The UK's Human Fertilisation and Embryology Authority (HFEA) recently announced that it is to review its rules on how many embryo can be implanted during IVF treatments. Transferring fewer embryos to all patients inevitably results in fewer multiple pregnancies, and we fully support measures making IVF safer. However, we recommend the HFEA critically examines the results of the current policy of transferring a maximum of two embryos for all women under the age of 40 before rushing into implementing single embryo transfer (SET). Such a policy will undoubtedly reduce multiple birth rates but at what cost?
While available evidence demonstrates that increasing the number of embryos transferred beyond two for younger women only increases the multiple birth rate, and not the pregnancy rate, the data have not been fully analysed with respect to multiple failed cycles, repeated miscarriage and type of infertility. Current policy is inflexible and favours patients with a good prognosis to the detriment of those with poor prognosis. This disregard for biological variance and previous history is not in the interests of all patients, ignores physician experience and eliminates the patient-physician decision-making process. For SET and other regulatory measures to be successful from all stakeholder perspectives, creative thinking and a degree of flexibility is required in the form of a decision-making matrix or algorithm based on evidence. Without these, regulation will favour only favourable patients.
So which patients should be offered SET? Until this question is properly answered with scientific evidence from this country, mandatory SET for all IVF patients may deny many couples the chance to conceive a child. Young, favourable IVF patients will, with time and adequate financial support, almost certainly conceive with SET - although we know from experience that some younger patients (and egg donors) do not have a good outcome despite expectations. Indeed, our experience of transferring a flexible number of embryos in Gamete Intra Fallopian Transfer (GIFT) procedures indicated that there is a sub-group of women who produced multiple embryos with IVF, but surprisingly had poor reproductive potential, even those less than 35 years of age. This is not well appreciated since most centres perform repeated IVF, and not GIFT. To such women a mandated policy of SET would be a disaster. Surely no-one would consider SET in fresh and subsequent repeated frozen embryo transfers, month in month out, if there was no potential baby in the entire cohort. Our GIFT experience confirms that this is a definite possibility in patients with repeated IVF failures. Such patients, despite being young, are likely to have a high incidence of embryo aneuploidy.
The aim of reducing multiple pregnancy, particularly triplets, to reduce premature birth and its consequences is clearly in the interests of both patients and their children. Indeed, in terms of healthcare costs, even twins are a worse option for society than singleton births. However, the conceptual leap that no-one should have twins through assisted conception does not sit well with recent findings that many patients desire twins (Ryan et al, 2004) and are unwilling to accept SET to reduce the incidence of twins (Porter and Bhattacharya, 2005) despite knowing the risks (Murray et al, 2004). In countries where SET has been successfully implemented, the women were predominantly state funded and relatively young. However, by paying the piper and calling the tune, the state removes patient choice and rights.
The Finnish (Tiitinen et al, 2003) and Belgian (De Sutter, 2003) studies demonstrating equivalent outcomes after either SET or two embryo transfer involved young women averaging 31 and 32 years respectively. In contrast, the average age of our IVF patients is 36 years and many have had multiple failures at other centres. Based on recent IVF outcome data from the United States (CDC, 2005) this age difference translates to a proportional reduction in live birth rate of around 20 per cent. It would be beneficial in formulating patient-orientated policies if the HFEA were to allow critical analysis of the large database they hold - which we have requested since 2001 - to evaluate the live birth and multiple pregnancy rates in patients of disparate age having their first, and third or greater, treatment cycles.
For SET to be successful, the following must be present: embryo selection needs to be more effective at eliminating embryos that have no chance of development to term, cryopreservation needs to be fully effective as a way of preserving embryos surplus to transfer, and/or all embryos need to have 100 per cent chance of successful implantation. Advances in embryo selection include chromosomal analysis by FISH or microarray methodologies, gene expression profiling, and even analysis of used embryo culture medium. However, the majority of IVF clinics still use only physical appearance as the means for embryo selection. In addition, embryo de-selection (whereby an embryo is never given the opportunity to be transferred) still carries the risk of disposal of potentially viable embryos. If an embryo cohort contains more than one fully viable embryo capable of developing to term, laboratories need to first maximise the chance of success at fresh transfer while effectively cryopreserving all potentially viable embryos.
The relatively high levels of abnormalities in human eggs and embryos make the prospect of having a cohort of embryos all with the ability to develop to term extremely unlikely. We urge the HFEA not to be mesmerized by the undoubted success of the SET revolution in favourable patients and to fully investigate the likely impact on patients with poorer prognosis through in-depth analysis of over a decade of data painstakingly collected in UK clinics. We believe that this analysis would aid the HFEA review. It would certainly be in the interests of the infertile.
Sources and References
2) Reproductive Biomedicine Online 6 (4) 464-469
1) Centers for Disease Control and Prevention (2005) Assisted Reproductive Technology Success Rates 2002.