Interpretation
This study demonstrates herein that markers such as E2, BMI and the
number of follicles ≥12mm at trigger are all independent significant
predictors of oocyte yield in women undergoing SEF. However, whilst AFC
and AMH were significant predictors of oocyte yield utilising univariate
analysis, the relationship was not significant when controlling for
other potential confounders. Whilst there are few previous studies
assessing these relationships in the context of SEF, comparisons can be
made from data from cycles performed for other indications, with
consideration for the differences in population characteristics.
AMH is considered a reliable predictor of oocyte
yield.17 However, it is well known that AMH levels are
strongly correlated with age.18 This study
demonstrates herein that AMH was a statistically significant predictor
of yield utilising univariate analysis, but when controlling for other
variables using multivariate analysis, no significant relationship was
identified. We propose therefore, that when assessing oocyte yield
controlling for confounders such as age; such interrelationships may
nullify the impact of AMH.
It is important to emphasise that women undergoing SEF are young and
fertile, unlike the vast majority of women undergoing IVF. AMH is often
used as a surrogate marker of ovarian reserve in women undergoing ART,
and therefore much of the evidence is limited to women with diminished
ovarian reserve.19 Causes of subfertility include
previous ovarian surgery or following gonadotoxic treatment with
chemotherapy or radiotherapy, resulting in diminished AMH regardless of
age.20 As such it is unsurprising that data in
infertile populations; AMH has been shown to be an independent
significant predictor of oocyte yield.21 However, as
demonstrated herein, in women who undergo SEF, age remained an
independent significant predictor even when controlling for other
variables, highlighting it as a more accurate predictor of oocyte yield
than AMH in this population.
BMI is also associated with oocyte yield.22 However,
whereas it was previously identified that oocyte quantity was lower in
obese women, compared with those with a normal BMI,23the findings demonstrated herein contrarily show that oocyte yield
increased by 2% per kg/m2 increase of BMI. The
majority of women in our cohort had a normal BMI 20.0-24.9 (n=111), less
were categorised as being underweight (BMI <20.0, n=34) and
very few were obese (BMI >30.0, n= 9). In contrast to
previous literature, the mean number of oocytes collected in the obese
group was higher than the underweight group, although not to a
significant extent (9.6 vs 8.5). This is further evidence that in the
context of SEF, patient demographics are dissimilar to the standard IVF
population. Obese infertile women may have associated subfertility
related to their body habitus, such as those with polycystic ovarian
syndrome; however overweight fertile women may not have a discernible
reduction in oocyte yield. This is exemplified by previous studies where
obese women contributed to 8.9% of the total cohort, compared to only
2.9% in our own cohort.24 This reinforces further
that much of the evidence on prediction of oocyte yield deduced from IVF
cycles in infertile women may not be extrapolatable to SEF populations.
At the time of writing 9.7% of the women who underwent SEF had returned
to use their oocytes, a mean of 3.7 years after cryopreservation. A
previous study reporting outcomes from 1382 women who underwent SEF at a
mean age of 37.7 years showed that 8.7% (n=120) women returned to use
their oocytes after a short follow up time of 2.2
years.25 Another study, using a smaller sample of 254
women in Sweden, reported that 15% (n=38) returned to use their oocytes
after a longer follow up period, returning after a mean of 4
years,26 whilst another survey reported just 6% of 96
women returned to use their oocytes, 2.8 years after undergoing
SEF.27 Current utilisation rates appear low as some
women, particularly those less than 35 years of age may subsequently
spontaneously conceive whilst their oocytes are cryopreserved.
The clinical pregnancy rate demonstrated in our cohort of women was
31.7% with a median age of 43 years old. This is comparable to the
average pregnancy rates reported by the Human Fertilisation and
Embryology Authority (HFEA) in women aged between 35-37
years.28 Such findings epitomises the reproductive
potential of SEF and provides further clinical correlation of the
concept. Just under a third (30.5%) of women who returned to use their
stored oocytes attained a livebirth. This is favourable compared to a
recent study analysing 10 years of data from two UK clinics who had a
success rate, pertaining to livebirths or ongoing pregnancies of
17.5%.29 In that study, which had a similar mean age
at cryopreservation of 37 years, successful outcomes including a
livebirth or ongoing pregnancy were achieved in 20-23% of women aged
<40. In the data presented herein, the success rate in those
who cryopreserved oocytes <40 years was higher, at 37%
(n=11/30). In the Swedish study that published outcomes of 38 women
after SEF, the cumulative live birth rate was 63%, 26% and 0% in
women of ages 36-37, 38-39 and ≥40 years at vitrification
respectively.26 When stratifying using similar age
groups in the cohort presented herein, this data presents findings, with
livebirth rates in women who underwent SEF ≤35 years of 33% (n=6),
37.5% aged 36-39 (n=24), and 0% ≥40 years (n=11).
In those women who underwent SEF over the age of 40 years old, no women
who returned to thaw their oocytes had a successful outcome, and of
those, almost three quarters (72.7%) had exhausted their oocyte store.
This proportion is more than double that reported following assessment
of outcomes from the aforementioned Swedish study, where in the 11 women
who underwent SEF over the age of 40, none achieved a livebirth, and
four (36%) had exhausted their oocyte supply.26 The
previously discussed UK study across two centres fared slightly better,
with 7% of those aged 40-42 having a successful
outcome.29 Whilst the overall numbers remain small, it
is clear undergoing SEF aged 40 or over is unlikely to be successful.
Not only are the success rates low, but the risk of miscarriage remains
elevated, exemplified by the fact the two women who suffered
miscarriages in this study were both aged >40. This is
reinforced by data that has identified the risk of miscarriage in women
aged 40-44 is 51%.30
This reaffirms that if women choose to undergo SEF, it is likely to
offer most benefit to do so by the age of 36. However, caution should be
taken advising women to cryopreserve ‘too’ early. Each case should be
individually considered, with appropriate contemplation of the
physiological, obstetric, legal and economic
considerations.31 Although storing oocytes earlier
optimises oocyte quality and enhances success rates, the likelihood of
spontaneous conception in those additional reproductive years is
greater, which would potentially have resulted in unnecessary physical
risk and substantial financial burden, in addition to the expense of
longer oocyte storage. Moreover, in the context of UK legislation,
current HFEA regulations permit the storage of oocytes for a maximum
period of 10 years.32 Therefore, storing oocytes
earlier to optimise future success may be counterproductive,
necessitating the need to prematurely use a sperm donor, to prevent the
oocytes being discarded. However, following concern regarding the
appropriateness of this legal time frame,4,33 it is
possible this legal chronological restriction may be alleviated in the
future.
The findings of this study add substantially to published literature to
identify factors that impact success following SEF. The associated
enhanced ability to counsel women regarding their probability of oocyte
yield, and subsequent livebirth is important as some women may not wish
to continue with cryopreservation if there is a suboptimal chance of
success. Whilst speculative, if women in this cohort were aware they had
a very low chance of success, they may have undergone further cycles to
optimise their future chances, or indeed if are 40 and above, not embark
upon treatment in the first place. Other studies have shown that women
are willing to undergo two or more cycles in order to retrieve
sufficient numbers of oocytes for storage.34Therefore, it is essential women have the most accurate individualised
estimate of their likelihood of future success, in order to make
informed choices regarding number of cycles and facilitate the
management of future expectations. However, it is paramount that no
matter how high the predicted percentage chance of achieving a
livebirth, women are made aware that the likelihood of a livebirth
cannot be guaranteed. This is important given evidence has suggested
women who overestimate expectancy of livebirth, or have few oocytes to
preserve often regret freezing, resulting in subsequent emotional and
psychological sequelue.35