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

Abstract

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 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. ResultsIn 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.Cribado rutinario en el primer trimestre para trisomías fetales en el embarazo de gemelos: prueba de ADN fetal en función de los resultados de una prueba combinada RESUMEN Objetivo Informar sobre la aplicación clínica rutinaria del análisis de ADN fetal (cfDNA, por sus siglas en inglés) en la sangre materna para las trisomías 21, 18 y 13, en función de los resultados de la prueba combinada del primer trimestre en el embarazo gemelar.Métodos Se llevó a cabo un cribado para las trisomías 21, 18 y 13 en 959 embarazos gemelares mediante la evaluación de una combinación de edad materna, grosor de la translucencia nucal del feto, y la ausencia en suero de la hormona gonadotrópica coriónica humana (subunidad B) y la proteína plasmática A asociada al embarazo a las 1...

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

“…In the third study, we reported performance of cfDNA testing in 417 prospectively examined pregnancies; the cfDNA test identified correctly all eight cases of trisomy 21, three of the four cases of trisomy 18, not the single case of trisomy 13 and 403 (99.8%) of the 404 non‐trisomic pregnancies. In the fourth study, we performed cfDNA testing in pregnancies identified by the combined test as being at intermediate or high risk for trisomy; the cfDNA test identified correctly all six cases of trisomy 21, two of the three cases of trisomy 18 and all 206 non‐trisomic pregnancies.…”

Clinical performance of non‐invasive prenatal testing for trisomies 21, 18 and 13 in twin pregnancies: A cohort study and a systematic meta‐analysis

“…Thus 32 studies remained to be assessed for eligibility by reading of the full text. Eventually, 21 relevant studies met all the inclusion criteria and were included in this meta‐analysis 9,19‐38 . A flow chart summarizing the selected eligible studies in systematic review is shown in Figure 1.…”

“…Two studies were also considered as high‐risk because they included confirmed aneuploid twin pregnancies as study subjects, which may overestimate the performance of NIPT 9,32 . Five studies were conducted among high‐risk pregnant populations, which may cause bias, and the risk connected with patient selection was unclear 19‐20,23,29,36 . The remaining 11 studies were rated as low‐risk.…”

“…All included studies were considered to be at low risk of bias because they all used karyotyping or clinical examination or follow up as the reference standard. In terms of flow and timing, four studies together with our study were assessed as unclear risk as they had a small population lost to follow up and adverse pregnant outcomes or the NIPT test failed to provide results in some cases 21,32,36,37 . Eight studies were rated as high‐risk because the population of lost to follow up and adverse pregnant outcomes was large 25‐28,30,33,35,38 .…”

“…The first domain refers to patient selection; five studies were classified as at high risk of concerns regarding applicability because they conducted NIPT in a high‐risk population 19‐20,23,29,36 . For the second and third domains, all studies were assessed as being at low risk of concerns regarding applicability.…”