Recurrent implantation failure

1. Recurrent implantation
failure
Prof. Aboubakr Elnashar
Benha University Hospital, Egypt
elnashar53@hotmail.comAboubakr Elnashar

2. Contents
1. Introduction
Definition, Incidence, Impact
2. Etiology
3. Investigations
4. Treatment
Conclusion
Aboubakr Elnashar

3. 1. Introduction
Definition
No universally accepted definition
Failure of implantation
After 3 consecutive IVF attempts,
after transfer of at least 4 good-quality embryos
in a woman under the age of 40 ys
(Simon and Laufer, 2012; Coughlan et al, 2013).
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4. Failure of implantation
after 2 consecutive cycles
after transfer of at least 4 good-quality embryos
or 2 blastocysts
(Polanski et al, 2014)
Not the same as R IVF F.
subgroup of R IVF F
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5. Incidence
10% of the cycles
(Margalioth et al, 2006).
Impact
Distress to couples
Frustration to doctor
Increases the cost of the procedure
 Management
Major challenge to clinicians and embryologists.
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6. 2. Etiology
I. Endometrial
II. Gamete/embryo
III. Multifactorial
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7. I. Endometrial factors
1. Anatomic causes:
Polyp, fibroid, adhesion, septum
2. Impaired function
Thin endometrium
Altered expression of adhesive molecules
3. Thrombophilia
4. Immunological factors
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8. II. Gamete/embryo factors
1. Parental chromosomal anomalies
2. Poor-quality oocyte
3. Poor-quality spermatozoa
4. Zona hardening
5. Suboptimal culture conditions
6. Suboptimal embryo quality
7. Suboptimal ET
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9. III. Multifactorial
1. Endometriosis
2. Hydrosalpinges
3. Suboptimal ovarian stimulation
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10. 3. Investigations
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11. Investigations for endometrial causes:
(Simon and Laufer, 2012)
1. Hysteroscopy: intra-uterine pathology
2. TVS/ MRI: Structural uterine anomalies
3. HSG: hydrosalpinges
4. Hormone profile: Endometrial defects secondary to
endocrine aberrations
5. Endometrial Biopsy: uNK cells
6. Blood tests for thrombophilia and
antiphospholipid antibodies.
7. All tests: normal: test for HLA similarity
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12.  Investigation of embriologic factors
(Simon and Laufer, 2012, Coughlan et al, 2013)
1. Ovarian reserve tests
basal FSH, AMH, AFC
to exclude any significant compromise of ovarian
function: help in the counseling.
2. Sperm DNA fragmentation:
Sperm Chromatin Structure Assay (SCSA):
Sperm chromatin dispersion test (SCD)
DNA fragmentation index
>27%: RIF
(Larson et al.,2000; Larson-Cook et al., 2003)
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13. Damaged DNA : no halo.
Intact DNA: chromatin dispersion halo
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14. 3. Karyotype
to rule out structural anomalies of chromosomes.
2.5%
(Stern et al., 1999)
4. If a structural anomaly:
preimplantation genetic diagnosis
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15. 4. Treatment
Individualized
Multidisciplinary
Experienced fertility specialist
Senior embryologist
±Reproductive surgeon
Local protocol
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16. I. Endometrial
1. Correction of anatomic factors
 Hysteroscopic correction of uterine cavity
pathology
(Demirol and Gurgan, 2004).
 Removal of fibroids
Distorting the uterine cavity
Intramural ≥5cm
(Donnez and Jadoul, 2002).
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17. 2. Improvement of endometrial function
a. Treatment of thin endometrium
To improve uterine blood
low-dose aspirin
(Weckstein et al., 1997)
vaginal sildenafil
(Sher and Fisch, 2002)
Freeze all embryos (when the endometrium <7
mm) and transfer them after stimulation with high-
dose estrogens
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18.  Vaginal micronized estradiol
(Tourgeman et al., 2001)
Antifibrotic: pentoxifylline (Trental) and
high-dose vitamin E
(Ledee-Bataille et al., 2002)
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19. b. Endometrial sctatching
 When:
cycle preceding the actual treatment cycle.
(Friedler et al., 1993; Barash et al., 2003; Raziel et al., 2007; Zhou et
al., 2008).
7 days prior to the onset of menstruation,
immediately before the start of ovarian stimulation
for IVF tt.
In the follicular phase of the index cycle : no
benefit
(Karimzade et al., 2010; Zhou et al., 2008).
Not on the day of OR:
significantly reduce CPR
(Nastri et al, 2012)
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20.  How
biopsy/scratch or hysteroscopy: CPR doubled.
(Raziel et al., 2007 ; Narvekar et al, 2010)
CPR: twice as high with biopsy/scratch as
opposed to hysteroscopy
(Potdar et al, 2012)
(2 syst reviews: Potdar et al, 2012; El-Toukhy et al, 2013)
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21. (A) First, the pipelle sample is inserted until it reaches the fundus.
(B) The inner plunger is withdrawn to apply a suction force to the endometrial cavity.
(C) Endometrial scratch of the superficial layer of the endometrium is performed with
the use of a ‘hoovering’ movement, combining a rotational and in-and-out movement
of the pipelle sampler several times.
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22.  Mechanisms:
1. Induce decidualization of the endometrium
2. Provoke wound healing, involving secretion
cytokines and growth factors
(Li and Hao, 2009).
3. Recruit stem cells to the endometrium, creating a
partially new endometrium free of epigenetic defects
(Taylor, 2004; Du and Taylor, 2007).
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23. 3. Thrombophilia
Thrombophilia: LMWH
Thrombophilic trait: prophylactic dose of LMWH:
improve IVF outcome
(Bohlmann et al, 2011; Qublan et al, 2008).
Antiphospholipid antibody syndrome:
 Empirical treatment:
LMWH, aspirin, or corticosteroids:
Not effective
Not advocated
(Seshadri et al, 2011; Berker et al, 2011).
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24. 4. Immunotherapy
 IVIG
Although data showing some benefit on ART
outcome.
SR does not support
{paucity, or poor quality of, the evidence}.
(SR: Polanski et al, 2014)
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25. Intralipid
Controlled, large-scale, confirmatory studies
are necessary to prove efficacy before it can be
recommended for routine use.
(Shreeve; Sadek, 2011)
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26. Intrauterine administration of autologous
peripheral blood mononuclear cells (PBMC)
Freshly isolated from patients: effectively
improves embryo implantation
(Yoshioka et al, 2006; Okitsu et al, 2011 Chen et al, 2011)
{1. Evoke favourable inflammatory reactions :
producing cytokines
2. secrete proteases: regulate endometrial
function}
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27. II. Treatment of the embryos
1. Chromosomal abnormality
Preimplantation genetic screening
 can clarify the reason for RIF.
(Caglar et al. ,2005)
 significantly lowered live birth rates in RIF
(Meta-analysis of RCT, Mastenbroek et al,2011)
 does not improve the live birth rates RIF
(ASRM, ESHRE, 2010).
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28. 2. Sperm DNA fragmentation
a. Oral antioxidant
reduce the incidence of sperm DNA fragmentation
(Greco et al., 2005 ; Isidori et al., 2006).
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29. b. Select spermatozoa with low levels of DNA
damage from the ejaculated semen samples
(Sakkas and Alvarez, 2010).
i. Annexin-V columns:
reduce the percentage of spermatozoa with
DNA fragmentation as measured by the
TUNEL test
ii. Sperm hyaluronic acid binding:
(Jakab et al., 2005; Said et al., 2005, 2006).
iii. Onfocal light absorption scattering
spectroscopy (CLASS) technology
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30. iv. Intracytoplasmic morphologically selected
sperm injection (IMSI)
high-magnification microscope (6000x), to identify
spermatozoa devoid of surface vacuoles
(Bartoov et al., 2003).
The only confirmed indication for IMSI is RIF.
(MA: Boitrelle et al, 2014)
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31. c. Use of testicular spermatozoa
{sperm DNA damage is lower in the seminiferous
tubules as compared with the cauda epididymis
and ejaculated spermatozoa}
(Greco et al., 2005; Steele et al., 1999; Suganuma et al., 2005)
Significant increase in PR
(Greco et al., 2005b; Weissman et al., 2008)
reduction of miscarriage rate
(Borini et al., 2006)
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32. 3. Assisted hatching
 Significant increases CPR in RIF
(Three RCTs: Chao et al., 1997; Magli et al., 1998; Nakayama et al.,
1999; Metaanalysis, Martins et al, 2011)
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33. 4. Suboptimal culture
a. Co-culture
 Homologous endometrial cells
(Jayot et al., 1995; Eyheremendy et al, 2010)
49% PR in RIF.
(Spandorfer et al. ,2004)
Most IVF units do not have facilities and experience
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34. b. Blastocyst transfer
 Significantly higher CPR
(Guerif et al., 2004; Levitas et al., 2004).
{Improved embryo selection and uterine receptivity}
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35. 5. Improving ET
 Essential in each cycle and must be reconsidered
in RIF.
Atraumatic, US guided
Embryos deposited in the mid uterine cavity
(Sallam, 2005)
 Avoidance of blood, mucus, bacterial
contamination, touching the fundus, and excessive
uterine contractions
 Trial transfer, filled bladder, soft catheters
(Schoolcraft et al, 2001)
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36.  Fibrin glue
doubled CPR in RIF
(Bar-Hava et al. ,1999).
Transfer large number of embryos
significant increase in CPR in RIF
(Azem et al.1995)
No comparative study.
Sequential embryo transfer
Interval double ET (on days 2 and 4 or 5):
improves CPR in RIF
(Loutradis et al, 2004; Almog et al., 2008)
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37. Personalized embryo transfer (pET)
ERA test to determine endometrium is receptive
or not)
pET performed on the day designated by the
ERA: 50.0% PR and 38.5% IR
(Ruiz-Alonso et al, 2013).
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38. III. Multifactorial treatment options
Lifestyle changes
Smoking
Alcohol consumption
BMI
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39. 1. Salpingectomy of hydrosalpinges
 CPR and live birth rates: doubled
(Strandell et al., 1999; Cochrane sys rev Johnson et al., 2004).
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40. 2. Treating endometriosis
 GnRHa for 3–6 months before ART: significantly
increases CPR
(Surrey et al., 2002).
increased CPR by 4-fold
(Sallam et al., 2006).
Endometrioma:
No benefit of removal before IVF
(Garcia-Velasco et al., 2004; Wong et al., 2004),
Surgery ± deleterious for ov reserve.
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41. 3. Danazol
 significantly increased CPR (40 vs 19.5%)
(Tei et al., 2003).
 {Immunosuppressive effects
increase receptivity of the endometrium
upgrade the endometrial αVβ3 integrin.}
(Hill et al., 1987).
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42. 4. Tailoring the stimulation protocols
GnRHan protocols:
improved blastocyst quality and pregnancy
outcome after RIF with GnRHa protocols
(Takahashi et al. ;2004).
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43. Addition of LH
1. Poor responders to FSH stimulation in down-
regulated cycles
(Phelps et al., 1999; Surrey and Schoolcraft, 2000).
2. Above 35 ys
(Balasch et al., 2001; Marrs et al.,2004; Phelps et al., 1999).
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44. Natural cycle
particularly with high uNK cell count
(Kadoch, 2003, Ledee-Bataille et al., 2004).
 No RCT to prove that changing any stimulation
protocol can improve treatment outcome.
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45. Conclusions
 Many known and unknown reasons for RIF, and
we do not have the tools to diagnose in each case
the exact cause.
 After failure of 2 or 3 transfers of good-quality
embryos in a unit with CPR of at least 30%, one
should take some special measures.
The management of RIF should be
individualized
multidisciplinary
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46. RCT: beneficial
Hysteroscopy procedures
Endometrial injury
IU administration of autologous PBMC
Blastocyst transfer
Assisted hatching
Salpingectomy for tubal disease
Aspirin, heparin, IVIG, intralipid does not have a
clear impact on tt outcome.
 Co cultures, sildenafil, transfer of six embryos,
natural IVF, and PGS await further clinical
assessment.
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47. Thank you
Aboubakr Elnashar
Benha university Hospital,
Egypt
elnashar53@hotmail.com
Aboubakr Elnashar