It is widely known that women encounter fertility challenges if they delay pregnancy until their 40s. This is not only limited to natural conception but it is also attributed to lower success rates with assisted reproduction techniques, including in vitro fertilization (IVF). In this webinar, Andreas Abraham, MD, MBA from the Eugin Clinic in Barcelona, Spain, talks about fertility treatments after the age of 40.
For the last forty years there has been a global trend for women to delay motherhood. Today, giving birth at 40 is 20 times more frequent than it was 20 years ago. It may give a somewhat false impression that advances in technology and medicine are able to balance out the age problem. However, according to Dr Andreas Abraham, it is not that simple. In fact, a lot of chromosomal disorders are linked to maternal age and the probability to have an increased risk of aneuploidy (the presence of an abnormal number of chromosomes in a cell) starts at 35. Aneuploides, the most common of which is Down syndrome, may also cause miscarriage and this is one reason why pregnancy success rates are generally low in women aged 40 and above.
Dr Abraham states that women who are 40 and older make up almost 50% of IVF clinics’ patients nowadays. Unfortunately, in this age group, up to 40% of the patients who start an IVF cycle and get stimulated, will have a transfer cancellation. It means that they undergo a complicated, invasive, and expensive procedure without the benefit of having the embryo transfer and the possibility of an ongoing pregnancy. Based on those observations, the UK scientific community coined an expression called ‘permanent involuntary childlessness (PIC)’. It means the risk of being left without a child even though every measure was taken to reach a pregnancy. If a woman starts looking for pregnancy at the age of 40, the risk of PIC is 35% – while at 30, it is as low as 6%. This undoubtedly proves that woman’s age has an enormous impact on reproductive outcome.
To offer an effective type of assisted reproductive treatment, it is crucial to undertake thorough assessment of patients of advanced maternal age. Dr Andreas Abraham says that the basis for good assessment is always ovarian reserve testing. Although there are a lot of different assessments available (including expensive genetic tests), a gold standard test is still the measurement of AMH (Anti-Müllerian Hormone) and AFC (antral follicle count). The combination of both has the best sensitivity and specificity to predict woman’s ovarian reserve and her ovarian response to the stimulation.
With AMH and AFC determined, doctors can start to consider different assisted reproduction techniques as well as the number of cycles needed for each technique. According to dr Abraham, it generally comes down to deciding whether to use intrauterine insemination (IUI) or ICSI (Intracytoplasmic Sperm Injection) – a refinement of the IVF technique.
Although opinions may vary, the clinical evidence leaves no doubts: as time is a key factor in older patients, it is highly advised to start ICSI immediately. However, if a patient insists on trying IUI, she should know that at the age of 41, she should switch to IVF latest with her sixth failed IUI cycle – and, if she’s 42, she should not do more than three IUI cycles. Another important decline in female fertility comes at the age of 43. Then, as studies show, clinical pregnancy rates after IVF become very poor and it is generally a clear indication for choosing the egg donation route.
In discussing treatment options for 40+ patients, Dr Abraham poses the question whether it is necessary to impose limits on patients instead of letting them decide themselves about their preferred type of assisted reproduction technique. The answer becomes easier when one considers IVF pregnancy outcome based on the age of the patient per retrieval. It clearly proves that from 45 years old onwards, live birth rate in IVF is close to zero. So, although IVF may help to overcome infertility in young women, it does not reverse the age-dependant decline in infertility. That is why setting an age limit for IVF treatment with own eggs makes sense – simply because the likelihood of success declines as a woman gets older. In such cases, even advanced IVF techniques do not do the trick and turn back the biological clock.
For IVF to be effective, one must obey not only patients’ age but also the recommended number of cycles. Dr Abraham provides an example of a study which demonstrated that patients who are 40-43 years old generally reach a plateau after three attempts. It means thereafter, there is no visible increase in success rates. If a woman is over 43, she has no realistic chance of achieving a delivery with her own oocytes.
It is widely believed that preimplantation genetic screening (PGS/PGT-A) increases the pregnancy chances and gives higher success rates in women over 40. Perceived as a way to top-up IVF cycles, it has to be handled with a lot of thought and care.
It is scientifically accepted that PGS must be done at day 5 of the embryo development – meaning the blastocyst stage. The criteria for a day 5 biopsy are strictly determined and they include minimum of 15 mature eggs or 8 (or more) top quality day 3 embryos. All the studies that indicate the usefulness of this technique have been performed in good prognosis patients under 35 who produce a lot of eggs. Taking the latter into consideration, one must realise that lot of 40+ patients will have 15 or more eggs retrieved and will not have 8 or more embryos of excellent quality. Besides, it is very likely that a lot of their embryos will simply not reach the blastocyst stage and this is the imperative to do the embryo biopsy if you want to benefit from this technique.
Another option that is often considered by advanced age patients is the vitrification of oocytes. However, according to Dr Abraham, it is not an option when you are over 40. It is important to know that the studies showing the efficacy of vitrification were performed in women under 37. The minimum number of mature eggs necessary to make an ongoing pregnancy probable is nine and, unfortunately, a lot of women who are 40 or older, will not have this number in one session. Dr Abraham shows a study from 2017 which proved that the likelihood of live birth for elective oocyte cryopreservation is directly proportional to the number of mature eggs and as we already know, the egg quantity and women’s age do not go together.
Having realised that a lot of assisted reproduction techniques do not meet the needs of women over 40, one must consider egg donation as the most effective treatment. It gives the highest success rates because it literally eliminates the age factor. Dr. Abraham admits that regardless of the recipient’s age, the success of the treatment is defined by the donor’s age and the latter is 25 years old on average. So no matter if you are 30, 40 or 51 (which is the legal age limit for egg donation in Spain), you still have the same success rates and equally high probability of an ongoing pregnancy and a live birth.
However, it is true that egg donation is not the first option that comes to a woman’s mind when she faces fertility challenges. In fact, it is probably one of the hardest decisions for fertility patients to make – often due to cultural and social reasons. It is not even mitigated by impressive success rates: 59% on first transfer and – in case of cumulative pregnancy rate after 3 cycles – even up to 93%.
Apart from advanced maternal age (43 years old and onwards), the indications for egg donation include previous IVF failures, premature ovarian failure, premature menopause, and genetic history. The limitations that patients may encounter most often refer to legal aspects (in some countries egg donation is not allowed) and the lack of appropriate donors.
It is obvious that social changes have significantly influenced reproductive behaviour and countries’ demography. Dr Abraham concludes that in the face of these modern challenges, health professionals should fight with ignorance concerning the reduced age-related fertility options and encourage women to have children sooner. When they deal with patients 40+, they should offer good counselling on available treatment methods, paying special attention to their effectiveness in this particular age group. Finally, they should not forget about informing the patients on the correlation between advanced maternal age and higher obstetrical risks. In fact, it should always be a part of a thorough counselling in the first visit.
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In the presentation, I showed you the study that basically gave the answer to your question. If you are 43 and you’ve already tried the IVF road and you had three failed cycles, it is a clear indication for egg donation. I can even use the words ‘rock-solid indication’. No matter how the cycles went – whether you had a good response or not or whether you reached day 3 or 5 – the sheer fact that you have tried with your own eggs and you failed three cycles means you should go for egg donation without any doubt. And the moment to change is now. When it comes to the follow-up question regarding donor availability: the legislation in the UK talks about an open donation – so it’s not anonymous. And this set up usually goes along with problems to find donors because it means the child has the right to know its genetic whereabouts. So usually there are more donors available in countries that have anonymous donation, like e.g. in Spain. Since we collaborate with clinics in the UK, I know that donor availability there is rather poor. Since you’re Caucasian, you have higher chances of finding a right donor but if you are of black or Asian ethnicity, it goes along with long waiting lists. So in general, donor availability in the UK is poor and they often seek for options abroad.
That’s a very good question. The presentation was my attempt to give you an idea about our decision-making process, our algorithms and the clinical evidence we use to reach the conclusion – meaning the right technique for every patient. And when I said that 43 is an indication to switch to egg donation, I also said that it’s a tough pill to swallow because nobody wants egg donation. I would gladly offer you a technique with your own eggs that gives you a good chance to have an ongoing pregnancy and a live birth. However, one has to be very critical as well. If the patient has been counselled properly and she’s aware of limited success rates, very limited options and a high probability to have a cycle cancellation but she still wants to go for it, we’ll obviously consider her case. We’ll explain to her what is possible and what’s not and if she’s really adamant to try with her own eggs, she’ll be able to do so at our clinic – of course, if there are no contraindications. Obviously somebody with low or undetectable AMH and no antral follicles will not be getting the go-ahead to try. Similarly, we will not let patients from the age of 46 onwards to go for IVF with their own eggs.
No, that accounts for the total number of cycles. Unfortunately, switching clinics doesn’t change your age. If you are 40-43 years old, you should not do more than three cycles in general. After three or four cycles you reach some sort of plateau. I know patients sometimes do much more cycles. Just recently we had a German patient who did an unbelievable number of thirteen IVF cycles before coming to us to switch to egg donation. So when I say three cycles, it’s the total number of three cycles.
There are a lot of treatments available nowadays – all of them with the aim to improve egg quality and/or quantity. If you search the internet, you’ll find treatments with human growth hormone, treatments with DHEA and a lot of other substances aimed at improving egg quantity and quality. But if you look at the studies with control groups that have shown more outcome, meaning more retrieved eggs and more retrieved embryos, you’ll see the truth. So to cut my long explanation short, the evidence-based answer to this question is: no.
Age is egg quality and AMH is egg quantity. So measuring AMH and antral follicle count enables us to predict how many follicles and eggs a patient will produce under the stimulation. Obviously, you need both quality and quantity. You have low value of AMH that tells us you’ll not produce a lot of eggs. However, you are 37 and the question when to switch to egg donation in younger women is a difficult one. My talk was about advanced maternal age. If you are 40+, you have neither good egg quality (which is age) nor – generally – good quantity. In women under 38, the decision-making process is a bit more tricky. One would be more likely to have a last try with own eggs since there is still quality – which is age . So it all does not only depend on AMH and how many eggs have been retrieved in the cycles you’ve done but also on how good the embryo development was. At 37, you produce various embryos and if you could transfer two day 3 or even day 5 embryos/blastocysts, you would still have a good probability of live birth. But obviously in your case, as you have already had various transfers, one would have to check if there’s nothing wrong on the endometrium. That is the case where I would need a little bit more information. We could dig a little bit deeper into the details to give you a more precise and detailed answer. So altogether, in your case – as you are 37 – one would be still a little bit more for trying with own eggs before going for egg donation completely.
This question is a bit in line with the previous one. Again, you’re under 40 but you have already had five transfers and four egg retrievals, so your case is worth examining for a while. I’m pretty sure you’ve done all the additional exams, like looking into the quality of the uterine cavity,(meaning a hysteroscopy), checking endometrial receptivity and other factors that are considered in cases of repeated miscarriages or failed IVFs. If you’ve not done those, there is a battery of tests to undergo. Because you’re under 40, one would always be more motivated to go along with own eggs – but obviously one has to investigate other factors more thoroughly. It is worthwhile to look into the sperm factors and do sperm DNA fragmentation tests because sperm can also account for failed fertilisation and failed implantations. You would need to get a good second opinion and just as with the patient asking before, in your case one would be a bit more motivated to try with own eggs again before going for egg donation.
Generally speaking, in patients and couples who are of overall good health and who have undergone various cycles with good response, successful fertilisation and the creation of embryos (regardless of the fact if they have implanted or not), it is a standard examination to look into the endometrium and to do a hysteroscopy/biopsy. At the same time, one could also look into endometrial receptivity because there might be an answer to the question why the pregnancy hasn’t happened so far. You might find an underlying problem – so that would be one way to look into possible failure factors.
It is a very interesting question – also for the greater audience. I will tell you a little bit about our donors and donors in Spain in general. In Spain, egg/sperm donation is anonymous. Our clinic is based in Barcelona and 85% of our donors are Spanish and 15% are not Spanish – but all of them are residents in Barcelona. Barcelona is the second biggest city in Spain and it is very cosmopolitan but we tend to have more immigration from Latin America than from Africa. In our clinic, we have the whole spectrum of ethnicities and since roughly 90% of our patients come from abroad – from all over Europe and overseas – you can imagine that we have all kinds of ethnicity on the patients’ side. That’s why we also have African or black ethnicity donors – there are waiting lists which usually not tend to exceed three months. If we do not face the crisis like the current pandemic – which is unprecedented – we have two sources of eggs. We have a big egg bank and one of the biggest egg donation programs in Europe. We have frozen/vitrified eggs and we also have donors under the stimulation so we have both a source of frozen eggs and a constant supply of fresh eggs. Naturally, it could happen that we have a perfect donor of black ethnicity straightaway – but usually, a patient with your background has to be prepared that there might be little waiting time for a donor. But as we have a lot of patients from France and the UK (with the colonial past), patients of black and Asian ethnicity as well as some mixed-race couples, we will surely find a donor for you.
There is a mix of factors here. Endometriosis affects the organs outside your uterus so it is not relevant in case of egg donation. It affects ovaries very much and it’s known to reduce ovarian reserve so the stimulation and IVF outcome when using your own eggs will be poorer. However, as I said, having endometriosis does not affect success rates in egg donation because in egg donation, we just need the inside of your uterine cavity. So that’s one thing. If your tube or tubes are removed, there is no problem whatsoever as this fact has no impact on the receptivity of your cavity. Fibroids are a different topic. Obviously, we would have to look into what kind of fibroids you have. There are three types of fibroids. The ones that are on the outside of the uterus, the so-called subserosal fibroids, don’t bother us and unless they are very big, we don’t touch them. The ones that are in the uterine wall, called intramural fibroids, do not bother us either – if they are asymptomatic and do not exceed 5 to 6 centimetres. They do not imprint or impact the cavity. The fibroids that cause problems and should be removed are the submucosal fibroids. By doing an ultrasound prior to the treatment, you will know what kind of fibroids you have and if you need any treatment before going ahead with an egg donation and the embryo transfer. That’s basically the answer. So in your case, there is no problem with endometriosis and with the removal of tubes – but when it comes to fibroids, you should know more about their location.
It is an excellent question. As I told you before, PGS or PGT-A (as it is called nowadays) is a vast topic and gives us enough material for another webinar. Yes, PGS is very expensive and as I tried to tell you, it is not recommendable in egg donation. It literally makes not much sense. Why? In egg donation we use young donors. That’s a highly selected group. Just to give you an idea of the donor selection process: our donors undergo 10 to 15 visits before they become donors. They’re tested and selected and just 30% of them reach donation. It means that 70% of the young women who present themselves in our clinic will not donate their eggs – for various reasons. So it’s a highly selected collective of young healthy women, without any problems in infertility and without any indications in their past medical history and the family history of severe genetic problems. They also undergo carrier screening for recessive diseases. So to cut long story short: there’s no indication to do PGS in young healthy women and since it is very expensive, one has to really ask the question why a clinic would recommend PGS in egg donation. I don’t really see any indication unless the male partner would have a specific genetic disease that needs a biopsy. But that is very rare. So in general, I don’t see any indication for PGS in egg donation.
I’ll come back to something what I said previously. There was a question regarding human growth hormone. You see, there are a lot of treatments out there with the intention to rejuvenate ovarian tissue cells. A good friend of mine, who is a professor at Stanford, is working with stem cells. They are working hard on this topic and so far, they have succeeded in mice. So in the future – but unfortunately not in the near future – we might have this option. We might be able to reprogram stem cells, create omnipotent stem cells and then tell them to develop into eggs, ovarian tissue or sperm cells. But now we are far away from that: it works in mice, it doesn’t work in humans. Unfortunately, anything on the market that promotes success can’t really be trusted. I strongly discourage you from doing these treatments. The only thing where there is slight evidence in regards to the increase in the number of eggs – so the egg quantity and not the quality – is DHEA. It’s not even regarded a medication, it’s a supplement. There are publications showing that it might increase the number of eggs but it’s controversial. The opinions are 50-50. So 50% of the publications say ‘yes’ and the other 50% say ‘no’. Unfortunately, there’s no treatment with scientific evidence to rejuvenate eggs or ovarian tissue. I hope my answer is sufficient to your question. I’d love to give you something but we can only offer things that are evidence-based. And so far, there’s nothing like that.
Yes, we do offer counselling. We have a lot of our doctors in home office and we do that now. You’re all very welcome to contact us. Obviously, we’re all in lockdown at the moment so as you’re at home, you might as well use this time to have a second opinion or to have counselling. Do your homework, update your medical file. I would advise you to contact us or other clinics to have counselling. Webinars are a very important tool but on a one-to-one basis, we obviously can dig much deeper into your case and go to the ground of the problem. So that’s something I would encourage you to do.
Actually, this is one of the most frequently asked questions during first visits in our clinic. We are a very big fertility centre. We do around 10,000 cycles every year in Barcelona. We usually do ICSI but sometimes we have patients who want to do conventional IVF. And we can do that – but on a regular basis, we do ICSI.
I can give you a lot of reassurance: don’t worry. In case of egg donation, there are no age groups. Your age as a recipient has no impact on the success rates of egg donation. So if, for example, you are an egg donation patient, you are 25 years old and you have premature menopause – and we have such patients although it’s rare – you don’t have higher chances of success than when being 44 years old. In Spain, the age limit for doing egg donation is 51. It means we would have to transfer the first embryo before your 51st birthday. So that’s the limit by law. And patients who are 50 don’t have lower chances of success with egg donation than you. So don’t worry, there is no impact on your success rates. Obviously, this pandemic impacts a lot of our patients and everybody is impatient and wants to start the treatment as soon as possible. However, this delay will not reduce your success rates at all.
That’s a very specific but a very good question. Let me dig deeper into the donor selection process. I’m totally with you as for thirteen years that I’ve been working here, I’ve seen many patients coming from abroad. We have a wide spectrum of very cosmopolitan clients, with all different ethnicities and phenotypes. You’re totally right that ‘Asian’ is a very broad term and I’m totally aware that saying ‘Asian ethnicity’ is not right – although it’s a true global term. Chinese has nothing to do with Japanese, Vietnamese or Malaysian – there are big differences in phenotypes and expressions. Unfortunately, if donation is anonymous by the law, it goes along with the fact that you cannot disclose more than the age and the blood group of a donor. I’m talking about Spain now. As I answered in the previous question, in our clinic in Barcelona 85% of the donors are Spanish and 15% are not of Spanish descent. We have Asian donors – but not a lot of them – and we also have mixed-raced donors. If the clinic told you that they had some frozen embryos which would match but they are not allowed to tell you the origin, it is true. We, as a clinic, always try to be as transparent as the law allows us to be and we’d always tell you that we do not have the ideal donor for you. In case of these rare phenotypes, there is usually a waiting list. When it comes to the topic of embryo donation, it is a very specific one because then the selection is even more limited. Why? The embryos that are donated originate from double donation – they are derived from an egg donor plus a sperm donor. If a couple or a single woman who used double donation has remaining embryos and they undergo an unsuccessful transfer, they will use up this reserve of frozen embryos. If a patient had a baby, she might use these frozen embryos for her baby’s future siblings. I’m telling this to make you realise that we do not have a high quantity of frozen embryos for embryo donation. We do have them but it’s a very limited number and then there’s not a lot of choice there. But coming back to your question: it’s true that we are not allowed by the law to disclose the nationality. In our case, the donor that we choose will always be as close as possible to your phenotype. And if we do not dispose of a donor or embryos to fit your criteria, we will tell you that. But when it comes to the information that can be revealed, we are allowed to tell you only the donor’s age and the blood group. Later on, if you are pregnant and have an ongoing pregnancy or when you’re close to delivery or when the baby is born, you can have some more details regarding the donor – but it’s still not the nationality. I think that would be the answer to your question.
That would be a nice topic for another presentation. Let me give you a brief summary. Actually, in our group, we have the clinic called Copenhagen Fertility Center. Its founder Professor Lindenberg is a world expert on mild stimulation. It is claimed to be more physiological and less invasive and is believed to produce the eggs that are of greater quality. However, there’s a lot of controversy around this idea. There are strong believers and strong disbelievers. I would say you have to be somewhere in the middle. I do not think you can say that less stimulation always produces higher quality eggs. But in a way, it might be a solution for advanced age. Of course, you have to be careful when saying that, in advanced age mothers, mild stimulation will produce better eggs. 40+ mothers usually have low quality eggs – that is always alike that when a woman ages. On top of that, most of them have low ovarian reserve so they lack quantity – which results in the fact that they usually do not respond well to the strong stimulation. So in this age segment, mild stimulation is actually a good idea. If a patient is between 40 and 43 and she is adamant and wants to try with her own eggs – but has low ovarian reserve – it is a fair approach. If I know that she will not respond well to conventional IVF hyperstimulation, I can choose a mild stimulation approach, knowing that she’ll give me less eggs. I’ll not go into the topic of the eggs quality. It’s so controversial that you’ll find the data to back both the ones who say that’s nonsense and the ones who are strong believers. I’m not going there. But it can be a good approach for the patients who want to try with their own eggs, have low AMH and have not responded well to a conventional cycle. However, you cannot say that this is always a good approach. But the fact is that, for example, a lot of German patients go to Copenhagen. I’m there every two months and we work together with their team and it’s a very fruitful and delightful collaboration. So if somebody thinks about mild stimulation, Copenhagen Fertility Center is for sure a good address because they have vast experience with this topic. And besides, Copenhagen is a very nice city.
In patients with lower ovarian reserve, you have to be a lot more creative. So I’m totally pro flare protocols. There can be patients who have lower ovarian reserve, maybe already some failed attempts, low response or cycle cancellation – so in these patients, before giving a second opinion, a doctor has to dig deep into the previous cycles. It means he/she has to check what type of protocol was used, what dosage, how many days of stimulation there were, how many follicles were retrieved, how many eggs were mature and so on. When I say you have to be creative, I may mean a flare protocol or treatment with estrogens in the cycle prior to the IVF cycle or double triggering – so there are lot of things in the toolbox where there is clinical evidence to use them. A flare protocol can be an option in low ovarian reserve but it’s always really worthwhile to have much more detailed information on the patient. But yes, flare protocols can be used in low response patients before passing to egg donation – in order to have some last reserve before changing the treatment technique.
In general, submucosal fibroids are an indication for removal. A 6-mm fibroid is very small, it is even hard to find. You’ll see it with an ultrasound but you might not even see it when you are on it. However, if you have a 17-mm fibroid and if it’s the case of an already failed IVF cycle, there’s a strong indication to remove it.
The answer is very easy: yes. We accept patients until the age of 51 so it means that we would have to do the embryo transfer before your 51st birthday. But as you might have learned from the previous question regarding embryo donation, we do not have a lot of embryos for embryo donation. So it means that there is some waiting time. When it comes to your Hashimoto’s, it is not a problem. We have a lot of patients with Hashimoto’s. Obviously, we need to check your TSH prior to the treatment and see if it’s properly levelled. It should be under 2.5 – then there’s no problem. And one more thing about your age: I don’t know if you’re 49 plus 1 month or 49 plus 11 months. Remember that there’s a clock ticking and be aware that at the time when you have your 51st birthday, everything ends. We would have to start the process a bit earlier as we obviously cannot do egg donation in one week – especially as there is a waiting list for the embryos.
You will find all the information on the success rates on our website. But I’ll explain it here as well. Again, I want to stress that your age doesn’t matter in regards to the success rates in egg donation. And it does not matter how old you are: if you’re 44, 50 or 25. You had three failed IVF cycles so it’s a classical indication for egg donation. It means that you’re a standard patient and with the first transfer, you’d have roughly 60% of success. Then there’s also the so-called cumulative pregnancy rate and it goes up. I’ll just skip back into nature to make you understand why the success rates in egg donation will go up. The average age of an egg donor is 25. So let’s imagine a 25-year old woman, having a normal partner and various intercourses around her ovulation. So this woman would have 20% of success rate in nature – we’d all agree that’s not a lot. Unfortunately, nature gave us not a very efficient reproductive system. However, if this woman would try every month, after one year (12 months), she would reach 90% of success rate. Why is that? 12 months means 12 ovulations and that means 12 eggs. And if we imagine fertilisation occurs every time -which is not always the case – that would mean 12 embryos. So in nature, you need 12 eggs and embryos to increase your chances from 20% to 90%. And that is reflected in the success rates of egg donation. That’s why after three cycles of egg donation, we have 93% of success rate. Obviously it is not 100% but it is very close. So I can tell you for sure that egg donation will work. Unfortunately, I cannot tell you when and with which transfer. I want to see my patients twice: in the first visit and at the first transfer – and then never again. That would mean we have 100% success rate – but of course, it’s not always like that. I always try to be transparent and say we often need more than one transfer. So to cut my long explanation short: at your age, if your uterine cavity is normal, you will have roughly 60% of success with the first transfer. And then, with each next transfer, it goes up consecutively.