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Modern Prenatal Tani

Modern Prenatal Tani. Serdar H. Ural, M.D., F.A.C.O.G . Director , Division of Maternal Fetal Medicine Medical Director, Labor and Delivery Unit Director, Obstetrical Ultrasound Unit Director, Fellowship Training Program Professor of Obstetrics & Gynecology and Radiology

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Modern Prenatal Tani

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  1. Modern Prenatal Tani Serdar H. Ural, M.D., F.A.C.O.G. Director, Division of Maternal Fetal Medicine Medical Director, Labor and Delivery Unit Director, Obstetrical Ultrasound Unit Director, Fellowship Training Program Professor of Obstetrics & Gynecology and Radiology The Pennsylvania State University College of Medicine, U.S.A.

  2. Prenatal Genetik Test Yontemleri • Amniyosentez (AS) • Koryonikvillusbiyopsisi (CVS) • Kordosentez/Fetal kannumunesi (Percutaneous umbilical blood sampling/fetal blood sampling (PUBS)) 4 Metot; • Sitogenetik test: kromozomsayiveyapianalizi • Fluorescence in situ hybridization: protein analizi/kromozomalaranjmanve protein marker incelenmesi • Biyokimyasaltestler: protein veenzimanalizi • DNA analizi (Carrier screening)

  3. Amniyosentez • 15-20 gebelikhaftalarinda • Sitogenetikdiyagnostikdogrulukorani>%99 • Guvenilirbiryontemolupabortusriski 1/250 • 1/1000 oranindakanama, amniyotiksivikaybi, koryoamniyonitriski • Fetal travma, kulturunuremebasarisizligisifirayakindir . Simpson JL, Elias S: Essentials of Prenatal Diagnosis, Churchill Livingstone, New York, 1993.

  4. Amniyosentez • FASTER trial data • 35,003 vaka, 3,096 amniosentez, 31,907 amniosentezolmayan • Multiple logistic analysis to adjust for potential confounders • <24 gebelikhaftasi • Prosedur’ebagligebelikkaybi %0.06 • Eddleman K et al. Pregnancy loss rates after midtrimester amniocentesis. ObstetGynecol 2006, 108 (5); 1067-72

  5. Amniyosentez • 14-24 hafta • 5780 hasta • %1.4 gebelikkaybi • Gaudry P et al. Fetal loss after amniocentesis in a series of 5780 procedures. • Fetal DiagnTher 2008; 23;3;217-21

  6. Amniyosentez • 3’cu trimester • Ilk 24 saat • 111 hasta • Komplikasyon %3.6 • Preterm eylem, ruptur, kanama • IUFD (-) • Acildogum (-)

  7. Amniyosentez • Chromosomal analysis (Trizomi 21, 18, 13, sekskromozomu), AFAFP, AChE studies • Aseptikkosullar • Cogulgebelikte, indigo carmine boyasiilegestasyonayrimi, metilenmavisikullanilmamali, kaliciboya, hemolytic anemia, methemoglobinemia • Hook E et al. Chromosomal abnormaility rates at amniocentesis and in live born infants. JAMA 1983; 249 (15): 2034-2038

  8. Amniyosentez • RhoGAM300 microgram anneRh (-) ise • Fetal hucrelerkulturedilipanalizedilir • Amniosentez sonrasi fetal kalp atimi olculmeli

  9. Amniyosentez • Genetik amniosentez ve fetal fizyolojik cevap • 117 hasta • 16.78 +/- 0.48 gebelik haftasi • Prosedur oncesi ve sonrasi 1’ci dakikada • Amniyotik sivi da azalma- Istatistiki fark • Fetal kalp hizinda artis- Istatistiki olmayan fark • Akut fetal hemodinamik degisiklikler • Ural SH, Deren O, Macones G et al. Is there a fetal physiologic response following a genetic amniocentesis? Presented at the 26th Annual Meeting of the Society for Maternal Fetal Medicine, Miami, Florida, February 2006 -Am J ObstetGynecolAralik 2005

  10. Amniyosentez • Erken AS 11-14 gebelik haftalarinda uygulanir • Abortus riski daha yuksektir, %3 • Fetal talipes riski 15 kat daha fazladir • Dahaazamniyotiksivicikar • Membrandelinmesidahazordur • Kultureetmekdahazordur • ABD’de erken AS onerilmemektedir • Elias S, Simpson JL: Diagnostic Ultrasound in Ob-Gyn, Techniques and safety of genetic amniocentesis and chorionic villus sampling. JB Lippincott Co, Philadelphia.

  11. Amniyosentez • Rapid aneuploidy screening • RAS • 24 saaticindecevap • Kultur’eyakindogrulukorani • Pahali • Yalnis (-) ve (+) riski • Azbilgi • Australian ObGyn Journal Nisan 2009

  12. Amniosentez • Rapid floresans in situ hibridizasyon (FastFISH) • 2 saaticindesonuc • CEP ve LSI probu • 100 amniyotiksividankulturlecogaltilmamisamniyositlerinincelemesi • %100 dogrusonuc • Choolani M et al HastFISH; technique for ultrarapidflurescence in situ hybridization on uncultured amniocytes yielding results within 2 hours of amniocentesis. Mol Hum Reprod 2007, 12 Nisan

  13. En YeniYontemler • Semin Fetal Neonatal Med. 2011 Apr;16(2):81-7 • Trizomi 21, 18, 13, sekskromozumu • En sikgorulenkromozomalanoplioditanisi • Hizlitestler • Interphase fluorescence in-situ hybridisation (iFISH) • Quantitative fluorescent polymerase chain reaction (QF-PCR) • Multiplex ligation-dependent probe amplification (MLPA)

  14. CVS • Koryonik villus biyopsisi (CVS) genelde 10-12 gebelik haftalarinda uygulanir • Daha erken taniya ve de olasi durumda daha erken terminasyona izin verebilir. Bu hasta icin operatif riskin daha az olmasi demektir • Sitogenetik diyagnostik dogruluk orani amniosentez de oldugu gibi >%99’dur • Maternal kontaminasyon, mozaik sonuc • Jackson L et al. A randomized comparison of TC and TA CVS. The US National Institute of Child Health and human development CVS and Amniocesntesis study Group. N Engl J Med 1992, 327; 594-598

  15. CVS • Transservikal (TC) ve de transabdominal (TA) yontemlerle uygulanir • TC yontemi hastanin rahatligi nedeniyle tercih edilebilir • Abortus riski yaklasik 1/100-200’dur. Bu TA ve TC icin esittir • RhoGAM if Rh (-) • Fetal kalpatisi • Rhoads G et al. The safety and efficacy of CVS for early prenatal diagnosis of cytogenetic abnormalities. N Engl J Med 1989, 320; 609-617

  16. CVS • Servikal/vajinalenfeksyon, veyaservikalkanalobstruksyonunda (myoma) TC kontrendikedir • Fundal or anterior placentas • USG ile TA 20 gauge uzun igne, TC anjiyokateterkullanilir • 10-25 mg villus • Sundber K et al. Randomised study of risk of fetal loss related to early amniocentesis vs. CVS. Lancet 1997; 350-697

  17. CVS • Ekstremite ve oromandibuler deformite riski CVS 10-12 haftalar arasinda yapildigi surece normal populasyon riskine (6/10,000) gore daha fazla degildir • Bu veriler Dunya Saglik Teskilatinin dunyada yaptigi arastirmalar sonucunda belirgin hale gelmistir • Bilhassa <10 gebelik haftalarinda risk artisi var

  18. CVS • Akut fetal hemodinamikdegisiklikler • Feta kalpatisindageciciartis • Uzunvadedezarar/yanetki? • CVS vs. amniosentezgebelikkaybiorani • 9,886 CVS, 30,893 amniosentez • 20 senelikcalisma, sonundakayiporanlaries, zamanlakayiporanindaazalma (yaklasik %<1) • Radunovic N et al. CVS significantly affects feta; cardiovascular function. J Matern Fetal Neonatal Med 2007 20 (4); 285-8 • Caughey A et al. CVS compared with amniocentesis and the difference in the rate of pregnancy loss. ObstetGynecol 2006, 108; 612-6

  19. InvazivSecenekler • Randomized controlled • Kohort, meta-analiz • Modern literaturkonsensus; • Tecrubeli operator ilearadafarkyok, yada minimal • Amniosentez-CVS • Evans M, Andriole S. CVS & amniocentesis in 2008 • CurrOpinObstetGynecol2008; 20;2;164-8.

  20. Kordosentez-PUBS • En invazivveriskliyontem • 24 haftadanevveltecrubeliellerdedusukriski % 2-3 • Genelde % 5-8 • 24 haftadansonra risk • Membranrupturu, preterm eylem, koryoamniyonit % 2-8 • Avantaj = iyilaboratuarteknigiilebirlikte 24 saaticindesonuc • Direk fetal hucreanalizi, %100 dogruluk • Pektercihedilmemekte; gec, riskli, her lab yapamayabilir, operator • 25 gauge ignecalismalari • 2009 Japonya

  21. Modern Prenatal Tani • AS ve CVS karari verilirken hastanin durumu goz onune alinmalidir • AS’nin baslica avantaji abortus riskinin daha az olmasidir • CVS’in baslica avantaji ise kromozomal taninin daha erken konulabilmesidir • Amniosentez halen CVS’e gore daha fazla sayida yapilmaktadir • Fakat bilhassa 1st trimester taramasiyle birlikte CVS sayisinda artis

  22. Prenatal TaramaYontemleri • Who to offer screen/diagnosis? • Maternal yassinirlamasiyok • > 35 uygundegil • Anomalilerinsadece40%’i tespit • Butungebelerebutunyontemlersunulmalidir • Artikyasfaktordegil , hem 35 ustu, hem de alti– • diyagnostik test onerilmesiacisindanesitsayilmakta

  23. Screening Tests • First Trimester Screen • Maternal Serum Screening • Triple Screen • Quad Screen • MS-AFP • Ultrasound • Cell-free DNA testing

  24. First Trimester Screen • Mix of ultrasound measurements and serum markers • Performed between ~11 and 14 weeks of pregnancy (Bas-makatmesafesi 45mm to 84mm) • Trisomy 21, 18, and 13 • Bazianomaliteshisi, kalp vs.

  25. Ultrasound • Mid-Sagital view • Image size >75% • Fetus away from amnion • Maximum lucency • Callipers on to on

  26. Pregnancy Associated Plasma Protein A (PAPP-A) • Glycoprotein - Protease for insulin-like growth factor (IGF) binding proteins 4 & 5 • Plasentalgelismevevaskularizasyon • Detectable at 8 weeks – rises throughout pregnancy • Dusukseviye; • Gebelikkaybi • IUGR • Digergebelikkomplikasyonlari • Down sendromlugebeliklerde8-13 haftalararasidusuksevidededir

  27. Free beta hCG or intact hCG • In the First Trimester • Glycoprotein hormone produced by placenta • Levels rise rapidly after conception • Peak at 8 to 11.5 weeks • Corpus luteum ve progesterone yapiminisaglar • May also affect immune tolerance of pregnancy • Down syndrome da yuksekseviyedeseyreder

  28. Prenatal Genetic Screening & Diagnosis • First trimester screening • 11 weeks and 13 weeks 6 days • NT < 3.4 mm • Free beta-hCG 1.98 MoM (higher) • Pregnancy associated plasma protein-A (PAPP-A) 0.43 MoM (lower) • CVS must be available; keep in mind dating issues • Nasal bone • Absence/presence

  29. Yuksek AFP • 80% acik NTD • 90% anencephaly • Also look for gastroschisis and other abdominal wall defects on ultrasound

  30. Prenatal Screening • Trisomy 21; triple and quadruple maternal serum screening test • AFP 0.74 MoM (dusuk) • hCG 2.06 MoM (yuksek) • u-estriol 0.75 MoM (dusuk) • Inhibin A 1.77 MoM (yuksek) • Trisomy 18; AFP, hCG, u-estrioldusuk

  31. Prenatal Screening • Triple screen (AFP, u-E3, hCG) 69% • Quadruple screen (AFP, u-E3, hCG, inhibin-A) 81% • NT 72-77% • Trisomy 18 75% • Trisomy 13 72% • 46,X 87% • Triploidy 59% • Other chromosomal defects 55% • PAPP-A + free beta-hCG 68% • Trisomy 18 90%

  32. Prenatal Screening • First trimester screen (NT, PAPP-A, free Beta-hCG) 82-91% • Trisomy18 + 1397% • First trimester screen with nasal bone 92-95%

  33. Prenatal Genetic Screening & Diagnosis • Twin gestations • Serum screening LESS ACCURATE • NT • Lower detection rates • Triplet and more gestations • Serum screening NOT AVAILABLE • NT; lower detection rates

  34. Fetal DNA Testi • Anne kandolasiminda fetal DNA taramatesti, placental ve fetal-hucrekokenli • Anne dolasiminda fetal hucrelerindagilmasi • Maternal plasmada fetal DNA tetkiki • Fetal ise placental orijinliz • Kisafragmanlardir (150-200 bp) • Butungenom’uicerir

  35. Fetal DNA • Sadeceyuksekrisklihastalarda; 35 ustu,anomaliteshisi, hikaye +, lab bulgusu • Trisomi 21,18,13, sekskromozomu • 10’cu haftadansonra • Anne kanindanstandart DNA ekstraksyonuyontemi • Sensitivite %99 Trizomi 21, hepsiicin %95 • Yalanci +/- % 0.05 • Cogulgebeliktesensitivitearastirilmakta • Normal risklihastalardasensitivitedahaaz, % 80 • Mart 2014, en son bilgiler, derleme

  36. Cell-Free DNA Testing

  37. Onumuzdeki 10 sene • Maternal kanda fetal DNA ve fetal kanhucrelerininincelenmesi • Sensitiviteoranlariartmakta • Teknolojiilerlemesiyle, maternal numunelerdeotomatik fetal DNA taramasi • Am J Obstet Gynecol. 2014 Mar 19. pii: S0002-9378(14)00270-1 • Noninvasive prenatal screening for fetal trisomies 21, 18, 13 and the common sex chromosome aneuploidies from maternal blood using massively parallel genomic sequencing of DNA. • Porreco RP, Garite TJ,

  38. Referans • Ural SH, Deren O, Macones G. Is there a fetal physiologic response following a genetic amniocentesis? Presented at the 26th Annual Meeting of the Society for Maternal Fetal Medicine, Miami, Florida, February 2006 Simpson JL, Elias S: Essentials of Prenatal Diagnosis, Churchill Livingstone, New York, 1993. • Hook E et al. Chromosomal abnormaility rates at amniocentesis and in live born infants. JAMA 1983; 249 (15): 2034-2038 • Gardner R et al.Prenatal diagnostic procedures. In: Chromosomal anomalies and genetic counseling 2nd ed. New York; Oxford University Press 1996; 336-344. Oxford Monographs on Medical Genetics No. 29 • Elias S, Simpson JL: Diagnostic Ultrasound in Ob-Gyn, Techniques and safety of genetic amniocentesis and chorionic villus sampling. JB Lippincott Co, Philadelphia. • Jackson L et al. A randomized comparison of TC and TA CVS. The US National Institute of Child Health and human development CVS and Amniocesntesis study Group. N Engl J Med 1992, 327; 594-598 • Rhoads G et al. The safety and efficacy of CVS for early prenatal diagnosis of cytogenetic abnormalities. N Engl J Med 1989, 320; 609-617 • Sundber K et al. Randomised study of risk of fetal loss related to early amniocentesis vs. CVS. Lancet 1997; 350-697 • Brambati B et al. CVS and amniocentesis. CurrOpinObstetGynecol 2005, 17 (2); 197-201 • Widlund K et al. Routine assessment of amniotic fluid AFP in early second trimester amniocentesis is no longer justified. ActaObstetGynecol Scand 2007, 86 (2): 167-71 • Choolani M et al HastFISH; technique for ultrarapidflurescence in situ hybridization on uncultured amniocytes yielding results within 2 hours of amniocentesis. Mol Hum Reprod 2007, 12 Nisan • Radunovic N et al. CVS significantly affects feta; cardiovascular function. J Matern Fetal Neonatal Med 2007 20 (4); 285-8 • Caughey A et al. CVS compared with amniocentesis and the difference in the rate of pregnancy loss. ObstetGynecol 2006, 108; 612-6

  39. References • Screening for fetal chromosomal abnormalities. ACOG Practice Bulletin 2007 # 77, Vol. 109, # 1 • Comstock CH et al. Is there a NT mm measurement above which there is no added benefit from 1st trimester screening? Faster research consortium. Am J ObstetGynecol 2006;195;843-7 • Malone F et al. 1st trimester or 2nd trimester screening or both for Down’s syndrome. 1st and 2nd trimester evaluation of risk (Faster) research consortium. N Eng J Med 2005;353;2001-11 • Makrydimas G et al. NT and fetal cardiac defects; a pooled analysis of major fetal echocardiography centers. Am J ObstetGynecol 2005;192;89-95 • Bahado-Singh R et al. The midtrimester genetic sonogram. SeminPerinatol 2005;29;209-14 • Nicolaides K. NT and other 1st trimester sonographic markers of chromosomal abnormalities. Am J ObstetGynecol 2004;191;45-67 • Snijders R et al. 1st trimester trisomy screening; NT measurement training and quality assurance to correct and unify technique. Ultrasound ObstetGynecol 2002;19;353-9

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