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 The provision of information for individuals  Women have the right to access information about the health of their fetus 32 nd RCOG Study Group SOGC Statement on Access to Genetic Screening January 2007 Objectives: Screening for Fetal Aneuploidy 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):

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 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 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 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) risk Nuchal Translucency Biochemistry New Marker X X Background risk X

Prenatal Screening in Alberta Detailed Anatomy Genetic 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 AMNIO CVS Pregnancy Outcome *Southern Alberta Center for Maternal Fetal Medicine (MFM Centre) Nuchal translucency screening* 2002 No MSS after NT, unless with genetic counseling 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

E arly R isk A ssessment 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

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 ( 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 weeks. Maternal serum Biochemical markers of chromosomal anomalies - free b-hCG & PAPP-A at 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 ( 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 * Mean T/O time 92 minutes

OSCAR in Calgary FTS Uptake March

Non-OSCAR in Calgary (2-Step Model) Woman arrives Blood sample Free b HCG,PAPP-A OSCAR facility NT Ultrasound Examination 2 MFM sites Risk Assessment Same day report Woman departs *Own MD, website, pamphlets U/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 Free Beta hCG / PAPP-A73%72%70%68%66% Spencer et. Al Ann. Clin. Biochem. 2003; 40: /250 Risk cut-off Biochemistry Works Better Earlier

“Non”-OSCAR Woman referred for FTS Directed to educational materials* Blood sample at any CLS facility starting at 9 weeks gestation NT Ultrasound At Beddington or Southport EFW MFM Clinics Risk Assessment Post-test counselling Woman departs Free b HCG PAPP-A Free b HCG PAPP-A NT Scan One Stop Clinic for Assessment of Risk Southern Alberta Centre for MFM

Mean Maternal Age Year of Program Mean Maternal Age (Range) in Years % ≥ 35 years; % ≥ 40 years Year 1: March 13, 2006-March 13, (15-49)31%* ; 4.6% Year 2: March 14, 2007 –March 13, (15-48)29.5% ; 4.0% Year 3: March 14, 2008 – July 31, (15-52)29.3% ; 3.9% (* 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 /23 (87%) 6.5% (325/5013) 1: /31 (93.5%) 6.3% (439/6984) 1: /54 (90.7%) 6.3% (764/11997) 1:15.5

FTS Performance March March Total number screened 6984 Initial 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: %93% 1: %93 % 1: %90% 1: %80.6%

FTS Performance March March 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 March 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 Mean GA 60 mm Mean T21 risk: 1:22 Mean NT: 3.6 (range mm) Average age 36.3 years (range 22-45, 68% over 35 years) Average f β-HCG 2.5 MOM (range ) Average PAPP-A 0.5 MOM (range ) OAPR: 1:16 Characteristics of the true +ve (T21) screens (n=20)

FTS in Calgary Mean GA 66 mm Mean T21 risk: 1:43 Mean NT: 3.9 Average age 36.7 years (range 22-45) Average f β-HCG 2.5 MOM (range ) Average PAPP-A 0.6 MOM (range ) OAPR: 1:15 Characteristics of the true +ve (T21) screens (n=29)

FTS in Calgary 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. 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;

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;

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) Trisomy /23 Trisomy 18314/4 Trisomy 13213/3 Other549 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) 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 HAFMCTOTAL Screened Increased Risk1344 (4.4%)1096 (7.6%)2440 (5.3%) T2170/77 (91%)75/81 (92%)145/158 (92%) T T x Triploidy9716 Other5611 Prospective 1st Trimester Screening singleton 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 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 Service by Service Delivery Model SiteVery Satisfied/ Satisfied Unsatisfied/ Very Unsatisfied Total OSCAR2551 (98.7%)34 (1.3%)2585 (100%) non-OSCAR993 (95.2%)50 (4.8%)1043 (100%) Total3544 (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 Study OSCAR Satisfaction Study *DR of T21 87% at 5% FPR Invasive 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 WEEK SCAN NT, NB Fetal anatomy UA Doppler Placental morphology 1st TM Volume (3D) Maternal Serum PAPP-A Free beta hCG Store sample DETAILED ANATOMY Fetal echo Uterine artery Doppler Placental morphology Timing of scan TV cervix clinic U/A Doppler Cervical length (c/w week ) Maternal Serum AFP,uE3,hCG DIA? Contingent screening Store sample PHASE 1: FTS PHASE 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, 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 ProgramDetection Rate Trisomy 13/18 Initial Positive Rate Cut-off 1:150 March 13, 2006 March 13, /5013) March 14, 2007 – March 13, % (80/6984) Total /54 (90.7%) 6.3% (764/11997)