A hybrid artificial intelligence model leverages multi-centric clinical data to improve fetal heart rate pregnancy prediction across time-lapse systems.

STUDY QUESTION: Can artificial intelligence (AI) algorithms developed to assist embryologists in evaluating embryo morphokinetics be enriched with multi-centric clinical data to better predict clinical pregnancy outcome? SUMMARY ANSWER: Training algorithms on multi-centric clinical data significantly increased AUC compared to algorithms that only analyzed the time-lapse system (TLS) videos. WHAT IS KNOWN ALREADY: Several AI-based algorithms have been developed to predict pregnancy, most of them based only on analysis of the time-lapse recording of embryo development. It remains unclear, however, whether considering numerous clinical features can improve the predictive performances of time-lapse based embryo evaluation. STUDY DESIGN, SIZE, DURATION: A dataset of 9986 embryos (95.60% known clinical pregnancy outcome, 32.47% frozen transfers) from 5226 patients from 14 European fertility centers (in two countries) recorded with three different TLS was used to train and validate the algorithms. A total of 31 clinical factors were collected. A separate test set (447 videos) was used to compare performances between embryologists and the algorithm. PARTICIPANTS/MATERIALS, SETTING, METHODS: Clinical pregnancy (defined as a pregnancy leading to a fetal heartbeat) outcome was first predicted using a 3D convolutional neural network that analyzed videos of the embryonic development up to 2 or 3 days of development (33% of the database) or up to 5 or 6 days of development (67% of the database). The output video score was then fed as input alongside clinical features to a gradient boosting algorithm that generated a second score corresponding to the hybrid model. AUC was computed across 7-fold of the validation dataset for both models. These predictions were compared to those of 13 senior embryologists made on the test dataset. MAIN RESULTS AND THE ROLE OF CHANCE: The average AUC of the hybrid model across all 7-fold was significantly higher than that of the video model (0.727 versus 0.684, respectively, P = 0.015; Wilcoxon test). A SHapley Additive exPlanations (SHAP) analysis of the hybrid model showed that the six first most important features to predict pregnancy were morphokinetics of the embryo (video score), oocyte age, total gonadotrophin dose intake, number of embryos generated, number of oocytes retrieved, and endometrium thickness. The hybrid model was shown to be superior to embryologists with respect to different metrics, including the balanced accuracy (P ≤ 0.003; Wilcoxon test). The likelihood of pregnancy was linearly linked to the hybrid score, with increasing odds ratio (maximum P-value = 0.001), demonstrating the ranking capacity of the model. Training individual hybrid models did not improve predictive performance. A clinic hold-out experiment was conducted and resulted in AUCs ranging between 0.63 and 0.73. Performance of the hybrid model did not vary between TLS or between subgroups of embryos transferred at different days of embryonic development. The hybrid model did fare better for patients older than 35 years (P < 0.001; Mann-Whitney test), and for fresh transfers (P < 0.001; Mann-Whitney test). LIMITATIONS, REASONS FOR CAUTION: Participant centers were located in two countries, thus limiting the generalization of our conclusion to wider subpopulations of patients. Not all clinical features were available for all embryos, thus limiting the performances of the hybrid model in some instances. WIDER IMPLICATIONS OF THE FINDINGS: Our study suggests that considering clinical data improves pregnancy predictive performances and that there is no need to retrain algorithms at the clinic level unless they follow strikingly different practices. This study characterizes a versatile AI algorithm with similar performance on different time-lapse microscopes and on embryos transferred at different development stages. It can also help with patients of different ages and protocols used but with varying performances, presumably because the task of predicting fetal heartbeat becomes more or less hard depending on the clinical context. This AI model can be made widely available and can help embryologists in a wide range of clinical scenarios to standardize their practices. STUDY FUNDING/COMPETING INTEREST(S): Funding for the study was provided by ImVitro with grant funding received in part from BPIFrance (Bourse French Tech Emergence (DOS0106572/00), Paris Innovation Amorçage (DOS0132841/00), and Aide au Développement DeepTech (DOS0152872/00)). A.B.-C. is a co-owner of, and holds stocks in, ImVitro SAS. A.B.-C. and F.D.M. hold a patent for 'Devices and processes for machine learning prediction of in vitro fertilization' (EP20305914.2). A.D., N.D., M.M.F., and F.D.M. are or have been employees of ImVitro and have been granted stock options. X.P.-V. has been paid as a consultant to ImVitro and has been granted stocks options of ImVitro. L.C.-D. and C.G.-S. have undertaken paid consultancy for ImVitro SAS. The remaining authors have no conflicts to declare. TRIAL REGISTRATION NUMBER: N/A.

Is it worth it to cryopreserve embryos with blastulation delay at day 5?

This is a retrospective study over a 5-year period. In total, 3139 embryos were individually cryopreserved (Cryotop®) and warmed using the Kitazato vitrification/warming kit. They were classified into three categories based on their expansion degree. Transfer, implantation and pregnancy rates were assessed for each embryo category and compared using SPSS (Statistical Package for the Social Sciences) software. In total, 1139 couples enrolled in infertility treatment programme benefitted from embryo vitrification at day 5. After warming, embryos belonging to the three categories showed similar success rates. Although there was a trend towards better outcomes when grade 3 embryos were transferred, the differences did not reach statistical significance: implantation rates (n fetal sac/n embryo transferred) grade 1: 21.9%, grade 2: 22.7% and grade 3: 30.3% (=0.19). Pregnancy rate (n clinical pregnancy/n transfer) (21.9%, 22.7%, 30.3%, respectively; P=0.11). Miscarriage rate was not statistically different in the three categories (14.5%, 20.4%, 20%, respectively, P=0.51). Our overall results show that it is worth vitrifying slow kinetics embryos as they provide a non-negligible chance to give rise to a pregnancy.

Longitudinal growth of French singleton children born after in vitro fertilization and intracytoplasmic sperm injection. Body mass index up to 5 years of age.

BACKGROUND: The literature presents conflicting results on the epigenetic effect of in vitro fertilization (IVF) on the short-term and mid-term growth of children. These contradictory results may be related to the use of heterogeneous methodologies and non-longitudinal data. The goal of this study was to compare the body mass index (BMI) of children conceived via IVF and spontaneous conception (SC) children, using longitudinal data from birth to 5 years. METHODS: This study compared 118 singleton children born after in vitro fertilization, with or without intracytoplasmic sperm injection (ICSI), selected from a pre-existing single-center cohort to 320 SC children from the same geographic area. BMI and its evolution were analyzed using the mixed-effect model during three periods: before standing acquisition (from birth to 1 year of age), during standing acquisition, and the following period from 2 to 5 years of age. RESULTS: BMI means were not significantly different between groups regardless of the period, when adjusting for confounding factors related to parents, pregnancy, and children's characteristics and lifestyle. Nevertheless, during the standing acquisition period, children born after IVF-ICSI presented a less significant decrease in BMI (P<0.05). In addition, for each period we identified influencing factors (maternal BMI, level of wealth indicator) associated with BMI. CONCLUSION: In the study population, the suspected epigenetic influence of IVF reported in the literature was not observed for BMI from birth to 5 years of age. Further investigations need to be conducted to determine if the suspected influence of IVF on adiposity could be expressed through other parameters.

Morphokinetics analysis of embryos derived from vitrified/warmed oocytes.

PURPOSE: Oocyte vitrification is a worldwide used technique that has proved its worth. Although it was shown not to alter oocyte integrity, a recent study concluded that it may affect oocyte embryo development. As the morphology and kinetics of embryos derived from sibling fresh and vitrified oocytes have not been described previously, the present study evaluates cleavage rate, blastomeres size, fragmentation rate, and blastocyst formation in vitrified/warmed oocyte derived embryos (VODE) as compared with sibling fresh oocytes derived embryos (FODE). METHODS: This investigation included 90 infertility cases displaying large cohort of mature oocytes at pick up, divided into 2 groups after denudation. A part of oocytes underwent ICSI while others were vitrified. Oocyte warming cycles were performed when no pregnancy was achieved using fresh eggs. Zygote to blastocyst development was recorded prospectively in an image database up to day 5. RESULTS: VODE did not show major difference as compared with FODE in terms of cleavage rate, number of blastomeres, fragmentation rate, and blastomeres size. Furthermore, percentage of morulae at day 4 and blastocysts at day 5 are not affected by oocyte vitrification. CONCLUSION: Although our results show that embryo development is not altered by oocyte vitrification, offspring follow-up is essential to exclude any adverse developmental effect of the technique.

[Adverse obstetric and perinatal outcome with in vitro fertilization technology: A French nationwide population-based study]. / Risques de morbidité maternelle et périnatale en fécondation in vitro : une étude nationale de cohorte française.

OBJECTIVES: The objective of this study was to quantify the risk of maternal and perinatal morbidity with in vitro fertilization (IVF) technology compared to non-IVF pregnancies in a recent French national cohort. METHOD: The data was extracted from the hospital information data system, including all pregnancies with a delivery from 2013 to 2016. The risks of preterm birth, maternal morbidity (venous and arterial thrombosis, gestational diabetes, vascular disorders, placenta previa, placenta abruption), hypotrophy and congenital malformation were compared in both groups in univariate and multivariate analysis after adjustment on the characteristics of women (age, parity, obesity, tobacco dependence, history of diabetes or high blood pressure), multiple deliveries and sex of children. RESULTS: In all, 2,875,662 pregnancies and 2,922,712 births were analyzed, of which 49,224 were derived from IVF (1.7%). In multivariate analysis, all risks were significantly higher in IVF: premature deliveries (ORajusted=1.28; CI95%=1.24-1.32), maternal morbidity (ORajusted=1.24; CI95%=1.21-2.28), (mainly for thrombosis venous, placenta previa and placenta abruption). The risks of hypotrophy (ORajusted=1.13; CI95%=1.10-1.16) and congenital malformations (ORajusted=1.11; CI95%=1.05-1.17) were slightly increased. CONCLUSION: The results of this study on a large cohort of recent births in France confirm that there was an increased risk of maternal and perinatal morbidities in IVF. These risks were similar to those published in the international literature. This study is the starting point for a forthcoming surveillance.

[Satisfaction survey on the use of autologous oocyte vitrification in Assisted Reproductive Technologies]. / Enquête de satisfaction des couples à propos de la vitrification ovocytaire autologue en assistance médicale à la procréation.

OBJECTIVES: We organized a survey for in-vitro fertilization couples who beneficiated on self-preservation of part of the oocyte cohort. The main objective was to measure couples' satisfaction. Secondary objectives were; to identify how patients had been informed; to verify that the use of the ART technique met their expectations, and how they felt about oocyte or embryo freezing. METHODS: The data were collected by a questionnaire sent electronically to couples who had undergone partial vitrification of the oocyte cohort and at least one warming cycle. The questionnaire consisted of 2 components; one for the women and another one for their husband. RESULTS: Eighty-eight women and 62 men responded to the survey respectively, representing 50.86% and 35.84% of the targeted patients. They were satisfied with a 90% rate, men and women combined. The information we give in the center is heard by couples and is part of the trust in the medical staff. Men are more worried than women about the risks of stimulation or ovarian pick-up and are not displeased to be called upon for sperm recovery for every attempt at oocyte warming. The ambiguity of the answers on the representation of the embryo confirms what is already described, but is independent of the acceptance of freezing whether it is oocyte or embryo. CONCLUSION: In the same way as evaluating the results, the evaluation of patient satisfaction is useful for the implementation of therapeutic strategies and care pathways.

[Oocyte vitrification in an ART laboratory]. / Apport de la vitrification ovocytaire dans un laboratoire d'AMP. Vitrification des ovocytes : l'âge mûr.

Oocyte vitrification has been authorized in France after the modification of French bioethics law in July 2011. This evolution will bring a dramatic change in patients' management since, from 2011, infertile couples, oocyte donation and fertility preservation programs will benefit this technique in France. We have introduced oocyte vitrification in our ART laboratory through a validation of the method using Evidence-Based Medicine model: open system Cryotop, Ethylène-glycol 15% and DMSO 15%. Based on our 1-year experience, oocyte vitrification upgrades our daily practice while also minimizing embryo cryoconservation as recommended by the law.

[Oocyte vitrification and its impact on the clinical practice of assisted reproduction]. / La vitrification des ovocytes et les changements induits dans nos pratiques d'AMP.

Oocyte vitrification is a new technique in cryobiology that will lead to a number of improvements in assisted reproduction practices, oocyte donation and the preservation of female fertility. Professionals already versed in the techniques of micromanipulation will be able to master the new procedures, which should not be delegated to unqualified staff. When adopted by clinical units, oocyte vitrification will require changes in laboratory and administrative organization. The technique will also modify the ethical outlines of reproductive biology. France today is running behind in the application of this major development in cryobiology. The reasons are many and have to do with a long waiting period for authorization from national health authorities, a lack of material and human resources and a foreseeable shake-up in the nationally established egg donation program. However, recently a new law of bioethics has recognized the breakthrough that this new technique represents by allowing couples covered by the French national health care program for Assisted Reproductive Technologies (ART) to choose oocyte vitrification as an option.