Minimal stimulation IVF options for various patients groups. Is it a “money saver” or valuable IVF protocol?

Dr Elias Tsakos, FRCOG, Medical Director at Embryoclinic – Assisted Reproduction Clinic in Thessaloniki, Greece, discussed mini/ mild IVF stimulation, its advantages over conventional IVF, and which group of patients would benefit most from that.

Conventional stimulation IVF aims to give drugs to the female patient to stimulate the ovaries and make them produce a sufficient number of eggs. Conventional stimulation dosages usually range between 200 and 400 units per day. This is the standard conventional protocol. That protocol aims to produce the maximum possible number of eggs. In the conventional stimulation cycle, there’s a trigger with beta HCG or with GnRH analogues or and then there’s an embryo transfer either in the first cycle or in a fresh cycle and a frozen cycle or just frozen cycles if we think that we should defer the fresh embryo transfer. In a standard patient, we would get enough embryos for a couple of embryo transfers. Such a patient would probably produce 5 to 10 eggs, and that would lead to a minimum of 2-3 or even up to 5 embryos. That would be enough for a minimum of 2 embryo transfers, sometimes more.

Mild stimulation IVF as a whole is a combination of either some oral treatments, Clomiphene or Letrozole or both alone or with a small dosage of FSH injections with a maximum of 150 units per day. The aim of mild stimulation is the production of a small number of eggs, so perhaps 1–4 eggs and then the trigger is the same the embryo transfer is the same. One of the differences is that invariably in the mild stimulation cycle, there are no surplus embryos. There’s no chance of a second embryo transfer, so 1 stimulation means 1 number transfer.

Mild stimulation IVF

What’s the rationale behind minimal stimulation? This is to balance the benefits and the risks. The benefits are sufficient ovarian stimulation, so to get enough eggs to produce embryos, at least 1 good embryo transfer with at least 1 or 2 good quality embryos, the production of 1 to 4 oocytes and the embryo transfer. One of the things the doctors wish to avoid is OHHS (Ovarian Hyperstimulation Syndrome), which is a production of a large number of eggs. This is usually associated with the production of maybe 12 or more eggs, and taking into account all the risks associated with that, the doctors want to avoid it. It’s very unlikely to have OHHS complications in a mild stimulation protocol. The doctors also want to avoid multiple pregnancies and the associated complications.

According to Dr Tsakos, nowadays, the majority of units in Europe don’t see that many cases of OHHS. The majority of modern, good-quality units don’t see more than perhaps 1 case every couple of years. However, when it happens, it’s associated with a lot of issues in most of the human organs, the respiratory tract (breathing difficulties), gastrointestinal tract (nausea, vomiting), the weight might be increasing rapidly, the ovarian organs are suffering, the urinary system is suffering (kidney failure), and the vascular system is suffering through dehydration and blood clotting, and potentially this could be a lethal complication.

The advantages of mild stimulation refer to the approach ‘less is more’. There’s a reduced chance of OHHS, in many studies and scientific publications, it shows 0 to 5% compared to conventional IVF. There is reduced risk of multiple gestations because perhaps 1 top-quality embryo is produced. Therefore, the chance of twins overall with mild IVF is much lower compared to conventional IVF, it’s 6 versus 32%. The pregnancy rates can be consistent in consecutive cycles, according to research, it’s about 50%. Another crucial advantage is fewer drugs, and fewer side effects, it’s not only a lower chance of getting OHHS but also less abdominal distension and pain, fewer gastrointestinal symptoms, less nausea, less vomiting and so forth. In general, mild IVF protocols are shorter and a bit more flexible.

Specific patient subgroups are more indicated to be managed with mild stimulation, in particular, poor responders, so women with a lower chance of response to medication and advanced reproductive age. Another benefit of mild stimulation is the better impact on endometrial receptivity. It has a smaller effect on endometrial receptivity. Mild stimulation is also associated with a lower cost of medication, which will translate to the opportunity to have more cycles and so forth. There’s always the option for oral medication only instead of injections. Then, there is also an option to start the cycle sooner, there’s no particular reason to wait a couple of months before the ovaries are stimulated again.

We need to keep in mind that no protocol is perfect. There are some drawbacks to mild stimulation. The first thing is the inferior pregnancy rates, overall the success is 15% vs. 29% respectively. There’s less chance of success with mild stimulation because it has been shown that the success of IVF is directly related to the number of oocytes retrieved. According to meta-analysis, there’s probably about half chance of success compared to the standard stimulation protocol. There’s also lower oocyte yield, significantly fewer oocytes compared to conventional stimulation IVF, and there is an increased chance of cancellation rates (at about 15-20%).

Current recommendations

According to ESHRE guidelines from 2019, there are three types of patients, high responders, normal responders and poor responders. For example, there is no point in giving Clomiphene in addition to gonadotropins in high responders. For normal responders, there’s perhaps no place for mild IVF stimulation. When it comes to poor responders, there’s strong evidence to suggest that they could be treated either with Clomiphene alone or with Clomiphene and small doses of gonadotropins. There’s no point in adding more than 150 units daily of gonadotropin. Another thing is that a dose higher than 200 (IU) units daily is not recommended for predicted poor responders.