Recurrent spontaneous abortion

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<ul><li>1.Recurrent Spontaneous Abortion (RSA) -How to manage genetic cause? </li></ul> <p>2. Fates of embryo after transferRSABoomsma, C.M. et al., Hum Reprod 2009 3. Definition of RSA (I) Traditionally, 3 clinical pregnancy losses before 20 weeks from the last menstrual period - occurs in about 1/300 pregnancies. Novak 15th ed., WILCOX et al, 1988 Risk of subsequent pregnancy loss 24% after 2 clinical losses 30% after 3 losses 40~50% after 4 losses Novak 15th ed., Regan et al, 1989 4. Definition of RSA (II) In 2008, the American Society for Reproductive Medicine (ASRM) defined RPL by two or more failed pregnancies, and pregnancy must be clinical : documented by ultrasound or histopathologic examination 5. Indications of clinical investigation Clinical investigation may be initiated after 2 consecutive SA especially, when fetal heart activity is identified when the women is older than 35 years old when the couple has had difficulty conceiving-1% of pregnant women Novak 15th ed., Alberman et al, 1988 6. Risk for subsequent pregnancy loss 40 -50%30%24%Pregnancy loss riskMore than 4 previous losses 3 previous losses2 previous losses50- 60% 70%76%Probability of live birthRegan et al., 1989 7. Etiology of RSA Genetic factor 2-5% Unexplained Including non-APA thrombophilia 50%Genetic Translocation 60.3%Anatomic factor 10-15%Anatomic Synechia 64.3% Ut. Septum 14.3%Unexplained Autoimmune 20% Endocrine factors 17-20%N = 881 (2005. 1.1 - 2009. 12. 31)Infections 0.5 -5%Endocrine Hyperthyroidism 71.4%Ford HB et al. Rev Obstet Gynecol 2009Infection Ureaplasma 89.5%50% of RSA classified as unexplained Allo-immune etiology? 8. Diagnosis &amp; management protocol of RSA History taking Routine lab Genetic evaluation Karyotyping of abortus Parental karyotypingGenital infection Cervical culture Chlamydia U. Urealyticum MycoplasmaAntibioticsUltrasonographic scanning / pelvic exam PGDUterine anomaly?HSG, MRIOvulatory dysfunction?LH/FSH, E2, PRL, TSH, T3/ freeT4Uterine anomaly (Septated uterus) Normal Hysteroscopy or Laparoscopy Surgery Immunologic evaluationAllo-immune study NK number (CD 16,56) NK cytolytic activityHormone therapyPrednisolone (PDS) Low molecular weight heparin (LMWH) IVIGAuto-immune study ACA (IgG/IgM) LAC Antithyroid Ab 9. Genetic evaluation of RSA Fetal karyotypingChorionic villus sampling Parental karyotyping : Parental lymphocytes 10. Trisomy 16Trisomy 22 11. Karyotyping of the abortus in RSA 41% of miscarriages are aneuploid in recurrent miscarriage.Ogasawara. et al., Fertil Steril 2000 12. Karyotyping of the abortus The prognosis is better after an aneuploid abortion than a euploidy miscarriage. 15% of patients will have repeat aneuploidy. : can be offered pre-implantation genetic screening (PGS). - Howard et al., IMAJ 2008 13. Parental karyotyping The value of parental karyotyping is limited in recurrent miscarriage. Seeks balanced translocations and inversions rather than the more common numerical aberrations such as trisomy. Parental karyotypic aberrations have been found in 310% of couples with recurrent miscarriage. : PGD is indicated - Howard et al., IMAJ 2008 14. Treatment options by the results of karyotyping in RSA NormalAbnormalOther RSA work up1st numerical abnormalitiesNumerical abnormalities Trisomy Monosomy PolyploidyStructural abnormalities Deletion Addition Inversion TranslocationRepeated numerical abnormalities Parental Karyotyping High dose folic acid : 5mg/day Timed intercourseNormalAbnormal PGD, PGS 15. Prevention of repeated aneuploidy pregnancy 1. Supplement of high dose folic acid 2. Timed intercourse 3. Prenatal Genetic Screening (PGS) 16. Folic acid supplementActivated folic acid 17. Folic acid supplementation in RSA patients Abnormal folate and methyl metabolism can lead to DNA hypo-methylation, instability, abnormal segregation and aneuploidy. Res. 2004- Fenech M. Mutat Res 2001, Wang X, Mutat Genomic instability is minimized when the plasma folate level exceeds about 34 nmol/l and the Hcy level is less than 7.5 mol/l. These levels can only be achieved when folic acid intake is above 5mg per day. - Fenech M. Mutat Res 2001 18. MTHFR gene mutation and folic acid supplement MTHFR (methylenetetrahydrofoloate reductase) gene C677T A1298C MTHFR gene mutation heterozygous MTHFR carriers - activate folate at 60-70% homozygous carriers - activate folate at 10% Activated folic acid or high dose folic acid supplement are recommended 19. Folic acid supplement 20. Folic acid supplementActivated folic acid 21. Timed intercourse for prevention of repeated aneuploidy Prevention of delayed fertilization Secondary oocyte remains in MII metaphase in the fallopian tube until it is fertilized. Ageing or over-ripeness of these cells could lead to a higher incidence of spindle defects and so increase the chance of non-disjunction. Chromosomal errors increase with delayed fertilization, although it is difficult to distinguish this from the maternal age effect. Ishikawa H et al., Hum Reprod 1995 22. IVF-PGD, PGS 2 7 12 14 OPU17 26 -hCG16 PCR FISH PCR FISH 23. Embryo Screening (PGS) 7 Preimplantation GeneticBy FISHProbe: 13, 16, 18, 21, 22 -&gt; Monosomy 18, 21, 22Probe: X, Y, 21 -&gt; Trisomy X, Monosomy 21A.Handyside, RBM Online 2011;23:686-91 24. Preimplantation Genetic Screening (PGS) By FISH The first techniques used for PGS were polar body biopsy or cleavage-stage blastomere biopsy followed by fluorescence in situ hybridization (FISH) analysis -&gt; first-generation PGS Initial studies with first-generation PGS suggested that implantation rates increased and loss rates decreased. However, other studies, including several randomized controlled trials (RCTs), showed no benefit or, worse, a negative impact on implantation, pregnancy, or loss rates. 25. PGS in RSAAneuploidy ScreeningPatients87Cycles148Age36.9 4.2 (26 ~ 46)Biopsied embryos1,413 (9.5 4.0)Diagnosed embryos1,316 (8.9 3.8) (93.5%)Normal or balanced262 (2.4 1.9) (19.9%)ET Cycles No. of transferred embryos Delivery rate/ET Abortion rate129 (87.2%) 314 (2.1 1.4) 15.5% (23.0% per patient) 10.3% 26. Comparative genomic hybridization (CGH) Array CGHTest DNANormalNormal DNATrisomyMonosomy 27. Euploid embryo 46, XYEuploid embryo 46, XXAneuploid embryo 47, XY, +7Aneuploid embryo 45, XY, -16arr 20q13.32-q.ter x 1arr CGH 22q11.1-q.ter x 1 27 28. An ideal technique would allow for the simultaneous analysis of all 24 chromosomes (autosomes 122, X, and Y) and less prone to technical issues that could lead to errors and misdiagnosis than earlier FISH methods. The first comprehensive analysis technique appearing after FISH was comparative genomic hybridization (CGH), but it was challenging to put into clinical practice because it needed at least three full days for the analysis to be completed. Finally, the advent of vitrification, which permitted the safe cryopreservation of biopsied embryos, allowed all the components for second-generation PGS to be assembled: complete chromosome screening (via CGH); less damaging embryo biopsy (at the blastocyst stage); and enough time to carry out the test (afforded by vitrification). 29. CGH was later displaced by more automated techniques, such as aCGH, single-nucleotide polymorphism (SNP) arrays, and quantitative fluorescent polymerase chain reaction (qPCR). Of these techniques, aCGH and qPCR have been shown in RCTs to improve pregnancy rates. 30. 575 couples: 169 (SNP-PGD; 2011.10.-2012.8.) + 406 (2005.1.-2011.10.) 31. Early Diagnosis for Early Cure!KFDA Certification BAC Chip H1440 was approved from the Korea Food and Drug Administration(KFDA) in March 2006 32. Chromosome 21 CC: centromere 33. Genetic cause of RSA Genetic factor 2-5% Unexplained Including non-APA thrombophilia 50% Parental chromosomalAnatomic factor 10-15%abnormalityAutoimmune 20% Endocrine factors 17-20% Balanced translocation most common Infections 0.5 -5% Monosomy X chromosome Inversions - not inv (9) Insertions Mosaicism Single gene defectsNeither family history nor a history of prior term births is sufficient to rule out a potential parental chromosomal abnormality 34. Reciprocal translocation (Adjacent 1) 111 1121212 50%12 35. (Alternate) 111 112121225%25% 12 36. Robertsonian translocation(13, 14, 15, 21, 22 chromosome) 21 (1/6)14211421 (2/3)1421211421 2114 (1/6)142114 37. Clinical outcome of PGD for reciprocal translocation Female carrierMale carrierTotalPatients353065Cycles7756133Mean female age33.0 3.930.8 2.732.1 3.6Retrieved oocytes1,2981,0382,336Injected oocytes1,1328772,009871 (77.0)704 (80.3)1,575 (78.4)Frozen zygotes98116214Thawed zygotes/embryos133120253Biopsyed embryos8987001598Diagnosed embryos8436651508Transferable embryos (%)158 (18.7)127 (19.1)282 (18.7)Unbalanced embryos (%)685 (81.3)538 (80.9)1,226 (81.3)6650116144 (2.1 1.1)105 (1.8 1.2)249 (1.9 1.1)771425 (37.9)25 (50.0)50 (43.1)Biochemical pregnancy (%)7 (10.6)10 (20.0)17 (14.6)On-going preg. or delivery (%)11 (18.2)14 (28.0)25 (21.6)7 (10.6)1 (2.0)8 (4.3)Fertilized oocytes (%)ET cycles Transferred embryos Frozen embryos Positive -hCG (%)Miscarriage (%) 38. Overall pregnancy outcomes of PGD for Robertsonian translocation carriers Female carrierMale carrierTotalPatients461662Cycles9426120Mean female age31.2 2.932.8 5.431.5 2.6Retrieved oocytes1,0674002,007Injected oocytes1,3103461,6561,035 (79.0)254 (73.4)1,289 (77.8)Frozen zygotes9821119Thawed zygotes/embryos161452061,0482631,3119952521,247Fertilized oocytes (%)Biopsied embryos Diagnosed embryos Transferrable embryos (%)246 (24.7)Unbalanced embryos (%)749ET cyclesab85 (33.7) 167ab331 (26.5) 9168924113221 (2.4 1.2)63 (2.4 1.3)284 (2.4 1.2)37 (41.1)12 (50.0)49 (43.4)10 (11.2)2 (8.3)12 (10.6)14 (15.7)8 (33.3)22 (19.5)8 (9.0)08 (7.1)3 (3.3)2 (8.3)5 (4.4)Termination of pregnancy101Stillbirth101Transferred embryos Positive -hCG (%)cBiochemical pregnancies (%) Deliveries (%)aMiscarriages (%)aFollow-up loss (%)a caP</p>


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