Han Witjes

Progesterone elevation does not compromise pregnancy rates in high responders: a pooled analysis of in vitro fertilization patients treated with recombinant follicle-stimulating hormone/gonadotropin-releasing hormone antagonist in six trials

OBJECTIVE To compare the impact of elevated P during the late follicular phase on the chance of pregnancy in low, normal, and high responders. DESIGN Retrospective combined analysis from six clinical trials. SETTING IVF centers. PATIENT(S) Women up to 39 years of age with a regular menstrual cycle and an indication for ovarian stimulation before IVF/intracytoplasmic sperm injection. INTERVENTION(S) Ovarian stimulation with recombinant (r) FSH in a GnRH antagonist protocol. MAIN OUTCOME MEASURE(S) Ongoing pregnancy rates (OPRs) assessed with the use of univariate and multivariate analyses according to serum P levels ≤ 1.5 ng/mL versus >1.5 ng/mL on the day of hCG administration and compared among low (1-5 oocytes), normal (6-18 oocytes), and high (>18 oocytes) responders. RESULT(S) A total of 157/1,866 women (8.4%; 95% confidence interval [CI] 7.2%-9.8%) had elevated P. Incidence of elevated P increased from 4.5% in low responders to 19.0% in high responders. Overall, OPRs were significantly lower in women with elevated P. Per started cycle, the >1.5 to ≤ 1.5 ng/mL adjusted odds ratio was 0.55 (95% CI 0.37-0.81). OPRs were not impaired in high responders with P elevation and were significantly higher compared with normal responders with P elevation. CONCLUSION(S) The incidence of elevated P increases with ovarian response, and elevated P at a threshold of 1.5 ng/mL is independently associated with a decreased chance of pregnancy in low to normal responders, but not in high responders, when using an rFSH/GnRH antagonist protocol.

High ovarian response does not jeopardize ongoing pregnancy rates and increases cumulative pregnancy rates in a GnRH-antagonist protocol

STUDY QUESTION Is the ovarian response to controlled ovarian stimulation (COS) related to the ongoing pregnancy rate when taking into account the main covariates affecting the probabilities of pregnancy following fresh embryo transfer? SUMMARY ANSWER In patients treated with corifollitropin alfa or daily recombinant FSH (rFSH) in a GnRH-antagonist protocol, a high ovarian response did not compromise ongoing pregnancy rates and increased cumulative pregnancy rates following fresh and frozen-thawed embryo transfer. WHAT IS KNOWN AND WHAT THIS PAPER ADDS A strong association between the number of oocytes and pregnancy rates has been described but this is the first comprehensive analysis assessing important confounders that might affect pregnancy rates. STUDY DESIGN In a large, prospective, double-blind, randomized trial (Engage; n = 1506), patients were treated with either a single dose of 150 μg corifollitropin alfa or daily 200 IU rFSH for the first 7 days of COS in a GnRH-antagonist (ganirelix) protocol. In this retrospective analysis, patients were categorized into five groups according to the number of oocytes retrieved (0-5, 6-9, 10-13, 14-18 and >18 oocytes). The number of good-quality embryos obtained and transferred, as well as the ongoing pregnancy rates, live birth rates and cumulative ongoing pregnancy rates per started cycle by group were evaluated. Univariate analysis was performed to identify factors that predict the chance of ongoing pregnancy. Logistic regression analysis on the dependent variables ongoing pregnancy and cumulative ongoing pregnancy, respectively, including oocyte category as an independent factor in the model, was performed by treatment group (corifollitropin alfa and rFSH) and overall. The likelihood of ongoing pregnancy and cumulative ongoing pregnancy was then evaluated taking into account ovarian response as well as other identified significant predictors of success. PARTICIPANTS AND SETTING In total, 1506 patients had been randomized in a ratio of 1:1 to either of the treatment groups. Patients were aged ≤ 36 years and had a body weight >60 kg. MAIN RESULTS AND THE ROLE OF CHANCE The ongoing pregnancy rates per started cycle increased in the corifollitropin alfa and rFSH groups from 31.9 and 31.3%, respectively, in the lowest response group (0-5 oocytes) to 41.9 and 43.4% in the highest response group (>18 oocytes) with a significant linear trend (P = 0.04). The cumulative pregnancy rates taking frozen-thawed embryo transfers into account increased from 33.0 and 31.3% to 60.8 and 55.9% in the corifollitropin alfa and rFSH groups, respectively. Univariate logistic regression analyses of ongoing pregnancy showed significant effects for the following factors: embryo transfer (double or single, P < 0.01), region of treatment (North America or Europe, P < 0.01), progesterone level on the day of hCG (>1.5 or ≤ 1.5 ng/ml, P < 0.01), start day of the stimulation (cycle day 2 or 3, P = 0.02) and age (P = 0.04). Logistic regression analysis of ongoing pregnancy using 10-13 oocytes as the reference category, per treatment group and overall revealed estimated odds ratios (OR) close to 1.0 versus the reference, without statistically significant differences with and without adjustment for significant predictive factors affecting pregnancy rates. Unadjusted OR for cumulative pregnancy reflected significantly lower odds of pregnancy for the lowest response group and significantly higher odds of pregnancy for the highest response group in comparison with the reference. When adjusted for the predictive factors, the cumulative ongoing pregnancy OR (95% confidence interval) of the highest response group versus the reference group was 1.87 (1.34-2.59) when the data of both treatment groups were pooled. BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION The number of covariates included in the final model was limited to five major factors and not all other potentially significant predictive factors were available for evaluation. GENERALIZABILITY TO OTHER POPULATIONS This analysis is limited to IVF patients with a regular menstrual cycle up to 36 years of age and a body weight >60 and ≤ 90 kg treated with a GnRH-antagonist protocol and cannot be extrapolated to other patient populations or treatment regimens.

Prognostic models for high and low ovarian responses in controlled ovarian stimulation using a GnRH antagonist protocol

STUDY QUESTION Can predictors of low and high ovarian responses be identified in patients undergoing controlled ovarian stimulation (COS) in a GnRH antagonist protocol? SUMMARY ANSWER Common prognostic factors for high and low ovarian responses were female age, antral follicle count (AFC) and basal serum FSH and LH. WHAT IS KNOWN ALREADY Predictors of ovarian response have been identified in GnRH agonist protocols. With the introduction of GnRH antagonists to prevent premature LH rises during COS, and the gradual shift in use of long GnRH agonist to short GnRH antagonist protocols, there is a need for data on the predictability of ovarian response in GnRH antagonist cycles. STUDY DESIGN, SIZE, DURATION A retrospective analysis of data from the Engage trial and validation with the Xpect trial. Prognostic models were constructed for high (>18 oocytes retrieved) and low (<6 oocytes retrieved) ovarian response. Model building was based on the recombinant FSH (rFSH) arm (n = 747) of the Engage trial. Multivariable logistic regression models were constructed in a stepwise fashion (P < 0.15 for entry). Validation based on calibration was performed in patients with equivalent treatment (n = 199) in the Xpect trial. PARTICIPANTS/MATERIALS, SETTING, METHODS Infertile women with an indication for COS prior to IVF. The Engage and Xpect trials included patients of similar ethnic origins from North America and Europe who had regular menstrual cycles. The main causes of infertility were male factor, tubal factor and endometriosis. MAIN RESULTS AND THE ROLE OF CHANCE In the Engage trial, 18.3% of patients had a high and 12.7% had a low ovarian response. Age, AFC, serum FSH and serum LH at stimulation Day 1 were prognostic for both high and low ovarian responses. Higher AFC and LH were associated with an increased chance of high ovarian response. Older age and higher FSH correlated with an increased chance of low ovarian response. Region (North America/Europe) and BMI were prognostic for high ovarian response, and serum estradiol at stimulation Day 1 was associated with low ovarian response. The area under the receiver operating characteristic (ROC) curve (AUC) for the model for a high ovarian response was 0.82. Sensitivity and specificity were 0.82 and 0.73; positive and negative predictive values were 0.40 and 0.95, respectively. The AUC for the model for a low ovarian response was 0.80. Sensitivity and specificity were 0.77 and 0.73, respectively; positive and negative predictive values were 0.29 and 0.96, respectively. In Xpect, 19.1% of patients were high ovarian responders and 16.1% were low ovarian responders. The slope of the calibration line was 0.81 and 1.35 for high and low ovarian responses, respectively, both not statistically different from 1.0. In summary, common prognostic factors for high and low ovarian responses were female age, AFC and basal serum FSH and LH. Simple multivariable models are presented that are able to predict both a too low or too high ovarian response in patients treated with a GnRH antagonist protocol and daily rFSH. LIMITATIONS, REASONS FOR CAUTION Anti-Müllerian hormone was not included in the prediction modelling. WIDER IMPLICATIONS OF THE FINDINGS The findings will help with the identification of patients at risk of a too high or too low ovarian response and individualization of COS treatment. STUDY FUNDING/COMPETING INTERESTS Financial support for this study and the editorial work was provided by Merck, Sharp & Dohme Corp. (MSD), a subsidiary of Merck & Co. Inc., Whitehouse Station, NJ, USA. F.J.B. received a grant from CVZ to his institution; P.J.M.V. and H.W. are employees of MSD, and B.M.J.L.M. was an employee of MSD at the time of development of this manuscript. TRIAL REGISTRATION NUMBERS NCT 00696800 and NCT00778999.

No association between endogenous LH and pregnancy in a GnRH antagonist protocol: part II, recombinant FSH

The association between endogenous LH concentrations during ovarian stimulation in a gonadotrophin-releasing hormone (GnRH) antagonist protocol and pregnancy likelihood was examined in a large combined analysis of individualized patient data obtained after treatment with recombinant FSH and a GnRH antagonist prior to IVF/intracytoplasmic sperm injection. Data from 1764 patients from six randomized controlled trials were pooled for retrospective analysis. Ongoing pregnancy and miscarriage rates for patients stratified by LH percentiles were assessed. Patients in the lowest LH quartile (< P25) were younger with a higher predicted ovarian reserve and response compared with patients in the highest quartile (> P75). With adjustment for identified predictive factors of pregnancy, estimated odds ratios (95% confidence interval) for ongoing pregnancy for LH categories < P25 versus ≥ P25, > P75 versus ≤ P75 and < P25 versus > P75 were 0.96 (0.75-1.22), 1.13 (0.88-1.45) and 0.89 (0.66-1.21) on stimulation day 8, and 0.96 (0.76-1.21), 1.03 (0.82-1.30) and 0.95 (0.72-1.26) on the day of human chorionic gonadotrophin, respectively. No significant differences in pregnancy or miscarriage rates between the LH categories were observed. Endogenous LH concentrations have no association with the likelihood of ongoing pregnancy in women undergoing ovarian stimulation using a recombinant FSH/GnRH antagonist protocol.

Large, comparative, randomized double-blind trial confirming noninferiority of pregnancy rates for corifollitropin alfa compared with recombinant follicle-stimulating hormone in a gonadotropin-releasing hormone antagonist controlled ovarian stimulation protocol in older patients undergoing in vitro fertilization

OBJECTIVE To compare corifollitropin alfa with recombinant FSH treatment in terms of the vital pregnancy rate in older patients undergoing IVF. DESIGN Phase 3 randomized, double-blind, noninferiority trial. SETTING Multicenter trial. PATIENT(S) A total of 1,390 women aged 35-42 years. INTERVENTION(S) A single injection of 150 μg of corifollitropin alfa or daily 300 IU of recombinant FSH for the first 7 days then daily recombinant FSH until three follicles reach ≥17 mm in size. Ganirelix was started on stimulation day 5 up to and including the day of recombinant hCG administration. If available, two good quality embryos were transferred on day 3. MAIN OUTCOME MEASURE(S) Vital pregnancy rate (PR), number of oocytes, and live birth rate. RESULT(S) Vital PRs per started cycle were 23.9% in the corifollitropin alfa group and 26.9% in the recombinant FSH group, with an estimated difference (95% confidence interval) of -3.0% (-7.4 to 1.4). The mean (SD) number of recovered oocytes per started cycle was 10.7 (7.2) and 10.3 (6.8) in the corifollitropin alfa and the recombinant FSH groups, respectively, with an estimated difference of 0.5 (-0.2 to 1.2). The live birth rates per started cycle were 21.3% in the corifollitropin alfa group and 23.4% in the recombinant FSH group, with an estimated difference (95% confidence interval) -2.3% (-6.5 to 1.9). The incidence of serious adverse events was 0.4% versus 2.7% in the corifollitropin alfa and recombinant FSH groups, respectively, and of ovarian hyperstimulation syndrome (OHSS; all grades) was 1.7% in both groups. CONCLUSION(S) Treatment with corifollitropin alfa was proven noninferior to daily recombinant FSH with respect to vital PRs, number of oocytes retrieved, and live birth rates, and was generally well tolerated. CLINICAL TRIAL REGISTRATION NUMBER NCT01144416.

Corifollitropin alfa in a long GnRH agonist protocol: proof of concept trial

Fifty healthy women, aged 18-39 years with no known risk of ovarian hyperstimulation were treated with 100 or 150 μg corifollitropin alfa (dependent on body weight) in a long GnRH agonist protocol. At these doses, corifollitropin alfa initiated and supported growth of a large cohort of follicles during the first week of ovarian stimulation.

No association between endogenous LH and pregnancy in a GnRH antagonist protocol: part I, corifollitropin alfa

The relationship between endogenous LH concentrations and ongoing pregnancy rates among normogonadotrophic patients undergoing ovarian stimulation in a gonadotrophin-releasing hormone antagonist protocol were examined. In the Engage trial, 1506 patients received corifollitropin alfa (150 μg) or daily recombinant FSH (rFSH) (200 IU) for the first 7 days of stimulation with 0.25mg ganirelix from stimulation day 5. Patients were retrospectively stratified by serum LH percentiles (< 25th, 25th-75th and >75th) on stimulation day 8 and day of human chorionic gonadotrophin administration. Odds ratios (OR) with and without adjustment for predictive factors for ongoing pregnancy were estimated. LH concentration was not associated with pregnancy rates in either treatment arm, in contrast to ovarian response and serum progesterone. With adjustment for these predictors and age, OR (95% confidence interval) for ongoing pregnancy on stimulation day 8 for LH categories < P25 versus ≥ P25, >P75 versus ≤ P75 and < P25 versus >P75 were 0.75 (0.53-1.06), 1.26 (0.87-1.83) and 0.70 (0.46-1.09) in the corifollitropin alfa arm and 0.80 (0.54-1.17), 1.28 (0.87-1.87) and 0.73 (0.46-1.16) in the rFSH arm respectively. There was also no significant difference in pregnancy rates between LH categories on day of human chorionic gonadotrophin administration with either treatment.

LH concentrations do not correlate with pregnancy in rFSH/GnRH antagonist cycles

The possible relationship between endogenous LH concentrations and clinical outcome was evaluated in 750 patients treated with a standardized gonadotrophin-releasing hormone (GnRH) antagonist and recombinant FSH (rFSH)-only protocol. Serum LH concentrations were measured during stimulation by a central laboratory and patients were stratified into quantiles of <P25, P25-P75, and >P75. The P25 values were 3.38 IU/l, 0.93 IU/l, and 0.91 IU/l on stimulation days 1, 5, and 8, respectively. The ongoing pregnancy rates per started cycle of patients within the <P25 subset on stimulation day 1, 5, or 8 were highly similar to those in the P25-P75, and >P75 subsets and ranged in the various subsets between 35.0% and 39.5%. In keeping with previous, smaller studies, these findings demonstrate that in good prognosis, non-obese patients endogenous LH in a GnRH antagonist protocol is able to support treatment with rFSH only.

A randomized controlled trial of the GnRH antagonist ganirelix in Chinese normal responders: high efficacy and pregnancy rates

Gonadotropin-releasing hormone (GnRH) antagonists for controlled ovarian stimulation (COS) were only recently introduced into China. The efficacy and safety of the GnRH antagonist ganirelix was assessed in a multicenter, controlled, open-label study, in which Chinese women were randomized to either ganirelix (n = 113) or a long GnRH agonist protocol of triptorelin (n = 120). The primary end point was the amount of recombinant follicle-stimulating hormone (rFSH) required to meet the human chorionic gonadotropin criterion (three follicles ≥17 mm). The amount of rFSH needed was significantly lower for ganirelix (1272 IU) vs. triptorelin (1416 IU; P< 0.001). Ongoing pregnancy rates per started cycle were 39.8% (ganirelix) and 39.2% (triptorelin). Although both treatments were well tolerated, cancellation due to risk of ovarian hyperstimulation syndrome (OHSS) was less frequent with ganirelix (1.8%) than triptorelin (7.5%) (P = 0.06). Less rFSH was needed in the ganirelix protocol than the long GnRH agonist protocol, with fewer reported cases of OHSS and similar pregnancy rates.

A comparison of live birth rates and cumulative ongoing pregnancy rates between Europe and North America after ovarian stimulation with corifollitropin alfa or recombinant follicle-stimulating hormone

OBJECTIVE To compare live birth rates after fresh embryo transfer (ET) and cumulative ongoing pregnancy rates after fresh ET and frozen-thawed (ET) between continents and overall after one treatment cycle with corifollitropin alfa or recombinant FSH. DESIGN Double-blind, multicenter, randomized controlled trial. SETTING Fourteen centers in North America (NA); 20 in Europe (EU). PATIENT(S) 804 NA patients and 702 EU patients. INTERVENTION(S) Patients >60 kg received a single dose of corifollitropin alfa or daily rFSH for the first 7 days of controlled ovarian stimulation. MAIN OUTCOME MEASURE(S) Live birth rates. RESULT(S) Within each continent no differences were noted between the two treatment groups; however, between continents, the cumulative ongoing pregnancy rate and live birth rate were considerably higher in NA than in EU. The live birth rate in NA was 39.2% in both treatment groups compared with 31.5% and 28.8% in EU after corifollitropin alfa and rFSH treatment, respectively. Considering the number of embryos transferred, the live birth rate per ET was still higher in NA than in EU (42.7% v.s 36.8% with corifollitropin alfa and 41.6% vs. 30.9% with rFSH). Overall live birth rates after fresh ET were 35.6% and 34.4% (estimated difference 1.1% [95% confidence interval -3.7-5.8]), and the estimated cumulative live birth rates were 43.4% and 41.3% with corifollitropin alfa and rFSH, respectively. CONCLUSION(S) Live birth rates and cumulative pregnancy rates were higher in NA than in EU after treatment with either corifollitropin alfa or daily rFSH; both treatment protocols provided equal success rates. CLINICALTRIALS.GOV IDENTIFIERS: NCT00703014 and NCT00702273.