Effect of the oxytocin receptor antagonist nolasiban on pregnancy rates in women undergoing embryo transfer following IVF: analysis of three randomised clinical trials.

STUDY QUESTION: Does a single oral dose of nolasiban 900 mg administered 4 h before embryo transfer (ET) increase pregnancy rates in women undergoing IVF? SUMMARY ANSWER: In an individual patient data (IPD) meta-analysis of three clinical trials, a single oral dose of nolasiban 900 mg was associated with an increased ongoing pregnancy rate of an absolute 5% (relative 15%). WHAT IS KNOWN ALREADY: Several clinical studies have shown that blocking activation of oxytocin receptors by an oxytocin receptor (OTR) antagonist has the potential to decrease uterine contractions, increase endometrial perfusion and enhance endometrial decidualisation and other parameters of endometrial receptivity. It has been hypothesised that antagonism of oxytocin receptors could improve the likelihood of successful embryo implantation and thus increase pregnancy and live birth rates following ET. STUDY DESIGN, SIZE, DURATION: This is an analysis of three randomised, double-blind, placebo-controlled trials, which randomised 1836 subjects between 2015 and 2019. We describe the results of a meta-analysis of individual participant data (IPD) from all three trials and the pre-specified analyses of each individual trial. PARTICIPANT/MATERIAL, SETTING, METHODS: Participants were patients undergoing ET following IVF/ICSI in 60 fertility centres in 11 European countries. Study subjects were below 38 years old and had no more than one previously failed cycle. They were randomised to a single oral dose of nolasiban 900 mg (n = 846) or placebo (n = 864). In IMPLANT 1, additional participants were also randomised to nolasiban 100 mg (n = 62) or 300 mg (n = 60). Fresh ET of one good quality embryo (except in IMPLANT 1 where transfer of two embryos was allowed) was performed on Day 3 or Day 5 after oocyte retrieval, approximately 4 h after receiving the study treatment. Serum hCG levels were collected at 14 days post oocyte retrieval (Week 2) and for women with a positive hCG result, ultrasound was performed at Week 6 post-ET (clinical pregnancy) and at Week 10 post-ET (ongoing pregnancy). Pregnant patients were followed for maternal (adverse events), obstetric (live birth, gestational age at delivery, type of delivery, incidence of twins) and neonatal (sex, weight, height, head circumference, Apgar scores, congenital anomalies, breast feeding, admission to intensive care and specific morbidities e.g. jaundice, respiratory distress syndrome) outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: In an IPD meta-analysis of the clinical trials, a single oral dose of nolasiban 900 mg was associated with an absolute increase of 5.0% (95% CI 0.5, 9.6) in ongoing pregnancy rate and a corresponding increase of 4.4% (95% CI -0.10, 8.93) in live birth rate compared to placebo. Similar magnitude increases were observed for D3 or D5 transfers but were not significantly different from the placebo. Population pharmacokinetics (PK) demonstrated a correlation between higher exposures and pregnancy. LIMITATIONS, REASON FOR CAUTION: The meta-analysis was not a pre-specified analysis. While the individual trials did not show a consistent significant effect, they were not powered based on an absolute increase of 5% in ongoing pregnancy rate. Only a single dose of up to 900 mg nolasiban was administered in the clinical trials; higher doses or extended regimens have not been tested. Only fresh ET has been assessed in the clinical trials to date. WIDER IMPLICATIONS OF THE FINDINGS: The finding support the hypothesis that oxytocin receptor antagonism at the time of ET can increase pregnancy rates following IVF. The overall clinical and population PK data support future evaluation of higher doses and/or alternate regimens of nolasiban in women undergoing ET following IVF. STUDY FUNDING/COMPETING INTERESTS: The trials were designed, conducted and funded by ObsEva SA. A.H., O.P., E.G., E.L. are employees and stockholders of ObsEva SA. E.L. is a board member of ObsEva SA. G.G. reports honoraria and/or non-financial support from ObsEva, Merck, MSD, Ferring, Abbott, Gedeon-Richter, Theramex, Guerbet, Finox, Biosilu, Preglem and ReprodWissen GmbH. C.B. reports grants and honoraria from ObsEva, Ferring, Abbott, Gedeon Richter and MSD. P.P. reports consulting fees from ObsEva. H.T. reports grants and or fees from ObsEva, Research Fund of Flanders, Cook, MSD, Roche, Gedeon Richter, Abbott, Theramex and Ferring. H.V. reports grants from ObsEva and non-financial support from Ferring. P.T. is an employee of Cytel Inc., who provides statistical services to ObsEva. J.D. reports consulting fees and other payments from ObsEva and, Scientific Advisory Board membership of ObsEva. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov: NCT02310802, NCT03081208, NCT03758885. TRIAL REGISTRATION DATES: December 2014 (NCT02310802), March 2017 (NCT03081208), November 2018 (NCT03758885). FIRST PATIENT'S ENROLMENT: January 2015 (NCT02310802), March 2017 (NCT03081208), November 2018 (NCT03758885).

Ascorbic acid and infertility treatment.

AIM OF THE STUDY: To assess the ascorbic acid (AA) in the follicular fluid in women treated by in vitro fertilization and embryonic transfer levels (IVF/ET) and to analyse the influence of vitamin C supplementation on the results of infertility treatment. TYPE OF THE STUDY: Prospective study in women treated by IVF/ET. METHODS: The influence of vitamin C supplementation on the outcome of infertility treatment in the assisted reproduction programme in 76 women (38 of them smokers, 38 non-smokers) was studied. Half the women (19 smokers and 19 non-smokers) were administered vitamin C in daily doses of 500 mg in so-called pellets allowing for gradual release over 8 to 12 hours. The control group consisted of the same number of smokers and non-smokers. In all the women, ascorbic acid levels were determined in two urine samples (prior to supplementation and at follicle retrieval) and in follicular fluid by means of a colorimetric method. Ovarian response to hormonal stimulation with gonadotropins (hMG, FSH) at a dosage of 150-225 IU per day combined with GnRH analogues in the short (buserelin) or long (triptorelin) protocols, and 5,000-10,000 IU of human chorionic gonadotropin was evaluated based on the number of follicles created and number of retrieved oocytes. Fertilisation was assessed, based on the number of successfully fertilised oocytes (fertilisation rate) and based on the number of cultivated embryos. The success of the infertility treatment was evaluated based on the number of pregnancies. RESULTS: Ascorbic acid levels in follicles were significantly higher (p < 0.001) in women with vitamin C supplementation than in the control group (8.98 +/- 5.09 vs. 5.04 +/- 2.85 mg/l). The administration of vitamin C during the period of hormonal stimulation showed a statistically insignificant impact in terms of the higher number of pregnancies (34.2% vs. 23.7%). Vitamin supplementation had a greater impact on the number of pregnancies in the non-smokers' group (57.9% vs. 31.6%). The pregnancy rate was significantly higher (p < 0.01) in non-smoking women than in smokers--44.7% vs. 13.2%, which appears to be a reason for asking women to cease smoking prior to infertility treatment.

[Importance of sensitization of insulin receptors in the prevention of ovarian hyperstimulation syndrome]. / Význam senzitizace inzulinových receptoru pro prevenci ovariálního hyperstimulacního syndromu.

OBJECTIVE: Aim of our study was to analyze the influence of insulin receptor sensitization on the course of controlled ovarian stimulation in the program of assisted reproduction and to identify the availability of ovarian response improvement due to the reduced production of intraovarian androgens. Further we tried to identify the preventive influence of metformin on development of ovarian hyperstimulation syndrome. DESIGN: Prospective randomized controlled study of 172 patients involved in the assisted reproduction program from May 2000 to December 2001. SETTING: Centre of Assisted Reproduction, Department of Gynecology and Obstetrics, Medical Faculty, Masaryk University and University Hospital, Brno. MATERIAL AND METHODS: Patients undergoing the ovarian stimulation with increased risk of development of ovarian hyperstimulation syndrome due to the polycystic ovarian syndrome were included in the study and randomized to two groups. (1) Women in the first group used the insulin receptor sensitizing drug metformin together with gonadotropins, and (2) women in the second group underwent the classic stimulation protocol alone. The control group (3) consisted of patients with intact ovarian function and different infertility factor. Complex hormonal status was assessed before the treatment initiation and the level of androgens in the follicular fluid was investigated in all patients. RESULTS: Metformin during gonadotropin stimulation has significantly reduced the risk of ovarian hyperstimulation syndrome in women with PCOS. Significantly lower intraovarian androgen levels were documented in comparison to women without metformin and also when compared to patients with intact ovarian function. Metformin had also significantly reduced estradiol blood levels at the day of hCG application without significant influence on the number of obtained oocytes. CONCLUSIONS: The risk of ovarian hyperstimulation syndrome development was significantly decreased in patients with PCOS in consequence to insulin receptors sensitization.

[Present possibilities of prevention of adhesions and their immunologic aspects]. / Soucasné moznosti prevence adhezí a jejich imunologické aspekty.

The study reviews recent developments with regard to postsurgical adhesion formation, the role of some cytokines and possible prevention. Interleukin-1 beta (IL-1 beta) levels in peritoneal fluid were assayed during 24 and 48 hours after laparoscopic or laparotomic surgery and the influence of diclofenac was evaluated. IL-1 beta levels in peritoneal fluid were substantially lower after laparoscopic adnexal surgery than after laparotomy. Application of diclofenac after abdominal hysterectomies reduced substantially intraperitoneal IL-1 beta levels.

[Cryopreservation of sperm before neoplasm therapy--7 years' experience]. / Kryokonzervace spermatu pred onkologickou lécbou--7 let zkuseností.

OBJECTIVE: To compare sperm count of cancer patients with health men, to analyze possible relation of sperm pathology and diagnosis of malignant disease and present experience of our cryopreservation programme for cancer patients. DESIGN: Retrospective clinical study. SETTING: Department of Obstetrics and Gynecology, Masaryk University, Brno, Czech Republic. METHODS: 215 patients (age 25.4 +/- 5.6 years) were referred to our unit by oncology specialists for semen cryopreservation before cancer treatment during 1995-2001. Sperm samples were analysed according to guidelines of WHO. Richardson's medium and Planer Kryo 10 were used for standard cryopreservation. Sperm count results were compared to control group of 84 men (23.1 +/- 3.6 year) examined as possible sperm donors. Program SPSS version 9 was used for statistical analysis. Standard intracytoplasmic sperm injection (ICSI) using frozen spermatozoa was used for infertility treatment following malignant disease recovery. RESULTS: Testicular cancer was diagnosed in 115 (53.5%) patients, malignant disease of lymphatic and haemopoetic tissue in 75 (34.9%) cases--out of them 35 (16.3%) Hodgkin's lymphoma. Twelve men (5.6%) were treated for osteosarcoma and 13 for other malignant disease. Only 2.8% patients had normospermia. Severe oligospermia < 5 mil/ml was found in 73 men (33.9%) including 22 cases of azoospermia (10.2%) and 12 cases (5.6%) of cryptozoospermia. 138 (64.2%) patients had asthenospermia < 10% of progressive motility, 49 (22.8%) had terratozoospermia < 10% spermatozoa with standard WHO morphology. Sperm concentration, progressive motility and morphology were in cancer patients significantly lower (P < 0.001) than in control group. Men with testicular cancer had significantly higher frequency of severe sperm pathology. Only 4 patients have returned for assisted reproduction treatment. In all cases ICSI was used, 1 pregnancy and delivery was achieved. During more than 4 years after cryopreservation died 16.6% of patients. CONCLUSION: Cancer patients has significantly higher frequency of severe sperm pathologies than healthy men. The most severe sperm pathologies are among men with testicular cancer. Only minority of patients return for fertility treatment. Cryopreserved spermatozoa of cancer patients are able to initiate pregnancy by assisted reproduction techniques.

[The National Register for Assisted Reproduction: results and analysis of complications]. / Národní registr asistované reprodukce: výsledky a analýza komplikací.

1. Analysis of achieved results of assisted reproduction provides evidence of a steadily increasing success of ART methods in the Czech Republic. 2. Analysis of results and complications makes it possible a) to prove optimal therapeutic procedures in different groups of patients b) to recommend preventive measures to avoid complications c) assess possible side-effects on women and the foetus.