Is it better to transfer embryos on day 3 or day 5 at blastocyst stage?

Do fertility experts recommend embryo transfer on day 3 or on day 5?

Embryo development is a complex topic – one which has far-reaching consequences on the entire process of pregnancy. Embryo quality, after all, is one of the deciding factors in embryo implantation. Only by closely observing the development process can we determine which embryos are healthy enough to be transferred, and which ones won’t result in a successful pregnancy.

The day at which the embryo is transferred is also a significant factor in the entire IVF process. Two main points of embryo development have been pinpointed as the best time to transfer: day 3 and day 5. Is one option better than the others?

In order to answer that question, we have invited three experts to share their knowledge and views with us:

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Dr. Aldo Isaac Meneses Rios, UR Ciudad de Mexico, Mexico

Answer from Dr. Rios

The implantation rate is better on Day 5 so we always prefer it for transferring blastocysts. There are several reasons for this. First, it helps to make a better selection of the embryos to transfer and to freeze because it’s a more morphological stage, when the embryo is attached across the endometrium during natural conception. Another advantage is that we have more information about the genetics, morphology, synchrony of the cells and the cleavage process. It allows greater synchronicity with the endometrium preparation. We can use more days of progesterone with the aim of having less contractive activity of the uterus since the progesterone acts as a uterine relaxant. It allows us to make a preimplantation genetic study to select euploid embryos in the fresh cycle without the need to freeze and refer the eggs for transfer. The culture of these low quality embryos to the blastocyst stage allows us to recover and freeze some embryos that would have otherwise been discarded. This action helps us to distinguish between viable embryos with the greatest potential for replantation. There is no consensus on deciding the fate of poor-quality embryos on day 3. The transfer of these embryos is highly inefficient due to their low implantation rates. However, by discarding the embryos, we risk losing embryos that might be implanted. The culture to blastocyst stage is an additional opportunity to assess whether it’s worth cryopreserving them. The best option to do this is to individualise the day of the embryo transfer according to both the maternal age and the number of available embryos on day 3 in order to decide if it is possible to carry it out on day 5, if the previous embryo transfer was unsuccessful on day 3.

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Dr. Robert Najdecki, Assisting Nature, Greece

Answer from Dr. Najdecki

The topic of our podcast, “Day 3 vs Day 5 embryo transfer”, is still a controversial issue with no common consensus yet reached. Early studies have failed to show a significant difference between day 3 ET and day 5 ET, where hCG levels, clinical pregnancy, implantation and early pregnancy loss are concerned, resulting in an individualised specialist approach.

But first, let’s just go back to the basics and review the sequence of events taking place after ovulation.  On day 14 of a 28 day cycle, the oocyte (egg) is released by the ovary and picked up by the fimbriae (finger-like projections) of the fallopian tube. The egg is moved along passively by the ciliated endothelial cells of the fallopian tubes, towards the uterus. If on its way, it is met and fertilised by sperm, it becomes a zygote, the very first cell of the whole new organism, consisting of the combined maternal and paternal genome.

Following a series of identical mitotic divisions, the embryo’s growth results solely from the oocyte’s potential to become a mass of 6-8 undifferentiated cells by day 3.  After the embryo’s own genomic activation, this mass of cells develops into the blastocyst.

By day 5, the blastocyst has a fluid-filled cavity surrounded by a layer of differentiated trophoblastic cells, which will form the placenta, and an inner cell mass, which will eventually become the fetus. By day 5, the blastocyst has entered the uterine cavity, and in the next day or so, it will hopefully manage to hatch out of its prospective protein coat, the Zona Pellucida, and successfully implant into the receptive endometrium.

During IVF, the oocytes are picked up by ultrasound-guided transvaginal aspiration on the designated day. They are appropriately prepped, evaluated and fertilised in the lab. The embryos produced are put under close supervision and strict lab conditions in specially designed cultivation media and incubators. The later, so-called Time-Lapse incubators, allow their 24 hour observation. All developing embryos seem to pause on day 3 and day 5, allowing us to evaluate their dynamic state and select the best looking ones, based on specific morphological criteria, for transfer into the uterine cavity. This is done via the cervical canal and onto the well-prepped, by progesterone, endometrium.

Some IVF specialists argue that day 3 embryo transfer is preferable in older patients and poor-responders, with a low number of good quality embryos. In this instance, day 3 embryo transfer is less expensive, with low risk of losing good embryos by culture, and can potentially yield better cumulative pregnancy rates, as studies have shown that even borderline quality embryos transferred on day 3 may potentially lead to pregnancy, compared to no embryos transferred.

Nowadays, however, and in clinics such as ours, with extensive experience in the cultivation process and excellent blastocyst survival, following the vitrification process, day 5 embryo transfer makes much more sense, even in poor responders. In labs, when the blastulation rate index is over 60%, and the possibility of achieving the blastocyst stage is high, day 5 embryo transfer is favoured. Allowing the embryo to reach the blastocyst stage allows us to make an educated guess on the embryos that have the highest potential to survive and successfully implant, thus avoiding futile attempts of transferring day 3 embryos destined to arrest, and reducing the time needed to achieve a successful pregnancy. Additionally, day 5 embryo transfer offers patients more transparency, giving them a clear view of the available embryos which are of the best quality, since they survived and grew through the biologically selective process. But, what if the embryos which are available on day 3 are of very poor quality? Is it a good idea to carry out the embryo transfer on day 3, rather than wait until day 5? In the group of fresh-cycle, followed by fresh embryo transfer, day 3 transfer is an acceptable decision. For us, it accompanied by a detailed discussion about the expected implantation success rates. However, in the case of frozen-cycles, which nowadays account for more than 70% of all cycles, day 5 transfer is the preferred approach to ensure that only the best quality embryos will be vitrified, thus yielding better pregnancy rate or subsequent transfers.

Lastly, day 5 embryo transfer reduces biopsy embryo loss rates. Performing a trophectoderm biopsy during PGT (prenatal genetic testing) in day 5 allow us to extract more cells, consequently improving the accuracy of the genetic diagnosis, with concomitant lower risk of embryo viability, compared to whole blastomere extraction during day 3 biopsy. From our own experience, day 5 ET have higher clinical pregnancy and live birth rates compared to day 3, especially with fresh-cycle.

In summary, day 5 embryo transfer is shown to be more transparent for the patients and reproductive scientists, giving them a clear view, as it acts as a biological filter on embryo quality. In the era of total freezing strategy, which includes 70% of all performed cycles, day 5 frozen embryo transfer shows higher percentages of clinical pregnancy, reaching up to 50%. In our lab, the survival rate after blastocyst thawing is over 95%, and strongly supports the use of frozen blastocysts. Day 5 blastocyst embryo stage makes it easy to use the NGS (next generation techniques) during prenatal genetic testing, which is shown to be the new trend in reproductive medicine, and by transferring the euploid blastocyst, we achieve over 60% in clinical pregnancy rate.

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Answer from Dr. Sanchez

The implantation rate is better on Day 5 so we always prefer it for transferring blastocysts. There are several reasons for this. First, it helps to make a better selection of the embryos to be transferred and to be frozen since we have more information about the genetics, morphology, synchrony of the cells and so on. Second, it allows a greater synchronicity with the endometrium preparation—more days of progesterone, less contractual activity of the uterus since the progesterone acts as a uterine relaxant. Third, it allows a preimplantation genetic study to be made to select euploid embryos.

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