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Blastocyst Transfer for IVF - Infertility article review and discussion
Advanced Fertility Center of Chicago
Fertility and IVF Specialist Clinic
Gurnee & Crystal Lake, Illinois
Title: Culture and transfer of human blastocysts increases implantation rates and reduces the need for multiple embryo transfers
Authors: D Gardner, W Schoolcraft, L Wagley, T Schlenker, J Stevens, J Hesla
Source: Human Reproduction, December 1998 (Vol. 13); Pages 3434-3440.
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Definitions:
Blastocyst - an embryo that has developed to the stage where it has two different cell types and a central fluid-filled cavity. The surface cells, called the trophectoderm, will become the placenta, and the inner cells, called the inner cell mass, will become the fetus itself. Blastocyst formation in the human usually occurs on the 5th day after fertilization.
High-quality day 5 blastocyst showing inner cell mass at 5-6 o'clock area
See more blastocyst pictures and grading details
A healthy blastocyst should hatch from its outer shell, called the zona pellucida by the end of the sixth day. Within about 24 hours after hatching, it should begin to implant into the lining of the mother's uterus.
Implantation rate - the percentage of embryos transferred to the woman that end up implanting and continuing development. For example, if we transfer 2 embryos that results in a singleton pregnancy then the implantation rate was 50%.
Background
The ultimate goal of in vitro fertilization (IVF) and embryo culture is to provide high quality embryos which are capable of continued normal development and result in live births. However, under standard IVF culture conditions, only about 20-40% of human embryos will progress to the blastocyst stage after 5 days of culture. This low rate of embryo development is the result of a less than optimal culture environment for the embryos. For this reason, embryos were usually transferred into the uterus after only 2-3 days of culture (this has changed since this study was published in 1998).
One problem with this is that 2 to 3-day-old embryos are normally found in the fallopian tubes, not in the uterus. The embryo first moves into the uterus at about 80 hours after ovulation. The embryo implantation process begins about 3 days later - after blastocyst formation and hatching have occurred. Therefore, if in vitro culture conditions could be improved so that blastocysts formed at a higher rate, then embryos could be placed into the uterus at the blastocyst stage - at a more "natural" time, and shortly before implantation should occur.
Transferring blastocysts following IVF also provides another benefit - reduction of the possibility of multiple pregnancy. Some 2 or 3-day-old embryos do not have the capacity to become high quality blastocysts and a viable pregnancy. However, on day two or three of culture we do not have reliable methods to determine which embryos will be viable long-term. By culturing embryos to the blastocyst stage we have more opportunity to choose the most competent ones for transfer. We may then be able to transfer fewer embryos and obtain an equivalent pregnancy rate with less risk for multiple pregnancy.
This study is a randomized trial of day 3 versus day 5 embryo transfer. In a randomized trial, the patients are allocated to either day 3 or day 5 treatment in a random manner - to eliminate any selection bias. This "randomization" was done by a computer generated randomization table.
To be eligible for the study, patients needed to have:
- An FSH under 15
- Female age under 45
- Normal uterine cavity
- Adequate sperm for conventional IVF or IVF with ICSI
- At least 10 follicles greater than 12 mm diameter on the day of HCG
How the study was done
Two groups were compared:
- For 47 patients, embryos were cultured in the usual way for that IVF program and (most) underwent assisted hatching and transfer to the uterus on day 3.
- For 45 patients, embryos were cultured in a different media (Gardner's sequential media, G1.2 and G2.2) for a total of 5 days and then transferred. No assisted hatching was done for this group, and no more than 3 embryos were transferred per patient.
Results
Day 3 transfers had a 30% implantation rate and a 66% "clinical pregnancy rate".
Day 5 transfers had a 51% implantation rate and a 71% "clinical pregnancy rate". This was the case even though 2 patients in this group had their embryos arrest at the 8-cell stage and therefore had no embryo transfer at all, and 2 more patients had no blastocysts, but had morulas transferred and became pregnant.
Comments about the study
Dr. Gardner has carefully studied embryonic needs at various cell stages and formulated this G1 - G2 system. The G1 medium supplies an excellent environment for the early cleavage-stage embryo (first 3 days) and then the embryos are moved into the G2 medium that is more complex and better satisfies the needs of the day 3 to day 5 embryo. This sequential media system yields very high rates of blastocyst development.
A 71% clinical pregnancy rate with transfer of an average of 2.2 blastocysts per patient is excellent. It would be interesting to know the final delivery rate in these same patients.
It would also be interesting to see what the results would have been if there had been a maximum of 2 blastocysts transferred per patient (some had 3 transferred). The 15 patients that had 3 blastocysts transferred had a triplet pregnancy in 31% of the resulting pregnancies. This is obviously far too high, and is why the authors cut back to transferring a maximum of 2 blastocysts by the end of the study.
Since one of the stated goals of blastocyst culture and transfer is to reduce triplet and higher-order pregnancy, we must be very careful to monitor multiple pregnancy rates in order to avoid increasing, rather than decreasing the percentage of triplet pregnancies.
The selection criteria of at least 10 follicles greater than 12 mm diameter on the day of HCG is very important. This is a select group of "good responders" to stimulation and we expect to see a higher implantation and pregnancy rate after IVF in such a group. It is appropriate to restrict access to blastocyst transfer to whatever patients a program believes is proper. However, we need to acknowledge that this group is not the same as a group that includes women that develop less follicles than this.
Another way to say this is that if they included all patients going through IVF in their center in this study, the pregnancy rate would very likely have been somewhat lower - unless they cancel all patients that do not have at least 10 follicles greater than 12 mm diameter on the day of HCG (which would not be the case).
The field of IVF and embryo culture needs more scientists like the authors of this study in order to continue advancing. They are to be commended for their excellent work.
