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Key components for improving IVF success rates over the last years

Vanessa Vergara Bravo
Medical Coordinator

Category:
Success Rates

Key components for improving success rates over the last years
From this video you will find out:
  • the definition of successful IVF treatment
  • how the IVF outcome is measured
  • different strategies to improve outcomes
  • key changes in IVF laboratory work in 2006-2020
  • implantation rate in standard IVF cycles with PGT-A

 

What are the new components to improve the IVF pregnancy rates?

Watch the webinar with Vanessa Vergara Bravo, Medical Coordinator at IVI Clinic Madrid, who discusses the components that are crucial in improving IVF pregnancy success rates and those that have been developed over the last few years.

Types of protocols

Vanessa started her presentation by explaining the different types of protocols that are available at the clinics. The most important protocols are defined as “Protocols to follow regulations”, which are divided into Local and Regional regulations. Firstly, local regulations are established by the European directive. In the same way, regional regulations are established by laws and regulations of different countries that ultimately determine what type of treatments are allowed.

Defining success rates

Additionally, Vanessa stated that several steps in the process of IVF and Egg donation treatment are measurable in terms of effectiveness by indicators. In particular, she mentioned the implantation rates and the proportion of blastocysts, among others. Accordingly, these indicators are useful to achieve the major objective and purpose of the treatment, which is to have a healthy child.

The major objective of the treatment is for the patient to have a healthy child at home.

Indicators

She later explained the difference between the indicators, which are all based on innovation and research. On the one hand, IVF is not only improving and measuring techniques but acquiring new technology and equipment as well. Besides, the training of the embryologists is also implied.

On the other hand, in the clinical work, the indicators are said to be based on a deep understanding of both the physiology and the individualization of controlled ovarian stimulation as well as the experience of the clinicians as these factors play a relevant role in the outcomes.

How outcomes are measured

The outcomes are measured as follows:

  • Implantation rate (Number of sacks that are seen in the first ultrasound divided by the number of embryos that were transferred.)
  • Pregnancy Rate (Unlike the previous one, the number of embryos is not taken into consideration, as only the procedure of the optic transfer is validated. Also, she states the importance of the comparison between single embryo transfer and double embryo transfer.)
  • Ongoing implantation rate (Refers to how many of these embryos that are transferred continue developing correctly during pregnancy and reach a level of twelve weeks.)
  • Life-birth rates (which is the number of births divided by the number of transfers.)

She added that the ongoing pregnancy rates and life-birth rates from all the transferred embryos obtained in one cycle are referred to as cumulative rates.
Moreover, according to Vanessa, all the outcomes are based on different consensus and international guidelines in terms of how the IVF laboratory outcomes should be measured in order to achieve an average objective.

Different strategies to improve outcomes

Above all, it was explained that there are a variety of different strategies to improve outcomes based on research. In the first place, in the IVF lab, the strategies are based on having the best possibility for both embryo selection and the best option for embryo culture.

In addition, as regards the clinical side, individualized controlled ovarian stimulation should be of the utmost importance due to the importance given to single embryo transfer.

On the graph shown, it is visible how the outcomes and implantation rates have improved over the last 15 years. There have been significant changes, such as transitioning from incubator-standardized protocols to gradually introducing benchtop incubators. In 2017, 100% of all incubators at the IVI clinic were of the benchtop type, enabling to implement of a policy of transferring all embryos at the blastocyst stage.

PGT-A testing has also been introduced, especially for patients over 44 years old and those undergoing egg donation. This allowed to improve outcomes by 20% across all age groups. However, there is a drop in success rates after the age of 40, particularly in cycles without PGT-A testing.

The implementation of blastocyst stage biopsy, time-lapse imaging, and the use of artificial intelligence for embryo selection are among the technologies introduced to enhance the lab’s capabilities. These advancements have enabled more information for better embryo selection and to implementation of a single embryo transfer strategy.

We believe in the benefits of preimplantation genetic testing for aneuploidy (PGT-A), not only because it improves implantation rates per embryo transfer but also because it is cost-effective. It reduces the treatment time and minimizes the risk of failed embryo transfer and pregnancy loss.

In general, all these changes in the IVF laboratory paved the way for single embryo transfer. With double embryo transfer, the possibility of having a twin pregnancy is higher, which might result in a series of fetal and maternal complications that can persist throughout childhood. Fetal complications are related to intrauterine growth restriction, while maternal complications cater to diseases such as diabetes and hypertension. The principal complications are based on the risk of premature delivery.

Considering that maternal age is the most important factor that affects the quality of the oocytes, all efforts are focused on obtaining euploid embryos. The number of mature oocytes that can be retrieved is still a clinical challenge for responders.

We have been working on strategies to have more oocytes available for an IVF cycle. One of the strategies is the accumulation of oocytes, made possible because of the high survival rates after thawing. This allowed us to do the accumulation of oocytes to get more for an IVF cycle. Dual stimulation is another promising strategy for patients with a low response. Two stimulations are performed during the same month, the first one in the follicular phase, and a few days after, retrieve all and start a new stimulation. We identify the corresponding individualization of ovarian stimulation, control of new stimulation, and the best approach. This gives a better chance of success and the best luteal phase support.

Clinical aspects: challenges

  • Considering that age is the most important factor that affects the quality and quantity of oocytes, all efforts may be made to improve these two aspects.
  • The possibility of obtaining a euploid embryo highly depends on the number of mature oocytes retrieved.
  • Poor responders are a great clinical challenge.
  • Many approaches have been developed in the last few years. Even though some of them look promising, a lack of evidence still exists.
- Questions and Answers

Do you use time-lapse incubators, and do you believe that they make a difference?

We use time-lapse incubators, it is a very interesting tool that we introduced a few years ago. It is a tool that helps to select better embryos. There are a lot of studies that find good results, some studies don’t. Scientific evidence is kind of contradictory. It is an incubator that permits us to see what’s going on with the embryo without opening the incubator every time and also, we use it but I cannot tell you how big is the impact of these incubators in the long term. Many studies established that we have some benefits.

What is the difference between PGT-A and PGS?

It is the same. PGs is just the previous terminology that was used. I don’t remember if it was one or two years ago that it changed and the PGT was proposed. PGT means pre-implantation testing, it gives us the ability to see some abnormalities of the embryo, so PGT-A or it could be a PGT-M which is the diagnosis of monogenic diseases in the embryo, or could be PGT-SR which is the structural identification of chromosome abnormalities in the embryo. But PGT-A and PGS it’s the same.

I am on an anti-seizure drug called lamotrigine because of a car accident (frontal lobe) does my medication make IVF more difficult, less successful?

It doesn’t have to be. The problem with the drugs is that we don’t exactly know how it is going to affect you. In these cases, we have a multidisciplinary group of specialists and a special person who has a speciality in maternal-fetal medicine, and we have this clinical special cases committee where we analyze all the recommendations of the neurologists of the embryologist, obstetrician etc. I don’t believe that we have evidence of teratogenic effects with this anti-seizure drug. In the transfer and the results of the pregnancy rate, it won’t have any impact in that. My only concern would be the teratogenic effect, but as far as I know, this doesn’t affect it. When we have these type of drugs, we have to compare, and we talk to the neurologist about the benefits of using the medication or stopping it. These medications have a very important indication, so usually, we keep them because there are no clear teratogenic effects. If we see a clear teratogenic effect of this anti-seizure drug we have to stop it, we have plan it with the neurologist and change it.

I am interested in your 100% blastocyst transfer. I have read that some women can not produce blastocysts, how do you manage those patients?

The thing with blastocyst is that we have to provide the best environment for the embryo. If the patient cannot get to a blastocyst stage, we can discuss options of transferring on a day-3, but we don’t find any benefit in transferring the embryos before. If they don’t survive in the laboratory, they will probably not survive in the maternal users, and so this will result in a negative pregnancy. If we don’t reach that stage, there are a few things we can do. What we do now, we try to have more available oocytes and give them the best environment in the IVF lab.

So you would recommend transferring only one embryo when receiving egg donation?

Absolutely, yes. We always recommend transferring only one embryo because as I said, we have a very high implantation rate which is going to give us the pregnancy rate. When you transfer just one embryo, the possibilities of a twin pregnancy are nearly zero, and we are going to avoid all the complications that I mentioned, so I am absolutely sure that we recommend doing a single embryo transfer.

I am in the UK. I feel very conflicted about PGT-A testing given that the HFEA advises very much against it arguing that there is no strong evidence for its use. What is your opinion?

What we have to look at here is what a patient wants and how the PGT-A is going to improve. Imagine that you have 6 oocytes and you will have 4 embryos if we do PGT-A, we have the opportunity of getting that pregnancy in the first try, a very high chance, and if you don’t do PGT-A, you are going to have the embryo transfer number 1, number 2 and then number 3 or 4. After transferring 4 embryos, in the end, you’re going to have the same possibilities of live birth, but per cycle, it shortens the time that you need to get pregnant, and it lowers miscarriage rates. There is no doubt of that, so I understand why and because in terms of public medicine and those things are kind of hard to say that it is going to improve the live birth rate. It is going to improve the live birth rate per transfer dramatically, and it is going to shorten the time that you need to get pregnant, and it is going to lower the miscarriage rate. If you are over 40 years old, you have a miscarriage rate of 30% without PGT-A, so you’re going to go through all these for a 30% possibility of miscarriage. It is very different in younger patients where the miscarriage rate is 11% of, and that’s what we reach when we find aneuploid embryo.

Why would the progesterone (P4) level be low on the day of ET? Is it something to do with different people absorbing progesterone differently?

It is not well known. I wish we had that answer because progesterone has been a part of many types of research and many investigations, but it depends on the way we are administering that progesterone. There are many types of administration of progesterone, we have the intramuscular one, we have the vaginal one, that is the one that is preferred in Spain. There are some groups in the United States would prefer the intramuscular one, and now we have the subcutaneous injection of progesterone.

What dose of vaginal pessary progesterone do you prescribe? 600mg, or 800 mg?

We use 800 mg of progesterone in egg donation or cycles where the patient doesn’t produce any progesterone. If you have an IVF with own eggs and you go for the embryo transfer, the luteal corpus in the ovaries produces progesterone, we do have to give some support, but it is not as high as 800mg.

For Duo-stim, how many days after first egg retrieval do you start the second stim? Three, five, seven or nine days?

It is from 3 to 5 days after the egg retrieval.

I am planning to do a budget egg donation programme. Its 12 frozen oocytes from 2 different donors (6 from each for example). I also use a sperm donor. I’m 38. I had 5 failed IVF with my own eggs. The doctor said I don’t need PGD/PGS in case of egg donation. What is your opinion on this? Isn’t it better to not fail again and not to transfer the wrong embryo again? Also, I really want to transfer 2 embryos, is this too risky?

This is a very easy question to answer for me. First of all, I don’t understand why you’re going to have 2 different donors. We have the egg donation of a good number of oocytes from one donor and we have very good fertilization rates with a sperm donor. Even with 6 oocytes, we have a good fertilization rate, and we’re getting the blastocysts. About what your doctor said in regards to PGD/PGS that you don’t need because of the egg and sperm donation, it’s true depending on the countries law. It’s not that you don’t need it, because of course if you did PGT-A you would have more possibilities of euploid embryos but this is not absolutely clear when the age of the donor is less than 35 years old, so in countries like Spain it is not allowed by the regulation on the law, we don’t have an indication of a PGT-A when we have an egg donation when we don’t have a male factor.

What is your opinion on ERA Test? How valuable is this information and can the receptivity change in time? How long is the result of ERA test valid (lifetime or a certain time)?

ERA test helps us to evaluate the endometrium. When we have patients that have failed in previous treatments. Imagine that we have very good embryos that were transferred and they were euploid embryos or embryos from an egg donation, and we don’t know what’s going, we do the ERA test to see the window of implantation of receptivity of that embryo, and it helps us to give more time of progesterone or less time of progesterone to fit our patient in that specific time where the endometrium is more receptive. I don’t know if it’s going to change in time, but we think that it won’t because the ERA test is based on how your body reacts with some medication to the expression of genes that may favour. I don’t have anything that can make me think that it’s not going to be valid. If you receive the same medication in one month or six months and I understand that your endometrium is going to respond in the same way.

I’m thinking of using egg donation at IVI Barcelona. Do all IVI clinics have the same equipment, incubators and protocols?

We do have the same protocols in all the clinics and the same equipment. In IVI Barcelona they have excellent results, and we are benchmarking of all of our outcomes every month, so this is something that you can be sure.

What do you recommend to support/enhance the implantation process? Any extra medicines (beside progesterone), supplements, acupuncture, anything else?

I know that some things may help, but there is no strong evidence with any type of extreme medicine after the embryo transfer. We don’t recommend supplements accepting except the folic acid f. e. It is true that some years ago some studies said that acupuncture helps the implantation, but we don’t recommend it.

I’m considering twins? Do you think that would cause complication as I am 44?

It is not recommended to look for a twin pregnancy at any age, and if you’re 40 or over 40, the risk of complications like preeclampsia, diabetes, premature delivery is even higher, so I won’t recommend that. You should go for one single embryo transfer, and after that, you can go for the next treatment a couple years after that.

Are differences in progesterone quality, absorption depending on the kind of administration (intramuscular vs oral vs vaginal)? Any of them is better than others?

There is no specific answer to that. All the ways of the administration seem to be good, we prefer the vaginal way of a route of administration because it doesn’t hurt, the intramuscular option hurts as it has to be injected daily. In some countries and some clinics like in the United States, there are a lot of doctors that prefer using the intramuscular option. The studies right now don’t show any big difference between the different routes and vaginal option works really well.

I was receiving 1200mg of progesterone (3 x a day 2 capsules), is it not too much? (I was not feeling very well when taking it) with no successful implantation.

First of all, it would be interesting to know why you were receiving that high dose of progesterone because it’s not the normal dose that we use. Possibly, your doctor has seen a problem in your previous treatments or maybe a certain progesterone level that was not okay, and they didn’t have any other option. For us, it is not the usual way to start a treatment, we do that when a patient has a very low progesterone level during the luteal phase.

Is every IVF pregnancy a risky one? Are there higher risks to lose the pregnancy with donor eggs than with own eggs?

Not all the IVF pregnancies are risky ones, and the studies on the obstetrical outcomes are the same if you transfer one embryo between natural and IVF record system. There is no higher risk of losing a pregnancy with the donor, considering that the donor is younger than 35 years old, we have a lower risk of failure if everything is ok with the uterus, and you have no other complications, you don’t have more risk of losing the pregnancy.

We were lucky to have a baby (5-month-old) from last years through fresh embryo transfer even though I’m in menopause. We still have 3 embryos left for FET, we’re trying for another one when the situation with the COVID is better since it’s in Prague and we’re from the US. How will the doctors know which one is the best to transfer?

These frozen embryos that you have it will be very important to know if they are on day-3 or they are day -5, so if they are at the cleavage or blastocyst stage. We have physical characteristics of the embryo, morphological characteristics of the embryos, and they choose the best. If they don’t have any PGT done on them, it’s only based on morphological basics of the embryos.

How do you select your donor? Is it base on finance or voluntary? What is ethnicity, any blacks? If so, where are they from?

We have a very strong program for selecting donors. We select the donors because it is a voluntary act, they come here because you know that Spain is the number one country in the world for organ donation and for that same reason the donation of tissues and cells is very well seen by society, and they are all altruistic girls that come to give their eggs to other couples. In Spain, it is not allowed to pay for the donors, as it happens in other countries, so what we can do is have some compensation for all the inconvenience of going to the clinic and the travels and everything, but we cannot pay them. Everything is voluntary, and it is an altruistic act. Ethnicity depends only on the ethnicity of the receptor. If you’re Caucasian, you’re going to get a Caucasian donor. If you’re African, you’re going to get such donor. We do have black donors, they usually come from Africa, immigrants that come from Africa to Spain and they live here.

Do you have better results, and proven results that the pregnancy was achieved after adapting the ERA test result?

Yes, we have better results and some studies show that we have good results and some studies show that it doesn’t help. We recommend it if you had recurrent implantation failure after transferring good embryos and after studying everything else. We should have some information about the endometrial receptiveness. We have a lot of cases where we have used it, and after that, we think they have changed, so it’s a tool that we use, and we recommend it.

I have read stories of people transferring a PGT-A abnormal embryo but then having a healthy child. This does concern me, how could this happen?

This is a very hard question. It is not exactly a PGT-A abnormal, it is how you do the diagnosis with the PGT-A and how does the genetic lab does the interpretation of those results. What had happened in the last day years is that the technique the next generation sequencing (NGS) can see in mosaic embryos and these mosaic embryos have an implantation potential, and they do have the potential of giving a healthy child. We have changed that policy during the recent years, and after the deep genetical counselling, we are transferring mosaic embryos. In those embryos, all these cells in a blastocyst are not the same time, and it seems that the embryo can grow and give a healthy child, even though you can have more lines in chromosomes in the cells.
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Authors
Vanessa Vergara Bravo

Vanessa Vergara Bravo

Dr. Vanessa Vergara Bravo is an obstetrician-gynecologist. She completed her degrees in Colombia, Panama and Spain. She has been a Medical Coordinator at IVI RMA since 2014. Dr. Bravo is a Global Associate of Fertility and Sterility Editorial Board and a member of many medical associations, among others ESHRE and SEF (Spanish Society of Fertility). Between 2016-2020 Dr. Vanessa Bravo was a Coordinator and Professor of Clinical Module of Master in Embryology of European University of Madrid and also a Lecturer in National and International congresses/ workshops of SEF, COGI, ESHRE.
Event Moderator
Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.
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