Photo: courtesy Travel Alberta

The provision of information for individuals Women have the right to access information about the health of their fetus

32nd RCOG Study Group

SOGC Statement on Access to Genetic Screening January 2007

Objectives:

Screening for Fetal Aneuploidy 11-13+6 weeks

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)

Recommendations J Obstet Gynaecol Can 2007;29 (2):146-161

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)

Wald et al. 2003; Nicolaides et al. 2005

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).

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).

Sensitivity (Detection rate): Abn screen, abn resultFalse Positive Rate*: Abn screen, normal resultFalse Negative Rate: Normal screen, abn resultSpecificity: Normal screen, normal result = 100-FPRLikelihood Ratio: Proportn Abn / Proportn Normal

Principles of Screening

Characteristics of Screening Test

* Also called initial positive rate, is used interchangeably with amniocentesis rate

Screening for trisomy 21

Adjusted risk = a priori risk x LR1 x LR2 x LR3…

LR of screening test

Adjusted risk =

X

Background- (a priori) riskNuchal Translucency

Biochemistry

New Marker

X

X

Background risk

X

Prenatal Screening in Alberta

Detailed AnatomyGenetic Sonogram*

Maternal Serum Screen

(MSS)AFP,uE3,hCG

Nuchal Translucency Screening* (NTS)

• Maternal age alone• MSS 1990’s

•Not a funded program, no audit or follow-up

AMNIOCVS

Pregnancy Outcome

*Southern Alberta Center for Maternal Fetal Medicine (MFM Centre)

• Nuchal translucency screening* 2002• No MSS after NT, unless with genetic counseling• 18-20 week scan

In Calgary

Prenatal Screening in Calgary

• 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

*Southern Alberta Center for Maternal Fetal Medicine (MFM Centre)

Nuchal Translucency Screening Clinic* (2002-March 2006)

UNACCEPTABLE FPR:

NEED BIOCHEMISTRY

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)

Screening for Trisomy 21

The Early Risk Assessment (ERA) Program:First Trimester Screening and

Early Detection of Pregnancy Complications

“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”.

GOAL

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 • Maternal age

• NT• Free-bHCG• PAPP-A

First Trimester Combined Screening

10 12 14 16 18

MSS

Early Risk Assessment Program: Early detection of Pregnancies at risk of Adverse Outcome

FTS

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

Genetic sonogram

Why “Point of Care?”

• 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

One Stop Clinics

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

• 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.

Evidence and Innovations leading to OSCAR

OSCAR in Calgary*One Stop Clinic for Assessment of Risk

Southern Alberta Centre for MFM

(NT clinic + Astraia) + (DELFIAXpress + Lifecycle) = OSCAR

Woman arrives

Pre-test counselling*

Blood sample

Ultrasound Examination (11-13+6 weeks scan)

Risk Assessment

Post-test counselling

Woman departs

Free b HCG

PAPP-A

*1-1 Counselling, video, pamphlets

U/S data

Invasive testing usually not same day

NT SCAN

www.earlyriskassessment.com

* Mean T/O time 92 minutes

OSCAR in Calgary

FTS Uptake March 2006-2007

0

100

200

300

400

500

600

Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar

Non-OSCAR in Calgary(2-Step Model)

Woman arrives

Blood sampleFree b HCG,PAPP-A

OSCAR facility

NT Ultrasound Examination2 MFM sites

Risk AssessmentSame day report

Woman departs

*Own MD, website, pamphletsU/S data

Step 1

Step 2

•Demographics reviewed•Counselling as needed•Consent signed

“-ve screen”Report mailed

“+ve screen”Nurse/ counsellor calls,appointment arranged

First Trimester Serum Screening Detection

Gestational Age (weeks)

Serum Markers 9 10 11 12 13

Free Beta hCG / PAPP-A 73% 72% 70% 68% 66%

Spencer et. Al Ann. Clin. Biochem. 2003; 40: 219-231

1/250 Risk cut-off

Biochemistry Works Better EarlierBiochemistry Works Better Earlier

“Non”-OSCAR

Woman referred for FTS

Directed to educational materials*

Blood sample at any CLS facility

starting at 9 weeks gestationNT Ultrasound

At Beddington or Southport EFW MFM

Clinics

Risk Assessment

Post-test counselling

Woman departs

Free b HCG

PAPP-A

Free b HCGPAPP-A NT Scan

One Stop Clinic for Assessment of RiskSouthern Alberta Centre for MFM

www.earlyriskassessment.com

Mean Maternal Age

Year of Program

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%

(* 18% in the CHR ≥ 35 years)

FTS Performance:Screening for Trisomy 21

Year of Progra

m

Detection Rate

Trisomy 21

Initial Positive Rate

Cut-off 1:300OAPR

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 6984Initial positive rate (or False Positive rate):T21

Screen cut-off T21 (12 weeks)

Number of screen +ve

Initial positive rate (or FPR)

Detection rate

1:300 439 6.3% 93%

1:250 299 4.2% 93 %

1:200 285 4.0% 90%

1:150 275 3.9% 80.6%

FTS PerformanceMarch 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 patientsOverall 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 2006-7FTS in Calgary 2006-7

Mean GA 60 mmMean T21 risk: 1:22Mean 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

Characteristics of the true +ve (T21) screens (n=20)

FTS in Calgary 2007-8FTS in Calgary 2007-8

Mean GA 66 mmMean T21 risk: 1:43Mean NT: 3.9Average 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

Characteristics of the true +ve (T21) screens (n=29)

FTS in Calgary 2006-8FTS 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 CalgaryFTS 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.

• 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.

Narelle Hadlow et al, BJOG 2005:112; 1561-1564

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 CalgaryOSCAR in Calgary

Number of abnormal cytogenetic results n= 39 (Ascertainment: electronic linkage with Alberta perinatal health database and cytogenetic lab; outcome not complete)

Trisomy 21 20 3 21/23

Trisomy 18 3 1 4/4

Trisomy 13 2 1 3/3

Other 5 4 9

Total detected prenatally 37/39 (95%)

+ve screen -ve screen

Nuchal Screening

NB, TC, DV, FMF Angle

Anatomic Survey

Placental hormones

Uterine Arteries

The First Trimester Scan (11-13 weeks 6 days)

11-13 weeks 6 days scan

Multiples

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

BH&R HA FMC TOTAL

Screened 31989 14383 46372

Increased Risk 1344 (4.4%) 1096 (7.6%) 2440 (5.3%)

T21 70/77 (91%) 75/81 (92%) 145/158 (92%)

T18 18 21 39

T13 10 10 20

45x 11 10 21

Triploidy 9 7 16

Other 5 6 11

Prospective 1st Trimester Screeningsingleton pregnancies over a 5 year period

NT alone would have picked up 70% of cases at a 5% FPR, Biochemistry alone would have picked up 70% at a 5% FPR

but combined a further 22% are identified

RESULTS

0

20

40

60

80

100

VerySatisfied

Satisfied Lesssatisfied

Notsatisfied

Pre-Test FTS BrochurePost-Test Appt lengthOverall service

These results were independent of maternal age, parity, education and screen result, except women with lower education levels were significantly more likely to be satisfied with pre-test counseling than women with higher education levels (p=0.0071)

Satisfaction with OSCAR program

Satisfaction with Overall Serviceby Service Delivery Model

Site Very Satisfied/ Satisfied

Unsatisfied/ Very Unsatisfied

Total

OSCAR 2551 (98.7%) 34 (1.3%) 2585 (100%)

non-OSCAR 993 (95.2%) 50 (4.8%) 1043 (100%)

Total 3544 (97.7%) 84 (2.3%) 3628 (100%)

Missing Responses: 135• Although 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 StudyOSCAR Satisfaction Study

*DR of T21 87% at 5% FPR

0

20

40

60

80Invasive uptake related to level of risk

1/100 1/100-1/1000 >1/1000

•Uptake of invasive testing in women attending the OSCAR clinic:

• Positive screen (T21): 49.1%• Negative screen: 2.7%

Early Prenatal Risk Assessment: More Than an Aneuploidy Screen

11-14 WEEK SCANNT, NBFetal anatomyUA DopplerPlacental morphology1st TM Volume (3D)

Maternal SerumPAPP-AFree beta hCGStore sample

DETAILED ANATOMYFetal echo Uterine artery DopplerPlacental morphologyTiming of scan

TV cervix clinicU/A Doppler

Cervical length(c/w 18-20 week)

Maternal SerumAFP,uE3,hCG

DIA? Contingent screening

Store sample

PHASE 1: FTSPHASE 2: Pregnancy complications

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).

OBJECTIVES

*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)