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Prenatal Screening Part Ifrom Embryo to 14 weeks
Ken Seethram, MD, FRCSC
Co-Director
Pacific Centre for Reproductive Medicine Clinics Vancouver, Edmonton
Clinical Associate Professor, Universities of British Columbia and Alberta
Faculty/Presenter Disclosure
Relationships with commercial interests:
Grants/Research Support:
Ferring Canada
EMD Serono
Merck Canada
Igenomix Global
Speakers Bureau/Honoraria/consulting fees: None
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Disclosure of Commercial Support
This program has not received financial support
This program has not received in-kind support
Potential for conflict(s) of interest: none
Mitigating Potential BiasAlthough research grants are received for other medical work, none of those grants apply to the content of prenatal screening
I am an accredited provider of the Fetal Medicine Foundation UK, for First trimester combined screening, which you will hear in this talk
Prenatal Screening - background
Prenatal screening is a very broad area of maternity care
Variations:Genetic screening
Anomaly screening
Twin screening
Hypertension/placental dysfunction screening
Prenatal genetic screening – has always been a key focus. It’s important, but keep in the front of your mind that we
are gradually moving towards screening that includes genetics, anomalies, and hypertension screening
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Prenatal Visits
24/28w
Shift in Care
Prenatal Visits
32/34/36w-43w1920
1TM 2TM 3TM
1970 Prenatal Visits 24/28w
Ultrasound 20w
Prenatal Visits
32/34/36-42w
1986-1996
Amniocentesis
CVS
Prenatal Visits 24/28w
Ultrasound 20w
Amniocentesis/CVS
16-20w TMS/QUAD
Amniocentesis/CVS
16-20w TMS/QUAD
First Trimester Screening (FTS)
1992-2011
Prenatal Visits
32/34/36-42w
Prenatal Visits 24/28w
Ultrasound 20w
2011-2020
Prenatal Visits
32/34/36-41w
Amniocentesis/CVS
16-20w TMS/QUAD
FTS and NIPT
Prenatal screening – the shift
We have seen an enormous shift from 2TM and 3TM focus, into First Trimester Screening focus
Driven by early screening, early diagnosis, early management
Risk reduction strategies and better care in the 2nd and 3rd trimesters with increased 1st trimester knowledge
Downside: shift has pushed essential elements of prenatal care into the realm of providers who may not be doing prenatal care
Therefore, the primary maternity care provider (Family Physician, Midwife, and Obstetrician) is fundamental to
successful outcomes by providing the right early prenatal screening.
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Prenatal Screening - outline
Prenatal genetic screening – what?What are we screening for?
Who do we screen?
Prenatal Genetic screening – how?1. Pre-implantation Genetics
2. First trimester screening
3. NIPT
4. SIPS/IPS
5. Combined/Contingency screening
Pearls
What are we screening for?
The big things: aneuploidyMajor chromosome number deviations such as Trisomy's 21/18/13 (T21/18/13) and monosomy X (45X)
Increased incidence with age
The little things: subchromosomalDeletions/duplications of chromosomal segments
Single gene disorders
Chorionicity in twins
These are independent of age
Prenatal Screening
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AneuploidyGeneral population prevalence is for Trisomy 21: ~1/700 in Canada
T21 and 45X are the only two common aneuploidy conditions which are compatible with life
Other sex chromosome aneuploidy like XXY/XXX/XYY are generally low impact on health outcomes
Population prevalence estimates put T21 at 8.3/10000 (31,100) in Canada
It is a continuum from conceptus onwards - How common is it embryonic stage?
Current estimates say that 60% of all embryos in a woman aged 40 will have aneuploidy
What is the chance of a pregnancy being normal at a given age?.....
Prenatal Screening - aneuploidy
Risk of Down syndrome at 10w by maternal age
Age Chance of T21 Chance of normal
30 1:576 99.82%
35 1:229 99.56%
40 1:62 98.39%
42 1:35 97.14%
45 1:15 93.33%
Prenatal Screening - aneuploidy
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So in the advanced maternal age patient (aged 35-45) the chance of a normal outcome will range from 93-99%
The primary message here - pregnancy is a normal conditionthe vast majority of times, even as a woman ages beyond 40, the outcomes are excellent
Despite that - why has prenatal screening become so prevalent?
New technology gives more accuracy - (First Trimester screening, Non Invasive prenatal testing)
Google (the great physician, the best doctor ever)
Increased patient knowledge and possibly anxiety
The marketing machine of big genome
Prenatal Screening - aneuploidy
Prenatal Screening - aneuploidy
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Prenatal Screening - aneuploidy
Prenatal Screening - aneuploidy
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Now what about the little things?
Deletions/duplications of chromosomal segments
Single gene disorders
Chorionicity in twins
These are all outcomes from non-invasive prenatal testing (NIPT) and they are all exceptionally rare
Examples of deletions: 22q11.2, Prader Willi, Angelman’s, 1p36 etc.
<1:5000-1:10000 newborns
Note that although rare, they are not age-related
Prenatal Screening - subchromosomal
The Big Thing:
Aneuploidy
The Little Things:
Deletion/duplications
Single Gene disorders
Quick Summary
SCREENING
Increasing prevalence
with increasing age
Not age related
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Who do we screen?
So we know what we’re screening for
But WHO do we screen?
What we used to do – just screen patients over age 35
Who do we screen?
What we do now is super simple….
• SOGC, ACOG, ISPD, CCMG
• Why? A pregnant patient doesn’t care about the risk of her peers, she only cares about her risk.
• Keep in mind that provincial resources determine what is offered – but it is necessary to counsel women about what is offered and what is available
Every pregnant woman, regardless of age, and after an
informed consent process, should be offered prenatal
genetic screening for the most common aneuploidies
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The Little Things:
Deletion/duplications
Single Gene disorders
Quick Summary
The Big Thing:
Aneuploidy
Everyone
Why Who How
That’s what we’re
going to talk about
now
Prenatal genetic screening – HOW?
First Trimester Screening
Serum Integrated Prenatal Screening
Integrated Prenatal Screening
Non invasive prenatal testing (NIPT)
Combinations/contingency models
Pre-Implantation Genetic Testing – PGT
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rapidly increasing as part of IVF treatment
trophectoderm biopsy, Next Gen Sequencing
Older terms were PGD, PGS, Comprehensive chromosome screening (CCS), but the new global terms are;
Preimplantation genetic testing (PGT)
For Monogenic disorders (PGT-M)
For Aneuploidy (PGT-A)
For Chromosomal Structural Rearrangements (PGT-SR)
Proving very useful for embryo selection, and for management of complex genetic conditions
Prenatal genetic screening – what tools do we have?
Pre-Implantation Genetic Testing – PGT
Due to false positive and false
negative risks, these patients still
require prenatal genetic screening –
although their a priori risks are
lower than age based
Prenatal genetic screening – HOW?
First Trimester Screening
Serum Integrated Prenatal Screening
Integrated Prenatal Screening
Non invasive prenatal testing (NIPT)
Combinations/contingency models
Pre-Implantation Genetic Testing – PGT ✓
All of these tools use either the fetus or the placenta to give us information
FTS
SIPS
IPS
NIPT
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Prenatal genetic screening – HOW?
PlacentaWe get information of biochemical markers which move up or down in different genetic syndromes
These can be done in the first trimester (1TM) or second trimester (2TM) or both
Includes: HCG, PAPP-A, Inhibin-A, estriol, Alpha fetoprotein (AFP)
The HCG we measure in the 1TM is different than 2TM, but they give the same info
We can also get DNA fragments which we can compile to genome the baby (NIPT)
FetalUltrasound in the first or second trimester – global drift towards first trimester
Nuchal Translucency
Nasal bone
ductus venosus flow
anatomy survey in 1TM and 2TM
soft genetic markers in the 2TM
Prenatal genetic screening – HOW?
How can we use placental serum markers, and ultrasound markers in combination?
• This is how we derived combined prenatal screening
• QUAD, SIPS, IPS, FTS
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Prenatal genetic screening – HOW?
HCG
AFP
uE3
Inhibin-A
15-22W blood11-14W blood
QUADRUPLE PREGNANCY SCREEN75%
11-14W US
Prenatal genetic screening – HOW?
HCG
AFP
uE3
Inhibin-A
15-22W blood11-14W blood
PAPP-A
SERUM INTEGRATED PREGNANCY SCREEN80-82%
11-14W US
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Prenatal genetic screening – HOW?
HCG
AFP
uE3
Inhibin-A
15-22W blood11-14W blood11-14W US
PAPP-ANuchal Translucency
INTEGRATED PREGNANCY SCREEN84-88%
Prenatal genetic screening – HOW?
HCG
AFP
uE3
Inhibin-A
15-22W blood11-14W blood
PAPP-ANuchal Translucency
FIRST TRIMESTER PREGNANCY SCREEN
HCG
85%
11-14W US
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Prenatal genetic screening – HOW?
11-14W blood
PAPP-ANuchal Translucency
FIRST TRIMESTER PREGNANCY SCREEN
HCGNasal Bone
Ductus Venosus
96%
11-14W US
Prenatal genetic screening – HOW?
So to summarize: you can use placental proteins, early or late, and ultrasound (early)
Timing for results:
FTS provides results at
11-14w
QUAD/SIPS/IPS all provide
results at 16-22w
Timing will impact decision making if
abnormal results require more testing
or termination
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Prenatal genetic screening – what tools do we have?
First Trimester Screening
Serum Integrated Prenatal Screening
Integrated Prenatal Screening
Non invasive prenatal testing (NIPT)
Combinations/contingency models
Pre-Implantation Genetic Testing – PGT ✓
✓
✓
✓
Prenatal genetic screening – NIPT and the genome
Non-invasive Prenatal Testing (NIPT)DNA is liberated from the developing placenta and can be fractioned away from maternal circulating DNA
This “cell-free” DNA is placental, not fetal, but fully represents the fetus
The fragments are 150 base pairs long, and the genome is 3B base pairs, but the entire fetal genome is represented in these fragments
By counting technologies, Array sequencing, or Next Gen Sequencing the genome of the fetus can be reconstructed to detect:
Aneuploidy
Microdeletions
Some single gene mutations
Placentation in twins
Don’t try to hard to understand the mathematics – whether you count genomic segments, or sequence them, the results are extremely accurate
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Prenatal genetic screening – NIPT and the genome
Non-invasive Prenatal Testing (NIPT) – performance?Aneuploidy
Performance for T21 is over 99% detection rates for 0.1% false positive rates
Tells us about the placental DNA but not the baby
Performance for T13/T18/Sex chromosomes less well but still high (about 90%)
What about microdeletions
SNP sequencing is the only NIPT which can look for small deletions in the chromosomes
Syndromes from microdeletions can be quite severe
What about Twins
Sequencing with Single nucleotide polymorphisms (SNPs) provides one thing: zygosity (if in doubt)
Prenatal genetic screening – NIPT and the genome
Free DNA comes from
apoptotic cells derived from:
• Maternal Circulation
• Adipocytes
• White Blood Cells
• “Fetal”
• Placental cells (trophoblasts) in
the maternal circulation
• Fetal Fraction – the percent ratio
between placental: maternal DNA
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Prenatal genetic screening – NIPT and the genome
You may have heard of fetal fraction?
Low FF seen in: Early gestation, high BMI, collection issues, aneuploidy
This can drop the accuracy of results
Minimum required: 4% for counting, 2.8% for SNP
If fetal fraction is low….
Redraw
Option of other screening methods
Up to 30% of people on redraw will still get non-reporting
So although it’s a great test, 3-5% of all patients will get non-reporting
Prenatal genetic screening – NIPT and the genome
NIPT - microdeletions?
DiGeorge syndrome 22q11.2 deletion risk: 1:2000-4000
Risk of dying in a car: 1:5000
Risk of dying in pregnancy in Canada: 1:8800
Risk of having a child with autism/spectrum: 1:68
What’s my point?
Microdeletion syndromes are rare
People read about these on the google and on the twitter, and they displace their baby concern with the concern for truly rare diseases
For the most part, don’t specifically order NIPT for microdeletion or single gene unless you have an at-risk patient. Array CGH platforms for NIPT can help with
Chorionicity
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Prenatal genetic screening – NIPT and the genome
What are the major NIPTs available?
Targeted (counting method) – example - Harmony©
Where we look for gene loci unique to certain chromosomes (like 21) and compare that number with the reads from other chromosomes (like 1)
If you get more reads from the locus on 21 in a ratio of 1.5X versus 1, then you have trisomy 21
SNP based – example - Panorama©
Where DNA sequence variations (normal in all of us) are compared between placental and maternal DNA
Variations of up to 1% are normal
This can then help segregate and compare maternal versus placental DNA
Benefits – microdeletions, zygosity, slightly lower fetal fraction threshold
Whole Genome sequencing – example NIFTYpro©
All chromosome numeric abnormalities
84 microdeletions
March 2018
Prenatal genetic screening – NIPT alone?
NIPT difficult situations?
Fetal demise in a twin pregnancy
Donor egg – yes
Donor sperm – yes
The big limitation of blood based screening (SIPS or NIPT):
Is that we don’t see the baby
In fact all screening tools which do not use ultrasound will miss up to 40% of abnormal pregnancies
NIPT in particular - High cost for detecting of T21
Misses up to 10% of atypical chromosomal’s like triploidy, and Non T21/18/13
3-5% risk of non reporting
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Prenatal genetic screening – NIPT alone?
Why not do NIPT alone?Ex. Ductus venosus screening will detect 93-96% of all cardiac anomalies at 11-14w
Kenkhuis March 2018 – 100% of severe structural anomalies will be picked up at the 11-14w scan
Abuhamad 2017 – 100% DR for acrania, omphalocele, gastroschisis, megacystis, body stalk anomaly, cloacal defect, amongst others
It’s important to understand that NIPT is really good at T21, but not great at other things – it catches the 60% of genomic anomalies, but at the cost of missing 40%
Hence our National Guidelines….
These guidelines are joint between Society of OBGYNs of Canada (SOGC) and Canadian College of Medical Geneticists (CCMG)
They also reflect the opinions of
• International Society of Prenatal Diagnosis (ISPD)
• American College of OBGYNs (ACOG)
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Hence our National Guidelines….
Guidelines - What you need to know:
A. First Trimester Ultrasound (11-14w) offers many advantages including dating, Chorionicity, early detection of major structural abnormalities, and aneuploidy risk
B. Second Trimester AFP is no longer required if a 20w ultrasound is done
C. In twin pregnancies, Nuchal Translucency alone is considered an acceptable first line test, better with serum proteins like HCG/PAPP-A
D. NIPT is a highly effective form of early prenatal screening of common trisomy's after 10w. NIPT as a primary screening is not cost effective, but offering it in a contingency program will give high performance at a reduced cost
Hence our National Guidelines….
Guidelines - What is actually happening
A. Due to direct to consumer marketing, NIPT is replacing screening
B. We are ignoring the benefits of early US for detection of genetics and structural anomalies
C. Due to big genomics, the costs of screening are being outsourced to the patient, instead of system pressures to improve the provision of prenatal care
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The future of Prenatal Screening
Future of Prenatal Screening
First Trimester
Screening
Multiple markers
NIPT (1TM) Genomic information
Second
Trimester
Ultrasound and medical screening
By 20w to triage those at very low risk, and those at high risk –
concentrating prenatal care on those who need it:
anomalies, PIH risk, Preterm birth risk, etc
Prenatal genetic screening – HOW?
First Trimester Screening
Serum Integrated Prenatal Screening
Integrated Prenatal Screening
Non invasive prenatal testing (NIPT)
Combinations/contingency models
Pre-Implantation Genetic Testing – PGT ✓
✓
✓
✓
✓
✓
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What do I offer patients today?
Wants to screen but
within insured
services
Wants to screen but
willing to pay and
wants better
performance
Wants to screen,
willing to pay, and
wants as much
information as
possible
Under 35
Over 35/twins/IVF-ICSI
SIPS
IPS (NT plus SIPS)
First Trimester Screening
(NT, NB, DV, serum HCG
and PAPP-A)
Any age, per national
guidelines
First Trimester Screening
with NIPT
What do I offer patients today?
Is there an
insured NIPT in
BC?
If any screening test
is abnormal, the
patient can choose to
do NIPT or
Amniocentesis/CVS
Previous
T21/T13/T18
pregnancy
This type of
contingency
model is very
efficient and
cost-effective
20w soft markers
increasing risk above
1:300
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PEARLS
Offer all forms of screening to all women regardless of their age based risk
Invasive testing follows if the screening test is positive
Conventional screening methods remain the most appropriate choice for first-line screening, with NIPT contingency
Patients who did IVF with PGT still require prenatal genetic screening
All of the genetic risks we seek to screen are rare – provide reassurance
New technology such as NIPT – don’t apply it alone – it is an excellent augmentation to conventional screening, but isn’t as broad as any screening which includes ultrasound
PEARLS
Recognize that some of the single gene and microdeletion panels are extremely rare and not a sole reason for doing NIPT
Don’t forget that the embryo can also be tested (PGT)– growing science
Work within what your patients want – 50% of all pregnant patients in this province decline any type of screening.
Educate them, let them know what is available, and help them reach a decision
Remember, all women, regardless of age, should have an informed choice about prenatal screening options
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Pearls
If you get lost and don’t know what to do?
[email protected] – you or your patient can email our counselors, or call us to assist
My talk – at pacificfertility.ca >top of the page – physician resources
Email me – [email protected]
Perinatal BC Prenatal Genetic screening website has a video and decision aides
How to order SIPS
Go to this link http://www.perinatalservicesbc.ca/Documents/Screening/Prenatal-HCP/PrenatalBiochemistryLabReq.pdf
Fill it out and the patient goes to the lab for the blood draw
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How to order IPS
Do the same requisition http://www.perinatalservicesbc.ca/Documents/Screening/Prenatal-HCP/PrenatalBiochemistryLabReq.pdf
You also have to do the Nuchal translucency requisition:
Found here: http://www.perinatalservicesbc.ca/Documents/Screening/Prenatal-HCP/NTSites.pdf - do up an ultrasound requisition and send patient for this ultrasound at 11-14 weeks
How to order NIPT
Go to this link: http://www.perinatalservicesbc.ca/Documents/Screening/Prenatal-HCP/DynacareLabRequisition_Funded.pdf
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How to order non-insured NIPT
Go to this link: https://www.lifelabsgenetics.com/product/non-invasive-prenatal-testing/
other providers:
Dynecare
PCRM
Olive Fertility
How to order First Trimester Screening
Go to this link: https://pacificfertility.ca/service-types/prenatal-screening
have patient speak with our genetic counselors about FTS/NIPT/Insured or non-insured prenatal screening
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