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Embryo Transfer on Day 3 Versus Day 5

The concept of blastocyst transfer (BT) is not new to the field of Assisted Reproduction. There have been reports of BT pregnancies in humans as early as 1990, and even earlier in animals. However, the ability to consistently produce a high percentage of blastocysts from cultured embryos is a relatively recent development.

The freshly fertilized embryo is called a zygote. After the first 24 hours, (Day 1) the embryo has divided into 2 cells. By Day 2, the embryo has 4 cells and by the third day, there should be 6-8 cells. Up to this point, embryonic development has been controlled by maternal genes in the oocyte. Around the 8 cell stage the embryonic genome is activated and the potential for further development is controlled by the embryo itself. By the fourth day the embryo has 16-32 cells and is called a morula. Until this stage, all the cells are the same.

English: 8-cell human embryo, day 3

English: 8-cell human embryo, day 3 (Photo credit: Wikipedia)

These embryonic stem cells are totipotential and at this stage a single cell can be removed to look for genetic diseases without damaging the embryo. By Day 5 differentiation of the cells begin. Cavity forms in the center of the morula called the blastocele, which fills with fluid that will eventually become the amniotic fluid (the fluid surrounding the baby while in the uterus). The cells on the outside of the morula grow together and develop into the trophectoderm, which will eventually form the placenta and fetal membranes, while the cells on the inside of the morula group together to form the inner cell mass, which will eventually develop into the fetus. This complex creation is now called a blastocyst. As the blastocyst cavity fills with fluid, the blastocyst expands, thinning and eventually “hatching” from its enveloping shell, the zona pellucida. The hatched blastocyst implants into the endometrium in 6-7 days after ovulation.

Human embryos need specific metabolic requirements in order to survive. The earliest culture media were relatively simple in their composition and could only support limited embryonic development. The majority of embryos cultured in simple media could only survive to the third day of culture before undergoing a developmental arrest. Optimization of the media allowed reliable culture to the third day, which has been the standard day for embryo transfer.

A new generation of culture media that reliably support the growth of embryos to the fifth or sixth day has been available. This development was based on the premise that the metabolic needs of the early embryo change as it moves from the fallopian tube to the endometrial cavity and the new media is designed to mimic these environmental changes. Using “sequential culture systems,” approximately 40-60% of ‘good quality” day 3 embryos can be grown to the blastocyst stage and have made blastocyst culture feasible for many IVF programs.

The current inability to predict with certainty which embryos will successfully implant into the uterine lining still prompts too many IVF practitioners, motivated with the desire to optimize IVF success rates, to transfer a large numbers of embryos at a time. While such practice indeed increases IVF pregnancy rates, it unfortunately also results in an unacceptably high incidence of multiple pregnancies, with devastating consequences to the resulting, often severely premature newborn babies.

It has long been recognized that the more advanced the embryo’s state and rate of development, the more likely it is to implant successfully into the uterine lining. It is also well established that “poor quality embryos” tend to divide (cleave) and develop more slowly, and are much more likely to arrest before reaching the blastocyst stage. It is therefore not surprising that researchers would focus on trying to grow embryos to the blastocyst stage in order identify “good quality embryos” that are more likely to implant successfully, by their ability to survive to the blastocyst stage of development.

It is important to note that in spite of the introduction of specialized culture media and new techniques for culturing blastocysts, not all embryos progress to blastocysts. However, since blastocysts are more likely to implant than are day 3 good quality embryos, it is possible through the selective transfer of fewer blastocysts to improve IVF success rates while at the same time, significantly limit the incidence of high-order multiple pregnancies (triplets or greater).

It has been believed for many years that the uterus likely provides a better environment for embryos to grow than the incubator in an IVF laboratory. The presumption has always been that it would probably be best to transfer healthy embryos to the uterus sooner rather than later. However, the embryos do not enter the uterine cavity until the 5th day of development in a physiological cycle and are in the fallopian tubes. Furthermore, 95% of all embryos that stop developing in culture and do not make it to the blastocyst stage (Day 5 embryo stage) are chromosomally abnormal based on comparative genomic hybridization (CGH). Therefore, we believe that the reason for the embryos to stop developing is due to the chromosomal abnormality associated with the embryos. Dr. Bayrak recommends day 5 embryo transfer to almost all of his patients with a few exceptions.

Blastocysts are graded on the basis of their cellularity, differentiation of the trophectoderm, the inner cell mass and the blastocele. As an example, a Grade 1 blastocyst when compared with Grades 2 or 3, contains more cells, has a more expanded blastocele, a more prominent inner cell mass and a hypercellular-well differentiated trophectoderm. Grades 1 & 2 blastocysts have approximately a 20-40% implantation rate, as compared to about 1-10% for Grade 3. We cryopreserve (freeze and store) only those embryos that make it to the blast stage that are of good quality (Grades 1 or 2). Since we prefer to perform all frozen embryo transfers (FET) at the blastocyst stage, cryopreserved blastocysts are thawed and the surviving ones are transferred on the same day.

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