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Getting pregnant in advanced maternal age (38+): success stories

Elias Tsakos, FRCOG
Medical Director at Embryoclinic , Embryoclinic

Advanced Maternal Age, Success Stories

From this video you will find out:
  • What are the chances of getting pregnant at 38 or older?
  • Why is parenthood being delayed?
  • How much can we expect from a fertility treatment after 38? What are the limitations?
  • What is the impact of ageing on clinical outcomes?
  • Does advanced maternal age increase high-risk pregnancy?

What IVF treatment options are there for women over the age of 38?

In this session, Dr Elias Tsakos, FRCOG, Medical Director at EmbryoClinic, Thessaloniki, Greece, has talked about advanced maternal age groups and explained multiple factors that can prevent such patients to achieve pregnancy but also provided best practices that can help to get a positive outcome.

There are two main types of IVF that we discuss with patients of advanced maternal age. The first is IVF with own eggs, and the other is the egg donation IVF. Maternal age is a huge factor of success in that age group, and it’s even more important when we’re talking about IVF, egg donation is there as an option that has been available quite for a few decades. Nowadays, it’s becoming more and more used in the last maybe 10-15 years.

Dr Tsakos started by explaining that the quality and the quantity of oocytes are reduced with advancing age, and this reduction starts in the mid-20s. Therefore, for females, it becomes even more profound after the age of 30. After the age of 35, it diminishes even more, and after 40, it diminishes to a great extent, as a result, the success rate of IVF has a lot of denominators, a lot of main factors and maternal age when we’re using own eggs is perhaps the most significant factor regardless of what method we use the stimulation protocol, the drugs we use and the methods in the lab and so forth. Female age of 38 plus by itself is an adverse factor of success, and not only for IVF success but also for pregnancy outcome in terms of either a miscarriage or complications in pregnancy.

Advanced female age is considered perhaps 38, but so is 40, 42, and so is 45, so the huge question is where do we draw the line? The answer is, it depends. According to Dr Tsakos, we can divide advanced female age between 38 and 42, from 43 to 46, and from 47 to 50. In most countries, including Greece, the upper age limit for performing IVF treatment for females is 50. In Greece, there’s a new law that has extended this limit to 52 in the light of the COVID-19 pandemia, which prevented lots of women from having IVF. At the moment, we can treat women until the age limit of 52 under certain conditions and under a special licence that is required. A woman between 50 and 52 will require a special licence from the health authorities to perform IVF.

Age group 38-42

We always need to assess and evaluate every patient as carefully as possible. We can’t afford to waste a lot of time on these patients, and the patients also need to understand that time is precious, sometimes, 6 or 8 months may make a big difference in regard to the outcome, the quantity, and the quality of their eggs. Therefore, for those patients, it’s very important to ensure that the team at the clinic will give them the best possible chance based on their individual characteristics.

We need to evaluate the AMH, the ultrasound characteristics, the hormonal profile, the history, some individual details in the particular case, and the male assessment is also significant to provide them with the best possible option. In this age group, we always aim for an adequate amount of eggs and embryos that would give us the best possible chance. For someone at 38-39, it would be good to have 4 or 5 oocytes and get 2-3 healthy embryos. How many will implant? That depends on the embryo quality, the wishes of the patients and the characteristics they have. Invariably some of those patients would have had already IVF cycles, they would have had perhaps failures in the past or even successes, so we take their history into account and try to aim at giving them the best possible chance we use all the proven tools of success in stimulation protocols, in terms of choosing the best-suited protocol, trying not to overstimulate them, but trying to stimulate them adequately with FSH hormones, sometimes with the add-on of LH and sometimes with the add-on of tablets like Clomiphene and so forth.

We’re fairly optimistic for this age group. In the age group of 38 to 42, the success is roughly 25% in terms of pregnancy, and we would like to offer our patients that opportunity.

Age group 43-46

For the age group beyond 43 to 46, things are getting more complex. The patients need to understand that the success rate is very low, perhaps less than 10%, in some cases less than 5% depending on the individual characteristics. Some pregnancy complications are much higher, pregnancy loss, miscarriages, and abnormalities limit the healthy take-home baby rate to very small numbers, perhaps in the region of 2 to 3%.

Many patients are not discouraged by that, it’s only logical for the majority of the patients wishing to try with their own eggs in this age group, although they understand that the odds are against them, and some lucky ones do succeed and do take home a healthy baby.

Age group 47-50

There’s only one report of a successful IVF pregnancy with a healthy birth in this age group, and the patients need to be aware of that. Sometimes, it’s very difficult to get to terms with this fact, but the scientific team has to be very realistic, but also be psychologically very close to the patients and help them understand the odds and make sure that any complications are minimized.

Egg donation

When we talk about egg donation, the success rate is different. Maternal age is still important both for the success of IVF and for the outcome of pregnancy, however, with the use of younger genetic material, we can be more confident about success. We still need to evaluate the couples, and the patients still need to be very careful in selecting the program, and the protocol before starting any treatments.

First, we should do no harm, and we should ensure that our treatment is safe before it is successful. I do insist on screening tests, I’m well aware that screening criteria differ from country to country, but I do insist that we don’t cut coordinates in safety, so the advanced maternal age, we need to ensure that it’s safe before they embark on IVF. Proper health screening, also general screening for standard conditions like thyroid disease, heart disease, lung disease, etc., should be evaluated.

Egg donation negates the adverse effect of genetic inadequacy associated with advanced maternal age, however, it’s not always successful, it’s not always safe to perform, and we need to be very careful in the pre-IVF phase, which is very significant, even more significant for the advanced maternal age patients.

We need to ensure single embryo transfers for those patients, although we are under a lot of pressure to perform double embryo transfers in the egg donation cycles to maximize success, and so forth. There’s a lot of understanding, a lot of counselling, and a lot of discussions to build the trusted relationship that is of paramount importance before we move on.

I don’t think scientifically there’s an age limit, however, we need to obey our guidelines and the legal scenarios, and we need to ensure that all our patients are screened adequately, and we stick to this age limit. Finally, I think we should not forget that apart from the effect on the oocyte quality associated with advanced maternal age, the uterus quality, the quality of the implantation environment is altered with advanced maternal age. The chance of developing fibroids, polyps or even cancer in the uterus is increased with maternal age, and we should be very much aware of that.’

What IVF treatment options are there for women over the age of 38? - Questions and Answers

I’m 41. My AMH was 3.59 pmol last year in March. I have frozen two embryos at 40, however, since July this year, I have not had a proper period. It was just spotting. Is it possible for this to be perimenopause? My periods were fairly regular before this. What can I do as I’d like to try to get more embryos before I am 42? Before implantation, I am due to start a long protocol, but not sure when due to lack of periods.  

I wouldn’t delay the embryo transfer very much for various reasons. Since you have two embryos frozen at the age of 40, I can’t see why you’re not implanting those. I’m not a big fan of accumulating embryos before we transfer. I prefer to transfer the embryos as soon as they are ready. Prolonging this process perhaps is posing you to unnecessary stress, medication and procedures, which are not always safe or stress-free.

My advice would be to investigate why you’re having these abnormalities through a scan and some hormonal tests, and perhaps just get on and have a frozen embryo transfer before you have any more stimulations. I hope you are not going to need any more stimulation. I hope you will be successful with those two babies you have in storage.

I had 4 IVF cycles at the age of 40-41. Each time 8 to10 eggs were retrieved, 6 to 8 matured, and 4 to 7 fertilized. Only 1 blastocyst of acceptable quality on day-5 was produced (3BB4AA, morphology not testing). Is there any possible way to know what follicle produces that one blastocyst? Maybe it’s the leading follicle that would perform anyway, and the rest is just ‘garbage in garbage out’ allowed to grow on excess FSH. Would it be sensible to change to mild IVF or even IUI in this specific case?

I think it would be sensible to move on to mild IVF, not IUI. I mean, in IUI at your age group, we would be looking at a very small single figure success, and most importantly, we wouldn’t know what went wrong if you didn’t get pregnant. So yes, maybe mild IVF would be a way forward. Possibly some details in the lab would give you a bit of better blastulation. I don’t think 6 or 8 mature oocytes are due to excessive FSH.

Potentially there’s a sperm factor associated somewhere there, so there are a lot of areas to be explored. Certainly, producing 6 or 8 mature eggs at your age is a very positive thing. So I would probably investigate the sperm a little more. I would probably look into the possibility of a mild IVF cycle, look into the lab techniques. It’s always optimistic if you’re producing eggs, and I think I would be guarded but optimistic for the future. However, it’s not just the eggs, it could be the sperm, it could be other factors that affect your blastulation outcome.

Would you recommend an ERA test after failed transfers or ALICE or EMMA? Are there better alternatives? How soon after an ERA test can you start taking meds for the next transfer? 

To be honest, I don’t use ERA of any sort. I haven’t been convinced by the evidence. Perhaps some other people have more experience, I have no experience at all with these tests. I do not recommend them. I have never used them. I honestly don’t know how to advise you on this. I think that monitoring the first embryo transfer or even the next embryo transfer with the standard methods is enough.

Scanning, blood testing, ensuring that the endometrium is healthy, perhaps with hysteroscopy or a biopsy. Maybe doing a panel of microbiology testing, in my opinion, is probably enough to ensure that we have a perfect or near-perfect implantation environment and also that the timing of implantation is near perfect.

How much time should a patient take after a failed transfer? I am 43, and I’m overweight though I’ve lost 15 kilos already.

There’s no real science behind all of this, to be honest. In my view, we have the body to recover, and we have the soul to recover, so it depends on how one feels. I don’t think we should be pushy to do an embryo transfer. I don’t think it’s only the logistics of it. I think there are more issues associated with failure and failed transfer and next transfer.

Overall, in my practice, I don’t tend to do back-to-back transfers. I tend to suggest and allow a couple of months between transfers to ensure that everything has gone back to normal. We have ways to monitor that hormonally, ultrasonically, but again there is also the psychological aspect, so there’s no very solid science behind it. I think it’s individualized depending on the patient and depending on the overall approach of the clinic, but I feel that perhaps a couple of months break is probably a reasonable time – a minimum of two months.

I had an actual pregnancy and birth at the age of 42 using my own eggs. My daughter was born. We have been trying for years since, but with no success. I have tried embryo transfer using donor eggs, two rounds without success. I’ve just had ERA. Do you think it’s worth it? We just found out that out of 18 embryos, 3 are suitable for PGS testing, because of my husband’s sperm. Do you think this is worth it?

As I said before, I don’t recommend ERA testing. When it comes to PGS, I think there is the value of PGS in your case. In anyone over 40, there is the value of PGS, as long as you understand that PGS does not increase your chances of pregnancy. However, it helps you avoid an unnecessary transfer and sometimes even an unnecessary miscarriage if all the embryos are abnormal. However, it has shortcomings: it is expensive, there is a bit of debate as to what we do with the mosaic embryos, so it’s not as straightforward as we would like. You were the lucky ones to have your daughter, and congratulations on that. As long as you produce healthy eggs and you’re still a reasonable age, in my opinion, you can keep trying with your own eggs with or without PGS.

This is very reassuring. It was a frozen cycle with embryos that were made when I was 37. We had nine viable embryos remaining.  

9 embryos is always a very good stock to work with, and I would be very optimistic that some of them would have healthy embryos and the result of healthy children.

I am 40, and I have had one failed IVF cycle. It was an antagonist cycle with only four eggs retrieved, three of which were fertilized and only one reached day five blastocyst. We had a frozen embryo transfer, but it was unsuccessful. Now we are considering moving to a flare procedure. Do you think the flare procedure is a good approach?

Under these circumstances, it is a difficult question. The flare protocol has been used for decades. I used it for well over 20 years. I don’t use it any more. It doesn’t mean that it’s not successful. In my opinion, the most important factor in the number of eggs that you produce is age, so perhaps there’s no huge difference between various protocols that would be used. If your doctors feel that a flare protocol would be suitable, I would go with that. The figures you’re quoting are very standard figures for your age group.

All I have to say is to trust the feeling of the doctor. The physician deciding on the stimulation protocol has a different feel once they’ve seen and examined how you responded. I wouldn’t object to flare protocol, and let’s hope that would go well. I wouldn’t expect huge differences in the outcome in terms of measurable outcome, in terms of numbers and the quality of eggs, but perhaps that might be more suitable for you, and that might produce the beautiful embryos that we all wish for.

 I meant to say, my AMH level is 20, which I was told is too high for my age. 

It is too high. But we have studied AMH for quite many years, we rely on it, but it’s not always 100% accurate. It’s always a good starting point, and it may mean that you may have an element of polycystic ovaries, which again may mean that you may produce a bigger number of oocytes of less good quality. It will be taken into account. In general, we would rather have a higher AMH than a lower one, as at least we have the numbers to work with.

I’m 42. I have had two failed IVF’s. We had 2 healthy blastocysts the first time and 1 at the second attempt, but none of them implanted. Could polyps interfere with implantation? Should we try again?

The answer is probably yes. Hysteroscopy has always been a viable tool in investigating and diagnosing problems and ensuring that the endometrial cavity is clear, however, there are some papers showing that a small polyp doesn’t make a huge difference in the implantation. In general, to my mind, I would like as normal an endometrial cavity as possible. If there is a suspicion of the polyp on the scan, it may be worth exploring further with hysteroscopy. Please remember that generally, the polyps we see on hysteroscopy are bigger than the ones we visualize on the scans. On the other hand, sometimes, we find polyps on hysteroscopy that have been missed on the scan. In my experience, I’m quite a big fan of hysteroscopy because I feel that there are a lot of factors associated with this test that can improve success.

Starting from simple things like a normal cervical canal. With hysteroscopy, we ensure that we have a normal embryo transfer afterwards. If we find any problems with the canal, we can fix them during the hysteroscopy, and also we ensure that the cavity is normal. Sometimes we take a biopsy also, which ensures that the histology is normal. Sometimes in advanced maternal age, we may find a pathology, which is even malignant, which can be a huge issue. In general, I feel that in the workup of fertility patients, hysteroscopy should have a valuable role, and more importantly, for women of advanced maternal age, in which the chance of having an abnormal finding is higher and certainly women with either implantation failures or miscarriages.

Is the AMH test the only way to check a woman’s potential ability to produce eggs at an older age?

No, AMH is one of the factors for assessing ovarian reserve. It is a fairly new factor, it’s become popular in the last 10 years. My team and I will have been amongst the first people who studied that, and we published findings that are now included in the ESHRE guidelines, and they show the value of AMH. It is an important factor in assessing ovarian reserve and also antral follicle count, which we produce in the ultrasound scan. Of course, there are other ways to do this, i.e., by the standard FSH measurement, the Inhibin B measurement and so forth.

AMH is not the absolute and only denominator of the reserve, but certainly one of the most valuable ones. Now in modern practice, most people use AMH including our team, we use the AMH and the antral follicle count.

If I have a PGT tested euploid embryo, I have done an ERA test and hysteroscopy, what are the chances of getting pregnant?

It is a difficult question. If you are 42, it may be difficult, perhaps less than a 10% chance, I’m afraid. I haven’t seen many studies, and a lot depends on what your uterus is like, whether there are any associated factors. There is certainly a fair chance, but not as big as we would like it to be. Honestly, it’s difficult to quote a figure, and again, it depends on the clinic as well.

The clinic said it is less than a 50% chance, and that was before ERA and hysteroscopy.

To be honest, I understand you’re stressed, but it’s very difficult. I don’t think this has been evaluated in general, but it’s a very good sign to have a euploid embryo at 42. You must understand it’s not just genetics that influences success, there are so many more factors. I would suggest going for it, and you will find out for yourself.

I’m 49, so I will probably have to resort to donor eggs. How will the embryo be affected just by carrying it? I am in very good health except for Hypermobile Ehlers-Danlos syndrome type 3. Would you consider me a good candidate?

I’m not very familiar, I have to dig back into my undergraduate books to see what could be the effect of your syndrome on pregnancy and pregnancy outcome. I would have to consult my physicians before I can answer this. We need to ensure that pregnancy and IVF will not compromise your condition. I cannot answer that off the top of my head. At 49, the logical way forward would be egg donation.

Do you believe that hysteroscopy increases the success rate with either own eggs or donor eggs?

I do. We have done our research and audit in my unit, and we found that it does, actually. We presented some of our findings at the British Fertility Society Conference a couple of years ago. There was a small increase in the success, so overall, the answer is yes, I feel it does increase the success. There have been some scientific reports, and the mechanisms are the ones that I mentioned before.

They can be as simple as facilitating the embryo transfer or removing pathology that hasn’t been diagnosed before, or ensuring that the endometrium is healthy. There are a lot of factors that influence the outcome. Of course, the question is who we perform it on. Do we perform it on everyone before IVF, or do we use it selectively? Or do we do the office hysteroscopy, in which we don’t have the facility to do dilatation because it hurts a little. These are remaining unresolved issues, but overall I feel that a hysteroscopy is a valuable tool in IVF.

If you use own eggs but with a younger surrogate mother, are the chances higher for our age group?

It depends on your health and your age group. It depends on the different age differences between you and the surrogate. For example, the surrogate carrier could be 40 while you could be 45. If you’re a healthy 45-year-old, I don’t think it makes a huge difference. Of course, if the surrogate is 25 and if you’re an unhealthy 45-47-year-old, then it may make a bit of a difference. I don’t think it’s very easy to quantify the differences, and it depends on the case.

I am a hyper responder: 8-10 eggs retrieved while the AMH is 24- 25 pmoles/L. If it is a genetic condition with FSH receptors not seeing FSH, can it be treated? I would love to have more eggs.  

To be honest, 8 to 10 eggs is not a bad score at 41. I mean, 8-10 eggs at 41 is a fantastic result. The standard at 41, we were happy with 3-4 eggs. You probably have double the number of eggs that we would expect for your age group. There’s always the chance of FSH receptor issues and all that, but I don’t think that’s a bad outcome. 8 to 10 eggs at 41 is good. It means that you have a good reserve, probably you’re very healthy, fit and a healthy young lady at 41. That would give you a fairly good chance of pregnancy, perhaps like the lady who spoke before, who wrote a question before, who got pregnant and delivered at 42. You would be amongst the fortunate 41-year-olds.

But I only got one blastocyst in 10 eggs, and I need more.  

Again, it could be a sperm factor. It could be other factors, like the lab factor. Still, one blastocyst at 41 is good. In my clinic, we don’t accept all 41-year-olds for the program if we feel that they wouldn’t have a good outcome. If they’ve had multiple failures, we don’t accept them for own eggs IVF. If they’ve had multiple failures before or if they have very low AMH or abnormal periods, or if they’ve produced one or no eggs, eggs not embryos, in the past.

From the ones we accept, we’re lucky if we have an embryo transfer. Not all 41 year-olds produce embryos of good enough quality for transfer. Having 1 blastocyst is a potential success. I wouldn’t be discouraged by that number. In another cycle, your 8 eggs or 10 eggs might be of better quality, or the sperm might be better or the dialogue between sperm and egg is better. I mean, at 41, if someone is producing a blastocyst, they could potentially be successful, so I would like to be optimistic.

What is your opinion on supplements DHEA in particular?

There is some evidence indicating that DHEA may be helpful in a subgroup of patients, and also DHEA has no major side effects. It’s inexpensive, widely available, so I use it for my patients. Either the ones that have not responded properly in previous stimulations or the ones of advanced age, of over 40 perhaps, before the IVF cycle. I think it does not harm, and it may benefit a small group of patients. Our problem at the moment is that we can’t identify which group that is, so we may be giving it unnecessarily to the others.

But as it’s inexpensive, widely available, with no serious side effects, we only give it for a couple of months, six weeks to two months before IVF, so I think there’s no harm using it. We do not expect miracles, we don’t expect a 42-year-old to produce five blastocysts with it. However, it may make a small difference and allow us to provide you with a healthy embryo and a healthy pregnancy.

Is there anything else that you can do to improve the quality of the eggs?

Of course, a healthy lifestyle helps. Make sure, however, you don’t lose a lot of weight quickly, because that may have an adverse effect. Generally, a healthy lifestyle and I’m not referring just to the body, but also the soul. Positive attitude, healthy lifestyle, a bit of extra time for meditation, for acupuncture, for anything that could pamper your body and soul. Perhaps, it will help, and if it doesn’t help in a quantifiable manner, it will help your experience. It will help you go through the IVF with less stress and a more positive attitude.

Would you suggest anything else to improve the chances for the next frozen embryo transfer except hysteroscopy after failed attempts (zero HCG of euploid embryos)?  

There are a lot of steps that could influence the outcome of the endometrial preparation, whether you would use tablets, or whether you would use down-regulation or not. Some people do, some people don’t. It depends on whether you would use a small, standard or a higher dose of estrogen and progesterone. The timing of the embryo transfer is also important. The timing and dosage of progesterone and the lab play a huge role in the outcome. The protocol they use to thaw, whether they do assisted hatching or not. This is something to be discussed. Of course, when it comes to the embryo transfer itself, the technique, how it’s done, when it’s done, is it done by a senior person in the unit, and so forth. It depends on whether they are happy with scanning images they’re getting, or is it done under ultrasound guidance or not.

There are a lot of factors that could influence embryo transfer and IVF itself. That’s why we value our team so much, because if one of us doesn’t do things optimally, then perhaps the outcome is influenced, even if everything else is done perfectly. Your overall approach is also extremely important. Try to be physically and emotionally as relaxed as possible and as positive as possible. I always say that once you’ve decided to follow a clinic or a doctor, just trust them and let them do what’s best for you. If you don’t trust them, just change them. I think there’s no third way around all of this, and let the people who care for you do the very best to help you.

Would you recommend any other supplements in addition to DHEA? 

Yes, some multi-vitamins contain some antioxidants and so forth. There is a bit of research behind them, so there are lots of commercially available multivitamins for use just before conception, but DHEA is the one associated with the potential increase of response to stimulation, so that’s why this is perhaps one of the most important supplements.

Do you have any views on whether it’s worthwhile having an endometrial scratch or EmbryoGlue? 

Well, when it comes to EmbryoGlue, there’s some evidence supporting it, although it has been challenged. We use it. I’m not convinced of its efficacy, however, we use it. As to endometrial scratch, there was some evidence to promote that, however, now it is a little disputed. I don’t think it would make huge harm to use it, to be honest, although the human fertilization authorities are a bit cautious now towards those add-ons.

Do you think it’s okay to use FFP2 face masks when pregnant?

FFP2 is protective. I haven’t seen any research on whether it affects pregnancy in any way, so I’m sorry I can’t answer that.

What vitamins would you recommend just before implantation?

Folic acid and probably vitamin D, depending on where you live and your lifestyle. I’d like to ensure that you know the general sort of food, blood count is normal. I don’t want them to start a pregnancy if they’re anaemic or if they’re low on iron, so it may be worth measuring your iron and ferritin levels, and having the full blood count to ensure that at least your standard blood component is normal.

How long can you take folic acid?

As long as you’re trying to get pregnant at 0.4 milligrams per day and the higher dose, if you have a history of Spina Bifida or any folic acid deficiency associated disease.

Is hCG infusion before transfer beneficial for a frozen embryo transfer?

I would probably say no. There’s no solid evidence to back it up.

Elias Tsakos, FRCOG

Elias Tsakos, FRCOG

Dr Elias Tsakos, FRCOG, is a Medical Director of Embryoclinic - Assisted Reproduction Clinic in Thessaloniki, Greece. He has received extensive and certified training in the United Kingdom and is a Fellow of the Royal College of Obstetrics & Gynaecology. Dr Tsakos is also a Board Member Representative of the Royal College for Greece and Cyprus and a Board Member of the Hellenic Society of Assisted Reproduction. He is a Member of the British, European and American Fertility Societies (BFS, ESHRE, ASRM). Dr Tsakos has been living and working in Thessaloniki, Greece, since 1999.
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