Document Type : Original Article
Authors
1 Oxford Fertility Unit, Institute of Reproductive Sciences, Oxford, United Kingdom
2 Oxford Fertility Unit, Institute of Reproductive Sciences, Oxford, United Kingdom;Department of Obstetrics and Gynaecology, Faculty of Medicine, Centre Hospitalier Universitaire de Quebéc, Université Laval, Quebéc, QC
Abstract
Keywords
Ovarian superovulation with gonadotropin stimulation is still the mainstay of
PCOS is probably the most frequently encountered
endocrinopathy in women of reproductive age (
In some cycles, patients may be overstimulated, resulting in a very high number of growing follicles and increased
levels of oestradiol. This group of patients is at higher risk
of developing OHSS (
On the other end of the spectrum, management of PCOS
women with poor ovarian response (POR) can be an equally frustrating challenge. Despite the high number of small
follicles per ovary (2-3 times that of normal) (
We report a cohort of overstimulated IVF patients, as
indicated by their rapidly increasing oestradiol levels and
the large number of follicles, and a cohort of poor responders to ovarian stimulation who converted to rescue
Unplanned IVM rescue cycles were undertaken for five PCOS patients who had abnormal responses to gonadotropin stimulation as part of their IVF treatment between 2007 and 2010 at the Oxford Fertility Clinic.
PCOS was defined according to the modified Rotterdam
criteria (
Our standard protocol for IVF and IVM treatments were
described previously (
This was a case series study produced as part of an IVM
programme at Oxford Fertility Unit, UK. Statistical analysis was carried out by a biostatistician at Oxford University. Statistical analyses were done using Microsoft Excel
(Microsoft Office 365). Table was produced using Microsoft Excel (Microsoft Office 365). Graphs were produced
using GraphPad Prism 8.0.0 on Mac OSX (Apple Inc.
USA). The case series was reported using the case report
(CASE) guidelines checklist (
We present five cases of PCOS patients (see criteria above) aged between 31 and 39 years who each underwent an unplanned rescue IVM cycle due to an abnormal ovarian response to gonadotropin stimulation at Oxford Fertility Clinic between 2007 and 2010. They agreed to undergo immature oocyte maturation retrieval with subsequent IVM of oocytes to rescue their IVF treatment. Prior to the treatment, they all had normal ovarian reserves according to their early follicular phase follicle stimulating hormone (FSH) and antral follicle counts (AFC). The main results examined were biochemical pregnancy [beta human chorionic gonadotropin (βhCG) positive], clinical pregnancy rate (defined as heart activity at 8 weeks on an ultrasonography scan) and live birth rate.
Three patients (group A) were offered the option of
converting to IVM rather than cancelling their IVF cycles
as they were deemed to be at risk of developing severe
OHSS. Average oestradiol on the day of cancellation was
11 078 ± 5141.9 pmol/L (
Numbers of oocyte retrieved and matured. Bar chart shows the numbers of oocytes retrieved and matured for each patient. Patients 1-3 represent group A and patients 4-5 represent group B.
ZKPQ score comparison between the CBRC and local groups according to IVF technique
Ptno. | Age | BMI | E2 onday ofcancellation | Oocytesretrieved | Oocytesreaching MIor MII(% of total) | No.ooc ytesinjected | Fertilizationrate | No.cleavingembryos | Embryostransferred | Pregnancytest | Cycleoutcome |
---|---|---|---|---|---|---|---|---|---|---|---|
1 | 32 | 23 | 6065 | 22 | 22 (100) | 22 | 17 (77) | 12 | 2 | + | Live birth |
2 | 31 | 21 | 16340 | 34 | 28 (82) | 28 | 15 (54) | 12 | 2 | + | Miscarriage21 weeks |
3 | 34 | 23 | 10830 | 12 | 8 (67) | 8 | 4 (50) | 4 | 2 | + | Live birth |
4 | 32 | 23 | 1800 | 13 | 11 (85) | 11 | 6 (55) | 5 | 2 | + | Live birth |
5 | 39 | 24 | 2483 | 13 | 11 (85) | 11 | 8 (73) | 8 | 2 | + | Biochemicalpregnancy |
Table showing baseline characteristics of each patient, oestradiol levels on the day of cancellation of IVF treatment, as well as parameters on oocytes and embryos obtained in each
case. Patients 1-3 represent group A. Patients 3-4 represent group B. Pt; Patient, no; Number, MI; Metaphase I, MII; Metaphase II, BMI; Body mass index, and IVF;
In group B, two patients were offered the option of
rescue IVM cycle because they had POR to gonadotropin stimulation. Average oestradiol level of the day
of cycle cancelation was 2141.5 ± 482.9 pmol/L (
In both groups, all patients had two fresh cleavage embryos transferred on day 3 of development and all (100%)
had positive pregnancy tests two weeks later. Three of
the five patients (60%) gave birth to healthy singletons at
term (38 and 40 weeks) or near term (35 weeks). Unfortunately, one patient in group A had a late second trimester
miscarriage and one patient in group B had an early first
trimester miscarriage (
Our case series study shows that rescue IVM could be a viable option in PCOS patients undergoing IVF treatment but failing to safely meet the criteria for hCG triggering because of either ovarian overresponse or underresponse to hormonal stimulation.
In our study, we did not use the conventional definition
of POR as defined by the European Society of Reproduction and Embryology (ESHRE) (
There have been efforts to identify an algorithm based
on the woman’s age and markers of ovarian reserve to
optimise the FSH starting dose in assisted reproductive
techniques (ARTs). A recent study suggested that the application of a nomogram could lead to a more tailored
approach, increasing the cost-effectiveness of infertility
treatment. In general, the starting dose of FSH as calculated by the nomogram was lower than the actual prescribed
dose, which might reduce the risk of OHSS. However, the
authors also suggested the inadequacy of the nomogram
in PCOS patients, especially in those with high AMH levels (
OHSS is an iatrogenic, systemic condition secondary
to gonadotropin stimulation that occurs either during
the luteal phase or during pregnancy. The most common
form happens a few days after the induction of follicular
rupture via injection of hCG when follicular growth has
been medically induced (
Despite the advances in ARTs, one of the main challenges is the management of patients who have POR. To
this end, luteal phase ovarian stimulation and dehydroepiandrosterone (DHEA) supplementation have shown
promising results in improving outcomes in PORs. Preliminary results from a single centre pilot study by Lin et
al. have demonstrated that luteal phase ovarian stimulation significantly improved oocyte retrieval and quality
when compared to follicular phase ovarian stimulation in
patients undergoing IVF (
The success rate with IVM is associated with the number of immature oocytes obtained, which is predicted by
the AFC. Women with PCOs have higher AFCs (
There are a number of potential explanations for this.
First, the study by Jaroudi et al. (
The main limitation of our study is the sample size the high clinical pregnancy rate and live birth rate requires caution. Whilst a biostatistician carried out the data analysis, we did not calculate the sample size required before the start of the study. This was due to logistical reasons of finding cases of cancelled IVF with subsequent agreement of undergoing IVM. Arguably this affects the generalisability of our study and the ability to draw definitive conclusions based on the findings of this mini case series. However, our aim is to highlight the possibility of IVM success in a proportion of PCOS patients who fail IVF treatment in a field that has the scope for further study and research.
IVM has an inherent advantage over conventional IVF by utilising the natural menstrual cycle, and bypassing the need for ovarian stimulation and pituitary suppression, albeit at the cost for reduced chances of success. Conventionally, IVM has been considered an alternative to IVF in women at risk of OHSS or in those who may have a POR to gonadotropin stimulation. Here, we present IVM as a potential add-on treatment, which is not considered as an alternative to IVF, but rather alongside it as a rescue strategy. The advantage is that potentially recoverable immature oocytes in cancelled cycles are not wasted and the emotional stress associated with facing a potentially cancelled cycle is reduced. Additionally, it may help prevent these patients from undergoing another costly, lengthy stimulation protocol.
We conclude that rescue IVM could be a viable option in PCOS patients undergoing IVF treatments who fail to safely meet the criteria for hCG triggering, either due to overresponse to ovarian stimulation or ovarian resistance to high doses of stimulation. Conversion to IVM can still result in reasonable oocyte retrieval and lead to clinical pregnancy and live births without the risks of OHSS. Further research is needed to determine the aetiology of POR and OHSS, and identify markers that will allow us to reliably predict which patients for whom IVF is less appropriate than IVM. Larger studies are needed to determine whether rescue IVM is a widely applicable strategy for women who respond inappropriately to ovarian stimulation and its success rate.