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recurrent pregnancy loss : new concept

recurrent miscarriage is a real clinical problem with different aetioogies. However, recent observations pointed to vascular dysfunction as a main underlying factor: how ? this talk may help in illustrating this

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recurrent pregnancy loss : new concept

  1. 1. RPL Role of endometrial vascularity HESHAM AL-INANY PROF. OB. & GYN. CAIRO UNIVERSITY
  2. 2.  Trilaminar endometrium as seen at the end of the follicular phase;  luteal endometrium as seen at about the time that implantation would normally occur.  This is what we know
  3. 3. Endometrial &subendometrial flow  This is what we want to talk about
  4. 4. OBJECTIVES  Understand the problem  Understand the emerging concept
  5. 5. The problem  RPL  ?underlying pathology
  6. 6. Definition : Updated  ACOG : Two or more : Because the risk of a recurrent loss is fairly high after 2 losses (26%), we have to start work-up after 2 losses.
  7. 7. MATERNAL AGE- RPL Maternal age Clinical Preclinical < 20 y 12.2 % 20 % 20-24 14.3 29 25-29 13.7 30 30-34 15.5 35 35-39 18.7 40 40-44 33.8 45 > 44 53.8 65
  8. 8. 50 % chromosomal 10-15 % Anatomic 17- 20 % 10-15 % Coagulation/ Immunity Endocrine
  9. 9. APAS Antiph. antibodies: 1- Lupus anticoagulant { IgG – IgM } 2- Anticardiolipin (aCL) antibodies {IgG – IgM}  NB : Definite APS is diagnosed when AB levels are repeatedly >20 units & levels <20 units are of uncertain significance
  10. 10. Vascular dysfunction  studies suggest that APAS is associated with arterial and venous thrombosis, thrombocytopenia, and livedo reticularis (Nayak & Komatireddy et al., 2002).
  11. 11. Another observation  Premature atherosclerosis is a clinical and histological feature of with primary APAS (Ames et al., 2009).
  12. 12. More Importantly  The live birth rate of women with RPL increased to 40% when they are treated with low-dose aspirin only  It is significantly improved to 70% when they are treated with low-dose aspirin in combination with low-dose heparin.  corticosteroids are not used anymore RCOG May 2003
  13. 13. Another underlying pathology :Thrombophilia Associated with:  Recurrent miscarriage  Pre eclampsia  IUGR  Placental abruption  Still birth
  14. 14. Thrombophilia  Mechanism: Microthrombosis in the placenta  Causes: 1. Activated protein C resistance {Factor V Leiden mutation} : the most prevalent cause 2. Prothrombin gene mutation 3. Antithrombin III deficiency 4. Protein C deficiency 5. Protein S deficiency.
  15. 15. Thrombophilia Treatment : studies have suggested that heparin therapy may improve the live birth rate for these women..
  16. 16. Another cause for RPL : Hyperhomocysteinemia  It is an inborn error of metabolism  Elevated levels of homocysteine in the bloodstream can irritate the blood vessels, which may eventually lead to hardening of the arteries  Treatment: 1. Oral administration of vit B6 & folate 2. Monthly injection of vit B12 (Mishell,2002). 3. SC heparin to reduce the risk of Venou thrombosis
  17. 17. Interestingly : Septate uterus  Is the most frequent anatomic abnormality associated with RPL. Suggested Mechanism:  Impaired vascularization of pregnancy
  18. 18. Recent data  Spontaneous RPL (>3) is associated with about five times higher risk of myocardial infarction later in life (Kharazmi et al., 2011)
  19. 19. The problem  RPL  Endometrial vascular dysfunction
  20. 20. Emerging concept  A considerable number of RPL could be due to endometrial vascular dysfunction whatever the underlying pathology
  21. 21. Can this vascular dysfunction be evaluated?  brachial-ankle PWV (baPWV) measurement can be performed easily by simultaneous oscillometric measurement of pulse waves in all four extremities  It is a promising technique to assess vascular dysfunction in women with RPL
  22. 22. Why not to hit the target?  Our target is the uterus  Specifically the endometrial and subendometrial vascularity
  23. 23. This concept has to be tested  Recent technology could help  3 D Doppler study for subendometrial blood flow
  24. 24. Anatomical Factors CONGENITAL : Septate . 60% Arcuate. Bicornuate. Unicornuate. 44 % Didelphic. 36 % DES Exposure – T shaped uterus
  25. 25. Endometrial volume and blood flow Subendometrial shell volume and blood flow
  26. 26. gives physiologic data, rather than anatomic information alone.
  27. 27. Endometrial volume calculation by using the VOCAL software after 3D.
  28. 28. Uterine Artery “PI” uterine artery Doppler (PI=3.16). uterine artery Doppler (PI=1.15).
  29. 29. The Histogram  The Vascularization Index (VI),in %, measures the number of the blood vessels within the tissue.  The Flow Index (FI) represents average colour intensity.  And the Vascular-Flow Index (VFI) represents both blood flow and vascularization
  30. 30. Determination of the subendometrial area volume by using the "shell" facility. In this case 5 mm has been chosen.
  31. 31. Vascularization of the subendometrial area by 3D-Power Doppler. VI, FI and VFI refers to the shell area, not the endometrium.
  32. 32. A proof of concept study  only one study on 40 women with unexplained RPL showing that 3D vascularisation indices could be affected in these women (Vaquero et al , Ultrasound Obstet Gynecol. ; 32:262–266)
  33. 33. Objective:  to evaluate subendometrial blood flow in women with a history of recurrent unexplained abortion compared to women who had at least 1 live child and no history of spontaneous abortions
  34. 34. Participants & Methods  Women with RPL were compared to women with no history of abortion and at least 1 child born at term.
  35. 35. Transvaginal 3D power Doppler  Subendometrial area to detect subendometrial blood flow presented by the indices:- vascularisation index (VI),  flow index (FI),  and vascular flow index (VFI). (Accuvix XQ, Medison, Korea)
  36. 36. Investigations done  activated partial thromboplastin time  antinuclear antibodies  lupus anticoagulant antibodies  Anticardioliplin abs  Thyroid : TSH, free T3, T4  Karyotyping  HSG
  37. 37. Results  Mean uterine artery pulsatility index(M UAPI) was higher in case group(2.319±0.5309)than in control group(1.689±0.4832) which was statistically significant (p value 0.000).  Vascularity index(VI) was higher in case group (2.726±3.0482)than in control group (2.29±3.03) which was statistically insignificant (p value 0.29).
  38. 38. Flow Index  flow index (FI) was higher in control group (23.975±4.1716) than in case group(19.138±6.9013) which was statistically significant(p value 0.002).
  39. 39. vascular flow index(VFI)  was higher in control (1.20±1.11)than in case group(0.71±0.65) which was statistically significant(p value 0.048).
  40. 40. How accurate it is !!
  41. 41. This means PI < 3 FI > 20% VFI > 20 %
  42. 42. Follow Up  patients who got pregnant and reached the third trimester had higher three subendometrial indices compared to those who aborted
  43. 43. Recent evidence  Decreased endometrial vascularity in patients with antiphospholipid antibodies-associated recurrent miscarriage during midluteal phase Chen et al, 2012 Fertil Steril
  44. 44. Limitations  no cut off values could be established  Should be conducted in tertiary centers with advanced facilities
  45. 45. Advantages  Non invasive  Relatively available  Relatively not so expensive
  46. 46. then how to manage :  Isosorbide mononitrite significantly decreased uterine artery and increased sub-endometrial blood flow indices (p < 0.001). abdelrazek et al, 2014  Follow up for pregnancy is ongoing
  47. 47. In conclusion,  vascular dysfunction may be the key to the pathophysiology of RPL.  3D vascular indices should be applied routinely for women with RPL
  48. 48. THANK YOU

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