Clinical outcomes of uninterrupted embryo culture with or without time-lapse-based embryo selection versus interrupted standard culture (SelecTIMO): a three-armed, multicentre, double-blind, randomised controlled trial

Summary

Background

Time-lapse monitoring is increasingly used in fertility laboratories to culture and select embryos for transfer. This method is offered to couples with the promise of improving pregnancy chances, even though there is currently insufficient evidence for superior clinical results. We aimed to evaluate whether a potential improvement by time-lapse monitoring is caused by the time-lapse-based embryo selection method itself or the uninterrupted culture environment that is part of the system.

Methods

In this three-armed, multicentre, double-blind, randomised controlled trial, couples undergoing in-vitro fertilisation or intracytoplasmic sperm injection were recruited from 15 fertility clinics in the Netherlands and randomly assigned using a web-based, computerised randomisation service to one of three groups. Couples and physicians were masked to treatment group, but embryologists and laboratory technicians could not be. The time-lapse early embryo viability assessment (EEVA; TLE) group received embryo selection based on the EEVA time-lapse selection method and uninterrupted culture. The time-lapse routine (TLR) group received routine embryo selection and uninterrupted culture. The control group received routine embryo selection and interrupted culture. The co-primary endpoints were the cumulative ongoing pregnancy rate within 12 months in all women and the ongoing pregnancy rate after fresh single embryo transfer in a good prognosis population. Analysis was by intention to treat. This trial is registered on the ICTRP Search Portal, NTR5423, and is closed to new participants.

Findings

1731 couples were randomly assigned between June 15, 2017, and March 31, 2020 (577 to the TLE group, 579 to the TLR group, and 575 to the control group). The 12-month cumulative ongoing pregnancy rate did not differ significantly between the three groups: 50·8% (293 of 577) in the TLE group, 50·9% (295 of 579) in the TLR group, and 49·4% (284 of 575) in the control group (p=0·85). The ongoing pregnancy rates after fresh single embryo transfer in a good prognosis population were 38·2% (125 of 327) in the TLE group, 36·8% (119 of 323) in the TLR group, and 37·8% (123 of 325) in the control group (p=0·90). Ten serious adverse events were reported (five TLE, four TLR, and one in the control group), which were not related to study procedures.

Interpretation

Neither time-lapse-based embryo selection using the EEVA test nor uninterrupted culture conditions in a time-lapse incubator improved clinical outcomes compared with routine methods. Widespread application of time-lapse monitoring for fertility treatments with the promise of improved results should be questioned.

Funding

Health Care Efficiency Research programme from Netherlands Organisation for Health Research and Development and Merck.

Introduction

The culture of embryos for medically assisted reproduction in an in-vitro fertilisation (IVF) laboratory usually involves regular morphological evaluations of the developing embryos outside the incubator. Nowadays, more and more IVF laboratories use time-lapse monitoring for the assessment of embryos. In time-lapse incubators, embryos are closely monitored by built-in cameras that take images at fixed time intervals resulting in videos of embryo development that can be analysed by embryologists, computer software, or artificial intelligence. Because embryo development is recorded continuously, and therefore in more detail than with standard assessments, important developmental events will not be missed.1, 2 With this method, embryo selection could be improved. In addition, as there is no need to remove embryos from the incubator for morphological assessments, stable culture conditions are provided. Potentially detrimental effects due to changes in temperature, gas concentration, or culture-medium pH are reduced while beneficial autocrine and paracrine factors could be accumulated. Furthermore, embryo handling and the risk of cell damage or loss are minimised.3, 4

Research in context

Evidence before this study

Time-lapse monitoring is routinely offered to patients in in-vitro fertilisation (IVF) centres worldwide even though its clinical benefits are still controversial. Two mechanisms are thought to have a role in improving clinical results: the time-lapse-based embryo selection procedures and the uninterrupted culture conditions that are part of the system. Systematic reviews of the available data from earlier studies show that there is insufficient good quality evidence for improved pregnancy results and well designed randomised controlled trials are needed to assess the clinical value of time-lapse monitoring for IVF and intracytoplasmic sperm injection (ICSI) treatments.

Added value of this study

The SelecTIMO study is the largest, sufficiently powered, multicentre, randomised controlled trial on time-lapse monitoring to date providing cumulative ongoing pregnancy and livebirth results for a follow-up period of 1 year. The comparison of three treatment groups allows, for the first time in one study, the distinction of the two mechanisms suspected to improve clinical results.

Implications of all the available evidence

We found no evidence that time-lapse monitoring improves the cumulative ongoing pregnancy or livebirth rate within 1 year, time to pregnancy, or pregnancy results after fresh embryo transfer only. Neither embryo selection based on a time-lapse-based selection algorithm in combination with morphology nor the uninterrupted culture conditions in a time-lapse incubator improved clinical results after IVF or ICSI treatments. Our findings, together with the available evidence from earlier studies, suggest that the widespread application of time-lapse monitoring for IVF and ICSI treatments with the promise of improved outcomes should be questioned. In the absence of adequately designed and executed trials proving efficacy, the practice to financially charge patients for the use of time-lapse monitoring as an add-on cannot be justified.

Time-lapse-based embryo culture and selection is offered increasingly to couples undergoing IVF with the promise of improved clinical results.⁵ However, systematic reviews have concluded that there is currently insufficient high-quality evidence supporting the routine use of time-lapse monitoring and that well designed randomised controlled trials (RCTs) are needed to assess its clinical value.6, 7, 8

We did a multicentre, double-blind, RCT to evaluate whether time-lapse monitoring can increase clinical results and if so, whether an improvement is caused by the time-lapse-based embryo selection method itself or the uninterrupted culture environment that is part of the system. A three-armed design along with culturing all embryos in the same incubator allows for a distinction between both suspected mechanisms for the first time in one RCT.⁸