Implications of Blastocyst transfers

FEWER RISKS, NEW HOPE:
THE REALITY OF BLASTOCYST TRANSFERS
Mark Perloe, M.D.
Michael John Tucker, Ph.D.

Introduction
The first thing that usually comes to mind when people hear the term, "infertility treatment," is the risk of multiple births. This worry has been fueled by the recent highly publicized multiple births in Iowa and Texas. While such cases are rare, the incidence of triplets or higher-order births as a result of assisted reproductive technology is of great concern to all infertility practitioners and patients. For countless couples, deciding against treatment may mean abandoning their dream of having a child.

But what if there was a way to reduce or even eliminate the risk of multiples? Not only would that help more couples become parents, it would also decrease maternal and neonatal risks. That possibility is becoming a reality, thanks to a new technique known as blastocyst transfer. With blastocyst transfer, fewer embryos are transferred while maintaining and even increasing pregnancy rates. This technique virtually eliminates the risk of triplets or greater.

The Significance of Blastocyst Transfer
In a typical non-blastocyst in vitro fertilization (IVF) cycle, a woman's eggs are retrieved and fertilized. If all goes well, the embryos are transferred into the uterus three days later. Due to the fact that it is difficult to predict on day three which embryos are more likely to produce a pregnancy, four or more embryos are frequently transferred in hopes that at least one will result in a live birth. Until now, this has been a reasonable approach in order to achieve acceptable pregnancy rates.

The downside is that sometimes all the embryos become ongoing pregnancies and the result is high-order multiple gestations (triplets or greater). In such pregnancies, there are considerable medical risks as well as financial and emotional considerations. So the couple is faced with the agonizing decision of whether to opt for selective reduction (the removal of one or more embryos) or to continue with a risky pregnancy. Although everyone agrees that every possible safeguard should be in place to avoid such unfortunate situations, the distressing reality is that multiple pregnancies sometimes do occur.

However, with blastocyst transfer, only two or three embryos are transferred, practically eliminating the possibility of triplets or greater. And the same pregnancy rates are achieved as would be expected when four or more embryos are transferred on day three. Some centers report achieving even better pregnancy rates with blastocysts. Implantation rates of 48-50% and pregnancy rates of up to 66.3% have been reported in patients who responded well to gonadotropins.

What is 1 Blastocyst?
A blastocyst is a highly developed embryo that has divided many times to a point where it is nearly ready to implant on the walls of the uterus. A blastocyst has come a long way from its beginning as a single cell.

During maturation, an embryo rests inside a protective shell called a zona pellucida. You can think of this protective shell as being much like a chicken egg. But, unlike chicken eggs, human embryos do not remain inside a shell. Instead, the embryo hatches (breaks out of the shell) on the fifth or sixth day so it can attach to the uterine wall (implantation). Just prior to hatching, an embryo becomes a blastocyst.

Embryos developing to the critical blastocyst stage have a much greater chance of implanting successfully and resulting in an ongoing pregnancy. That is because these embryos have passed an important test. During the first few days, the embryo relies on the mother's egg for all its nutrients. However, in order to 15 survive past day three or four, the embryo must activate its own genes. Not all embryos are successful. In fact, only about one-third of the embryos become blastocysts. Yet these embryos are more highly-developed, healthier, and stronger, and have a higher rate of implantation when compared to day three embryos. Due to the higher probability of survival, we transfer fewer back into the uterus.

Getting to Day Five
For many years, infertility practitioners have known that day three transfers were too early when compared to what is physiologically normal. In naturally conceived pregnancies, a day three embryo resides in the fallopian tube, not in the uterus. The embryo does not even reach the uterus until the fifth or sixth day. Yet traditional IVF has always transferred on day three because, up until now, we have not been able to delay the transfer to day five. Previous laboratory culture media could only sustain an embryo's growth for three days. Now we have the ability to develop an embryo to the blastocyst (day five) stage.

What has made the difference is the recognition that the nutritional requirements of the embryo change as it develops. That knowledge led to the development of different laboratory culture media for the embryo's specific developmental stages. This so-called "sequential media" attempts to reproduce the natural environment of the maternal reproductive tract. The nutrients are designed to meet the requirements of the rapidly developing embryo and have led to the development of blastocysts with better viability and higher implantation rates.

Redefining Developmental Potential
The ability to develop embryos to the blastocyst stage allows clinicians to have greater certainty about which embryos are more likely to implant. Interestingly, no correlation has been found between what is traditionally considered a "good embryo" on day three and a "good blastocyst" on day five. Previously, Dr. Tucker reported a "significant disparity between the two stages in embryo viability estimates," meaning that even the best embryologists cannot tell which day three embryos have the potential to develop into a blastocyst.

While the quality of blastocysts is determined by examining morphology and development, it is important to point out that blastocyst grading standards are currently under development. Although the ability for the embryo to grow into a blastocyst is a milestone, other factors also play a role in its further development. In the near future, we believe we will be able to accurately predict which blastocysts are destined for success. When that happens, single blastocyst transfers will be considered the norm, and IVF will likely be considered the first-line infertility treatment.

Who Does it Help?
Determining who is a good candidate for blastocyst transfer is another rapidly evolving area. As more information becomes available and our knowledge base grows, guidelines based on actual clinical experience will be developed. Until then, we can offer some preliminary observations.

In general, blastocyst transfer is more advantageous for patients who develop a number of eggs and embryos. A significant correlation has been reported between the number of eggs and the number of blastocysts developed, as well as the number of day three embryos and the number of blastocysts developed. Other candidates for blastocyst transfer include those who would not consider fetal reduction or those in whom delivering multiple pregnancies would be of particular concern. Blastocyst transfer is probably not advantageous for patients who develop few eggs or embryos.

A side benefit of a blastocyst transfer is the fact that the ability to generate a blastocyst provides important information about the likelihood of pregnancy. In general, pregnancy rates are higher in those whose embryos grow to the blastocyst stage. Conversely, pregnancy rates are lower in those whose embryos do not develop into blastocysts.

Maternal Age and Blastocyst Development
Does maternal age have any bearing on the production of blastocysts? Although some studies have shown advanced maternal age to be a factor in blastocyst production, Schoolcraft found "no correlation between percentage of blastocyst formation and increasing maternal age" in a population of women who responded well to gonadotropins. However, implantation rates and pregnancy rates in this study decreased with maternal age, with women over 40 faring the worst.

What Happens When Embryos Do Not Become Blastocysts?
Because only a few embryos develop to the blastocyst stage, it is possible to have no embryos survive to day five to transfer. This is especially true if the cycle begins with only a few fertilized eggs. When no embryos survive to become blastocysts, it is a tremendous disappointment. The looming question then becomes, "Would the embryos that did not survive to become blastocysts have implanted if transferred at day three?" Unfortunately, we simply do not have enough clinical data at this time to answer that question. In our opinion, pregnancy would have been unlikely in that situation. But since that outcome is not a certainty, day three transfers may still be a reasonable option for some patients.

Genetic Testing And Blastocysts
Another benefit of blastocyst transfer is the ability to perform biopsies on a more highly-developed embryo in order to test for genetic diseases. In the future, immunofluorescent testing techniques will allow practitioners to remove a few cells from the blastocyst, stain them, and examine them under the microscope to detect any genetic anomalies. While that type of testing is not currently available on a day-to-day basis, we believe it will be considered routine within the next two to five years.

Frozen Blastocyst Cycles
Blastocysts tend to have a very good survival rate after cryopreservation (freezing). Menezo and his colleagues have reported that "the recovery after thawing is equivalent, if not superior to, that of thawing of earlier embryonic stages."

Because blastocysts are superior to earlier stage embryos in terms of development, they are easier to freeze, store, and thaw. Additionally, because blastocysts have higher implantation rates, it is possible for a couple to go through IVF once and have enough blastocysts for the current cycle as well as any future cycles.

The Future
We are just beginning to understand the implications of blastocyst transfer for both practitioners and patients. ,We believe infertility treatment centers will soon be able to reliably grow blastocysts and accurately assess which embryos are destined to implant and develop into an ongoing pregnancy. When that happens, the transfer of a single blastocyst will become the norm. And today's risk of high-order multiples will become a memory. The future holds much hope, much promise, and considerably fewer risks.