COMMENTARY

Can Time-Lapse Morphokinetics Improve Pregnancy Rates in IVF?

Peter Kovacs, MD, PhD

Disclosures

April 11, 2016

Does the Addition of Time-Lapse Morphokinetics in the Selection of Embryos for Transfer Improve Pregnancy Rates? A Randomized Controlled Trial

Goodman LR, Goldberg J, Falcone T, Austin C, Desai N
Fertil Steril. 2016;105:275-285.e10

Background

In vitro fertilization has improved significantly since the first successful treatment in 1978.[1] Intracytoplasmic sperm injection, assisted hatching, embryo cryopreservation, gamete cryopreservation, embryo biopsy, and genetic testing have been developed and introduced into routine daily care. Embryos are now routinely cultured to the blastocyst stage before they are transferred. The technological improvements have been paralleled by increasing success rates.

The pregnancy and live birth rates, however, have not improved to such degree that would have been expected based on the technological innovations. This could be explained in many ways. One explanation, for example, could be that technological improvements allow us to treat couples with more complex fertility problems. Another explanation is that in the developed world, there is a clear tendency towards delaying pregnancy to an older age. Women of more advanced age ovulate poorer-quality eggs and produce more aneuploidy embryos.[2]

Furthermore, when embryos for transfer are selected on the basis of morphology alone, we are limited in our ability to identify embryos with the highest implantation potential, and only a small subset of embryos chosen this way will eventually implant.[3] Therefore, it is important to explore tools that could improve embryo selection. Time-lapse (TL) embryo observation technology is one of these new tools. The current study by Goodman and colleagues has assessed whether TL technology improves embryo selection.

The Study

This was a randomized controlled trial in which all embryos were cultured in TL (embryoscope) incubators. In the control group, embryos were assessed once a day for morphologic changes. In the TL group, precise timing of various kinetic events (time to pronuclear fading, two-cell, three-cell, four-cell, five-cell, eight-cell stage, start of compaction, time to morula/ blastocyst, expanded blastocyst formation) as well as cleavage anomalies were used to identify the embryo to be transferred. Embryos were scored using these markers. Points were given if the embryo reached the five-cell stage within 45.8-57 hours, when the three- to four-cell stage was less than 1 hour, when the five- to eight-cell stage lasted for 1.4-7 hours, and when the embryo started blastulation under 100 hours. Points were deducted when multinucleation or irregular division were seen or when the two- to three-cell stage was less than 5 hours.

Three hundred patients were randomly assigned; retrieval was carried out in 287 patients, and 235 patients had four or more embryos and were randomly assigned. Demographic and cycle parameters were not significantly different in the control and experimental groups.

Pregnancy (68.1% vs 62.9%) and implantation (51% vs 45.2%) rates were higher in the TL group but the differences were not significantly different. When the analysis was limited to cycles with blastocyst stage transfer only, the trend was similar, with higher pregnancy (73.6% vs 67%) and implantation (55.5% vs 51.2%) rates, but these differences did not reach significance either.

Multinucleation and uneven cleavage were significantly more often seen using TL among embryos that failed to implant. Significantly more embryos implanted that had achieved five-cell stage, two- to three-cell division, and time to start of blastulation in the prespecified time ranges. Of these markers, time to start of blastocyst formation was the most predictive of implantation (odds ratio, 3.32; 95% confidence interval, 1.61-6.96).

The study authors concluded that the use of TL morphokinetic parameters did not improve clinical outcome, but the absence of multinucleation and timing of blastocyst formation did improve their ability to predict blastocyst implantation.

Viewpoint

TL technology involves the use of an incubator equipped with a camera that records embryo development at preset intervals. For this, the embryo does not need to be removed from the incubator and we do not have to worry about harmful changes in the culture medium pH or temperature. Pictures taken every 10-20 minutes can be used to create a short movie of embryonic development that can be analyzed using computer software. This allows us to time the cleavages and to observe temporary morphologic changes as well as any further morphologic changes (fragmentation, vacuolization, etc.).

The technology has been shown to exert no negative influence on the embryos.[4,5] Previous studies have shown that certain morphokinetic parameters can be used to identify embryos that are more likely to reach the blastocyst stage, implant, be aneuploidy, and result in pregnancy.[5,6,7,8,9,10] These studies, however, were affected by methodologic issues, small sample size, or the lack of transfer of the observed embryos. A typical critique of some of these studies is that control embryos were cultured in different incubators, and therefore one could not differentiate between a benefit of the undisturbed culture conditions or the selection based on morphokinetic parameters.

In this study, both control and experimental embryos were cultured in TL incubators under similar conditions, and only the selection for transfer differed. The implantation and pregnancy rates were higher in the TL selection group but the difference did not reach significance. The authors speculated that if more patients had been involved, they could have reached significance, but this also means that impact (if any) is not great. This study used morphology as the initial identifier of the embryo(s) for transfer in both groups, but TL parameters were then used to identify the embryo to be transferred in the TL group. Relying solely on TL parameters could have resulted in a slightly different outcome. A retrospective analysis of the data based on embryos with known implantation (implanted or not) showed that multinucleation and direct cleavage were more common in embryos that failed to implant. In addition, the time to start of blastocyst formation was predictive of implantation.

TL embryo monitoring offers several benefits: undisturbed embryo culture, recording of embryo development for quality control, and standardization of morphologic assessment (timing of kinetics). It appears that there are various morphokinetic parameters that are useful for embryo selection, but the "ideal" model that helps embryo grading/selection has not yet been determined.

Abstract

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