Recurrent implantation failure


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Recurrent implantation failure

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Recurrent implantation failure

  1. 1. Recurrent implantation failure Prof. Aboubakr Elnashar Benha University Hospital, Egypt elnashar53@hotmail.comAboubakr Elnashar
  2. 2. Contents 1. Introduction Definition, Incidence, Impact 2. Etiology 3. Investigations 4. Treatment Conclusion Aboubakr Elnashar
  3. 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. 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. 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. 6. 2. Etiology I. Endometrial II. Gamete/embryo III. Multifactorial Aboubakr Elnashar
  7. 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. 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. 9. III. Multifactorial 1. Endometriosis 2. Hydrosalpinges 3. Suboptimal ovarian stimulation Aboubakr Elnashar
  10. 10. 3. Investigations Aboubakr Elnashar
  11. 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. 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. 13. Damaged DNA : no halo. Intact DNA: chromatin dispersion halo Aboubakr Elnashar
  14. 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. 15. 4. Treatment Individualized Multidisciplinary Experienced fertility specialist Senior embryologist ±Reproductive surgeon Local protocol Aboubakr Elnashar
  16. 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. 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. 18.  Vaginal micronized estradiol (Tourgeman et al., 2001) Antifibrotic: pentoxifylline (Trental) and high-dose vitamin E (Ledee-Bataille et al., 2002) Aboubakr Elnashar
  19. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 34. b. Blastocyst transfer  Significantly higher CPR (Guerif et al., 2004; Levitas et al., 2004). {Improved embryo selection and uterine receptivity} Aboubakr Elnashar
  35. 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. 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. 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. 38. III. Multifactorial treatment options Lifestyle changes Smoking Alcohol consumption BMI Aboubakr Elnashar
  39. 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. 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. 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. 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. 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. 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. 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. 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. 47. Thank you Aboubakr Elnashar Benha university Hospital, Egypt Aboubakr Elnashar