Dr. dr. M ADRIANES BACHNAS, SpOG (K) FM Ketua Divisi Fetomaternal, Bagian Obstetri dan Ginekologi, FK UNS/ RSDM Solo + Vice Coordinctor Research Committee Indonesian Society of Maternal Fetal Medicine + Secretary General oj Nationel Committeeon Ultrasound in Obstetrics and Gyrecolagy Indonesian Society of Obstetrics and Gynecology * Executive Boord htember of Committee on Skils Taining - Indonesian College of Obsteuies end Gynecovogy * Executive Boord Member of Reducing National Maternal Mortality TaskForce- Indonesian Society of Obstetrics nd Gynecology * Head of Maternal Fetal Medicine Sub Dvicion- Faculty of Medicine Universitas Sebelas Ware Dr. Maewardi Hospital + secretary Generalo{ Residency Program -Faculty of Medicine Universitas Sebelas Maret/ Or. Moewerdi Hospitalenc ar Tne Ma Indonesia adalah negara dalam sabuk talasemia dengan 3,8 % seexrem eeosrn sera DONE, penduduknya pembawa sifat Talasemia yang menelan pembiayaan hingga kurang lebih 2,1 T selama periode 2014 s/d September 2018-JKN. 2500 kasus baru) tahun biaya perawatan 3 O O juta rupiah/tahun/ penderita Vai ata ee Apakah bisa diketahui prenatal e dan Apakah menguntungkan untuk © o diketahui prenatalPRENATAL DIAGNOSIS For Hemoglobinopathy THE OUTLINE 1. PRENATAL DIAGNOSIS: AT A GLANCE 2. PLUS AND MINUS OF PRENATAL DIAGNOSIS FOR HEMOGLOBINOPATHY 3. FETAL THERAPY STRATEGY Lp maay os 5 PRENATAL DIAGNOSIS: AT A GLANCEPRENATAL DIAGNOSIS ©) @ @@ © “SOLVING THE UNSOLVED BUSINESS OF Cee ee > GENE DEFECT & \. > CHAIN of HEMOGLOBIN FETALPROBLEM se - > HEMOLYSIS = BlomaRkers — CVS, > IMPACT AMNIOC ENTESIS “TRADITIONAL i) cians OBSTETRICS’ = owe Re RuS of PRENATAL DIAGNOSIS FOR HEMOGLOBINOPATHYmas OO Catarect, microphtalmia, enophtelmia,cyclopia, sipciypttoast choanal — \ atresia, micrognathia, facial asymmetry, nasal bone hypoplasia, cleft lip, ear ‘malformations, abnormal skull shape, brain fluid, endocranial cyst, ventriculomegely, macro-microcephaly, parenchym agenesis, dandy-walker, hholoprocencephaly, neural tube defect, vertebrae and rib anomalies, cystic hygroma, inereased nuchal fold, omphelecele, endothoracie mess, abnormal axis of the heart, funnel chest, anterior abdomen wall abnormalities, diaphragmatic hernia, echogenic bowel, intestinal obstruction, echogenic mass of the abdomen, ascites, stomach absence, hydronephrosis, renal agenesis or dysplasia, megacystis, kidney enlargement, abnormal genitalia, bone fractures, polydactly-syndactiy, TM extremities assymetry, short femur bone, shortening and bowing of long bones, [Abnecral NT, abnrmal NF, long club foot, osteogenesis imperfecta, umblical mass and cyst, hydrops fetalis, bones shortening, echogenicheart | | decreased fetal movements, IUGR, placentomegaly, oligo-pelyhiydramnios, cardiac Joaus chorod pexuseyst, eter ventricles dilatation, echogenic defects, and doppler vascular flow abnormalities, ECC bel, cancun pesto ver eee eee ent | HEAD: BRAIN, SKULL, FACE NECK-VERTEBI ener THORAX: HEART, LUNG, RIB Soin tdpyekeinis edguie | ABDOMEN: WALL, GL-TRACT bereyswthnornel ermioté fue, | PELVIS: KIDNEYS AND U-TRACT *:bad cexterded amnion cheiendlssecton, GROWTH, WELL-BEING, ee ANOGENITAL prognosis EXTREMITIES: FUNCTION, COMPLEXITY + CHEAP > AFORDABLE LACK OF ACCURACY: (5-95% DETECTION RATE) > BROAD SPECT USAGE: EXPERT DEPENDENCY ISOLATED ANOMALY STRUCTURE RELATED, MACHINE+SOFTWARE. NON GENETIC ADVANCE, FETAL POSITION, OBESITY, ETC NON SYNDROMIC 13-40% related to chromosomal or geneUltrasound in hemoglobinopathy ‘© 6 WHAT WE SEE IN ULTRASOUND IS THE IMPACT OF HEMOLYSIS... is the ‘hallmark’ of ultrasound marker until recent >1.5 MoM J Ultrasound Med 2015 3497-206 [0273-4297 | wowaiumergUltrasound in hemoglobinopathy | sty Stoupunt ea ‘CTR >0.5Ultrasound in hemoglobinopathy a= AP)S OC) os) USNIH SCORE 2 3 Bad PrognosisUltrasound in hemoglobinopathy 1 Hepatal Length? | 27mm,18WGA_ I 1 1 N 1 ee Placental thickness 2 30 mm, 18 WGA \ Study ® Method CutoffValueSE.% _SP.% PPS NPV.% FPR.M% Leung eta® 832 AV >8mm ™m 810 ND ND. 190 Leungeta® 593 T’W >8mm m9 588383 90a jongsong etal® 345 ia >30mmn we 02785598 Ghosh ea? 7 ™ oie 280 m0 0 «ND ND 30 109 TA >M250 %0 © 960 ND ND 40 TA DM+28D___100 960 ND ND 40a aye TRIMESTER (+) AK x Peripheral Blood Count Hb, MCV, MCH, reticulocytes Electrophoresis HPLC DNA Analysis ACOG, SOGC, RCOG (2017)and | 36 TRIMESTER (+) i Peripheral Blood Count Hb, MCV, MCH, reticulocytes Electrophoresis HPLC DNA Analysis ACOG, SOGC, RCOC (01Om@Be WHAT WE SEE IS THE IMPACT OF HEMOLYSIS... IT’S LIMITED ON 2°4 AND 3° TRIMESTER > AFTER 18 WEEKS OF GA zu SO ITS USE IS MORE ON SAVING THE FETUS INTRAUTERINE TRANSFUSION‘Biomarker | > Nene 248 sint897-28 DRAENEI Fah 06 A 2 Role of Genomic Biomarkers in Increasing Fetal Hemoglobin Levels Upon Hydroxyurea Therapy and in §~Thalassemia Intermedia: A Validation Cohort Study ‘eat aie Sec 8 ya inns rrgota cain, Scar Abstract Hemodiobinorathies exit a remarkable phenctypicdivorsiy in terms of disease soverty, while Invidual genetic background plays a hey role in ferent response o dug eat ment. nthe ast ‘decade, genomic variants in genes located within. as wel as ouside the human B-gobin custer have been shown tobe sigrificantly esocieted wilh Hb Fincreese ia elation te hyeroxyatea HU) ‘theraoyn patients with these diseases, Here, we aim to determine the effect of genomic variants locatedin genes, sch as MAPKS, ASS1, NOSZA, TOY, POET, NOSI, FTI end ARG2, previously ‘shown to modulate fetl hemoglobin (Hb levels inpatients with 8 type hemoglobinopathies and ‘effecting dceseo severity and recponce to HU therapy in an indopondont cohort of Grock ptionte ith these ciseases, We recruted and genetyoed 46 B-thaassemia patents f-tal, ether ‘ranetusin-dependent (TOT) ornon transfusio-dopondort (NTOT), 42 Hb (HBB: ¢20A>T| ‘tna compound retroz/gotes, who were treated with HU, as Well as 53 Meaty Inaiiouas alot Hoenie origin Our study showed that ganeme variants of th HAP2KS, NOS2A and ARG? gee ‘ae associated wth HU therapy efficacy In Hb S-B-thal compounc heterczygotes, We nave ao shown that Fat ARG2 poner vatint fe associated wih here henotype of NTT ‘could be considered as genomic bomsskers to predict HU therapy efficacy in H -S-thal ‘compound heterozygotes anda te descrbe seas seve natin with type Keywords: fetal hemoglobin bF); genemic variants; hycrenyurea (HU) therapy: ‘pharmacogenomics; sickle col csvase;f- Thalassemia (6-1)‘GENE-ANALYSIS. GO THIS IS ACTUALLY THE TRULY ‘BREAKTHROUGH’ PRENATAL DIAGNOSIS IN 21°* CENTURY GENOMIC MAPPING va SINGLE GENE YOK wi pages * === DY Ha WY it SEqUENCINE cx. : wu ow yg Yoyo cate & SS AS CHROMOSOMAL ABNORMALITIES TRISOMY 13, 1 “mg "07 FOR UNRELATED GENE CHROMOSOMAL BIRTH DEFECT EXTREMELY EXPENSIVE GOLD STANDARD PRENATAL DIAGNOSIS, RELATED TO CHROMOSOMAL) CENE ANOMALYA a pts wsertie 4 j mb j 0 to ovat ete Hao 2g 10 0 3 6 9 Ad me months post conception Ss Origins Features of homozygotes Hemoglobinopathies Hos ‘Mit, Middle East India dcont05 pohymeteaien, epee Hoc tien ‘i nena, peomesa HE Scuth Asia natal mid hemo solnomesay Thalassemia ° ‘Sout Asia, Medteranean,Afica yseps Hats, teneyte meni, spereneaay 6 ‘Scuth Asia, Mediterranean, Aca Yansaien depencert Ngoandstelnberg EMC Medal Genomics (015) 8144(DA) deletion (28) deletion” (-02?/) éetetion (-a42) éetetion (024) aetetion (-a2'*/) deletion (-a27/ éctetion (a2) cetetion (-a'2) éetetion® HBA2:c 377T>€ (Hb OS) HBAL:c223G>C with 042 (Hb Q Thailand) HBAI:c353_355¢upTCA (Hb Phnom Penh) HBA2:c.178G>C (Hb Zurich-Abisricden) HBAL:CS9G>A (HD Amsterdam) HRAL:C.1A>G, ise eden HBA2, HBB may include common/ target deletion/duplication a thalassemia modifier KF ‘Structural hemoglobin variants HBA1: c84G>T (Hb Hekinan) ‘HBB: c.68A>C (HD G-Coushatta) HBB: c.170G>A (Hb }Bangkok) HBB: c341T>A (HD New York) HBB: ¢.34G>A (Hb Hamilton) HBB: ¢.352C>T (Hb Tsukumi) HBB: cAG>T (Hb Nigata) HBB: ¢328G>A (Hb San Diego) HBB:c.265C>G(Hb Oofuna) HBB: ¢.41C>T (New abnormal Hb)* ‘CNV variants cxo7/ oat) excecra 847° aaaa""*/* ona HKaa/ 678k dup £8204K dup" HDB: 124 127detTTCT HBB: ¢52A>T. HDB; c316~197C>T HBB: c.~78A>G HDB; ¢216.217insA HBB: c79G>A (Hb E) HDB; 92-+1G>T HBB: -79A>G. NDB: «1306-7 HBB: ¢84_85insC HDB: 315-456 HBB: c.~1006>A, HBB .—140¢>T HBB: c113G>A HDB: c45_46insG HBB: c*110T>C HDB: c-11_-Bde1AAAC HBB: ¢ 304G>C (Hb Rush) HBB; c316-3¢-T HBB: ¢316-90A>G Chinese det SEA-HPFH Tren abel areata Beene RE Neon cuecce tice Ge ecRCueuc atSovlGoemicANASs | #00: ‘eset We review and repot here the gentypes and snenctypes ef 60 navel thalassemia ard stnormal Bemoslebia 8) metatens scored folowing the acon of rone NA Sequencing of bth and Balabn genes for all UX Remeslbhoaathy ses ered or ‘molec investigation Ths renin strategy over th st 10 yas ha evened 8 olf TY few Beran varent. 15.2 chan wefan. 10 fhabssemle (tha) mutatens and 1S ‘thasemia (tha metatons The lige rab few thlaisema lees crf the ‘nde ncal herogaety of mustions inthe UK tomigrane pepeson. Ben ofthe et ‘rans ran wth He Aon high perfomance lui cvomategepy (PLC) demonstrating the ‘nlue of reutne Seauencng of beth 2 and Plein pores oral nemogobinapehy Iveta, ‘he new chan vasats ae: Ho buy (pzZBOKU — Aip MBE COOA>" Mo Food (G33) bc 105TC), HD ile Vee f421)PRe > Cys BB C1 28T> GI AD Cook BSTENAS Ser UB: C173K>G1 HO Saungsoke FT INGHIPhe Ser (BR: {-356T>C), Hb Howden [UOG2Wa-~ Ala (KBE cADT> C), HD Wen [SIC Les (HE c126C> Al, Hb Belize Pak [BT2UGHSILYs Asn HE CISA. Hb Hamostead Hah BANADHS—-GrehI6BEGlsiys (we cl6c>G79G>AD], Hb Ganda (BBS yes Cys Wile e257T>C) ae HD Caos) (BAERIGY Val HEB: 1667, The naw chan varant ie Hb fscburh (aOE'O)a--Gy (Ban eT SCL Ho Walsgave ett6GiGu-=Yol (82 3S04™T), Hb Wesham (e171GHS) and 1188) Irseten Sor IAT cQ5435SMSTCA). No Coombe, fore (aI270NOLs cla VBA EDEATGI. Ho Overs HIMAINal Asp UOA2 eS3T>AL, "Nb Dedlngten [G3QB13)Met—Te GBA e96T>O, Hb Wevetarplon GOUFASe Tyr (BA CSUSC>AL, FD. Live. Walham IVATIAa "ASS MEAZ cAIC>A, Hb Deby [GonEIOLs wg rsa: C1eSA>o), HB Utoxter [QF -oASp PAL: C2236> Th, Fp Wateas (21 247Ser—= Cy ONT: C274C> GHD Heian (28H Ap BATE S452], HD Mantota 1 (s10269Ser—Arq VAI" CS07A>CL Ho Vitam [an390ICiys—varg (BAZ. C419A>G) and. Mb Farborcugh [o91A7An Asp BAT: 28436. Madton 10 mee paraogoes lois chan vant have ben dszovered. ‘Tee novel Petal ales mer MBB CTMC>G MAB CcTICST. HOR c-80T™>G HOR 18. T9deMG, HBB €219_220nsT, HEB e315 +2 315+ TSRMTGAGTCTATGSG. HOB C316 Fea 6, HOB e315 SUGosICTCLTS, WOR cOSidelC HED. 3768'SACCIGT, HO C300 A HEB £304 305nch HBB 75 27Gruh BB e495 \O7GRTGCATICTnC, Habs sitar ReRAA 18 eos 112A, HOB CSDKCS T FOB C27IdniC and MBB CSTE. The novel "tl alles om: HBA: 9501626, MOAT: €313C>6 Mb Dominion, OMGTIIGS Tp) FSA: c3z7eRK, HA: C358 SASL MSA: C¥9RG>APOAD ATG, RAZ 11200, HOAD CIASGEA, PAZ CM. 14OUUACT, HERZ «156157196, uaz €220 225d0G1G6, HAD c30ST>C Mb Ssopsiown, 101(GMLeU Hi, HAAZ: C169. TEdAA, HEAD C1A™T and HAD c34e.INVASIVE Vs NON-INVASIVE ve a cee After year of 2005 CHORIONICVILLUS SAMPLING | NON INVASIVE PRENATAL PREIMPLANTATION GENETIC (CVS): 10-13 w (11) TESTING] DIAGNOSIS SCREENING DIAGNOSIS/ SCREENING (PGD/ PGS) AMNIOCENTESIS: 15-20 (16 w)|_(NIPT/DIS) NON- INVASIVE coRDocENTESIS INVASIVE NON- INVASIVE FRacmenTeD ona | FULL-SET DONA COULD ONLY BEDONE IN VF, cSt BLASTOMER on DAY 193 95 or 6of DEVELOPMENT (MOZAICISM) (MAINLY FOR SEX SELECTION INSTEAD (OF FOR GENETIC DISEASE SCREENING AND NOW AS OF HLA CHECK TOBE A FULL-SET DNA MISCARRIAGE, LIMB REDUCTION WK 0.4L RISK IN AUNIOCENTESIS 2% 0.2% RISK INCVS COSTLY PROCEDURE feontnin aocarocrecacrearocrmaceta | ANONO AND HIGHLY SKILLED DerECHION HATE wanes EXPERT TO TAKE RELATED TO WHAT WEWANT TOSEE TECHNIC | LOWER PREGNANCY RATE TAKE SAMPLE (MPSS, ERPS, SNPs) FETALFRACTION (0.32402 | HOME BABY, NEURODEGENERATIVE sean: 79), ete DISORDERS, COGNITIVEIMPAIRMENT ‘THE MOST ACCURATE: Even for sex detecton isnot root accurate ‘issues "REMAINS THE JUDGE of PO" BLT COLID BF at 99, 2 DRFOR OS DETECTION RATE COMPARABLE TO CVS ‘American Collage of Obstetrsians and Gynscaleqist* Commitee cn Pracice Buletne—Oosietics, Commitee on Ganatics, Society orMateral-Fetal ‘Medicine, racica Bulein No. 162: Prenatal agnostic Testing lr Garete Disorders. Obstet Gyrocol 2015; 1272108, ‘he naw COG Geen top Guideline on Nor-Invasve Prenatal Testing. hs wil be the fst eition ofthis gudeing, beng produced janty wih Brtsh ctor te i a =FETAL THERAPY STRATEGYFEAL Tay. nsuTENoB1000 TRANSFUSION | HOO seenpnmzon coun Acts ISS 2-082 etme oem iccunctahenamtcnie dee 26 a)o4 Rnd Ste erp 014 oh pedo 04 ——SsSsSSSSSSS—SFSsSéCSr Intrauterine Blood Transfusion: Current Indications and Associated Risks. Non-immune hydrops fetalis eet iudebos IneLmting Odo blood transfusion \ through the umbilical Cc vein in the FIV (Bh wtet Ht es sample) placenta -———_ ‘door lod umblical cord FV eon) = 10464014 strsondesite el west) pubic bone ia ultrasound transducer placenta fotus uterus “Tat — ea, SO ant age of hee Oy, enact ad pases (PLT, fran erin vagina cervix test UT ‘Nem GO| age + | semis) Hab, S20 i627 | | 508, He) 25261) | #8400 | | 0309 | 1530 ‘Hen Vielen STS om) [280 a7 [ween aeit io IM for long term ‘harapeutiechimerism, which may be ‘enhanced with postnatal cell boosting Injection of ® Stem Cell Autologo a LenivrsiT wil allogenic target c ramet, Ce tiemopeietc Fool pro lifelongnormalised stem cellls cs so Bec Prosteton 1 eo Normal donor cells overtake function of target organwww.ucsfedu» news » 2018/05 > baby-bom-worlds-f.. ¥ Baby Born in World's First In Utero Stem Cell Transplant Trial .. May 25, 2018 - The infant, who had been critically ill during the second-trimester of pregnancy due to alpha thalassemia, is the first patient enrolled in the world's 3 ‘Clncalrais gov iene: NOTI265606 ocrutmort Status © : ecutng Ft Ported @ Dreeber 8 2016 at Updo Pesta © May 12020CONCLUSIONPRENATAL DIAGNOSIS STRATEGY { FOR HEMOGLOBINOPHATY aN Ur ULTRASOUND PSV: >1.5 MoM (60 cm/s} DIAGNOSIS. 18-22 weeks: Hyperplacel ATORY aU aaah) Ge | Hepatosplenomegaly cardiomegaly (CTR >5) MCV, MCH iow , ROW high, i is: PBS Parents with Hydrops fetalis: USNIH. ib ecineprrcae ini thalassemia Parents known as CHROMOSOMAL GENE ANALYSIS thalassemia carrier = OVS W - AMNIOCENTESIS: 16 W Unknown risk for - PGD/PGS (IVF/ICSI) - CORDOCENTESIS thalassemia - NIPT/ NIPD/NIPS (cff-DNA) PREMARITAL COUNSELING. FETAL Mil ataag IUT, Stern Cells NON LETHAL CONSERVATIVE LETHAL Top [Fenncers anokos c1ec0e@G6° We a DIAGNOSIS IS NOT THE END BUT T EGINNING OF PRACTICE... Terimakasih ates perhatiannys...