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Time Lapse Microscopy: Is tincture of time truly the answer?

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Reproductive specialists are always looking for ways to improve outcomes for patients, and nowhere do improvements come more rapidly than in the realm of in vitro fertilization. However, while pregnancy rates using IVF have risen over the past decades, even patients with the best prognosis do not always achieve a pregnancy, so there is still room for improvement. Efforts to improve pregnancy rates have included standardization of grading criteria for embryos, but even the “best-looking” embryos do not always result in pregnancy! The use of time-lapse microscopy represents one of the latest advances in a technology that focuses not only on the “looks” of the embryo but on its developmental pattern, i.e. how it got to look that way.

In the IVF lab, embryos are handled with extreme care to optimize their growth and development during incubation. The embryologists who work with them directly monitor the progression of each embryo over time, with the understanding that embryonic development is dependent on a series of events and attainment of certain milestones. Embryos that develop too slowly or quickly may be less likely to implant. Typically, assessment of those milestones occurs at discrete intervals during the three to five days of embryo incubation. But that methodology may soon change. Special incubation systems are now available that are capable of capturing digital images of the embryo at regular intervals without jeopardizing embryo development. This is referred to as “time-lapse microscopy.” The available commercial systems are either unique incubators that contain a microscope and image-capture software (e.g. EmbryoScopeTM) or standard incubators that are then fitted with such equipment (e.g. Early Embryo Viability AssessmentTM), allowing for image capture every 5-20 minutes.

The timing and appearance of different cellular divisions can thus be recorded as a composite video image. Compared with standard incubators used within an IVF lab, time-lapse incubation systems require much less manipulation of embryos and therefore provide for a very stable incubation environment, which is potentially more optimal for embryo development. In fact, embryo development in these incubators has been either equivalent to or surpassed the development of embryos in standard incubators. The digital images that are generated can then be reviewed by the physicians/embryologists either in real-time or retrospectively to determine the best embryo for transfer.

Research is focusing on using the data collected from these systems to develop algorithms that can accurately predict an embryo’s likelihood of (a) developing to the blastocyst stage, (b) being chromosomally normal and/or (c) implanting in the uterus. A normal embryo divides from a single fertilized cell to 2 daughter cells. These 2 cells then each divide, yielding a 4-cell embryo. This cycle continues until the time of embryo transfer. On day three of development, an embryo is generally 6-10 cells whereas, with a day five transfer, the embryo has reached the blastocyst stage and is composed of hundreds of cells. Using time-lapse systems, the duration of each cell division and stage can be recorded. In addition, abnormal events that might otherwise not be seen in standard incubators are recorded, such as cells with more than one nucleus or single cells that divide directly into 3 daughter cells, rather than 2.

Parameters that have been found to be indicative of embryo “health” include:

• Duration of the first and second cellular divisions
• Time between completion of the first cellular division and initiation of the second
• Time interval between the second and third cellular divisions
• Time at which an embryo reaches 5 cells
• Time at which an embryo initiates compaction (a necessary stage before becoming a morula, the stage before blastocyst)
• Time at which an embryo reaches the full blastocyst stage

Some researchers have found that the earlier cell divisions are important, whereas others have found that the later events are more critical. This is likely due in part to variations in practice between clinics and differences in patient populations as these studies have been performed throughout the world (e.g. Spain, Denmark, the United Kingdom and the U.S.). Furthermore, while some of the work to date has predicted an embryos’ ability to develop to the blastocyst stage, this did not necessarily correlate with an improvement in pregnancy rates. It should also be noted that the current cost associated with these incubators is substantial, and much of the current research is in the university-setting or at large, multi-site IVF centers. The impact that the cost of this technology will have on the future costs of IVF treatment remains to be studied.

Time-lapse microscopy is undoubtedly a promising new tool in the embryology lab. Reproductive endocrinologists and embryologists around the globe are hoping that the data these systems generate will improve our ability to overcome infertility. However, given the variability in findings to date, more research needs to be done in order to clarify how this tool can be used in practical ways to help our patients. It may be that some parameters measured by time-lapse are applicable to certain populations, whereas others are not. Ultimately, the goal is the creation of algorithm that can be applied to predict the pregnancy potential of a given embryo based on its recorded developmental pattern. If we are indeed able to develop such predictive algorithms, the use of time-lapse incubation systems will most certainly increase, heralding another achievement towards maximizing pregnancy outcomes in our patients.

Katherine Melzer Ross, M.D. is a reproductive endocrinologist at GENESIS Fertility & Reproductive Medicine in Brooklyn, N.Y.