1. VI. Hrvatski kongres o ginekološkoj endokrinologiji, humanoj reprodukciji i menopavzi s međunarodnim sudjelovanjem 13.-16-9-2007, Brijuni DARIJA STRAH Diagnostic Centre Strah, Domžale MAJA POHAR - PERME Institute for Biostatistics and Medical Informatics, Faculty of Medicine, University of Ljubljana KSENIJA GERŠAK Department of Obstetrics and Gynecology, University Medical Centre Ljubljana FIRST TRIMESTER SCREENING FOR TRISOMY 21 BY MATERNAL AGE, FETAL NUCHAL TRANSLUCENCY AND NASAL BONE IN 13.049 UNSELECTED PREGNANCIES IN SLOVENIA

2. VIII. Hrvatski kongres o ginekološkoj endokrinologiji, humanoj reprodukciji i menopavzi s međunarodnim sudjelovanjem 8.-11.-9.-2011, Brijuni Prenatal screening programs provide information with which couples can make appropriate decisions, rather than focusing on disabilities and their eradications. (Royal College of Obstetricians and Gynaecologists, 1977)‏ Definition

3. VIII. Hrvatski kongres o ginekološkoj endokrinologiji, humanoj reprodukciji i menopavzi s međunarodnim sudjelovanjem 8.-11.-9.-2011, Brijuni The natural frequency of chromosomal abnormalities at birth in the absence of any prenatal diagnosis is 6 / 1.000 births. Aneuploidies are the most frequent: T 21: 1 IN 800 (Hook, 1992)‏ T 18: 1 IN 6.500 T 13: 1 IN 12.500. Sex aneuplodies: Turner sy (45, x0), Klinefelter sy (47, xxy), triploidy type I (diandry) and type II (digyny). Incidence I

4. VIII. Hrvatski kongres o ginekološkoj endokrinologiji, humanoj reprodukciji i menopavzi s međunarodnim sudjelovanjem 8.-11.-9.-2011, Brijuni Age dependent - due to shift to women having babies at an older age the general prevalence for T 21  from 1 in 740 (1974) to 1 in 504 (1997) (Egan et al., 2000). The actual frequency changes with gestational age and intrauterine lethality of various aneuploidies. T 21: 40 % fetal loss  12. W term 30 % fetal loss  16. W term T 18,13: 80 % fetal loss  12. W term 40 % fetal loss  16. W term (Snijders et al.,1995)‏ Incidence II

5. VIII. Hrvatski kongres o ginekološkoj endokrinologiji, humanoj reprodukciji i menopavzi s međunarodnim sudjelovanjem 8.-11.-9.-2011, Brijuni Screening for T21 has become an established part of obstetric practise over last 20 years by second trimester maternal serum biochemical markers. (Spencer, 1999; Cuckle, 2000; Muller et al., 2002; Wald, 2003)‏ AFP, free  -hCG, unconjugated ESTRIOL, inhibin A; DR: 60 – 70 % at 5 % FPR (Nicolaides KH, 2004)‏ First trimester combined prospective screening: DR: 88 % at 5 % FPR (Nicolaides KH, 2005, Malone, 2005, O'Leary et al., 2006, Wright at al, 2008, Kagan KO et al, 2008)‏ Second trimester screening

6. VIII. Hrvatski kongres o ginekološkoj endokrinologiji, humanoj reprodukciji i menopavzi s međunarodnim sudjelovanjem 8.-11.-9.-2011, Brijuni First trimester screening Earlier reassurance: - Higher detection rate (Nicolaides, 2005, 2011, Malone, 2005, O'Leary et al., 2006)‏ - Lower invasive testing rate (Tabor, 2008) - Termination is safer earlier (Lawson et al., 1994)‏

7. VIII. Hrvatski kongres o ginekološkoj endokrinologiji, humanoj reprodukciji i menopavzi s međunarodnim sudjelovanjem 8.-11.-9.-2011, Brijuni OSCAR Clinic: contemporaneous approach - one stop Clinic (Bindra et al., 2002, Avgidou et al., 2005, Nicolaides et al., 2005, Tabor 2007)‏ Concurrent testing: biochemistry available after US, counselling delayed (Czech Republic, Germany, Italy, Finland, Slovenia, Stenhouse et al., 2004)‏ Sequential testing: biochemistry taken before, counselling on the day of US (Borell et al., 2004),  DR blood at 9 -10 w Two stage testing: biochemistry taken if risk > 1/1.000 (Kagan KO, 2010) First trimester screening modes

8. VIII. Hrvatski kongres o ginekološkoj endokrinologiji, humanoj reprodukciji i menopavzi s međunarodnim sudjelovanjem 8.-11.-9.-2011, Brijuni NT is the single most effective marker for fetal aneuploidy evaluated by Mahalanobis distance – relative clinical effectiveness. Mahalanobis distance = Markers in discriminating normal pregnancies and T 21 in the first trimester: NT 11,00 PAPP-A 2,48 Free  -hCG 1,74 Nuchal translucency - NT

9. VIII. Hrvatski kongres o ginekološkoj endokrinologiji, humanoj reprodukciji i menopavzi s međunarodnim sudjelovanjem 8.-11.-9.-2011, Brijuni - First trimester screening Additional sonographic markers: - Nasal bone – NB, - Tricuspid flow –TR, - Ductus venosus flow, - Frontomaxilary angle – FMF, - Intracranial Translucency – IT (Spina bifida) DR: about 95 % at 2,5 % FPR (Nicolaides KH, 2011)‏

10. VIII. Hrvatski kongres o ginekološkoj endokrinologiji, humanoj reprodukciji i menopavzi s međunarodnim sudjelovanjem 8.-11.-9.-2011, Brijuni The nasal root depth is abnormally short in 50 % of T21 cases (Cicero et al., 2003) in the first trimester. - Mid saggital view of the fetal profile - Three lines: skin, tip of the nose, NB (thicker and more echogenic) Second trimester: 65 % of T21 has an absent or short NB (charts) Fetal Nasal bone - NB

11. VIII. Hrvatski kongres o ginekološkoj endokrinologiji, humanoj reprodukciji i menopavzi s međunarodnim sudjelovanjem 8.-11.-9.-2011, Brijuni First – stage policy of screening without biochemistry has advantages: -Detailed examination of fetal anatomy – early diagnosis in all pregnancies, -Reduction in the cost of screening (Nicolaides KH, 2011) Biochemistry in subgroup with positive first – stage screening results Sonographic screening by maternal age, NT and NB

12. VIII. Hrvatski kongres o ginekološkoj endokrinologiji, humanoj reprodukciji i menopavzi s međunarodnim sudjelovanjem 8.-11.-9.-2011, Brijuni Objectives To examine the effectiveness of first - stage screening using maternal age, NT and NB in the detection of T 21 at 11-14 weeks in a low risk obstetric population.

13. VIII. Hrvatski kongres o ginekološkoj endokrinologiji, humanoj reprodukciji i menopavzi s međunarodnim sudjelovanjem 8.-11.-9.-2011, Brijuni Methods Period: January 2005 – April 2010 13.535 women: singleton pregnancies 12 4/7 (11 1 / 7 – 14 0 /7) ‏ CRL: 63 mm (45 – 83) 9 NT: 1,7 mm (0, 9 – 13,4) ‏ Excluded: twin pregnancies (3,6 %) fetal deaths no follow up Final analysis: 13.049 women, 29 median maternal age (28,9 in pop)

14. VIII. Hrvatski kongres o ginekološkoj endokrinologiji, humanoj reprodukciji i menopavzi s međunarodnim sudjelovanjem 8.-11.-9.-2011, Brijuni Results 1: 45 chromosomal abnormalities 34 detected (17 T 21, 17 other) %, NB present in 98,5 %, absent in 25 % of abnormalities % DR: 85 % at 2,8 FPR for T 21 % DR: 75,6 % at 2,8 FPR for all % DR: 68 % at 2,8 FPR for other % T 21 ( NT >95 c in 75 % T 21 (15/20) NT >95 c in 64 % other (16/25)

15. VIII. Hrvatski kongres o ginekološkoj endokrinologiji, humanoj reprodukciji i menopavzi s međunarodnim sudjelovanjem 8.-11.-9.-2011, Brijuni Risk  1 : 300 Results 2: 3 % normal pregnancies 85 % T 21 68 % other chromosomal abnormalities PPV T 21: 4,3 % (17/394) NPV T 21: 99,9 % (12.652/12.655) PPV other: 4,3 % (17/394) NPV other: 99,9 % (12.647/12.655) DR T 21: 85 % (17/20)‏

16. VIII. Hrvatski kongres o ginekološkoj endokrinologiji, humanoj reprodukciji i menopavzi s međunarodnim sudjelovanjem 8.-11.-9.-2011, Brijuni The change (lowering) of risk treshold  DR of other chromosomal abnormalities. Change would result in  pregnancy loss due to  FPR and  invasive testing rate. Results 3:

17. VIII. Hrvatski kongres o ginekološkoj endokrinologiji, humanoj reprodukciji i menopavzi s međunarodnim sudjelovanjem 8.-11.-9.-2011, Brijuni Trend of ageing of population of pregnant women results in  FPR at risk cut - off 1: 300. DR at 2,8 % FPR adequate according to FMF standards, no change of lowering the risk limit need. Results 4:

18. VIII. Hrvatski kongres o ginekološkoj endokrinologiji, humanoj reprodukciji i menopavzi s međunarodnim sudjelovanjem 8.-11.-9.-2011, Brijuni Conclusions 1 DR %; for all chromosomal aneuploidies 75,6 %; for T 21 85 % for other chromosomal aneuploidies 68 %. One of twelve women defined as high risk pregnancy carried a child with chromosomal aneuploidy. NB  DR from 75 % (age, NT) to 85 % at low FPR.

19. VIII. Hrvatski kongres o ginekološkoj endokrinologiji, humanoj reprodukciji i menopavzi s međunarodnim sudjelovanjem 8.-11.-9.-2011, Brijuni Conclusions 2 Our first – stage screening results: DR for T 21 compared to reference centre Fetal Medicine Foundation (FMF), London: 85 % (at 2,8 % FPR) Slovenia 85 % (at 2,7 % FPR) FMF

20. References Genetics and Etiology of Down Syndrome, 2011, ISBN 978-953-307-631-7 http://www.intechopen.com/articles/show/title/first- trimester-screening-for-tris omy-21-by-maternal-age-nuchal-translucency-and-fetal- nasal-bone-in VIII. Hrvatski kongres o ginekološkoj endokrinologiji, humanoj reprodukciji i menopavzi s međunarodnim sudjelovanjem 8.-11.-9.-2011, Brijuni