Cerebroplacental ratio in predicting adverse perinatal outcome : a meta-analysis of individual participant data

Acknowledgement We would like thank Dr F. Figueras, Prof. E. Gratacos, Dr F. Crispi and Dr J. Miranda for sharing data for this project. The CPR IPD Study Group: Asma Khalil (Fetal Medi- cine Unit, St George’s Hospital Medical School and St George’s University of London, London, UK; Vascular Biology Research Centre, Molecular and Clinical Sciences Research Institute, St George’s University of London, Lon- don, UK), Basky Thilaganathan (Fetal Medicine Unit, St George’s Hospital Medical School and St George’s Univer- sity of London, London, UK; Vascular Biology Research Centre, Molecular and Clinical Sciences Research Institute, St George’s University of London, London, UK), Ozhan M Turan (Departments of Obstetrics, Gynecology and Repro- ductive Sciences, University of Maryland School of Medi- cine, Baltimore, MD, USA), Sarah Crimmins (Departments of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA), Chris Harman (Departments of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA), Alis- son M Shannon (Departments of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA), Sailesh Kumar (School of Medicine, The University of Queensland, Brisbane, QLD, Australia; Mater Research Institute – University of Queensland, South Brisbane, QLD, Australia), Patrick Dicker (Department of Epidemiology and Public Health, Royal College of Surgeons in Ireland), Fergal Malone (Departments of Obstetrics and Gynaecology, Royal College of Surgeons in Ireland), Elizabeth C Tully (Departments of Obstetrics and Gynaecology, Royal College of Surgeons in Ireland), Julia Unterscheider (Department of Maternal Fetal Medicine, The Royal Women’s Hospital, Melbourne, VIC, Australia), Isabella Crippa (Department of Obstetrics and Gynaecology, University of Milano-Bicocca, Monza, Italy), Alessandro Ghidini (Department of Obstetrics and Gynae- cology, University of Milano-Bicocca, Monza, Italy), Nadia Roncaglia (Department of Obstetrics and Gynaecology, University of Milano-Bicocca, Monza, Italy), Patrizia Ver- gani (Department of Obstetrics and Gynaecology, Univer- sity of Milano-Bicocca, Monza, Italy), Amarnath Bhide (Fetal Medicine Unit, St George’s Hospital Medical School and St George’s University of London, London, UK), Fran- cesco D’Antonio (Fetal Medicine Unit, St George’s Hospital Medical School and St George’s University of London, London, UK), Gianluigi Pilu (Policlinico S. Orsola-Mal- pighi, University of Bologna, Bologna, Italy), Alberto Galindo (Fetal Medicine Unit-SAMID, Department of Obstetrics and Gynaecology, University Hospital 12 de Octubre, 12 de Octubre Research Institute (imas12), Com- plutense University of Madrid, Madrid, Spain), Ignacio Herraiz (Fetal Medicine Unit-SAMID, Department of Obstetrics and Gynaecology, University Hospital 12 de Octubre, 12 de Octubre Research Institute (imas12), Com- plutense University of Madrid, Madrid, Spain), Alicia Vazquez-Sarandeses(FetalMedicineUnit-SAMID,Depart- ment of Obstetrics and Gynaecology, University Hospital 12 de Octubre, 12 de Octubre Research Institute (imas12), Complutense University of Madrid, Madrid, Spain), Cath- rine Ebbing (Department of Obstetrics and Gynaecology, Haukeland University Hospital, Bergen, Norway), Synnøve L Johnsen (Department of Obstetrics and Gynaecology, Haukeland University Hospital, Bergen, Norway), Henriette O Karlsen (Research Group for Pregnancy, Fetal Develop- ment and Birth, Department of Clinical Science, University of Bergen, Bergen, Norway).Peer reviewedPublisher PD

Planned Cesarean or planned vaginal delivery for twins: secondary analysis of randomized controlled trial

Objective: To evaluate whether there is a differential benefit of planned Cesarean delivery (CD) over planned vaginal delivery (VD) in women with a twin pregnancy and the first twin in cephalic presentation, depending on prespecified baseline maternal and pregnancy characteristics, and/or gestational age (GA) at delivery. Methods: This was a secondary analysis of the Twin Birth Study, which included 2804 women with a twin pregnancy and the first twin (Twin A) in cephalic presentation between 32 + 0 and 38 + 6 weeks\u27 gestation at 106 centers in 25 countries. Women were assigned randomly to either planned CD or planned VD. The main outcome measure was composite adverse perinatal outcome, defined as the occurrence of perinatal mortality or serious neonatal morbidity in at least one twin. The baseline maternal and pregnancy characteristics (markers) considered were maternal age, parity, history of CD, use of antenatal corticosteroids, estimated fetal weight (EFW) of Twin A, EFW of Twin B, \u3e 25% difference in EFW between the twins, presentation of Twin B, chorionicity on ultrasound, method of conception, complications of pregnancy, ruptured membranes at randomization and GA at randomization. Separate logistic regression models were developed for each marker in order to model composite adverse perinatal outcome as a function of the specific marker, planned delivery mode and the interaction between these two terms. In addition, multivariable logistic regression analysis with backward variable elimination was performed separately in each arm of the trial. The association between planned mode of delivery and composite adverse perinatal outcome, according to GA at delivery, was assessed using logistic regression analysis. Results: Of the 2804 women initially randomized, 1391 were included in each study arm. None of the studied baseline markers was associated with a differential benefit of planned CD over planned VD in the rate of composite adverse perinatal outcome. GA at delivery was associated differentially with composite adverse perinatal outcome in the treatment arms (P for interaction \u3c 0.001). Among pregnancies delivered at 32 + 0 to 36 + 6 weeks, there was a trend towards a lower rate of composite adverse perinatal outcome in those in the planned-VD group compared with those in planned-CD group (29 (2.2%) vs 48 (3.6%) cases; odds ratio (OR) 0.62 (95% CI, 0.37–1.03)). In pregnancies delivered at or after 37 + 0 weeks, planned VD was associated with a significantly higher rate of composite adverse perinatal outcome, as compared with planned CD (23 (1.5%) vs 10 (0.7%) cases; OR, 2.25 (95% CI, 1.06–4.77)). Conclusion: The perinatal outcome of twin pregnancies with the first twin in cephalic presentation may differ depending on GA at delivery and planned mode of delivery. At 32–37 weeks, planned VD seems to be favorable, while, from around 37 weeks onwards, planned CD might be safer. The absolute risks of adverse perinatal outcomes at term are low and must be weighed against the increased maternal risks associated with planned CD. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology

The FOAM study : Is Hysterosalpingo foam sonography (HyFoSy) a cost-effective alternative for hysterosalpingography (HSG) in assessing tubal patency in subfertile women? Study protocol for a randomized controlled trial

This is an investigator initiated trial, VU medical center Amsterdam is the sponsor, contact information: prof. CJM de Groot, Department of Obstetrics and Gynaecology, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands, Tel: + 31-204444444. This study is funded by ZonMw, a Dutch organization for Health Research and Development, project number 837001504. ZonMW gives financial support for the whole project. IQ Medical Ventures provides the ExEm FOAM® kits. The funding bodies have no role in the design of the study; collection, analysis, and interpretation of data; and in writing the manuscript.Peer reviewedPublisher PD

Can hysterosalpingo-foam sonography replace hysterosalpingography as first-choice tubal patency test? A randomized non-inferiority trial

Funding Information: The FOAM study was an investigator-initiated study funded by ZonMw, The Netherlands organization for Health Research and Development (project number 837001504). ZonMw funded the whole project. IQ Medical Ventures provided the ExEm-foamVR kits free of charge. The funders had no role in study design, collection, analysis and interpretation of the data. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.Peer reviewedPublisher PD

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting

Hysterosalpingo-foam sonography versus hysterosalpingography during fertility work-up: an economic evaluation alongside a randomized controlled trial

STUDY QUESTION: What are the costs and effects of tubal patency testing by hysterosalpingo-foam sonography (HyFoSy) compared to hysterosalpingography (HSG) in infertile women during the fertility work-up? SUMMARY ANSWER: During the fertility work-up, clinical management based on the test results of HyFoSy leads to slightly lower, though not statistically significant, live birth rates, at lower costs, compared to management based on HSG results. WHAT IS KNOWN ALREADY: Traditionally, tubal patency testing during the fertility work-up is performed by HSG. The FOAM trial, formally a non-inferiority study, showed that management decisions based on the results of HyFoSy resulted in a comparable live birth rate at 12 months compared to HSG (46% versus 47%; difference −1.2%, 95% CI: −3.4% to 1.5%; P¼ 0.27). Compared to HSG, HyFoSy is associated with significantly less pain, it lacks ionizing radiation and exposure to iodinated contrast medium. Moreover, HyFoSy can be performed by a gynaecologist during a one-stop fertility work-up. To our knowledge, the costs of both strategies have never been compared. STUDY DESIGN, SIZE, DURATION: We performed an economic evaluation alongside the FOAM trial, a randomized multicenter study conducted in the Netherlands. Participating infertile women underwent, both HyFoSy and HSG, in a randomized order. The results of both tests were compared and women with discordant test results were randomly allocated to management based on the results of one of the tests. The follow-up period was twelve months. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied 1160 infertile women (18–41 years) scheduled for tubal patency testing. The primary outcome was ongoing pregnancy leading to live birth. The economic evaluation compared costs and effects of management based on either test within 12 months. We calculated incremental cost-effectiveness ratios (ICERs): the difference in total costs and chance of live birth. Data were analyzed using the intention to treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: Between May 2015 and January 2019, 1026 of the 1160 women underwent both tubal tests and had data available: 747 women with concordant results (48% live births), 136 with inconclusive results (40% live births), and 143 with discordant results (41% had a live birth after management based on HyFoSy results versus 49% with live birth after management based on HSG results). When comparing the two strategies—management based on HyfoSy results versus HSG results—the estimated chance of live birth was 46% after HyFoSy versus 47% after HSG (difference −1.2%; 95% CI: −3.4% to 1.5%). For the procedures itself, HyFoSy cost e136 and HSG e280. When costs of additional fertility treatments were incorporated, the mean total costs per couple were e3307 for the HyFoSy strategy and e3427 for the HSG strategy (mean difference e−119; 95% CI: e−125 to e−114). So, while HyFoSy led to lower costs per couple, live birth rates were also slightly lower. The ICER was e10 042, meaning that by using HyFoSy instead of HSG we would save e10 042 per each additional live birth lost. LIMITATIONS, REASONS FOR CAUTION: When interpreting the results of this study, it needs to be considered that there was a considerable uncertainty around the ICER, and that the direct fertility enhancing effect of both tubal patency tests was not incorporated as women underwent both tubal patency tests in this study. WIDER IMPLICATION OF THE FINDINGS: Compared to clinical management based on HSG results, management guided by HyFoSy leads to slightly lower live birth rates (though not statistically significant) at lower costs, less pain, without ionizing radiation and iodinated contrast exposure. Further research on the comparison of the direct fertility-enhancing effect of both tubal patency tests is needed. STUDY FUNDING/COMPETING INTEREST(S): FOAM trial was an investigator-initiated study, funded by ZonMw, a Dutch organization for Health Research and Development (project number 837001504). IQ Medical Ventures provided the ExEm®-FOAM kits free of charge. The funders had no role in study design, collection, analysis, and interpretation of the data. K.D. reports travel-and speakers fees from Guerbet and her department received research grants from Guerbet outside the submitted work. H.R.V. received consulting—and travel fee from Ferring. A.M.v.P. reports received consulting fee from DEKRA and fee for an expert meeting from Ferring, both outside the submitted work. C.H.d.K. received travel fee from Merck. F.J.M.B. received a grant from Merck and speakers fee from Besins Healthcare. F.J.M.B. is a member of the advisory board of Merck and Ferring. J.v.D. reported speakers fee from Ferring. J.S. reports a research agreement with Takeda and consultancy for Sanofi on MR of motility outside the submitted work. M.v.W. received a travel grant from Oxford Press in the role of deputy editor for Human Reproduction and participates in a DSMB as independent methodologist in obstetrics studies in which she has no other role. B.W.M. received an investigator grant from NHMRC GNT1176437. B.W.M. reports consultancy for ObsEva, Merck, Guerbet, iGenomix, and Merck KGaA and travel support from Merck KGaA. V.M. received research grants from Guerbet, Merck, and Ferring and travel and speakers fees from Guerbet. The other authors do not report conflicts of interest. TRIAL REGISTRATION NUMBER: International Clinical Trials Registry Platform No. NTR4746