Cribado primer trimestre. Marcadores ecográficos de primer trimestre y cribado combinado

CRIBADO DE CROMOSOMOPATÍAS
Laura Sotillo Mallo
Marcadores ecográficos del primer trimestre y cribado combinado.

1.  Introducción.
2.  Cribado combinado de primer
trimestre en gestaciones ÚNICAS.
3.  Cribado combinado de primer
trimestre en gestaciones GEMELARES.
4.  Cribado contingente ecográfico.
5.  Recurrencia
Marcadores ecográficos del primer trimestre y cribado combinado. Laura Sotillo Mallo.

CRIBADO/ SCREENING/ TAMIZAJE:
Es la aplicación sistemática de un test para identificar en una población sujetos con un riesgo
suficiente de presentar una enfermedad para la cual no presentan ni síntomas ni signos.
CROMOSOMOPATÍAS:
•  Trisomía 21:
•  Descrito en 1866 por Down: aumento de la piel y ausencia de hueso nasal.
•  Anomalía cromosómica descrita en 1959.
•  Trisomía más frecuente.
•  Prevalencia de 1/740 ( 1974) a 1/540 (1997).
•  Trisomía 18 (Sd de Edward): 1/6,500.
•  Trisomía 13 (Sd de Patau): 1/12.500.
Tipos de cribado:
•  Cribado combinado del primer trimestre.
•  Cuádruple screening (del segundo trimestre).
•  Cribado integrado.
•  Integrado analítico.
•  Contingente.
•  Secuencial.

Cribado combinado de primer trimestre en
gestaciones únicas:

RIESGO COMBINADO
T21,T18,T13
ECO
• TN
• CRL
Analítica/
Bioquímica
• PAPP-A
• β-HCG
Clínicos
• Edad

Edad materna:
ura 4. Riesgo de anomalías cromosómicas en función de la edad materna.
.0 0001
0.001
0.01
0.1
1
10
20 25 30 35 40 44
Edad materna (años)
Riesgo %
Trisomía 21
Trisomía 18
Trisomía 13
XXX/XXY/XYY
45XO
Triploidía
XXX/XXY/XYY
100
Trisomia 21,13 y 18
Turner
Triploidías
Trisomías de los
cromosomas sexuales

Edad materna y
edad gestacional:
Tabla 2. Riesgo estimado para las trisomías 21, 18 y 13 (1/número que aparece en la tabla) en función de la edad materna y la edad gestacional.
Edad Trisomía 21 Trisomía 18 Trisomía 13
Materna Gestación (semanas) Gestación (semanas) Gestación (semanas)
(años)
12 16 20 40 12 16 20 40 12 16 20 40
20 1068 1200 1295 1527 2484 3590 4897 18013 7826 11042 14656 42423
25 946 1062 1147 1352 2200 3179 4336 15951 6930 9778 12978 37567
30 626 703 759 895 1456 2103 2869 10554 4585 6470 8587 24856
31 543 610 658 776 1263 1825 2490 9160 3980 5615 7453 21573
32 461 518 559 659 1072 1549 2114 7775 3378 4766 6326 18311
33 383 430 464 547 891 1287 1755 6458 2806 3959 5254 15209
34 312 350 378 446 725 1047 1429 5256 2284 3222 4277 12380
35 249 280 302 356 580 837 1142 4202 1826 2576 3419 9876
36 196 220 238 280 456 659 899 3307 1437 2027 2691 7788
37 152 171 185 218 354 512 698 2569 1116 1575 2090 6050
38 117 131 142 167 272 393 537 1974 858 1210 1606 4650
39 89 100 108 128 208 300 409 1505 654 922 1224 3544
40 68 76 82 97 157 227 310 1139 495 698 927 2683
41 51 57 62 73 118 171 233 858 373 526 698 2020
42 38 43 46 55 89 128 175 644 280 395 524 1516
éEdad materna é Riesgo de Trisomía 21,18 y 13.
éEdad gestacional êRiesgo de Trisomía 21,18 y 13.
Pérdida 40% Pérdida del 80%
16 La ecografía de las 11–13+6
se
La estimación del riesgo de trisomía 21 al nacimiento en func
de la edad materna se basa en estudios anteriores a la introducc
del diagnóstico prenatal (Hecht y Hook 1994). En los últim
15 años, con la introducción de la bioquímica sérica en san
materna y el cribado ecográfico de anomalías cromosómicas
distintas etapas del embarazo, ha sido necesario establecer ries
Figura 5. Riesgo de anomalías cromosómicas en función de la edad gestacional. Las líneas represent
el riesgo relativo en función del riesgo en la semana 10 de gestación.
Figura 4. Riesgo de anomalías cromosómicas en función de la edad materna.
.0 0001
0.001
0.01
20 25 30 35 40 44
Triploidía
10 15 20 25 30 35 40
Trisomía 21
Trisomía 18
Trisomía 13
Triploidía
XXX/XXY/XYY
45XO
0
20
40
60
80
100
%
Gestación (semanas)
16 La ecografía de las 11–13+6
semanas
La estimación del riesgo de trisomía 21 al nacimiento en función
de la edad materna se basa en estudios anteriores a la introducción
del diagnóstico prenatal (Hecht y Hook 1994). En los últimos
15 años, con la introducción de la bioquímica sérica en sangre
materna y el cribado ecográfico de anomalías cromosómicas en
distintas etapas del embarazo, ha sido necesario establecer riesgos
Figura 5. Riesgo de anomalías cromosómicas en función de la edad gestacional. Las líneas representan
el riesgo relativo en función del riesgo en la semana 10 de gestación.
Figura 4. Riesgo de anomalías cromosómicas en función de la edad materna.
.0 0001
0.001
0.01
0.1
1
10
20 25 30 35 40 44
Trisomía 21
Trisomía 18
Trisomía 13
XXX/XXY/XYY
45XO
Triploidía
10 15 20 25 30 35 40
Trisomía 21
Trisomía 18
Trisomía 13
Triploidía
XXX/XXY/XYY
45XO
0
20
40
60
80
100
%
Gestación (semanas)
Triploidías > R de
pérdida a lo largo de la
gestación por tanto < R
a lo largo de la
gestación.Al contrario
que las trisomías
sexuales.

Riesgo específico de cada paciente.
§  Cada paciente tiene un riesgo a priori determinado por su
edad y la edad gestacional.
§  El riesgo individual se calculará multiplicando ese riesgo a
priori por el cociente de probabilidad (likelihood ratio, LHR)
de cada prueba que se realiza (Ej:TN, Bioquímica).
§  El riesgo obtenido se convertirá en el nuevo riesgo a priori de
la siguiente prueba.
LHR:
Número de fetos aneuploídes
Número de fetos euploídes
Para un determinada medida.
18Laecografíadelas11–13+6
semanas
Tabla 2. Riesgo estimado para las trisomías 21, 18 y 13 (1/número que aparece en la tabla) en función de la edad materna y la edad gestacional.
Edad Trisomía 21 Trisomía 18 Trisomía 13
Materna Gestación (semanas) Gestación (semanas) Gestación (semanas)
(años)
12 16 20 40 12 16 20 40 12 16 20 40
20 1068 1200 1295 1527 2484 3590 4897 18013 7826 11042 14656 42423
25 946 1062 1147 1352 2200 3179 4336 15951 6930 9778 12978 37567
30 626 703 759 895 1456 2103 2869 10554 4585 6470 8587 24856
31 543 610 658 776 1263 1825 2490 9160 3980 5615 7453 21573
32 461 518 559 659 1072 1549 2114 7775 3378 4766 6326 18311
33 383 430 464 547 891 1287 1755 6458 2806 3959 5254 15209
34 312 350 378 446 725 1047 1429 5256 2284 3222 4277 12380
35 249 280 302 356 580 837 1142 4202 1826 2576 3419 9876
36 196 220 238 280 456 659 899 3307 1437 2027 2691 7788
37 152 171 185 218 354 512 698 2569 1116 1575 2090 6050
38 117 131 142 167 272 393 537 1974 858 1210 1606 4650
39 89 100 108 128 208 300 409 1505 654 922 1224 3544
40 68 76 82 97 157 227 310 1139 495 698 927 2683
41 51 57 62 73 118 171 233 858 373 526 698 2020
42 38 43 46 55 89 128 175 644 280 395 524 1516

Bioquímica:
PAPP-A
ü  Las concentraciones
é exponencialmente
durante la gestación.
ü  Los niveles x 2, cada
3-4 días durante el 1T.
}  Glicoproteína producida por sincitotrofoblasto
y por decidua (células de la granulosa,
fibroblastos, osteoblastos, células del musculo
liso vascular).
}  Cromosoma 9q.
}  Niveles BAJOS:
}  Trisomías.
}  Parto prematuro.
}  EHE.
}  CIR/PEG (é biodisponibilidad el IGF).
}  Niveles ALTOS, no se han asociado a ninguna
patología obstétrica.
}  Mejores tasas de detección que la β-HCG.
cytotrophoblasts [17] from where it is secreted without pro-
peptide cleavage. The process of PAPP-A/proMBP complex
formation occurs in the extracellular, probably at the surface
of the syncytiotrophoblast. In normal pregnancy, the con-
centration of PAPP-A in maternal circulation increases with
gestational age. Its concentrationincreases exponentially with
adoublingtimeof3–4 daysduringthefirsttrimesters(Fig. 3),
then the level continues to rise throughout pregnancy until
delivery. The rapid increase in PAPP-A levels during the first
trimester causes the interpretation of a given value to be very
dependentongestationalage.Commonpracticeistherefore to
use the unit multiple of median (MoM) as a gestational age-
dependent expression of PAPP-A concentration. The average
but also in
is also sai
[21]. As
tional-age
are found
complicat
PAPP-A a
tion, ges
with prote
Studies
growth fa
serum lev
abortion i
serum PA
cental sy
expression
drome pl
serum an
Down’s p
decrease
and may
releasing
of the sec
nificantly
A values
No signifi
with elev
able level
females. I
Fig. 3 Exponential rise of PAPP-A in the first trimester of normal
pregnancy
6
REVIEW ARTICLE
First Trimester Maternal Serum Screening Using Biochemical
Markers PAPP-A and Free b-hCG for Down Syndrome, Patau
Syndrome and Edward Syndrome
S. Shiefa • M. Amargandhi • J. Bhupendra •
S. Moulali • T. Kristine
Received: 8 July 2012/ Accepted: 30 September 2012/ Published online: 12 October 2012
Ó Association of Clinical Biochemists of India 2012
Abstract The first trimester screening programme offers a
noninvasive option for the early detection of aneuploidy
pregnancies. This screening is done by a combination of two
biochemical markers i.e. serum free b-human chorionic
gonadotrophin (free b-hCG) and pregnancy associated
of first trimester maternal serum screening programs is to
identify women at increased risk of having a baby affected
with Down syndrome, Patau syndrome, and Edward syn-
drome defects and those that will benefit from the testing.
The association between advancing maternal age [1] and
Ind J Clin Biochem (Jan-Mar 2013) 28(1):3–12
DOI 10.1007/s12291-012-0269-9

Bioquímica:
La concentración alcanza un
pico máximo entre la semana
8-10 de gestación y luego
disminuye sus niveles hasta la
semana 20-22 cuando se
alcanza una meseta.
freeβ-HCG:
[31]. These observations are supported by the relative
immaturity of the placenta, which continues to release
large amounts of hCG as in the first trimester [32].
within short time of obtaining a blood sample makes it
possible to combine biochemical and ultrasonographic
testing for early assessment so that patients assessment and
stress may be reduced. Separation of the sera for Down
syndrome screening in 4 h after withdrawal is necessary.
Cooling during any storage, including transportation is
highly recommended as the preanalytical phase has a high
impact for the analysis.
Serum samples for free b-hCG and PAPP-A are stable at
4 °C for whole blood or separated serum for 1 week. Reliable
results are obtained if separated serum samples are stored at
20 °C up to 2 days and 1 day for whole blood. At 30 °C
reliable results were obtained only if the samples were ana-
lyzed within 2 h collection.
In whole blood, free b-hCG levels increased more rapidly
compared to serum, especially at 30 °C [33]. Several studies
have reported that a high storage temperature and a long
interval between collection and analysis of the sample pro-
duce an increase in the concentration of free b-hCG because it
is liberated by the dissociation or degradation of intact hCG
[34]. In whole blood kept at room temperature, the mean
serum concentration of free b-hCG was reported to increase
by 10–15 % after 24 h, by about 25 % after 3 days and by
45 % after 4 days [34]. Another study showed that PAPP-A
Fig. 6 Total hCG and free beta hCG during first trimester of
pregnancy
REVIEW ARTICLE
First Trimester Maternal Serum Screening Using Biochemical
Markers PAPP-A and Free b-hCG for Down Syndrome, Patau
Syndrome and Edward Syndrome
S. Shiefa • M. Amargandhi • J. Bhupendra •
S. Moulali • T. Kristine
Received: 8 July 2012/ Accepted: 30 September 2012/ Published online: 12 October 2012
Ó Association of Clinical Biochemists of India 2012
Abstract The first trimester screening programme offers a of first trimester maternal serum screening programs is to
DOI 10.1007/s12291-012-0269-9
•  HCG proteína producida por el sincitotrofoblasto,
formado por dos subunidades:
•  α
•  Cromosoma 6.
•  Compartida con la FSH, LH y TSH.
•  β
•  Cromosoma 19.
•  Única, no compartida con otras
glicoproteínas.
•  Funciones:
•  Supresión del sistema inmune materno.
•  Desarrollo del sincitotrofoblasto.
•  Niveles BAJOS:
•  Trisomías 18 y 13.
•  Niveles ALTOS:
•  Trisomía 21.

Medición de la bioquímica
MoM: Múltiplos de la Media
MoM:
Concentración media en la población euploide de la misma EG.
Concentración de la glicoproteína en nuestra paciente
Ventaja de los MoMs con respeto a valores absolutos:
1)  Las concentraciones de la PAPP-A y la β-HCG se modifican con la edad
gestacional.
2)  Se puedan interpretar igualmente resultados de diferentes laboratorios.

Bioquímica:
In unaffected pregnancies, the median free b-hCG was 1.0
MoM (range 0.03–30.4) and the median PAPP-A was 1.0
MoM (range 0.02–7.9), in the trisomy 21 pregnancies the
median free b-hCG was 2.0 MoM (range 0.1–11.3) and
the median PAPP-A was 0.5 MoM (range 0.05–2.2), in the
trisomy 18 pregnancies the median free b-hCG was 0.2
MoM (range 0.02–4.7) and the median PAPP-A was 0.2
MoM (range 0.03–4.1) and in the trisomy 13 pregnancies the
dian
8
4
0
4
Figure 2: Distribution of MoM values of free b-hCG and of PAPP-A
in normal fetuses (dark shaded ellipse), and fetuses with trisomies 21,
18 and 13 (open ellipses containing 90% of cases).
2.2)
5)
%)
%)
%)
4.0)
%)
http://humrep.oxfordjournals.Downloadedfrom
Screening for trisomies 21, 18 and 13 by maternal age,
fetal nuchal translucency, fetal heart rate, free b-hCG
and pregnancy-associated plasma protein-A
Karl O. Kagan1,2,4, Dave Wright3, Catalina Valencia1, Nerea Maiz1 and Kypros H. Nicolaides1,4
1
Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital, Denmark Hill, London SE5 8RX, UK; 2
Department of
Obstetrics and Gynaecology, University of Tuebingen, Germany; 3
Department of Mathematics and Statistics, University of Plymouth, UK
4
Correspondence address. E-mail: kypros@fetalmedicine.com.
BACKGROUND: A beneﬁcial consequence of screening for trisomy 21 is the early diagnosis of trisomies 18 and 13.
Our objective was to examine the performance of ﬁrst-trimester screening for trisomies 21, 18 and 13 by maternal age,
fetal nuchal translucency (NT) thickness, fetal heart rate (FHR) and maternal serum-free b-hCG and pregnancy-
associated plasma protein-A (PAPP-A). METHODS: Prospective screening for trisomy 21 by maternal age, fetal
NT, free b-hCG and PAPP-A at 1110
–1316
weeks in singleton pregnancies, including 56 376 normal cases, 395
with trisomy 21, 122 with trisomy 18 and 61 with trisomy 13. Risk algorithms were developed for the calculation
Human Reproduction Vol.23, No.9 pp. 1968–1975, 2008 doi:10.1093/humrep/den224
Advance Access publication on June 10, 2008
hDownloadedfrom
Aneuplodía Freeβ-HCG PAPP-A
T21 éé ê
T18 êê êê
T13 ê ê
Turner = ê
Triploidía materna êêê êêê
Triploidía paterna éééé ê
s. In a study done by Spencer et al.
rst trimester biochemical marker
n (Indian, Pakistan, Bangladesh)
In screening for trisomy 21 by maternal age and serum free
b-hCG and PAPP-A, the detection rate is about 65 % for a
false-positive rate of 5 %. The performance is better at
-
Aneuploidy NT Free b-hCG PAPP-A Detection rate (%)
Trisomy 21 2.67 MOM 2.15 MOM 0.15 MOM 90
45, x 4.76 MOM 1.11 MOM 0.49 MOM [90
Triploidy maternal 0.88 MOM 0.18 MOM 0.06 MOM [90
Triploidy paternal 2.76 MOM 8.04 MOM 0.75 MOM [90

Analítica ¿Cuándo?:
Ultrasound Obstet Gynecol 2008; 31: 618–624
Published online 6 May 2008 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.5331
Screening for trisomy 21 by maternal age, fetal nuchal
translucency thickness, free beta-human chorionic
gonadotropin and pregnancy-associated plasma protein-A
K. O. KAGAN*†, D. WRIGHT‡, A. BAKER‡, D. SAHOTA§ and K. H. NICOLAIDES*
*Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital, London and ‡Department of Mathematics and Statistics,
University of Plymouth, Plymouth, UK, †Department of Obstetrics and Gynecology, University of Tuebingen, Tuebingen, Germany and
§Department of Obstetrics and Gynecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
KEYWORDS: first-trimester screening; free β-hCG; nuchal translucency; PAPP-A; trisomy 21
ABSTRACT
Objectives To derive a model and examine the perfor-
mance of first-trimester combined screening by mater-
nal age, fetal nuchal translucency (NT) thickness and
maternal serum free beta-human chorionic gonadotropin
(β-hCG) and pregnancy-associated plasma protein-A
(PAPP-A).
Methods Prospective combined screening for trisomy 21
was carried out at 11 + 0 to 13 + 6 weeks in 56 771
singleton pregnancies, including 56 376 cases with a
normal karyotype or delivery of a phenotypically normal
baby (unaffected group) and 395 cases with trisomy
21. The blood test and ultrasound scan were carried
out in the same visit. In each case the maternal age-
related risk for trisomy 21 at term was calculated and
adjusted according to the gestational age at the time of
screening to derive the a-priori risk. The measured NT
Results The performance of screening based on the
model was in good agreement with that observed in
our population. In a strategy for first-trimester combined
screening where the blood test and scan are carried out in
the same visit it was estimated that, for false-positive rates
of 3% and 5%, the detection rates were 92% and 94%,
respectively, at 11 weeks, 85% and 90% at 12 weeks, and
79% and 83% at 13 weeks. In an alternative strategy,
with the blood taken at 10 weeks and the measurement of
NT performed at 12 weeks, the estimated detection rates
were 94% and 96% for false-positive rates of 3% and
5%, respectively.
Conclusions The aim of the first-trimester scan is not just
to screen for trisomy 21 but also to diagnose an increasing
number of fetal malformations. In this respect the ability
to visualize fetal anatomy is better at 12–13 weeks
than at 11 weeks. Consequently, the ideal gestation for
combined testing in the same visit would be 12 weeks.
screening in terms of detection rate may be eroded by the
likely increased non-compliance with the additional step.
Another element to be considered in terms of alternative
policies of early screening is the contribution of additional
sonographic markers, such as absent nasal bone, wide
frontomaxillary facial angle, reversed end-diastolic flow
in the ductus venosus and tricuspid regurgitation, which
sonographic markers of chromosomal abnormalities. Am J
Obstet Gynecol 2004; 191: 45–67.
5. Wright D, Kagan KO, Molina FS, Gazzoni A, Nicolaides KH.
A mixture model of nuchal translucency thickness in screening
for chromosomal defects. Ultrasound Obstet Gynecol 2008; 31:
376–383.
6. Kagan KO, Wright D, Spencer K, Molina FS, Nicolaides KH.
First-trimester screening for trisomy 21 by free beta-human
chorionic gonadotropin and pregnancy-associated plasma
Table 5 Estimated detection rates of trisomy 21 from different policies on screening according to the timing of biochemical testing and
ultrasound scanning
Detection rate (%)
Scan and blood at same visit Scan 12 weeks Scan 13 weeks
False-positive
rate (%) 11 weeks 12 weeks 13 weeks Blood 10 weeks Blood 11 weeks Blood 10 weeks Blood 11 weeks
1 83 76 69 88 81 85 78
2 88 83 75 92 87 90 83
3 92 85 79 94 89 92 86
4 93 88 81 95 91 94 88
5 94 90 83 96 92 95 90
10 97 94 89 98 96 97 94
Copyright © 2008 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2008; 31: 618–624.Screening combinado en dos
etapas:
-Analítica: 9-10 semanas
-Ecografías: 12-13 semanas.
Pasamos de TD ≈ 90% a TD ≈ 95%.
Las diferencias en los niveles de PAPP-A
entre los fetos trisómicos y los euploides es
mayor a edades gestacionales menores.Y
aunque las diferencias en los niveles de β-
HCG aumenta con las gestación. Esta
diferencia es de menor magnitud que la de
PPAP-A.

Translucencia Nucal
}  Acumulo de líquido en tejido
subcutáneo en el cuello fetal
(tabicado o no).
}  Marcador más eficaz en la
detección de aneuploidías.
}  Aumenta con la edad gestacional
(17%/semana). Importante una
correcta DATACIÓN-CRL.
AUMENTADA:
§  Cromosomopatías:T21,Turner.
§  Sd genéticos:
§  Smith Lemli Opitz.
§  Noonan.
§  Akinesia fetal.
§  Malformaciones: Cardiopatías.
§  Infecciones: PVB19.
§  Mal resultado perinatal. Retraso
psicomotor.
MAYOR TN MAYORES RIESGOS Souka AP,Am J Obstet Gynecol. 2005 Apr;192(4):1005-21.

Medición de la TN:
}  CRL 45-84 mm.
}  Mediana: 1,2 mm y 1,9.
}  Percentil 95: 2,1mm y 2,7 mm.
}  Plano sagital medio.
}  Posición neutra. (Flexión <0,4
mm, Extensión >0,6 mm).
}  Magnificación de la cabeza y 1/3
superior tórax.
}  Máximo grosor. Bajar ganancia.
}  En caso de circular medir a un
lado y al otro y coger la media.
}  Diferenciar el amnios de la TN.
}  Realizar varias medidas,
quedarnos con la MAYOR.
ON TO ON
Cálipers sobre las líneas

Tasa de detección de T21 (TFP
5%),T18 y T13 (TFP 0,5%).
T21 T18 T13
81 68 61
67 80 59
91 97 84
Screening for trisomies 21, 18 and 13 by maternal age,
fetal nuchal translucency, fetal heart rate, free b-hCG
and pregnancy-associated plasma protein-A
Karl O. Kagan1,2,4, Dave Wright3, Catalina Valencia1, Nerea Maiz1 and Kypros H. Nicolaides1,4
1
Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital, Denmark Hill, London SE5 8RX, UK; 2
Department of
Obstetrics and Gynaecology, University of Tuebingen, Germany; 3
Department of Mathematics and Statistics, University of Plymouth, UK
4
Correspondence address. E-mail: kypros@fetalmedicine.com.
BACKGROUND: A beneﬁcial consequence of screening for trisomy 21 is the early diagnosis of trisomies 18 and 13.
Our objective was to examine the performance of ﬁrst-trimester screening for trisomies 21, 18 and 13 by maternal age,
fetal nuchal translucency (NT) thickness, fetal heart rate (FHR) and maternal serum-free b-hCG and pregnancy-
associated plasma protein-A (PAPP-A). METHODS: Prospective screening for trisomy 21 by maternal age, fetal
NT, free b-hCG and PAPP-A at 1110
–1316
weeks in singleton pregnancies, including 56 376 normal cases, 395
with trisomy 21, 122 with trisomy 18 and 61 with trisomy 13. Risk algorithms were developed for the calculation
Human Reproduction Vol.23, No.9 pp. 1968–1975, 2008 doi:10.1093/humrep/den224
Advance Access publication on June 10, 2008
httpDownloadedfrom
§  Edad materna sólo 30% de Detección.
§  TN mayor poder de detección que la
Bioquímica.
§  Cribado combinado Tasa de detección
superior al 90%, Falsos positivos del 5%.
§  Mayor tasa de detección de T18 que de T13.

1
Sociedad Española de Ginecología y Obstetricia
Pº de la Habana, 190 Bajo (28036) Madrid. E-mail: sego@sego.es | Tel.: 91 350 98 16 | Fax: 91 350 98 18
Diagnóstico prenatal de los defectos congénitos.
Cribado de las anomalías cromosómicas.
actualizad en noviembre de 2010
1. DEFINICIÓN
El término "diagnóstico prenatal" agrupa todas aquellas acciones
diagnósticas encaminadas a descubrir durante el embarazo un "defecto
congénito", entendiendo por tal "toda anomalía del desarrollo
morfológico, estructural, funcional o molecular presente al nacer
(aunque puede manifestarse más tarde), externa o interna, familiar o
esporádica, hereditaria o no, única o múltiple" (Comités de Trabajo de
la OMS, 1970, 1975, 1982).
El diagnóstico prenatal tiene como finalidad diagnosticar con la mayor
precocidad posible un defecto congénito o bien establecer la ausencia
del mismo, ya que la confirmación de la normalidad contribuye a
reducir la ansiedad materna durante el resto de la gestación.
2. ÁMBITO DEL DIAGNÓSTICO PRENATAL
Alrededor del 3% de nacidos vivos presentan algún tipo de anomalía,
pero esta cifra se incrementa hasta el 4-7% al año de vida. De acuerdo
con la causa subyacente se distinguen en la práctica:
• Enfermedades hereditarias mendelianas o monogénicas, presentes
en el 1-1.5% de nacidos y responsables de alrededor del 25% de las
anomalías. Los mecanismos de transmisión responden a su carácter
recesivo, dominante, autosómico o ligado a los cromosomas
sexuales. Aunque individualmente son poco frecuentes, en conjunto
incluyen un gran número de errores metabólicos congénitos,
aunque sus frecuencias varían en distintas poblaciones. En nuestro
medio se dan con mayor frecuencia relativa la fibrosis quística,
distrofia miotónica, riñón poliquístico y neurofibromatosis. El riesgo de
recurrencia oscila entre el 25-50%.
principales ventajas son su elevada sensibilidad y la precocidad con la
que permite conocer qué gestaciones son de alto riesgo. De esta
manera abre la posibilidad tanto de aplicar técnicas invasivas de
manera precoz, principalmente la biopsia corial, como de interrumpir las
gestaciones afectas de manera precoz. Este cribado debe ser ofrecido
a todas las gestantes, independientemente de su edad, puesto que la
edad materna ya entra como variable en el programa de cálculo. De
existir algún factor de riesgo preconcepcional que haga recomendable
la realización de una técnica invasiva, la realización previa del cribado
combinado, aunque es opcional, sí es recomendable dada la
información que proporciona.
Figura1. Algoritmodel cribado combinadode I trimestre
Día0: información sobre el cribado.
Día1: (entre 11 - 13+6 semanas)
• extracción de sangre: fβ-HCG+PAPP-A.
• ecografía: TN y edad gestacional.
Estimación del riesgo combinado clínico-bioquímico-ecográfico
<1/250-300 ≥ 1/250-300
Seguimiento normal
Ofrecer técnicainvasiva
(ver apartado de métodosinvasivos)
Consentimiento Informado
Día0: información sobre el cribado.
Día1: (entre 8 - 13+6 semanas)
• extracción de sangre: fβ-HCG+PAPP-A.
Día2: (entre 11+0 - 13+6 semanas)
• ecografía: TN y edad gestacional.
Cribadocombinadoen un tiempo Cribadocombinadoen dostiempos
El cálculo del riesgo del cribado combinado del I trimestre se establece
teniendo en cuenta los valores obtenidos en la determinación de los
marcadores bioquímicos y el valor de la TN obtenida por ecografía. Tal y
NO EXITE UNIFORMIDAD EN EL
PUNTO DE CORTE.

GESTACIONES
GEMELARES:
BICORIALES
Riesgo
INDIVIDUAL
para cada feto.
Cada feto su CRL
y su TN.
RIESGO FETAL ESPECÍFICO
MONOCORIALES
Slo se emite UN
riesgo.
CRL mayor y
Media de las TN.
RIESGO
GESTACIONAL
UN solo feto
evolutivo.
SÍ
Riesgo por TN
NO botón
embrionario
Igual que una
gestación única.Gestaciones >2.

CRIBADO CONTINGENTE DEL 1ER TRIMESTRE
CRIBADO COMBINADO: EDAD + TN + BIOQUÍMICA
<1/1000 1/101-1/1000 ≥1/100
Riesgo bajo Riesgo intermedio Riesgo alto
HN IT DV
1 Patológico
3 OK
Técnica
invasiva

Cribado contingente:
¿Por qué si uno positivo ofrecer técnica invasiva?
1/1000 Falta de Hueso nasal: 1/1000 x 3,9 = 1/256.
¿Por qué si los tres negativos no técnica invasiva?
1/101 y todos negativos: 1/101 x 0.82 x 0.49 x 0.53: 1/100 X 0.21= 1/480.
Si los tres negativos para recalcular el riesgo x 0,21
E-Mail karger@karger.com
Original Paper
Fetal Diagn Ther 2013;34:116–120
DOI: 10.1159/000351854
Likelihood Ratios to Apply for Nasal Bone, Ductus
Venosus and Tricuspid Flow at the 11–13 Weeks’
Scan in Down Syndrome Screening
Miriam Illa Raquel Mula Marta Arigita Maribel Grande Anna Gonce
Virginia Borobio Antoni Borrell
Department of Maternal-Fetal Medicine (Institut Clínic de Ginecologia, Obstetrícia i Neonatologia),
Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Catalonia, Spain
tion of NB, DV and TF likelihood ratios to the combined test
risk, either in an expanded or contingent strategy, result in a
FPR reduction. Copyright © 2013 S. Karger AG, Basel
Introduction
In the last decade, the first trimester combined test,
based on maternal serum Pregnancy Associated Plasma
Protein A (PAPP-A), free-β human chorionic gonadotro-
phin (fβ-hCG) and fetal nuchal translucency (NT), has
become the standard of care in Down syndrome screen-
ing in many countries and regions. For a 3–5% false pos-
itive rate, the combined test can identify up to 90% of all
fetuses with trisomy 21 [1–3]. Adding first trimester ul-
trasound markers other than NT, such as the nasal bone
(NB), ductus venosus (DV) and tricuspid flow (TF), has
been demonstrated to improve the screening perfor-
mance of the combined test [4–10]. They can be concur-
rently assessed in all pregnancies (expanded combined
test), or sequentially in selected pregnancies, with either
lower (stepwise sequential screening) or intermediate
risk (contingent screening) [11–13]. Typically these ad-
ditional markers may decrease the false positive rate re-
sulting from the combined test [14, 15].
The purpose of the present study was to evaluate the
feasibility and efficacy of the NB, DV and TF in Down
Key Words
Antenatal screening · Down syndrome · Ductus venous ·
Fetal nuchal translucency · First trimester · Noninvasive
prenatal diagnosis · Ultrasound screening · Ultrasound
markers · Nasal bone · Tricuspid flow
Abstract
Objective: To assess the feasibility of nasal bone (NB), ductus
venosus (DV) and tricuspid flow (TF) at the 11–13 weeks’
scan, calculate likelihood ratios for each of the markers and
evaluate their efficacy in expanded and contingent screen-
ing strategies for Down syndrome. Material and Methods:
NB, DV and TF were assessed in 11,261 singleton fetuses un-
dergoing first trimester combined screening. For each mark-
er, Down syndrome detection rate (DR), false positive rate
(FPR), positive, negative and isolated likelihood ratios (PLR,
NLR and iLR) were calculated. Likelihood ratios were multi-
plied to the combined test risk either to the entire popula-
tion or to the intermediate risk group (expanded and se-
quential strategies, respectively). Results: Down syndrome
was diagnosed in 101 pregnancies. Feasibility for marker as-
sessment ranged from 71 to 97%, DRs for isolated markers
from 20 to 54% and FPRs from 1.3 to 5.3%. PLR ranged from
10 to 15, NLR from 0.5 to 0.8 and iLR from 3.9 to 5.6. When
ultrasound markers were added to both strategies, a signifi-
cant FPR reduction was observed. Conclusion: The applica-
Received: January 24, 2013
Accepted after revision: April 23, 2013
Published online: June 27, 2013
Antoni Borrell, MD, PhD
Senior Consultant in Fetal Medicine, Maternal-Fetal Medicine Department
Hospital Clinic – Universitat de Barcelona, Sabino de Arana 1
ES–08028 Barcelona, Catalonia (Spain)
E-Mail aborrell @ clinic.cat
© 2013 S. Karger AG, Basel
1015–3837/13/0342–0116$38.00/0
www.karger.com/fdt
The trisomy 21 DR achieved by each ultrasound markers
were: 20% for NB, 54% for DV, and 49% for TF, all below
the 69% NT DR observed in our series. The correspond-
ing FPR for each marker were 1.3, 5.8 and 3.4%. PLR
ranged from 10 to 15, whereas NLR from 0.5 to 0.8. The
resulting iLR were 3.9, 4.4 and 5.8, respectively (table 1).
The combined test selected 92% of the Down syn-
drome fetuses, and 6.9% of the euploid pregnancies. The
addition of the studied ultrasound markers to the com-
bined test in the entire study population (expanded com-
bined screening) and in the intermediate risk group (con-
tingent strategy) resulted in a significant FPR decrease,
maintaining a similar DR (table 2). Among the different
NT (NB, DV and TF). We aimed to apply these likeli-
hood ratios when pregnant women request further in-
formation after the first trimester combined test (name-
ly advanced maternal age, assisted reproduction, bor-
derline risk) to refine risk estimation and no appropriate
software is available. In those pregnancies, we suggest
using the same methodology that Nicolaides [20, 21]
proposed for second trimester ultrasound markers, ap-
plying positive and negative likelihood ratios for each of
the markers.
Individual Performance and the Likelihood ratios of
each Marker
In our series, we obtained DR for the 3 studied mark-
ers in the lower range of previously described results.
Hence, DR for Doppler markers were lower (54% DV and
49% TR) than previously described (65–70%) [6, 7, 10],
while FPR were similar (5.3% DV and 3.4% TR) [9, 19].
The marker with the lowest DR was observed for NB (20
vs. 50–60% reported in literature) [4, 22], although the
FPR was also lower (1.3 vs. 2.5% described by Kagan and
co-workers [8]). Low DRs may be explained by the fact
that 18 different sonologists (the entire Ultrasound Unit)
participated to the present study, in contrast to our previ-
ous studies conducted in a highly experienced unit (Pre-
natal Diagnosis Unit). Focusing on NB remarkably low
DR, three facts may explain why in our center and in oth-
er reported studies [24], DR is well below 50%. Firstly, it
is highly dependent on fetal position. In our center, we
are unable to reschedule pregnancy scans exclusively for
NB assessment. This may be a crucial factor in the com-
parison with other centers with better rates. Secondly,
there is a known overlap between those fetuses where the
NB ‘cannot be examined’ (due to the presence of the mid-
line gap [23], inappropriate insonation angle or subopti-
mal ultrasound visualization) and those that are ‘absent’.
A third specific limitation for NB assessment is its ethni-
Table 1. Detection and False Positive Rates (with 95% confidence
intervals), and Positive and Negative Likelihood Ratios obtained
by NB, DV and TF together with Nuchal Translucency. Isolated
Likelihood Ratios are calculated with the Positive Likelihood Ra-
tios of the marker and the Negative Likelihood Ratios of the re-
maining two markers
Detection
rate
False
positive rate
PLR NLR iLR
Nuchal translucency
Rate 69% (68/99) 5.0% (549/11,014) – – –
95% CI 60–78 4.6–5.4
Nasal bone
Rate 20% (15/77) 1.3% (108/8,506) 15 0.82 3.9
95% CI 11–28 10.5–14.9
Ductus venosus
Rate 54% (50/93) 5.3% (572/10,830) 10.2 0.49 4.4
95% CI 44–64 4.9–5.7
Tricuspid flow
Rate 49% (17/35) 3.4% (37/1,078) 14.3 0.53 5.8
95% CI 32–65 2.4–4.5
PLR = Positive likelihood ratio; NLR = negative likelihood ra-
tios; iLR = isolated likelihood ratio.

DUCTUS VENOSO:
}  Un vaso venoso que conecta la
vena umbilical con la vena cava
inferior.
}  ¿Cómo medirlo?
}  CRL 45-84 mm.
}  Corte parasagital derecho.
}  Magnificación: torax y abdomen.
}  Doppler color: seguir la vena
umbilical y ALIASING.
}  Ventana del doppler pulsado de
1 mm.
}  Ángulo de insonación <30º.
}  Filtro de baja frecuencia
(50-70 Hz) para visualizar toda
la onda.
}  Velocidad de barrido: Alta
2-3 cm/s.
PATOLÓGICA: “onda a”
AUSENTE O REVERSA

INSUFICIENCIA TRICUSPÍDEA:
}  ¿Cómo medirla?
}  CRL 45-84 mm.
}  Feto en reposo.
}  Torax fetal ocupar toda la
pantalla.
}  Corte de 4 C apical o basal.
}  Ángulo de insonación con
respecto al tabique
interventricular debe ser
inferior a 30º.
}  Ayuda del Doppler
COLOR.
}  Ventana 2-3 mm, colocación
transvalvular.
}  Velocidad de barrido alta 2-3
cm/s.
}  Varías mediciones (3).
Basal
Apical
PATOLÓGICO:
Flujo retrógrado
-Más de la mitad de la sístole.
->60 cm/s

HUESO NASAL:
}  ¿Cómo medirla?
}  CRL 45-84 mm.
}  Magnificación de la cabeza y el tórax
superior.
}  Plano sagital medio dorso posterior del
perfil fetal.
}  Sonda paralela al hueso (ángulo de
insonación del 90º) y mover el
transductor lateralmente a ambos lados.
}  Visualización: TRES LÍNEAS.
}  SIGNO IGUAL
}  Línea superior: piel de la nariz.
}  Línea inferior más gruesa y ecogénica es el
hueso.
}  Tercera línea enfrente del hueso y
superior que es el punto de la naríz
PATOLÓGICO: ausente o inferior
ecogenicidad a la piel.
Si 11-12 semanas reevalorar en 1 sem.

Cribado contingente:
Reduce a la mitad el nº de técnicas invasivas.
Aé TD (95%), êêFP (2,5%)
DV, IT, HN En 1/101-1/1000.
Cribado contingente.
Cribado combinado Tasa de detección de 90% FP5%.
CRL 45-84 mm

RECURRENCIA:
Dra. García de Santiago
Dra. Mansilla Aparicio

RESEARCH ARTICLE
Recurrence Risks for Trisomies 13, 18, and 21
Elizabeth De Souza,1
Jane Halliday,2
Annabelle Chan,3
Carol Bower,4
and Joan K. Morris1
*
1
Barts & The London School of Medicine and Dentistry, Queen Mary University of London, Wolfson Institute of Preventive Medicine, London, UK
2
Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia
3
South Australian Birth Defects Register, Children, Youth and Women’s Health Service, North Adelaide, South Australia
4
Birth Defects Registry of Western Australia and the Telethon Institute for Child Health Research, Centre for Child Health Research,
University of Western Australia, West Perth, Western Australia
Received 25 June 2009; Accepted 17 August 2009
the earliest and then latest maternal date of birth to be correct in the
seven women whose birth dates differed by more than a year left the
relative risks unaltered to one decimal place. Similarly, assuming
trisomic pregnancy data to be correct in BDRWA records with
inconsistent maternal dates of birth rather than using their modes
and means left relative risks unchanged to one decimal place.
As expected, there was signiﬁcant evidence that women with a
previous trisomy 21 pregnancy have greater risk of a future trisomy
21pregnancy,RR ¼ 2.295%CI(1.6,2.9)(seeTableIV).Therewasa
suggestion that the risk of a subsequent pregnancy being affected by
trisomy 13 after a previous trisomy 21 pregnancy was increased
(RR ¼ 2.0), and that the risk of subsequent trisomy 18 was also
was evidence that women who have had a pregnancy with either
trisomy 13 or 18 were at greater risk of the same trisomy recurring,
RR ¼ 3.8, 95% CI (1.5, 7.9). The risk of a woman with a previous
trisomy 13 or 18 pregnancy having a future pregnancy affected by a
different trisomy did not appear to be elevated, RR ¼ 1.1.
Table V shows the relative risks according to the age of the
mother at the previous trisomic pregnancy. The relative risk of
trisomy 21 subsequent to trisomy 21 was greater for women under
35 years at the previous pregnancy, as was the risk of the same
trisomy and of a different trisomy subsequent to trisomy 13 or 18.
The relative risks of a different trisomy subsequent to trisomy 21
were similar for women under 35 and women 35 and over at their
T13 199 2 1 1 257 0 1 0 56
T18 314 0 2 2 385 0 0 0 81
T21 1,242 2 1 14 1,381 0 1 6 437
All 1,755 4 4 17 2,023 0 2 6 574
a
Regardless of outcome/time at outcome.
TABLE IV. Observed and Expected Numbers of Subsequent Trisomic Pregnancies, and Relative Risk, by Trisomy in Previous and Subsequent
Pregnancies
Previous trisomy Subsequent trisomy Observed numbera
Expected number Relative risk (95% CI)
Raw data
T13 T13 1.9 0.2 9.5 (1.1, 35.3)
T18 2.0 0.6 3.3 (0.4, 12.0)
T21 1.0 2.0 0.5 (0.0, 2.8)
T18 T13 0.0 0.5 0
T18 4.9 1.6 3.1 (1.0, 7.2)
T21 5.9 4.8 1.2 (0.4, 2.7)
T21 T13 3.9 2.0 2.0 (0.5, 5.0)
T18 7.8 6.2 1.3 (0.5, 2.5)
T21 42.8 19.6 2.2 (1.6, 2.9)
Grouped data
T13 or T18 Same 6.8 1.8 3.8 (1.5, 7.9)
Different 8.9 7.9 1.1 (0.5, 2.1)
T21 Same 42.8 19.6 2.2 (1.6, 2.9)
Different 11.7 8.2 1.4 (0.7, 2.5)
a
After adjustment for terminations before 15 weeks.
El AP de trisomía 13 o 18 NO aumenta el riesgo de T21 en
subsiguientes gestaciones.
Recurrencia:

RESEARCH ARTICLE
Recurrence Risks for Trisomies 13, 18, and 21
Elizabeth De Souza,1
Jane Halliday,2
Annabelle Chan,3
Carol Bower,4
and Joan K. Morris1
*
1
Barts & The London School of Medicine and Dentistry, Queen Mary University of London, Wolfson Institute of Preventive Medicine, London, UK
2
Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia
3
South Australian Birth Defects Register, Children, Youth and Women’s Health Service, North Adelaide, South Australia
4
Birth Defects Registry of Western Australia and the Telethon Institute for Child Health Research, Centre for Child Health Research,
the earliest and then latest maternal date of birth to be correct in the
seven women whose birth dates differed by more than a year left the
relative risks unaltered to one decimal place. Similarly, assuming
trisomic pregnancy data to be correct in BDRWA records with
inconsistent maternal dates of birth rather than using their modes
and means left relative risks unchanged to one decimal place.
As expected, there was signiﬁcant evidence that women with a
previous trisomy 21 pregnancy have greater risk of a future trisomy
21pregnancy,RR ¼ 2.295%CI(1.6,2.9)(seeTableIV).Therewasa
suggestion that the risk of a subsequent pregnancy being affected by
trisomy 13 after a previous trisomy 21 pregnancy was increased
(RR ¼ 2.0), and that the risk of subsequent trisomy 18 was also
was evidence that women who have had a pregnancy with either
trisomy 13 or 18 were at greater risk of the same trisomy recurring,
RR ¼ 3.8, 95% CI (1.5, 7.9). The risk of a woman with a previous
trisomy 13 or 18 pregnancy having a future pregnancy affected by a
different trisomy did not appear to be elevated, RR ¼ 1.1.
Table V shows the relative risks according to the age of the
mother at the previous trisomic pregnancy. The relative risk of
trisomy 21 subsequent to trisomy 21 was greater for women under
35 years at the previous pregnancy, as was the risk of the same
trisomy and of a different trisomy subsequent to trisomy 13 or 18.
The relative risks of a different trisomy subsequent to trisomy 21
were similar for women under 35 and women 35 and over at their
T13 199 2 1 1 257 0 1 0 56
T18 314 0 2 2 385 0 0 0 81
T21 1,242 2 1 14 1,381 0 1 6 437
All 1,755 4 4 17 2,023 0 2 6 574
a
Regardless of outcome/time at outcome.
TABLE IV. Observed and Expected Numbers of Subsequent Trisomic Pregnancies, and Relative Risk, by Trisomy in Previous and Subsequent
Pregnancies
Previous trisomy Subsequent trisomy Observed numbera
Expected number Relative risk (95% CI)
Raw data
T13 T13 1.9 0.2 9.5 (1.1, 35.3)
T18 2.0 0.6 3.3 (0.4, 12.0)
T21 1.0 2.0 0.5 (0.0, 2.8)
T18 T13 0.0 0.5 0
T18 4.9 1.6 3.1 (1.0, 7.2)
T21 5.9 4.8 1.2 (0.4, 2.7)
T21 T13 3.9 2.0 2.0 (0.5, 5.0)
T18 7.8 6.2 1.3 (0.5, 2.5)
T21 42.8 19.6 2.2 (1.6, 2.9)
Grouped data
T13 or T18 Same 6.8 1.8 3.8 (1.5, 7.9)
Different 8.9 7.9 1.1 (0.5, 2.1)
T21 Same 42.8 19.6 2.2 (1.6, 2.9)
Different 11.7 8.2 1.4 (0.7, 2.5)
a
After adjustment for terminations before 15 weeks.
El riesgo de recurrencia de la MISMA trisomía siempre es mayor que
el de otra trisomía.
El riesgo de recurrencia de la misma trisomía es mayor cuanto más
rara es la trisomía (T13>T18>T21).
Recurrencia:

Ideas clave:
}  La edad materna sólo presenta una tasa de detección del
30%. Constituye el riesgo a priori.
}  A mayor edad mayor es la tasa de detección de los
diferentes cribados.
}  El cribado combinado del 1T tasa de detección >90%.
Analítica 10 y eco 12.
}  Cribado contingente. êTFP. êTécnicas invasivas.
}  Cribado depende de la edad gestacional: IMPORTANTE
CORRECTA DATACIÓN.
}  Gestaciones gemelares importante la CORIONICIDAD.
}  Recurrencia depende del tipo de trisomía y de la edad
materna al caso.

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