IVF DE – a complete guide on phenotype matching and genetic inheritance

Stavros Natsis, MD
Fertility Expert at Gennima , Gennima IVF

From this video you will find out:

IVF DE – a complete guide on phenotype matching and genetic inheritance

Donor eggs and phenotype matching revealed

There are many difficult decisions when it comes to infertility treatment and – especially – IVF with donor eggs. Many patients cannot get rid of questions popping into their heads, like: ‘How are the egg donor and the egg recipient matched?’, ‘What about genetic inheritance?’, ‘Will the baby look like me?’ and probably the most important one: ‘Will the baby be healthy?’ In this webinar, Dr Stavros Natsis from the reputable GENNIMA IVF clinic in Athens provides a clear explanation of these terms. Dr Natsis starts by explaining that among all factors affecting fertility, woman’s age is the most important. Women are born with a certain amount of eggs and they grow older with them. A 22-year-old girl is at the highest level of her fertility, which is still only 25%. Three out of her four eggs have chromosomal abnormalities. At the age of 35, there is only one good egg out of five. Then there is a significant drop and at the age of 42, fertility level is only 4%, meaning one good egg every 20 eggs. Additionally, the miscarriage rate at the age of 44 skyrockets up to 50%. However, one has to remember that in the case of egg donation, a female patient’s age is not an issue. Dr Natsis states that patients coming for consultation often wonder if egg donation is a right decision for them. It is probably one of the toughest decision they have to make in their life. It is generally difficult to convince a woman that the quality of her eggs are not good and that egg donation is the only suitable solution. In this case it’s highly important to find a professional IVF clinic that has a lot of experience with the egg donation procedure and has high success rates. Then, there is the choice of an ideal egg donor. The donor is understood as a person who looks phenotypically like the female patient. It is also crucial that this person is healthy and has similar social, educational and religious background.

How donors are chosen?

Dr Natsis explains how donors are chosen. In Greece, egg donation is completely anonymous and a couple cannot find out the identity of the donor or see her present picture. In the same way, the donor has no idea where her eggs have gone. The procedure of choosing a donor starts with phenotype matching during which doctors have to make sure that the donor looks similar to the female patient. They choose donors out of a large database, focusing on those who have matching body type, hair and eyes colour as well as the smile. The clinic also conducts a thorough medical history including donor’s personal and family history. According to Dr Natsis, the donors usually are honest when they answer the questionnaire. However, if they tried to hide things, the questionnaire is made in a certain way that allows to pick up answers that are not true. Additionally, there are all the necessary blood tests for genetic conditions performed, like cystic fibrosis or muscular dystrophy, as well as for transmitted diseases like hepatitis, syphilis or HIV. Prenatal testing is also obligatory. If the couple is afraid of a certain genetic disorder, an additional genetic test can also be performed to the donor. Similarly, a donor can undergo a proper psychiatric evaluation conducted by psychiatrists. Of course, every donor needs to be screened for their fertility. The medical team will do all the necessary hormonological tests and the ultrasound scans. It would be good if a donor had already one child of her own as well.

HLA typing of donor

Dr Stavros Natsis refers to the HLA (Human leukocyte antigen) typing of a donor that many clinics offer today. It is a way to see if the donor and the recipient are matching immunologically. Although it’s not medically proven, some clinics use that in case they have recurrent failures with egg donation. Intended parents can also consider selecting a donor with a matching blood group – especially if they do not want to reveal the method of conception to their children. When the clinic finds the ideal donor, they inform the couple immediately. There are two ways of embryo donation: the first is a fresh cycle and the second is to a thawed embryos transfer. If doctors go ahead with the fresh cycle, they try to synchronize the cycle between the donor and the recipient. The donor receives injections of GnRH analogues in order to start the hormonal stimulation. At the same time, the recipient starts a substituted cycle where she is given mild hormone replacement treatment (oestrogen) that helps to build up the lining of the womb. The donor always undergoes a tailor-made stimulation according to their fertility assessment in order to take the maximum amount of mature eggs. Dr Natsis says it would be ideally to take more than 10-12 eggs. Then the eggs get fertilised with IVF or ICSI, depending on sperm characteristics. At Dr Natsis’s clinic, the embryos are put into the incubator where they start to develop. Clinics that have excellent results use new generation incubators which have time-lapse technology. Such incubators have slots for each embryo. After the embryo is inserted inside, the incubator will not open until the embryo transfer day. It has built-in cameras that monitor the way the embryo is developing. A big advantage of these new generation incubators is the fact that they do not open and they keep the stable microenvironment for the embryo development. Dr Natsis admits that they have seen quite a big improvement in the success rate by the time lapse technology. When the embryos reach day 5, they have to be transferred back to their mother. The Greek law allows clinics to transfer up to two embryos. In case there are additional embryos/blastocysts, they can be cryopreserved for a future embryo transfer or for a second attempt or another baby in the future. According to Dr Natsis, if the clinic transfers two good quality blastocysts, the suggested success rate will be of 70 to 75 %, irrespectively of a mother’s age. Eight out of ten times that two embryos are transferred, the pregnancy will be a singleton but two out of ten will be a twin pregnancy. If it is not possible for a patient to undergo a fresh cycle, the blastocysts are cryopreserved and the transfer is done later, with similarly excellent success rates.

Pregnancy after egg donation

A pregnancy following egg donation treatment is the same as all other pregnancies, either natural or IVF. The mother is advised to have all the necessary pregnancy scans and tests. According to Dr Natsis, the possibility for Down syndrome and other chromosome abnormalities is much lower as they are calculated on the basis of the donor’s age and not the maternal age. The general health status of children under 5 conceived with egg donation is the same as the one of kids conceived with standard IVF.

Egg donation – will the baby look like the recipient?

Dr Natsis goes on to answer the most important question asked by most intended mothers: Will the baby look like me? The answer is: yes. There are a few reasons for that.

Firstly, the clinics do their best when matching the donor with the recipient, both in case of phenotype and psychological preferences.
Secondly the role of Epigenetics is now at the centre of egg donation research. Epigenetics has demonstrated that normal development does not depend only on a healthy genome but also on a healthy environment that the baby’s growing in.

Dr Natsis gives a beautiful metaphor, comparing genetics and DNA to a musical composition.

Genetics is a score of a musical composition whilst epigenetic is how the orchestra interprets the score.

So summing up, although donor egg recipients cannot pass on DNA to their children, they can strongly affect their children’s genes. In fact, there are several data supporting beneficial effects of a healthy lifestyle during pregnancy on the developing fetus.

Should I tell my children how they were conceived?

Another very difficult question asked by couples is that whether they should tell their children how they were conceived. According to Dr Natsis, there is no right or wrong answer. It depends on various factors, including couple’s social status, their needs and how open they want to be about it. Dr Natsis also highlights that if for some reason the family needs to track down the donor, they can contact their IVF clinic. Clinics keep a database and they can easily find the donor, especially for medical reasons. You may be interested in reading: Telling kids they were conceived via egg donation In conclusion, Dr Natsis gives some tips on how to find an ideal IVF clinic. Most couples usually know from the first visit to a clinic whether they like and trust the team there. Additionally, all good and reputable IVF clinics should work under strict regulations and follow strict protocols. There are some organizations that can ensure the correct functioning of an IVF clinic, like ISO or ESHRE (the European Society of Human Reproduction). Other important things patients should pay attention to include whether there is easy access to the clinic, a dedicated egg donation team that speaks fluent English and tailor-made treatments guaranteeing that each patient is treated individually. According to Dr Natsis, Greece is an ideal solution for egg donation. It is not only a perfect holiday destination where one can prepare for their IVF treatment in a beautiful and relaxing environment but also a country with a lot of benefits (e.g. clear laws, experienced medical teams) and reasonably low treatment costs as compared to the UK and the USA.

Donor eggs and phenotype matching revealed - Questions and Answers

How is it that an excellent quality embryo doesn’t take on but a good quality one does ?

Unfortunately, it’s just biology. Today we can keep the embryos outside the uterus up to day 5. Some embryos are doing more than the right things up to day 5 and they can stop two days later, even if they are morphologically excellent. It’s really something weird. The embryologist usually selects the excellent quality embryos because statistics have shown that they have slightly higher percentage of achieving pregnancy. It doesn’t mean that the good or the medium quality embryos don’t have success rates. We have seen many times pregnancies from poor quality embryos or even from medium quality embryos. It’s biology. The morphology of the embryo is not an indicating factor for success. It helps a little with the selection of the embryo but it’s not something definite.

Does Gennima have a location in Mexico?

Unfortunately not at the moment. It would be great to have it there. It’s a sunny nice place. I’ll talk to the manager here and maybe we can arrange something. We are located in Greece but it’s easy to come here. Actually, we had a couple that came from Mexico and it wasn’t that difficult for them to travel here.

What do you mean by the study of phenotype? Do you make a match with the donor’s and receiver’s genes?

Phenotype is actually the way that we look. It’s our external appearance. We don’t match the donor’s and the receiver’s genes, we try to find physical similarity between them. Let’s say the receiver is 1,70 m tall and she’s 50 kilograms. Then we have to find the donor that is tall and slim as well. If she has green eyes, then we try to match the colour of the eyes, too. We try to match the hair colour. This is phenotype matching. There is no specific genetic test. It’s just using pictures and trying to see who looks similar to whom. Some clinics are trying to see if a donor and a recipient match immunologically. It’s like doing a transplantation: when you do a transplantation of the kidney, you try to make sure that a receiver has a compatible immunological system with a donor’s. It’s something like that as well. It has nothing to do with genes. It’s more like an immunologic aspect.

If the transportation of the eggs happens later (not at the same time with egg production), what is the procedure for the recipient? If the eggs are frozen, what happens with the recipient? Does she take medicines to be prepared? If yes, for how long?

It’s a common condition, especially with couples that e.g. travel from the United States to Greece. Sometimes it’s difficult to do the synchronization of the cycles and in that case we can proceed using frozen embryos. The procedure is very easy. Usually, a recipient informs the clinic of the first day of her menstrual periods and then she starts taking oestrogen. It’s a very mild hormonal replacement treatment. It’s usually two milligrams of oestrogen three times a day. The recipient can take it for about ten days and on day 10 we would perform an ultrasound scan. The ultrasound scan will show whether the lining of the womb has reached a certain level, let’s say nine millimetres. When she is ready with the thickness, then she starts taking another hormone called progesterone. She takes it orally for about five days. On day 5 of the progesterone we do the embryo transfer. These medications are very well tolerated. It takes about 14 days if we want to transfer day 5 embryos which are called blastocysts. The studies have shown that frozen embryos have excellent results, completely comparable with the fresh cycle. So it’s not a problem at all.

Is the 50 year old age (49 years old and 364 days) limit Greek law or is it clinics’ policy?

Exactly, it’s the Greek law. In some other countries they might be able to do that up to the age of 52 to 54. Unfortunately, here in Greece the law is very strict. When the age is 49 years and 365 days, we cannot do anything. However, we can transfer embryos one day before you are 50, but afterwards we cannot do anything.

How to prepare the best environment for the embryo as a future mom?

That’s a really good question. It’s very difficult to answer that in a short way. First of all when, women should choose to follow a healthy lifestyle. Nowadays women who are above 40 look as if they were 30 or 25 years old .The age is just a number, especially when they are following a healthy lifestyle. Exercise and healthy diet is the first step to create a very good environment for the embryo. And you should follow the same rules while you’re pregnant. Usually, before starting IVF procedure or egg donation, we give vitamins to help the embryo grow in a much healthier way. In terms of environment, we can do something to help the uterus. Before embryo transfer, some clinics can perform a hysteroscopy to help the embryo to be implanted and make sure that the lining of the womb is much more receptive. This needs a specific indication. But when using a short way, you can help build a good environment just by following a very healthy lifestyle.

Can you influence the DNA of the egg? There are some reports from Spain saying that the female carrying the baby can influence the DNA of the egg?

That’s a very good question. There are some experimental procedures at the moment which are the transfer of trunk DNA . It means that you can take the donor’s and the recipient’s egg and transfer the core that the recipient has into the egg of the donor after you remove the core there. So you just use a part of the donor egg and you keep the DNA of the mother. This is actually very experimental. The last Congress of the European Society of Human Reproduction that took place in Vienna stated that this still needs to be further examined. We cannot guarantee that it’s going to work or it’s going to produce a healthy baby. In experimental way, it can influence the DNA but it’s not something that we can use in the everyday practice. Maybe it will be possible to use it in a few years’ time if the safety of the procedure has been well demonstrated.

What is the percentage of success of egg donation over 45?

To be honest it’s excellent. Age is not playing any role when you go ahead with egg donation. If the whole procedure goes according to a plan and we collect a large amount of donor eggs and we have good fertilisation from the partner sperm, usually we’re talking about 70 to 75 % of success rate. This is a very moderate number with I’m giving you. Some studies have suggested even higher success rates, even in women that are 49 years of age. If it depends only on the quality of the eggs, we are talking about 70 to 75 %. Of course each woman is a completely individual person and we don’t know what’s going on with the uterus and whether the uterus is receptive for the embryos. Of course she needs to be healthy and she needs to do not carry extra weight. All these factors can affect the success rate. But if we’re talking only from the embryos point of view, we’re talking about 70-75 % so it’s quite high.

Is there a risk over 45 to transfer 2 eggs at a time?

Transferring two eggs, two embryos, it’s something that most of the clinics do but usually we recommend to transfer one. We know that the twin pregnancy carries risk, especially of pre-term deliveries and some additional stress to the body of the recipient. We have seen that the majority of women don’t have any problems transferring two embryos but what we would ideally want is to achieve a single-child pregnancy. We don’t mean only for women over 45 but for all the age groups as well. If you have excellent quality embryos, we would usually recommend to transfer only one. Of course in cases that we have failed in the first attempt, a lot of women want to transfer two to maximise the success rate. It’s something that we understand and we go ahead and usually we do not have any problems when we transfer two embryos. Even if we transfer two 8 out of 10 times, only one will continue. Only 20% of patients will have a twin pregnancy.

I am 43 and I know that odds of succeeding with own eggs are little. I just cannot accept that being in great shape, I cannot have influence on quality of my eggs. How are you helping to accept that and proceed with donor eggs?

It’s really difficult to convince someone that she might not be able to achieve a pregnancy on her own. Of course in medicine the doctors usually cannot say something with a 100% accuracy. Of course you can become pregnant when you’re 43 and no one can say that you cannot. It’s just the chances might be lower. Unfortunately, women are born with their own eggs and even if they do the most healthy diet and have the healthiest way of life, DNA is something completely out of our reach. We are born this way and there is nothing we can do to influence DNA to make it better. If that was the case, then people wouldn’t have cancer or other genetic diseases. The only thing that you can do is to keep up with your very healthy lifestyle. Because if you become pregnant on your own, then your baby is going to grow in very healthy environment. About the second part: how we are helping to accept that a woman is not able to become pregnant easily at the age of 43? We cannot do anything special to convince you. Daily we see couples that have had a long time trying to conceive. We see couples that have been trying for 10 years, they have done 10 times IVF attempts and they have failed and had miscarriages. Usually when you try and you’re not successful, it’s something that changes inside you. When we first discuss this, 99 %of women are completely negative of doing the egg donation. But after a while, when they do another IVF attempt and it fails or they have a miscarriage, women start to think in a different way. Usually we have noticed that women accept it easier than the partners. The partner is always a very important factor. Usually partners are a little negative but the circumstances make you rethink everything at the end.

Is there anything that you can suggest for the recipient to do in order to have the best environment for a more successful implantation other than the medication recommended by the clinic? Or should the medication be more than enough?

When we transfer the embryo, it has to be done on a certain day which is called the implantation window. We cannot transfer the embryo on any day we want because the uterus will think that this is an enemy and it will try to fight it. But the days on which we know the uterus is receptive are usually the 4 days following the ovulation. When we do the embryo transfer, it’s sometimes very difficult to identify the implantation window and that’s why sometimes we have to give medication to do a substituted cycle. There we can control the days on which we will do the embryo transfer. Many women don’t want to take any medication at all and go on with a natural cycle. This can work as well. The worst case scenario is not to be able to identify the implantation and wait until next month with transferring the embryo. Apart from medication and healthy lifestyle, there is nothing else that we would suggest for the recipient to do to have a better environment. Many women think that stress is a factor that they should work on. We agree as stress doesn’t help in anything. On the other hand, here in Athens the highest pregnancy rate was recorded during the second world world where stress was really high. So we cannot just say to people ‘Don’t be stressed’. Stress is always going to be there but it doesn’t play such a big role as we think.

I had an embryo transfer last week (embryo donation) and I found out today that I am pregnant. I am taking 800 mg of Utrogestan every day. Is Utrogestan not harmful to a baby? What about Progynova?

Congratulations, I’m sure your baby will be great and will be a healthy child. To be honest, in all fertility clinics we we use a lot of Utrogestan. For people who do not know, Utrogestan is progesterone. Progesterone is a hormone that supports the embryo. The reason is, in the pregnancy you have to balance the oestrogen and the progesterone levels. Oestrogen’s are quite high because of the whole process and you have to give additional progesterone to balance the levels and make the uterus keep the baby inside. It’s like hiding the baby. 800 milligrams is a normal dose. A couple of months ago in our congress in Vienna, there was a big discussion about progesterone and how we support the baby. It was shown that giving progesterone orally, at least 600 milligrams, is helpful for the first weeks of the pregnancy. So I can definitely agree that it’s not going to be harmful to your baby at all. Progynova is also progesterone. You can take it vaginally but the latest discussion suggested that it is slightly better when you take progesterone orally. Of course, if you have a lot of symptoms and you cannot tolerate it well orally, if you feel very nauseous or sleepy all the time, you can use Progynova vaginally. It could be a solution as well. But it’s surely not harmful to your baby. My congratulations again!

When you are 35 years old with FSH at 43 and AMH at 0.1 is egg donation the only way?

Usually we try many times to succeed with your own eggs. When you’re 35 and we know that you produce only one egg, you have about 20% chance of fertilisation and a healthy pregnancy. Here in our clinic we have seen that scenario daily. A lot of women come here with premature ovarian failure, because this is probably the condition in your case. Definitely it’s not easy but in your case we wouldn’t immediately go ahead with egg donation. We would do a few attempts with natural cycles. FSH, which is a follicular stimulating hormone, is 43 which means that your brain is forcing your ovaries to work a lot. We wouldn’t be able to give any other medication to produce more eggs. We would go ahead probably with a few natural cycles and if we couldn’t achieve anything, after six months we could discuss egg donation. But because you’re very young, you’re only 35, you have good chances. Maybe in a couple of months FSH might be lower, it can happen. We would recommend you to take some vitamins that have DHF. Some studies have shown that they can help improve the condition a little. And then we would try to do some natural cycles. If you got tired with natural cycles, then you could explore the other solutions. But you still have time for the egg donation.

Some clinics do not have embryoscopes. Does that reduce the chances of success ?

To be honest, it doesn’t reduce the chances of success. Each clinic should be obliged to show their results, they should send it to the regulatory organisation they belong to. Let’s say a clinic has 70% of success rate with an old embryoscope – it’s not going to become worse because they don’t have the new generation embryoscopes. It means that if they used the new generation embryoscopes, their success rate could go up to 80%. This is something that we noticed when we introduced the new generation embryoscope. We saw a significant increase in our success rates. What the embryo scope does, is like doing a pre-implantation testing and non-invasive re-implantation testing. It gives some additional information about the health of the developing embryo. It only increases the percentage of the success with the old embryoscope, it doesn’t reduce it so don’t worry about that.We are just ‘trying to find a non-invasive way to identify the healthiest embryos. At the moment we know that there is something called pre-implantation testing where they take some cells from the embryo. But this is an invasive technique. It might reduce the potential of the healthy embryo to grow because it’s like doing a surgical procedure. Again, it’s not 100 % accurate so we’re trying to find ways to work around it. We think the new step is using the new generation embryoscopes with time-lapse technology.

I have multiple polyps in the uterus. Would it be enough just to remove them via hysteroscopy procedure right before implantation? Or the biopsy needs to be done in advance?

I definitely agree the polyps is like having a foreign body inside your uterus. It’s like a coil, it’s something that will definitely reduce the success rate. Usually in our practice, when a woman has polyps, we would like to remove them one month before going ahead with any IVF treatment. Because by removing them with hysteroscopy and gently scratching the lining of the womb, we usually make the uterus more receptive. We have noticed that after removing polyps with a hysteroscopy or doing cervix curettage, success rates are a little higher because the lining of the womb becomes more receptive. We can reset some cells that live in the area called uterine natural killers and make them work within the normal range again. So my advice would be as follows: do a hysteroscopy a month before doing the embryo transfer, then remove the polyps and ask your doctor to perform gentle curettage in the lining of the womb to help the implantation.

What happens if the baby/child has some health issues in the future and the donor’s medical history is needed. How can this be gained if the donor is to remain anonymous?

That is the reason why you have to go to a well-established IVF clinic that works for a long time and it’s gonna be there for many many years. When we do an anonymous donation, the clinic keeps a track of the donors. We have very good database and the donors can always be found by the clinic. Let’s say, unfortunately ten years later the baby has problems, like e.g. leukemia, and we have to find a donor because they may be compatible to help with a bone-marrow transplant. In that case, the clinic will identify and find the donor and we’ll do all the necessary things but the anonymity of the family it’s going to be kept safe. This is the reason why picking up clinics that work in the right way is something that will help you and will ensure your and your child well-being for all your life. So it can be gained. Don’t worry about that, we have ways to do that.

In some clinics, especially in Greece and Northern Cyprus, they administer baby aspirin (100mg) once a day before and after transfer and until the 7th month of pregnancy. Does it have any side effects on the baby?

I agree it’s a common practice for many IVF clinics to give routinely aspirin. I have to say that when we give aspirin, we have to have a clear indication what we want to achieve. I want to reassure you that it doesn’t cause any harm to your baby even if you take it up to the 7th month, usually we stopped aspirin when you are 32 weeks of pregnancy. A recent study, that was performed by a very well known person that invented the nuchal translucency test, demonstrated that when women who are above the age of 40 take small dose of aspirin, it helps the invasion of the placenta. This way we avoid possible conditions like pre-eclampsia because a proper placenta actually helps to deliver a healthy baby at full term. For that reason in many places they give a baby aspirin for women above 40. In our practice, we usually do some thrombophilia testing and we decide whether we have to give aspirin or not. So we wouldn’t give it routinely but if you take it, it’s not gonna cause any problem to your baby. Don’t worry about that.

Is it safe to fly after the implantation? Sometimes I get menstruation starting after the flight.

Usually we advise our couples to fly two or three days after the embryo transfer. It is completely safe to fly and it doesn’t cause any problems. The moment the baby goes inside the womb, it’s completely protected. The womb is like a cage full of muscles that keeps the baby completely safe. If you have to fly after implantation, it’s not going to cause any problems. We just give you some instructions, like e.g. to be well hydrated. If the fly is very long, wear compression stockings and walk inside the airplane every 40-45 minutes. Sometimes, especially if you are later in the pregnancy, it may be a good idea to do a blood thinner injection on the day of the flight – just to be on the safe side. Usually a flight doesn’t affect the menstrual period, I don’t know why you get menstruation after the flight but it shouldn’t be like that. So my answer is: yes, it’s completely safe. Most of our couples fly two or three days after the embryo transfer. They even fly to Singapore and it is a 14-15-hour flight. Honestly, it’s not causing any problems at all.

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Authors

Stavros Natsis, MD

Dr Stavros Natsis is a fertility expert at Gennima IVF since 2017 and an associate of Dr Mantoudis, head fertility expert at Gennima IVF. He is especially interested in fertility preservation. Author of several clinical research papers. He performs monitoring scans and egg retrievals. International patients will meet Dr Natsis for their free Skype meeting and again when they come to Athens for their treatment. Dr Natsis' professional experience starts with Degree in Medicine by the University of Ioannina, MSc in High Risk Pregnancy by the University of Athens. Specialty in Obstetrics by the University of Athens. Clinical Research Fellow at the University of Oxford (Fetal Maternity Unit Department of Obstetrics and Gynaecology – High Risk Pregnancy Unit). He is also UK-trained in Gynaecological Oncology and Fertility Preservation (Senior Fellow). A warm and caring doctor with a big smile on his face. Thorough and precise, hard-working and passionate when it comes to helping our patients become parents. Fluent in English, great in communication and happy to answer all your fertility questions.

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