Screening for trisomies by cfDNA testing of maternal blood in twin pregnancy: update of The Fetal Medicine Foundation results and meta-analysis.

OBJECTIVES: To report on the routine clinical implementation of cell-free DNA (cfDNA) analysis of maternal blood for trisomies 21, 18 and 13 in twin pregnancy and to define the performance of the test by combining our results with those identified in a systematic review of the literature. METHODS: The data for the prospective study were derived from screening for trisomies 21, 18 and 13 in twin pregnancies at 10 + 0 to 14 + 1 weeks' gestation. Two populations were included; first, self-referred women to the Fetal Medicine Centre in London or Brugmann University Hospital in Brussels and, second, women selected for the cfDNA test after routine first-trimester combined testing at one of two National Health Service hospitals in England. This dataset was used to determine the performance of screening for the three trisomies. Search of MEDLINE, EMBASE, CENTRAL (The Cochrane Library), ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (ICTRP) was carried out to identify all peer-reviewed publications on clinical validation or implementation of maternal cfDNA testing for trisomies 21, 18 and 13 in twin pregnancy. A meta-analysis was then performed using our data and those in the studies identified by the literature search. RESULTS: In our dataset of 997 twin pregnancies with a cfDNA result and known outcome, the test classified correctly 16 (94.1%) of the 17 cases of trisomy 21, nine (90.0%) of the 10 cases of trisomy 18, one (50.0%) of the two cases of trisomy 13 and 962 (99.4%) of the 968 cases without any of the three trisomies. The literature search identified seven relevant studies, excluding our previous papers because their data are included in the current study. In the combined populations of our study and the seven studies identified by the literature search, there were 56 trisomy-21 and 3718 non-trisomy-21 twin pregnancies; the pooled weighted detection rate (DR) and false-positive rate (FPR) were 98.2% (95% CI, 83.2-99.8%) and 0.05% (95% CI, 0.01-0.26%), respectively. In the combined total of 18 cases of trisomy 18 and 3143 non-trisomy-18 pregnancies, the pooled weighted DR and FPR were 88.9% (95% CI, 64.8-97.2%) and 0.03% (95% CI, 0.00-0.33%), respectively. For trisomy 13, there were only three affected cases and two (66.7%) of these were detected by the cfDNA test at a FPR of 0.19% (5/2569). CONCLUSIONS: The performance of cfDNA testing for trisomy 21 in twin pregnancy is similar to that reported in singleton pregnancy and is superior to that of the first-trimester combined test or second-trimester biochemical testing. The number of cases of trisomies 18 and 13 is too small for accurate assessment of the predictive performance of the cfDNA test. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Detección de trisomías mediante la prueba del ADN fetal de la sangre materna en el embarazo de gemelos: actualización de los resultados de The Fetal Medicine Foundation y metaanálisis OBJETIVOS: Informar sobre la implementación clínica rutinaria del análisis de ADN fetal (cfDNA, por sus siglas en inglés) de la sangre materna para las trisomías 21, 18 y 13 en embarazos de gemelos y definir el rendimiento de la prueba mediante la combinación de los resultados de este estudio con los identificados en una revisión sistemática de la literatura. MÉTODOS: Los datos para el estudio prospectivo se derivaron del cribado de las trisomías 21, 18 y 13 en embarazos de gemelos entre 10+0 a 14+1 semanas de gestación. Se incluyeron dos poblaciones: la primera, las mujeres que acudieron sin recomendación de especialista al Centro de Medicina Fetal de Londres o al Hospital Universitario Brugmann de Bruselas y, la segunda, las mujeres seleccionadas para la prueba de cfDNA después de la prueba combinada rutinaria del primer trimestre en uno de los dos hospitales del Servicio Nacional de Salud de Inglaterra. Este conjunto de datos se utilizó para determinar el rendimiento de la detección de las tres trisomías. Se realizó una búsqueda en MEDLINE, EMBASE, CENTRAL (The Cochrane Library), ClinicalTrials.gov y en la Plataforma Internacional del Registro de Ensayos Clínicos (ICTRP, por sus siglas en inglés) de la Organización Mundial de la Salud para identificar todas las publicaciones revisadas por pares sobre la validación clínica o la implementación de pruebas de cfDNA materno para las trisomías 21, 18 y 13 en el embarazo de gemelos. A continuación, se realizó un metaanálisis de los datos propios y de los de los estudios identificados por la búsqueda bibliográfica. RESULTADOS: En el conjunto de datos propios de 997 embarazos de gemelos con un resultado de cfDNA conocido, la prueba clasificó correctamente 16 (94,1%) de los 17 casos de trisomía 21, nueve (90,0%) de los 10 casos de trisomía 18, uno (50,0%) de los dos casos de trisomía 13 y 962 (99,4%) de los 968 casos sin ninguna de las tres trisomías. La búsqueda bibliográfica identificó siete estudios relevantes, que excluyeron los artículos de los autores de este estudio ya que sus datos están incluidos en este estudio. En las poblaciones combinadas de este estudio y los siete estudios identificados por la búsqueda bibliográfica, hubo 56 embarazos gemelares con trisomía-21 y 3718 sin trisomía-21; la tasa de detección (TD) combinada ponderada y la tasa de falsos positivos (TFP) fueron del 98,2% (IC 95%: 83,2-99,8%) y del 0,05% (IC 95%: 0,01-0,26%), respectivamente. En el total combinado de los 18 casos de trisomía-18 y los 3143 embarazos sin trisomía-18, la TD combinada ponderada y la TFP fueron del 88,9% (IC 95%, 64,8-97,2%) y del 0,03% (IC 95%, 0,00-0,33%), respectivamente. Para la trisomía 13, sólo hubo tres casos afectados y dos (66,7%) de ellos fueron detectados por la prueba de cfDNA con una TFP del 0,19% (5/2569). CONCLUSIONES: La bondad del desempeño de la prueba de cfDNA para la trisomía 21 en el embarazo de gemelos es similar a la reportada en embarazos con feto único y es superior a la de la prueba combinada del primer trimestre o a la de la prueba bioquímica del segundo trimestre. El número de casos de trisomías 18 y 13 es demasiado pequeño para una evaluación precisa de la bondad de predicción de la prueba de cfDNA.

Outcome reporting across randomised controlled trials evaluating therapeutic interventions for pre-eclampsia.

BACKGROUND: Standardising outcome collection and reporting in pre-eclampsia trials requires an appraisal of current outcome reporting. OBJECTIVES: To map maternal and offspring outcome reporting across randomised trials evaluating therapeutic interventions for pre-eclampsia. SEARCH STRATEGY: Randomised trials were identified by searching bibliographical databases from inception to January 2016. SELECTION CRITERIA: Randomised controlled trials. DATA COLLECTION AND ANALYSIS: We systematically extracted and categorised outcome reporting. MAIN RESULTS: Seventy-nine randomised trials, reporting data from 31 615 maternal participants and 28 172 of their offspring, were included. Fifty-five different interventions were evaluated. Included trials reported 119 different outcomes, including 72 maternal outcomes and 47 offspring outcomes. Maternal outcomes were inconsistently reported across included trials; for example, 11 trials (14%) reported maternal mortality, reporting data from 12 422 participants, and 16 trials (20%) reported cardiovascular morbidity, reporting data from 14 963 maternal participants. Forty-three trials (54%) reported fetal outcomes and 23 trials (29%) reported neonatal outcomes. Twenty-eight trials (35%) reported offspring mortality. There was poor reporting of childhood outcomes: six trials (8%) reported neurodevelopmental outcomes. Less than half of included trials reported any relevant information regarding harms for maternal participants and their offspring. CONCLUSIONS: Most randomised trials evaluating interventions for pre-eclampsia are missing information on clinically important outcomes, and in particular have neglected to evaluate efficacy and safety in the offspring of participants. Developing and implementing a minimum data set, known as a core outcome set, in future pre-eclampsia trials could help to address these issues. TWEETABLE ABSTRACT: Future #preeclampsia research requires a core outcome set to reduce #research waste. @coreoutcomes @jamesmnduffy International Prospective Register of Systematic Reviews: CRD42015015529; www.crd.york.ac.uk/PROSPERO/display_record.aspID=CRD42015015529.

Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis.

OBJECTIVES: To review clinical validation or implementation studies of maternal blood cell-free (cf) DNA analysis and define the performance of screening for fetal trisomies 21, 18 and 13 and sex chromosome aneuploidies (SCA). METHODS: Searches of PubMed, EMBASE and The Cochrane Library were performed to identify all peer-reviewed articles on cfDNA testing in screening for aneuploidies between January 2011, when the first such study was published, and 31 December 2016. The inclusion criteria were peer-reviewed study reporting on clinical validation or implementation of maternal cfDNA testing in screening for aneuploidies, in which data on pregnancy outcome were provided for more than 85% of the study population. We excluded case-control studies, proof-of-principle articles and studies in which the laboratory scientists carrying out the tests were aware of fetal karyotype or pregnancy outcome. Pooled detection rates (DRs) and false-positive rates (FPRs) were calculated using bivariate random-effects regression models. RESULTS: In total, 35 relevant studies were identified and these were used for the meta-analysis on the performance of cfDNA testing in screening for aneuploidies. These studies reported cfDNA results in relation to fetal karyotype from invasive testing or clinical outcome. In the combined total of 1963 cases of trisomy 21 and 223 932 non-trisomy 21 singleton pregnancies, the weighted pooled DR and FPR were 99.7% (95% CI, 99.1-99.9%) and 0.04% (95% CI, 0.02-0.07%), respectively. In a total of 563 cases of trisomy 18 and 222 013 non-trisomy 18 singleton pregnancies, the weighted pooled DR and FPR were 97.9% (95% CI, 94.9-99.1%) and 0.04% (95% CI, 0.03-0.07%), respectively. In a total of 119 cases of trisomy 13 and 212 883 non-trisomy 13 singleton pregnancies, the weighted pooled DR and FPR were 99.0% (95% CI, 65.8-100%) and 0.04% (95% CI, 0.02-0.07%), respectively. In a total of 36 cases of monosomy X and 7676 unaffected singleton pregnancies, the weighted pooled DR and FPR were 95.8% (95% CI, 70.3-99.5%) and 0.14% (95% CI, 0.05-0.38%), respectively. In a combined total of 17 cases of SCA other than monosomy X and 5400 unaffected singleton pregnancies, the weighted pooled DR and FPR were 100% (95% CI, 83.6-100%) and 0.004% (95% CI, 0.0-0.08%), respectively. For twin pregnancies, in a total of 24 cases of trisomy 21 and 1111 non-trisomy 21 cases, the DR was 100% (95% CI, 95.2-100%) and FPR was 0.0% (95% CI, 0.0-0.003%), respectively. CONCLUSIONS: Screening by analysis of cfDNA in maternal blood in singleton pregnancies could detect > 99% of fetuses with trisomy 21, 98% of trisomy 18 and 99% of trisomy 13 at a combined FPR of 0.13%. The number of reported cases of SCA is too small for accurate assessment of performance of screening. In twin pregnancies, performance of screening for trisomy 21 is encouraging but the number of cases reported is small. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

[Critical reading of systematic reviews and meta-analyses about diagnostic imaging]. / Lectura crítica de revisiones sistemáticas y metanálisis en el diagnóstico por imagen.

Systematic reviews of diagnostic validity have been proposed as the best methodological tool to integrate all the available evidence and to help physicians decide whether to use a given diagnostic test. These studies aim to synthesize the results obtained in different primary studies into a couple of indices, generally sensitivity and specificity, or into a summary receiver operating characteristic (ROC) curve. Although there is a certain parallelism with reviews about the efficacy of therapeutic interventions, reviews of diagnostic validity have certain peculiarities that add complexity to the analysis and interpretation of the results. This article emphasizes the methodological aspects that make it possible to critically assess the extent to which the results of a review of the validity of diagnostic tests are valid and provides rudimentary knowledge of the statistics necessary to understand the results.

First-trimester uterine artery Doppler and adverse pregnancy outcome: a meta-analysis involving 55,974 women.

OBJECTIVES: To determine the accuracy with which uterine artery Doppler in the first trimester of pregnancy predicts pre-eclampsia and fetal growth restriction, particularly early-onset disease. METHODS: We searched MEDLINE (1951-2012), EMBASE (1980-2012) and the Cochrane Library (2012) for relevant citations without language restrictions. Two reviewers independently selected studies that evaluated the accuracy of first-trimester uterine artery Doppler to predict adverse pregnancy outcome and performed data extraction to construct 2 × 2 tables. We synthesized sensitivity and specificity for various Doppler indices using a bivariate random-effects model. RESULTS: From 1866 citations, we identified 18 studies (55,974 women). The sensitivity and specificity of abnormal uterine artery flow velocity waveform (FVW) in the prediction of early-onset pre-eclampsia were 47.8% (95% CI: 39.0-56.8) and 92.1% (95% CI: 88.6-94.6), and in the prediction of early-onset fetal growth restriction were 39.2% (95% CI: 26.3-53.8) and 93.1% (95% CI: 90.6-95.0), respectively. The sensitivities for predicting any pre-eclampsia and fetal growth restriction were 26.4% (95% CI: 22.5-30.8) and 15.4% (95% CI: 12.4-18.9), respectively, and the specificities were 93.4% (95% CI: 90.4-95.5%) and 93.3% (95% CI: 90.9-95.1), respectively. The number needed to treat (NNT) with aspirin to prevent one case of early-onset pre-eclampsia fell from 1000 to 173 and from 2500 to 421 for background risks varying between 1% and 0.4%, respectively. CONCLUSIONS: First-trimester uterine artery Doppler is a useful tool for predicting early-onset pre-eclampsia, as well as other adverse pregnancy outcomes. Based on the NNT, abnormal uterine artery Doppler in low-risk women achieves a sufficiently high performance to justify aspirin prophylaxis in those who test positive.

Accuracy of CT angiography in the diagnosis of acute gastrointestinal bleeding: systematic review and meta-analysis.

OBJECTIVE: To assess the diagnostic accuracy of computed tomography (CT) angiography in the evaluation of patients with an episode of acute gastrointestinal haemorrhage. METHODS: Systematic review and meta-analysis to estimate pooled accuracy indices. A bivariate random effects model was adjusted to obtain a summary receiver-operating characteristic (sROC) curve and the corresponding area under the curve (AUC). RESULTS: Twenty-two studies were included and provided data on 672 patients (range of age 5-74) with a mean age of 65 years. The overall sensitivity of CT angiography for detecting active acute GI haemorrhage was 85.2 % (95 % CI 75.5 % to 91.5 %). The overall specificity of CT angiography was 92.1 % (95 % CI 76.7 % to 97.7 %). The likelihood ratios for positive and negative test results were 10.8 (95 % CI 3.4 to 34.4) and 0.16 (95 % CI 0.1 to 0.27) respectively, with an AUC of 0.935 (95 % CI 0.693 to 0.989). The sources of heterogeneity explored had no significant impact on diagnostic performance. CONCLUSIONS: CT shows high diagnostic accuracy and is an excellent diagnostic tool for detection and localising of intestinal bleeding sites. It is highly available, provides fast detection and localisation of the bleeding site, and is minimally invasive. KEY POINTS: • CT angiography is increasingly used for investigating severe gastrointestinal bleeding. • This systematic review and meta-analysis updates previous ones. • In patients with massive gastrointestinal bleeding, CT angiography/MDCT detects bleeding accurately. • CT angiography is useful in locating the bleeding site and determining appropriate treatment.

[Store-and-forward teledermatology: assessment of validity in a series of 2000 observations]. / Teledermatología diferida: análisis de validez en una serie de 2.000 observaciones.

BACKGROUND AND OBJECTIVES: The aim of this study was to assess the validity of store-and-forward teledermatology as a tool to support physicians in primary care and hospital emergency services and reduce the requirement for face-to-face appointments. Diagnostic validity and the approach chosen for patient management (face-to-face vs teledermatology) were compared according to patient origin and diagnostic group. MATERIAL AND METHODS: Digital images from 100 patients were assessed by 20 different dermatologists and the diagnoses offered were compared with those provided in face-to-face appointments (gold standard). The proposed management of the different groups of patients was also compared. RESULTS: The percentage complete agreement was 69.05% (95% confidence interval [CI], 66.9%-71.0%). The aggregate agreement was 87.80% (95% CI, 86.1%-89.0%). When questioned about appropriate management of the patients, observers elected face-to-face consultation in 60% of patients (95% CI, 58%-61%) and teledermatology in 40% (95% CI, 38%-41%). Diagnostic validity was higher in patients from primary care (76.1% complete agreement and 91.8% aggregate agreement) than those from hospital emergency services (61.8% complete agreement, 83.4% aggregate agreement) (p < 0.001) and teledermatology was also chosen more often in patients from primary care compared with those from emergency services (42% vs 38%; p=0.003). In terms of diagnostic group, higher validity was observed for patients with infectious diseases (73.3% complete agreement and 91.3% aggregate agreement) compared to those with inflammatory disease (70.8% complete agreement and 86.4% aggregate agreement) or tumors (63.0% complete agreement and 87.2% aggregate agreement) (p <0.001). Teledermatology was also chosen more often in patients with infectious diseases (52%) than in those with inflammatory disease (40%) or tumors (28%) (p <0.001). CONCLUSIONS: Store-and-forward teledermatology has a high level of diagnostic validity, particularly in those cases referred from primary care and in infectious diseases. It can be considered useful for the diagnosis and management of patients at a distance and would reduce the requirement for face-to-face consultation by 40%.

Recommendations for the treatment of anti-melanoma differentiation-associated gene 5-positive dermatomyositis-associated rapidly progressive interstitial lung disease.

OBJECTIVES: The study aimed to develop evidence-based recommendations for the treatment of rapidly progressive interstitial lung disease (RPILD) associated with the anti-Melanoma Differentiation-Associated Gene 5-positive dermatomyositis (DM) syndrome. METHODS: The task force comprised an expert panel of specialists in rheumatology, intensive care medicine, pulmonology, immunology, and internal medicine. The study was carried out in two phases: identifying key areas in the management of DM-RPILD syndrome and developing a set of recommendations based on a review of the available scientific evidence. Four specific questions focused on different treatment options were identified. Relevant publications in English, Spanish or French up to April 2018 were searched systematically for each topic using PubMed (MEDLINE), EMBASE, and Cochrane Library (Wiley Online). The experts used evidence obtained from these studies to develop recommendations. RESULTS: A total of 134 studies met eligibility criteria and formed the evidentiary basis for the recommendations regarding immunosuppressive therapy and complementary treatments. Overall, there was general agreement on the initial use of combined immunosuppressive therapy. Combination of high-dose glucocorticoids and calcineurin antagonists with or without cyclophosphamide is the first choice. In the case of calcineurin antagonist contraindication or treatment failure, switching or adding other immunosuppressants may be individualized. Plasmapheresis, polymyxin B hemoperfusion and/or intravenous immunoglobulins may be used as rescue options. ECMO should be considered in life-threatening situations while waiting for a clinical response or as a bridge to lung transplant. CONCLUSIONS: Thirteen recommendations regarding the treatment of the anti-MDA5 positive DM-RPILD were developed using research-based evidence and expert opinion.