In Vitro Fertilization with Blastocyst Culture and Transfer on Day 5 - we can reduce the number of embryos transferred and increase IVF success rates
Page author Richard Sherbahn MD
We have been doing day 5 blastocyst transfer since 1998 at the Advanced Fertility Center of Chicago, IL.
Blastocyst hatching from its shell - at lower right
After hatching, the embryo implants in the uterus lining
Photo just before embryo transfer procedure
Balance risks and benefits with IVF
Couples with infertility often express a desire for delivering twins instead of a single child. They may think; "we want kids, and all this treatment is expensive and unpleasant, so let's just have 2 kids and get it over with".
When they are fully aware of the risks to the children if delivery is premature, some couples no longer prefer a multiple pregnancy. However, after full disclosure of the risks, many couples still hope for twins. Of course, they are also hoping that their children will be perfectly healthy.
The psychological, social, and economic stresses involved with caring for twins is substantial, but patients often say they would welcome facing those stresses if they were so blessed.
The risks of a multiple pregnancy are high. These expectant mothers face an increased risk for developing complications of pregnancy such as gestational diabetes, pre-eclampsia, preterm labor, hemorrhage, and other complications. The risks to the fetuses and children are mostly related to premature delivery and can be very severe.
Compared to a singleton, a twin is about five times more likely to die in the first year of life. For a triplet, this risk is about 13 times that of a singleton. The risk of having a lifelong handicap (e.g., cerebral palsy, mental retardation) is increased about 10 times for twins compared to singles, and these risks are substantially higher for triplets. Quadruplet and other high-order pregnancies are much riskier. Fortunately, with current embryo transfer policies, pregnancies beyond triplets are rare with IVF.
Statistics about the number of embryos transferred and multiple pregnancies
The U.S. Centers for Disease Control and Prevention (CDC) and the Society for Assisted Reproductive Technology (SART) gather, tabulate, and publish annual national summaries and clinic-specific reports of IVF statistics.
- These reports cover live birth rates, twin and triplet rates, the average number of embryos transferred per patient and other variables
The report for IVF cycles in 2013 is currently available on the SART website, the CDC report lags behind the SART report - 2012 data is the most recent available from CDC.
These annual reports show the trend in the United States toward transferring fewer embryos.
- In 1997, the average number of embryos transferred to women under 35 was 3.7
- By 2000, it was down to 2.9
- Over the same time period, there was a significant increase in the overall live birth rates for IVF procedures
- At the same time, the percentage of births that were triplets or more dropped from about 14% to about 9%
- However, over the same period of time, no progress was made with regard to reducing the rate of twin pregnancies, which remained at about 32% of births.
- Over that 4-year period, US IVF centers transferred less embryos, resulting in higher success rates, a lower percentage of triplets, but no change in the percentage of twins.
In general, European infertility clinics are transferring fewer embryos as compared to American IVF centers. On average, they have lower pregnancy rates and a lower percentage of multiple births than clinics in the United States.
There are several factors involved in this difference. In some European countries, physicians are restricted by law so that they cannot transfer more than two embryos. Also, IVF is more commonly paid for by insurance or socialized medical systems in Europe.
In the United States, couples with insurance coverage for IVF services are more likely to prefer fewer embryos for transfer. By comparison, couples who must pay out of pocket for IVF often request that more embryos be transferred. They tend to be fearful of failure because of the high financial costs associated with repeating the IVF process.
What is the appropriate number of embryos to transfer?
In 2009, the American Society for Reproductive Medicine (ASRM) published revised guidelines regarding the appropriate maximum number of embryos to transfer. The ASRM guidelines suggest a maximum number of embryos to transfer based on the day of transfer (cleavage stage vs. blast), "prognosis category" (favorable vs. all others) and female age.
Current ASRM guidelines on maximum number of embryos to transfer
|Maximum Number of Embryos to Transfer
Cleavage-stage Embryos (day 2 or day 3 ET)
|Age < 35||Age 35-37||Age 38-40||Age > 40|
|Maximum Number of Embryos to Transfer
Blastocyst Embryos (day 5 or day 6 ET)
|Age < 35||Age 35-37||Age 38-40||Age > 40|
The ASRM identifies the following characteristics as being associated with a "more favorable prognosis":
- First cycle of IVF
- Good embryo quality by morphology grading criteria
- Excess embryos available for freezing
- Having a previous successful IVF cycle
These guidelines have been helpful in limiting the number of embryos transferred, particularly in patients with the most favorable prognosis. However, many couples in the other categories who choose to have more than two transferred could still be at high risk for multiples, including triplets. Also, patients with embryos that have a high potential for implantation might have a high risk of twins if they have two transferred.
Couples with a very high chance for pregnancy can be identified on the day of embryo transfer and can be offered the option of transferring one or two embryos.
In my experience, if a couple has high-quality embryos available for transfer on day 5 and they are offered the options of transferring one embryo with a 50% expectation for pregnancy (almost all singles) or two embryos with an 75% expectation for pregnancy (about 50% twins, 50% single, and about 3% triplets), very few patients choose to transfer only one.
They want the higher chance for pregnancy and are accepting (even welcoming) the risks of a multiple pregnancy. The few who do choose to have a single embryo transferred almost always have excellent insurance coverage for IVF and often have at least one child already.
What is blastocyst culture and transfer?
A blastocyst is an embryo that has developed for 5 to 7 days after fertilization and has just started to differentiate. It has developed two different cell types and a central cavity. One group of cells will become the placenta, and the other group will become the fetus. A healthy blastocyst will begin hatching from its outer shell by the sixth or seventh day. Shortly after hatching from the shell, it should begin to implant into the lining of the mother's uterus.
In past years, the majority of embryo transfers were done on day 3 (after the egg retrieval) at the "cleavage stage" when the embryos have four to eight cells. One problem with this is that day 3 embryos normally are 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.
The other problem with transferring on day 3 is that many embryos at that stage do not have the capacity to continue development and become high-quality blastocysts. We do not have reliable methods to determine which of the day 3 embryos will be viable long-term. Therefore, the tendency has been to transfer more embryos on day 3 in an attempt to achieve good pregnancy rates.
When embryos are cultured from day 3 to day 5, some will stop developing and others (usually 25% to 60%) will continue to become blastocysts. Therefore, by choosing the best blastocysts for transfer on day 5, we can choose much more reliably those with the best potential for implanting and making a baby.
In the past it was difficult to get good numbers of high-quality blastocysts with in vitro culture systems. However, advanced culture media have been developed that provide the proper balance of nutrients at the various stages of early embryo development. Proper culture techniques with these new media formulations yield excellent blastocyst formation rates. This makes blastocyst transfer a viable option for some couples with infertility.
A few programs are doing all IVF cases with day 5 transfers. One of the issues with this is that a small proportion of couples will have embryos that are growing on day 3, but by day 5, all of their embryos have stopped developing. These patients could have had a day 3 embryo transfer, but because their embryos were kept in culture and arrested after day 3, they will not have an embryo transfer at all. This has been reported to occur in about 5% of cases if all patient's embryos are cultured for 5 days.
The ultimate outcome of the cycle may be exactly the same either way (a failed cycle), but patients would probably prefer to have an embryo transfer and then not be pregnant as opposed to being called and told that their embryos have stopped developing and therefore they will not have an embryo transfer at all.
Our IVF program and many others perform blastocyst transfers in selected cases. Most IVF centers (including ours) that perform day 5 transfers have selection criteria for deciding which cases are transferred on day 3 versus day 5. The criteria often involve a minimum number of fertilized eggs or a minimum number of good-quality embryos on day 3.
In our IVF program, we (currently) usually perform day 3 transfers for couples with less than 4 day 3 embryos that look "good", and day 5 transfers for couples with 4 or more high grade day 3 embryos. This has been working well for us with very rare cases having no embryos available for transfer on day 5. Individual factors such as the age of the female partner, information from previous IVF cycles, etc., can play a part in our decision regarding the best day to do the transfer in an individual case.
Do blastocyst transfers correlate with higher pregnancy rates than day 3 transfers?
Yes, in most published studies, and in the experience of many IVF programs, pregnancy rates are higher with blastocyst transfers when a given number of embryos are transferred (e.g. two). This is because of the higher potential for implantation of the blastocyst.
However, the issue is complicated because some IVF centers have seen no improvement or even lower pregnancy rates with blastocyst transfers. This is because blastocyst culture and transfer is technically more complicated and difficult as compared to day 3 transfer. Some laboratories are not able to maintain the stable and exacting culture environment for 5 days that allows the optimal development of the embryos.
Therefore, it is not surprising that extended culture and transfer of two embryos on day 5 can show excellent pregnancy rates in some centers and significantly lower results in others. This concept is well-understood in the embryology world, but it is not widely discussed in public forums.
How can blastocyst transfer benefit couples needing IVF?
Because blastocysts have a significantly higher implantation potential than day 3 embryos, the physician can transfer only two embryos and keep pregnancy rates high (over 50% per egg retrieval procedure in some programs for women under age 40) and triplet pregnancy rates down in the 2% to 4% range (one of the two embryos can split into identical twins to make triplets).
Transferring only two embryos on day 3 results (on average) in an even lower rate of twin and triplet pregnancies (a good thing), but this happens at the cost of a substantially lower overall pregnancy rate.
Because of the very high implantation potential of quality blastocyst embryos, we should be cautious about the high potential for twins. Transfer of two excellent blastocysts can result in twin pregnancy rates as high as 50-60%. Therefore, transferring only one should be considered in young women (or in egg donation cycles) with high-quality blastocysts. Pregnancy rates with single embryo transfer (SET) in these patients can be in the 40-50% range with a very low risk of twins (perhaps 2%) and almost zero risk for triplets.
In conclusion, blastocyst culture and transfer of one or two embryos in IVF centers that are proficient with this technique currently offers the best balance between the chances of any pregnancy ensuing and the risks involved with a multiple pregnancy.
Cost of blastocyst transfer
We are not currently charging extra for blastocyst transfer (for self-pay situations)Our current fees for IVF