UNASSIGNED: Decision analysis can play an essential role in informing practice guidelines. The American Society of Hematology (ASH) thrombophilia guidelines have made a significant step forward in demonstrating how decision modeling integrated within Grading of Recommendations Assessment, Developing, and Evaluation (GRADE) methodology can advance the field of guideline development. Although the ASH model was transparent and understandable, it does, however, suffer from certain limitations that may have generated potentially wrong recommendations. That is, the panel considered 2 models separately: after 3 to 6 months of index venous thromboembolism (VTE), the panel compared thrombophilia testing (A) vs discontinuing anticoagulants (B) and testing (A) vs recommending indefinite anticoagulation to all patients (C), instead of considering all relevant options simultaneously (A vs B vs C). Our study aimed to avoid what we refer to as the omitted choice bias by integrating 2 ASH models into a single unifying threshold decision model. We analyzed 6 ASH panel\'s recommendations related to the testing for thrombophilia in settings of \"provoked\" vs \"unprovoked\" VTE and low vs high bleeding risk (total 12 recommendations). Our model disagreed with the ASH guideline panels\' recommendations in 4 of the 12 recommendations we considered. Considering all 3 options simultaneously, our model provided results that would have produced sounder recommendations for patient care. By revisiting the ASH guidelines methodology, we have not only improved the recommendations for thrombophilia but also provided a method that can be easily applied to other clinical problems and promises to improve the current guidelines\' methodology.

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BACKGROUND: Practice variation in recurrent pregnancy loss (RPL) care is common. International guidelines vary in their recommendations for the management of RPL couples, which could lead to an increase of cross border reproductive care. Currently, the Dutch RPL guideline is being adapted from the European Society for Human Reproduction and Embryology (ESHRE) guideline. We aim to identify discrepancies between RPL guidelines and RPL practice. These discrepancies could be considered in the development of a new guideline and implementation strategies to promote adherence to new recommendations.
METHODS: A nationwide survey on the management of RPL patients was conducted across all 107 hospital-based obstetrics and gynaecology practices in the Netherlands. The survey was sent via the Dutch Society for Obstetricians and Gynaecologists to all affiliated clinicians. The questionnaire consisted of 36 questions divided in four sections: clinician\'s demographics, RPL definition, investigations and therapy. The data were compared to the recommendations given by the Dutch national guideline and the most recent guideline of the ESHRE.
RESULTS: All hospital-based practices (100%; n = 107) filled in the online questionnaire. The majority of respondents defined RPL similarly, as two or more pregnancy losses (87.4%), not obligatory consecutive (93.1%). More than half of respondents routinely perform thrombophilia screening ( 58%), although not advised by the ESHRE, while thyroid function (57%), thyroid auto-immunity (27%) and β2-glycoprotein antibodies (42%) in the context of antiphospholipid syndrome (APS) are recommended but investigated less often. Regarding parental karyotyping, 20% of respondents stated they always perform parental karyotyping, without prior risk assessment. because of RPL. Treatment for hereditary thrombophilia was frequently (43.8% (n = 137)) prescribed although not recommended. And finally, a considerable part (12-16%) of respondents prescribe medication in case of unexplained RPL.
CONCLUSIONS: While many clinicians perform investigations recommended by the ESHRE, there is a considerable variation of RPL practice in the Netherlands. We identified discrepancies between RPL guidelines and RPL practice, providing possibilities to focus on multifaceted implementation strategies, such as educational intervention, local consensus processes and auditing and feedback. This will improve the quality of care provided to RPL patients and may diminish the necessity felt by patients to turn to multiple opinions or cross border reproductive care.

UNASSIGNED: Recurrent pregnancy loss (RPL) is one of the most frustrating clinical entities in reproductive medicine requiring not only diagnostic investigation and therapeutic intervention, but also evaluation of the risk for recurrence.
UNASSIGNED: The aim of this study was to review and compare the most recently published major guidelines on investigation and management of RPL.
UNASSIGNED: A descriptive review of guidelines from the Royal College of Obstetricians and Gynaecologists, the European Society of Human Reproduction and Embryology, the American Society for Reproductive Medicine, the French College of Gynecologists and Obstetricians, and the German, Austrian, and Swiss Society of Gynecology and Obstetrics on RPL was carried out.
UNASSIGNED: There is consensus among the reviewed guidelines that the mainstays of RPL investigation are a detailed personal history and screening for antiphospholipid syndrome and anatomical abnormalities of the uterus. In contrast, inherited thrombophilias, vaginal infections, and immunological and male factors of infertility are not recommended as part of a routine RPL investigation. Several differences exist regarding the necessity of the cytogenetic analysis of the products of conception, parental peripheral blood karyotyping, ovarian reserve testing, screening for thyroid disorders, diabetes or hyperhomocysteinemia, measurement of prolactin levels, and performing endometrial biopsy. Regarding the management of RPL, low-dose aspirin plus heparin is indicated for the treatment of antiphospholipid syndrome and levothyroxine for overt hypothyroidism. Genetic counseling is required in case of abnormal parental karyotype. The Royal College of Obstetricians and Gynaecologists, the European Society of Human Reproduction and Embryology, and the French College of Gynecologists and Obstetricians guidelines provide recommendations that are similar on the management of cervical insufficiency based on the previous reproductive history. However, there is no common pathway regarding the management of subclinical hypothyroidism and the surgical repair of congenital and acquired uterine anomalies. Use of heparin for inherited thrombophilias and immunotherapy and anticoagulants for unexplained RPL are not recommended, although progesterone supplementation is suggested by the American Society for Reproductive Medicine and the German, Austrian, and Swiss Society of Gynecology and Obstetrics.
UNASSIGNED: Recurrent pregnancy loss is a devastating condition for couples. Thus, it seems of paramount importance to develop consistent international practice protocols for cost-effective investigation and management of this early pregnancy complication, with the aim to improve live birth rates.

Hereditary and acquired thrombophilia are risk factors for venous thromboembolism (VTE). Whether testing helps guide management decisions is controversial. These evidence-based guidelines from the American Society of Hematology (ASH) intend to support decision making about thrombophilia testing. ASH formed a multidisciplinary guideline panel covering clinical and methodological expertise and minimizing bias from conflicts of interest. The McMaster University GRADE Centre provided logistical support, performed systematic reviews, and created evidence profiles and evidence-to-decision tables. The Grading of Recommendations Assessment, Development, and Evaluation approach (GRADE) was used. Recommendations were subject to public comment. The panel agreed on 23 recommendations regarding thrombophilia testing and associated management. Nearly all recommendations are based on very low certainty in the evidence due to modeling assumptions. The panel issued a strong recommendation against testing the general population before starting combined oral contraceptives (COCs) and conditional recommendations for thrombophilia testing in the following scenarios: (a) patients with VTE associated with nonsurgical major transient or hormonal risk factors; (b) patients with cerebral or splanchnic venous thrombosis, in settings where anticoagulation would otherwise be discontinued; (c) individuals with a family history of antithrombin, protein C, or protein S deficiency when considering thromboprophylaxis for minor provoking risk factors and for guidance to avoid COCs/hormone replacement therapy; (d) pregnant women with a family history of high-risk thrombophilia types; and (e) patients with cancer at low or intermediate risk of thrombosis and with a family history of VTE. For all other questions, the panel provided conditional recommendations against testing for thrombophilia.

The collected evidence on thrombophilia guidelines is scarce and data about their impact on clinical decisions are unknown. We aimed to investigate the adherence to thrombophilia testing guidelines, its therapeutic impact in patients with guideline-adherent and non-adherent testing and identify the patients\' clinical characteristics mostly associated with treatment decisions.
We conducted a single-center cross-sectional study of patients referred for thrombophilia testing at the outpatient clinic of a tertiary hospital between 01/2010-10/2020. We systematically evaluated the adherence of thrombophilia testing to internal guidelines and the influence of test results on anticoagulation therapy. Using multivariable logistic regression, we evaluated the association between clinical characteristics and influence of thrombophilia tests on anticoagulation therapy in the entire cohort and by indication for referral.
Of 3686 included patients, mostly referred for venous thromboembolism (2407, 65 %) or arterial thrombosis (591, 16 %), 3550 patients (96 %) underwent thrombophilia testing. Indication for testing was according to guidelines in 1208 patients (33 %). Test results influenced treatment decisions in 56 of 1102 work-ups (5.1 %) that were adherent to guidelines, and in 237 of 2448 (9.7 %) non-adherent work-ups (absolute difference, 4.3 %; 95 % confidence interval, 2.9-6.3 %). Age < 50 years, female sex, absence of risk factors and co-morbidities, weakly provoked venous thromboembolism and referral indication other than venous thromboembolism were associated with influence on anticoagulation therapy.
Adherence to guidelines for thrombophilia testing was poor and did not have an impact on treatment decisions. Refinement of selection criteria is needed to increase the therapeutic impact of thrombophilia testing.

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Several trials have been conducted in the last decades that challenged the management of patients with acute pulmonary embolism (PE) in terms of diagnosis and treatment. Updated international clinical practice guidelines (CPGs) endorsed the evidence from these trials. The aim of this document was to adapt recommendations from existing CPGs to assist physicians in decision making concerning specific and complex scenarios related to acute PE.
The flow for the adaptation procedure was first the identification of unsolved clinical issues in patients with acute PE (PICOs), then critically appraise the existing CPGs and choose the recommendations, which are the most applicable to these specific and complex scenarios.
Five PICOs were identified and CPGs appraisal was performed. Concerning diagnosis of PE when computed tomographic pulmonary angiography is not available/contraindicated and d-dimer is less specific, perfusion lung scan is the preferred option in the majority of clinical scenarios. For the treatment of PE when relevant clinical conditions like pregnancy or severe renal failure are present heparin is to be used. Poor evidence and low-level recommendations exist on the best bleeding prediction rule in patients treated for PE. The duration of anticoagulation needs to be tailored concerning the presence of predisposing factors for index PE and the consequent risk for recurrence. Finally, recommendations on the opportunity to screen for cancer and thrombophilia patients without recognized thrombosis risk factors for PE are reported. Overall, 35 recommendations were endorsed and the rationale for the selection is reported in the main text.
By the use of proper methodology for the adaptation process, this document offers a simple and updated guide for practicing clinicians dealing with complex patients.