IVF - ICSI - IVM

ART – what?

ART stands for Assisted Reproductive Treatment. This is the general term for the different fertility treatments: artificial insemination, IVF, IVF-ICSI, IVM, etc.

If spontaneous natural conception is proving difficult, various ART treatments are available. The best method of treatment depends on the nature of your fertility problem.
The CRG doctor will perform tests to find the cause of your reduced fertility: see examinations man and woman.

About insemination and stimulation tells you more about the other ART treatments at the CRG, such as artificial insemination.
But sometimes another treatment is not recommended or does not result in pregnancy.
  • If that is the case IVF or IVF with ICSI may provide a solution.
    In IVF, fertilisation (coming together of sperm and egg) does not happen in a woman's body, but in a dish in the laboratory ('in vitro' means 'in glass'). The embryos form in the dish, hence the name 'test tube baby'.
  • And then there is in-vitro maturation (IVM), a patient-friendly treatment yielding increasingly better results.
    IVM allows in vitro-development of embryos after collecting and maturing immature eggs.

In-vitro maturation of eggs: the future?

In-vitro maturation (IVM) literally means ‘maturing in glass’ of eggs, i.e. in a Petri dish in the laboratory. But in practice we use the term for the whole treatment that women undergo who want to have children (in the future) when immature eggs are collected.
In other words, IVM is an artificial reproductive technique whereby under ultrasound guidance and via the vagina small antral follicles are punctured in the ovaries (see Physiology of egg maturation).
This is how we collect immature eggs, which we then mature in the laboratory in a specific environment for 24 to 48 hours. As soon as they are mature, the eggs can be fertilised with sperm of your partner or a donor.


     

In terms of procedure an IVM-treatment at the CRG is the same as any other fertility treatment. Please read all the relevant information under IVF|ICSI, from ART Treatment at the CRG in practice to  Follow-up of pregnancy.

  • In the preliminary stage a consultation is scheduled with the CRG doctor who will evaluate whether you are suitable for IVM. The most important question is whether your ovaries contain enough follicles.
However, no guidelines exist about the minimum required number. The CRG doctor will evaluate this based on the results of a blood analysis and an ultrasound.
  • If you come into consideration for IVM, an interview with the CRG counsellor is planned and the IVM cycle is planned.
  • Day 1 of your cycle

    Day 1 of your cycle is the day you get up with bright red menstrual blood loss.
    If your period starts during the day or the blood only turns bright red over the course of the day, the next day applies as day 1.

    The IVM treatment itself also starts with an ultrasound at the start of your cycle.
    IVM is not recommended in the period around ovulation.
  • Only minimal hormonal stimulation of the ovaries (or even no stimulation at all) is required for an IVM treatment.
    We can usually collect the egg cells within a few days after the ultrasound evaluation.
  • For this we perform an ovarian punction under ultrasound monitoring: the follicles will be punctured and collected transvaginally.
  • The procedure is performed under local anaesthesia, or under general anaesthesia upon request.
    For more details about the procedure, see ‘The collection of eggs’ under IVF|ICSI Step by Step.
  • The egg cells thus collected will mature in the laboratory in a specific environment for 24 to 48 hours. The matured egg cells can then be frozen and preserved.
  • The matured egg cells:
    • can then be frozen and preserved, or
    • fertilised with your partner’s sperm or donor sperm.
      We do this through ICSI (injection of one sperm into each egg) because that technique offers the best guarantee for fertilisation.
      The embryos thus generated are frozen and preserved.
    Please make sure to also read the information about the storage of gametes and embryos.

Physiology of egg maturation

Ovarian stimulation with IVF

Ovarian stimulation with IVM

IVM as a technique


The major advantage of IVM is that you don't or hardly need any hormonal ovarian stimulation because you are not seeking superovulation of (many) mature eggs. This is the case in conventional IVF, where mature eggs are collected (also via an intravaginal puncture) and then fertilised to develop into embryos in vitro. The hormonal ovarian stimulation required for this and the superovulation can be very taxing for a patient.

IVM is therefore a more patient-friendly treatment than IVF. But although the technique has been successfully applied for decades in animals, the results were not good and stable in humans. This meant IVM was not (yet) an established practice in assisted human reproduction.
However, a number of fertility centres – including the CRG – did not lose faith in the possibilities offered by IVM. Thanks to the persistence of a number of scientists to fully understand the complexity of human egg maturation and ovulation, we can say today that IVM is on the edge of a huge breakthrough.

Physiology of egg maturation    

Before she is even born, every girl has a pool of eggs, approximately one million in each ovary. Shortly after birth these eggs stop their development in a specific division phase. They end up in a long-term situation of dormancy as ‘primordial’ follicles surrounded by feeding granular cells.
These primordial follicles – a woman's so-called ovarian reserve – can be activated. That process already starts before birth, it peaks just after puberty and ends shortly after menopause. For most follicles the activation results into programmed cell death sooner or later (atresia). This explains why a girl's egg reserve at puberty has dropped to about 300,000 to 400,000 primordial follicles.
A minority of primordial follicles develops during the fertile stage of life into antral follicles, over several months every time.
Our body uses this reserve of antral follicles during the menstrual cycle:
  • under the influence of the follicle stimulating hormone (FSH) one dominant follicle usually develops, 
  • which matures under influence of the luteinising hormone (LH), and 
  • during ovulation ends up in the fallopian tube 
  • where fertilisation by a sperm is possible.

    In women with a regular menstrual cycle usually one dominant follicle is ‘recruited’ every month. The other antral follicles – which develop in two to three waves per menstrual cycle – die.

    Ovarian stimulation with IVF     

    Standard IVF procedure is as follows (see also Used hormone preparations under IVF|ICSI-step-by-step):

    • ovarian stimulation via FSH-injections causes several pre-ovulatory follicles to develop.
    • Under the influence of a LH-trigger – also administered with injections – they mature,
    • after which they can be collected via an ovarian puncture.
    • Finally they go to the laboratory where they are fertilised with the sperm of the partner or a donor.
    • To counteract early ovulation, we suppress the spontaneous, physiological LH-increase by administering a GnRH-analogues.

     

    The so-called superovulation we want to achieve usually requires daily FSH-injections. The dose is chosen meticulously – depending on the woman's age and her ovarian reserve – to come to an ‘ideal number’ of mature eggs. ‘Ideal’ in this case means ‘as many as is necessary to guarantee the greatest likelihood of the birth of a child’.
    This individualised approach aspires to an optimum balance between the chances of success of IVF treatment and the risks. We try to avoid two risks in particular:

      But despite the ever increasing refinement in terms of composition and doses of injectable hormones, the individual ovarian reaction is often still unpredictable.
      And the impact of IVF on a patient and her partner is often underestimated. Despite reproductive medicine's decades long search for personalised, patient-friendly IVF, many couples still give up after a failed IVF-cycle because they find the treatment too hard, both physically and psychologically.
      Patients' request for a fertility treatment with less hormonal side effects and a less intensive follow-up is gradually growing. It goes without saying that wanting to have children still prevails and that a fertility treatment has to withstand the test of efficiency. But more and more patients seek a compromise: they are prepared to lose a degree of efficiency if this means less side effects.

      Ovarian stimulation with IVM     

      In IVM a much lower dose of gonadotrophins is administered, sometimes none at all. This drastically reduces the side effects for the patient.
      But in the evolution of IVM – the application and the success rate of which are increasing – there is also an economic reason. In countries where ART-treatments are not reimbursed by the government and the patients usually have to pay the expensive hormone injections themselves, IVM results in major cost cuts.

      IVM as a technique   

      Positive evolution but not yet standard

      IVM requires a degree of practice of the fertility specialist.
      Like in IVF the eggs are punctured during a transvaginal puncture under ultrasound guidance and local (sometimes general) anaesthetic. But differently to IVF the follicles are punctured at an early stage of their development, best before the selection of one dominant follicle (i.e. well before ovulation).

      In standard IVF the follicles have a diameter between 12 and 23 mm, in IVM usually between 6 and 12 mm. Smaller follicles are difficult to get to with a puncture needle.
      Moreover, immature eggs are surrounded by a compact layer of support cells (cumulus cells), which means they are harder to retrieve from the follicle wall.
      Although there are a lot of current studies into the technique of IVM egg puncture, there is no consensus about the best conditions for an optimum yield of eggs. This lack of standardisation affects the efficiency and is a hurdle in the progress of IVM.

      A lot of progress is also still possible in the field of in-vitro maturation of the eggs. A positive thing is that the study of the natural ovulation processes has led to experiments with an improved, ‘more natural’ maturation system. The results are promising and allow us to hope for a major leap forward for IVM as a fully recognised fertility technique.

      This ultrasound shows a multitude of fluid filled sacs in the fallopian tube

      Women with Polycystic Ovarian Syndrome (PCOS) form an important group in the waiting room of a fertility clinic. About ten percent of all young women have PCOS. More than a third seeks the help of a fertility specialist to help them get pregnant, usually due to ovulation problems.

      Are you a woman with PCOS for whom the first-line treatment with ovulation induction did not help? Or does your partner have low quality sperm?
      Then you are an excellent candidate for IVM-treatment.

      • In a standard IVF treatment, women with PCOS have an increased risk of OHSS and other side effects of the hormone treatment.
        Because there is little therapeutic margin to adjust the ovarian response to the gonadotrophins, the result of the standard treatment can be disappointing.

        What is AMH?

        AMH is an hormone produced by the granular cells around the primordial follicles which makes it the measure for the reserve of eggs.

      • At the same time, women with PCOS have a big reserve of antral follicles. Their development is inhibited by a high concentration of antimullerian hormone (AMH) – because a high concentration of AMH content disturbs the efficient operation of FSH.
        But for IVM high AMH-values are a blessing: the chances of success of the treatment largely depend on the reserve of antral follicles. The higher the AMH, the more eggs we can collect and mature and the greater the chances that several embryos will develop after fertilisation of the eggs.

      In fact, the mother of the first IVM baby that was born had PCOS, and this was in 1994 already. Over the years the IVM experience of fertility centres is based chiefly on the treatment of women with PCOS.
      Gradually, the indication for IVM was expanded to other patients, more specifically with a view to fertility preservation (see infra).

      IVM's role in fertility preservation


      Fertility preservation is a relatively young discipline in reproductive medicine.
      It targets (young) people with a high risk of premature infertility. It aims to improve their chances of getting pregnant in the future by freezing and storing their reproductive cells.
      Since the development of vitrification, an efficient freezing technique, the frozen storage of eggs has increased. Vitrified eggs can be stored for years, the risk of them dying after thawing is limited.

      Fertility preservation largely targets children and young adults with cancer, hence the often used term ‘oncofertility’.
      See www.oncofertility.be .

      Over the past decades cancer treatments have become increasingly efficient. This means the group of ‘healthy survivors’ has also increased. This includes many young people who want children.
      Unfortunately, as former cancer patient they were often confronted with the toxic effects of chemotherapy and radiotherapy on their reproductive cells. Population studies show that this group has 30 to 50 percent less chance of having children. And this has a huge impact on their quality of life after surviving cancer.

      This is why the CRG developed a fertility preservation programme, which allows girls and young women to freeze ovarian tissue and/or eggs in the short term, before starting chemo- or radiotherapy. In boys and young men we freeze testicular tissue and/or sperm.
      Thanks to this preventive approach the chances of reproduction of this group of patients have improved greatly.

      The role of IVM in fertility preservation     

      Young women diagnosed with cancer have been able to have mature eggs frozen after hormonal ovarian stimulation followed by an egg puncture for longer.
      The problem is that hormonal stimulation usually takes two to three weeks. Delaying the start of an oncological treatment can be dangerous for some cancers. Collecting immature eggs from the ovary offers a good alternative. An IVM egg puncture can be planned in the very short term, without prior hormone treatment. The collected immature eggs can be matured in the laboratory, after which they are frozen.
      For oncological patients with hormone sensitive tumours IVM is also a safe alternative to freeze eggs.

      A recent, still experimental application of IVM targets patients who had an operation to remove (an) ovary (tissue) for freezing. This is mostly done as part of an urgent cancer treatment or for prepubertal girls with cancer. Hormonal stimulation is not possible before puberty.
      Thanks to frozen storage of (the outer layer of) the ovary we can save the primordial follicles stored here. Later the tissue can – after recovery – be transplanted if the patient shows signs of ovarian insufficiency as a result of the cancer treatment. By transplanting thawed ovarian tissue we try to restore the ovarian function.

      After removing the ovarian outer layer we cut it into small fragments, which we freeze. This gives us several pieces of tissue to thaw and transplant – possibly in different phases.
      During the procedure immature eggs are often released as well in the laboratory. They can be matured in vitro and then vitrified in the same way as the maturation and vitrification of eggs we collected via a transvaginal egg puncture. Because this concerns eggs from the ovary after it was removed from the body, this technique is also referred to as ‘ex vivo’ IVM.

      For a growing group of young cancer patients ‘ex vivo’ eggs are a potentially important source of reproductive cells that allows us to treat their possible infertility after cancer therapy.

      When a technique is launched in reproductive medicine, studies test the safety and the health effect on children born thanks to this technique.
      The fear with IVM was that it might be unsafe to use eggs collected before the pre-ovulation stage as antral follicles and which still need to develop in a culture system outside the body.
      Meanwhile, a number of fertility centres with considerable IVM expertise have published studies based on follow-up data of IVM children. This shows no differences concerning the risk of congenital defects between children born from IVM and children born after IVF/ICSI. The same applies to the weight at birth: it does not differ for either group of children, nor does it compared to children born following a spontaneous pregnancy.
      The risk of minor and major abnormalities after IVM amounts to less than five percent in all published studies. And studies into the possible effect of in-vitro culture on the epigenetic context of eggs also show reassuring findings.
      In other words, gradually we can start considering IVM as a routine fertility treatment and no longer as an ‘experimental’ technique.

      However, we have to bear in mind that worldwide it is estimated only about 5,000 children have been born after IVM. This number is in sharp contrast with the more than four million IVF children that have been born over the last decades. More follow-up studies are necessary and are being conducted.
      Without wanting to state that conventional IVF is over its peak as a fertility technique, we notice a growing demand in prospective parents for a shorter, less hormonally taxing and safer treatment.
      IVM meets this request and is far more patient-friendly. The number of check-up visits to follow up the treatment is lower, less injections are needed for ovarian stimulation and the cost of the medication is significantly lower than conventional IVF treatment. Moreover, the chances of success of IVM treatment have increased over the last years: the chance of a pregnancy often amounts to more than thirty percent per cycle.
      However, the technique is only available in a small number of centres. And even in these ‘expert centres’ the chances of pregnancy are still higher with a standard IVF treatment.
      This is why further research is being conducted, both clinical and scientific, to increase the efficiency of the technique and to refine the IVM culture method.
      Whether this research and its promising results will result in a more widespread application of IVM in the end we will have to wait and see. The centres offering treatment are enthusiastic and see their efforts rewarded by a growing number of healthy babies.