Review Elective single embryo transfer

Transcription

1 The Obstetrician & Gynaecologist /toag ;10: Review Review Elective single embryo transfer Authors Ioannis Kosmas / Jossiane Van der Elst / Paul Devroey / Herman Tournaye Key content: Elective single embryo transfer has been implemented in Belgium and Scandinavian countries to decrease the incidence of twin pregnancy and the associated complications. The extra cost associated with achieving an equal number of pregnancies through elective single embryo transfer needs to be considered in the context of any additional neonatal care expenses associated with double embryo transfer. Acceptable ongoing pregnancy and delivery rates have been obtained when comparing single with double embryo transfer. Maternal age, previous attempts, day of embryo transfer and cost should be taken into account. Learning objectives: To understand the issues raised when helping a couple choose single or double embryo transfer. Ethical issues: Where does patient autonomy over treatment end and national regulation begin? The management of obstetric complications and the long-term sequelae of premature birth should be factored in when considering treatment costs. Keywords blastocyst / embryo transfer / in vitro fertilisation (IVF) / pregnancy outcome / reproduction Please cite this article as: Kosmas I, Van der Elst J, Devroey P, Tournaye H. Elective single embryo transfer. The Obstetrician & Gynaecologist 2008;10: Author details Ioannis Kosmas MSC MD Clinical and Research Fellow Centre for Reproductive Medicine, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium Jossiane Van der Elst PhD Head of Staff, IVF Laboratory Centre for Reproductive Medicine, Universitair Ziekenhuis Brussel, Belgium Paul Devroey MD PhD Head of Department Centre for Reproductive Medicine, Universitair Ziekenhuis Brussel, Belgium Herman Tournaye MD PhD Senior Medical Director Centre for Reproductive Medicine, Universitair Ziekenhuis Brussel, Belgium herman.tournaye@uzbrussel.be (corresponding author) (page 1 of 8)163

2 Review 2008;10: The Obstetrician & Gynaecologist Figure 1 Clinical pregnancy rates in randomised controlled trials comparing eset with DET a Introduction Multiple pregnancy is a major complication of in vitro fertilisation (IVF). There are serious risks of neonatal morbidity and mortality. 1 These problems can be virtually eradicated, however, by controlling the number of embryos transferred. It has been standard practice for several years in the UK to transfer two embryos in women under 40 years of age and, occasionally, and as an absolute maximum, three embryos in women over Recently, however, the statistics behind elective single embryo transfer (eset) have been re-examined for two reasons: firstly, overall pregnancy rates per embryo transferred have continued to improve and, secondly, multiple pregnancy complications and associated neonatal morbidity have become increasingly unacceptable. The first retrospective analysis by Vilska et al. 3 in 1999 showed no difference in clinical pregnancy rate between eset and double embryo transfer (DET), except for an absence of twins in the eset group. Subsequently, other trials have shown similar results. 4 6 What is the pregnancy rate for routine eset? Four randomised trials compared eset with DET. 4,5,7,8 To summarise the data, lower clinical pregnancy rates (OR 0.48, 95% CI ) (Figure 1) and lower delivery rates (OR 0.51, 95% CI ) (Figure 2) were demonstrated for eset. Surprisingly, however, pre-existing retrospective studies did not show this difference in clinical pregnancy rate when comparing eset with DET (OR 0.91, 95% CI ) (Figure 3). All studies to date have shown that eset reduces the twin pregnancy rate to virtually zero and, therefore, eliminates the associated morbidity. In the seven observational studies 3,9 14 comparing eset with DET, twin rates varied from % for eset and from % for DET. These results indicate an overall reduction in twin pregnancy rate for eset (OR 0.02, 95% CI ) (Figure 4). In four randomised comparisons undertaken in the same period, 3,4,7,8 twin rates ranged from % for eset and % for DET. By synthesising these data, a significantly higher twin rate was observed in the DET group (OR 0.05, 95% CI ) (Figure 5). The fate of supernumerary embryos An effective and efficient embryo cryopreservation programme is essential for the implementation of a successful eset strategy. Tiitinen et al. 6 clearly showed the value of cryopreservation by achieving a clinical pregnancy rate of 17.4% with single frozen embryo transfer. If this is factored into the pregnancy rates for eset and DET, the lower clinical pregnancy and delivery rate observed in the randomised controlled trials comparing eset with DET can be increased significantly by adding even one single frozen embryo transfer to a fresh eset cycle. The cumulative clinical pregnancy rate (where pregnancy is defined as the presence of fetal sacs with cardiac activity) for one eset plus one single frozen embryo transfer showed no difference when compared to DET (OR 0.86, 95% CI ) (Figure 6), but the twin pregnancy rates remained significantly higher in the DET group (OR 0.01, 95% CI ) (Figure 7). It is obvious that the combination of a fresh eset cycle with a subsequent frozen eset achieves similar clinical pregnancy rates to one DET. Pregnancy outcome and numbers of embryos transferred During pregnancy, women who received eset had significantly fewer days sick leave on average, while the preterm delivery rate ( 37 weeks) and the low birthweight rate ( 2500 g) were significantly higher in the DET group. 15 De Sutter et al. 16 reported a significant decrease in the caesarean section rate in singleton (15.8%) (page 2 of 8)

3 The Obstetrician & Gynaecologist 2008;10: Review Figure 2 Delivery rates in randomised controlled trials comparing eset with DET a compared with twin (48.8%) pregnancies and fewer twin pregnancies continued beyond 37 weeks of pregnancy (44.1%). Doubt remains, though, whether a percentage of the problems seen in pregnancies resulting from assisted reproduction are specific to that group of women, whether they have singleton or multiple pregnancies. Poikkeus et al. 17 addressed these issues by comparing eset and DET to a non-ivf control group and a control group of women who had no option but to have eset as there was only one embryo available for transfer. They reported increased rates of placental abruption after DET but increased rates of vaginal bleeding and preterm contractions after eset. Increased rates of preterm birth were observed in the eset compared with the non-ivf group. Labour induction rates were similar in both the eset and DET groups and there were no significant differences in vacuum extractions and emergency caesarean sections for delivery of singleton pregnancies, whether they Figure 3 Clinical pregnancy rates in retrospective studies comparing eset with DET Figure 4 Twin pregnancy rates in retrospective studies comparing eset with DET a (page 3 of 8)

4 Review 2008;10: The Obstetrician & Gynaecologist Figure 5 Twin rate in randomised controlled trials comparing eset with DET a Figure 6 Clinical pregnancy rates when comparing treatment with one fresh and one frozen eset with DET treatment a Figure 7 Twin pregnancy rates when comparing treatment with one fresh and one frozen eset with DET treatment a originated from eset or DET. The authors concluded that a decline in DET may contribute to an overall improvement in maternal and neonatal morbidity but that eset is not free from pregnancy complications. Cost-effectiveness of eset versus DET In their cost-effectiveness model, De Sutter et al. 16 included two randomised and two cohort studies. In the randomised studies they found a slight difference in economic benefit after eset but in the nonrandomised studies they demonstrated a difference of 5 6% in cost per child born, favouring eset. Overall, the cost per live birth was similar, whether one or two embryos were transferred; the extra cost associated with achieving an equal number of pregnancies through eset was balanced by the additional neonatal care expenses associated with DET. It is obvious, however, that these calculations were made using a small sample size and that larger numbers of women are needed to confirm these conclusions. Furthermore, to attempt accurate data analysis, only randomised studies should be included.a sensitivity analysis 18 by the same authors found that by varying the cost parameters as a simulation of different cost conditions, eset continued to be much more cost-effective than DET when considering the total cost per live birth. (page 4 of 8)

5 The Obstetrician & Gynaecologist 2008;10: Review In another study, 19 treatment with two consecutive esets was compared with DET. In women under 35 years of age, a 5% difference in live birth rates was observed, favouring the approach of two consecutive esets. Costs per live birth, calculated until 6 weeks after delivery, were similar. A further study 15 extended the cost calculation for up to 6 months after delivery. The authors showed a lower average total cost with eset. For every extra delivery obtained from DET, there was a significant increase in cost, either from health care (paediatric care and the costs of re-admittance to hospital) or from loss of productivity. Overall, more studies to evaluate uniformly the daily and long-term costs of eset and DET are needed. 20 When optimised, eset can be a high impact strategy for reducing costs in IVF treatment. It must be remembered, however, that data synthesis has to be done on data from randomised controlled trials without economic evaluation, to suit the local financial model for healthcare provision. Stages of development and embryo transfer Embryo transfer is typically performed on day 2 or 3 after egg retrieval, or day 5 in the case of blastocyst transfer. The Scandinavian groups used day 2 or 3 embryo transfer. 10,21 A top-quality embryo was defined as having: 2 pronuclei, indicating normal fertilisation 4 5 blastomeres on day 2 or 8 blastomeres on day 3 20% fragmentation no multinuclear blastomeres. Where day 3 top-quality embryos were transferred, pregnancy and live birth rates per embryo transfer were similar in the eset and DET groups. A similar outcome was achieved when transferring a single blastocyst, compared to two blastocysts, 22 although higher pregnancy rates (positive pregnancy test, i.e. hcg) (OR 1.45, 95% CI ) (Figure 8) and clinical pregnancy rates (heartbeat present on ultrasound scan) (OR 1.63, 95% CI ) (Figure 9) were observed with single blastocyst transfer compared with day 3 eset in women under 36 years of age. 23,24 Although results favour a day 5 transfer, more randomised studies are needed to define its role within eset strategy. Whilst there is clear evidence for women under 36 years, data on an eset strategy in older women are scarce. In their study,veleva et al. 21 focused on women aged who had had eset of a top- or medium-quality embryo. When comparing pregnancy rates between eset and DET, they found significantly higher cumulative pregnancy rates and live birth rates per oocyte retrieval for the eset group. In parallel, significantly higher multiple pregnancy rates were observed for the DET group. Figure 8 Clinical pregnancy rate/transfer when comparing blastocyst eset with day 3 eset in randomised controlled trials a Figure 9 Pregnancy rate/transfer comparing blastocyst eset with day 3 eset in randomised controlled trials a (page 5 of 8)

6 Review 2008;10: The Obstetrician & Gynaecologist Figure 10 Clinical pregnancy rate comparing eset with DET in women aged (retrospective studies) Figure 11 Multiple pregnancy rate comparing eset with DET in women aged (retrospective studies) Another study 25 showed similar results. When synthesising these data, similar clinical pregnancy rates are observed in both groups (OR 1.08, 95% CI ) (Figure 10), increased multiple pregnancies are evident in the DET group (OR 0.03, 95% CI ) (Figure 11) and similar miscarriage rates are evident in both groups (OR 0.84, 95% CI ) (Figure 12).These results indicate that women aged years can be candidates for eset. It would be fair, however, to say that, whilst eset in older women appears to give comparable results with DET up to 39 years of age, these data need to be confirmed with larger randomised controlled trials. Ovarian stimulation protocols and single embryo transfer Together with single embryo transfer strategies, less aggressive ovarian stimulation protocols have been promoted. In one study 26 a gonadotrophinreleasing hormone (GnRH) antagonist protocol in combination with single embryo transfer was compared with a long GnRH agonist protocol in combination with DET. Similar cumulative live birth rates at 12 months were observed between the two groups but there were significantly higher multiple pregnancy rates in the DET group. Although after minimal IVF fewer embryos were available overall, by using eset, embryos were still available for cryopreservation. Similar results were achieved for both groups in terms of live births (per started cycle) and for cryopreserved embryos. Greater physical discomfort was experienced in the DET/conventional IVF group. When cycle cancellation took place, fewer negative emotions were experienced in the eset/mild stimulation protocol group. 27 In another study, 28 the total follicle-stimulating hormone (FSH) dose was reduced for the eset group. Long agonist downregulation was combined with recombinant FSH and DET, while in the eset group, recombinant FSH was replaced with recombinant hcg 250 µg when the leading follicle reached a diameter of 14 mm. Similar pregnancy rates were observed between the two groups, while multiple pregnancy was nonexistent in the eset group. Single embryo transfer and ovarian hyperstimulation syndrome Contrary to the belief that multiple embryo transfer can exacerbate ovarian hyperstimulation syndrome, a similar incidence is observed in twin and singleton pregnancies. 29 How many cycles of eset? When retrospectively comparing fresh eset and DET for the first three treatment cycles, 30 no significant differences in ongoing pregnancy rates were found for each cycle. Women had to have at least one good-quality embryo to undergo eset. Overall, higher cumulative pregnancy rates were observed using eset and the authors suggest that for the first three treatment cycles, in women 38 years old, eset yields similar results to DET. (page 6 of 8)

7 The Obstetrician & Gynaecologist 2008;10: Review After eset, more embryos were cryopreserved and cumulative pregnancy rates (eset plus frozen embryo transfer) were significantly higher when compared with DET cycles. Cumulative pregnancy rates after three cycles, when comparing eset with DET, are in accordance with results derived from retrospective studies for one cycle (Figure 3). Further prospective studies are needed to evaluate cumulative pregnancy rates and the optimal number of eset cycles needed to achieve similar results to DET. Couples attitudes towards eset When mothers of children resulting from IVF or intracytoplasmic sperm injection were questioned about the choice between eset and DET, they chose eset only once the potential complications associated with multiple pregnancy, such as prematurity, were explained. Otherwise, they felt that a twin pregnancy was their ideal choice, enabling them to complete their family in one treatment cycle. 31 Couples are, indeed, eager to accept twin pregnancy when unaware of the related risks. 32 Couples were also eager to undergo DET to increase pregnancy rates if they had had previous attempts at assisted reproduction. 33 Women who prefer eset tend to be younger. In addition, the availability of frozen embryos and the reported improvement in pregnancy rates after eset are two important factors in their decision. From previous studies, it appears that counselling women about the risks of multiple pregnancy after DET is an important issue in the implementation of eset. 34,35 Murray et al., 36 however, stated the opposite: couples will not significantly change their attitudes about eset, even if additional information in the form of leaflets and discussion, is provided. Nonetheless, in New Zealand, Coetzee et al. 37 showed a trend for increased patient acceptance of eset from , with a marked overall increase in eset (with the greatest level of acceptance from women under 36 years of age). The authors attributed this to a change of philosophy regarding IVF success in their clinic, putting the emphasis on the delivery of a healthy singleton child rather than a positive pregnancy test. Legislation Some European countries have already implemented the eset policy by legislation. In Sweden, from 1993 onwards a voluntary reduction of the number of embryos transferred (from three to two) resulted in an almost complete elimination of triplets. Twin rates, however, remained at around 25% of deliveries after assisted reproduction. Sweden has, therefore, introduced a law promoting eset from January 2003, 38 while in Finland a similar process was initiated by the IVF clinics themselves. Belgium introduced an eset policy in July 2003, coupled with reimbursement of IVF/intracytoplasmic sperm injection laboratory costs for couples where the woman is under 43 years, for a maximum of six treatment cycles per lifetime. 39 Belgian IVF centres have retrospectively analysed their results to assess the impact of this new legislation and found no significant difference in pregnancy rates before and after the policy implementation, except for twin pregnancy. 40,41 In Belgium, for women up to 36 years of age, eset is now considered to be the norm. Conclusion In this review, the most important studies on the eset strategy have been presented. Studies were conducted in the general population. Controversies still exist, since all studies compare different outcomes; for instance, delivery, live birth or ongoing pregnancy rates. In our experience, eset can be incorporated into an IVF programme while preserving high pregnancy rates. 4 In our study, 41,42 eset accounted for 57% of all transfers, while the overall pregnancy rates, measured by positive hcg tests, remained 50%. Maternal age, day of embryo transfer, number of previous attempts, reimbursement policy (if any) and patient acceptance remain the most important factors for successful implementation of an eset strategy. All these factors have been defined in studies performed in the general population and do not Figure 12 Miscarriage rate comparing eset with DET in women aged (retrospective studies) (page 7 of 8)

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