Assisted reproductive technology is an important component of clinical care for couples presenting for fertility treatment, with in vitro fertilisation (IVF) contributing to 14,000 births in Australia in 2018.¹ However, risks of IVF include the occurrence of ovarian hyperstimulation syndrome (OHSS) especially in women with polycystic ovarian morphology (PCOM) or polycystic ovarian syndrome (PCOS). An alternative, incorporating the technique of oocyte in vitro maturation (IVM), provides results comparable to conventional IVF, while avoiding the risk of OHSS.²

IVM describes the maturation in vitro of immature cumulus oocyte complexes (COCs) retrieved from antral follicles as opposed to in vivo maturation as occurs in conventional IVF where mature oocytes are retrieved.³ Edwards first observed in vitro maturation occurring spontaneously in 1965, and early attempts at IVM used oocytes from unstimulated ovaries. The first IVM baby was born in 1991 using donor oocytes from unstimulated ovaries.⁴ Subsequently, in 1994, Trounson et al reported a pregnancy following IVM in an unstimulated cycle in a woman with PCOS.⁵ However, pregnancy rates at that time were very low, hence there was little uptake of this technique. Subsequently, work was done on specific culture conditions as well as patient selection and variations in stimulation and priming protocols. FSH priming was eventually adopted by some groups, resulting
in better outcomes; however; the pregnancy rates were still low.⁶

Attempts to improve outcomes using hCG trigger improved maturation rates and fertilisation with pregnancy rates around 30%.⁷ However, the collected COCs had to be assessed at multiple time points to identify the extrusion of polar bodies resulting in multiple rounds of intracytoplasmic sperm injection (ICSI) for a single egg collection, an impractical methodology. In the last 20 years, significant progress has been made. We first published our work on IVM in 2012 reporting a pregnancy rate per embryo transfer from IVM with FSH priming but no hCG trigger, comparable to that of conventional IVF.² Recently, pre-maturation protocols and the discovery of new culture media additives have demonstrated potential to further maximise maturation and oocyte developmental competence. There are now more than 5,000 babies estimated to have been born via IVM.⁸

Indications for IVM

Women with high antral follicle counts requiring IVF have a significant risk of OHSS. This can be a serious iatrogenic, potentially life-threatening condition that results from excessive ovarian follicular response to gonadotrophins during the course of IVF. The reported incidence of OHSS ranges from mild, which is seen in almost 20%–33% of cycles, whereas a moderate to severe form is found in approximately 3%–6% of cycles, and a severe form in approximately 1% of cycles.⁹ Women with PCOM or PCOS are a higher risk for OHSS. A diagnosis of PCOS characterises 37–63% of all women who experience severe OHSS.^{10 11} IVM is an alternative approach as it avoids the risk of OHSS while achieving comparable pregnancy and live birth rates to conventional IVF. In our clinic, we recorded live birth rate of 45% per embryo transfer with no episodes of OHSS in women with PCOM or PCOS.² We use IVM in the first treatment cycle for patients who are considered to have a high risk of developing OHSS, often women with PCOS. We also use IVM in women who had conventional IVF cancelled due to over-response to gonadotrophins, and in patients who previously experienced OHSS. There may be a possible role for IVM in women at risk of OHSS living in rural or remote areas, who might otherwise require intensive monitoring following transvaginal oocyte aspiration in conventional IVF.

IVM has a role in fertility preservation for women with hormone-sensitive cancer (eg. breast/oestrogen-sensitive tumours) who need to minimise their exposure to high oestradiol concentrations during the treatment cycle. Additionally, it is possible to retrieve immature oocytes at any time in the menstrual cycle, including luteal phase, thus offering flexible options for urgent fertility preservation. Grynberg et al found there was no major difference in the number of COCs recovered or their in vitro maturation rates, irrespective of the phase of the cycle at which egg retrieval is performed, suggesting that IVM is a promising tool for breast cancer patients seeking urgent oocyte cryopreservation.¹² Creux et al also found no significant difference in the number of oocytes retrieved, maturation rates after 48 hours of culture, or the number of oocytes cryopreserved for COCs retrieved for IVM at different stages of the menstrual cycle in women with cancer requiring gonadotoxic therapy.¹³ However, there is a paucity of data regarding the outcome of oocytes cryopreserved in cancer patients regardless of technique, with very few live births having been reported in this group, thus caution is recommended.

The IVM procedure

Our treatment protocol involves a short duration of stimulation, usually five to seven days of gonadotrophins, without hCG trigger, scheduling the retrieval once the lead follicle measures 1.2 cm. The average number of oocytes retrieved following an IVM cycle at our unit is 13.¹⁴ We use a 16-gauge double lumen needle, and the yield is approximately 55% of follicles aspirated. The oocytes are cultured in the laboratory for 24 hours using a combination of culture media supplemented with maternal serum, recombinant FSH and hCG. In our experience, the maturation rate is approximately 73%. Fertilisation of IVM oocytes has traditionally been done using ICSI, but our group reported similar outcomes using IVF with 68% fertilisation.¹⁵ Blastocyst development is comparable, but the total number of blastocysts available is less than in a conventional IVF cycle, a factor of the number of eggs retrieved and lower fertilisation rates. Our earlier experience found a lower pregnancy rate with fresh embryo transfer, so we adopted a ‘freeze all’ approach, transferring a blastocyst in a subsequent frozen embryo cycle, an approach which has resulted in a live birth rate that approximates those of a standard IVF cycle.¹⁴

Clinical pregnancy rates have been reported to range from 0–14.8% for cycles with no hormonal priming and between 9%–21% for cycles with hormonal priming.^{16 17 18} In a retrospective case-control study of 121 women with polycystic ovaries who underwent 178 treatment cycles from our clinic, we found an overall cumulative live birth rate of 41% with IVM and 55% with conventional IVF.¹⁴ This is likely due to the lower number of mature oocytes obtained in the IVM group (9.6 vs 12) leading to a lower number of resultant blastocysts compared to IVF/ICSI in PCOS women. Similar results have been described elsewhere.¹⁹ In women with PCOM or PCOS, IVM has a significantly lower rate of OHSS than conventional IVF, with no cases of OHSS occurring in IVM and moderate to severe OHSS occurring in approximately 7–11% of IVF-treated women.^{14 20 21}

Long-term safety

There have been concerns about the longer-term safety of this technique, but to date no difference in congenital malformations has been reported with IVM compared to conventional IVF. Roesner et al in 2017 reported on a two-year developmental follow-up of children conceived by IVM, finding no difference in cognitive development and biometric parameters compared with children conceived by conventional IVF.²² Concerns were raised that IVM oocytes might harbour epigenetic disorders such as those associated with Beckwith-Wiedemann Syndrome or Angelmans syndrome.²³ However, Kuhtz et al did not detect major epigenetic alterations in IVM oocytes.²⁴ They concluded that optimised human IVM procedures had no significant effects on the establishment of DNA methylation patterns at three maternally and one paternally imprinted genes. Additionally, Pliushch et al in 2015 did not detect any impact of IVM on methylation levels of six imprinted, five tumour-suppressor, two pluripotency and two metabolic genes in umbilical cord samples and placental tissues of children conceived by IVM compared to those conceived by conventional assisted reproduction.²⁵

In a retrospective study, Fadini et al examined obstetric and perinatal outcomes of children born from IVM oocytes comparing them to children conceived from mature oocytes, reporting comparable obstetric and perinatal outcomes.²⁶ Buckett et al found no difference in birthweight nor congenital abnormalities in babies born from IVM compared with conventional IVF.²⁷ Soderstrom-Anttila also reported normal birth weights in children born following IVM.²⁸ A separate analysis by Buckett et al found that clinical miscarriage rates were slightly higher in women undergoing IVM compared to conventional IVF. However, this difference was attributable to underlying PCOS, as rates were similar for IVM and conventional IVF in women with PCOS. Similarly, in our clinic we noticed no significant difference in miscarriage rates in PCOS women following IVM treatment compared to PCOS women who underwent conventional IVF. We did notice higher birthweights (3.34 kg vs 3.20 kg) with IVM compared with conventional IVF in women with polycystic ovaries.¹⁴

Conclusion

There are now effective ways of reducing the risk of OHSS within an IVF, cycle but the risk is still present. With IVM the risk of OHSS is avoided, with current protocols achieving comparable pregnancy rates to conventional IVF. Thus IVM is an effective and safer alternative to conventional IVF in patients at high risk of OHSS. IVM may also be offered to women in circumstances where conventional IVF poses other risks, or urgent fertility preservation is required.

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