1 Department of Obstetrics and Gynecology, Oulu University Central Hospital, Oulu, 2 The Family Federation of Finland, Oulu, 3 The Family Federation of Finland, Helsinki and 4 Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland
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Abstract |
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Key words: assisted reproductive technology/IVF/ICSI/multiple pregnancy
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Introduction |
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We have previously studied the efficacy of elective one embryo transfer (Vilska et al., 1999). When at least two embryos were available, a high pregnancy rate (29.8) was achieved. When only one embryo was available, the pregnancy rate was lower, 20% per transfer.
It has been estimated that one embryo transfer is more cost-effective than two embryo transfer when all the costs associated with multiple gestations are taken into account (Wolner-Hanssen and Rydhstroem, 1998). A prospective randomized multicentre study was carried out to compare the effectiveness of one and two embryo transfer in a good prognosis group of patients. The main outcome measure was the cumulative pregnancy rate after fresh and frozen embryo transfers.
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Materials and methods |
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A total of 1301 couples fulfilled the inclusion criteria, and 144 agreed to participate in the randomized study. In all, 187 chose elective one embryo transfer and 970 two embryo transfer (Figure 1).
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Oocytes/embryos were cultured in MediCult medium (Medi-Cult A/S, Copenhagen, Denmark), IVF-500 medium (Scandinavian IVF Science, Gothenburg, Sweden) or Sydney IVF Medium (Cook IVF, Queensland, Australia). One or two embryos were transferred into the uterine cavity 4650 h after oocyte retrieval. Supernumerary good quality embryos were frozen using a slow freezing protocol with 1,2-propanediol as the cryoprotectant.
Natural progesterone (Lugesterone, Leiras, Finland) was given transvaginally for luteal support for 14 days. Clinical pregnancies were confirmed by transvaginal ultrasonography.
The frozen embryo transfers were carried out in natural or stimulated cycles. In natural cycles, the LH surge was determined using a home kit (ClearPlan; Unipath Ltd, Bedford, England), and embryo transfer was performed 34 days later. In stimulated cycles, down-regulation using a gonadotrophin-releasing hormone agonist (Suprecur, Synarela or Zoladex 3.6 mg) was started on day 2123 of the previous cycle. On day 3 of the cycle, oestradiol valerate (4 mg/day) was started, and vaginal progesterone 600 mg daily was started 3 days before the embryo transfer. The replacement of frozen embryos was not subjected to any protocol policy related to the present study.
Statistical analysis
Variables in the study groups were compared using by 2-tests and two-tailed t-tests.
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Results |
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The implantation rate of the fresh embryos transferred was quite similar (33.8 versus 30.7%) in the one and the two embryo transfer groups. The pregnancy rate was slightly but not significantly higher (47 versus 32%) when two embryos were transferred (Table II). There was no significant difference in the incidence of miscarriages or extrauterine pregnancies between the two groups. In the two embryo transfer group 11 (38%) of the deliveries were twins. The number of preterm deliveries (gestation age <37 weeks) was six (21%) in the two embryo transfer and one (5%) in the one embryo transfer group. The number of low birthweight infants (<2500 g) was 10 (26%) in the two embryo and two (9%) in the one embryo transfer group.
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Discussion |
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The pregnancy rate achieved in the one embryo transfer group was much higher than that reported previously by ourselves (Vilska et al., 1999) and other authors (Walters, 1996
) for one embryo transfer in cycles where no embryo selection was possible. During the study period in the participating centres a pregnancy rate of 14% was achieved among women who had only one embryo available for transfer. Among those who fulfilled the inclusion criteria but chose one embryo transfer, the pregnancy rate was 37%, and among those women who chose a two embryo transfer, the pregnancy rate of 40% was associated with a 32% twin rate. These figures match well with the results obtained in the study population.
Recently the results of another prospective randomized study were published, in which one and two embryo transfers were compared in a relatively small and highly selected population (Gerris et al., 1999). As in the present study, a high ongoing pregnancy rate (38.5%) was achieved after one embryo transfers. The investigators achieved a very high pregnancy rate (74%) when transferring two embryos accompanied by a high twin rate (30%). The higher pregnancy rate than in our study may be explained by more strict inclusion criteria. They transferred only top quality embryos characterized by four or five blastomeres at day 2 and at least seven blastomeres on day 3, the absence of multinucleated blastomeres and <20% cellular fragments. The twin rate was also high (35.8%) in the non-eligible population, which means that these criteria proved too strict for clinical practice. The cumulative pregnancy rate after frozen embryo transfers was not analysed in the study reported.
In this study, most of the women were younger than 36 years old age. In a retrospective analysis of our overall patient population, a remarkably lower twin rate was observed in women older than 35 years when two good quality embryos were transferred (6 versus 30%, unpublished data). Hence, in our opinion, in order to lower multiple pregnancy rate, one embryo transfer is most effective in the women younger than 36 years old.
According to the literature, the implantation potential of embryos varies greatly. In our study the implantation rate was quite similar in both groups and showed that the implantation process of each embryo was not affected by the presence of another embryo in the uterus. However, even higher implantation rate can be achieved by careful selection of embryos for transfer (Van Royen et al., 1999). We have previously shown that the pregnancy/implantation rates were highest if the embryo had reached the 45-cell stage on day two or 68-cell stage on day 3 after fertilization and, if the embryos had <20% fragmentation (Vilska et al., 1999
). Besides the commonly used morphological criteria, polarity of embryos at pronuclear stage (Garello et al., 1999
) or variations in thickness of zona pellucida (Palmstierna et al., 1998
) might be applicable in clinical practice. It remains to be shown if culturing to blastocyst stage can improve the implantation rate.
All good quality extra embryos were frozen. In the one embryo group, the number of embryos frozen was slightly higher, as expected, than in the two embryo group. Until now, when most but not all these embryos have been transferred, cumulative pregnancy rate of 47.3% has been achieved, which is identical to that obtained in our previous study (Vilska et al., 1999). Because two frozen embryos were transferred to those who desired it, one set of dizygotic twins was also achieved. The overall implantation rate of the frozen embryos was much lower (~10%) than that of the fresh embryos. However, in the future, single embryo transfer might also be warranted after embryo freezing.
On the basis of the success rates in this study and in our overall patient population we have estimated that, to achieve the same clinical pregnancy rates in both groups, ~20% (if two embryos are replaced in the subsequent cycle) more treatment cycles must be performed in the one embryo transfer group. These figures are quite close to those estimated previously by other investigators (Coetsier and Dhont, 1998).
When the treatment methods are evaluated, the costs associated with maternity and neonatal health care should be taken into account. Our results support the assumption that one embryo transfer would be more cost-effective than two embryo transfer (Wolner-Hanssen and Rydhstroem, 1998). Based on the available data, we suggest that one embryo should be transferred in the first treatment cycle to women younger than 36 years who have good quality embryos; 4-cell stage on day 2 or 8-cell stage on day 3 after fertilization, equal-sized blastomeres and <20% fragmentation.
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Acknowledgements |
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Notes |
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* The Finnish ET Study Group: Department of Obstetrics and Gynecology, University of Oulu, Oulu: Laure Morin-Papunen, Riitta Koivunen, Ilkka Järvelä, Jouni Lakkakorpi; The Family Federation of Finland, Oulu: Sinikka Nuojua-Huttunen, Kaisa Juntunen; The Family Federation of Finland, Helsinki: Tarja Bützow, Tuija Foudila, Tiina Hakala-Ala-Pietilä, Seija Kaukoranta, Jarna Moilanen, Sirpa Mäkinen, Rita Siegberg, Viveca Söderström-Anttila, Maija Tulppala, Timo Tuuri; Department of Obstetrics and Gynecology, University of Helsinki: Mervi Halttunen, Päivi Härkki-Siren.
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References |
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Submitted on February 7, 2001; accepted on May 27, 2001.