Pretreatment with luteal estradiol for programming antagonist cycles compared to no pretreatment in advanced age women stimulated with corifollitropin alfa: a non-inferiority randomized controlled trial.

STUDY QUESTION: Does luteal estradiol (E2) pretreatment give a similar number of retrieved oocytes compared to no-pretreatment in advanced-aged women stimulated with corifollitropin alfa in an antagonist protocol? SUMMARY ANSWER: Programming antagonist cycles with luteal E2 gave similar number of retrieved oocytes compared to no-pretreatment in women aged 38-42 years. WHAT IS KNOWN ALREADY: Programming antagonist cycles with luteal E2 pretreatment is a valuable tool to organize the IVF procedure better and is safe without any known impact on cycle outcome. However, variable effects were observed on the number of retrieved oocytes depending on the treated population. In advanced-age women, recruitable follicles tend to decrease in number and to be more heterogeneous in size but it remains unclear if estradiol pretreatment could change the oocyte yield through its negative feed-back effect on FSH intercycle rise. STUDY DESIGN, SIZE, DURATION: This non-blinded randomized controlled non-inferiority trial was conducted between 2016 and 2022 with centrally computerized randomization and concealed allocation. Participants were 324 women aged 38-42 years undergoing IVF treatment. The primary endpoint was the total number of retrieved oocytes. Statistical analysis was performed with one-sided alpha risk of 2.5% and 95% confidence interval (CI) with the non-inferiority of E2 pretreatment proved by a P value <0.025 and a lower delta margin of the CI within two oocytes compared to no pretreatment. Secondary endpoints were duration and total dosage of recombinant FSH, cancellation rate, percentage of oocyte pick-up (OPU) on working days, total number of metaphase II oocytes and obtained embryos, fresh transfer live birth rate, and cumulative live birth rate. PARTICIPANTS/MATERIALS, SETTING, METHODS: This multicentric study enrolled women with regular cycles, weight >50 kg and body mass index <32, IVF cycle 1-2. According to randomization, micronized estradiol 2 mg twice a day was started on days 20-24 and continued until Wednesday beyond the onset of menses followed by administration of corifollitropin alfa on Friday, i.e. stimulation (S)1 or from D1-3 of a natural cycle in unpretreated patients. GnRH antagonist was started at S6 and additional FSH at S8. MAIN RESULTS AND THE ROLE OF CHANCE: Basal characteristics were similar in patients randomized in E2 pretreated (n = 164) and non-pretreated (n = 160) groups (intended to treat (ITT) population). A total of 291 patients started treatment (per protocol (PP) population), 147 in E2 pretreated group with a mean number [SD] of pre-treatment days 9.8 [2.6] and 144 in the non-pretreated group. Despite advanced age, oocyte yields ranged from 0 to 29 in both groups with a median number of 6 retrieved oocytes in accordance with a mean anti-Müllerian hormone (AMH) level above 1.2 ng/ml. We demonstrated the non-inferiority of E2 pretreatment with a mean difference of -0.1 oocyte 95% CI [-1.5; 1.3] P = 0.004 in the PP population and a mean difference of -0.44 oocyte [-1.84; 0.97] P = 0.014 in the ITT population. Oocyte retrieval was more often on working days in E2 pretreated patients (91.9 versus 74.2%, P < 0.001). In patients reaching OPU, the duration of stimulation was statistically significantly longer (11.7 [1.7] versus 10.8 [1.8] days, P < 0.001) and the extra FSH dosage in addition to corifollitropin alfa was statistically significantly higher (1040 [548] versus 778 [504] IU, P < 0.001) in E2 pretreated than non-pretreated patients. We did not observe any significant differences in the number of retrieved oocytes (8.4 [6.1] versus 9.1 [6.0]), in the number of Metaphase 2 oocytes (7 [5.5] versus 7.3 [5.2]) nor in the number of obtained embryos (5 [4.6] versus 5.2 [4.2]) in E2 pretreated patients compared to non-pretreated patients. The live birth rate after fresh transfer (16.2% versus 18.5%, respectively), and the cumulative live birth rate per patient (17.7% versus 22.9%, respectively) were similar in both groups. Among the PP population, 31.6% of patients fulfilled the criteria for group 4 of Poseïdon classification (AMH <1.2 ng/ml and/or antral follicle count <5). In this sub-group of patients, we observed in contrast a statistically higher number of retrieved oocytes in E2 pretreated patients compared to non-pretreated (5.1 [3.8] versus 3.4 [2.7], respectively, the mean difference of +1.7 oocyte [0.2; 3.2] P = 0.022) but without significant difference in the cumulative live birth rate per patient (15.7% versus 7.3%, respectively). LIMITATIONS, REASONS FOR CAUTION: Our stimulated women older than 38 years obtained a wide range of collected oocytes suggesting very different stages of ovarian aging in both groups. E2 pretreatment is more likely to increase oocyte yield at the stage of ovarian aging characterized by asynchrony of a reduced follicular cohort. Another limitation is the sample size in sub-group analysis of patients with AMH <1.2 ng/ml. Finally, the absence of placebo for pretreatment could also introduce possible bias. WIDER IMPLICATIONS OF THE FINDINGS: Programming antagonist cycles with luteal E2 pretreatment seems a useful tool in advanced age women to better schedule oocyte retrievals on working days. However, the potential benefit of the number of collected oocytes remains to be demonstrated in a larger population displaying the characteristics of decreased ovarian reserve encountered in Poseïdon classification. STUDY FUNDING/COMPETING INTEREST(S): Research grant from (MSD) Organon, France. I.C., S.D., B.B., X.M., S.G., and C.J. have no conflict of interest with this study. I.C.D. declares fees as speaker from Merck KGaA, Gedeon Richter, MSD (Organon, France), Ferring, Theramex, and IBSA and participation on advisory board from Merck KGaA. I.C.D. also declares consulting fees, and travel and meeting support from Merck KGaA. N.M. declares grants paid to their institution from MSD (Organon, France); consulting fees from MSD (Organon, France), Ferring, and Merck KGaA; honoraria from Merck KGaA, General Electrics, Genevrier (IBSA Pharma), and Theramex; support for travel and meetings from Theramex, Merck KGaG, and Gedeon Richter; and equipment paid to their institution from Goodlife Pharma. N.C. declares grants from IBSA Pharma, Merck KGaA, Ferring, and Gedeon Richter; support for travel and meetings from IBSA Pharma, Merck KGaG, MSD (Organon, France), Gedeon Richter, and Theramex; and participation on advisory board from Merck KGaA. A.G.L. declares fees as speaker from Merck KGaA, Gedeon Richter, MSD (Organon, France), Ferring, Theramex, and IBSA. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02884245. TRIAL REGISTRATION DATE: 29 August 2016. DATE OF FIRST PATIENT'S ENROLMENT: 4 November 2016.

Heavy metals and diminished ovarian reserve: single-exposure and mixture analyses amongst women consulting in French fertility centres.

RESEARCH QUESTION: Do heavy metals affect the risk of diminished ovarian reserve (DOR) in women of reproductive age? DESIGN: A total of 139 cases and 153 controls were included between 2016 and 2020. The participants were aged between 18 and 40 years and attended consultations for couple infertility in one of four fertility centres in western France. Cases of DOR were defined as women with an antral follicle count less than 7, anti-Müllerian hormone levels 1.1 ng/ml or less, or both. Controls were frequency matched on age groups and centres, and were women with normal ovarian reserve evaluations, no malformations and menstrual cycles between 26 and 35 days. Heavy metals (lead, mercury, cadmium and chromium) were measured in whole blood at inclusion. Single-exposure associations were examined with multivariable logistic regressions adjusted on potential confounders. Mixture effects were investigated with quantile g-computation and Bayesian kernel machine regression (BKMR). RESULTS: Chromium as a continuous exposure was significantly associated with DOR in unadjusted models (OR 2.07, 95% CI 1.04 to 4.13) but the association was no longer significant when confounders were controlled for (adjusted OR 2.75, 95% CI 0.88 to 8.60). Similarly, a statistically significant association was observed for the unadjusted second tercile of cadmium exposure (OR 1.87, 95% CI 1.06 to 3.30); however, this association was no longer statistically significant after adjustment. None of the other associations tested were statistically significant. Quantile g-computation and BKMR both yielded no significant change of risk of DOR for the mixture of metals, with no evidence of interaction. CONCLUSIONS: Weak signals that some heavy metals could be associated with DOR were detected. These findings should be replicated in other studies.

Both high and low HCG day progesterone concentrations negatively affect live birth rates in IVF/ICSI cycles.

RESEARCH QUESTION: Can previous reports of a decreased probability of success in stimulated IVF cycles with premature rise of progesterone, as determined by progesterone concentration on HCG day (PHCG), be confirmed? DESIGN: Retrospective, observational, single-centre cohort study conducted on 5447 IVF and intracytoplasmic (ICSI) cycles carried out among 2192 patients between 2009 and 2015, with conventional ovarian stimulation. This large database was used to develop a non-linear mixed prognosis model of live birth rate (LBR) incorporating PHCG as a predictor. RESULTS: In addition to known predictors (age, body mass index, anti-Müllerian hormone, type of infertility), PHCG was associated with a linear effect (OR 0.78 per Log[PHCG]ng/ml, 95% CI 0.611 to 0.997, P = 0.047) combined with a strong quadratic effect (OR 0.585 per Log2(PHCG)ng/ml, 95% CI 0.444 to 0.775, P < 0.001) resulting into a parabolic reverse-U curve. A significant interaction (P = 0.038) was found between PHCG and number of oocytes if three or less, but the effect of PHCG remains modest. For higher oocyte numbers, LBR rapidly increases with number of retrieved oocytes; however, LBR becomes more sensitive to PHCG as the number of oocytes increases. Higher live birth prognoses occur for optimal PHCG but are sharply reduced for lower or higher PHCG. CONCLUSIONS: Evidence is provided of an important negative effect of PHCG at lower and higher values, independent of oocyte number, thus defining appropriate ranges for fresh embryo transfer or freeze-all strategy. In poor responders, premature progesterone rise may be ignored, thus avoiding unnecessary cancellations or embryo freezing. Conversely, in higher responders, the negative effect of progesterone elevation is more pronounced, suggesting that freeze-all policy should be applied more widely.

Prospective multicenter observational real-world study to assess the use, efficacy and safety profile of follitropin delta during IVF/ICSI procedures (DELTA Study).

OBJECTIVE: To describe the use, efficacy and safety profile of follitropin delta in women undergoing IVF/ICSI in routine clinical practice after one treatment cycle. STUDY DESIGN: This was a French multicenter, prospective, observational study conducted in 14 fertility centers between June 2020 and June 2021. During this period, 248 women undergoing IVF or ICSI were treated with follitropin delta for the first time. Women were followed up to 10-11 weeks after the first fresh or frozen embryo transfer. The main outcomes were use of dosing algorithm, follitropin delta dosing patterns, ovarian response, pregnancy, and adverse drug reactions in routine clinical practice. RESULTS: The analyzable population consisted of 223 patients with mean ± SD age of 33.0 ± 4.4 years, body weight of 65.7 ± 11.8 kg, and the median (IQR) AMH level was 2.6 (1.5-4.0) ng/mL. For 193 patients (86.5 %) it was the first IVF/ICSI cycle and for 30 (13.5 %) the second. The algorithm was used for the calculation of the starting dose for 88.3 % of the patients. The mean daily starting dose of follitropin delta was 11.4 ± 4.1mcg for the whole analyzable population and 14.4 ± 5.2 mcg for the sub-group of 26 patients dosed without the algorithm. The mean duration of stimulation with follitropin delta was 10.8 ± 5.2 days. The mean total dose of follitropin delta administered was 122.2 ± 80.0 mcg. An antagonist protocol was used in 90.3 % of patients. The mean ± SD number of oocytes retrieved among patients that started stimulation was 11.3 ± 6.8 and 46.1 % of patients achieved the targeted response of the algorithm of 8-14 oocytes retrieved. A fresh transfer was performed for 77.6 % of patients; the mean ± SD number of embryos transferred was 1.3 ± 0.5. The implantation rate was 36.0 %. Per started cycle, clinical pregnancy was reported in 35.0 % of the patients and ongoing pregnancy in 29.6 %. In total, 5 patients (2.2 %) reported an event of OHSS. CONCLUSION: Clinical results as collected in routine clinical practice are promising, showing a favorable effectiveness-safety profile of follitropin delta for a very varied patient population (including anovulatory PCOS, very poor responders, or non-IVF naïve patients). These real-world data complement results from clinical trials and provide useful information for usual clinical practice within a heterogeneous population group.

Birthweight difference of singletons conceived through in vitro fertilization with frozen versus fresh embryo transfer: An analysis of 5406 embryo transfers in a retrospective study 2013-2018.

INTRODUCTION: Perinatal risks after frozen embro transfer (FET) have been reassuring but some authors suggest that birthweights are higher after FET than after fresh embryo transfer (ET). The primary objective of this retrospective study, conducted in Clinique de la Sagesse, Rennes (France) from December 2013 to March 2017, was to determine whether a difference in birthweight exists between children conceived through in vitro fertilization (IVF) with frozen versus fresh ET. The secondary objective was to compare live birth rates after frozen versus fresh cycles. MATERIAL AND METHODS: All couples undergoing IVF were included. Cycles with gamete donation and twin pregnancies were excluded. Hormone therapy was used in all embryo transfers. The main outcome measures were the child's birthweight, mode of delivery, gestation length and sex, maternal characteristics, and IVF characteristics. The primary endpoint was birthweight. RESULTS: We studied 5406 embryo transfers and the 708 resulting singleton live births on which birthweight data were available. Mean birthweight was 3357g after frozen embryo transfer versus 3183g after fresh embryo transfer (p<0.001). After adjusting for confounding factors, the children born after frozen embryo transfer were 165.2g heavier (95%CI [92.96-237.51]). No difference was found in gestation length. Live birth was obtained after the 1.6th IVF attempt. Live birth rate was higher for fresh cycles (19% versus 12%, p<0.001), and the caesarean rate lower (16% versus 21%). DISCUSSION: Birthweight was higher after frozen embryo transfer for a similar gestational age. Further research is needed to elucidate the mechanisms responsible for this difference.

Equivalent live-birth rate in antagonist IVF/ICSI protocol after oocyte triggering with GnRH agonist supplemented with 1500 r-hCG the day of oocyte retrieval vs r-hCG : A case-control study.

OBJECTIVE: To compare live birth rate after fresh transfer and cumulative birth rates after vitrified embryo transfer in patients triggered by GnRHa, and 1500 r-hCG bolus on the day of the pick up to a selected population of patients triggered by r-hCG. DESIGN: Retrospective case-control study SETTING: Private hospital, Rennes, France PATIENTS: Patients with more than 18 follicles greater than 11 mm on the day of the triggering, or patients with a history of OHSS INTERVENTION: We triggered according to the European protocol by GnRHa and a bolus of 1500 UI of r-HCG on the day of the pick-up and performed if possible a fresh transfer on day 2, 3 or 5. MAIN OUTCOME MEASURE: The live birth rate using fresh transfer (FT) and the cumulative birth rate by cycle of FT and frozen embryo transfer (FET) between patients triggered by GnRHa with a bolus injection of 1500 r-hCG and patients triggered by r-hCG. RESULTS: Patients triggered by GnRHa and supplemented with a bolus injection of 1500 IU r-hCG one hour after the pick up had FT birth rates equivalent to those seen after r-hCG triggering: 32.0% vs 31.8% (p = 0.9687). There was a non significant trend for better results for cumulative birth rates in FT + FET after agonist triggering. CONCLUSION: Our approach proposed may be suitable as an alternative to freeze all in centers where embryonic vitrification is not optimal, and for patients for whom freeze all is not possible for legal or ethical reasons.

Pretreatment with estrogen does not affect IVF-ICSI cycle outcome compared with no pretreatment in GnRH antagonist protocol: a prospective randomized trial.

OBJECTIVE: To assess effects of estrogen pretreatment in GnRH antagonist protocol. DESIGN: Prospective, randomized multicenter study. SETTING: Ten private or university-based centers. PATIENT(S): A total of 472 patients undergoing IVF/ICSI. INTERVENTION(S): Randomization by sealed envelopes to receive 17ß-estradiol (4 mg/d) or no pretreatment before daily recombinant FSH administration started on the first day of estrogen discontinuation or on cycle day 2 in nonpretreated women. MAIN OUTCOME MEASURE(S): The primary outcome measure was the number of retrieved oocytes. Secondary efficacy variables included total FSH dose, cycle duration, and outcome. RESULT(S): The mean numbers of retrieved oocytes (10.9 ± 5.7 vs. 10.2 ± 5.6) and obtained embryos (5.5 ± 3.7 vs. 4.8 ± 3.7) were not significantly different between women allocated to estrogen pretreatment (n = 238) and no pretreatment (n = 234). Total FSH amount (1,557 ± 408 vs. 1,389 ± 347 IU) and stimulation duration (10.8 ± 1.4 vs. 10.0 ± 1.5 days) were slightly but significantly increased in pretreated patients. Positive pregnancy tests, ultrasound pregnancy rate, and delivery rate per cycle were similar (36%, 33%, and 26.6%, respectively, vs. 38.2%, 35.4%, and 30%). CONCLUSION(S): These data confirm that estrogen pretreatment is associated with requirement of higher FSH doses and longer duration of stimulation without any significant increase in the number of retrieved oocytes. However, estrogen does not affect cycle outcome and therefore might be used in clinical practice for programming IVF retrievals during working days. CLINICAL TRIALS REGISTRATION NUMBER: NCT01489852.

Programming in vitro fertilization retrievals during working days after a gonadotropin-releasing hormone antagonist protocol with estrogen pretreatment: does the length of exposure to estradiol impact on controlled ovarian hyperstimulation outcomes?

OBJECTIVE: To verify whether a variable number of days beyond the menses of estrogen (E) pretreatment may impact on controlled ovarian hyperstimulation (COH) outcomes and birth rate using a GnRH antagonist protocol. DESIGN: Single center, prospective, nonrandomized study. SETTING: Nonacademic fertility unit. PATIENT(S): A total of 1,080 women, aged 25-38 years, consecutively included (1,603 cycles). INTERVENTION(S): Given 4 mg/d E(2) valerate, started 3 days before the theoretical date of the next menses up to the first day of stimulation (S1). MAIN OUTCOME MEASURE(S): Hormone serum levels, drug exposure, and main IVF outcomes. RESULT(S): The cancellation rate was similar in the six similarly sized groups according to the number of days with E(2) pretreatment beyond the menses (1-8 days). The mean serum E(2) and LH levels at S1 gradually increased along with E(2) exposure, whereas the mean serum P level decreased. The mean serum E(2) level on the day of hCG administration gradually increased along with E(2) exposure. Serum LH level at S1 correlated significantly and positively to the length of E(2) exposure and to E(2) level on the day of hCG administration. No significant difference was observed for the number of oocytes retrieved and the number of embryos obtained. Women exposed the longest to exogenous E(2) tended to have higher pregnancy rates (PR). CONCLUSION(S): Extending E(2) pretreatment beyond the menses had no deleterious effect on the main COH outcomes and proved to be slightly beneficial.