Cell-free DNA testing of maternal blood in screening for trisomies in twin pregnancy: updated cohort study at 10-14 weeks and meta-analysis.

OBJECTIVE: To expand the limited knowledge on cell-free DNA (cfDNA) analysis of maternal blood for trisomies 21, 18 and 13 in twin pregnancy by updating the data from The Fetal Medicine Foundation (FMF) on prospective first-trimester screening and those identified in a systematic review of the literature. METHODS: The FMF data were derived from prospective screening for trisomies 21, 18 and 13 in twin pregnancies at 10 + 0 to 14 + 1 weeks' gestation using the Harmony® prenatal test. A search of MEDLINE, EMBASE, CENTRAL (The Cochrane Library), ClinicalTrials.gov and the International Clinical Trials Registry Platform (World Health Organization) 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, irrespective of gestational age at testing, in which data on pregnancy outcome were provided for at least 85% of the study population. Meta-analysis was performed using the FMF data and data from the studies identified by the literature search. This review was registered in the PROSPERO international database for systematic reviews RESULTS: In the FMF study, cfDNA testing was carried out in 1442 twin pregnancies and a result was obtained, after first or second sampling, in 1367 (94.8%) cases. In 93.1% (1272/1367) of cases, there was prenatal or postnatal karyotyping or birth of phenotypically normal babies; 95 cases were excluded from further analysis either because the pregnancy ended in termination, miscarriage or stillbirth with no known karyotype (n = 56) or there was loss to follow-up (n = 39). In the 1272 pregnancies included in the study, there were 20 cases with trisomy 21, 10 with trisomy 18, two with trisomy 13 and 1240 without trisomy 21, 18 or 13. The cfDNA test classified correctly 19 (95.0%) of the 20 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 1235 (99.6%) of the 1240 cases without any of the three trisomies. The literature search identified 12 relevant studies, excluding our papers because their data are included in the current study. In the combined populations of our study and the 12 studies identified by the literature search, there were 137 trisomy-21 and 7507 non-trisomy-21 twin pregnancies; the pooled weighted detection rate (DR) and false-positive rate (FPR) were 99.0% (95% CI, 92.0-99.9%) and 0.02% (95% CI, 0.001-0.43%), respectively. In the combined total of 50 cases of trisomy 18 and 6840 non-trisomy-18 pregnancies, the pooled weighted DR and FPR were 92.8% (95% CI, 77.6-98.0%) and 0.01% (95% CI, 0.00-0.44%), respectively. In the combined total of 11 cases of trisomy 13 and 6290 non-trisomy-13 pregnancies, the pooled weighted DR and FPR were 94.7% (95% CI, 9.14-99.97%) and 0.10% (95% CI, 0.03-0.39%), respectively. CONCLUSIONS: In twin pregnancy, the reported DR of trisomy 21 by cfDNA testing is high, but lower than that in singleton pregnancy, whereas the FPR appears to be equally low. The number of cases of trisomy 18 and more so trisomy 13 was too small for accurate assessment of the predictive performance of the cfDNA test. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

First-trimester screening for trisomies by cfDNA testing of maternal blood in singleton and twin pregnancies: factors affecting test failure.

OBJECTIVE: To examine factors affecting the rate of failure to obtain a result from cell-free DNA (cfDNA) testing of maternal blood for fetal trisomies 21, 18 and 13 in singleton and twin pregnancies in the first trimester. METHODS: This was a prospective study of 23 495 singleton and 928 twin pregnancies undergoing screening for fetal trisomy by targeted cfDNA testing at 10 + 0 to 14 + 1 weeks' gestation. Multivariate logistic regression analysis was used to determine significant predictors of failure to obtain a result after first sampling. RESULTS: There was no result from cfDNA testing after first sampling in 3.4% (798/23 495) of singletons, 11.3% (91/806) of dichorionic twins and 4.9% (6/122) of monochorionic twins. Multivariate logistic regression analysis demonstrated that the risk of test failure, first, increased with increasing maternal age (odds ratio (OR), 1.02; 95% CI, 1.01-1.04) and weight (OR, 1.05; 95% CI, 1.04-1.05), decreasing gestational age (OR, 0.85; 95% CI, 0.79-0.91), serum pregnancy-associated plasma protein-A (PAPP-A) multiples of the median (MoM) (OR, 0.56; 95% CI, 0.49-0.65) and free ß-human chorionic gonadotropin (ß-hCG) MoM (OR, 0.67; 95% CI, 0.60-0.74), second, was higher in women of black (OR, 1.72; 95% CI, 1.33-2.20) and South Asian (OR, 1.99; 95% CI, 1.56-2.52) than those of white racial origin, in dichorionic twin than in singleton pregnancy (OR, 1.75; 95% CI, 1.34-2.26) and in pregnancies conceived by in-vitro fertilization than in those conceived naturally (OR, 3.82; 95% CI, 3.19-4.55) and, third, was lower in parous than in nulliparous women (OR, 0.63; 95% CI, 0.55-0.74). CONCLUSIONS: Maternal age, weight, racial origin and parity, gestational age, dichorionicity, method of conception and serum levels of free ß-hCG and PAPP-A are independent predictors of cfDNA test failure. The risk of test failure is higher in dichorionic twin than in singleton pregnancies, mainly because a higher proportion of twins are conceived by in-vitro fertilization and more of the women are nulliparous. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

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

OBJECTIVE: 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. METHODS: 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 ß-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. RESULTS: 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. CONCLUSION: 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.

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.

Screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks' gestation.

OBJECTIVE: To examine the performance of screening for early, preterm and term pre-eclampsia (PE) at 11-13 weeks' gestation by maternal factors and combinations of mean arterial pressure (MAP), uterine artery (UtA) pulsatility index (PI), serum placental growth factor (PlGF) and serum pregnancy-associated plasma protein-A (PAPP-A). METHODS: The data for this study were derived from three previously reported prospective non-intervention screening studies at 11 + 0 to 13 + 6 weeks' gestation in a combined total of 61 174 singleton pregnancies, including 1770 (2.9%) that developed PE. Bayes' theorem was used to combine the prior distribution of gestational age at delivery with PE, obtained from maternal characteristics, with various combinations of biomarker multiples of the median (MoM) values to derive patient-specific risks of delivery with PE at < 37 weeks' gestation. The performance of such screening was estimated. RESULTS: In pregnancies that developed PE, compared to those without PE, the MoM values of UtA-PI and MAP were increased and those of PAPP-A and PlGF were decreased, and the deviation from normal was greater for early than late PE for all four biomarkers. Combined screening by maternal factors, UtA-PI, MAP and PlGF predicted 90% of early PE, 75% of preterm PE and 41% of term PE, at a screen-positive rate of 10%; inclusion of PAPP-A did not improve the performance of screening. The performance of screening depended on the racial origin of the women; on screening by a combination of maternal factors, MAP, UtA-PI and PlGF and using a risk cut-off of 1 in 100 for PE at < 37 weeks in Caucasian women, the screen-positive rate was 10% and detection rates for early, preterm and term PE were 88%, 69% and 40%, respectively. With the same method of screening and risk cut-off in women of Afro-Caribbean racial origin, the screen-positive rate was 34% and detection rates for early, preterm and term PE were 100%, 92% and 75%, respectively. CONCLUSION: Screening by maternal factors and biomarkers at 11-13 weeks' gestation can identify a high proportion of pregnancies that develop early and preterm PE. © 2018 Crown copyright. Ultrasound in Obstetrics & Gynecology © 2018 ISUOG.