Hum. Reprod. Advance Access originally published online on June 24, 2004
Human Reproduction 2004 19(9):1939-1942; doi:10.1093/humrep/deh379
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
What is the most relevant standard of success in assisted reproduction?
Redefining success in the context of elective single embryo transfer: evidence, intuition and financial reality
Department of Obstetrics and Gynaecology, University of Aberdeen, Aberdeen Maternity Hospital, Cornhill Road, Aberdeen AB25 2ZD, UK
1 To whom correspondence should be addressed. Email: s.bhattacharya{at}abdn.ac.uk
 |
Abstract |
|---|
 Top Abstract IntroductionEvidenceDefining success in IVFSelectivity of a SET...Financial arrangementsCouples' viewsConclusionsReferences |
|---|
Treatment-related multiple pregnancy poses the biggest threat to the safety of IVF. Despite a double embryo transfer (DET) policy in most European centres, twin rates continue to be unacceptably high, at 20–35%. Elective single embryo transfer (SET) is an effective way to minimize twin pregnancies, but the debate surrounding its routine clinical use continues. A review of the literature was undertaken in order to seek evidence about the effectiveness of SET, and identify barriers to its acceptance in clinical practice. Data from randomized controlled trials (RCTs) indicate that SET results in lower live birth rates per fresh IVF cycle (odds ratio 0.53; 95% confidence interval 0.31–0.89; P=0.02) in comparison with DET. Data on cumulative live birth rates are unavailable from RCTs, although the expectation is that these are comparable in the two groups. SET is unlikely to be suitable for all women undergoing IVF and outcomes may be sensitive to different laboratory protocols. The perceived effectiveness of SET is influenced by the way existing evidence is interpreted. Other factors affecting the routine use of SET include laboratory techniques, individual preferences and funding issues.
Key words: single embryo transfer/assisted reproduction/patient acceptability
|
Introduction |
|---|
|
TopAbstractIntroductionEvidenceDefining success in IVFSelectivity of a SET...Financial arrangementsCouples' viewsConclusionsReferences |
|---|
The debate about single embryo transfer (SET) as a step towards eliminating multifetal gestation is not new (Bronson, 1997
). Treatment-related multiple pregnancies, including twins, are acknowledged to be the biggest threat to the future safety and success of IVF (Bhattacharya and Templeton, 2000; ESHRE Campus Report, 2001). Most European centres have moved away from a three-embryo to a two-embryo transfer policy. As a consequence, triplet rates have fallen, but the twin rate continues to be unacceptably high, at 20–35% (Nyboe Andersen et al., 2004). The immediate perinatal and maternal complications associated with twins are well known (Yokoyama et al., 1995; Bergh et al., 1999; Campbell and Templeton, 2004). In addition, twin pregnancies add substantially to the cost of pre-natal and neonatal intensive care, and can impose an additional long-term societal and economic burden (Garel and Blondel, 1992; Callahan et al., 1994).
Primary prevention, by limiting the numbers of embryos transferred, is a logical and effective way to minimize iatrogenic twin pregnancies (Coetsier and Dhont, 1998; Templeton, 2000; ESHRE Campus Report, 2001). Nevertheless, countries adopting an elective SET policy have been in the minority. Worldwide, the views on SET are polarized. Some countries have incorporated SET within their day-to-day clinical practice, and others have accepted, at least in principle, the justification for this course of action. This still leaves many more that are yet to concede that limiting the number of embryos has any effect other than reduction of success rates. What is the reason for this disparity in opinions and practices? Is there a social and cultural context that defines our attitudes towards SET? In this article, we propose to analyse the evidence for such a recommendation and argue that a change in practice can only be achieved if we can convince those seeking treatment as well as those responsible for delivering it.
|
Evidence |
|---|
|
TopAbstractIntroductionEvidenceDefining success in IVFSelectivity of a SET...Financial arrangementsCouples' viewsConclusionsReferences |
|---|
Most clinicians accept the need to minimize multiple pregnancies and readily acknowledge that the most desirable outcome of IVF treatment is a singleton pregnancy. At the same time, many are reluctant to reduce the number of embryos transferred in the context of IVF, for fear of compromising pregnancy rates. Their anxieties have been compounded by reports in the literature demonstrating poor pregnancy rates in women where only a single embryo was available (Hunault et al., 2002
). Few studies have specifically addressed the issue of SET (Ozturk et al., 2004). Their results indicate that, in specific groups of women, using strict embryo selection criteria, SET results in acceptable pregnancy rates while virtually eliminating twin pregnancies. A policy of repeated transfer of thawed cryopreserved spare embryos can lead to a cumulative live birth rate comparable to that achieved by double embryo transfer (DET) (47–53%) (Vilska et al., 1999). The actual numbers of randomized controlled trials (RCTs) performed so far have been small (Gerris et al., 1999; Martikainen et al., 2001; Lukassen et al., 2002). A meta-analysis of their results indicates that, compared with DET, SET results in lower clinical pregnancy [odds ratio (OR) 0.48; 95% confidence interval (CI) 0.29–0.8; P=0.01] and live birth (OR 0.53; 95% CI 0.31–0.89; P=0.02) rates per woman per fresh IVF cycle. Predictably, the multiple pregnancy rate following SET is substantially reduced (OR 0.10; 95% CI 0.03–0.38; P=0.01). Unfortunately, data on cumulative live birth rates are unavailable from these RCTs, although the expectation is that these may be comparable between the two groups, as is suggested by observational studies (Tiitinen et al., 2001). |
Defining success in IVF |
|---|
|
TopAbstractIntroductionEvidenceDefining success in IVFSelectivity of a SET...Financial arrangementsCouples' viewsConclusionsReferences |
|---|
As long as outcomes in IVF are defined in terms of a fresh IVF cycle, the results shown above are unlikely to convince the majority of doctors or patients about the desirability of SET. Yet, for a number of historic, bureaucratic and financial reasons, this is how success rates in IVF are generally presented. ‘Live birth per cycle’ has become the currency of IVF around the world, and is understood and accepted by consumers, service providers and regulatory bodies (Human Fertilization and Embryology Authority, 2003
). Many workers have suggested that expressing outcomes as live birth per woman makes better practical and statistical sense (Vail and Gardener, 2003). Others have argued that live birth per oocyte retrieval may be more logical. This would include results after fresh and frozen embryo transfer of all embryos created as a result of a single fresh treatment cycle (Ozturk et al., 2001). It is easy to see why these views have not been popular with researchers and clinicians in the past. Expressing the outcome as live birth per couple per oocyte recovery will mean an indefinite period of follow-up, as not all couples will use their spare embryos within a constant and predictable period of time. It will also introduce further complexities if women have multiple pregnancies from the same set of embryos created from a single oocyte retrieval process. From a practical point of view, annual reports of success rates per clinic as currently drawn up by the Human Fertilization and Embryology Authority would be difficult to generate. Other outcomes that have been suggested include singleton live births and term singleton live births (Min et al., 2004). While both these approaches underline the importance of a healthy singleton birth as the desired outcome of fertility treatment, they still focus on outcomes per (treatment) cycle. While these terms will appeal to obstetricians, they are unlikely to find favour with patients. Couples on the threshold of IVF treatment may find it difficult to see beyond the short-term gains of a pregnancy, and focus on the longer term benefits of a healthy singleton child. |
Selectivity of a SET policy |
|---|
|
TopAbstractIntroductionEvidenceDefining success in IVFSelectivity of a SET...Financial arrangementsCouples' viewsConclusionsReferences |
|---|
A major problem with the option of SET is the fact that it has never been, and cannot be, implemented as part of a universal clinical policy. Available data indicate that SET should be reserved only for women who are at significant risk of multiple gestation. This includes those who are relatively young, in their first or second IVF cycle, and who possess a number of good-quality embryos (Hunault et al., 2002
). The SET policy is thus only applicable for a subgroup of ‘twin prone’ couples whose precise definition has varied from centre to centre. As a result of this, the generalizability of the evidence generated so far can be questioned. One of the key questions about SET is therefore not just whether the policy works, but in whom it works best. This needs greater clarification if SET is to become part of routine IVF, instead of being the preserve of a few who are skilled at spotting the right woman and the right embryo.
Even among those who have argued in favour of SET, there is still some uncertainty about the best laboratory protocol. Many workers will ensure that only the ‘top’ embryo, i.e. one with potentially the best chance of implantation, is transferred, in order to optimize the chances of pregnancy in that (fresh) treatment cycle. This can involve observing embryos in culture in order to select the best for transfer (Van Royen et al., 1999), and relies on a cull of other embryos of relatively poor quality. This can limit the numbers of embryos available for cryopreservation and replacement in future cycles. Such an approach challenges the proposed argument that SET can achieve high cumulative pregnancy rates by maximizing embryo cryopreservation and multiple single embryo transfers (Templeton, 2000; Tiitinen et al., 2001). The two approaches may not be mutually compatible. One relies on multiple fresh cycles with repeated transfer of top quality (single) embryos, and the other relies on the availability of an active and efficient freezing programme. The truth is that freezing standards are not uniform and funding arrangements for IVF are complex.
|
Financial arrangements |
|---|
|
TopAbstractIntroductionEvidenceDefining success in IVFSelectivity of a SET...Financial arrangementsCouples' viewsConclusionsReferences |
|---|
As long as couples have to bear the costs of IVF treatment and are charged either for multiple IVF cycles (resulting in a transfer of the single best embryo) or both for cryopreservation and for thawing and replacement of embryos, they will be reluctant to opt for SET. A policy of SET has, so far, worked well in European settings where IVF is subsidized. In the case of Belgium, prior to 2002, 75% of the costs of IVF were reimbursed. In 2002, infertility officially gained recognition as a medical condition and the Belgian Society for Reproductive Medicine proposed a move to abolish triplets and reduce twins by 50%. Under these new proposals, women under the age of 42 years would be eligible for six fully funded cycles of IVF with a policy of SET in place for the first and second cycles for women under 35 years old. Assuming 1750 pregnancies from 7000 cycles in Belgium, the additional costs of treatment would be
8.4 million. These costs would be offset completely by 9.1 million saved by eliminating triplets and minimizing twins (W.Ombelet, personal communication). The feasibility and ultimate success of such a policy is dependent on the circumstances of the funding arrangements for IVF. Implementation of such a plan may be problematic in other settings, such as in the UK, where many couples pay directly for IVF, while the cost of neonatal care is borne by the National Health Service (NHS). The recently published NICE guidelines on infertility (National Collaborating Centre for Women's and Children's Health, 2004) has partially addressed this problem by recommending at least one NHS-funded IVF cycle for all eligible couples in England and Wales. For many couples this will be their only chance of IVF, while for others it means having to pay for subsequent attempts. Without the reassurance of multiple funded IVF attempts, a national SET policy looks far from feasible. |
Couples' views |
|---|
|
TopAbstractIntroductionEvidenceDefining success in IVFSelectivity of a SET...Financial arrangementsCouples' viewsConclusionsReferences |
|---|
Although some clinicians feel that a high twin rate is an unacceptable consequence of trying to increase pregnancy rates (Hazekamp et al., 2000
), some couples think differently (Goldfarb et al., 1996). Others may actually see twins as a desirable outcome of IVF (Gleicher et al., 1995). This view is particularly strongly expressed in mothers of IVF twins (Pinborg et al., 2003). To many couples undergoing IVF, the immediate concern is failure of treatment, not the more remote risk of feto-maternal complications. To many, having twins offers a cost-effective way of completing their family and may represent a willingness to take risks in order to achieve a pregnancy. This may be due to insufficient information about the risks of twins. The source of much of the information acquired by couples is the IVF clinic itself. While it is possible that improved methods of communicating risks to couples may achieve the desired effect, this is not inevitable (Murray et al., 2004). What could change the minds of these women is relief of the financial burden currently in place in some situations, where most couples are charged for cryopreservation of embryos and again for replacement. It is clear that instinctive acceptance of SET is low (20%) in many couples (Pinborg et al., 2003; Murray et al., 2004). In a study by Murray et al. (2004), fewer than one-third of UK couples in their early to mid-thirties, embarking on their first IVF cycle, felt that a hypothetical policy of SET was acceptable if it meant slightly reduced pregnancy rates. Over 50% would favour SET, as long as they were not charged separately for cyropreservation of spare embryos and all embryo transfers accruing from a single oocyte retrieval. If pregnancy rates were on par with a DET policy, the uptake of SET would increase to >80% Thus a policy of SET is not one that couples find instinctively appealing, but one that they would be prepared to consider subject to a number of pre-conditions. Thus, as Pinborg et al. (2003) concluded, if legislation is considered as the final step in implementing SET, this will need to be backed up with adequate funding for multiple treatments. |
Conclusions |
|---|
|
TopAbstractIntroductionEvidenceDefining success in IVFSelectivity of a SET...Financial arrangementsCouples' viewsConclusionsReferences |
|---|
The available data about the effectiveness of SET are open to interpretation, depending on what outcomes are considered meaningful. In our approach to the use of SET in minimizing twin pregnancies, we have yet to overcome a tendency towards an intuitive interpretation of the limited body of evidence. Choice of treatment for infertility is highly sensitive to individual preferences. This raises important questions about the extent to which couples can, and do, influence clinical decisions. As a profession, we need to be consistent in our approach to this clinical dilemma and sensitive to factors that affect decision making in our patients. Six years on from the first open debate about SET in this journal, it would appear that we still have a long way to go. We may well need to start all over again, and this time, we need to carry our patients with us.
|
References |
|---|
|
TopAbstractIntroductionEvidenceDefining success in IVFSelectivity of a SET...Financial arrangementsCouples' viewsConclusionsReferences |
|---|
Bergh T, Ericson A, Hillensjo T, Nygren KG and Wennerholm UB (1999) Deliveries and children born after in-vitro fertilisation in Sweden 1982-95: a retrospective cohort study. Lancet 354, 1579–1585.[CrossRef][ISI][Medline]
Bhattacharya S and Templeton A (2000) In treating infertility, are multiple pregnancies unavoidable? N Engl J Med 343, 58–59.
Bronson R (1997) How should the number of embryos transferred to the uterus following in-vitro fertilization be determined to avoid the risk of multiple gestation. Hum Reprod 12, 1605–1618.
Callahan TL, Hall JE, Ettner SL, Christiansen CL, Greene MF and Crowley W Jr (1994) The economic impact of multiple gestation pregnancies and the contribution of assisted reproduction techniques to their incidence. N Engl J Med 331, 244–249.
Campbell D and Templeton A (2004) Maternal complications of twin pregnancy. Int J Obstet Gynecol 84, 71–73.
Coetsier T and Dhont M (1998) Avoiding multiple pregnancies in in-vitro fertilization: who's afraid of single embryo transfer? Hum Reprod 13, 2663–2664.
ESHRE Campus Report (2001) Prevention of twin pregnancies after IVF/ICSI by single embryo transfer. Hum Reprod 16, 790–800.
Garel M and Blondel B (1992) Assessment at one year of the psychological consequences of having triplets. Hum Reprod 7, 729–732.
Gerris J, De Neubourg D, Mangelschots K, Van Royen E, Van de Meerssche M and Valkenburg M (1999) Prevention of twin pregnancy after in-vitro fertilization or intracytoplasmic sperm injection based on strict embryo criteria: a prospective randomized clinical trial. Hum Reprod 14, 2581–2587.
Gleicher N, Campbell DP, Chan CL, Karande V, Rae R, Balin M and Pratt D (1995) The desire for multiple births in couples with infertility problems contradicts present practice patterns. Hum Reprod 10, 1079–1084.
Goldfarb J, Kinzer DJ, Boyle M and Kurit D (1996) Attitudes of in vitro fertilisation and intrauterine insemination couples towards multiple gestation pregnancy and multifetal pregnancy reduction. Fertil Steril 65, 815–820.[ISI][Medline]
Hazekamp J, Bergh C, Wennerholm UB, Hovatta O, Karlstrom PO and Selbing A (2000) Avoiding multiple pregnancies in ART. Hum Reprod 15, 1217–1219.
Human Fertilization and Embryology Authority (2003) [On-line]. http://www.hfea.gov.uk/Downloads/PatientsGuide/PGAggData9901.pdf (date last accessed 15/01/04).
Hunault CC, Eijkemans MJC, Pieters MHEC, te Velde ER, Habbema JD, Fauser BC and Macklon NS (2002) A prediction model for selecting patients undergoing in vitro fertilisation for elective single embryo transfer. Fertil Steril 77, 725–732.[CrossRef][ISI][Medline]
Lukassen HGM, Braat DDM, Zeilhuis GA, Adang EM and Kremer JAM (2002) 2x1 versus 1x2, a randomised study. Hum Reprod 0-005 Abstracts V-0064 of the 18th Annual Meeting of the ESHRE, Vienna, Austria, 2002.
Martikainen H, Tiitinen A, Candido T, Tomas C, Tapanainen J, Orava M, Tuomivaara L, Vilska S, Hyden-Graskog C, Hovatta O et al. (2001) One versus two embryo transfer after IVF and ICSI: a randomized study. Hum Reprod 16, 1900–1903.
Min JK, Breheny SA, MacLachlan V and Healy DL (2004) What is the most relevant standard of success in assisted reproduction? The singleton, term gestation, live birth rate per cycle initiated: the BESST endpoint for assisted reproduction. Hum Reprod 19, 3–7.
Murray S, Shetty A, Rattray A, Taylor V and Bhattacharya S (2004) A randomized comparison of alternative methods of information provision on the acceptability of elective single embryo transfer. Hum Reprod 19, 911–916.
National Collaborating Centre for Women's and Children's Health (2004) Fertility: Assessment and Treatment for People with Fertility Problems. In Commissioned by the National Institute for Clinical Excellence. RCOG Press, London, UK.
Nyboe Andersen A, Gianaroli L and Nygren KG (2004) The European IVF-monitoring programme (EIM) for the European Society of Human Reproduction and Embryology (ESHRE), Assisted reproductive technology in Europe, 2000. Results generated from European registers by ESHRE. Hum Reprod 19, 490–503.
Ozturk O, Bhattacharya S and Templeton A (2001) Avoiding multiple pregnancies in ART: evaluation and implementation of new strategies. Hum Reprod 16, 1319–1321.
Ozturk O, Bhattacharya S, Serour GI and Templeton A (2004) Number of embryos for transfer following in-vitro fertilisation or intra-cytoplasmic sperm injection (protocol for a Cochrane Review). In The Cochrane Library, Issue 2. John Wiley & Sons, Chichester, UK.
Pinborg A, Loft A, Schmidt L and Andersen AN (2003) Attitudes of IVF/ICSI twin mothers towards twins and single embryo transfer. Hum Reprod 18, 621–627.
Templeton A (2000) Avoiding multiple pregnancies in ART. Replace as many embryos as you like - one at a time. Hum Reprod 15, 1662.
Tiitinen A, Halttunen M and Harkki P (2001) Elective single embryo transfer: the value of cryopreservation. Hum Reprod 16, 1140–1144.
Vail A and Gardener E (2003) Common statistical errors in the design and analysis of subfertility trials. Hum Reprod 18, 1000–1004.
Van Royen E, Mangelschots K, De Neubourg D, Valkenburg M, Van de Meerssche E, Ryckaert G, Eestermans W and Gerris J (1999) Characterization of a top quality embryo, a step towards single-embryo transfer. Hum Reprod 14, 2345–2349.
Vilska S, Tiitinen A, Hydén-Granskog C and Hovatta O (1999) Elective transfer of one embryo results in an acceptable pregnancy rate and eliminates the risk of multiple birth. Hum Reprod 14, 2392–2395.
Yokoyama Y, Shimizu T and Hayakawa K (1995) Incidence of handicaps in multiple births and associated factors. Acta Genet Med Gemellol (Roma) 44, 81–91.[Medline]
Submitted on March 18, 2004; accepted on May 24, 2004.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Polinder, E.M.E.W. Heijnen, N.S. Macklon, J.D.F. Habbema, B.J.C.M. Fauser, and M.J.C. Eijkemans Cost-effectiveness of a mild compared with a standard strategy for IVF: a randomized comparison using cumulative term live birth as the primary endpoint Hum. Reprod., February 1, 2008; 23(2): 316 - 323. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Stillman A 47-Year-Old Woman With Fertility Problems Who Desires a Multiple Pregnancy JAMA, February 28, 2007; 297(8): 858 - 867. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Porter, and S. Bhattacharya Investigation of staff and patients' opinions of a proposed trial of elective single embryo transfer Hum. Reprod., September 1, 2005; 20(9): 2523 - 2530. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. N. Barri Multiple pregnancies: a plea for informed caution Hum. Reprod. Update, January 1, 2005; 11(1): 1 - 2. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||