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.
Other publications by Dr Natalia Szlarb