The egg that came in from the cold: ASRM lifts 'experimental' label from social egg freezing

Cryobiology has allowed us to separate, both temporally and spatially, the act of gamete production from that of fertilisation and conception.

Gamete providers no longer need to be on the same continent or even be alive in order to become 'parents' in the strictly biological sense. But perhaps one of the most intriguing aspects of cryopreservation is the claim that it will allow women to 'cheat biology' and safely defer motherhood till a time of their choosing rather than a time dictated by their biological clock.

After a decade of claiming that the technique was only applicable to young cancer patients whose treatment would render them prematurely infertile, the American Society for Reproductive Medicine (ASRM) has decided that vitrification and warming of unfertilised oocytes followed by fertilisation by ICSI results in acceptable subsequent pregnancy rates. Accordingly, 'this technique should no longer be considered experimental', the organisation says.

It is now 13 years since I first suggested that elective 'social' egg freezing may offer a technological solution to the dilemma of women who long to be biological mothers but for many reasons, mostly beyond their control, are unable to have children at the time they would choose (1). The announcement from the ASRM Practice Committee gives us the opportunity to revisit the hype and hope of egg freezing.

The first 'frozen egg' baby was born in 1986, but success rates were initially so low that the potential of egg freezing was rightly neglected even as embryo freezing began to contribute to the overall success of assisted reproductive technologies worldwide. Three technologies (dehydro-cryoprotectants, ICSI and vitrification) have transformed the outlook , and now women with (young) frozen eggs have the same probability of live birth per embryo transfer as women undergoing IVF or ICSI with fresh eggs.

The ASRM systematic review identified 80 relevant articles on oocyte cryopreservation efficacy and four significant randomised controlled trials (RCTs) directly compared outcomes with cryopreserved and fresh oocytes in IVF/ICSI cycles. Two of the trials were donor/recipient cycles and two were infertile couples where supernumery oocytes were vitrified and thawed if pregnancy was not achieved in the fresh cycle.

The largest and most compelling RCT (2) compared fresh versus vitrified donor oocytes in 600 recipients. Investigators found that 92.5 percent of the vitrified eggs survived warming. Furthermore, there were no significant differences in fertilisation rates (74.2 vitrified versus 73.3 percent fresh), implantation rates (39.9 versus 40.9 percent) and pregnancy rates per transfer (55.4 versus 55.6 percent) between groups with a mean of 1.7 embryos transferred.

The ASRM committee did stress that these encouraging results may not translate to other centres with more limited experience or smaller programmes and that they represented oocytes obtained from young (under 30 years old) donors.

Larger observational studies have been carried out in Italy, where the law limited the number of oocytes that may be fertilised in an IVF attempt as surplus embryos could not be frozen. A large multi-centre prospective cohort study of infertile couples with supernumery oocytes cryopreserved using a slow freeze protocol demonstrated a higher fertilization rate (78.3 versus 72.5 percent), implantation rate (15.4 versus 10.1 percent) and pregnancy rate per transfer (27.9 versus 17 percent) with fresh rather than frozen-thawed oocytes in cycles where an average of two embryos were transferred. The lower results for the frozen oocytes may represent a selection bias in that the 'best' eggs were chosen for fresh insemination.

Several studies have assessed the impact of age on the success of oocyte cryopreservation. In the large Italian cohort, oocyte survival was similar among women of different ages and women over 38 years of age had lower implantation rates (6.5 versus 10.9 percent) and pregnancy rates (10.1 versus 18.7 percent).

In another Italian study (3) of 182 oocyte vitrification/warming cycles, on-going age-stratified pregnancy rates per embryo transfer were 48.6 percent in under-34-year-olds, 24.1 percent in 35-to-37-year-olds, 23.3 percent in 38-to-40-year-olds and 22.2 percent in 41-to-43-year-olds.

We may conclude, with the ASRM, that far from being ineffective, egg freezing, may offer women a realistic chance of biological motherhood at an age when the chance of spontaneous conception, or even conception with IVF, is unlikely.

Recent projections (4) have estimated that approximately 30 percent of graduate women in the UK will end up childless by the age of 45 and for most this childlessness will be both involuntary and age-related.

Becoming a parent remains an ideal ambition for over 90 percent of young people, but, on current trends, a significant proportion will be disappointed. Social, educational and financial pressures often lead couples to delay starting a family until their mid to late thirties and, by then, low fecundity rates and rapidly increasing rates of miscarriage, will compromise their chance of a healthy child, let alone the two children that the majority claim to want.

What are the implications of seeing early elective oocyte cryopreservation for young women as an obvious technological response to a significant social and economic problem?

An oocyte freeze cycle in a young woman in her early twenties is likely to produce a good number of high quality oocytes using a low dose of fertility medication. Contrast this with ovarian stimulation of the same woman 15 years later where a high dose of drugs is likely to produce only a low number of poor and probably mainly aneuploid oocytes.

If the woman never needs to use her frozen eggs then they can be donated or discarded. Of course there is no guarantee that these eggs will produce a pregnancy for her, but there is a better chance than trying with her own fresh eggs once she is over 40. Fifteen percent of all IVF and ICSI cycles in the UK are carried out on women of 40 or over using their own fresh eggs, and the live birth rates are very disappointing, falling to single figures by the age of 42.

However, as a society, we may want to consider some wider implications of encouraging young women to defy their biological destiny and defer breeding to their fifth decade and beyond.

The natural 'generation gap' has been historically about 20 to 25 years, so that grandparents are generally in good health and able to enjoy (and help!) with their grandchildren when they are young. But if 40 becomes a typical age for first birth, then there is a real possibility, that the mother will not only have challenging teenagers to look after by her late fifties, while juggling a career, but her own parents may well be frail and in need of support themselves.

Finally there is a risk that the knowledge that having 20 top grade eggs in the freezer may encourage women to become 'perpetual postponers' when it comes to commitment and procreation. Free of the relentless ticking of the biological clock, will women hold out for perfection in a partner and end up childless and alone?

Fortunately at least half of all babies get made 'by accident' in that the conception was unplanned and human nature, being what it is, most women continue to believe that 'the one' is just around the corner and there is no need to consider an 'insurance policy' against future age related infertility.

Cancer patients and women with medical conditions which will severely curtail their reproductive lifespan should be encouraged to freeze their eggs as it will offer them a realistic chance of genetic motherhood. In my experience, the majority of women who request purely 'social' egg freezing may have already left it too late.