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Huisartsensym

posium 2014

NIPT (or NIPS?)

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Huisartsensym

posium 2014

NIPT

NON – INVASIVE PRENATAL TESTING

Testing of cff DNA (cell free fetal DNA)

from maternal blood during pregnancy

for trisomy 21, 18 and 13

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Huisartsensym

posium 2014

Trisomy 21, 18, 13 screening

Trisomy 21 (Down syndrome)

Trisomy 18 (Edwards syndrome)

Trisomy 13 (Patau syndrome)

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Huisartsensym

posium 2014

Risk Down syndrome versus Maternal Age

Age Frequency (live births)

< 35 < 0.3 %

37 0.5 %

40 1 %

50 10 %

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Huisartsensym

posium 2014

History Down syndrome screening

• 1980 : Amniocentesis (advanced maternal age)

• 1990 : Triple screening (T21, T18 and T13)

• 2000 : First trimester screening (T21, T18 and T13)

• 2012 : First trimester screening + NIPT (T21, T18

and T13)

• 201? : NIPT (extensive genetic screening)

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Huisartsensym

posium 2014

Serum Down syndrome screening

• Triple screening ( > 1990)

– Maternal age

– Serum : AFP, HCG, free oestriol

• Combi test ( > 2000)

– Maternal age

– Nuchal translucency (NT)

– Serum : free B-HCG, PAPP-A

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Huisartsensym

posium 2014

Classical Down syndrome screening First trimester serum screening (combi test)

Combi test: Risk calculated from:

1. Maternal age: the higher the age, the higher the risk of T21, T18, T13

2. Nuchal translucency (NT): the higher the NT,

the higher the risk of T21, T18, T13

3. Serum parameters PAPP-A and free B HCG

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Huisartsensym

posium 2014

NIPT history

• 1997: Lo et al.:cff DNA in maternal circulation

• 2006: Sexing fetus for:

1. X-linked genetic disorders

2. Sexing in China

300.000 girls / yr killed

• 2011: Detection trisomy 21/18/13

• 2013: Daily > 2000 NIPT tests worldwide

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Huisartsensym

posium 2014

NIPT essentials1. TEST : trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome),

trisomy 13 (Patau syndrome).Also sex of the fetus is determined.

2. SAMPLE: Specific test kits provided by GENDIA3. TIMING: > week 104. TURNAROUND TIME: < 2 weeks5. RELIABILITY: > 99% for trisomy 216. INDICATIONS: Although NIPT can be performed in every pregnancy, it is

especially indicated: • If the triple test or first trimester screening indicates an increased risk• Advanced maternal age • Anxiety for invasive procedures

7. CONTRAINDICATIONS: NIPT is not the test of choice when there is : • Fetal anomalies on ultrasound • Severely elevated NT (nuchal translucency) with normal PAPP-A and

free B HCG• A triplet pregnancy, vanished twin

8. PRICE: 450,- Euro

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Huisartsensym

posium 2014

NIPT cff DNA

• < 1 % of total DNA in maternal circulation is fetal

• 5-30 % of cell-free DNA in maternal circulation is fetal

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Huisartsensym

posium 2014

NIPT for trisomy 21

NIPT measures the ratio of

chromosome 21 sequence versus

control chromosome sequence to

exclude trisomy 21.

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Huisartsensym

posium 2014

NIPT Indications

NIPT is currently the test of choice when there is:

• Increased maternal age

• Increased risk on Combination or triple test

• Down syndrome in previous pregnancy

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Huisartsensym

posium 2014

NIPT Contra indications

NIPT is NOT the test of choice when there is:

• Fetal anomalies on ultrasound

• Severely elevated NT (nuchal translucency) with normal PAPP-A and HCG

• A triplet pregnancy

• Vanishing twin

• Known genetic anomalies that cannot be diagnosed by NIPT

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Huisartsensym

posium 2014

NIPT advantages versus combi test with AC / CVS

• High sensitivity (few false-negatives)

• High specificity (few false-positives)

• Non-invasive: no fetal risk• CVS: Risk of miscarriage: 1-2 %• AC: Risk of miscarriage: 0.5 %

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Huisartsensym

posium 2014

NIPT versus classical screening in a country with 10 million inhabitants

Classical NIPT

Number screenings 100.000 100.000

Expected T21 200 (1/500) 200 (1/500)

Detection rate 73 % < 99 %

T21 146 199

False-negatives 54 (27 %) < 1 (0.3 %)

False-positives 4990 (4.8 %) < 100 (0.03 %)

Iatrogenic Miscarriage 50 1

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Huisartsensym

posium 2014

30 year old mother 1-1000 child with down syndrome

Down syndrome pregnancy Unaffected pregnancy

Test positive99.5 (True positive) 100 (False positive)

Test negative0.5 (False negative) 99,800 (True Negative)

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Huisartsensym

posium 2014

NIPT : the future

1. Comparative genomic hybridization– All chromosomes– Small deletions - duplications

2. Detection common monogenic mutations - cystic fibrosis- Spinale musculaire atrofie

3. Whole exome / genome sequencing

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Huisartsensym

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dewereldmorgen.beBart Moens gezinswetenschapper

• Zullen ouders zich in de toekomst alsmaar meer moreel en/of sociaal verplicht voelen om te kiezen voor prenatale diagnostiek?

• Zullen ouders in de toekomst nog vrij kunnen en mogen kiezen om een problematische zwangerschap uit te dragen?

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Huisartsensym

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Mark Leach is an attorney with a Master's in

Bioethics, focusing on health law and public.• not the holy grail

of prenatal testing• it is a screening

test, of placental DNA, effective in high-risk populations

• fewer invasive diagnostic procedures

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Huisartsensym

posium 2014

INN

OVATIE

Huisartsensym

posium 2014

Harmony(Ariosa – USA)

KUL(Leuven)

Trisomies T21, T18, T13 T21

Turnaround time 11 days 21 days

External validation +++++++++ ---------Twins Yes No

Egg donor Yes NoWomen > 100 kg Yes No

Total patients analysed > 300.000 < 1000

Fetal fraction Yes ??????

Publications with clinical studies 6 0

Earlist sample Week 10 Week 11

Logistics Sample taken by AML ??????

Price 450 Euro 460 Euro

ARIOSA vs KUL