Prospective randomized study comparing two soft catheters for embryo transfer

P-357 Microdose gonadotrophin releasing hormone agonist (GnRH-A) flare protocol compared with standard long protocol GnRH-A for ovarian stimulation in patients undergoing in vitro fertilization. Simon M. Kelly, Imran R. Pirwany, Simon J. Phillips, Seang Lin Tan. McGill Reproductive Ctr, Royal Victoria Hosp, McGill Univ, Montreal, QC, Canada. Objective: One of the most difficult challenges in assisted reproduction is the management of patients who respond poorly to gonadotrophin stimulation. Among a variety of strategies aimed at improving response is the follicular phase administration of microdoses of GnRH-a (Fertil.Steril, 1998; 69:419 – 424). However, it has been suggested that the beneficial effects of this protocol may result from the concomitant use of the oral contraceptive pill (Fertil.Steril, 1999; 72:1018 –1023). The objective of this study was to compare the response and outcomes of microdose GnRH-a flare protocol with a standard dose long GnRH-a protocol utilizing the oral contraceptive pill in age matched patients undergoing in vitro fertilization. Design: Retrospective cohort study of eighty-two patients who underwent IVF between 2000 and 2001. Materials/Methods: Forty-two patients with a previous poor response to standard long protocol IVF were commenced on a microdose flare protocol following at least 14 days of the oral contraceptive pill (OCP). This protocol involved a twice-daily 50g dose of buserelin followed by the addition of gonadotrophin stimulation on day 4. A control group of 40 age matched patients received standard fourteen days of 500g buserelin (following OCP) to achieve downregulation before commencing gonadotrophin stimulation. The main outcomes measured were number of days of stimulation, number of ampoules gonadotrophin, peak estradiol, number oocytes retrieved, embryo quality and clinical pregnancy rate. Results are expressed as mean with 95% confidence intervals. Nonparametric statistical analysis was used. p ⬍0.05 was considered statistically significant. Results: Despite similar ages, patients in the microdose flare group had higher mean FSH levels {7.6iu (6.6 – 8.6) vs. 6.3iu (5.6 –7.1); p ⫽ 0.039}, smaller ovarian volume {4.6cm3 (8.0 –5.3) vs 6.60cm3 (5.50 –7.69); p ⫽ 0.004}, and lower mean antral follicle count {3.4 (2.6 – 4.1) vs 5.6 (4.2–7.0); p ⫽ 0.013}compared to the control group. There was no difference in the number of days of stimulation required between the two groups although the microdose flare group required a larger total number of ampoules of gonadotrophin {77.4 (68.1– 86.7) vs 46.3 (40.1–52.5); p ⫽ ⬍0.0001} The peak estradiol concentrations were higher in the control group {7446 pmol/l (5954 – 8939)} compared with the microdose flare patients {5094pmol/l (3702– 6485); p ⫽ 0.008} The total number of oocytes retrieved was lower in the microdose flare group {7.8 (6.1–9.6) vs 11.0 (9.4 –12.6)} compared to the control group (p ⫽ 0.004). There was no significant difference in embryo quality based on a cumulative embryo score (CES) or in the clinical pregnancy rate between the two groups. Conclusions: This study demonstrates that in age matched women deemed to have poor ovarian reserve,the use of GnRH-a microdose flare protocol results in comparable embryo quality, and clinical pregnancy rates compared to a standard dose long GnRH-a protocol. Supported by: Study supported by McGill Reproductive Centre.

P-358 Antagonist/letrozole protocol for patients failing microdose agonist flare stimulation. William Schoolcraft, Eric Surrey, Deb Minjarez, David K. Gardner. Colorado Ctr for Reproductive Medicine, Englewood, CO. Objective: To assess the response to a protocol utilizing GnRH antagonist (Antagon) and the aromatase inhibitor Letrozole (Ant/Let) for patients exhibiting a poor response to a microdose flare (micro/LA) protocol. Design: Nonrandomized prospective analysis of patients receiving Ant/ Let after micro/LA failure. Materials/Methods: Twenty-seven patients who were either canceled on micro/LA or failed to conceive and demonstrated a poor response (less than six oocytes) were treated in their next cycle with the same dose of FSH (450 IU per day) beginning on cycle day 3 of menses. No oral contraceptive pretreatment or microdose LA was given. Antagon was administered to avoid premature ovulation and Letrozole 2.5 mg per day was given continuously with FSH. Cycle outcomes were compared to 258 patients undergoing stimulation with micro/LA who had not previously been canceled or exhibited a poor response.

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Abstracts

Results: Patients receiving Ant/Let demonstrated the following means: age (37.3), FSH (9.3 IU/ml), oocytes (9.2), days of stimulation (9.6), number of oocytes fertilized (4.6), ongoing pregnancy rate (45%), implantation rate (24.3%). In comparison with micro/LA cycles, age, FSH, days of stimulation were all similar. Ongoing pregnancy rate (46%), and implantation rate (24.1%) were similar despite the production of more oocytes (12.7 versus 9.2) and more embryos (7.2 versus 4.6) in the micro/LA group. Conclusions: Patients receiving Ant/Let with a history of prior cycle cancellation or poor response exhibited equivalent pregnancy and implantation rates when compared to micro/LA cycles that did not have a prior history of cycle cancellation or poor response. These equivalent results were obtained despite the recruitment of more oocytes and embryos in the better prognosis micro/LA group. Letrozole, an aromatase inhibtior, may augment stimulation response by increasing intraovarian androgens, which have been shown to increase FSH receptors in the developing follicle. Supported by: CCRM.

P-359 Influence of endometrial motility on the outcome of ART. Wolfgang Elmar Paulus, Erwin Strehler, Natalie Reeka, Wolfgang Huetter, Karl Sterzik. Christian-Lauritzen-Institut, Ulm, Germany. Objective: Uterine peristaltic waves may displace the embryo droplet at the time of embryo transfer. To investigate the possible consequences of uterine contractions on the outcome of in-vitro fertilization and embryo transfer, we visualized the motility of the endometrium by ultrasound just before embryo transfer. Design: Prospective cohort study. Materials/Methods: 301 patients undergoing ART (ICSI, IVF) in our fertility centre were included in this study. Inclusion criteria were a morphologically normal uterus and at least two good quality embryos transferred. In all cases pituitary was down-regulated with nafarelin acetate (Synarela威) in a short protocol. Ovarian stimulation was performed with 2– 4 ampoules hMG (Menogon威) beginning on cycle day 3. Transvaginal ultrasound-guided needle aspiration of follicular fluid was carried out 36 to 38 hours after hCG administration (Pregnesin威). After in-vitro fertilization up to three embryos were transferred into the uterine cavity on day 2 to 6 after oocyte retrieval. Just before embryo transfer all patients underwent ultrasound scans of a sagittal uterine plane using a 7 MHz transvaginal probe (LOGIQ 400, GE Medical Systems). A sequence of two minutes was video recorded. For evaluation of uterine contractions the videotape was visually assessed in a fivefold speed. The total time of endometrial movements during the 40 s period of accelerated reproduction was measured. The group of patients with embryo transfer on day 2 or 3 after oocyte retrieval (n⫽169) was compared with the group of patients with embryo transfer on day 5 or 6 after oocyte retrieval (n⫽132). For statistical evaluation of endometrial motility t-test was used. The main outcome measure was clinical pregnancy defined by the presence of a fetal sac at ultrasound examination 6 weeks after embryo transfer. To examine the influence of endometrial motility on the pregnancy rate we compared the low motility group (period of contractions ⬍30% of total time; n⫽121) with the high motility group (period of contractions ⬎70% of total time; n⫽80) by chi-square test. Results: Comparing the group of embryo transfers on day 2 or 3 after oocyte retrieval (n⫽169) with the group of embryo transfers on day 5 or 6 after oocyte retrieval (n⫽132) endometrial motility significantly decreased with growing interval (24.2s ⫾ 11.4s vs 8.3s ⫾ 9.1s; t-test: p ⬍0.001). On the other hand the pregnancy rate of the low motility group did not differ from the high motility group: 33.1% (40/121) vs 37.5% (30/80). Conclusions: Uterine contractility decreases at the time of blastocyst transfer, high motility of the endometrium however seems not to be a handicap for implantation. Supported by: Christian-Lauritzen-Institut, Ulm, Germany.

P-360 Prospective randomized study comparing two soft catheters for embryo transfer. Paolo Emanuele Levi-Setti, Elena Albani, Anna Maria Baggiani, Elena Zannoni, Giulia Colombo, Valeria Liprandi. UO di Medicine della Riproduzione Inst Clinico Humanitas, Rozzano, Italy.

Vol. 78, No. 3, Suppl. 1, September 2002

Objective: The aim of this study was to investigate the performance of two widely used catheters for embryo transfer and evaluate their performance in terms of visualisation and the rate of difficult transfers. Design: Prospective randomized study. Materials/Methods: At the time of embryo transfer, couples undergoing IVF⶿ICSI cycles were equally randomised to one of two groups: in group 1, the transfer was made using a Cook soft trans catheter and, in group 2 by means of a Wallace catheter. Only women aged less than 37 years and with at least two type 1 or 2 embryos were selected for the study; no more than three embryos were transferred, all of which were performed under transabdominal ultrasound guidance. A record was kept of all difficult transfers, catheter visualisation and the need to use the obturator as scored by the operator or embryologist. The clinical and evolutive pregnancy rates, as well as the implantation and evolutive implantation rates, were statistically analysed using the Mann-Whitney U test and multivariate analysis as required. Results: The study involved 200 patients with a mean age of 31.2 ⫹ 2.7 years, and a mean duration of infertility of 3.2 ⫹ 3.5 years after a previous mean number of 1.6 ⫹ 1.6 attempts. A total of 591 embryos were transferred (200 type 1, 158 type 2 and 20 type 3), a mean of 2.9 ⫹ 0.20 embryos per patient.There were no between-group differences in terms of mean age, the number of attempts, indication for treatment, or the number and quality of the embryos transferred. The clinical pregnancy rate was 40% (4.5% abortions and 1.5% extrauterine pregnancies); the implantation and evolutive implantation rates were respectively 20.9% and 17.5%. An obturator was used in 32% of the cases, and the transfer was considered difficult in 10%. Ultrasound catheter visualisation was considered good in 75% of the transfers. There were no differences between group 1 and group 2 in terms of the clinical pregnancy rate (43% vs. 37%), the evolutive pregnancy rate (37% vs. 31%) or the number of clinical abortions and extrauterine pregnancies (3% and 3% vs. 6% and 0%). Catheterisation visualisation was good in 82% of the cases in group 2 and 68% of those in group 1 (p ⬍0.002). No differences were found in the use of the obturator or the number of difficult transfers (31% and 11% in group 1, and 33% and 9% in group 2). Conclusions: The results of this randomised study of two soft coaxial catheters used for embryo transfer under ultrasound guidance did not reveal any significant differences in pregnancy rates, but visualisation during the procedure was much better with the Wallace catheter. Supported by: This project was supported by the Humanitas Scientific Comitee.

P-361 Vaginal sildenafil improves ART outcome in a large cohort of patients with multiple prior ART failures attributed to poor endometrial development. Jeffrey D. Fisch, G. Sher. Sher Institute for Reproductive Medicine, Las Vegas, NV; Sher Institute for Reproductive Medicine, and Dept of Ob/Gyn, Univ of Nevada Sch of Medicine, Las Vegas, NV. Objective: Vaginally administered Sildenafil (SDF), in combination with controlled ovarian hyperstimulation, improved uterine artery blood flow and sonographic endometrial appearance in 4 women with repeated IVF failure attributed to inadequate endometrial development. These findings, while interesting, were inconclusive due to the low number of patients studied. This follow-up study evaluated the effect of vaginally administered SDF on peak endometrial thickness and ART outcome in a large cohort of infertile women with prior ART failures attributed to a thin endometrial lining. Design: Retrospective cohort analysis in a private practice setting. Materials/Methods: A cohort of 105 infertile women under age 40, with normal ovarian reserve and 2 or more consecutive prior IVF failures attributed to inadequate endometrial development, underwent ART using a long GnRHa protocol for pituitary desensitization and recombinant gonadotropins to promote follicular development. In addition, SDF suppositories prepared for us by a local pharmacy, were administered vaginally at a dose of 25mg 4 ⫻ /d for 3–10 days. Peak endometrial development was assessed by vaginal ultrasound on the day of hCG administration. Pregnancy and implantation rates were analyzed based on the response to SDF. Results: Of 105 patients, 73 (70%) (Group A), attained an endometrial thickness of ⱖ9 mm with a trilaminar pattern on the day of hCG administration, while 32 (30%) (Group B) did not. Implantation and ongoing pregnancy rates were significantly higher for Group A (29% and 45%), than for Group B (2% and 0%). Of 11 women in Group B who had embryos transferred in that cycle, only 1 conception occurred, which resulted in a

FERTILITY & STERILITY威

first trimester miscarriage. Among the patients in Group B, 59% had a history of endometritis, compared to 44% in Group A. Conclusions: Vaginal administration of SDF enhanced endometrial development in 70% of patients studied and 45% conceived an on-going gestation. The present data support our previously reported findings and lend credence to the idea that high implantation and on-going pregnancy rates can be achieved in a cohort traditionally given a poor-prognosis for success. However, SDF did not improve endometrial development in all patients studied, and especially those with a previous history of endometritis may have a decreased response to SDF therapy. Further, randomized controlled trials will be needed to objectively validate the effectiveness of SDF on endometrial development. Supported by: None.

P-362 The safety and efficacy of vaginal micronized progesterone (Crinone威 8%) indicated as luteal phase support evaluated in a large prospective, multicenter, multinational study in ART. Brian Kaplan. Project Americas Study Group and Highland Park Fertility Ctr, Highland Park, IL. Objective: To evaluate the safety and efficacy of vaginal micronized progesterone (Crinone威 8%). Design: Multicenter, multinational, prospective, trial conducted in 32 ART centers. Materials/Methods: Data from 682 patients is presented. GnRHa started 7– 8 days post ovulation (0.5 mg/d) until down regulation was achieved. The dose was decreased to 0.25 mg/d thereafter until d/hCG. Patients received 150 –225 IU of FSH for 5 days. On day 6 the dose was adjusted according to the patient⬘s response. Serum estradiol (E2) and US were used to monitor patient⬘s response. hCG 10,000 U was administered to trigger ovulation. OPU and IVF/ICSI were performed according to each center⬘s protocol. Transfer was limited to 3 embryos or 2 blastocysts. Luteal phase was supported with Crinone威 8% administered vaginally daily until pregnancy test or twelve weeks in pregnant patients. Treatment was initiated with one applicator (90 mg) the day of oocyte retrieval or the day after. The first pregnancy test was done on day 14 –17 following oocyte retrieval. Results: Results are expressed in means (⫾SD) or percentages. 97.1% of the patients received hCG (662). The duration of FSH stimulation was 10.1 days (⫾1.9) and the number of ampules utilized was 28.2 (⫾11.2). The number of follicles ⱖ14 mm was 9.4 (⫾4.3). The total number of oocytes retrieved was 11.1 (⫾6.4) where 8.3 (⫾4.8) were MII (ICSI patients only). The number of embryos obtained was 6.0 (⫾3.7). The mean number of embryos transferred was 2.5 (⫾0.8). 83.3% of the patients with one positive pregnancy test reached clinical pregnancy confirmed by US. Only 27 patients presented intermenstrual bleeding as adverse event (3.8%). The implantation rate (defined as number of sacs at US over number of embryos transferred) was 22.1% (⫾31.7). The clinical pregnancy rate per cycle, OPU and transfer were 35.2%, 36.5% and 38.6% respectively. Five patients (0.7%) suffered from severe OHSS. The duration of the luteal phase in pregnant and non-pregnant patients was similar 14.9 (⫾1.8) vs. 14.2 (⫾4.5) days respectively (NS). Other adverse events reported with known association with progesterone treatment were breast tenderness 1.3%, somnolence 0.4% and depression 0.3%. Adverse events reported associated with vaginal administration of progesterone were leukorrea 0.8% and vaginal discomfort 0.4%. Conclusions: Single agent therapy with FSH delivered excellent outcomes for all evaluated parameters. The implantation rate obtained with Crinone威 8% is comparable to those obtained with other forms of luteal phase support. Episodes of early bleeding are considered acceptable and always associated with lack of pregnancy. The pregnancy rate obtained in this study is higher but comparable to the pregnancy rate reported by SART for the year 1999 (30.6% per cycle) where other forms of progesterone were commonly used. Crinone威 8% is safe and effective, delivering excellent luteal phase support without masking the length of the luteal phase in non-pregnant patients. Very low incidence of local and general side effects associated with this route of administration plus acceptable cycle outcome makes this vaginal progesterone the treatment of choice for luteal phase support in ART patients. Supported by: Serono Inc, Rockland, MA.

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