Time lapse incubation and morphokinetic embryo evaluation are not enough. Results from a Randomized controlled PILOT study

Abstract Study question Does the TLI have an added value in reproductive outcome when separating the system’s two components, undisturbed culturing, and morphokinetic embryo grading? Summary answer The TLI system itself does not have a significant added value. More advanced algorithms should be applied to aid in embryo selection process. What is known already The TLI technology has been widely used for over two decades for embryo culturing. A Cochrane meta-analysis found no significant difference in clinical pregnancy rate using TLI compared to conventional incubators. Another RCT concluded that the addition of TLI morphokinetic data did not significantly improve clinical reproductive outcomes. On the other hand, the benefit of TLI is the identification of abnormal cleavage dynamics and analysis of other morphokinetic parameters although no proven increase in pregnancy rate was shown. Several Artificial intelligence algorithms use TLI data to increase the pregnancy rate and embryo selection process. Study design, size, duration A prospective, randomized, double-blinded, single-center, controlled study. After applying inclusion criteria, 102 women were included in the analysis, 34, 32, and 36 in arms 1,2, and 3 respectively, with a total of 1061 embryos evaluated, 420 in arm 1, 285 in arm 2, and 356 in arm 3. Patients were recruited between November 2017- July 2020. Participants/materials, setting, methods University-affiliated Medical Centre in vitro fertilization (IVF) clinic. Patients were randomized into 3 groups: 1) conventional incubator with morphological evaluation only; 2) TLI incubator with both morphological and morphokinetic evaluation; 3) TLI incubation with morphological evaluation only. All were cultured in MIRI ESCO incubators. The primary outcome was live birth rates. Secondary outcomes were clinical pregnancy rates and cumulative pregnancy rates. Embryo quality and morphokinetic scores. Main results and the role of chance No differences were found in the rated day 2 top quality embryos (TQE), day 3 TQE or blastocyst stage TQE, and a similar number of embryos were suitable for either transfer or cryopreservation between the groups. On the other hand, higher rates of multinucleation were found in group 1 (31.9±6 vs. 16.6±5 vs.14.9±5, p = 0.03 for groups 1,2 and 3 respectively). Regarding primary outcome, we did not find any significant difference in live birth rate between the groups, neither for single embryo transfer cycles (SET) (35% vs. 31.6% vs. 24%, p = 0.708) nor for double embryo transfer cycles (DET) (41.7% vs. 38.5% vs. 36.4%, p = 0.966 for groups 1,2 and 3 respectively). Also, no differences were noted between pregnancy rates and clinical pregnancy rates. After concluding the first part of the study, embryos in arm 3 were retrospectively reevaluated, gaining additional morphokinetic data for the embryo selection process. In more than half of the embryos selected for transfer, the morphokinetic and morphologic evaluations were similar. For the additional 32 embryos from a total of 12 cycles, there was a discrepancy between the grades. In the other cases, the use of morphokinetic scoring would not have changed significantly the end point of pregnancy. Limitations, reasons for caution The pandemic affected patient recruitment and smaller numbers than intended were achieved leaving the study sample underpowered for the primary endpoint. Both day 3 and day 5 transfers were performed, and cycles were not always restricted to single embryo transfer, although the study was designed as such. Wider implications of the findings This study underlines the maybe unjustified morphkinetic scoring grading system which requires much time and attention from the embryologist to view and annotate and should be reconsidered especially with the rise of substitute software-assisted assessment algorithms showing an additional advantage in embryo selection and implantation rate. Trial registration number ClinicalTrials.gov Identifier: NCT02657811.