During natural conception, as you can see from the chart below, each day after fertilization the embryo develops more cells as it works its way from the fallopian tube into the uterus where it will approach the uterus’s wall, and hopefully implant and lead to a pregnancy.
During IVF it’s the laboratory’s job to recreate the environment within the fallopian tube and uterus so that embryos can grow just as they do in the human body and be transferred into the uterus.
Growing embryos is difficult, and for decades IVF laboratories were only able to “culture” (a clinical term for “grow”) embryos to the “cleavage” stage, when an embryo has only 5 to 8 cells. That worked reasonably well and most IVF babies born outside of the US are still born from embryos grown to the cleavage stage and then transferred.
In the last decade, clinics have learned how to grow embryos to a more advanced stage, known as “blastocyst” — a stage when the embryo has developed at least 60 to 100 cells, and has differentiated parts that can be identified as an inner cell mass (the future fetus) and an outer layer (known as the trophectoderm) which is the future placenta.
In many ways, growing embryos to the blastocyst stage weeds out less promising embryos before transfer because only the hardiest, strongest, most “developmentally competent” embryos can advance to the blastocyst stage. Unfortunately the lower quality embryos “arrest” or stop growing in the petri dish.
However not all laboratories are able to grow embryos to the blastocyst stage of development, and not all patients create embryos that can reach this stage in the laboratory. As a result, there’s a debate about when to grow embryos to the blastocyst stage verses growing them only to the cleavage stage and immediately transferring them. Let’s take a look.
A crucial concept to get down is that embryos that are grown to the blastocyst stage are far more likely to lead to a live birth than embryos that have arrived only at the cleavage stage. Below is an analysis of over 1,600 patients across 15 studies that demonstrates that transfers that use blastocysts are nearly 1.5x more likely to lead a live birth than transfers that use cleavage-stage embryos. The net effect is that patients suffer fewer failed transfers when they have blastocysts transferred than when they have cleavage stage embryos transferred.
An additional benefit of having more confidence in an embryo’s potential is that doctors and patients are much more prepared to transfer one embryo at a time. Below you can see data on all elective single embryo transfers in the United States from 1999 - 2010: nearly 80% were done using embryos grown to the blastocyst stage. Just how reluctant were doctors to do a single embryo transfer with cleavage stage embryos? Less than 0.6% of transfers relying upon cleavage stage embryos occurred using just one embryo.
The reason that’s a important is because the likelihood of twins and triplets drops when embryos are transferred one at a time. As you can see below, twin and triplet pregnancies present a threat to both the mother and offspring. Thus, some would argue using blastocyst stage embryos is safer because it helps us avoid the temptation of risky transfer behavior that could endanger mother and offspring.
Next, growing embryos to blastocyst helps if someone wants to have embryos genetically tested before transfer. As you’ll see in the next lesson, when testing predicts that an embryo has the wrong number of chromosomes, it almost never results in a live birth. As a result, genetic testing can help cut down on transfers that don’t implant or end in miscarriage. But it costs $5,000 and does not do anything to change the underlying quality of a patient's embryos, meaning it doesn’t change the odds that an egg retrieval cycle will work. Thus, many debate the value of genetic testing of the embryos.
Genetic screening requires a fertility clinic to cut off a few cells from the embryo to test. As you can see from a well-regarded (but still small, single center) study below, taking a few cells from a cleavage stage embryo does more harm than taking cells from a blastocyst stage embryo. The impact shows up in the form of lower implantation rates (and presumably lower birth rates). Thus, if you want to do genetic testing, it’s far safer to grow embryos to the blastocyst stage. In fact, if your clinic does genetic testing on cleavage stage embryos, that’s a red flag.
In many ways, growing an embryo to the blastocyst stage and then genetically testing it applies two selection filters on which embryo to use. Should the transfer fail (remember, most do), having characterized the embryo as strong enough to reach blastocyst stage and as being “chromosomally-normal” often allows doctors to rule out the embryo as the “culprit” and focus their attention to possibly another issue, like the uterus.
If any embryos is grown only to cleavage stage, it’s unclear if it was strong enough to reach the blastocyst stage and we weren’t given the chance to know if it was chromosomally normal. As a result, it can be harder to determine whether the cause of a failed transfer was due to poor embryo quality or another issue with implantation.
Finally, growing embryos to the blastocyst stage can be a good idea if the patient wants to freeze embryos and transfer them later. As we’ll show in a future lesson, freezing embryos and delaying a transfer allows a woman’s hormonal balance to restabilize and for the transfer to happen when her uterus is most receptive.
Many doctors believe the freeze-thaw process is more likely to go well with blastocysts rather than cleavage stage embryos. Below are the better run studies (the names in each blue box represent the study’s author) characterizing how often embryos are frozen and then thawed intact. As you can see on the right, over 90% of embryos that are frozen can be thawed intact. For cleavage stage embryos that number is in the high 70s to mid 80s. In practical terms, compared with blastocysts, this means one additional cleavage stage embryo will get lost for every ten frozen. In our minds that is a moderate difference and in the grand scheme of things is one of the slightly less compelling reasons to favor blastocysts over cleavage stage embryos.
IVF is complicated and, while we wish we could say that it's possible to absorb all the details during the 5 - 30 minute visits with your doctor, that's really not the case. This comprehensive guide to IVF boils down every major issue you'll encounter -- a high level overview of the IVF process, a deeper dive into the IVF process, IVF success rates and how they differ depending on diagnosis and age, the medication protocols that can be used during IVF, the choice of inseminating eggs either using ICSI fertilization or conventional insemination, the pros and cons of growing embryos to Day 3 cleavage stage or Day 5 blastocyst stage, the decisions around genetic screening of embryos, deciding which embryo to transfer, deciding how many embryos to transfer at once, the ways the IVF laboratory can impact your odds of success and the things you need to know up front to avoid going to the wrong lab for you, the risks of IVF, and the costs of IVF. We're always sure to provide details about how data might be different depending on different unique types of patients -- because in the world of fertility, it's really not one-size-fits-all. We truly believe this guide is the foundation every fertility patient should start with when they're navigating the world of treatments.