3 - Praenatal-Medizin und Genetik

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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]