Serum Free Β-human Chorionic Gonadotropin Research Articles

Atypicality index as an add-on to combined first-trimester screening for chromosomal aberrations.

To compute a set of atypicality indices based on combined first-trimester screening (cFTS) markers and second-trimester estimated fetal weight (EFW), and to demonstrate their potential in identifying pregnancies at reduced or increased risk of chromosomal aberrations following a low-risk cFTS result. The atypicality index quantifies the unusualness of an individual set of measurements relative to a reference distribution and can be computed from any variables or measurements available. A score of 0% on the atypicality index represents the most typical profiles, while a score of 100% indicates the highest level of atypicality. From the Danish Fetal Medicine Database, we retrieved data on all pregnant women seen for cFTS in the Central Denmark Region between January 2008 and December 2018. All pregnancies with a cytogenetic or molecular analysis obtained prenatally, postnatally or following pregnancy loss or termination were identified. A first-trimester atypicality index (AcFTS) was computed based on nuchal translucency (NT) thickness, maternal serum free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A). Furthermore, a second-trimester index (AcFTS + EFW) was computed from cFTS markers and EFW from a routine second-trimester anomaly scan. All pregnancies were stratified into subgroups based on their atypicality levels and their cFTS risk estimates. The risk of chromosomal aberrations in each subgroup was then compared with the overall prevalence, and a graphical presentation of the multivariate measurement profiles was developed. We retrieved data on 145 955 singleton pregnancies, of which 9824 (6.7%) were genetically examined. Overall, 1 in 122 (0.82% (95% CI, 0.77-0.87%)) of all pregnancies seen for cFTS were affected by a fetal chromosomal aberration, and in screen-negative pregnancies (cFTS trisomy 21 risk < 1 in 100 and/or trisomy 18/13 risk < 1 in 50), 0.41% (95% CI, 0.38-0.44%) were affected. In screen-negative pregnancies with a typical first-trimester profile (AcFTS < 80%), the risk of chromosomal aberrations was significantly reduced (0.28%) compared with the overall risk. The risk of chromosomal aberrations increased with higher atypicality index to 0.49% (AcFTS [80-90%)), 1.52% (AcFTS [90-99%)) and 4.44% (AcFTS ≥ 99%) and was significantly increased in the two most atypical subgroups. The same applied for the second-trimester atypicality index, with risks of chromosomal aberrations of 0.76% and 4.16% in the two most atypical subgroups (AcFTS + EFW [90-99%) and AcFTS + EFW ≥ 99%, respectively). As an add-on to cFTS, the atypicality index identifies women with typical measurement profiles, which may provide reassurance, whereas atypical profiles may warrant specialist referral and further investigation. In pregnancies identified as low risk on cFTS but with a highly atypical distribution of NT, PAPP-A and β-hCG, the risk of a chromosomal aberration is substantially increased. The atypicality index optimizes the interpretation of pre-existing prenatal screening profiles and is not limited to cFTS markers or EFW. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

The role of second trimester uterine artery Doppler in predicting obstetric and neonatal outcomes in abnormal first trimester maternal serum pregnancy-associated plasma protein-A and free β-human chorionic gonadotropin values.

This study aims to determine whether second-trimester uterine artery (UtA) Doppler combined with first-trimester abnormal pregnancy-associated plasma protein-A (PAPP-A) and β-human chorionic gonadotropin (β-Hcg) levels predicts adverse obstetric and neonatal outcomes. This study of 289 pregnant women included 196 with normal PAPP-A and free β-HCG values (control group) and 93 with abnormal values (study group) in the first-trimester screening test. Second-trimester UtA Doppler sonography was done in these pregnancies. The perinatal prediction and screening potential of UtA Doppler pulsatility index (PI) parameters were examined in the study group. UtA PI >95 percentile increased birth before the 37th week by 4.46 times, birth before the 34th week by 7.44 times, preeclampsia risk by 3.25 times, fetal growth restriction (FGR) risk by 4.89 times, and neonatal intensive care unit (NICU) admission rates by 3.66 times in the study group (p < 0.05 for all). UtA PI >95 percentile had 49.2% sensitivity and 82.1% specificity for birth before 37 weeks. For birth before 34 weeks, sensitivity was 80.0% and specificity 65.0%. FGR has 70.5% sensitivity and 67.1% specificity. Screening for preeclampsia has 66.6% sensitivity and 61.9% specificity. Adding UtA Doppler in the second trimester to pregnancies with abnormal PAPP-A and/or free β-Hcg values in the first trimester may be a useful screening method for adverse outcomes.

Atypicality index: avoiding false reassurance in prenatal screening.

To demonstrate the application of the atypicality index as an adjunct to first-trimester risk assessment for major trisomies by the combined test. This was a study of 123 998 Danish women with a singleton pregnancy who underwent routine first-trimester screening, including risk assessment for major trisomies. An atypicality index, which is a measure of the degree to which a profile is atypical, was produced for measurements of fetal nuchal translucency thickness and maternal serum free β-human chorionic gonadotropin and pregnancy-associated plasma protein-A. The incidence of adverse pregnancy outcome, including miscarriage, intrauterine death and termination of pregnancy, was tabulated according to the screening result and atypicality index. In pregnancies with low risk and those with high risk for major trisomies according to the combined screening test, the incidence of adverse pregnancy outcome increased with increasing atypicality index. In pregnancies with a low risk for trisomies and atypicality index of ≥ 99%, the incidence of adverse outcome was 5.1 (95% CI, 3.4-7.6) times higher compared with that in low-risk pregnancies with a typical measurement profile, reflected by an atypicality index of < 80%. Similarly, in high-risk pregnancies, the incidence of adverse outcome was 7.9 (95% CI, 4.4-14.5) times higher in those with an atypicality index of ≥ 99% compared to those with an atypicality index of < 80%. Using individual profile plots, we were able to demonstrate a transparent and intuitive method for visualization of multiple variables, which can help interpret the individual combination of measurements and level of atypicality. In pregnancies undergoing first-trimester combined screening and classified as being at low risk for major trisomies, profiles that are typical of pregnancies with normal outcome provide additional reassurance, whereas those with an atypical profile may warrant further investigation. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

REFERENCE CENTILE CHARTS OF PAPP-AAND FREE β-HCG IN INDIAN PREGNANT WOMEN.

The combined rst-trimester screening (CFTS) for fetal aneuploidy involves a combination of maternal age, fetal nuchal translucency (NT), maternal serum pregnancy-associated plasma protein-A(PAPP-A) and free β-human chorionic gonadotropin (β-hCG) from 11+0 to 13+6 weeks of gestation [1]. International prescriptive standards for early fetal linear size and ultrasound dating of pregnancy in the rst trimester are available and used throughout the world. Ethnicity has an effect on the biochemical parameters of rst trimester screening. As there is a lack of reference chart for the women of Indian ethnicity, we aimed to nd out the level of PAPP-Aand free β-hCG for fetal crown rump length (CRL) of 40-84 mm in the rst trimester of pregnancy and construct the centile charts for both the parameters. Asignicant but weak correlation between the individual models of PAPP-A and β-hCG and CRL (P&lt;0.001). In conclusion, the normal range of PAPP-A and free β-hCG depending on the gestation (CRL) was derived in this cohort study. This would act as a reference for our population and would be helpful in calculating the risk of an adverse maternal and fetal outcome.

First trimester combined screening in patients with systemic lupus erythematosus: impact of pre-analytical variables on risk assessment

BackgroundPrenatal diagnosis of fetal trisomy 21 and other chromosomal abnormalities is based on invasive tests, such as amniocentesis and chorionic villus sampling, which are carried out in women identified through screening as being at high risk for these abnormalities. The most widely used method of screening is the first-trimester combined test which utilizes maternal age, and measurements of fetal nuchal translucency thickness (NT) and maternal serum pregnancy-associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotropin (hCG).ObjectivesTo assess the influence of SLE on the levels of NT, PAPP-A, and β-hCG and whether any alterations in such levels may increase the rate of false positives and the subsequent number of invasive tests.MethodThis was a prospective first-trimester screening study for trisomies 21, 18, and 13 by a combination of maternal age, fetal nuchal translucency thickness, and serum PAPP-A and β-hCG at King’s College Hospital, London, between March 2006 and February 2011. The study population included 47 cases with maternal SLE and 45,493 without SLE. The results of biomarkers in the SLE and non-SLE groups were compared.ResultsIn the SLE group, compared to the non-SLE group, there were no significant differences in median maternal age, fetal NT, or serum PAPP-A MoM, but serum free β-hCG MoM was increased (1.402, IQR 0.872–2.290 vs 0.994, IQR 0.676–1.508).ConclusionIn first trimester screening for trisomies, the measured value of free ß-hCG should be adjusted for maternal SLE to avoid false positive results and overuse of invasive tests.

Routine first-trimester screening for fetal trisomies in twin pregnancy: cell-free DNA test contingent on results from combined test.

To report on the routine clinical implementation of cell-free DNA (cfDNA) analysis of maternal blood for trisomies 21, 18 and 13, contingent on the results of the first-trimester combined test in twin pregnancy. Screening for trisomies 21, 18 and 13 was carried out in 959 twin pregnancies by assessment of a combination of maternal age, fetal nuchal translucency thickness, and serum free β-human chorionic gonadotropin and pregnancy-associated plasma protein-A at 11-13 weeks' gestation in two UK NHS hospitals. Women in the high-risk group (risk ≥ 1 in 100) were offered the option of invasive testing, cfDNA testing or no further testing, and those in the intermediate-risk group (risk 1 in 101 to 1 in 2500 in the first phase of the study and 1 in 101 to 1 in 500 in the second phase) were offered cfDNA or no further testing. The trisomic status of the pregnancies was determined by prenatal or postnatal karyotyping or examination of the neonates. In 42 (4.4%) of the 959 pregnancies, there was termination, miscarriage or stillbirth with no known karyotype or there was loss to follow-up. The 917 pregnancies with known trisomic status of both twins included six that were discordant for trisomy 21, four that were discordant for trisomy 18 and 907 with no trisomy 21, 18 or 13. Following combined screening, 47 (5.1%), 203 (22.1%) and 667 (72.7%) of the pregnancies were classified as high risk, intermediate risk and low risk, respectively. The high-risk group included five (83.3%) cases of trisomy 21 and three (75.0%) of trisomy 18. The cfDNA test was carried out in 224 pregnancies and results were provided in 214 (95.5%); this group included six pregnancies with trisomy 21, three with trisomy 18 and 206 with no trisomy 21, 18 or 13. The cfDNA test classified correctly as screen positive all six cases of trisomy 21 and two of the three with trisomy 18, and as screen negative for each of the trisomies all 206 unaffected pregnancies. Contingent screening led to prenatal detection of all cases of trisomy 21 and three of four with trisomy 18. This study has demonstrated the feasibility of introducing cfDNA testing, contingent on the results of the first-trimester combined test for major trisomies, in a routine population of twin pregnancies. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

First-trimester risk assessment based on ultrasound and cell-free DNA vs combined screening: a randomized controlled trial.

This was a randomized controlled trial to compare risk assessment by first-trimester combined screening (FTCS) with an approach that combines a detailed ultrasound examination at 11-13 weeks' gestation and cell-free DNA (cfDNA) analysis. Pregnant women with a normal first-trimester ultrasound examination at 11-13 weeks' gestation (fetal nuchal translucency (NT)≤ 3.5 mm and no fetal defects) were randomized into one of two groups. In the first group, risk of aneuploidy was assessed using FTCS based on the most recent UK Fetal Medicine Foundation algorithm. In the second group, risk assessment was based on ultrasound findings and cfDNA analysis. An additional tube of blood was collected for FTCS in case the cfDNA analysis was uninformative. Primary outcome was false-positive rate in screening for trisomy 21. A case was considered false positive if the karyotype was not trisomy 21 and if the risk for trisomy 21 was >1:100, irrespective of the method of risk calculation. Results were compared using 95% CIs using the Clopper-Pearson method. Between October 2015 and December 2016, 1518 women with singleton pregnancy underwent first-trimester screening. Thirty-one (2.0%) pregnancies were not eligible for randomization due to increased NT (> 3.5 mm) and/or fetal defect. After exclusion of women who declined randomization (n= 87) and cases of fetal death and loss to follow-up (n= 24), 688 pregnancies were randomized into the FTCS arm and 688 into the ultrasound + cfDNA analysis arm. There were no differences in maternal and gestational age, maternal weight and BMI, ethnicity, use of assisted reproduction and cigarette smoking between the two arms. In the ultrasound + cfDNA analysis arm, median risk for trisomy 21 was 1 in 10 000. None of the cases had a risk above 1: 100 (95% CI, 0.0-0.5%). In the FTCS arm, the median risk for trisomy 21 was 1 in 3787 and in 17 cases, the risk was higher than 1:100, which corresponds to 2.5% (95% CI, 1.5-3.9%) of the FTCS study-arm population. Our study has shown that first-trimester risk assessment for trisomy 21 that includes a detailed ultrasound examination as well as NT measurement and is followed by cfDNA testing is associated with a significant reduction in the false-positive rate compared with FTCS. This approach obviates the need for maternal serum free β-human chorionic gonadotropin and pregnancy-associated plasma protein-A in screening for fetal aneuploidy. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Normative weight-adjusted models for the median levels of first trimester serum biomarkers for trisomy 21 screening in a specific ethnicity.

ObjectiveTo establish normative weight-adjusted models for the median levels of first trimester serum biomarkers for trisomy 21 screening in southern Thai women, and to compare these reference levels with Caucasian-specific and northern Thai models.MethodsA cross-sectional study was conducted in 1,150 normal singleton pregnancy women to determine serum pregnancy-associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotropin (β-hCG) concentrations in women from southern Thailand. The predicted median values were compared with published equations for Caucasians and northern Thai women.ResultsThe best-fitting regression equations for the expected median serum levels of PAPP-A (mIU/L) and free β- hCG (ng/mL) according to maternal weight (Wt in kg) and gestational age (GA in days) were: and Both equations were selected with a statistically significant contribution (p< 0.05). Compared with the Caucasian model, the median values of PAPP-A were higher and the median values of free β-hCG were lower in the southern Thai women. And compared with the northern Thai models, the median values of both biomarkers were lower in southern Thai women.ConclusionThe study has successfully developed maternal-weight- and gestational-age-adjusted median normative models to convert the PAPP-A and free β-hCG levels into their Multiple of Median equivalents in southern Thai women. These models confirmed ethnic differences.

Accuracy of first-trimester combined test in screening for trisomies 21, 18 and 13.

To examine the diagnostic accuracy of a previously developed model for the first-trimester combined test in screening for trisomies 21, 18 and 13. This was a prospective validation study of screening for trisomies 21, 18 and 13 by assessment of a combination of maternal age, fetal nuchal translucency, fetal heart rate and serum free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 11 + 0 to 13 + 6 weeks' gestation in 108 982 singleton pregnancies undergoing routine care in three maternity hospitals. A previously published algorithm was used to calculate patient-specific risks for trisomy 21, 18 and 13 in each patient. The detection rate (DR) and false-positive rate (FPR) at estimated risk cut-offs from 1 in 2 to 1 in 1000 were determined. The proportions of trisomies detected were compared to their expected values in different risk groups. In the study population, there were 108 112 (99.2%) cases with normal fetal karyotype or birth of a phenotypically normal neonate and 870 (0.8%) cases with abnormal karyotype, including trisomy 21 (n = 432), trisomy 18 (n = 166), trisomy 13 (n = 56), monosomy X (n = 63), triploidy (n = 35) or other aneuploidy (n = 118). The screen-positive rates, standardized according to the maternal age distribution in England and Wales in 2011, of fetuses with abnormal or normal karyotype were compatible with those predicted from the previous model; at a risk cut-off of 1 in 100, the FPR was about 4% and the DRs for trisomies 21, 18 and 13 were 90%, 97% and 92%, respectively. There was evidence that the algorithm overestimated risk. This could, to some degree, reflect under-ascertainment in pregnancies ending in miscarriage or stillbirth. In a prospective validation study, the first-trimester combined test detected 90%, 97% and 92% of trisomies 21, 18 and 13, respectively, as well as > 95% of cases of monosomy X and triploidies and > 50% of other chromosomal abnormalities, at a FPR of 4%. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Prediction of stillbirth from biochemical and biophysical markers at 11-13 weeks.

To develop a model for the prediction of stillbirth that is based on a combination of maternal characteristics and medical history with first-trimester biochemical and biophysical markers and to evaluate the performance of screening with this model for all stillbirths and those due to impaired placentation and unexplained causes. This was a prospective screening study of 76 897 singleton pregnancies, including 76 629 live births and 268 (0.35%) antepartum stillbirths; 157 (59%) were secondary to impaired placentation and 111 (41%) were due to other or unexplained causes. Multivariable logistic regression analysis was used to determine if there was a significant contribution to prediction of stillbirth from the maternal factor-derived a-priori risk, fetal nuchal translucency thickness, ductus venosus pulsatility index for veins (DV-PIV), uterine artery pulsatility index (UtA-PI) and maternal serum free β-human chorionic gonadotropin and pregnancy-associated plasma protein-A (PAPP-A). The significant contributors were used to derive a model for first-trimester prediction of stillbirth. Significant contribution to prediction of stillbirth was provided by maternal factors, PAPP-A, UtA-PI and DV-PIV. A model combining these variables predicted 40% of all stillbirths and 55% of those due to impaired placentation, at a false-positive rate of 10%. Within the impaired-placentation group, the detection rate of stillbirth < 32 weeks' gestation was higher than that of stillbirth ≥ 37 weeks (64% vs 42%). A model based on maternal factors and first-trimester biomarkers can potentially predict more than half of subsequent stillbirths that occur due to impaired placentation. The extent to which such stillbirths could be prevented remains to be determined. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Maternal serum PAPP‐A and free β‐hCG at 12, 22 and 32 weeks' gestation in screening for pre‐eclampsia

To examine the distribution of maternal serum pregnancy-associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotropin (β-hCG) at 12, 22 and 32 weeks' gestation in singleton pregnancies which develop pre-eclampsia (PE) and examine the performance of these biomarkers in screening for PE. Serum PAPP-A and free β-hCG were measured in 94 989 cases at 11-13 weeks, 7597 at 19-24 weeks and 8088 at 30-34 weeks' gestation. Bayes' theorem was used to combine the a-priori risk from maternal characteristics and medical history with PAPP-A and free β-hCG. The empirical and model-based performance of screening for preterm PE requiring delivery < 37 weeks' gestation and term PE with delivery ≥ 37 weeks was estimated. Combined screening with maternal factors and serum PAPP-A at 11-13 and 30-34 weeks and with maternal factors and serum free β-hCG at 19-24 and 30-34 weeks improved the prediction provided by maternal factors alone for preterm PE. The detection rate, at a 10% false-positive rate, for preterm PE by screening with maternal factors was about 45% which improved to 51% and 53% by combined screening with PAPP-A at 11-13 weeks and 30-34 weeks, respectively, and 55% and 54% by combined screening with free β-hCG at 19-24 weeks and 30-34 weeks, respectively. Measurement of serum PAPP-A and free β-hCG was not useful in the prediction of term PE. Measurement of serum PAPP-A and free β-hCG could improve the prediction of preterm PE provided by maternal characteristics and medical history alone. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Screening for trisomies by cell-free DNA testing of maternal blood: consequences of a failed result.

First, to report the distribution of the fetal fraction of cell-free (cf) DNA and the rate of a failed cfDNA test result in trisomies 21, 18 and 13, by comparison with pregnancies unaffected by these trisomies, second, to examine the possible effects of maternal and fetal characteristics on the fetal fraction, and third, to consider the options for further management of pregnancies with a failed result. This was a cohort study of 10 698 singleton pregnancies undergoing screening for fetal trisomies 21, 18 and 13 by cfDNA testing at 10-14 weeks' gestation. There were 160 cases of trisomy 21, 50 of trisomy 18, 16 of trisomy 13 and 10 472 were unaffected by these trisomies. Multivariate regression analysis was used to determine significant predictors of fetal fraction and a failed cfDNA test result amongst maternal and fetal characteristics. Fetal fraction decreased with increasing body mass index and maternal age, was lower in women of South Asian racial origin than in Caucasians and in assisted compared to natural conceptions. It increased with fetal crown-rump length and higher levels of serum pregnancy-associated plasma protein-A and free β-human chorionic gonadotropin. The median fetal fraction was 11.0% (interquartile range (IQR), 8.3-14.4%) in the unaffected group, 10.7% (IQR, 7.8-14.3%) in trisomy 21, 8.6% (IQR, 5.0-10.2%) in trisomy 18 and 7.0% (IQR, 6.0-9.4%) in trisomy 13. There was a failed result from cfDNA testing after first sampling in 2.9% of the unaffected group, 1.9% of trisomy 21, 8.0% of trisomy 18 and 6.3% of trisomy 13. In the cases with a failed result, 7% of women had invasive testing, mainly because of high risk from the combined test and/or presence of sonographic features suggestive of trisomies 18 and 13. All cases of trisomies were detected prenatally. In cases of a failed cfDNA test, the rate of trisomies 18 and 13, but not trisomy 21, is higher than in those with a successful test. In the management of such cases, the decision in favor of invasive testing should depend on the risk of prior screening and the results of detailed ultrasound examination. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Serum free β-human chorionic gonadotropin in the three trimesters of pregnancy: effects of maternal characteristics and medical history.

To define the contribution of maternal variables which influence the measured level of maternal serum free β-human chorionic gonadotropin (β-hCG) in screening for pregnancy complications. Maternal characteristics and medical history were recorded and serum free β-hCG was measured in women with a singleton pregnancy attending for three routine hospital visits at 11 + 0 to 13 + 6, 19 + 0 to 24 + 6 and 30 + 0 to 34 + 6 weeks' gestation. For pregnancies delivering phenotypically normal live births or stillbirths ≥ 24 weeks' gestation, variables from maternal demographic characteristics and medical history that are important in the prediction of free β-hCG were determined from a linear mixed-effects multiple regression. Serum free β-hCG was measured in 94 985 cases in the first trimester, 7879 in the second trimester and 8424 in the third trimester. Significant independent contributions to serum free β-hCG were provided by gestational age, maternal weight, age and racial origin, cigarette smoking, method of conception, diabetes mellitus and family history of pre-eclampsia (PE) in the mother of the patient. The effects of some variables were similar and those for others differed in each trimester. Random-effects multiple regression analysis was used to define the contribution of maternal variables that influence the measured level of serum free β-hCG and express the values as multiples of the median (MoMs). The model was shown to provide an adequate fit of MoM values for all covariates both in pregnancies that developed PE and in those without this pregnancy complication. A model was fitted to express measured serum free β-hCG across the three trimesters of pregnancy as MoMs after adjusting for variables from maternal characteristics and medical history that affect this measurement.

A unified approach to risk assessment for fetal aneuploidies.

To examine the potential impact of combining measures from cell-free DNA (cfDNA) testing with maternal age and first-trimester biomarkers in screening for fetal trisomies. This was a theoretical study using Bayes' theorem to combine the a priori risk for fetal trisomy 21 derived from maternal age with likelihoods from nuchal translucency thickness, serum pregnancy-associated plasma protein-A, serum free β-human chorionic gonadotropin and plasma cfDNA. We adopted a binomial counting model for the cfDNA likelihoods and developed a model to account for errors in estimating fetal fraction. When Bayes' theorem was used to combine the a priori risk for trisomy 21 derived from the first-trimester combined test with likelihoods from the cfDNA test, and when the true fetal fraction was known, the detection rate increased from 62% at a fetal fraction of 4% to 100% at a fetal fraction of ≥ 9%; the positive likelihood ratio (trisomic/euploid) increased from 620 to 1000 and the negative likelihood ratio (euploid/trisomic) increased from 3 to > 10 000. When the fetal fraction is < 4%, the cfDNA test has traditionally been considered to be a failure, but the cfDNA results can be used to improve the performance of screening by the combined test. In contingent policies that use the first-trimester combined test for first-line screening to select the subgroup for cfDNA testing, the data from the latter should be used to update the risk from the former. Individual patient results from cfDNA testing depend crucially on the fetal fraction and the precision of its measurement.

First-Trimester Contingent Screening for Trisomies 21, 18, and 13 by Biomarkers and Maternal Blood Cell-Free DNA Testing

Objective: To examine potential performance of screening for trisomies by cell-free (cf) DNA testing in maternal blood contingent on results of first-line testing by combinations of fetal translucency thickness (NT), fetal heart rate (FHR), ductus venosus pulsatility index (DV PIV), and serum-free β-human chorionic gonadotropin (β-hCG), pregnancy-associated plasma protein-A (PAPP-A), placental growth factor (PLGF) and α-fetoprotein (AFP). Methods: Performance was estimated for firstly, screening by cfDNA in all pregnancies and secondly, cfDNA testing contingent on results of firstline testing by combinations of ultrasound and biochemical markers. Results: In first-line screening by cfDNA testing, the detection rate for trisomy 21 and trisomies 18 or 13 would be 99 and 96%, respectively, after invasive testing in 1% of the population. In contingent screening, a detection rate of 98% for trisomy 21 and 96% for trisomy 18 or 13, at an invasive testing rate of 0.7%, can be achieved by carrying out cfDNA testing in about 35, 20 and 11% of cases identified by

Diagnosis of fetal chromosomal aneuploidy by free fetal DNA in maternal plasma in the first trimester

Objective To assess the clinical value of fetal chromosomal aneuploidy diagnosed by free fetal DNA in maternal plasma in 11-13+6 gestational weeks.Methods A total of 2 650 pregnant women who had prenatal care in Tianjin Center Hospital of Obstetrics and Gynecology from January 1,2010 to December 31,2010 were included.Each of them had an ultrasound scan to measure fetal nuchal translucency thickness.Maternal serum free β-human chorionic gonadotropin and pregnancy-associated plasma protein A test was performed as part of screening for chromosomal abnormalities.Results of ultrasound and maternal plasma biochemical analysis were entered into the database,and converted into multiple of median (MoM) by factors such as maternal age,weight,ethnicity,smoking history and mode of conception.The cutoff value was 1 ∶ 270.Meanwhile,20 cases had cell free fetal DNA (cffDNA) test and the ratio of the single nucleotide polymorphism on two alleles of plancenta-specific 4 (PLAC4) were measured in 16 cases.T-test,rank sum test,MannWhitney U test and Chi-square test were used as statistical methods.Results (1) A total of 74 cases were judged as high-risk,among which 35 cases underwent transabdominal chorionic villus sampling (18 cases had cffDNA test),37 cases underwent amniocentesis at the week of 20,and two cases of Rh negative did not receive the invasive examination.Totally 20 cases,including two Rh negative cases,had the cell-free fetal DNA test.(2) By cffDNA test of maternal plasma,two cases of 21 trisomy,one case of 18 trisomy,two cases of 45,XO and one case of balanced translocation were diagnosed.(3) In the two cases of 21 trisomy,maternal plasma G/A ratio ofPL4C4 RNA-single nucleotide polymorphism alleles was 1.00 (0.98,1.02) ; in 14 pregnancies with normal chromosome,the ratio was 1.055 (1.02,1.13,Z=3.5).There was no significant difference (P=0.066).Conclusion Diagnosing of fetal chromosomal aneuploidy by cffDNA in maternal plasma is feasible and noninvasive with high negative predictive value,and can be used in Rh-negative pregnant women for prenatal screening and diagnosis. Key words: Aneuploidy; Prenatal diagnosis; DNA; Pregnancy trimester, first

First-Trimester Screening for Trisomies 21, 18 and 13 by Ultrasound and Biochemical Testing

Objective: To examine the performance of screening for trisomies 21, 18 and 13 at 11-13 weeks' gestation using specific algorithms for these trisomies based on combinations of fetal nuchal translucency thickness (NT), fetal heart rate (FHR), ductus venosus pulsatility index for veins (DV PIV), and serum free β-human chorionic gonadotropin (β-hCG), pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PLGF) and α-fetoprotein (AFP). Methods: Model-based estimates of screening performance were produced for the distribution of maternal ages in England and Wales in 2011, and prospectively collected data on fetal NT, FHR, DV PIV, β-hCG, PAPP-A, PLGF and AFP from singleton pregnancies undergoing aneuploidy screening. Results: In screening by NT, FHR, free β-hCG and PAPP-A, using specific algorithms for trisomy 21 and trisomies 18 and 13 at the risk cutoff of 1:100, the estimated detection rate (DR) was 87.0% for trisomy 21 and 91.8% for trisomies 18 and 13, at a false-positive rate (FPR) of 2.2%. Addition of PLGF, AFP and DV PIV increased the DR to 93.3% for trisomy 21 and 95.4% for trisomies 18 and 13 and reduced the FPR to 1.3%. Conclusions: Effective screening for trisomies can be achieved using specific algorithms based on NT, FHR, DV PIV, β-hCG, PAPP-A, PLGF and AFP.

First-Trimester Contingent Screening for Trisomies 21, 18 and 13 by Biomarkers and Maternal Blood Cell-Free DNA Testing

Objective: To examine potential performance of screening for trisomies by cell-free (cf) DNA testing in maternal blood contingent on results of first-line testing by combinations of fetal translucency thickness (NT), fetal heart rate (FHR), ductus venosus pulsatility index (DV PIV), and serum-free β-human chorionic gonadotropin (β-hCG), pregnancy-associated plasma protein-A (PAPP-A), placental growth factor (PLGF) and α-fetoprotein (AFP). Methods: Performance was estimated for firstly, screening by cfDNA in all pregnancies and secondly, cfDNA testing contingent on results of first-line testing by combinations of ultrasound and biochemical markers. Results: In first-line screening by cfDNA testing, the detection rate for trisomy 21 and trisomies 18 or 13 would be 99 and 96%, respectively, after invasive testing in 1% of the population. In contingent screening, a detection rate of 98% for trisomy 21 and 96% for trisomy 18 or 13, at an invasive testing rate of 0.7%, can be achieved by carrying out cfDNA testing in about 35, 20 and 11% of cases identified by first-line screening with the combined test alone (age, NT, FHR, β-hCG, PAPP-A), the combined test plus PLGF and AFP and the combined test plus PLGF, AFP and DV PIV, respectively. Conclusions: Effective first-trimester screening for trisomies can be achieved by contingent screening incorporating biomarkers and cfDNA testing.

Detection of triploidy at 11-14 weeks' gestation: a cohort study of 198 000 pregnant women

To assess the detection rate of triploidy at first-trimester screening for trisomy 21 and evaluate outcome in triploid pregnancies. From 2008 to 2011, 198 427 women with singleton pregnancies underwent first-trimester screening between 11 + 2 and 14 + 0 weeks' gestation. Screening parameters included nuchal translucency, maternal serum free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A). In all triploid fetuses, these parameters were re-evaluated. Karyotypes were established by invasive testing (chorionic villus sampling or amniocentesis) or postabortem and obtained from the Danish Cytogenetic Central Register and the Danish Fetal Medicine Database. A total of 30 triploid fetuses underwent first-trimester screening. Twenty-five were diagnosed as a result of abnormal first-trimester scan findings, a detection rate of 83.3%. Twenty-three fetuses were identified due to a high risk for trisomy 13, 18 or 21 and two fetuses due to structural abnormalities. The incidence of triploidy at first-trimester screening was 1:6614. A smaller crown-rump length than that estimated by date of last menstrual period was found in 95% of the fetuses with data available for evaluation. Eight fetuses had a larger biparietal diameter than expected for gestational age. Fetuses with a 69,XXX karyotype had significantly lower multiples of the median values for β-hCG and PAPP-A than did 69,XXY fetuses (P = 0.045 and P = 0.02 forβ-hCG and PAPP-A, respectively). No infants with triploidy were born in the study period. Among the triploid gestations detected on first-trimester screening, 20 (80.0%) women chose termination of pregnancy, four (16.0%) had spontaneous miscarriage and one (4.0%) was stillborn. First-trimester screening for trisomy 21 also provides a high detection rate for triploidy.

First‐trimester contingent screening for trisomy 21 by biomarkers and maternal blood cell‐free DNA testing

To define risk cut-offs with corresponding detection rates (DR) and false-positive rates (FPR) in screening for trisomy 21 using maternal age and combinations of first-trimester biomarkers in order to determine which women should undergo contingent maternal blood cell-free (cf) DNA testing. From singleton pregnancies undergoing screening for aneuploidies at three UK hospitals between March 2006 and May 2012, we analyzed prospectively collected data on the following biomarkers: fetal nuchal translucency thickness (NT) and ductus venosus pulsatility index for veins (DV-PIV) at 11 + 0 to 13 + 6 weeks' gestation and serum free β-human chorionic gonadotropin (β-hCG), pregnancy-associated plasma protein-A (PAPP-A), placental growth factor (PlGF) and alpha-fetoprotein (AFP) at 8 + 0 to 13 + 6 weeks. Estimates of risk cut-offs, DRs and FPRs were derived for combinations of biomarkers and these were used to define the best strategy for contingent cfDNA testing. In contingent screening, detection of 98% of fetuses with trisomy 21 at an overall invasive testing rate < 0.5% can be potentially achieved by offering cfDNA testing to about 36%, 21% and 11% of cases identified by first-line screening using the combined test alone, using the combined test with the addition of serum PlGF and AFP and using the combined test with the addition of PlGF, AFP and DV-PIV, respectively. Effective first-trimester screening for trisomy 21, with DR of 98% and invasive testing rate < 0.5%, can be potentially achieved by contingent screening incorporating biomarkers and cfDNA testing.