testing (PGT-A) using their own oocytes in patients with mosaic Turner Syndrome (MTS). The impact of the assisted reproduction technique (ART) performed (PGT-A or oocyte donation) and the type of absence of the X chromosome (total or partial) were considered. DESIGN: Retrospective observational multicenter study. SETTING: University-affiliated private in vitro fertilization center. PATIENT(S): Fifty-six patients with MTS with whom 65 ovarian stimulation cycles for PGT-A (fluorescence in situ hybridization/arrays-next generation sequencing) were performed. The study included 90 women with MTS and 20 women with pure Turner Syndrome (PTS) who underwent 140 and 25 oocyte donation (OD) cycles, respectively. INTERVENTION(S): In vitro fertilization for PGT-A (fluorescence in situ hybridization/arrays-next generation sequencing) or OD. MAIN OUTCOME MEASURE (S): Reproductive outcome and feto-maternal outcomes. RESULTS: The live birth rate (LBR) per embryo transfer in patients with MTS tended to be higher in OD 37.7% (95% confidence interval [CI]: 29.3-46.1) than that observed for PGT-A 22.5% (95% CI 7.8-38.2), and the cumulative LBR (CLBR), with 77.6% vs. 43.3%, respectively. Likewise, the LBR per patient was significant when comparing PGT-A vs. OD, with 12.5% (95 CI 3.9-21.1) vs. 51.1% (40.7-61.4), respectively. While focusing on the X chromosome, partial MTS (PTS), we found significant differences in the CLBR per embryo transfer, with 77.6% vs. 29.2%, and also in the LBR per patient: 51.1% (40.7-61.4) in MTS vs. 15% (95 CI 0.0-30.1) in PTS. CONCLUSION(S): Oocyte donation is the best reproductive option in females with Turner Syndrome with or without mosaicisms. Nevertheless, PGT-A is a valid therapeutic option in patients with MTS using their own oocytes, and OD should not necessarily be directly recommended.

Novel noninvasive embryo selection algorithm combining time-lapse morphokinetics and oxidative status of the spent embryo culture medium.

OBJECTIVE: To develop a noninvasive embryo selection algorithm consisting of time-lapse morphokinetics and the oxidative status of the spent embryo culture medium determined using the Thermochemiluminescence (TCL) Analyzer. DESIGN: Retrospective cohort. SETTING: Not applicable. PATIENT(S): From women participating in the oocyte donation program, data from 505 samples of spent embryo culture media samples from 292 intracytoplasmic sperm injection cycles. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Morphokinetic parameters assessed during incubation in the time-lapse system Embryoscope. Oxidative parameters (H1sm, H2sm, and H3sm) from the spent culture medium on day 5 of incubation measured using the TCL assay; and a combined assessment algorithm, including morphology, morphokinetics, and the embryo's culture medium oxidative status, developed as a tool for embryo selection, based on implantation success and confirmed ongoing pregnancy. RESULT(S): The levels of the oxidative parameters H1sm, H2sm, and H3sm on day 5 of incubation were statistically significantly higher in transferred and vitrified embryos compared with discarded embryos and in successfully implanted embryos compared with those that did not result in pregnancy. The assessment algorithm resulted in a hierarchical classification with six embryo quality categories (A to F), associated with implantation rates of between 76.5% and 29.2%. CONCLUSION(S): An assessment algorithm combining morphology, morphokinetics and the embryo's culture medium oxidative status may help to improve current embryo selection methods criteria and in vitro fertilization success.

Analysis of the morphological dynamics of blastocysts after vitrification/warming: defining new predictive variables of implantation.

OBJECTIVE: To describe the morphological dynamics of vitrified/warmed blastocysts and to identify quantitative morphological variables related to implantation. Subsequently, by using the most predictive parameters, to develop a hierarchical model by subdividing vitrified/warmed blastocysts into categories with different implantation potentials. DESIGN: Observational, retrospective, cohort study. SETTING: University-affiliated private IVF center. PATIENT(S): The study included 429 vitrified/warmed blastocysts with known implantation data, which were evaluated by time-lapse imaging. Blastocysts were routinely placed in EmbryoScope (Vitrolife) immediately after warming until transfer. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Embryos were vitrified and warmed by the Cryotop method (KitazatoBiopharma). The studied variables included the initial and minimum thicknesses of zona pellucida (µm), the initial and maximum areas (µm2), the area of inner cell mass (µm2), expansion (whether the embryo reexpands or not after warming), and collapsing or contraction after warming. After defining the optimal ranges according to the consecutive quartiles with the highest probability of implantation, a logistic regression analysis was performed by combining the former variables and the blastocyst morphological classification criteria defined by the Spanish Association of Embryologists into A, B, C, or D categories. RESULT(S): Reexpansion of vitrified/warmed blastocysts correlated strongly with implantation (44.6% for reexpanded vs. 6.5% for the blastocysts that did not reexpand after warming). Throughout the logistic regression analysis, the model identified the maximum blastocyst area, odds ratio (OR) = 0.41 (95% confidence interval [CI], 0.22-0.77), followed by the initial area, OR = 0.62 (95% CI, 0.35-1.08) as the most predictive variables related to implanting embryos. Blastocyst morphology was not considered relevant in our model. The hierarchical tree model subdivided embryos into four categories, A-D, with lowering expected implantation potentials (from 47.3% for A to 14.2% for D). CONCLUSION(S): The analysis of warmed blastocysts by time-lapse imaging may provide objective quantitative markers for the blastocyst implantation potential. We propose a hierarchical model to classify vitrified/warmed blastocysts according to their implantation probability. The observed correlations and the proposed algorithm should be validated in a prospective trial to evaluate its efficacy.