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.

Pesticides in roof runoff: study of a rural site and a suburban site.

The quality of stored roof runoff in terms of pesticide pollution was assessed over a one-year period. Two tanks, located at a rural and suburban site, respectively, were sampled monthly. The two studied collection surface were respectively a tile slope roof and a bituminous flat roof. Four hundred and five compounds and metabolites were screened using liquid and gas chromatography coupled with various detection systems. Principal Component Analysis was applied to the data sets to elucidate patterns. At the rural site, two groups of compounds associated with two different types of agriculture, vineyard and crops, were distinguished. The most frequently detected compound was glyphosate (83%) which is the most commonly used herbicide in French vineyards. At the suburban site, quantified compounds were linked to agriculture rather than urban practices. In addition, all samples were contaminated with mecoprop which is a roof-protecting agent. Its presence was attributed to the nature of roofing material used for rainwater collection. For both sites, the highest number and concentrations of compounds and metabolites were recorded at the end of spring and through summer. These results are consistent with treatment periods and higher temperatures.

Impact of dry weather discharges on annual pollution from a separate storm sewer in Toulouse, France.

The city of Toulouse with its separate sewer system is ideal for studying stormwater. However, during dry weather, the storm sewer also discharges water into the environment, and it is the impact of these discharges on annual pollution from storm sewer that is the object of this study. Samples have been taken from the outlets of two storm drains located in heavily and moderately urbanized areas. Sampling has been undertaken during wet weather and during dry weather between January 2010 and February 2011. Three dry weather and two wet weather samples have been taken every three months and from each outlet. The overall pollution parameters have been analyzed (chemical oxygen demand, biological oxygen demand, total nitrogen, ammonium, nitrate, total phosphorus, suspended solid matter, volatile suspended matter, pH, conductivity, turbidity). Characterization has been completed by analysis of trace organic compounds: polycyclic aromatic hydrocarbons, total hydrocarbons, methyl tert-butyl ether, diethylhexylphthalate, nonylphenols, hormones (estradiol, ethinylestradiol). For certain parameters, the results obtained did not conform to legislative requirements concerning discharge into the natural environment. Correlations between these parameters have been studied, and identified between several of them using principal component analysis. The most important correlation observed was between conductivity and concentration in total phosphorus for one of the outlet. Results showed that dry weather had an impact on annual pollution load from separate storm sewer and that level of urbanization was also a factor. The effect of season has been studied but no significant impact was found.

Priority organic pollutants in the urban water cycle (Toulouse, France).

Application of the European Water Framework Directive requires Member States to have better understanding of the quality of surface waters in order to improve knowledge of priority pollutants. Xenobiotics in urban receiving waters are an emerging concern. This study proposes a screening campaign of nine molecular species of xenobiotics in a separated sewer system. Five sites were investigated over one year in Toulouse (France) using quantitative monitoring. For each sample, polycyclic aromatic hydrocarbons, polychlorinated biphenyls, nonylphenols, diethelhexylphthalate, linear alkylbenzene sulphonates, methyl tert-butylether, total hydrocarbons, estradiol and ethinylestradiol were analysed. Ground, rain and roof collected water concentrations are similar to treated wastewater levels. Run-off water was the most polluted of the five types investigated, discharged into the aquatic environment. The wastewater treatment plant reduced xenobiotic concentrations by 66% before discharge into the environment. Regarding environmental quality standards, observed concentrations in waters were in compliance with standards. The results show that xenobiotic concentrations are variable over time and space in all urban water compartments.

Monitoring of water quality from roof runoff: Interpretation using multivariate analysis.

The quality of harvested rainwater used for toilet flushing in a private house in the south-west of France was assessed over a one-year period. Temperature, pH, conductivity, colour, turbidity, anions, cations, alkalinity, total hardness and total organic carbon were screened using standard analytical techniques. Total flora at 22 °C and 36 °C, total coliforms, Escherichia coli and enterococci were analysed. Overall, the collected rainwater had good physicochemical quality but did not meet the requirements for drinking water. The stored rainwater is characterised by low conductivity, hardness and alkalinity compared to mains water. Three widely used bacterial indicators - total coliforms, E. coli and enterococci - were detected in the majority of samples, indicating microbiological contamination of the water. To elucidate factors affecting the rainwater composition, principal component analysis and cluster analysis were applied to the complete data set of 50 observations. Chemical and microbiological parameters fluctuated during the course of the study, with the highest levels of microbiological contamination observed in roof runoffs collected during the summer. E. coli and enterococci occurred simultaneously, and their presence was linked to precipitation. Runoff quality is also unpredictable because it is sensitive to the weather. Cluster analysis differentiated three clusters: ionic composition, parameters linked with the microbiological load and indicators of faecal contamination. In future surveys, parameters from these three groups will be simultaneously monitored to more accurately characterise roof-collected rainwater.

Impact of carwash discharge on stormwater quality (Toulouse, France).

The contribution of discharge from carwashes to pollutant levels in stormwater was evaluated. Five carwashes and two outlets in the city of Toulouse (France) were selected. Water samples were collected from December 2006 to December 2007. Concentrations and loadings of classical water quality parameters (conductivity, pH, turbidity, chemical oxygen demand, nitrogen, phosphorus, ammonium, nitrate, suspended solid and volatile suspended solid) and five groups of organic compounds (polycyclic aromatic hydrocarbons, polychlorinated biphenyls, lauryl alkyl benzene sulphonates, methyl tert-butyl ether and total hydrocarbons) were determined. The results suggest that the wastewater derived from carwashes was negligible compared to the volume and flow rates within the stormwater network. However, high concentrations of polycyclic aromatic hydrocarbons, phosphorus and lauryl alkyl benzene sulphonates in liquid waste from carwashes, and the impact of these pollutants on stormwater quality could not be neglected.

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.

[Myocardial protection by perfusion in deep hypothermia (10 degrees C) with or without cardioplegia (author's transl)]. / Protection myocardique par perfusion en hypothermie profonde (10 degrees C) avec ou sans cardioplégie.

A technique of myocardial protection using a perfusion circuit in deep hypothermia via the ascending aorta or by selective cannulation of the coronaries has been used over a period of 2 years in almost 200 patients undergoing surgery requiring prolonged aortic clamping. It ensures rapid and homogeneous cooling of the myocardium (10-12 degrees C) and meets its reduced oxygen needs. It may be completed by cardioplegia (infusion of potassium chloride or lidocaine using an automatic syringe at a determined level). This simple technique permits a rapid spontaneous return of normal effective cardiac action. No low cardiac output syndromes have been seen since it has been used. Laboratory, histological, biochemical and haemodynamic studies carried out have confirmed its harmless nature.