First trimester screeningThe Danish Experiences Vårmötet 2007 Lennart Friis-Hansen Dept. of Clinical Biochemistry Rigshospitalet Univeristy of Copenhagen Denmark
Historical overview of thePrenatal screening in Denmark • Early 1970s First antenatal diagnosis of DS • 1978 Introduction of national guidelines for when offer karyotyping • All women > 35 years • Women with known risk factors: • Previous birth of a child with karyotype anomalies • Carrier state of a known disease, e.g. thalassemia, CF, • 1980 Screening for NTD using MS-AFP and ultrasound • 1990 Screening for DS using MS-AFP, HCG and uE3 as part of trials in parts of Denmark
In the late 1990s and early 2000s the overall invasive rate reaches 10-12 % for all pregnancies. 40% detection rate 60% of the Downs being born by women < 35 years of age. DS epidemiology – problems with the old screening policy
1st trimester Combined test (“Double test” + NT) free β-hCG, PAPP-A, NT and maternal age 2nd trimester Triple test AFP, uE3, total hCG/free β-hCG and maternal age. Quadruple test AFP, unconjugated oestriol (uE3), free β-hCG/total hCG, inhibin-A and maternal age. 1st + 2nd trimester Integrated test a single test result = the integration of NT and PAPP-A in the first trimester + the quadruple test in the second. Serum integrated test A variant of the integrated test using serum markers only Types of tests 1st trimester 2nd trimester Week 8 - 14 11 – 14 15-18 PAPP-A/bhCG NT AFP, uE3, βhCG/hCG, inhibin-A Suruss, 2003
Detection rate (%) Performans af forskellige screeningsstrategier Integreret (1+2 trim) NT + doubletest(1 trim) NT (1 trim) Doubletest (1 trim) Quadrupletest (2 trim) Tripletest(2 trim) Alder > 34 år(1 trim) Ingen test Simulation by H. Cuckle Screen positive (%)
Why 1st trimester screening is preferred Faster result -> the pregnant women have less time in which to worry If needed abortion can be performed almost within limits for “free abortion” High % of attendance because: Pregnant women want to see the baby – they accept the NT as part of “seeing the baby”. However, once they’ve seen it, they are less likely to come back. (Programs combining 1st and 2nd trimester screening suffer from patients not attending the 2nd trimester screening.) Types of tests 1st trimester 2nd trimester Week 8 - 14 11 – 14 15 - 20 PAPP-A/bhCG NT AFP, uE3, βhCG/hCG, inhibin-A
Initial questions from the Danish National board of health • Can foreign programs be copied? • can their performance be achieved?
1st Trimester screening trials in Denmark Copenhagen first trimester study (HS) (1997-2001) (Wøjdeman et al., 2005) Intervention study – by NT only • NT was measured in 8622 singleton pregnancies (97.5% of the screened cases) GA 10 + 3 and 13 + 6 weeks. DR for DS with NT alone 75%, FPR 1.8%. • beta-hCG and PAPP-A were analyzed in 6441 cases. DR 73%, FPRs of 8.8% • the combined test (NT + biochemistry) DR 91%, FPR 2.1% • Low beta-hCG and PAPP-A values (below 0.4 MoM) were observed in 0.5% of the women including all cases of triploidy and trisomy 18 and 13. Skejby study (Schøidt et al., 2006) Intervention study by Double + NT • 881 had the full test. • Screen positive = 34. • CVS with aneuploidy = 11 (6 trisomy-21, 5 others). • FPR = 3.2%. Positive Predictive Value (PPV) = 17.6% for T-21. Bent Nørgaard-Pedersen and Michael Chistriansen, both Statens Serum Institut
Antenatal care in Denmark2004/5 -> ”Fetal Diagnostics and Risk Evaluation”A report from Danish National Board of Health, April 1st 2003 • Week 8-10 (-12) GP (confirmatory) pregnancy testing, general information about the pregnancy and information 1st trimester scrrening program for DS • Week 8-10 (-12) Blood sampling for biochemistry performed at GP or at the hospital • Week 11-13+6 NT (maybe one-stop) • If screen positive CVS/AC • Week 18-20 malformation screening by ultrasound
National guidelines for quality assurance of the 1st trimester screening • Ultrasound • Certification of sonographers • Continuous monitoring (>500 scan/year) • Each centre should handle at least 1,000 deliveries per year • Biochemistry • Internal & external quality control • Minimal number of test required • > 5,000 tests/year -> the laboratory can operate independently • < 5,000 tests/year -> the laboratory can only operate if they collaborate with a another laboratory on quality assurance • Screening program performance • Screen positive rates should be monitored • False negative rates should be monitored • A National center for monitoring the quality of the program should be established
Implementation of 1. trimester screening NT + biochemistry Copy the FMF program to the very point => • known screen positive rates • Known detection rates
Implementation of 1. trimester screening NT + biochemistry The sonography followed FMF guidelines • NT had already been established at several centers • Major Departments of Fetal medicine performing the NT had all been trained by the Fetal Medicine Foundattion, London, all sonographers were already FMF-certified. • NT QC • All sonographers are FMF certified • Software • All Departments of Fetal medicine were using the Astraia software (FMF approved)
Implementation of 1. trimester screening NT + biochemistry Biochemistry • Exclusively performed at Depts. of Clinical biochemistry • It was decided to follow the FMF standards and only use FMF certified platforms because only data generate using these platforms can be entered into the Astraia software • Brahms Kryptor • Perkin Elmer Delphia Systems • QC • Internal and external controls. • All Depts. Of Clinical biochemistry are participating in the UK-NEQAS 1. trimester QC program • Monitor screenpostive rate • Monitor medians MoM
Implementation of 1. trimester screening NT + biochemistry Risk estimation • All centers performing NT sonography use the Astraia software • Biochemical data generated using FMF approved platforms can be entered directly into Astraia • Astraia could be used for risk estimation • Astraia could be used for quality assurance.
Setup • Week 8 - 13+6 • PAPP-A + bhCG • Patient ID (age) CALCULATE RISK • Week 11 - 13+6 • NT • Weight • Gestational age • Additional risk factors
Challenges - 1 • Astraia • The window for which biochemistry is accepted in Astraia • Expanded from 10+0 – 13+6 to 8+0 – 13+6 in 2005 • Inability of Astraia to communicate with the Hospital Laboratory Information Management System • All data have to be manually entered into Astraia. This is associated with a great risk for typing mistakes. • Astraia are currently working on making the necessary changes – deadline?
Challenges - 2 • Default medians – can they be used • Initial study 1500 samples analyzed at Hvidovre and Rigshospitalet -> Yes • Follow-up 20000 samples analyzed at Hvidovre and Rigshospitalet -> Yes but ability to modify medians would be preferable
Conclusion Medians • Medians can be used during start up phase of a first triemster program. • The bigger Danish centres would like to be able to individualise the Kryptor medians (scheduled to take place with the next Astraia update) • The Delphia Express medians needed a major adjustment (which has taken place)
Challenges - 3 • Pre-analytical – can samples be sent by mail to the laboratories • Pilot experiment • Compare medians
1.25 1.20 1.15 Ratio after 72 hrs in mail vs 72 hrs at 4C 1.10 1.05 1.00 0.95 0.90 free-beta PAPP-A
No differences between medians • No differences between medians obtained at a center that receive samples by mail and centers collecting and analyzing samples in house.
Conclusions transport • Sending the samples to the laboratories using mail does not affect medians. • However, care should be taken to avoid exposing samples to high temperatures.
Danish centers performing 1. trimester screening 1. Trimester NT + Biochem (Brahms) 1. Trimester NT + Biochem (Delphia) • Trimester NT only, external • source for Biochemistry 3 2
North Jutland, Aalborg 4000 tests/year Western Jutland, Holstebro 3500 tests/year Mid Jutland, Skejby 12000 tests/year Southern Jutland, Sønderborg 4000 tests/year Funen, Vejle 6000 tests/year National Serum Institute ? tests/year Northern Zealand, Hillerød 5000 test/year Copenhagen County Gentofte 2000 tests/year Herlev 2000 tests/year Glostrup 2000 tests/year Copenhagen City Hvidovre 6000 tests/year Rigshospitalet 5000 tests/year Roskilde 3000 tests/year Western Zealand, Slagelse 2000 tests/year Southern Zealand, Næstved 3000 tests/year The expected volumne at Danish centres performing the biochemistry (b-hCG and PAPP-A)
Regimes at the centers • One stop • Samples drawn and NT performed at the same day at the hospital in weeks 11-13+6 (Copenhagen County) • Two stop • Samples drawn at the GP in weeks 8-10, NT 11-13+6 at the Hospital (most hospitals) • Samples drawn at the hospital in weeks 8-13+6, NT 11-13+6 at the Hospital (Hvidovre and Rigshospitalet) • Risk calculation • Only the final risk is calculated. • An independent risk based on PAPP-A and b-hCG is NOT calculated
How the pregnant women choose Accept to be screened Yes > 80% RH Accept having a CVS if screen positive Yes - CVS Wants a diagnostic despite a low risk estimate Few Choses abortion after the fetus has been found to carry trisomi 21 All but one!
Number of test per month in 2005 at Rigshospitalet K Sundberg, unpublished data
Reasons for not enroling in the first trimester screening • Percentage not enroling 6% - 8% • Late bookers • Ethnic minorities • Unaware of the screening program • Don’t wish to be screened (few) K Sundberg, unpublished data
Invasive procedures in Denmark 5.0% 12.2%
Number of invasive tests i Copenhagen City K Sundberg, unpublished data
Newborns with Down syndrome Tabor, 2007
1st trimester questionaire, Jan 04 - April 05 Number of children? • 59% - 72% nullipara From where did you get the information about the 1. trimester screening? • 58% - 81% GP • 12% - 14% friends • 8% - 10% media • 7% - 10% internet • 4% - 5% previous contact with health services • 1% - 3% Midwifes • 8% - 16% unanswered / other • 12% - 8% Acknowledge more than one source K Sundberg, unpublished data
Future tasks • Establishment of a national QC database which will pair data from • Astraia • NT data • Biochemistry data • The Danish Cytogenetic Central register (DCCR) • National patient register (LPR) which includes data from the Danish newborn register and the Danish abortion register • Better information to the pregnant women
New markers and new strategies • ADAM12 • Contingent testing • Repeated measurement
PAPP-A MoM b-hCG MoM 1 1 Time Time First Trimester Second Trimester First Trimester Second Trimester D Wright, 2006
Conclusions • It has been possible to offer all pregnant women first trimester screening in Denmark by • Duplicating an existing well proven program (for instance the FMF program) • Having well educated staff • Nuchal translucency • Biochemistry • Adhering to the strict quality control rules (e.g. the rules set up by the FMF) • Nuchal translucency • Biochemistry • Choosing components that work well together • Software • Analytical platform
Acknowlegdements • Karin Sundberg, Rigshospitalet • Ann Tabor, Rigshospitalet • Connie Jørgensen, Rigshospitalet • Niels Tørring, Skejby Hospital • Steen Sørensen, Hvidovre Hospital
Outline • How it was • Prevention oriented, age determined • The new policy • Informed Choice • Implementation • Choice of program to chose • Choice of analytical platform • Status 2006 • Where are we in Denmark • New markers and new strategies