In Vitro Maturation (IVM)

With in vitro fertilization (IVF) accounting for 14,000 births in Australia in 2018 alone, assisted reproductive technology is an important part of clinical care for couples seeking fertility therapy. Ovarian hyperstimulation syndrome (OHSS), particularly in women with polycystic ovarian morphology (PCOM) or polycystic ovarian syndrome (PCOS), is one of the risks associated with IVF. Oocyte in vitro maturation (IVM), an alternative that avoids the risk of OHSS, produces outcomes that are comparable to those of traditional IVF.

In contrast to traditional IVF, which retrieves mature oocytes, IVM describes the in vitro maturation of immature cumulus-oocyte complexes (COCs) obtained from antral follicles. In the 1960s, Edwards made the first spontaneous observation of in vitro maturation, and the earliest attempts at IVM used oocytes from unstimulated ovaries. In the 1990s, using donated oocytes from unstimulated ovaries, the first IVM infant was born. Trounson et al then reported a pregnancy in 1994 in a PCOS lady who had undergone IVM during an unstimulated cycle. The low pregnancy rates at the time prevented this procedure from being widely used. Then, research was conducted on particular culture settings, patient selection, and modifications to stimulation and priming techniques. Eventually, other groups utilized FSH priming, leading to better results, but the conception rates remained low.

Utilizing hCG results in higher maturation and fertilization rates, as well as pregnancy rates of about 30%. However, to identify the extrusion of polar bodies, the collected COCs had to be evaluated at various time intervals, which was an inefficient process that required numerous rounds of intracytoplasmic sperm injection (ICSI) for a single egg collection. There has been a lot of growth in the last 20 years. In 2012, when researchers originally published their research on IVM, they found that IVM with FSH priming but no hCG trigger had pregnancy rates per embryo transfer that were similar to those of traditional IVF. Pre-maturation methods and the identification of novel culture media additives recently showed promise for enhancing maturation and oocyte developmental competence. It is estimated that more than 5,000 infants have been delivered using IVM as of this point.

 

What is IVM Treatment?

In-vitro maturation, also known as IVM, is an assisted reproductive technology (ART) that involves taking eggs from a woman before hormone injections cause them to mature. Immature eggs are obtained with a simple surgical procedure, and after that, they are matured in culture using hormones or, shortly, an oocyte protein dimer that occurs naturally. The mature eggs are then often manually fertilized using a procedure known as intracytoplasmic sperm injection (ICSI). The embryos are placed in the woman's uterus once they have had time to start growing and then wait to see if pregnancy occurs. Oocyte IVM has been an option since the 1990s, but it hasn't been utilized frequently because in-vitro fertilization (IVF) produces superior results (healthier matured eggs).

 

In Vitro Maturation Benefits

As a result of FSH medication, patients with Polycystic Ovarian Syndrome (PCOS), a metabolic condition, are more likely to experience Ovarian Hyperstimulation Syndrome (OHSS). Cysts, stomach bloating, nausea, and uncontrollable weight gain are side effects of OHSS. A dangerous volume of extra fluid moves from the blood vessels to the abdomen and chest in severe cases of OHSS, which can lead to kidney and breathing issues. These consequences frequently need prolonged medical care, hospitalization, or surgical procedures, as well as the termination of the cycle.

The risk of OHSS is reduced with IVM since the FSH treatment period is substantially shorter (3 days as opposed to 10-14+ days for conventional IVF). Not only are PCOS patients helped by this reduced FSH therapy cycle, but also cancer patients. A patient who has received a cancer diagnosis, particularly breast cancer, is likely to have an extraordinary sensitivity to estrogen, which makes undergoing a long course of FSH medication challenging, if not impossible. In the past, a patient who wanted to have her mature eggs retrieved for cryopreservation would have to postpone her cancer treatment by 10 to 14 days to do so. With IVM, the patient might start their cancer treatment sooner due to the shorter course of FSH treatment.

 

In Vitro Maturation Indications

There is a large risk of OHSS for women who need IVF and have high antral follicle numbers. Because of an overactive ovarian follicular response to gonadotrophins during IVF, this potentially fatal iatrogenic disease might develop. The incidence rate of OHSS ranges from mild, which is seen in around 20-35% of cycles, to moderate to severe, which is seen in roughly 3-5% of cycles, and severe, which is found in roughly 1% of cycles. An increased risk of OHSS arises in women with PCOM or PCOS. Between 35 and 65 percent of all women with severe OHSS have a PCOS diagnosis. IVM is an alternative strategy since it reduces the risk of OHSS while achieving conception and live birth rates that are on par with those of traditional IVF. In certain clinics, PCOM or PCOS-affected women saw a live birth rate of 45% per embryo transfer with no OHSS episodes. Patients with PCOS who are thought to have a high risk of developing OHSS receive IVM during the first treatment cycle. Specialists also employ IVM in patients who have previously suffered OHSS and in women whose traditional IVF had to be stopped due to an excessive gonadotrophin response. IVM may play a role in OHSS-at-risk rural or isolated women who would otherwise need to undergo extensive monitoring after transvaginal oocyte aspiration in traditional IVF.

Women with hormone-sensitive malignancy (such as breast estrogen-sensitive cancers) who need to reduce their exposure to high estrogen concentrations during the treatment process can use IVM to preserve their fertility. Additionally, immature oocytes can be extracted at any point during the menstrual cycle, including the luteal phase, providing a variety of alternatives for urgent fertility preservation. Grynberg et al. discovered that regardless of the stage of the cycle at which egg retrieval is carried out, there was little difference in the number of COCs recovered or their in vitro maturation rates, indicating that IVM is a promising method for breast cancer patients wanting urgent oocyte cryopreservation. The number of oocytes recovered, maturation rates after 48 hours of culture, or the number of oocytes cryopreserved for COCs collected for IVM at various phases of the menstrual cycle in cancer patients requiring gonadotoxic medication were likewise not significantly different, according to Creux et al. However, there is a paucity of knowledge regarding the results of oocytes cryopreserved in cancer patients regardless of the procedure, and as this group has had relatively few live births documented, caution is advised.

 

Differences Between Old and New In Vitro Maturation Procedures

The only significant difference between the old and new IVM processes is in one area. The immature eggs are grown in cell culture after being removed from the woman's ovaries. The new technique uses a protein dimer called cumulin in place of the previous method's use of hormones to mature the eggs. The new approach generates 50% more healthy mature eggs than the old IVM did, which did not yield very healthy mature eggs.

The School of Women and Children's Health at UNSW's Associate Professor Robert Gilchrist is in charge of a group of researchers looking at these improvements to the conventional IVM method. They have discovered the power of an oocyte protein (a growth factor) that stimulates maturation instead of employing hormones to assist the egg to reach maturity. A protein dimer known as cumulin was found by Gilchrist and his colleagues to have a similar effect by interacting with the cells that support the oocyte. These two can generate healthier mature oocytes when combined with cell signaling molecules known as cyclic-AMP (c-AMP) modulators.

The problem with the IVM treatment, which is routinely practiced all over the world, is that mature eggs produced were of lower quality than those obtained by IVF. Now, it appears that cumulin and c-AMP could be used to solve the issue.

 

IVF vs IVM

Multiple hormone injections are administered to women during the egg retrieval portion of the IVF technique to promote egg maturation while the eggs are still in the ovaries. Hormone injections into the mother are not essential because the eggs are matured after retrieval using IVM. This is especially good news for women with the polycystic ovarian syndrome (PCOS), other pre-existing reproductive disorders, cancer patients, and women in remission owing to hormone-related issues or side effects.

Within a month, hormone injections, three ultrasounds, and five blood tests are all performed on IVF patients. The new IVM treatment takes less than a week and just needs a few transvaginal ultrasounds and blood tests. The hormones are normally administered as a tablet or suppository, and even if there are limited amounts of hormones with IVM, they are pared back 90 percent from what patients with IVF take. The new IVM is anticipated to cost substantially less than IVF because it involves fewer tests and labs, reduced time, and little to no hormonal injections (gonadotropins can be highly expensive).

The IVF and new IVM procedures are very similar after the egg retrieval and maturation. Both can choose to manually fertilize the eggs using intracytoplasmic sperm injection (ICSI) or mixing the eggs and sperm in a dish.

 

In Vitro Maturation Steps

The following are the main steps of the IVM Procedure:

• Step 1. To help decide the optimal moment to remove the eggs, some initial testing is conducted with ultrasound scans and a blood test. Before the procedure, women may also be advised to take hormones in pill or suppository form in tiny amounts.
• Step 2. Once the appropriate time for extraction has been determined, immature eggs are extracted using a minor surgical procedure with little to no ovarian stimulation. Ultrasound imaging is performed to direct a hollow needle through the pelvic cavity to extract the eggs. To lessen and eliminate any potential discomfort, medication is given.
• Step 3. OLD: Hormones are used to activate the immature eggs in cell culture until they develop. NEW: To stimulate the immature eggs until they mature, cumulin and c-AMP are added to cell culture. In this stage, both new and old take roughly 24 to 48 hours.
• Step 4. Manual fertilization of the eggs often involves intracytoplasmic sperm injection (ICSI) (using a tiny needle to introduce one sperm into each matured egg).
• Step 5. The doctor will perform a simple surgical procedure to inject one to four embryos into the perspective mother shortly after the eggs are fertilized and start to grow. Less than 12 days pass before knowing if implantation was successful.
• Step 6. The recently pregnant woman or couple will shift their care to an OBGYN if the cycle is successful. If the cycle is unsuccessful, the woman or the couple may decide to have another IVM cycle.

 

In Vitro Maturation Risks

IVM virtually drastically reduces the risk of developing ovarian hyperstimulation syndrome (OHSS) compared to IVF patients because there is little to no hormone stimulation of the ovaries with this procedure. Patients undergoing IVF, especially those with the polycystic ovarian syndrome (PCOS), run the risk of experiencing this. If more than one embryo is placed, there is also a likelihood of a multiple pregnancy, just like with any method of ART.

 

In Vitro Maturation Long-Term Safety

Although there have been concerns raised regarding the longer-term safety of this procedure, there has been no difference documented in congenital abnormalities between IVM and conventional IVF yet. Roesner et al. reported on a two-year developmental follow-up of kids born using IVM in 2017. They found no differences in the kids' physical and cognitive development compared to kids born via conventional IVF. There have been worries that IVM oocytes may include epigenetic diseases such Beckwith-Wiedemann syndrome or Angelman syndrome. Kuhtz et al. did not find any significant epigenetic changes in IVM oocytes, nevertheless. They concluded that the creation of DNA methylation patterns at three maternally (from mother) and one paternally (from father) imprinted genes were not significantly affected by optimized human IVM methods.

In addition, Pliushch et al in 2015 found no difference between children conceived by IVM and those conceived through conventional assisted reproduction in the methylation levels of six imprinted, five tumor-suppressor, two pluripotency, and two metabolic genes in umbilical cord samples and placental tissues.

Fadini et al. compared the obstetric and perinatal results of children born from IVM oocytes to those of infants conceived from mature oocytes in a retrospective study, reporting similar obstetric and perinatal outcomes. In comparison to traditional IVF, Buckett et al. discovered no difference in birth weight or congenital malformations in children born via IVM. Children born after IVM had normal birth weights, according to Soderstrom-Anttila. According to a different study by Buckett et al, clinical abortion rates were marginally higher in women receiving IVM than in those receiving traditional IVF. However, rates for IVM and traditional IVF in PCOS-affected women were similar, indicating that the reason for this discrepancy was underlying PCOS. Similarly, researchers found no noticeable difference in miscarriage rates between PCOS patients who had IVM treatment and those who received traditional IVF in different clinics. In women with polycystic ovaries, they did observe increased birthweights with IVM compared to traditional IVF.

 

Conclusion

IVM may produce results that are comparable to those of traditional IVF and may even be superior. The process is straightforward without pituitary downregulation. A very little hormone is provided, if any, to stimulate the IVM cycle. Because of the short treatment duration and minimal adverse effects (no OHSS), the emotional impact is minimized. IVM has significant promise as an alternative to assisted reproductive technologies and may be the preferred treatment for individuals who are not only infertile but who also wish to obtain oocytes for donation or fertility preservation in addition to those who are infertile. It is hoped that increasing endometrial/uterine receptivity by medication or other methods may increase embryonic-endometrial synchronization and increase IVM success rates. The patients should receive appropriate counseling regarding the advantages and disadvantages of the procedure.