Over the years, blastocyst transfer (BT) or Day 5 transfer has become increasing prevalent among IVF programs and transfer of good quality blastocysts is associated with high rate of implantation/pregnancy and low rate of multiple pregnancy.
Using advanced reproductive technologies (ART), multiple mature eggs can now be recovered from a woman in a single cycle. However, many of these eggs will be genetically abnormal and therefore incapable of developing into a viable gestation. Approximately 50% of the good quality embryos on day 3 will not survive until day 5, although those embryos that do survive have a good chance of implantation. This means that high pregnancy rates can be achieved from the transfer of fewer embryos on day 5 with a reduction in the risk of high-order multiple gestations.
The down-side of transferring embryos on the 5th day versus the 3rd day is that some patients may not have any embryos to transfer on day 5, which is almost always due to the chromosomal abnormality of the embryos (95%). This approach may be frustrating in some patients without any embryos to transfer, but at the same time gives more realistic and correct information about the health of the embryos. If those embryos had been placed on the third day, they would have stopped growing inside the uterus as opposed to the laboratory where observation can be correctly done and the number of embryos transferred can be limited to one or two.
It is important to understand the progression of normal early embryonic development. The freshly fertilized pre-embryo prior to the first cell division is called a zygote and displays two pronuclei, one structure of chromosomes derived from each parent. Within the pronuclei are smaller intracellular structures called nucleoli, containing the genetic material, which should be aligned symmetrically along the pronuclear axis in preparation for cell division. Between 24 and 30 hours after fertilization, (Day 1) the embryo should have divided into 2 cells. By Day 2 the embryo should have 4 cells and by the third day, there should be 6-8 cells. Until this point, all the cells are identical and it is at this stage that a single cell can be removed with minimal risk to the embryo to screen for genetic diseases in a process known as preimplantation genetic screening/diagnosis (PGS or PGD). Prior to this point, embryonic development has been controlled by maternal genes in the oocyte. At around the 8-cell stage the embryonic genome is activated and the potential for further development comes under the control of the embryo itself.
By the fourth day the individual cells begin to fuse together and compact, allowing better communication between the cells with 16-32 cells called a morula. By Day 5 the cells have started to differentiate into specific types, each with a specialized function. The cells on the outer surface of the morula grow together and develop into the trophectoderm, which produces hormones and will eventually form the placenta and fetal membranes. Secretions from inner cells of the morula collect in a central cavity, called the blastocele and this fluid eventually becomes the amniotic fluid. Specialized cells on the inner surface of the morula group together to form the inner cell mass (ICM), which will eventually develop into the fetus. This complex creation is now called a blastocyst. As the cavity fills with fluid, the blastocyst expands, thinning and eventually “hatching” from its enveloping “shell,” the zona pellucida. The hatched blastocyst then implants into endometrium 6-7 days after ovulation.
Embryos need specific metabolic requirements in order to survive and develop optimally. Fertilization normally occurs in the fallopian tube, which is a metabolically distinct environment, having less oxygen and less glucose, than the endometrial cavity. The earliest culture media were relatively simple in their composition and could only reliably support limited embryonic development. The majority of embryos cultured in simple media survive only to the cleavage stage before undergoing a developmental arrest. Optimization of simple culture media has resulted in reliable in vitro survival to the third day of culture, which has been the standard day for embryo transfer in many programs.
By culturing the embryos for an additional 48 hours (Day 3 to 5), many of the suboptimal ones will experience developmental arrest, leaving only the best ones to select from for transfer. Unfortunately, some women will not have any of their embryos survive to blastocyst, despite appearing good on day 3. It would be easy to believe those embryos that did not survive would not have made a pregnancy, even if transferred on day 3 and now we have evidence through the new genetic test called CGH that once an embryo stops developing in culture, it is almost always chromosomally abnormal (95%).
It has long been thought that the more rapidly an embryo develops, the more likely it is to successfully implant and develop into a healthy gestation, although, overly rapid growth, (>10 cells on day 3), may be associated with decreased pregnancy rates compared to embryos with 6-8 cells on day 3. It is also well-established that “poor quality embryos” tend to divide (cleave) and develop slower and are much more likely to arrest before reaching the blastocyst stage than “normal quality” ones. In this sense, extended embryo culture can be used as a type of “biologic assay,” to help select the best quality embryos for transfer.
The argument has been that the incubator of an IVF laboratory may not provide an optimal environment for embryo development compared to the fallopian tubes. Interestingly, day 3 embryos don’t actually belong into the uterus as they are in the fallopian tubes until day 5 in a natural conception cycle. The presumption has always been that it would be better to transfer embryos back into the uterus sooner rather than later once the best ones for transfer have been identified. While most programs culture embryos in groups, preventing the serial evaluation of any specific embryo, some centers now culture embryos individually (including ours), allowing the developmental progression of a specific embryo to be monitored over time. By serially evaluating the achievement of certain critical developmental milestones, such as pronuclear morphology, cleavage speed, and cell morphology on day 3, it has been possible for us to predict on day 3 with some level of certainty which embryos are likely to survive until day 5.
It is important not to lose sight of the fact that the optimal goal of fertility treatment is to recreate the natural situation of a singleton gestation. As our knowledge of embryo development increases, so will our ability to select embryos with a good prognosis for causing a pregnancy. In the future, it is very likely that we will be able to achieve high pregnancy rates from the transfer of a single embryo. Until that time, extended embryo culture and/or early embryo grading are the best tools available to identify those embryos most likely to implant.
In the final analysis, blastocyst transfer has helped in improving the conception rate in ART especially in patients with a good number of blastocysts, while at the same time reduced the risk of high-order multiple gestation. Dr. Bayrak recommends blastocyst transfer to most of his patients based on the facts mentioned above.
