Cross-Validierung des Screening-Algorithmus der FMF London an 38 700 Ersttrimester-Untersuchungen in Deutschland

Zusammenfassung

Ziel: Überprüfung der Testgüte des Algorithmus der FMF London für das Screening auf Trisomie 21 im ersten Trimester mittels Nackentransparenz (NT), PAPP-A und freiem β-hCG in einem deutschen Patientenkollektiv. Material und Methoden: In 39 004 Schwangerschaften wurde zwischen 2002 und 2007 im Rahmen des Ersttrimester-Screenings die NT, PAPP-A und freies β-hCG gemessen und die Trisomie-21-Risiken mit dem jeweils gültigen Algorithmus der FMF London berechnet. Im Rahmen dieser Studie erfolgte die erneute Auswertung der Trisomie-21-Risiken mit dem neuen Algorithmus der FMF London, der für die NT das Mixture Model verwendet. Ergebnisse: 38 751 Fälle mit Einlingsschwangerschaften konnten in die Auswertung einbezogen werden. Bei 109 Fällen wurde eine Trisomie 21 nachgewiesen. Nur 35 % der NT-Messwerte euploider Feten lagen oberhalb des Medianwerts der FMF London und in 25 % der Fälle wurde ein NT-Wert unterhalb der 5. Perzentilenkurve der FMF London gemessen. Die mediane NT von Feten mit Trisomie 21 lag bei Auswertung durch DEGUM-II/III-qualifizierte Frauenärzte 0,9 mm oberhalb des Medians, bei Auswertung durch nicht entsprechend qualifizierte Frauenärzte nur 0,5 mm oberhalb des Medians der FMF London. Trotz der eingeschränkten Performance der NT-Messung betrug die Erkennungsrate, jeweils unter Berücksichtigung des mütterlichen Alters, bei einer 5 %igen Falsch-Positivrate 90,8 % für die Kombination aus NT + Biochemie. Die Falsch-Positivrate betrug bei einem Cut-off von 1:300 zum Zeitpunkt der Untersuchung 6,5 %. Schlussfolgerung: Diese Studie konnte zeigen, dass trotz in Deutschland überwiegend zu klein gemessener NT durch Anwendung des neuen Algorithmus der FMF London in Kombination mit der Serum-Biochemie eine Detektionsrate der Trisomie 21 von ca. 90 % bei 5 % Falsch-Positivrate erreicht wird.

Abstract

Purpose: Validation of the performance of the new algorithm of the FMF London for screening for trisomy 21 using a combination of maternal age, fetal nuchal translucency (NT) and maternal serum free β-hCG and PAPP-A. Materials and Methods: Between 2002 and 2007, NT was measured prospectively in 39 004 pregnancies in the context of routinely performed first trimester screening in Germany. Individual trisomy 21 risks were calculated by a combination of NT, maternal age, free β-hCG, and PAPP-A using the FMF algorithm in force at the time of investigation. In this study we recalculated the trisomy 21 risks applying the new algorithm of the FMF UK that includes the new mixture model for the NT measurement. Results: 38 751 singleton pregnancies could be included in the study of which 109 (0.3 %) had a trisomy 21. Only 35 % of the NT measurements of euploids were above the median and 25 % of the NT measurements were below the 5th percentile of the FMF UK. For sonographers that were qualified according to level II or III of the German DEGUM system, the median NT of fetuses with trisomy 21 was 0.9 mm above the median of the FMF UK and only 0.5 mm above the median for all other sonographers. Despite the limited performance of the NT measurement, the overall detection rate for a trisomy 21 was 90.8 % when combining the NT with maternal age, PAPP-A and free β-hCG. The overall false-positive rate for a trisomy 21 was 6.5 % at a cut-off value of 1:300. Conclusion: In this study we were able to show that the use of the new risk algorithm of the FMF UK leads to a trisomy 21 detection rate of about 90 % at a 5 % false-positive rate in a German collective despite a significant underestimation of the NT.

nuchal translucency - first trimester - screening - serum biochemistry

Literatur

• 1 Nicolaides K H. Nuchal translucency and other first-trimester sonographic markers of chromosomal abnormalities.  Am J Obstet Gynecol. 2004;  191 45-67
• 2 Kagan K O, Etchegaray A, Zhou Y et al. Prospective validation of first-trimester combined screening for trisomy 21.  Ultrasound Obstet Gynecol. 2009;  34 14-18
• 3 Nicolaides K H, Spencer K, Avgidou K et al. Multicenter study of first-trimester screening for trisomy 21 in 75,821 pregnancies: results and estimation of the potential impact of individual risk-orientated two-stage first-trimester screening.  Ultrasound Obstet Gynecol. 2005;  25 221-226
• 4 Eiben B, Thode C, Glaubitz R. Das neue Ersttrimesterscreening-Programm PRC der FMF-Deutschland: erste Erfahrungen zur Trisomie-21-Entdeckungsrate.  Frauenarzt. 2007;  48 2-4
• 5 Spencer K, Souter V, Tul N et al. A screening program for trisomy 21 at 10 – 14 weeks using fetal nuchal translucency, maternal serum free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A.  Ultrasound Obstet Gynecol. 1999;  13 231-237
• 6 Lüthgens K. Comparison of the new PRC software with the established algorithm of the FMF UK for the detection of trisomy 21 and 18 / 13.  Fetal Diagn Ther. 2008;  24 376-384
• 7 Snijders R JM, Noble P, Sebire N et al. UK multicentre project on assessment of risk of trisomy 21 by maternal age and fetal nuchal-translucency thickness at 10 – 14 weeks of gestation.  Lancet. 1998;  351 343-346
• 8 Wright D, Kagan K O, Molina F S et al. A mixture model of nuchal translucency thickness in screening for chromosomal defects.  Ultrasound Obstet Gynecol. 2008;  31 376-383
• 9 Kagan K O, Wright D, Spencer K et al. First-trimester screening for trisomy 21 by free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A: impact of maternal and pregnancy characteristics.  Ultrasound Obstet Gynecol. 2008;  31 493-502
• 10 Kagan K O, Frisova V, Nicolaides K H et al. Dose dependency between cigarette consumption and reduced maternal serum PAPP-A levels at 11 – 13 + 6 weeks of gestation.  Prenat Diagn. 2007;  27 849-853
• 11 Cuckle H S, Wald N J, Thompson S G. Estimating a woman’s risk of having a pregnancy associated with Down’s syndrome using her age and serum alpha-fetoprotein level.  Br J Obstet Gynaecol. 1987;  94 387-402
• 12 Snijders R J, Sundberg K, Holzgreve W et al. Maternal age- and gestation-specific risk for trisomy 21.  Ultrasound Obstet Gynecol. 1999;  13 167-170
• 13 Spencer K. Accuracy of Down syndrome risks produced in a first trimester screening programme incorporating fetal nuchal translucency thickness and maternal serum biochemistry.  Prenat Diagn. 2002;  22 244-246
• 14 Kagan K O, Wright D, Baker A et al. Screening for trisomy 21 by maternal age, fetal nuchal translucency thickness, free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A.  Ultrasound Obstet Gynecol. 2008;  31 618-624
• 15 Wald N J, Rodeck C, Hackshaw A K et al. SURUSS in perspective.  Semin Perinatol. 2005;  29 225-235
• 16 Logghe H, Cuckle H, Sehmi I. Centre-specific ultrasound nuchal translucency medians needed for Down syndrome screening.  Prenat Diagn. 2003;  23 389-392
• 17 Kozlowski P, Knippel A J, Stressig R. Comparing first trimester screening performance: routine care gynaecologists’ practices vs. prenatal centre.  Ultraschall in Med. 2007;  28 291-295
• 18 Abele H, Wagner N, Hoopmann M et al. Effect of deviation from the mid-sagittal planeon the measurement of fetal nuchal translucency.  Ultrasound Obstet Gynecol. 2010;  35 525-529
• 19 Kagan K O, Wright D, Etchegaray A et al. Effect of deviation of nuchal translucency measurements on the performance of screening for trisomy 21.  Ultrasound Obstet Gynecol. 2009;  33 657-664
• 20 Snijders R J, Thom E A, Zachary J M et al. First-trimester trisomy screening: nuchal translucency measurement training and quality assurance to correct and unify technique.  Ultrasound Obstet Gynecol. 2002;  19 353-359
• 21 Palomaki G E, Neveux L M, Donnenfeld A et al. Quality assessment of routine nuchal translucency measurements: a North American laboratory perspective.  Genet Med. 2008;  10 131-138
• 22 Koster M P, Wortelboer E J, Engels M A et al. Quality of nuchal translucency measurements in The Netherlands: a quantitative analysis.  Ultrasound Obstet Gynecol. 2009;  34 136-141
• 23 Abele H, Hoopmann M, Wright D et al. Intra- and interoperator reliability of manual and semi-automated measurement of fetal nuchal translucency by sonographers with different levels of experience.  Ultrasound Obstet Gynecol. 2010;  36 417-422