The BISTIM study: a randomized controlled trial comparing dual ovarian stimulation (duostim) with two conventional ovarian stimulations in poor ovarian responders undergoing IVF.

STUDY QUESTION: Is the total number of oocytes retrieved with dual ovarian stimulation in the same cycle (duostim) higher than with two consecutive antagonist cycles in poor responders? SUMMARY ANSWER: Based on the number of total and mature oocytes retrieved in women with poor ovarian response (POR), there is no benefit of duostim versus two consecutive antagonist cycles. WHAT IS KNOWN ALREADY: Recent studies have shown the ability to obtain oocytes with equivalent quality from the follicular and the luteal phase, and a higher number of oocytes within one cycle when using duostim. If during follicular stimulation smaller follicles are sensitized and recruited, this may increase the number of follicles selected in the consecutive luteal phase stimulation, as shown in non-randomized controlled trials (RCT). This could be particularly relevant for women with POR. STUDY DESIGN, SIZE, DURATION: This is a multicentre, open-labelled RCT, performed in four IVF centres from September 2018 to March 2021. The primary outcome was the number of oocytes retrieved over the two cycles. The primary objective was to demonstrate in women with POR that two ovarian stimulations within the same cycle (first in the follicular phase, followed by a second in the luteal phase) led to the retrieval of 1.5 (2) more oocytes than the cumulative number of oocytes from two consecutive conventional stimulations with an antagonist protocol. In a superiority hypothesis, with power 0.8 alpha-risk 0.05 and a 35% cancellation rate, 44 patients were needed in each group. Patients were randomized by computer allocation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eighty-eight women with POR, defined using adjusted Bologna criteria (antral follicle count ≤5 and/or anti-Müllerian hormone ≤1.2 ng/ml) were randomized, 44 in the duostim group and 44 in the conventional (control) group. HMG 300 IU/day with flexible antagonist protocol was used for ovarian stimulation, except in luteal phase stimulation of the duostim group. In the duostim group, oocytes were pooled and inseminated after the second retrieval, with a freeze-all protocol. Fresh transfers were performed in the control group, frozen embryo transfers were performed in both control and duostim groups in natural cycles. Data underwent intention-to-treat and per-protocol analyses. MAIN RESULTS AND THE ROLE OF CHANCE: There was no difference between the groups regarding demographics, ovarian reserve markers, and stimulation parameters. The mean (SD) cumulative number of oocytes retrieved from two ovarian stimulations was not statistically different between the control and duostim groups, respectively, 4.6 (3.4) and 5.0 (3.4) [mean difference (MD) [95% CI] +0.4 [-1.1; 1.9], P = 0.56]. The mean cumulative numbersof mature oocytes and total embryos obtained were not significantly different between groups. The total number of embryos transferred by patient was significantly higher in the control group 1.5 (1.1) versus the duostim group 0.9 (1.1) (P = 0.03). After two cumulative cycles, 78% of women in the control group and 53.8% in the duostim group had at least one embryo transfer (P = 0.02). There was no statistical difference in the mean number of total and mature oocytes retrieved per cycle comparing Cycle 1 versus Cycle 2, both in control and duostim groups. The time to the second oocyte retrieval was significantly longer in controls, at 2.8 (1.3) months compared to 0.3 (0.5) months in the duostim group (P < 0.001). The implantation rate was similar between groups. The cumulative live birth rate was not statistically different, comparing controls versus the duostim group, 34.1% versus 17.9%, respectively (P = 0.08). The time to transfer resulting in an ongoing pregnancy did not differ in controls 1.7 (1.5) months versus the duostim group, 3.0 (1.6) (P = 0.08). No serious adverse events were reported. LIMITATIONS, REASONS FOR CAUTION: The RCT was impacted by the coronavirus disease 2019 pandemic and the halt in IVF activities for 10 weeks. Delays were recalculated to exclude this period; however, one woman in the duostim group could not have the luteal stimulation. We also faced unexpected good ovarian responses and pregnancies after the first oocyte retrieval in both groups, with a higher incidence in the control group. However, our hypothesis was based on 1.5 more oocytes in the luteal than the follicular phase in the duostim group, and the number of patients to treat was reached in this group (N = 28). This study was only powered for cumulative number of oocytes retrieved. WIDER IMPLICATIONS OF THE FINDINGS: This is the first RCT comparing the outcome of two consecutive cycles, either in the same menstrual cycle or in two consecutive menstrual cycles. In routine practice, the benefit of duostim in patients with POR regarding fresh embryo transfer is not confirmed in this RCT: first, because this study demonstrates no improvement in the number of oocytes retrieved in the luteal phase after follicular phase stimulation, in contrast to previous non-randomized studies, and second, because the freeze-all strategy avoids a pregnancy with fresh embryo transfer after the first cycle. However, duostim appears to be safe for women. In duostim, the two consecutive processes of freezing/thawing are mandatory and increase the risk of wastage of oocytes/embryos. The only benefit of duostim is to shorten the time to a second retrieval by 2 weeks if accumulation of oocytes/embryos is needed. STUDY FUNDING/COMPETING INTERESTS: This is an investigator-initiated study supported by a research Grant from IBSA Pharma. 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. I.A. declares honoraria from GISKIT and support for travel and meetings from GISKIT. G.P.-B. declares Consulting fees from Ferring and Merck KGaA; honoraria from Theramex, Gedeon Richter, and Ferring; payment for expert testimony from Ferring, Merck KGaA, and Gedeon Richter; and support for travel and meetings from Ferring, Theramex, and Gedeon Richter. 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. E.D. declares support for travel and meetings from IBSA pharma, Merck KGaG, MSD (Organon France), Ferring, Gedeon Richter, Theramex, and General Electrics. C.P.-V. declares support for travel and meetings from IBSA Pharma, Merck KGaA, Ferring, Gedeon Richter, and Theramex. M.Pi. declares support for travel and meetings from Ferring, Gedeon Richetr, and Merck KGaA. M.Pa. declares honoraria from Merck KGaA, Theramex, and Gedeon Richter; support for travel and meetings from Merck KGaA, IBSA Pharma, Theramex, Ferring, Gedeon Richter, and MSD (Organon France). H.B.-G. declares honoraria from Merck KGaA, and Gedeon Richter and support for travel and meetings from Ferring, Merck KGaA, IBSA Pharma, MSD (Organon France), Theramex, and Gedeon Richter. S.G. and M.B. have nothing to declare. TRIAL REGISTRATION NUMBER: Registration number EudraCT: 2017-003223-30. ClinicalTrials.gov identifier: NCT03803228. TRIAL REGISTRATION DATE: EudraCT: 28 July 2017. ClinicalTrials.gov: 14 January 2019. DATE OF FIRST PATIENT'S ENROLMENT: 3 September 2018.

[Dydrogesterone versus micronized vaginal progesterone as luteal phase support after fresh embryo transfer in IVF]. / Dydrogestérone vs progestérone vaginale micronisée dans le soutien de la phase lutéale après transfert frais d'embryons.

OBJECTIVES: The objective of the study was to compare the live birth rate and miscarriage rate after fresh embryo transfer (Fresh ET) when patients are treated either with oral dydrogesterone or micronized vaginal progesterone (MVP) as luteal phase support (LPS). The vaginal route is still preferred, despite the discomfort for the patients and recent RCTs showing similar results for dydrogesterone and MVP. METHODS: All 556 consecutive Fresh ET after autologous IVF procedure, from December 2011 to March 2013 in one centre in France were included. Patients were treated either with dydrogesterone 10mg every 12hours (n=267) or MVP 200mg every 12hours (n=289), the physician's arbitrary choice on the day of the oocyte aspiration procedure. RESULTS: The groups were comparable regarding the demographic data and stimulation protocols, except for the rank of the oocyte pickup procedure [1.54±0.80 vs. 1.74±0.96, (P=0.01)], with no significant difference in live birth rates (22.4% vs. 23.8%, P=0.77) and miscarriage rates (4.1% vs. 5.5%, P=0.55) for dydrogesterone vs. MVP respectively. The results were similar in a good prognosis patients' subgroup. CONCLUSIONS: LPS with either dydrogesterone or MVP after Fresh ET showed similar live birth rates and miscarriage rates. The benefits of the oral over vaginal route might be higher tolerance and possibly better compliance. Dydrogesterone seems to be a safe treatment, but its long-term innocuity needs to be further proven.

Random antral follicle count performed on any day of the menstrual cycle has the same predictive value as AMH for good ovarian response in IVF cycles.

OBJECTIVE: To determine whether the predictive value of AFC for ovarian response to stimulation for IVF depends on the day of the menstrual cycle when ultrasound is performed. METHODS: 410 women undergoing their first IVF cycle were included. All the women had AFC performed twice. The first measurement, random AFC (r-AFC), was performed during the fertility workup whatever the day of their menstrual cycle. Three groups were constituted according to the period of ultrasound performance: at early follicular phase i.e., day 1 to day 6 (eFP-AFC); at mid follicular phase i.e., day 7 to 12 (mFP-AFC) and at luteal phase i.e., day 13 or after (LP-AFC). A second AFC measurement was performed before the start of the ovarian stimulation (SD1-AFC). AMH dosing was done in the early follicular phase. RESULTS: Random AFC (r-AFC) was correlated to AMH (r = 0.69; p<0.001), SD1-AFC (r = 0.75; p<0.001) and number of oocytes retrieved (r = 0.49; p<0.001). When regarding AFC depending on the cycle day group, the correlation with AMH was 0.65, 0.66 and 0.85 for the eFP-AFC, the mFP-AFC and the LP-AFC respectively (all p were <0.001). The ROC analysis showed the same predictive value for good ovarian response (more than 6 oocytes retrieved) for the eFP-AFC, mFP-AFC and LP-AFC (AUC 0.73, 0.75 and 0.84 respectively; p = 0.28). The AUC of r-AFC (0.76) were similar to those of AMH (0.74) and SD1-AFC (0.74) (p = 0.21 and 0.92 respectively). CONCLUSION: AFC is strongly correlated with AMH and highly predictive of good ovarian response during the whole menstrual cycle.

Anatomic relations between the cephalic vein and the sensory branches of the radial nerve: How can nerve lesions during vein puncture be prevented?

UNLABELLED: The cephalic vein of the forearm is often used for IV catheters because of its ease of access for peripheral venous cannulation. But its close relation to the sensory branch of the radial nerve sometimes causes it to be damaged when the vein is cannulated. Our anatomic study conducted on 33 specimens confirmed the risk of nerve lesion. However, it is impossible to define a safe zone, because of the randomly located nerve and vein crossing zones, where the iatrogenic risk of damaging the radial nerve is maximum. We suggest that to avoid incidents, the cephalic vein should be punctured above the emergence of the sensory branch of the radial nerve, e.g., at least 12 cm above the level of the styloid process of the radius. IMPLICATIONS: We attempted to determine the relationship between the cephalic vein and the sensory branch of the radial nerve at the wrist to help prevent lesions of the radial nerve when the cephalic vein is cannulated. We examined the anatomy of 33 postmortem specimens and suggest that puncture of the cephalic vein 12 cm or more proximal to the styloid process can prevent radial nerve lesions.