1 The Family Federation of Finland, Infertility Clinic, PO Box 849, FIN-00101 Helsinki and 2 Department of Obstetrics and Gynaecology, University Central Hospital of Helsinki, FIN-00290 Helsinki, Finland
3 To whom correspondence should be addressed. e-mail: viveca.soderstrom-anttila{at}vaestoliitto.fi
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: multiples/oocyte donation/pregnancy rate/recipients/single embryo
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In the European Society of Human Reproduction and Embryology (ESHRE) there is general agreement that twin pregnancy is the most severe complication of IVF/ICSI, resulting in considerable medical risks for the mother and offspring, as well as excess obstetric and neonatal costs (ESHRE Campus Course Report, 2001). Recommendations for elective single embryo transfer (eSET) in certain groups of subjects with top-quality embryos have been presented (ESHRE Campus Course Report, 2001
). The recommendations are based on experience with eSET in conventional IVF/ICSI cycles (Gerris et al., 1999
; Van Royen et al., 1999
; Vilska et al., 1999
; Martikainen et al., 2001
; Tiitinen et al., 2001
). Thus far, there have been no corresponding recommendations for women receiving oocytes from donors and, to our knowledge, no reports of eSET in recipients of donated oocytes.
During the last 10 years, at the Infertility Clinic of the Family Federation of Finland, Helsinki, Finland, we have made an effort to decrease the frequency of multiple births by reducing the number of embryos transferred at any one time. Since 1993, no more than two embryos at a time have been transferred in our OD programme. Supernumerary embryos have been cryopreserved for later use. However, even with this strategy the number of twin pregnancies remained high. From the beginning of 1996 we began to transfer only one embryo at a time in recipients with a medical contraindication for twin pregnancy, as in patients with diabetes, Turners syndrome, previous hysterotomy or a uterine malformation. Good pregnancy results, together with experience of eSET in conventional IVF (Vilska et al., 1999) inspired us to change the embryo transfer policy one step further.
From the beginning of 2000, we started to recommend SET to all our recipients, independent of their age or number of treatment cycles, if there was at least one good quality embryo available. For example, if the couple had two good-quality embryos, one embryo was transferred and the other was cryopreserved for later use. If the quality of the embryos was poor and they could not be cryopreserved, double embryo transfer (DET) was recommended. The recipients received extensive counselling about the risks involved in multiple pregnancy. The final decision on SET or DET was made in conditions of mutual understanding between the clinician and the couple, taking into account the medical situation and the wishes of the couple.
The primary purpose of this work is to report our OD results from 20002001, when eSET was introduced as a recommended policy for all oocyte recipients if one good-quality embryo was available for transfer. The results are compared with those in 19981999, when usually two embryos were transferred at a time. The preliminary cumulative pregnancy rates, including those resulting from frozenthawed embryo transfer, are presented.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Recipients
The oocytes obtained from a single anonymous donor were allocated to two recipients if the number of collected oocytes was at least 10, and to one recipient if fewer than 10 oocytes were retrieved. In 19981999, 76 recipient couples received donated oocytes, and in 20002001, 59 couples received oocytes. The mean age of the recipient women was 35 years. At our clinic the upper age limit for a recipient woman who wants to have anonymously donated oocytes is 42 years. If she is older, the couple has to arrange their own donor. In 19981999, the oldest recipient woman was 48 years, and in 20002001, 47 years. During both time periods, approximately half of the OD treatments (49 and 51% respectively) were carried out because of primary or secondary ovarian failure, and in the other cases, the indication for treatment was poor response to ovarian stimulation, repeated failures in earlier IVF treatments, suspicion of oocyte abnormality or because the woman was a carrier of a genetic disease. The recipients were going through their first ODembryo transfer in 72% of the treatments in 19981999, and in 69% in 20002001 (not significant). The number of treatment cycles with ICSI was 10 (13.2%) in 19981999, and five (8.5%) in 20002001 (not significant). In 2001, one embryo transfer was carried out via a transmyometrial route because of congenital absence of the cervix.
Priming of the endometrium in oocyte recipients has been described previously (Söderström-Anttila et al., 1996). Briefly, women with ovarian failure used estradiol valerate, 46 mg/day, for 1216 days before embryo transfer. Vaginally administered micronized progesterone (Lugesteron®; Leiras, Turku, Finland), 600 mg/day, was started on the day of donor oocyte collection. Women with functioning ovaries underwent pituitary down-regulation with a GnRH agonist and thereafter they used the same HRT as those with ovarian failure. If pregnancy was achieved, estrogen therapy was continued until 1011 weeks of gestation and progesterone replacement until 12 weeks gestation. A similar HRT protocol was carried out in cases of frozenthawed embryo transfer cycles.
Embryology
The embryos were cultured in standard media (IVF-Universal; MediCult, Copenhagen, Denmark). Cleavage rates and embryo grading were assessed 4852 h after ovum retrieval, and in the case of day-3 transfer, 72 h after ovum retrieval. The embryos were scored as regards the number and regularity of blastomeres, the amount of fragmentation and the presence of multinucleated blastomeres (Scott et al., 1991). The following grades were used: grade 1, no fragments and even-sized blastomeres; grade 2, <20% fragmentation; grade 3, 2050% fragmentation; and grade 4, >50% fragmentation. A good-quality embryo was defined as follows: an embryo in the 2- to 5-cell stage on day 2 and at least in the 5-cell stage on day 3 after ovum retrieval, with mononuclear blastomeres and fragmentation not more than 20%. Supernumerary good-quality embryos were cryopreserved by using 1,2-propanediol (Lassale et al., 1985
).
Statistics
Students t-test was used to compare the characteristics of the donors and the recipients, and the weight of the infants. In the other comparisons the 2-test was employed.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Most centres involved in OD report a clinical pregnancy rate of 2060% per embryo transfer (Paulson et al., 1997; Remohí et al., 1997
; Yaron et al., 1997
; Toner et al., 2002
). Mostly, at least two to three embryos are transferred at a time, but it is not unusual that up to five embryos are transferred at one time. Yaron et al. (1997)
stated that the success rate increases with increasing number of transferred embryos. They concluded that limiting the number of transferred embryos to two would give a very low pregnancy rate, of only 16.4% per embryo transfer. If five embryos were transferred, the pregnancy rate would be 36.7%, with a 44.4% risk of multiple pregnancy. Another group has stated that among recipients who had supernumerary embryos cryopreserved, transferring more than two embryos increased the multiple pregnancy risk, with no corresponding increase in the chance of a live birth (Reynolds et al., 2001
). Increased pregnancy rates have been noted after extended culture and blastocyst transfer. A pregnancy rate of 88% per embryo transfer was found when an average of 2.1 blastocysts were transferred (Schoolcraft and Gardner, 2000
). Of these pregnancies, 44% were multiples, and the authors recommended single blastocyst transfer in OD programmes.
Recently, statements have been made regarding the situations in which eSET should be carried out in conventional IVF cycles in order to reduce the number of multiple pregnancies (ESHRE Campus Course Report, 2001). Oocyte recipients differ in many aspects from standard IVF subjects and these differences must be taken into consideration when the embryo transfer policy is planned. The success rate after OD is independent of the age of the recipient woman, at least up to the age of 45 years (Legro et al., 1995
; Toner et al., 2002
). In contrast to standard IVF subjects, advanced age of the recipient does not reduce the risk of multiple birth (Reynolds et al., 2001
). Oocyte donation has also mostly been associated with similar prognosis regardless of the indication for treatment (Paulson et al., 1997
; Remohí et al., 1997
). The most important factors determining the success rate of OD are the age of the donor and the quality of the oocytes, in combination with a well-prepared endometrium (Navot et al., 1991
; Edwards, 1992
; Cohen et al., 1999
). Support for this theory can perhaps be seen in our study, as we found no difference in the pregnancy and delivery rates in cycles with only one embryo available compared with those with eSET and with DET. This is in contrast to earlier results among women undergoing conventional IVF (Vilska et al., 1999
). This difference is not unexpected, as the donated oocytes originated from healthy women of normal ovarian status. Thus, the outcome of OD is more a reflection of embryo quality than the number of embryos.
There are also other important considerations in planning an optimal embryo transfer strategy for oocyte recipients. A high risk of obstetric complications has been demonstrated in OD pregnancies, even singleton ones (Pados et al., 1994; Söderström-Anttila et al., 1998
; Sheffer-Mimouni et al., 2002
). One of the most frequently observed obstetric complications is pregnancy-induced hypertension, which occurs in 2338% of recipients (Pados et al., 1994
; Abdalla et al., 1998
; Söderström-Anttila et al., 1998
; Yaron et al., 1998
; Salha et al., 1999
; Sheffer-Mimouni et al., 2002
). These pregnancies are also complicated by a high incidence of gestational diabetes, as well as first and second trimester vaginal bleeding (Sheffer-Mimouni et al., 2002
). In general, 1545% of all OD pregnancies are reported to be multiples (Pados et al., 1994
; Applegarth et al., 1995
; Abdalla et al., 1998
; Yaron et al., 1998
; Schoolcraft and Gardner, 2000
; Toner et al., 2002
). Multiple pregnancy will further increase the risks of obstetric complications and health problems for the children involved (Bergh et al., 1999
). There are good reasons why multiples should be avoided, and the only way to achieve this goal is to transfer only one embryo at a time. In this study the reduction of multiples to 10% did not reach statistical significance because of the small sample size, but the tendency was obvious and undeniable.
Very often, couples are not greatly aware of the increased health risks and the added psychosocial burden involved in multiple pregnancy. They need thorough counselling about these facts, as well as information about prognosis with various transfer policies. At our clinic the practice of transferring only one embryo has not been forced on the couples but rather presented as a safer option. We have informed the recipients that if two good-quality embryos are transferred, the risk of having twins will be about 30% if pregnancy is achieved. After counselling it has often been the wish of the couples that only one embryo is transferred at a time. Mostly, however, the couples leave the final decision to be made by the doctor, in regard to the quality of the embryos. We try to achieve a situation in which the recipients feel comfortable with the decision. If the recipient couple, after counselling, expresses a strong wish for DET independent of embryo quality, and there is no medical contraindication for twins, we support them and share the responsibility for this decision. The recipients have also been informed that, thus far, we cannot predict individual embryos likely to implant.
Our present results show that it is possible to achieve a delivery rate of 33.3% after SET carried out on day 2 or 3 after ovum retrieval. It is worth pointing out that 42% (24 out of 57) of these embryos were not classified as top-quality according to criteria recently presented in the literature (Gerris et al., 1999; Van Royen et al., 1999
). In subjects undergoing conventional IVF/ICSI, late cleaving embryos have been linked to lower implantation rates compared with those showing early cleavage (Bos-Mikich et al., 2001
; Lundin et al., 2001
). In contrast to some other investigators, we included 2- and 3-cell stage embryos in the definition of good embryos. This group was analysed separately from the 4-cell cleavage stage embryos on day 2 (Table V). We found good implantation rates in the 2- and 3-cell embryos with no more than 20% fragmentation. These embryos resulted in pregnancy at a rate of 55.6% per embryo transfer and may be recommended for eSET. However, the number of embryos analysed was too small to draw firm conclusions on their implantation potential. Nevertheless, it is interesting to speculate that there may be differences in endometrial receptivity in relation to embryo cleavage stage between women undergoing conventional IVF and oocyte recipients, depending on the different hormonal treatment regimens. Consistent with earlier findings (Ziebe et al., 1997
; Vilska et al., 1999
), we noted higher implantation rates among embryos with low fragmentation, although the results did not reach statistical significance because of the small sample size (Table V).
Centres in which eSET is carried out need a well-functioning cryopreservation system. During the last 2 years we have mostly transferred only one embryo at a time in frozenthawed embryo transfer cycles, and the results are reassuring. At this point, of the 59 recipients treated in 20002001, 20 women have given birth after fresh embryo transfer and 10 after frozenthawed embryo transfer, i.e. at least one-third of all the infants originated from frozenthawed embryos. Using primarily single embryo transfers we have achieved a 50% cumulative delivery rate per recipient cycle.
In conclusion, oocyte recipients constitute a special group of subjects. They have excellent pregnancy results but also high risks of obstetric complications. Multiple pregnancies further increase the risks for mother and offspring and should therefore be particularly avoided in this group of women. We have shown that by increasing the proportion of eSETs it is possible to reduce the number of twins without affecting pregnancy and delivery rates. Based on our experience, we recommend eSET to oocyte recipients.
![]() |
Acknowledgements |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Applegarth, L., Goldberg, N.C., Cholst, I., McGoff, N., Fantini, D., Zellers, N., Black, A. and Rosenwaks, Z. (1995) Families created through ovum donation: A preliminary investigation of obstetrical outcome and psychosocial adjustment. J. Assist. Reprod. Genet., 12, 574580.[ISI][Medline]
Bergh, T., Ericson, A., Hillensjö, T., Nygren K.G. and Wennerholm, U.B. (1999) Deliveries and children born after in-vitro fertilisation in Sweden 19821995: a retrospective cohort study. Lancet, 354, 15791585.[CrossRef][ISI][Medline]
Bos-Mikich, A., Mattos, A.L.G. and Ferrari, A.N. (2001) Early cleavage of human embryos: an effective method for predicting successful IVF/ICSI outcome. Hum. Reprod., 16, 26582661.
Cohen, M.A., Lindheim, S.R. and Sauer, M.V. (1999) Donor age is paramount to success in oocyte donation. Hum. Reprod., 14, 27552758.
Edwards, R.G. (1992) Why are agonadal and post-amenorrhoeic women so fertile after oocyte donation? Hum. Reprod., 7, 773774.
ESHRE Campus Course Report (2001) Prevention of twin pregnancies after IVF/ICSI by single embryo transfer. Hum. Reprod., 16, 790800.
Gerris, J., 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, 25812587.
Lassale, B., Testart, J. and Renad, J.P. (1985) Human embryo features that influence the success of cryopreservation with the use of 1,2 propanediol. Fertil. Steril., 44, 645651.[ISI][Medline]
Legro, R.S., Wong, I.L., Paulson, R.J., Lobo, R.A. and Sauer, M.V. (1995) Recipients age does not adversely affect pregnancy outcome after oocyte donation. Am. J. Obstet. Gynecol., 172, 96100.[CrossRef][ISI][Medline]
Lundin, K., Bergh, C. and Hardarson, T. (2001) Early embryo cleavage is a strong indicator of embryo quality in human IVF. Hum. Reprod., 16, 26522657.
Martikainen, H., Tiitinen, A., Tomás, C., Tapanainen, J., Orava, M., Tuomivaara, L., Vilska, S., Hydén-Granskog, C., Hovatta, O. and the Finnish ET Study Group (2001) One versus two embryo transfer after IVF and ICSI: a randomized study. Hum. Reprod., 16, 19001903.
Navot, D., Bergh, P.A., Williams, M., Garrisi, G.J., Guzman, I., Sandler, B., Fox, J., Schreiner-Engel, P., Hofmann, G.E. and Grunfeld, L. (1991) An insight into early reproductive processes through the in vivo model of ovum donation. J. Clin. Endocrinol. Metab., 72, 408414.[Abstract]
Pados, G., Camus, M., Van Steirteghem, A., Bonduelle, M. and Devroey, P. (1994) The evolution and outcome of pregnancies from oocyte donation. Hum. Reprod., 9, 538542.[Abstract]
Paulson, R.J., Hatch, I.E., Lobo, R.A. and Sauer, M.V. (1997) Cumulative conception and live birth rates after oocyte donation: implications regarding endometrial receptivity. Hum. Reprod., 12, 835839.[Abstract]
Remohí, J., Gartner, B., Gallardo, E., Yalil, S., Simón, C. and Pellicer, A. (1997) Pregnancy and birth rates after oocyte donation. Fertil. Steril., 67, 717723.[CrossRef][ISI][Medline]
Reynolds, M.A., Schieve, L.A., Jeng, G., Peterson, H.B. and Wilcox, L.S. (2001) Risk of multiple birth associated with in vitro fertilization using donor eggs. Am. J. Epidemiol., 154, 10431050.
Salha, O., Sharma, V., Dada, T., Nugent, D., Rutherford, A.J., Tomlinson, A.J., Philips, S., Allgar, V. and Walker, J.J. (1999) The influence of donated gametes on the incidence of hypertensive disorders of pregnancy. Hum. Reprod., 14, 22682273.
Schoolcraft, W.B. and Gardner, D.K. (2000) Blastocyst culture and transfer increases the efficiency of oocyte donation. Fertil. Steril., 74, 482486.[CrossRef][ISI][Medline]
Scott, R.T., Hofmann, G.E., Veeck, L.L., Jones, H. W. and Muasher, S.J. (1991) Embryo quality and pregnancy rates in patients attempting pregnancy through in vitro fertilization. Fertil. Steril., 55, 426428.[ISI][Medline]
Sheffer-Mimouni, G., Mashiach, S., Dor, J., Levran, D. and Seidman, D.S. (2002) Factors influencing the obstetric and perinatal outcome after oocyte donation. Hum. Reprod., 17, 26362640.
Simón, C., Cano, F., Valbuena, D., Remohí, J. and Pellicer, A. (1995) Clinical evidence for a detrimental effect on uterine receptivity of high serum estradiol levels in high and normal responder patients. Hum. Reprod., 10, 24322437.[Abstract]
Söderström-Anttila, V., Foudila, T. and Hovatta, O. (1996) A randomized comparative study of highly purified follicle stimulating hormone and human menopausal gonadotrophin for ovarian hyperstimulation in an oocyte donation programme. Hum. Reprod., 11, 18641870.[Abstract]
Söderström-Anttila, V., Tiitinen, A., Foudila, T. and Hovatta, O. (1998) Obstetric and perinatal outcome after oocyte donation comparison with in vitro fertilization pregnancies. Hum. Reprod., 13, 483490.[CrossRef][ISI][Medline]
Tiitinen, A., Halttunen, M., Härkki, P., Vuoristo, P. and Hydén-Granskog, C. (2001) Elective single embryo transfer: the value of cryopreservation. Hum. Reprod., 16, 11401144.
Toner, J.P., Grainger, D.A. and Frazier, L.M. (2002) Clinical outcomes among recipients of donated eggs: an analysis of the U.S. national experience, 19961998. Fertil. Steril., 78, 10381045.[CrossRef][ISI][Medline]
Van Royen, E., Mangelschots, K., De Neubourg, D., Valkenburg, M., Van de Meerssche, M., Ryckaert, G., Eestermans, W. and Gerris, J. (1999) Characterization of a top quality embryo, a step towards single-embryo transfer. Hum. Reprod., 14, 23452349.
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, 23922395.
Yaron, Y., Amit, A., Kogosowski, A., Peyser, M.R., David, M.P. and Lessing, J.B. (1997) The optimal number of embryos to be transferred in shared oocyte donation: walking the thin line between low pregnancy rates and multiple pregnancies. Hum. Reprod., 12, 699702.[Abstract]
Yaron, Y., Ochshorn, Y., Amit, A., Kogosowski, A., Yovel, I. and Lessing, J.B. (1998) Oocyte donation in Israel: a study of 1001 initiated treatment cycles. Hum. Reprod., 13, 18191824.[Abstract]
Ziebe, S., Petersen, K., Lindenberg, S., Andersen, A.-G., Gabrielsen, A. and Nyboe Andersen, A. (1997) Embryo morphology or cleavage stage: how to select the best embryos for transfer after in-vitro fertilization. Hum. Reprod., 12, 15451549.[Abstract]
Submitted on April 14, 2003; accepted on June 3, 2003.