NIPT
NON – INVASIVE PRENATAL TEST
GENDIA
Antwerp, Belgium
NIPT
NON – INVASIVE PRENATAL TEST
Testing of cff DNA (cell free fetal DNA)
from maternal blood during pregnancy
for trisomy 21, 18 and 13
www.DOWNsyndromeNIPT.info
Frequency of fetal aneuploidies
Aneuploidy
Syndrome
Frequency (live births)
Trisomy 21
Down syndrome
1 in 700
Trisomy 18
Edwards syndrome
1 in 5,000
Trisomy 13
Patau syndrome
1 in 16,000
Trisomy 21, 18, 13 screening
Trisomy 21 (Down syndrome)
Trisomy 18 (Edwards syndrome)
Trisomy 13 (Patau syndrome)
Risk Down syndrome versus Maternal Age
Age
Frequency (live births)
< 35
37
< 0.3 %
0.5 %
40
1%
50
10 %
History of Down syndrome screening
• 1980 : Amniocentesis (advanced maternal age)
• 1990 : Triple screening (T21, T18 and T13)
• 2000 : First trimester screening (T21, T18 and T13)
• 2013 : Start of NIPT
• 2015 : NIPT greatly replaces first trimester screening
First trimester serum screening (FTS - 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
If the combi risk is increased ( > 1/300 in Belgium or > 1/200 in The Netherlands)
an invasive procedure (CVS / AC) or NIPT is recommended
Classical Down syndrome screening
NT (mm)
PAPP-A (MoM)
B-HCG (MoM)
Normal : 2.0
Normal : 1.0
Normal : 1.0
T21 :
3.4
T21 :
0.5
T21 :
2.0
T18 :
5.5
T18 :
0.2
T18 :
0.2
T13 :
4.0
T13 :
0.3
T13 :
0.5
Nicolaides et al 2008
NIPT history
•
1997 : Lo et al. :cff DNA in maternal circulation
•
2001 : Fetal Rh(D) genotype
•
2006 : Sexing fetus for :
1. X-linked genetic disorders
2. Sexing (China)
•
2011 : Detection trisomy 21/18/13 becomes possible
•
2012 : > 100.000 patients screened in China / USA
•
2013 : GENDIA starts with NIPT in Belgium and the Netherlands
•
2015 : GENDIA has completed 10.000 NIPT tests
NIPT essentials
1.
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 GENDIA
3.
TIMING: > week 10 (preferentially week 11-12)
4.
TURNAROUND TIME: < 2 weeks
5.
RELIABILITY: 99% for trisomy 21
6.
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
Cell Free Fetal DNA (cff DNA) in Maternal Blood
NIPT cff DNA
• < 1 % of total DNA in maternal circulation is fetal
• 5-30 % of cell-free DNA in maternal circulation is fetal
NIPT for trisomy 21
NIPT measures the ratio
of chromosome 21 sequence
versus control chromosome sequence
to exclude trisomy 21
NIPT cffDNA
cffDNA
Nl
T21
DNA
Nl
T21
Fetal
Maternal
• <1
of
Importance of fetal fraction
Fetal
Fraction
Expected
ratio for
Trisomy
4%
1.02
Maternal
10%
1.05
cfDNA
20%
1.10
40%
1.20
Fetal cfDNA
Reference
Chromosome
Chromosome 21
Sensitivity of NIPT for T21, T18, T13
Sensitivity
T21 : 99 %
T18 : 98 %
T13 : 90 %
False-negatives
If NIPT is normal, the residual risk for
trisomy 21, 18, 13 < 1 / 10.000
Specitivity NIPT for T21, T18, T13
Specitivity
T21 > 99 %
T18 > 99 %
T13 > 99 %
False-positives
If NIPT is abnormal, the risk that the fetus
has no trisomy 21, 18, 13 is very small
NO NIPT for sex aneuploidies
• Phenotype for sex aneuploidies is highly variable
• Mosaicism in the fetus is a problem
• Mosaicism in the mother is a problem
• NIPT for sex aneuploidies is less accurate
NIPT Indications
NIPT is the test of choice when there is :
• Increased maternal age
• Increased risk on Combination or triple test
• Anxiety for invasive procedure (AC / CVS)
NIPT Contra indications
NIPT is NOT the test of choice when there is :
•
Fetal anomalies on ultrasound
• A triplet pregnancy
• Vanishing twin
• Known genetic anomalies that cannot be diagnosed by NIPT
NIPT Advantages versus
combi test with AC / CVS
• High sensitivity (few false-negatives)
• High specificity (few false-positives)
• More than T21
• Non-invasive : no fetal risk
• CVS : Risk of miscarriage : 1-2 %
• AC : Risk of miscarriage : 0.5 %
NIPT versus FTS
FTS
NIPT
False negatives
> 20 %
2%
False positives
95 %
2%
NIPT
versus classical screening
Classical
AC / CVS
NIPT
Safe
Not safe
Safe
Not reliable
Reliable
Reliable
Companies offering NIPT
• ARIOSA (US)
• VERINATA (US)
• NATERA (US)
• SEQUENOM (US)
• BGI (China)
• LIFE-CODEXX (Germany)
Academic Hospitals offering NIPT
None of the genetic centers
in the academic centres
in Belgium or the Netherlands
currently offers a validated NIPT test
with published results
GENDIA offers
the HARMONY test from ARIOSA
• ARIOSA (Harmony)
GENDIA offers the Harmony test from ARIOSA
• Almost 400.000 Harmony tests performed
• > 20.000 tests in clinical trials
• > 20 scientific papers
• Very low false-positive and false-negative rate
• Low failure rate (0.6 %)
• Fast turnaround
NIPT results
1. Normal result : no specific follow up necessary,
unless ultrasound examination of the fetus reveals anomalies
2. Test failure : in < 2 % pregnancies not enough fetal DNA :
NIPT repeated at no extra cost.
3. Abnormal NIPT result : confirmation by amniocentesis or
chorionic biopsy
NIPT versus FTS in Belgium
FTS
NIPT
Number screenings
100.000
100.000
Expected T21
200 (1/500)
200 (1/500)
Detection rate
75 %
99 %
T21
150
198
False-negatives
50 (25 %)
2 (1 %)
False-positives
4990 (4.8 %)
< 100 (0.03 %)
Iatrogenic Miscarriage
50
1
NIPT results GENDIA
• Total number NIPT : 10.000
• Total number of trisomies : 131
» T21 : 111
» T18 : 11
» T13 :
9
• 1 false-positives (T13)
• 4 false-negatives (T21, T13, twice T18)
• 2 inconclusive results (T18, T13)
• No result : 0.7 %
How offer NIPT to your patients ?
1. Refer to the consultation :
Email : NIPT@GENDIA.net to ask for an appointment
2. Take blood yourself with our sample kit :
Email : NIPT@GENDIA.net to ask for kits
www.DOWNsyndromeNIPT.info
www.DOWNsyndromeNIPT.info