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Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied. We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death. A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days. Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).

Abstract STUDY QUESTION What are the updates for the recommended management of women with recurrent pregnancy loss (RPL) based on the best available evidence in the literature from 2017 to 2022? SUMMARY ANSWER The guideline development group (GDG) updated 11 existing recommendations on investigations and treatments for RPL, and how care should be organized, and added one new recommendation on adenomyosis investigation in women with RPL. WHAT IS KNOWN ALREADY A previous ESHRE guideline on RPL was published in 2017 and needs to be updated. STUDY DESIGN, SIZE, DURATION The guideline was developed and updated according to the structured methodology for development and update of ESHRE guidelines. The literature searches were updated, and assessments of relevant new evidence were performed. Relevant papers published between 31 March 2017 and 28 February 2022 and written in English were included. Cumulative live birth rate, live birth rate, and pregnancy loss rate (or miscarriage rate) were considered the critical outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS Based on the collected evidence, recommendations were updated and discussed until consensus was reached within the GDG. A stakeholder review was organized after the updated draft was finalized. The final version was approved by the GDG and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE The new version of the guideline provides 39 recommendations on risk factors, prevention, and investigation in couples with RPL, and 38 recommendations on treatments. These includes 62 evidence-based recommendations—of which 33 were formulated as strong recommendations and 29 as conditional—and 15 good practice points. Of the evidence-based recommendations, 12 (19.4%) were supported by moderate-quality evidence. The remaining recommendations were supported by low (34 recommendations; 54.8%), or very low-quality evidence (16 recommendations; 25.8%). Owing to the lack of evidence-based investigations and treatments in RPL care, the guideline also clearly mentions those investigations and treatments that should not be used for couples with RPL. LIMITATIONS, REASONS FOR CAUTION The guidelines have been updated; however, several investigations and treatments currently offered to couples with RPL have not been well studied; for most of these investigations and treatments, a recommendation against using the intervention or treatment was formulated based on insufficient evidence. Future studies may require these recommendations to be revised. WIDER IMPLICATIONS OF THE FINDINGS The guideline provides clinicians with clear advice on best practice in RPL, based on the best and most recent evidence available. In addition, a list of research recommendations is provided to stimulate further studies in RPL. Still, the absence of a unified definition of RPL is one of the most critical consequences of the limited scientific evidence in the field. STUDY FUNDING/COMPETING INTEREST(S) The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the dissemination of the guideline. The guideline group members did not receive payment. O.B.C. reports being a member of the executive board of the European Society for Reproductive Immunology and has received payment for honoraria for giving lectures about RPL in Australia in 2020. M.G. reports unconditional research and educational grant received by the Centre for Reproductive Medicine, Amsterdam UMC from Guerbet, Merck and Ferring, not related to the presented work. S.L. reports position funding from EXAMENLAB Ltd. and ownership interest by stock or partnership of EXAMENLAB Ltd (CEO). S.Q. reports being a deputy director of Tommy’s National centre for miscarriage research, with payment received by the institution for research, staff time, and consumables for research. H.S.N. reports grants with payment to institution from Freya Biosciences ApS, Ferring Pharmaceuticals, BioInnovation Institute, the Danish ministry of Education, Novo Nordic Foundation, Augustinus Fonden, Oda og Hans Svenningsens Fond, Demant Fonden, Ole Kirks Fond, and Independent Research Fund Denmark and speakers’ fees for lectures from Ferring Pharmaceuticals, Merck A/S, Astra Zeneca, IBSA Nordic and Cook Medical. She also reports to be an unpaid founder and chairman of a maternity foundation. M.-L.v.d.H. received small honoraria for lectures on RPL care. The other authors have no conflicts of interest to declare. DISCLAIMER This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type. ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at www.eshre.eu/guidelines.)

Venous thromboembolism (VTE), which may manifest as pulmonary embolism (PE) or deep vein thrombosis (DVT), is a serious and potentially fatal condition. Treatment and prevention of obstetric-related VTE is complicated by the need to consider fetal, as well as maternal, wellbeing when making management decisions. Although absolute VTE rates in this population are low, obstetric-associated VTE is an important cause of maternal morbidity and mortality. This manuscript, initiated by the Anticoagulation Forum, provides practical clinical guidance on the prevention and treatment of obstetric-associated VTE based on existing guidelines and consensus expert opinion based on available literature where guidelines are lacking.

Abstract STUDY QUESTION What is the recommended management of women with recurrent pregnancy loss (RPL) based on the best available evidence in the literature? SUMMARY ANSWER The guideline development group formulated 77 recommendations answering 18 key questions on investigations and treatments for RPL, and on how care should be organized. WHAT IS KNOWN ALREADY A previous guideline for the investigation and medical treatment of recurrent miscarriage was published in 2006 and is in need of an update. STUDY DESIGN, SIZE, DURATION The guideline was developed according to the structured methodology for development of ESHRE guidelines. After formulation of key questions by a group of experts, literature searches and assessments were performed. Papers published up to 31 March 2017 and written in English were included. Cumulative live birth rate, live birth rate and pregnancy loss rate (or miscarriage rate) were considered the critical outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS Based on the collected evidence, recommendations were formulated and discussed until consensus was reached within the guideline group. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline group and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE The guideline provides 38 recommendations on risk factors, prevention and investigations in couples with RPL, and 39 recommendations on treatments. These include 60 evidence-based recommendations – of which 31 were formulated as strong recommendations and 29 as conditional – and 17 good practice points. The evidence supporting investigations and treatment of couples with RPL is limited and of moderate quality. Of the evidence-based recommendations, only 10 (16.3%) were supported by moderate quality evidence. The remaining recommendations were supported by low (35 recommendations: 57.4%), or very low quality evidence (16 recommendations: 26.2%). There were no recommendations based on high quality evidence. Owing to the lack of evidence-based investigations and treatments in RPL care, the guideline also clearly mentions investigations and treatments that should not be used for couples with RPL. LIMITATIONS, REASONS FOR CAUTION Several investigations and treatments are offered to couples with RPL, but most of them are not well studied. For most of these investigations and treatments, a recommendation against the intervention or treatment was formulated based on insufficient evidence. Future studies may require these recommendations to be revised. WIDER IMPLICATIONS OF THE FINDINGS The guideline provides clinicians with clear advice on best practice in RPL, based on the best evidence available. In addition, a list of research recommendations is provided to stimulate further studies in RPL. One of the most important consequences of the limited evidence is the absence of evidence for a definition of RPL. STUDY FUNDING/COMPETING INTEREST(S) The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the dissemination of the guideline. The guideline group members did not receive payment. J.E. reports position funding from CARE Fertility. S.L. reports position funding from SpermComet Ltd. S.M. reports research grants, consulting and speaker’s fees from GSK, BMS/Pfizer, Sanquin, Aspen, Bayer and Daiichi Sankyo. S.Q. reports speaker’s fees from Ferring. The other authors report no conflicts of interest. ESHRE Pages are not externally peer reviewed. This article has been approved by the Executive Committee of ESHRE.

Andexanet alfa, a catalytically inactive decoy of factor Xa, successfully reversed the factor Xa inhibitory effects of rivaroxaban and apixaban in a small study involving patients with acute major bleeding. In randomized clinical trials, factor Xa inhibitors have been shown to be safe and effective for the treatment and prevention of venous thromboembolism and for stroke prevention in patients with atrial fibrillation. 1 – 4 However, factor Xa inhibitors have been associated with major and even fatal bleeding events. 1 – 4 Such episodes of acute major bleeding may be difficult to treat because there is no reversal agent. Andexanet alfa (andexanet) has been designed and developed specifically to reverse the effects of both direct and indirect factor Xa inhibitors. It is a recombinant, modified human factor Xa decoy protein that binds factor Xa . . .

Approximately 1–2 per 1000 pregnancies are complicated by venous thromboembolism (VTE). VTE includes deep vein thrombosis (DVT) and pulmonary embolism (PE) and the diagnostic management of pregnancy-related VTE is challenging. Current guidelines vary greatly in their approach to diagnosing PE in pregnancy as they base their recommendations on scarce and weak evidence. The pregnancy-adapted YEARS diagnostic algorithm is well tolerated and is the most efficient diagnostic algorithm for pregnant women with suspected PE, with 39% of women not requiring computed tomographic pulmonary angiography. Low-molecular-weight heparin is the first-choice anticoagulant treatment in pregnancy and should be continued until 6 weeks postpartum and for a minimum of 3 months. Direct oral anticoagulants should be avoided in women who want to breastfeed. Management of delivery needs a multidisciplinary approach in order to decide on an optimal delivery plan. Neuraxial analgesia can be given in most patients, provided time windows since last low-molecular-weight heparin dose are respected. Women with a history of VTE are at risk of recurrence during pregnancy and in the postpartum period. Therefore, in most women with a history of VTE, thromboprophylaxis in subsequent pregnancies is indicated. The reviews of this paper are available via the supplemental material section.

Superficial thrombophlebitis in the leg is associated with an increased risk of subsequent thromboembolic events; however, intervention to alter the risk has not been well studied. This study compared fondaparinux with placebo for patients with superficial thrombophlebitis in the leg. Superficial-vein thrombosis of the legs is a common condition, 1 , 2 with an estimated incidence that may exceed that of deep-vein thrombosis. 3 , 4 Patients with isolated superficial-vein thrombosis — that is, without concomitant deep-vein thrombosis or symptomatic pulmonary embolism at presentation — are at risk for subsequent symptomatic venous thromboembolic complications. 1 – 7 In a large, prospective, observational study, the 3-month risk of such complications was 8.3%, with a 3.3% risk of deep-vein thrombosis or pulmonary embolism. 8 The treatment of this disease has not been adequately addressed in randomized trials. Accordingly, the recommendations in various guidelines are weak, and in practice, therapeutic . . .

Objective To investigate the association between weight or body mass index (BMI) and the development of hand osteoarthritis. Methods Systematic review of observational studies. Medical databases were searched up to April 2008. Articles that presented data on the association between weight and hand osteoarthritis were selected. The qualities of these studies were then assessed by two independent reviewers using a 19 criteria scoring system. Using the mean scores of all studies as a cut-off value, the studies were deemed as high or low quality. Study quality and study designs were combined to determine the level of evidence using best-evidence synthesis, which consisted of five levels of evidence. Results From the 25 studies included, two had cohort, three case–control and 20 cross-sectional study designs. Fifteen studies were considered high-quality studies. Of these high-quality studies, one cohort, two case–control and seven cross-sectional studies showed a positive association between weight or BMI and hand osteoarthritis. Based on three high-quality studies with preferred study designs (one cohort and two case–control) with a positive association, the level of evidence of the association between overweight and developing hand osteoarthritis is moderate. The approximate risk ratio of this association is 1.9. Conclusion Weight or BMI is associated with the development of hand osteoarthritis. The level of evidence of published studies is moderate according to best-evidence synthesis. Further high-quality cohort or case–control studies are needed to elucidate the role of weight in hand osteoarthritis.

Placenta-mediated pregnancy complications include pre-eclampsia, late pregnancy loss, placental abruption, and birth of a small-for-gestational-age (SGA) neonate. These complications are leading causes of maternal, fetal, and neonatal morbidity and mortality in high-income countries. Affected women are at high risk of recurrence in subsequent pregnancies; however, effective strategies to prevent recurrence are absent. Findings from our previous study-level meta-analysis suggested that low-molecular-weight heparin reduced the risk of recurrent placenta-mediated pregnancy complications. However, we identified significant heterogeneity in the results, possibly due to trial design or inclusion criteria. To identify which patients benefit from, and which outcomes are prevented by, low-molecular-weight heparin, we did an individual patient data meta-analysis. We did a systematic review in May, 2013, which identified eight eligible randomised trials done between 2000 and 2013 of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications. We excluded studies on the basis of the wrong population, the study being ongoing, inability to confirm eligibility of participants, intervention stopped too early, and no response from the principal investigator. We requested individual patient data from the study authors for eligible women (women pregnant at the time of the study with a history of previous pregnancy that had been complicated by one or more of the following: pre-eclampsia, placental abruption, birth of an SGA neonate [<10th percentile], pregnancy loss after 16 weeks' gestation, or two losses after 12 weeks' gestation) and recoded, combined, and analysed the data for our meta-analysis. The primary outcome was a composite of early-onset (<34 weeks) or severe pre-eclampsia, birth of an SGA neonate (<5th percentile), late pregnancy loss (≥20 weeks' gestation), or placental abruption leading to delivery, assessed on an intention-to-treat basis. We assessed risk of bias with the Cochrane Risk of Bias tool. This study is registered with PROSPERO, number CRD42013006249. We analysed data from 963 eligible women in eight trials: 480 randomly assigned to low-molecular-weight heparin and 483 randomly assigned to no low-molecular-weight heparin. Overall, the risk of bias was not substantial enough to affect decisions regarding trial inclusion. Participants were mostly white (795/905; 88%) with a mean age of 30·9 years (SD 5·0) and 403/963 (42%) had thrombophilia. In the primary analysis, low-molecular-weight heparin did not significantly reduce the risk of recurrent placenta-mediated pregnancy complications (low-molecular-weight heparin 62/444 [14%] versus no low-molecular-weight heparin 95/443 (22%) absolute difference −8%, 95% CI −17·3 to 1·4, p=0·09; relative risk 0·64, 95% CI 0·36–1·11, p=0·11). We noted significant heterogeneity between single-centre and multicentre trials. In subgroup analyses, low-molecular-weight heparin in multicentre trials reduced the primary outcome in women with previous abruption (p=0·006) but not in any of the other subgroups of previous complications. Low-molecular-weight heparin does not seem to reduce the risk of recurrent placenta-mediated pregnancy complications in at-risk women. However, some decreases in event rates might have been too small for the power of our study to explore. Canadian Institutes of Health Research.

Objectives Closer reading of computed tomography pulmonary angiography (CTPA) scans of patients presenting with acute pulmonary embolism (PE) may identify those at high risk of developing chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to validate the predictive value of six radiological predictors that were previously proposed. Methods Three hundred forty-one patients with acute PE were prospectively followed for development of CTEPH in six European hospitals. Index CTPAs were analysed post hoc by expert chest radiologists blinded to the final diagnosis. The accuracy of the predictors using a predefined threshold for ‘high risk’ (≥ 3 predictors) and the expert overall judgment on the presence of CTEPH were assessed. Results CTEPH was confirmed in nine patients (2.6%) during 2-year follow-up. Any sign of chronic thrombi was already present in 74/341 patients (22%) on the index CTPA, which was associated with CTEPH (OR 7.8, 95%CI 1.9–32); 37 patients (11%) had ≥ 3 of 6 radiological predictors, of whom 4 (11%) were diagnosed with CTEPH (sensitivity 44%, 95%CI 14–79; specificity 90%, 95%CI 86–93). Expert judgment raised suspicion of CTEPH in 27 patients, which was confirmed in 8 (30%; sensitivity 89%, 95%CI 52–100; specificity 94%, 95%CI 91–97). Conclusions The presence of ≥ 3 of 6 predefined radiological predictors was highly specific for a future CTEPH diagnosis, comparable to overall expert judgment, while the latter was associated with higher sensitivity. Dedicated CTPA reading for signs of CTEPH may therefore help in early detection of CTEPH after PE, although in our cohort this strategy would not have detected all cases. Key Points • Three expert chest radiologists re-assessed CTPA scans performed at the moment of acute pulmonary embolism diagnosis and observed a high prevalence of chronic thrombi and signs of pulmonary hypertension. • On these index scans, the presence of  ≥  3 of 6 predefined radiological predictors was highly specific for a future diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH), comparable to overall expert judgment. • Dedicated CTPA reading for signs of CTEPH may help in early detection of CTEPH after acute pulmonary embolism.