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GANIN FERTILITY CENTER

GANIN FERTILITY CENTER. Dr . ABDLRAHIM OBEID FRCOG (London) IVF Consultant Dr . NEVEN ADLI MD . Obstetrics & gynaecology (S.M.S.B). WH A T IS NEW IN RIF?. Definition of RIF. Number of  cycles Number of embryos Cleavage vs blastocyst embryos Fresh vs frozen embryos

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GANIN FERTILITY CENTER

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  1. GANIN FERTILITY CENTER

  2. Dr.ABDLRAHIM OBEID FRCOG (London) IVF Consultant Dr.NEVEN ADLI MD . Obstetrics & gynaecology(S.M.S.B) WHAT IS NEW IN RIF?

  3. Definition of RIF • Number of  cycles • Number of embryos • Cleavage vsblastocyst embryos • Fresh vs frozen embryos Failure to achieve a clinical pregnancy after transfer of at least 4 good-quality embryos in a minimum of three fresh or frozen cycles in a woman under the age of 40 years (Couglan et al.RBM Online 2014)

  4. Probability of failed implantation-good quality cleavage stage

  5. Probability of failed implantation-poor quality cleavage stage

  6. Probability of failed implantation-good quality blastocyst stage

  7. Pragmatic classification of RIF • Expected-recurrent IVF failure • Unexpected-recurrent implantation failure

  8. Expected RIF • Advanced maternal age • Reduced ovarian reserve • Poor quality embryos • Atrophic endometrium Do we need To investigate Further?

  9. Expected RIF-anticipated implantation rate<=10%

  10. App 70% of patients not pregnant after 4 treatment cycles

  11. Unexpected RIF • Young age • Adequate ovarian reserve • Good quality embryos • No pelvic pathology on routine scan INVESTIGATE

  12. Unexpected RIF-anticipated implantation rate >=30%

  13. App25%ofpatientsnotpregnantafter4treatmentcycles

  14. INVESTIGATION GAMETE AND EMBRYO FACTORS • Ovarian function test(FSH-AMH-AFC) to exclude any significant compromise of ovarian function associated with RIF, which may help in the counselling process. • Sperm DNA integrity testingIt is widely accepted that conventional semen analysis parameters do not accurately reflect sperm quality. Genetic tests are more likely to be useful as genome and epigenome integrity is essential for fertilization, normal embryo development and successful implantation. • karyotyping

  15. INVESTIGATION Uterine factors • Imaging of the pelvis • Uterus • Ovaries • Tubes • Hysteroscopy • Evaluation of possible immunological problems

  16. Detailed Imaging • Transvaginal high resolution US+3D-intracavitary and intramural lesions • HSG-synechia, hydrosalpinx • MRI-adenomyosis, fibroids

  17. The effect of non-cavity-distorting fibroids on IVF outcome There are three recent meta-analyses published on this particular subject all three analysis concur that women with intramural fibroids appear to have reduced implantation rates ,however, myomectomy did not appear to significantly increase the clinical pregnancy and live birth rates. A most recent study suggested that magnetic resonance –guided focused U/S surgery is possible noninvasive therapy for intramural fibroids as the pregnancy outcome after the treatment encouraging (Rabinovici et al..2010).

  18. Hydrosalpinx • It is advisable to exclude hydrosalpinges as a cause of RIF, regardless of the initial infertility diagnosis leading to IVF treatment. • Ultrasound examination should not be relied upon to rule out hydrosalpinges as it may not always be visualized by ultrasonography. If the HSG is inconclusive , laparoscopic examination should confirm or refute the diagnosis beyond doubt.

  19. Effect of untreated hydrosalpinx

  20. Endometriosis • Only 1 study showed that surgical treatment of endometriosis may be beneficial in women with RIF • Retrospective 23 patients • Almost half of the patients conceived spontaneously after laparoscopy

  21. Adenomyosis • Recently associated with RIF Only 2 prospective studies • Universal agreement on diagnosis ?? • USG • Doppler • MRI

  22. Hysteroscopy-emerging role in IVF and RIF • ¨The incidence of abnormal hysteroscopic findings in women with recurrent IVF failures varies between 25% and 50%(Makrakis and Pantos,2010) • After 2 or more failed cycles 15-40% of patients will have an intra-cavitary lesion(Oliveraetal.,2003;LeviSetti,2004;Urman,2005) • Polyps • Adhesions • Small fibroids • Arcuate / subseptate uterus • Endometritis • Hyperplasia

  23. Immunological disorders associated with RIF • Autoantibodies • Thrombophilia • Antithyroid antibodies • Abnormal NK cell number/function

  24. Antibodies in IVF patients

  25. Antiphospholipid antibodies and IVF outcome • Antiphospholipid antibodies do not affect IVF success(ASRMPracticeCommitteeReport,FertilSteril2004

  26. Antiphospholipid antibodies & IVF outcome

  27. Anti-thyroid antibodies • Is their prevalence increased in RIF vs infertile controls?   • YES (22-52%) • Birkenfeld, 1994 HR Geva, 1995 HR Bussen, 2000 HR Bellver, 2008 HR • Do they reduce success rate of IVF? • Contradictory data • 2 studies = yes Geva, 1996 HR Kim, 1998 AJRI  • 2 studies = no Kutteh, 1999 HR • Negro, 2007 J Endocrinol Invest

  28. Thrombophilia • Conflicting evidence in relation to RIF • Five studies showed higher prevalence of one or more marker in women with RIF Grandome,2001 FS - Azem, 2004 HR - Coulam, 2006 RBM - Qublan, 2006 HR -Bellever, 2008 HR • One study showed no difference in prevalence Martinelli, 2003 Haematol

  29. NATURALKILLERCELLS • A number of studies have shown an increased number of PB NK cells in women with RIF, and in one study, the pregnancy rate of those women with high NKcells (approximately 12%) was lower than those with normal NK cells.

  30. Natural killer cells • A systematic review carried out by Tang et al.11 suggested that abnormal uNK cell numbers could not predict pregnancy outcome in women undergoing IVF. However, the number of uNK cells is likely to be altered by the hormonal regimens used in IVF treatments and this may affect the results obtained.

  31. Natural killer cells • Although abnormal PB NK or uNK cell counts may contribute to RIF, there is insufficient evidence from which to draw firm conclusions.

  32. Natural killer cells???? • Is it worth measuring NK cells?  • Are blood and endometrial levels concordant? • Is there an effective treatment? • IVIG • Intralipid • Does the treatment improve IVF success rates?

  33. MANAGEMENTOFRIF • A multidisciplinary approach should be adopted in the management of a couple with RIF. It should involve not only an experienced fertility specialist but also a senior embryologist and, where appropriate, a reproductive surgeon or a counsellor.

  34. MANAGEMENTOFRIF • The couple should have explained to them that any treatment plan recommended would be discussed and confirmed in a multidisciplinary team meeting and the final decision confirmed in writing. • Secondly, there ought to be an agreed local protocol as to how couples with RIF should be further investigated and managed. This is particularly important as there is still no universally agreed protocol for the investigation and management of this condition.

  35. Management-accepted • Remove intracavitary impediments to implantation  • Fibroids • Polyps • Septum • Remove hydrosalpinx • Improve transfer technique-difficult transfers (Asystematic review and meta-analysis of prospective, randomized, controlled trials comparing ultrasound with clinical touch methods of embryo catheter guidance concluded that ultrasound-guided embryo transfer significantly increases the chance of live birth and ongoing and clinical pregnancy rates (Abou-Setta et al., 2007).

  36. Management-less controversial • Review stimulation protocols There is no firm evidence that antagonist protocol is better than agonist protocol or vice versa. There is some evidence to suggest that poor responders to FSH stimulation in down-regulated cycles may benefit from the addition of LH. • Evidence also points to a possible benefit from the addition of LH to the cycles of women older than 35 years of age . • Transfer at the blastocyst stage

  37. Management-more controversial • Treatment of thrombophilia • Treatment of thyroid autoimmunity in the euthyroid patient  • Intralipid and IVIG • Heparin • PGS • IntracavitaryhCG ,Intracavitary GCSF • Multi drug approach  • Antibiotics, aspirin, corticosteroids, multi-agent luteal phase support

  38. Endometrial scratch • studies suggests that endometrial scratch is of benefit in women with RIF but it should be carried out approximately 7 days prior to the onset of menstruation, immediately before the start of ovarian stimulation for IVF treatment.

  39. IVIG for treatment of RIF • Meta-analysis of published trials showed that IVIG significantly improves the live birth rate in couples with unexplained RIF • NNT = 6 • Clark et al, AJRI 2006; 23: 1-13 • But… included 2 unpublished datasets Few RCTs

  40. Intralipid therapy • Intralipid therapy for recurrent implantation failure: new hope or false dawn? Shreeve and Sadek J ReprodImmunol 2012 • Intralipid Contains soya oil, glycerine and egg phosholipids • Inhibits proinflammatory mediators specifically Th 1 cytokines • All patients showed a reduction in their Th1/Th2 ratio

  41. PGS for RIF • There is no evidence to suggest that the embryos produced by women with RIF are more likely to be abnormal. The frequency of aneuploidy (67%) in embryos from women with RIF was rather similar to the frequency (64%) in women without the condition. • A recent review by Donoso et al. (2007) also concluded that PGD should not be implemented in women with RIF on a routine basis. • No beneficial effect of PGS with FISH • No studies with newer techniques such as array CGH

  42. Conclusions-RIF • Only a few of the potential causes are known  • Most treatment options are experimental and empiric  • Well designed studies are urgently needed

  43. THANKS

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