Post on 14-Sep-2019
Test di screening per le anomalie cromosomiche nel 2018:
come condurre il counselling, come documentare le scelte
Dipartimento di Ostetricia e Ginecologia
Università di Brescia / ASST Spedali Civili di Brescia
federico.prefumo@asst-spedalicivili.it
Federico Prefumo
Primi anni 2010
Ecografia + biochimica
Test invasivi
Studio osservazionale multicentrico sul ricorso alle procedure di valutazione del rischio e/o di diagnosi prenatale Tesi di dottorato di SIMONA FUMAGALLI SCUOLA DI DOTTORATO IN SCIENZE FISIOPATOLOGICHE, NEUROPSICOBIOLOGICHE E ASSISTENZIALI DEL CICLO DELLA VITA Università di Milano A.A. 2010/2011
SERVIZIO IN GRAVIDANZA
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ginecologo privato consultorio ambulatorioospedaliero
patologia
fisiologia
ostetriche
Rischio, probabilità e scelta
Royal College of Obstetricians and Gynaecologists. Clinical Governance Advice No. 7, 2008
Rischio, probabilità e scelta
Royal College of Obstetricians and Gynaecologists. Clinical Governance Advice No. 7, 2008
Rischio, probabilità e scelta
Zipkin DA et al. Ann Intern Med. 2014;161:270-280.
Rischio, probabilità e scelta
Zipkin DA et al. Ann Intern Med. 2014;161:270-280.
Rischio, probabilità e scelta
OAPR: odds of being affected after a positive result Dopo uno screening a rischio, si conferma che il feto è affetto ogni X amniocentesi/villocentesi eseguite
Screening su cffDNA
Results
Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-
analysis MM Gil et al., UOG 2017
Aneuploidy No. of studies
No. of affected fetuses
No. of unaffected fetuses
Pooled detection rate (95% CI)
Pooled false-positive rate (95% CI)
Trisomy 21
30 1963 223 932 99.7% (99.1 to 99.9%) 0.04% (0.02 to 0.07%)
Trisomy 18 25 563 222 013 97.9% (94.9 to 99.1%) 0.04% (0.03 to 0.07%)
Trisomy 13 23 119 212 883
99.0% (65.8 to 100%) 0.04% (0.02 to 0.07%)
Monosomy X
11 36 7676
95.8% (70.3 to 99.5%) 0.004% (0.0 to 0.08%)
Other sex aneuploidies
8 17 5403
100% (83.5 to 100.0%) 0.004% (0.0 to 0.08%)
Trisomy 21 in twins
5 24 1111 100% (95.2 to 100.0%) 0.0% (0.0 to 0.003%)
Screening su cffDNA - fallimento
Wang E et al. Prenatal Diagnosis 2013, 33, 662–666
Screening su cffDNA - fallimento
Wang E et al. Prenatal Diagnosis 2013, 33, 662–666
Integrare NT+biochimica e cffDNA
First-line screening by cfDNA testing alone in a population of 100000 pregnancies,
including 294 with trisomy 21
First-trimester contingent screening for trisomy 21 by biomarkers and maternal blood
cell-free DNA testing Nicolaides et al., UOG 2013
100,000 pregnancies
Unaffected n=99,706 Trisomy 21 n=294
Maternal blood cfDNA testing
Positive n=96
Result n=95,718
No result N=3,988
Chorionic villus sampling 471 / 100,000 (0.47%)
False positive rate 180 / 99,706 (0.18%)
Positive n=281
No result n=12
Positive n=10
Result n=282
Detection rate 291 / 294 (99.0%)
4% 4%
0.1% 99.5%
85.2%
Combined test
risk ≥ 1:100
Positive n=84 2.1%
Contingent screening by combined test and cfDNA testing in pregnancies with a risk
of ≥ 1:3000 in a population of 100000, including 294 with trisomy 21
First-trimester contingent screening for trisomy 21 by biomarkers and maternal blood
cell-free DNA testing Nicolaides et al., UOG 2013
100,000 pregnancies
Unaffected n=99,706 Trisomy 21 n=294 Risk >1:3,000 in screening by:
MA, fetal NT, ß-hCG, PAPP-A
Unaffected n=24,229 Trisomy 21 n=288
Maternal blood cfDNA testing 24,517 / 100,000 (24.5%)
Positive n=83
Result n=23,260
Positive n=23
No result n=23,260
Chorionic villus sampling 391 / 100,000 (0.39%)
False positive rate 106 / 99,706 (0.11%)
Positive n=275
No result n=12
Positive n=10
Result n=276
Detection rate 285 / 294 (96.9%)
4% 4%
0.1% 99.5%
87.0%
97.9%
8.6%
24.3%
Combined test
risk ≥ 1:100
Fetal Medicine Foundation, 2004
Linee guida ISUOG Primo trimestre
Ultrasound Obstet Gynecol 2013; 41: 102–113
Organ/anatomical area
Present and/or normal ?
Head Present; Cranial bones; Midline falx; Choroid-
plexus-filled ventricles
Neck Normal appearance; Nuchal translucency
thickness (if accepted after informed consent and
trained/certified operator available)*
Face Eyes with lens* Nasal bone*
Normal profile/mandible* Intact lips*
Spine Vertebrae (longitudinal and axial)* Intact overlying
skin*
Chest Symmetrical lung fields; No effusions or masses
Heart Cardiac regular activity; Four symmetrical
chambers*
Abdomen Stomach present in left upper quadrant; Bladder*
Kidneys*
Abdominal wall Normal cord insertion
No umbilical defects
Extremities Four limbs each with three segments; Hands and
feet with normal orientation*
Placenta Size and texture
Cord Three-vessel cord*
The role of NIPT as an alternative to standard invasive testing
in women considered to be at very high risk (>1:10) after
combined screening but with no ultrasound anomaly should
be evaluated in prospective studies. Expert opinion currently
suggests that NIPT should not replace invasive testing in this
group. This is based on the fact that only 70% of
chromosomal abnormalities in this population are trisomy 21,
18 or 13.
In the presence of a fetal structural anomaly, the indications
for fetal karyotyping and/or microarray testing should not be
modified by a normal NIPT result obtained previously.
Results
Clinical implementation of cfDNA testing MM Gil et al., UOG 2016
• 12 134 women offered combined screening, 11 921 accepted (98.2%)
• 229 (1.9%) excluded from analysis due to pregnancy loss with no known karyotype (n=169)
or lost to follow-up (n=60)
• Mean maternal age in study population: 31 years
• Based on results of the combined screening, the 11 692 pregnancies were classified as
– High risk: 460 women (3.9%)
– Intermediate risk: 3552 women (30.4%)
– Low risk: 7680 women (65.7%)
• Diagnosis of trisomies in the study population of 11 692 pregnancies was
– Trisomy 21: 47 cases
– Trisomy 18: 24 cases
– Trisomy 13: 4 cases
– No trisomies: 11 617 pregnancies
Results: parental decision regarding further investigations
Clinical implementation of cfDNA testing MM Gil et al., UOG 2016
• In the high-risk group, 38% opted for CVS, 60% for cfDNA and 2% for no further investigation
• In the intermediate-risk group 92% opted for cfDNA and 9% for no further investigation
Results: pregnancy outcome in trisomies
Clinical implementation of cfDNA testing MM Gil et al., UOG 2016
• Among 43 prenatally detected cases of trisomy 21
– 74% (32/43) opted for pregnancy termination
– 26% (11/43) chose to continue with pregnancy
• 32% (15/47) of trisomy 21 fetuses were live born
• Among 28 prenatally detected cases of trisomy 18 or 13
– 82% (23/28) opted for termination of pregnancy
– 18% (5/28) chose to continue with pregnancy (resulting in 3 miscarriages or fetal deaths and 2
neonatal deaths)
Scelta informata
Lewis C et al. Prenatal Diagnosis 2017, doi: 10.1002/pd.5154
Scelta informata
Lewis C et al. Prenatal Diagnosis 2017, doi: 10.1002/pd.5154
Scelta informata
Lewis C et al. Prenatal Diagnosis 2017, doi: 10.1002/pd.5154
RAPID Evaluation Study
Routine prenatal care
Informed choice
93.5% 76.5%
Good knowledge
96.7% 88.8%
Primi anni 2010
Ecografia + biochimica
Test invasivi
2018
Ecografia + biochimica
Test invasivi
cffDNA
Array
2018
Ecografia + biochimica
Test invasivi
cffDNA
Array
13,18,21,X,Y 13,18,21,X,Y Altre aneuploidie
Sindromi Malformazioni
Aneuploidie ≥10MB
Aneuploidie ≅250 kB
2018
Ecografia + biochimica
Test invasivi
cffDNA
Array
13,18,21,X,Y 13,18,21,X,Y Altre aneuploidie
Sindromi Malformazioni
Aneuploidie ≥10MB
Aneuploidie ≅250 kB
Tasso
perdita
fetale 1%
2018
Ecografia + biochimica
Test invasivi
cffDNA
Array
13,18,21,X,Y 13,18,21,X,Y Altre aneuploidie
Sindromi Malformazioni
Aneuploidie ≥10MB
Aneuploidie ≅250 kB
Tasso
perdita
fetale <1%
www.ecm.aogoi.it
Punti chiave
• Differenza tra test di screening e test diagnostici
• Accuratezza e limitazioni dei diversi test di screening
• Rischio dei test diagnostici
• Test di screening a rischio ≠ feto malato
• Test di screening a rischio possibilità di eseguire test diagnostico
• Test diagnostico non è automatico in caso di screening a rischio
• Test diagnostico patologico possibilità di proseguire o meno con la gravidanza, percorso perinatale dedicato
• Accessibilità in regime di SSN e costi
www.sieog.it
Grazie