- If multiple embryo transfers result in increased success rates
- If a single transfer gives higher chances of a live birth
- What the consequences and possible risks of a multiple embryo transfer are
- If a single transfer is more recommended – and if so, why?
Single or multiple embryo transfer - best practices
In many IVF cases, more than one good embryo is obtained. Having many good embryos available allows fertility specialists to grade them and choose the best ones for transfer. But this also causes a common dilemma – how many embryos should be transferred?
Interested? Read what Dr Jessica García [Fertility Specialist at Clinica Tambre] says about Single embryo vs. multiple embryos for transfer. Best practices and recommendations during this #IVFWEBINARS.
An embryo transfer – the background
An embryo transfer is the last part of the fertility treatment. The last – but also the most important one. Using ultrasound for accuracy, the doctor will pass a catheter through the woman’s cervix and into the womb. From there, the embryos are passed through the tube and placed into the endometrium. Dr Jessica García starts her presentation with explaining that an embryo transfer is quite a simple procedure that does not require anaesthesia. There are three types of embryo transfers: a single transfer or elective single transfer (when there is more than one embryo of good quality), a double transfer and a multiple transfer (when 3 or more embryos are transferred). Dr Garcia admits that in Spain, there is usually the choice between options 1 and 2. However, there are still countries that transfer more than 3 embryos.
Dr Garcia sheds some light on the history of embryo transfers. In late 1970s, as there was no vitrification method yet, doctors were forced to transfer all the good embryos they had retrieved. It meant transferring 3-5 embryos at once. It resulted in lots of twin/multiple pregnancies through IVF. In 1980s, the lab culture of embryos started to prolong and embryo transfers slowly moved from day 1 to day 3. When the incidence of multiple gestations increased to 15-30%, entailing a risk of pregnancy complications, fertility specialists started looking for new technologies to improve embryo selection. Late 1990s brought first attempts of a single embryo transfer.
Improving embryo selection with long culture
Dr García says there are almost 9 million babies born through IVF in the world today. This impressive number was achieved partially thanks to new technologies that have significantly improved the process of embryo selection. One of them is the so-called long culture. Culture is used to recreate the environment within the fallopian tube and uterus, so that embryos can grow just as they do in the human body. Embryology labs have become capable of culturing embryos safely for longer periods of time – up to the stage of a blastocyst (day 5). Blastocysts, being embryos with the greatest potential, have more psychological synchronisation with the endometrium. They are the ones with activated genome and – what is more – they have a lower rate of early miscarriage when being transferred. Dr Garcia admits that only the hardest and strongest embryos can advance to the blastocyst stage. Thus, the latter is also the best stage to conduct genetic testing on embryos.
Embryo vitrification as the solution
According to Dr Garcia, nowadays embryos can be successfully frozen and thawed better than ever. Thanks to the vitrification method, good quality embryos, that are not immediately transferred to the patient, are placed in cryostorage. It means that they are frozen and stored until they are needed for later transfer – without decreasing their quality. Compared with the times when only fresh embryos could be transferred, that is a really significant improvement.
Time lapse and higher rate of blastocysts
A new generation of time lapse incubators enables embryologists to culture embryos from day 1 till the blastocyst stage – without the need to remove them. These incubators help to maintain uninterrupted culture environment, including constant factors such as temperature, oxygen and light exposure. Additionally, there is a possibility of real time image recording and embryo development monitoring. All of this helps to select the best embryos to transfer as well as decide which of them should be transferred first. Dr Garcia also mentions one very important issue – the rate of blastocysts is noticeably higher when using time lapse incubators. And the advantages of blastocyst transfers are more than clear – it has already been proved in the previous paragraphs.
PGS for chromosomally normal embryos
Of all new technologies improving embryo selection, pre-implantation genetic screening (PGS) is of highest importance. In this procedure, cells taken from developing embryos during a biopsy are sent to the lab where they are assessed in terms of chromosomal euploidy. PGS helps to select chromosomally healthy embryos and, as a result, increases the chances of a healthy baby. Thanks to this technology, it is possible to reduce the risk of miscarriage and increase the chance of pregnancy per transfer. Additionally, doctors can reduce the duration of treatments and the number of cycles to achieve pregnancy.
However, Dr Garcia stresses that PGS is not indicated for everyone. It should be considered mainly by women over 37 years old, patients who suffered from two or more miscarriages or those who previously had a genetically abnormal pregnancy. It is also a good idea for people who underwent multiple IVF cycles with no successful outcomes.
Single embryo transfer vs. multiple embryos transfer results
Despite the use of the most up-to-date technologies designed to improve the embryo selection process, some patients still believe that the best way to increase the chances of a live birth is by multiple embryo transfer. Dr. García clearly highlights that multiple embryos very often mean a higher risk of a multiple pregnancy. Even if you transfer just one embryo, there is still a 1% chance of it splitting into identical twins. So, when you decide to transfer two embryos, bear in mind that the possibility of twins or even triples is quite real.
Dr Garcia states that the chances of pregnancy by either a single or a double embryo transfer are more or less the same. According to the Spanish Fertility Society (SEF) data from 2017, the pregnancy rate in case of a single embryo transfer (SET) was 53%, while in case of a double embryo transfer (DET) – 56%. However, taking into account the possibility of a twin pregnancy, the difference is much more significant. In case of SET, it is only 1,3%, but with DET – it is 31%. When we realise that each twin pregnancy entails much more risks and complications, this last comparison takes on a completely new meaning.
Twin pregnancy – the facts
Dr Garcia says that patients are not willing to acknowledge the fact that a twin pregnancy poses some real threat. On the contrary, they seem to treat it as a reward after their long and complicated fertility treatment. But one has to have a realistic overview of the situation to be able to make conscious decisions. The truth is that all the possible pregnancy risks are increased in case of double pregnancies. Firstly, and most importantly, the miscarriage rate is much higher in case of the latter. Additionally, twins are not always born healthy and they are at risk of lower birth weight and prematurity, including all related complications. Twin pregnancies are also less beneficial for mothers. The women may suffer from pregnancy-induced hypertension, gestational diabetes and pregnancy bleeding. They are in the need of a caesarean section much more often, too.
In conclusion Dr Garcia points to a few factors that should be considered when deciding between a single embryo transfer and multiple embryo transfer. The most important is the cause of infertility – every patient’s case is different and that is why the treatment plan always has to be individualised. Another factor is maternal age – here, the older the mother, the higher the risk of pregnancy-related complications. One also must take patient’s medical conditions into account. Diseases, such as diabetes or high blood pressure, can only get worse in case of multiple pregnancies. Finally, the possibilities of implantation can differ depending on the embryo quality. Transfers during the blastocyst stage generally give more possibilities of a pregnancy – it is a meaningful argument for single transfers and – at the same time – against multiple transfers. The quality of embryos is higher in egg donation and IVF treatment with PGS as well.
According to Dr García, discussing one’s own medical case with the doctor is crucial before deciding on the type of an embryo transfer. Additionally, using all the described new technologies for embryo selection is advisable in order to improve pregnancy rates – without bearing unnecessary risks.
Questions and Answers from the event
Can you tell more about low level mosaicism?
When we do PGS, we can have 3 results: euploid (which is a healthy embryo we can transfer), aneuploid (which is a totally abnormal embryo and we don’t recommend it to be transferred) and mosaic. When we have a low level of mosaicism, we have to consider which chromosomes are impacted by mosaicism. I would recommend doing a genetic consultation to decide about possibilities. At our clinic, we have had a couple of transfers of mosaic embryos. We’ve had really good results and pregnancies. So you have to consider the level of mosaicism and which chromosomes are influenced by it. Consult with the geneticist if it is worth to do a transfer or not and what to expect afterwards.
Is it still only 1% with ICSI or higher percentage?
According to the results from the Spanish Fertility Society (SEF), it seems to be something around 1%.
I’ve had 3 embryos frozen on day 1 and my country does not allow genetic tests – only with a special petition. Do you think it is a good idea to ship my embryos somewhere and cultivate them until day 5, then refreeze and test them? Or maybe I should just try to get a blastocyst and transfer it without testing? I’m 42 and have diminished ovarian reserve (DOR).
If it is possible for you, I’d definitely recommend to send the embryos to another country and cultivate them until the blastocyst stage. You could do the transfer on day 5 and have really good possibilities for the embryos to survive. Maybe not all of them are going to survive until day 5. However, if it is possible, I’d also recommend to do PGS and then decide if you want to transfer them or not.
I understand you never recommend implanting 2 embryos. Or would you recommend it in some cases? What cases would it be? Based on egg’s age?
Sometimes when the lab cannot culture embryos till day 5, it might be a good idea to transfer 2 embryos just to have good pregnancy rate – depending on the maternal age, eggs’ stage and quality.
How long would you recommend a woman of 37 years old and lower AMH to wait for the transfer before the blastocyst stage: 1, 2 or 3 days? Would you also recommend any type of tests before the transfer?
I’d recommend waiting until the blastocyst stage. Sometimes we’re afraid of not having a transfer at all but all the information that we have now supports the idea of doing long-culture. Many of embryos will cease to develop on day 2 or 3. I think you also have to talk with your doctor because sometimes you can decide to do it on day 3, basing on the quality of the embryos. But I would recommend to do it at the blastocyst stage if it’s possible.
I had 2 embryos transferred, resulting in a twin pregnancy, and had a miscarriage at 11 weeks. I will have next transfer soon. Do you think it is less likely to have miscarriage when transferring 1 embryo? I am a healthy 39-year-old.
It seems that the miscarriage rate is higher when we have a twin pregnancy. I don’t know your medical history but if you have other medical issues, I’d recommend doing more tests before the transfer. It’s important to see if everything is normal and then I’d recommend doing a single transfer to avoid the possibility of a miscarriage. I mean, the possibility of a miscarriage is not that different in case of a single and a double embryo transfer, but it’s still a little bit higher when we’re transferring two embryos.
What would you recommend to a patient after 5 implantation failures? Is transferring 2 embryos recommended in this case?
Depending on the quality of the embryos, I’d recommend increasing the analysis you’ve already done. You should try to see if there’s another thing that’s causing implantation failure. I’d try to see the endometrium and do some blood tests to make sure you don’t have anything else causing the failure. The first and most important thing is the quality of the embryos. Maybe the quality is not that good and it can be blamed for your medical history. The embryo quality may be the reason why the transfer of two embryos is recommended in your case.
I’m 45 years old. I’ve had 9 rounds of own egg / own sperm IVF over the last 7 years. I had implantation once (5 years ago), but this ended in a miscarriage at 10 weeks. Now we are doing donor egg IVF. We did a frozen cycle and got 6 good quality embryos from the donor egg cycle. I have had two frozen embryo transfers since, with 1 top quality AA blastocyst transferred each time – however, both cycles were negative. We’re about to start preparing for my next FET and trying to decide if I should transfer 1 or 2 embryos this time, given how many years we have been going through this. The embryos we have left are: AA, AB and 2 x BB. What are your thoughts?
If you’ve already had two implantation failures with good quality embryos, I’d stop for a little while. I’d do some more analysis to discover if you have some other medical issues causing the failure. The medical history of yours could have been caused by the quality of your own eggs – because of the age. Since we are having two good blastocysts now and a history of miscarriages, I’d recommend you to do some more analysis. It’d be good to see if the endometrium is fine and do some blood tests towards thrombophilia, before doing another transfer.
You said that I should look at other investigations before my next FET. But I have had hysteroscopy, aqua scans, Chicago immunes blood tests, the ERA test, blood clotting tests. I’ve also just had the EMMA test and I’m awaiting the results. It seems I’ve had every test available! Is there anything else you would suggest before my next FET?
It seems that you’ve already done everything. I think in some cases we just don’t know the cause as the science is not there yet. Maybe we’ll have to wait until we have the results of the EMMA test. And then, if everything is normal, the doctors will decide. Sometimes we’re also talking about possibilities. Even when we’re doing egg donation, there’s no 100% possibility of success. That’s why we sometimes might not reach the pregnancy. But I think you’ve done everything that’s possible and I hope you’ll have good luck with the transfer.
How successful are the implementations of eggs from young donors at the blastocyst stage vs. older women?
When we’re doing egg donation, the age of a woman that is receiving the eggs does not matter. Egg donation at the age of 30 or 45 has the same implantation rates. The differences in implantation rates when we’re using our own eggs result from the quality of the eggs. When we change it for egg donation and good quality eggs, we all have the same possibilities.
Do you often do hysteroscopy before the transfers? Does it raise the success rates?
We usually do not do it unless it is indicated. We do it only in special cases when we have had, for instance, an implantation failure. We try to see if everything is normal in the uterus cavity. Sometimes we can miss a couple of small things in the scans, such as adhesions or polyps. But we do not do it in every patient.
I just removed uterine adhesions (scars from a myomectomy 5 years ago). The doctor mentioned 20-30% damage on walls. Can endometrium recover its damaged parts? Or will the embryo need to find a way to implant on the other 70% of the remaining area? Do embryos move around to get a better place to implant?
Depending on the damage, the endometrium can sometimes recover. Embryos do not move around to get a better place – maybe just a little bit in the area where they are left after the embryo transfer. I think you have good possibilities of having your endometrium recovered. Maybe you’ll have to wait a little bit after the surgery and then, if you still have issues while doing the endometrial preparation, we may see if the damaged parts are still there.
Can you please explain the difference between Era, Alice and Emma tests? How reliable are they?
The ERA test allows us to see the endometrial receptivity. We may find out how many days of progesterone you need to see the implantation window. The Alice test allows us to see if you have chronic endometritis. It’s like the infection in the endometrium. We can decide if you need to take antibiotics or something. Chronic endometritis can cause abortions or implantation failures, so the Alice test is a good thing. The Emma test allows us to see if you have the normal microbiome in the endometrium or if you have to take some probiotics to improve the flora in the endometrium. It seems all these tests are really reliable. In our clinic, we have very good results when we’re using the EndomeTRIO (all 3 tests). They seem to improve the implantation rate.
Are you doing genetic testing of a donor and a partner (whose sperm will be used ) to confirm the matching?
Yes, we have something called genetic matching which allows us to detect recessive illnesses. We can do the test between the couple and between the donor and the partner to see if they match. With this test, we can test over 300 recessive illnesses and see what happens if both parties involved have the same illness. On the basis of this, we can change the donor and try to look for another one that matches. In this way, we’re reducing the risk of having a sick baby.
If a polyp has been found in the cervix (when having a scan) before the transfer – will this cause a problem with the transfer?
No, usually it won’t. Basing on the information that we have, polyps in the endometrium can cause a failure in the implantation or reduce the possibilities of implantation. If the polyp is in the cervix, I do not think there will be any issues with that. The transfer may be a little bit more difficult at the beginning but then everything should be normal. So I wouldn’t worry about that.
Do you have experience in your clinic with the embryo implantation despite adenomyomas? Are implantation windows different then? What about miscarriage prevention? What do you recommend to do in this case?
We have lots of patients with adenomyomas and we have really good results. It doesn’t seem that it affects the implantation window. We obviously don’t have that many patients with the ERA test and adenomyosis. If adenomyosis is severe, we can use the agonist of GnRH to avoid the consequences of the disease. But we have good pregnancy rates even with adenomyomas. We do not do any different in this case to prevent miscarriage. We usually use the same protocol – unless we have severe disease. Then we have to do the pretreatment before the transfer to try to reduce the effects of the disease in the endometrium.
Till what week of pregnancy do you give progesterone?
Till the 10th week of pregnancy. It is very controversial. We know that the placenta starts producing progesterone from 6-7th week of pregnancy but we usually keep it until the 10th week just to be safe.
I wanted to ask my doctor for a few inflammation check-ups and immunological tests. I was told we have just had too many tests. Which ones would you say are the most basic ones?
We always check the antiphospholipid syndrome (APS), the factor II and V of the coagulation, as well as protein S and C (also C3 and C4). We also check the intolerance to gluten. They’re all blood tests. I think these are the basic tests we’re doing.
Are there any tips or pieces of advice you can give for what to do after the embryo transfer? This will be my first one. Should I fly back home soon after or the day after?
According to all the information we have now, it is not recommended to do anything special. You will have the transfer and then you’ll rest a little bit, for e.g. 20 minutes. Then you can lead a normal life. You can even fly – that’s ok. I wouldn’t only recommend immersion baths, going to a pool or sauna. Of course, I don’t recommend smoking and drinking alcohol at that time. Besides that, there are no other recommendations. It’s not proven that having rest after the embryo transfer will increase the chances or is necessary at all. So I wouldn’t recommend you to do anything else than that.
Do you think that ICSI increases the chances of pregnancy?
Well, it doesn’t seem so. When we compare regular IVF with ICSI, the results seem to be about the same. Sometimes we’re a little bit scared that we will have a failure in fecundation while doing IVF – it happens in very rare cases. And this is probably the reason why in all the clinics they usually do ICSI. However, it does not seem to improve anything. We have very similar results. It seems that there are equal chances of a pregnancy with both methods.
What do you mean by ‘good endometrium lining’ and what you need to see in the ultrasound exactly to say “This is good endometrium and it’s well-prepared to receive the embryo”?
It has to be over 8 mm and it has to look well. It has to have a ”triple line” appearance. In the scan, the triple lining is very clear. So yes, that would be really good endometrium to have.
Do you check the endometrium before the transfer and what is the minimum number of millimetres you recommend?
We do check the endometrium before the transfer. The minimum will be 7 mm. Of course, some patients have a lot of issues when it comes to the preparation of the endometrium. Sometimes we have to accept the transfer with less than 7 mm but it is really rare. Nowadays we have lots of therapies we can use to try to improve the embryo lining. But I’d recommend having at least 7 mm. If it’s possible, it would be better to have more than 8 mm as it seems to improve the pregnancy rates. However, I think there are some studies showing pregnancies with 3 mm of the endometrium lining, too.
Is there a maximum number of mm of the embryo lining and do you recommend acupuncture before and after the transfer?
We would recommend you to have more than 14 mm. When it comes to acupuncture, I do not think we have any information in the studies available to confirm that acupuncture improves pregnancy rates. But it won’t hurt you either so if you want to do it – it’s fine. It won’t reduce pregnancy rates. So if it works – great, if not – it’s still ok.
My lining thickens up quite well with the progesterone preparation, but there is often no triple layer seen. My clinic does not seem overly concerned that the triple layer is not seen and is more concerned with the thickness. Do you think the triple layer is more important than thickness? Have you seen success in women who don’t have the triple layer appearance?
It also seems to be very important. But the truth is that sometimes some patients do not have the typical triple lining because the uterus is not in the regular form. Sometimes it’s one side or the other, sometimes it’s in a different position. That’s why it is not often easy to see the endometrial triple layer. But if it’s over 8 mm and we have the progesterone test done as well – and it’s almost zero – then we can be relaxed about that. Even if we cannot see the triple layer.
Do you see any connection between the psychological state and success rates?
Not really. Of course, when you’re stressed and sad, the cortisol levels are higher and could have some impact. But it still does not seem to reduce the pregnancy rates. So I don’t think that the psychological state affects success rates that much.
Do you think being on anti-depressant medications can affect the IVF outcome? Do you see success in women who stay on their anti-depressants during IVF?
I’d recommend you to stay on your anti-depressants if you need them. I don’t think it’s going to affect the results. It’s really important to be in a good state and feel ok when doing the treatment. So stay on your anti-depressants if it’s possible to do it. Sometimes it’s necessary to change the anti-depressant and find a new one that is not affecting the pregnancy. But if yours is ok, I’d suggest to keep it. I don’t think it’s going to affect your success.
Could you help me to transfer my day 1 embryos to your clinic so we can try to reach the blastocyst stage and do the genetic tests? Is this something you normally do? They are in another EU country now.
Yes, but we have to see what other country and clinic you mean. Let’s keep in contact and I’ll try to do it. We did it in the past and I think we can do it now as well.