Combined First Trimester Screening and Cell-Free Fetal DNA – “Next Generation Screening”

Abstract

!In the last decades, prenatal screening for aneuploidy has become increasingly effective. While first trimester combined screening is considered to be the current gold standard, the use of cellfree fetal DNA (cffDNA), which is also called noninvasive prenatal testing (NIPT), will result in a change of paradigm. Respective studies indicate that in screening for trisomy 21, the detection and false-positive rates are 99 % and 0.1 %, respectively. For trisomies 18 and 13, there is less evidence but recent studies report detection rates of 98 % and 86 %. Despite the excellent results in screening for trisomy 21, NIPT should not be considered as a diagnostic test. Due to the costs of NIPT, it is unlikely that NIPT will be applied in the near future in population-based screening for trisomy. In addition, the scope of the current approach in first trimester screening exceeds the screening for aneuploidy as it is possible to assess the risk for various pregnancy complications. Therefore, a combination of both NIPT and first trimester combined screening seems reasonable. Both examinations could be applied in a contingent model where the latter is offered to everyone and NIPT is restricted to women with an intermediate risk after first trimester combined screening. Such a policy would result in a detection rate of about 97 % for a falsepositive rate of about 1 %. While NIPT currently focuses on screening for trisomy 21, 18, 13 and sex chromosomal abnormalities, the scope of NIPT will soon become broader. In this respect, some study groups have managed to examine the whole fetal genome within the course of the pregnancy. However, moral and ethical considerations need to be taken into account. Zusammenfassung

Contingent non-invasive prenatal testing: an opportunity to improve non-genetic aspects of fetal aneuploidy screening

“…Because the current cost per test is high, the introduction of NIPT as a national health care service is hampered in many countries . Offering NIPT in a contingent screening setting after conventional first trimester screening is often considered a valuable alternative for universal NIPT screening . In this perspective, population screening for fetal aneuploidy and other anomalies still requires the availability of a high quality first trimester ultrasound service …”

“…1 Offering NIPT in a contingent screening setting after conventional first trimester screening is often considered a valuable alternative for universal NIPT screening. [2][3][4] In this perspective, population screening for fetal aneuploidy and other anomalies still requires the availability of a high quality first trimester ultrasound service. 5 In Belgium today, fetal aneuploidy screening is fully reimbursed to all pregnant women, and overall uptake is high at 80%.…”

Single Nucleotide Polymorphism-Based Analysis of Cell-Free Fetal DNA in 3000 Cases from Germany and Austria

“…As of now, we are not aware of any false-negative cases or other discrepancies. Despite the obvious progress through these new techniques, NIPT is not considered a diagnostic test and cannot be used as a standalone test without ultrasound examination [27] or invasive confirmation. Because nuchal translucency provides more information than just aneuploidy status, detailed ultrasound is strongly recommended for all patients.…”

Die Untersuchung zellfreier DNA durch Liquid Biopsy in der Medizin

“…In der pränatalen Routinediagnostik werden seit etwa 8 Jahren Liquid-Biopsy-Methoden basierend auf NGS-Techniken erfolgreich eingesetzt und haben heute ihren festen Platz in der vorgeburtlichen Risikoabschätzung für die häufigsten Aneuploidien [18][19][20]. Dass diese Methode über ein reines pränatales Screening hinaus sehr empfindlich ist, lässt sich aus verschiedenen Veröffentlichungen ersehen [21,22], die über Befunde berichten, welche mit dem eigentlichen Ziel der Untersuchung, nämlich des Screenings auf fetale Aneuploidien, nichts zu tun hatten, aber einen Hinweis durch Kopienzahlveränderungen auf eine bis dahin nicht erkannte Krebserkrankung bei der Schwangeren gaben.…”