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

Term preeclampsia (tPE), ≥37 weeks, is the most common form of PE and the most difficult to predict. Little is known about its pathogenesis. This study aims to elucidate the pathogenesis and assess early prediction of tPE using serial integrated metabolomic and proteomic systems biology approaches. Serial first- (11–14 weeks) and third-trimester (30–34 weeks) serum samples were analyzed using targeted metabolomic (1H NMR and DI-LC-MS/MS) and proteomic (MALDI-TOF/TOF-MS) platforms. We analyzed 35 tPE cases and 63 controls. Serial first- (sphingomyelin C18:1 and urea) and third-trimester (hexose and citrate) metabolite screening predicted tPE with an area under the receiver operating characteristic curve (AUC) (95% CI) = 0.817 (0.732–0.902) and a sensitivity of 81.6% and specificity of 71.0%. Serial first [TATA box binding protein-associated factor (TBP)] and third-trimester [Testis-expressed sequence 15 protein (TEX15)] protein biomarkers highly accurately predicted tPE with an AUC (95% CI) of 0.987 (0.961–1.000), sensitivity 100% and specificity 98.4%. Integrated pathway over-representation analysis combining metabolomic and proteomic data revealed significant alterations in signal transduction, G protein coupled receptors, serotonin and glycosaminoglycan metabolisms among others. This is the first report of serial integrated and combined metabolomic and proteomic analysis of tPE. High predictive accuracy and potentially important pathogenic information were achieved.

Objective To estimate the chorionic villus sampling (CVS)‐related risk of fetal loss in twin pregnancy after adjustment for chorionicity, nuchal translucency thickness (NT), intertwin discordance in crown–rump length (CRL), maternal demographic characteristics and serum pregnancy‐associated plasma protein‐A (PAPP‐A) and free β‐human chorionic gonadotropin (β‐hCG). Methods This was a multicenter study from eight fetal medicine units in which the leadership were trained at the Harris Birthright Research Centre for Fetal Medicine in London, UK, and in which the protocols for screening, invasive testing and pregnancy management are similar. Data were obtained prospectively from women with twin pregnancy undergoing routine ultrasound examination at 11–13 weeks' gestation. Multivariable logistic regression analysis with backward stepwise elimination was used to examine whether CVS provided a significant independent contribution to the prediction of risk of fetal loss after adjusting for maternal and pregnancy characteristics, including maternal age, racial origin and weight, method of conception, smoking status, parity, chorionicity, intertwin discordance in CRL, fetal NT ≥ 95th percentile and free β‐hCG and PAPP‐A multiples of the median. Similarly, within the CVS group, multivariable logistic regression analysis was used to investigate the effect of the number of intrauterine needle insertions and size of the needle on the risk of fetal loss. Results The study population of 8581 twin pregnancies undergoing ultrasound examination at 11–13 weeks' gestation included 316 dichorionic and 129 monochorionic twins that had CVS. First, in twin pregnancies undergoing CVS, compared to those not undergoing CVS, there was a 2‐fold increased risk of fetal loss at < 24 weeks' gestation and of loss at any stage in pregnancy. Second, the factors providing a significant independent contribution to the prediction of miscarriage or fetal loss in twin pregnancy were increased maternal weight, black racial origin, monochorionicity, and more so monoamnionicity, large intertwin discordance in CRL and increased fetal NT, and, in the case of fetal loss at any stage, there was also a contribution from assisted conception and low serum PAPP‐A. Third, after adjustment for maternal and pregnancy characteristics, CVS did not provide a significant contribution to the risk of fetal loss. Fourth, in twin pregnancies that had CVS, there was no significant contribution to fetal loss from the number of intrauterine needle insertions or needle size. Conclusion The 2‐fold increased risk of fetal loss following CVS in twin pregnancy can, to a great extent, be explained by maternal and pregnancy characteristics rather than the invasive procedure itself. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Background and aim of the study: Scientific Societies do not recommend the use of cell-free DNA (cfDNA) testing as a first-tier screening for microdeletion and microduplication syndromes (MMs). The aim of this study was to review the current available literature on the performance of cell-free DNA as a screening for MMs.Methods: Medline, Embase and the Cochrane Library were searched electronically from 2000 to January 2020 and articles reporting the diagnostic performance of cfDNA screening for MMs in large (>5000 cases) series were included. Betweenstudy heterogeneity and random effect model for screen positive rate (SPR), false positive rate (FPR) and positive predictive value (PPV) were calculated. Results:We identified 42 papers, seven included, for a total of 474,189 pregnancies and 210 cases of MMs. Diagnostic verification of positive cases was available overall in 486 (71.68 %) of 678 cases. The weighted pooled SPR, FPR and PPV were 0.19% (95% CI = 0.09-0.33), 0.07 (95% CI = 0.02-0.15) and 44.1 (95% CI = 31.49-63.07).In conclusion, the pooled PPV of cfDNA testing in screening for MMs was about 40%, ranging from 29% to 91%, for an overall FPR <0.1%. Conclusions:No confirmatory analysis was available in cases that did not undergo invasive testing, which were the vast majority of cases with a negative test, and therefore, the DR and the negative predictive value cannot be determined. K E Y W O R D Scell-free DNA, fetal cells, fetal diseases, fetal genetic analysis, genetic counseling, nucleic acids & proteins, noninvasive prenatal testing, fetal medicine and diagnostic procedures, whole genome sequencing Key PointsWhat's already known about this topic? � Cell-free DNA (cfDNA) as screening test for microduplication (MMs) is burdened by a high variability of positive predictive value (PPV) which is far from being considered acceptable. Scientific Societies worldwide are concordant in recommending not to offer cfDNA testing for MMs outside well-defined research protocols.