McGill Reproductive Center, Department of Obstetrics and Gynecology, Royal Victoria Hospital, McGill University, Montreal, H3A 1A1, Canada
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Abstract |
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Key words: cancellation rates/IVF/poor responders/pregnancy rates
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Introduction |
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Materials and methods |
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Two regimens of buserelin administration were used. In the `long' protocol, patients received pre-treatment with an oral contraceptive (OC) containing 150 µg of desogestrel and 30 µg of ethinyl oestradiol (Marvelon®; Organon). The OC was started on day 1 of the menstrual cycle and continued for a period of 14 days. Buserelin was commenced on the last day of OC administration. The treatment with gonadotrophins commenced following satisfactory pituitary suppression at least 14 days later (Biljan et al., 1998). In the `short' protocol, buserelin was administered from day 2 and gonadotrophins from day 5 of the menstrual cycle (Tan et al., 1992a
).
The initial dose of gonadotrophins was determined according to the patients' age, the basal FSH concentrations, and the presence or absence of polycystic ovaries on ultrasound scan (Adams et al., 1985). Starting daily doses of gonadotrophins in relation to patient age were as follows: age <30 years, 150 IU; 3037 years, 225 IU; 3840 years, 300 IU; and >40 years, 375 IU. Patients with polycystic ovaries and aged >35 years were started on 75 IU of gonadotrophins per day less than was appropriate for their age; patients with a serum FSH concentration >10 IU/l were started on 75 IU per day more than was appropriate for their age. Subsequent adjustments were then made according to the follicular response as determined by serial ultrasound scans.
Patients who produced fewer than three follicles following 12 days of ovulation stimulation, were offered either to have their cycle cancelled, to have intrauterine insemination if there was no tubal or severe male factor infertility present, or to continue with the IVFembryo transfer treatment cycle. Physicians played no part in the patient's decision to proceed with oocyte collection or cycle cancellation, but simply pointed out to the patient that at the time the study was conducted, no data were available about which management option would be more advantageous. Human chorionic gonadotrophin (HCG; 10 000 IU; Profasi®, Serono) was administered when there was at least one follicle with a mean diameter (measured in three planes) of at least 18 mm. Transvaginal oocyte recovery was performed 36 h after HCG administration using an ultrasound scanner with a 5 MHz vaginal probe (Cheetah 2003, B&K Medical, Gentofte, Denmark). Oocyte recovery was performed using a double-lumen needle (16 gauge; K-OPSD-1635, W.A.Cook, Brisbane, Australia), a K-MAR 5000 vacuum pump (W.A.Cook) with an aspiration pressure of 100 mmHg, and a K-MAR-4000 automatic follicle flushing system (W.A.Cook). Each visible follicle, regardless of diameter, was aspirated in both ovaries (Biljan et al., 1997). All oocytes were examined at regular intervals following insemination, and only those in which two pronuclei were visualized were considered to have been fertilized normally.
The maximum number of embryos to be transferred was determined as follows: age <35 years, n = 2; age 3540 years, n = 3; and age >40 years, n = 4. Fewer than the maximum number appropriate for the patient's age were transferred when an insufficient number of embryos was available, or if requested by the patient. Five embryos were replaced only exceptionally in women aged over 40 years who had poor-quality embryos and who previously had multiple unsuccessful IVF treatments. Embryos were transferred between 48 and 72 h after oocyte collection, at which time embryos had undergone at least one mitotic cellular division. Before embryo transfer, all embryos were graded and rated according to blastomere quality: grade I, equal-sized symmetrical blastomeres with <10% fragmentation were given a rating of 4; grade II, uneven blastomeres with <10% fragmentation were rated 3; grade III, 1050% fragmentation were rated 2; and grade IV, >50% fragmentation were rated 1. An embryo score per individual embryo was calculated by multiplying the rating of the embryo by the number of blastomeres. The scores of all embryos transferred per patient were summed to give the cumulative embryo score (CES) (Steer et al., 1992).
Statistical analysis
The normality of data distribution was tested using the ShapiroWilks test. As the results were found not to be normally distributed, the data were analysed using the MannWhitney, 2 and FisherIrwin tests. In view of the mode of data distribution, the level of uncertainty was expressed using median difference (MD) and 95% confidence intervals (CI). A P-value < 0.05 was considered statistically significant.
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Results |
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Patients aged <40 years
Of all patients treated, 639 (77.2%) were aged <40 years. Of these patients, 29 (4.5%) developed 3 follicles, and 11 of these (38.0%) decided to have their cycle cancelled while the remaining 18 (62%) continued their IVF treatment cycle. No patient in this group was suitable to have their cycle converted to intrauterine insemination (IUI).
When compared with 610 patients who developed >3 follicles, patients with 3 follicles who decided to continue the treatment cycle were: older (MD = 2.7 years; CI = 1.14.1); required more gonadotrophins (MD = 20 ampoules; CI = 1329); and had a lower serum oestradiol concentration on the day of HCG administration (MD = 1358 pg/ml; CI = 9801751). However, these patients required a similar period of time to meet the criteria required for oocyte collection (MD = 0 days; CI = 1 to 1). Additionally, in this group, the oocyte collection rates (78.7 versus 77.9%; OR = 1.04; CI = 0.522.26) and fertilization rates (51.4 versus 56.8%; OR = 0.81; CI = 0.421.57) were similar to those achieved in patients who developed >3 follicles (Table I
). Interestingly, in the group who developed <3 follicles, despite a lower number of oocytes harvested, the quality of embryos transferred was similar to that achieved in patients who developed >3 follicles (MD = 1.3; CI = 14.7). Moreover, similar implantation rates were achieved in both groups of patients (27.8 versus 20.4%; OR = 1.6; CI = 0.222.16).
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Patients aged 40 years
A total of 189 cycles was performed in patients aged 40 years (22.8%). In this group, 36 patients (19.4%) developed
3 follicles. Of these patients, four (11.1%) had IUI, eight (22.2%) had a cycle cancelled, and 24 (66.6%) decided to continue their treatment cycle. No pregnancies were recorded in couples who either had their cycle cancelled or had IUI.
Patients who had decided to proceed with their treatment cycle required a significantly greater amount of gonadotrophins to achieve satisfactory growth of at least one follicle (MD = 10 ampoules; CI = 221), had significantly fewer oocytes collected (MD = 5 eggs; CI = 47) and fertilized (MD = 2 embryos; CI = 23). In this group of patients, although the collection rate was lower (73.3 versus 87.3%; OR = 2.56; CI = 1.334.7), fertilization rate (63.4 versus 53.5%; OR = 1.5; CI = 0.783.0) was not affected. However, due to a lack of choice at the time of embryo transfer, the number (MD = 2 embryos; CI = 23) and quality of embryos transferred (embryo score/embryo) (MD = 2; CI = 0.44) were lower in the group of poor responders. This resulted in an apparently poorer implantation, pregnancy and live-birth rates, but none of these differences was significant (Table II).
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The number of follicles recruited had a different implication in younger and older patients. While in older poor responders, the fertilization rate was similar to that achieved in younger poor responders (63.4 versus 51.4%; OR = 1.6; CI = 0.64.5), the quality of embryos (based on CES) available for transfer was significantly lower (MD = 4; CI = 010).
However, in older patients who developed 3 folliclesdue to a better choice of embryos at the time of transfer, and replacement of more embryosCES (MD = 2; CI = 2 to 2) were similar to those achieved in younger good responders. As a result of this, while in the group of patients who developed
3 follicles, an age of more 40 years played a moderate role in the chances of achieving a pregnancy (18.3 versus 36.7%; OR = 2.6; CI = 1.64.1), in the group of patients who had poor recruitment, younger patients had a more than six-fold greater chance of conceiving (4.2 versus 27.8%; OR = 6.4; CI = 0.82.23).
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Discussion |
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Continuation of treatment cycles in patients who develop <3 follicles has been investigated previously (Roest et al., 1996). In their retrospective analysis of patients who had transport IVF treatment, these authors found low pregnancy rates in patients who developed <4 follicles. It was reported that only in a subgroup of patients aged <30 years did pregnancy rates justify continuation of the treatment cycle. In a separate retrospective study (Hanoch et al., 1998
), the outcome of cycles was investigated where, on the day of HCG administration, the serum concentration of oestradiol level failed to exceed 1000 pg/ml. In that study the number of follicles recruited was not reported, but an average of between 3.8 and 6 oocytes were retrieved. The authors reported a pregnancy rate of 19.3% in patients aged <30 years, and 6.0% in older patients. Both these studies, though published recently, reported on the results of treatment cycles performed between 5 and 10 years ago, before the recent improvements in IVF techniques.
Additionally, the outcomes of 44 236 cycles recorded in the UK by the Human Fertilization and Embryology Authority were reported recently (Templeton and Morris, 1998). It was shown that there was a decreased likelihood of pregnancy in patients where
3 oocytes were collected. However, in that study the number of follicles was not reported. Moreover, due to the diversity of cancellation policies in the 78 centres contributing to the data-base, it is impossible to estimate the percentage of patients who had their cycles discontinued due to poor follicular recruitment. Nevertheless, in patients who had
3 oocytes collected, similar pregnancy rates were reported up to the age of 35 years, and only a moderate decrease in pregnancy rate was observed in the group of patients aged between 36 and 39 years.
The results of the present study are somewhat different from those previously reported. We confirmed previous observations which related the incidence of poor follicular recruitment to the patients' age (Tanbo et al., 1989; Roest et al., 1996
). However, in the group of women aged <40 years (median age = 37.4 years) who had poor follicular recruitment, we found a relatively high pregnancy rate of 27.8%. In this group of patients, the quality of embryos transferred was comparable with that in patients who developed more follicles. This suggests that in younger poor responders, suboptimal follicular recruitment does not reflect a poor quality of oocytes. Moreover, this group of patients had a good implantation rate. It is possible that the low serum oestrogen concentrations achieved in this group of patients allowed a more physiological endometrial development, and an environment which was more conducive to implantation (Chenette et al., 1990
; MacDougall et al., 1993
; Kolb et al., 1997
; Simon et al., 1998
).
The anti-nidational effect of higher concentrations of oestrogen however is controversial. The effect of oestradiol concentrations on implantation was investigated previously (Chenette et al., 1990). A higher number of embryos was obtained, with higher pregnancy rates in patients who achieved higher oestradiol concentrations. However, these authors did not report on either the quality of embryos transferred or the implantation rates, which would have given a better perspective of the endometrial receptivity in their patients. It is possible that the higher pregnancy rates observed in patients with high oestradiol concentrations were due to a superior quality of embryos available, which superseded a lower endometrial receptivity.
In a mouse embryo donation model, lower implantation rates were reported in animals which had high oestradiol concentrations following stimulation with gonadotrophins (Fossum et al., 1989). Moreover, by comparing implantation rates in oocyte donation and standard IVF cycles, up to a 60% decrease in endometrial receptivity has been reported in IVF patients who had higher oestradiol concentrations (Paulson et al., 1990
). Finally, a significant increase in implantation rates was reported in patients who achieved lower oestradiol concentrations following a milder regimen of ovarian stimulation (Simón et al., 1998
).
Based on these studies it is reasonable to postulate that patients with oestradiol concentrations more similar to those present in natural cycles may achieve higher implantation rates.
An additional positive element observed is the absence of multiple pregnancies observed in the patients who developed fewer follicles. It is well recognized that multiple pregnancies lead to significantly higher prenatal and post-natal complications (Jonas and Lumley, 1993). In patients aged >40 years, however, good follicular recruitment seems to be a crucial element in the establishment of successful pregnancy. In humans, the number of chromosome abnormalitiesespecially aneuploidyincreases with age (Harrison et al., 1989
), and this phenomenon is probably exaggerated after the age of 40 years. Our data confirm previously published results showing that, in patients aged >40 years, poor oocyte quality can be overcome only if the number of embryos available for transfer is high (Widra et al., 1996
; Templeton and Morris, 1998
). In a group of older patients where
3 follicles were recruited, very low implantation and pregnancy rates were obtained.
We conclude that in patients aged <40 years, continuation of IVF treatment in spite of poor follicular recruitment is a reasonable option. In older patients, due to age-related poor quality of oocytes, it seems that the chances of successful treatment following poor follicular recruitment are very low, and thus in this group, cancellation of the treatment cycle may be a more appropriate option.
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Notes |
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References |
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Submitted on March 8, 2000; accepted on June 5, 2000.