This document discusses recurrent implantation failure (RIF) after in vitro fertilization. It defines RIF and reviews its potential causes and treatments. The etiology of RIF may involve endometrial factors, gamete/embryo issues, or multifactorial causes. Investigations aim to identify specific causes, and treatments target the endometrium, embryos, or multiple contributing issues. While some interventions like hysteroscopy, endometrial injury, and blastocyst transfer have shown benefits, individualized, multidisciplinary care is needed given the complex, multifactorial nature of RIF.

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).
Aboubakr Elnashar

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
Aboubakr Elnashar

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.
Aboubakr Elnashar

6. 2. Etiology
I. Endometrial
II. Gamete/embryo
III. Multifactorial
Aboubakr Elnashar

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
Aboubakr Elnashar

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
Aboubakr Elnashar

9. III. Multifactorial
1. Endometriosis
2. Hydrosalpinges
3. Suboptimal ovarian stimulation
Aboubakr Elnashar

10. 3. Investigations
Aboubakr Elnashar

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
Aboubakr Elnashar

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)
Aboubakr Elnashar

13. Damaged DNA : no halo.
Intact DNA: chromatin dispersion halo
Aboubakr Elnashar

14. 3. Karyotype
to rule out structural anomalies of chromosomes.
2.5%
(Stern et al., 1999)
4. If a structural anomaly:
preimplantation genetic diagnosis
Aboubakr Elnashar

15. 4. Treatment
Individualized
Multidisciplinary
Experienced fertility specialist
Senior embryologist
±Reproductive surgeon
Local protocol
Aboubakr Elnashar

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).
Aboubakr Elnashar

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
Aboubakr Elnashar

18.  Vaginal micronized estradiol
(Tourgeman et al., 2001)
Antifibrotic: pentoxifylline (Trental) and
high-dose vitamin E
(Ledee-Bataille et al., 2002)
Aboubakr Elnashar

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)
Aboubakr Elnashar

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)
Aboubakr Elnashar

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.
Aboubakr Elnashar

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).
Aboubakr Elnashar

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).
Aboubakr Elnashar

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)
Aboubakr Elnashar

25. Intralipid
Controlled, large-scale, confirmatory studies
are necessary to prove efficacy before it can be
recommended for routine use.
(Shreeve; Sadek, 2011)
Aboubakr Elnashar

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}
Aboubakr Elnashar

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).
Aboubakr Elnashar

28. 2. Sperm DNA fragmentation
a. Oral antioxidant
reduce the incidence of sperm DNA fragmentation
(Greco et al., 2005 ; Isidori et al., 2006).
Aboubakr Elnashar

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
Aboubakr Elnashar

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)
Aboubakr Elnashar

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)
Aboubakr Elnashar

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)
Aboubakr Elnashar

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
Aboubakr Elnashar

34. b. Blastocyst transfer
 Significantly higher CPR
(Guerif et al., 2004; Levitas et al., 2004).
{Improved embryo selection and uterine receptivity}
Aboubakr Elnashar

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)
Aboubakr Elnashar

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)
Aboubakr Elnashar

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).
Aboubakr Elnashar

38. III. Multifactorial treatment options
Lifestyle changes
Smoking
Alcohol consumption
BMI
Aboubakr Elnashar

39. 1. Salpingectomy of hydrosalpinges
 CPR and live birth rates: doubled
(Strandell et al., 1999; Cochrane sys rev Johnson et al., 2004).
Aboubakr Elnashar

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.
Aboubakr Elnashar

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).
Aboubakr Elnashar

42. 4. Tailoring the stimulation protocols
GnRHan protocols:
improved blastocyst quality and pregnancy
outcome after RIF with GnRHa protocols
(Takahashi et al. ;2004).
Aboubakr Elnashar

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).
Aboubakr Elnashar

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.
Aboubakr Elnashar

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
Aboubakr Elnashar

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.
Aboubakr Elnashar

47. Thank you
Aboubakr Elnashar
Benha university Hospital,
Egypt
elnashar53@hotmail.com
Aboubakr Elnashar