First-trimester Combined Screening Research Articles

Noninvasive prenatal testing in megacity

Introduction. The article presents an analysis of the use of non-invasive prenatal testing for chromosomal abnormalities in the fetal extracellular DNA in the blood of pregnant women in Moscow. Materials and methods. When processing materials and research results, authors considered all available clinical data: findings of an ultrasound examination, medical history and results of additional laboratory tests. Results. The article presents results of invasive prenatal diagnostics and pregnancy outcomes in patients with high NIPT risks. Discussion. Authors analyzed diagnostic capabilities of NIPT, its limitations, false-positive and false- negative results, and described 3 cases of prenatal diagnosis of fetal aneuploidy identified in patients who are in the «gray zone» of risk based on the results of combined screening of the first trimester of pregnancy. Conclusion. Prenatal diagnosis of the described aneuploidy is difficult due to individual risk of developing chromosomal abnormalities of the fetus based on the results of combined first-trimester screening in the range of 1:101-1: 2500 and lack of indications for invasive prenatal diagnostics.

Reexamining the optimal nuchal translucency cutoff for diagnostic testing in the cell-free DNA and microarray era: results from the Victorian Perinatal Record Linkage study

The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine recently recommended offering genetic counseling and diagnostic testing for enlarged nuchal translucency at ≥3.0 mm, regardless of previous negative screening with noninvasive prenatal testing. This study aimed to perform a population-based, individual record linkage study to determine the optimal definition of an enlarged nuchal translucency for the detection of atypical chromosome abnormalities. This was a retrospective study of women resident in Victoria, Australia, undergoing combined first-trimester screening during the 24-month period from January 2015 to December 2016. Linkages between statewide results for combined first-trimester screening, prenatal diagnostic procedures, and postnatal cytogenetic results from products of conception and infants up to 12 months of age were used to ascertain the frequency and type of chromosome abnormality by gestation and nuchal translucency measurement. An atypical chromosome abnormality was defined as any major chromosome abnormality other than whole chromosome aneuploidy involving chromosomes 21, 18, 13, X, and Y. Of the 81,244 singleton pregnancies undergoing combined first-trimester screening, 491 (0.60%) had a nuchal translucency of ≥3.5 mm, 534 (0.66%) had a nuchal translucency of 3.0 to 3.4 mm, and 80,219 (98.74%) had a nuchal translucency of < 3.0 mm. When grouped by nuchal translucency multiples of the median (MoM), 192 (0.24%) had a nuchal translucency of ≥3.0 MoM, 513 (0.63%) had a nuchal translucency of 1.9 to 2.9 MoM, and 80,539 (99.13%) had a nuchal translucency of <1.9 MoM. A total of 1779 pregnancies underwent prenatal or postnatal diagnostic testing, of which 89.60% were performed by whole-genome single-nucleotide polymorphism chromosomal microarray. The frequency of total major chromosome abnormalities was significantly higher in the group with a nuchal translucency of ≥3.5 mm (147 of 491, 29.94%) than the group with a nuchal translucency of 3.0 to 3.4 mm (21 of 534, 3.93%) or a nuchal translucency of <3.0 mm (71 of 80,219, 0.09%) (P<.001). There were 93 atypical chromosome abnormalities in the total screened cohort. The frequency of an atypical chromosome abnormality was 4.07% (95% confidence interval, 2.51-6.22), 0.37% (95% confidence interval, 0.05-1.35), and 0.09% (95% confidence interval, 0.07-0.11) in the groups with a nuchal translucency of ≥3.5 mm, 3.0 to 3.4 mm, and <3.0 mm, respectively. The frequency of atypical chromosome abnormalities was 4.69% (95% confidence interval, 2.17-8.71), 2.53% (95% confidence interval, 1.36-4.29), and 0.09% (95% confidence interval, 0.07-0.11) in the groups with a nuchal translucency of ≥3.0 MoM, 1.9 to 2.9 MoM, and <1.9 MoM, respectively. When defining thresholds for offering diagnosis with chromosomal microarray at 11 to 13 weeks, both a nuchal translucency threshold of 1.9 MoM and a fixed threshold of 3.0 mm captured 22 of 93 fetuses (23.7%) with an atypical chromosome abnormality. Of these, 50.0% had a coexisting fetal abnormality on ultrasound. However, the gestation-specific threshold of 1.9 MoM had a better specificity than 3.0 mm. The positive predictive value of an enlarged nuchal translucency for any atypical chromosome abnormality was 1 in 47 for nuchal translucency of >3.0 mm and 1 in 32 for nuchal translucency of >1.9 MoM. Our nuchal translucency threshold of 1.9 MoM captured 0.87% of fetuses, thus approximating the 99th centile. A gestational age-adjusted nuchal translucency threshold of 1.9 MoM or 99th centile is superior to the fixed cutoff of 3.0 mm for the identification of atypical chromosome abnormalities. The risk of an atypical chromosome abnormality in a fetus with an enlarged nuchal translucency is more than tripled in the presence of an additional ultrasound abnormality.

Diagnostic accuracy of the Gaussian first-trimester combined screening for pre-eclampsia to predict small-for-gestational-age neonates.

Pre-eclampsia and delivery of small-for-gestational-age (SGA) neonates can be predicted from the first trimester. A Gaussian model for prediction of PE has recently been described, although its capacity to predict SGA is still unknown. This was a secondary analysis of a prospective cohort study conducted at Vall d'Hebron University Hospital (Barcelona) in 2483 single pregnancies from October 2015 to September 2017. Mean arterial blood pressure and mean uterine artery pulsatility index were recorded at the first-trimester scan. Serum concentrations of placental growth factor and pregnancy-associated plasma protein-A were assessed between 8+0 and 13+6 weeks. The predictive capacities of early (<32weeks) and preterm (<37weeks) SGA were tested. For SGA without pre-eclampsia, detection rates of 25.0% (95% confidence interval [CI] 0-75.0) for early SGA and 14.3% (95% CI 3.6-28.6) for preterm SGA were achieved. For SGA with pre-eclampsia, the algorithm showed detection rates of 100.0% (95% CI 25.0-100.0) for early SGA and 56.3% (95% CI 31.3-81.3) for preterm SGA. This algorithm identifies 62.5% of early SGA and 27.3% of preterm SGA. Combined screening for predicting both pre-eclampsia and SGA by using the Gaussian algorithm is feasible and would simplify clinical practice.

Prevalence threshold of screening tests in obstetrics and gynecology

ObjectiveWe define the prevalence threshold as the prevalence level below which a test’s positive predictive value (PPV) declines most sharply relative to disease prevalence – and thus the rate of false positive results/false discovery rate increases most rapidly. The objective of this study is to determine the prevalence threshold of various screening tests used in obstetrics and gynecology among low-risk women in modern clinical practice. MethodsWe searched Medline, EMBASE, Google Scholar, Scopus, ISI Web of Science, Cochrane database, and PubMed to obtain the sensitivity and specificity estimates for the following screening tests: 50 g-oral glucose tolerance test (GDM-50 g), non-invasive prenatal testing (NIPT), combined first trimester screening (FTS), vagino-rectal swab for group B streptococcus (GBS) in pregnancy, cervical cytology (Pap) and HPV testing, mammography and manual breast exam, urinary PCR and cervical-vaginal swab testing for gonorrhoea and chlamydia as well as AMH for the diagnosis of PCOS. We used these estimates to calculate disease-specific prevalence thresholds, comparing them to the actual estimates of disease prevalence. ResultsThe prevalence thresholds and average estimates of disease prevalence (shown in brackets) are as follows: GDM-50 g 31 % (6%), NIPT 7% (0.2 %), combined FTS 19.5 % (0.2 %), GBS swab 18 % (15–45 %), Pap 21 % (0.2 %), HPV 27 % (0.2 %), mammography 25 % (12.5 %), breast exam 25 % (12.5 %), gonorrhoea -chlamydia 6–13 % (4.2–4.7 %), AMH for PCOS 32 % (10 %). ConclusionThe prevalence thresholds of various screening tests used in obstetrics and gynecology are well above the estimated disease prevalence. This implies that when undertaking population-level screening a significant proportion of positive screening tests obtained are likely false-positives. Attempts at individualizing pre-test probability when undertaking population-level screening are needed in order to best interpret the results of screening tests.

State-Wide Utilization and Performance of Traditional and Cell-Free DNA-Based Prenatal Testing Pathways: The Victorian Perinatal Record Linkage (PeRL) Study

(Abstracted from Ultrasound Obstet Gynecol 2020;56:215–224) In recent years, the use of combined first-trimester screening (CFTS) and cell-free DNA (cfDNA) screening has increased. With the rise of CFTS and cfDNA prenatal testing, there has been a dramatic decrease in the number of invasive diagnostic tests performed during pregnancy.

First-trimester maternal serum biomarkers and the risk of cerebral palsy.

To investigate whether combined first-trimester screening (cFTS) biomarkers are associated with cerebral palsy (CP) and to identify CP characteristics associated with abnormal biomarker levels. In this retrospective case-control data linkage study, we matched mothers of 435 singletons with CP from a population register to their cFTS records and selected 10 singleton pregnancy controls per case. We compared mean and abnormal levels (expressed as multiples of the median [MoMs]) of pregnancy-associated plasma protein-A (PAPP-A), beta subunit of human chorionic gonadotrophin (β-hCG), and nuchal translucency between cases and controls and between CP subgroups. Compared with control pregnancies, CP pregnancies had lower mean levels of PAPP-A (0.95 vs 1.01 MoM, p=0.02) and β-hCG (0.93 vs 0.99 MoM, p=0.02). Biomarker levels in CP pregnancies were 1.8 times more likely to be associated with abnormally low levels of PAPP-A (p<0.01), 1.4 times for β-hCG (p=0.12), and 2.6 times for low PAPP-A and β-hCG together (p=0.04). In cases with CP, an abnormally low PAPP-A level was associated with moderate preterm birth, low Apgar scores, and Gross Motor Function Classification System level V. Low β-hCG was associated with very low birthweight. Low first-trimester biomarker levels suggest a role for early pregnancy factors in some causal pathways to CP. Low first-trimester levels of biomarkers in maternal serum are associated with later cerebral palsy (CP). Early pregnancy factors have potential importance in causal pathways to CP. Causal pathways involving preterm birth, term neonatal encephalopathy, and genetic syndromes may be implicated.

A Randomized Controlled Trial on the Influence of Prenatal Counseling on the Attitudes and Preferences Toward Invasive Prenatal Testing Among Women in Their First Trimester of Pregnancy (INVASIVE).

ObjectiveTo assess the impact of prenatal genetic counseling on the attitudes and preferences toward invasive testing in first-trimester pregnant women.MethodsThis is a randomized open-label study, of pregnant women undergoing first trimester combined screening for aneuploidies. Women were divided into the experimental or control groups in a 1:1 design. The intervention consisted of 15-min extra counseling about prenatal screening and diagnosis. The main outcome was the desire to choose an invasive testing as their first prenatal testing option which was measured as absolute risk.ResultsAfter excluding those with incomplete data, 75 women remained in the experimental group and 75 as controls. Women receiving counseling were 32% more likely to choose an invasive prenatal testing as their first-line option after extra 15-min extensive counseling, reducing the first-trimester combined screening by 20% and the cell-free DNA by 12%. If given the opportunity, 59% of the women would like to be able to choose the prenatal test that suits their needs.ConclusionWomen given an extensive prenatal counseling are more likely to choose an invasive testing as their first-line test in spite of the concerning risks.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier NCT04119349.

Increased prenatal detection of 22q11.2 deletion and 22q11.2 duplication after introduction of nationwide prenatal screening for trisomy 21, trisomy 13, and trisomy 18

To evaluate time of diagnosis of 22q11.2 deletion and 22q11.2 duplication as well as trisomies 21, 13, and 18 before and after introduction of a prenatal screening program including combined first-trimester screening (cFTS) for the trisomies in Denmark in 2004. Cross-sectional, population-based register study employing The Danish Cytogenetic Central Register. Proportions of cases diagnosed 1998-2004 and 2005-2017 were compared before 14+0 and 22+0 weeks and birth (prenatal cases) or up to 1 or 10 years of age (postnatal cases). In total, 4562 cases were included. From 1998-2004 to 2005-2017, the proportion of 22q11.2 deletion cases identified prenatally increased from 4.3% (95% CI: 0.9-12.0%) to 27.3% (21.2-34.0%), while for 22q11.2 duplication an increase from 0/6 to 26/87 (prenatal cases/all cases) was observed. Similarly, proportions of trisomies 21, 13, and 18 detected before birth increased. A greater proportion of the studied conditions was identified earlier in pregnancy, but not generally earlier in the postnatal course. Proportions of 22q11.2 deletion and 22q11.2 duplication identified prenatally increased after introduction of a prenatal screening program not aimed specifically to identify these conditions,. A greater proportion of all cases were detected earlier in pregnancy, but not earlier postnatally, following introduction of screening.

AIUM Practice Parameter for the Performance of Detailed Diagnostic Obstetric Ultrasound Examinations Between 12 Weeks 0 Days and 13 Weeks 6 Days.

AIUM Practice Parameter for the Performance of Detailed Diagnostic Obstetric Ultrasound Examinations Between 12 Weeks 0 Days and 13 Weeks 6 Days.

State-wide utilization and performance of traditional and cell-free DNA-based prenatal testing pathways: the Victorian Perinatal Record Linkage (PeRL) study.

To perform individual record linkage of women undergoing screening with cell-free DNA (cfDNA), combined first-trimester screening (CFTS), second-trimester serum screening (STSS), and/or prenatal and postnatal cytogenetic testing with the aim to (1) obtain population-based estimates of utilization of prenatal screening and invasive diagnosis, (2) analyze the performance of different prenatal screening strategies, and (3) report the residual risk of any major chromosomal abnormality following a low-risk aneuploidy screening result. This was a retrospective study of women residing in the state of Victoria, Australia, who underwent prenatal screening or invasive prenatal diagnosis in 2015. Patient-funded cfDNA referrals from multiple providers were merged with state-wide results for government-subsidized CFTS, STSS and invasive diagnostic procedures. Postnatal cytogenetic results from products of conception and infants up to 12 months of age were obtained to ascertain cases of false-negative screening results and atypical chromosomal abnormalities. Individual record linkage was performed using LinkageWizTM . During the study period, there were 79 140 births and 66 166 (83.6%) women underwent at least one form of aneuploidy screening. Linkage data were complete for 93.5% (n = 61 877) of women who underwent screening, and of these, 73.2% (n = 45 275) had CFTS alone, 20.2% (n = 12 486) had cfDNA alone; 5.3% (n = 3268) had STSS alone, 1.3% (n = 813) had both CFTS and cfDNA, and < 0.1% (n = 35) had both STSS and cfDNA. CFTS had a combined sensitivity for trisomies 21 (T21), 18 (T18) and 13 (T13) of 89.57% (95% CI, 82.64-93.93%) for a screen-positive rate (SPR) of 2.94%. There were 12 false-negative results in the CFTS pathway, comprising 10 cases of T21, one of T18 and one of T13. cfDNA had a combined sensitivity for T21, T18 and T13 of 100% (95% CI, 95.00-100%) for a SPR of 1.21%. When high-risk cfDNA results for any chromosome (including the sex chromosomes) and failed cfDNA tests were treated as screen positives, the SPR for cfDNA increased to 2.42%. The risk of any major chromosomal abnormality (including atypical abnormalities) detected on prenatal or postnatal diagnostic testing after a low-risk screening result was 1 in 1188 for CFTS (n = 37) and 1 in 762 for cfDNA (n = 16) (P = 0.13). The range of chromosomal abnormalities detected after a low-risk cfDNA result included pathogenic copy-number variants (n = 6), triploidy (n = 3), rare autosomal trisomies (n = 3) and monosomy X (n = 2). Our state-wide record-linkage analysis delineated the utilization and clinical performance of the multitude of prenatal screening pathways available to pregnant women. The sensitivity of cfDNA for T21, T18 and T13 was clearly superior to that of CFTS. While there was no statistically significant difference in the residual risk of any major chromosomal abnormality after a low-risk CFTS or cfDNA result, there were fewer live infants diagnosed with a major chromosomal abnormality in the cfDNA cohort. These data provide valuable population-based evidence to inform practice recommendations and health policies. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Screening for Preeclampsia in the First Trimester and Aspirin Prophylaxis: Our First Year.

Preeclampsia is a major cause of perinatal and maternal morbidity and mortality. Our objective is to assess the performance of a combined screening test for preeclampsia in the first trimester and the prophylactic use of low-dose aspirin. Prospective study of all women attending our hospital for the first-trimester screening of aneuploidies, between March 2017 and February 2018 (n = 1,297). The exclusion criteria were multiple pregnancy and major fetal abnormalities. Preeclampsia screening was performed with an algorithm that includes maternal characteristics, and biophysical and biochemical biomarkers. High-risk was defined as a risk ≥ 1:50 of early-onset preeclampsia (before 34 weeks), in which cases low-dose aspirin (150 mg at night) was offered to these women from screening until 36 weeks. From the 1,272 enrolled participants, the majority were Caucasian (1,051; 82.6%) and multiparous (658, 51.7%). Fifty patients (3.9%) screened high-risk for preeclampsia, and all started a low-dose aspirin regimen, with good compliance (96%). Early-onset preeclampsia was found in 3 pregnant women (0.24%), and total preeclampsia was diagnosed in 25 (2.02%), compared with 28 (0.75%) cases of early preeclampsia (p = 0.0099) and 98 (2.62%) of total preeclampsia (p = 0.2904) before the implementation of screening. There was a lower incidence of both, early-onset and total preeclampsia, after the introduction of universal screening and prophylactic use of low-dose aspirin. This reduction was statistically significant in early-onset preeclampsia. The association of a first-trimester combined screening model and aspirin prophylaxis appears to be useful in predicting and reducing the incidence of early-onset preeclampsia, in a routine care setting.

A Retrospective Analysis Of Different Contingent Screening Models For Fetal Down Syndrome In Southwestern China

To discuss combinations of traditional screening and noninvasive prenatal screening (NIPS) and to compare which traditional screening is the most suitable first-line screening approach to NIPS, pregnant women were recruited in this retrospective observational study. Pregnant women underwent one of four traditional screening tests. The 9 contingent models were combined by high risk cut-offs of 1:50, 1:100, 1:270 and intermediate risk cut-offs of 1:1000, 1:1500, 1:2000. We analyzed cost and performance of various screening models with contingent screening of different risk cut-offs. Compared with other screening tests, combined first-trimester screening (CFTS) had the lowest proportion of high risk (≥1:270) with the highest detection rate (DR) (78.79%) and the lowest proportion of intermediate risk (1:271~1:1000). When intermediate risk was 1:51 ~1:1500, CFTS as first-line screening had the lowest cost with DR of 93.94%. Other screening tests as the first-line screening with intermediate risk of 1:51~1:1000 had the lowest cost, there DR were 90.91%, 84.62%, 91.67%, respectively. Our study demonstrated if only one traditional screening was allowed to screen pregnant women, CFTS was recommended as the first choice. According to local health and economic conditions, adopting appropriate traditional screening with suitable cut-offs as first-line screening will contributed to a cost-effective screening model.

Detection rates and residual risk for a postnatal diagnosis of an atypical chromosome aberration following combined first‐trimester screening

To determine the detection rates of all types of chromosome aberrations and the residual risk for postnatal diagnosis of an atypical chromosome aberration depending on the strategy for further investigation with either noninvasive prenatal testing (NIPT) or invasive testing in pregnancies with increased risk following combined first-trimester screening (cFTS). A review of all pregnancies examined with cFTS during 2010 to 2017. The cohort consisted of 129 493 pregnancies. There were 852 (0.7%) clinically significant chromosome aberrations, including aberrations detected later on or after birth. A total of 12% were atypical chromosome aberrations. Considering that 40% were detected due to a miscarriage/intrauterine fetal death or a malformation on ultrasound there is a 0.05% (1:2000) background risk of a postnatal diagnosis of a liveborn child with an atypical chromosome aberration if no further invasive test is performed during pregnancy. If all women with an increased risk (≥1:200) had an invasive test and NIPT was performed up to a risk of 1:1000, 95% of common trisomies/sex chromosome aberrations and 55% of atypical aberrations would be detected. If NIPT was offered to all women with an increased risk following cFTS it would imply that three times as many children would be born with an atypical chromosome aberration.

Тенденции раннего пренатального скрининга хромосомных аномалий и врожденных пороков развития плода в России в 2018 г

В ходе анализа результатов раннего пренатального скрининга (РПС) в России за 2018 г. (Аудит-2019) дана оценка качества мероприятий, общей эффективности и тенденций развития системы РПС в субъектах РФ посредством сравнения рассчитанных основных организационных, методологических и интегральных показателей с международными референтными значениями. In the course of analyzing the results of early prenatal combined first-trimester screening (FTS) in Russia for 2018 (Audit-2019) the assessment of the quality of measures, the overall effectiveness and trends in the development of the FTS system in the regions of Russia. They are presented by comparing the calculated main organizational, methodological and integral indicators with international reference values.

First-trimester screening for trisomies in pregnancies with vanishing twin.

To examine multiples of the median (MoM) values of serum free beta-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in a large series of pregnancies with a vanishing twin, determine the association of these values with the interval between embryonic death and blood sampling, and develop a model that would allow incorporation of these metabolites in first-trimester combined screening for trisomy. This was a retrospective study comparing maternal serum free β-hCG and PAPP-A levels at 11-13 weeks' gestation in 528 dichorionic pregnancies with a vanishing twin, including 194 (36.7%) with an empty gestational sac and 334 (63.3%) with a dead embryo, with those in 5280 normal singleton pregnancies matched for method of conception and date of examination. In vanishing-twin pregnancies with a dead embryo, marker levels were examined in relation to the estimated time between embryonic death and maternal blood sampling. First, in pregnancies with a vanishing twin, median free β-hCG MoM was not significantly different from that in normal singleton pregnancies (1.000; 95% CI, 0.985-1.016 vs 0.995; 95% CI, 0.948-1.044; P = 0.849). Second, PAPP-A MoM was higher in vanishing-twin pregnancies than in normal singleton pregnancies (1.000; 95% CI, 0.985-1.015), both in the group with an empty gestational sac (1.165; 95% CI, 1.080-1.256; P = 0.0001) and in that with a dead embryo (1.175; 95% CI, 1.105-1.249; P < 0.0001). Third, in vanishing-twin pregnancies with a dead embryo, PAPP-A MoM was related inversely to the interval between estimated gestational age at embryonic demise and blood sampling (P < 0.0001). Fourth, in first-trimester screening for trisomy 21 in singleton pregnancies, the estimated detection rate, at a 5% false-positive rate, was 82% in screening by a combination of maternal age and fetal nuchal translucency thickness, and this increased to 86% with the addition of serum free β-hCG and to 91% with the addition of serum PAPP-A. Fifth, similar performance of screening can be achieved in pregnancies with a vanishing twin, provided the appropriate adjustments are made to the level of PAPP-A for the interval between estimated gestational age at embryonic demise and blood sampling. First-trimester screening for trisomy in pregnancies with a vanishing twin should rely on a combination of maternal age, fetal nuchal translucency thickness and serum free β-hCG, as in singleton pregnancy, without the use of serum PAPP-A. Alternatively, PAPP-A can be included but only after appropriate adjustment for the interval between estimated gestational age at fetal demise and blood sampling. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Prospective Validation of First-Trimester Ultrasound Characteristics as Predictive Tools for Twin-Twin Transfusion Syndrome and Selective Intrauterine Growth Restriction in Monochorionic Diamniotic Twin Pregnancies

Objective: Monochorionic diamniotic (MCDA) twins are at increased risk of adverse outcome due to unequal placental sharing and placental vascular communications between the fetal circulations. Most centres perform ultrasound examination every 2–3 weeks to identify these complications. Identifying a high-risk cohort of MCDA twins in the first trimester would allow more efficient surveillance. We have attempted to validate first-trimester ultrasound characteristics as predictive tools for twin-twin transfusion syndrome (TTTS) and selective intrauterine growth restriction (sIUGR) in MCDA twins. Material and Methods: This is a prospective cohort study including MCDA twins enrolled at the time of first-trimester combined screening. Differences in crown-rump length (CRL), nuchal translucency (NT) thickness, ductus venosus pulsatility index for veins (DV PIV), presence or absence of tricuspid regurgitation and right ventricular E/A ratio were assessed. Receiver operating characteristic (ROC) curves were used to assess the potential value of these measures as predictive tools for identifying a cohort of MCDA pregnancies at high risk of adverse pregnancy outcome. Results: Sixty-five MCDA pregnancies were included in the analysis. Nine (14%) developed TTTS, 17 (26%) developed sIUGR. The best predictive marker for TTTS was NT discordance of ≥20% (ROC AUC = 0.79; 95% CI 0.59–0.99). Combining measures did not improve performance (AUC = 0.80; 95% CI 0.62–0.99). Conclusion: NT discordance was the most effective characteristic at predicting TTTS but still had a relatively poor positive predictive value (36%). Intertwin differences in CRL, DV PIV and E/A ratio were not predictive of subsequent pregnancy complications. None of these characteristics have sufficient efficacy to be used to triage MCDA twin pregnancies ongoing obstetric surveillance.

From first-trimester screening to risk stratification of evolving pre-eclampsia in second and third trimesters of pregnancy: comprehensive approach.

Preeclampsia and associated hypertensive disorders of pregnancy represent a leading cause of global maternal and neonatal morbidity and mortality. Identification of women at high risk for developing preterm-preeclampsia and prophylaxis with low-dose aspirin has the potential to significantly reduce the rate of preterm-preeclampsia. In addition, risk assessment and monitoring of women in the second and third trimester of pregnancy, to aid in early detection of evolving disease, timely referral to specialist care, and active monitoring of women with confirmed or suspected preeclampsia is essential for improving maternal and neonatal outcomes. The angiogenesis-related biomarkers sFlt-1 and PlGF have been shown to have clinical value to aid in the prediction, diagnosis, and risk stratification of preeclampsia when used either alone or in combination with other risk factors. However, currently there is no consensus on the optimum strategy to link first trimester screening for preterm-preeclampsia with appropriate second and third trimester risk assessment strategies. This opinion paper will outline the current evidence for first trimester preeclampsia screening and prevention, as well as the evidence for various risk stratification approaches for detection of evolving preeclampsia through the second and third trimesters of pregnancy, and proposes a potential model integrating these tools. This article is protected by copyright. All rights reserved.

Amniocentesis Following Positive First Trimester Combined Screening: A Comparative Study

Abstract- The birth of a neonate with chromosomal abnormalities, e.g. Down syndrome has very serious problems for family, society, and for the neonate itself, and therefore prenatal evaluation is imperative in determining the fate of the fetus. This research aimed to assess the association and accuracy of amniocentesis with first-trimester combined screening. In this study, specimens from 1066 cases were analyzed for free Beta human chorionic gonadotropin, pregnancy-associated plasma protein A, along with nuchal translucency and nasal bone ultrasonography from October 2013 till November 2014. Upon observing positive screening, mothers underwent amniocentesis. Finally the amniocentesis results were compared with that of first-trimester screening. Our results determined a direct relation between the high age of the mother and gravidity with P of 0.001 and 0.020 with positive first-trimester screening. Our study attained a 92% accuracy rate of amniocentesis due to one case of mosaicism of trisomy 21, that was not diagnosed, because it was not requested by physician. Only 12 (17.1%) cases out of 70 (mothers with positive first-trimester screening) showed positive amniocentesis, which had a significant relationship with chromosomal abnormality. First trimester combined screening has very high accuracy (94.6%) in prediction of genetic abnormalities. The probability of positive first-trimester screening is directly influenced by number of factors, including the mother age and gravidity. Amniocentesis is necessary for all of mothers with positive first-trimester screening and will almost always detect chromosomal abnormalities.

Isolated 'soft signs' of fetal choroid plexus cysts or echogenic intracardiac focus - consequences of their continued reporting.

Choroid plexus cysts (CPC) and echogenic intracardiac focus (EIF) are obsolete soft markers found on morphology ultrasound and not a valid reason for adjusting fetal risk of aneuploidy. We conducted a retrospective audit of women referred to genetic counsellor and fetal medicine services at St George Hospital (SGH) and the Royal Hospital for Women (RHW) for CPC and EIF from 1 January 2006 to 31 December 2016 inclusive. In total, 208 CPC and/or EIF referrals were identified, 118 (57%) of which were for isolated CPC and/or EIF and 102 (49%) occurring in women low risk for aneuploidy prior to morphology ultrasound. Significantly, more women had undergone combined first-trimester screening in the 2014 to 2016 epoch vs. previous years at both SGH (P=0.03) and RHW (P=0.004). However, the number of women referred for CPC and EIF remained relatively constant. No fetus was born with a major structural or chromosomal abnormality in the group of low-risk women with isolated signs. However, 18% of these women were referred to both genetic counselling and fetal medicine services, 7% had NIPT after morphology, 14% had amniocentesis, and 33% had additional ultrasound(s). Despite advances in screening technology, low-risk women are still referred to specialist services for these 2 soft signs and undergoing unnecessary follow-up, NIPT and amniocentesis.

OC01.03: State‐wide performance of traditional and cell‐free DNA‐based prenatal testing pathways: the Victorian Perinatal Record Linkage (PeRL) study

OBJECTIVES: Women's choices of prenatal screening and diagnostic pathways have increased in complexity since the introduction of cell-free DNA (cfDNA) screening and chromosomal microarrays. We performed individual record-linkage of women undergoing screening with cfDNA, combined first trimester screening (CFTS), second trimester serum screening (STSS), and/or prenatal and postnatal cytogenetic testing to (i) obtain population-based estimates on women's utilization of screening and diagnosis, (ii) analyse the performance of different screening strategies, and (iii) report the residual risks of any major chromosome abnormality following a low risk aneuploidy screen. METHODS: Retrospective study of women resident in Victoria, Australia, undergoing screening or prenatal diagnosis in 2015. Patient-funded cfDNA referrals from multiple providers were merged with state-wide results for government-subsidized CFTS, STSS and invasive diagnostic procedures. Postnatal cytogenetic results from products of conception and infants up to 12 months of age were obtained to ascertain cases of false negative screening results and atypical chromosome abnormalities. Individual record-linkage was performed with LinkageWizTM and statistical analyses with STATA v14.0. RESULTS: There were 79,140 births during the study period; 66,166 women (83.4%) underwent at least one form of aneuploidy screening. Linkage data were complete for 92.4% of women undergoing screening (n=61,911) and of these, 73.1% (n=45,275) used CFTS alone, 20.2% (n=12,520) used cfDNA alone; 5.3% (n=3268) used STSS alone, 1.3% (n=813) used both CFTS and cfDNA, and < 0.1% (n=35) used both STSS and cfDNA. CFTS had a combined sensitivity for trisomies 21, 13 and 18 of 89.57% (95%CI 82.64-93.93) for a screen positive rate (SPR) of 2.94%. There were 12 false negative results in the CFTS pathway (10 trisomy 21, 1 trisomy 18 and 1 trisomy 13). CfDNA had a combined sensitivity of 100% (95% CI 95.0-100.0) for trisomies 21, 13 and 18 for a 1.21% screen positive rate. When high risk cfDNA results for any chromosome, including the sex chromosomes, and failed cfDNA tests were treated as screen positives, the cfDNA SPR increased to 2.42%. The risk of any major chromosome abnormality (including atypical abnormalities) detected on prenatal or postnatal diagnostic testing after a low risk screening result was 1 in 1188 for CFTS (n=37) and 1 in 762 for cfDNA (n=16) (p= 0.13). The range of chromosome abnormalities detected after low risk cfDNA included pathogenic CNVs (n=6), triploidy (n=3), rare autosomal trisomies (n=3) and monosomy X (n=2). CONCLUSIONS: Our state-wide linkage analysis delineated the utilization and clinical performance of the multitude of screening pathways available to pregnant women. The sensitivity of cfDNA for trisomies 21, 13 and 18 was clearly superior to CFTS. While there was no statistically significant difference in the residual risk of any major chromosome abnormality after low risk CFTS or cfDNA result, there were fewer live infants diagnosed with a major chromosome abnormality in the cfDNA cohort. These data provide valuable population-based evidence to inform practice recommendations and health policy. This article is protected by copyright. All rights reserved.