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recent evidence of unfractionated heparin and aspirin in recurrent miscarriage

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recent evidence of unfractionated heparin and aspirin in recurrent miscarriage

  1. 1. Ahmed Mostafa Sadek Lecturer of Obs / Gyn Benha Faculty of Medicine
  2. 2. Objectives • INTRODUCTION • INCIDENCE • RISK FACTORS • IMPACT • TYPES • LOW DOSE ASPIRIN • UNFRACTIONATED HEPARIN
  3. 3. INTRODUCTION According to the Royal College of Obstetricians and Gynecologists (RCOG) , a miscarriage can be defined as the spontaneous loss of a pregnancy before the fetus has reached viability at 24 weeks . ( Regan I. et al , 2011 )
  4. 4. The American Society for Reproductive Medicine defines recurrent miscarriage (RM) as two or more failed pregnancies, which have been documented by either ultrasound or histopathological examination . Ectopic and Molar pregnancy are not included
  5. 5. INCIDENCE . RM occurs in ( 1 - 2 % )of women in reproductive age 1 st T : 75 % 2 nd T : 25 % (Alijotas-Reig & Garrido- Gimenez, 2013 )
  6. 6. Recurrence suggests a persistent cause which must be identified and treated
  7. 7. RISK FACTORS only in 50 % , the cause can be determined 1- Anatomical 10 % 2- Immune dysfunction 5 - 15 % 3- Maternal Thrombophilic disorder 4- Chromosomal anomalies 5 % 5- Endocrine disorder 5% 6- Epidemiological However non of these factors are specific to RM (Laresen et al , 2013 )
  8. 8. Impact It is emotionally traumatic to the parents similar to neonatal death And frustrating to the Doctor as etiology is not determined in 50 %
  9. 9. TYPES - Primary : couples never had a live birth - Secondary : couples had a previous successful pregnancy
  10. 10. Work up U/S , 3 D U/S , HSG , and HysteroscopyAnatomical Anticardiolipin antibodies & Lupus anticoagulant and Anti B2 – glycoprotien -1 abs APL Factor V Leiden, Prothrombin gene Mutation and protein S/C deficiency Thrombophilia Diabetes ,Thyroid disorder and PCOEndocrine KaryotypingChromosomal
  11. 11. MANGMENT - RM remains a great challenge as 50 % are idiopathic - Aspirin and Unfractionated Heparin are used in RM caused by : 1- APS, 2- Inherited thrombophilia and 3- Unexplained RM
  12. 12. ASPIRIN Its acetyl derivative of salicylic acid 3 hoursHalf life 80 % in liverMetabolism kidneyExcretion
  13. 13. Low dose Aspirin therapy (60 – 150 mg/day ) is safe during pregnancy
  14. 14. 1- Irreversible blocking action of platelet cyclo- oxygenase enzyme inhibit platelet thromboxane A2 prevent platelet aggregation 2 -The daily administration of LDA induce a shift in the balance towards prostacycline , leading to VD and enhanced blood flow . (Patrono C.et al, 2005).
  15. 15. 3- APL abs bind to negative charged phospholipid membranes - Activation of endothelial cells activate complement pathway . -Aspirin has capacity in complement inactivation protective effect against RPL and Thrombosis . (ALvaro -Danzo et al , 2011 )
  16. 16. Role in Unexplained RM - In Unexplained RM recent studies show impaired uterine perfusion with decrease uterine and sub – endometrial blood flow which play a central core in the pathogenesis ( Gunzel- Apel et al , 2009 ) - LDA shift balance towards Prostacycline synthesis in endothelial cells  enhance Nitric Oxide production  increase uterine and sub-endometrial blood flow ( Rouzer &Marnett , 2009 )
  17. 17. - Highly sulfated glycosaminoglycan . - Its molecular weight ranges from 3 kD to 30 kD, containing approximately 45 monosaccharide chains. - Its anticoagulant activity varies because only one third of Heparin has anticoagulant function. ( Hirsh et al , 2008 ) Heparin
  18. 18. LMWHUFH 1000 - 100003000 - 30000Mol. Wt. range Inhibit - FXaBind to (AT- IIIMechanism of action Anti – FXaaPPTMonitoring 3 - 7 h1 - 5 hHalf - life Partially reversedFully reversedProtamine sulfate LessOsteoporosis- HIT Side effects
  19. 19. Role of Heparin in preventing RM Heparin may act to reduce fetal loss by ; 1-Binding to phospholipid Abs thus protecting trophoblast phospholipid from attack. 2-Anti-coagulant action (Mcintry JA. et al , 1995) 3-Recent studies show that Heparin possibly can improve implantation (Check et al , 2012)
  20. 20. There are multiple questions required to be answered for evaluation of efficacy of anti-thrombotic therapy for women with RM: 1-Is it mandatory to use combination of heparin and aspirin ? 2-Which type of heparin to be used ? unfractionated heparin (UFH) or low-molecular weight heparin (LMWH) ?
  21. 21. 3. If antithrombotic therapy succeeded to control early pregnancy loss, is it effective for prevention of late pregnancy loss and prevent maternal morbidity?
  22. 22. Meta-analysis of randomized controlled trials in women with RM has shown that : Combination of UFH and LDA could reduce further pregnancy loss by 54 % . ( Empson et al, 2005 )
  23. 23. Meta-analysis studies of Randomized Controlled Trials examined the outcomes of various treatment including Aspirin, Steroids , I.V. Globulin and Heparin given to improve pregnancy outcomes of women with RM associated with APL reported that , The only treatment accompanied by significant live birth rates are among women treated by Aspirin + UFH (Cochrane library . 2005 )
  24. 24. In Unexplained RM and Inherited Thrombophilia , LDA plus Heparin could potentially increase live birth rates, since hyper coagulability might result in RM . ( Cochrane Library . 2009 )
  25. 25. Systematic Review and Meta – analysis on 292 studies show that : - The combination of UFH and Aspirin had a significant benefit in live birth rates . ( 0bst Gyne ,june 2010,115 (6) 1256-62. )
  26. 26. Meta -analysis studies show that : The combination of Heparin and Aspirin is superior to Aspirin alone in enhancing live birth rates in women with RM and + ve APL abs (Mak A. et al , 2010)
  27. 27. RCOG guidelines 2011 , Although Aspirin plus Heparin treatment improves the live birth rate of women with these pregnancies remain atRM with APL abs , high risk of developing complications during .all three trimesters
  28. 28. Combined aspirin / heparin treatment versus placebo in women with unexplained RM No difference in Live birth rate ( Kaandorp , 2010 )
  29. 29. In 2011; Histological examination of the placenta from pregnancies complicated with APS and IT showed that : Anticoagulant therapy does not prevent either fibrin deposits or other placental changes (Skrzypczak et al , 2011).
  30. 30. In 2012; Check et al; found that : -Either UFH or LMWH is recommended for APS. -Possibly UFH is superior to LMWH in improving implantation. -There is no evidence that UFH has any benefit in preventing miscarriage from unexplained causes. -However the exact timing of heparin is still being evaluated.
  31. 31. In 2014; de Jesús et al., documented that Treatment of patients with APS during pregnancy with UFH and aspirin can act by : improving live birth rates, but other obstetric morbidities remain high.
  32. 32. Finally according to Royal Collage green top guidelines, April 2011 -No difference in efficacy and safety between UFH and LMWH when combined with aspirin in recurrent miscarriage with APS. -LMWH is safe as UFH and have a potential advantage during pregnancy since it is once daily , less thrombocytopenia and low risk for osteoporosis. - Empirical treatment with Aspirin alone or combined with heparin is unnecessary for unexplained RM.
  33. 33. - Neither corticosteroids nor intravenous immunoglobulin therapy improve live birth rate of women with RM associated with APL abs , their use may provoke significant maternal and fetal morbidity -Women with APL should considered for postpartum thrombo-prophylaxis.
  34. 34. conclusions - RM has multi factorial causes with bad psychological impact on parents. - LDA plus UFH are used safely in RM with APL abs , Thrombophilia and Unexplained RM .
  35. 35. - Postpartum thrombo-prophylaxis is mandatory . - Considering cost/effectiveness, UFH is available, cheap and with the same efficacy on pregnancy as LMWH, so it is advocated as a therapeutic modality.

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