Embryo quality – What Could Be Done Differently when IVF Fails?

The webinar is hosted by Laura Van Os, an embryologist from IVF Spain. In the webinar she focuses on the 5-day period after the insemination when the embryo stays in culture. Laura tries to answer the question why IVF cycles fail and if modern science can do anything about it.

Factors explaining IVF failure

Laura starts with listing the factors that can explain IVF failure. These can be:

• immunological factors,
• coagulation disorders,
• endometrial receptivity problems,
• all sorts of uterine and tubal pathologies or hormonal problems.

Of course one of the reasons why IVF cycle fails is the embryo quality itself. In this case, it can be either the environment surrounding the embryo which is failing or it can be the quality of the embryo itself which is curtailing a successful pregnancy.

Embryo quality = oocyte + sperm quality

Every conversation about embryo quality should be proceeded by a talk about egg quality and sperm quality. Unfortunately, there are not many markers for egg quality. It is impossible to determine egg quality and its ability to give rise to an viable embryo just by looking at it under a microscope. Another important thing to know is that not all eggs are mature (only the eggs at metaphase II stage are the ones that can be successfully fertilised). However, among mature eggs there might be some eggs with abnormalities. Some eggs with abnormalities will be excluded from the cycle but most of them will be inseminated (as these abnormalities are mostly harmless). And finally, even among the good-looking mature eggs it is very difficult to tell if they are of good quality or not. It is impossible to know if they can give rise to viable embryos or not.

Laura explains that contradictory to the eggs, the quality of a sperm sample can be simply assessed just by looking at it under a microscope. The main parameters which we usually look at in a sperm analysis are:

• concentration,
• motility
• and morphology.

According to the World Health Organisation, concentration in a normal sample should be about 50 million per milliliter. Progressive motility should be about 32 percent and normal morphology should be above or equal to 4 percent. When there is a little deviation from these parameters it is actually very easy to solve inside the IVF laboratory. Simple sperm problems can be solved just by conventional sperm selection techniques (density gradients, swim-up, etc.) plus an ICSI procedure. Then there are some very specific molecular problems which require different approaches. There’s a wide range of pathologies and each of them has a specific treatment.

Eggs fertilisation

Once we have the mature egg and the processed sperm samples, the next step is the insemination of the eggs. This can happen through various techniques and one technique is called ICSI. This means that we inject the sperm cell directly into the egg. The other technique is conventional insemination. Whichever technique is used, the day after egg retrieval doctors will evaluate fertilisation of the eggs. Fertilised eggs (zygotes) have two little bubbles inside of them, with male and female genetic material. This genetic material will unite to form an embryo.

An Embryo dividing

From then on, the embryo will start dividing. Ideally on day 2 it should have around 3 cells, on day 3 around 8 cells and from then on the embryo should keep growing exponentially to 16 cells, 32 cells, 64 cells, etc. Before this increase takes place, the cells in the embryo will compact. This is called the morula stage and this is how the embryo looks like on day 4. After this a little cavity will start to appear in the embryo, it will grow and grow and it will fill with liquid until finally we’ll have a blastocyst. It is composed of two main parts. Inside it has some inner cell mass that will become the future baby. It also has some outer layer of cells called the trophectoderm, the future placenta.

Number of oocytes retrieved vs. number of embryos

At this point Laura throws down a common myth that seems to be widespread among patients. She explains that the number of eggs retrieved in an egg retrieval is not always proportional to the number of blastocysts. Nor their quality. Actually the number of blastocysts per egg retrieval is variable among patients and even from one cycle to the other among the same patients. Some patients seem to be very discouraged when they don’t retrieve enough eggs. They think it’s impossible that they will become pregnant. However, this is really not always the case. As Laura says: all you need to become pregnant is one top quality embryo, not thirty of regular quality.

Embryo grading framework

Laura also explains that embryos are usually given grades such as A B C and D. It is a grading framework which is used in clinics worldwide. A and B embryos will always be transferred and cryopreserved, whereas D – quality embryos will never be transferred nor cryopreserved. When it comes to C-quality embryos, there are subtypes and situations so not all C quality embryos are the same. It is good to remember that embryo scoring systems are a simplification. The grading systems are useful to rank embryos within a cycle to know which embryo should be transferred in first place. Different laboratories and even operators within the same laboratory may be more or less strict when classifying the embryos.

The embryos’ (and blastocysts’) quality can be categorised in three different ways. The classical way is the morphological assessment at a fixed time point. It includes the trophectoderm quality, inner cell mass quality and the expansion degree.

Embryo monitoring using time-lapse systems

The most powerful technique used to assess embryo quality is called time-lapse. It is performed in incubators that have cameras inside them. Thanks to the cameras, doctors can look at the embryos anytime of the day just by opening their computer. They do not need to open the incubator and take the embryo out to look at it under a microscope. In this way, they do not disturb the stable culture conditions. Additionally, the time-lapse technique has individual patients’ chambers and it allows to perform a morpho kinetic analysis of the embryo. With time-lapse, doctors can predict the implantation potential of the embryos and select the best embryos for transfer. The embryos’ (and blastocysts’) quality can be categorised in three different ways. The classical way is the morphological assessment at a fixed time point. It includes the trophectoderm quality, inner cell mass quality and the expansion degree. The most powerful technique used to assess embryo quality is called time-lapse. It is performed in incubators that have cameras inside them. Thanks to the cameras, doctors can look at the embryos anytime of the day just by opening their computer. They do not need to open the incubator and take the embryo out to look at it under a microscope. In this way, they do not disturb the stable culture conditions. Additionally, the time-lapse technique has individual patients’ chambers and it allows to perform a morpho kinetic analysis of the embryo. With time lapse, doctors can predict the implantation potential of the embryos and select the best embryos for transfer.

Embryo quality and PGS – Preimplantation Genetic Screening

The last tool to assess embryo quality is PGT – pre-implantation genetic testing. Laura says that not all embryos are normal and some to them have genetic errors. The percentage of abnormal embryos increases with maternal age. When you transfer an abnormal embryo, in most cases and it will not implant. If it implants, it will lead to a miscarriage and in a few cases, the pregnancy will go on but the baby will have a disease. This problem may be solved with the PGT technique. Its main benefit is diagnostic value. Thanks to it, patients will know if their embryos are normal or not. Laura adds that PGT also helps to reduce time to pregnancy. Simply put, a patient avoids useless transfers and excludes embryos which are not going to implant or which are going to miscarriage.

Summing up, if you need to decide how to go on in a future cycle, you have to know which problem to address.

Laura Van Os says that thanks to high quality, modern technology professionals are able to fully assess the quality of their embryos. If it turns out that the embryo quality is not a reason for a failure, they will be able to focus more on the environment of the embryo and search for medical solutions of their problems.

Other resources worth reading:

• Complete guide on IVF lab techniques and procedures
• Insight into embryology lab