The University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School at Camden, Cooper Hospital/University Medical Center, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Camden, NJ, USA
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Abstract |
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Key words: frozen embryo transfer/implantation rates/shared oocyte
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Introduction |
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When embryos are cryopreserved, implantation and subsequent pregnancy rates may be adversely affected by freeze/thawing and ice crystal damage to the embryos and by cryopreserved embryos frequently being the result of de-selection, i.e. the best quality embryos are transferred fresh and the poorer quality ones are cryopreserved (Check et al., 2000b). On the other hand, implantation and pregnancy rates can be theoretically helped with frozen embryo transfer if the controlled ovarian stimulation regimen adversely affects implantation (Check et al., 1999
, 2000a
).
Frequently, because of the risk of ovarian hyperstimulation syndrome, or less frequently because of a substandard endometrium as determined by sonography (Smith et al., 1984; Fleischer et al., 1986
; Gonen et al., 1989
; Gonen and Casper, 1990
; Check et al., 1991
, 1993c
, d
; Sher et al., 1991
; Dickey et al., 1992
), fresh embryo transfer is cancelled and all embryos are cryopreserved.
The study presented herein compared pregnancy rates in a shared oocyte programme of the donor versus their paired recipients in fresh embryo transfers, versus frozen embryo transfers that represented the first transfer (because the fresh transfer was deferred), and versus second frozen embryo transfers. Amongst other things, the study would help to determine how important it is to synchronize donor and recipient cycles to allow fresh transfer versus the easier method of merely cryopreserving the donor oocytes fertilized by the recipient's male partner's spermatozoa and transferring them back at a more convenient time.
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Materials and methods |
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Frozen embryo transfer cycles were limited to those patients who participated in the shared programme in the designated time period. Thus, patients who cryopreserved their embryos prior to January 11, 1997 were not included even if they had embryos transferred during this time period.
The pregnancy and implantation rates were computed and statistically analysed for: (i) embryo transfer cycles immediately following the retrieval; (ii) frozen embryo transfer cycles for patients who had all embryos cryopreserved and (iii) frozen embryo transfer cycles for patients who had a transfer following retrieval and are now having a second transfer, but with frozen/thawed embryos (Figure 1).
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The donor undergoes a luteal-phase leuprolide acetate/gonadotrophin ovarian stimulation regimen. Beginning 1 week after ovulation, leuprolide acetate is started at 0.5 mg for 10 days s.c., when serum oestradiol and progesterone concentrations are measured. If the oestradiol concentration is <50 pg/ml and the serum progesterone <2 ng/ml, the leuprolide acetate is reduced further, to 0.25 mg s.c. daily. If the oestradiol and/or progesterone concentrations are not sufficiently suppressed, leuprolide is continued for a few more days and the measurements are repeated. Once the dosage is down to 0.25 mg, 300 IU of gonadotrophins [various combinations of either all FSH, half human menopausal gonadotrophin (HMG) and half FSH, or all HMG] are initiated s.c. and/or i.m. in two divided doses. Human chorionic gonadotrophin (HCG; 10 000 IU) is given i.m. when two lead follicles attain an average diameter of 20 mm and the serum oestradiol is >1000 pg/ml. Rarely, a follicular stimulation protocol was used (Garcia et al., 1990).
Recipients without ovarian function were treated with oral micronized oestradiol, 2 mg x5 days, 4 mg x4 days, then 6 mg x5 days, beginning on the sixth day of the donor's leuprolide acetate treatment. Recipients with ovarian function are suppressed with leuprolide acetate before starting the oestradiol. Recipients are given progesterone vaginal suppositories, 200 mg twice daily, and frequently 50 mg i.m. progesterone beginning the day after the donor takes HCG, and transfer occurs on the fourth day of progesterone supplementation. Donors and standard IVF patients also take supplemental progesterone after transfer.
Supernumerary embryos not used for fresh embryo transfer were cryopreserved and thawed for subsequent transfer in an unstimulated cycle. Also, in cases where the patient was at risk for ovarian hyperstimulation syndrome, or the patients had inadequate endometrial development, all embryos were cryopreserved and thawed at a later time for transfer. In general, patients were considered at risk for ovarian hyperstimulation if the serum oestradiol was >5000 pg/ml on the day of, or the day after, HCG injection or if there were >30 follicles. The endometrium was considered inadequate if the thickness was <8 mm or there was a homogeneous hyperechogenic pattern on the day of HCG injection (Check et al., 1991, 1993c
). Frozen embryo transfer could be performed after a deferred fresh embryo transfer cycle or pregnancy failure, but would be deferred for at least one cycle following controlled ovarian stimulation to dilute any persisting negative effects of hyperstimulation on the uterine environment (Figure 1
).
The main outcome measures were: clinical pregnancy rate (sonographic evidence of a gestational sac in the uterus); viable pregnancy rate (live fetus at end of the first trimester) and implantation rate (number of gestational sacs per embryo transferred). Chi-square analysis was used to compare the rates obtained using fresh or frozen embryos within each patient group. The rates between the two patient groups for each type of embryo transfer were also compared using 2 analysis. A P value of 0.05 was used to determine significance, 95% confidence intervals for the rates were also computed.
The ICSI technique was performed as previously described (Palermo et al., 1993; Van Steirteghem et al., 1993
, 1994
). The technique for assisted embryo hatching using acidic Tyrode's solution was based on the one described originally by Cohen et al. (Cohen et al., 1992
) and has been previously described for frozen embryos (Hoover et al., 1995
; Check et al., 1996
).
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Results |
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There was a significantly higher clinical pregnancy rate for recipients who had a fresh embryo transfer compared with recipients whose first embryo transfer consisted of frozen/thawed embryos (63.4 versus 43.6%) because of cancellation of fresh transfer (usually because of failure to synchronize cycles) (Figure 1). However, no differences were found when comparing first embryo transfers in donors (fresh versus frozen) (47.7 versus 40.9%) (Figure 1
).
The implantation rates, as seen in Table I also showed a significant difference in fresh versus frozen/thawed (but first transfer) in recipients (31.8 versus 15.3%) but once again did not reach a significant difference (26.4 versus 19.9%) when comparing first transfer fresh versus frozen in donors. Actually if all frozen embryo transfer cycles are combined, the difference of fresh versus frozen embryo transfer implantation rates increased more (32.4 versus 14.0%) in recipients but became narrower in donors (26.4 versus 20.9%). No differences were seen between recipients and donors in implantation rates after fresh embryo transfers though there was a trend toward a higher rate in recipients (31.8 versus 26.4%).
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When the data was evaluated the results were similar whether ICSI was performed or not (Table III). Thus, although embryo quality may depend on paternal factors (Oehninger et al., 1996
; Terriou et al., 1997
; Host et al., 1999
) in this study it did not seem to matter.
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Discussion |
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On the other hand, since the pregnancy rates and implantation rates with fresh versus frozen embryo transfer were at least comparable in donors, these data reconfirm our policy of freezing all embryos in patients having IVFembryo transfer if there is a risk, in our judgement, of severe ovarian hyperstimulation syndrome if complicated by a pregnancy and continued HCG secretion, or an endometrium that does not seem to be ideal for implantation based on ultrasound criteria. Since one of the drawbacks of being a shared-oocyte donor is that they are not allowed to be on protocols aimed at stimulating only a few follicles, it is heartening to know that they can be advised that if their fresh cycle is deferred for subsequent frozen embryo transfer, because of the risk of ovarian hyperstimulation syndrome, that it does not seem detrimental for their chances of conception.
The higher clinical pregnancy and implantation rates in recipients versus donors, despite equal sharing of oocytes, but similar pregnancy and implantation rates in recipients versus donors following the first frozen embryo transfer with fresh transfer deferred, corroborate previous data. It has been shown (but with a much larger series) that the medication used for controlled ovarian stimulation may create a hostile uterine environment that is not conducive for successful implantation (Check et al., 1995, 1999
, 2000a
). The higher pregnancy and implantation rates in recipients receiving fresh embryos versus frozen/thawed ones clearly shows that the frozen/thawed embryo, even when given the opportunity for selection of the morphologically `best' embryo (higher blastomere number and less fragmentation) is not as good as the fresh one. Thus, similar pregnancy and implantation rates with fresh and frozen transfer in our centre in our general IVF population has to be related, to a significant degree, to an adverse effect of the controlled ovarian stimulation regimen for implantation. If a uterine defect, per se, even without the use of the controlled ovarian stimulation regimen, could explain the difference between fresh pregnancy and implantation rates in donors versus recipients, then these same differences would have been seen when comparing frozen transfers, but they were, in fact, similar.
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Notes |
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References |
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Submitted on November 17, 2000; accepted on March 21, 2001.