Objective:Assessment of the risk associated with the implementation of the Geri® Assess 2.0 semi-automated time-lapse system for the morphokinetic analysis of embryos, from fertilisation to blastocyst, using artificial intelligence (iDAscore) to predict implantation quality and capacity; with integration of the results on software reliability through the Euro-GTP II framework.
Methods: The risk assessment was carried out according to the three phases foreseen by EuroGTP II, taking into consideration the results of the study “Investigation of the reliability of semi-automatic annotation by the Geri time-lapse system” (Reprod Biomed Online, 2022), including the identification of the technological novelty, the risk analysis and the determination of the extent of the necessary studies. The reliability of the software was evaluated by comparing automatic and manual blinded annotation on 513 oocytes from 34 patients, analysing sensitivity, specificity, concordance and the system's ability to detect critical abnormalities such as direct and reverse cleavage.
Risciplinary studies were also conducted to assess the reliability of the software.
Results: The EuroGTP II analysis identified critical risks related to failure to detect anomalies (R=16) and over-reliance on software (R=20). The experimental study showed automatic detection rates between 0% and 94.4%, with sensitivity; 68.2–94.4% and specificity; 63.8–97.3%. Automatic annotation required manual intervention in 55.2% of the oocytes and showed a concordance with manual scoring of 42.1%, which increased to 66.0% after correction. The software showed important limitations in detecting “direct cleavage” (in some cases 0%) and“reverse cleavage”.
Conclusions: Geri Assess 2.0 is a useful tool as an aid to morphokinetic assessment, but it cannot be used as a primary decision-making system so verification with the EURO GPT II system results in a moderate risk. The EuroGTP II approach enables systematic risk management by defining the necessary mitigation measures to ensure quality and safety in clinical use. Compulsory review of all automatic annotations by qualified embryologists è manual audit è essential for risk mitigation.
Introduction
Substances of Human Origin (SoHO) are being used in an increasing number of innovative clinical applications, including time-lapse technologies applied to medically assisted procreation (MPA). The rapid development of new blood, tissue and cell (BTC) components, as well as new preparation protocols, makes it necessary to adopt standardised processes to identify, quantify and manage the potential risks associated with their clinical implementation.
In this context, the EuroGTP II tool, developed by EDQM, is a risk assessment system designed to:
- determine whether a BTC or a process represents a novelty with respect to the standard (Stage 1);
- assess the associated risks through a combination of probability, severity and detectability (Step 2);
- .
- define the extent of studies and follow-up necessary to ensure safety and efficacy (Phase 3);
The introduction of the Geri Assess 2.0 semi-automated time-lapse system for embryonic morphokinetic annotation is fully among the processes requiring EuroGTP II evaluation, given the innovative nature of the technology and its potential impact on the quality of clinical outcomes. GERI 2.0 iDAscore è a semi-automated time-lapse system that analyses embryo morphokinetics, from fertilisation to blastocyst, using advanced imaging and artificial intelligence. It provides a score (iDAscore) to predict the quality and implantation capacity of embryos, optimising selection and improving results in assisted fertilisation treatments.
Materials and Methods
Evaluation process using the EuroGTP II methodology applied to the Geri Assess 2.0 system followed the three planned phases:
Phase 1 – New Technology
Geri Assess 2.0 è been classified as “new process”, requiring:
- in-depth local validation,
- specific staff training,
- enhancement of the quality system,
- definition of performance criteria (performance specifications),
Phase 2 – Risk Analysis
Risks related to:
were identified and assessed.
- lack of detection of critical anomalies,
- excessive dependence on automation,
- variability between operators,
- incorrect timing of kinetic events,
- possible integration errors and loss of data.
Each risk has been classified on the basis of the EuroGTP II criteria:
Probability; (P), Gravity; (G), Detectability; (R)
with risk calculation: R = P × G
Phase 3 – Extension of the Study
The phase involved:
- definition of the validation extension,
- implementation of specific KPIs,
- introduction of detailed Operating Procedures,
- indication of mandatory manual review,
513 oocytes from 34 women were analysed. Annotations made by the Geri Assess 2.0 system for ten kinetic events (time of pronuclei (PN) appearance and disappearance, cleavage time for two-, three-, 4-, and up to 8-cell (t2–t8) cell divisions up to the annotation of blastocyst formation time) were compared with manual annotations made blindly by embryologists.
The following were evaluated:
- detection rates,
- sensitivity and specificity,
- concordance of embryonic scores,
- abilityà to identify “direct cleavage” and“reverse cleavage”,
- percentage of images/events that required manual review.
Results
EuroGTP II Evaluation
Phase 1 – Evaluation of the new process (GERI 2.0)
The technology è was new to the Centre for Medically Assisted Reproduction, requiring full validation.
Stage 2 – Risk assessment
| Risk Identification | Prob. (1–5) | Grav. (1–5) | Rilev. (1–5) | Risk (PxG) | Level | ||
| False negatives (direct/reverse cleavage) | 4 | 4 | 2 | 16 | Critic | ||
| False positives: wrongly reported events | 3 | 3 | 2 | 9 | Moderate | ||
| Incorrect timing (t2, t3, PN) | 3 | 4 | 2 | 12 | High | ||
| Software dependency/non-review | 4 | 5 | 2 | 20 | Critic | ||
| Integration errors/data loss | 2 | 4 | 3 | 8 | Moderate | ||
| Variability between operators | 3 | 3 | 3 | 9 | Moderate | ||
| Insufficient | 2 | 4 | 3 | 8 | Moderate | ||
Table 1
Results of the experimental study
- Detection rates: 0–94.4%
- Sensitivityà: 68.2–94.4%
- Specificityà: 63.8–97.3%
- Concordance with manual annotation: 42.1%
→ 66% after manual review - Corrections required: 55.2% of oocytes
- Direct cleavage: detection also 0%
- Reverse cleavage: low and variable detection
These results confirm the need for expert review to ensure accuracy and safety.
Risk mitigation measures
- Mandatory review of all automated annotations by qualified embryologists
- Double verification for embryos intended for transfer/biopsy.
- Detailed Operating Procedures for Correction of Annotations.
- Initial and periodic system validation on local dataset.
- Comprehensive audit trail with logging of all changes.
- Data backup and version control.
- Regular staff training on time-lapse reading.
- Monthly KPIs for monitoring concordance and error rates.
- Introduction of quality controls aimed at monitoring Critical Process Parameters (CPPs)
Discussion
The integration of the EuroGTP II results with the experimental study clearly shows that Geri Assess 2.0 can contribute to the standardisation of morphokinetic annotation, but it cannot replace the embryologist's analysis. The main critical issues are related to the detection of cleavage abnormalities (e.g. t1-t3 “direct cleavage” or t2-t1 “reverse cleavage”), which have a direct clinical impact on embryo developmental potential.
È the risk assessment was repeated using the EuroGTP II tool, systematically reviewing the critical points highlighted by the article from the expert embryologist’s point of view: the process was reclassified as new and all the risk mitigation strategies listed above were applied. On the basis of these measures, the risk level calculated by the system è was low, with a residual risk of 6, as shown in Figure 1, indicating that the GERI 2.0 technology can be safely used only as a support and not as a primary decision-making tool.
Figure 1 Risk assessment
The new tool also emphasises the need to accompany the introduction of the technology with a structured clinical follow-up programme, allowing rigorous comparison of the results obtained before and after its implementation and to verify its effectiveness over time. This evaluation must be complemented with a systematic comparison with data available in the literature to ensure that the performance obtained is consistent with morphokinetic data reported by other centres. With this new GERI 2.0 è it is possible to have under control the main embryo morphokinetic points and to standardise laboratory KPIs ensuring an objective evaluation in the critical steps from fertilisation to blastocyst.
Conclusions
The EuroGTP II report explicitly concludes:
“Geri's semi-automated annotation system can only be used safely with mandatory manual review and after documented local validation. Residual risk è acceptable as an aid, not as a primary decision-making tool.”
Bibliography
- EDQM. Guide to the Quality and Safety of Tissues and Cells for Human Application. Council of Europe; latest edition.
- EuroGTP II Consortium. EuroGTP II – Good Practices for Tissues and Cells: Risk Assessment Tool. EDQM, Council of Europe; accessed materials and guidelines.
- Cirillo F, et al. Time-lapse technology in IVF: current insights and future prospects. Reprod Biomed Online. 2023.
- Paternot G, et al. Automated and semi-automated embryo annotation systems: accuracy and clinical performance. Hum Reprod. 2019;34(8):152–164.
- Kieslinger DC, et al. Limitations of automated embryo morphokinetics: evaluation of misannotations and clinical implications. Fertil Steril. 2020;113(4):723–731.
- Armstrong S, et al. Time-lapse systems and embryo selection: systematic review and meta-analysis. Cochrane Database Syst Rev. 2019.
- Rubio I, et al. Morphokinetic markers associated with embryo viability: a multicentre evaluation. Hum Reprod. 2020.
- Meseguer M, et al. Direct and reverse cleavage in embryos: clinical impact and detection challenges. Reprod Biomed Online. 2017.
- Petersen BM, et al. Embryo assessment and annotation variability among embryologists. Hum Reprod. 2016.
- Herrero J, et al. Time-lapse annotation systems in reproductive medicine: validation and limitations. J Assist Reprod Genet. 2021.
- Geri® Assess 2.0 – Manufacturer Technical Documentation (Vitrolife).
