1 The Center for Reproductive Medicine at Mobile Infirmary Medical Center, 3 Mobile Infirmary Circle, Suite 213, Mobile, AL 36607, USA and 2 Bourn Hall Clinic, Bourn, Cambridge CB3 7TR, UK
3 To whom correspondence should be addressed at. The Center for Reproductive Medicine, Mobile Infirmary Medical Center, 3 Mobile Infirmary Circle, Suite 213, Mobile, AL 36607, USA. Email: gingel10216{at}aol.com
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Abstract |
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Key words: IVF/live birth rates/oocyte numbers/ovarian stimulation
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Introduction |
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Oocytes per live birth, 19781983 |
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During the early 1980s, after pioneering research carried out at the Jones Institute in the United States (Jones et al., 1982; Garcia et al., 1983a
,b
), stimulated cycles were reintroduced successfully at Bourn Hall, initially using clomiphene and/or HMG. In 1983, the Bourn Hall team reported detailed results describing the treatment of 1200 patients. Between October 1980 and December 1982, 139 babies were delivered after IVF treatment cycles that produced a maximum of four oocytes per retrieval, with a mean of 2.12.6, and fertilization rates of 8892%, depending on the type of stimulation used (Edwards and Steptoe, 1983
). The majority of patients had only one or two embryos available for transfer: 56% had one embryo transferred, 38.6% had two, 4.3% had three, and only one patient had four embryos transferred. The clinical pregnancy rate per oocyte retrieval rose from 16% in October 1980, to 23.5% in September 1982 and to almost 30% in 1983. Five hundred births were reported by the end of July 1985 (Steptoe et al., 1986
), by which time combined clomiphene/HMG stimulation protocols yielded an average of 5.6 oocytes per laparoscopic retrieval (Bourn Hall archive records). The GnRH analogues were introduced into stimulation regimes at Bourn Hall during 1985, and the births of 1000 babies were celebrated at the end of 1987.
In order to assess the efficiency of the new treatment protocols that were developed subsequently over the following 15 years, we analysed our data from the year 2000, using luteal phase long downregulation and recombinant human FSH (r-hFSH) stimulation protocols. The current Bourn Hall policy for follicular stimulation aims to maintain high delivery rates with relatively conservative stimulation protocols, and the average oocyte yield is in the range of 1012 oocytes per retrieval. All supernumerary embryos that are suitable are cryopreserved for future use in order to maximize the potential of each stimulation cycle to achieve a live birth.
A series of 844 consecutive long downregulation GnRH analogue IVF cycles carried out at BHC between January and December 2000 was reviewed. The protocol for mid-luteal start downregulation, stimulation and cycle management has been described previously (Brinsden, 1999). For the purpose of data analysis, nine cycles in which there was complete failure of fertilization, and 30 cycles in which all embryos were frozen due to risk of ovarian hyperstimulation syndrome (OHSS) were excluded from the study; the outcome of 805 cycles resulting in fresh embryo transfer was confirmed by follow-up. The mean patient age was 33.5, with a range of 2147 years. Generally, patients aged <35 years started with 150 IU of r-hFSH, those aged 3539 years with 225 IU of r-hFSH and patients aged 40 years or older started with 300 up to a maximum of 450 IU of r-hFSH. A policy of transferring two embryos as a routine was introduced during that year, and two embryos were transferred in the majority of cycles; three embryos were transferred in 54 out of the 808 cycles (6.7%). The embryo transfer procedure was carried out on day 2 or 3 after oocyte collection, using the EdwardsWallace soft embryo transfer catheter.
The data were tabulated according to age and grouped by the number of oocytes retrieved. Low yield (LY) patients were defined as those in whom 15 oocytes were retrieved, intermediate yield (IY) patients had 615 oocytes retrieved and high yield (HY) patients had 16 oocytes retrieved.
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Oocytes per live birth, 2000 |
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Table II illustrates the data for patients 38 years of age. LY patients utilized 28.4 oocytes for each live birth, compared with 42.8 in the IY patients. Only six patients in the older age group fell into the HY category, but none achieved a live birth after fresh embryo transfer. In contrast to the younger patients, the delivery rate was higher in the IY than in the LY group: 21.5 versus 12.7%.
Patients of all ages in the HY group, with 16 or more oocytes retrieved, represented 15.6% of all cycles. This figure excludes another 43 cycles (4% of the total) in patients who did not have fresh transfer, as all embryos were frozen (FAE cycles) to reduce the risk of OHSS. The mean age of the total HY group, including FAE cycles, was 32.0 (range 2342) and a mean of 27 oocytes were retrieved per cycle (range 1642).
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Conclusion |
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Our data from the year 2000 described 126 (15.6%) cycles as HY, and patients under the age of 38 utilized 51 oocytes to achieve one live birth. Live births were achieved in the IY group of patients with half this number of eggs (25.1) and the group of LY patients used only 9.6 oocytes to achieve one live birth. Although our pregnancy and delivery rates have improved overall in 25 years, the oocyte utilization in younger patients with low numbers of oocytes retrieved remains similar to that reported in 19801983, when all patients fell into this LY category. Since all three groups achieved similar live birth rates, it would appear that there is significant oocyte wastage in this age group when large numbers of oocytes are produced. A different trend is seen in patients 38 years, who show a higher pregnancy rate with intermediate yields of oocytes. However, the numbers of patients are too small to draw any meaningful conclusions from these data, especially as many confounding variables exist in patients of older age. There were no live births in the older patients who produced 16+ oocytes, but they represent only 4.7% (six patients) of the age
38 population in this study; the prognosis for this group of patients may also be affected by the adverse effects of polycystic ovary syndrome (PCOS) as part of the aetiology of their infertility.
In 1996, Edwards, Lobo and Bouchard published an Editorial in Human Reproduction entitled: Time to revolutionize ovarian stimulation. This called for a reappraisal of our current strategies for controlled ovarian stimulation and a kinder-gentler approach. Meniru and Craft (1997) followed this Editorial with a report on utilization of oocytes as an index of efficiency, with the observation that the proportion of retrieved oocytes resulting in quality embryos fell significantly with increasing oocyte numbers. A recalculation of the results reported by Meniru and Craft produces a figure of one pregnancy for every 39 oocytes.
More recently, the efficacy of natural cycle IVF has been reviewed (Pelinck et al., 2002) as a strategy for a low-cost, low-risk procedure, and protocols for more patient-friendly treatments have been introduced, with the aim of reducing the risks of multiple pregnancy and OHSS. These include double embryo (Templeton and Morris, 1998) or even single embryo transfer (Gerris et al., 1999) and shortened protocols using a GnRH antagonist. With this report, we would like to support the views expressed in the Editorials by Edwards et al. in 1996 and 1997 (Edwards et al., 1996
, 1997
) and suggest that milder stimulation strategies may be appropriate in order to reduce the number of high responders and the consequent oocyte wastage. Numerous publications and reports followed this Editorial, which offered alternative strategies, including: aiming to optimize estradiol levels per retrieved oocyte (Loumaye et al., 1997
); milder stimulation (Devroey et al., 1998
; Olivennes and Frydman, 1998
; Devreker et al., 1999
; Out et al., 2000
; Hohmann et al., 2001
; Kligman and Rosenwaks, 2001
; Latin-American Puregon IVF Study Group, 2001
); single embryo transfer (Gerris et al., 1999; Martikainen et al., 2001
; Hunault et al., 2002
); and unstimulated cycle IVF (Nargund et al., 2001
). Several authors discussed the negative impact of high oocyte numbers and supraphysiological estrogen levels on the embryo and/or endometrium (Pellicer et al., 1989
, 1996
; Aboulghar et al., 1997
; Meniru and Craft, 1997
; Fauser et al., 1999
; Ng et al., 2000
; Valbuena et al., 2001
; Thomas et al., 2002
). Some authors questioned the need to revolutionize ovarian stimulation (Fleming, 1996
) while others challenged that there was a negative impact for high responders on the embryo and/or endometrium (Sharara and McClamrock, 1999
; Levi et al., 2001
). Debate on high responders has also focused attention on the current incidence of OHSS in IVF treatment (Rizk and Aboulghar, 1991
; Abramov et al., 1999
; Forman, 1999
; Mathur and Jenkins, 1999
; Roest, 1999
; Egbase, 2000
).
In a Unit with a successful cryopreservation programme, cumulative pregnancy rates per stimulated cycle increase with the cryopreservation of any additional embryos. Tables III and IV represent a theoretical extrapolation, based upon freeze/thaw and clinical pregnancy rates obtained from BHC's current embryo cryopreservation programme. The efficiency of oocyte utilization theoretically would be improved if all cryopreserved embryos in each group were to be utilized. However, this calculation depends upon maintaining a consistently successful cryopreservation programme, and the advantage must be weighed against the additional cost and the ethical issues that arise when storing (and subsequently disposing of) large numbers of surplus embryos. In our series, the majority of patients in the IY group had embryos cryopreserved for future treatment; this group is likely to have the best overall prognosis in terms of cumulative pregnancy rate (and reduced cost per baby) after transfer of their stored embryos. We know from past experience that storage of excessive numbers of cryopreserved embryos, as may result from HY patients, can lead to logistic, administrative and ethical problems. (Brinsden and Avery, 1996; Avery, 1999
).
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In conclusion, although the total live birth rate has improved after >20 years of experience with controlled ovarian stimulation for IVF treatment, our recent data suggest that the efficiency of oocyte utilization has not improved significantly since the early 1980s. It takes only one oocyte to produce a baby, irrespective of the level of stimulation; the problem continues to lie with finding and identifying the right oocytes. Our LY group of patients had the highest level of multiple birthscould it be that the competent oocytes are just as likely to be found in cohorts containing low oocyte numbers? We are not able to answer the question of whether the excess oocytes produced in larger cohorts are wasted, or simply biologically non-competent. Does collecting fewer oocytes provide a better clinical strategy for oocyte selection than does the harvesting of large numbers of oocytes? Is the drive towards producing more eggs justified? Is oocyte yield or competence fundamentally directed by female physiology/endocrinology, and not significantly influenced by exogenous ovarian stimulation? We would be interested to learn whether other IVF teams have evidence to support a real benefit to patients of producing high numbers of oocytes.
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References |
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Submitted on October 19, 2004; accepted on October 26, 2004.
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