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Early trigger modified natural cycle IVF/IVM as an attractive option for poor responders. Women with unexplained poor quality embryos

Seang Lin Tan, MBBS, FRCOG, FRCSC, FACOG, MMed(O&G), MBA
IVF Specialist & Medical Director

Category:
Failed IVF Cycles, Low Ovarian Reserve

Poor responders - is a natural cycle a good option to increase their chances
From this video you will find out:
  • What is IVM?
  • What are the indications of In Vitro Maturation in infertility treatment?
  • Natural IVF cycle, modified cycle, mild IVF and conventional IVF – what are the differences?
  • How does GnRha early trigger work?
  • What are the advantages of IVM in unstimulated ovaries? What is the cost?
  • What are the patient case studies of women who had success with this method?

 

Is modified natural IVF cycle suitable for poor responders?

In this session, Dr. Seang Lin Tan, MBBS, FRCOG, FRCSC, FACOG, MMed(O&G), MBA, Professor in Obstetrics and Gynaecology, Medical Director, OriginElle Fertility Clinic and Women’s Health Centre; Founding Director, McGill Reproductive Centre has been talking about IVM as an option for poor responders and how can it improve their chances to achieve pregnancy.

Dr. Seang Lin Tan started by defining “In vitro” which means in the laboratory. Thus, In vitro fertilization means fertilization of the eggs outside the body, whereas In vitro maturation means maturing the eggs outside the body.

Typically, in the treatment of IVF, the patients do not necessarily need medication depending on the case. Then, the biggest follicles in the ovary containing the eggs are awaited until they reach a stage when the maturation of eggs is obtained, typically when follicles are up to 20 millimetres in diameter. By that time, if no drugs are prescribed, there is usually only one follicle in the ovary.

On the other hand, if eggs were to be collected with follicles up to 14 millimetres in diameter, most of the eggs would not be mature regardless of some exceptions. Thus, IVM refers to the maturing of these immature eggs in the laboratory.

Poor responders and women with unexplained poor-quality embryos

It is known that a proportion of women undergoing IVF treatment do not respond appropriately to medication. Although it is expected that women over 40 years are not expected to respond to medication, some young women who are in their early 30s with a normal ovarian reserve might also not respond well despite a high or low dose.

Every country has different practices. For instance, in Europe, most doctors stop at 300 or 459 international medications per day while the dose of medication can be as high as 600 units in North America. However, regardless of the dosage and stimulation treatment, if few follicles are developing, patients are called poor responders. Depending on age, the percentage of poor responders can vary significantly.

It is stated that poor responders represent high proportions of women undergoing fertility treatment, as well as patients of advanced maternal age and low ovarian reserve. Some younger patients also unexpectedly demonstrate poor-quality embryos in repeated IVF treatment cycles despite a variety of ovarian stimulation regimes. In such cases, modified natural cycle IVF/IVM can be successfully used.

IVM definition and indications

In Vitro, Maturation of Eggs (IVM) is the maturing of immature eggs in culture after their recovery from small antral follicles. The reasons why IVM is used are the following:

  • The most common reason was that women with polycystic ovarian syndrome were at very high risk of developing Ovarian hyperstimulation syndrome (OHSS). Nowadays, despite all methods of stimulation, women still develop OHSS. Large doses of illegal drugs must be avoided.
  • Patients with previous poor responders or unexpected poor quality embryos for no obvious reason.
  • Alternative to FSH/ hMG IUI
  • IVM egg or embryo freezing for fertility preservation. Recommended for women who have cancer or any medical condition requiring eggs to be frozen as it is unwise to provide fertility drugs to stimulate the ovaries.

As shown in the chart in conventional IVF, patients are given stimulation protocols, either conventional FSH/hMG dose using antagonist protocols.

While in classical natural cycle IVF, no medications are given yet the patient is monitored until the biggest follicles reach 18 millimetres in diameter, and injection of hCG is given to collect 1 egg.

In Mild IVF, low doses of FSH/hMG along with antagonist or oral compounds are given with the aim of 2- 7 eggs.

The most common way is early stimulation, early trigger modified natural cycle IVF/ IVM. In this method, no drugs are given until the biggest follicles are 14 millimetres in diameter. FHS is given every day until the follicle is 17 or 18 millimetres in diameter.

GnRHa trigger in early short stimulation

Early trigger natural cycle IVF IVM without any drugs at all runs a 30% chance of premature ovulation/LH surgery and a 10% pregnancy rate. If the patient has an irregular period, we induce withdrawal bleeding by giving them medication until the follicle is 14 mm. Thanks to this method there was no case of OHSS in over 10 years (>1000 cycles).

Advantages of IVM in unstimulated ovaries compared with conventional IVR

It is a simpler treatment and reduces cost because the price of medication in some countries is high. It avoids potential side effects – weight gain, bloating, breast tenderness, nausea, mood swings and OHSS

Case study

Case 1 – A 25-year-old lady is reported to have previous severe OHSS.

A tiny dose of Puregon was provided when the 2 biggest follicles were 12 millimetres in diameter. Injection of Dalarelin (which is a GnRHa antagonist) was given afterward. It was possible to collect from her 10 mature eggs and 17 immature eggs. Only 13 of them matured after one day. In a total of 23 matured eggs, only 20 were fertilized by the sperm.  Only a grade 2 single embryo was transferred, and she got pregnant and delivered a baby boy. Four good-quality embryos at the blastocyst stage were vitrified.

IVM vs IVF egg collection

According to the paper presented in the slide, when comparing IVM to IVF, the results are about the same. In addition, the length of time to perform the egg collection is similar as well as the degree of discomfort, infection, and so forth.

Another paper from Dr Dahan showed a world record of collecting 125 eggs in early stimulation early trigger modified natural cycle IVF and IVM.

Immature eggs are collected for later maturation process in the laboratory. As soon as those eggs are matured, they are fertilized. Otherwise, those eggs will become overmatured.

Unlike IVF where estrogen levels are high due to medication, in IVM medication is not highly requested besides estrogen entrance, which is a preparation of estrogen for oral consumption one tablet three times a day starting on the day of egg collection. The dose or medication depends on the lining of the womb.

As shown in a landmark paper from 1999:

  • Cycles of IVM. 25
  • Age. 35.4+ 4.7
  • Eggs retrieved (%) 10.3 + 5.4
  • Motivation rate: 84%
  • Fertilization rate: 87%
  • Cleavage rate: 95%
  • Embryos transferred: 2.9 +0.6%
  • Clinical pregnancies- no (%) 10(40)

Dr Chen published this paper and presented that the live birth rate was at 40% in those 25 women who went through this IVM protocol.

Results of IVM treatment (2009)

After ten years the success rate increased from 40% to 56% in the cycle of egg collection while the implantation rate was 20- 23% for each embryo.

In the group where women had previous poor response of IVF, patients were given big doses of medication while in the IVM group, no medication was given. Despite this, both groups produced the same number of eggs at the end, and an average of the same number of embryos transferred. As a result, a pregnancy was achieved in the IVM. Therefore, egg donation is supposedly a viable option for women in this condition.

Conclusions

In conclusion, the injection of hCG increases the number of mature (MII) eggs and the rate of maturation. IVM is useful in unexplained, repeated poor embryo quality or poor responders. IVM in these cases can produce a 35 to 50% pregnancy rate per cycle in young women. Also, obstetric and live birth outcomes of these babies born after IVM/IVF are similar. IVM fresh embryo transfer may not be as good as IVF, but if you freeze the embryos and then transfer them, the pregnancy rate is the same. Early stimulation IVF IVM method may be a first-line approach in the number of patients and can have good results in new centres as well.

 

- Questions and Answers

In my surrogate, ‘a functional cyst’ has been found when my doctor checked her when she visited the clinic at the beginning of her cycle, so she could not be given the Diphereline shot to start the process. The doctor gave her some medication and will check it again to see if it was gone. She could take the Diphereline at the beginning of her next period. Is this something I should be worried about?

I don’t think this is something you should be very worried about. This can happen to some patients, we are talking here about preparing the surrogate for embryo transfer. Sometimes, some women especially, if they’re young do produce functional cysts, and this functional cyst may stay there for a month or two months or three months, but they invariably go with themselves. I think here is where patience is of the virtue because the surrogate is obviously young, I would just wait for the surrogate to have the cyst disappear before starting the cycle. In the meantime, freeze the embryos for the transfer in preparation for the surrogate, that’s all.

Could someone with an AMH level of 0.44 get a successful pregnancy with IVM?

We’re talking here about a potential poor responder with a low AMH level. I would say that in most cases, we would try IVF in the first instance. Here, in Montreal and Ottawa, we have had healthy babies born with IVF even if the AMH level is lower than that level. Having said that, if we get a poor response to IVF, then in the case we would use IVM, and we’ve had healthy babies born with IVM. These patients are the ones who are likely to b poor responders.

I’m 41years. My AMH is 0.2, FSH 32, I have very irregular periods. In a recent blood test, the doctor said my AMH is undetectable? Can I take DHEA, or what else can I do? I am a poor responder, I had only 3 follicles respond to stimulation during the last cycle.

I would need to know a bit more details about that previous cycle. In principle, as I said, an FSH of 32 and an AMH at 0.2 obviously says that there is an ovarian failure. The irregular periods are probably because of ovarian failure. Now, if the doctor wishes to do IVF, you can try IVF first. However, if you try IVF and you’ll find that there are virtually no eggs, you are the type of patient that is the topic of today’s lecture, we could try IVM. If you live in North America, we would have you come to Montreal for about two weeks and do everything here. If you live in Europe, we could work together with the center in Europe, do a telephone consultation, you would give them our protocol, they could do all the blood work and the essential, tests in Europe, have the first one or two ultrasound scans are done there, and we might give them a small dose of Puregon or Gonal-F f on day-4, day-6, then day-8, as I showed you on the slide. After that, as soon as the biggest follicle is 8-10 millimeters, you would need to come to Montreal or Ottawa, and then after that, as soon as the biggest follicle is 12 to 14 mm, we trigger and collect the eggs. The length of time you’ll need to spend in Canada will be about a week to 10 days if you’re doing a fresh transfer. We can also freeze the embryo, you fly back to Europe, and then you come back as a subsequent time to do the transfer. Nowadays, flying from Europe to Canada is pretty easy except for the pandemic obviously, which changed our lives but normally there are daily flights from London, Paris, Rome, Spain, all the major capitals in Europe, so coming to Montreal or Toronto is very easy. From Montreal, for example, it’s a 1.5 hour or 2-hour drive to Ottawa. We can fly directly to Ottawa as well, then have a stopover in Montreal.

What’s the cost of IVM at your clinic (Originelle, Montreal)?

If you exclude the cost of drugs an IVM cycle, we’re talking about 4 to 5 thousand dollars. The cost of drugs depends on where you buy them, you need a bit of a drug. I would suggest buying drugs in Europe because the cost of drugs, in Europe, is a fraction of the cost of drugs in North America. Drugs in North America for IVM might add an extra 1 or 2 thousand dollars, but in Europe, it might cost a couple of hundred dollars.

I have recently experienced a failed ICSI cycle after getting 11 fertilized eggs. Unfortunately, none were of good quality after day-3 and seemed not viable for transfer by day-6. Egg donation was recommended for me now. Would IVM be an option for me?

IVM would be an option. Whether it would be the best option for the next cycle, I can’t really know. In these cases, I would say it’s probably best if you contact us directly. You can send us a copy of your medical file, we could examine it in detail first before giving some advice. The information you’ve provided is just too general. Obviously, 11 fertilized eggs and then to get poor quality embryos in one cycle itself is not an absolute indication for IVM, but it would be an option. It will depend on your age, other factors, the partner’s DNA fragmentation, whether any other factors are important to consider first, whether PGT-A is considered or can be done in your country, and so on.

Can egg quality be improved with DHEA and CoQ10 alone? Is there anything else I can do to improve egg quality? If IVM isn’t an option for me?

There are many different ancillary treatments, which can so-called improve egg quality. DHEA, CoQ10 is widely known, there’s Myo-inositol that you can try, there’s MACA from South America that you can try, some people have taken baby aspirin, and so on, but none of these methods are guaranteed to work. We ourselves do give, in some cases, growth hormone to improve egg quality as well. Regarding this method, you should probably discuss it with your own doctor because I would never like to give patients advice that is overruling the patient’s own doctor.

Is there any age limit for IVM?

The age limit for IVM is the same as it is for IVF. Some doctors will stop doing IVF for women who are 41-43. They will not do IVM as well in such a case. The law here in Quebec says that it’s not possible to treat a woman with her own eggs if she’s more than 46 years old. Obviously, for IVM, it’s the same, we have to stop it if a woman is 46, but in Ontario, there’s no age limit, so long as the patient has a chance and she understands the chances are small, the treatment can be done.

What is your opinion about Duo Stimulations- is it a similar method to IVM?

It’s not the same. Duo-stim is a method of stimulation for IVF. In Duo-stim, what they do is that they will stimulate ovaries by the antagonist protocol, collect all the eggs above about 10 or 12 diameters, and about two days later, after the egg collection, start stimulation again and then do a second egg collection. In our center, we even did the triple stim, and you do get some successes. However, medication cost is expensive because we’re talking about 2 or 3 rounds of egg collections in one cycle. The cost of distribution methods is quite different from IVM, where we are trying to give little medications and collecting eggs when they are immature to be collected. So, no, Duo-Stimulations is not similar to IVM.
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Authors
Seang Lin Tan, MBBS, FRCOG, FRCSC, FACOG, MMed(O&G), MBA

Seang Lin Tan, MBBS, FRCOG, FRCSC, FACOG, MMed(O&G), MBA

Dr Seang Lin Tan is an internationally recognized IVF specialist. He was awarded the Howard Eddey Gold Medal by the Royal Australasian College of Surgeons and the MRCOG Gold Medal by the Royal College of Obstetricians and Gynaecologists in London, UK. He undertook a fellowship in REI with Prof. Howard Jacobs at Middlesex Hospital in London and another fellowship with Prof. Robert Edwards, (Nobel Laureate in Medicine 2010 and inventor of IVF) and Prof. Stuart Campbell at King’s College Hospital in London. He was the Founding Medical Director of the London Women’s Clinic, UK. He was appointed James Edmund Dodds Professor and Chairman of the Department of ObGyn at McGill University and served 3 terms from 1994 to 2010. He founded the McGill Reproductive Centre and led it for 16 years, establishing it as one of the premier IVF centres in the world. His team achieved one of the highest pregnancy rates in the world and had many national and world firsts, including the first IVM (IVF without hormonal stimulation), the first babies born after PGD and the first egg freezing baby born in Canada. He reported the world’s first 4 children born from combined IVM and egg freezing and have had over 40 babies born from women who froze their own eggs and then used them to conceive. He has referred patients from around the world for fertility treatment, including from the major centres across North America and Europe and has trained doctors who have gone on to lead major programs in Canada, USA, Oxford, Turkey, Middle East and New Zealand. A review for the Canadian Institute of Health Research (CIHR) by John Collins showed that he had the highest number of papers published of any IVF doctor in Canada and his work has been published in leading medical journals, including The Lancet, New England Journal of Medicine and Nature. Most recently, his research won the 2016 best basic science research award at the ESHRE scientific conference. I was founding President of the International Society of IVM, founding President of the Global Chinese Association of Reproductive Medicine and Vice-President of the International Society of IVF. In 2018, he was invited by the American Society of Reproductive Medicine as one of the top 40 IVF specialists in the field to contribute to a special volume commemorating the 40th anniversary of the birth of Louise Brown, the first IVF baby born in the world. He receives patients from around the world for egg freezing, IVM, egg donation and surrogacy. He is regularly invited to speak at international medical conferences and has published almost 300 peer-reviewed articles, 15 books and hundreds of presentations and book chapters.
Event Moderator
Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.
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