Early Prenatal Screening in
Primary Care
BC College of Family Physicians
21st Annual Scientific Assembly
Ken Seethram,
MD, FRCSC, FACOG
Pacific Centre for Reproductive Medicine
Clinical Lecturer, University of British Columbia
kseethram@pacificfertility.ca
Outline and Objectives


Update Family physicians on early prenatal
screening
What’s new and exciting?


1st and 2nd trimester screening strategies
ACOG and SOGC guidelines

What will your patients want, and where to get it?

Presentation: pacificfertility.ca
One thing to keep in mind
Screening is Simple


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Know what’s there
Find out what your patients wish
Put the two together
History: A Canadian Invention


Medical ultrasound is
derived from Sound
Navigation and Ranging
discoveries (SONAR)
First SONAR was built in the
USA by Canadian Reginald
Fessenden, 1914
Life Magazine® in
1954
The Somascope is
a water immersion
motorised B-mode
scanner
Posakony was the
subject and his
scanned kidney can
be seen on the
oscilloscope screen
Early Prenatal Screening
What are we screening for?

Most associate prenatal screening with aneuploidy,
commonly Trisomy 21, 18, 13, monosomy X
But there is a lot more than aneuploidy:





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Congenital defects
Post dates screening
Twin screening (chorionicity, anomalies)
TTTS
Complex congenital cardiac defects
Pre-eclampsia screening
Screening is simple:
there are only four ways to check a pregnancy
1.
2.
3.
4.
Check the blood of the mother
Check the baby by sonography
Do both
Make wild assumptions without doing any of the
above (aka voodoo)
Remember:
Screening is Simple
What are all of the screening options prior to
20 weeks?
NT/Nuchal Translucency
NB/Nasal Bone determination
FTS serum (PAPP-A, free-beta hCG)
DV (Ductus Venosus)
FMF angle (Frontomaxillary facial angle)
TR (Tricuspid Regurgitation)
Uterine artery dopplers
Quadruple screen (uE3, dimeric Inhibin-A, total hCG, AFP)
IPS (1st and 2nd combined)
SIPS (1st and 2nd serum combined)
Sequential screening
Contingency Screening
Detailed sonogram
I know what you’re thinking



When did all this happen?
What ever happened to the amnio?
Why is he telling us that screening is
simple?

Because it is:



Maternal Serum
Ultrasound
or both
When did all this change?


era of age-based screening
recommendations began in the 1970’s


When the statistical increase of aneuploidy
started exceeding the risks of amniocentesis,
that age 35 be established as a cut-off (Resta)
1970’s
1980’s introduction of AFP screening leading to
Triple Marker Serum screening which in
combination with age, increased detection rates
of DS to 50-70%.


False positive rates ranged from 10-25%,
increasing with maternal age
Also 60% Detection rate for Trisomy 18
1980’s
When did all this change?

1996 – introduction of Quad screen
(TMS + dimeric inhibin A).


Detection rate for Down syndrome increased
to 75-77% with a 5% false positive rate
Around the same time, a pivotal paper
was published in 1992 in the BMJ by
Nicolaides (Kings College, London)

describing nuchal translucency (NT) which
gave a 75% DR at 11-13w6d via ultrasound
1990’s
Nuchal Translucency (NT)
Nuchal Translucency (NT)
-midsagittal
-zoom
-Settings
-Calipers
-Flexion
-Amnion
-Size (CRL)
-FMF born
When did all this change?

1996 – Nicolaides introduced first trimester
serum (using free beta hCG and PAPP-A) to
give DR with NT of 85-88% with a 4-5% false
positive rate

called FTS or First Trimester screening

PAPP-A
Mid1990’s
(pregnancy associated placental protein A, made by embryo
and placenta, immune function, increases placental growth)

1996-2000 – numerous papers looking at
combining 1st and 2nd trimester screening:


With serum (serum integrated pregnancy
screening/SIPS)
With NT (integrated pregnancy screening/IPS)
Early
2000’s
When did all this change?

2003 – Wald SURUSS Trial, compared FTS,
SIPS, IPS, and Quad screening

Setting an 85% DR

IPS with lowest FPR (1%).

SIPS with 2-3% FPR

FTS with 4% FPR

Quad with 6% FPR

NT alone with 15% FPR

Flaws – obtaining NT was an issue
When did all this change?

2003-2008 – Nicolaides introduces a
new series of markers to increase DR to
95-96% with 4-5% FPR in the first
trimester

Nasal Bone

FMF angle

Ductus Venosus

Tricuspid Regurgitation
20032008
What are these exciting new markers?

Nasal Bone

70-80% of
T21 do not
have nasal
calcification
(vs. 0.5% in euploidy)

Gives DR up
to 97% with
5% FPR
What are the exciting new
markers?

Ductus
Venosus
What are the exciting new
markers?


FMF Angle
Increased
beyond 85
with T21
What are the exciting new
markers?

Tricuspid
Regurgitation
The new techniques
Blood only


Second Trimester Quad (16-20w)
First (PAPP-A – 12w) + Second Trimester
Quad (16-20w)
QUAD
SIPS
Ultrasound and Blood


First Trimester NT (12w) + SIPS
First Trimester NT/NB/other markers +
hCG/PAPP-a
IPS
FTS
All stacked up
Markers
Detects?
When
Sensitivity
FPR
Name
Age
Trisomy 21,
18, 13
@Conception/
@Delivery
30%
Age + TMS
Trisomy 21,
18, 45X,
NTD’s
16-20w
50-70% (for
DS)
10-25%
TMS
Age + Quad
Trisomy 21,
18, ONTDs
16-20w
75-77%
(for DS)
5.2%
Quad
Age +
NT+PAPP-A +
fβhCG
Trisomies
21,18,13
11-13w6d
85-88%
5%
FTS
Age + NT+
PAPP-A+ fβhCG+Nasal
bone
Trisomies 21,
18, 13
11-13w6d
92-97%
4-5%
FTS with
Nasal Bone
Age + PAPP-A
+ fβ hCG
+Quad
Trisomies 21
+18, ONTDs
12w and
again at 1620w
84-86%
5%
SIPS
Age+NT+
PAPP-A+
Quad
Trisomies 21
+18,ONTDs
12w and
again at 1620w
92-96%
3-5%
IPS
Archaic
Sequential versus integrated?

You hear the terms a lot –


Integrated is blinded/Sequential is not
What is the difference?

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Sequential screening means that people go through
some form of 1st +2nd combined screening, but if
their 1st marker (eg, NT) is abnormal, they are
informed and offered invasive testing
Gives the benefit of identifying patients at risk
earlier, and offering earlier testing, but at the cost
of declining detection rates when the Quad is added
IPS currently in BC is a sequential model, and
therefore does not perform at 92-96% DR
Why did 1st and 2nd trimester screening
evolve

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Largely due to a patent interest on free beta hCG in
the US, which made FTS limited until recently
To maintain high DR without fb-hCG, had to
combine NT/PAPP-A with total hCG in the Quad
screen
Currently Nick Wald (SURUSS trial) holds a patent
on any screening performed which uses 1st and 2nd
Trimester markers
Moving On
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
While aneuploidy detection is
important, it is only one of the
possible array of screening results
Let’s move on to other conditions
that can be screened for
congenital defect screening


Conventional 18-20w sonograms will give
information on anatomic defects and ‘soft
markers’ (intracardiac focus, choroid plexus
cysts)
However, increasing use of sonography before
13w to determine:



Limb deformities, hydrocephalus, holoprosencephaly,
renal and GI abnormalities, exomphalos
Still 18-20w scan is best for heart, brain, spine
Ample evidence now that 18-20w sonogram is
almost diagnostic for neural tube defects


DR=90-95%
MS-AFP DR=80%
post dates screening
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Ample evidence that an early ultrasound
(first trimester) is useful to reduce
incidence of post-dates induction of
labour and to rule out ectopic and
multiple gestations
In some countries with FTS programs, the
FTS is the only early ultrasound required,
giving aneuploidy and other information
in the single visit
twins
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Establish Chorionicity
In monochorionic twins, the largest risk is that of
twin-twin transfusion syndrome (TTTS)
Available evidence suggests that monochorionic
twins should share the same NT and, if not, this is
an early sign of impending severe TTTS
Quad screening hard to interpret with twins
FTS now includes serum analysis (September
2008) for twins
cardiac defect screening


An elevated NT has a 6X increased
association with complex congenital heart
disease (as opposed to 2-3% in the
patient with a prior history) and therefore
is a very important marker for disease
An abnormal NT in the presence of
normal karyotype requires fetal
echocardiography
pre-eclampsia and adverse prenatal
outcomes screening
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PAPP-A and (uterine artery dopplers) at 11-14w to predict
adverse outcomes (Faster Trial)
Odds ratios of PAPP-A < 5th percentile:

Intrauterine growth restriction 3.22
Birth weight at or below fifth percentile 2.81
Fetal loss before 24 weeks 2.50
Fetal or neonatal loss 2.15
Preterm birth at or before 32 weeks 2.10
Preterm birth at or before 37 weeks 1.87
Placental abruption 1.80
Premature preterm rupture of membranes 1.54
Preeclampsia 1.54

Gestational hypertension 1.47
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If abnormal, increased surveillance to detect early
oligohydramnios, IUGR, or hypertension is essential
The first problem with quality
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Nuchal translucency training and quality assurance
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Appropriate training of sonographers and adherence to
standard technique for NT are essentials for good clinical
practice.
success of a screening program necessitates system for
regular audit continuous assessment of the quality of images.
Training is based on theoretical course + practical instruction
on how to obtain the appropriate image, make the correct
measurement of NT, and presentation of a logbook of images.
Ongoing quality assurance is based on assessment of the
distribution of fetal NT measurements and examination of a
sample of images
Current standard: Fetal Medicine Foundation (UK,
Canada, USA) for initial accreditation, and yearly QA
The second problem with quality

Accredited NT is not meaningful by
itself, and must be part of a
screening program,


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using software to ‘adjust’ risks,
in concert with age,
laboratory, and
counselling
ACOG and SOGC


ACOG released similar guidelines in January
2007, and SOGC in February 2007
Basics:


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Triple screening is no longer good enough
Don’t use age as a screening tool
Aim for highest DR’s and lowest FPR’s in any
method
Consent and review all options
2008 Minimum standard: 75% DR, 5% FPR
Quality assurance important in FTS programs
ACOG and SOGC



Regardless of which screening tests you decide to offer
your patients, information about the detection and
false-positive rates, advantages, disadvantages,
limitations, and risks and benefits of diagnostic
procedures, should be available to patients so they can
make informed decisions.
All women regardless of age should be offered and
consented to screening for the most significant
aneuploidies and a second trimester sonogram for
dating, growth and anomalies
Amnio/CVS can be offered to women over age 40
without screening, but screening should still be
offered.
ACOG and SOGC

The practice of solely using
maternal age of 35 or older at the
estimated date of delivery (EDD) to
identify at-risk pregnancies should
be abandoned
ACOG and SOGC

One size does not fit all
 As long as the definitive diagnosis involves
an invasive procedure which can cause
miscarriage, there is simply no substitute to
explaining all the options, their benefits, and
risks

best screen is the one which will address the
patient’s needs in terms of time of results
and action depending on the results
Conclusions to take home

Adjust Risks


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Don’t use age alone anymore
Use age plus a high detection screening tool
Highest are:
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FTS with Nasal Bone (11-14w)
IPS (1st TM NT, PAPP-A + Quad) (12w+16-20w)
Any NT/NB must be performed by accredited
facilities – look for ‘program based screening’
Offer all options
Beware that screening isn’t just aneuploidy, it’s
much more
Screening is simple
11-13w6d
16-20w
Blood
Blood
Blood
Ultrasound
Blood
Ultrasound
Blood
Blood
hCG,
AFP, uE3,
Inhibin
Quad
75-77%
17w
Quad +
PAPP-a
SIPS
SIPS +
NT
IPS
92-95%
NT+NB+
PAPPa+hCG
FTS with
Nasal
Bone
92-95%
82-84%
to
20w
13w
Where?
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Quad - all women (MSP)
SIPS - over age 38
IPS 
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

over age 40
Twins/Prior aneuploidy/HIV
Over age 35 with 3 prior miscarriages
Accredited NT + SIPS, report sent to MD at 1718w or later
Options (Non-MSP, accredited)
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Pacific Centre for Reproductive Medicine
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Calgary Health Region
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PacificFertility.ca
NT+NB+serum
EarlyRiskAssessment.com
NT+NB+serum
Genesis Fertility Centre
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Genesis-fertility.com
NT + serum
Other Web Resources
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www.mfmedicine.com
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www.fetalmedicine.com
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Fetal Medicine Canada
Fetal Medicine UK
Video from Prof Nicolaides
SOGC statement:

http://www.sogc.org/guidelines/documents/18
7E-CPG-February2007.pdf
FMF reports
2008
•Age
•Weight
•Ethnic
•Parity
•FHR
•markers