Recurrent pregnancy loss

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Recurrent pregnancy loss

  1. 1. { Recurrent Pregnancy Loss Dr. Priya Bhave Chittawar Professor and Head, Reproductive Medicine, Sri Aurobindo Institute of Medical Sciences
  2. 2. Dr. Priya Bhave Chittawar  MBBS 1999( Gandhi Medical College, Bhopal): with distinction in 8 subjects and 15 gold medals. Awarded 'Dr.Vishal Vikram Singh Award' for highest marks in MBBS (1994-1999). President of India Dr. Shankar Dayal Sharma Award for the Best Outgoing student MBBS (1994-1999).  Served in various capacities in the Students Union and awarded " Dr. Suresh Kak Memorial Award for best All Rounder MBBS 1994-1999)  Fellowship in Reproductive Medicine (Christian Medical College, Vellore) 2008- 2010 : passed with distinction  Awarded by the Chief Minister Shri Shivraj Singh Chouhan in June 2008 for exemplary work in emergency Obstetrics  Best Paper award for thesis on Role of GnRH antagonists in IUI- ISAR 2010  Best Paper award in ISAR 2012 for paper on “ Hysteroscopic Management of adenomyotic myometrial cysts”  Author of Cochrane review ( Menstrual disorder and subfertility group)  Author of Cochrane sexually transmitted infections group.
  3. 3.  Nagpur Obs Gyne society  Dr. D. K. Tank Foundation  AOFOG  Merck Serono Thanks!
  4. 4. The stories that end badly are sad, sadder still are the ones that never began….
  5. 5.  What we know: KNOWN KNOWN  What we know we do not know: KNOWN UNKNOWN  What we know but do not do: UNKNOWN KNOWN  What we do not know that we do not know UNKNOWN UNKNOWN OUTLINE….
  6. 6. Ohh No!
  7. 7. {Recurrent miscarriages… The Known Known
  8. 8.  Three or more consecutive miscarriages  Risk of miscarriage in is 30% after 2 losses, 33% after 3 losses among patients without a history of a live birth.  15% sporadic miscarriage  By chance alone 1 in 300 couples What?
  9. 9.  Age  Genetic : embryonic and parental  Immune: autoimmune/alloimmune  Anatomic  Endocrine  Others Why?
  10. 10.  12-19 year:13%  20 -24 year: 11%  25-30 year: 12%  31-35 year: 15%  36-40 year: 25%  >40 year: 50%  Previous miscarriage Age
  11. 11.  Nondisjunction during meiosis  Autosomal trisomy, monosomy X, triplody, tetraploidy, translocations  Incidence increases with maternal age  60% of conceptus Genetic: Embryonic
  12. 12.  Carriers of balanced chromosomal abnormalities  3-5% of RPL couples  Risk of severely handicapped child due to aneuploidy  Chances of miscarriage greater than those of RPL couples who are not carriers ( 49% vs. 30%). (Franssen,BMJ;2006) Genetic: paternal
  13. 13. Balanced translocation: carrier
  14. 14. { Mechanism of abnormal embryonic karyotype in offspring of carriers of balanced translocations
  15. 15.  Antiphospholipid antibody syndrome: 15% women with RPL vs 2% with low risk Obs. hist  ACA, LA , anti beta2 glycoprotein 1 antibody  Trophoblast function, activation complement at fetal maternal interface, thrombosis at placental villi  Without heparin, LBR<10% Alloimmune
  16. 16.  Septum: partial, complete  Bicornuate, unicornuate uteri  Poor vascularity of the septum, disordered myometrial contractions  1.8-37% of RPL couples Anatomic
  17. 17.  Untreated hypothyroidism  Poorly controlled diabetes Endocrine
  18. 18.  History including family history of miscarriages, Toxin exposure  Age, BMI,Examination; Ultrasound  TSH, HbA1c, VDRL, ACA, LAC, Anti Beta 1 glycoprotein  Karyotyping  Karyotyping of products of conception Workup
  19. 19. {Recurrent pregnancy loss… The Unknown Known
  20. 20. What your brain does not know, your eyes cannot see…
  21. 21. Uterine Septum
  22. 22. Recurrent Pregnancy Loss..
  23. 23.  Not a valid cause of infertility or RPL  Reflection of an inadequate follicular phase or an incompetent pregnancy (Bukulmez, OGClinNA,2004) Luteal Phase defect
  24. 24.  Similar rate of aneuploidy of products of conception (Lathi, JARG,2007,24; Munoz, FS,2007,94:7)  Type of aneuploidy might differ (viable autosomal trisomies( 9,13,21) and monosomy X significantly lower when no fetal pole seen  Early embryonic demise is similar event occurring earlier temporally. Early fetal demise vs. early embryonic demise
  25. 25.  Recommended in third miscarriage ( Greentop no 17)  Maternal tissue contamination ( Jarret,AJOG,2001)  Failure to grow ( 20-30%)  Failure to look for other causes  Abnormal embryonic dev reported with normal karyotype ( dimorphic embryos) with embryoscopy.  Villi have to separated from maternal tissue  Microsatellite analysis: differentiate from maternal tissue Karyotyping of POC
  26. 26.  Only if karyotyping of POC reveals unbalanced numerical defects ( Greentop)  In all cases of RPL ( ASRM)  In couples at high risk of being carriers ( risk=>2.2%) (ESHRE) Parental Karyotyping
  27. 27.  Low maternal age at second miscarriage,  A history of three or more miscarriages  A history of two or more miscarriages in a brother or sister  A history of two or more miscarriages in the parents of either partner increase the probability of carrier status( Jauniaux, HR,2006) Parental Karyotyping
  28. 28. 1. Normal karyotype in the conceptus 2. Carrier status of same balanced structural abnormality 3. Unbalanced structural abnormality1% ( Miscarriage, Stillbirth, child with handicap) chances of having a healthy child are as high as for non-carrier couples (over 80%) Chances of subsequent miscarriage higher (50%) compared to non carrier couples with RPL (30%) (Franssen,BMJ;2006) Consequences of carrier state
  29. 29.  LBR in PGD group 31%  LBR in natural conception 55.5%  Miscarriage rate in PGD group 0- 50% ( median 0%)  Miscarriage rate in natural conception 34% ( Franssen, HR,2011) PGD for carrier couples
  30. 30.  Cochrane: A statistically significant benefit in using hCG (risk ratio (RR) 0.51, 95% confidence interval (CI) 0.32 to 0.81; five studies, 302 women ( Jan 2013) HCG for RPL
  31. 31. { Generate evidence Evaluate evidence Apply evidence Read the fine print!
  32. 32.  High heterogeneity ( 39%)  After excluding data from poorly designed studies, revised RR 0.74 (CI 0.44 to 1.23).  Small numbers  Chromosomal analysis not carried out HCG for RPL
  33. 33.  PROMISE trial underway  760 women randomised  Immunomodulatory action: upregulate TGF-β secretion in response to trophoblast, blocks Thl immunity to trophoblast.  Upregulates STAR  Myometrial relaxation Progesterone for RPL
  34. 34.  Three small non randomized trials (Stray-Pederson, Liddel 1991, Clifford 1997)  Control groups not matched and small  No testing for APS  Livebirth rates claimed to increase by 50% for groups receiving TLC Tender loving care…
  35. 35.  Combined aspirin/heparin treatment versus placebo in women with unexplained RM ( Kaandorp2010, NEJM)  NO difference in LBR  Significant side effects in treatment group Anticoagulation for unexplained RPL
  36. 36.  HepASA trial: no difference in LBR between ASA alone versus ASA and heparin (Laskin, Journal of Rheumatology,2009)  Trial stopped prematurely due to equivalent LBR in both groups. Anticoagulation for RPL with ANA/thrombophilia
  37. 37. {Recurrent pregnancy loss… The Unknown Unknown..
  38. 38. “Real knowledge is to know the extent of one’s ignorance”
  39. 39.  Luteal phase defect  Early fetal demise and early embryonic demise  Karyotying of POC  Parental karyotyping  HCG and progesterone for RPL  TLC  Anticoagulation for unexplained RPL  Anticoagulation for ANA/thrombophilia
  40. 40.  Type 1 unexplained RPL: occurring by chance  Type 2 unexplained RPL: due to an underlying pathology that is not currently identified by routine clinical investigations or due to significant environmental and lifestyle risk factors. Younger women, higher order miscarriages (Saravelos, HR2012) Unexplained RPL
  41. 41. Now we know.. What we don’t know…
  42. 42.  Think septum!  A good 2D TVS.  HSG/office hysteroscopy  LBR 85% after septal resection. Doing what we know…
  43. 43.  Pool our knowledge and patient base  Well designed RCT looking at treatments for RPL  Multicentric Trying to know the unknown..
  44. 44. When you know something, to hold that you know it. When you do not know a thing, to allow that you do not know it, this is knowledge Confuscious THANKS !!!

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