Contribution of medico-administrative databases to health vigilance: example of post-oocyte retrieval infections.

STUDY QUESTION: Can we monitor post-oocyte retrieval infections in the French national health data system to complement the French ART vigilance system? SUMMARY ANSWER: Medico-administrative databases provide a more comprehensive view of post-oocyte retrieval infections and can be used to detect abnormal increases in frequency and outlier ART centers as a complementary tool to the ART vigilance system. WHAT IS KNOWN ALREADY: The various studies of ART complications are reassuring, showing relatively low overall complication rates. Nonetheless, the European Union has set up a vigilance system to monitor these complications. However, this system is not an exhaustive source of information and does not provide a complete overview of post-ART complications. STUDY DESIGN, SIZE, DURATION: The study population was identified from the comprehensive French national hospital discharge database. It included women under 46 years of age undergoing an oocyte retrieval in 2019, classified into three population subgroups according to the indication of oocyte retrieval: infertility (IF) , fertility preservation (FP), and oocyte donation (OD) . The study population included 52 098 women who had undergone 65 948 oocyte retrievals in 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: Hospital stays and delivery of antibiotics within 31 days after oocyte retrieval were analyzed. Women and infections were characterized according to various characteristics (age, comorbidities, indication of oocyte retrieval, type of hospital stay, length of hospital stay, type of antibiotherapy, etc.). Multivariate analysis was performed to determine the relation between the occurrence of infection and women's characteristics, and results are expressed as odds ratios (ORs) and 95% CI. A funnel plot and a box plot were used to compare the infection rate per center with the national average and to detect outliers. MAIN RESULTS AND THE ROLE OF CHANCE: Infections in the month following the oocyte retrieval represented 6.9% of the procedures in 2019 (n = 4522). Of these infections, 112 were hospitalized (0.2% of oocyte retrievals), and 4410 were non-hospitalized (6.7% of oocyte retrievals). The hospitalized infections were essentially gynecological infections (40.9%) and urinary tract infections (23.5%). In 87.9% of non-hospitalized infections, a single antibiotic therapy was prescribed. Mixed-effect model analysis showed that the risk of infection was significantly higher in women under 30 years of age, in the FP population, in supplementary universal health coverage (CMU-C) beneficiaries, and women with endometriosis. Funnel plot and box plot analysis showed that three ART centers have an infection rate significantly higher than the national average. In the three centers that stand out from all the others, the objective is to return to these centers to understand the possible reasons for this observed rate and to implement corrective measures. LIMITATIONS, REASONS FOR CAUTION: Despite all its advantages, the French national health data system presents some limitations, such as the risk of inappropriate coding. Another limitation of this study is that we cannot confirm an attributable relation between the infection and the ART procedure, even if the delay of 31 days after oocyte retrieval is consistent with the occurrence of a post-retrieval complication. In addition, antibiotics may be prescribed as a 'precautionary' measure in certain situations (women with a susceptibility to infection, complicated procedures), or as antibiotic prophylaxis for embryo transfer. WIDER IMPLICATIONS OF THE FINDINGS: Despite the limits in identifying post-ART infections in medico-administrative databases, this approach is a promising way to complement the ART vigilance reporting system. This concept developed for infections will also be generalized to other complications with regular feedback to professionals. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was sought for the study. The study was supported by the Agence de la biomédecine, France. The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

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.

Impact of endometrial preparation on early pregnancy loss and live birth rate after frozen embryo transfer: a large multicenter cohort study (14 421 frozen cycles).

STUDY QUESTION: Does the endometrial preparation protocol (artificial cycle (AC) vs natural cycle (NC) vs stimulated cycle (SC)) impact the risk of early pregnancy loss and live birth rate after frozen/thawed embryo transfer (FET)? SUMMARY ANSWER: In FET, ACs were significantly associated with a higher pregnancy loss rate and a lower live birth rate compared with SC or NC. WHAT IS KNOWN ALREADY: To date, there is no consensus on the optimal endometrial preparation in terms of outcomes. Although some studies have reported a higher pregnancy loss rate using AC compared with NC or SC, no significant difference was found concerning the pregnancy rate or live birth rate. Furthermore, no study has compared the three protocols in a large population. STUDY DESIGN SIZE DURATION: A multicenter retrospective cohort study was conducted in nine reproductive health units in France using the same software to record medical files between 1 January 2012 and 31 December 2016. FET using endometrial preparation by AC, modified NC or SC were included. The primary outcome was the pregnancy loss rate at 10 weeks of gestation. The sample size required was calculated to detect an increase of 5% in the pregnancy loss rate (21-26%), with an alpha risk of 0.5 and a power of 0.8. We calculated that 1126 pregnancies were needed in each group, i.e. 3378 in total. PARTICIPANTS/MATERIALS SETTING METHODS: Data were collected by automatic extraction using the same protocol. All consecutive autologous FET cycles were included: 14 421 cycles (AC: n = 8139; NC: n = 3126; SC: n = 3156) corresponding to 3844 pregnancies (hCG > 100 IU/l) (AC: n = 2214; NC: n = 812; SC: n = 818). Each center completed an online questionnaire describing its routine practice for FET, particularly the reason for choosing one protocol over another. MAIN RESULTS AND THE ROLE OF CHANCE: AC represented 56.5% of FET cycles. Mean age of women was 33.5 (SD ± 4.3) years. The mean number of embryos transferred was 1.5 (±0.5). Groups were comparable, except for history of ovulation disorders (P = 0.01) and prior delivery (P = 0.03), which were significantly higher with AC. Overall, the early pregnancy loss rate was 31.5% (AC: 36.5%; NC: 25.6%; SC: 23.6%). Univariable analysis showed a significant association between early pregnancy loss rate and age >38 years, history of early pregnancy loss, ovulation disorders and duration of cryopreservation >6 months. After adjustment (multivariable regression), the early pregnancy loss rate remained significantly higher in AC vs NC (odds ratio (OR) 1.63 (95% CI) [1.35-1.97]; P < 0.0001) and in AC vs SC (OR 1.87 [1.55-2.26]; P < 0.0001). The biochemical pregnancy rate (hCG > 10 and lower than 100 IU/l) was comparable between the three protocols: 10.7% per transfer. LIMITATIONS REASONS FOR CAUTION: This study is limited by its retrospective design that generates missing data. Routine practice within centers was heterogeneous. However, luteal phase support and timing of embryo transfer were similar in AC. Univariable analysis showed no difference between centers. Moreover, a large number of parameters were included in the analysis. WIDER IMPLICATIONS OF THE FINDINGS: Our study shows a significant increase in early pregnancy loss when using AC for endometrial preparation before FET. These results suggest either a larger use of NC or SC, or an improvement of AC by individualizing hormone replacement therapy for patients in order to avoid an excess of pregnancy losses. STUDY FUNDING/COMPETING INTERESTS: The authors declare no conflicts of interest in relation to this work. G.P.-B. declares consulting fees from Ferring, Gedeon-Richter, Merck KGaA, Theramex, Teva; Speaker's fees or equivalent from Merck KGaA, Ferring, Gedeon-Richter, Theramex, Teva. N.C. declares consulting fees from Ferring, Merck KGaA, Theramex, Teva; Speaker's fees or equivalent from Merck KGaA, Ferring. C.R. declares a research grant from Ferring, Gedeon-Richter; consulting fees from Gedeon-Richter, Merck KGaA; Speaker's fees or equivalent from Merck KGaA, Ferring, Gedeon-Richter; E.M.d'A. declares Speaker's fees or equivalent from Merck KGaA, MSD, Ferring, Gedeon-Richter, Theramex, Teva. I.C-D. declares Speaker's fees or equivalent from Merck KGaA, MSD, Ferring, Gedeon-Richter, IBSA. N.M. declares a research grant from Merck KGaA, MSD, IBSA; consulting fees from MSD, Ferring, Gedeon-Richter, Merck KGaA; Speaker's fees or equivalent from Merck KGaA, MSD, Ferring, Gedeon-Richter, Teva, Goodlife, General Electrics. TRIAL REGISTRATION NUMBER: N/A.

Emergency IVF for embryo freezing to preserve female fertility: a French multicentre cohort study.

STUDY QUESTION: What are the outcomes of French emergency IVF procedures involving embryo freezing for fertility preservation before gonadotoxic treatment? SUMMARY ANSWER: Pregnancy rates after emergency IVF, cryopreservation of embryos, storage, thawing and embryo transfer (embryo transfer), in the specific context of the preservation of female fertility, seem to be similar to those reported for infertile couples undergoing ART. STUDY DESIGN, SIZE, DURATION: A French retrospective multicentre cohort study initiated by the GRECOT network-the French Study Group for Ovarian and Testicular Cryopreservation. We sent an e-mail survey to the 97 French centres performing the assisted reproduction technique in 2011, asking whether the centre performed emergency IVF and requesting information about the patients' characteristics, indications, IVF cycles and laboratory and follow-up data. The response rate was 53.6% (52/97). PARTICIPANTS/MATERIALS, SETTING, METHODS: Fourteen French centres reported that they performed emergency IVF (56 cycles in total) before gonadotoxic treatment, between 1999 and July 2011, in 52 patients. MAIN RESULTS AND THE ROLE OF CHANCE: The patients had a mean age of 28.9 ± 4.3 years, and a median length of relationship of 3 years (1 month-15 years). Emergency IVF was indicated for haematological cancer (42%), brain tumour (23%), sarcoma (3.8%), mesothelioma (n = 1) and bowel cancer (n = 1). Gynaecological problems accounted for 17% of indications. In 7.7% of cases, emergency IVF was performed for autoimmune diseases. Among the 52 patients concerned, 28% (n = 14) had undergone previous courses of chemotherapy before beginning controlled ovarian stimulation (COS). The initiation of gonadotoxic treatment had to be delayed in 34% of the patients (n = 19). In total, 56 cycles were initiated. The mean duration of stimulation was 11.2 ± 2.5 days, with a mean peak estradiol concentration on the day on which ovulation was triggered of 1640 ± 1028 pg/ml. Three cycles were cancelled due to ovarian hyperstimulation syndrome (n = 1), poor response (n = 1) and treatment error (n = 1). A mean of 8.2 ± 4.8 oocytes were retrieved, with 6.1 ± 4.2 mature oocytes and 4.4 ± 3.3 pronuclear-stage embryos per cycle. The mean number of embryos frozen per cycle was 4.2 ± 3.1. During follow-up, three patients died from the consequences of their disease. For the 49 surviving patients, 22.5% of the couples concerned (n = 11) requested embryo replacement. A total of 33 embryos were thawed with a post-thawing survival rate of 76%. Embryo replacement was finally performed for 10 couples with a total of 25 embryos transferred, leading to one biochemical pregnancy, one miscarriage and three live births. Clinical pregnancy rate and live birth per couple who wanted a pregnancy after cancer were, respectively, 36% (95% CI = 10.9-69.2%) and 27% (95% CI = 6.0-61%). LIMITATIONS, REASONS FOR CAUTION: The overall response rate for clinics was 53.6%. Therefore, it is not only that patients may not have been included, but also that those that were included were biased towards the University sector with a response rate of 83% (25/30) for a small number of patients. WIDER IMPLICATIONS OF THE FINDINGS: According to literature, malignant disease is a risk factor for a poor response to COS. However, patients having emergency IVF before gonadotoxic treatment have a reasonable chance of pregnancy after embryo replacement. Embryo freezing is a valuable approach that should be included among the strategies used to preserve fertility. STUDY FUNDING/COMPETING INTEREST(S): No external funding was sought for this study. None of the authors has any conflict of interest to declare.

Diagnosis and management of adenocarcinoma of the ampulla of Vater during pregnancy.

BACKGROUND: Cancer of the biliary tract has a poor prognosis and its association with pregnancy is uncommon. Early diagnosis allowing curative surgical resection offers the only hope of long-term survival. CASE: This report describes the case of a young 26-week-pregnant woman admitted for cholestatis documented by clinical and laboratory examination. Ultrasonography (US) and magnetic resonance cholangiopancreatography (MRCP) were indicative of common bile tract obstruction. Caesarian section was performed at 32 weeks of pregnancy and the tumor was promptly biopsied. Histology demonstrated carcinoma of the ampulla of Vater. The patient underwent a Whipple procedure. Both mother and baby survived. CONCLUSION: Pregnant patients with digestive cancer require careful management. Acute non-invasive assessment and radical surgery improve outcome for both the mother and fetus.

[Pregnancy outcome and the status of the newborn infant after ICSI at La Conception Hospital in Marseille]. / Evolution des grossesses et état des enfants à la naissance après ICSI à l'hôpital de La Conception à Marseille.

OBJECTIVE: To evaluate obstetric outcome of pregnancies and pediatric follow-up of children born after ICSI procedure. MATERIAL AND METHOD: Prospective study from october 1994 to September 1998 in medical assisted procreations center in La Conception hospital in Marseilles. Three hundred forty-two couples undergoing ICSI procedures. INTERVENTIONS: analysis of pregnancy rates, prematurity rates, obstetric outcome and frequency of congenital malformations. RESULTS: One hundred seventy-eight pregnancies have been obtained with 111 children. Multiple pregnancy rate arise 29.7%. The average term at birth in the singleton pregnancies (38.7 weeks) is higher than in the twins (35.7 weeks). The prematurity rate of delivery before 35 weeks of gestation is about 9.6%. Seven of 111 neonates was born with a congenital malformation, no cardiovascular one. One of boys presents a bilateral cryptorchidism with severe bilateral hypotrophy. CONCLUSIONS: Our results are similar with those of others teams. Congenital malformation rates is near rates reported in others studies. However, no bilateral cryptorchidism with bilateral severe hypotrophy has been yet reported in literature.