Review Single embryo transfer state of the art

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1 RBMOnline - Vol 7. No Reproductive BioMedicine Online; on web 17 October 2003 Review Single embryo transfer state of the art Diane De Neubourg graduated from Medical School at the University of Antwerp in She became a specialist in Obstetrics and Gynaecology in 1995 at the University of Antwerp, Master in Assisted Reproduction Technologies in 1996 at the University of Nottingham, where she worked with Simon Fishel on apoptosis in human granulosa cells. Presently, she is in charge of the IVF/ICSI programme of the Centre for Reproductive Medicine of the Middelheim Hospital Antwerp. She is Secretary to the Belgian College of Specialists in Reproductive Medicine (quality control), an active member of the special interest group (SIG) on Safety and Quality in ART and lecturer at the Antwerp School for nursery and midwifery. Her fields of interest are reproductive endocrinology and assisted reproduction technology. Dr Diane De Neubourg Diane De Neubourg 1, Jan Gerris Centre for Reproductive Medicine, Middelheim Hospital, Lindendreef 1, B-2020 Antwerp, Belgium 1 Correspondence: Tel: ; diane.de.neubourg@skynet.be Abstract Every practitioner active in the field of assisted reproduction treatment is aware of the risks and complications related to twin and higher-order multiple pregnancies. Introduction of single embryo transfer (SET) into IVF/intracytoplasmic sperm injection (ICSI) is one of the possible ways of reducing the rate of twin pregnancy. Careful selection of patients, in combination with elective SET, has been shown to decrease the twin pregnancy rate while maintaining a stable ongoing pregnancy rate. The combination of a woman younger than 38 years of age, in her first or second IVF/ICSI cycle and with an embryo with a high implantation potential is the key to successful SET. This article will discuss embryo selection and patient selection and review the data published on SET. In the Centre for Reproductive Medicine at Middelheim Hospital, 39% of all transfers in 2002 were SET; the ongoing pregnancy rate remained stable at 30.6%. The twin (multiple) pregnancy rate declined to 11.7%. Particular attention should be drawn to the augmenting effect of the pregnancy rate of frozen thawed cycles. Health economic data available so far subscribe the plea for SET. Keywords: embryo quality, prevention of multiple pregnancies, prevention twin pregnancies, single embryo transfer Rationale for single embryo transfer Multiple pregnancies are the most important complication of assisted reproduction techniques because of their impact on obstetrical outcome and of possible neonatal complications (Bergh et al., 1999). The implications on the economic situation of the future parents, the psychosocial impact of complicated multiple pregnancies and affected children are well known (Scholz et al., 1999). These complications are well known to the treating physicians, but it is difficult to estimate the implications for the economic situation of the future parents and for the psychosocial impact of the affected children, let alone calculate the direct and indirect costs for the whole family and for society. Collins (2002) estimated the excess costs of twin births due to IVF/intracytoplasmic sperm injection (ICSI) per births to be US$26 million. Multiple pregnancies were an acceptable price to be paid in compensation for the relatively poor success rates after IVF in the early days. However, with improved quality of the IVF laboratory, success rates have increased, as has the incidence of multiple pregnancies. Efforts were made in the early 1990s to show that in a selected population the transfer of two instead of three embryos was possible with complete disappearance of triplet pregnancies and with steady pregnancy rates (Staessen et al., 1992, 1993). However, the twin pregnancy rate remained unaffected. Data from the Belgian Register for Assisted Procreation (2001) show the same tendency: a decline in the number of triplet pregnancies with a stable number of twin pregnancies of 23% for the year Further reduction in twin pregnancies can be achieved through the introduction of single embryo transfer (SET). How to apply single embryo transfer? The most important prerequisite for introducing SET into daily practice is a good running IVF laboratory with steady results and good pregnancy rates. Many centres nowadays obtain excellent pregnancy rates and are ready to introduce SET into practice. Key factors in the SET strategy are embryo selection and patient selection. In the present authors experience, successful SET is equally dependent on both factors. If you transfer only one embryo irrespective of its quality, pregnancy rates will drop and become unacceptably low to both patients and clinicians (Giorgetti et al., 1995). 615

2 616 Embryo selection Morphologic analysis The aim of embryo selection is to select the embryo with the highest implantation potential. In the early days of IVF, Edwards and co-workers showed that cleavage rate is a beneficial factor, with 40% pregnancy rate for an embryo with rapid cleavage versus ±10% for an embryo with slow cleavage (Edwards et al., 1984). Later, Cummins et al. (1986) and Claman et al. (1987) confirmed the importance of cleavage rate and fragmentation in the assessment of embryo quality. Both parameters remain of pivotal importance in embryo selection. For that purpose, the present authors have derived a number of criteria from a retrospective analysis of 23 twin pregnancies after double embryo transfer (DET) (Van Royen et al., 1999). From that study it was concluded that embryos that had four or five cells on day 2 (41 44 h after fertilization/insemination) and seven or more on day 3 (66 71 h after fertilization/insemination), showed not more than 20% of fragmented cells and never showed the presence of multinucleated blastomeres were considered as embryos with excellent implantation potential. The ongoing implantation rate of these embryos was 49%, and they were therefore named top quality embryos. These criteria were tested in a randomized prospective trial comparing SET with DET in a twin-prone patient group (Gerris et al., 1999) (see Single embryo transfer in clinical practice below). Subsequently, these criteria were validated in a separate analysis (Van Royen et al., 2001). In this study, 213 embryos, of which a direct relationship between embryo quality and pregnancy existed, were analysed. This study confirmed the above-mentioned criteria of top quality embryos with a high implantation potential. In addition, the range of high implantation potential embryos was broadened due to subsequent continuous evaluation of embryos with known implantation. Embryos with two blastomeres on day 2 and six or more cells on day 3, and embryos with six cells on day 2 and ten or more on day 3, always with an absence of multinucleated blastomeres, also showed high implantation potential. This analysis shows that embryo quality is not a binary characteristic with the simple dichotomic characterization of good and bad. It clearly demonstrates that embryogenesis is a continuum for which the estimation of some morphological and dynamic aspects of cell cleavage gives indications for embryo selection of the available embryos with high implantation potential. This implies that the absence of embryos with high implantation potential does decrease the chance of pregnancy, and this should be taken into account at the time of embryo transfer. The importance of detection of multinucleation was shown (Pickering et al., 1995; Jackson et al., 1998; Pelinck et al., 1998). Embryos with multinucleated blastomeres showed a very low implantation rate of 4.3% in SET and 5.7% in DET (Van Royen et al., 2003). Another potential marker of early embryogenesis is scoring of the pronucleus. This was first reported by Scott and Smith (1998). Many groups have confirmed the importance of scoring the pronucleus for alignment and/or polarization of the nucleolar precursor bodies (Tesarik et al., 2000; Lundqvist et al., 2001; Montag and van der Ven, 2001; Nagy et al., 2003). Recently, the presence of early cleavage at h postinsemination or post-icsi has been shown to be a characteristic of embryos with high developmental competence (Shoukir et al., 1997; Lundin et al., 2001). This was confirmed in a study with SET early cleaving embryos, which showed a significantly higher implantation potential (Salumets et al., 2003). Blastocyst transfer has been suggested as another solution to improving embryo selection. The underlying idea is that through extended embryo culture a better embryo selection can be made or is made by the embryo itself. This presumption takes for granted that a good embryo will benefit from a longer culture and that an embryo that is not reaching the blastocyst stage is a poor quality embryo. However, Coskun et al. (2000) clearly demonstrated that overall pregnancy rates with day 3 and day 5 embryo transfers were the same, but in the absence of good quality day 3 embryos no pregnancies occurred in day 5 embryo transfers, whereas these day 3 transfers had a 33% pregnancy rate. The discussion of the composition of the media in relationship with culture to the blastocyst stage and on the type of sequential medium is beyond the scope of this article. In a Dutch study (Macklon et al., 2002), it was shown that the same blastulation, implantation and pregnancy rates were obtained with embryos grown in the monoculture Rotterdam medium, the sequential Rotterdam culture medium or the commercially available G1/G2. Biggers (2001) described the search for the optimal composition of chemically defined media as the back to nature or empirical optimization approach. He suggested that the current media contain only a subset of compounds found in the natural environment, causing a lot of stress for the embryo. Further empirical optimization is needed to cope with these putative stresses. The superiority of day 5 over day 3 embryo selection is still not proven. Kolibianakis and Devroey (2002) reviewed the results of eight randomized controlled trials. With the limitations of some of these studies for the manner of randomization, the use of sequential media, patient selection and the difference in the number of embryos transferred, there is no support for the view that day 5 transfers perform better than day 3 transfers when applied to an unselected patient population. The study by Bungum et al. (2003) comparing two embryo transfers on day 3 and day 5 in patients with more than two 8-cell embryos with less than 20% fragmentation showed no advantage for blastocyst transfer. Proposing blastocyst culture as a tool to decrease high order multiple pregnancies (Gardner et al., 1998) was the initial target, but the true indication for blastocyst culture should be SET. Genetic analysis Selection of embryos on the basis of morphologic and growth characteristics allows the formulation to some extent of the prognosis for implantation. However, not every top quality day 3 embryo, nor every top quality blastocyst, will lead to a pregnancy, let alone an ongoing pregnancy. With an ongoing implantation rate of 40% for the most ideal top quality embryos, one can hardly speak about an excellent selection technique. It is a method to obtain the least compromised

3 pregnancy rate, since 60% of all transfers are not followed by an ongoing pregnancy. In a poor prognosis patient group, 50% of all embryos are known to be aneuploid (Magli et al., 1998), and one can wonder whether one has not reached the natural selection limit in this population. It was shown that culture to the blastocyst stage is not a reliable tool to select against clinically relevant chromosome abnormalities (Evsikov and Verlinsky, 1998; Evsikov et al., 2000; Sandalinas et al., 2001). Theoretically, preimplantation genetic diagnosis (PGD) may give the necessary extra information. The selection of chromosomally normal embryos for replacement can increase implantation rate, decrease spontaneous abortion rate and avoid aneuploid conceptions (Munné, 2002). This has been shown for women above 37 years of age. The technique itself still has a number of limitations, and therefore PGD for the whole IVF population is not a suitable option at this moment. DNA fingerprinting using micro-array analysis of biopsied blastomeres has been proposed (Katz et al., 2002). However, this technique is invasive, and no clinical data are available as yet. Patient selection Clinical experience has been a helpful tool in counselling patients about their embryo transfer. However, every major change in embryo transfer strategy has been successfully introduced because of precise analysis of the patient population with regard to parameters such as age, indication, response profile to gonadotrophin stimulation and, last but not least, the cohort of embryos present at the day of the transfer. In the early 1990s, Staessen and co-workers clearly showed the relationship between embryo quality and the occurrence of pregnancy and multiple pregnancies (Staessen et al., 1993). These authors defined an IVF patient population at risk for multiple pregnancies as women younger than 37 years of age who had at least six good quality embryos in the first three IVF cycles. Good quality embryos were defined as embryos in which the 4-cell stage was reached at h after insemination with less than 20% of the volume filled with anucleate fragments. Coetsier and Dhont (1998) considered patients at risk for multiple pregnancies as women younger than 36 years of age, in the first three IVF cycles with at least three embryos with a good embryo score. In two studies, a multivariate analysis for the risk for multiple pregnancies was performed. Strandell et al. (2000) showed that age of the patient and number of embryos transferred were independent factors for predicting multiple birth. Hunault et al. (2002) showed that young age and high quality of the transferred embryos were the best predictors of increased risk of multiple pregnancies. The present authors analysed their own patient population to define patients at risk for twin pregnancies. It was found that 80% of the twin pregnancies occurred in first and second cycles of IVF/ICSI. The overall implantation rate of all transferred embryos was stable (25% for patients younger than 35 and 23% for women between 35 and 38) but showed a steep fall from the age of 38 onwards, with an overall implantation rate of 11% (Figure 1). Older patients ( 38 years) who experience a decreased implantation rate are not the primary target group for SET. However, discussion on embryo transfer sometimes reveals the wish of some couples to try to prevent mutiple pregnancies. Experience in this is rather limited. The ovum recipient patient group could theoretically benefit from SET if the endometrium is not compromised by older age, and particularly if SET is coupled to the age of the donor. Single embryo transfer in clinical practice In order to objectively analyse the impact of the introduction of SET into clinical practice, the present authors set up a prospective randomized trial (Gerris et al., 1999). Patients younger than 34 years of age, in their first IVF/ICSI cycle ever, who had at least two embryos of excellent quality were randomized to have either one or two embryos transferred. Fifty-three patients were included in the final analysis, 26 in the SET study arm and 27 in the DET study arm (Table 1). After SET, the ongoing conception and implantation rate was 38.5%; there was one monozygotic twin pregnancy. For the DET group, the ongoing conception rate was 74.1% with an implantation rate of 48.1%. In this group, six twin pregnancies led to a multiple pregnancy rate of 30%. This study proved again that the chance of conception and of multiple pregnancies was related to the number of excellent quality Figure 1. Implantation rate of the whole IVF/intracytoplasmic sperm injection (ICSI) programme related to age. Table 1. Outcome of the prospective randomized single embryo transfer double embryo transfer (SET DET) trial. SET DET (n) (%) (n) (%) Patients Conceptions Ongoing pregnancies Twin pregnancies Implantations

4 618 embryos transferred. The high ongoing pregnancy rates with DET should be interpreted in relation to the excellent prognosis patient group. The most important conclusion was that SET can lead to a conception and ongoing pregnancy rate comparable to the conception and ongoing pregnancy rate for the whole programme. So SET could be introduced into IVF/ICSI without a decline in conception rate. From January 2000 until December 2001, SET in the first cycle was offered to all patients <38 years of age. The impact of patient choice for SET of a top quality embryo versus DET in the first IVF/ICSI cycle was evaluated (De Neubourg et al., 2002). This study analysed the outcome of 243 transfers in 262 patients. Sixty-four per cent of the patients chose the transfer of a single top quality embryo, if available, and two non-top quality embryos if no top quality embryo was available; 36% of the patients chose to have a DET regardless of embryo quality (Table 2). The SET group had an ongoing pregnancy rate of 40% with 2% twin pregnancies; the DET group had an ongoing pregnancy rate of 44% with 26% twin pregnancies. This study showed that the introduction of SET of a top quality embryo in the first IVF/ICSI cycle could be introduced systematically in the programme, which has been done since then. It became clear that SET had to be further implemented into the whole programme if the twin pregnancy rate was to be decreased substantially. As previously mentioned, it was found that the second cycle also contains a high risk for twin pregnancy in the case of DET. Effect of single embryo transfer implementation on the general IVF/intracytoplasmic sperm injection programme SET was gradually implemented into the whole IVF/ICSI programme. Many of the patients were convinced in the second cycle to choose SET, and the SET strategy was counselled in the third and fourth attempts if patients were motivated to prevent a twin pregnancy. This was much easier to do in the group of patients who had already conceived with IVF/ICSI and thus felt more confident with the technique and the treatment. The impact of the introduction of SET was reported in 2001 (Gerris et al., 2001). In 2002, the present authors first described that the twinning rate was halved since Table 2. Impact of patient choice for single embryo transfer (SET) or double embryo transfer (DET) in the first IVF/intracytoplasmic sperm injection (ICSI) cycle (total n = 243). Chose SET (%) Chose DET (%) Patients 156 (64) 87 (36) Received SET Received DET Ongoing 63 (40) 38 (44) pregnancies Twin 1 (2) 10 (26) pregnancies Values in parentheses are percentages. the introduction of SET in 1998 (Gerris et al., 2002). An update of five years of SET is shown in Table 3. The number of SET gradually increased from 13% in 1998 to 39% in This has led to a decline in the mean number of embryos transferred from 2.26 in 1998 to 1.67 in The pregnancy rate for the whole programme remained stable, with an ongoing pregnancy rate of 30.6%. The twin and multiple pregnancy rates showed a steady decline from 29.5% (twin) and 33.6% (multiple) in 1998 to 11.7% in 2002 (Figure 2). Other experiences with single embryo transfer Vilska et al. (1999) also reported that elective transfer of one embryo results in an acceptable pregnancy rate and eliminates the risk of multiple births. This retrospective analysis of elective versus compulsory SET showed that elective SET gives a pregnancy rate of 29.7%, which is comparable with 29.4% in the DET group. In the latter group, however, 23.9% were twin pregnancies. These authors concluded that elective SET can be highly recommended, at least in women younger than 35 years of age who have grade 1 or grade 2 embryos available for transfer. A multicentre prospective randomized analysis by Martikainen et al. (2001) compared SET with DET in 144 patients, who had no more than one previous failed treatment cycle and who had at least four good quality embryos available for transfer. The clinical pregnancy rate per transfer was 32.4% in the SET group and 47.1% in the DET group. When the outcome of subsequent cryopreservation cycles was included, this was 47.3% in the SET group and 58.6% in the DET group. The twin pregnancy rate in the DET group was 38%. Again, the conclusion can be drawn that changing the embryo transfer policy to SET can be done without remarkable decrease in the success rate. Obasaju et al. (2001) reported on single normal embryo transfer in women older than 40 years. He analysed the pregnancy potential of PGD-screened embryos versus multiple embryo transfer in the older age group. Out of 27 cycles, 17 cycles had a single normal embryo transferred; six cycles had an ongoing pregnancy, which gives a 35% clinical ongoing pregnancy rate per transfer and 22% per started cycle. This was compared with 69 cycles with an average of four embryos transferred. There was an ongoing clinical pregnancy in 19 cycles (28%) per transfer and per cycle. Surrey et al. (2002) published preliminary data on a prospective randomized trial that compared one grade 1 day 5 blastocyst transfer to two grade 2 day 5 blastocyst transfers. Patients were randomized 5 days after oocyte aspiration. Forty-two patients had until than been enrolled in the study: 20 with grade 1, and 22 with grade 2, embryo transfer. The ongoing pregnancy rate was 55% (11/20) in the grade 1 embryo transfer group and 72% (16/22) in the grade 2 embryo transfer group. The implantation rate was 55% for grade 1 and 50% for grade 2 blastocyst embryo transfers. All the pregnancies from grade 1 embryo transfers were singletons, whereas grade 2 embryo transfers resulted in 37.5% twin pregnancies.

5 A five-year appraisal of the Ghent University experience with single embryo transfer was published by De Sutter and coworkers (De Sutter et al., 2003). They compared the early days of SET ( ) with 1.5% SET to the period between 1999 and 2002 with 17.5% SET. A total of 20% of all transfers were SET in The overall pregnancy rate was 35% and 34%, respectively, and the twinning rate dropped from 30% to 14% in Impact (and augmentation) of cryopreservation programme It has been shown previously (De Neubourg et al., 2002) that after introduction of SET in the first IVF/ICSI cycle there were 1.5 embryos for cryopreservation in the group who chose SET of a top quality embryo versus 0.5 embryos in the group of patients choosing DET. To fully appreciate the pregnancy chances with SET, the pregnancies occurring after frozen thawed cycles should be added to the fresh data. This was shown by Tiitinen and co-workers (Tiitinen et al., 2001). They analysed 127 fresh SET cycles (clinical pregnancy rate of 38.6%) and 129 frozen thawed cycles in 83 patients. In 46 frozen thawed cycles one embryo was transferred (clinical pregnancy rate of 17%), and in 83 frozen thawed cycles two embryos were transferred (clinical pregnancy rate of 37.3%). The cumulative delivery rate per oocyte retrieval was 52.8%, with a twin pregnancy rate of 7.6%. These authors clearly show the importance of a good cryopreservation programme and the way it can augment the success of fresh SET. Impact on the child(ren) Until the introduction of SET in 1998, in the Centre for Reproductive Medicine at Middelheim Hospital as many IVF/ICSI babies were born from singleton pregnancies as from multiple pregnancies. Figure 3 shows that with the introduction of SET this trend was broken, and in 2002, 79% of IVF/ICSI babies were born from singleton pregnancies. This will have its implication on the neonatal outcome of IVF/ICSI babies. Impact on cost of an IVF/intracytoplasmic sperm injection baby From a medical point of view, reduction of the number of twin pregnancies after IVF/ICSI, combined with an attractive ongoing pregnancy rate that does not decline because of SET, is the ideal goal for all practitioners involved in assisted reproduction treatment. As the present authors and others have shown previously, the pregnancy rate after SET is related to the transfer of an embryo with a high implantation potential. Table 3. Outcome variables over a 5-year period since the introduction of single embryo transfer (SET) % SET No. of embryos/transfer Ongoing pregnancy rate/oocyte retrieval (%) Ongoing pregnancy rate/transfer (%) Ongoing implantation rate (%) Twin pregnancy rate (%) Multiple pregnancy rate (%) Figure 2. Evolution of outcome over the period : evolution of multiple pregnancy rate (PR), ongoing pregnancy rate (OPR) and number of embryos per transfer. Figure 3. Number and origin of children born after IVF/intracytoplasmic sperm injection (ICSI). 619

6 620 However, when compared with DET, SET needs an increased number of IVF/ICSI cycles per live born child. Taking into account that the cost of IVF/ICSI varies a lot between different countries, the economical aspect of SET/DET could further persuade patients (and doctors) to stick to DET. This is a shortsighted view, since a fast success with IVF/ICSI due to DET with a high chance of twin pregnancy leads to a lot of problems (and costs) in the mid- to long term. Therefore, a meticulous analysis of all aspects of SET and DET needs to be done before any conclusion on the economical aspect can be drawn. First of all, there is the increased risk of obstetric and neonatal complications of twin pregnancies. This has been calculated in a decision-analytical model by De Sutter and co-workers (De Sutter et al., 2002). They used the Markov model to calculate the cost per child born taken into account the IVF procedure-related, pregnancyrelated and neonatal care-related costs. Costs of neonatal mortality and long-term morbidity were not taken into account. Using the pregnancy rates from four published studies, a sensitivity analysis was performed. Independently of the pregnancy rates in the different studies, the cost per child born after SET and DET was concluded to be the same. More IVF/ICSI cycles are needed to obtain the same number of children born. The conclusion was that the real benefit of SET is to avoid the very high long-term costs from the increased morbidity after twin pregnancies. Prospective clinical and health economic impact studies that compare SET to DET are on their way. In addition, performing SET results in a higher number of embryos being cryopreserved (De Neubourg et al., 2002). The pregnancies ensuing from the frozen thawed cycles increase the cumulative delivery rate per oocyte retrieval (Tiitinen et al., 2001). This augmented pregnancy rate should be calculated when a correct comparison to DET is made for the economical aspects. Concluding remarks Singleton pregnancies after IVF/ICSI are the ultimate goal for practitioners in assisted reproduction treatment. This implies a gradual though firm implementation of SET. In the Centre for Reproductive Medicine at Middelheim Hospital, 39% of all transfers in 2002 were SET; this led to an ongoing pregnancy rate of 30.6%, with 11.7% twin pregnancies. The target group is twin-prone patients. These are women younger than 38 years of age in their first or second IVF/ICSI cycle. As important for the success of SET as patient selection is embryo selection. This implies the search for the embryo with the highest possible implantation potential. To fully evaluate the success rate after SET, one should take into account the pregnancies arising from frozen thawed embryos in consecutive cycles in case of no pregnancy. Thus the cumulative pregnancy rate per oocyte harvest should be compared. This point remains controversial and is not always fully accepted. One of the problems is that there is not one single ideal method for selecting embryos. Each stage of embryo development presents morphological characteristics that are relatively easy to observe in daily practice by any IVF embryologist. What is needed is for each centre to determine which characteristics are most readily used within the organizational and practical framework in which the laboratory work is conducted. In many centres, embryo selection is probably performed suboptimally. This may be due to many reasons, from sub-optimal techniques and instruments to unpredictable availability of physicians. A strict time schedule to assess all embryos is a mandatory prerequisite for good selection, not simply replaced by commodity solutions, for example allowing time to select which embryos will grow to become blastocysts. It will be interesting to see the development of new techniques for embryo selection: preimplantation aneuploidy screening and non-invasive assessment of embryo function. However, any novel approach will have to prove in a prospective randomized trial its superiority over the relatively simple, cheap, low-tech, easily learned, universally applicable methods of morphological embryo assessment. Another point of concern is that the medical profession is not sufficiently aware of the risks involved in twin pregnancy. Many reproductive physicians and, a fortiori, IVF embryologists, do not have first-hand experience with the risks and tragedies of multiple pregnancies. In many countries, reducing high-order multiple pregnancy is already considered the nec plus ultra of high quality care, whereas twins are not even considered a complication. This is not to create any feeling of guilt in those who do have twins, but to induce practitioners and future patients not to underestimate these risks. Many parents of twins, while considering their infertility problem being solved successfully, fully agree to the fact that twins do create many underestimated problems, even if both children are in beaming health. While there are some reasons to understand this, this is not the same corroborating it. Financial arguments are futile, because twins will ultimately cost much more than an extra IVF cycle. Reimbursement of IVF/ICSI, either by government or private insurers, may in part facilitate the acceptance of SET by patients, but it may appear not to be the only answer. IVF remains a challenging treatment, putting a heavy physical and emotional burden on patients. Therefore, the greatest mistake would be to force SET when it is inappropriate. Accepting SET is primarily a matter of integrated ethics. 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8 Van Royen E, Mangelschots K, De Neubourg D et al Calculating the implantation potential of day 3 embryos in women younger than 38 years of age: a new model. Human Reproduction 16, Van Royen E, Mangelschots K, Vercruyssen M et al Multinucleation in cleavage stage embryos. Human Reproduction 18, Vilska S, Tiitinen A, Hydèn-Granskog C et al Elective transfer of one embryo results in an acceptable pregnancy rate and eliminates the risk of multiple birth. Human Reproduction 14, Received 9 June 2003; refereed 14 July 2003; accepted 2 September