Fertility Institute of New Orleans, 6020 Bullard Avenue, New Orleans, LA 70128, USA
Dear Sir,
We read with great interest the recent article (Gardner et al., 1998), in which a 50% implantation rate (IR) and a 71% pregnancy rate (PR) were reported after 45 cases of day 5 blastocyst transfer, using a sequential culture media of their design, compared with a 30% IR and 66% PR after 47 cases of day 3 transfers, using Ham's F10 media, in a `prospective randomized trial'. We question whether these extraordinary rates are the result of superior culture media, as the authors claim, or the result of patient selection. More importantly, do these results indicate that all patients should have embryos transferred as blastocysts?
For an answer we reviewed a larger `prospective randomized trial' of 410 cases of day 5 blastocyst transfers and 233 cases of day 3 transfers for which Ham's F10 had been used throughout (Scholtes and Zeilman, 1996). Both studies employed Ham's F10 as culture media for embryos transferred after 3 days. The latter found only a 13% IR after day 3 transfers, a 2.3-fold difference compared to Gardner et al. (1998). This significant difference may be explained by patient selection. Gardner et al. (1998) reported only patients who had at least 10 follicles 12 mm and at least three follicles
16 mm on the day human chorionic gonadotrophin (HCG) was given. They do not state the number of patients who initiated cycles and subsequently failed to meet their inclusion criteria. Scholtes and Zeilman (1996) included all patients who underwent in-vitro fertilization (IVF) during a 6 month period randomized and allocated to embryo transfer on day 3 or 5 depending on the weekday of oocyte retrieval. If the 2.3-fold correction, due to patient selection, were also applicable to blastocyst transfer, Gardner et al. (1998) would have had a 22% IR for day 5 transfers. Scholtes and Zeilman (1996) found that only 55% of unselected patients developed blastocysts and only 35% had expanded blastocysts to transfer, compared with 91% for Gardner et al. (1998). When Scholtes and Zeilmaker (1998) included cases in which embryos did not develop to the blastocyst stage by day 5, they found no difference in IR between day 3 and day 5 transfers. In a subsequent study of 909 consecutive first or second IVF cycles of blastocyst transfer (Scholtes and Zeilmaker, 1998
) a 23% IR using Ham's F10 was reported. We retrospectively reviewed our 1998 IVF results and found that only 33% of IVF patients fulfilled the criteria of Gardner et al., of those who did, the IR for day 3 transfer after culture with human tubal fluid (HTF, Irvine Scientific, CA, USA) was 32% and the pregnancy rate was 68%.
Thus far, all studies that have reported implantation rates higher than 25% for fresh blastocyst transfers, have consisted of <50 patients (Desai et al., 1998). The influence of the numbers of patients studied is illustrated in Figure 1, derived from Desai et al. (1998) and Gardner et al. (1998). As would be expected, there is a negative regression toward the true mean as the number of patients increases.
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References
Desai, N.N. (1998) The road to blastocyst transfer. Hum. Reprod., 13, 32923294.[ISI][Medline]
Gardner, D.K., Schoolcraft, W.B., Wagley, L. et al. (1998) A prospective randomized trial of blastocyst culture and transfer in in-vitro fertilization. Hum. Reprod., 13, 34343440.[Abstract]
Scholtes, M. and Zeilmaker, G. (1996) A prospective randomized study of embryo transfer after 3 or 5 days of embryo culture in in vitro fertilization. Fertil. Steril., 65, 12451248.[ISI][Medline]
Scholtes, M. and Zeilmaker, G. (1998) Blastocyst transfer in day-5 embryo transfer depends primarily on the number of oocytes retrieved and not on age. Fertil. Steril., 69, 7883.[ISI][Medline]
Colorado Center for Reproductive Medicine, Englewood, CO 80110, USA14
Dear Sir,
We read with interest the letter of Dickey and Pyrzak. It appears that the presence of the phrase `prospective randomized trial' in the title was not understood. Their proposition is that the high implantation rates after blastocyst transfer presented in the paper (Gardner et al., 1998) were due to patient selection. However, Dickey and Pyrzak have failed to appreciate that the control group undergoing day 3 transfers were taken from the same patient population. Therefore, although the population (as clearly stated in the paper), was taken from moderate to good responders, the beneficial effects of blastocyst culture and transfer cannot be ignored. Furthermore, with reference to the high pregnancy rates in the day 3 group, this was not as implied due to patient selection, as the day 3 data from the paper is equivalent to that obtained by our clinic for the entire year of 1995 as published in the 1996 SART report.
Dickey and Pyrzak go on to compare the data in Gardner et al. (1998) with that of Scholtes and Zeilmaker who used a single medium (and not sequential media) for the extended culture of human embryos (Scholtes and Zeilmaker, 1996). Indeed Scholtes and Zeilmaker did not even use a medium designed for any mammalian embryo, but rather a mixture of Earle's salts and Ham's F10, a tissue culture medium. Therefore, to compare embryo development in physiological sequential media, developed specifically for the human embryo at different stages of development, as used by Gardner et al. (1998), to the culture system employed by Scholtes and Zeilmaker is not only comparing apples with oranges, but also shows a basic lack of understanding regarding embryo physiology. This is most lamentable.
Regarding the suitability of blastocyst culture and transfer for a non-selected group of patients, Dr Kevin Doody, Bedford, Texas, has performed over 300 cases of blastocyst culture and transfer using sequential culture media in non-selected patients (personal communication). In all age groups, and irrespective of oocyte number, sequential media and blastocyst transfer were shown to increase implantation rates, decrease the number of embryos transferred and increase overall pregnancy rates. Significantly, the cancellation rate from retrieval to embryos transfer was <7%, a figure comparable to that when embryo transfer on day3 is employed.
In conclusion, there are no extraordinary claims in the paper of Gardner et al. (1998). Rather Gardner et al. (1998) present evidence based medicine, with many years of basic research supporting the culture system. Blastocyst culture and transfer has an important role to play in human assisted reproduction.
Notes
1 To whom correspondence should be addressed.
References
Gardner, D.K., Schoolcraft, W.B., Wagley, L. et al. (1998) A prospective randomized trial of blastocyst culture and transfer in in-vitro fertilization. Hum. Reprod., 13, 34343440.[Abstract]
Scholtes, M.C.W. and Zeilmaker, G.H. (1996) A prospective randomized study of embryo transfer results after 3 or 5 days of embryo culture in in vitro fertilization. Fertil. Steril., 65, 12451248.[ISI][Medline]