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Cancellation of fresh embryo transfer: A future perspective
Middle East Fertility Society Journal (2010) 15, 240–242
Middle East Fertility Society
Middle East Fertility Society Journal www.mefsjournal.com www.sciencedirect.com
OPINION ARTICLE
Cancellation of fresh embryo transfer: A future perspective A. Rahim a, P. Devroey b, K. Diedrich a, S. Al-Hasani a b
a,*
Department of Gynecology and Obstetrics, University of Schleswig-Holstein, Ratzeburger Allee 160, 23560 Lu¨beck, Germany Free University Brussels, Reproductive Medicine Center, Brussels, Belgium
Received 7 July 2010; accepted 7 September 2010 Available online 13 October 2010
Keywords Embryo transfer; Vitrification
Abstract The implantation of embryo depends on the quality of the embryo and the receptivity of the endometrium. While the factors affecting embryo quality were optimized, the implantation rates did not reach the desirable levels. This directs the blaming for endometrial receptivity which already has been affected by supra-physiological levels of hormone, namely estradiol in controlled ovarian hyperstimulation (COH) cycle. On the other hand, cryopreservation, especially the vitrification method, has been highly improved to give almost the same results of fresh state, in addition to decreased rate of blastogenesis birth defects. All these encourage us to put our opinion to overcome the problem of endometrial receptivity by cancellation of the fresh embryo transfer (fresh ET) and to perform the frozen–thawed embryo transfer (FET) in cases of excessive response to COH. Ó 2010 Middle East Fertility Society. Production and hosting by Elsevier B.V. All rights reserved.
1. Introduction The birth of Louise Brown in 1978 was a revolutionary point in the treatment of infertility, where it opened widely the door to great hope for infertile couples to make their dream real in * Corresponding author at: Department of Gynecology and Obstetrics, University of Schleswig-Holstein, Ratzeburger Allee 160, 23560 Lu¨beck, Germany. E-mail address: [email protected] (S. Al-Hasani). 1110-5690 Ó 2010 Middle East Fertility Society. Production and hosting by Elsevier B.V. All rights reserved. Peer review under responsibility of Middle East Fertility Society. doi:10.1016/j.mefs.2010.09.004
Production and hosting by Elsevier
getting their own baby. Since that time on, there is a continuous research to optimize the outcomes of Assisted Reproduction Technologies (ART). It is known that a successful implantation, and as a result, pregnancy rate depends on a competent embryo and a receptive endometrium with a synchronized dialogue between maternal and embryonic tissues (1). Regarding a competent or high quality embryo, this is related to the age of the patient, to controlled ovarian hyperstimulation (COH) program and to the effectiveness of in vitro culture system (2). However, pregnancy and birth rates following in vitro fertilization (IVF) attempts remain low, where two out of three IVF cycles fail to result in pregnancy and more than eight out of 10 transferred embryos fail to implant (3). Depending on real advancements in getting high embryo quality, the endometrium receptivity and growth synchrony with the embryo become a crucial point in reaching a successful implantation and pregnancy. Therefore, blaming the endometrium for such low success rates is rather clear.
Cancellation of fresh embryo transfer: A future perspective What is eventually the solution to overcome this problem? 2. Cryopreservation Cryopreservation of human gametes and embryos is a mandatory technique in ART that leads to increased cumulative outcomes while decreasing costs (4). This is because this approach limits the number of embryos transferred, while supernumerary oocytes and/or embryos can be used in subsequent treatment cycles (5). Cryopreservation is carried out by two techniques; the slowfreezing method, and the more recently used rapid procedure called vitrification. Vitrification has gradually replaced the old slow-freezing method due to its success rates and simplicity. Also, there are many other advantages of the vitrification method over slow-freezing method such as, reducing osmotic injury, no ice crystal formation or zona pellucid fracture, no need of special devices and less cost, and extremely less time needed when compared with slow-freezing method. So, vitrification seems to be the cryopreservation method of the near future. It has been shown that the same number of oocytes is needed in fresh and vitrified cycles to obtain similar results in terms of embryo development; also, the percentage of top quality embryos per fertilized oocyte was about 52% in fresh and vitrified group of oocytes (6). Regarding oocyte donation, Cobo et al. (7) found that from 231 vitrified donated MII oocytes the survival rate, fertilization rate and ongoing pregnancy (number of transfers were 23 and mean number of embryos was 2.1) were 96.9%, 76.3% and 48%, respectively. Kalar et al. (8) showed that the rate of hCG rise following FET is significantly greater than what was seen with fresh ET and accordingly they postulated that such a difference may reflect that the healthiest embryos survive the freeze–thaw process or may be secondary to the more physiologic endocrine environment at the time of implantation. China et al. (9) noticed that pregnancies and infants conceived following oocyte vitrification are not associated with increased risks of adverse obstetric and perinatal outcomes. Moreover, frozen–thawed embryo transfer (FET) is the most common way to prevent serious late OHSS and to increase the cumulative pregnancy rate (2,10). 3. Endometrium receptivity Normally, the endometrium undergoes morphological and biochemical changes in response to cyclic regulation by hormones that make up a critical period during luteal phase in which the endometrium is accessible to embryo, and this period is called implantation window (11,12). The main goal of COH program is to recruit a large number of follicles to obtain enough mature oocytes that will be the bases to obtain a cohort of embryos for better selection for transfer (13). What about the effect of supra-physiological hormonal levels on the endometrium and its receptivity? It has been shown that a cumulative exposure to high estradiol levels during the follicular phase of IVF cycles with COH negatively affect implantation and pregnancy as it can be associated with severe down regulation of the expression of endometrial progesterone receptors (14) where excessive ovarian
241 response to stimulation leads to insufficient secretory transformation of the endometrium as well as discordant glandular and stromal development at a time that coincides with the period of maximum uterine receptivity (15). On the other hand, Arslan et al. (14) showed that different levels of estradiol exposure did not likely affect oocyte and embryo quality during the follicular phase of IVF cycles with COH. Recently, it has been found that gonadotrophin treatment in COH cycles led to disruptions of the transcriptional activation of genes involved in normal endometrial receptivity (1). Some studies can support this indirectly, where it has been shown that higher embryo implantation and clinical pregnancy rates are achieved in FET when compared with fresh ET especially for those patients with a strong ovarian response (2,16). Also, it was found that multiple pregnancy rates in FET was very high; and hence it was suggested to carry out FET cycles with single high quality embryos to decrease multiple pregnancy rate and improve the overall embryo utilization rate (2). Moreover, in a novel study done by Halliday et al. (17), they found that the increase in blastogenesis birth defects appear greater for fresh ET than for FET with the risk for fresh ET relative to controls being more than 3-fold and depending on this observation an interpretation that cryopreservation process acting as ‘‘selecting gate’’ for more viable embryos can be considered (18). Alternatively, or in addition, the excessive ovarian hormonal exposure related to oocytes collection which occurs immediately before fresh ET, but not for FET, could have a variety of adverse effects on the very early pregnancy (19). 4. To conclude our opinion We can summarize what is mentioned above in the following points: Outcomes of vitrification of oocytes and embryos regarding quality and viability are almost equivalent to fresh oocytes and embryos. Implantation rate and pregnancy rate in FET are higher when compared with fresh ET in cycles with high number of follicles or high estradiol level. The rate of blastogenesis birth defects is higher in fresh ET than in FET. Receptivity of endometrium decreased with excessive estradiol levels. After regarding all these points, we provide our opinion that cancellation of fresh ET and vitrifying all zygotes or embryos will be a routine work in IVF cycles in case of presence of a high number of follicles (increased estradiol effect on endometrium) and make a transfer in a natural or programmed cycle to optimize the outcomes regarding implantation and pregnancy rates and healthy children (20). Hypothetically speaking, if the FET proved its superiority, as is shown above, upon which ground fresh ET, in cases of excessive ovarian response, could stand and compete? Yet, practically speaking, prospective randomized studies are highly recommended in order to prove clear evidence of superiority of routine FET over fresh ET in these cases.
242
A. Rahim et al.
References (1) Haouzi D, Assou S, Mahmoud K, Tondeur S, Re´me T, Hedon B, et al. Gene expression profile of human endometrial receptivity: comparison between natural and stimulated cycles for the same patients. Hum Reprod 2009;24:1436–45. (2) Zhou F, Xiao-na L, Xiao-me T, Chao L, Liu L, Xiao-ying J, et al. A frozen–thawed embryo transfer program improves the embryo utilization rate. China Med J 2009;122:1974–8. (3) Kovalevsky G, Patrizio P. High rates of embryo wastage with use of assisted reproductive technology: a look at the trends between 1995 and 2001 in the United States. Fertil Steril 2005;84:325–30. (4) Al-Hasani S, Ozmen B, Koutlaki N, Schoepper B, Diedrich K, Schultze-Mosgau A. Three years of routine vitrification of human zygotes: is it still fair to advocate slow-rate freezing? Reprod Biomed Online 2007;14:288–93. (5) Ozmen B, Al-Hasani S. Techniques of ovarian tissue, whole ovary, oocyte and embryo cryopreservation. J Reprod Infertil 2010;11:3–15. (6) Rienzi L, Romano S, Albricci L, Maggiulli R, Capalbo A, Baroni E, et al. Embryo development of fresh ‘versus’ vitrified metaphase II oocytes after ICSI: a prospective randomized study. Hum Reprod 2010;25:66–73. (7) Cobo A, Kuwayama M, Perez S, Ruiz A, Pellicer A, Remohi J. Comparison of concomitant outcome achieved with fresh and cryopreserved donor oocytes vitrified by the Cryotop method. Fertil Steril 2008;89:1657–64. (8) Kalar S, Molinaro A and Sammel D. Viable pregnancies following fresh versus frozen embryo transfer: is there a difference in the rate of serum human Chorionic Gonadotropin (hCG) rise? Fertil Steril 2008; abstract, S205. (9) China RC, Huang JY, Tan SL, Lucena E, Saa A, Rojas A, et al. Obstetric and perinatal outcome in 200 infants conceived from vitrified oocytes. Reprod Biomed Online 2008;5:608–10. (10) Griesinger G, von Otte S, Schroer A, Ludwig A, Diedrich K, AlHasani S, et al. Elective cryopreservation of all pronuclear
(11) (12)
(13)
(14)
(15)
(16) (17)
(18) (19)
(20)
oocytes after GnRH agonist triggering of final oocyte maturation in patients at risk of developing OHSS: a prospective, observational proof-of-concept study. Hum Reprod 2007;22:1348–52. Wilcox A, Baird D, Weinberg C. Time of implantation of the conceptus and loss of pregnancy. N Engl J Med 1999;340:1796–9. Bergh P, Navot D. The impact of embryonic development and endometrial maturity on the timing of implantation. Fertil Steril 1992;58:537–42. Horcajadas J, Gimeno P, Pellicer A, Simon C. Uterine receptivity and ramifications of ovarian stimulation on endometrial function. Semin Reprod Med 2007;25:454–60. Arslan M, Bocca S, Ozturk E, Duran E, Stadtmauer L, Oehninger S. Cumulative exposure to high estradiol levels during follicular phase of IVF cycles negatively affects implantation. J Assist Reprod Genet 2007;24:111–7. Basir G, Wai-sum O, Ng E, Ho P. Morphometric analysis of periimplantation endometrium in patients having excessively high estradiol concentrations after ovarian stimulation. Hum Reprod 2001;16:435–40. Aflatoonian A, Oskouian H, Ahmadi S, Oskouian L. J Assist Reprod Genet; 2010. Halliday J, Ukoumunne O, Baker H, Breheny S, Jaques A, Garrett C, et al. Increased risk of blastogenesis birth defects, arising in the first 4 weeks of pregnancy, after assisted reproductive technologies. Hum Reprod 2010;25:59–65. Michelmann H, Nayudu P. Cryopreservation of human embryo. Cell Tissue Bank 2006;7:135–41. Shih W, Rushford DD, Bourne H, Garrett C, McBain JC, Healy DL, et al. Factors affecting low birthweight after assisted reproductive technology: difference between transfer of fresh and cryopreserved embryos suggest an adverse effect of oocyte collection. Hum Reprod 2008;23:1644–53. Baker H, Garrett C, Breheny S, Healy D, Jaques A and Halliday J. Outcomes after ART mainly occur with fresh not frozen embryo transfers: significance and implications. Fertil Steril 2008; abstract, S29.
Middle East Fertility Society
Middle East Fertility Society Journal www.mefsjournal.com www.sciencedirect.com
OPINION ARTICLE
Cancellation of fresh embryo transfer: A future perspective A. Rahim a, P. Devroey b, K. Diedrich a, S. Al-Hasani a b
a,*
Department of Gynecology and Obstetrics, University of Schleswig-Holstein, Ratzeburger Allee 160, 23560 Lu¨beck, Germany Free University Brussels, Reproductive Medicine Center, Brussels, Belgium
Received 7 July 2010; accepted 7 September 2010 Available online 13 October 2010
Keywords Embryo transfer; Vitrification
Abstract The implantation of embryo depends on the quality of the embryo and the receptivity of the endometrium. While the factors affecting embryo quality were optimized, the implantation rates did not reach the desirable levels. This directs the blaming for endometrial receptivity which already has been affected by supra-physiological levels of hormone, namely estradiol in controlled ovarian hyperstimulation (COH) cycle. On the other hand, cryopreservation, especially the vitrification method, has been highly improved to give almost the same results of fresh state, in addition to decreased rate of blastogenesis birth defects. All these encourage us to put our opinion to overcome the problem of endometrial receptivity by cancellation of the fresh embryo transfer (fresh ET) and to perform the frozen–thawed embryo transfer (FET) in cases of excessive response to COH. Ó 2010 Middle East Fertility Society. Production and hosting by Elsevier B.V. All rights reserved.
1. Introduction The birth of Louise Brown in 1978 was a revolutionary point in the treatment of infertility, where it opened widely the door to great hope for infertile couples to make their dream real in * Corresponding author at: Department of Gynecology and Obstetrics, University of Schleswig-Holstein, Ratzeburger Allee 160, 23560 Lu¨beck, Germany. E-mail address: [email protected] (S. Al-Hasani). 1110-5690 Ó 2010 Middle East Fertility Society. Production and hosting by Elsevier B.V. All rights reserved. Peer review under responsibility of Middle East Fertility Society. doi:10.1016/j.mefs.2010.09.004
Production and hosting by Elsevier
getting their own baby. Since that time on, there is a continuous research to optimize the outcomes of Assisted Reproduction Technologies (ART). It is known that a successful implantation, and as a result, pregnancy rate depends on a competent embryo and a receptive endometrium with a synchronized dialogue between maternal and embryonic tissues (1). Regarding a competent or high quality embryo, this is related to the age of the patient, to controlled ovarian hyperstimulation (COH) program and to the effectiveness of in vitro culture system (2). However, pregnancy and birth rates following in vitro fertilization (IVF) attempts remain low, where two out of three IVF cycles fail to result in pregnancy and more than eight out of 10 transferred embryos fail to implant (3). Depending on real advancements in getting high embryo quality, the endometrium receptivity and growth synchrony with the embryo become a crucial point in reaching a successful implantation and pregnancy. Therefore, blaming the endometrium for such low success rates is rather clear.
Cancellation of fresh embryo transfer: A future perspective What is eventually the solution to overcome this problem? 2. Cryopreservation Cryopreservation of human gametes and embryos is a mandatory technique in ART that leads to increased cumulative outcomes while decreasing costs (4). This is because this approach limits the number of embryos transferred, while supernumerary oocytes and/or embryos can be used in subsequent treatment cycles (5). Cryopreservation is carried out by two techniques; the slowfreezing method, and the more recently used rapid procedure called vitrification. Vitrification has gradually replaced the old slow-freezing method due to its success rates and simplicity. Also, there are many other advantages of the vitrification method over slow-freezing method such as, reducing osmotic injury, no ice crystal formation or zona pellucid fracture, no need of special devices and less cost, and extremely less time needed when compared with slow-freezing method. So, vitrification seems to be the cryopreservation method of the near future. It has been shown that the same number of oocytes is needed in fresh and vitrified cycles to obtain similar results in terms of embryo development; also, the percentage of top quality embryos per fertilized oocyte was about 52% in fresh and vitrified group of oocytes (6). Regarding oocyte donation, Cobo et al. (7) found that from 231 vitrified donated MII oocytes the survival rate, fertilization rate and ongoing pregnancy (number of transfers were 23 and mean number of embryos was 2.1) were 96.9%, 76.3% and 48%, respectively. Kalar et al. (8) showed that the rate of hCG rise following FET is significantly greater than what was seen with fresh ET and accordingly they postulated that such a difference may reflect that the healthiest embryos survive the freeze–thaw process or may be secondary to the more physiologic endocrine environment at the time of implantation. China et al. (9) noticed that pregnancies and infants conceived following oocyte vitrification are not associated with increased risks of adverse obstetric and perinatal outcomes. Moreover, frozen–thawed embryo transfer (FET) is the most common way to prevent serious late OHSS and to increase the cumulative pregnancy rate (2,10). 3. Endometrium receptivity Normally, the endometrium undergoes morphological and biochemical changes in response to cyclic regulation by hormones that make up a critical period during luteal phase in which the endometrium is accessible to embryo, and this period is called implantation window (11,12). The main goal of COH program is to recruit a large number of follicles to obtain enough mature oocytes that will be the bases to obtain a cohort of embryos for better selection for transfer (13). What about the effect of supra-physiological hormonal levels on the endometrium and its receptivity? It has been shown that a cumulative exposure to high estradiol levels during the follicular phase of IVF cycles with COH negatively affect implantation and pregnancy as it can be associated with severe down regulation of the expression of endometrial progesterone receptors (14) where excessive ovarian
241 response to stimulation leads to insufficient secretory transformation of the endometrium as well as discordant glandular and stromal development at a time that coincides with the period of maximum uterine receptivity (15). On the other hand, Arslan et al. (14) showed that different levels of estradiol exposure did not likely affect oocyte and embryo quality during the follicular phase of IVF cycles with COH. Recently, it has been found that gonadotrophin treatment in COH cycles led to disruptions of the transcriptional activation of genes involved in normal endometrial receptivity (1). Some studies can support this indirectly, where it has been shown that higher embryo implantation and clinical pregnancy rates are achieved in FET when compared with fresh ET especially for those patients with a strong ovarian response (2,16). Also, it was found that multiple pregnancy rates in FET was very high; and hence it was suggested to carry out FET cycles with single high quality embryos to decrease multiple pregnancy rate and improve the overall embryo utilization rate (2). Moreover, in a novel study done by Halliday et al. (17), they found that the increase in blastogenesis birth defects appear greater for fresh ET than for FET with the risk for fresh ET relative to controls being more than 3-fold and depending on this observation an interpretation that cryopreservation process acting as ‘‘selecting gate’’ for more viable embryos can be considered (18). Alternatively, or in addition, the excessive ovarian hormonal exposure related to oocytes collection which occurs immediately before fresh ET, but not for FET, could have a variety of adverse effects on the very early pregnancy (19). 4. To conclude our opinion We can summarize what is mentioned above in the following points: Outcomes of vitrification of oocytes and embryos regarding quality and viability are almost equivalent to fresh oocytes and embryos. Implantation rate and pregnancy rate in FET are higher when compared with fresh ET in cycles with high number of follicles or high estradiol level. The rate of blastogenesis birth defects is higher in fresh ET than in FET. Receptivity of endometrium decreased with excessive estradiol levels. After regarding all these points, we provide our opinion that cancellation of fresh ET and vitrifying all zygotes or embryos will be a routine work in IVF cycles in case of presence of a high number of follicles (increased estradiol effect on endometrium) and make a transfer in a natural or programmed cycle to optimize the outcomes regarding implantation and pregnancy rates and healthy children (20). Hypothetically speaking, if the FET proved its superiority, as is shown above, upon which ground fresh ET, in cases of excessive ovarian response, could stand and compete? Yet, practically speaking, prospective randomized studies are highly recommended in order to prove clear evidence of superiority of routine FET over fresh ET in these cases.
242
A. Rahim et al.
References (1) Haouzi D, Assou S, Mahmoud K, Tondeur S, Re´me T, Hedon B, et al. Gene expression profile of human endometrial receptivity: comparison between natural and stimulated cycles for the same patients. Hum Reprod 2009;24:1436–45. (2) Zhou F, Xiao-na L, Xiao-me T, Chao L, Liu L, Xiao-ying J, et al. A frozen–thawed embryo transfer program improves the embryo utilization rate. China Med J 2009;122:1974–8. (3) Kovalevsky G, Patrizio P. High rates of embryo wastage with use of assisted reproductive technology: a look at the trends between 1995 and 2001 in the United States. Fertil Steril 2005;84:325–30. (4) Al-Hasani S, Ozmen B, Koutlaki N, Schoepper B, Diedrich K, Schultze-Mosgau A. Three years of routine vitrification of human zygotes: is it still fair to advocate slow-rate freezing? Reprod Biomed Online 2007;14:288–93. (5) Ozmen B, Al-Hasani S. Techniques of ovarian tissue, whole ovary, oocyte and embryo cryopreservation. J Reprod Infertil 2010;11:3–15. (6) Rienzi L, Romano S, Albricci L, Maggiulli R, Capalbo A, Baroni E, et al. Embryo development of fresh ‘versus’ vitrified metaphase II oocytes after ICSI: a prospective randomized study. Hum Reprod 2010;25:66–73. (7) Cobo A, Kuwayama M, Perez S, Ruiz A, Pellicer A, Remohi J. Comparison of concomitant outcome achieved with fresh and cryopreserved donor oocytes vitrified by the Cryotop method. Fertil Steril 2008;89:1657–64. (8) Kalar S, Molinaro A and Sammel D. Viable pregnancies following fresh versus frozen embryo transfer: is there a difference in the rate of serum human Chorionic Gonadotropin (hCG) rise? Fertil Steril 2008; abstract, S205. (9) China RC, Huang JY, Tan SL, Lucena E, Saa A, Rojas A, et al. Obstetric and perinatal outcome in 200 infants conceived from vitrified oocytes. Reprod Biomed Online 2008;5:608–10. (10) Griesinger G, von Otte S, Schroer A, Ludwig A, Diedrich K, AlHasani S, et al. Elective cryopreservation of all pronuclear
(11) (12)
(13)
(14)
(15)
(16) (17)
(18) (19)
(20)
oocytes after GnRH agonist triggering of final oocyte maturation in patients at risk of developing OHSS: a prospective, observational proof-of-concept study. Hum Reprod 2007;22:1348–52. Wilcox A, Baird D, Weinberg C. Time of implantation of the conceptus and loss of pregnancy. N Engl J Med 1999;340:1796–9. Bergh P, Navot D. The impact of embryonic development and endometrial maturity on the timing of implantation. Fertil Steril 1992;58:537–42. Horcajadas J, Gimeno P, Pellicer A, Simon C. Uterine receptivity and ramifications of ovarian stimulation on endometrial function. Semin Reprod Med 2007;25:454–60. Arslan M, Bocca S, Ozturk E, Duran E, Stadtmauer L, Oehninger S. Cumulative exposure to high estradiol levels during follicular phase of IVF cycles negatively affects implantation. J Assist Reprod Genet 2007;24:111–7. Basir G, Wai-sum O, Ng E, Ho P. Morphometric analysis of periimplantation endometrium in patients having excessively high estradiol concentrations after ovarian stimulation. Hum Reprod 2001;16:435–40. Aflatoonian A, Oskouian H, Ahmadi S, Oskouian L. J Assist Reprod Genet; 2010. Halliday J, Ukoumunne O, Baker H, Breheny S, Jaques A, Garrett C, et al. Increased risk of blastogenesis birth defects, arising in the first 4 weeks of pregnancy, after assisted reproductive technologies. Hum Reprod 2010;25:59–65. Michelmann H, Nayudu P. Cryopreservation of human embryo. Cell Tissue Bank 2006;7:135–41. Shih W, Rushford DD, Bourne H, Garrett C, McBain JC, Healy DL, et al. Factors affecting low birthweight after assisted reproductive technology: difference between transfer of fresh and cryopreserved embryos suggest an adverse effect of oocyte collection. Hum Reprod 2008;23:1644–53. Baker H, Garrett C, Breheny S, Healy D, Jaques A and Halliday J. Outcomes after ART mainly occur with fresh not frozen embryo transfers: significance and implications. Fertil Steril 2008; abstract, S29.