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:

16 La ecografía de las 11–13+6 semanas

La estimación del riesgo de trisomía 21 al nacimiento en funciónde la edad materna se basa en estudios anteriores a la introduccióndel diagnóstico prenatal (Hecht y Hook 1994). En los últimos15 años, con la introducción de la bioquímica sérica en sangrematerna y el cribado ecográfico de anomalías cromosómicas endistintas etapas del embarazo, ha sido necesario establecer riesgos

Figura 5. Riesgo de anomalías cromosómicas en función de la edad gestacional. Las líneas representanel 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

Edad materna (años)

Riesgo %

Trisomía 21

Trisomía 18Trisomía 13

XXX/XXY/XYY

45XO

Triploidía

10 15 20 25 30 35 40

Trisomía 21


Triploidía

XXX/XXY/XYY

45XO

0

20

40

60

80

100

%

Gestación (semanas)

Trisomia 21,13 y 18

Turner Triploidías Trisomías de los cromosomas sexuales


Edad materna y edad gestacional:

18La ecografía de las 11–13

+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 13Materna 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

éEdad materna é Riesgo de Trisomía 21,18 y 13. éEdad gestacional êRiesgo de Trisomía 21,18 y 13.

Pérdida 40% Pérdida del 80%





.0 0001

0.001

0.01

0.1

1

10

20 25 30 35 40 44


Riesgo %

Trisomía 21


XXX/XXY/XYY

45XO

Triploidía

10 15 20 25 30 35 40

Trisomía 21


Triploidía

XXX/XXY/XYY

45XO

0

20

40

60

80

100

%






.0 0001

0.001

0.01

0.1

1

10

20 25 30 35 40 44


Riesgo %

Trisomía 21


XXX/XXY/XYY

45XO

Triploidía

10 15 20 25 30 35 40

Trisomía 21


Triploidía

XXX/XXY/XYY

45XO

0

20

40

60

80

100

%


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.


18La ecografía de las 11–13

+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 13Materna 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 complexformation occurs in the extracellular, probably at the surface

of the syncytiotrophoblast. In normal pregnancy, the con-

centration of PAPP-A in maternal circulation increases withgestational age. Its concentration increases exponentially with

a doubling time of 3–4 days during the first trimesters (Fig. 3),

then the level continues to rise throughout pregnancy untildelivery. The rapid increase in PAPP-A levels during the first

trimester causes the interpretation of a given value to be very

dependent on gestational age. Common practice is therefore touse the unit multiple of median (MoM) as a gestational age-

dependent expression of PAPP-A concentration. The average

half life of PAPP-A after normal delivery is 53 ± 26 h (meanplus SD) [18]. PAPP-A concentrations are 100-fold and

1,000-fold lower in fetal blood and in amniotic fluid, respec-

tively, compared with maternal blood [19].About 99 % of PAPP-A is covalently bound in a 2:2

complex to the proform of eosinophil major basic protein(proMBP) during pregnancy. The proMBP functions as an

endogenous inhibitor of the proteolytic activity of PAPP-A

(a protease inhibitor in vivo) whose mechanism of inhibi-tion is currently unknown. Substrates of PAPP-A include

insulin-like growth factor binding proteins (IGFBPs) 4 and

5, whose role is in the inhibition of the biological activitiesof insulin-like growth factors 1 and 2. PAPP-A acts as a

‘protease’ for IGFBPs [20] there by helping in the release

of IGF from these binding proteins so that it is free tointeract with its cell receptor in an autocrine or paracrine

manner (Fig. 4). IGF is thought to play an important role in

trophoblast invasion and hence the early development andvascularization of the placenta and the placental bed.

Decreased levels of PAPP-A are found in association

with abnormal placental function which has formed thebasis for the first trimester screening of fetal Down syn-

drome [13, 16]. Low first trimester maternal serum levels

are found not only in trisomy 21, trisomy 18 and trisomy 13,

but also in non-Down syndrome fetal aneuploidies. PAPP-A

is also said to have a positive relationship with birth weight[21]. As PAPP-A decreases, the risk of small-for-gesta-

tional-age infants increases. PAPP-A levels in blood stream

are found to be depressed in ectopic gravidity. Some of thecomplications associated with an unexplained isolated low

PAPP-A are preterm delivery, intrauterine growth restric-

tion, gestational hypertension, gestational hypertensionwith proteinuria [22].

Studies have shown that down regulation of insulin-likegrowth factor-II availability due to a decreased PAPP-A

serum level may be one of the causes of spontaneous

abortion in these women [23]. The decrease in maternalserum PAPP-A is not associated with any change in pla-

cental synthesis of this protein, since PAPP-A mRNA

expression is not significantly decreased in Down’s syn-drome placentas. Furthermore, the correlation between

serum and tissue expression levels of PAPP-A is lost in

Down’s pregnancies. These observations suggest that thedecrease in maternal serum PAPP-A is posttranslational

and may be caused by an alteration of the placenta-

releasing mechanisms or by a modification of the stabilityof the secreted protein [24]. PAPP-A is found to be sig-

nificantly higher in twin pregnancy. On an average PAPP-

A values are 1.86 times greater in twins than in singletons.No significant obstetrical outcomes have been described

with elevated PAPP-A in the first trimester [22]. Measur-

able levels have been found in males and non pregnantfemales. In non-pregnancy individuals PAPP-A is found as

a 400 kDa homodimer.

Maternal serum free b-hCG hormone

Human chorionic gonadotropin is a 39,500-Da glycoprotein

hormone normally found in blood and urine only duringpregnancy. In 1987, Bogart et al. [25] reported an elevated

levels of maternal serum hCG in Down’s syndrome preg-

nancies, and since then hCG has been introduced in mostscreening programs. For the initiation and maintenance of

pregnancy, hCG mediates multiple placental, uterine and

fetal functions. Some of these include development of syn-cytiotrophoblast cells, mitotic growth and differentiation of

the endometrium, localized suppression of the maternal

immune system, modulation of uterine morphology and geneexpression and coordination of intricate signal transduction

between the endometrium [26].

Chemistry

Human chorionic gonadotropin hormone is composed of twononcovalently linked subunits, a and b, and is produced by

Fig. 3 Exponential rise of PAPP-A in the first trimester of normalpregnancy

6 Ind J Clin Biochem (Jan-Mar 2013) 28(1):3–12

123

REVIEW ARTICLE

First Trimester Maternal Serum Screening Using BiochemicalMarkers PAPP-A and Free b-hCG for Down Syndrome, PatauSyndrome 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! Association of Clinical Biochemists of India 2012

Abstract The first trimester screening programme offers anoninvasive 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 chorionicgonadotrophin (free b-hCG) and pregnancy associated

plasma protein A (PAPP-A), maternal age and fetal nuchal

translucency (NT) thickness at 11 ? 0–13 ? 6 weeks ofgestation. A beneficial consequence of screening is the early

diagnosis or trisomies 21, 18 and 13. At 11 ? 0–13 ? 6

weeks, the relative prevalence of trisomies 18 and 13 totrisomy 21 are found to be one to three and one to seven,

respectively. All three trisomies are associated with

increased maternal age, increased fetal NT and decreasedPAPP-A, but in trisomy 21 serum free b-hCG is increased

whereas in trisomies 18 and 13 free b-hCG is decreased.

Keywords PAPP-A ! Free b-hCG ! Nuchal translucency !Down syndrome ! Patau syndrome ! Edward syndrome

Prenatal screening for trisomies based on the analysis ofbiochemical markers in maternal serum has become an

established part of obstetric practice in many countries. Resentinterest in prenatal screening for trisomies has focused on the

first trimester. Of the biochemical markers that have been

investigated, only maternal serum free b-human chorionicgonadotrophin (freeb-hCG) and pregnancy associated plasma

protein-A (PAPP-A) has been shown to be of value. The goal

of first trimester maternal serum screening programs is toidentify 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

increased risk of trisomy 21 (Table 1) is well known, and

pregnant women older than 35 years at delivery are rou-tinely offered invasive prenatal diagnostic testing. The

most commonly used test for genetic diagnosis is amnio-

centesis, but the rate of spontaneous fetal loss related toamniocentesis averages about one in every 200 [2] proce-

dures. Because of this risk, serum analyte testing has

become an important, noninvasive first step in detectingpatients at risk for congenital abnormalities.

Current studies done on first trimester maternal serum

screening has shown that the double marker test helps toidentify 90 % of women at risk for Down syndrome, 94 % of all

major chromosomal defects such as Patau syndrome, Edward

syndrome, triploidy and Turner syndrome, and 60 % of otherchromosomal defects, such as deletions, partial trisomies,

unbalanced translocations, and sex chromosome aneuploidiesother than turners [3]. Some of the advantages of first-trimester

biochemical screening over second trimester biochemical

screening include providing clinicians and patients with thesubstantial advantage of an earlier diagnosis, higher detection

rates for fetal Down syndrome i.e; 90 % [4] or even higher,

compared to 80 % for the second trimester quadruple test [5, 6]and 70 % for the older triple screening test [7], and detection of

most major chromosome abnormalities other than trisomy 21. It

also acts as a nonspecific marker for other birth defectsincluding some major cardiac defects and syndromic condi-

tions. It can detect a number of major structural birth defects

associated with normal chromosomes.Maternal serum screening has some limitations. One dis-

advantage is that neural tube defect detection would require

S. Shiefa (&) ! M. Amargandhi ! J. Bhupendra ! S. Moulali !T. KristineSRL Diagnostics, Fortis Healthcare Enterprise, ClinicalBiochemist, 64, Al Razi Unit 1007, Block A, P.O. Box 505143,Dubai Health Care City, United Arab Emiratese-mail: [email protected]

123

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 relativeimmaturity of the placenta, which continues to release

large amounts of hCG as in the first trimester [32].

Methods Used to Measure PAPP-A and Free b-hCG

The new technology for biochemical analysis, which pro-vides automated, precise and reproductive measurement

within short time of obtaining a blood sample makes itpossible to combine biochemical and ultrasonographic

testing for early assessment so that patients assessment and

stress may be reduced. Separation of the sera for Downsyndrome screening in 4 h after withdrawal is necessary.

Cooling during any storage, including transportation is

highly recommended as the preanalytical phase has a highimpact 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. Reliableresults 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 studieshave 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 itis 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 increaseby 10–15 % after 24 h, by about 25 % after 3 days and by

45 % after 4 days [34]. Another study showed that PAPP-A

levels are stable in serum for 142 days at 2–8!, 37 days atroom temperature and 20 days at 30 !C. There was no sig-

nificant change with either analyte after -20 !C storage for up

to 240 days or after six repeated freeze-thaw cycles [33].Presently, virtually all commercial assays are the enzyme

Fig. 5 Structure of intact hCGand hCGb

Fig. 6 Total hCG and free beta hCG during first trimester ofpregnancy


123

REVIEW ARTICLE

First Trimester Maternal Serum Screening Using BiochemicalMarkers PAPP-A and Free b-hCG for Down Syndrome, PatauSyndrome 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! Association of Clinical Biochemists of India 2012

Abstract The first trimester screening programme offers anoninvasive 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 chorionicgonadotrophin (free b-hCG) and pregnancy associated

plasma protein A (PAPP-A), maternal age and fetal nuchal

translucency (NT) thickness at 11 ? 0–13 ? 6 weeks ofgestation. A beneficial consequence of screening is the early

diagnosis or trisomies 21, 18 and 13. At 11 ? 0–13 ? 6

weeks, the relative prevalence of trisomies 18 and 13 totrisomy 21 are found to be one to three and one to seven,

respectively. All three trisomies are associated with

increased maternal age, increased fetal NT and decreasedPAPP-A, but in trisomy 21 serum free b-hCG is increased

whereas in trisomies 18 and 13 free b-hCG is decreased.

Keywords PAPP-A ! Free b-hCG ! Nuchal translucency !Down syndrome ! Patau syndrome ! Edward syndrome

Prenatal screening for trisomies based on the analysis ofbiochemical markers in maternal serum has become an

established part of obstetric practice in many countries. Resentinterest in prenatal screening for trisomies has focused on the

first trimester. Of the biochemical markers that have been

investigated, only maternal serum free b-human chorionicgonadotrophin (freeb-hCG) and pregnancy associated plasma

protein-A (PAPP-A) has been shown to be of value. The goal

of first trimester maternal serum screening programs is toidentify 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

increased risk of trisomy 21 (Table 1) is well known, and

pregnant women older than 35 years at delivery are rou-tinely offered invasive prenatal diagnostic testing. The

most commonly used test for genetic diagnosis is amnio-

centesis, but the rate of spontaneous fetal loss related toamniocentesis averages about one in every 200 [2] proce-

dures. Because of this risk, serum analyte testing has

become an important, noninvasive first step in detectingpatients at risk for congenital abnormalities.

Current studies done on first trimester maternal serum

screening has shown that the double marker test helps toidentify 90 % of women at risk for Down syndrome, 94 % of all

major chromosomal defects such as Patau syndrome, Edward

syndrome, triploidy and Turner syndrome, and 60 % of otherchromosomal defects, such as deletions, partial trisomies,

unbalanced translocations, and sex chromosome aneuploidiesother than turners [3]. Some of the advantages of first-trimester

biochemical screening over second trimester biochemical

screening include providing clinicians and patients with thesubstantial advantage of an earlier diagnosis, higher detection

rates for fetal Down syndrome i.e; 90 % [4] or even higher,

compared to 80 % for the second trimester quadruple test [5, 6]and 70 % for the older triple screening test [7], and detection of

most major chromosome abnormalities other than trisomy 21. It

also acts as a nonspecific marker for other birth defectsincluding some major cardiac defects and syndromic condi-

tions. It can detect a number of major structural birth defects

associated with normal chromosomes.Maternal serum screening has some limitations. One dis-

advantage is that neural tube defect detection would require

S. Shiefa (&) ! M. Amargandhi ! J. Bhupendra ! S. Moulali !T. KristineSRL Diagnostics, Fortis Healthcare Enterprise, ClinicalBiochemist, 64, Al Razi Unit 1007, Block A, P.O. Box 505143,Dubai Health Care City, United Arab Emiratese-mail: [email protected]

123

Ind J Clin Biochem (Jan-Mar 2013) 28(1):3–12

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:

and 13 and unaffected fetuses that followed the CRL-independentdistribution were 95%, 70%, 85% and 5%, respectively. Themedian CRL-independent NT was 2.0 mm for the euploidgroup, 3.4 mm in trisomy 21, 5.5 mm in trisomy 18 and4.0 mm in trisomy 13 (Wright et al., 2008, Table II).

Maternal serum biochemistry

Contour plots for free b-hCG and PAPP-A MoM in trisomies21, 18 and 13 and unaffected pregnancies are shown in Fig. 2.

In unaffected pregnancies, the median free b-hCG was 1.0MoM (range 0.03–30.4) and the median PAPP-A was 1.0MoM (range 0.02–7.9), in the trisomy 21 pregnancies themedian free b-hCG was 2.0 MoM (range 0.1–11.3) andthe median PAPP-A was 0.5 MoM (range 0.05–2.2), in thetrisomy 18 pregnancies the median free b-hCG was 0.2MoM (range 0.02–4.7) and the median PAPP-A was 0.2MoM (range 0.03–4.1) and in the trisomy 13 pregnancies themedian free b-hCG was 0.5 MoM (range 0.19–3.3) and themedian PAPP-A was 0.3 MoM (range 0.09–1.2).

Details on the biochemical parameters estimates for eachchromosomal abnormality are given in Tables II and III. Intrisomy 21 pregnancies, there was a significant increase withgestation in both log MoM PAPP-A (P , 0.0001) and logMoM free b-hCG (P ¼ 0.039). In trisomy 18 pregnancies,there was no significant association with gestation for eitherlog MoM free b-hCG (P ¼ 0.879) or log MoM PAPP-A(P ¼ 0.900). In trisomy 13 pregnancies, there was no signifi-cant association between log MoM MoM PAPP-A and ges-tation (P ¼ 0.38). The association between log MoM freeb-hCG and gestation was approaching significance (P ¼ 0.07).

Fetal heart rate

In the multiple regression analysis of the FHR, there were sig-nificant effects of gestational age (quadratic), maternal age,ethnicity, smoking status (P , 0.0001) and IVF conception(P ¼ 0.004) but not maternal weight (P ¼ 0.57). However,for the purpose of screening, we took into account only theeffect of gestation because the effects of maternal age (over a25 year range), ethnicity, smoking status and IVF conceptionwere ,1 bpm:

Mean FHR ¼ 265.98 – 1.7631 ! gestation in days þ0.0064445 ! gestation in days2.

Parameters for the fitted Gaussian distributions are given inTable IV. There was no significant association between NT anddelta FHR (P ¼ 0.61). Although there were significant

Table II. Ultrasonographic and biochemical characteristics ofchromosomally normal fetuses and of those with trisomy 21, 18 and 13,respectively.

CRL (mm) Median

Normal karyotype 62.8Trisomy 21 62.4Trisomy 18 52.0Trisomy 13 59.4Fetal NT (mm)Normal karyotype 2.0Trisomy 21 3.4Trisomy 18 5.5Trisomy 13 4.0Delta fetal heart rate (bpm)Normal karyotype 0Trisomy 21 1.4Trisomy 18 22.8Trisomy 13 11 weeks 20.0Trisomy 13 12 weeks 17.2Trisomy 13 13 weeks 14.4PAPP-A MoMNormal karyotype 1.0Trisomy 21 0.5Trisomy 18 0.2Trisomy 13 0.3Free b-hCG MoMNormal karyotype 1.0Trisomy 21 2.0Trisomy 18 0.2Trisomy 13 0.5

PAPP-A, pregnancy-associated plasma protein-A; MoM, multiples of themedian; bpm, beats per minute; NT, nuchal translucency.

Figure 2: Distribution of MoM values of free b-hCG and of PAPP-Ain normal fetuses (dark shaded ellipse), and fetuses with trisomies 21,18 and 13 (open ellipses containing 90% of cases).

Table I. Characteristics of the study population.

Maternal characteristicsMaternal age in years, median (range) 35.4 (14.1–52.2)Maternal weight in kg, median (range) 63.6 (34–165)Spontaneous conception, n (%) 54 306 (95.3%)Smoker, n (%) 2583 (4.5%)EthnicityCaucasian, n (%) 50 872 (89.3%)Afro-Caribbean, n (%) 2437 (4.3%)East Asian, n (%) 644 (1.1%)South Asian, n (%) 2224 (3.9%)Mixed, n (%) 777 (1.4%)Gestational age11þ0–11þ6 weeks, n (%) 5631 (9.9%)12þ0–12þ6 weeks, n (%) 31 958 (56.1%)13þ0–13þ6 weeks, n (%) 34.0 (34.0%)CRL in mm, median (range) 62.8 (45.0–84.0)KaryotypeNormal karyotype, n (%) 56.376 (99.0%)Trisomy 21, n (%) 395 (0.7%)Trisomy 18, n (%) 122 (0.2%)Trisomy 13, n (%) 61 (0.1%)TOTAL 56 954

CRL, crown-rump length.

Kagan et al.

1970

at Hospital L

a Paz on April 12, 2015

http://humrep.oxfordjournals.org/

Dow

nloaded from

Screening for trisomies 21, 18 and 13 by maternal age,fetal nuchal translucency, fetal heart rate, free b-hCGand pregnancy-associated plasma protein-A

Karl O. Kagan1,2,4, Dave Wright3, Catalina Valencia1, Nerea Maiz1 and Kypros H. Nicolaides1,4

1Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital, Denmark Hill, London SE5 8RX, UK; 2Department ofObstetrics and Gynaecology, University of Tuebingen, Germany; 3Department of Mathematics and Statistics, University of Plymouth, UK

4Correspondence address. E-mail: [email protected].

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, fetalNT, free b-hCG and PAPP-A at 1110–1316 weeks in singleton pregnancies, including 56 376 normal cases, 395with trisomy 21, 122 with trisomy 18 and 61 with trisomy 13. Risk algorithms were developed for the calculationof patient-specific risks for each of the three trisomies based on maternal age, NT, FHR, free b-hCG and PAPP-A.Detection (DR) and false positive rates (FPR) were calculated and adjusted according to the maternal age distributionof pregnancies in England and Wales in 2000–2002. RESULTS: The DR and FPR were 90% and 3%, respectively, fortrisomy 21, 91% and 0.2% for trisomy 18 and 87% and 0.2% for trisomy 13. When screen positivity was defined by anFPR of 3% on the risk for trisomy 21 in conjunction with an FPR of 0.2% on the maximum of the risks for trisomies 13and 18, the overall FPR was 3.1% and the DRs of trisomies 21, 18 and 13 were 91%, 97% and 94%, respectively.CONCLUSIONS: As a side effect of first-trimester screening for trisomy 21, !95% of trisomy 13 and 18 fetusescan be detected with an 0.1% increase in the FPR.

Keywords: nuchal translucency; pregnancy-associated plasma protein-A; serum-free b-hCG; first trimester; trisomy

Introduction

Effective screening for trisomy 21 is provided by acombination of maternal age, fetal nuchal translucency (NT)thickness and maternal serum-free b-hCG and pregnancy-associated plasma protein-A (PAPP-A) at 11þ0–13þ6 weeksof gestation with a detection rate of !90% for a false positiverate (FPR) of 5% (Snijders et al., 1998; Nicolaides et al., 2005).A beneficial consequence of screening for trisomy 21 is theearly diagnosis of trisomies 18 and 13, which are the secondand third most common chromosomal abnormalities. At11þ0–13þ6 weeks, the relative prevalence of trisomies 18and 13 to trisomy 21 are one to three and one to seven, respect-ively (Snijders et al., 1994, 1995, 1999). All three trisomies areassociated with increased maternal age, increased fetal NT anddecreased maternal serum PAPP-A, but in trisomy 21 serum-free b-hCG is increased whereas in trisomies 18 and 13 thisis decreased (Snijders et al., 1994, 1995, 1998, 1999; Tulet al., 1999; Spencer et al., 2000; Nicolaides et al., 2005;Wright et al., 2008). In addition, trisomy 13, unlike trisomies

21 and 18, is associated with fetal tachycardia (Hyett et al.,1996; Liao et al., 2000; Papageorghiou et al., 2006).

We have recently reported the development of a specificalgorithm for trisomy 18 (Kagan et al., 2008a). When the algor-ithm for trisomy 21 (Kagan et al., 2008b) was used and screenpositivity was fixed at an FPR of 3%, and in addition the algor-ithm for trisomy 18 was used and screen positivity was fixed atan FPR of 0.2%, the overall FPR was 3.1% and the detectionrates of trisomies 21 and 18 were 90% and 97%, respectively(Kagan et al., 2008a).

The aims of this study are: first, to derive a specific algorithmfor trisomy 13 based on maternal age, fetal NT thickness, fetalheart rate (FHR) and maternal serum-free b-hCG and PAPP-A;secondly, to incorporate FHR in our previously reportedspecific algorithms for trisomies 21 and 18 based on maternalage, fetal NT thickness and maternal serum biochemistry(Kagan et al., 2008a, b) and thirdly, to examine the perform-ance of each of the three algorithms and in combination inthe early detection of the three trisomies.

# The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

All rights reserved. For Permissions, please email: [email protected]

1968

Human Reproduction Vol.23, No.9 pp. 1968–1975, 2008 doi:10.1093/humrep/den224

Advance Access publication on June 10, 2008

at Hospital La Paz on A

pril 12, 2015http://hum

rep.oxfordjournals.org/D

ownloaded from

Aneuplodía Freeβ-HCG PAPP-A

T21 éé

ê

T18 êê êê

T13 ê ê

Turner = ê

Triploidía materna êêê êêê

Triploidía paterna éééé ê

1.0 MoM at all gestations. In a study done by Spencer et al.

[42] on variation in first trimester biochemical markerlevels in Asian woman (Indian, Pakistan, Bangladesh)

compared to Caucasian woman (reference group) it was

found that in asian population, median PAPP-A wasincreased by 9 % and free b-hCG by 6 % from the refer-

ence group (Table 3). The Asian population was found to

be 6.9 kg lighter than Caucasian woman. In trisomies lowPAPP-A values are seen, which typically are 0.15 MoM for

trisomy 21, that is, Down’s syndrome; 0.25 MoM for tri-somy 13 or Patau syndrome; 0.18 MoM for trisomy 18 or

Edward’s syndrome; and 0.49 for Turner’s syndrome

(Table 4).The laboratory uses different mathematical model to

calculate a woman’s risk of having a baby with Down syn-

drome, trisomy 18 and trisomy 13. Some of the mathematicalmodels include Prisca, Viewpoint, Astria etc. These mathe-

matical model takes into consideration the maternal age, the

serum levels of various biochemical markers and the fetusultrasound measurements. In addition, a number of factors

play an important role in the calculation of the risk as they

will affect the values of the maternal serum biochemicalanalytes. This includes gestational age, weight, race, smok-

ing, diabetic status of the individual, the number of fetuses

present, and whether IVF treatment was used for conceiving.In some rare cases like ovum donor pregnancy aneuploidy

risk calculations, the use of the age of the ovum donor instead

of the ovum recipient reduces the false-positive rate andimproves screening efficacy.

Inaccurate information can lead to significant alterations

in the estimated risk. Hence it is very important that, accurateinformation is provided when the sample is submitted to the

laboratory for analysis. For first trimester serum screening, a

screen-positive or screen-negative result is based on thelaboratory-specific cutoffs. Using maternal age the estimated

risks for fetal trisomies 21, 18 and 13 for a woman aged

20 years at 12 weeks of gestation are about 1 in 1,000, 1 in2,500 and 1 in 8,000, respectively, and the risk of such

woman delivering an affected baby at term are 1 in 1,500, 1 in

18,000 and 1 in 42,000, respectively. The respective risks forthese aneuploidies for a woman aged 35 years at 12 weeks of

gestation are about 1 in 250, 1 in 600 and 1 in 1,800, and the

risk of such woman delivering an affected baby at term are 1in 350, 1 in 4,000 and 1 in 10,000.

In screening for trisomy 21 by maternal age and serum free

b-hCG and PAPP-A, the detection rate is about 65 % for afalse-positive rate of 5 %. The performance is better at

9–10 weeks than at 13 weeks because the difference in PAPP-

A between trisomic and euploid pregnancies is greater inearlier gestations [43, 44]. Although the difference in free b-

hCG between trisomic and euploid pregnancies increases with

gestation, the magnitude of the difference is smaller than thatof the opposite relation of PAPP-A. In trisomies 18 and 13,

maternal serum free b-hCG and PAPP-A are decreased [45,46]. In cases of sex chromosomal anomalies, maternal serum

free b-hCG is normal and PAPP-A is low [46]. The overall

performance of screening by combined test is better at11 weeks than 13 weeks, with a greater contribution from

PAPP-A at 11 weeks and from free b-hCG at 13 weeks. In

trisomy 21 pregnancies the median MoM free b-hCGincreases from 1.8 at 11 weeks to 2.09 at 13 weeks, and the

respective values for PAPP-A are 0.38 and 0.65 MoMs.

Screening for biochemical testing and ultrasound scan-ning can also be carried out in two separate visits, with the

first done at 9–10 weeks and the second at 12 weeks [44, 47,

48]. It has been estimated that this approach would improvethe detection rate from 90 % to 93 to 94 %. Another option

would be to perform the scan at 12 weeks and optimize the

performance of biochemical testing by measuring PAPP-Aat 9 weeks and free b-hCG at the time of the scan at 12 weeks

or even later with an estimated detection rate of 95 %.

References

1. Snijders RJM, Sundberg K, Holzgreve W, Henry G, NicolaidesKH. Maternal age- and gestation-specific risk for trisomy 21.Ultrasound Obstet Gynecol. 1999;13:167–70.

2. Wilson RD. Amended Canadian Guideline for prenatal diagnosis(2005) change to 2005—techniques for prenatal diagnosis. SOGCClinical Practice Guidelines, No. 168, November 2005. J ObstetGynaecol Can. 2005;27:1048–54.

3. Bindra R, Liao VHA, Spencer K, Nicolaides KH. One stop clinicfor assessment of risk for trisomy 21 at 11–14 weeks: a pro-spective study of 15030 pregnancies. Ultrasound Obstet Gynecol.2002;20:219–25.

4. Nicolaides KH. Screening for fetal aneuploides at 11 to13 weeks. Prenat Diagn. 2011;1(31):7–15.

5. Dugoff L, Hobbins JC, Malone FD, et al. Quad screen as a pre-dictor of adverse pregnancy outcome. Obstet Gynecol. 2005;106:260–7.

Table 4 Marker pattern inmultiple of median anddetection rates in differentaneuploidies

MOM multiple of median, b-hCG human chorionicgonadotropin, NT nuchaltranslucency, PAPP-Apregnancy-associated plasmaprotein-A. [49]

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


123


Analítica ¿Cuándo?:

Ultrasound Obstet Gynecol 2008; 31: 618–624Published online 6 May 2008 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.5331

Screening for trisomy 21 by maternal age, fetal nuchaltranslucency thickness, free beta-human chorionicgonadotropin 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 andmaternal serum free beta-human chorionic gonadotropin(β-hCG) and pregnancy-associated plasma protein-A(PAPP-A).

Methods Prospective combined screening for trisomy 21was carried out at 11 + 0 to 13 + 6 weeks in 56 771singleton pregnancies, including 56 376 cases with anormal karyotype or delivery of a phenotypically normalbaby (unaffected group) and 395 cases with trisomy21. The blood test and ultrasound scan were carriedout in the same visit. In each case the maternal age-related risk for trisomy 21 at term was calculated andadjusted according to the gestational age at the time ofscreening to derive the a-priori risk. The measured NTwas transformed into a likelihood ratio using the mixturemodel of NT distributions. The measured free β-hCG andPAPP-A were converted into a multiple of the median(MoM) for gestational age, adjusted for maternal weight,ethnicity, smoking status, method of conception andparity, and a likelihood ratio was subsequently calculated.The likelihood ratios for NT and for the biochemicalmarkers were multiplied by the a-priori risk to derivethe patient-specific risk. Detection rates and false-positiverates were calculated by taking the proportions withrisks above a given risk threshold after adjustment formaternal age according to the distribution of pregnanciesin England and Wales in 2000–2002. These standardizedrates were compared with detection and false-positiverates estimated using Monte Carlo methods to samplefrom the modeled Gaussian distributions.

Results The performance of screening based on themodel was in good agreement with that observed inour population. In a strategy for first-trimester combinedscreening where the blood test and scan are carried out inthe same visit it was estimated that, for false-positive ratesof 3% and 5%, the detection rates were 92% and 94%,respectively, at 11 weeks, 85% and 90% at 12 weeks, and79% and 83% at 13 weeks. In an alternative strategy,with the blood taken at 10 weeks and the measurement ofNT performed at 12 weeks, the estimated detection rateswere 94% and 96% for false-positive rates of 3% and5%, respectively.

Conclusions The aim of the first-trimester scan is not justto screen for trisomy 21 but also to diagnose an increasingnumber of fetal malformations. In this respect the abilityto visualize fetal anatomy is better at 12–13 weeksthan at 11 weeks. Consequently, the ideal gestation forcombined testing in the same visit would be 12 weeks.An alternative strategy, with the blood taken at 10 weeksand the measurement of NT performed at 12 weeks,is associated with higher detection rates of trisomy 21.However, the cost of two-stage screening would be higherand, in addition, the potential advantage in terms ofdetection rate may be eroded by the likely increased non-compliance with the additional step. Copyright © 2008ISUOG. Published by John Wiley & Sons, Ltd.

INTRODUCTION

Effective screening for trisomy 21 is provided byassessment of a combination of maternal age, fetalnuchal translucency (NT) thickness, and maternal serum

Correspondence to: Prof. K. H. Nicolaides, Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital, Denmark Hill,London SE5 8RX, UK (e-mail: [email protected])

Accepted: 3 March 2008

Copyright © 2008 ISUOG. Published by John Wiley & Sons, Ltd. ORIGINAL PAPER

Combined screening 623

Table 3 Accuracy of estimated risk of trisomy 21 by a combination of maternal age, fetal nuchal translucency thickness, and maternal serumfree beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A

Estimated risk of trisomy 21Trisomy 21 Unaffected Observed

Range Median (n (%)) (n (%)) risk

≥ 1 in 10 1 in 5 273 (69.1) 340 (0.6) 1 in 21 in 11 to 1 in 50 1 in 28 60 (15.2) 909 (1.6) 1 in 161 in 51 to 1 in 100 1 in 74 16 (4.1) 947 (1.7) 1 in 601 in 101 to 1 in 250 1 in 173 15 (3.8) 2305 (4.1) 1 in 1551 in 251 to 1 in 1000 1 in 579 19 (4.8) 7362 (13.1) 1 in 3881 in 1001 to 1 in 5000 1 in 2443 10 (2.5) 16 685 (29.6) 1 in 1 670< 1 in 5000 1 in 16 144 2 (0.5) 27 828 (49.4) 1 in 13 915

Table 4 Modeled detection rates (DRs) and false-positive rates(FPRs) for given risk cut-offs for trisomy 21

Total 11 weeks 12 weeks 13 weeks

Risk cut-offDR(%)

FPR(%)

DR(%)

FPR(%)

DR(%)

FPR(%)

DR(%)

FPR(%)

1 in 20 71 0.6 78 0.6 71 0.6 62 0.51 in 50 79 1.4 86 1.4 79 1.4 71 1.31 in 100 84 2.6 90 2.5 85 2.5 77 2.51 in 150 87 3.6 92 3.5 87 3.5 81 3.61 in 200 89 4.6 93 4.3 89 4.5 83 4.71 in 300 91 6.3 95 5.8 91 6.1 86 6.71 in 1000 95 15.9 98 13.3 96 15.2 93 17.9

first done at 10–11 weeks and the second at 12–13 weeks.For false-positive rates of 3% and 5%, the estimateddetection rates of combined testing with the blood takenat 10 weeks and the measurement of NT performed at12 weeks are 94% and 96%, respectively. The cost andpatient acceptability of the two alternative policies of first-trimester testing will depend on the existing infrastructureof antenatal care. The potential advantage of two-stagescreening in terms of detection rate may be eroded by thelikely increased non-compliance with the additional step.Another element to be considered in terms of alternativepolicies of early screening is the contribution of additionalsonographic markers, such as absent nasal bone, widefrontomaxillary facial angle, reversed end-diastolic flowin the ductus venosus and tricuspid regurgitation, which

have already been incorporated into routine practice insome specialist centers3,16–19.

ACKNOWLEDGMENT

This study was supported by a grant from The FetalMedicine Foundation (charity number 1037116).

REFERENCES

1. Snijders RJ, Noble P, Sebire N, Souka A, Nicolaides KH. UKmulticentre project on assessment of risk of trisomy 21by maternal age and fetal nuchal-translucency thickness at10–14 weeks of gestation. Lancet 1998; 352: 343–346.

2. Spencer K, Souter V, Tul N, Snijders R, Nicolaides KH. Ascreening program for trisomy 21 at 10–14 weeks using fetalnuchal translucency, maternal serum free beta-human chorionicgonadotropin and pregnancy-associated plasma protein-A.Ultrasound Obstet Gynecol 1999; 13: 231–237.

3. Nicolaides KH, Spencer K, Avgidou K, Faiola S, Falcon O.Multicenter study of first-trimester screening for trisomy 21in 75 821 pregnancies: results and estimation of the potentialimpact of individual risk-orientated two-stage first-trimesterscreening. Ultrasound Obstet Gynecol 2005; 25: 221–226.

4. Nicolaides KH. Nuchal translucency and other first-trimestersonographic markers of chromosomal abnormalities. Am JObstet Gynecol 2004; 191: 45–67.

5. Wright D, Kagan KO, Molina FS, Gazzoni A, Nicolaides KH.A mixture model of nuchal translucency thickness in screeningfor 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-humanchorionic 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 andultrasound scanning

Detection rate (%)

Scan and blood at same visit Scan 12 weeks Scan 13 weeksFalse-positiverate (%) 11 weeks 12 weeks 13 weeks Blood 10 weeks Blood 11 weeks Blood 10 weeks Blood 11 weeks

1 83 76 69 88 81 85 782 88 83 75 92 87 90 833 92 85 79 94 89 92 864 93 88 81 95 91 94 885 94 90 83 96 92 95 9010 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-hCGand pregnancy-associated plasma protein-A

Karl O. Kagan1,2,4, Dave Wright3, Catalina Valencia1, Nerea Maiz1 and Kypros H. Nicolaides1,4

1Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital, Denmark Hill, London SE5 8RX, UK; 2Department ofObstetrics and Gynaecology, University of Tuebingen, Germany; 3Department of Mathematics and Statistics, University of Plymouth, UK

4Correspondence address. E-mail: [email protected].

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, fetalNT, free b-hCG and PAPP-A at 1110–1316 weeks in singleton pregnancies, including 56 376 normal cases, 395with trisomy 21, 122 with trisomy 18 and 61 with trisomy 13. Risk algorithms were developed for the calculationof patient-specific risks for each of the three trisomies based on maternal age, NT, FHR, free b-hCG and PAPP-A.Detection (DR) and false positive rates (FPR) were calculated and adjusted according to the maternal age distributionof pregnancies in England and Wales in 2000–2002. RESULTS: The DR and FPR were 90% and 3%, respectively, fortrisomy 21, 91% and 0.2% for trisomy 18 and 87% and 0.2% for trisomy 13. When screen positivity was defined by anFPR of 3% on the risk for trisomy 21 in conjunction with an FPR of 0.2% on the maximum of the risks for trisomies 13and 18, the overall FPR was 3.1% and the DRs of trisomies 21, 18 and 13 were 91%, 97% and 94%, respectively.CONCLUSIONS: As a side effect of first-trimester screening for trisomy 21, !95% of trisomy 13 and 18 fetusescan be detected with an 0.1% increase in the FPR.

Keywords: nuchal translucency; pregnancy-associated plasma protein-A; serum-free b-hCG; first trimester; trisomy

Introduction

Effective screening for trisomy 21 is provided by acombination of maternal age, fetal nuchal translucency (NT)thickness and maternal serum-free b-hCG and pregnancy-associated plasma protein-A (PAPP-A) at 11þ0–13þ6 weeksof gestation with a detection rate of !90% for a false positiverate (FPR) of 5% (Snijders et al., 1998; Nicolaides et al., 2005).A beneficial consequence of screening for trisomy 21 is theearly diagnosis of trisomies 18 and 13, which are the secondand third most common chromosomal abnormalities. At11þ0–13þ6 weeks, the relative prevalence of trisomies 18and 13 to trisomy 21 are one to three and one to seven, respect-ively (Snijders et al., 1994, 1995, 1999). All three trisomies areassociated with increased maternal age, increased fetal NT anddecreased maternal serum PAPP-A, but in trisomy 21 serum-free b-hCG is increased whereas in trisomies 18 and 13 thisis decreased (Snijders et al., 1994, 1995, 1998, 1999; Tulet al., 1999; Spencer et al., 2000; Nicolaides et al., 2005;Wright et al., 2008). In addition, trisomy 13, unlike trisomies

21 and 18, is associated with fetal tachycardia (Hyett et al.,1996; Liao et al., 2000; Papageorghiou et al., 2006).

We have recently reported the development of a specificalgorithm for trisomy 18 (Kagan et al., 2008a). When the algor-ithm for trisomy 21 (Kagan et al., 2008b) was used and screenpositivity was fixed at an FPR of 3%, and in addition the algor-ithm for trisomy 18 was used and screen positivity was fixed atan FPR of 0.2%, the overall FPR was 3.1% and the detectionrates of trisomies 21 and 18 were 90% and 97%, respectively(Kagan et al., 2008a).

The aims of this study are: first, to derive a specific algorithmfor trisomy 13 based on maternal age, fetal NT thickness, fetalheart rate (FHR) and maternal serum-free b-hCG and PAPP-A;secondly, to incorporate FHR in our previously reportedspecific algorithms for trisomies 21 and 18 based on maternalage, fetal NT thickness and maternal serum biochemistry(Kagan et al., 2008a, b) and thirdly, to examine the perform-ance of each of the three algorithms and in combination inthe early detection of the three trisomies.

# The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

All rights reserved. For Permissions, please email: [email protected]

1968

Human Reproduction Vol.23, No.9 pp. 1968–1975, 2008 doi:10.1093/humrep/den224

Advance Access publication on June 10, 2008

at Hospital La Paz on A

pril 12, 2015http://hum

rep.oxfordjournals.org/D

ownloaded from

§  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: [email protected] | Tel.: 91 350 98 16 | Fax: 91 350 98 18

Diagnóstico prenatal de los defectos congénitos.Cribado de las anomalías cromosómicas.

*XtD�SUiFWLFD�GH�DVLVWHQFLD actualizadD en noviembre de 2010

1. DEFINICIÓN

El término "diagnóstico prenatal" agrupa todas aquellas accionesdiagnósticas encaminadas a descubrir durante el embarazo un "defectocongénito", entendiendo por tal "toda anomalía del desarrollomorfológico, estructural, funcional o molecular presente al nacer(aunque puede manifestarse más tarde), externa o interna, familiar oesporádica, hereditaria o no, única o múltiple" (Comités de Trabajo dela OMS, 1970, 1975, 1982).

El diagnóstico prenatal tiene como finalidad diagnosticar con la mayorprecocidad posible un defecto congénito o bien establecer la ausenciadel mismo, ya que la confirmación de la normalidad contribuye areducir 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 acuerdocon la causa subyacente se distinguen en la práctica:

• Enfermedades hereditarias mendelianas o monogénicas, presentesen el 1-1.5% de nacidos y responsables de alrededor del 25% de lasanomalías. Los mecanismos de transmisión responden a su carácterrecesivo, dominante, autosómico o ligado a los cromosomassexuales. Aunque individualmente son poco frecuentes, en conjuntoincluyen un gran número de errores metabólicos congénitos,aunque sus frecuencias varían en distintas poblaciones. En nuestromedio se dan con mayor frecuencia relativa la fibrosis quística,distrofia miotónica, riñón poliquístico y neurofibromatosis. El riesgo derecurrencia oscila entre el 25-50%.

0HGLFLQD�SHULQDWDO

9

Sociedad Española de Ginecología y Obstetricia

Pº de la Habana, 190 Bajo (28036) Madrid. E-mail: [email protected] | Tel.: 91 350 98 16 | Fax: 91 350 98 18

entre las 8-13 semanas y ecografía entre las 11+0 y la 13+6). Susprincipales ventajas son su elevada sensibilidad y la precocidad con laque permite conocer qué gestaciones son de alto riesgo. De estamanera abre la posibilidad tanto de aplicar técnicas invasivas demanera precoz, principalmente la biopsia corial, como de interrumpir lasgestaciones afectas de manera precoz. Este cribado debe ser ofrecidoa todas las gestantes, independientemente de su edad, puesto que laedad materna ya entra como variable en el programa de cálculo. Deexistir algún factor de riesgo preconcepcional que haga recomendablela realización de una técnica invasiva, la realización previa del cribadocombinado, aunque es opcional, sí es recomendable dada lainformación que proporciona.

Figura 1. Algoritmo del cribado combinado de I trimestre

Día 0: información sobre el cribado.Día 1: (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 técnica invasiva (ver apartado de métodos invasivos)

Consentimiento Informado

Día 0: información sobre el cribado.Día 1: (entre 8 - 13+6 semanas)

• extracción de sangre: fβ-HCG + PAPP-A.Día 2: (entre 11+0 - 13+6 semanas)

• ecografía: TN y edad gestacional.

Cribado combinado en un tiempo Cribado combinado en dos tiempos

El cálculo del riesgo del cribado combinado del I trimestre se estableceteniendo en cuenta los valores obtenidos en la determinación de losmarcadores bioquímicos y el valor de la TN obtenida por ecografía. Tal ycomo se mencionaba anteriormente, el programa estadístico querealiza el cálculo debe tener en cuenta unos determinados factores decorrección: peso materno, consumo de tabaco, grupo racial-étnico dela madre, diabetes mellitus insulino-dependiente, gestación gemelar,etc. Una vez introducida toda la información, el programa establece uníndice de riesgo para trisomía 21. El punto de corte para recomendar un

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 [email protected]

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 DepartmentHospital Clinic – Universitat de Barcelona , Sabino de Arana 1 ES–08028 Barcelona, Catalonia (Spain) E-Mail aborrell @ clinic.cat

© 2013 S. Karger AG, Basel1015–3837/13/0342–0116$38.00/0

www.karger.com/fdt

Illa/Mula/Arigita/Grande/Gonce/Borobio/Borrell

Fetal Diagn Ther 2013;34:116–120DOI: 10.1159/000351854

118

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 combinations of added ultrasound markers, the inclusion of DV and NB + DV into the expanded combined screen-ing and all combinations of ultrasound markers in the contingent strategy but NB alone, were found to be the most useful combinations to significantly reduce the FPR ( table 2 ).

4 Discussion

To the best of our knowledge, this is the largest first trimester series to provide likelihood ratios for the 3 most commonly used ultrasound markers other than

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-cal variability [22] .

One of the main contributions of our study is the cal-culation of likelihood ratios for individual first trimester ultrasound markers by using the established method for second trimester ultrasound markers, without requiring specific software [20, 21] . In this regard, Down syndrome risk decreases between 20 to 50% (NLR ranging from 0.49 to 0.82) with normal markers, while in abnormal markers this risk increases about 10 to 15 times (PLR ranging from 10.2 to 15.0). When a single marker is ab-normal and the remaining 2 are normal, the resulting risk may increase up to 6-fold.

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 translucencyRate 69% (68/99) 5.0% (549/11,014) – – –95% CI 60–78 4.6–5.4

Nasal boneRate 20% (15/77) 1.3% (108/8,506) 15 0.82 3.995% CI 11–28 10.5–14.9

Ductus venosusRate 54% (50/93) 5.3% (572/10,830) 10.2 0.49 4.495% CI 44–64 4.9–5.7

Tricuspid flowRate 49% (17/35) 3.4% (37/1,078) 14.3 0.53 5.895% 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%), êêFP (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 21Elizabeth De Souza,1 Jane Halliday,2 Annabelle Chan,3 Carol Bower,4 and Joan K. Morris1*1Barts & The London School of Medicine and Dentistry, Queen Mary University of London, Wolfson Institute of Preventive Medicine, London, UK2Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia3South Australian Birth Defects Register, Children, Youth and Women’s Health Service, North Adelaide, South Australia4Birth 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

Theobjectivewas to establishwhether the riskof trisomies 13, 18,and 21 (Patau, Edwards, and Down syndrome, respectively) in asubsequent pregnancy is raised for women who have had aprevious pregnancy with trisomy 13, 18, or 21. Birth defectregister data were used to investigate this issue. Pregnancy datafrom three Australian population-based birth defect registerscontained 5,906 women with a previous trisomy 13, 18, or 21pregnancy inwhom therewere 3,713 subsequent pregnancies, 75of which were trisomic. Relative risk of subsequent trisomy at15 weeks gestation was estimated by comparing the observednumber of subsequent trisomies with the expected number ofsubsequent trisomies based on maternal age-related risk. Therewas evidence of increased risk of the same trisomy subsequent toa previous pregnancy with trisomy 13 or 18 (RR¼ 3.8 (1.5, 7.9)),the increase in risk being greater for women aged under 35 at theprevious trisomic pregnancy (RR¼ 7.8 (2.1, 20.2)). There wasalso evidence of increased risk of trisomy 21 subsequent toprevious trisomy 21 (RR¼ 2.2 (1.6, 2.9)), again higher in womenunder 35 at previous affected pregnancy (RR¼ 3.5 (2.1, 5.5)).There was a suggestion that the risk of a different trisomysubsequent to trisomy 21 may also be increased (RR¼ 1.4(0.7, 2.5)). In conclusion, women who have had a previoustrisomic pregnancy, particularly those under 35 years of age atthe time, appear to be at an increased risk of future pregnanciesbeing trisomic. ! 2009 Wiley-Liss, Inc.

Key words: trisomy; recurrence risk; Down syndrome; Patausyndrome; Edwards syndrome

INTRODUCTION

The risk of a future pregnancy being affected by trisomy 21 is knownto be increased for women who have already had a trisomy 21pregnancy. The amount by which their risk increases is a constantdetermined by the age at which the first affected pregnancyoccurred, and is greater for younger women than older women[Morris et al., 2005]. Less is known about whether the risk of othertrisomies behaves in a similar way.

Warburton et al. [2004] estimated trisomy recurrence risk invarious trisomies by analyzing subsequent cases identified by

prenatal diagnosis in women with a previous prenatal diagnosisof trisomy, monosomy X, or triploidy. They compared the numberof cases observed in the prenatal diagnoses to the numbers expectedbased on the maternal age-related risk for the women undergoingprenatal diagnosis. They reported a significantly increased risk oftrisomy 13 or 18, XXX or XXY following a trisomy 21 diagnosis(SMR¼ 2.3 (90% CI 1.5, 3.8)). They also found that following anyof trisomy 13, 18, or 21, XXX or XXY, the risk of a different trisomywas significantly increased, supporting the hypothesis that somewomen have a higher risk for nondisjunction than others of thesame age [Warburton et al., 2004]. In order to providemore specificevidence that would be relevant to antenatal screening, geneticcounseling, and research into nondisjunction and risk of trisomy,we investigated the risks of the sameor different trisomies followingtrisomies 13, 18, and 21. More accurate estimates of the maternalage-related risks of each trisomy and of fetal loss are available nowthanwhenWarburton et al. conducted their analysis, and thesehavebeen used in this study [Savva et al., 2006;Morris and Savva, 2008].

MATERIALS (PREGNANCIES STUDIED)

Data in this study were provided by three Australian registers:the South Australian Birth Defects Register (SABDR, http://www.wch.sa.gov.au/services/az/other/phru/birthdefect .html,

*Correspondence to:Joan K. Morris, Barts & The London School of Medicine and Dentistry,Queen Mary University of London, Wolfson Institute of PreventiveMedicine, Charterhouse Square, London EC1M 6BQ, UK.E-mail: [email protected] online 16 November 2009 in Wiley InterScience(www.interscience.wiley.com)DOI 10.1002/ajmg.a.33099

How to Cite this Article:De Souza E, Halliday J, Chan A, Bower C,Morris JK. 2009. Recurrence risks fortrisomies 13, 18, and 21.

Am J Med Genet Part A 149A:2716–2722.

! 2009 Wiley-Liss, Inc. 2716

the earliest and then latestmaternal date of birth to be correct in thesevenwomenwhose birth dates differed bymore than a year left therelative risks unaltered to one decimal place. Similarly, assumingtrisomic pregnancy data to be correct in BDRWA records withinconsistent maternal dates of birth rather than using their modesand means left relative risks unchanged to one decimal place.

As expected, there was significant evidence that women with aprevious trisomy 21 pregnancy have greater risk of a future trisomy21pregnancy,RR¼ 2.2 95%CI (1.6, 2.9) (seeTable IV). Therewas asuggestion that the risk of a subsequent pregnancy being affected bytrisomy 13 after a previous trisomy 21 pregnancy was increased(RR¼ 2.0), and that the risk of subsequent trisomy 18 was alsoincreased slightly (RR¼ 1.3). Combining trisomies 13 and 18 insubsequent pregnancy, the RR of a different trisomy subsequent totrisomy 21 was 1.4.

There was a significantly increased risk of recurrence of thesame trisomy following trisomy 13 (RR¼ 9.5) and trisomy 18(RR¼ 3.1). When combining previous trisomies 13 and 18, there

was evidence that women who have had a pregnancy with eithertrisomy 13 or 18 were at greater risk of the same trisomy recurring,RR¼ 3.8, 95% CI (1.5, 7.9). The risk of a woman with a previoustrisomy 13 or 18 pregnancy having a future pregnancy affected by adifferent trisomy did not appear to be elevated, RR¼ 1.1.

Table V shows the relative risks according to the age of themother at the previous trisomic pregnancy. The relative risk oftrisomy 21 subsequent to trisomy 21 was greater for women under35 years at the previous pregnancy, as was the risk of the sametrisomy and of a different trisomy subsequent to trisomy 13 or 18.The relative risks of a different trisomy subsequent to trisomy 21were similar for women under 35 and women 35 and over at theirprevious pregnancy.

DISCUSSION

This study found similar patterns in the recurrence of trisomies 13and18 to those already established for trisomy21 [Warburton et al.,

TABLE III. Number of Subsequent Pregnancies to Women With a Previous Trisomic Pregnancy When Aged <35 Years and At Least OneSubsequent Pregnancy, by Previous Trisomy and Age at Subsequent Pregnancy

Previoustrisomy

Number ofwomen <35 years

Subsequent pregnanciesa <35 years Subsequent pregnanciesa "35 years

T13 T18 T21 Unaffected T13 T18 T21 UnaffectedT13 199 2 1 1 257 0 1 0 56T18 314 0 2 2 385 0 0 0 81T21 1,242 2 1 14 1,381 0 1 6 437

All 1,755 4 4 17 2,023 0 2 6 574

aRegardless of outcome/time at outcome.

TABLE IV. Observed and Expected Numbers of Subsequent Trisomic Pregnancies, and Relative Risk, by Trisomy in Previous and SubsequentPregnancies

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 0T18 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 dataT13 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)

aAfter adjustment for terminations before 15 weeks.

DE SOUZA ET AL. 2719

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 21Elizabeth De Souza,1 Jane Halliday,2 Annabelle Chan,3 Carol Bower,4 and Joan K. Morris1*1Barts & The London School of Medicine and Dentistry, Queen Mary University of London, Wolfson Institute of Preventive Medicine, London, UK2Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia3South Australian Birth Defects Register, Children, Youth and Women’s Health Service, North Adelaide, South Australia4Birth 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

Theobjectivewas to establishwhether the riskof trisomies 13, 18,and 21 (Patau, Edwards, and Down syndrome, respectively) in asubsequent pregnancy is raised for women who have had aprevious pregnancy with trisomy 13, 18, or 21. Birth defectregister data were used to investigate this issue. Pregnancy datafrom three Australian population-based birth defect registerscontained 5,906 women with a previous trisomy 13, 18, or 21pregnancy inwhom therewere 3,713 subsequent pregnancies, 75of which were trisomic. Relative risk of subsequent trisomy at15 weeks gestation was estimated by comparing the observednumber of subsequent trisomies with the expected number ofsubsequent trisomies based on maternal age-related risk. Therewas evidence of increased risk of the same trisomy subsequent toa previous pregnancy with trisomy 13 or 18 (RR¼ 3.8 (1.5, 7.9)),the increase in risk being greater for women aged under 35 at theprevious trisomic pregnancy (RR¼ 7.8 (2.1, 20.2)). There wasalso evidence of increased risk of trisomy 21 subsequent toprevious trisomy 21 (RR¼ 2.2 (1.6, 2.9)), again higher in womenunder 35 at previous affected pregnancy (RR¼ 3.5 (2.1, 5.5)).There was a suggestion that the risk of a different trisomysubsequent to trisomy 21 may also be increased (RR¼ 1.4(0.7, 2.5)). In conclusion, women who have had a previoustrisomic pregnancy, particularly those under 35 years of age atthe time, appear to be at an increased risk of future pregnanciesbeing trisomic. ! 2009 Wiley-Liss, Inc.

Key words: trisomy; recurrence risk; Down syndrome; Patausyndrome; Edwards syndrome

INTRODUCTION

The risk of a future pregnancy being affected by trisomy 21 is knownto be increased for women who have already had a trisomy 21pregnancy. The amount by which their risk increases is a constantdetermined by the age at which the first affected pregnancyoccurred, and is greater for younger women than older women[Morris et al., 2005]. Less is known about whether the risk of othertrisomies behaves in a similar way.

Warburton et al. [2004] estimated trisomy recurrence risk invarious trisomies by analyzing subsequent cases identified by

prenatal diagnosis in women with a previous prenatal diagnosisof trisomy, monosomy X, or triploidy. They compared the numberof cases observed in the prenatal diagnoses to the numbers expectedbased on the maternal age-related risk for the women undergoingprenatal diagnosis. They reported a significantly increased risk oftrisomy 13 or 18, XXX or XXY following a trisomy 21 diagnosis(SMR¼ 2.3 (90% CI 1.5, 3.8)). They also found that following anyof trisomy 13, 18, or 21, XXX or XXY, the risk of a different trisomywas significantly increased, supporting the hypothesis that somewomen have a higher risk for nondisjunction than others of thesame age [Warburton et al., 2004]. In order to providemore specificevidence that would be relevant to antenatal screening, geneticcounseling, and research into nondisjunction and risk of trisomy,we investigated the risks of the sameor different trisomies followingtrisomies 13, 18, and 21. More accurate estimates of the maternalage-related risks of each trisomy and of fetal loss are available nowthanwhenWarburton et al. conducted their analysis, and thesehavebeen used in this study [Savva et al., 2006;Morris and Savva, 2008].

MATERIALS (PREGNANCIES STUDIED)

Data in this study were provided by three Australian registers:the South Australian Birth Defects Register (SABDR, http://www.wch.sa.gov.au/services/az/other/phru/birthdefect .html,

*Correspondence to:Joan K. Morris, Barts & The London School of Medicine and Dentistry,Queen Mary University of London, Wolfson Institute of PreventiveMedicine, Charterhouse Square, London EC1M 6BQ, UK.E-mail: [email protected] online 16 November 2009 in Wiley InterScience(www.interscience.wiley.com)DOI 10.1002/ajmg.a.33099

How to Cite this Article:De Souza E, Halliday J, Chan A, Bower C,Morris JK. 2009. Recurrence risks fortrisomies 13, 18, and 21.

Am J Med Genet Part A 149A:2716–2722.

! 2009 Wiley-Liss, Inc. 2716

the earliest and then latestmaternal date of birth to be correct in thesevenwomenwhose birth dates differed bymore than a year left therelative risks unaltered to one decimal place. Similarly, assumingtrisomic pregnancy data to be correct in BDRWA records withinconsistent maternal dates of birth rather than using their modesand means left relative risks unchanged to one decimal place.

As expected, there was significant evidence that women with aprevious trisomy 21 pregnancy have greater risk of a future trisomy21pregnancy,RR¼ 2.2 95%CI (1.6, 2.9) (seeTable IV). Therewas asuggestion that the risk of a subsequent pregnancy being affected bytrisomy 13 after a previous trisomy 21 pregnancy was increased(RR¼ 2.0), and that the risk of subsequent trisomy 18 was alsoincreased slightly (RR¼ 1.3). Combining trisomies 13 and 18 insubsequent pregnancy, the RR of a different trisomy subsequent totrisomy 21 was 1.4.

There was a significantly increased risk of recurrence of thesame trisomy following trisomy 13 (RR¼ 9.5) and trisomy 18(RR¼ 3.1). When combining previous trisomies 13 and 18, there

was evidence that women who have had a pregnancy with eithertrisomy 13 or 18 were at greater risk of the same trisomy recurring,RR¼ 3.8, 95% CI (1.5, 7.9). The risk of a woman with a previoustrisomy 13 or 18 pregnancy having a future pregnancy affected by adifferent trisomy did not appear to be elevated, RR¼ 1.1.

Table V shows the relative risks according to the age of themother at the previous trisomic pregnancy. The relative risk oftrisomy 21 subsequent to trisomy 21 was greater for women under35 years at the previous pregnancy, as was the risk of the sametrisomy and of a different trisomy subsequent to trisomy 13 or 18.The relative risks of a different trisomy subsequent to trisomy 21were similar for women under 35 and women 35 and over at theirprevious pregnancy.

DISCUSSION

This study found similar patterns in the recurrence of trisomies 13and18 to those already established for trisomy21 [Warburton et al.,

TABLE III. Number of Subsequent Pregnancies to Women With a Previous Trisomic Pregnancy When Aged <35 Years and At Least OneSubsequent Pregnancy, by Previous Trisomy and Age at Subsequent Pregnancy

Previoustrisomy

Number ofwomen <35 years

Subsequent pregnanciesa <35 years Subsequent pregnanciesa "35 years

T13 T18 T21 Unaffected T13 T18 T21 UnaffectedT13 199 2 1 1 257 0 1 0 56T18 314 0 2 2 385 0 0 0 81T21 1,242 2 1 14 1,381 0 1 6 437

All 1,755 4 4 17 2,023 0 2 6 574

aRegardless of outcome/time at outcome.

TABLE IV. Observed and Expected Numbers of Subsequent Trisomic Pregnancies, and Relative Risk, by Trisomy in Previous and SubsequentPregnancies

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 0T18 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 dataT13 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)

aAfter adjustment for terminations before 15 weeks.

DE SOUZA ET AL. 2719

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. êTFP. êTécnicas 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. Marcadores ecográficos del primer trimestre y cribado combinado. Laura Sotillo Mallo.

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

Health & Medicine

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