1. GANIN FERTILITY CENTER

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

3. Definition of RIF Number of cycles Number of embryos
Cleavage vs blastocyst 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
Number of embryos transferred
Probability of failed implantation 1
70% 2
49% 3
34% 4
24% 5
17% 6
12%

5. Probability of failed implantation-poor quality cleavage stage
Number of embryos transferred
Probability of failed implantation 1
90% 2
73% 3
66% 4
59% 5
53% 6
48%

6. Probability of failed implantation-good quality blastocyst stage
Number of embryos transferred
Probability of failed implantation 1
60% 2
36% 3
22% 4
13%

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

8. Do we need To investigate Further?
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%
Cycle number
Number pregnant out of 100 1 10 2 19 3 24 4 31

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

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

12. Unexpected RIF-anticipated implantation rate >=30%
Cycle number
Number pregnant out of 100 1 30 2 51 3 65 4 75

13. App 25% of patients not pregnant after 4 treatment cycles

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. Evaluation of possible immunological problems
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
Meta analysis
Outcome criteria
Group with hydrosalpinx (%)
Group without hydrosalpinx (%)
Odd
ratio
Confidence interval
Pregnant rate
19.67
31.2
0.64
Implantation rate
8.53
13.68
0.63
Delivery rate
13.4
23.44
0.58
Early pregnancy loss rate
43.65
31.11
1.72
Odd ratio significantly different from 1(p<0.05)

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(Olivera et al., 2003; Levi Setti, 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
Auto antibodiy
Frequency in infertile women
Infertility association
Known associations
antiphospholipid
Increased
Unproven
Recurrent pregnancy loss
antithyroid
Slightly
increased
Thyroiditis ,
miscarriage
antigliadin
Celiac disease
antisperm
No difference
Fertilization faliure
antinuclear
Autoimmune
disease
antiovarian
Ovarian failure

25. Antiphospholipid antibodies and IVF outcome
Antiphospholipid antibodies do not affect IVF success(ASRM Practice Committee Report, Fertil Steril 2004

26. Antiphospholipid antibodies & IVF outcome
Authors
Odd ratio
(95%CI)
Pregnancy
Birdsall et al
1.65
(0.50, 5.46)
Denis et al
0.91
(0.42, 1.97)
El roiey et al
0.26
(0.04, 1.83)
Glicher et al
1.34
(0.36, 4.95)
Kutteh et al
.85
(0.21, 3.50)
Sher et al
.55
(0.13, 2.34)
Average from pregnancy live birth
.99
(0.64, 2.34)
1.67
(0.50, 5.56)
.94
(0.44, 1.98)
.18
(0.02, 2.14)
1.60
(0.39, 6.53)
Kowalik et al
1.10
(0.42, 2.90)
Average from live birth
1.07
(0.66, 1.75)
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, HR Kim, AJRI 
2 studies = no Kutteh, 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, RBM - Qublan, 2006 HR -Bellever, 2008 HR
One study showed no difference in prevalence Martinelli, 2003 Haematol

29. NATURAL KILLER CELLS
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. MANAGEMENT OF RIF
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. MANAGEMENT OF RIF
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
Intracavitary hCG ,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 Reprod Immunol 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