1. האם יש מקום למתן קלקסן בכשלון בטיפולי הפריה ? פרופ ' דניאל זיידמן אגף נשים ויולדות, מרכז רפואי שיבא, תל - השומר

2. How do improve our pregnancy rates?  Clexane is directly or indirectly involved in adhesion of the blastocyst to the endometrium and the subsequent invasion (?!)

3. How can clexane help with so many genetically abnormal embryos? normal chromosomal status (46,XX) abnormal chromosomal status (45,XY,-12)

6. Association of common thrombophilias and antiphospholipid antibodies with success rate of in vitro fertilisation. None of the common thrombophilias tested was found to be significantly associated with the number of IVF cycles or with lower fertility success rate.

7. Association of common thrombophilias and antiphospholipid antibodies with success rate of in vitro fertilisation. Women who had APCR and /or factor V Leiden and lupus anticoagulant had significantly higher live birth rates (12.3% and 12.6%, respectively) in comparison to women who were tested negative (9.0% and 9.7%, respectively).

8. Association of common thrombophilias and antiphospholipid antibodies with success rate of in vitro fertilisation. Hypercoagulability is not associated with failure to achieve pregnancy. These data suggest that neither screening for thrombophilia nor anticoagulant treatment is indicated in cases with unexplained reproductive failure.

9. " In GOD we trust; all others must bring data.” - W. Edwards Deming

10. The Evidence Pyramid

11. GiGo ‘Garbage in – Garbage out’ principle

12. Meta-analysis = Cooking Pot All depends on the quality of the ingredients

13. מטא אנליזה זה כמו נקניק :

14. מטא אנליזה זה כמו נקניק : רק אלוהים והקצב יודעים מה שמו בפנים

15. “A meta-analysis is like a sausage, only God and the butcher knows what goes in it, neither would ever eat any.”

17. Conclusions and Relevance Estimation of treatment outcomes in meta-analyses differs depending on the strategy used. This instability in findings can result in major alterations in the conclusions derived from the analysis and underlines the need for systematic sensitivity analyses.

18. Caution ! “Despite the lack of evidence-based information, empirical low-molecular- weight heparin (LMWH) is widely used in recurrent implantation failures.” Bulent Berker, M.D. Salih Ta¸skın, M.D. Department of Obstetrics and Gynecology, Medical School, Ankara University, Ankara, Turkey

20. Conclusions: “In women with ≥3 RIF, the use of adjunct LMWH significantly improves LBR by 79% compared with the control group.“

21. "There are three kindsof lies: lies, damned lies and statistics.“ - Benjamin D’Israeli (1804-1881)

24. Live birth rate (LBR) in women with ≥3 recurrent implantation failure and LMWH as treatment adjunct ?

25. 2013 Impact Factor: 1.018

26. ’Risk of bias’ summary: review authors’ judgments about each risk of bias item for each included study.

27. Live birth rate of 2.4%?! 3 consecutive failed IVF cycle, Age <35 years with at least one coagulation defect

28. Implantation rate (IR) in women with ≥3 recurrent implantation failure and LMWH as treatment adjunct IR was not significantly improved !

29. Shortcomings in the study by Qublan et al., 2008 Included women with both inherited and acquired thrombophilia. Acquired thrombophilia like APA are associated with recurrent miscarriage and possibly RIF compared with certain heterozygous inherited thrombophilia. In this study, a third of the patients were carriers of MTHFR C677T polymorphism, and there is no conclusive evidence in the literature regarding the adverse effect of this heterogeneous mutation on IVF or pregnancy outcomes

30. Shortcomings in the study by Qublan et al., 2008 A single test with low positivity cut-off was used in this study to check for lupus anticoagulant and anticardiolipin antibodies, yet for diagnosis of acquired thrombophilia these antibodies should be confirmed by a repeat test 12 weeks apart (Miyakis et al., 2006). These observations indicate that the study population was heterogenous and that the women did not necessarily have thrombophilia which is associated with adverse IVF or pregnancy outcomes.

31. Conclusions: “In women with ≥3 RIF, the use of adjunct LMWH significantly improves LBR by 79% compared with the control group; however, this is to be considered with caution, since the overall number of participants in the studies was small. Further evidence from adequately powered multi- centered RCTs is required prior to recommending LMWH for routine clinical use. This review highlights the need for future basic science and clinical research in this important field.”

32. Live birth rate(LBR) in women with ≥3 unexplained recurrent implantation failure and LMWH as treatment adjunct “It is important to note that these beneficial effects of LMWH were not significant when only the two studies with unexplained RIF were pooled.”

34. Flow chart of the study

37. Conclusion The data in this study show that low-dose aspirin and/or heparin as adjuvant therapies during IVF do not improve live birth rates in an unselected group of subfertile women who have previously had one or more unexplained implantation failure following IVF.

40. Results Control groupLMWH group 33.9%34.6%Clinical pregnancy rate 29.1%30.7%Live birth rate 21.1%22.6%Implantation rate 42.8%41.6%Multiple pregnancy rate No statistically significant difference

41. Conclusion No beneficial effect of LMWH on pregnancy outcomes in patients with two or more implantation failures and without coagulation disorders. Use of LMWH should be limited to research purposes until its beneficial effects have been proved by studies

42. Clexane: Hemorrhagic Side effects Occur in 3% to 7% of patients. A meta-analysis of published studies reported an overall incidence of major bleeding with low molecular weight heparins of 0.7% to 1.4%. Hemorrhage may occur at any site in the body.

43. Clexane Side effects Hematologic side effects including: wound hematoma (11%) anemia (3%) ecchymosis (3%) thrombocytopenia (1.5%) Local side effects have included pain erythema ecchymosis hematoma

44. Clexane Side effects Heparin-induced thrombocytopenia (HIT) is an immune-mediated, prothrombotic reaction that occurs in less than 1% of patients treated with a low molecular weight heparin (LMWH).

45. “My lovely clexane bruises!”

46. “Clexane Pain!!!”

47. עלות קלקסן 60 מ " ג, 2 מזרקים, 70.76 שקל. מזרק קלקסן ליום = 1,061 שקל לחודש

50. Cochrane Conclusion The results of this Cochrane review of three randomised controlled trials with a total of 386 women suggested that peri- implantation LMWH in assisted reproduction treatment (ART) cycles may improve the live birth rate in women undergoing assisted reproduction.

51. Cochrane Conclusion However, these results were dependent on small low quality studies with substantial heterogeneity, and were sensitive to the choice of statistical model. There were side effects reported with use of heparin, including bruising and bleeding, and no reliable data on long- term effects.

52. Cochrane Conclusion “Overall, this evidence does not justify the present widespread use of LMWH in this population subgroup (previous failed IVF), outside well-conducted randomised trials. Such trials should be a priority.”

53. Thank You!