Genetic factors in rpl

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Genetic factors in rpl

  1. 1. Genetic Factors & Recurrent Pregnancy Loss Dr. Raju R Sahetya M.D., D.G.O., D.F.P., F.C.P.S., F.I.C.O.G., OBSTETRICIAN & GYNAECOLOGIST Specialist: Infertility & Maternal Fetal Medicine Hospital Pushpaa Hospital Mumbai, India www.pushpaahospital.com , [email_address] Mobile 9821090102 Honorary Hinduja Hospital * BSES Hospital Mumbadevi Hospital * Hiranandani Hospita
  2. 2. Vice President Indian Society for Prenatal Diagnosis & Fetal Therapy (ISPAT) Member Excecutive Council Mumbai Obstetrics & Gynaecology Society (MOGS) Association of Fellow Gynaecologist (AFG) Assciation of Medical Consultant (AMC) Current Position Held MOGS – PNDT & Academic Cell, FOGSI – Sexual Medicine Committee Editorial Board – ISPAT International Journal of Prenatal Diagnosis & AFG Times Rotarian Past President Rotary Club of Bombay Airport
  3. 3. “ I OWE TO MY ALMA MATER !”
  4. 4. Recurrent Pregnancy Loss
  5. 5. possible causes <ul><li>Recurrent miscarriage is a heterogeneous condition that has many possible causes; more than one contributory factor may underlie the recurrent pregnancy losses. </li></ul><ul><li>each Loss may have had a different or multiple causes. </li></ul>
  6. 6. Genetic factors Anatomical factors Endocrine Infective agents Immune factors Inhereted Thrombophilic defect Explained Un-explained Recurent Miscarriage Enviromental factors Body Cervix Paternal karyotyping Cytogenetic Of miscarriage C I Uterine anomalies APS Bacterial Vaginosis
  7. 7. <ul><li>50 % of all conception are lost (includes early abortions). </li></ul><ul><li>15-20 % of recognized pregnancies. </li></ul><ul><li>70% of these early losses is due to cytogenetic </li></ul><ul><li>50% between 8-15 weeks. </li></ul><ul><li>5 – 10 % still births. </li></ul>Frequency
  8. 8. Pregnancy Loss
  9. 9. <ul><li>Chromosomal </li></ul><ul><li>Mendelian Inheritance . </li></ul><ul><li>Multifactorial. </li></ul>Genetic Causes
  10. 10. <ul><li>Establish the etiology </li></ul><ul><li>Investigate the couple </li></ul><ul><li>Estimate recurrence risk </li></ul><ul><li>Provide accurate genetic counseling. </li></ul><ul><li>Discuss reproductive options. </li></ul><ul><li>Essential as patients have small planned families. </li></ul>Aim Of Genetic Evaluation
  11. 11. <ul><li>Denovo, paternal or maternal meiotic or post zygotic division or abnormal fertilization. </li></ul><ul><li>26 % are trisomies including trisomy 16. </li></ul><ul><li>10 % are triploidy , tetraploidy. </li></ul><ul><li>10 % are sex chromosomal monosomy (45,X) </li></ul><ul><li>2% are unbalanced or double trisomies. </li></ul><ul><li>.?9% trisomy and still birth </li></ul><ul><li>Histopathology / morphology insufficient to asses etiology . </li></ul>Cytogenetic Abnormalities
  12. 12. Karyotype
  13. 13. <ul><li>Tissues usually used for karyotype from abortuses . </li></ul><ul><li>Chorionic Villi from products in normal saline </li></ul><ul><li>P iece of placenta at cord insertion in normal saline. </li></ul><ul><li>Fetal cord / cardiac blood, in sodium heparin vaccutainers. </li></ul><ul><li>No formalin or freezing for preservation </li></ul><ul><li>S hould reach within 24-36 hours at Room Temperature.   </li></ul>Tissue, Collection & Transport
  14. 14. Choosing A Centre.
  15. 15. NABL ACCREDITED (ISO / IEC – 17025) Accreditations Experienced Medical Geneticist Qualified staff State of the art equipment. Reliable reports Minimum turn around time. Interaction with physician. Choosing the Centre Accessibility
  16. 16. Methods Of Study
  17. 17. <ul><li>History taking. </li></ul><ul><li>Genetic counseling </li></ul><ul><li>Examination of the Fetus, Villi and Placenta. </li></ul><ul><li>Correlation with CRL and stage ( milestones) </li></ul><ul><li>Morphology of the villi. ( hydropic, hypoplastic etc.) </li></ul><ul><li>Review of Ultrasound reports .( Syndrome assignment.) </li></ul><ul><li>Photography and / or Radiology ( skeletal dysplasias ) </li></ul><ul><li>Karyotype studies and FISH for fetal chromosomal abnormalities. </li></ul><ul><li>Histopathology studies for infection and vascular insufficiency. </li></ul><ul><li>Karyotype of the couple - for transmissible chromosomal error. </li></ul><ul><li>Prenatal Genetic Diagnosis in subsequent pregnancy </li></ul>
  18. 18. <ul><li>Medical and Maternal </li></ul><ul><li>Family </li></ul><ul><li>Previous and present pregnancy. </li></ul><ul><li>Antenatal </li></ul><ul><li>Fetal wellbeing </li></ul><ul><li>Labor and Postnatal. </li></ul>History
  19. 19. <ul><li>Level 1 – Obstetrician </li></ul><ul><li>Discussing causes for Pregnancy Loss </li></ul><ul><li>Investigations required </li></ul><ul><li>Role of Geneticist </li></ul><ul><li>Level 2 – Clinical Geneticist </li></ul><ul><li>Details about causes in RPL </li></ul><ul><li>To evaluate, Diagnose and Prognosis </li></ul><ul><li>Discuss recurrences </li></ul>
  20. 20. C E MORPHOLOGY & KARYOTYPE OF VILLI NORMAL-46,XX/46,XY CLUBBING- VARIABLE - - MOLAR- 46,XX / 46,XY HYPOPLASTIC- 45,XO CYSTIC- 69,XXX/XXYTRI-16
  21. 21. Exomphalos. Trisomy 18. Holoprosencephaly Trisomy13, 15. Choroid Plexus Cyst Trisomy 18. Nuchal Translucency Trisomy 21.45X. Ventriculomegaly 13,18,21 Cystic Hygroma 45X. Abnormal USG Findings
  22. 22. Correlation With Developmental Age
  23. 23. Trisomy 18 Monosomy X Triploidy Trisomy 13 Trisomy 21 Fetuses With Visible Malformations
  24. 24. <ul><li>FISH (Fluroscent Insitu Hybridization) </li></ul><ul><ul><li>Permits detection of specific nucleic acid sequences in morphologically preserved chromosomes, cells, and tissues. </li></ul></ul><ul><ul><li>Specific probes are utilized for the purpose. </li></ul></ul>Newer Technique
  25. 25. Karyotype FISH Needs viable ,specific tissues Any fetal tissue either fresh, frozen or paraffin block Culture essential Uncultured cells work. Selective growth of maternal decidua Not possible. Screens all chromosomes and used for > 40 yrs now for establishing etiology. Screens for major aneuploidies (13, 18, 21, X and Y) Turn around time 2 weeks Turn around time 2 days Ideal for focal anomalies
  26. 26. FISH Newer Techniques
  27. 27. Karyotypes & Prognostic Significance
  28. 28. <ul><li>DEPENDS ON : </li></ul><ul><li>Parental age . </li></ul><ul><li>Advanced maternal age : Trisomic conceptus Monosomy X. </li></ul><ul><li>Cytogenetic status of the spontaneous abortion. </li></ul><ul><li>Exponential increase in the rate of trisomy </li></ul><ul><li>Karyotype of parents (balanced translocations). </li></ul><ul><li>Leads to deficiencies and duplication of chromosomes in the fetus </li></ul>Prognostic Significance of the Abortus karyotype
  29. 29. Risk Estimation & Follow Up
  30. 30. <ul><li>Parental Karyotype. </li></ul><ul><li>Prenatal Diagnosis PGD / CVS / Amniocentesis </li></ul><ul><li>Gamet Donation. </li></ul>Follow Up
  31. 31. Subsequent Pregnancy CHORIONIC VILLUS SAMPLING 10-11 WEEKS AMNIOCENTESIS 15-17 WEEKS
  32. 32. <ul><li>Frequency : 2-3 per 1000. </li></ul><ul><li>Inheritance : Multifactorial, single gene / chromosomal. </li></ul><ul><li>Recurrence risk : 9% / 2-3%. </li></ul><ul><li>Periconceptional folic acid supplement . </li></ul>Neural Tube Defects Multifactorial
  33. 34. <ul><li>Genetic Factors more often responsible for RPL </li></ul><ul><li>Genetic Counseling plays an important role in RPL management. </li></ul><ul><li>Cytogenetic/FISH and morphological evaluation of products of conception is a valuable tool for assessing a cause of fetal loss. </li></ul><ul><li>Prenatal Genetic Diagnosis in subsequent pregnancy </li></ul>Conclusion
  34. 35. Thank you

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