Transcript ERA Prenatal Screening Advisory Committee Meeting

Photo: courtesy Travel Alberta
Screening for Fetal Aneuploidy 11-13+6 weeks
Objectives:
The provision of information for
individuals
32nd RCOG Study Group
Women have the right to access
information about the health of their
fetus
SOGC Statement on Access to Genetic Screening
January 2007
Recommendations
J Obstet Gynaecol Can 2007;29 (2):146-161
1. All pregnant women in Canada, regardless of age, should
be offered through an informed consent process, a prenatal
screening test for the most common clinically significant
fetal aneuploidies in addition to a second trimester
ultrasound for dating, growth and anomalies. (I-A)
AMNIOCENTESIS
2. Maternal age screening is a poor minimum standard
for prenatal screening for aneuploidy and should be
removed as an indication for invasive testing.
Amniocentesis/chorionic villi sampling (CVS) should not
be provided without multiple marker screening results
except for women over the age of 40. Patients should be
counseled accordingly. (I-A)
3. In 2007, as a minimum standard, any prenatal screen
offered to Canadian women should have a 75% detection
rate with no more than a 5% false positive rate (3% by
2008) for Down syndrome. The performance should be
substantiated by annual audit. (III-B).
Wald et al. 2003; Nicolaides et al. 2005
11. By 2008,
screening programs
should aim to provide
a screen that, as a
minimum, offers
women who present
in the first trimester a
detection rate of 75%
for Down syndrome,
with no more than a
3% false positive
rate. (III-B)
4. First trimester nuchal translucency should be
interpreted for risk assessment only when performed by
sonographers/sonologists trained and accredited to
provide this service and with ongoing quality
assurance.(II-2A)
It should not be offered as a
screen without biochemical
markers except in the context
of multiple gestation
pregnancies (I-A).
Principles of Screening
Characteristics of Screening Test
Sensitivity (Detection rate): Abn screen, abn result
False Positive Rate*: Abn screen, normal result
False Negative Rate: Normal screen, abn result
Specificity: Normal screen, normal result = 100-FPR
Likelihood Ratio: Proportn Abn / Proportn Normal
* Also called initial positive rate, is used
interchangeably with amniocentesis rate
Screening for trisomy 21
Adjusted risk =
Background risk
X
Background- (a priori) risk
X
LR of screening test
Nuchal Translucency
X
Biochemistry
X
Adjusted risk = a priori risk x LR1
x LR2 x LR3…
New Marker
Prenatal Screening in Alberta
• Maternal
age alone
• MSS 1990’s
•Not a funded program, no audit or follow-up
In Calgary
• Nuchal translucency screening* 2002
• No MSS after NT, unless with genetic counseling
• 18-20 week scan
Nuchal
Translucency
Screening*
(NTS)
CVS
Maternal Serum
Screen (MSS)
AFP,uE3,hCG
AMNIO
Detailed Anatomy
Genetic Sonogram*
Pregnancy
Outcome
*Southern Alberta Center for
Maternal Fetal Medicine (MFM Centre
Prenatal Screening in Calgary
Nuchal Translucency Screening Clinic* (2002-March 2006)
• Pre- and post-NT counselling
• 18 “NT certified” technologists
• # of patients given NT-adjusted risk n= 9,971
• DR 75%, FPR 9 % at 1/300 (mid-TM risk)
• 32% ≥ 35 years of age
UNACCEPTABLE FPR:
NEED BIOCHEMISTRY
*Southern Alberta Center for
Maternal Fetal Medicine (MFM Centre)
Screening for Trisomy 21
Fetal NT + maternal free ß-hCG & PAPP-A (FTS)
•The best marker is NT
•Inclusion of ß-hCG and PAPP-A improves DR
by 15-20%
•Five prospective studies of FTS (n=76,977),
DR of Tr21 362/409 (89% for 5% FPR)
The Early Risk Assessment (ERA) Program:
First Trimester Screening and
Early Detection of Pregnancy Complications
GOAL
“To promote the health and well-being of pregnant
women through a collaborative and
multidisciplinary prenatal risk assessment program
that would enable early, more accurate
identification and management of pregnancies at
increased risk for adverse perinatal health
outcomes”.
Early Risk Assessment Program
: Prenatal Screening for
Chromosome Disorders
Purpose:
•To introduce FTS (OSCAR model)
•To develop patient and physician
educational materials
•To evaluate program performance
and patient satisfaction
First Trimester
Combined
Screening
• Maternal age
• NT
• Free-bHCG
• PAPP-A
Early Risk Assessment Program: Early detection of
Pregnancies at risk of Adverse Outcome
1. To examine the predictive value certain
biochemical/US markers (11 -20 w) in
detection of women at increased risk of
poor pregnancy outcome (pre-eclampsia,
IUGR, preterm labor),
2. To identify risk factors and interventions
that may improve pregnancy outcome in
this group
MSS
FTS
10
12
14
16
Genetic
sonogram
18
Why “Point of Care?”
One Stop Clinics
• One stop clinics have developed in several
clinical areas
– breast cancer screening, menopausal clinics,
oncology assessment, cardiovascular risk clinics,
one-stop surgical clinics
• Benefits:
– integration of clinical and diagnostic services
– better use of clinical time, improved diagnostic
efficiency
OSCAR: “One-Stop Clinic
Assessment of Risk”
Patient advantages:
•Maximizes patient satisfaction
•Reduced number of patient visits
•Decreased patient travel costs,
(missing work, babysitting, parking),
anxiety, and stress especially that
associated with waiting for results
•Allows for timely, qualified
interpretation of results
Evidence and Innovations leading to OSCAR
• Ultrasound markers of chromosomal anomalies - fetal
nuchal translucency thickness at 11-14 weeks.
• Maternal serum Biochemical markers of chromosomal
anomalies - free b-hCG & PAPP-A at 10-14 weeks.
• Development of new rapid assay
technology for biochemical marker
measurement leading to Point of
Care testing.
OSCAR in Calgary*
One Stop Clinic for Assessment of Risk
Southern Alberta Centre for MFM
(NT clinic + Astraia) + (DELFIAXpress + Lifecycle) = OSCAR
Woman departs
Woman arrives
Post-test counselling
Pre-test counselling*
Free b HCG
NT SCAN
PAPP-A
Blood sample
Risk Assessment
U/S data
Ultrasound
Examination (11-13+6 weeks scan)
www.earlyriskassessment.com
* Mean T/O time 92 minutes
*1-1 Counselling, video, pamphlets
Invasive testing usually not same day
OSCAR in Calgary
FTS Uptake March 2006-2007
600
500
400
300
200
100
0
Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar
Non-OSCAR in Calgary
(2-Step Model)
“-ve screen”
Report mailed
“+ve screen”
Nurse/ counsellor calls,
appointment arranged
Woman arrives
Step 1
•Demographics reviewed
•Counselling as needed
•Consent signed
Risk Assessment
Same day report
Woman departs
Blood sample
NT Ultrasound
Examination
2 MFM sites
Free b HCG,PAPP-A
U/S data
Step 2
OSCAR facility
*Own MD, website, pamphlets
First Trimester Serum Screening Detection
Gestational Age (weeks)
Serum Markers
Free Beta hCG / PAPP-A
9
10
11
12
13
73% 72% 70% 68% 66%
1/250 Risk cut-off
Biochemistry Works Better Earlier
Spencer et. Al Ann. Clin. Biochem. 2003; 40: 219-231
“Non”-OSCAR
One Stop Clinic for Assessment of Risk
Southern Alberta Centre for MFM
Woman departs
Woman referred for FTS
Directed to
educational materials*
Post-test counselling
Free b HCG
PAPP-A
NT Scan
Risk Assessment
Blood sample at any
CLS facility
starting at 9 weeks gestation
NT Ultrasound
At Beddington or
Southport EFW MFM
Clinics
Free b HCG
PAPP-A
www.earlyriskassessment.com
Mean Maternal Age
Mean Maternal Age
(Range) in Years
% ≥ 35 years;
% ≥ 40 years
Year 1: March 13,
2006-March 13,
2007
32 (15-49)
31%* ; 4.6%
Year 2: March 14,
2007 –March 13,
2008
31.6 (15-48)
29.5% ; 4.0%
Year 3: March 14,
2008 – July 31,
2008
31.5 (15-52)
29.3% ; 3.9%
Year of Program
(* 18% in the CHR ≥ 35 years)
FTS Performance:
Screening for Trisomy 21
Year of
Program
Detection
Rate
Trisomy 21
Initial Positive
Rate
Cut-off 1:300
OAPR
13.03.06-07
20/23 (87%)
6.5% (325/5013)
1:16
14.03.07-08
29/31 (93.5%)
6.3% (439/6984)
1:15
2006-2008
49/54 (90.7%)
6.3% (764/11997)
1:15.5
FTS Performance
March 13 2007- March 13 2008
Total number screened 6984
Initial positive rate (or False Positive rate):T21
Screen cut-off Number of Initial positive Detection
T21 (12 weeks) screen +ve rate (or FPR) rate
1:300
1:250
439
299
6.3%
4.2%
93%
93 %
1:200
1:150
285
275
4.0%
3.9%
90%
80.6%
FTS Performance
March 13 2007- March 13 2008
Screening for Trisomy 21
• DR Trisomy 21 93% (29/32), FPR 6.5% (1/300)
• 2 “false negative” cases:
•1 negative screen for T21, +ve T13,18 (had invasive)
• Other case: no blood obtained, NTS alone.
Characteristics of the T21 cases
•27/ 31 Trisomy 21 (87%) detected prenatally
•CVS 17/27 (63%), amnio 10/26 (38.4%)
• 3 LB T21 in screen +ve group (declined invasive)
•1 had no invasive (FN result)
• Risk assessment on NT alone due to unsuccessful
phlebotomy
FTS Performance
March 13 2007- March 13 2008
Invasive testing in FTS screened patients
Overall invasive rate: 292/6983 = 4.1 %
•Invasive rate among screen +ve patients: 229/439 = 52%
•Average risk of screen positive patients who had
invasive testing 1:90
•Average age 34 years, 53% over 35,13% over 39
•Average risk of screen positive patients who did not
have invasive testing 1:151
•Average age 34 years, 53% over 35, 20% over 39
FTS in Calgary 2006-7
Characteristics of the true +ve (T21) screens (n=20)
Mean GA 60 mm
Mean T21 risk: 1:22
Mean NT: 3.6 (range 1-8.2 mm)
Average age 36.3 years (range 22-45, 68%
over 35 years)
Average fβ-HCG 2.5 MOM (range 0.7-4.24)
Average PAPP-A 0.5 MOM (range 0.12-0.95)
OAPR: 1:16
FTS in Calgary 2007-8
Characteristics of the true +ve (T21) screens (n=29)
Mean GA 66 mm
Mean T21 risk: 1:43
Mean NT: 3.9
Average age 36.7 years (range 22-45)
Average fβ-HCG 2.5 MOM (range 0.5-6.0)
Average PAPP-A 0.6 MOM (range 0.1-2.1)
OAPR: 1:15
FTS in Calgary 2006-8
Characteristics of the Trisomy 21 cases (n=23)
•Average age 36.5
•Average risk in true positives: 42
•26/49 (53%) had 1:2,
•37/49 (77%) 1:10 or higher.
• 44/49 (89%) 1:150 or higher
FTS Program in Calgary
Key Points
•One-stop multidisciplinary approach associated with high
patient satisfaction
•Operationally efficient (few call backs, demographic and
ultrasound information available, collaborative atmosphere
between disciplines (MFM, genetics, ultrasound, lab,
nursing).
•Established infrastructure for efficient high quality
ultrasound as well as audit and research (linked to Alberta
Perinatal Health database)
• Ability to introduce new markers/ protocols
•Performance excellent and within expected range
Province of Alberta: Proposed Program
• For women presenting for prenatal care before 13
weeks and 6 days of pregnancy, there would be two
options:
– Where Nuchal Translucency available:
• First trimester Combined Screening (FTS, GOLD STANDARD)
– Where Nuchal Translucency not available:
• Early Contingent Screening
• Combines maternal age with blood test (biochemical markers:
PAPP-A and free beta HCG )
• If risk assessment is above the predetermined risk cut-off, a nuchal
translucency ultrasound would be recommended (estimate10- 20%
of population).
• For women presenting for prenatal care after 14
weeks and before 19 weeks and 6 days:
– Second trimester Quad Maternal Serum Screening
Community-based screening for Down’s
Syndrome in the first trimester using
ultrasound and maternal serum biochemistry
• 2 year pilot study in Western
Australia, a geographically isolated
state with an annual birth rate of
25,000.
• Outcomes linked to State wide birth
and anomaly information systems.
Narelle Hadlow et al, BJOG 2005:112; 1561-1564
• FTS is largely community based
with women accessing a variety of
independent ultrasound practices
and local collection centres served
by one central laboratory with
distances in some instances over
1000 Km away.
Community-based screening for Down’s Syndrome in the first
trimester using ultrasound and maternal serum biochemistry
• In the study period NT was only concentrated in the Perth Metro
area.
• Women had blood collected at their local collection centre in their
rural community (over 100 sites). Separated, frozen and sent by air
or land transport in frozen state.
• Women travelled to Perth for NT, biochemistry result available on
day of scan in 96% of cases, and after the NT in 4% of cases.
• Study screened over 10,000 women and detection rate was 90.6%
with a false positive rate of 3.6% (Mean age 30.7 )
• All sonographers/obstetricians FMF approved and either trained in
London or via the FMF delegated RANZCOG program
Narelle Hadlow et al, BJOG 2005:112; 1561-1564
Delivery of Screening
• Multidisciplinary !!
• Numerous stakeholders:
– Pregnant women, MFM, obstetrics, family medicine,
midwives, radiology, sonography, lab services,
genetics, pathology………
• Direction of flow
Ultrasound
Biochemistry
OSCAR in Calgary
Number of abnormal cytogenetic results n= 39
(Ascertainment: electronic linkage with Alberta perinatal
health database and cytogenetic lab; outcome not complete)
+ve screen -ve screen
Trisomy 21
20
3
21/23
Trisomy 18
Trisomy 13
Other
3
2
5
1
1
4
4/4
3/3
9
Total detected prenatally 37/39 (95%)
Uterine Arteries
NB, TC, DV, FMF Angle
Placental hormones
11-13 weeks 6 days scan
Anatomic Survey
Multiples
Nuchal Screening
The First Trimester Scan (11-13 weeks 6 days)
Biochemical Screening: Centralized vs POC
Centralized laboratory services
• Minimizes costs
• High standards
• Can serve locally, regionally, nationally
“Point of Care”
• Not as common in non-private HC
systems
• Costs offset by operational efficiency,
consolidation of services, fewer patient
visits, better care
Prospective 1st Trimester Screening
singleton pregnancies over a 5 year period
BH&R HA
FMC
TOTAL
Screened
31989
14383
46372
Increased Risk 1344 (4.4%) 1096 (7.6%) 2440 (5.3%)
T21
70/77picked
(91%)up 70%
75/81of(92%)
NT alone would have
cases at145/158
a 5% FPR,
(92%)
Biochemistry alone would have picked up 70% at
a 5% FPR
but combined
a further21
22% are identified
T18
18
39
T13
10
10
20
45x
Triploidy
Other
11
9
5
10
7
6
21
16
11
RESULTS
Satisfaction with OSCAR program
100
These results were independent of
Pre-Test
80maternal age, parity, education
and
FTS Brochure
Post-Test
screen
result,
except
women
with
lower
60
Appt length
Overall service
education levels were significantly
more
40likely to be satisfied with pre-test
20counseling than women with higher
education levels (p=0.0071)
0
Very
Satisfied
Satisfied
Less
satisfied
Not
satisfied
Satisfaction with Overall Service
by Service Delivery Model
Site
OSCAR
non-OSCAR
Total
• Although
Very Satisfied/
Satisfied
Unsatisfied/
Very Unsatisfied
Total
2551 (98.7%)
34 (1.3%)
2585 (100%)
993 (95.2%)
50 (4.8%)
1043 (100%)
3544 (97.7%)
84 (2.3%)
3628 (100%)
Missing Responses: 135
satisfaction with overall service was
high for
both the one-stop and two-stop service delivery
models, women who had the one-stop service were
more likely to be satisfied than women who had the
two-stop service (p<0.0001).
OSCAR Satisfaction Study
•Uptake of invasive testing in women
attending the OSCAR clinic:
• Positive screen (T21): 49.1%
• Negative screen: 2.7%
Invasive uptake related to level of risk
80
60
40
20
0
1/100
1/100-1/1000 >1/1000
*DR of T21 87% at 5% FPR
Early Prenatal Risk Assessment:
More Than an Aneuploidy Screen
11-14 WEEK SCAN
NT, NB
Fetal anatomy
UA Doppler
Placental morphology
1st TM Volume (3D)
Maternal Serum
PAPP-A
Free beta hCG
Store sample
PHASE 1: FTS
PHASE 2: Pregnancy complications
DETAILED ANATOMY
Fetal echo
Uterine artery Doppler
Placental morphology
Timing of scan
Maternal Serum
AFP,uE3,hCG
DIA?
Contingent screening
Store sample
TV cervix clinic
U/A Doppler
Cervical length
(c/w 18-20 week)
OBJECTIVES
Purpose:
1.) To evaluate women’s satisfaction with first
trimester combined screening (FTS),
2.) To compare delivery models (one-stop
(OSCAR*) versus 2-stop screening).
*March 13, 2006- March 13, 2007
# Women screened n= 5013
# Completed surveys n= 3763 (75%)
Eligible OSCAR patients n=2670/3763 (71%)
CONCLUSIONS
• The Calgary FTS OSCAR model meets women’s
expectations, is associated with a high degree of
satisfaction and was preferred over the 2-stop
model
• Receiving results early in pregnancy and same day
is important
• A high proportion of women were reassured by
their results regardless of whether they were
screen negative or positive.
• Uptake of invasive prenatal diagnosis among
screen positive patients correlated with level of risk
CONCLUSIONS cont’d
• These results may imply that
– Women favor individualized risk
assessment versus being categorized as
screen negative or positive
– Immediate access to 1-1 post-test
counseling with a health professional, as in
the OSCAR model, has important impact on
perception of test results
– Further research to evaluate this is under
consideration
• The 2 stop model has been revised …
FTS Performance:
Screening for Trisomy 13/18
Year of Program
Detection Rate
Trisomy 13/18
Initial Positive Rate
Cut-off 1:150
March 13, 2006
March 13, 2007
325/5013)
March 14, 2007 –
March 13, 2008
1.1% (80/6984)
Total 2006-2008
49/54 (90.7%)
6.3% (764/11997)