Avoiding multiple pregnancies in ART

Evaluation and implementation of new strategies

O. Ozturk,1, S. Bhattacharya and A. Templeton

Department of Obstetrics and Gynaecology, University of Aberdeen, Aberdeen, UK


    Abstract
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 Abstract
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Strategies for reducing the multiple pregnancies which increase perinatal mortality and morbidity in women undergoing IVF are discussed. Elective single embryo transfer with the promise of subsequent transfer of frozen–thawed embryos would achieve the goal of a single healthy child as a result of IVF treatment. The urgent establishment of a definitive trial comparing elective single versus double embryo transfer is advocated.


    Introduction
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 Abstract
 Introduction
 References
 
Women undergoing IVF treatment face a 20-fold increased risk of twins and 400-fold increased risk of higher order pregnancies (Martin and Welch, 1998Go). This is related to the current practice of transferring multiple embryos into the uterus. Such a policy challenges safe practice, increases perinatal mortality and morbidity (Lieberman, 1998Go; Sebire, 2000Go; Wennerholm et al., 2000Go) and imposes a steep financial burden on maternity and neonatal services (Callahan et al., 1994Go). The medical, social and economic consequences of multiple gestation have been the subject of much recent discussion and several preventive strategies have been identified (Hazekamp et al., 2000Go).

Selective fetal reduction remains a morbid procedure with serious ethical and legal implications (Berkowitz et al., 1996Go; McKinney et al., 1996Go). Blastocyst transfer has been proposed as a possible means of restricting multiple pregnancies by replacing fewer but more competent embryos. This service has yet to be offered by all laboratories. Unresolved issues such as criteria for selection of the most viable blastocysts (Bavister and Boatman, 1997Go), the possibility of failure to produce blastocysts in extended culture and the likelihood of fewer embryos for cryopreservation argue against routine introduction of this intervention. Currently, the best available strategy for preventing multiple births is to limit the number of embryos for transfer. The risk of triplets can be minimised without affecting the overall live birth rate by transferring two embryos instead of three (Karlstrom et al., 1999Go). The British Fertility Society encourages units in the UK to limit themselves to two embryos per transfer (Murdoch, 1998Go). But this cannot prevent twin pregnancies, which are more frequent than higher order multiples and contribute substantially to perinatal morbidity. If the ultimate goal of IVF is the birth of a single healthy child, the way ahead must lie with elective single embryo transfer (Templeton, 2000Go) with the promise of subsequent transfer of frozen–thawed embryos.

Such a policy may not necessarily appeal to all patients, some of whom may find it difficult to look beyond conception rates per treatment and focus instead on the cumulative live birth rate per couple as a measure of treatment success. Many potential parents consider multiple pregnancy to be an innocuous treatment-related side-effect (Goldfarb et al., 1996Go). Others may actually desire multiple gestation with only half of the couples in one survey having any objection to triplets and 20% deeming quadruplets acceptable (Gleicher et al., 1995Go). However, there are scanty data to indicate how aware these couples are about the complications of multiple gestation and therefore whether their decisions are indeed based on informed choice. Many are unaware that compared with singletons, twins have a 6-fold increased risk of mortality (Luke and Keith, 1992Go) and a 1:13 risk of handicap (Yokoyama et al., 1995Go). It has also been reported that after the initial achievement of parenthood, the rearing of children in these cases is stressful and fraught with practical difficulties (Doyle, 1996Go).

Another barrier to a universal policy of elective single embryo transfer is the fear of reducing existing pregnancy rates. An obvious solution here is to consider an individualised embryo transfer policy based on the identification of clinical and laboratory predictors of a higher implantation rate (Templeton et al., 1996Go). Female age, the number of embryos available for transfer and their quality (Templeton and Morris, 1998Go; Abdalla et al., 2000Go) have all been identified as key prognostic factors. Evidence from retrospective studies and prediction models suggest that an acceptable balance can be struck between a reduction in multiple gestation and overall pregnancy rates (Coetsier and Dhont, 1998Go; Strandell et al., 2000Go).

Reports of poor pregnancy rates in women where only one embryo was available for transfer (Ludwig et al., 2000Go) have been responsible for the feeling of negativity among many clinicians and patients regarding single embryo transfers. It is now clear, that in selected patients opting for elective single embryo transfers, pregnancy rates comparable with those achieved by a two embryo transfer policy (29.7% per embryo transfer) can be achieved (Vilska et al., 1999Go). Although more embryo transfers may be needed to achieve a similar live birth, the lower twin pregnancy rate of single embryo transfers is likely to make this a more cost effective option (Wolner-Hanssen and Rydhstroem, 1998Go). These data have been supported by results of the first prospective randomized trial comparing elective single embryo transfer with two-embryo transfer (Gerris et al., 1999Go) which showed similar implantation rates in both groups. More trials are underway (Strandell et al., 2000Go) but in order to have a significant impact on current practice what is urgently required is a definitive trial comparing a policy of elective single versus double embryo transfer in terms of clinical and cost effectiveness.

This should be a pragmatic randomized controlled trial with cumulative live birth as the primary outcome and multiple pregnancy and perinatal morbidity as secondary outcomes (Sibbald and Roland, 1998Go). A study aiming to show equivalence between two randomized arms will require a large sample size and a multi-centre trial is the only realistic option. An essential component of the trial would be a patient-centred outcome, such as acceptability, as well as a formal comparison of the cost effectiveness of the two protocols including a detailed analysis of obstetric and neonatal costs. To have adequate internal validity, randomization should be secure and blinding enforced. Because of the overwhelming influence of age, parity and duration of infertility on pregnancy rates, minimisation of these variables should be incorporated within the randomisation programme. Defining the sample population will not be easy. The literature highlights the importance of both patient selection as well as assessment of embryo quality (Van Royen et al., 1999Go, 2001Go; Strandell et al., 2000Go). Despite the obvious dangers of using restrictive inclusion criteria in the context of a large multi-centre trial, it is clear that an upper age limit as well as a minimum number of available embryos will need to be specified for participating women. Excessively strict eligibility criteria as well as recruitment bias due to patient preferences could threaten the external validity of the findings. The solution would lie in a hybrid design incorporating either a patient preference arm or a non-randomized cohort (Reeves et al., 1998Go). A pilot project would be helpful in assessing the feasibility of the trial while involvement of patients and clinics in the trial design could enhance acceptability. An independent data monitoring committee would help protect the interests of patients and reassure participating clinics.

Even if a trial were to be successfully conducted and the findings published, what effect would it have? It is somewhat simplistic to assume that availability of research evidence alone is enough for it to be accessed, appraised and applied in practice (Effective Health Care, 1999Go). Any proposed change would first require the development of an effective dissemination and implementation strategy. To achieve this, it is important to identify patients and clinic staff affected by the proposed change, and assess the willingness of health professionals to adapt. Undoubtedly other key factors in this context are the availability of resources and skills necessary for a successful embryo cryostorage programme.

There now appears to be enough evidence in the literature to suggest that elective single embryo transfers may eliminate multiple pregnancies without compromising the cumulative live birth rate per couple. The ongoing debate in this journal reflects collective equipoise among clinicians on this issue which is sufficient to make a randomised trial ethical as well as timely (Freedman, 1987Go). If debate is ever to be translated into action, clinicians must now take the lead in devising a clear protocol to evaluate the intervention in question. Individual clinics should be honest enough to want to participate in a trial and strong enough to accept its results.


    Notes
 
1 To whom correspondence should be addressed. E-mail: o.ozturk{at}abdn.ac.uk Back


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