PGD in recurrent pregnancy loss

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Hans van der Slikke, MD, PhD:  “It’s April 2003 and we are in Berlin at the Controversies in Obstetrics and Gynaecology conference, and next to me is Professor Verlinsky from Chicago.  Welcome Professor Verlinsky!”

Yuri Verlinsky, MD:  “Thank you.”

Hans van der Slikke, MD, PhD:  “You have a very interesting presentation here, where you told us how PGD can help us in preventing recurrent pregnancy loss.  Pregnancy loss seems very hopeless now and then.  Can you tell us how PGD can help us to overcome this problem?”

Yuri Verlinsky, MD:  “I think we have to look at the basic of the pregnancy loss.  With pregnancy loss, we’re talking about the first trimester pregnancy loss where the majority of pregnancy losses occur, or by failure of the in vitro fertilisation they cannot get pregnant.  And what we know from the history of analysis of the products of conception in the first trimester was that 85% of them are chromosomal abnormal.  And I think this is the biggest contribution to pregnancy loss ,in the recurrent pregnancy loss, when we have chromosomal abnormality.  So by working this pre-implantation genetic diagnosis for chromosomal aneuploidia we can only transfer normal embryos in this way, overcoming 85% of the problem. 

By analysis of embryos before implantation by polar bodies, where we can analyse meiotic events in first and second meiotic division, we can look at the source of chromosomal aneuploidia abnormality and we have found that out this is 50% – 75%.  So by doing the analysis by fluorescent in situ hybridisation for the major chromosomes what is involved in recurrent pregnancy loss we can avoid, like I mentioned, 85% of sources of pregnancy loss.  Another contribution to recurrent pregnancy loss is chromosomal translocation, when patients carry an arrangement of chromosomes producing in 45% of the time abnormal offspring, abnormal conception. This we can diagnose also by pre-implantation genetic diagnoses.   

So by now we did around 2,000 of these kinds of diagnoses and we reduce recurrent pregnancy loss, let’s say in translocation patients, from 90% of the pregnancy where pregnancy with translocation was lost to 15% to 20%, so it is a huge reduction.  If you’re talking about the chromosomal aneuploidia, when we are analysing the five to seven chromosomes that can produce abnormal children and contribute to miscarriages, like chromosome 13, 16, 18, 21, 22, then we can do X and Y if it is necessary because some abnormalities come from X and Y.  Or we can reduce all this to the minimum like 85% chance to lose a pregnancy.   

If we are including in this kind of chromosomal studies, if we can do it right away, chromosome 15 and 17, we’ll probably increase the implantation rate.   So by doing pre-implantation genetic diagnosis from a chromosome sample aneuploidia or translocation we can increase implantation rates two to three times. Pregnancy rate with live born children double compared to the regular IVF population.  Like I mentioned, from the scientific point of view, if it’s 85% of chromosomal abnormal embryon induce first trimester abortion, that’s beneficial pre-implantation genetic diagnosis.” 

Hans van der Slikke, MD, PhD:  “That’s a lot!  You said you did the diagnosis from the polar body?  You are one of the few people in the world who use the polar body for PGD.” 

Yuri Verlinsky, MD:  “This is the topic of my second talk at this conference:  Polar body or embryo biopsy?  Why polar body?  I think polar body is the by-product of meiotic division.  First polar body is the by-product of the first meiotic division, and secondly polar body is the by-product of the second meiotic division.  And we know from molecular studies that 99.9 trisomies aneuploidy come from meiotic non disjunction.  So if I look in meiosis I actually cover 99.9 % of all events.   

So we were the first to introduce this kind of idea but it somehow was an indirect way to do it.  It’s like checking the garbage can to find out what is cooking.  That is because the polar body is extra material, never used in embryo development and by taking this you don’t do any harm to the embryo.  Plus you have a lot of time for analysis.  That’s why I feel it is very good.  But, you have to figure out what happens, because it is the opposite result of what is left in the egg.  So yes, you say, we’re probably one of the few who introduce polar body analysis.  First of all you have to take in account: if we are one of the few but still in world data probably only 8% of world data from polar body, because we do it probably 50% - 60% of our pre-implantation analysis.   

But anyhow, as it’s emerging in the world literature, I can show the polar body has a huge advantage to embryo biopsy.  But then if you want to cover all events and there’s many reasons, one of the reasons human embryo is mosaic.  Take one cell you don’t do diagnosis.  But because mosaicism comes from abnormal meiosis, that’s why you do it at meiosis, you resolve mosaic issue.  You have, like I mentioned, a lot of time for analysis.  Another thing you have: you don’t reduce the embryonic mass so that’s good.  But ideally if you want to look sperm contribution, it’s about 2% of abnormalities come from sperm you have to do polar body to have meiotic events and then take one blastomere because one blastomere alone is 10% misdiagnosis.  Ten percent misdiagnosis is not really contest.  But do a polar body it’s only 2% misdiagnosis because it’s from sperm.  So then if you add embryo biopsy you must come to 99% accuracy.  And that’s what we’re looking for.” 

Hans van der Slikke, MD, PhD:  “So that’s the reason you use the polar body?” 

Yuri Verlinsky, MD:  “Right.” 

Hans van der Slikke, MD, PhD:  “Back to the recurrent pregnancy loss.  Especially in IVF, but apart from that most women are getting pregnant without IVF, and many of them, especially when they get older, have many miscarriages.  After how many times of loosing a pregnancy would you advise to do IVF in order to do PGD?” 

Yuri Verlinsky, MD:  “That’s a difficult question.  The standard of care is that after two miscarriages you should do a chromosomal analysis of the parents to see if  there is a translocation.  I would say if you find in miscarriage and products  of conception aneuploidy, you should go to pre-implantation.  And the reason for this is because some patients, some women, have a higher tendency to have multi aneuploidies than other ones.  Not sure of the reason why, but it happens.  Like we have women who do not become pregnant with IVF, women who produce chaotic embryos.  That’s something in…and I think it’s polymorphic characteristic of the patient.  They have a tendency to have different trisomies.  We had a patient that had two miscarriages for different trisomies.  So what I recommended to this patient is 'you better go through IVF'. We did IVF with a normal embryo transferred, and she’s pregnant.  And you have plenty of cases like that.” 

Hans van der Slikke, MD, PhD:  “So this will become more and more an indication for doing IVF?” 

Yuri Verlinsky, MD:  “You know we do a lot of things now.  Yesterday I was thinking: we have sex for pleasure and IVF for reproduction.  But I think it’s just some kind of joke, it’s not true.  But the reality is it depends on the individual patient.  How much the patient can take, to have miscarriages, to have an abnormal pregnancy, to go through the struggle of carrying a pregnancy, no pregnancy and things like that, and some don’t want to take a chance and go right away.  Some of them will take a chance, they don’t want to have IVF done.  And I think that maybe we will find the reason of increasing non-disjunction in repeating miscarriage patients.  From molecular ones, then we can diagnose the reason why this happens.” 

Hans van der Slikke, MD, PhD:  “Don’t you think much of it is just the age of the egg?” 

Yuri Verlinsky, MD:  “No, no!  We want to find out… we were thinking first, what a lot of patients will reply to because the patient what is recommended prenatal diagnosis, the diagnosis for maternal age and in IVF population probably 50%  or 60% of women are 34 and older. 

These patients can go through pre-implantation for aneuploidy and have a double benefit.  You avoid Down’s Syndrome, the Patau and Edwards Syndrome, miscarriages, and on top of it you increase the chance to get pregnant : implantation like I mentioned almost doubles.  So it was first thought the patient that we found out, and we find increasingly a number of chromosomal abnormalities with age, up to 75% with age 40 and older.  But when we analysed younger women what happens? The number of chromosomal abnormal eggs probably is never less than 50%, but increasing different chromosomes.  What is  not increasing with maternal age.  So that’s what I think it is.  It is a unique mechanism that humans have: we use meiosis to regulate our reproduction.” 

Hans van der Slikke, MD, PhD:  “This is very interesting.  So this means that we have to find why and how we do this?” 

Yuri Verlinsky, MD:  “I think that definitely for every IVF cycle we have to do it.  There´s only one way to predict whether the embryo is healthy or not healthy.  There’s no other criteria at all, not morphological, not the developing stage, nothing works.  Chromosomal status is the only scientific proof of a healthy embryo.  It doesn’t prove that it’s 100% healthy but at least it removes unhealthy ones from being implanted. It’s probably 100% abnormality positive.  But if it’s abnormality negative, it’s not 100%, I would say 85%.” 

Hans van der Slikke, MD, PhD:  “You can never have this…?" 

Yuri Verlinsky, MD:  “That’s right.  You have to do this for patients with in vitro fertilisation for everyone.  The advantages are multiple, there are a lot of benefits from it.  You can have the embryos in your hands and you can analyse for a normal one. 

The other reason indications are increased with pre-implantation genetics for every single gene disorder is that with a family carrier of single gene disorders we can do a chromosomal assessment. We’re doing the late onset disorders, hereditary cases for cancer, for Alzheimer.  We now implement a pre-implantation genetic protocol actually typing for life saving for creating stem cells from umbilical cord to treat sick sibling.  So it expands, it expands all the time.” 

Hans van der Slikke, MD, PhD:  “That you very much for this interesting explanation.” 

Yuri Verlinsky, MD:  “You’re welcome.”