Follicular flushing increases the number of oocytes retrieved: a randomized controlled trial.

STUDY QUESTION: Does follicular flushing increase the number of cumulus-oocyte complexes (COCs) retrieved compared to single aspiration? SUMMARY ANSWER: Follicular flushing significantly increases the number of COCs retrieved compared to single aspiration. WHAT IS KNOWN ALREADY: On the basis of published meta-analyses, follicular flushing does not seem to increase the number of oocytes retrieved, the probability of clinical pregnancy, or that of live birth and has been associated with an increase in the duration of oocyte retrieval. It should be noted, however, that all the eligible randomized controlled trials (RCTs) in these meta-analyses have randomized patients into either single aspiration or follicular flushing. This study design might not allow the detection of the true effect of follicular flushing. Despite randomization, this might still be obscured, to an extent, by heterogeneity in patients, stimulation characteristics, and differences in the oocyte retrieval procedure. STUDY DESIGN, SIZE, DURATION: A prospective, single centre, RCT, including 105 patients was performed between July and December 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligible patients were those undergoing oocyte retrieval for ICSI, aged <43 years, with BMI 18-35 kg/m2. Patients with all types of ovarian response (low-normal-high), as assessed on the day of triggering final oocyte maturation, were included. Random allocation of the ovaries of each patient to either single aspiration or follicular flushing was performed on the day of oocyte retrieval, using a computer-generated randomization list. Patients could enter the study only once. All follicles from ovaries allocated to either follicular flushing or single aspiration, were aspirated by the same 16G double lumen needle, with a constant aspiration pressure of 190 mmHg, resulting in flow rate of 0.42 ml/s. In the ovaries allocated to the follicular flushing group, if a COC was not recovered in the initial aspirate of each follicle, follicular flushing was performed until a COC was retrieved, up to a maximum of five times. The primary outcome measure was the number of COCs retrieved. Secondary outcomes were oocyte recovery rate, oocyte maturation rate, fertilization rate, and rate of good quality embryos on Day 2. Values are expressed as a median (inter-quartile range). MAIN RESULTS AND THE ROLE OF CHANCE: Significantly more COCs were retrieved in the follicular flushing as compared to the single aspiration group in all patients [5 (7) vs 2 (3), P < 0.001, respectively], as well as in patients with high [9 (3) vs 5 (4), P < 0.001, respectively], normal [5 (2) vs 2 (3), P < 0.001, respectively] and low [1 (1) vs 1 (1), P < 0.001, respectively] ovarian response. In patients with low ovarian response, no COCs were retrieved in 5.7% of the ovaries in the flushing group vs 42.8% of the ovaries in the single aspiration group (P < 0.001). The oocyte retrieval rate was significantly higher in the follicular flushing vs the single aspiration group, in all patients [88.9% (25.0) vs 45.5% (37.5), P < 0.001, respectively], as well as in patients with high [81.8% (15.9) vs 45.5% (22.2), P < 0.001, respectively], normal [85.7% (28.6) vs 40.0% (30.0), P < 0.001, respectively], and low [100% (0) vs 50.0% (100), P < 0.001, respectively] ovarian response. No significant difference was observed regarding maturation rate [85.2% (30.8) vs 100% (33.3), P = 0.78], fertilization rate [76.4% (50) vs 83.3% (50) P = 0.42], and the proportion of good quality embryos on Day 2 [83.3% (40) vs 100% (50), P = 0.62]. Similarly, no differences in the above variables were observed in patients with different types of ovarian response. Follicular flushing as compared to single aspiration was associated with a significant increase in the duration of oocyte retrieval in all patients [248 s (332) vs 135 s (164), respectively], as well as in patients with high [464 s (225) vs 237 s (89), P < 0.001, respectively], normal [248 s (108) vs 141 s (95), P < 0.001, respectively], and low [64 s (59) vs 48 s (10), P < 0.001, respectively] ovarian response. LIMITATIONS, REASONS FOR CAUTION: Although the current study design allows for a more accurate evaluation of the true effect of follicular flushing on the number of COCs retrieved, it does not permit the evaluation of its role on the probability of pregnancy. WIDER IMPLICATIONS OF THE FINDINGS: This is the first RCT to suggest that follicular flushing increases the number of COCs retrieved compared to single aspiration, independently of ovarian response. This implies that follicular flushing plays an important role in the optimization of oocyte retrieval. These results, however, need to be confirmed in future studies, in which an equal flow rate should be used during oocyte retrieval. STUDY FUNDING/COMPETING INTEREST(S): No external funding was obtained for this study. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: NCT05473455. TRIAL REGISTRATION DATE: 15 July 2022. DATE OF FIRST PATIENT'S ENROLMENT: 27 July 2022.

Patient burden and healthcare resource utilization of regimens for ovarian stimulation.

RESEARCH QUESTION: Do women receiving corifollitropin alfa with a gonadotrophin-releasing hormone (GnRH) antagonist experience less emotional and/or physical exhaustion than women receiving standard of care gonadotrophin with daily administration of GnRH agonist or antagonist? DESIGN: The CoRifollitropin EvAluation in PracTicE (CREATE) study was a prospective observational study of fertility clinics in 17 countries in Europe and the Asia-Pacific region. Women undergoing IVF were categorized by treatment. Group A received single-dose corifollitropin alfa plus a GnRH antagonist; group B received usual care daily gonadotrophin regimens with a GnRH agonist or antagonist; and group B1i received daily GnRH agonist injections. For the primary analysis, two items from the Controlled Ovarian Stimulation Impact questionnaire were used to assess the level of emotional and physical exhaustion associated with ovarian stimulation. Secondary end-points included the impact of ovarian stimulation-related healthcare resource use. RESULTS: No statistical difference was found between the percentage of participants reporting emotional exhaustion in group A (11.6%) and B (13.1%) or the percentage reporting being 'often' or 'always' physically exhausted. More participants in group B1i (16.4%) reported being emotionally exhausted 'often' or 'always' during ovarian stimulation compared with group A (11.6%; P = 0.026). Patient questionnaire scores for psychological impact were higher in group A compared with group B, indicating less negative impact (72.7 versus 70.9; P = 0.004). Group A had fewer clinic visits, physician consultations, nurse contacts and transvaginal ultrasound scans (all P < 0.001) than group B1. CONCLUSIONS: Treatment with corifollitropin alfa resulted in similar or numerically small differences in psychological impact and lower clinic service use compared with daily gonadotrophin regimens.

Is the probability of pregnancy after ovarian stimulation for IVF associated with serum estradiol levels on the day of triggering final oocyte maturation with hCG? A systematic review and meta-analysis.

PURPOSE: The objective of this systematic review and metaanalysis was to examine if the probability of pregnancy after ovarian stimulation for in vitro fertilization (IVF), using GnRH analogues and gonadotrophins is associated with serum estradiol level (Ε2) on the day of triggering final oocyte maturation with human chorionic gonadotrophin (hCG). METHODS: Twenty-one studies were eligible for this systematic review, including 19,598 IVF cycles, whereas three studies were eligible for metaanalysis, including 641 IVF cycles. The main outcome measure was achievement of ongoing pregnancy/live birth and, if not available, clinical pregnancy or biochemical pregnancy. RESULTS: Pooling of data showed no differences in the probability of clinical pregnancy between patients with high and low Ε2 levels on the day of triggering final oocyte maturation. The pooled effect sizes for the Ε2 thresholds groups constructed, regarding clinical pregnancy were 2000-3000 pg/mL-OR 0.91, 95% CI 0.55 to 1.50, (fair quality/moderate risk of bias, n = 1 study), 3000-4000 pg/mL-OR 0.89, 95% CI 0.46 to 1.70, (fair quality/moderate risk of bias, n = 1 study, good quality/no information on which to base a judgement about risk of bias n = 2 studies), 4000-5000 pg/mL-OR 0.74, 95% CI 0.37 to 1.49 fair quality/moderate risk of bias, n = 1 study), 5000-6000 pg/mL-OR 0.62, 95% CI 0.19 to 1.98, (fair quality/moderate risk of bias, n = 1 study). In addition, no difference was observed in the probability of ongoing pregnancy for the Ε2 threshold group of 3000-4000 pg/mL OR 0.85, 95% CI 0.40 to 1.81(good quality/no information on which to base a judgement about risk of bias, n = 1 study). CONCLUSION: Currently, there is insufficient evidence to support or deny the presence of an association between the probability of pregnancy and serum Ε2 levels on the day of triggering final oocyte maturation with hCG in women undergoing ovarian stimulation for IVF.

Higher probability of live-birth in high, but not normal, responders after first frozen-embryo transfer in a freeze-only cycle strategy compared to fresh-embryo transfer: a meta-analysis.

STUDY QUESTION: Does the outcome of the comparison of live birth rates between the first frozen embryo transfer (ET) (in a freeze-only cycles strategy, i.e. frozen ET group) and a fresh embryo transfer (fresh ET group) differ considering the type of ovarian response? SUMMARY ANSWER: Α significantly higher probability of live birth is present in high, but not normal, responders, after the first frozen ET in a freeze-only cycle strategy as compared to a fresh ET. WHAT IS KNOWN ALREADY: It has been hypothesised that freezing all good embryos in a fresh in-vitro fertilisation (IVF) cycle and deferring embryo transfer in subsequent cycles may provide a more physiological endometrial environment for embryo implantation when compared to a fresh ET. However, currently, three relevant meta-analyses have been published with conflicting results, while none of them has taken into consideration the type of ovarian response. Recently, the publication of additional, large relevant randomised controlled trials (RCTs) in patients with different types of ovarian response makes possible the comparative evaluation of the first frozen ET (in a freeze-only cycle strategy) versus fresh ET, considering the type of ovarian response. STUDY DESIGN, SIZE, DURATION: A systematic review and meta-analysis was performed aiming to identify RCTs comparing the first frozen ET (in a freeze-only cycle strategy) to a fresh ET. The main outcome was live birth, while secondary outcomes included ongoing pregnancy, clinical pregnancy, moderate/severe ovarian hyperstimulation syndrome (OHSS) and miscarriage. PARTICIPANTS/MATERIALS, SETTING, METHODS: We identified eight eligible RCTs, including 5265 patients, which evaluated the first frozen ET in a freeze-only cycle strategy versus a fresh ET either in high responders (n = 4) or in normal responders (n = 4). No relevant RCTs were present in poor responders. Meta-analysis of weighted data using fixed and random effects model was performed. Results are reported as relative risk (RR) with 95% confidence interval (CI). MAIN RESULTS AND THE ROLE OF CHANCE: Eligible RCTs were published between 2011 and 2018. Four RCTs (n = 3255 patients) compared the first frozen ET (in a freeze-only cycle strategy) to a fresh ET in normal responders and four RCTs (n = 2010 patients) did the comparison in high responders. In high responders, a significantly higher probability of live birth was observed in the frozen ET group when compared with the fresh ET group (RR: 1.18, 95% CI: 1.06-1.31; fixed effects model; heterogeneity: I2 = 0%; three studies; n = 3398 patients). However the probability of live birth was not significantly different between the frozen ET group and the fresh ET group in normal responders (RR: 1.13, 95% CI: 0.90-1.41; random effects model; heterogeneity: I2 = 77%; three studies; n = 1608 patients). The risk of moderate/severe OHSS was significantly lower in the frozen ET group when compared with the fresh ET group both in high (RR: 0.19, 95% CI: 0.10-0.37; fixed effects model; heterogeneity: not applicable; a single study; n = 1508 patients) and normal responders (RR: 0.39, 95% CI: 0.19-0.80; fixed effects model; heterogeneity: I2 = 0%; two studies; n = 2939 patients). LIMITATIONS, REASONS FOR CAUTION: Considerable heterogeneity was present among the studies, regarding ovarian stimulation protocols and the triggering signal used for inducing final oocyte maturation as well as the cryopreservation methods, while the quality of evidence was poor for the live birth rate in high responders. Moreover, the analysis did not apply a standard for determining 'high' or 'normal' responders since the type of ovarian response followed the characterisation of populations as reported by the authors of the eligible studies. WIDER IMPLICATIONS OF THE FINDINGS: A freeze-only cycle strategy should be the preferred option in high responders since it enhances the probability of live birth, while reducing the chance of moderate/severe OHSS. In normal responders, the same strategy could be applied, in the interest of patient safety or clinic convenience, without compromising the chances of live birth. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used and there were no competing interests. PROSPERO REGISTRATION NUMBER: PROSPERO registration number: CRD42018099389.

Is oocyte maturation rate associated with triptorelin dose used for triggering final oocyte maturation in patients at high risk for severe ovarian hyperstimulation syndrome?

STUDY QUESTION: Are oocyte maturation rates different among 0.1, 0.2 and 0.4 mg triptorelin used for triggering final oocyte maturation in patients at high risk for ovarian hyperstimulation syndrome (OHSS) undergoing ICSI? SUMMARY ANSWER: A dose of 0.1 mg triptorelin results in similar oocyte maturation rates compared to higher doses of 0.2 and 0.4 mg in patients at high risk for OHSS undergoing ICSI. WHAT IS KNOWN ALREADY: The GnRH agonist triptorelin is widely used instead of hCG for triggering final oocyte maturation, in order to eliminate the risk of severe OHSS in patients undergoing ovarian stimulation for IVF/ICSI. However, limited data are currently available regarding its optimal dose use for this purpose in patients at high risk for OHSS. STUDY DESIGN, SIZE, DURATION: A retrospective study was performed between November 2015 and July 2017 in 131 infertile patients at high risk for severe OHSS undergoing ovarian stimulation for ICSI. High risk for severe OHSS was defined as the presence of at least 19 follicles ≥11 mm in diameter on the day of triggering final oocyte maturation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian stimulation was performed with recombinant FSH and GnRH antagonists. Patients received 0.1 (n = 42), 0.2 (n = 46) or 0.4 mg (n = 43) triptorelin for triggering final oocyte maturation. Hormonal evaluation of FSH, LH, estradiol (E2) and progesterone (PRG) was carried out on the day of triggering final oocyte maturation, 8 and 36 hours post triggering and 3, 5, 7, and 10 days after triptorelin administration. During this period, all patients were assessed for symptoms and signs indicative of severe OHSS development. Primary outcome measure was oocyte maturation rate, defined as the number of metaphase II (MII) oocytes divided by the number of cumulus-oocyte-complexes retrieved per patient. Results are expressed as median (interquartile range). MAIN RESULTS AND THE ROLE OF CHANCE: No significant differences in patient baseline characteristics were observed among the 0.1 mg, the 0.2 mg and the 0.4 mg groups. Regarding the primary outcome measure, no differences were observed in oocyte maturation rate among the three groups compared [82.6% (17.8%) versus 83.3% (18.8%) versus 85.1% (17.2%), respectively, P = 0.686].In addition, no significant differences were present among the 0.1 mg, 0.2 mg and 0.4 mg groups, regarding the number of mature (MII) oocytes [21 (13) versus 20 (6) versus 20 (11), respectively; P = 0.582], the number of oocytes retrieved [25.5 (13) versus 24.5 (11) versus 23 (12), respectively; P = 0.452], oocyte retrieval rate [81.0% (17.7%) versus 76.5% (23.5%) versus 75.0% (22.5), respectively; P = 0.088], the number of fertilized (two pronuclei) oocytes [12.5 (9) versus 14.5 (7) versus 14.0 (8), respectively; P = 0.985], fertilization rate [71.7% (22%) versus 77.1% (19.1%) versus 76.6% (23.3%), respectively; P = 0.525] and duration of luteal phase [7 (1) versus 8 (2) versus 7 (1) days, respectively; P = 0.632]. Moreover, no significant differences were present among the three triptorelin groups regarding serum levels of LH, FSH, E2 and PRG at any of the time points assessed following triggering of final oocyte maturation. LIMITATIONS, REASONS FOR CAUTION: This is a retrospective study, and although there were no differences in the baseline characteristics of the three groups compared, the presence of bias cannot be excluded. WIDER IMPLICATIONS OF THE FINDINGS: Based on the results of the current study, it appears that triggering final oocyte maturation with a lower (0.1 mg) or a higher dose (0.4 mg) of triptorelin, as compared to the most commonly used dose of 0.2 mg, does not confer any benefit in terms of oocyte maturation rate in patients at high risk for severe OHSS. STUDY FUNDING/COMPETING INTEREST(S): No external funding was obtained for this study. There are no conflicts of interest.

Are singleton pregnancies after assisted reproduction technology (ART) associated with a higher risk of placental anomalies compared with non-ART singleton pregnancies? A systematic review and meta-analysis.

BACKGROUND: Placental anomalies (placenta praevia, placental abruption, morbidly adherent placenta and cord insertion anomalies) are associated with maternal and fetal morbidity and mortality. It has been suggested these might be more prevalent in pregnancies after assisted reproduction technology (ART). OBJECTIVES: To determine whether ART singleton pregnancies are associated with an increased risk of placental anomalies compared with non-ART singleton pregnancies. SEARCH STRATEGY: MEDLINE, EMBASE, CENTRAL, Web of Science and Scopus (January 2018). SELECTION CRITERIA: Cohort studies reporting placental anomalies in ART and non-ART singleton pregnancies. DATA COLLECTION AND ANALYSIS: We report pooled odds ratios (OR) for the comparisons: (1) ART versus SC (spontaneously conceived), (2) ART versus non-ART (unspecified), (3) FET-ART (frozen-embryo transfer) versus SC, (4) ART versus non-ART (subfertile patients). Study quality was assessed using a modified Newcastle -Ottawa scale. MAIN RESULTS: 33 low/moderate quality studies evaluated 124 215 ART and 6 054 729 non-ART singleton pregnancies. Risk of placenta praevia, placental abruption and morbidly adherent placenta was higher in ART than SC pregnancies: odds ratio (OR) (OR 3.76, 95% CI 3.09-4.59); (OR 1.87, 95% CI 1.70-2.06) and (OR 2.27, 95% CI 1.79-2.87) respectively. Risk of placenta praevia and placental abruption was higher in ART than in non-ART (subfertile patients): (OR 2.51, 95% CI 2.12-2.98) and (OR 1.61, 95% CI 1.33-1.95) respectively. Results were similar when comparing ART with unspecified non-ART pregnancies. Risk of placenta praevia was higher, but not significantly so, in FET-ART than in SC pregnancies (OR 2.42, 95% CI 0.63-9.30). CONCLUSIONS: Singleton ART pregnancies are associated with an increased risk of placental anomalies compared with non-ART singleton pregnancies. TWEETABLE ABSTRACT: A review of over 6 million singleton pregnancies finds increased risk of placental anomalies after ART.

Ultrasound and hematological changes during early luteal phase in women at high risk for developing ovarian hyperstimulation syndrome.

OBJECTIVE: To assess ultrasound and hematological changes during the early luteal phase following triggering of final oocyte maturation with human chorionic gonadotropin (hCG) in women at high risk for developing ovarian hyperstimulation syndrome (OHSS). METHODS: This was a retrospective cohort study of 319 women undergoing in-vitro fertilization who were at high risk for OHSS following administration of hCG for the triggering of final oocyte maturation. Patients were treated with a gonadotropin-releasing hormone agonist or antagonist protocol and were monitored for 5 days post-oocyte retrieval (early luteal phase). Severe OHSS was diagnosed in the presence of at least moderate ascites and two or more of the following: maximum ovarian diameter (MOD) > 100 mm, hematocrit (Ht) > 45%, white blood cell count (WBC) > 15 000/mm3 , hydrothorax, dyspnea and oliguria. Outcome measures included change in Ht, ascites grade, WBC and MOD, as well as the association between these changes during the early luteal phase. RESULTS: Ascites grade, Ht and WBC increased significantly (P ≤ 0.001) during the early luteal phase, both in patients who developed and in those who did not develop severe early OHSS. MOD increased significantly (P = 0.001) only in patients who developed severe early OHSS. On multivariable analysis, both time following oocyte retrieval and whether severe early OHSS developed were significantly associated with ascites grade, Ht, WBC and MOD; furthermore, there was also a significant interaction between time and development of severe early OHSS for all four variables (P ≤ 0.001). CONCLUSIONS: In women at high risk of OHSS, ascites grade, Ht and WBC significantly increased with time over the 5-day observation period, in line with the pathophysiology of the syndrome. Our data support the use of MOD in the diagnosis of severe early OHSS, and provide novel evidence for the role of change in Ht as a patient-specific hemoconcentration marker during development of OHSS. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Transdermal testosterone pretreatment in poor responders undergoing ICSI: a randomized clinical trial.

STUDY QUESTION: Does pretreatment with transdermal testosterone increase the number of cumulus-oocyte complexes (COCs) retrieved by more than 1.5 in poor responders undergoing intracytoplasmic sperm injection (ICSI), using recombinant follicle stimulating hormone (FSH) and gonadotrophin releasing hormone agonists (GnRHa)? SUMMARY ANSWER: Testosterone pretreatment failed to increase the number of COCs by more than 1.5 as compared with no pretreatment in poor responders undergoing ICSI (difference between medians: 0.0, 95% CI: -1.0 to +1.0). WHAT IS KNOWN ALREADY: Androgens are thought to play an important role in early follicular development by enhancing ovarian sensitivity to FSH. In a recent meta-analysis, testosterone pretreatment resulted in an increase of 1.5 COCs as compared with no pretreatment. However, this effect was based on the analysis of only two randomized controlled trials (RCTs) including 163 patients. Evidently, there is a need for additional RCTs that will allow firmer conclusions to be drawn. STUDY DESIGN, SIZE, DURATION: The present RCT was designed to detect a difference of 1.5 COCs (sample size required = 48 patients). From 02/2014 until 04/2015, 50 poor responders fulfilling the Bologna criteria have been randomized (using a randomization list) to either testosterone pretreatment for 21 days ( ITALIC! n = 26) or no pretreatment ( ITALIC! n = 24). PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients underwent a long follicular GnRHa protocol. Recombinant FSH stimulation was started on Day 22 following GnRHa initiation. In the testosterone pretreatment group, a daily dose of 10 mg of testosterone gel was applied transdermally for 21 days starting from GnRHa initiation. Results are expressed as median (interquartile range). MAIN RESULTS AND THE ROLE OF CHANCE: No differences in baseline characteristics were observed between the two groups compared. Testosterone levels [median (interquartile range)] were significantly higher in the testosterone pretreatment on the day of initiation of FSH stimulation [114 (99.5) ng/dl versus 20 (20) ng/dl, respectively, ITALIC! P < 0.001]. Duration of FSH stimulation [median (interquartile range)] was similar between the groups compared [12.5 (3.0) days versus 12 (3.0) days, respectively, ITALIC! P = 0.52]. The number of COCs retrieved [median (interquartile range)] was not different between the testosterone pretreatment and the no pretreatment groups [3.5 (4.0) versus 3.0 (3.0), 95% CI for the median: 2.0-5.0 versus 2.7-4.3, respectively; difference between medians: 0.0, 95% CI: +1.0 to -1.0). Similarly no differences were observed regarding fertilization rates [median (interquartile range)] [66.7% (32.5) versus 66.7% (42.9), respectively, ITALIC! P = 0.97] and live birth rates per randomized patient (7.7% versus 8.3%, respectively, rate difference: -0.6%, 95% CI: -19.0 to +16.9). LIMITATIONS, REASONS FOR CAUTION: The study was not powered to detect differences less than 1.5 COCs, although it is doubtful whether these differences would be clinically relevant. Moreover, due to sample size restrictions, no conclusions can be drawn regarding the probability of live birth. WIDER IMPLICATIONS OF THE FINDINGS: The results of this randomized clinical trial, suggesting that pretreatment with 10 mg of transdermal testosterone for 21 days does not improve ovarian response by more than 1.5 oocytes, could be used to more accurately consult patients with poor ovarian response. However, an improvement in IVF outcome using a higher dose of testosterone or a longer pretreatment period cannot be excluded. STUDY FUNDING/COMPETING INTEREST: The study was partially funded by a Scholarship from the Academy of Athens. C.A.V. reports personal fees and non-financial support from Merck, Sharp and Dome, personal fees and non-financial support from Merck Serono, personal fees and non-financial support from IPSEN Hellas S.A., outside the submitted work. B.C.T. reports grants from Merck Serono, grants from Merck Sharp & Dohme, personal fees from Merck Serono, personal fees from Merck Sharp & Dohme, personal fees from IBSA & Ferring, outside the submitted work. TRIAL REGISTRATION NUMBER: NCT01961336. TRIAL REGISTRATION DATE: 10 October 2013. DATE OF FIRST PATIENT'S ENROLLMENT: 02/2014.

Corifollitropin alfa compared with follitropin beta in poor responders undergoing ICSI: a randomized controlled trial.

STUDY QUESTION: Does substituting 150 µg corifollitropin alfa for 450 IU follitropin beta during the first 7 days of ovarian stimulation in proven poor responders, result in retrieval of a non-inferior number (<1.5 fewer) of cumulus oocyte complexes (COCs)? SUMMARY ANSWER: A single s.c. dose of 150 µg corifollitropin alfa on the first day of ovarian stimulation, followed if necessary, from Day 8 onwards, with 450 IU of follitropin beta/day, is not inferior to daily doses of 450 IU follitropin beta. The 95% CI of the difference between medians in the number of oocytes retrieved was -1 to +1 within the safety margin of 1.5. WHAT IS KNOWN ALREADY: Recent data from retrospective studies suggest that the use of corifollitropin alfa in poor responders is promising since it could simplify ovarian stimulation without compromising its outcome. STUDY DESIGN, SIZE, DURATION: Seventy-nine women with previous poor ovarian response undergoing ICSI treatment were enrolled in this open label, non-inferiority, randomized clinical trial (RCT). PARTICIPANTS/MATERIALS, SETTING, METHODS: Inclusion criteria were: previous poor response to ovarian stimulation (≤4 COCs) after maximal stimulation, age <45 years, regular spontaneous menstrual cycle, body mass index: 18-32 kg/m(2) and basal follicle stimulating hormone ≤20 IU/l. On Day 2 of the menstrual cycle, patients were administered either a single s.c dose of 150 µg corifollitropin alfa (n = 40) or a fixed daily dose of 450 IU of follitropin beta (n = 39). In the corifollitropin alfa group, 450 IU of follitropin beta were administered from Day 8 of stimulation until the day of human chorionic gonadotrophin (hCG) administration, if necessary. To inhibit premature luteinizing hormone surge, the gonadotrophin releasing hormone antagonist ganirelix was used. Triggering of final oocyte maturation was performed using 250 µg of recombinant hCG, when at least two follicles reached 17 mm in mean diameter. MAIN RESULTS AND THE ROLE OF CHANCE: The number of COCs retrieved was not statistically different between the corifollitropin alfa and the follitropin beta groups [Median 3 versus 2, 95% CI 2-4, 2-3, respectively, P = 0.26]. The 95% CI of the difference between medians in the number of oocytes retrieved was -1 to +1. A multivariable analysis adjusting for all the potential baseline differences confirmed this finding. No significant difference was observed regarding the probability of live birth between the corifollitropin alfa and the follitropin beta group (live birth per patient reaching oocyte retrieval: 7.9 versus 2.6%, respectively, difference +5.3%, 95% CI: -6.8 to +18.3). LIMITATIONS, REASONS FOR CAUTION: The present study was not powered to test a smaller difference (e.g. 1 COC) in terms of COCs retrieved as well as to show potential differences in the probability of pregnancy. Moreover, it would be interesting to assess whether the continuation of stimulation in the long acting FSH arm, where necessary, with 200 IU instead of 450 IU of follitropin beta would have altered the direction or the magnitude of the effect of the type of FSH, observed on the number of COCs retrieved. WIDER IMPLICATIONS OF THE FINDINGS: Corifollitropin alfa simplifies IVF treatment because it is administered in a GnRH antagonist protocol and replaces seven daily FSH injections with a single one of a long acting FSH without compromising the outcome. It could greatly reduce the burden of treatment for poor responders and this deserves further investigation.