The process of assisted hatching refers to procedures done to the zona pellucida. The zona pellucida is the shell that surrounds the egg. Its clearest purpose in nature is to become suddenly hardened once one sperm has entered the egg. This prevents other sperm from entering the egg.

But this hardening of the egg shell can happen at other times too. For some women with egg quality concerns, perhaps women over thirty-seven years, the zona pellucida is hard from the beginning and this otherwise fertile egg will not be able to be fertilized naturally.

Under these circumstances, ICSI (intracytoplasmic sperm injection, the placement of sperm inside the egg) should help. But it still leaves a very hardened zona pellucida behind, and this can cause problems later in development.

By day five of embryo development, there are enough cells within the embryo that it is generally at the “blastocyst” stage, and the embryo attempts to hatch out of the zona pellucida. This generally goes without incident, but if the zona pellucida is too hard and too thick, the hatching may not occur and implantation will be compromised.

Assisted hatching is the process by which, generally on day three of embryo development, the integrity of the zona pellucida is compromised to weaken it to allow for the embryo to hatch more easily later on.

Historically, this was done chemically, but the problem with this approach was that the chemicals could sometimes leach further than the zona pellucida, damaging the embryo itself.

Modern technique is to use a laser, which can be so finely calibrated, that we routinely see no compromise at all. For that reason, assisted hatching can be offered with relative safety, for the downside risks appear to be small. There have been some worries that, even with a laser, there could be some residual damage. What if, for example, the sharpened edges associated with the laser would somehow damage an embryo that is hatching, perhaps severing the embryo in two? Were that to be the case, one would anticipate increased risk of monozygotic twinning (identical twins) associated with assisted hatching. People have looked to this in great detail with no definitive answers.

In our practice, we do see a heightened chance of monozygotic twinning compared to the background rate that might be expected in the general population, but have been unable to ascribe this to assisted hatching (or, in fact, to any particular event that occurs in the lab. It is possible that a subset of fertility patients is simply more at risk of monozygotic twinning than the background population).

It is not just women with egg-quality concerns that it may be beneficial for. For all embryos that are being cryopreserved, the zona pellucida is expected to come out harder than on a fresh embryo. Any couple with these circumstances may benefit from assisted hatching.

Furthermore, assisted hatching is helpful when doing pre-implantation genetic screening; it allows the biopsy catheter to access the cells to be assessed.

Does all of this mean that assisted hatching is right for you? That is a conversation for you and your physician, but assisted hatching is something that we are willing to consider for the majority of our patients at our clinic who are looking to IVF.

The post Assisted Hatching: When is it necessary? appeared first on Fertility.ca.

It holds great promise for maximizing pregnancy rates. Most IVF failures can be attributed back to embryo quality.

Is PGS right for you? Perhaps, but it’s a highly personal choice. It depends a lot on your circumstances and needs to be explored with your doctor.

PGS is expensive and complicated. Neither of these things are great to hear, of course, but the promise inherent in this level of testing is profound and, for some couples, it can be an extremely beneficial solution.

Why is it so difficult? To understand the science, I recommend starting with www.chromosome-screening.org. The short version is, the process is a part of IVF.

As you know, IVF is when your eggs are retrieved and inside a laboratory introduced to sperm. Some days later, the fertilized eggs are placed back into the womb. Before that happens, PGS can be done.

To do PGS, we remove one or more cells from the embryo. These cells are then analyzed in the laboratory or they’re shipped to an external lab.  We look at the number of chromosomes that those cells carry. The idea is, that the cells accurately represent the embryo about to be implanted.

There are two kinds of lab analysis done on the cells: The laboratory can look for specific and known genetic diseases or can count the number of chromosomes.

Most people choose to count chromosomes. Most people aren’t looking for any specific disease because both partners aren’t predisposed to any diseases that are inheritable. What they’re looking for is to find out if their embryo is going to be of sufficient quality to be consistent with an ongoing pregnancy.

The most common reason that embryos are not healthy is something called aneuploidy – that means the embryo has too many or too few chromosomes. PGS checks to make sure the embryo has the correct number of chromosomes or anything else that would be abnormal or not suitable for transfer.

PGS is not all that new but the techniques involved have been changing over time.

One aspect that has not changed – you will need to do ICSI and assisted hatching as part of the process. ICSI is the placement of the sperm into the eggs, and it is necessary rather than traditional fertilization (where many sperm are placed around the egg), as with traditional fertilization there are going to be extra sperm stuck to the edge of the zona pellucida (egg shell). That means when the biopsy is done, an extra sperm could accidentally come along with the cell and the test will appear to be abnormal when, in fact, the cells were just fine. Doing ICSI, where we place the sperm into the egg, negates that risk.

Assisted hatching is where a laser penetrates the zona pellucida, at least partially in this case, so that the biopsy needle can be placed against the cells for removal.

Before PGS is even started, you are looking at the costs and complications implicit in IVF with ICSI and assisted hatching. But there are other expenses too. Most laboratories will charge a biopsy fee, the lab will also charge a diagnostic fee for the genetic testing and there can be some shipping charges when external labs are used.

Are the added expenses worth it? Well, in select circumstances, absolutely! If the technology can deliver on its promise, I’m willing to guess most of our patients would be more than happy. After all, many couples who have completed IVF without success can become frustrated by the apparent transfer of high-quality embryos into a healthy woman and still no pregnancy.

This happens because many so-called healthy-looking embryos, in fact, are aneuploid. Depending on the age group, only 30%-70% of apparently healthy, day-five embryos are, in fact, normal (and the ratio is even less for day-three embryos). Any technique that allows us to find the best embryo could be highly advantageous.

Historically, we have looked at cell number and the relative fragmentation of embryos to guess at an embryo most likely to be consistent with ongoing pregnancy. In more recent years, many labs strongly favour growing embryos to the blastocyst stage, which is five days of growth in the lab, to further differentiate the best-growing embryos. Finally, some laboratories are using “embryo scopes”, camera systems to allow constant visualization of the developing embryo. Huge amounts of data are being generated with such techniques, though it is difficult to say, of all this data, which of it is actually useful to predict who is going to have a baby.

And there’s the appeal of PGS: It gets right to the heart of the matter as we confirm whether or not there are the right number of chromosomes to be consistent with an ongoing pregnancy.

It is not that a euploid embryo is guaranteed to result in pregnancy, but some labs are reporting pregnancy rates in the range of 80% when euploid embryos are transferred. So, this is not a guarantee, but a far higher pregnancy rate than any other therapeutic approach to date.

But of note, I also mention the technical complications.

The chief amongst the complications are this: The biopsy and embryo manipulation.

Does the biopsy harm embryos? It may: There are some data suggesting embryos biopsied on day three do not fare as well as those biopsied on day five. Like any ongoing scientific processes, there remains debate on this point, but at this time, based on what information is available right now, I believe day-five biopsy makes the most sense. I may have to change my mind again in the future, the subject really is changing that quickly!

Though the day-five biopsy appears to be safe – cells are taken from the outer trophectoderm (cells that will eventually become the placenta) rather than from the inner cell mass (cells that will become the baby) – the challenge is deciding how best to handle the embryo from that point forward. There is going to be, after all, a waiting period while we look to the results of the PGS. This can be as short as twenty-four hours, or up to a week, depending on how the technique is done; but it necessitates for a day-five biopsy, either day six embryo transfer, or a freeze-all technique. Freeze-all meaning the embryos are frozen to be transferred in a future cycle (this will also add to the expense).

So, which is better? A day-six transfer or vitrification and transfer on a future cycle? I favour the latter, but again, this is lab dependent and you can get various opinions depending on which clinicians you speak to and the latest paper on the subject.

Lastly: The results that come from the laboratories regarding PGS are not always as reliable as we would like. There are some reports of embryos being retested and having completely different results than they did the first time around. Could this happen to you? Well, yes, it could and it is partly a limitation of the nature of the process: We are biopsying so few cells. This has to be contrasted with an amniocentesis, for example, done at sixteen weeks of pregnancy when literally hundreds of cells could be tested at a single time. It is much more accurate and you will find that even as PGS purportedly can rule out, for example Down’s Syndrome, you will be asked to have a definitive test later in pregnancy, regardless. PGS cannot be and is not definitive.

I like to write articles that discuss complicated subjects in transparent and easy-to-understand ways. PGS is a topic that is changing, at the information becomes more settled, I will continue to post information that I feel will be useful to a wider population.

At this time, the best I can say is that an educated conversation with your clinician is going to provide you the best sense for whether PGS is going to be helpful to you. That said, if you do not have confidence that you can generate a good number of blastocysts that PGS probably is not going to be helpful. After all, it is a sorting mechanism, and if you only have one or two embryos for transfer, sorting is not required. Careful transfer of your embryos may be all that is necessary.

The post Will pre-implantation genetic screening improve my IVF chances? appeared first on Fertility.ca.

Choosing the best embryo

The next day -day 1- each healthy embryo will still be a single cell, now at the two-Pro-Nucleii (2PN) stage. It is a black-or-white assessment, with little room for interpretation: either you have 2PN embryos, or you don’t. Most couples can expect 80-90% of the mature eggs to turn into 2PN embryos.

Embryos are rarely transferred at this point, because you really can’t tell which embryos of the group will be the most likely to continue to grow properly.

By day 2, the embryo should be 3-4 cells.

By day 3, the lab staff can finally grade the quality of the embryos by looking at them under a microscope. It is not a perfect science, but, it is our standard of care for the moment. The grading is done in two ways:

• We count cells. The ideal embryo has 8, 7, or 6 cells. More than this, and embryos may be growing too fast, using up the energy stored by the egg, and therefore more likely to burn out before they get the chance to implant. Slower than this, and the concern is that the embryos won’t continue to divide at all.
• As cells divide, they leave fragments behind…and too many fragments suggest that cells may not be dividing properly. We grade fragmentation on a 5 point scale, and ideally your embryos will be grade 1 or 2.

A perfect grading system would allow us to spot the ideal embryo every time. We’re working on that*, but in the meantime, to make up for our uncertainty, we usually encourage the transfer of more than one embryo.

For greater specificity in embryo selection , some doctors will encourage you to grow embryos along to day 5.

By day 5, listed in increasing order for pregnancy, we hope to see:

• morula
• cavitating morula
• blastocyst
• hatching blastocyst

A blastocyst will be about twice as likely to result in pregnancy as a morula.

Sometimes we will allow an embryo to grow to day 6 to become a blastocyst, but we won’t go further than that.

The pregnancy rate per blastocyst transferred is certainly higher than per day 3 embryo transferred, because the extra two days has allowed greater selection to occur. But in some ways, it isn’t a fair comparison. Perhaps pregnancy rates would have been just as good transferring 3 embryos on day 3 cf. 2 embryos on day 5.

In fact, doctors and laboratory staff will cite many factors when comparing day 3 to day 5, including patient age (some say >40y should always be day 3), optimization for freezing (historically better on day 3, but perhaps vitrification changes this equation), embryo health, the implantation window, uterine contractility…the debate goes on. Good people can disagree.

My advice would be to accept the day that your particular lab favours. In this way, you will be maximizing your chances as your work to the strengths of your particular group.

* Note that there are newer systems for embryo grading, include proteomics, metabolomics, and other variations in preimplantation genetic screening (PGS). I am happy to write to these topics, but they generally will not be offered in most laboratories in Canada or elsewhere.

The post IVF: choosing the best embryo, and the best day for embryo transfer appeared first on Fertility.ca.

We judge embryo quality in three ways: the number of embryos present, embryo grading, and PGS. In this post, we’ll talk about PGS.

Our current gold standard for judging embryo quality is pre-implantation genetic screening. PGS allows us screen embryos for genetic issues during an IVF fertility procedure. First, the embryo is extracted and fertilized in the lab. It’s given a few days to mature. Then the embryologist removes a few cells from the embryo and examines the chromosomes. Embryos with normal chromosomes are implanted in the woman’s uterus or frozen for implantation later.

The benefits of doing PGS are strong. For example, compared to an unscreened embryo, a single embryo screened with PGS typically:

• Implants more successfully

• Has higher delivery rates

• Reduces the risk of multiple pregnancies

• Reduces the risk of preterm delivery

For more on the science of PGS, you may want to visit www.chromosome-screening.org.

Note: Embryos are just one element in implantation. Implantation challenges can be related to embryos, the uterus and overall health. We’ll have another post shortly on how the uterus, its shape and lining, may impact odds for implantation.

The post What are the recent developments in implantation? (Part Three: PGS) appeared first on Fertility.ca.

We judge embryo quality in three ways: the number of embryos present, embryo grading, and PGS. In this post, we’ll talk about embryo grading.

Stretched over the first 96 hours of development, we remove embryos from the incubator for about two minutes to look at the embryo and assess its capacity for ongoing development.

Two minutes doesn’t seem like a lot of time, but it’s enough. The gases and temperatures outside of the incubator are inappropriate for embryo development, so limiting their exposure to a non-incubator environment is important. We grow embryos to the blastocyst stage. If the embryo has survived that long, there is a greater likelihood it will continue to develop. This increases your chances for pregnancy.

By day one of development, we should see cells that have two “balls” of DNA collected, from the egg and from the sperm. If there is only one or there are three, or even zero, the embryo is not developing well.

By day three, the embryo should have six, seven, or eight cells.

By day five, the size of the blastocyst is measured instead of the number of cells. A number (usually 1 through 6) represents the size and letters (A through D) make note of the inner cell mass and what will make the placenta (trophectoderm) in the future.

These grading systems are okay, but not ideal. Not all high-quality embryos will implant, and not all low-quality embryos will fail.

To improve our information, there are newer techniques for grading embryos. We now have the ability to watch embryos grow in the incubator for the full 96 hours, their development captured on video throughout. This removes the need to take the embryos out of the incubator, and we collect a lot more data.

The current challenge is to know what exactly to do with that data. Researchers and scientists are working to generate new algorithms to help identify which embryos are most likely to continue to grow. Different companies are working to provide solutions to fertility clinics. The EEVA test, in partnership with Auxogyn/EMD Serono is one example.

Note: Embryos are just one element in implantation. Implantation challenges can be related to embryos, the uterus and overall health. We’ll have another post shortly on how the uterus, its shape and lining, may impact odds for implantation.

The post What are the recent developments in implantation? (Part Two: Embryo grading) appeared first on Fertility.ca.

How significant this is depends on the circumstances.

When sperm are frozen, there are generally millions to spare. You can be confident that there will be viable sperm when a sample thaws. Sometimes the sperm lose the capacity to enter eggs on their own, but this can be treated through IVF with ICSI. If sperm counts are good going into the freezer, we generally expect them to be good coming out – even years later!

Meanwhile, a single egg taken for pre-implantation genetic screening can start to break down very quickly, even after only a week.

So what about the embryos themselves? We’ve found that embryo quality does not change over hours, days or weeks. But it can over several years.

It’s also worth a reminder that, in my experience, frozen-embryo transfer are not as successful as a fresh ones. There’s a lot of conflicting information on this subject, though. Some groups claim significantly higher success rates with frozen-embryo transfer versus fresh. In many labs, however, freezing truly does compromise embryos when they thaw, and can have significantly lower success rates.

As the technology advances, we hope to see substantially better frozen-embryo transfer success rates in late 2014 and beyond.

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