Diagnostik in der Früh-Schwangerschaft

Transcrição

24.11.14 Screening bedeutet: Sieben
Fetale Untersuchung in der
Früh-Schwangerschaft,
neue Techniken
Boris Tutschek, Zürich/Düsseldorf
Boris Tutschek
Praenatal-Zuerich.ch
Boris Tutschek
Bei 12 Wochen intakte
Schwangerschaften
100 Die „top ten“
100 90 99 80 Aneuplodie 70 60 98 Aneuplodie 97 Angeborene Fehlbildungen 96 50 95 Angeborene Fehlbildungen 40 Spontane Aborte 94 Spontane Aborte 30 Als normal geboren 20 10 93 91 0 90 Schwangerscha7en Boris Tutschek
Boris Tutschek
Als normal geboren 92 Schwangerscha7en Boris Tutschek
(Risiken bei Geburt mit 40 Wochen)
Boris Tutschek
1 24.11.14 Pathologischer fetaler Karyotyp
NT <3 mm
1% (10/776)
NT >3 mm 35% (18/51)
Nicolaides et al. BMJ 1992
Abnormaler Karyotyp (%)
100
80
+
+
60
40
20
0
1
2
3
4
5
6
7
Nackentransparenz (mm)
8
Boris Tutschek
Boris Tutschek
45-85mm (11+0-13+6 Wo.)
Kopf und Thorax füllen das Bild
Medianschnitt
Hals-Kopf-Halatung neutral
Messkreuze on-to-on "
(Amnion sichtbar)
Tipps: •  Vergrößerung
•  Helligkeit reduzieren
•  Nasenspitze und Thalamus im Bild
•  mehrfach messen, höchste NT
• 
• 
• 
• 
• 
Nasenspitze
Thalamus
Boris Tutschek
Nackentransparenz
Individuelle Berechnung: Praktisches
Vorgehen
1.  Messung der SSL
2.  Datierung mittels letzter Regel
•  entweder durch SSL bestätigen oder
•  nach SSL korrigieren
3.  Messung der NT
4.  Bewertung der NT in Bezug auf die SSL
Boris Tutschek
Boris Tutschek
Berechnung des individuellen Risiko
•  Hintergrundrisiko = Altersrisiko
(+ evtl. belastender Anamnese)
•  NT-Werte werden auf den Normbereich für jedes
Gestationsalter (bzw. SSL) bezogen:
–  Werte oberhalb des Normbereichs „erhöhen“ das individuelle Risiko
–  Ein Wert im oberen Normbereichs bestätigt das Risiko
–  Werte unterhalb des oberen Normbereichs „senken“ das Risiko
•  Praktisches Vorgehen:
–  Datierung durch L.R. entweder durch SSL bestätigen oder nach SSL
korrigieren
Boris Tutschek
2 24.11.14 mm,50%
50%for
fornuchal
nuchaltranslucency
translucencyof
of5.5–
5.5–6.4
6.4mm,
mm,and
and
mm,
75% for
for nuchal
nuchal translucency
translucency of
of 8.5
8.5 mm
mm or
or more.
more. In
In
75%
the majority
majority of
of fetuses
fetuses with
with trisomy
trisomy 21,
21, the
the nuchal
nuchal
the
translucency thickness
thickness was
was less
less than
than 4.5
4.5 mm,
mm, whereas
whereas
translucency
in the
the majority
majority of
of fetuses
fetuses with
with trisomies
trisomies 13
13 or
or 18,
18, itit
in
was4.5–
4.5–8.4
8.4mm,
mm,and
andin
inthose
thosewith
withTurner
Turnersyndrome,
syndrome,
was
was 8.5
8.5 mm
mm or
or more.
more.
itit was
The observed
observed prevalence
prevalence of
of trisomies
trisomies 21,
21, 18,
18, and
and
The
Beispiel:
Werte oberhalb der
13,
Turner syndrome,
syndrome, other
other sex
sex chromosome
chromosome
aneuoberenaneuNormgrenze
13,
Turner
erhöhen
das
ploidies,
and triploidy
triploidy was
was higher
higher than
than the
the respective
respective
SSL = 70mm
ploidies,
and
Hintergrundrisiko
NT = 2.0mm
oder on
prevalences
estimated
onthe
thebasis
basisof
ofthe
thematernal
maternalage
age
prevalences
estimated
Ein Wert in der oberen
2,6mm oder
and gestational
gestational
age distribution
distribution of
of the
the
population
and
age
population
Norm
bestätigt das
3,6mm Hintergrundrisiko
(Table 2).
2). The
The observed-to-expected
observed-to-expected ratio
ratio
increased
(Table
increased
significantly with
with nuchal
nuchal translucency
thickness for
for
significantly
Werte unterhalb der
trisomy 21
21 (r(r !
! 0.919,
0.919, PP !
! .008),
.008), trisomy
trisomy
18 (r(r !
!
oberen Normgrenze
trisomy
18
senken das Risiko
0.970, PP "
" .001),
.001), trisomy
trisomy 13
13 (r(r !
! 0.870,
0.870, PP !
! .007),
.007),
0.970,
Turner syndrome
syndrome (r(r !
! 0.987,
0.987, PP "
" .001)
.001) and
and other
other sex
sex
Turner
chromosome abnormalities
abnormalities (r(r !
! 0.759,
0.759, PP !
! .011)
.011) but
but
chromosome
not for
for triploidy
triploidy (r(r !
! 0.684,
0.684, PP !
! .255)
.255) (Fig.
(Fig. 1).
1).
not
type of
of chromosomal
chromosomal defect.
defect. Thus,
Thus, the
the nuchal
nuchal transtranstype
lucency thickness
thickness was
was less
less than
than 4.5
4.5 mm
mm in
in approxiapproxilucency
mately 50%
50% of
of fetuses
fetuses with
with trisomy
trisomy 21
21 and
and those
those with
with
mately
triploidy. In
In contrast,
contrast, the
the nuchal
nuchal translucency
translucency thickthicktriploidy.
ness was
was 4.5
4.5 mm
mm or
or more
more in
in approximately
approximately 60%
60% of
of
ness
fetuses with
with trisomy
trisomy 13,
13, 75%
75% of
of those
those with
with trisomy
trisomy 18,
18,
fetuses
and 90%
90% of
of fetuses
fetuses with
with Turner
Turner syndrome.
syndrome. AdditionAdditionand
ally, the
the observed-to-expected
observed-to-expected ratio
ratio of
of trisomies
trisomies 21,
21,
ally,
18, and
and 13
13 increases
increases with
with nuchal
nuchal translucency
translucency thickthickRisiko (%) für ein fetales Down-Syndrom
18,
ness to
to aa peak
peak at
at approximately
approximately 88–9
–9 mm
mm and
and therethere100
ness
after decreases,
decreases, whereas
whereas in
in the
the case
case of
of Turner
Turner synsynafter
NT
drome, the
the ratio
ratio increases
increases exponentially
exponentially with
with fetal
fetal
drome,
10
nuchal translucency.
translucency. For
For other
other sex
sex chromosome
chromosome dedenuchal
fectsthe
theratio
ratiodecreases
decreaseswith
withnuchal
nuchaltranslucency,
translucency,and
and
fects
NT
for triploidy
triploidy itit does
does not
not change
change significantly
significantly with
with1
for
nuchal translucency.
translucency.
nuchal
The difference
difference in
in phenotypic
phenotypic pattern
pattern of
of nuchal
nuchal
The
0.1
thickness characterizing
characterizing each
each chromochromotranslucency
somal defect
defect presumably
presumably reflects
reflects the
the heterogeneity
heterogeneity in
in
somal
causes for
for the
the abnormal
abnormal accumulation
accumulation of
of subcutanesubcutane0.01
causes
25
30
35
40
45
ous fluid
fluid in
in the
the nuchal
nuchal region.
region. Suggested
Suggested mechanisms
mechanisms 20
ous
Maternales Alter
for increased
increased nuchal
nuchal translucency
translucency include
include cardiac
cardiac
for
dysfunction in
in association
association with
with abnormalities
abnormalities of
of the
the
dysfunction
8,9
heart and
and great
great arteries;
arteries;8,9
superior mediastinal
mediastinal comcomheart
superior
pression due
due to
to diaphragmatic
diaphragmatic hernia,
hernia, which
which isis comcompression
Boris Tutschek 10,11
monly found
found in
in fetuses
fetuses with
with trisomy
trisomy
18;10,11 failure
failure of
of
monly
18;
lymphatic drainage
drainage due
due to
to impaired
impaired development
development of
of
lymphatic
the lymphatic
lymphatic system,
system, which
which has
has been
been demonstrated
demonstrated
the
by immunohistochemical
immunohistochemical studies
studies in
in nuchal
nuchal skin
skin tissue
tissue
by
from fetuses
fetuses with
with Turner
Turner syndrome;
syndrome;1212 and
and altered
altered
from
composition of
of the
the subcutaneous
subcutaneous connective
connective tissue,
tissue,
composition
leading to
to the
the accumulation
accumulation of
of subcutaneous
subcutaneous edeedeleading
13,14
ma.13,14
Although cardiac
cardiac defects
defects are
are commonly
commonly
ma.
Although
found in
in association
association with
with all
all major
major chromosomal
chromosomal
found
+
+
+
DISCUSSION
DISCUSSION
Thefindings
findingsof
ofthis
thisstudy
studyconfirm
confirmthe
thehigh
highassociation
association
The
between increased
increased nuchal
nuchal translucency
translucency and
and trisomy
trisomy
between
1–3
1–3
21
as
well
as
other
chromosomal
defects.
Thus, the
the
21 as well as other chromosomal defects. Thus,
incidence of
of chromosomal
chromosomal defects
defects increases
increases with
with nunuincidence
Boris Tutschek
chal translucency
thickness from
from approximately
approximately 7%
7%
chal
for those
those with
with nuchal
nuchal translucency
translucency between
between the
the 95th
95th
for
centile for
for CRL
CRL and
and 3.4
3.4 mm
mm to
to 75%
75% for
for nuchal
nuchal
centile
translucency of
of 8.5
8.5 mm
mm or
or more.
more.
translucency
The data
data demonstrate
demonstrate that
that in
in fetuses
fetuses with
with ininThe
creased nuchal
nuchal translucency
translucency approximately
approximately one
one half
half
creased
of the
the chromosomally
chromosomally abnormal
abnormal group
group isis affected
affected by
by
of
defects other
other than
than trisomy
trisomy 21.
21. Furthermore,
Furthermore, the
the disdisdefects
tribution of
of nuchal
nuchal translucency
translucency isis different
different for
for each
each
tribution
NT und relatives Risiko der häufigsten Aneuploidien
Grafik © FMF London
freies beta-hCG & PAPP-A
20
T18 Euploid
n
Trisomie 21
10
T13 Turner 0
0 0.4 1.2
T21 2.0 2.8 3.6 4.4 4.8
Freies ß-hCG (MoM)
Fig. 1.
1. Relation
Relation between
between fetal
fetal nuchal
nuchal
Fig.
thickness and
and the
the obobtranslucency
served-to-expected
ratio
for
trisomy
served-to-expected ratio for trisomy
21 (——),
(——), trisomy
trisomy 18
18 (••••••••
(••••••••
21
trisomy 13
13 (–
(– –– –– –),
–), triploidy
triploidy
••••), trisomy
••••),
(• –– •• –– •• –),
–), and
and other
other sex
sex chromochromo(•
somedefects
defects(••
(••––••
••––••
••–)
–)on
onthe
the
some
left and
and Turner
Turner syndrome
syndrome on
on the
the right.
right.
left
Triploidie andere gonos. Boris Tutschek
nach Kagan et al. OG 2006
VOL. 107,
107, NO.
NO. 1,
1, JANUARY
JANUARY 2006
2006
VOL.
Kagan et
et al
al
Kagan
Euploid
4
0
0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8
Serum PAPP-A (M0M)
Kagan. Increased
Increased Nuchal
Nuchal Translucency.
Translucency.
Kagan.
Boris2006.
Tutschek
Obstet Gynecol
Gynecol
2006.
Obstet
FMF London
Increased Nuchal
Nuchal Translucency
Translucency 99
Increased
Blutwerte
•  hCG (freies beta-hCG)
Trisomie 21
8
n
Screening früher und jetzt
•  FRÜHER „Wie alt sind Sie?“
–  bei T21 obere Norm, bei T13/18 vermindert
•  PAPP-A
–  bei T21 leicht vermindert, bei T13/18 vermindert
•  Bewertung über
–  MoM
–  DoE
= Mehrfache des Mittelwertes {0.5...2.5}
= Degree of Extremeness {-1.0...+1.0)
•  erhöhen die Erkennungsrate z.B. für T21
–  von 65% für NT allein
–  auf 85% für NT plus Biochemie
Boris Tutschek
•  DANN „Wie alt sind Sie?“
plus „Ist die NT grösser als ‚normal‘ ?“
plus „Sind Ihre Blutwerte ‚normal‘ ?“
•  JETZT (seit 2012)
„Wollen Sie € 1000 aufwenden, um das Down-Syndrom
praktisch auszuschliessen?“
Boris Tutschek
3 24.11.14 Historische Perspektive
Heute Früher Pränatalmedizin GeneEk •  1980er Jahre
–  mütterliches Alter > 35 Jahre (damals: 5%; heute:
23%)
–  DRT21 1/3 - Aneuploidien bei 2% der „Auffälligen“
•  Frühe 1990er Jahre
–  Zweit-Trimester maternale Serummarker
Validation
Validationstudy
studyofofcfDNA
cfDNAtesting
testingusing
using
SNPsT21 2/3 - Aneuploidien bei 4% der „Auffälligen“
– SNPs
DR
577
577
•  Späte1990er, frühe 2000er Jahre
NTchorionic
mit hCG
und
PAPP-A
Table
Table11Fetal
Fetalkaryotype
karyotypeobtained
obtained– 
from
from
chorionic
villus
villus
sampling
sampling
ofofchromosome
chromosomeYYwas
waszero,
zero,both
bothwith
withsample-specific
sample-specificaccuaccuininthe
the229
229cases
caseswith
withresults
resultsfrom
fromcell-free
cell-freeDNA
DNAtesting
testingand
andthe
the racy
racy
ofof6%
99.9%.
99.9%.
For
For
the
the triploidy
triploidy case,
case, the
the copy
copy number
number ofof
– 
DR
5/6
Aneuploidien
bei
der
„Auffälligen“
T21
predicted
predictedcopy
copynumber
numberfor
forchromosomes
chromosomesX,X,Y,Y,21,
21,18,
18,and
and13
13
Boris Tutschek
chromosomes
chromosomes13,
13,18,
18,21,
21,and
andXXwas
wasthree,
three,and
andthe
thecopy
copynumber
number
ofofchromosome
chromosome
YYwas
was
zero.
zero.
Because
Because
ofofthe
thesmall
smallnumber
numberofof
mod.
nach
Benn
PD 2013
chromosomes:
chromosomes:
trisomy
trisomy13,
13,trisomy
trisomy18,
18,monosomy
monosomyX,X,and
andtriploidy
triploidysamples,
samples,
sensitivities
sensitivitiesand
andspecificities
specificitiesare
arenot
notreported.
reported.InInthe
the116
116male
male
Downloaded from on September 21, 2014
XX
YY
21
21
18
18
13
13
fetuses,
fetuses,there
therewas
wasone
onecopy
copynumber
numberfor
forchromosome
chromosomeXXwith
with
11
11
33
22
22
accuracy
accuracy
ofof99.9%
99.9%
ininThe
all
allauthor
cases,
cases,
and
and
one
one
for
for4chromosome
chromosomeYYwith
with
06) for supporting
this work.
holds
or has
filed
8. Acknowledgements
applications on aspects of non-invasive prenatal diagaapatent
median
median
accuracy
accuracyofof99.9%
99.9%(range:
(range:96.0–99.9%),
96.0–99.9%),and
andininthe
the109
109
22
00
33
22
22
nosis. Part of this patent portfolio has been licensed to
The author thanks the University Grants Committee of the
Sequenom.
The author
is a consultant
to two
Sequenom,
holdsand
female
female
fetuses,
fetuses,
excluding
excluding
the
the
twoTurner
Turner
andone
onetriploidy
triploidycases,
cases,
Government of 2the
Administration
2 Hong
00 Kong2Special
2
33
22
equities
in
and
receives
research
support
from
Sequenom.
Region, China—Areas of Excellence Scheme (AoE/M-04/
the
thecopy
copynumber
numberofofchromosome
chromosomeXXwas
wastwo,
two,and
andchromosome
chromosomeYY
11
11
22
22
33
was
was zero
zero with
with aa median
median sample-specific
sample-specific accuracy
accuracy ofof 99.9%
99.9%
11
00
22
22
22
(range:
(range:96.0–100%).
96.0–100%).
Boris Tutschek
Predicted
Predictedcopy
copynumber
numberfor
for
Fetal
Fetalkaryotype
karyotype
47,XY,+21
47,XY,+21(n(n==10)
10)
47,XX,+18
47,XX,+18(n(n==3)3)
47,XY,+13
47,XY,+13(n(n==1)1)
Nicht-invasive pränatale Testung NIPT
45,X
45,X(n(n==2)2)
69,XXX
69,XXX(n(n==1)1)
33
00
33
33
rsob.royalsocietypublishing.org
47,XX,+21
47,XX,+21(n(n==15)
15)
AUTHOR
PROFILE
33
Dennis Lo is the Director of the Li Ka Shing Institute of Health Sciences, Li Ka Shing Professor of
22
22
22
Medicine and Professor of Chemical Pathology at The Chinese University of Hong Kong. He received
46,XY,del(2)(q37.1)
46,XY,del(2)(q37.1)(n(n==1)1)
11
11his undergraduate
22
22education
22from the University of Cambridge, and his Doctor of Medicine and
Doctor of Philosophy degrees from the University of Oxford. His research interests focus on the
of cell-free nucleic acids in plasma. In particular, he discovered
46,XX,+der(9)t(9;15)(q33.2;q11.2)pat,
46,XX,+der(9)t(9;15)(q33.2;q11.2)pat, 22
00biology2and
2 diagnostic
22 applications
22
the presence of cell-free foetal DNA in maternal plasma in 1997 and has since then been pioneering
!15
!15(n(n==1)1)
Validation study of cfDNA testingnon-invasive
using SNPs prenatal diagnosis using
This
This
externally
externally
blinded
blinded
validation
study
study
hasdemonstrated
demonstratedthat
that
this technology.
He has
received validation
numerous
awards
for577
hishas
research, including a State Natural Sciences Award from the State Council of China (2005), the InterSNP-based
SNP-basedanalysis
analysisofofcfDNA
cfDNAininmaternal
maternalblood
bloodobtained
obtainedatat11
11
46,XY,t(8;10)(p23.1;q24.1)pat
46,XY,t(8;10)(p23.1;q24.1)pat(n(n==1)1)
11
11
22
22
22
national Federation of Clinical Chemistry and Laboratory Medicine (IFCC)—Abbott Award for
Table 1 Fetal karyotype obtained
from chorionic
villus sampling
of chromosome
Y was
zero,
both
with
sample-specific
accu- singleton
Outstanding
Contribution
to Molecular
(2006),
the US
National
Academy
of Clinical
13
13weeks’
weeks’
gestation
gestation
from
from
high-risk
high-risk
singletonpregnancies
pregnancies
45,XX,der(14;21)(q10;q10)mat
45,XX,der(14;21)(q10;q10)mat
(n=229
=1)1)cases 2
2 results
00from
22 DNA
2testing
2
22the totoDiagnostics
in (n
the
with
cell-free
and
racy of 99.9%.
thea triploidy
case, Scholars
the copyAchievement
number of
Biochemistry (NACB) Distinguished Scientist
Award For
(2006),
Cheung Kong
predicted copy number for chromosomes X, Y, 21, 18, and 13
correctly
correctly
identified
identified
allthree,
cases
cases
of
of
trisomies
trisomies
21,18,
18,and
and13,
13,Turner
Turner
chromosomes
18, 21,
X all
was
and
the
copy
number
of
of China 13,
(2006),
a and
Silver
Bauhinia
Star
from
the
Hong 21,
46,XY
46,XY(n(n==103).
103).
11
11Award2from
2 the 2Ministry
2
22Education
ofsyndrome,
chromosome
Yand
was
Because
ofwith
the
small
number
ofpositives
Kong SAR
Government
andforthe American
Association
forzero.
Clinical
Chemistry
(AACC)—NACB
Predicted
copy number
syndrome,
and
triploidy
triploidy
with
no
no
false
false
positivesand
andcorrectly
correctly
chromosomes:
Award
for
Outstanding
Contribution
to
Clinical
Chemistry
in
a
Selected
Area
of
Research
(2012).
He
was
elected
a
Fellow
of
trisomy
13,
trisomy
18,
monosomy
X,
and
triploidy
samples,
46,XX
46,XX(n(n==89)
89)
22
00
22
22
22
determined
determined
the
thefetal
fetal
sex
sex
ininall
all
cases.
The
Thetest
testdid
didnot
notprovide
provide
the Royal Society of London in 2011.
sensitivities
and specificities
are not
reported.
In cases.
the
116 male
X
Y
21
18
13
Fetal karyotype
fetuses, there was one copy number for chromosome X with
results
resultsinin5.4%
5.4%ofofcases,
cases,for
forwhich
whichaaredraw
redrawand
andreanalysis
reanalysis
47,XY,+21 (n = 10)
1
1
3
2
2
accuracy of 99.9% in all cases, and one for chromosome Y with
a would
median accuracy
of 99.9% (range: 96.0–99.9%), and in the 109
47,XX,+21 (n = 15)
2
0
3
2
2
would
be
berecommended.
recommended.
female fetuses, excluding the two Turner and one triploidy cases,
(nWapner
= 3)
2
2 for noninvasive
3
2
prenatal diagnosis.
Am.pregnancies
J.pregnancies
Hum.
pregnant women:
prospective feasibility
Br.
1.47,XX,+18
EvansThe
MI,
RJ. 2005 Invasiverisk
prenatal
identified
identifiedasastriploid
triploid(69,XXX).
(69,XXX).
The
estimated
estimated
risk
for
for0aneuploidies
aneuploidies
The
had
hadstudy.
undergone
undergone
screening
screening for
for
the The
copy
number
of chromosomeexamined
Xexamined
was two, and chromosome
Y
(doi:10.1086/301800)
Med. J. 336,
816–818. (doi:10.1136/bmj.39518.
diagnostic(n procedures
2005. Semin. Perinatol.
47,XY,+13
= 1)
1 29,1
2 Genet. 62,
2 768 –775.
3
was
zero with 21,
a 21,
median
sample-specific
accuracy
of 99.9%
by
bythe
thecombined
combinedtest
testisis45,X
compared
compared
with
with
the
the1result
result
ofofcfDNA
cfDNA
trisomies
trisomies
18,
18,
and
and13
13by
by
aacombination
combination
ofofmaternal
maternalage,
age,
463206.25)
215–218.
(n = 2) (doi:10.1053/j.semperi.2005.06.004)
0 9. 2 Lun FMF,
2 Chiu RWK,
2 Chan KCA, Leung TY, Lau TK,
T21
(range:
Lo YMD. 2008 Microfluidics
digital96.0–100%).
PCR reveals a
16. Poon LLM, Leung TN, Lau TK, Chow KC, Lo YMD.
2. Malone FD et al. 2005 First-trimester or second-
11
11
DISCUSSION
DISCUSSION
Open Biol 2: 120086
47,XY,+22
47,XY,+22(n(n==1)1)
Principal
Principalfindings
findingsofofthis
thisstudy
study
References
•  Späte 2010er Jahre
–  NIPT
–  DR >99% - Aneuploidien bei 66% der „Auffälligen“
Boris Tutschek
(n = 1)
3
0copy
3 number
3
3
testing
testingininFigure
Figure1.1.InInall
all69,XXX
cases
cases
ofoftrisomy
trisomy21,
21,the
thecopy
number
ultrasound
ultrasound examination,
examination,
and
and maternal
maternal serum
serum biochemical
biochemical
higher than expected fraction of fetal DNA in
2002 Differential DNA methylation between fetus
trimester screening, or both, for Down’s syndrome.
47,XY,+22 (n = 1)
1
1
2
2
DISCUSSION
maternal2 plasma.
Clin. testing,
Chem.
54, 1664–1672.
and mother
as a strategy for as
detecting
fetal DNA at
N. Engl.
J. Med.aa
353,
2001 –2011. (doi:10.1056/
ofofchromosome
chromosome21
21was
wasthree
three
with
with
sample-specific
sample-specific
accuracy
accuracy
ofof
testing,
most
mostwere
were
identified
identified
asbeing
being
athigh
highrisk
riskfor
forthese
these
46,XY,del(2)(q37.1)
1
1
2 (doi:10.1373/clinchem.2008.111385)
2
2
in maternal plasma. Clin. Chem. 48, 35 –41.
NEJMoa043693) (n = 1)
Boris
Tutschek
99.9%
99.9%(sensitivity:
(sensitivity:100%;
100%;
CI:
CI:
86.3–100%;
86.3–100%;
specificity:
100%;
CI:
CI:
aneuploidies
and
the
parents
parents
tohave
havechorionic
chorionicvillus
villus
Principal
study
Lo YMD,2 Zhang
J,2 Leunganeuploidies
TN,
Lau TK, findings
Chang AM,of this
17.and
Chimthe
SSC
et al.
2005 Detection chose
of chose
the placentalto
3.46,XX,+der(9)t(9;15)(q33.2;q11.2)pat,
Bianchi
DW,
Williams JM, Sullivanspecificity:
LM,
Hanson
2 FW,0 10.
2100%;
!15
(n
=
1)
Hjelm NM. 1999 Rapid clearance
of fetal DNA blinded
from
epigenetic study
signature
the maspin gene
in
KW, Shuber AP. 1997 PCR quantitation of
This externally
validation
hasofdemonstrated
98.2–100%).
98.2–100%).InInall
allcases
casesofKlinger
oftrisomy
trisomy
18,
18,the
thecopy
copynumber
number
ofof sampling
sampling
for
for fetal
fetal
karyotyping.
karyotyping.
InInthat
this
this respect,
respect, the
the study
study
Genet. 64, 218–224.
maternal
plasma. Proc.
Natl Acad.
Sci. USAat102,
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SNP-based
analysis of cfDNA
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(n = in
1) normal
1 and1
2 maternal2 plasma.2Am. J. Hum.
(doi:10.1086/302205)
14 753high-risk
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18was
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withpregnancies.
accuracy
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99.9%,
in2the
the2case
case
population
reflects
reflects
current
current
clinical
clinical
practice
practiceininthe
theUK
UKand
and
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1)
2 61,0 in
2
11. Smid M et al. 2003 No evidence
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DNA
TongofYKtrisomies
et al. 2006 21,
Noninvasive
prenatal
detection
822–829. (doi:10.1086/514885)
correctly
identified
all 18.
cases
18, and
13, Turner
46,XY
(n = 103). ofchromosome
1
1 13was
2
2three
2
ofoftrisomy
trisomy13,
13,the
thecopy
copy4.number
number
was
three
many
other
other
countries
countries
where
screening
screening
and
and diagnosis
diagnosis ofof
persistence
in maternal many
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of fetal
18where
by epigenetic
allelic ratio
Bianchi DW et of
al. 2002 chromosome
Fetal gender and aneuploidy13
syndrome,
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notrisomy
false positives
and correctly
46,XX (n = 89)
0
2
2
Hum. Genet.
112,2 617–618.
in maternal
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theoretical
and
detection
using
fetal of
cells
in Turner
maternal 2 blood:
determined
the fetal sex
all
cases.
The
did first
not
provide
with
withaccuracy
accuracyofof99.9%;
99.9%;in
in
the
thecases
cases
ofTurner
syndrome,
syndrome,
the
the
aneuploidies
aneuploidies
isisinanalysis
based
based
on
ontest
the
the
first
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test
12. Bianchi DW, Zickwolf GK,results
Weil GJ, Sylvester
S, of cases, empirical
considerations.
Clin. reanalysis
Chem. 52,
analysis of NIFTY I data. National Institute of
in 5.4%
for which
a redraw and
copy
copynumber
numberofofchromosome
chromosome
XXwas
was
one,
one,and
and
thecopy
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number
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and
chorionic
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villus
villus
sampling,
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DeMaria
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(doi:10.1373/clinchem.2006.076851)
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Fetal
Cellthe
Isolation
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in aneuploidies
maternal blood for asThe
longpregnancies
as 27 years examined
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22, 609–615.
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identified
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The estimated
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V, Carter NP, Patsalis
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–708.number
(doi:10.1073/pnas.93.2.705)
methylation
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noninvasive
5.
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J-L, Nicod
LP, Kurt 21, the705
testing
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of trisomy
copy
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and DNA
maternal
serum
biochemical
13. Biochemie
Devaney
SA, Palomaki
Scott JA, most
Bianchi DW.
prenatalas diagnosis
trisomyrisk21.for
Nat.these
Med.
A-M, Lyautey J,21Lederrey
C, Anker
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aP, sample-specific
accuracy
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were identified
being atof high
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Microsatellite alterations in plasma DNA of small
99.9% (sensitivity: 100%; CI: 86.3–100%; specificity: 100%; CI:
aneuploidies and the parents chose to have chorionic villus
NIPT
free fetal DNA: a systematic review and meta20. Lo YMD et al. 2007 Plasma placental RNA
allelic
cell lung cancer patients. Nat. Med. 2,
98.2–100%). In all cases of trisomy 18, the copy number of
sampling for fetal karyotyping. In this respect, the study
analysis. JAMA 306, 627–636. (doi:10.1001/jama.
ratio permits noninvasive prenatal chromosomal
1033–1035. (doi:10.1038/nm0996-1033)
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population reflects current clinical practice in the UK and
2011.1114)
aneuploidy detection. Nat. Med. 13, 218– 223.
6. Nawroz H, Koch W, Anker P, Stroun M, Sidransky D.
of trisomy 13, the copy number of chromosome 13 was three
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14. Lo YMD, Hjelm NM, Fidler C, Sargent IL, Murphy
(doi:10.1038/nm1530)
1996 Microsatellite alterations in serum DNA of
with accuracy of 99.9%; in the cases of Turner syndrome, the
aneuploidies is based on the first trimester combined test
MF, Chamberlain PF, Poon PMK, Redman CWG,
21. Chan KCA et al. 2004 Size distributions of maternal
head and neck cancer patients. Nat. Med. 2,
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Wainscoat JS. 1998 Prenatal diagnosis of fetal
and fetal DNA in maternal plasma. Clin. Chem. 50,
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RhD status by molecular analysis of maternal
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plasma. N. Engl. J. Med. 339, 1734–1738.
22. Li Y, Zimmermann B, Rusterholz C, Kang A,
Sargent IL, Redman CWG, Wainscoat JS 1997
Holzgreve W, Hahn S. 2004 Size separation of
Presence of fetal DNA in maternal plasma and
(doi:10.1056/NEJM199812103392402)
circulatory DNA in maternal plasma permits
serum. Lancet 350, 485 –487. (doi:10.1016/S014015. Finning K, Martin P, Summers J, Massey E, Poole G,
ready detection of fetal DNA polymorphisms.
6736(97)02174-0)
Daniels G. 2008 Effect of high throughput RHD
Clin. Chem. 50, 1002 –1011. (doi:10.1373/
8. Lo YMD et al. 1998 Quantitative analysis of fetal
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clinchem.2003.029835)
DNA in maternal plasma and serum: implications
of anti-RhD immunoglobulin in RhD negative
Figure 1 Distribution of risk for aneuploidies by the combined test (left) and cfDNA testing (right) in euploid (black) and aneuploid (red)
Boris Tutschek
pregnancies
plotted on the fetal crown-rump length
Boris Tutschek
Figure
Figure11Distribution
Distributionofofrisk
risk
for
foraneuploidies
aneuploidiesby
bythe
thecombined
combined
test
test(left)
(left)PD
and
and
cfDNA
cfDNA
testing
testing
(right)
(right)inineuploid
euploid(black)
(black)and
andaneuploid
aneuploid(red)
(red)
Nicolaides
2013
(SNP,
Panorama/NATUS/Natera)
pregnancies
pregnanciesplotted
plottedon
onthe
the
fetal
fetal
crown-rump
crown-rump
length
length
Prenatal
Diagnosis
2013, 33, 575–579
Prenatal
PrenatalDiagnosis
Diagnosis2013,
2013,33,
33,575–579
575–579
© 2013 John Wiley & Sons, Ltd.
©©2013
2013John
JohnWiley
Wiley&&Sons,
Sons,Ltd.
Ltd.
4 24.11.14 Entdeckungsraten (%) für Trisomie 21
> 35 J, (1980) > 35 J. (heute) Triple-‐Test NT und Alter ETT NIPT 0 Boris Tutschek
FAZ 21.08.12 20 40 60 80 100 Boris Tutschek
Anatomische Untersuchung mit
12-13 Wochen
NIPT als Konkurrenz zum
NT-Aneuplodie-Screening (ETT)?
•  Zahlreiche nicht-chromosomale Besonderheiten
sind beim NT-Schall erkennbar.
•  Solche strukturellen Diagosen können in bis zu
2% der „gescreenten“ Schwangeren gestellt
werden (also bei vermeintlichen NiedrigrisikoFällen).
Boris Tutschek
Boris Tutschek
Fetale Anatomie mit 11-14 Wochen
American Journal of Obstetrics and Gynecology (2005) 192, 535–42
www.ajog.org
Basis-Untersuchung mit 13 Wochen
•  SSL und/oder BPD
•  Gliedmaßenknospen
•  Ausschluss Hydrops (incl. Nackenödem)
•  geschlossene Kalotte
•  keine zystische RF>2cm
•  Ausschluss Bauchwanddefekt (ab 12+0)
Schädel
geschlossen
SSL
Fetal transabdominal anatomy scanning using standard
views at 11 to 14 weeks’ gestation
Constantin S. von Kaisenberg, MD, PhD,a Heidi Kuhling-von Kaisenberg, MD,a
Elfriede Fritzer,b Sandra Schemm, MD,a Ivo Meinhold-Heerlein, MD,a
Walter Jonat, MD, PhDa
Department of Obstetrics and Gynecology, University Hospital, Kiel, Germany,a MedStatistik, Gettorf, Germanyb
Received
for publication May 5, 2004; revised August 24, 2004; accepted August 24, 2004
Boris
Tutschek
KEY WORDS
Nuchal translucency
Anatomy
Standard views
Scoring system
Visualization
Objectives: This study was undertaken to investigate fetal anatomy with the use of standard views
and a scoring system, to investigate interobserver variability, and to compare ultrasound modes
simultaneously with the measurement of nuchal translucency (11-14 weeks’ gestation).
Study design: Twelve fetal anatomic regions were defined as standard views (n Z 60) and assessed
with the use of a scoring system (1 Z not seen, 2 Z seen uncertainly, 3 Z seen acceptably, 4 Z well
seen, and 5 Z very well seen). The variation of scores and interobserver variability were analyzed
(n Z 40), the B-mode was compared with tissue harmonic and compound imaging (n Z 60).
Results: The overall average score (11 C 0 to 13 C 6 weeks) with tissue harmonic and compound
imaging was 3.56 (well seen) and increased with gestation. The highest score was for the neck and
the lowest for the cerebellum. The proportion of identical scores for each given region showed
a range of 58% to 83%. Tissue harmonic and compound imaging was significantly better than the
plain B-mode, P ! .001 (sign test).
Conclusion: Transabdominal fetal anatomy scanning with standard fetal anatomy views at 11 to 14
weeks of gestation is possible with good reproducibility and demonstrability when harmonic and
compound imaging are used.
! 2005 Elsevier Inc. All rights reserved.
A study of 97 pregnancies that used transvaginal
ultrasound examined the fetuses from 9 to 14 weeks and
was aimed at body contours, long bones, fingers, face,
palate, feet, toes, and the heart 4-chamber view, showing
sonography and was a valuable tool in complementing
abdominal sonography.2,3 A study investigating fetal
anatomy at 11 to 14 weeks’ gestation that used both
transabdominal and vaginal ultrasound found improved
Boris Tutschek
5 24.11.14 Untersuchung mit 13 Wochen
Erweiterter US mit 11 bis 13+6 Wochen
Ultrasound Obstet Gynecol 2006; 27: 613–618
Published online 28 March 2006 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.2709
Plexus
choroid.
BPD
Detailed screening for fetal anomalies and cardiac defects at
the 11–13-week scan
Nabel
Profil
kein Nackenödem,
R. BECKER and R.-D.
WEGNER
kein Hydrops
Schädel
geschlossen
Center for Prenatal Diagnosis, Berlin, Germany
Magen
Nabel, kein Bauchwanddefekt
K E Y W O R D S: fetal anomalies; fetal echocardiography; nuchal translucency; 11–13-week scan
Rücken
Blase
ABSTRACT
Boris Tutschek
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 wasand
92.7%cardiac
(3117/3363).
Detailed screening for fetal
anomalies
defects at
Fehlbildungen US 11-‐13 Wochen the 11–13-week scan
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%
R. BECKER and R.-D. WEGNER
(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
K E Y W O R D S: fetal anomalies; fetal echocardiography;
nuchal
translucency;
11–13-week
detection
rate
of major
CHD atscan
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
ABSTRACT
at the
end ofdefects
the first following
trimester, which
offers parents
including fetal
cardiac
a specialist
scanthe
of 6deciding
in pregnancy
how to deal
with
at 11 + 0 tooption
13 +
weeks’early
gestation
is about
84%
fetuses affected by genetic or structural abnormalities
and
increased when NT ≥ 2.5 mm. This extends
Objective To assess the diagnostic efficacy of
the is
firstwithout pressure of time. Copyright © 2006 ISUOG.
the possibilities
of
a
first-trimester
scan
beyond
risk
trimester anomaly scan including first-trimester
fetal
Published by John Wiley & Sons, Ltd.
echocardiography
as a screening procedure in aassessment
‘medium- for fetal chromosomal defects. In experienced
Boris
Tutschek
risk’ population.
hands with adequate equipment, the majority of severe
Methods In a prospective study, we evaluated
3094
malformations
asR O
well
asT major
INT
DUC
I O N 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
Boris Tutschek
fetuses affected
by genetic or structural abnormalities
without pressure of time. Copyright © 2006 ISUOG.
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
Detailed
screening
for fetal
and cardiac defects at
half of pregnancy.
So the ‘established’
21–22-week
scan anomalies
is
able to provide information that supports the health and
the 11–13-week scan
life of both mother and child. If we accept that there is
an obligation to detect diseases prior to delivery, we also
R. BECKER and R.-D. WEGNER
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
ethical
dilemmas
K E Y W O R D age,
S: fetalleading
anomalies;to
fetal
echocardiography;
nuchal translucency; 11–13-week scan
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
A B S T Rshould
A C T be to provide as much relevant
at the end of the first trimester, which offers parents the
prenatal diagnosis
option of deciding early in pregnancy how to deal with
information as possible to the pregnant woman as early
fetuses affected by genetic or structural abnormalities
as possible. Objective To assess the diagnostic efficacy of the firstwithout pressure of time. Copyright © 2006 ISUOG.
trimester
anomaly
scan
including
first-trimester
fetal
Assessing the thickness of nuchal translucency (NT)
echocardiography as a screening procedure in a ‘mediumhas become arisk’
well
established
method
in
early
pregnancy.
population.
Initially the method focused on risk assessment for trisomy
Methods In a prospective study, we evaluated 3094
INTRODUCTION
extended fetuses
to thewith
detection
of trisomies 13
214 – 6 , later consecutive
a crown–rump length (CRL)
and 18. Forofmore
a decade
have11shown
45–84than
mm and
gestationalstudies
age between
+ 0 and
7
–
9
Boris
13 Tutschek
+
6 weeks, using
transabdominal
and transvaginal
and fetal
echocardiography
at
that anomaly
scans
ultrasonography.
The majority
patients diagnostic
were referred
diagnosis may be helpful or even life saving1 – 3 . For cases
the end of
the first trimester
are ofuseful
addition,
a
few
reports
describe
the
tools10 – 12 . In
translucency (NT) thickness, the median maternal age
seems sufficient to arrive at the diagnosis in the second
•  Fehlbildungen von 11 und 13+6
–  Inzidenz 2,8% (86/3094)
–  Erkennungsrate insgesamt 84%
•  bei NT < 2,5mm
14 / 27
•  bei NT >= 2,5mm
58 / 59
52%
98%
consecutive fetuses with a crown–rump length (CRL)
was, however, 35 (range, 15–46) years, and 53.8% of the
half of pregnancy. So the ‘established’ 21–22-week scan is
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
diagnosis may be helpful or even life saving1 – 3 . For cases
percentage
of older mothers
opting
for prenatal
diagnosis.
Correspondence
to:
Prof.
R.
Becker,
Free
University
of
Berlin,
Center
for
Prenatal
Diagnosis,
Kurf
ürstendamm
199,
D-10719
Berlin,
The follow-up rate was 92.7% (3117/3363).
Germany
[email protected])
translucency (NT) thickness, the median maternal
age(e-mail:
seems
sufficient to arrive at the diagnosis in the second
a poor prognosis. The physiological and psychological
Results
The
prevalence
of
major
abnormalities
in
3094
was, however, 35 (range, 15–46) years, and 53.8%
of
the
half
of
pregnancy.
So
the
‘established’
21–22-week
scan
is
Accepted: 26 August 2005
fetuses
was
2.8%
(86/3094).
The
detection
rate
of
major
increasing gestational age, leading to ethical dilemmas
(72/86), 51.9% (14/27) for NT < 2.5 mm and 98.3%
percentage of older mothers opting for prenatal diagnosis.
(58/59)
for
NT
≥
2.5
mm.
The
prevalence
of
major
©
2006
ISUOG.
Published
by
John
Wiley
&
Sons,
Ltd.
O
R
I
G
I
N
A
L
P
A
P
E
R
Copyright
The follow-up rate was 92.7% (3117/3363).
a poor prognosis. The physiological and psychological
Results The prevalence of major abnormalities in 3094
detection rate of major CHD at the 11 to 13 + 6-week
prenatal diagnosis should be to provide as much relevant
fetuses was 2.8% (86/3094). The detection rate of major
scan
was
84.2%
(32/38),
37.5%
(3/8)
for
NT
<
2.5
mm
increasing gestational age, leading to ethical dilemmas
and 96.7% (29/30) for NT ≥ 2.5 mm.
as possible.
(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
has become a well established method in early pregnancy.
including fetal cardiac defects following a specialist scan
at 11 + 0 to 13 + 6 weeks’ gestation is about 84%
detection rate of major CHD at the 11 to 13 + 6-week
prenatal diagnosis should be to provide as much relevant
214 – 6 , later extended to the detection of trisomies 13
and is increased when NT ≥ 2.5 mm. This extends
scan was 84.2% (32/38), 37.5% (3/8) for NT < 2.5 mm
and 18. For more than a decade studies have shown
the possibilities of a first-trimester scan beyond risk
and 96.7% (29/30) for NT ≥ 2.5 mm.
as possible.
that anomaly scans7 – 9 and fetal echocardiography at
assessment for fetal chromosomal defects. In experienced
the end of the first trimester are useful diagnostic
has become a well established method in early pregnancy.
including fetal cardiac defects following a specialist scan
tools10 – 12 . In addition, a few reports describe the
malformations as well as major CHD may be detected
at 11 + 0 to 13 + 6 weeks’ gestation is about 84%
214 – 6 , later extended to the detection of trisomies 13
and is increased when NT ≥ 2.5 mm. This extends
and 18. For more than a decade studies have shown
the possibilities of a first-trimester scan beyond risk
Correspondence to: Prof. R. Becker, Free University of Berlin, Center for Prenatal Diagnosis, Kurfürstendamm 199, D-10719 Berlin,
that anomaly scans7 – 9 and fetal echocardiography at
assessment for fetal chromosomal defects. In experienced
Germany (e-mail: [email protected])
the end of the first trimester are useful diagnostic
tools10 – 12 . In addition, a few reports describe the
malformations as well as major CHD may be detected
• 
• 
• 
• 
• 
Angeborene Fehlbildungen
Chromosomenstörungen
Frühgeburtlichkeit
Geburt
Maternale Erkrankungen
•  Vielen Dank für Ihre Aufmerksamkeit
Copyright © 2006 ISUOG. Published by John Wiley & Sons, Ltd.
ORIGINAL PAPER
Correspondence to: Prof. R. Becker, Free University of Berlin, Center for Prenatal Diagnosis, Kurfürstendamm 199, D-10719 Berlin,
Germany (e-mail: [email protected])
© 2006 ISUOG. Published by John Wiley & Sons, Ltd.
Copyright
Boris
Tutschek
ORIGINAL PAPER
Boris Tutschek
6

Diagnostik in der Früh-Schwangerschaft

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