3 - Praenatal-Medizin und Genetik
Transcription
3 - Praenatal-Medizin und Genetik
Seminar Pränatalmedizin Peter Kozlowski praenatal.de Kinderklinik HHU 11. Januar 2016 Beratung über optionale Angebote Screening gewünscht Beratung Nicht-Wissen Mutterschafts-Richtlinien, Neufassung seit 1.7.2013 nur Biometrie mit Morphologie ohne Sonographie 3 - 4% Basisrisiko fetaler Störungen minor malformations 39% Chromosomenanomalie 9% Sonstige 4% Syndrome 3% Urogenital 18% Bauchwand / Haut 3% Gesichtsspalten 5% ZNS 6% Herz / Gefäße 6% Romosan 2009 Skelett / Muskel 7% Risiken für Chromosomenstörungen Anteil der Trisomien 13,18, 21 und Alter 3 2,5 Übrige Chromosomenanomalien 2 1,5 Trisomien 13,18,21 1 0,5 0 25 Jahre 35 Jahre 40 Jahre Je jünger die Schwangere, desto geringer der Anteil der im Trisomie-Screening erfassten Störungen. Risikoanamnese Risikobefund Auffälliger US Feindiagnos:k 1. Trimenon CVS Beratung über Umfang des Screening US-‐Screening 1 8+0 bis 12+0 AC Feindiagnos:k 2. Trimenon US-‐Screening 2 /2b 18+0 bis 22+0 US-‐Screening 3 28+0 bis 32+0 Opportunis:sches (unorganisiertes) Screening Feindiagnos:k 12+0 bis 13+0 fr ß-‐HCG PAPP-‐A PL GF > 1:100 oder US auffällig inter-‐ mediär >1:1000 NIPT Praeeklampsie Feindiagnos:k 20+0 bis 22+0 8+1 -12+0 11+1 -15+0 18+1 - 22+0 15+1 - 18+0 Chorionzottenbiopsie (CVS) Invasive Diagnostik incl. gezielter US-Diagnostik 17+1 -20+0 20+1 - 22+0 8+1 -12+0 18+1 - 22+0 11+1 – 15+0 15+1 - 18+0 17+1 -20+0 Amniozentese (AC) Invasive Diagnostik incl. gezielter US-Diagnostik 20+1 - 22+0 8+1 -12+0 18+1 - 22+0 11+1 – 15+0 15+1 - 18+0 17+1 -20+0 20+1 - 22+0 17+1 -40+0 Nabelschnurpunktion (NSP, FBS) Invasive Diagnostik incl. gezielter US-Diagnostik 12+ 3 SSW ETS 13+6 SSW Ductus venosus 13 SSW 12+5 SSW 11+6 SSW Organdiagnostik 11-13 SSW früh erkennbar An-/Exencephalus Holoprosencephalie Hygroma colli Body stalk Anomalie Teratom Megazystis Omphalocele Laparoschisis Amelie Pleuraerguss Aszites Gestörte Mehrlinge fakultativ erkennbar Zwerchfellhernie Spina bifida Gesichtsspalte Herzfehler Aorta, Art. pulmonalis Ultrasound Obstet Gynecol 2006; 27: 613 – 618 Published online 28 March 2006 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.2709 Detailed screening for fetal anomalies and cardiac defects at the 11 – 13-week scan R. BECKER and R.-D. WEGNER Center for Prenatal Diagnosis, Berlin, Germany K E Y W O R D S: fetal anomalies; fetal echocardiography; nuchal translucency; 11 – 13-week scan ABSTRACT Objective To assess the diagnostic efficacy of the firsttrimester anomaly scan including first-trimester fetal echocardiography as a screening procedure in a ‘mediumrisk’ population. Methods In a prospective study, we evaluated 3094 consecutive fetuses with a crown – rump length (CRL) of 45 – 84 mm and gestational age between 11 + 0 and 13 + 6 weeks, using transabdominal and transvaginal ultrasonography. The majority of patients were referred without prior abnormal scan or increased nuchal translucency (NT) thickness, the median maternal age was, however, 35 (range, 15 – 46) years, and 53.8% of the mothers (1580/2936) were 35 years or older. This was therefore a self-selected population reflecting an increased percentage of older mothers opting for prenatal diagnosis. The follow-up rate was 92.7% (3117/3363). Results The prevalence of major abnormalities in 3094 fetuses was 2.8% (86/3094). The detection rate of major anomalies at the 11 + 0 to 13 + 6-week scan was 83.7% (72/86), 51.9% (14/27) for NT < 2.5 mm and 98.3% (58/59) for NT ≥ 2.5 mm. The prevalence of major congenital heart defects (CHD) was 1.2% (38/3094). The detection rate of major CHD at the 11 to 13 + 6-week scan was 84.2% (32/38), 37.5% (3/8) for NT < 2.5 mm and 96.7% (29/30) for NT ≥ 2.5 mm. Conclusion The overall detection rate of fetal anomalies including fetal cardiac defects following a specialist scan at 11 + 0 to 13 + 6 weeks’ gestation is about 84% and is increased when NT ≥ 2.5 mm. This extends the possibilities of a first-trimester scan beyond risk assessment for fetal chromosomal defects. In experienced hands with adequate equipment, the majority of severe malformations as well as major CHD may be detected at the end of the first trimester, which offers parents the option of deciding early in pregnancy how to deal with fetuses affected by genetic or structural abnormalities without pressure of time. Copyright © 2006 ISUOG. Published by John Wiley & Sons, Ltd. INTRODUCTION There is increasing evidence that, in certain cases of fetal cardiac and other structural anomalies, prenatal diagnosis may be helpful or even life saving1 – 3 . For cases requiring specific therapy during and after delivery it seems sufficient to arrive at the diagnosis in the second half of pregnancy. So the ‘established’ 21 – 22-week scan is able to provide information that supports the health and life of both mother and child. If we accept that there is an obligation to detect diseases prior to delivery, we also have to accept that we inevitably diagnose conditions with a poor prognosis. The physiological and psychological impacts of a termination of pregnancy (TOP) increase with increasing gestational age, leading to ethical dilemmas in the second half of pregnancy, especially in cases of severely handicapped but viable fetuses. Given the right of a pregnant woman to decide against continuing a pregnancy with a severe anomaly, one main aim of prenatal diagnosis should be to provide as much relevant information as possible to the pregnant woman as early as possible. Assessing the thickness of nuchal translucency (NT) has become a well established method in early pregnancy. Initially the method focused on risk assessment for trisomy 214 – 6 , later extended to the detection of trisomies 13 and 18. For more than a decade studies have shown that anomaly scans7 – 9 and fetal echocardiography at the end of the first trimester are useful diagnostic tools10 – 12 . In addition, a few reports describe the Correspondence to: Prof. R. Becker, Free University of Berlin, Center for Prenatal Diagnosis, Kurfürstendamm 199, D-10719 Berlin, Germany (e-mail: [email protected]) Accepted: 26 August 2005 Copyright © 2006 ISUOG. Published by John Wiley & Sons, Ltd. ORIGINAL PAPER spät manifestierend Mikrocephalie Balkenagenesie Infektionsfolgen Lungenfehlbildung Linksherzhypoplasie Aortenisthmusstenose Darmobstruktion Tumor Prädiktion Biochemie und NT PAPP-A ß-HCG NT Risiko Trisomie 21 Trisomie 13,18 patern. Triploidie matern. Triploidie Praeeklampsie Combined test Combined Screening Alter, NT, FHR, ß-HCG, PAPP-A positiv Risiko > 1:100 Kontrollgruppe 1:100>Risiko<1:1000 negativ Risiko < 1:1000 <5% Trisomien 90% Sonstige 87% 20% Trisomien 5-10% > 75% Trisomien 2-3% Menschliche DNA Adenin - Thymin Guanin - Cytosin 3 Milliarden Basen 20.000 Gene 10 Millionen Stellen möglicher Variationen 1997 Entdeckung von zellfreier fetaler DNA im maternalen Plasma Lo Lancet 1997 Hoher maternaler Hintergrund Anteil zellfreier fetaler (cf) DNA 5-10% Lo Am J Hum Genet 1998, Lun Clin Chem 2008 Zellfreie fetale DNA ist stark fragmentiert (ca. 140bp) Lo Sci Transl Med 2010 Zellfreie fetale DNA stammt aus degradierten Zellen der Plazenta Bianchi Placenta 2004 Fetale DNA-Fraktion: Einflussfaktoren § Hoher BMI korreliert mit low fetal fraction § Korrelation mit PAPP-A und fß-HCG Ashoor Fetal Diagn Ther 2012 Poon Fetal Diagn Ther 2013 (DR %) „Falsch“ positiv (FPR %) Trisomie 21 99,2 0,09 Trisomie 18 96,3 0,13 Trisomie 13 91,0 0,13 Monosomie x 90,3 0,23 47,XXY 47,XXX 47,XYY 93,0 0,14 Erkennung Gil 2015 UOG FPR Summe 0,72% 1:140 falsch positiv Ursachen diskrepanter Befunde § methodisch bedingt (Trisomie 13) § frühzeitiger vanishing twin § plazentares Mosaik (Trisomie 18) § maternales Mosaik (z.B. 46,XX/45,X) Prävalenz und prädiktiver Wert: NIPT Erkennung 100%, falsch positiv 2 von 1.000, n=1.000 Tests Prävalenz 1:50 Betroffene 20 richtig erkannt 20 falsch positiv 2 Gesamtzahl positiv 22 Prädiktiver Wert 91 % nicht zutreffend 9% zutreffend 91% Die Relation „Prävalenz zu FPR“ macht´s Erkennung 100%, falsch positiv 2 von 1.000, n=1.000 Tests Prävalenz 1:500 Betroffene 2 richtig erkannt 2 falsch positiv 2 Gesamtzahl positiv 4 Prädiktiver Wert 50 % nicht zutreffend 50% zutreffend 50% PAPP-A < 0,3 MoM Wahrscheinlichkeit von § Praeeklampsie § FGR < p5 § Intrauteriner Tod § Vorzeitige Plazentalösung § Entbindung < 34 SSW 5-fach erhöht Praeeklampsie-Screening early onset PE late onset PE 0,5 % 1,5 % Entbindung < 34 SSW > 33 SSW Häufigste Schwangerschaftskomplikation 25% der maternofetalen Mortalität ETS und PE-Risiko Akolekar 2011 ASS und frühe Intervention Bujold 2010 Risikoanamnese Risikobefund Auffälliger US Feindiagnos:k 1. Trimenon CVS Beratung über Umfang des Screening US-‐Screening 1 8+0 bis 12+0 AC Feindiagnos:k 2. Trimenon US-‐Screening 2 /2b 18+0 bis 22+0 US-‐Screening 3 28+0 bis 32+0 Opportunis:sches (unorganisiertes) Screening Feindiagnos:k 12+0 bis 13+0 fr ß-‐HCG PAPP-‐A PL GF > 1:100 oder US auffällig inter-‐ mediär >1:1000 NIPT Praeeklampsie Feindiagnos:k 20+0 bis 22+0 Risikoanamnese Risikobefund Auffälliger US Feindiagnos:k 1. Trimenon CVS Beratung über Umfang des Screening US-‐Screening 1 8+0 bis 12+0 Opportunis:sches (unorganisiertes) Screening Feindiagnos:k 12+0 bis 13+0 US auffällig AC PAPP-‐A PL GF Feindiagnos:k 2. Trimenon US-‐Screening 2 /2b 18+0 bis 22+0 US-‐Screening 3 28+0 bis 32+0 Praeeklampsie Feindiagnos:k 20+0 bis 22+0 [email protected]