In this session, Dr Daniel Bodri, MD, MSc, PhD, a Gynaecologist at IVF-Spain, Alicante, Spain, discussed single embryo transfer, its advantages, success rates, and why it is recommended.
Dr Bodri begins the session with a short historical background on a single embryo transfer, which reveals that IVF has been in existence for over 40 years. In its early days, laboratory techniques were not as advanced as they are today. As a result, it was a routine practice to transfer multiple embryos to achieve acceptable success rates. However, this approach often led to twins and high-order multiple pregnancies, which were associated with poor obstetric and neonatal outcomes.
In the 2000s, there was a push, particularly from Scandinavian countries in Europe, for trials proposing an elective single embryo transfer (eSET) strategy for selected patients. This approach aimed to reduce the number of multiple pregnancies.
From the 2010s onwards, the single embryo transfer (SET) approach has increasingly become the norm, especially in advanced clinics. This shift was made possible by significant improvements in embryo selection methods, including blastocyst culture, time-lapse incubators, and preimplantation genetic screening. As a result, the focus shifted from pregnancy rates per embryo transfer to healthy singleton live births as the most desirable outcome of IVF treatment. With the advancement of vitrification, a highly efficient method for freezing oocytes and embryos, the focus has also expanded to cumulative live birth rates, which are now considered the key measure of a successful IVF clinic outcome.
The situation of single embryo transfer (SET) varies across different regions of the world. In some countries, the proportion of multiple births after IVF treatment is very low, not exceeding 2 or 3%. However, in other regions, this figure can be as high as 30%. It is also important to note that multiple pregnancies are not solely caused by IVF. Non-IVF treatments, such as ovulation induction and intrauterine insemination, can also contribute to multiple pregnancies if not carefully controlled.
There is a large variability in the uptake of the single embryo transfer (SET) policy across different countries. Some countries, such as Japan, Australia, and New Zealand, are at the forefront, where almost all transfers are single embryo transfers. In the Asia-Pacific region and Scandinavian countries in Europe, SET is also widely adopted. Dr Bodri mentions in Japan he witnessed how a well-known Catholic clinic uses single embryo transfer for all patients, regardless of age, and achieves excellent results. Significant progress has been made in countries like the United States and the United Kingdom over the past 10 years, where the proportion of single embryo transfers has increased significantly. However, there are still regions where SET adoption lags, such as Eastern Europe, the Middle East, Africa, Latin America, and some Asian countries. In these regions, 2 or even 3 embryos are still routinely transferred, likely because clinics are not yet confident enough to switch to a single embryo transfer policy.
Dr Bodri cites the “one-at-a-time” campaign in the UK as an example of a successful initiative. This campaign, designed by the Human Fertilisation and Embryology Authority (HFEA), the government regulator, successfully reduced the number of multiple births from 28% to 10% between 2008 and 2017, with 10% being the target. During this period, live birth rates after IVF were maintained at the same level. The success of the campaign was due to the involvement of not only the regulator but also patient groups and fertility professionals.
Data from the clinic from 2019-2020 illustrates the current situation regarding embryo transfer proportions across different treatment types. This includes treatments with donor eggs or own eggs, preimplantation genetic screening (PGT-A), and both fresh and frozen embryo transfers. The data shows that single embryo transfer is practically the norm. For example, with PGT-A, very few cases involve the transfer of more than one embryo. The same trend is seen with donor eggs, where the proportion of double embryo transfers is minimal, typically between 10 and 14%. In cases involving own eggs, particularly for patients with poorer prognoses and fewer high-quality embryos without PGT, two embryos may be transferred, although this is an exception. Generally, Dr Bodri says the approach at the clinics he works for follows a single embryo transfer protocol, especially for patients with chromosomally normal embryos following pre-implantation genetic testing. This protocol is also applied to recipients of donor eggs over the age of 45, where single embryo transfer is routine and without exception. Additionally, medical circumstances may require single embryo transfer as the standard approach.
Moreover, Dr Bodri highlights the advantages and disadvantages of double embryo transfer versus single embryo transfer, emphasizing the numerous medical, psychological, and economic reasons supporting the single embryo transfer policy. From a medical perspective, he points to a recent systematic review of maternal complication rates in twins versus singleton deliveries, which involved 60 studies. The review shows that hospital treatment during pregnancy, gestational diabetes, high blood pressure, preeclampsia, pre-term labour before the 37th week, the risk of a C-section, and bleeding after delivery are all much higher in multiple pregnancies. The odds of these complications are significantly increased, with the risk ranging from 1.2 to 6.3 times higher in multiple pregnancies compared to singletons. This illustrates the higher maternal complication rates associated with multiple pregnancies.
Complication rates for babies are similarly higher in multiple pregnancies. Preterm births, including early preterm (less than 32 weeks) and very early preterm (less than 28 weeks), are more frequent in multiple pregnancies. As a result, low birth weight occurs more often, and the need for treatment in the neonatal intensive care unit is significant. Unfortunately, perinatal mortality and stillbirth rates are also higher. The odds of these complications occurring in twin pregnancies are between 1.1 and 10.6 times higher than in singleton pregnancies. These medical factors strongly support the transfer of a single embryo.
For patients with chromosomally normal embryos, it is crucial to thoroughly test the uterus and address any issues to optimize the uterine environment. The embryo transfer must be performed flawlessly, as typically only one chromosomally normal embryo is available in advanced-age patients. Ensuring the best technique is vital. Even with a positive pregnancy test, the pregnancy is carefully monitored during the first three months, sometimes with adjuvant therapy to ensure sustained implantation. This approach to embryo transfer results in much higher success rates.
Dr Bodri explains that many of their patients are affected by diminished ovarian reserve, meaning they have low anti-Müllerian hormone (AMH) levels and few follicles visible on ultrasound. As a result, even with vigorous stimulation, these patients typically produce only three eggs or fewer. While this issue cannot be corrected, it can be compensated for by performing multiple stimulation cycles—two to four cycles, or sometimes even more if the patient is motivated. These cycles may be done consecutively or with a short pause in between, a strategy known as embryo accumulation or embryo banking.
The goal is to obtain four to six blastocysts (day 5–6 embryos) and submit them for genetic testing. If a chromosomally normal, genetically tested embryo is obtained, the success rates are not significantly impacted by the patient’s age. If there are no significant uterine issues, success rates of 80-90% can be expected. He says this approach, often referred to as “stay young” compensates for advanced maternal age by using a more complex strategy to achieve high success rates.
Dr Bodri explains that the so-called double stimulation approach allows for back-to-back stimulation cycles with only a short pause of two or three days between them. This new approach involves performing a second stimulation cycle just two or three days after completing the first, which may last 11 to 13 days. New follicles can be stimulated and punctured during the second cycle, resulting in two egg collections. The eggs and embryos from both cycles are submitted for pre-implantation genetic testing, and the resulting embryos are frozen for later transfer.
This approach is particularly beneficial for low-responder patients who produce few eggs, as it allows them to obtain twice as many eggs in one month compared to a single stimulation cycle. Dr Bodri explains that many patients undergo several stimulation cycles and months of effort, including ovarian stimulation, egg collections, and pre-implantation genetic testing, only to end up with a single chromosomally normal embryo. This is often the case for patients aged 42, 43, or 44. In such cases, it is crucial to perform the embryo transfer using the best available method.
Dr Bodri says that while most clinics perform embryo transfers with ultrasound guidance, typically using a full bladder for transabdominal ultrasound, the clinic he currently works for employs a more precise method called transvaginal ultrasound-guided embryo transfer. This technique, developed in Japan, uses a transvaginal scan to allow for a much more accurate, almost surgically precise, embryo implantation. The slide shown above shows a 3D image as an example, the image is used to choose the ideal spot for the embryo, typically in the centre of the uterine cavity.
Dr Bodri also mentions this method is also less cumbersome for the patient, as it does not require a full bladder. Dr Bodri emphasizes that every detail of the process, including the embryo transfer, is carefully attended to in their clinic.
Dr Bodri explains that one of the most important embryo selection methods used is pre-implantation genetic testing for aneuploidy (PGT-A). Aneuploidy refers to an abnormal number of chromosomes in an egg or embryo. Unfortunately, the incidence of aneuploidy increases with advancing female age. Even younger women can produce chromosomally abnormal embryos, meaning there is an extra or missing chromosome. However, after the age of 35, the rate of aneuploidy increases dramatically, and by age 40, it becomes very difficult to find a chromosomally normal egg or embryo.
To address this issue, blastocysts can be tested for chromosomal normality. A large study shows the likelihood of obtaining a chromosomally normal embryo, with the proportion of normal blastocysts (day 5 or 6 embryos) varying by age. For women over 38, the proportion of normal embryos can range from a maximum of 30% to less than 10%. This is why it is important to accumulate several blastocysts and analyze them together, which is the approach used at Dr Bodri’s clinic.
Dr Bodri explains that pre-implantation genetic testing for aneuploidy (PGT-A) is routinely performed in their clinic. In cases without PGT-A, embryos are cultured until the advanced blastocyst stage, typically day five or six. At this stage, the embryo contains around 120 cells. For PGT-A testing, a sample of up to 10 cells is removed from the embryo for chromosomal analysis.
On the slide shown above, we can see a time-lapse incubator is used for embryo culture, which is a highly advantageous method. This system allows continuous monitoring of embryos with a camera that captures images every five minutes without disturbing the embryos or removing them from the incubator. The biopsy process, known as trophectoderm biopsy, involves removing a small sample of cells from the embryo, which is then analyzed in the clinic’s genetic lab. The genetic material is amplified, and the number of chromosomes is tested. A normal embryo has two copies of each chromosome in the 23 chromosome pairs.
The test uses the most sophisticated next-generation sequencing method. If an embryo is found to be genetically abnormal, with an extra or missing chromosome, it is discarded.
Later on, Dr Bodri explains that the success rates in their clinic depend on the patient’s age, the use of their own eggs or donor eggs, and whether pre-implantation genetic testing (PGT) is performed. For patients under 38 years of age who do not undergo PGT-A, the success rate for a single blastocyst transfer is approximately 62%. However, in older patients who do not undergo PGT-A, the success rate is much lower. It is important to note that most patients in this group do undergo PGT, and the low success rate reflects the poor prognosis of these patients.
For patients over 38 years of age who undergo pre-implantation genetic testing, and if a chromosomally normal embryo is obtained, the success rate can reach up to 91%. In some cases, PGT is also performed when using donor eggs, particularly for patients who have had previous failed egg donation cycles. In these cases, success rates exceed 90%.
Almost by the end of the session, Dr. Bodri emphasizes the importance of investigating the uterus in achieving high success rates. In their clinic, a comprehensive examination of the uterine factors and the endometrium is offered. This includes 3D ultrasound scanning, office hysteroscopy, measurement of uterine contractions, and, most importantly, an endometrial biopsy. During this process, a small sample of the endometrial lining is taken after the patient undergoes a mock cycle, which is a three-week preparation of the uterine lining. The patient only needs to visit the clinic once for a quick examination, where all tests can be completed within 2 hours, typically without anaesthesia, as an outpatient procedure. After 2 to 3 weeks, the results of the tests are available.
On the slide above, Dr Bodri illustrates the importance of 3D ultrasound in modern fertility workups. It is used routinely in their clinic to detect fibroids, polyps, and uterine malformations. Additionally, hysterosonography is performed, which involves introducing a small amount of liquid into the uterine cavity to test for anatomical abnormalities. As mentioned, this 3D method is also utilized during the embryo transfer procedure itself.
Moreover, office hysteroscopy is a minimally invasive procedure that can be completed in three to four minutes to examine the inside of the uterine cavity. It is almost painless and does not require anaesthesia, allowing the patient to observe the procedure on the screen. If any pathology, such as polyps, fibroids, or adhesions, is discovered, the patient is referred for an operative hysteroscopy under anaesthesia.
Dr Bodri highlights the endometrial biopsy, which involves taking a small sample of uterine tissue, is of particular importance in assessing endometrial receptivity. This test, known as ERMAP, was developed by their clinic’s own genetic laboratory. It is a highly precise test of gene expression for the genes responsible for embryo implantation. The test can accurately determine whether the uterine lining is suitable to receive an embryo and whether the implantation window is open. Typically, the implantation window is expected to occur on day five of progesterone intake. However, studies, including those conducted by their clinic, have shown that this window can vary widely between days 4 and 8.
According to Dr Bodri with this test, it is possible to diagnose whether a patient has a shifted or a normal implantation window. In up to 30% of cases, the implantation window is shifted, requiring the embryo to be implanted in a personalized manner—either 1 or sometimes 2 days earlier or later than expected. If this correction is not made, even a genetically tested embryo may have very low chances of implantation, or if implantation does occur, the pregnancy is often lost during the first few weeks.
Another test developed is a sophisticated immune testing approach called IM MAP. Using the same sample from the endometrial receptivity test, several immune cells—such as natural killer cells, T helper cells, and B lymphocytes—can be analyzed to determine if immune factors contribute to issues like repeated implantation failures or recurrent miscarriages, especially biochemical pregnancies or early miscarriages. If any alterations are found, this test helps identify the most suitable form of immune therapy to address these problems and improve early pregnancy outcomes during the first 3 months.
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A smear test or a cervical smear test, of course, is a screening test to check that there are no cancerous or pre-cancerous cells in the uterine cervix. It might not be directly related to embryo implantation, but it’s simply good practice to have a recent smear test before contemplating fertility treatment or, in the case of contemplating pregnancy, if it’s successful, then, of course, one has to know whether there is any alteration in the smear or not. Of course, different countries have different guidelines. In Spain, for example, in many European countries, a smear test is done yearly, while in the UK, it is done every three years. At least within the regulations of one’s own country, it is a good idea to have a recent smear test done.
Again, it depends on what kind of alteration was seen. Usually, it could be related to a local infection, so this could be treated. Also, if there’s any alteration, a colposcopy, which is a test of magnification, is done, or sometimes we do an HPV test to check for the presence of human papillomavirus because some strains are more dangerous than others. So, if a smear test is altered, it is possible to quickly do some other tests. Only if there are some really important alterations with the smear or the colposcopy would a surgical intervention be required to remove a so-called colonization or to remove a small part of the cervix if there’s any real significant alteration. But after the smear, the first step would be to do a colposcopy and maybe an altered smear, colposcopy, and HPV testing.
APCR is a sort of relatively simple clotting screening test. So, somebody who has an altered APCR test might have this so-called mutation or ligand mutation or some mutation of the coagulation, which predisposes the patient to suffer clots. So, it’s an important test, but before undergoing ovarian stimulation or before pregnancy, if somebody has risk factors, then it’s a useful test to do. Meaning risk factors, a history of thrombosis in the family or close relatives, or a personal history. In some cases, we do ask for a clotting screen if the patient has, of course, recurrent implantation failure or recurrent miscarriages. If in the UK it’s difficult to do, for example, for those patients who come to our clinic, you could simply do it here. Sometimes it’s even cheaper than in the UK, so we could do all these blood tests too, at the same time as we do, for example, the other uterine testing. That could be also considered.
It’s a very, very good question. Yes, I mean the flawless embryo transfer. I’m quite, quite passionate about embryo transfer because, I mean, I’ve done thousands of them, and I think it’s something more like an art. Doing a good quality embryo transfer, of course, one has to be supported by an excellent laboratory, and it’s always teamwork. So, this means if we don’t have, for example, an excellent-quality embryo or a chromosomally tested embryo, then even the best embryo transfer technique will not be successful. For example, here in several clinics over my life, I’ve always been monitoring. It’s part of the quality assurance to monitor each doctor’s embryo transfer rates.
There are differences, possible differences between operators, and it has been described in the literature. So, for example, with this kind of method that I’ve explained, it’s a particular method which is not practised so much in all clinics. But, I mean, any good embryo transfer, particularly this method with a good quality embryo, could achieve very high success rates, like close to between 70 and 90 per cent in some cases. So, that’s what I mean by flawless embryo transfer: paying attention to detail, doing a mock transfer, for example, for a patient, doing a thorough 3D ultrasound, and then, of course, when we do the embryo transfer, it is also done in a very laid-back way—like also not hurry it the whole embryo transfer procedure, and doing it, of course, automatically, which is well described.
I understand your question, that you’re suggesting that in an older patient, if no pre-implantation genetic screening is done, then one could allow the transfer of more embryos so that maybe one could implant. Four would be too excessive, so it depends on each clinic’s expected success rate. In some cases, as you have seen, maybe in an older patient, if no genetic testing was done, we have transferred, two embryos. So definitely not four. In some cases, maybe two could be transferred, but the ideal would be not to increase the number of embryos on untested embryos, but consider doing implantation genetic screening, or maybe to do treatment in a clinic that does it routinely. There’s no point in transferring several embryos if none of them is chromosomally normal.
It’s a tricky question. Well, one alternative, of course, is to become a cross-border reproductive care patient, and we have many patients indeed who come to us to do maybe a last attempt using pre-implantation genetic screening. Of course, there are other embryo selection methods. As mentioned, time-lapse nowadays is becoming more and more sophisticated, so it is possible to select if we have several embryos to select from, to test the embryos using this sophisticated incubator, the time-lapse. We are also, in our clinic, developing a non-invasive pre-implantation genetic testing, which does not require any biopsies. The embryo is not touched; actually, DNA could be extracted just from the medium where the embryo is cultivated. Possibly this could be an alternative, but it’s still relatively experimental and will come in the next years.
Of course, it’s very important to define precisely the success rate. In the slides that I’ve shown, I’ve shown it’s a clinical pregnancy rate, so it’s not the live birth rate, meaning it’s a fetal heartbeat on a six- to seven-week ultrasound scan. Before that, of course, we have a positive pregnancy rate, which would be like 10 days after a blastocyst transfer. So, it’s very important to define success rates exactly. Of course, what we’re interested in is the live birth rate, but for that, our patients have to be followed up, and it takes time until we get the results from all patients, especially if they are coming from abroad as cross-border reproductive care patients, to have all the live births accounted for.
This Japanese method, I observed that myself in Japan, and when I came back to Spain, I also did randomised clinical trials with this method. So, it’s a very interesting method. Anybody can do it who is familiar with the transvaginal ultrasound method. So, why is it not widely used? Probably because I mean, some doctors might be resistant or reluctant to change the method that they feel comfortable with. Embryo transfer is indeed a very personal, subjective method. Everybody has their own method and has to feel comfortable. So, switching, even changing a small part of the whole process, sometimes could feel daunting, especially if you change from an abdominal ultrasound to a transvaginal ultrasound. At this link that I’ve mentioned, you can see an entire tutorial about it. So, I would be happy to show it to other colleagues. The idea is that if it’s done in more centres, then this could be very helpful to increase the success rates potentially, or even for the patient to observe more precisely the area of implantation and see it being implanted in a very precise way.
After embryo transfer in our clinic, for example, patients stay and remain in their, well, it’s not a bed, it’s sort of a reclining chair that we use for the embryo transfer. This lasts for only 20 minutes. So, afterwards, they could go to their hotel, they could go home, and they could lead a normal lifestyle. In the literature, some studies have looked at this question of bed rest, and they found that it’s not beneficial to contemplate long bed rest after embryo transfer. So, a more normal lifestyle without avoiding any strenuous physical exercise is okay.
There are no exact studies. Of course, with our experience, I mean, most of our patients are cross-border reproductive care patients, so usually we recommend them to take a flight the next day. But we still have some patients who, for logistical reasons, fly on the same day as the embryo transfer, and we haven’t observed any kind of deleterious effect. So, if they could manage to fly the next day, it’s okay. If there’s no reason, probably, to stay very long after the embryo transfer unless the patients want to have a little bit of a vacation afterwards or just to chill out. But we don’t have any evidence that shows that immediate flying would be very deleterious. Also, as a precaution, probably flying the next day is a sensible choice.
We do offer acupuncture, for example, at our clinic before the embryo transfer and after the embryo transfer. We have an acupuncturist who has experience with fertility patients. There’s no clear consensus—some studies say that there’s a benefit, while other studies say that there’s no apparent positive effect. Definitely, it probably doesn’t do any harm, so if somebody considers acupuncture, it is possible to do it.
Food types? Well, a healthy lifestyle could affect fertility. I mean, I’m not a nutrition expert, but, like, avoiding unhealthy diets would only have a positive effect, especially before starting fertility treatment. It probably would take some time for changes in nutrition to take effect. For polycystic ovary syndrome patients, losing some weight could be useful. These would be my ideas on this topic.
We had patients who transferred their embryos to our clinic, and we do have experience with this double thawing, meaning that these embryos that have been frozen once, need to be thawed. A sample of cells has to be removed, and because it takes two weeks to have the result, these embryos need to be frozen a second time again. I mean, vitrification is quite efficient, so even if embryos are thawed for some reason twice, this doesn’t seem to affect them. It’s a good thing that you have seven blastocysts left. At some point, after 2 failed cycles, it’s not unreasonable to consider implantation genetic testing, even if you have to transfer your embryos to a clinic where they can be tested. Tomorrow, they will have another webinar with our embryologist, and I advise you maybe to ask the same question to our embryologist, who can give you an even more precise answer. I would recommend considering it.
Laparoscopic, so meaning with keyhole surgery, if a fibroid is removed with keyhole surgery, it’s better than if it’s opened, I mean, in a conventional way. Of course, it depends on how many fibroids were removed, so seeing a report of the intervention would be useful, but probably a six-month wait would be sufficient after this procedure to consider embryo transfer. Yeah, I see, like, so 6 centimetres, about 3 of them. So yes, it’s logical to wait at least 6 months.
I think, in my practice, I have a 45-year-old patient using her eggs. Yes, of course, so that would be probably the sort of extreme case. I don’t have exactly the whole statistical data, like, I mean, who’s the oldest patient, taking into account all the cycles that have been done in our clinics. In the literature, there are some cases, even without PGT, but like extreme cases, maybe 48 years of age. So 45, or 44-45, would be probably, in most cases, the sort of extreme where we can obtain a chromosomally normal embryo, but in the literature, there are some cases at 46, 48 too.
It’s a good question, a little bit of a controversial question because there’s sort of conflicting data on whether it’s necessary or not. I mean, I’m not an expert on endoscopic surgery myself, so the pros and cons have to be assessed. If such a surgery is done, of course, it’s usually done with hysteroscopy, which is less invasive, but there’s a risk of creating some adhesions. Probably, it depends on the history of the patient and how severe the T-shaped uterus is. Probably, some centres would tend to do an intervention, especially if the patient already had a failed implantation or failed cycles. I would suggest contacting, for example, we have patient meetings, and we have two of our doctors who are experts in endoscopic hysteroscopic surgery. You could ask them, free of charge, for advice about this question.
