No matter if this is your first failed IUI, second Clomid cycle, or third failed IVF cycle, they can all be a huge blow. After the failure there comes disappointment, grief, and an important question “should I try again ?” Every IVF attempt is linked to physical, emotional and financial demands. It is understandable that some couples give up after a few failed cycles, either because of emotional or financial reasons. They are under the impression that their prognosis for IVF success looks bleak after so many failures. Is this really the case? Is hanging in there through many IVF cycles worth it? Should you consider trying again? Are your chances for success growing with every cycle?
IVF isn’t a magic bullet that solves every infertility issue. In fact, as we learned during Jennifer Palumbo’s patient story webinar, only just under a third of all patients deliver a child after their first IVF cycle. In spite of those odds and the mounting costs of treatment, is it worth it to keep going? In today’s webinar, Dr Natalia Szlarb will explain why it’s important to keep going. Egg quality is the biggest factor causing IVF failures; as women get older, their ovarian reserve depletes and egg quality goes down. As Dr Szlarb explained in her webinar on egg donation treatments, because of the current socio-economic climate, women tend to delay having children in order to focus on their careers and education. However, by delaying motherhood past the age of 35, their chances of a successful pregnancy drop dramatically; egg quality goes down, which in turn leads to a higher chance of genetically abnormal embryos.
Even IVF doesn’t solve this problem outright. Simply put, as patients get older, their bodies can’t produce as many eggs during the hormonal stimulation stage as those of younger women. Fewer eggs mean fewer embryos; fewer embryos mean fewer chances for a genetically normal embryo. In women under 35, about half of all embryos generated are genetically normal. Over the next six to seven years, however, that number drops dramatically, reaching a low point of about 11% in women over 42.
Genetic testing of frozen embryos helps mitigate that issue somewhat; by opting for PGT-A testing (otherwise known as PGS), patients save themselves time and stress that could result from a failed pregnancy as a result of implanting a genetically abnormal embryo. The success rate of IVF treatment in women over the age of 35 is about 18.3% without genetic testing. With testing, however, it shoots up to a staggering 81.1%.
The discovery of so-called mosaic embryos is a relatively recent development in the field of reproductive science. Usually, embryos are classified as euploid and aneuploidy–containing cells that are genetically normal and abnormal, respectively. Mosaic embryos contain both types of cells. Dr Szlarb says that they should be used only if completely euploid embryos cannot be generated; mosaic embryos tend to result in lower implantation rates and a higher chance for miscarriage.
Some mosaic embryo transfers do result in successful pregnancies, however, because every mosaic embryo is different, depending on how much of the embryo is affected by aneuploidy. Patients who are considering this route need to be fully informed of the potential risks of implanting a mosaic embryo, as well as having access to appropriate counselling.
Another option – especially for patients with low AMH – is embryo banking. The way the procedure works is simple: the patient undergoes a cycle of hormonal stimulation and generates as many eggs as possible, which are then fertilized. The embryos that reach the blastocyst stage are then frozen, while the patient is allowed two or three months to recover. The process is then repeated and the IVF clinic suddenly has twice the amount of embryos to work with. Following those cycles, the embryos undergo PGT-A testing.
As Dr Szlarb is fond of saying – if the patient has low AMH, they have to work twice as hard to achieve the results of someone younger than 35. This is why at least two cycles are recommended for this procedure.
Transferring embryos at the right time is also a huge factor; by simply performing a biopsy of the uterine lining, the most optimal timing window can be determined for each patient.
If all else fails, however, Dr Szlarb recommends egg donation. Patients undergoing egg donation treatments bypass the most common causes of failure of regular IVF treatments. Egg donors are y young and the existing mandatory regulations means they have to be heavy screened for any health issues which could negatively impact the recipient or the child. Success rates for egg donation treatments are higher across the board for most patients and they are not affected by the recipient’s age.
So, first things first – the genetic selection of embryos. We need to find out if the embryos you still have left are genetically normal – you will be able to look at the charts that I was presenting – the number of genetically normal embryos is age-dependent, so you can calculate that out of these four, if you are 35, then statistically 50% of them are good ones, whereas if you are 40, then maybe 1 or 2 will be good ones. As for the endometrium biopsy, there are two kinds of biopsies: one type is to show the immunology (measuring NK cells, Th1, Th2 cells and their ratios) and depending on the number of NK cells and cytokines, we make decisions on if we do a scratching or if we put patients on intralipids or Humira. So, there are a lot of immunological protocols depending on the kind of abnormality you have in your immune cells, but it’s not receptivity. The endometrium receptivity map is the test that tells me how many days of progesterone you need for your implantation window to open – 70% of the patients we have, need 5 days of progesterone to be receptive, so to open the implantation window. In the case that I was showing you earlier – she needed 7 days of progesterone to open the implantation window. I gave the patient 7 days of progesterone and implanted 5-day-old blastocysts, and this is where her body made the click and when she got pregnant. So, it’s important to differentiate the endometrium biopsy into two things: immunology and receptivity. Receptivity tells us about the timing of your endometrium – how many days of progesterone do you need and how many hours of progesterone do you need to open your implantation window, but the biopsy that you had was for the immunology. I do agree that scratching is a classical tool, I’ve seen it in the States – this improves the implantation rate, but a more sensitive tool is the endometrium biopsy where you perform the biopsy and instead of throwing away the biopsied piece of tissue, you send it to a special lab which tells you how many hours of progesterone you need to open your implantation window. Definitely, before you do the next transfer, I would perform the uterus lining biopsy for receptivity and timing, because maybe this is the reason why it’s not working. If you know the timing and you are not getting pregnant with the embryos you have frozen, then you need another cycle with embryo development to the blastocyst stage and genetic testing of them. If you need to, feel free to contact us and we’ll be happy to help.
Actually, the majority of transfers which we perform are with heparin – it is usually given until the tenth to twelfth week of pregnancy. If we see recurrent implantation failure or we have data that the patients have a Factor V mutation or a Factor II mutation or other thrombophilia issues, then we recommend heparin until you deliver, or in some centres such as Berlin, is even given until the mobilisation of the patient after delivery. This can even mean three to four days if the patient has had a c-section and is able to get up and start taking care of the baby – at this moment we would stop the administration of Clexane. It has to be decided individually, but definitely, if you have had so many negative results then this is something to consider.
The best results from egg donation cycles are when we use fresh donor eggs – we perform 600 egg donation cycles annually, so I have some experience in this, and I have seen cycles in my life where the same donor has beautiful blastocysts during one cycle and then two months later has no blastocysts. Don’t give up, you have to be aware of how old the donor was – if it was egg sharing, so you are getting eggs from someone who is undergoing IVF treatment, then these are probably not the best eggs, so you should look for a young donor under 35 years old, with proven fertility, meaning that she has children or children have been born from her previous egg donations, and someone trustworthy, and definitely use fresh cycle. If with 6 eggs you had less fertilisation than with your own eggs, I would recommend for you to change the centre and go to professionals who specialise in doing these types of cycles only.
Before we transfer, in egg donation, you can live a normal life. You have to take your prenatal vitamins and before transfer in the egg donation cycle, we usually perform a mock cycle, so you will be given oral oestrogens and later vaginal progesterone, so please be compliant with your medication, stick to the schedule that we give you for the mock and then for the transfer cycle. In the transfer cycle, with the fresh cycle, it is really important that you have your period at the same time as your donor, so in case your period is not coming on time, let us know because we are able to alter the donor’s cycle to adjust it to your body. There is no more magic to be done before the transfer. Each patient after the transfer is given the same recommendation – you should not work hard, no bathing, no swimming – only showers. No sexual activities for ten days, you should also not use tampons, only pads, and you should not ride a bicycle. In around 70% of all cases, patients have positive results, so I would focus more on the care after the egg donation transfer.
If you were unsuccessful with donor eggs, then you have to be aware that adenomyosis should not be the cause of why you are unsuccessful. Adenomyosis is an immunological factor for us, and each patient after egg donation is prescribed Prednisone to calm down their immune system. Adenomyosis is endometriosis in the wall of your womb. What this injection that you mention does, is that it puts you into menopause artificially, so for three months you will not have cycles, so this will stop your bleeding and it will stop the development of adenomyosis or endometriosis. You can experience the side effects of this injection – you can have all the symptoms of the menopause like hot flushes or mood swings. In egg donation, when the patient still has their own cycles before the transfer, we give them the same injection that you get for adenomyosis, but we still give you supplementary hormones so you do not experience the side effects of the lack of estrogen, so you have to be aware how you might feel. If you’ve failed before with an egg donation cycle, and you are going for a second donor, we have to see what kind of donor you need. If the first cycle was with fresh or frozen eggs, I would prefer to do the second cycle with fresh eggs – I would even consider doing preimplantation genetic testing of the donor embryos because the selection through genetic testing is more sensitive and will usually speed up the process of you getting pregnant. I, unfortunately, can’t tell you more about receptivity as I am not a fortune-teller, and I can’t come to you and tell you just from looking at you that you need 7 days of progesterone. Before I tell you how many days of progesterone you need, you need to do a mock cycle with 5.5 days of progesterone to see with a biopsy if after this you are or are not receptive. If you are not receptive, then the biopsy can tell you how many days of progesterone you need to open the implantation window. I can give you one or two days of progesterone, more or less, depending on this test result. You need some systematic work to make this happen in your life.
First things first: embryos. Fresh cycle, five-day blastocysts. Of course, we have programmes with three-day embryos, but we do not recommend them, because the success rates with these embryos are lower. We have to focus on the blastocysts – if you belong to the group of recurrent implantation failure patients, which means three transfers without pregnancy, then we need to focus on the uterus lining receptivity, and a biopsy could also be done for immunology, so NK cells and Th1 and Th2 ratio, which can help us decide what sort of immunological protocol you need.
Usually, patients with complicated stories are not coming for their first appointment to see what the doctors look like, but you are usually coming to us under a mock cycle so we can do a uterus lining biopsy, and then we define what kind of medication plan you need, and depending on the result, how many days of progesterone you need, and depending on the immunological results, what kind of immunological protocol we should put you on.
In dermatology, there are a few creams that are described under any circumstances when patients are getting pregnant – vitamin A analogues, so retinol, cannot be used as they can cause harm to the baby, even though it is just a cream. There are some papers published saying that when you use this kind of medication, you should wait six months before you get pregnant again, so this kind of cream really should not be used.
The first training I received was in Berlin, and my ex-boss used to say that he will do everything that the patient wants, as long as he can take responsibility for it, and I’m slowly following in his footsteps. You can request whatever you want to, but on the day of the first appointment, we have to discuss if there are indications to do this in your individual case, and if there are indications, then I am more than happy to do it, but if there are not, then you can do it because you want to, but myself and my colleagues will allow ourselves to tell you our opinion – sometimes patients who have done two or three cycles with us and have not developed blastocysts, especially when you do embryo banking, and you do one cycle with a middle dose of hormones and no blastocysts, then another with a low dose of hormones and no blastocysts – then you know there’s no medication that can make it happens. Then, we recommend egg donation to these patients. Sometimes patients are not ready for this psychologically – I will never forget a patient who had 7 IVF cycles with her own eggs – I was telling her that I do not want to work with her own eggs any more, but she was so smart and she was giving me her own medication plans and gave me a week in June when she wanted to come to me to Alicante for treatment. Sometimes you have to listen to your doctor, and if you think you know better, then as long as I can take responsibility for it, then I will watch your work.
Yes, I am famous for saying that with good-looking embryos it’s the same story as with good- looking men; you trust them but you control them through genetic testing. I prefer to do my job correctly, and I have seen young ladies under 35 years old who have failed cycles in different centres, like the example I gave of my friend, who failed two IVF cycles in two different centres – when I was talking to her and saying once sentence, she was crying, then I’d say another sentence and she was crying even more. So, when I have these kinds of stories, I want to apply all the technology which I am aware of, to shorten the time it takes for you to get pregnant as much as possible. As for PGS, I’d be more than happy to do this type of cycle with you.
I think what you are asking me is if DNA damage means that you have a pathologic FISH result – as you can imagine, I have seen a couple of cycles where men have had pathologic FISH results and were able to generate genetically normal, euploid embryos. I have seen cycles where good egg donors were able to correct genetic abnormalities of the sperm. When we have results which show DNA fragmentation or pathologic FISH, we should consider genetic testing of the embryos – a lot more important for males is not pathologic FISH of the sperm but pathologic karyotype of the male. Then, the situation gets more difficult and the quality of the embryos can be affected.
When I was pregnant myself, I had such bad reflux and I was writing my PhD – I also have low blood pressure so I was drinking lots of coffee, which made it even worse, so there is medication which you are allowed to take during pregnancy, such as PPIs like Pantoprazole or Omeprazole, oR H2 blockers.
That’s a very good question. This is because these tests are very complicated and expensive. Also, when you are doing your residency in gynaecology, you have to read a lot of books and a lot of guidelines – in our guidelines, in order to do testing for thrombophilia, it says it can be considered, not necessarily indicated after recurrent implantation failure or 3 miscarriages.
I’d be more than happy to do it, please contact: firstname.lastname@example.org
Please say that you had a webinar with us, and we have assistants that schedule our Skype calls with patients – if it is urgent and has to be done this week, then it has to be done before Thursday because on Friday we are travelling to Germany with a German group, but if it can wait until next week, then please also email us and and I’ll be more than happy to help you.
All patients after the embryo transfer are given heparin and methylprednisolone 10 mg. If you have a history of autoimmunological factors, we start with methylprednisolone before, but methylprednisolone for endometriosis is not a cure for you to have a healthy baby. First things first, we need to see your ovarian reserve, and this is the 3 As age, AMH and your antral follicle count. We need to see how many eggs you can generate and how many embryos you can generate that will be genetically normal, and if I have a euploid embryo, the chance of a single embryo transfer with a genetically normal embryo is around 70% per transfer. If you come to me and show me this list, then this gives me the whole story of what you have done, and if you belong to the group with recurrent implantation failure, then before we do anything else, then we have to do a uterus lining biopsy for receptivity and for immunology. Then, if you have high NK cells, we will decide if we should put you on prednisone or intralipid – don’t focus on the endometriosis. Endometriosis is the presence of endometrium, so the uterus lining, outside the womb – this could be the belly, the fallopian tubes, the ovary or the muscle of the uterine wall. So, the endometriosis is causing adhesions, and it is diminishing your ovarian reserve, so don’t focus on the endometriosis, but focus on the eggs that you have left, so work on your fertility. If you have good AMH and you are able to generate five blastocysts, and you’re let’s say 35, so 2-3 of them are genetically normal, then I don’t care about your endometriosis – I will downregulate you and give you medication before I transfer that stops all the production of all-female hormones in your body, I’ll give you estrogen so the lining will grow artificially, support you immunologically and see what happens.
When I was 34, I’ll never forget the gift that the doctors gave me – they gave me the package of medications for IVF, and they said to me that I have to freeze my eggs, and I was very surprised and confused, but now, I bless them because I can use my eggs that I froze when I was 34, and I’m over 40 now, and I still have the chance to use them, and 50% of them will be good, genetically normal embryos. When you are over 40, the problems are getting complicated, which means we have to see your age, AMH and antral follicle count. I’m like a broken record: ovarian reserve – we need to see where you are. If your AMH is low, so under 1, the best solution would be for you to slowly start thinking about egg donation. If you are a fighter, and you say no, and you want to try more blastocysts, then I will say okay, and we will try and we will do embryo banking, so two or three cycles, which is a time-consuming process. We repeat cycles every two or three months, so this will be around 9 months of treatment. You have to answer the questions yourself – are you strong enough after everything that has happened? Will you be able to survive 3 more cycles? Or if you decide that you’ve been through enough, and you decide that you want to have a child this year, then egg donation will be the best solution for you. We measure our goals depending on ovarian reserve and our psychological state – feel free to contact me and let us talk about what exactly has happened and what we can offer you, but we will need more data.
Because of the Buserelin, it sounds to me like you are using the long protocol – the majority of the protocols that we perform are the antagonist (short) protocols, and then the literature about PCOS tells us the same stories as Professor Masterbrook was telling us about genetic testing of embryos in 2007. All the PCOS or high responder cycles, according to literature, should be treated with a low dose of hormones which will not hyperstimulate you. We developed our own protocol for high responders – as you can imagine, the majority of the donors that we have are young and fertile, and they are high responders, so we generate 16- 20 eggs per cycle. Believe it or not, all of them go home an hour after egg retrieval, and for the last two years, we haven’t had any after hyperstimulation, bleeding or infections after egg retrieval, even though we were generating so many eggs. We also developed certain protocols of medications that the patients are given before egg retrieval that support their coagulation, clotting and of course antibiotics. You have to be aware that if we do an IVF cycle with a high responder, then we generate a lot of eggs at once, which generates a lot of hormones. When we have more than 2000 estradiol in the blood, we are afraid that we are going to hyper-stimulate you, because we trigger ovulation with procrin, with an agonist, which stops the production of all the female hormones in your body, but this makes your uterus lining unreceptive. So, what we first do is generate eggs and embryos, and to make your time until pregnancy as short as possible, examine the embryos genetically, freeze them, and during the cycle where we did egg retrieval, we then perform the endometrial scratch. Then you fly back home, your body can then recover for a period, and we transfer the embryo in the next cycle when the (inaudible) with oral estrogen, where the dose of hormones makes your blood estrogen to be 600-700 units, which is physiological. With genetically normal, euploid frozen embryos of high responders, we have higher success rates than transferring fresh. This is the kind of cycle that I would recommend for you based on your eggs only. When I would see the sperm quality of your husband, I would have to have some more data to see what kind of issues we have.
I would like to do one cycle with you the way that I have just described, and if with this type of cycle we cannot reach the blastocyst stage, then the next cycle that we would perform, we would do 50% fertilisation of the eggs with your partner’s sperm and 50% with donor sperm. However, before I would say donor sperm, you would need to fail at least 2 cycles with your own eggs and your partner’s sperm. There is a decision process which in your case has to be made.
I do not like to talk about medicine and restrictions, as I would like medicine to be without borders, but there are recommendations and laws of the countries in which we live that we need to obey, and in Spain, we can transfer embryos from an egg donor until you are 50 years and 11 months old. If you are older, then we need to treat your case individually. The oldest patient pregnant after an egg donation cycle was 54 years old and I’ll never forget this lady – it was an African girl, and her genetic children didn’t survive the war in Rwanda, and we had to do a cycle when she was older than 51 years old. Of course, you have to undergo health testing, you need to give us letters of support from your doctors from your country, and all the doctors meet and discuss. I still hope that I’ll be able to help you.
This is not a typical side effect of Progynova – you should really see if it is due to Progynova. There are some extra supporting factors given in the tablet that hold the Progynova together, and this could be causing the problem which you are facing. There are different types of estradiol valerate – oral, vaginal and transdermal. If you believe that the problem started with Progynova after you took it orally, then you can start taking it vaginally and if the problem still continues then there are also patches. So, observe yourself for two or three days and if the issue continues, then speak to your doctor and discuss if you can change the form.
It’s usually two months. Why? Because we have to perform a test cycle of yours, which is one month, and then the cycle with the donor is: period for 5 days, estradiol intake 14-15 days, then egg collection from the donor and fertilisation with your partner’s sperm, then waiting for the embryo to develop for 5 days, so two months in total. However, it’s two months of work, not waiting around for things to happen. So, you can imagine, when you meet a member of our team, this is when work starts, as we put you on medication and we don’t want to have waiting times longer than necessary.
In my life, in order to survive, I had to go to American medicine and ask for help there to make it happen in my life. You have to fight for yourself and fight for your dreams. So, if you want to be a mum and you are 49, then we have 2 legal years to make it happen in Spain. When you have the ERA test – good – see what it says: receptive, pre-receptive or post-receptive. If it doesn’t say “receptive”, then you need to do a confirmatory test. I like challenging cases. I want to see what has happened in your life previously that the egg donation cycles did not succeed. If the cycles were with frozen eggs, how many eggs were given, and what were the fertilisation rates? There must be something in your puzzle that we must improve to have you in this 90% cumulative pregnancy rate per cycle. So, when people are coming to us after failed cycles in different clinics, we always verify receptivity and immunology – we are that far that we match donors to patients like tissues, and I’ll have a webinar about it. We match HLA-C, and we see what kind of immunology you like and what kind you reject.
The second egg donation for us is a challenge, it’s not only phenotypical matching based on what you look like, but we also put a little internal medicine into your embryo selection, as well as receptivity testing and to make the time until achieving pregnancy as short as possible, I’d also recommend PGS to give you the finest and most sensitive selection of embryos. So, this is something that we can do better. Drop us an email, send us your history form, and let’s Skype next week.