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 cell-free 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 false-positive 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

In den vergangenen Jahrzehnten wurden zunehmend komplexere und effektivere Methoden im pränatalen Screening auf Chromosomenstörungen entwickelt. Während heute noch das kombinierte Ersttrimesterscreening als Goldstandard betrachtet wird, ist in baldiger Zukunft durch den Einsatz der zellfreien fetalen DNA (cffDNA) im Sinne eines „non-invasive prenatal testing“ (NIPT) ein Paradigmenwechsel zu erwarten. Diesbezügliche Studien verweisen auf eine Detektionsrate von etwa 99 % für Trisomie 21 bei einer Falsch-Positiv-Rate von 0,1 %. Die Studienlage für Trisomie 18 und 13 ist erheblich dünner, wobei die Detektionsraten derzeit bei etwa 98 und 86 % liegen. Trotz der guten Testgüte im Hinblick auf das Screening auf Trisomie 21 darf der Test auch weiterhin nicht als diagnostischer Test verstanden werden. Aufgrund der derzeit noch hohen Kosten der Untersuchung ist eine flächenhafte Anwendung noch nicht sinnvoll. Zudem beschränkt sich das heutige Ersttrimesterscreening nicht nur auf ein Aneuploidiescreening sondern erlaubt die Beurteilung zahlreicher schwangerschaftsspezifischer Risiken. Insofern ist eine kombinierte Anwendung beider Untersuchungen sinnvoll. Diese könnte beispielsweise gestaffelt erfolgen. Zunächst würde ein kombiniertes Ersttrimesterscreening erfolgen, welches bei einem intermediären Risiko durch die NIPT-Untersuchung erweitert wird. Dadurch läge die Detektionsrate für Trisomie 21 bei etwa 97 % bei einer Falsch-Positv-Rate von etwa 1 %. Während sich die NIPT-Untersuchung derzeit noch auf das Screening auf Trisomie 21, 18, 13 und gonosomale Aberrationen konzentriert, ist in der Zukunft eine deutliche Erweiterung des Untersuchungsspektrums zu erwarten. So ist es einzelnen Arbeitsgruppen in der Schwangerschaft bereits gelungen, das gesamte Genom mittels cffDNA-Analysen zu entschlüsseln. Dabei dürfen moralische und ethische Aspekte aber nicht außer Acht gelassen werden.

Key words

cellfree fetal DNA - first trimester screening - trisomy - ultrasound

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