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Non-Invasive Prenatal Screeningand
Other Screening
Dr Jay MarlowObstetrician and
Maternal Fetal Medicine
Sub-Specialist
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Choice
• Nothing
• Combined Screening
• NIPT
• Why? Knowledge? Options? Change
care?
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COMBINED FIRST TRIMESTER
SCREEN
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Maternal Risk of T21 increase with age
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Aneuploidy Screening Approach:
Observed Detection Rates
1960 1980 1990 2005 2011
Det
ecti
on
Rat
e (%
)
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CFTS
• Maternal bloods
– From 10 weeks
– PAPP-A
– Free HCG
• Nuchal translucency
– 11-13+6 weeks
• Combined
– DR of 91-92%
– FPR 5%
• However NSU
– DR 72-75%
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Nuchal Translucency
• Subcutaneous fluid-filled space located between back of fetal neck and skin
• Measured on USS between 11-13+6 weeks• measurement is not valid outside of this time period
• NT increases with gestational age
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NT Standard (FMF)
• CRL 45 – 84mm
• Midline- Sagittal plane
• Mid sag face echogenic tip of nose
• Neutral position• not extended or flexed
• Away from amnion
• Head and thorax occupy >1/3 of the image
• Widest part of translucency measured• “on-to-on technique”
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Nuchal Translucency
• Between 11-13+6 weeks >3.5mm considered elevated• Diagnostic testing indicated
• Tertiary anatomy scan at 18-20 weeks
• Fetal screening echocardiogram indicated ~24 weeks
• Increased NT thickness is associated with:
• Trisomies 21, 18, 13, triploidy and Turner syndrome• Spontaneous fetal loss• With normal chromosomes:
• cardiac defects, diaphragmatic hernia, pulmonary defects, skeletal dysplasias
• congenital infection• metabolic/haem disorders • rare single gene disorders
Nicolaides. Am J Obstet Gynecol 2004;191:45Souka et al. Ultrasound Onstet Gyncol 2001;18:9
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Chance of a normal birth varies with size of NT measurement
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Nasal Bone
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WHY IS OUR DETECTION
RATE SO LOW?
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Standard View
Nasal Bone
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Case
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Nuchal Comparison
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Case
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Nasal Bone Comparison
Nasal Bone
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Why is our detection rate so low?
• Incorrect maternal data
• Lack of certification/quality control for nuchal
• Erroneous reporting of the nasal bone
• Self reported postnatal diagnosis of T21.
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SNP-based NIPTNon-Invasive Prenatal Testing
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What’s in a name?
• NIPTest
• NIPScreen
• Down Syndrome blood test
SCREENING TEST
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What is NIPT?
• Screening test to prenatally detect – Down syndrome
– other aneuploidies (extra or missing chromosomes)• trisomy 21, 18, 13
• trisomy of sex chromosomes (XXX, XXY, XYY)
• Turner syndrome (monosomy X)
• triploidy (extra copy of all chromosomes)
– Microdeletions
– Chorionicity in twins
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NIPT
• Measures circulating cell-free DNA (cfDNA) from placenta present in maternal blood
• ~10% of DNA in maternal blood– Increases with gestational
age
• As early as 9-10 weeks gestation – (company specific)
• Dating U/S –– viability, accurate GA,
exclude multiples
cfDNA comes from apoptotic cells derived from:
Maternal Circulation• Adipocytes
• White Blood Cells
• Fetal• Placental cells (trophoblasts) in the
maternal circulation
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The Evolution of NIPT
24
2011 2012 2013 2014-2017
Other labs enter domestic NIPT space using
1st generation counting technologies
1st generation:Quantitative or
“Counting”
2nd generation:Qualitative or “SNP-based”
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NIPT Methodologies
25
Counting SNP
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SNP-based NIPT
27
Whole chromosome conditions
• Trisomy 21, 18, 13
• Monosomy X
• Sex chromosome trisomies
• Triploidy
• Complete molar pregnancy
Optional
• 22q11.2 deletion syndrome
• Additional microdeletions
• Fetal sex
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Counting
28
Chromosome 3Chromosome 21
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Counting
29
Chromosome 3Chromosome 21
Expected Amount: 20% 80%
Observed Amount: 25% 75%
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SNP = Single Nucleotide Polymorphism
• A DNA sequence variation occurring when a single base pair is changed
• Normal genetic changes that occur in every person
• SNP-based NIPT analyzes more than 13,000 SNPs
30
A A C C T A
T T G G A T
A A C T T A
T T G A A T
SNP
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SNP-based NIPT Technology
31
Proprietary SNP analysis distinguishes between maternal & fetal DNA
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Clinical Advantages of SNP-based NIPT
• Fetal fraction
• Maternal contribution
• Vanishing twins
• Fetal sex accuracy
• Triploidy/complete mole
32
Uniquely differentiates between maternal and fetal DNA
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SNP-based Aneuploidy Screening for Twins
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Benefits of NIPT
• Fewer women having diagnostic tests – associated risk of pregnancy loss
• Early test result (drawn at ≥ 9-10 weeks at earliest)
• No risk of miscarriage
• Detects the most common chromosomal aneuploidies
• Higher detection rates and lower false positive rates than CFTS
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What can go wrong with NIPT?
• Unusual result
• Not a true result
• Only detects those conditions it tests for
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False negative/positive
• Check with invasive testing if you are
going to act on the result
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Do I still need a nuchal scan?
• Yes…..Early anatomy scan
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What if an anomaly occurs later?
• False negative
• Another anomaly
• A non-genetic syndrome
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How do I counsel?
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Results
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Perinatology.com
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Questions???