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Fertility preservation: when, how and what I can expect

César Díaz García, MD PhD Assoc Prof
Fertility Specialist & Medical Director
Category:
Egg Freezing
Fertility preservation: when, how and what I can expect
From this video you will find out:
  • What is oocyte vitrification, and how does this process work in the context of fertility preservation?
  • Is oocyte vitrification a safe procedure, and what are the potential risks or side effects involved?
  • How effective is oocyte vitrification in preserving fertility, and what factors can influence its success rates?
  • What is the efficiency of oocyte vitrification compared to other fertility preservation methods, and how many eggs should be stored to optimize future pregnancy chances?

 

Egg freezing - indications and outcomes

Dr César Díaz García, Medical Director at IVI Clinic London, is talking about fertility preservation and egg freezing – indications and outcomes.

Dr César Díaz introduces the topic by clarifying that fertility preservation can be done for many different reasons. People usually tend to think that it’s mainly to postpone maternity because of professional reasons, but the preservation techniques they use nowadays are mainly because of social reasons. However, in some contexts, it’s because there aren’t other options.

Egg freezing - indications

The doctor then explains that for a long time, in some countries, the freezing of embryos has been banned; therefore, when the patient wanted to accumulate chances of having a successful treatment, they had to freeze their eggs or, in order not to fertilize all the embryos, all the eggs that weren’t fertilized were spared and frozen. In addition to this, there are many cultures in which the freezing or generating of embryos isn’t allowed. Therefore, Dr. Díaz considers this, as another good reason to preserve eggs or sperm.

Another good and important reason to preserve fertility, according to the doctor, is when the patient undergoes a very aggressive treatment that will harm their fertility, one of the toxic treatments linked to cancer. For this reason, before undergoing chemotherapy, they can harvest eggs, ovarian tissue, and all those treatments considered to be fertility preservation techniques.

Fertility preservation – how does it work?

Dr Díaz explains that when they’re freezing, no matter what, the physical phenomenon of freezing is always the same. He then provides an example of what would happen to a cell when they freeze it:

It’s basically what will happen with a bottle full of liquid. So, if we freeze the bottle, the content will expand and break the bottle and will break the seal. So, it happens sadly the same thing when we’re freezing cells.

The volume of the water that’s inside the cell will increase, and the membrane of the cell can break. This happens because when the water is at a nice stage, ice crystals will be formed. The molecules of water will get together in a particular way forming hexagons, and there would be a lot of space in between molecules, and, therefore, the volume will increase.

To avoid that, cryoprotectants are used so that, even though the water is frozen, there won’t be the formation of ice crystals. For this reason, the water molecules will remain in a random state, meaning that they’ll mix and not be organized so that the volume will be less.

Nowadays, they do an ultra-rapid freezing method in which they add cryoprotectants and avoid completely the formation of ice crystals. This stage, in which the water will be solid but won’t form ice crystals, is called a “glassy state.”

The glassy state is what allows the doctor to freeze the cells without increasing the volume and without destroying the membranes that protect the cells.

Is this technique effective?

According to Dr Díaz, it’s effective, and it depends on how they measure the effectiveness and what patients expect. This is something he always explains to his patients, he says, “What do you expect? What is good enough?”
The Doctor goes on by showing a picture to state that people can see things differently. By referring to the picture, people can see things empty, full, or half full. This will depend on the information that the patient had before.

The egg vitrification technique, technically known as effect freezing used nowadays, is not a freezing process, but the crystallization of the water which is vitrification.

We have been using this technique since 2005. In IVI, we were pioneers in using this technique, we developed a very effective method with a Japanese company called Kitazato.

Oocyte survival rate

In all those years, they’ve been retrieving data together with other groups on the effectiveness of the technique. The first thing they noticed was that when they compared it with a classic freezing technique, which was a real freezing technique, and the ice crystal formation wasn’t avoided 100 percent, the survival of the eggs was much better.

It was as good as the survival of fresh eggs. Moreover, Dr. Díaz mentions the meta-analysis in the graphic to establish that they did the biggest randomized controlled trials (highest degree of scientific evidence), and both showed a better outcome when the egg was vitrified as compared to when the eggs were frozen.

Ongoing pregnancy rates

Almost 10 years ago, the doctor did a randomized controlled trial comparing the use of frozen eggs with those of fresh eggs. This study was done with eggs of the highest quality coming from donors. They randomized the patients, meaning they allocated the patients to have vitrified eggs and allocated patients to have fresh eggs. The outcomes were compared, and they saw that the pregnancy rates and ongoing pregnancy rates, which are very similar to life birth rates, in the vitrified egg group were 43 percent similar compared to the 41% in the fresh egg group.

This doesn’t mean that the vitrified eggs work better than the fresh ones, since the 2% difference cannot be attributed to the technique. However, this means that they are equivalent.

Is this technique safe?

The doctor explains that:

When we do fertility treatments, we’re talking about a lifetime plan, and safety is an issue that’s extremely important for us.

Potentially doing a technique like vitrification, can have some risks because the egg is a cell, compared to other cells of the body, is quite a big cell, so it contains a lot of water. As it contains a lot of water, it’s much more difficult to avoid the formation of ice crystals. The cryoprotectants can also be distributed unevenly in the cell, which means that part of the cells will be better protected than others.

It is mentioned that we need to be aware of the cryoprotectants used in the vitrification process because if used in very high contents and concentrations and not used properly, they can damage the cell. When the eggs are frozen or vitrified, the spindle can also be damaged.

The spindle is the structure created when the cells have to divide. It’s almost like a scaffolding that will divide the genetic material in two when the eggs are fertilized.

As there were a few factors to be concerned about during the process, the doctor wanted to see if the results that they had using the techniques were different in terms of those that could be obtained with fresh eggs. This technique has been used since 2012 in the clinic in New Jersey. They also experimented by comparing the chromosomal abnormality rates in treatments done with vitrified eggs versus fresh eggs. It was seen that there were no statistical differences regarding the amount of embryos they had at the end of the process and, most importantly, that the chromosomal abnormality rates in those embryos were similar regardless of the technique used.

Epigenetics

Epigenetics are molecular modifications of the genome that make people different. Dr Díaz goes on by explaining:

 

There’s a lot of data in the literature suggesting that any intervention that we do on the eggs and the sperm, could potentially change the epigenetic patterns of our genome.

There was another published study made in 2010 by Di Pietro’s group in which they compared the most important genes and their methylation patterns. They were the same. This is also called “housekeeping genes.”

Perinatal outcome

Dr César Diaz mentions that the most important things aren’t the molecular changes but how the babies look like, how the pregnancies go on, and if the patients undergoing treatments with vitrified eggs have higher risks of having complications. Moreover, the Doctor reassures that the data comes from their own clinic, with more than a thousand cycles analyzed.

  • The graphic below shows the comparison of the results of the pregnancies obtained in the clinic, until a certain point, using fresh oocytes or vitrified oocytes.
  • There were groups split into patients who had 1 or 2 babies, since it can also have an impact on the outcomes.
  • There were two groups separated: Patients who used their own eggs and patients who used donated eggs (it can also have an impact on the outcomes as well).

How efficient is the technique?

Dr Díaz goes on to explain that there are a lot of models comparing the use of vitrified eggs when patients do it at a younger age as treatments are done later on in life using fresh eggs. Some models combine different scenarios in which the patients can use their eggs and, if they don’t get pregnant, they can try for natural conception. Patients can also just try for the natural approach or, if it doesn’t work, try for IVF. According to the doctor:

If you do not succeed, you will probably continue trying.

In addition to this, Dr César mentions that there are also models in which there’s a comparison of potential scenarios. For example:

  • A patient decides whether to preserve the eggs or not.
  • A patient who later on finds a male partner or not.
  • A patient who has a partner and will try to conceive naturally or not. If not in the natural approach, she may use the eggs and may succeed or not.

When it comes to money, they evaluate the whole treatment and scenario using an index called ICER. They plot that, especially, against the age at which the eggs were frozen.

It’s worth mentioning that the treatments are very cost-effective when the patients do them in the second part of their 30s. Dr César explains this by saying the following:

If you do it before and don’t take me wrong, the treatment is going to be more effective, but it’s also very likely that you’re not going to use the eggs. Why? Because probably you will find a partner if you don’t have one, or maybe you’ll decide to use a donor’s sperm and then, you will not need to use those eggs that you vitrified.

He goes on by stating that only around 10% of the patients return to use those eggs. For this reason, Dr Díaz explains that it’s more cost-effective to do it a little bit later on in life. Nevertheless, it must be taken into account that if the patient does it later, although it’s more cost-effective, it’s less effective from a general point of view. This means that the patient will get fewer pregnancies paired with egg vitrified.

How many eggs to freeze?

The “survival curve” in which they can plot the chances of having a life birth or having a child as compared to the number of eggs needed to thaw after the vitrification. For patients below the age of 35, the more eggs they have, the higher the chances of having a live birth. This also happens for patients over the age of 35 but, after a certain number of eggs, if the patient didn’t get pregnant, it’s very unlikely to get pregnant. This is because of the chromosomal abnormalities linked to the egg and the age of the patient.

Therefore, Dr. Díaz states:

The older the patient is, the more chromosomal abnormalities the eggs are going to carry.

This is something that cannot be bypassed if the treatment is done later on in life.  In general, Dr. César doesn’t advise patients to freeze eggs after the age of 40, but it will be reassessed case by case. For patients between 36 and 40 years old, it usually works quite well as well for patients under 36. There is a link in which people can introduce their age and the number of matured eggs they have, or have retrieved, to calculate the chances of having one, two, or even three children. This is because the patient may not need the eggs for a first child but, even though the patient conceives naturally the first child, they may like to use the eggs for a second or third child.

The amount of eggs they can retrieve per treatment for ovarian stimulation will depend on the ovarian reserve of the patient. This is also linked to age, but not always. Therefore, the average amount of eggs they can get from patients below the age of 25 to 40, or more than 40.

Nevertheless, there is a lot of interindividual evaluation of the ovarian reserve. So, when a patient goes to the clinic, the first thing the Doctor does is to evaluate the ovarian reserve using an ovarian reserve marker called AMH (Anti-Mullerian Hormone). Based on the body’s AMH, for example in lower ranges, it can be predicted how many matured eggs are going to be collected. On the other hand, in the upper ranges, the figures shown by the Doctor change significantly. This is always informed in an individualized way, depending on the values of the patient’s AMH.

Most patients who go to the clinic to do treatments are around the mid or late 30s because that’s when people usually socially need it, meaning that people start thinking about conceiving.

Summary

As a summary, Dr Díaz states the following take-home messages:

  • The vitrification works very well.
  • It’s a very safe technique.
  • It’s very cost-effective if people do it in the second half of their 30s, but they have to always keep in mind that the younger they are, the better results they get.
- Questions and Answers

When is the best time to freeze your eggs?

This is a kind of question that I cannot answer. The best time is not based on a medical aspect, from a medical point of view, the younger you are, the best. From a practical point of view, patients will freeze their eggs whenever they think that they need it. If you are f. e. are in a stable relationship and you are very young, and you are thinking about having kids tomorrow so to speak, probably you don’t need to freeze your eggs, especially if you only want to have one child. On the other hand, maybe you don’t know when you’re going to be a mom, and you don’t want to be in a rush, anytime is a good moment to freeze your eggs. It really depends on the characteristics of the patients and also on personal preferences, so in order to answer this question, I think we need to know more about the personal circumstances of the patients.

How many cycles would it take to freeze the right amount of the eggs at 30?

In fact, we have two questions here. The first one: what is the right amount of eggs depends on your ovarian reserve, and it also depends on how many children do you want to have. If you are thinking only about having one, you don’t need to freeze as many eggs as if you want to have more than one. Having said that if you have a good ovarian reserve which is the case in a patient at the age of 30, most of the time one cycle of ovarian stimulation will be enough to have a very good chance of having at least one live birth. If you are thinking about having more than one more child, maybe you will need to do more than one round, and this is what you can see on one of the graphics that I showed you before. Let’s say for one child, at the age of 30 usually one round of IVF is needed.

If you are to use your frozen eggs. What is the process of getting pregnant?

The process is very simple, especially from a medical point of view. When someone wants to use the frozen eggs, we need to fertilize them with the sperm of the partner or with the sperm of a donor, and we do that by doing ICSI, which means Intracytoplasmic Sperm Injection, so we take the egg, and we inject directly one spermatozoid inside, we do not do a classic IVF, we do not let them mix naturally, because after the freezing process the external shield of the egg what we call the zona pellucida becomes so hard that the eggs spermatozoids cannot penetrate it, so we need to inject the egg inside, and we do that in the lab. Then we let the embryos grow, and after five days of growth when the embryo reaches what we call the blastocyst stage, we put it back into the womb. To put it back into the womb, we previously prepare the uterus to be receptive, to do that we just basically give pills, mimicking the natural cycle, so basically natural estradiol and natural progesterone. There is no need for injections at that point. It’s very friendly, it usually takes about 15 days, then we put the embryo back, to put the embryo back there’s no need of sedation, we can even do it in a consultation, we usually do it in the operating theatre, just beside the embryology lab because we don’t want to move the embryo and 11 days later you will do a pregnancy test.

Is there a significant drop-off in fertility over 35. I am 34. Is it best to do it before 35 or would you say the difference is minimal between 34 vs 36?

We usually tend to present data in a categorized way, so we tend to do groups, but age is what we call a continuous variable. It does not mean that for example after 35 everything is going to be dramatically different, so everything drops slightly step-by-step, so obviously the younger you are, and you do it, the better results you’ll get. A two-year delay, when you are 34 as compared to 36, it will have an impact, I cannot say the opposite, but the impact is not going to be as high as for example if you compare 38 versus 40. Then the gap even it is the same time interval, the gap is huge. In terms of results, I will say that at that specific point around 35 it is when things they really get to drop a little bit quicker, so if you are already thinking about it and you are 34, my advice would be to do it now.

Is there an age limit for freezing your eggs? Is it so possible and worth it to freeze eggs when you are over 40?  

Obviously, we really respect the right of the patient to decide it, as far as the patient has the information to make a decision and if the patient is aware of the chances at such age and if you want to do egg freezing, it is a very valid treatment. It happens quite a lot that the patients cannot become a mom, or they don’t want to become a mom at the age of 40 for many different reasons, and maybe they are considering doing it 1 or 3 years later. What I can tell you for sure, is that whenever you try one or two years later is going to work much much worse, so if you already know that you are going to postpone your maternity, it is better to freeze eggs at the age of 40 than trying to do a fresh IVF at the age of 42, that’s for sure. Then the results that you can expect are not going to be those of a woman at the age of 35. The pregnancy rates are going to be lower but still, we can achieve very good pregnancy rates. So at those ages, we usually have a very deep discussion with the patient to give very realistic information about what they can expect, we give figures based not only on their age but also on their ovarian reserve. It’s not the same being 40 years old and has 20 eggs in one cycle, then being 40 years old and getting only one egg, that can also happen. The scenarios can be very different in the same age group.

Is it true that the survival rate of frozen embryos is higher than the frozen eggs?

Yes, it is true. It’s not so different f. e. the embryo survival rate in patients who have euploid blastocyst in our clinic is 98%, and the survival rate of vitrified eggs below the age of 35 is between 90- 96%. Having said that the survival rate of vitrified eggs after the age of 38 f. e. is lower than that, it is around 80-85%. Then also you have to be very conscious because people think that it is better to generate embryos, so my chances of having my fertility preserved is going to be higher, that is not true. If you confirm everything at the beginning of the process, let’s say today before you have started the process, what is going to happen is that when we do the ovarian stimulation, we are going to have much more eggs than embryos. Then when we retrieve the eggs maybe not a 100% of them are going to be mature, but even those that are mature, not 100% of them will fertilize and not all the embryos that are fertilized the first day will reach the blastocyst stage. We only freeze the embryos at the very end of the process which means that f. e. in a patient at the age 40 years old on average we usually vitrify 2 to 3 blastocyst, so yes those blastocysts will survive better than the eggs, but you should compare the chances of having a baby with 10 vitrified eggs as to those having a baby with having 2 or 3 blastocysts because that’s what we usually get. The thing with vitrified embryos is that you will be 3 or 4 steps ahead in the process. You will probably know how good are your eggs because it can also happen that you vitrify your eggs, they look beautiful, but you have to be aware that 15% of the population have fertility problems. What if you are within these 15%, very likely you will find out about it until the moment comes to using the eggs. This is why when I talk to my patients, I always say, please keep in mind that even if you have a lot of eggs, we cannot guarantee a 100% success rates because that’s almost impossible in biological science. The problems can happen in between, and obviously, the more you are advanced in your fertility journey, the more information you will have. So vitrifying embryos is more reassuring in a way that you will have more information, but from a practical point of view at the end of the process you will get to the same point, but you will know it before. There’s also another implication especially if the patient is in a relationship, they usually tend to vitrify the embryos using the sperm of the partner and then there is also very important implication because while the eggs strictly belong to the patient, the embryos belong to the couple so both partners, so for whatever reason the patient’s they Split, it can happen that even though they have embryos, they cannot use them in the future because they need the permission of the partner to do so. Unfortunately, in my experience when couples want to get permission to get the embryo back is quite difficult.
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Authors
Picture of César Díaz García, MD PhD Assoc Prof

César Díaz García, MD PhD Assoc Prof

César Díaz, MD PhD Assoc Prof, is a Medical Director at IVI Clinic, London, UK. He has completed his medical training in Spain and Sweden. Dr. Díaz is Board certified in Endoscopic Surgery (ESHRE). From 2009, he joined the Swedish program of uterus transplantation and was a part of the first team to obtain a live birth from uterus transplantation in 2012. In 2013, Dr. Diaz returned to Valencia and led the Valencian Program for Fertility Preservation, which is one of the most internationally recognised programs of fertility preservation for oncological patients. He was also part of La Fe University IVF program, the largest Spanish public IVF program, performing more than 2000 IVF cycles/year. He combined his medical duties in the field of fertility with his surgical activities at La Fe University Hospital within the fertility surgery unit and gynae-oncology units for national referral centres. His main research interests are ovarian rejuvenation, fertility preservation, with a special interest in ovarian cortex transplantation, uterus transplantation and poor response in IVF. Within his fields of interest, he obtained numerous awards, several grants from the Spanish Ministry of Health and the Valencian Health Agency as well as from different private institutions. He is a former Associate Editor of Human Reproduction (2013-2016), and he has published more than 100 peer-reviewed scientific papers and book chapters.
Event Moderator
Picture of 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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