Preimplantation genetic testing – patient’s guide

Alpesh Doshi
Consultant Embryologist
Preimplantation genetic testing - patient's guide #IVFWEBINARS
From this video you will find out:
  • What benefits of preimplantation genetic testing there are
  • What are the most common disorders that PGD looks for
  • What type of patients generally decide on PGD
  • How to differentiate between PGD and PGS (PGT-A)
  • If it is worth applying PGS on every patient
  • Why ovarian reserve test (ORT)is important in terms of PGT
  • How IVF has changed in times of Covid-19

All you need to know about genetic embryo testing - PGT

Preimplantation genetic testing helps the embryology team to identify which embryos are chromosomally normal and can be used for the embryo transfer. But are such techniques for everybody and who benefits most from them? In this webinar, dr Alpesh Doshi, Consultant Clinical Embryologist & Co-founder of IVF London, walks us through the journey of IVF and explains why genetic testing has become an important element of it.

IVF is undeniable one of the fastest-growing and most cutting-edge areas of medicine. And although one can have a feeling that we are still at the tip of the iceberg in terms of how many discoveries have been made, a lot of treatments and procedures – considered impossible about 20 years ago – are in common use nowadays. It is especially true about preimplantation genetic testing. The idea of testing human embryos for genetic disorders has revolutionised the concept of infertility treatment – but still, it is not free of pitfalls and risks.

Forms of reproductive genetic testing

Dr Alpesh Doshi starts his presentation with differentiating among various forms of reproductive genetic testing. The first one is preconception testing – when a couple knows that one of them carries a genetic disorder, they may decide to get tested to find out if the disorder is going to be transposed over to their offspring. Other forms of genetic testing in reproductive medicine are preimplantation genetic testing (when patients have their embryos screened for a genetic disorder) and prenatal genetic testing (meaning testing the pregnancy to see if it’s got a genetic disorder or not).

According to dr Doshi, out of the three mentioned forms, preimplantation genetic testing is the most important. The reason is the fact that we simply do not want a pregnancy affected with a genetic disorder to start at all.

Pre-implantation genetic diagnosis – the advantage

PGD, preimplantation genetic diagnosis (nowadays referred to as PGT-SR and PGT-M) means screening for a specific genetic disorder that a couple may carry. The most common disorders that PGD looks for are: cystic fibrosis, Tay-Sachs disease (in Jewish couples), breast cancer, thalassemia (mostly prevalent in Asian couples) and sickle cell anemia (occurring in Afro-Caribbean populations most often).

Dr Doshi pays our attention to the fact that a lot of those disorders may be transposing over from generation to generation and persist in the form of a carrier status. It means that although each partner of the couple alone may feel perfectly well and may not be influenced by a particular genetic disorder in their daily life, they are at a risk of having an affected baby. And that’s where PGD comes in. It is the screening of a specific gene mutation which a couple may be aware of having. By using this procedure, they make sure that they will not pass over these faulty genes to their babies. Dr Doshi says that one of the most important advantages of PGD is the possibility of eradicating specific genetic disorders in the future generations.

Dr Alpesh Doshi stresses that not all patients that undergo PGD are necessarily infertile. However, they have to go through the IVF journey in order to collect eggs and create embryos they want to screen. Their main goal is to identify embryos without genetic conditions to be transferred using IVF. Some of these couples may even already have an affected child – and then, thanks to genetic testing, they may bring to life its ‘saviour sibling’. The latter term means a second baby born from a tested embryo that can save the life of the baby number one. And although dr Doshi admits that the issue of saviour siblings raises a lot of controversy and ethic dilemmas, he says it also perfectly illustrates the breakthrough and possibilities that PGD has brought into reproductive medicine.

Reproductive options to consider

Luckily, nowadays the patients who know that there is a genetic aberration in their family history (possibly resulting in inherited disorders in their baby) have much more options than only taking a reproductive chance or remaining childless. They can either get pregnant naturally, have a prenatal diagnosis and then risk having a termination (if the baby or the fetus is found to be affected from the genetic disorder) or have preimplantation genetic diagnosis to screen the embryos before transferring them in the IVF procedure. Dr Doshi says there are over 300 genetic disorders that can now be screened for at the embryonic level – and this number is still growing. The other options include going for egg or sperm donation (depending on which partner in a couple carries the genetic disorder) and adoption.

According to dr Doshi, the decision-making process is often governed by various factors. Patients sometimes try to identify what is the age of onset of the disorder. If it is a very late-onset disorder – and it only affects the life of a child in their 30s or 40s – they may take a goal not to do the genetic testing. Alternatively, they may look at the penetration rate of the disorder, the fact whether it is very severe or not and make sure that there are medications, treatments or prophylactic surgeries available.

All these factors also play a role in a couple’s decision making whether they want to go through PGD or not. Dr Doshi says that patients who choose the PGD-route are mostly those who have an objection to termination, infertility issues and repeated miscarriages (due to chromosomal abnormalities) or a history of terminations (because of affected fetus).

What PGS is about

Preimplantation genetic screening (PGS), also called preimplantation genetic testing for aneuploidy (PGT-A), checks whether all the chromosomes which are necessary for the embryo to develop normally are present in a balanced manner.

The most common chromosomal abnormalities that PGS is testing for are:

  • trisomy 21 (Down syndrome – when the embryo has three sets of chromosome 21),
  • trisomy 13 (Patau syndrome)
  • and Edward’s Syndrome (trisomy 18).

All of them can result in live births but – unfortunately – they are quite debilitating in terms of the health of the resulting child.

While PGD is looking for a very specific area on the DNA to see if there is any specific genetic disorder that a couple may know of, PGS looks at the total number of chromosomes that are present in embryonic cells. In other words, it is picking up abnormalities which are related to whole chromosomes rather than specific locations on the DNA. And this plays an enormous role in the whole IVF procedure.

Dr Doshi says that half of the embryos that are potentially produced in an IVF laboratory are chromosomally abnormal. This may be the reason why patients fail to get pregnant. Embryos with chromosomal variations may simply not implant or – if they do implant – lead to miscarriages later on. The role of PGS is screening 23 pairs of chromosomes for chromosomal errors called aneuploidies – and excluding them from the embryo transfer. Dr Doshi admits that if a genetically normal embryo (the so-called ‘golden embryo’) is transferred, then there is a much higher chance of pregnancy and a live-birth.

PGS stages and indications

In order to conduct preimplantation genetic testing, IVF is a prerequisite. It is so because the lab has to produce embryos to perform the biopsy on them. The latter is done by taking a small sample of the embryonic cells from the external layer called the trophectoderm (that gives rise to the placenta). The final and the most important stage is the cell diagnosis when a genetics laboratory does the complex genetic testing on the cells.

Generally, PGS (PGT-A) is advised in couples who have either had repeated implantation failure or repeated miscarriages. It is also recommended in case of women over the age of 38 or 39 who would like to optimise their chances of getting pregnant and shortening the time to pregnancy. However, dr Doshi reveals that many clinics in the US are routinely applying PGS on every patient as an embryo selection tool. And, in fact, a lot of patients and doctors would probably agree with such an approach – especially, since even younger patients may produce a small proportion of chromosomally abnormal embryos as well.

Understanding IVF journey

In order to map and join the whole process of IVF together, dr Alpesh Doshi goes back to its beginning – namely, the ovarian reserve test (ORT). Everything starts with the female patient having anti-Müllerian hormone checked as well as antral follicular scan done to see how many antral follicles are present in her ovaries. And in the process of preimplantation genetic testing, the number of eggs is crucial. Dr Doshi says that in cases of some patients, the rarity of finding a normal embryo is quite large. It results from the fact that in some genetic disorders, it is easy to find a lot of normal embryos while in others, it is not. That’s why ORT is necessary at the outset of the IVF journey to tailor the stimulation plan, the ideal number of cycles to offer and a starting dose of gonadotropins.

There are, of course, some exclusions in reference to IVF treatment, such as very low (less than 18) or very high (more than 35) BMI and patient’s age. It is known that the older the woman, the higher the number of chromosomal abnormalities. That’s why it is strongly recommended that IVF should not be used in women over 50 (and in case of using donor eggs – over 55).

Dr Doshi emphasises that the process of IVF starts off with the consultation. And there are various elements of counselling involved in the treatment, such as emotional support, genetics counselling, or virology testing (sexual health screen). The process of stimulation starts on day 2 of a woman’s cycle (the so-called short protocol) and lasts 12-14 days. Typically, a patient would attend the clinic every two to three days for a scan to see how her follicles are growing. Once those follicles have reached a good size, there comes a procedure called egg collection (or egg retrieval). Afterwards, an embryologist fertilises the eggs in a laboratory. In IVF, the egg and sperm are left in a petri dish to fertilise on their own. In ICSI, one sperm is directly injected into the egg. The latter is recommended when there is a severe male factor infertility, including low sperm concentration, poor motility and blockages in the male reproductive tract. The fertilisation process results in the formation of an embryo that undergoes a number of cell divisions in vitro. Nowadays, embryo development is continuously monitored by time-lapse photography (EmbryoScope). It maintains constant embryo culture environment and provides information not seen with static observations. The desired stage for the embryo to develop to is the blastocyst stage (day 5 to 6 embryo) – this is when it gets biopsied for genetic testing.

After the biopsy, the embryo has to be frozen. And the necessity of doing a frozen embryo transfer (FET) in probably one of the limitations of the preimplantation genetic testing. However, according to dr Doshi, it should not be a matter of any concern. The current freezing procedure called vitrification works perfectly well. 98% of embryos go through it without any harm and there is enough evidence that pregnancy rates achieved with frozen embryos are as good as in case of fresh embryo transfers. Dr Doshi reveals that it is more and more popular amongst clinics nowadays to move towards a frozen embryo transfer. Many studies have shown that frozen cycles are more popular as the levels of hormones are lower and patients are less at risk of ovarian hyperstimulation syndrome (OHSS). Additionally, it is worth adding that the UK’s Human Fertilisation and Embryology Authority (HFEA) recommends an elective single embryo transfer in order to reduce multiple pregnancy and risks associated with it.

IVF in times of Covid-19

At the end of his presentation, dr Doshi refers to one of the most often discussed issues in the field of assisted reproduction nowadays: the relation between COVID-19 and IVF. He reassures that fertility clinics worldwide are doing everything they can to minimise the risk of any transmission of the virus in between patients and between patients and staff. Social distancing measures, as well as disinfection and cleaning of the lab and the rooms between patients are the norm. Staff and patients undergo screening for COVID-19 and regular triangle and if patients become COVID-positive during their IVF journey, their treatment may have to be postponed for later. Telemedicine is in common use and lot of the appointments, such as nurse’s and doctor’s consultations, collecting consent forms or issuing prescriptions will be done digitally via teleconferencing. All of this is done to assure patients’ safety and peace of mind in current turbulent and difficult times.

- Questions and Answers

I have an implantation failure diagnosis and embryos with PGT always result in a negative transfer or a biochemical pregnancy. The embryos were from one cycle. The doctor has tested sperm with the FISH test. Could it be a problem with embryos? Should we make the Fertile Chip? I am 35 and my husband is 40.

You’ve asked some very vital questions. You have had and implantation failure and you have also said that you’ve had a biochemical pregnancy – so what you presumably mean is that you haven’t had a pregnancy to term. I’m assuming that it has obviously been a missed miscarriage. I would definitely suggest that both you and your partner have an initial genetic test called a karyotype done. It’s simply a blood test to make sure that you or your partner are not carrying a genetic disorder that you are unaware of. I’m sure that it is normal and if it is normal, then I would suggest that you do end up screening your embryos in the next cycle with PGS. Doing the FISH test of the sperm may not give you the entire story because it’s not always the sperm that results in chromosomal abnormalities in the embryos. It could be the eggs as well and sometimes it’s also post-zygotic or purely derived from the embryo – and it has not even necessarily to do with the egg or the sperm. The embryo just develops these genetic disorders as it develops. So I’d certainly recommend you to do PGS. I believe your question about the Fertile Chip refers to a sperm DNA fragmentation test – selecting the healthiest form. Although the evidence is very limited, certainly there is no harm to use it.

Is PGT-A or PGS recommended for donor eggs fertilised with my partner’s sperm?

It’s a very good question because in theory, if a donor is young, there shouldn’t be a need to screen the embryos. But we know that although the rate of genetic abnormalities in young women is very low, it’s not zero. Some people have suggested that even in young women, you can have around 15- 20% of the abnormal embryos. I want you to understand that genetic abnormalities are simply part and parcel of embryos developing – but yes, their rate is much lower in younger women. I presume that when you’re talking about donor eggs, you mean eggs coming from a young donor – so then the need for genetic testing would be quite low as they are bound to produce quite a few healthy eggs. But that’s not to say that there are no genetic abnormalities. I have known patients who have combined genetic screening even when using donor eggs. Hence, if you really want to shorten your time to pregnancy, you can do it.

I am 40 and my partner is 43. What important preimplantation testing should we be doing on our embryos, considering the fact that these tests are very expensive?

You are right, the tests are expensive. Typically, having PGS as an add-on to your IVF cycle can cost up to 500 pounds for embryo, depending on the number of embryos you have. Again, there is a cap on it so many clinics would not charge you over a certain amount. Certainly, at IVF London, we charge for an embryo and then we have a cap over a certain number of embryos that patients do not get charged for more. But you’re absolutely right in saying that this is an expensive technology. However, you’re 40 and your partner’s 43 and – although I’m not saying that there isn’t a sperm related genetic impact – we know that in women over 40, the chances of chromosomal abnormality can be quite high in their eggs. So it would not be wrong to suggest that you may see a benefit in using PGS as a combination to your IVF treatment. What you want to prevent is just transferring embryos and then finding out that either the cycle has not worked or, most importantly, you get pregnant and it results in a miscarriage – which is the thing you absolutely do not want to go through. So this is where PGS really has the edge, in my opinion.

My question refers to egg donation and PGT. There is a test called KIR – testing the immunological compatibility between a donor and a recipient. Would you advise to do this test to prevent preeclampsia later on?

This question actually sits out of my experience as an embryologist because I’m not an immunologist. So I would kindly ask you to ask this question to an immunology specialist. I appreciate that there’s quite a bit of immunological testing going on in reproductive medicine nowadays and again, a lot of it is very controversial. We don’t know whether it actually does have a benefit in terms of the outcomes or not. I would certainly recommend that you speak to someone independent who knows the subject well and is an expert in immunology. It’s definitely out of my boundaries.

How debilitating is hemochromatosis 63 Asp identified in HFE if both a donor and my husband have it? I’ve been told it may affect the children of parents who are over 40/50 years old.

Firstly, there are so many different genetic disorders that it’s almost impossible to keep on top of every one of them. Presumably, you’ve had genetic counselling over a specific genetic disorder which is hemochromatosis. So it would be very important that you essentially follow the guidelines of the genetics counsellor. As doctors or embryologists, we would not know the conditions or the impact factor of every genetic abnormality or chromosomal abnormality because there are hundreds of them – especially in case of a single gene mutation and this is a single gene mutation. So I would strongly suggest that you seek genetic counselling which I’m sure you’ve potentially already had. If you need to know the penetration rate in your embryos is, I’m sure the genetics counsellor may have said if it’s 25%, 10% or 50% of your embryos that may be affected. So all of this will really have to be factored in, before you decide whether you want to have pre-implantation genetic diagnosis. And if it’s a very late onset genetic disorder, some couples may wonder how severe its effect is. So they can take a calculated call on whether they want to combine preimplantation genetic testing for this specific genetic disorder.

Could multiple hereditary osteochondromatosis cause implantation failure?

In my opinion: ‘no’ because this sounds like a single gene mutation. But as I said earlier, it would be difficult to know each and every genetic disorder because there are hundreds of them. Again, I would seek the opinion of a genetics counsellor because they can review what we call the genetics report. If either one partner of the couple is the carrier or both of them are carriers, they need to look at what the recurrence rate is. So do seek that opinion from a genetics counsellor, especially if you know that this specific genetic disorder sits in the family’s history. I don’t think this has to do with an implantation failure – but it may have. So please make sure that you do seek an expert opinion from someone who has worked with this specific genetic disorder.

I have read stories of women in the U.S. insisting on transferring a PGT abnormal embryo (not mosaic) and who have given birth to a healthy baby. This concerns me – how can this be explained?

I will explain this to you. You have said ‘not mosaic’ – generally, in the UK we would not transfer abnormal embryos. Let me just say that no technique is infallible – no technique has an accuracy rate of 100%. With PGT-A, there is 98% accuracy rate in terms of what the cells are going to be. And then just the biology of embryos is such that some of the cells around the embryo are not going to be all uniform in terms of the genetic complement and there may be some cells in an embryo that may show some abnormalities. Again, it is very little known about the fate of such embryos called ‘mosaic’ embryos. What a mosaic embryo means is that by and large, there are normal cells which are genetically normal or healthy but there are also some cells that have shown some form of genetic abnormalities. And this is what adds the hammer in the works: because these embryos have both kinds of cells, they are categorised as mosaic. The true fate of these embryos has been unknown. Certainly, after genetics counselling, patients may have the right to select what we call a low-grade mosaic embryo where there are more normal cells and very few abnormal cells. Some people believe that – to a certain extent – we are all mosaic. Every human being is mosaic because the cells in our body are not necessarily all showing the universal genetic complement. Some cells in our kidneys may be showing different genetic complement from those in our liver so the tissues that we may have in our body may show variations and so on. Again, this may not be an abnormal concept when it comes to the development of the embryo because there will be some level of abnormal cells which are going to be sent to different parts of the body – so we can pick this up via mosaicism. But this is where the complexities of the results lie. I want to reassure viewers by saying that mosaicism is between 3 and 5% – it is not as high as 40-50%. However, in the UK we are not allowed to transfer a genetically abnormal embryo. In your question, you made a reference that you’ve heard of someone having an abnormal embryo transferred in the U.S. I’m not sure if this strictly refers to an abnormal embryo or a mosaic embryo – but, on the other hand, you’ve been very clear in saying it’s not mosaic. In such a case, I would find it very difficult to accept a clinic transferring an abnormal embryo – because who would be taking the risks then?

I am a carrier for Hereditary fructose intolerance ALDOB c.1005C > G (p.Asn335Lys) Autosomal recessive. I’m also a carrier for Leber congenital amaurosis 10/ CEP290-related disorders nCEP290 c.5493delA Autosomal (p.Ala1832Profs*19) recessive. Will this have impact on me in later life ?

You carry multiple genetic aberrations and we would need to know the impact factor of all these individual genetic conditions. You would have to meet a genetics counsellor and they would have to look at the penetration rate. Sometimes people carry a genetic aberration but the penetration rate may be very low so it doesn’t affect their lifestyle in any way. They simply carry this mutation but they have a very normal lifestyle. We also know that the same genetic disorder is very multifactorial and you would need to have an expert opinion – especially because there are two conditions here that you’re talking about. I would certainly get an expert opinion with a consultant clinical geneticist and with a genetics counsellor. But your first port of call should be a consultant clinical geneticist.

Would you suggest PGT with an inversion on chromosome 9 p12q13? I am 35 years old, I had 3 miscarriages with IUI and IVF. Would egg donation be a better solution for me?

You’re talking about an inversion of a chromosome. I believe that most likely your miscarriages are due to this chromosomal rearrangement. Unless these have been natural miscarriages, what I would suggest you to do is to start the procedure by contacting a fertility clinic that does PGT for structural rearrangement (PGT-SR) – so it’s actually preimplantation genetic diagnosis (PGD) and not PGS. I would firstly get in contact with the clinic that does PGD, then they would send your genetics report – which you have because you clearly know where the breakpoints in your chromosomes are – to the genetics laboratory which is going to do the genetic testing. They will be able to say whether they have a test ready that can screen those breakpoints. Only the genetics lab will able to give you the clearance because there could be so many different breakpoints and sometimes you may have to wait for about two to three months whilst the lab optimises the protocol. So the genetics lab will tell the clinic whether PGD can be done on this specific breakpoints. If it can be done, then bingo! You should certainly go for PGD if the attribution of those miscarriages has to do with those chromosomal breakpoints and chromosomal rearrangements – then your best bet is to go towards PGT-SR. I wouldn’t go for egg donation that fast. But again, it’s totally your call. Yes, one of the options is to change the eggs, especially if you know that you carry that chromosomal rearrangement. But if you haven’t had any kind of genetic testing on your embryos, then it might be worth attempting it first in the pursuit to have your own genetic child.

I often hear the argument by clinics who perform PGT-A that older women who produce only a few embryos should not have PGT-A – but if they produce multiple embryos, they would advise it. Why would the advice differ based on the number of embryos produced? Surely the reason for PGT-A is the same for both scenarios?

You’re absolutely right. You know, there could sometimes be variable recommendations about PGS in younger women or older women. I want to kind of remove some haziness around this decision making and just to give you some information on what’s the basis around the numbers game. So as you know, as women grow older, their ovarian reserve declines. Younger women may be able to produce a lot more eggs. We know that for any kind of preimplantation genetic testing, it’s important to have big numbers – as a rule of thumb, the probability of finding a normal embryo is much higher if you have more of them. For example, if you have five blastocysts, the chances of you having a normal embryo are much higher than when you have one blastocyst. So this ties in with the recommendation that, if you do have a lower ovarian reserve, your doctor may recommend you not to have PGS. However, in my opinion, I would still feel that these are the women who are older and yet potentially don’t have the satisfying ovarian reserve, that are more in need of PGS. So what I generally recommend these patients to do is to have multiple cycles of IVF – we call it embryo banking. For example, if we know that in one cycle you can only typically produce four eggs and you may only have one embryo being formed every time, then my recommendation would be to attempt multiple cycles of IVF. During each of these cycles, we’d be trying to get four eggs every time, create an embryo and freeze all those embryos. And once we’ve frozen all the embryos, we do a biopsy on those embryos – all at one go – to identify which one is the normal embryo that we can transfer. So I would not take away PGT from all the women with low ovarian reserve. I would rather encourage them to consider what we call embryo banking.

What is your take on non-invasive PGT-A? Since apparently there is DNA in the blastocoele fluid of the blastocysts and in the spent embryo culture media. Is it as accurate as the traditional biopsy method?

This is a very good question and I’m absolutely super amazed at our audience today. I must say that there is so much amazing knowledge and this question has blown me away because this is such new science. If someone talks about non-invasive PGT, it means they are really on the ball! Basically, non-invasive PGT-A is a very novel technology which is still under validation. You are right, embryos – when they develop – release some DNA in the fluid in the middle of the embryo called the blastocoele fluid. This fluid is in the middle of the embryo and it has the DNA which may subsequently enter the culture media in which the embryo is growing as well. When it comes to what non-invasive PGT-A is: it is literally just taking a sample of that fluid or the culture media in which the embryo is growing and sending it to the genetics lab rather than performing any kind of invasive biopsy which can potentially damage the embryo. Again, as I said, if done by skilled hands, a biopsy wouldn’t damage the embryo, but there’s always a theoretical risk – like in every invasive procedure. Here we’re talking about the process where there is no invasive procedure. We’re literally taking that spent culture media and sending it to the genetics lab and they’re doing the genetic analysis. Now to answer your question: this is still under research and development. We believe that this technology is still about a year away from being applied clinically. The technique is very promising, I must say. In fact, a few days ago I’ve just had a conversation with the genetics lab that is developing this technology for clinical use – to apply it with patients. They told me that the robustness is just over 80% at the moment. For any procedure to be clinically validated, we want the robustness or the validation to be over 90% accurate – so I think there is still some time to go. More studies need to be done on the accuracy of this test as compared to the current invasive tests that we’re doing. But watch the space and I’m sure that next year or in a year-and-a-half, non-invasive PGT-A is going to be a clinical reality.

What is the cost of PGT?

Typically, doing PGT-A, which is aneuploidy screening, is around 500 pounds per embryo but clinics can be quite variable in their charges. At IVF London, we charge 500 pounds per embryo but there is a cap of 3300 pounds at the most, after which – regardless of the fact if have five embryos or ten embryos – you would not pay more than that. So that is the top level that any couple would be spending if they’re having PGT-A. But if they only have one or two embryos to biopsy, they’re only going to be charged for an embryo – which is 500 pounds.

I am adopted and have a normal karyotype. Could I be a carrier of a genetic disease that causes my implantation failure? Should I have a genetic test in my case?

Certainly, if you’ve had multiple implantation failures, it might be worth for your clinic to investigate your reasons for a failure to conceive. I would suggest that the karyotype is one of such tests that both you and your partner need to have before you go through any further treatment. If you live in the UK, then your clinic may refer you to your GP and your GP could do all these tests. So from a cost perspective, you would not be subjected to more costs – because the tests such as the karyotype are not cheap.

I am 41. I had 3 cycles of IVF last year with PGS due to my age and history of type 2 DM. In the first cycle, 2 abnormal embryos. In the 2nd cycle, 4 abnormal embryos and 2 of quality insufficient for interpretation. In the 3rd cycle, 6 abnormal embryos and 3 of insufficient quality again. What are the possible reasons for ‘quality insufficient’?

I understand when the patient is saying ‘quality insufficient’, it means that there was not a conclusive result that was obtained for the embryo. However, I’m quite amazed at such high numbers. I’m presuming that in your third cycle, you had nine embryos out of which six were abnormal and three were inconclusive or could not be diagnosed. I find three out of nine to be a quite high number. I would really question the biopsy in the first place and most importantly, I would also question the genetics lab. Again, we want to make sure that the clinic where these procedures are being done is very robustly equipped. A biopsy is a very skilled procedure and it requires a lot of expertise. Some embryologists take very few cells which may not be enough to get a result. So the reasons could be very far and wide. I’m sorry it doesn’t help you but certainly, in case of getting three out of nine embryos inconclusive, I would really start questioning why it is so high. Inconclusive results are very rare – usually we would get a result from every embryo. In my experience, 99.7% of the embryos give a result. I’m not sure what you mean when you say ‘quality insufficient’. Did you mean that they did not reach the blastocyst stage so a biopsy could not be done? In such a case, it is quite expected. Not every embryo is going to make it to the blastocyst stage so if ‘quality insufficient’ means that an embryo did not make it to a blastocyst, then that’s normal. I would not question anything there. But if it means that there was a biopsy taken and there was no result, then that would concern me.

How accurate is PGS? What is the margin of error?

It’s a very good question. I think every patient deserves the right to know this because it’s important that patients embark on choosing PGS knowing what its flaws can be. No technique can be 100% sure and PGS is also not 100%. The accuracy of PGS is anything from 95% to 98%. There is that small rate of error whereby there could potentially be a misdiagnosis of an embryo. The genetics lab is basing the diagnosis on just a very few cells and as I explained earlier, there are concepts in the embryos where all the cells may not be uniform – you may be taking a snapshot of an embryo from one side and yet the other side is showing a completely different genetic status. This is not necessarily a flaw of the technique but it is simply the dynamics of embryonic development. So I think the answer to your question is that PGS is quite accurate because it does translate into pregnancy rates which, in my opinion, are actually quite high. If there was a high level of inaccuracy in the technique, then the pregnancy rates would not sit hand-in-hand with the whole technique. We know that when we get genetically normal embryos, the pregnancy rates are expected to be very high.

Are there any tests that I can do if I have an underlying health condition (hypothyroidism, prediabetes & my partner has thalassemia) and I don’t want my baby to have it?

It depends whether thalassemia is a major problem or not. Again, you need to be seen by an expert consultant geneticist. If you completely want to remove the carrier status of the thalassemic condition, then yes, by having PGD, you can select embryos which are completely free of even the carrier status. As you know with thalassemia, it’s a condition where two carriers have to potentially come together. But as I said, I’m not an expert at all these individual genetic disorders. I would certainly recommend that you take expert advice from a consultant clinical geneticists before you plan your family. If you are planning to have kids, you definitely want to remove this gene from your gene pool, even if your partner is a carrier and even if your child can potentially only be a carrier. Otherwise, the risk still would be there for the baby when he or she gets married and they carry this gene – they would have to make sure that their partner is free from being a carrier. That’s why many patients just choose to eradicate the gene, once the technology is available to do so.

My PGS normal embryo failed to implant even though I have had immune testing, receptivity testing and all physiological errors ruled out. Is it possible that my eggs are of poor quality metabolically?

A genetically normal embryo or a golden embryo doesn’t necessarily mean there is a guarantee of pregnancy. We know that even with PGS, the top success rates that are published by many studies are around 70% – so there’s still a 30% chance that the embryo may not implant. Unfortunately, a miscarriage or a failure to implant is not necessarily only related to the chromosomal status of the embryo. By large it is, but it is not the only reason why embryos fail to implant. Of course, you’re referring to having immunological tests done, etc. but these are simply majors. If you’ve just had one failed embryo transfer where a golden embryo was transferred and it did not implant, it may simply be a chance. So if you do have another golden embryo in the freezer, it might be worth giving it another shot. As I said, the chances of pregnancy even with euploid golden embryos are around 70% – they’re not 100%. And you have made a reference to the embryo quality as well. Obviously, I don’t have that information but if the embryo quality is a bit more inferior, then it may also be the reason why these genetically normal embryos may not implant.

Whats about NGS techniques when comparing PGT-A and PGT-M?

For PGT-A, the technique used nowadays is next-generation sequencing. PGT-M is relating to PGD for a single gene disorder or monogenic disorder – that’s why it’s called PGT-M because M refers to monogenic. For example, when I say ‘monogenic disorders’, I’m referring to what we call a single gene mutation, such as cystic fibrosis, thalassemia, breast cancer, etc. For the monogenic disorders, the technique used by the genetics lab is called karyomapping. So these are different genetic tests. Of course, it still relies on some key basic principles of amplifying the DNA from a single cell or the small cluster of cells that are taken out of the embryo. So the basic principles are the same but the platforms are very different. There is no one test for all – it really depends on the test and the genetic condition that is being looked for.

With embryo banking in advance of PGS, do you need to defrost the first batch, biopsy it and then re-freeze it? Or can the biopsy be done on the fresh embryos of the first batch which are somehow stored later on until the second batch is ready?

It’s a very good question and you’re absolutely right. It is definitely a possible strategy as well that embryos can be biopsied fresh and the cells that are biopsied are then stored in a -80 (degrees) C freezer. If the cells are stored in -80 degrees in the freezer, you can batch the cells which means that there would be only one freezing process that the embryo would have to go through. But routinely, many clinics do embryo batching or embryo banking in a following manner: they freeze the embryos, they defrost the embryos, take the biopsies and then they re-freeze the embryos. We know that refreezing embryos works perfectly well. There is absolutely no risk apart from a very tiny risk that the embryo may not survive the freezing process – but it’s less than 2% risk. Both the strategies are very viable and it can be done either way.

Is there a risk of damaging a blastocyst when taking a biopsy resulting in it no longer being able to be transferred? Clearly it would be extremely upsetting if results would come back showing it was good for the transfer.

You’re absolutely right, there is always a risk – even in the best of hands. However, in my experience, I have not seen an embryo damage as a result of a biopsy. I teach the biopsy procedure around the world, I go around training embryologists around the world to do this procedure which is a highly skilled procedure and I know there are some embryologists who do damage these embryos – so it can happen. And you’re right, it would be very upsetting if the only normal embryo that you had was damaged by the biopsy. You have identified that there is a risk and in my opinion, this risk is theoretical. If you go to a clinic where they know what they’re doing and how they’re doing it, then these risks are very negligible.

I am looking at genetic testing of the NF1 gene but the clinic will test for the common 5 chromosomes (including NF1) on day 3 of the embryo instead of day 5 – and then it will do the transfer within the same cycle. Is this type of day 3 testing (instead of day 5 testing) okay?

No, I do not recommend the embryos being tested on day 3 for various reasons. Firstly, there have been enough studies that have shown that if you’re going to be testing for the five chromosomes on day 3, you will not get accurate results. As much as you may test for the NF1 gene, when it comes to the common chromosomes X, Y, 13, 18, and 21, you are not going to get accurate results which may lower your chances of getting pregnant. So there is no reason why the clinic you are at cannot do a day 5 biopsy unless they have the skills to do it. he most common way of doing it – and how every clinic should be doing it – is on day 5. As I said, I’m quite fortunate that I travel the world teaching this technology and I condemn day 3 testing because it is inaccurate. There are a lot of drawbacks about testing embryos on day 3 and I think it is within my responsibility to guide patients not to have their embryos tested on day 3, just because they want a fresh embryo transfer. Yes, in this way you will have a fresh embryo transfer but you are not really going to be doing justice to something that you’re really highly investing in – which is the genetic testing. And that’s what’s really important. So don’t worry about the freezing of the embryos and having a frozen embryo transfer. Please make sure that the diagnosis that you’ve been given is absolutely accurate and robust.

Are embryo biopsied for PGS (which have not reached the blastocyst stage) more likely to return as ‘quality insufficient for interpretation’?

A very good question and my answer to this question is: yes, if the embryos have not made it to the blastocyst stage, we know that the most likely reason for it is a chromosomal disorder or a chromosomal error. The embryos that do not make it to the blastocyst stage, have chromosomal errors and hence, they have stopped growing in the laboratory. So the answer to the question is: yes, most likely these embryos are not genetically normal.

Is NGS different to PGT?

NGS is a technique that is used for PGT. PGT just stands for preimplantation genetic testing and NGS is a specific methodology for PGT – and so is karyomapping. So the technology of testing is called PGT and the specific test that does the PGT is called next-generation sequencing – NGS in short.

You’ve mentioned it’s good to make sure that the lab we’re using is of top quality. How can you check this yourself?

When I say top quality, I mean everything that I’ve explained in terms of the expertise and the embryologists. If you as a patient want to determine the standards of the laboratory, the best way is to look at what their pregnancy rates with PGT embryos are. So ask them for the stats: what is the pregnancy rate in patients who have had PGT? Look at what the miscarriage rates are as well because this is where you’re really going to get that information from – whether the clinic is specialising in biopsying human embryos or not. Because, as I said, if the expertise is not there, you could be doing more damage than good to those embryos.
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Alpesh Doshi

Alpesh Doshi is a consultant Clinical Embryologist and a co-founder of IVF London. He is also a co-founder and director of the Embryology and PGD Academy. Alpesh previously worked at the Centre for Reproductive and Genetic Health in the leading capacity as a Director of Embryology for 19 years and was pivotal in optimising the success rates. He was also an honorary consultant at the Reproductive Medicine Unit at UCLH NHS Trust. He holds a postgraduate degree in Human Reproductive Medicine and has qualified from the prestigious Imperial College School of Medicine. Alpesh is a Diplomate of the Royal College of Pathologists and also an ESHRE certified Senior Embryologist. He has been an executive committee member of several international embryology societies and holds a very active interest in promoting education platforms through these professional bodies. He was among the first scientists to bring the egg and embryo freezing technology of ‘vitrification’ to the UK in 2007. He is a world-renowned expert in the biopsy of human embryos for genetic testing. Alpesh has authored several papers in high impact journals and written several book chapters in addition to being an honorary lecturer at University College London where he teaches embryology on two of the Master’s courses. He has been an invited speaker in many international conferences and workshops as well as several Health chat shows on television including Zee TV and ITV’s This morning. Alpesh has a special interest in fertility preservation, preimplantation genetic diagnosis and genome editing of embryos.
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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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