Human Reproduction, Vol. 14, No. 1, 83-89,
January 1999
© 1999 European Society of Human Reproduction and Embryology
Comparison of two elective transfer policies of two embryos to reduce multiple pregnancies without impairing pregnancy rates
Clinic of Fertility, Department of Obstetrics and Gynaecology, Hospital Erasme, Route de Lennik 808, 1070 Brussels, Belgium
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Abstract |
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A first elective transfer policy of two embryos based solely on embryo morphology was compared to a more restrictive policy transferring two embryos to all patients aged <35 years with less than three previous cycles to reduce the incidence of multiple pregnancies. With a significant reduction in the number of triple transfers from 72.4 to 44.3%, the delivery rates were similar for both policies, 31 and 32.1%. However, the multiple pregnancy rates per transfer significantly decreased from 12.5 to 7.8% (P < 0.05). Of 99 pregnancies, only 24.2% were multiple including 1% of triplets compared to 40.7% multiple pregnancies including 6.7% of triplets for the first policy. Forty-eight transfers of two average embryos with the new policy were compared to 264 transfers of three average embryos with the old policy. Multiple pregnancy rates per transfer were significantly reduced by a third from 23 to 8% (P < 0.05) without a reduction of the pregnancy rates (42 and 48%). This study demonstrated that elective transfer of two embryos reduced the number of multiple pregnancies without impairing the pregnancy rates even with the transfer of average embryos.
Key words: double transfer/embryo quality/in-vitro fertilization/multiple pregnancy
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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High obstetrical morbidity and high neonatal morbidity and mortality make the reduction of the number of multiple pregnancies in assisted reproductive techniques a priority (Gonen et al., 1990
; Friedler et al., 1992; Seoud et al., 1992; FIVNAT, 1995). Even if ovulation induction for infertility is the major contributor to the number of multiple pregnancies, in-vitro fertilization (IVF) and embryo transfer is also accountable for the increase in the incidence of the number of multiple pregnancies observed since the early 1990s (Derom et al., 1993; Doyle, 1996). Rates up to 33% including between 5 and 9% of triplets have been published (SART, 1993; FIVNAT, 1995; HFEA, 1996). To achieve high pregnancy rates in IVF–embryo transfer, it is common practice to transfer more than one embryo into the uterus in order to increase the chance for at least one embryo to implant. However, the multiple pregnancy rates rise more rapidly than the pregnancy rate starting at two transferred embryos (Claman et al., 1987; Puissant et al., 1987; Staessen et al., 1992; FIVNAT, 1995). Compared to the natural history of multiple pregnancies, the frequency of twins in IVF is 20-fold higher and that of triplets is ~400-fold higher.
Despite this high incidence of multiple pregnancies, there is still no consensus among IVF programmes on the number of embryos to be transferred. Several authors (Svendsen et al., 1996; Elsner et al., 1997) recommend to transfer three or four embryos depending on the woman's age while others limit the number of embryos to a maximum of two if at least one good quality embryo is available for the transfer (Staessen et al., 1993; Kodama et al., 1995). Pregnancy rate is clearly correlated with the number of replaced embryos. It rises steadily with the number of transferred embryos and reaches a plateau at three replaced embryos (Wood et al., 1985; Sharma et al., 1988; FIVNAT, 1995). The best solution would be to limit the number of transferred embryos to two in all patients, although this will probably be associated with a significant reduction of the pregnancy rate for patients with impaired prognosis of conception by factors such as high maternal age or poor embryo quality (Roseboom et al., 1995). Another possibility would be to selectively reduce all triplet pregnancies but this will no doubt raise some medical, ethical and psychosocial dilemma (Donner et al., 1990; Vauthier-Brouzes and Lefèbvre, 1992). The main question is therefore how to reduce the incidence of multiple pregnancies and eradicate high order multiple pregnancies without diminishing the pregnancy rates.
A policy of elective transfer of two embryos by identifying situation at high risk of multiple pregnancies could prevent the occurrence of multiple pregnancies with a limited loss of the chances of pregnancies. Previous authors observed that elective transfers of two good quality embryos did not reduce the pregnancy rate (Staessen et al., 1992, 1993; Englert et al., 1993; Nijs et al., 1993; Waterstone et al., 1993). However, the incidence of multiple pregnancies remained high. If the risk of multiple pregnancies is clearly related to the number of transferred embryos, other factors have also been incriminated such as maternal age, male infertility, embryo quality, cleavage rate or the number of oocytes collected (Wood et al., 1985; Cummins et al., 1986; Puissant et al., 1987; Bollen et al., 1991; Staessen et al., 1992; Leroy et al., 1992; Logerot et al., 1993; Svendsen et al., 1996).
This study analysed the evolution of the pregnancy and multiple pregnancy rates obtained with two different elective transfer policies of two embryos. The first one, applied from 1994 to 1996, was based solely on embryo morphology where three embryos were replaced to all patients except in situations considered to be at high risk of multiple pregnancies (i.e. when three good embryos were available only two were replaced). Because the proportion of multiple pregnancies was still too high, a second more restrictive policy was applied after 1997, taking into account embryo quality, maternal age and the number of previous cycles. With this policy, a maximum of two embryos was replaced to all patients <35 years old with less than three previous cycles except when the quality of the embryos was poor. For patients with more than three cycles or >38 years, the first policy based on embryo morphology was applied.
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Materials and methods |
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Patients
From January 1994 until January 1998, all patients undergoing fresh embryo transfers after either IVF or intracytoplasmic sperm injection (ICSI) were selected for the analysis (n = 1200). Oocyte receivers were excluded.
The women's age was 32.5 ± 4.7 years and the duration of infertility was 5.2 ± 3.4 years. The causes of infertility were mainly tubal (20%), male (31%), mixed male and female (44%) and idiopathic (5%). The overall pregnancy rate was 44.5% including 31.2% of ongoing pregnancies and 12% miscarriages. The implantation rate per embryo reached 22%.
Ovarian stimulation and IVF protocol
The ovarian stimulation has been described previously (Devreker et al., 1996). Briefly, infertile patients undergoing IVF were first treated with luteinizing hormone-releasing hormone agonist (Buserelin, Suprefact; Hoechst, Brussels, Belgium) to achieve suppression of ovarian activity. When oestradiol concentrations were <100 pmol/l, ovarian stimulation was started with human menopausal gonadotrophin (HMG; Pergonal, Serono, Brussels, Belgium; Humegon, Organon, Oss, The Netherlands). Ovulation was induced by injection of 10 000 UI of human chorionic gonadotrophin (HCG, Pregnyl; Organon; and Profasi ; Serono). Oocyte retrieval took place 36 h later.
Preincubation and insemination or ICSI of oocytes, and embryo culture before transfer, were carried out in Earle's balanced salt solution containing 5.56 mM glucose and supplemented with 25 mM sodium bicarbonate (Sigma, Bornem, Belgium), 0.33 mM pyruvic acid (Sigma) and 0.5% human albumin (Red Cross, Brussels, Belgium) under a gas phase of 5% CO2, 5% O2 and 90% N2 (Van den Bergh et al., 1995). Normal fertilization was confirmed 14–16 h after insemination by the presence of two pronuclei (day 1). On the morning of embryo transfer, 42–44 h after insemination, embryos were examined under an inverted microscope to determine the evenness and number of blastomeres as well as the extent of extracellular fragmentation and a numerical score was calculated on the basis of embryo morphology and cleavage rate (Puissant et al., 1987). A score of 4 points was given for an embryo with regular blastomeres and no anucleate fragments, 3 points for an embryo with uneven blastomeres and one or two anucleate fragments, scores 2 or 1 for an embryo with uneven blastomeres and anucleate fragments of the embryonic surface 
1/3 or 
1/3 respectively. Two more points were added if the embryo had reached the 4-cell stage. Good embryos were those with a 5 or 6 point score, average embryos those with a score of 3 or 4 and poor embryos those with a score of 1 or 2 points. The total score of transferred embryos is the sum of the score obtained for each selected embryo reaching a maximum of 12 in double transfers and 18 in triple transfers. Embryos that had undergone at least one mitotic division were transferred vaginally through a Frydman® catheter (CCDT, Paris, France). Luteal support was maintained by daily injection of 100 mg i.m. of progesterone in oil or with intravaginal pessaries (3x 200 mg/day of micronized progesterone).
The transfers of two or three embryos were analysed according to the total score obtained by the transferred embryos and split into three groups representing the transfer of poor, average and good quality embryos. An ongoing pregnancy was defined as a pregnancy that continues to develop after 20 weeks of gestation. The ratio between the number of ongoing pregnancies and the number of transfers represents the pregnancy rate. Multiple pregnancy rate is defined by the number of multiple ongoing pregnancies divided by the number of transfers. Miscarriages occurring before 20 weeks of gestation were excluded from the analysis. The total number of fetal sacs divided by the total number of transferred embryos characterized the implantation rate. In the 18 triplet pregnancies observed, nine underwent selective fetal sac reduction. These nine pregnancies were considered as ongoing triplet pregnancies for the analysis.
Embryo transfer policies
First policy
From January 1994 until December 1996, elective transfers of two embryos based solely on embryo morphology were performed (n = 892). The policy concerning the number of embryos to be transferred was that when the three best embryos' total score was 15 only two embryos were replaced, n = 99 (a situation suggested to present a high risk of multiple pregnancies: Puissant et al., 1987; Staessen et al., 1993). For all the other couples three embryos were replaced if available (n = 603) except for patients who specifically requested a transfer of two embryos (n = 40) or a transfer of three embryos (n = 43). Sixty-six patients had two transferred embryos because only two embryos were available and 41 had one transferred embryo.
Second policy
From January 1997 until January 1998 a more restrictive embryo transfer policy was applied (n = 308): a maximum of two embryos were transferred for all patients <35 years old and with less than three previous attempts (n = 113) except for women with a total score of <8 for the two best embryos for which a third embryo was transferred (n = 43). When the criteria for double transfer were fulfilled, triple transfers were no longer allowed. Patients 35 years of age or with more than three attempts followed the first transfer policy (n = 96) and patients 38 years old had three embryos transferred if available (n = 51).
Statistical analysis
Statistical evaluation was performed by applying analysis of variance, 
2-test or by the Fisher's exact probability test when appropriate. Analysis was carried out using the SPSS 6.1 for Windows 95.
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Results |
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Women's age, duration of infertility, number of previous attempts, ovarian stimulation, number of oocytes and embryos obtained were similar for the two transfer policy groups analysed (Table I
). The indications for male infertility, a factor suggested to increase the risk of multiple pregnancies (Leroy et al., 1991; Logerot et al., 1993), represented 31% of the indications for both transfer policies. The mean number of transferred embryos significantly decreased after the second policy was applied (P < 0.001). Despite the reduction in the number of transferred embryos, the number of frozen embryos was similar for the two groups. This can be explained by the fact that in the second group, the number of transferred embryos was also limited for patients with average quality embryos that were considered unsuitable for freezing.
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Pregnancy and multiple pregnancy rates for the first transfer policy
Pregnancy rates increased with the number of transferred embryos, already reaching a plateau when two embryos were replaced (Table II
). It was more than twice as high for double and triple transfers compared to single transfers, 32 and 12% respectively (P < 0.03). The multiple pregnancy rate per transfer increased significantly from 9% for two transferred embryos to 14.5% for three transferred embryos (P < 0.03). Moreover, 18 triplets occurred after the replacement of three embryos (3%). The proportion of multiple pregnancies for the transfers of three embryos was as high as 45.6% compared to 27.7% for the transfers of two embryos. No multiple pregnancies occurred after the transfers of a single embryo and no triplets resulted from the transfers of two embryos.
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Pregnancy rates depended on the quality of the transferred embryos. Transfers of average or good quality embryos doubled the pregnancy rate compared to transfers of poor quality embryos for the transfers of two (P = 0.055) and three embryos (P < 0.001) (Table III
). Poor quality embryos had an implantation rate significantly lower than average or good quality embryos (Table III). On the contrary, multiple pregnancies were not associated with embryo quality. A similar proportion of multiple pregnancies was observed for the transfers of two and three average or good quality embryos. Furthermore, the majority of triplets occurred with the transfers of three average quality embryos (Table III). Multiple pregnancies were only reduced when considering the transfers of poor quality embryos for the transfers of two (P < 0.03) or three embryos (P < 0.01) (Table III).
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Elective transfer of two good quality embryos (n = 99) did not reduce the pregnancy rate compared to the transfer of three good quality embryos, 33.3 and 37.2% respectively. However, this transfer group represented only 11% of the total number of transfers during the application of the first transfer policy.
Pregnancy rates decreased significantly by half after the age of 38 years (P < 0.001) (Figure 1). On the contrary, twin gestations were remarkably stable until the age of 40 years. Between 35 and 40 years of age, the proportion of multiple pregnancies remained close to 30%. However, the majority of the multiple pregnancies occurred preferentially with younger patients. Of 112 multiple pregnancies, 97 (86.6%) were in patients aged <35 years including 17 triplets.
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Pregnancy rates decreased significantly only after the fifth IVF cycle, from 36.7% for the first cycle to 17.7% (P < 0.003) (Figure 2
). The proportion of multiple pregnancies did not decrease with the number of attempts, except after the fifth cycle. Patients treated for their first four IVF cycles experienced a higher risk of triplets, with 9.3% of triplets at the first attempt (Figure 2).
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Pregnancy and multiple pregnancy rates for the second transfer policy
The transfers of two embryos represented almost 50% of the transfers (Table IV
). The same relations as those observed for the first policy were observed between the number and the quality of the embryos replaced and the pregnancy rates. The pregnancy rate was three times higher for the transfers of two or three embryos compared to the transfers of one embryo. However, multiple pregnancy rates were similar between the transfers of two or three embryos reaching 10.5 and 7.3% per transfer respectively (Table IV). The embryo quality was higher for the transfers of two embryos compared to the transfers of one or three embryos. This is reflected by the high embryo scores and the implantation rate that reached 28.3% for the replacement of two embryos (P < 0.05) (Table IV). Only one triplet occurred after the transfer of three poor embryos in a patient <35 years old. Because of a more restrictive policy, patients were significantly younger for the transfers of two embryos compared to the transfers of one or three embryos (P < 0.001) (Table IV).
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Comparison between the two transfer policies
The proportion of the transfers of two embryos significantly increased from 23 to 49.5% since the new policy was applied (P < 0.01; Table V
). Despite the reduction of the number of transfers of three embryos, the pregnancy rates were similar for the two transfer policies, 31 and 32.5% for the first and the second one respectively. On the other hand, the number of multiple pregnancies dropped significantly with the new policy from 12.5% per transfer to 7.8% per transfer (Table V). This reduction is even more impressive when the proportion of multiple pregnancies is expressed as a function of the total ongoing pregnancies. Multiple pregnancies decreased by half during the second period, from 40.7 to 24.2% (P < 0.01). Moreover only one triplet in 24 multiple pregnancies (4.2%) occurred with the second policy compared to 18 triplets in 112 multiple pregnancies (16.1%) with the first one (P = 0.057) (Table V).
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When patients that benefited from the new policy (n = 161) were matched for their age and for the number of attempts with patients from the first policy (n = 495), differences were even more pronounced. The number of transfers of two embryos represented 70% (n = 113) of all the transfers performed during 1997–1998 compared to 23.6% (n = 117), P < 0.0001. Elective transfers of two embryos represented 31.4% (n = 97) of all transfers with the new policy compared to only 11% (n = 99) with the previous policy, P < 0.001. With comparable pregnancy rates (37% for the old policy and 39% for the new one), the multiple pregnancey rate dropped by nearly half from 16% per transfer during 1994–1996 to 9% per transfer in 1997–1998 (P < 0.01). Triplet pregnancies were also reduced, only one (0.6%) triplet from 161 transfers occurred compared to 16 from 495 (3.2%) transfers (P = 0.052).
With the second transfer policy, patients with average embryos benefited from a double transfer provided they were <35 years old and had had less than three previous cycles. They were compared to a group of similar patients who had three average embryos replaced during 1994–1996 (Table VI) which represented the group including most of the multiple gestations (55% of the pregnancies). The pregnancy rates achieved by the two groups were similar, 42 and 48% with the old and the new transfer policies respectively (Table VI). The number of multiple pregnancies for the transfers of two embryos was only one-third of the number of multiple pregnancies for the transfers of three embryos (P < 0.05). Despite the fact that these embryos were classified as average quality, they had a high viability reflected by the high implantation rates achieved both in transfers of two and three embryos, 33 and 28% respectively.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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This study demonstrated that a policy of elective transfers of two embryos helped to reduce the number of multiple pregnancies without impairing the pregnancy rates. During the first period analysed from 1994 to 1996, the decision to transfer a maximum of two embryos was based solely on embryo morphology; three embryos were replaced except for patients considered to be at high risk of multiple pregnancies (i.e. when at least three good quality embryos were available for the transfer). Patients that benefited from an elective transfer of two embryos had effectively a pregnancy rate similar to those who had three good or average quality embryos replaced. The high embryo viability was reflected by the high implantation rate achieved for these patients (26.5%), which was similar to the implantation rate for the transfers of three embryos (Table III
). On the other hand, their risk of multiple pregnancies was significantly reduced and triplets were avoided; the transfers of three embryos experienced a multiple pregnancy rate twice as high compared to the transfers of two embryos (P < 0.01; Table III). However, the total number of multiple pregnancies for 1994–1996 was still excessively high. Over the 405 babies born, more than half (242, 60%) came from a multiple gestation. This is due to the fact that elective transfers of two embryos were applied to only 11% of the patients and that implantation rates for average and good embryos were similar, minimizing the impact the transfer policy could have on the incidence of multiple pregnancies. Half of the pregnancies were multiple after the transfers of three average embryos including 6% of triplets. If considering the number of sacs visualized by ultrasonography, the proportion of multiple gestations is even higher (Table II). Opposed to previous studies which observed a higher incidence of multiple pregnancies with the number of good quality embryos replaced (Puissant et al., 1987; Staessen et al., 1992, 1993; Steer et al., 1993; Kodama et al., 1995), this study shows that embryo quality does not identify patients at risk of multiple pregnancies, which emphasizes the fact that embryo morphology imperfectly reflects the embryo viability.
Pregnancy and multiple pregnancy rates were only significantly reduced when considering the transfer of poor quality embryos for the transfers of either two or three embryos, illustrating the well-known relationship between embryo quality and pregnancy rates (Puissant et al., 1987; Staessen et al., 1992).
In order to reduce even more the multiple gestations and to avoid triplets, a more restrictive policy had to be applied. Analysis of the data demonstrated that pregnancy rate declined significantly after the age of 38 years reaching only 13% after 40 years (Figure 1). This relationship between maternal age and pregnancy rates has been well-documented previously (Piette et al., 1990; Stolwijck et al., 1997). This drop in pregnancy rate is a consequence of the ageing of the oocytes as shown in oocyte donor programmes (Navot et al., 1991) associated with a higher incidence of chromosomal abnormalities within the embryos (Plachot et al., 1986). The majority of multiple pregnancies (86%) occurred before the age of 35 years because the number of pregnancies was higher for patients <35 years old. However, the risk of multiple pregnancies remained equivalent until the age of 40 years, although no triplets occurred after the age of 35 years (Figure 1). Once they are fertile, older patients face a risk of twin gestations similar to that of their younger counterparts (Senöz et al., 1997). The impression that younger women are at a higher risk of multiple pregnancies is mostly due to their higher pregnancy rates. To have a major impact on the number of multiple pregnancies, it was decided to limit the number of transferred embryos before the age of 35 years.
Opposed to earlier studies, the aetiology of infertility (Leroy et al., 1992; Logerot et al., 1993) was not correlated with the risk of multiple pregnancies. Pregnancy rate and multiple pregnancy rate remained stable until the fifth cycles when they both decreased by the progressive selection of a population with a poor pregnancy prognosis. Male infertility was not responsible for a higher number of multiple pregnancies compared to other aetiology of infertility (data not shown).
A new group of patients at high risk of multiple pregnancies was defined and the transfer policy was opposed to the previous one (i.e. to transfer two instead of three embryos to all patients except for situations considered to be at lower risk of multiple pregnancies).
The proportion of triple transfers significantly decreased and 50% of the patients benefited from a double transfer. This was associated with a significant reduction in the proportion of multiple pregnancies from 40.7 to 25% (P = 0.01). Moreover, only one (1%) triplet occurred with this policy compared to 18 (6.5%) with the old one. During 1994–1996, the majority of the multiple pregnancies including the triplets occurred with the transfer of three average embryos. Since pregnancy rates are also related to embryo quality (Puissant et al., 1987; Roseboom et al., 1995), the reduction of the number of transferred embryos could have impaired the chances of pregnancies for these patients. On the contrary, the application of an elective transfer of two embryos for this subgroup of patients significantly decreased their risk of multiple pregnancies without lowering their pregnancy chances.
The results observed in this study confirm previous reports (Englert et al., 1993; Staessen et al., 1993, 1995; Nijs et al., 1993) that elective transfers of two embryos reduce the risk of multiple pregnancy without impairing the pregnancy rate. However, those authors wanted to limit the number of transferred embryos only when at least two good quality embryos were available. In this study, the transfer policy was more restrictive since patients with average embryos had also a maximum of two embryos replaced, without taking into account the fact that supernumerary embryos could be frozen.
Elective transfer policy of two embryos could also be applied in oocyte donation programmes where oocyte receivers are known to have an endometrial receptivity superior to their IVF counterparts. The difference in endometrial receptivity is probably due to the high oestradiol concentrations obtained with ovarian stimulation in IVF that have adverse effect on endometrium. However, in a recent reports (Yaron et al., 1998) up to five or six embryos were transferred resulting in unacceptably high rates of multiple pregnancies (44.4% including 8.3% of triplets). No clear benefit was observed between the transfers of two, three or four embryos as pregnancy rates were not statistically different; however, up to 5.5% of triplets occurred with four transferred embryos. With regard to the data, the number of transferred embryos could have been limited at two, eventually three to obtain acceptable multiple pregnancy rates without compromising the pregnancy rate. This underscores the need for specific guidelines regarding the number of transferred embryos in oocyte donation programmes.
The results observed with the new transfer policy compared favourably with the Belgian national results (Belgian Register for Assisted Procreation, 1997). Previously, both the delivery rates per cycle and the proportion of multiple deliveries were above the Belgian rates, 22.1 and 17.9% of pregnancy rate, and 40.7 and 29% of multiple pregnancy rate respectively. With the new policy, the pregnancy rate is similar to the Belgian rate (1996), 22.2 and 23% respectively, but the multiple pregnancy rate is lower, 24.2% compared to 34.1% respectively. Triplets were four times less frequent compared to the Belgian results for 1996 (Belgian Register, 1997), 1 and 4.5% respectively.
Despite a significant reduction in the number of transferred embryos, the twin rate (24%) remained high for patients aged <35 years. With such a high embryo viability reflected by an implantation rate of 30%, the transfer a single embryo is now a matter of debate for these patients. Until now, pregnancy rates reported for single transfers were considered for patients who had only one embryo available at the time of transfer, a situation hardly comparable when a selection of the best transferred embryos is possible. The overall implantation rate observed in this study for single transfers is comparable with the one observed by Giorgetti et al. (1995) for good embryos, 14.6 and 15.4% respectively. On the other hand, Ziebe et al. (1997) observed that the transfers of one embryo achieved implantation rates similar to the transfer of two or more embryos of the same quality. Taking into account the results observed for the transfer of two embryos, the maximum implantation rate that could be expected for the transfer of one embryo is ~30%. When including miscarriages, this means that for these patients the pregnancy rates will probably be reduced by 15%.
Elective transfer policy of two embryos relying solely on embryo morphology has proven its limits to prevent the risk of multiple pregnancies. The first policy decreased the risk of multiple pregnancies only for patients with good embryos preserving their chances of pregnancy. However, because it concerned only a small number of women the impact on the total number of multiple pregnancies was minimized. The majority of them including triplets occurred after the replacement of three average embryos. The second policy demonstrated that for patients with a good prognosis, the reduction of the number of transferred embryos decreased significantly their risk of multiple pregnancies and avoided triplets without decreasing their chances of pregnancy even for average embryos. However, the twin rate remained high for young patients. Twin gestations are relatively well tolerated by patients and with the improvement in the neonatal management twins are doing fairly well. The transfers of a single embryo for these patients are still controversial because although they will almost eradicate all multiple gestations, they might significantly reduce their chances of pregnancies. This reduction will oblige patients to undergo more IVF cycles. All this still has to be balanced with the risks encountered by twin gestations.
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Acknowledgments |
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Fabienne Devreker is Scientific collaborator to the Belgian National Funds for Scientific Research and is supported by a grant from `la Fondation Erasme'. We are thankful to Isabelle Place for manuscript revision.
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Notes |
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1 To whom correspondence should be addressed
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References |
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Submitted on May 18, 1998; accepted on September 16, 1998.
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