ABSTRACT
Abstract: Sex steroids are converted to bioactive metabolites and vice versa by endometrial steroid-metabolising enzymes. Studies indicate that alterations in this metabolism might affect endometrial receptivity. This pilot study determined whether the endometrial formation and inactivation of 17ß-oestradiol differed between the supposedly embryo-receptive endometrium and non-receptive endometrium of women undergoing IVF/intracytoplasmic sperm injection (ICSI). Endometrial biopsies were obtained from IVF/ICSI patients 5-8 days after ovulation in a natural cycle, prior to their second IVF/ICSI cycle with fresh embryo transfer (ET). Endometrial biopsies from patients who achieved clinical pregnancy after fresh ET (n = 15) were compared with endometrial biopsies from patients that did not conceive after fresh ET (n = 15). Formation of 17ß-oestradiol (oxidative 17ß-hydroxysteroid dehydrogenases (HSDs)), oestrone (reductive HSD17Bs) and inhibition of HSD17B1 activity were determined by high-performance liquid chromatography. The endometrial transcriptome was profiled using RNA sequencing followed by principal component analysis and differentially expressed gene analysis. The false discovery rate-adjusted P < 0.05 and log fold change >0.5 were selected as the screening threshold. Formation and inactivation of 17ß-oestradiol resulted similar between groups. Inhibition of HSD17B1 activity was significantly higher in the non-pregnant group when only primary infertile women (n = 12) were considered (27.1%, n = 5 vs 16.2%, n = 7, P = 0.04). Gene expression analysis confirmed the presence of HSD17B1 (encoding HSD17B1), HSD17B2 (encoding HSD17B2) and 33 of 46 analysed steroid metabolising enzymes in the endometrium. In the primary infertile subgroup (n = 10) 12 DEGs were found including LINC02349 which has been linked to implantation. However, the exact relationship between steroid-metabolising enzyme activity, expression and implantation outcome requires further investigation in larger, well-defined patient groups. Lay summary: Sex hormones are produced and broken down by enzymes that can be found in the endometrium (the inner lining of the womb). This enzyme activity might influence the chances of becoming pregnant. We compared (i) enzyme activity in the endometrium of 15 women who did and 15 women who did not become pregnant in their second in vitro fertilisation attempt, (ii) how enzyme activity can be blocked by an inhibitor, and (iii) differences in gene expression (the process by which instructions in our DNA are converted into a product). Enzyme activity was similar between groups. We found that in women who have never been pregnant in the past, inhibition of enzyme activity was higher and found differences in a gene that has been linked to the implantation of the embryo, but future studies should be performed in larger, well-defined patient groups to confirm these findings.
Subject(s)
Infertility, Female , Male , Pregnancy , Animals , Female , Pilot Projects , Infertility, Female/genetics , Infertility, Female/therapy , Infertility, Female/metabolism , Infertility, Female/veterinary , Semen , Estradiol/metabolism , Endometrium/metabolismABSTRACT
Background: Fear of cancer recurrence (FCR) is one of the greatest problems with which cancer survivors have to deal. High levels of FCR are characterized by intrusive thoughts about cancer-related events and re-experiencing these events, avoidance of reminders of cancer, and hypervigilance, similar to post-traumatic stress disorder (PTSD). Eye movement desensitization and reprocessing (EMDR) therapy focuses on these images and memories. It is effective in reducing PTSD and may be effective in reducing high levels of FCR.Objective: The aim of the present study is to investigate the effectiveness of EMDR for severe FCR in breast and colorectal cancer survivors.Method: A multiple-baseline single-case experimental design (n = 8) was used. Daily repeated measurements for FCR were taken during the baseline phase and treatment phase, post-treatment, and at the 3 month follow-up. Participants answered the Cancer Worry Scale (CWS) and the Fear of Cancer Recurrence Inventory, Dutch version (FCRI-NL) five times, i.e. at the start and at the end of each phase (baseline, treatment, post-treatment, and follow-up). The study was prospectively registered at clinicaltrials.gov (NL8223).Results: Visual analysis and effect size calculation by Tau-U were executed for the daily questionnaire on FCR. The weighted average Tau-U score was .63 (p < .01) for baseline versus post-treatment, indicating large change, and .53 (p < .01) between baseline and follow-up, indicating moderate change. The scores on the CWS and FCRI-NL-SF decreased significantly from baseline to follow-up.Conclusion: The results seem promising for EMDR therapy as a potentially effective treatment for FCR. Further research is recommended.
Patients who experience high fear of cancer recurrence (FCR) often have intrusive memories and images about (future) cancer-related events.Eye movement desensitization and reprocessing (EMDR) therapy can focus on these intrusions.EMDR therapy is found to be a promising therapy for patients experiencing high FCR.
Subject(s)
Cancer Survivors , Eye Movement Desensitization Reprocessing , Neoplasms , Humans , Eye Movement Desensitization Reprocessing/methods , Eye Movements , Fear , Research DesignABSTRACT
STUDY QUESTION: For couples with unexplained subfertility and a poor prognosis for natural conception, is 6 months expectant management (EM) inferior to IUI with ovarian stimulation (IUI-OS), in terms of live births? SUMMARY ANSWER: In couples with unexplained subfertility and a poor prognosis for natural conception, 6 months of EM is inferior compared to IUI-OS in terms of live births. WHAT IS KNOWN ALREADY: Couples with unexplained subfertility and a poor prognosis are often treated with IUI-OS. In couples with unexplained subfertility and a relatively good prognosis for natural conception (>30% in 12 months), IUI-OS does not increase the live birth rate as compared to 6 months of EM. However, in couples with a poor prognosis for natural conception (<30% in 12 months), the effectiveness of IUI-OS is uncertain. STUDY DESIGN, SIZE, DURATION: We performed a non-inferiority multicentre randomized controlled trial within the infrastructure of the Dutch Consortium for Healthcare Evaluation and Research in Obstetrics and Gynaecology. We intended to include 1091 couples within 3 years. The couples were allocated in a 1:1 ratio to 6 months EM or 6 months IUI-OS with either clomiphene citrate or gonadotrophins. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied heterosexual couples with unexplained subfertility and a poor prognosis for natural conception (<30% in 12 months). The primary outcome was ongoing pregnancy leading to a live birth. Non-inferiority would be shown if the lower limit of the one-sided 90% risk difference (RD) CI was less than minus 7% compared to an expected live birth rate of 30% following IUI-OS. We calculated RD, relative risks (RRs) with 90% CI and a corresponding hazard rate for live birth over time based on intention-to-treat and per-protocol (PP) analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Between October 2016 and September 2020, we allocated 92 couples to EM and 86 to IUI-OS. The trial was halted pre-maturely owing to slow inclusion. Mean female age was 34 years, median duration of subfertility was 21 months. Couples allocated to EM had a lower live birth rate than couples allocated to IUI-OS (12/92 (13%) in the EM group versus 28/86 (33%) in the IUI-OS group; RR 0.40 90% CI 0.24 to 0.67). This corresponds to an absolute RD of minus 20%; 90% CI: -30% to -9%. The hazard ratio for live birth over time was 0.36 (95% CI 0.18 to 0.70). In the PP analysis, live births rates were 8 of 70 women (11%) in the EM group versus 26 of 73 women (36%) in the IUI-OS group (RR 0.32, 90% CI 0.18 to 0.59; RD -24%, 90% CI -36% to -13%) in line with inferiority of EM. LIMITATIONS, REASONS FOR CAUTION: Our trial did not reach the planned sample size, therefore the results are limited by the number of participants. WIDER IMPLICATIONS OF THE FINDINGS: This study confirms the results of a previous trial that in couples with unexplained subfertility and a poor prognosis for natural conception, EM is inferior to IUI-OS. STUDY FUNDING/COMPETING INTEREST(S): The trial was supported by a grant of the SEENEZ healthcare initiative. The subsidizing parties were The Dutch Organisation for Health Research and Development (ZonMW 837004023, www.zonmw.nl) and the umbrella organization of 10 health insurers in The Netherlands. E.R.G. receives personal fees from Titus Health care outside the submitted work. M.G. declares unrestricted research and educational grants from Guerbet, Merck and Ferring not related to the presented work, paid to their institution VU medical centre. A.B.H. reports receiving travel and speakers fees from Nordic Pharma and Merck and he is member of the Nordic Pharma ANGEL group and of the Safety Monitoring Board of Womed. C.B.L. reports speakers fee from Inmed and Yingming, and his department receives research grants from Ferring, Merck and Guerbet paid to VU medical centre. B.W.J.M. is supported by a NHMRC Investigator grant (GNT1176437) and reports consultancy for ObsEva and Merck. M.v.W. received a grant from the Netherlands Organisation for Health Research and Development ZonMW (80-8520098-91072). F.M. received two grants from the Netherlands Organisation for Health Research and Development ZonMW (NTR 5599 and NTR 6590). The other authors report no competing interest. TRIAL REGISTRATION NUMBER: Dutch Trial register NL5455 (NTR5599). TRIAL REGISTRATION DATE: 18 December 2015. DATE OF FIRST PATIENT'S ENROLMENT: 26 January 2017.
Subject(s)
Infertility , Watchful Waiting , Pregnancy , Male , Female , Humans , Adult , Pregnancy Rate , Infertility/therapy , Ovulation Induction/methods , Insemination, Artificial/methods , PrognosisABSTRACT
STUDY QUESTION: What are the facilitators and barriers concerning the implementation of home-based monitoring for natural cycle frozen embryo transfer (NC-FET) from the perspectives of patients and healthcare providers in the Netherlands? SUMMARY ANSWER: The most important facilitator was optimal pregnancy chance for both the patients and healthcare providers, and the most important barriers were the risk of missing an ovulation for the patients and laboratory capacity for the healthcare providers. WHAT IS KNOWN ALREADY: The share of FET cycles in IVF treatments is increasing and, therefore, it is important to optimize protocols for FET. Monitoring of ovulation, which is used in NC-FET, can be hospital-based (ultrasounds and ovulation triggering) or home-based (LH urine tests). Home-based monitoring has the advantage of being the most natural protocol for FET and provides the feeling of empowerment and discretion for patients. A systematic approach for the implementation of home-based monitoring has to start with an exploration of the perspectives of all stakeholders. STUDY DESIGN SIZE DURATION: Stakeholders (patients and healthcare providers) involved in the implementation process in the Netherlands participated in the present study. Patients were represented by the Dutch Patient Organisation for Couples with Fertility Problems (FREYA) and healthcare providers were represented by gynaecologists and their society (The Netherlands Society of Obstetrics and Gynaecology), embryologists and their society (The Dutch Federation of Clinical Embryology) as well as fertility doctors. A panel of experts hypothesized on barriers and facilitators for the implementation of home-based monitoring during the proposal phase of the Antarctica-2 randomized controlled trial (RCT). PARTICIPANTS/MATERIALS SETTING METHODS: All stakeholders were represented during the study. Two different questionnaires were developed in order to investigate facilitators and barriers for the patients and for healthcare providers. The facilitators and barriers were ranked on a scale of 1-10 with 10 being the most important. Based on our power analysis, we aimed for a minimum of 300 completed questionnaires for the patients and a minimum of 90 completed questionnaires for the healthcare providers. Facilitators and barriers were analysed using frequencies, mean (SD) and ranking. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 311 patients filled out the questionnaire of whom 86.8% underwent FET previously. The most important facilitator for the patients was to implement the strategy with the highest chance of pregnancy (mean 9.7; 95% CI 9.6-9.7) and the most important barrier was risk of missing ovulation (mean 8.4; 95% CI 8.2-8.6). A total of 96 healthcare providers filled out the questionnaire. According to healthcare providers, patients would accept the strategy when it causes less interference with their work and private life (mean 7.5; 95% CI 7.1-8.0) and has a low risk of missing the ovulation (mean 7.6; 95% CI 7.1-8.0). The most important facilitator for the implementation of home-based monitoring for healthcare providers was optimizing cumulative pregnancy rates (mean 8.1; 95% CI 7.7-8.4) and the most important barrier was the lack of laboratory capacity and flexibility (mean 6.4; 95% CI 5.8-7.0). LIMITATIONS REASONS FOR CAUTION: Facilitators and barriers were selected based on expert opinion. Currently, there are no validated questionnaires that aim to assess facilitators and barriers for the implementation of treatments in fertility care. WIDER IMPLICATIONS OF THE FINDINGS: During our study, we gained insight into barriers and facilitators for the implementation of home-based monitoring of NC-FET at an early phase. Early sharing and discussion of the results of this study with all stakeholders involved should stimulate a fast incorporation in guidelines, especially as key professionals in guideline development took part in this study. Also, based on our results, we can advise guideline developers to add tools to the guideline that may help overcome the implementation barriers. STUDY FUNDING/COMPETING INTERESTS: The Antarctica-2 RCT is supported by a grant from the Netherlands Organisation for Health Research and Development (ZonMw 843002807). No authors have any competing interests to declare. TRIAL REGISTRATION NUMBER: Trial NL6414 (NTR6590).
ABSTRACT
STUDY QUESTION: Is a single endometrial scratch prior to the second fresh IVF/ICSI treatment cost-effective compared to no scratch, when evaluated over a 12-month follow-up period? SUMMARY ANSWER: The incremental cost-effectiveness ratio (ICER) for an endometrial scratch was 6524 per additional live birth, but due to uncertainty regarding the increase in live birth rate this has to be interpreted with caution. WHAT IS KNOWN ALREADY: Endometrial scratching is thought to improve the chances of success in couples with previously failed embryo implantation in IVF/ICSI treatment. It has been widely implemented in daily practice, despite the lack of conclusive evidence of its effectiveness and without investigating whether scratching allows for a cost-effective method to reduce the number of IVF/ICSI cycles needed to achieve a live birth. STUDY DESIGN, SIZE, DURATION: This economic evaluation is based on a multicentre randomized controlled trial carried out in the Netherlands (SCRaTCH trial) that compared a single scratch prior to the second IVF/ICSI treatment with no scratch in couples with a failed full first IVF/ICSI cycle. Follow-up was 12 months after randomization.Economic evaluation was performed from a healthcare and societal perspective by taking both direct medical costs and lost productivity costs into account. It was performed for the primary outcome of biochemical pregnancy leading to live birth after 12 months of follow-up as well as the secondary outcome of live birth after the second fresh IVF/ICSI treatment (i.e. the first after randomization). To allow for worldwide interpretation of the data, cost level scenario analysis and sensitivity analysis was performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: From January 2016 until July 2018, 933 women with a failed first IVF/ICSI cycle were included in the trial. Data on treatment and pregnancy were recorded up until 12 months after randomization, and the resulting live birth outcomes (even if after 12 months) were also recorded.Total costs were calculated for the second fresh IVF/ICSI treatment and for the full 12 month period for each participant. We included costs of all treatments, medication, complications and lost productivity costs. Cost-effectiveness analysis was carried out by calculating ICERs for scratch compared to control. Bootstrap resampling was used to estimate the uncertainty around cost and effect differences and ICERs. In the sensitivity and scenario analyses, various unit costs for a single scratch were introduced, amongst them, unit costs as they apply for the United Kingdom (UK). MAIN RESULTS AND THE ROLE OF CHANCE: More live births occurred in the scratch group, but this also came with increased costs over a 12-month period. The estimated chance of a live birth after 12 months of follow-up was 44.1% in the scratch group compared to 39.3% in the control group (risk difference 4.8%, 95% CI -1.6% to +11.2%). The mean costs were on average 283 (95% CI: -299 to 810) higher in the scratch group so that the point average ICER was 5846 per additional live birth. The ICER estimate was surrounded with a high level of uncertainty, as indicated by the fact that the cost-effectiveness acceptability curve (CEAC) showed that there is an 80% chance that endometrial scratching is cost-effective if society is willing to pay â¼17â500 for each additional live birth. LIMITATIONS, REASONS FOR CAUTION: There was a high uncertainty surrounding the effects, mainly in the clinical effect, i.e. the difference in the chance of live birth, which meant that a single straightforward conclusion could not be ascertained as for now. WIDER IMPLICATIONS OF THE FINDINGS: This is the first formal cost-effectiveness analysis of endometrial scratching in women undergoing IVF/ICSI treatment. The results presented in this manuscript cannot provide a clear-cut expenditure for one additional birth, but they do allow for estimating costs per additional live birth in different scenarios once the clinical effectiveness of scratching is known. As the SCRaTCH trial was the only trial with a follow-up of 12 months, it allows for the most complete estimation of costs to date. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by ZonMW, the Dutch organization for funding healthcare research. A.E.P.C., F.J.M.B., E.R.G. and C.B. L. reported having received fees or grants during, but outside of, this trial. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NL5193/NTR 5342).
Subject(s)
Fertilization in Vitro , Sperm Injections, Intracytoplasmic , Birth Rate , Cost-Benefit Analysis , Female , Fertilization in Vitro/methods , Humans , Live Birth , Male , Pregnancy , Pregnancy Rate , Sperm Injections, Intracytoplasmic/methodsABSTRACT
STUDY QUESTION: Is pregnancy success rate after a concise infertility work-up the same as pregnancy success rate after the traditional extensive infertility work-up? SUMMARY ANSWER: The ongoing pregnancy rate within a follow-up of 1 year after a concise infertility work-up is significantly lower than the pregnancy success rate after the traditional and extensive infertility work-up. WHAT IS KNOWN ALREADY: Based on cost-effectiveness studies, which have mainly focused on diagnosis, infertility work-up has become less comprehensive. Many centres have even adopted a one-stop approach to their infertility work-up. STUDY DESIGN SIZE DURATION: We performed a historically controlled cohort study. In 2012 and 2013 all new infertile couples (n = 795) underwent an extensive infertility work-up (group A). In 2014 and 2015, all new infertile couples (n = 752) underwent a concise infertility work-up (group B). The follow-up period was 1 year for both groups. Complete follow-up was available for 99.0% of couples in group A and 97.5% in group B. PARTICIPANTS/MATERIALS SETTING METHODS: The extensive infertility work-up consisted of history taking, a gynaecological ultrasound scan, semen analysis, ultrasonographic cycle monitoring, a timed postcoital test, a timed progesterone and chlamydia antibody titre. A hysterosalpingography (HSG) was advised routinely. The concise infertility work-up was mainly based on history taking, a gynaecological ultrasound scan and semen analysis. A HSG was only performed if tubal pathology was suspected or before the start of IUI. Laparoscopy and hormonal tests were only performed if indicated. Couples were treated according to the diagnosis with either expectant management (if the Hunault prognostic score was >30%), ovulation induction (in case of ovulation disorders), IUI in natural cycles (in case of cervical factor), IUI in stimulated cycles (if the Hunault prognostic score was <30%) or IVF/ICSI (in case of tubal factor, advanced female age, severe male factor and if other treatments remained unsuccessful). The primary outcomes were time to pregnancy and the ongoing pregnancy rates in both groups. The secondary outcomes were the number of investigations, the distribution of diagnoses made, the first treatment (started) after infertility work-up and the mode of conception. MAIN RESULTS AND THE ROLE OF CHANCE: The descriptive data, such as age, duration of infertility, type of infertility and lifestyle habits, in both groups were comparable. In group A, more than twice the number of infertility investigations were performed, compared to group B. An HSG was made less frequently in group B (33% versus 42%) and at a later stage. A Kaplan-Meier curve shows a shorter time to pregnancy in group A. Also, a significantly higher overall ongoing pregnancy rate within a follow-up of 1 year was found in group A (58.7% versus 46.8%, respectively, P < 0.001). In group A, more couples conceived during the infertility work-up (14.7% versus 6.5%, respectively, P < 0.05). The diagnosis cervical infertility could only be made in group A (9.3%). The diagnosis unexplained infertility differed between groups, at 23.5% in group A and 32.2% in group B (P < 0.001). LIMITATIONS REASONS FOR CAUTION: This was a historically controlled cohort study; introduction of bias cannot be ruled out. The follow-up rate was similar in the two groups and therefore could not explain the differences in pregnancy rate. WIDER IMPLICATIONS OF THE FINDINGS: Re-introduction of an extensive infertility work-up should be considered as it may lead to higher ongoing pregnancy rates within a year. The therapeutic effects of HSG and timing of intercourse may improve the fertility chance. This finding should be verified in a randomized controlled trial. STUDY FUNDING/COMPETING INTERESTS: No funding was obtained for this study. No conflicts of interest were declared. TRIAL REGISTRATION NUMBER: N/A.
ABSTRACT
STUDY QUESTION: The objective of this trial is to compare the effectiveness and costs of true natural cycle (true NC-) frozen embryo transfer (FET) using urinary LH tests to modified NC-FET using repeated ultrasound monitoring and ovulation trigger to time FET in the NC. Secondary outcomes are the cancellation rates of FET (ovulation before hCG or no dominant follicle, no ovulation by LH urine test, poor embryo survival), pregnancy outcomes (miscarriage rate, clinical pregnancy rates, multiple ongoing pregnancy rates, live birth rates, costs) and neonatal outcomes (including gestational age, birthweight and sex, congenital abnormalities or diseases of babies born). WHAT IS KNOWN ALREADY: FET is at the heart of modern IVF. To allow implantation of the thawed embryo, the endometrium must be prepared either by exogenous oestrogen and progesterone supplementation (artificial cycle (AC)-FET) or by using the NC to produce endogenous oestradiol before and progesterone after ovulation to time the transfer of the thawed embryo (NC-FET). During an NC-FET, women visit the hospital repeatedly and receive an ovulation trigger to time FET (i.e. modified (m)NC-FET or hospital-based monitoring). From the woman's point of view, a more natural approach using home-based monitoring of the ovulation with LH urine tests to allow a natural ovulation to time FET may be desired (true NC-FET or home-based monitoring). STUDY DESIGN SIZE DURATION: This is a multicentre, non-inferiority prospective randomised controlled trial design. Consenting women will undergo one FET cycle using either true NC-FET or mNC-FET based on randomisation. PARTICIPANTS/MATERIALS SETTING METHODS: Based on our sample size calculation, the study group will consist of 1464 women between 18 and 45 years old who are scheduled for FET. Women with anovulatory cycles, women who need ovulation induction and women with a contra indication for pregnancy will be excluded. The primary outcome is ongoing pregnancy. Secondary outcomes are cancellation rates of FET, pregnancy outcomes (including miscarriage rate, clinical pregnancy, multiple pregnancy rate and live birth rate). Costs will be estimated by counting resource use and calculating unit prices. STUDY FUNDING/COMPETING INTERESTS: The study received a grant from the Dutch Organisation for Health Research and Development (ZonMw 843002807; www.zonmw.nl). ZonMw has no role in the design of the study, collection, analysis, and interpretation of data or writing of the manuscript. F.B. reports personal fees from member of the external advisory board for Merck Serono, grants from Research support grant Merck Serono, outside the submitted work. A.E.P.C. reports and Unrestricted grant of Ferring B.V. to the Center for Reproductive medicine, no personal fee. Author up-to-date on Hyperthecosis. Congress meetings 2019 with Ferring B.V. and Theramex B.V. M.G. reports Department research and educational grants from Guerbet, Merck and Ferring (location VUMC) outside the submitted work. E.R.G. reports personal fees from Titus Health Care, outside the submitted work. C.B.L. reports grants from Ferring, grants from Merck, from Guerbet, outside the submitted work. The other authors have none to declare. TRIAL REGISTRATION NUMBER: Dutch Trial Register (Trial NL6414 (NTR6590), https://www.trialregister.nl/). TRIAL REGISTRATION DATE: 23 July 2017. DATE OF FIRST PATIENT'S ENROLMENT: 10 April 2018.
ABSTRACT
STUDY QUESTION: Does endometrial scratching in women with one failed IVF/ICSI treatment affect the chance of a live birth of the subsequent fresh IVF/ICSI cycle? SUMMARY ANSWER: In this study, 4.6% more live births were observed in the scratch group, with a likely certainty range between -0.7% and +9.9%. WHAT IS KNOWN ALREADY: Since the first suggestion that endometrial scratching might improve embryo implantation during IVF/ICSI, many clinical trials have been conducted. However, due to limitations in sample size and study quality, it remains unclear whether endometrial scratching improves IVF/ICSI outcomes. STUDY DESIGN, SIZE, DURATION: The SCRaTCH trial was a non-blinded randomised controlled trial in women with one unsuccessful IVF/ICSI cycle and assessed whether a single endometrial scratch using an endometrial biopsy catheter would lead to a higher live birth rate after the subsequent IVF/ICSI treatment compared to no scratch. The study took place in 8 academic and 24 general hospitals. Participants were randomised between January 2016 and July 2018 by a web-based randomisation programme. Secondary outcomes included cumulative 12-month ongoing pregnancy leading to live birth rate. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with one previous failed IVF/ICSI treatment and planning a second fresh IVF/ICSI treatment were eligible. In total, 933 participants out of 1065 eligibles were included (participation rate 88%). MAIN RESULTS AND THE ROLE OF CHANCE: After the fresh transfer, 4.6% more live births were observed in the scratch compared to control group (110/465 versus 88/461, respectively, risk ratio (RR) 1.24 [95% CI 0.96-1.59]). These data are consistent with a true difference of between -0.7% and +9.9% (95% CI), indicating that while the largest proportion of the 95% CI is positive, scratching could have no or even a small negative effect. Biochemical pregnancy loss and miscarriage rate did not differ between the two groups: in the scratch group 27/153 biochemical pregnancy losses and 14/126 miscarriages occurred, while this was 19/130 and 17/111 for the control group (RR 1.21 (95% CI 0.71-2.07) and RR 0.73 (95% CI 0.38-1.40), respectively). After 12 months of follow-up, 5.1% more live births were observed in the scratch group (202/467 versus 178/466), of which the true difference most likely lies between -1.2% and +11.4% (95% CI). LIMITATIONS, REASONS FOR CAUTION: This study was not blinded. Knowledge of allocation may have been an incentive for participants allocated to the scratch group to continue treatment in situations where they may otherwise have cancelled or stopped. In addition, this study was powered to detect a difference in live birth rate of 9%. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study are an incentive for further assessment of the efficacy and clinical implications of endometrial scratching. If a true effect exists, it may be smaller than previously anticipated or may be limited to specific groups of women undergoing IVF/ICSI. Studying this will require larger sample sizes, which will be provided by the ongoing international individual participant data-analysis (PROSPERO CRD42017079120). At present, endometrial scratching should not be performed outside of clinical trials. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by ZonMW, the Dutch organisation for funding healthcare research. J.S.E. Laven reports grants and personal fees from AnshLabs (Webster, Tx, USA), Ferring (Hoofddorp, The Netherlands) and Ministry of Health (CIBG, The Hague, The Netherlands) outside the submitted work. A.E.P. Cantineau reports 'other' from Ferring BV, personal fees from Up to date Hyperthecosis, 'other' from Theramex BV, outside the submitted work. E.R. Groenewoud reports grants from Titus Health Care during the conduct of the study. A.M. van Heusden reports personal fees from Merck Serono, personal fees from Ferring, personal fees from Goodlife, outside the submitted work. F.J.M. Broekmans reports personal fees as Member of the external advisory board for Ferring BV, The Netherlands, personal fees as Member of the external advisory board for Merck Serono, The Netherlands, personal fees as Member of the external advisory for Gedeon Richter, Belgium, personal fees from Educational activities for Ferring BV, The Netherlands, grants from Research support grant Merck Serono, grants from Research support grant Ferring, personal fees from Advisory and consultancy work Roche, outside the submitted work. C.B. Lambalk reports grants from Ferring, grants from Merck, grants from Guerbet, outside the submitted work. TRIAL REGISTRATION NUMBER: Registered in the Netherlands Trial Register (NL5193/NTR 5342). TRIAL REGISTRATION DATE: 31 July 2015. DATE OF FIRST PATIENT'S ENROLMENT: 26 January 2016.
Subject(s)
Live Birth , Sperm Injections, Intracytoplasmic , Belgium , Birth Rate , Female , Fertilization in Vitro , Humans , Netherlands , Pregnancy , Pregnancy RateABSTRACT
OBJECTIVE: The new 2019 guideline of the European Society for Vascular Surgery (ESVS) recommends consideration for elective iliac artery aneurysm (eIAA) repair when the iliac diameter exceeds 3.5 cm, as opposed to 3.0 cm previously. The current study assessed diameters at time of eIAA repair and ruptured IAA (rIAA) repair and compared clinical outcomes after open surgical repair (OSR) and endovascular aneurysm repair (EVAR). METHODS: This retrospective observational study used the nationwide Dutch Surgical Aneurysm Audit (DSAA) registry that includes all patients who undergo aorto-iliac aneurysm repair in the Netherlands. All patients who underwent primary IAA repair between 1 January 2014 and 1 January 2018 were included. Diameters at time of eIAA and rIAA repair were compared in a descriptive fashion. The anatomical location of the IAA was not registered in the registry. Patient characteristics and outcomes of OSR and EVAR were compared with appropriate statistical tests. RESULTS: The DSAA registry comprised 974 patients who underwent IAA repair. A total of 851 patients were included after exclusion of patients undergoing revision surgery and patients with missing essential variables. eIAA repair was carried out in 713 patients, rIAA repair in 102, and symptomatic IAA repair in 36. OSR was performed in 205, EVAR in 618, and hybrid repairs and conversions in 28. The median maximum IAA diameter at the time of eIAA and rIAA repair was 43 (IQR 38-50) mm and 68 (IQR 58-85) mm, respectively. Mortality was 1.3% (95% CI 0.7-2.4) after eIAA repair and 25.5% (95% CI 18.0-34.7) after rIAA repair. Mortality was not significantly different between the OSR and EVAR subgroups. Elective OSR was associated with significantly more complications than EVAR (intra-operative: 9.8% vs. 3.6%, post-operative: 34.0% vs. 13.8%, respectively). CONCLUSION: In the Netherlands, most eIAA repairs are performed at diameters larger than recommended by the ESVS guideline. These findings appear to support the recent increase in the threshold diameter for eIAA repair.
Subject(s)
Iliac Aneurysm/surgery , Aged , Aged, 80 and over , Endovascular Procedures/methods , Endovascular Procedures/mortality , Endovascular Procedures/statistics & numerical data , Female , Guideline Adherence/statistics & numerical data , Humans , Iliac Aneurysm/epidemiology , Iliac Aneurysm/mortality , Iliac Aneurysm/pathology , Iliac Artery/pathology , Iliac Artery/surgery , Male , Netherlands/epidemiology , Registries , Retrospective Studies , Sex Factors , Treatment OutcomeABSTRACT
STUDY QUESTION: What are the patient-reported outcomes (PROs) and patient-reported experiences (PREs) in home-based monitoring compared to those in hospital-based monitoring of ovulation for scheduling frozen-thawed embryo transfer (FET)? SUMMARY ANSWER: Women undergoing either home-based or hospital-based monitoring experience an increase in anxiety/sadness symptoms over time, but women undergoing home-based monitoring felt more empowered during the treatment and classified the monitoring as more discreet compared to hospital-based monitoring. WHAT IS KNOWN ALREADY: FET is at the heart of modern IVF. The two types of FET cycles that are mainly are used are artificial cycle FET, using artificial preparation of the endometrium with exogenous progesterone and oestrogen, and natural cycle FET (NC-FET). During a natural cycle FET, women visit the hospital repeatedly and receive an ovulation trigger to time FET (i.e. modified NC-FET or hospital-based monitoring). The previously published Antarctica randomised controlled trial (NTR 1586) showed that modified NC-FET is more cost-effective compared to artificial cycle FET. From the women's point of view a more natural approach using home-based monitoring of ovulation with LH urine tests to time FET may be desired (true NC-FET or home-based monitoring). Currently, the multicentre Antarctica-2 randomised controlled trial (RCT) is comparing the cost-effectiveness of home-based monitoring of ovulation with that of hospital-based monitoring of ovulation. The Antarctica-2 RCT enables us to study PROs, defined as the view of participating women of their healthcare status, and PREs, defined as the perception of the received care of participating women, in both FET strategies. STUDY DESIGN, SIZE, DURATION: PROs and PREs were assessed alongside the Antarctica-2 RCT. PROs were assessed using the validated EuroQol-5D-5L questionnaire. Currently, there are no guidelines for assessing PREs in this population. Therefore, members of the Dutch Patient Organisation for Couples with Fertility Problems (FREYA) filled out an online survey and selected the following PREs to assess (i) anxiety about missing ovulation, (ii) perceived level of partner participation, (iii) level of discretion, (iv) feeling of empowerment and (v) satisfaction with treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women participating in the RCT also participated in PRO and PRE assessment. We assessed PROs and PREs at three time points: (i) before randomisation, (ii) at the time of the FET and (iii) at the time of the pregnancy test. A sample size of 200 participants was needed to find a difference of 0.3 with a standard deviation in both groups of 0.7, an alpha of 5%, power of 80% and a drop-out rate of 10%. We performed mixed model analysis for between-group comparison of treatment and time effects. MAIN RESULTS AND ROLE OF CHANCE: A total of 260 women were randomised. Of these, 132 women were treated with home-based monitoring and 128 women were treated with hospital-based monitoring. Data before randomisation were available for 232 women (home-based monitoring n = 116, hospital-based monitoring n = 116). For the PROs, we found a significant increase in anxiety/sadness symptoms over time (P < 0.001) in both groups. We found no treatment effect of home-based versus hospital-based monitoring for the PROs (P = 0.8). Concerning the PRES, we found that women felt more empowered during home-based monitoring (P = 0.001) and classified the home-based monitoring as more discreet (P = 0.000) compared to the hospital-based monitoring. LIMITATIONS, REASONS FOR CAUTION: The results are applicable only to women undergoing NC-FET and not to women undergoing artificial cycle FET. WIDER IMPLICATIONS OF THE FINDINGS: Apart from clinical outcomes, PROs and PREs are also of importance in clinical decision-making and to support tailoring treatment even more specifically to the wishes of patients. Measurement of PROs and PREs should therefore be incorporated in future clinical research. STUDY FUNDING/COMPETING INTEREST(S): The Antarctica-2 RCT is supported by a grant of the Netherlands Organisation for Health Research and Development (ZonMw 843002807). J.B. receives unconditional educational grants from Merck Serono and Ferring and is a member of the medical advisory board of Ferring. C.L. reports that his department receives unrestricted research grants from Ferring, Merck and Guerbet. E.G. receives personal fees from Titus Health Care outside submitted work. The remaining authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: Trial NL6414 (NTR6590). TRIAL REGISTER DATE: 23 July 2017. DATE OF FIRST PATIENT'S ENROLMENT: 10 April 2018.
Subject(s)
Embryo Transfer , Hospitals , Antarctic Regions , Female , Humans , Netherlands , Ovulation Induction , Patient Reported Outcome Measures , Pregnancy , Pregnancy RateABSTRACT
STUDY QUESTION: What are the preferences of women with an increased risk of ovarian hyperstimulation syndrome (OHSS) for characteristics of IVF treatments? SUMMARY ANSWER: In women with increased risk of OHSS, the chance of OHSS is a strong attribute in determining women's preference for IVF treatment and women are willing to trade off burden (side effects), costs and chance of pregnancy for lower risks of OHSS. WHAT IS KNOWN ALREADY: OHSS is the most serious iatrogenic complication of ovarian stimulation. Polycystic ovaries, high antral follicle count (AFC) and previous OHSS increase the risk of developing OHSS. IVM of oocytes offers great potential for patients with high AFC, since there is no risk of OHSS. With regard to patients' perspectives on fertility treatments, it has been shown that women undergoing IVF place different values on treatment characteristics, such as effectiveness (pregnancy rate), cancellation risk, safety (OHSS risk) and burden (side effects). To our knowledge, the preferences for different IVF treatments in women with increased risk of OHSS have not been studied yet. STUDY DESIGN SIZE DURATION: A multicentre discrete choice experiment (DCE) was performed between 2012 and 2016. The selected attributes offered were chance of OHSS, which represents safety; number of injections; chance of cycle cancellation (the latter two represent burden); chance of pregnancy; and out-of-pocket costs/willingness to pay. A target sample size was calculated by including 20 patients for five attributes resulting in the aim to include 100 women. PARTICIPANTS/MATERIALS SETTING METHODS: We invited subfertile women who were diagnosed with normogonadotrophic ovulation disorder and were undergoing treatment with gonadotrophins and/or had experienced (imminent) OHSS in a previous IVF treatment in the fertility clinic of four hospitals (three teaching and one academic). Women received a printed questionnaire with fictional scenarios and were asked, for each scenario, to choose their preferred treatment. We used a multinominal logit model to determine the preferences of women and investigated heterogeneity in preferences through latent class analysis. The decrease in OHSS risk required for women to accept an increased level of an undesirable attribute, i.e. their willingness to trade off, was calculated. MAIN RESULTS AND THE ROLE OF CHANCE: We distributed 120 questionnaires with a response rate of 79% (95/120). There were 91 questionnaires included in the analysis. All five attributes influenced women's treatment preference. About half of the women considered chance of pregnancy to be more important, while the other half considered prevention of OHSS and lower costs to be more important. Women were willing to trade off cancellation rate, number of injections, chance of pregnancy and costs for lower OHSS chances. We found that women were willing to accept 5% more chance on cycle cancellation if the OHSS rate dropped with 2%. Women were willing to accept one extra treatment for a reduction of 3.9% in OHSS risk. With respect to costs, women were willing to pay 1000 instead of no costs for a decrease in OHSS rate of 5.4%. LIMITATIONS REASONS FOR CAUTION: The sample size of our study is relatively small which may limit the generalizability and sensitivity of the study. WIDER IMPLICATIONS OF THE FINDINGS: The results of this DCE help us to understand the trade-off that women at risk of OHSS make in their preference for characteristics on IVF treatments. This knowledge may be used during the counselling of couples about their treatment options. STUDY FUNDING/COMPETING INTERESTS: B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for Merck, ObsEva and Guerbet. J.P.d.B. reports personal fees from the Ferring Medical Advisory Board and grants from Ferring B. V and Merck Serono B. V outside the submitted work. There are no other conflicts of interest to declare. TRIAL REGISTRATION NUMBER: None.
ABSTRACT
STUDY QUESTION: Does pain or volume of used contrast medium impact the effectiveness of oil-based contrast during hysterosalpingography (HSG)? SUMMARY ANSWER: In women who report moderate to severe pain during HSG, the use of oil-based contrast resulted in more ongoing pregnancies compared to the use of water-based contrast, whereas in women who reported mild or no pain, no difference in ongoing pregnancies was found. WHAT IS KNOWN ALREADY: We recently showed that in infertile women undergoing HSG, the use of oil-based contrast results in more ongoing pregnancies within 6 months as compared to the use of water-based contrast. However, the underlying mechanism of this fertility-enhancing effect remains unclear. STUDY DESIGN, SIZE, DURATION: We performed a post-hoc analysis of the H2Oil study, a multicentre randomised controlled trial (RCT) evaluating the therapeutic effect of oil- and water-based contrast at HSG. Here, we evaluated the impact of pain experienced at HSG and volume of used contrast media during HSG on ongoing pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS: In a subset of 400 participating women, pain during HSG by means of the Visual Analogue Scale (VAS) (range: 0.0-10.0 cm) was reported, while in 512 women, we registered the volume of used contrast (in millilitres). We used logistic regression analyses to assess whether pain and volume of used contrast media modified the effect of oil-based contrast on ongoing pregnancy rates. Data were analysed according to intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: In 400 women in whom pain scores were reported, the overall median pain score was 5.0 (Interquartile range (IQR) 3.0-6.8) (oil group (n = 199) 4.8 (IQR 3.0-6.4); water group (n = 201) 5.0 (IQR 3.0-6.7); P-value 0.28). There was a significant interaction between pain (VAS ≤5 versus VAS ≥6) and the primary outcome ongoing pregnancy (P-value 0.047). In women experiencing pain (VAS ≥6), HSG with oil-based contrast resulted in better 6-month ongoing pregnancy rates compared to HSG with water-based contrast (49.4% versus 29.6%; RR 1.7; 95% CI, 1.1-2.5), while in women with a pain score ≤5, 6-month ongoing pregnancy rates were not significantly different between the use of oil- (28.8%) versus water-based contrast (29.2%) (RR 0.99; 95% CI, 0.66-1.5). In the 512 women in whom we recorded contrast, median volume was 9.0 ml (IQR 5.7-15.0) in the oil group versus 8.0 ml (IQR 5.9-13.0) in the water group, respectively (P-value 0.72). Volume of used contrast was not found to modify the effect of oil-based contrast on ongoing pregnancy (P-value for interaction 0.23). LIMITATIONS, REASONS FOR CAUTION: This was a post-hoc analysis that should be considered as hypothesis generating. The RCT was restricted to infertile ovulatory women, younger than 39 years of age and with a low risk for tubal pathology. Therefore, our results should not be generalised to infertile women who do not share these features. WIDER IMPLICATIONS OF THE FINDINGS: The underlying mechanism of the fertility-enhancing effect induced by HSG with the use of oil-based contrast remains unclear. However, these findings suggest a possible mechanistic pathway, that is increasing intrauterine pressure occurring prior to dislodging pregnancy hindering debris or mucus plugs from the proximal part of otherwise normal fallopian tubes. This information might help in the search of the underlying fertility-enhancing mechanism found by using oil-based contrast during HSG. STUDY FUNDING/COMPETING INTEREST(S): The original H2Oil RCT was an investigator-initiated study that was funded by the two academic institutions (AMC and VUmc) of the Amsterdam UMC. The funders had no role in study design, collection, analysis and interpretation of the data. K.D. reports consultancy for Guerbet. H.V. reports consultancy fees from Ferring. C.B.L. reports speakers' fees from Ferring and research grants from Ferring, Merck and Guerbet. V.M. reports receiving travel and speakers fees as well as research grants from Guerbet. B.W.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck KGaA and Guerbet and travel and research grants from Merck KGaA and Guerbet. The other authors do not report conflict of interests. TRIAL REGISTRATION NUMBER: The H2Oil study was registered at the Netherlands Trial Registry (NTR 3270). TRIAL REGISTRATION DATE: 1 February 2012. DATE OF FIRST PATIENT'S ENROLMENT: 3 February 2012.
Subject(s)
Contrast Media , Ethiodized Oil , Hysterosalpingography/adverse effects , Iothalamic Acid/analogs & derivatives , Pain, Procedural/etiology , Pregnancy Rate , Adult , Female , Humans , PregnancyABSTRACT
BACKGROUND: In the Netherlands, couples with unexplained infertility and a good prognosis to conceive spontaneously (i.e. Hunault > 30%) are advised to perform timed intercourse for at least another 6 months. If couples fail to conceive within this period, they will usually start assisted reproductive technology (ART). However, treatment of unexplained infertility by ART is empirical and can involve significant burdens. Intentional endometrial injury, also called 'endometrial scratching', has been proposed to positively affect the chance of embryo implantation in patients undergoing in vitro fertilization (IVF). It might also be beneficial for couples with unexplained infertility as defective endometrial receptivity may play a role in these women. The primary aim of this study is to determine whether endometrial scratching increases live birth rates in women with unexplained infertility. METHOD: A multicentre randomized controlled trial will be conducted in Dutch academic and non-academic hospitals starting from November 2017. A total of 792 women with unexplained infertility and a good prognosis for spontaneous conception < 12 months (Hunault > 30%) will be included, of whom half will undergo endometrial scratching in the luteal phase of the natural cycle. The women in the control group will not undergo endometrial scratching. According to Dutch guidelines, both groups will subsequently perform timed intercourse for at least 6 months. The primary endpoint is cumulative live birth rate. Secondary endpoints are clinical and ongoing pregnancy rate; miscarriage rate; biochemical pregnancy loss; multiple pregnancy rate; time to pregnancy; progression to intrauterine insemination (IUI) or IVF; pregnancy complications; complications of endometrial scratching; costs and endometrial tissue parameters associated with reproductive success or failure. The follow-up duration is 12 months. DISCUSSION: Several small studies show a possible beneficial effect of endometrial scratching in women with unexplained infertility trying to conceive naturally or through IUI. However, the quality of this evidence is very low, making it unclear whether these women will truly benefit from this procedure. The SCRaTCH-OFO trial aims to investigate the effect of endometrial scratching on live birth rate in women with unexplained infertility and a good prognosis for spontaneous conception < 12 months. TRIAL REGISTRATION: NTR6687 , registered August 31st, 2017. PROTOCOL VERSION: Version 2.6, November 14th, 2018.
Subject(s)
Birth Rate , Endometrium/surgery , Infertility, Female/therapy , Reproductive Techniques, Assisted , Abortion, Spontaneous , Adolescent , Adult , Female , Humans , Live Birth , Luteal Phase , Multicenter Studies as Topic , Netherlands , Prognosis , Randomized Controlled Trials as Topic , Reproductive Techniques, Assisted/economics , Young AdultABSTRACT
Interactions between the constituents of a condensed matter system can drive it through a plethora of different phases due to many-body effects. A prominent platform for it is a dilute two-dimensional electron system in a magnetic field, which evolves intricately through various gaseous, liquid and solid phases governed by Coulomb interaction. Here we report on the experimental observation of a phase transition between the composite fermion liquid and adjacent magnetic field induced phase with a character of Wigner solid. The experiments are performed in the lowest Landau level of a MgZnO/ZnO two-dimensional electron system with attributes of both a liquid and a solid. An in-plane magnetic field component applied on top of the perpendicular magnetic field extends the Wigner-like phase further into the composite fermion liquid phase region. Our observations indicate the direct competition between a composite fermion liquid and a Wigner solid formed either by electrons or composite fermions.
ABSTRACT
STUDY QUESTION: Is FSH or clomiphene citrate (CC) the most effective stimulation regimen in terms of ongoing pregnancies in couples with unexplained subfertility undergoing IUI with adherence to strict cancellation criteria as a measure to reduce the number of multiple pregnancies? SUMMARY ANSWER: In IUI with adherence to strict cancellation criteria, ovarian stimulation with FSH is not superior to CC in terms of the cumulative ongoing pregnancy rate, and yields a similar, low multiple pregnancy rate. WHAT IS ALREADY KNOWN: FSH has been shown to result in higher pregnancy rates compared to CC, but at the cost of high multiple pregnancy rates. To reduce the risk of multiple pregnancy, new ovarian stimulation regimens have been suggested, these include strict cancellation criteria to limit the number of dominant follicles per cycle i.e. withholding insemination when more than three dominant follicles develop. With such a strategy, it is unclear whether the ovarian stimulation should be done with FSH or with CC. STUDY DESIGN, SIZE, DURATION: We performed an open-label multicenter randomized superiority controlled trial in the Netherlands (NTR 4057). PARTICIPANTS/MATERIALS, SETTING, METHODS: We randomized couples diagnosed with unexplained subfertility and scheduled for a maximum of four cycles of IUI with ovarian stimulation with 75 IU FSH or 100 mg CC. Cycles were cancelled when more then three dominant follicles developed. The primary outcome was cumulative ongoing pregnancy rate. Multiple pregnancy was a secondary outcome. We analysed the data on intention to treat basis. We calculated relative risks and absolute risk difference with 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: Between July 2013 and March 2016, we allocated 369 women to ovarian stimulation with FSH and 369 women to ovarian stimulation with CC. A total of 113 women (31%) had an ongoing pregnancy following ovarian stimulation with FSH and 97 women (26%) had an ongoing pregnancy following ovarian stimulation with CC (RR = 1.16, 95% CI: 0.93-1.47, ARD = 0.04, 95% CI: -0.02 to 0.11). Five women (1.4%) had a multiple pregnancy following ovarian stimulation with FSH and eight women (2.2%) had a multiple pregnancy following ovarian stimulation with CC (RR = 0.63, 95% CI: 0.21-1.89, ARD = -0.01, 95% CI: -0.03 to 0.01). LIMITATIONS, REASONS FOR CAUTION: We were not able to blind this study due to the nature of the interventions. We consider it unlikely that this has introduced performance bias, since pregnancy outcomes are objective outcome measures. WIDER IMPLICATIONS OF THE FINDINGS: We revealed that adherence to strict cancellation criteria is a successful solution to reduce the number of multiple pregnancies in IUI. To decide whether ovarian stimulation with FSH or with CC should be the regimen of choice, costs and patients' preferences should be taken into account. STUDY FUNDING/COMPETING INTEREST(S): This trial received funding from the Dutch Organization for Health Research and Development (ZonMw). Prof. Dr B.W.J. Mol is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for Merck, ObsEva and Guerbet. The other authors declare that they have no competing interests. TRIAL REGISTRATION NUMBER: Nederlands Trial Register NTR4057. TRIAL REGISTRATION DATE: 1 July 2013. DATE OF FIRST PATIENT'S ENROLMENT: The first patient was randomized at 27 August 2013.
Subject(s)
Clomiphene/therapeutic use , Fertility Agents, Female/therapeutic use , Follicle Stimulating Hormone/therapeutic use , Ovulation Induction/methods , Sperm Injections, Intracytoplasmic/drug effects , Adult , Birth Rate , Female , Humans , Infertility, Female/drug therapy , Pregnancy , Pregnancy, Multiple/drug effectsABSTRACT
BACKGROUND: Success rates of assisted reproductive techniques (ART) are approximately 30%, with the most important limiting factor being embryo implantation. Mechanical endometrial injury, also called 'scratching', has been proposed to positively affect the chance of implantation after embryo transfer, but the currently available evidence is not yet conclusive. The primary aim of this study is to determine the effect of endometrial scratching prior to a second fresh in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycle on live birth rates in women with a failed first IVF/ICSI cycle. METHOD: Multicenter randomized controlled trial in Dutch academic and non-academic hospitals. A total of 900 women will be included of whom half will undergo an endometrial scratch in the luteal phase of the cycle prior to controlled ovarian hyperstimulation using an endometrial biopsy catheter. The primary endpoint is the live birth rate after the 2nd fresh IVF/ICSI cycle. Secondary endpoints are costs, cumulative live birth rate (after the full 2nd IVF/ICSI cycle and over 12 months of follow-up); clinical and ongoing pregnancy rate; multiple pregnancy rate; miscarriage rate and endometrial tissue parameters associated with implantation failure. DISCUSSION: Multiple studies have been performed to investigate the effect of endometrial scratching on live birth rates in women undergoing IVF/ICSI cycles. Due to heterogeneity in both the method and population being scratched, it remains unclear which group of women will benefit from the procedure. The SCRaTCH trial proposed here aims to investigate the effect of endometrial scratching prior to controlled ovarian hyperstimulation in a large group of women undergoing a second IVF/ICSI cycle. TRIAL REGISTRATION: NTR 5342 , registered July 31st, 2015. PROTOCOL VERSION: Version 4.10, January 4th, 2017.
Subject(s)
Embryo Transfer/methods , Endometrium/surgery , Fertilization in Vitro/methods , Live Birth , Sperm Injections, Intracytoplasmic/methods , Adolescent , Adult , Birth Rate , Embryo Implantation , Endometrium/injuries , Female , Humans , Netherlands , Pregnancy , Pregnancy Rate , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Chemotherapy for breast cancer may have a negative impact on reproductive function due to gonadotoxicity. Fertility preservation via banking of oocytes or embryos after ovarian stimulation with FSH can increase the likelihood of a future live birth. It has been hypothesized that elevated serum estrogen levels during ovarian stimulation may induce breast tumour growth. This has led to the use of alternative stimulation protocols with addition of tamoxifen or letrozole. The effectiveness of these stimulation protocols in terms of oocyte yield is unknown. METHODS/DESIGN: Randomized open-label trial comparing ovarian stimulation plus tamoxifen and ovarian stimulation plus letrozole with standard ovarian stimulation in the course of fertility preservation. The study population consists of women with breast cancer who opt for banking of oocytes or embryos, aged 18-43years at randomisation. Primary outcome is the number of oocytes retrieved at follicle aspiration. Secondary outcomes are number of mature oocytes retrieved, number of oocytes or embryos banked and peak E2 levels during ovarian stimulation. DISCUSSION: Concerning the lack of evidence on which stimulation protocol should be used in women with breast cancer and the growing demand for fertility preservation, there is an urgent need to undertake this study. By performing this study, we will be able to closely monitor the effects of various stimulation protocols in women with breast cancer and pave the way for long term follow up on the safety of this procedure in terms of breast cancer prognosis. TRIAL REGISTRATION: NTR4108.
Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Fertility Preservation/methods , Follicle Stimulating Hormone/therapeutic use , Ovulation Induction/methods , Adolescent , Adult , Age Factors , Antineoplastic Agents/administration & dosage , Body Mass Index , Estrogens/blood , Female , Follicle Stimulating Hormone/administration & dosage , Humans , Letrozole , Nitriles/therapeutic use , Oocytes , Research Design , Socioeconomic Factors , Tamoxifen/therapeutic use , Triazoles/therapeutic use , Young AdultABSTRACT
OBJECTIVE: To study the effectiveness of four cycles of intrauterine insemination (IUI) with ovarian stimulation (OS) by follicle-stimulating hormone (FSH) or by clomiphene citrate (CC), and adherence to strict cancellation criteria. SETTING: Randomised controlled trial among 22 secondary and tertiary fertility clinics in the Netherlands. PARTICIPANTS: 732 women from couples diagnosed with unexplained or mild male subfertility and an unfavourable prognosis according to the model of Hunault of natural conception. INTERVENTIONS: Four cycles of IUI-OS within a time horizon of 6 months comparing FSH 75 IU with CC 100 mg. The primary outcome is ongoing pregnancy conceived within 6 months after randomisation, defined as a positive heartbeat at 12 weeks of gestation. Secondary outcomes are cancellation rates, number of cycles with a monofollicular or with multifollicular growth, number of follicles >14 mm at the time of ovulation triggering, time to ongoing pregnancy, clinical pregnancy, miscarriage, live birth and multiple pregnancy. We will also assess if biomarkers such as female age, body mass index, smoking status, antral follicle count and endometrial aspect and thickness can be used as treatment selection markers. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethical Committee of the Academic Medical Centre and from the Dutch Central Committee on Research involving Human Subjects (CCMO NL 43131-018-13). Results will be disseminated through peer-reviewed publications and presentations at international scientific meetings. TRIAL REGISTRATION NUMBER: NTR4057.
Subject(s)
Clomiphene/therapeutic use , Fertility Agents, Female/therapeutic use , Follicle Stimulating Hormone/therapeutic use , Infertility, Female/therapy , Insemination, Artificial, Homologous , Ovulation Induction/methods , Adult , Female , Humans , Insemination, Artificial, Homologous/methods , Meta-Analysis as Topic , Netherlands , Pregnancy , Pregnancy Outcome , Pregnancy Rate/trends , Time FactorsABSTRACT
Hostile infrarenal aortic neck anatomy presents a challenge for the endovascular treatment of abdominal aortic aneurysm. Open surgical repair has been seen as the gold standard treatment for juxtarenal abdominal aortic aneurysm; however, endovascular techniques are now becoming more prevalent, particularly in patients deemed high risk for morbidity and mortality with open repair. The morphology of an aneurysm is a determinant of long-term outcomes, and short aneurysm necks are associated with poorer outcomes and a higher rate of secondary reinterventions. Parallel grafts have been used in combination with endovascular aneurysm repair to elongate the sealing zone into the paravisceral segment of the aorta. This technique is associated with a risk of proximal Type I endoleak due to "guttering." This risk may be decreased when parallel grafts are used in combination with endovascular aneurysm sealing and, as such, this technique may represent an alternative to current techniques for the treatment of juxtarenal abdominal aortic aneurysm, such as the use of conventional bifurcated grafts (with or without parallel grafts) and fenestrated endovascular stent grafts.
Subject(s)
Aortic Aneurysm, Abdominal/surgery , Blood Vessel Prosthesis Implantation/instrumentation , Blood Vessel Prosthesis , Endovascular Procedures/instrumentation , Stents , Aortic Aneurysm, Abdominal/diagnostic imaging , Aortography/methods , Blood Vessel Prosthesis Implantation/adverse effects , Computed Tomography Angiography , Endoleak/etiology , Endoleak/prevention & control , Endovascular Procedures/adverse effects , Humans , Prosthesis Design , Registries , Risk Factors , Treatment OutcomeABSTRACT
BACKGROUND: The chimney technique using parallel grafts offers an alternative to fenestrated or branched endovascular solutions for juxtarenal and suprarenal aneurysms. Endograft deployment proximal to the renal or visceral ostia is combined with parallel stents to the aortic side branches. Application of the chimney technique using the Nellix device (Ch-EVAS) may offer some potential advantages with respect to the seal between the endograft and the parallel grafts. This study aimed to investigate the feasibility and efficacy of the Nellix endovascular aneurysm sealing (EVAS) system in conjunction with parallel grafts for the treatment of juxtarenal and suprarenal aneurysms. METHODS: A prospective evaluation of patients treated for juxtarenal and suprarenal non-ruptured aortic aneurysms using Ch-EVAS was undertaken in a single vascular unit. Patients were treated with this technique if they were unsuitable for either open repair or a custom-made complex branched/fenestrated endograft. Procedural, postoperative morbidity, and mortality data were recorded. RESULTS: Between March 2013 and April 2015, 28 patients were treated with Ch-EVAS. The median age was 75 years (range 60-87 years) and the median aneurysm diameter 66 mm (IQR 60-73 mm). Eight patients underwent suprarenal aneurysm repair including parallel grafts in the superior mesenteric artery and renal arteries. Five patients had a double chimney configuration; all the other patients were treated with a single chimney configuration. There was one 30-day or in-hospital mortality in a patient with a symptomatic aneurysm (4%) and three further deaths within 1 year of follow-up. One proximal type I endoleak and one type II endoleak occurred. Four patients underwent a reintervention. One patient experienced a transient ischemic attack and two patients suffered from a minor stroke (7%), therefore the total number of cerebrovascular complications was 11%. No patient required postoperative renal replacement therapy. CONCLUSIONS: Ch-EVAS appears to offer a feasible solution for juxtarenal and suprarenal aneurysms with adverse morphology. In this short-term follow-up endoleak rates were low and re-intervention rates were acceptable. Outcomes over extended follow-up will determine the application of this novel technique and better define which patients and aneurysm morphology can be treated effectively.