Understanding egg and embryo quality in women over 40

I have to say yes. Well, one thing is chromosomal abnormalities, and another thing is genetic abnormalities. In PGT-A, we don’t see the genes, we see the chromosomes. After PGT-A, the genetist will say: number 1 has 46 chromosomes, it’s normal. Number 2 is, as we said, chaotic because there are abnormalities in chromosome pairs 2 and 21 and 22 and 14. And the other one is euploid, it’s normal. And number 4 has an abnormality in chromosome 14. That is 100% sure, what they’re saying.

A different thing is when the embryo may come with a genetic problem. For example, cystic fibrosis is a genetic disease. A baby born with cystic fibrosis has 46 normal chromosomes, but there is, in a chromosome, a bit of a protein change, and that causes the disease.

I don’t know what the patient says about the genetics, whether they say those are genetically normal or abnormal. But if we are talking PGT-A or PGT-M, we are not looking at the gene; we are looking at that particular disease.

If we’re talking about PGT-A, the report says: this embryo comes with an abnormality. We don’t know why, only 56% of those normal ones will lead to a pregnancy, and another 40-something will not give a positive pregnancy test — what’s going on? Is it the biopsy that has damaged the embryo? Or is it because the embryo is far more than just chromosomes? That’s a question to be resolved.

Yes. That is what we call mosaicism. Nowadays, we do the biopsy, the geneticist does the biopsy, and sometimes they report that this embryo is a mosaic. It means that they have some cells that are normal cells and some abnormal cells. As the embryo goes ahead and becomes more complicated, it may get rid of those abnormal ones and go ahead with the normal ones.

That’s why, after a PGT-A, if we have 5 embryos — let’s say 4 euploid and 1 mosaic — the geneticist will tell us: yes, leave the mosaic for last, but you may transfer this particular one because those abnormal cells are not compatible with life. The most it can cause is a miscarriage, but it cannot lead to, say, Down syndrome, Edwards, or Turner. If those abnormal cells are compatible with life, nobody can bet whether the embryo is going to divide the bad ones or the good ones.

It’s something very common — not all cells in an embryo, in those mosaics, are exactly normal. That is a criticism of PGT-A, where we cannot study all the cells of the trophectoderm, just a group — I don’t remember if it’s six or twelve — and maybe you are just putting the needle in a place where all the cells are normal, but then there’s another area where many are abnormal. And vice versa. Embryos may get rid of the bad ones, and that’s something we assume they are doing very often.

I don’t see the age here, but I understand you had 6 embryos transferred in 3 separate transfers — so every time, you had 2 embryos transferred — and had 2 biochemical miscarriages.

Is the issue egg quality?
We cannot say that. Look, now we are facing a very common problem. Every week, we have to talk about this with patients, and it is related to the guidelines for the failure of implantation. There are different definitions, but one of them is that a woman aged 37 or less who has had 3 embryos-3 — 3 blastocysts of good quality—and didn’t get pregnant, or a woman older than that with 3 PGT-A euploid embryos and she didn’t get pregnant. For one reason or another, that is a very complicated case.

Because then, that causes a lot of anxiety in women, and in doctors, like: “Now what am I going to do with this woman?” The first step is to recommend PGT-A. The first thing is to check: are we transferring normal embryos or not, euploid or not? Then it becomes necessary to send the patient to a haematologist to see if she needs heparin, aspirin, etc.

Then comes the uterus — what part is the uterus playing? I mean, hysteroscopy to check if there is chronic endometritis, endometriosis, dysmorphic uterus — anything that may prevent the embryo from implanting. Then, the people who are very keen on hysteroscopy think this subject is the most important one. If the uterus is even slightly abnormal, they say, “That’s the reason why she’s not getting pregnant.” Then we publish that, and women, desperate, read it on the internet and come saying: “That’s the reason I can’t get pregnant — because my uterus is this way or that way — or because I don’t take heparin.”

Now with haematology — because that’s another subject, also related to failure of implantation — we send the patient to the haematologist. Then they ask for a very large block of tests. If something shows up, they recommend heparin. If nothing shows up, they still recommend heparin. In a very empirical and non-scientific way.

Then the last point is the immunological system, where the doctor and patient are not compatible, and the body is rejecting the baby. There are many theories. This subject has been criticised. There is nothing clear about it yet. Then that woman ends up in a very stressful situation. But I would tell her: yes, so many embryos transferred — the first step is the next one. She’s got good ovarian reserve, a large number of embryos to study. The first step would be PGT-A, and see what we have in our hands.

If all of them are abnormal, then we say something is wrong. Maybe it’s my husband. Maybe it’s me. Then we study the husband. It has not been demonstrated — the European society does not approve yet — the scientific reasons for doing DNA fragmentation or FISH chromosomal study of the spermatozoa. But we have these kinds of tests — like karyotyping — to see if it’s the husband or not.

That’s a very complicated subject when the woman reaches that point. As I said — and I don’t want to repeat myself — the next step is to analyse the embryos.

Because you have a polycystic ovary and you are offering such a large number of eggs, it is inviting you to do it. If you had an AMH of 0.5, then the question would be: okay, don’t do it anymore — try to go to egg donation.

Here, you say: “Well, if we are able to get 14–15 eggs,” then remember the statistics. We say that at 41, one out of 10 oocytes may come out normal. So that invites you to repeat. If you had done just one retrieval, 41, 42 years old with a polycystic ovary, then it would be very tough to say, “Go to egg donation.”  I would do PGT-A, in my opinion, above all when we have such a large number, probably of blastocysts, to discard those that are not going to give a pregnancy, and to give us some information.

How to answer that? As I said, we have to think case by case. The bad thing: you are 41–42. The good thing: you have an excellent ovary.
I mean, why not? We are going to find a good embryo if we have such a large number of eggs. Yes, there’s a chance — a high chance.

We don’t use mini IVF or natural cycles. I’ve never found any reason to do that. I mean, if a woman is able to give 4 eggs, why are we going to go with 1? That thing that was proposed — that less is better — has been demonstrated not to be true. I mean, we saw that before.
Remember: 4 eggs at less than 35 — if we have 4 eggs, we have more chances to find the good one.

To give more than 300 units of FSH per stimulation, it has been demonstrated that this is not worth doing. I always use the stimulating cycle, not giving very high doses of hormones, but enough to obtain what she is able to give me. Of course, I’ve got cases. Because when you work in this field, you see the whole range — women with just one follicle who say, “Doctor, it doesn’t matter. You have explained to me what my chances are, but I want to try.” She goes with one.

So there is no point in giving a lot of hormones — just enough to grow that follicle properly. I don’t do natural or mini IVF. I’ve been told that this mini IVF or natural cycles were invented in Holland. Where it was said that a woman with good chances, less than 35, with probably blocked tubes, etc., may go through 6 low-profile IVF cycles. Then it’s low-cost, no need for anaesthesia, no need for hospital, and because of her probabilities, after six cycles with no FSH or very low doses, it’s very cheap, etc. — then a 30-something per cent will get pregnant after that period of time.

Those who haven’t reached the standard will go to the standard one. It’s been designed for that very good prognosis woman, not for the others.

The first thing is that AMH is not true. You see, it’s been, they took the blood and left it on the table for some time, or it reached the lab later, and it’s been degraded. It cannot match 0.14 with 6-9 follicles, because of what we explained before.

Again, that’s why I said it’s better to do the ultrasound scan rather than just AMH. AMH may give you an idea about things, but it has to be rechecked with an ultrasound scan.

Then, 1 or 2 of them were mature. Then there are 2 reasons for that: the age of that woman and how she was treated.
I mean, sometimes we have these sorts of results. All specialists who work in reproduction, we have better and good results in our life, and when we face this low rate of maturity, then our option is to say, “Okay, next time we are going to try the trigger with two different hormones — with analogues and with beta hCG, or similar — to try to get better maturity.”

Sometimes that maturity or that lower number of embryos comes because, well, she may have 6-9 follicles. The first thing that caught my attention is that the AMH doesn’t match.

Not at all. Because we are not entitled to transfer it. A chaotic or not chaotic aneuploid embryo, just an embryo proven by PGT-A by a geneticist that the number 17 has 3 chromosomes, which is not compatible with life, and we are not going to transfer it.
Because it will not be ethical.

I’ve probably transferred many of this kind, but I didn’t know because that woman didn’t do a PGT-A. By doing PGT-A, there is no way. I mean, this embryo goes to the trash, because this is not going to give a pregnancy at all.

You’re talking about the maturity of the eggs in the lab. Yes, to obtain MI’s, not MII’s to perform the retrieval when the follicles are 14 mm, for example, or 13, instead of more than 17.

I don’t have that experience. I will tell you that we do artificial in-lab maturity when — just — we have, in fact, last week we had one case where there were six mature ones and another seven or eight immature. Those were left, and they became MII mature eggs in the end, and then were fertilised. I think that from that group, she got one more embryo.

As I said before, my cut-off line for not treating any patient is 44. Once they are 43, 45, we say we are not going to do it because we have never seen a pregnancy. Then, you’ve already had — if I read well — 10 IVF. I mean, you have gone to the theatre 10 times. I think you’ve done enough for yourself. After 132, I mean this is far more than enough to say, “I give up,” and I go for another way, which is egg donation.

I mean, and this is telling, what we said before about the number of eggs and what we said with another patient. This is a bad thing — that you have such a good ovary in number, but age is age. Those eggs are not coming well. I mean, you’ve done a lot — I mean 10 IVF — it’s time to change, in my opinion, and go for egg donation if you are prepared for that, and not to do that anymore.

If you want to analyse them to biopsy embryos, that’s okay. But use those. If you don’t get pregnant, I would not go again for another retrieval for that.

Implantation depends on the quality of the egg and the quality of the endometrium. We have to improve implantation, as we may do at any age.
I mean, not only in a woman more than 40, because a woman less than 40 may have a very bad endometrium, and a woman more than 40 may have a very nice endometrium.
So, analysing: can I do something for the endometrium? Can I do something for the embryo? Treating you one way or the other.
After 40 — how can we improve it? By trying to get the best of the ovary, waiting for the month when that woman in particular is coming with the best number of follicles to be used, and being very careful and very delicate with the embryo, with a natural cycle if possible, and doing things well, preparing the endometrium.

Then, that’s another subject — whether we should have platelets in the uterus or not in case of poor implantation. That’s a very complicated thing, but just to try to do things as well as possible.
Even now, the probiotics, vitamin D, things like that — ESHRE says that nothing has been proved about the chances of increasing success by doing something in fertility.

At the moment, we are living in a time of fertility where many things that were assumed to be nice, that were useful, now seem not to be doing anything. We have to keep all this in mind.

In my career, I’ve done many things. There was a period of time, years ago, where something was published in the States about Filgrastym, which is a medication given to patients after anemia to recover the cells in the bone marrow and then we used to put it inside the uterus, because something was published that, for implantation and bad endometriums, it could get better and implant better.

Then it was demonstrated that it was not good. Then I’ve been using the ERA test, the biopsy, to see the window of implantation. Then it’s been published that, after a large and very well-done study, done by the same people who were promoting that, saying that in an 800-patient study, the group not having had the ERA got pregnancy at a higher rate than those who had the window scan to see whether to put the embryo on day 5 or day 6, or one day less or one day more.

In the end, now what we are doing is just an ultrasound scan to check how nice it is or not. Then hysteroscopy, and check whether there is chronic endometritis, or if there’s any abnormality in the uterus that can be corrected.

Then, if we are very desperate, sometimes we use the platelets. That probably, in the future, we will change because now we are just putting the platelets as if it were an insemination, just moistening the endometrium. Probably to work as it works in orthopaedics, in the joints, it may be injected inside by a hysteroscopy, injecting the platelets into the endometrium. At the moment, we are not doing that.

After using platelets, I have never seen the endometrium increase the thickness of that endometrium. If you put it in and then she gets pregnant, then it was because of the platelets. If not, even with the platelets, I couldn’t get pregnant. That is why we carry on doing these things, which have not been fully demonstrated.

So at the moment, I’m just showing you: It’s just a good ultrasound scan and hysteroscopy. These are the weapons.

If we could know that — I mean, that anxiety that you have is the same one that your doctor, your specialist, has. We don’t know. That’s the problem. That’s why immunological treatment exists, and that’s why so many things that are done exist.
And I say, “Okay, I think I’ve done this treatment, and it’s been fine,” and then everybody does.

As I said before, any of these euploid embryos has a 56% chance of giving a pregnancy. Unfortunately, 2 embryo transfers, then you start investigating, as you’ve done, all the span of available things about failure of implantation, although it has not been demonstrated.
But you want to do everything possible. Two embryo transfers, blastocyst transfers, euploid — is within the possibility. The statistics say that one of the definitions of failure of implantation is three blastocyst euploid transfers with no pregnancy.
Of course, we are not going to wait till the third one.

After the first one, we start doing these sorts of things: going to the haematologist, to the immunologist, whoever may help the patient. That’s why we have to be very strict with what is scientifically demonstrated or not.

What you may try — go for the third one, if you have, or try again and do your best, and your doctors as well, trying to study your husband, if possible, and then the endometrium, as we said: a hysteroscopy, and do everything that we know is available. Then cross your fingers because, unfortunately, nowadays, we don’t know everything.

In that case, we would not have this, we wouldn’t be having this meeting today, because everything would be sorted. It’s very hard to have 2 embryo transfers and not be successful. You have to carry on trying and do what you are doing: immunology, haematology, and these sorts of things — and try to look for the reason.

We have FSH, recombinant FSH, not recombinant FSH, and the other group with the LH factor. And well, over 40, it’s always been said that the use of the LH component after 35 is better. After 40 as well. It’s what we call in Spain “the combo” — recombinant FSH.  Menopur, HMG, is the old one. Or the Pergoveris, which is pure FSH with LH. I think that most of us agree that at this stage, it’s good to have this LH component in the stimulation.

Well, that is the thing. It has been seen that in that study, those women who had the biopsy and the window study and change, they got pregnant less than the other group. It seems that even the window may change. Furthermore, it’s been demonstrated that the window may change, and how important it is. At the moment, we are not doing that. We are not taking care of the window of implantation at all.

We are — if the blastocyst is a 5-day blastocyst — we will give 5 days of progesterone before transferring, and that’s it. That’s everything I can say at the moment. In a woman, it may be recommended in the past to be transferred on day 4, or 12 hours before. Then, if they repeat it, they find that in another cycle it may be later. It seems that that is not so important.

Probably the embryo is going to find its place within a period, sooner or later. If you’re going to transfer a blastocyst with only three days of progesterone, the chances of being pregnant will decrease a lot.