Stimulation protocols – what can possibly go wrong?

Natalia Szlarb, MD
Gynaecologist & Fertility Specialist, UR Vistahermosa
From this video you will find out:
  • What exactly is an IVF stimulation protocol?
  • How are stimulation protocols tailored to individual patients?
  • What are the differences between long and short IVF stimulation protocols?
  • What role does PGT-A testing play in enhancing IVF outcomes?
  • How do stimulation protocols cater to patients with conditions like polycystic ovary syndrome (PCOS)?

IVF stimulation protocols - what can we do differently after failed IVF cycle?

What is an IVF stimulation protocol?

The term “stimulation protocol” may sound intimidating at first, but once we realise it refers simply to hormonal medication, it becomes familiar. Simply put, stimulation protocols are medication regimes aimed at stimulating the ovaries through certain dosages of hormones. As a result, fertility doctors are able to retrieve more than one oocyte in a cycle, increasing the treatment’s chances of success.

The “s” in protocols do imply that there are multiple types and variations of stimulation protocols – indeed, they should be carefully adjusted and tailored for each individual patient, as each person can respond differently to a treatment.

To help us understand stimulation protocols better, we invited Dr Natalia Szlarb, their benefits, and – most importantly – their risks. While stimulation protocols do not have a major impact on IVF per se, a poor choice can lead to diminished egg quality or health complications – an unsuccessful IVF outcome can often be attributed to using the wrong type of treatment.

Stimulation protocols were developed as a way of fighting the natural age-associated fertility decline in women. As women age, their egg quality drops significantly, especially past the age of 35 – low egg quality means a higher chance of genetic defects in the embryo, which in turn results in a higher chance of implantation failure or miscarriage. Not all eggs are defective, of course, but their percentage increases. The goal of a stimulation cycle is to press the ovaries into producing more than one egg per cycle – the idea being that if we retrieve, say, ten eggs, at least two or three will be genetically normal. Embryos can then be created – if the embryologists end up with more than one viable embryo, the surplus ones are frozen for future attempts, if needed, which removes the need for another stimulation cycle.

The choice of protocol and adjustments needed for a given patient are mostly decided by their ovarian reserve. The ovarian reserve – the total reproductive capability of an ovary – is determined through three factors:

  • the patient’s age,
  • their antral follicle count,
  • their Anti-Müllerian Hormone levels.

Together, these factors determine not only how many eggs we can reasonably expect to retrieve from a stimulation cycle, but also estimate how many of them will be genetically normal. This information is invaluable when planning a patient’s stimulation protocol.

IVF stimulation protocols

Two main kinds of protocols exist: long and short. In the general population, they differ as to pregnancy rates – long protocols are more successful (27.4% pregnancy rate) compared to short ones (23.8%). Those odds, however, are not satisfactory, which is why it’s better to use the clinic’s own variant of the short protocol with antagonists. Embryos created following such a protocol are developed until day 5 before being sent for PGS testing. Because of that, their pregnancy rates reach around 70% in most cases. It also avoids hyper-stimulating the patient’s ovaries.

Protocols using antagonists are gaining more mainstream acceptance; there are many advantages to using such a cycle over a more traditional agonist cycle. The shorter treatment time is an obvious advantage. Less obvious are the health benefits of using fewer gonadotropins, as well as the reduced risk of follicular cyst formation and ovarian hyper-stimulation syndrome (OHSS). They result in similar live birth rates, although available research only concerns day three embryos; all should be focused on developing embryos to the blastocyst stage, which increases their pregnancy rates significantly.

The full protocol developed by the clinic consists of two steps. The first step consists of a one-week stay at their Alicante clinic, where the patient undergoes controlled ovarian hyper-stimulation. Due to the specific approach, this process carries an almost non-existent risk of inducing OHSS in the patient. Following the stimulation and egg retrieval, embryos are developed for five days. Those who successfully reach the blastocyst stage undergo a biopsy for PGT-A testing and are frozen.

The second step consists of just the embryo transfer; by now, the doctors know which embryos are genetically normal and have the best chance of implantation. Only one, however, is transferred – the rest are kept in storage in case more transfers are needed. Because of this approach, we can boast an impressive 70% pregnancy rate per transfer and a 90% cumulative pregnancy rate after three transfers.

Patients affected by polycystic ovary syndrome present a special treatment case. Until recently, the common wisdom was to give PCOS patients the lowest possible dosages of hormones, as these kinds of patients are very susceptible to overstimulation. This, however, leads to poor quality eggs and a smaller than expected number of embryos per cycle, and low pregnancy rates – definitely not an ideal situation. A breakthrough, however, came when fertility specialists started using the antagonist protocol developed for egg donors on PCOS patients. This results in PCOS patients generating higher amounts of eggs – while their fertilisation rates and quality are somewhat poorer than in the general population, the higher number of eggs compensates for that, giving those patients a better fighting chance, while almost entirely eliminating the possibility of hyper-stimulation.

Patients with a low ovarian reserve also require a different approach – as Dr Szlarb puts it, “they have to work double” to achieve the results of a person with a good ovarian reserve. What this means in practice is that the patient must undergo one cycle in order to determine how many embryos can be generated; even if they manage three or four embryos, they may not be genetically normal, especially if the patient is older than 35. Embryo banking is then used to store a decently sized reserve of embryos – usually six – created over two or more cycles before attempting a transfer.

Related reading:

- Questions and Answers

I had a failed cycle with donor eggs in April. I have one 3BB and two 5BB blastocysts frozen. Is it possible to have two blastocysts transferred during my next cycle to increase the chances of success? I was 46 in March.

We do not recommend double transfers in egg donation cycles. The pregnancy rates are comparable, but there is a higher than 35% chance of you having twins. Keep in mind that twin pregnancies are always high risk, which means more doctor visits, an increased chance of pre-term delivery – and an eventual caesarean section in order to deliver the children, as nobody in Europe delivers twins the regular way anymore. Before I tell you yes, we can go forward with a double transfer, but be aware of these complications, I recommend you perform an endometrial receptivity test, because that may be the reason why the first transfer failed.

I’m 38 years old and I have gone through two failed IVF cycles in the USA. One of my ovaries is not responding. My AMH level is 0.3-0.4 and in both cycles my AFC was 4-5 follicles in the good ovary. What protocol would you recommend for me next? I plan to do another cycle in the next six months.

Like I said during the presentation, we use antagonist protocols; the precise doses need to be adjusted for each patient. As your AMH is low, so we would use low doses of FSH. Speak to your doctor – maybe it’s time to try something different, like using 150 units of pre-combined FSH to see how many eggs you can develop?

I’m a patient and I’m 31 years old, my AMH is 5.99. I underwent my first stimulation cycle last month – twelve follicles collected, ten eggs matured, seven fertilised, but only two reached the blastocyst stage. Embryo banking was suggested to us, which we agreed to. Is there a chance we will get more blastocysts during my next stimulation in August?

When we see a cycle history like this, we need to investigate what kind of protocols were used and what we can improve – if it’s a matter of egg or sperm quality, et cetera. Normally, out of seven eggs, I would expect at least four blastocysts. We discuss these cases among a group of doctors in order to determine the best course of action. In some cases, the only thing that’s required is more work – just keep doing cycles and banking embryos until you reach your goal.

What percentage of people do not achieve a genetically suitable blastocyst for transfer?

It depends on the patient’s age. It almost never happens in patients under 35. For patients over 40, though, 80% of all blastocysts will be genetically abnormal; in those over 44 or 45, this percentage can rise as high as 99%.

I’m 38 years old. I have low AMH and my husband has low sperm. I’m considering a new treatment (I had two previous failed attempts in London), but I’m not sure if I should try with my own eggs or go for donor eggs/sperm?

While this may seem counterintuitive, sometimes donor eggs can correct poor characteristics in the sperm. While overall sperm count may be low, its motility and morphology may be good; switching to a donor egg may allow us to generate blastocysts. You shouldn’t swap both factors at once – go for egg donation first.

I’m 34 years old. My AMH is 0.7. Two of my IVF cycles were cancelled as 0 eggs matured. Would you recommend trying another cycle with own eggs or moving onto donor eggs?

At 34, your AMH should allow you to have ten or fifteen eggs per cycle, at least. If none of them are mature, you should start preparing yourself for egg donation.

Do you use oestrogen priming for your antagonist protocols? I’m asking particularly in the case of patients after 40 in which you don’t want to risk too much ovarian suppression with BCP.

We use either birth control pills or oestrogen priming – it depends on the patient.

Does fragmentation/quality affect the 70% implantation rate of a euploid embryo transfer?

In a previous webinar, we showed pictures of Charlie Chaplin and Pablo Picasso, who fathered children, despite an older age and rather demanding lifestyles. I have had patients with pathologically abnormal FISH test results, patients with pathological karyotypes, and patients with high fragmentation who were able to generate genetically normal embryos for me. Not as many as healthy patients, obviously, but still – healthy embryos. Fragmentation itself does not impact implantation rates or euploidy rates, rather, it’s the karyotype and the FISH test results.

For your older patients that only get one or two blastocysts, would you skip PGT-A and just do the transfer to save the patient costs? Also, if a patient waited until the blastocyst stage only to find out that none of the embryos made it, would it then be better to do a day three transfer? Some of us are overseas and embryo banking in Spain is not feasible due to travel costs

For patients who don’t develop blastocyst, the “old school” way of thinking used to recommend transferring day three embryos since the environment in the womb was ostensibly better than a lab. The modern approach, however, is to develop embryos to day five and then perform genetic testing. If there are no blastocysts, try again, but just once – and then move on to egg donation.

Depression is not a genetic disorder. It’s an invented category within the DSM based on a cluster of arbitrary characteristics voted on by committee. I am surprised you reject donors because they achieve a diagnosis of depression and place so much weight on the opinion of a psychiatrist.

When we refer to depression in our qualification requirements, we don’t refer to “light” depression, which can be treated with medication; we refer to major depressive disorders – a condition where a person is too weak to get up from their bed. Although depression isn’t hereditary, other disorders, such as autism or schizophrenia have a genetic background, which necessitates psychiatric testing.

Do you offer psychological counselling for egg donation? Is it difficult to move on to egg donation?

We have a psychologist on staff which provides our patients with counselling. Right now we’re in the process of hiring an additional psychologist. We deal with moving on to egg donation and how to explain it to your child on the very first counselling session.

Can adenomyosis and fibroids impact IVF treatments? What protocol is suitable for them?

Adenomyosis is a form of endometriosis, in which the endometrial tissue is found in the wall of your uterus. It has an immunological impact – we treat it by giving the patient prednisone after the transfer in order to suppress the immune system. Fibroids impact the transfer stage. It’s crucial that you undergo a sonography or a hysteroscopy to ensure that the fibroids will have no impact on the uterine lining. If they are large, or if they are likely to grow during pregnancy removing them before the transfer should be considered.
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Natalia Szlarb, MD

Dr Natalia Szlarb a Gynaecologist & Fertility Specialist at UR Vistahermosa, Alicante. She graduated from a medical university in Poland in 2002 and then worked in gynaecology and obstetrics wards at several German hospitals. She also participated in international internships in Egypt, Brazil and Poland during her medical studies. In 2011 Dr Szlarb obtained her PhD in Immunology in the United States of America. She has extensive experience in IVF with donor eggs and is known by patients as a friendly and warm doctor. Dr Szlarb speaks fluent English, Polish, German and Russian.
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