To examine the efficacy and safety of frozen-thawed embryo transfer (FTET) cycles with supernumerary embryos cryopreserved during a randomized controlled clinical trial in women ages 35 to 42. A follow-up clinical study of FTET cycles using embryos cryopreserved during the PURSUE clinical trial. In PURSUE, women were randomized to a single injection of 150 μg corifollitropin alfa (CFA; n=694) or daily 300 IU recombinant follicle-stimulating hormone (rFSH; n=696) for the first 7 days of controlled ovarian stimulation (COS) in a gonadotropin-releasing hormone (GnRH) antagonist protocol. A follow-up study was conducted to collect efficacy and safety data regarding FTET cycles after cryopreservation of embryos in PURSUE. The primary endpoint was the cumulative vital pregnancy rate per subject by treatment group as assessed at least 35 days (≥5 weeks) after embryo transfer in the COS cycle in PURSUE or in a subsequent FTET cycle. The key secondary endpoint was the cumulative live birth rate per subject by treatment group as assessed after a COS cycle in PURSUE or an FTET cycle. Rates were estimated in each group separately with point estimates and 95% CI based on the Clopper-Pearson method. The occurrence of adverse events in (pregnant) women and their infants, and the incidence of congenital malformations in the infants were evaluated. Of the 1390 women treated in PURSUE, 307 were enrolled in the follow-up FTET study. The cumulative vital pregnancy rate (per subject) was 31.1% (95% CI: 27.7%; 34.7%) in CFA group versus 33.0% (95% CI: 29.6%; 36.7%) in the rFSH group, for a treatment difference of -1.8% (95% CI: -6.5%; 3.0%). The cumulative live birth rate (per subject) was 28.2% (95% CI: 24.9%; 31.8%) in the CFA group versus 29.5% (95% CI: 26.1%; 33.0%) in the rFSH group, for a treatment difference of -1.2% (95% CI: -5.7%; 3.4%). There were no clinically relevant differences in safety outcomes collected from pregnant women or their infants following transfer of cryopreserved embryos obtained by treatment with CFA or rFSH. In PURSUE, single-cycle COS across 1390 women demonstrated vital pregnancy rates of 23.9% with CFA (166/694) versus 26.9% with rFSH (187/696), the primary outcome of this study. In a post-hoc descriptive summary of vital pregnancy rates, 298 women with embryo transfer enrolled in the follow-up FTET study demonstrated per-cycle vital pregnancy rates of 32.0% with CFA (58/181) versus 32.7% with rFSH (54/165). There were 346 cycles among the 298 women, translating to per subject rates of 37.5% for CFA (57/152) versus 36.3% for rFSH (53/146). The cumulative vital pregnancy and live-birth rates (from fresh cycles and FTET) were similar in older women treated with CFA and rFSH. No new safety signals were detected in this follow-up FTET study.

BackgroundA growing percentage of women undergoing in vitro fertilization (IVF) are aged 35 years and older. In older women, a reduced ovarian reserve is a critical factor associated with a poor response to ovarian stimulation with gonadotropin compounds.ObjectiveTo compare the IVF cycle characteristics (follicular growth and serum hormone levels) during ovarian stimulation in older women with corifollitropin alfa (CFA) or recombinant follicle-stimulating hormone (rFSH).Materials and MethodsTabled 1Pre-doseDay 5*Day 6Day 7Day 8Day of hCGMean Number of follicles during stimulation ≥11 mmCFA0.13.76.08.29.811.9rFSH0.13.75.97.79.310.9P-value0.7670.8560.0990.1720.003 ≥15 mmCFA0.00.31.02.54.37.5rFSH0.00.41.32.84.57.2P-value0.011<0.0010.0020.1280.099 ≥17 mmCFA0.00.10.30.91.94.9rFSH0.00.10.31.02.34.8P-value0.0480.0170.0230.0010.853Median hormone levels during stimulation E2 [pg/mL]CFA38.3408.5518.0665.0855.51320.0rFSH40.1343.0455.0657.0931.01360.0P-value<0.0010.0150.9930.0080.901 FSH [IU/L]CFA6.928.923.318.615.017.1rFSH7.017.518.319.019.419.1P-value<0.001<0.0010.190<0.001<0.001 LH [IU/L]CFA4.62.41.61.61.62.0rFSH4.72.11.52.02.32.3P-value<0.0010.237<0.001<0.0010.002 P [ng/mL]CFA0.600.720.700.710.711.15rFSH0.610.640.720.851.031.27P-value<0.0010.843<0.001<0.001<0.001Statistically significant between-treatment differences (P<0.01) appear in bold font.*GnRH antagonist started. Open table in a new tab ConclusionsThe relationship between follicular growth and endocrine parameters indicate a stronger initial stimulation with CFA compared with rFSH. Differences in serum hormone concentrations occurred from day 5 onwards, and were followed by differences in follicular response.Financial SupportMerck & Co., Inc., Whitehouse Station, NJ. BackgroundA growing percentage of women undergoing in vitro fertilization (IVF) are aged 35 years and older. In older women, a reduced ovarian reserve is a critical factor associated with a poor response to ovarian stimulation with gonadotropin compounds. A growing percentage of women undergoing in vitro fertilization (IVF) are aged 35 years and older. In older women, a reduced ovarian reserve is a critical factor associated with a poor response to ovarian stimulation with gonadotropin compounds. ObjectiveTo compare the IVF cycle characteristics (follicular growth and serum hormone levels) during ovarian stimulation in older women with corifollitropin alfa (CFA) or recombinant follicle-stimulating hormone (rFSH). To compare the IVF cycle characteristics (follicular growth and serum hormone levels) during ovarian stimulation in older women with corifollitropin alfa (CFA) or recombinant follicle-stimulating hormone (rFSH). Materials and MethodsTabled 1Pre-doseDay 5*Day 6Day 7Day 8Day of hCGMean Number of follicles during stimulation ≥11 mmCFA0.13.76.08.29.811.9rFSH0.13.75.97.79.310.9P-value0.7670.8560.0990.1720.003 ≥15 mmCFA0.00.31.02.54.37.5rFSH0.00.41.32.84.57.2P-value0.011<0.0010.0020.1280.099 ≥17 mmCFA0.00.10.30.91.94.9rFSH0.00.10.31.02.34.8P-value0.0480.0170.0230.0010.853Median hormone levels during stimulation E2 [pg/mL]CFA38.3408.5518.0665.0855.51320.0rFSH40.1343.0455.0657.0931.01360.0P-value<0.0010.0150.9930.0080.901 FSH [IU/L]CFA6.928.923.318.615.017.1rFSH7.017.518.319.019.419.1P-value<0.001<0.0010.190<0.001<0.001 LH [IU/L]CFA4.62.41.61.61.62.0rFSH4.72.11.52.02.32.3P-value<0.0010.237<0.001<0.0010.002 P [ng/mL]CFA0.600.720.700.710.711.15rFSH0.610.640.720.851.031.27P-value<0.0010.843<0.001<0.001<0.001Statistically significant between-treatment differences (P<0.01) appear in bold font.*GnRH antagonist started. Open table in a new tab Statistically significant between-treatment differences (P<0.01) appear in bold font. *GnRH antagonist started. ConclusionsThe relationship between follicular growth and endocrine parameters indicate a stronger initial stimulation with CFA compared with rFSH. Differences in serum hormone concentrations occurred from day 5 onwards, and were followed by differences in follicular response. The relationship between follicular growth and endocrine parameters indicate a stronger initial stimulation with CFA compared with rFSH. Differences in serum hormone concentrations occurred from day 5 onwards, and were followed by differences in follicular response.

The large database from the Pursue and Engage trials of older and younger women, respectively, provides an opportunity to assess safety parameters by age group following ovarian stimulation with corifollitropin alfa or recombinant follicle-stimulating hormone (rFSH) for in vitro fertilization (IVF). To assess the age-relation of safety parameters following ovarian stimulation with corifollitropin alfa or rFSH. In the Pursue trial, 1390 women, aged 35–42 years, were treated with either a single injection of 150 μg corifollitropin alfa (n=692) or daily 300 IU rFSH (n=698) for the first 7 days of ovarian stimulation in a gonadotropin-releasing hormone (GnRH) antagonist protocol. In the North American centers of the Engage trial, 804 women, aged 18–36 years, were treated with 150 μg corifollitropin alfa (n=400) or daily 200 IU rFSH (n=404), also in a GnRH antagonist protocol. Cycle discontinuations due to an adverse event (AE), serious AEs, and incidence of any grade of ovarian hyperstimulation syndrome (OHSS) were assessed by age class according to Society for Assisted Reproductive Technology (SART) criteria: <35, 35–37, 38–40, and >40 years. Age trends were tested using a Cochran-Mantel-Haenszel (CMH) test with one degree of freedom. The incidence of safety parameters by age class are shown in the Table. The most common AE leading to discontinuation was OHSS (0.4%, pooled treatment groups) AE-related cycle discontinuation rates decreased with increasing age class in the corifollitropin alfa group (P=0.037; CMH test), but there was no apparent trend in the rFSH group (P=0.34). Treatment by age class interaction was statistically significant (P=0.041), suggesting that the trends were different in the 2 treatment groups. The most common serious AEs were ectopic pregnancy (0.9%), and OHSS (0.7%, pooled treatment groups). Serious AE rates decreased with increasing age class in the corifollitropin alfa group (P=0.024). A similar trend was seen in the rFSH group, but this was not statistically significant (P=0.14). OHSS rates decreased with increasing age class in the corifollitropin alfa group (P<0.0001) as well as in the rFSH group (P<0.0001), mainly caused by the difference between women aged <35 years versus ≥35 years.Tabled 1Cycle discontinuation due to AE, serious AEs and incidence of OHSS by age classEndpointAge (years)Corifollitropin alfarFSHn%n%Cycle discontinuation due to AE<353092.33030.335–374081.04210.738–402630.82551.2>401120.01230.8Serious AE<353093.23034.035–374081.04213.138–402630.82553.1>401120.91230.8OHSS<3530911.03039.635–374081.74212.438–402632.72551.2>401120.91230.0Numbers based on all-subjects-as-treated. n: number of women assessed. Open table in a new tab Numbers based on all-subjects-as-treated. n: number of women assessed. The incidence of cycle discontinuations due to an AE, serious AEs, and the incidence of OHSS following ovarian stimulation with corifollitropin alfa statistically significantly decreased with increasing age. These incidences also decreased after ovarian stimulation with rFSH, but there the trend was only statistically significant for OHSS.

A growing percentage of women undergoing in vitro fertilization (IVF) are aged 35 years and older. In older women, a reduced ovarian reserve is a critical factor associated with a poor response to ovarian stimulation with gonadotropin compounds. To assess any differences in age-related decline in efficacy following ovarian stimulation with corifollitropin alfa or recombinant follicle-stimulating hormone (rFSH) based on data from 2 randomized controlled trials, Pursue and Engage. In the Pursue trial, 1390 women, aged 35–42 years, were randomized to a single injection of 150 μg corifollitropin alfa (n=694) or daily 300 IU rFSH (n=696) for the first 7 days of ovarian stimulation in a gonadotropin-releasing hormone (GnRH) antagonist protocol. In the North American centers of the Engage trial, 804 women, aged 18–36 years, were randomized to 150 μg corifollitropin alfa (n=401) or daily 200 IU rFSH (n=403), also in a GnRH antagonist protocol. Live birth rates were assessed by age class according to Society for Assisted Reproductive Technology (SART) criteria: <35, 35–37, 38–40, and >40 years. Age trends were tested in the 2 trials separately. The mean number of embryos transferred in women aged <35, 35–37, 38–40, and >40 years were 1.8, 1.8, 1.8 and 1.7 with corifollitropin alfa and 1.8 in all age classes with rFSH treatment. Live birth rates in the corifollitropin alfa treatment group decreased from 40.6% in women aged <35 years to 29.4%, 19.2%, and 7.1% in women aged 35–37 years, 38–40 years, and >40 years, respectively. In the rFSH treatment arm, live birth rates dropped from 38.1% in women aged <35 years to 31.8%, 22.1%, and 13.0% in women aged 35–37 years, 38–40 years, and >40 years, respectively (Table). In women aged 18–36 years (Engage trial), live-birth rates declined with age, but the trend was not statistically significant (P=0.22 and P=0.48 in the corifollitropin alfa and rFSH groups, respectively). In women aged 35–42 years (Pursue trial), the decline in live-birth rates was statistically significant (P<0.0001 in both groups). Differences between the ovarian stimulation compounds were not statistically significant.Tabled 1Live birth rates by age classAge (years)Corifollitropin alfarFSHn%n%Live birth rate<3531040.630238.135-3740829.442131.838-4026519.225322.1>401127.112313.0Numbers based on Intent-to-Treat; n: number of women with outcome assessed. Open table in a new tab Numbers based on Intent-to-Treat; n: number of women with outcome assessed. Live-birth rates following ovarian stimulation with different compounds were similar and declined only slowly with age in women aged 18–36 years, but declined rapidly in those aged 35–42 years.

ObjectiveIt has been demonstrated that computer-automated measurements of key time-lapse parameters can aid in the selection of embryos with the highest potential to develop to the blastocyst stage (Conaghan et al. 2013). However, the impact of this novel test on clinical outcomes for patients in different age groups remains unclear. The objective of this study was to examine the correlation between computer-automated time-lapse analysis results and embryo implantation for patients in different age groups.DesignBlinded, multi-center study.Materials and Methods205 patients from 6 clinics consented to have embryos imaged using the Eeva® System, a platform technology that automates the analysis of P2 (time between first and second mitosis) and P3 (time between second and third mitosis) and generates a test score of High or Low regarding developmental potential. For this non-selection study, High/Low scores were blinded, and embryos were selected for transfer using only morphology evaluation. Two age groups were analyzed: egg age <35 years and egg age ≥35 years. Implantation was defined by fetal heartbeat at the 6-7 week ultrasound. χ2-test was used for statistical analysis.ResultsTabled 1IR<35 years>=35 yearsEeva High52% (31/60)20% (10/51)Eeva Low35% (34/97)13% (16/123)p-value0.02NS Open table in a new tab ConclusionIt is well known that egg age highly correlates to implantation rates. In this blinded, non-selection study, we have demonstrated that in younger patients Eeva High/Low scores generated from automated cell division timings, correlate well with embryo implantation. We postulate that Eeva Test scores may reflect embryo quality independent of age and that the use of Eeva Test scores to aid embryo selection may improve overall implantation rates. The study is currently ongoing and with increased sample size, will allow us to further evaluate such phenomenon in older patients. ObjectiveIt has been demonstrated that computer-automated measurements of key time-lapse parameters can aid in the selection of embryos with the highest potential to develop to the blastocyst stage (Conaghan et al. 2013). However, the impact of this novel test on clinical outcomes for patients in different age groups remains unclear. The objective of this study was to examine the correlation between computer-automated time-lapse analysis results and embryo implantation for patients in different age groups. It has been demonstrated that computer-automated measurements of key time-lapse parameters can aid in the selection of embryos with the highest potential to develop to the blastocyst stage (Conaghan et al. 2013). However, the impact of this novel test on clinical outcomes for patients in different age groups remains unclear. The objective of this study was to examine the correlation between computer-automated time-lapse analysis results and embryo implantation for patients in different age groups. DesignBlinded, multi-center study. Blinded, multi-center study. Materials and Methods205 patients from 6 clinics consented to have embryos imaged using the Eeva® System, a platform technology that automates the analysis of P2 (time between first and second mitosis) and P3 (time between second and third mitosis) and generates a test score of High or Low regarding developmental potential. For this non-selection study, High/Low scores were blinded, and embryos were selected for transfer using only morphology evaluation. Two age groups were analyzed: egg age <35 years and egg age ≥35 years. Implantation was defined by fetal heartbeat at the 6-7 week ultrasound. χ2-test was used for statistical analysis. 205 patients from 6 clinics consented to have embryos imaged using the Eeva® System, a platform technology that automates the analysis of P2 (time between first and second mitosis) and P3 (time between second and third mitosis) and generates a test score of High or Low regarding developmental potential. For this non-selection study, High/Low scores were blinded, and embryos were selected for transfer using only morphology evaluation. Two age groups were analyzed: egg age <35 years and egg age ≥35 years. Implantation was defined by fetal heartbeat at the 6-7 week ultrasound. χ2-test was used for statistical analysis. ResultsTabled 1IR<35 years>=35 yearsEeva High52% (31/60)20% (10/51)Eeva Low35% (34/97)13% (16/123)p-value0.02NS Open table in a new tab ConclusionIt is well known that egg age highly correlates to implantation rates. In this blinded, non-selection study, we have demonstrated that in younger patients Eeva High/Low scores generated from automated cell division timings, correlate well with embryo implantation. We postulate that Eeva Test scores may reflect embryo quality independent of age and that the use of Eeva Test scores to aid embryo selection may improve overall implantation rates. The study is currently ongoing and with increased sample size, will allow us to further evaluate such phenomenon in older patients. It is well known that egg age highly correlates to implantation rates. In this blinded, non-selection study, we have demonstrated that in younger patients Eeva High/Low scores generated from automated cell division timings, correlate well with embryo implantation. We postulate that Eeva Test scores may reflect embryo quality independent of age and that the use of Eeva Test scores to aid embryo selection may improve overall implantation rates. The study is currently ongoing and with increased sample size, will allow us to further evaluate such phenomenon in older patients.

Non-invasive image markers have the potential to improve selection of viable embryos. We have demonstrated that measurements of cell cycle divisions are correlated with blastocyst formation and gene expression (Wong et al, Nature Biotech 2010). The objective of this study was to develop and prospectively validate a robust model for early prediction of embryo development. Multi-site, prospective, cohort study. Patients undergoing blastocyst culture and transfer consented to have their embryos imaged using a time-lapse imaging system, Eeva (Early Embryo Viability Assessment). Embryologists who were blinded to the embryo outcome independently reviewed videos for specific cell division time intervals P2 (time between cytokinesis 1 and 2) and P3 (time between cytokinesis 2 and 3). A classification and regression tree model was developed to predict blastocysts based on P2 and P3. The prediction model was validated on an independent set of 188 embryos and assessed for performance. A total of 480 embryos from 65 patients were included. The Eeva model predicts a high probability of blastocyst development when both P2 and P3 are within specific cell division timing ranges (9.33≤P2≤11.45 and 0≤P3≤1.73). The average P2 and P3 values of blastocysts in the Development and Validation datasets were highly consistent. Prospectively using Eeva, the specificity of blastocyst prediction was significantly improved (85%) over the average prediction made by experienced embryologists using cleavage morphology (57%).Tabled 1Eeva Blastocyst Prediction Model & PerformanceDataset# EmbryosP2 (hrs)P3 (hrs)SpecificityDevelopment29210.5±2.51.1±2.586%Validation18810.7±2.41.0±1.685% Open table in a new tab We have developed and validated a model for predicting viable blastocyst formation by the cleavage stage. Eeva predictions are specific, non-invasive and easily integrated into the workflow of day 3 or 5 transfer procedures. Parallel studies are evaluating Eeva predictions for improvement to embryo selection.

To report live birth rates following fresh embryo transfer (ET) and cumulative ongoing pregnancy rates (OPRs) from fresh or frozen-thawed embryo transfer (FTET) after a single ovarian stimulation (COS) cycle with corifollitropin alfa or rFSH in North American (NA) and European (EU) IVF units. Randomized, double-blind trial (Engage) involving 14 centers in NA (N = 804) and 20 in EU (N = 702). Patients >60 kg received a single dose of 150 μg corifollitropin alfa or daily 200 IU rFSH for the first 7 days of COS in a GnRH antagonist protocol. Implantation rates (IR) after corifollitropin alfa or rFSH treatment and fresh ET at day 3 were respectively 38.5% and 31.7% in NA vs 31.0% and 23.2% in EU. Both region (P<0.01) and treatment (P = 0.01) had a significant effect on IR. Accordingly, OPRs were 45.4% (182/401) and 45.7% (184/403) in NA and 31.5% (112/355) and 29.4% (102/347) in EU in corifollitropin alfa and rFSH groups, respectively. Live birth rates were 39.2% in each treatment group in NA and 31.5% and 28.8% in EU for corifollitropin alfa and rFSH group, respectively. The mean (SD) number of good-quality embryos in NA was 5.3 (4.6) and 5.1 (4.4) compared with 3.4 (3.7) and 3.5 (3.0) in EU for corifollitropin alfa and rFSH, respectively. The number of fresh embryos transferred for both treatment groups was 1.9 (0.3) in NA and 1.5 (0.5) in EU. Multiple PRs of 34.6% and 28.8% in NA compared with 17.9% and 12.7% in EU for corifollitropin alfa and rFSH, respectively. Cumulative OPRs including FTET were 53.1% (213/401) and 51.9% (209/403) in NA and 40.6% (144/355) and 36.9% (128/347) in EU for corifollitropin alfa and rFSH, respectively. IR significantly higher in NA than in EU and (cumulative) OPRs and live birth rates were also higher in NA than in EU. Possible explanations are a higher recovery of good-quality embryos, better embryo selection, and a higher frequency of double instead of single ET.

BACKGROUND: In a recent, prospective, double-blind, randomized, IVF trial (Engage), subjects in the reference group were treated with a standardized rFSH/GnRH antagonist protocol. The North American (NA) cohort made up 54% of these subjects, providing an opportunity to study the impact of patient demographics and clinical characteristics on clinical outcome with this simplified treatment regimen. METHOD(S): In this retrospective analysis, data collected from 14 centers in NA were analyzed. Patients (n = 403) were treated once daily with 200 IU rFSH follitropin beta (Follistim AQ Cartridge/Puregon, NV Organon, The Netherlands) starting on day 2–3 of menses, followed by daily rFSH (≤ 200 IU/day) from controlled ovarian hyperstimulaton (COS) day 8 onward, as required, to meet the criterion of at least three follicles ≥17 mm for hCG (Pregnyl, NV Organon) administration. All received 0.25 mg of the GnRH antagonist ganirelix (Ganirelix Acetate, NV Organon) daily from COS day 5 until induction of oocyte maturation by urinary hCG. EET was on day 3 or day 5 with one or two embryos transferred. Ongoing pregnancy rate (PR) and implantation rate (IR) were examined across patient age, occurrence of a previous IVF cycle, number of oocytes retrieved, stimulation day 1 serum FSH, and cause of infertility. RESULT(S): In this NA cohort, 403 subjects were randomized to the rFSH/ganirelix reference arm, 399 (99%) had an oocyte retrieval, and 380 (94.3%) had an ET with equivalent day 3 (48.9%) and day 5 (49.5%) ETs; 88.9% had two embryos transferred. Mean age, weight, and body mass index were 31.7 years, 68.1 kg, and 25 kg/m2, respectively. Ongoing PR was 45.7%, and IR was 36.8%. The table summarizes PR and IR stratified by patient demographics and clinical characteristics: younger patients and those without a previous IVF cycle trended toward a higher PR and IR; oocyte number lowered PR only when less than six oocytes were obtained More oocytes and good-quality embryos were obtained in younger patients (18–29 years: 15.7 [7.0] and 6.3 [4.6]; compared with older patients 30–33 years: 14.0 [7.4] and 5.3 [4.8]; and 34–36 years: 11.1 [7.0] and 4.4 [3.6], respectively). CONCLUSION(S): A simplified, patient-focused rFSH/GnRH antagonist treatment regimen attained high treatment success for patients across demographics and clinical characteristics within this study population. As often seen in everyday clinical practice, a trend toward higher PR was observed for the best prognosis patients. KEY WORDS: Follitropin beta, rFSH, GnRH, ongoing pregnancy rate.TableClinical outcome by patient demographics and clinical characteristics.% PR (95% confidence interval)IR, %Age: 18–29 (n = 101)53.5 (43.3; 63.5)43.2 30–33 (n = 149)42.3 (34.2; 50.6)35.5 34–36 (n = 153)43.8 (35.8; 52.0)34Previous IVF cycle: 0 (n = 342)47.1 (41.7; 52.5)38.3 1–3 (n = 61)37.7 (25.6; 51.0)28.8Oocyte no. >18 (n = 93)48.4 (38.0; 58.9)38.2 13–18 (n = 93)47.3 (36.9; 57.9)39.9 6–12 (n = 160)46.9 (39.0; 54.9)35.1 <6 (n = 55)34.5 (22.2; 48.6)34.1Stimulation day 1 FSH: <6 (n = 145)37.9 (30.0; 46.4)31.2 6–8 (n = 150)52.7 (44.4; 60.9)42.1 >8 (n = 55)41.8 (28.7; 55.9)33.3Cause of infertility: Male factor (n = 168)48.2 (40.5; 56.0)38 Tubal (n = 109)43.1 (33.7; 53.0)37 Endometriosis (n = 95)45.1 (35.0; 55.8)38.2 Unexplained (n = 131)46.6 (37.8; 55.5)37.3 Open table in a new tab

BACKGROUND: Sperm DNA damage (fragmentation) is a known cause of male factor infertility and has been shown to negatively impact pregnancy outcomes in couples undergoing IVF with intracytoplasmic sperm injection (ICSI). Previous studies have shown that sperm DNA damage may occur after the sperm have exited the testicle and that levels of DNA fragmentation are lower in testicular sperm than in ejaculated sperm.OBJECTIVE(S): To evaluate the results of IVF/ICSI using testicular sperm in couples who failed to achieve pregnancy on prior IVF cycles and who had high levels of sperm damage as a cause of their infertility.MATERIALS AND METHOD(S): We retrospectively reviewed the charts of 24 consecutive patients who underwent testicular sperm extraction for use with ICSI between January 1, 2008, and August 1, 2008. All patients had sperm present in the ejaculate that tested with a high DNA fragmentation index (DFI) as measured by sperm chromatin structure assay. All patients had failed to achieve pregnancy during prior IVF cycles using ejaculated sperm. In an effort to improve the chances of conception, couples elected to have sperm harvested directly from the testicle and used for IVF/ICSI. Ovarian hyperstimulation was performed by one of 10 different reproductive endocrinologists at five different assisted reproductive technology laboratories in the Los Angeles area. Testicular sperm extraction was performed by a single surgeon (PW) on the day of oocyte retrieval or 1 day prior.RESULT(S): All men had at least one abnormal semen parameter and a high DFI (>30%) ranging from 32% to 82%, with a mean of 51.6%. The etiology of sperm damage included varicocele, pyospermia, infection, partial obstruction, cryptorchidism, steroid abuse, and idiopathic. The average age of the female partner was 36.4 years, with a range of 32–46 years. Two couples used an egg donor, and the wives' ages were excluded from the aforementioned calculation. All couples had undergone between one and seven prior ICSI attempts with a mean of three failed cycles. A pregnancy rate of 62.5% was achieved when testicular sperm were used. An 83% pregnancy rate was achieved when the DFI was over 65%. A 75% pregnancy rate was achieved in couples who underwent four or more prior failed IVF cycles.CONCLUSION(S): These data show that the use of testicular sperm/ICSI provides an efficient treatment option for couples who fail multiple IVF cycles because of high levels of sperm DNA fragmentation. Neither the degree of sperm DNA damage nor the number of prior failed IVF cycles appeared to affect the ability to achieve pregnancy when testicular sperm were used. BACKGROUND: Sperm DNA damage (fragmentation) is a known cause of male factor infertility and has been shown to negatively impact pregnancy outcomes in couples undergoing IVF with intracytoplasmic sperm injection (ICSI). Previous studies have shown that sperm DNA damage may occur after the sperm have exited the testicle and that levels of DNA fragmentation are lower in testicular sperm than in ejaculated sperm. OBJECTIVE(S): To evaluate the results of IVF/ICSI using testicular sperm in couples who failed to achieve pregnancy on prior IVF cycles and who had high levels of sperm damage as a cause of their infertility. MATERIALS AND METHOD(S): We retrospectively reviewed the charts of 24 consecutive patients who underwent testicular sperm extraction for use with ICSI between January 1, 2008, and August 1, 2008. All patients had sperm present in the ejaculate that tested with a high DNA fragmentation index (DFI) as measured by sperm chromatin structure assay. All patients had failed to achieve pregnancy during prior IVF cycles using ejaculated sperm. In an effort to improve the chances of conception, couples elected to have sperm harvested directly from the testicle and used for IVF/ICSI. Ovarian hyperstimulation was performed by one of 10 different reproductive endocrinologists at five different assisted reproductive technology laboratories in the Los Angeles area. Testicular sperm extraction was performed by a single surgeon (PW) on the day of oocyte retrieval or 1 day prior. RESULT(S): All men had at least one abnormal semen parameter and a high DFI (>30%) ranging from 32% to 82%, with a mean of 51.6%. The etiology of sperm damage included varicocele, pyospermia, infection, partial obstruction, cryptorchidism, steroid abuse, and idiopathic. The average age of the female partner was 36.4 years, with a range of 32–46 years. Two couples used an egg donor, and the wives' ages were excluded from the aforementioned calculation. All couples had undergone between one and seven prior ICSI attempts with a mean of three failed cycles. A pregnancy rate of 62.5% was achieved when testicular sperm were used. An 83% pregnancy rate was achieved when the DFI was over 65%. A 75% pregnancy rate was achieved in couples who underwent four or more prior failed IVF cycles. CONCLUSION(S): These data show that the use of testicular sperm/ICSI provides an efficient treatment option for couples who fail multiple IVF cycles because of high levels of sperm DNA fragmentation. Neither the degree of sperm DNA damage nor the number of prior failed IVF cycles appeared to affect the ability to achieve pregnancy when testicular sperm were used.

Corifollitropin alfa, a fusion protein lacking LH activity, has a longer elimination half-life and extended time to peak levels than recombinant FSH (rFSH). A single injection of corifollitropin alfa may replace seven daily gonadotrophin injections during the first week of ovarian stimulation.In this large, double-blind, randomized, non-inferiority trial the ongoing pregnancy rates were assessed after one injection of 150 mu g corifollitropin alfa during the first week of stimulation and compared with daily injections of 200 IU rFSH using a standard GnRH antagonist protocol.The study population comprised 1506 treated patients with mean age of 31.5 years and body weight of 68.6 kg. Ongoing pregnancy rates of 38.9% for the corifollitropin alfa group and 38.1% for rFSH were achieved, with an estimated non-significant difference of 0.9% [95% confidence interval (CI): -3.9; 5.7] in favor of corifollitropin alfa. Stratified analyses of pregnancy rates confirmed robustness of this primary outcome by showing similar results regardless of IVF or ICSI, or number of embryos transferred. A slightly higher follicular response with corifollitropin alfa resulted in a higher number of cumulus-oocyte-complexes compared with rFSH [estimated difference 1.2 (95% CI: 0.5; 1.9)], whereas median duration of stimulation was equal (9 days) and incidence of (moderate/severe) ovarian hyperstimulation syndrome was the same (4.1 and 2.7%, respectively P = 0.15).Corifollitropin alfa is a novel and effective treatment option for potential normal responder patients undergoing ovarian stimulation with GnRH antagonist co-treatment for IVF resulting in a high ongoing pregnancy rate, equal to that achieved with daily rFSH. The trial was registered under ClinicalTrials.gov identifier NTC00696800.

OBJECTIVE: To investigate the efficacy and safety of a single injection of corifollitropin alfa to induce multifollicular development for controlled ovarian stimulation using daily recombinant FSH (recFSH) as a reference. DESIGN: A phase III, multicenter, multinational, randomized, double-blind double-dummy, active controlled, non-inferiority clinical trial. MATERIALS AND METHODS: A total of 1509 patients was recruited in 34 IVF units in North-America and Europe. Patients were randomized to treatment with either a single dose of 150 μg corifollitropin alfa (Org 36286, NV Organon) or daily 200 IU recFSH (follitropin beta, Puregon®/ Follistim® AQ Cartridge, NV Organon) followed by recFSH (maximum 200 IU/day) from stimulation day 8 onwards. Starting on stimulation day 5 all patients were scheduled to receive 0.25 mg ganirelix (Orgalutran®/ Ganirelix Acetate Injection, NV Organon) until induction of oocyte maturation by urinary hCG. Non-inferiority in ongoing pregnancy rates (assessed at 10 weeks or more after embryo transfer) was defined as primary endpoint and number of oocytes retrieved as co-primary endpoint. RESULTS: Following a single injection of corifollitropin alfa the subjects needed on average 2 days of stimulation with 200 IU recFSH to reach the criterion to administer hCG. This matched the average duration of stimulation of 9 days of the reference group treated with daily recFSH. The mean number of oocytes retrieved per started cycle in the corifollitropin alfa group was 13.7 versus 12.5 in the reference group. The mean total number of embryos as assessed on day 3 of culture was 8.4 for the corifollitropin alfa group versus 7.5 for the recFSH group. The ongoing pregnancy rate, assessed at or beyond 10 weeks after transfer of 1 or 2 embryos, was 38.9% for the corifollitropin alfa group and 38.1% for the recFSH reference group. The estimated risk difference, adjusted for covariates was +0.9% (95% confidence interval: -3.9%, 5.7%) in favor of corifollitropin alfa and well within the pre-defined non-inferiority margins for this primary endpoint. The total number of subjects with OHSS was 7.0% versus 6.3%, which includes 1.9% and 1.2% of subjects hospitalized due to OHSS, respectively. Incidences of (Serious) Adverse Events reported by subjects in both groups were comparable. CONCLUSIONS: A single dose of 150 μg corifollitropin alfa can effectively and safely replace daily recFSH for the first 7 days of COS.

OBJECTIVE: To determine whether MicroSort® sperm separation improved the efficiency of in vitro fertilization/pre-implantation genetic diagnosis (IVF/PGD) when performed for gender selection. DESIGN: This was a retrospective cohort study. MicroSort® is an investigational device and is being used as part of an institutional review board approved, United States Food and Drug Administration supervised clinical trial. MATERIALS AND METHODS: The subjects were patients under 40 years old who presented to our clinic between January 2005 and December 2007 requesting IVF/PGD for gender selection. The patients underwent IVF/PGD in the usual fashion. The sperm used for fertilization was either sorted into X- or Y-predominant fractions (Group A) using a modified flow cytometer (MicroSort®) or simply washed (Group B). We then assessed whether or not euploid embryos of the desired gender were available for transfer and whether or not clinical pregnancy occurred. Age and number of embryos transferred were compared using the t-test. Odds ratios and 95% confidence intervals were calculated for percentage with embryo transfers, percentage with no transfer and clinical pregnancy rate. RESULTS: 289 patients underwent IVF/PGD for gender selection within the study period. 265 of these patients were less than 40 years old at the time of egg retrieval and were included in this study. Group A consisted of 146 patients. Group B consisted of 119 patients. The results are summarized below:Table 1ResultsnMean Age# embryos transferredTransfer rateNon-transfer rateClinical pregnancy rate∗OR = 1.85 (1.12-3.04).Group A14633.9 ±3.12.01 ± 0.7129/146 = 88.3%17/146 = 11.6%72/146 = 49.3%Group B11933.2 ± 3.52.02 ± 0.996/119 = 80.6%23/119 = 19.3%41/119 = 34.4%∗ OR = 1.85 (1.12-3.04). Open table in a new tab There was no significant difference in the mean age (p=0.38), number of embryos transferred (p=.87) or transfer rate/non-transfer rate (OR=1.8, 0.92-3.58). Group A had a significantly higher pregnancy rate per cycle than group B (OR=1.85, 1.12-3.04). CONCLUSIONS: MicroSort® significantly improves per cycle clinical pregnancy rates in patients having IVF/PGD for gender selection.

Background: Currently, the majority of mixed-medication stimulation protocols for IVF gonadotropin therapy necessitate 2–4 daily injections for the patient. The addition of needle anxiety to the already stressful IVF therapy may potentially have a negative impact on outcome. The current proposal puts forward a stimulation protocol that utilizes a single gonadotropin injection per day, with a single depot dose GnRH antagonist for down-regulation, for a total of 9–11 injections for the entire cycle. Objective: To describe the efficacy of a human-derived gonadotropin stimulation protocol utilizing 9–11 injections in total for IVF. Materials and Methods: Patients began their stimulation cycle using Bravelle® (hp-FSH). Once the lead follicle reached ≥14 mm, a single dose of 3-mg GnRH antagonist was administered at the doctor's office. Menopur® (hp-hMG) was added to the protocol consequently with the antagonist and continued as single daily combination dose of Bravelle and Menopur until the day of hCG. Results: Twenty-six patients, aged 18–37 years (mean, 33.0), with BMI <30 kg/m2 (mean, 21.9), and basal FSH <9 mL/IU (mean, 5.8) participated in the study. Twenty-three patients underwent a 3-day embryo transfer, and of these, 15 had positive pregnancies (11 singleton, 4 twins), for a 65% ongoing pregnancy rate. Three patients had suboptimal responses to stimulation and did not reach the criteria for hCG administration. On average, patients underwent 10 days of ovarian stimulation (range 8–11), with mean dose of 2990 IU FSH and 335 IU hMG. Mean peak estradiol measured 1379 pg/mL, with mean number of oocytes retrieved and MII oocytes 11 and 13, respectively. The mean number of embryos from standard insemination and ICSI was 8. Conclusions: Single daily dose administration of gonadotropins, in conjunction with a single dose of GnRH antagonist, provides a convenient and simple approach to minimize compliance issues for patients undergoing COH and IVF. Our data indicates that aside from the advantages of a more injection friendly stimulation, the use of a single dose GnRH antagonist on the morning of the lead follicle reaching 14 mm results in high ongoing pregnancy rates in this prospective study.