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RECURRENT IMPLANTATION FAILURE : an evidence-based approach

RECURRENT IMPLANTATION FAILURE : an evidence-based approach. Prof T C LI Professor of Reproductive Medicine & Surgery Sheffield, England. Istanbul, June 2010. Outline. Definition Endometrial factors Causes of endometrial abnormality How to investigate Treatment options.

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RECURRENT IMPLANTATION FAILURE : an evidence-based approach

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  1. RECURRENT IMPLANTATION FAILURE : an evidence-based approach Prof T C LI Professor of Reproductive Medicine & Surgery Sheffield, England Istanbul, June 2010

  2. Outline • Definition • Endometrial factors • Causes of endometrial abnormality • How to investigate • Treatment options

  3. WHAT IS RECURRENT IMPLANTATION FAILURE?

  4. RECURRENT IMPLANTATION FAILURE • About 2/3 of centres in UK defined recurrent IVF failure as a failure to achieve a pregnancy after 3 completed fresh IVF-ET cycles (often excluding FER) (Tan et al 2005) • Failure to achieve a pregnancy after 3 IVF cycles, in which reasonably good embryos were transferred (Margalioth et al 2006) • Failure to achieve a pregnancy after a total of 10 or more embryos had been transferred to the uterus (Stern et al 2003) • Failure to achieve a clinical pregnancy following the transfer of six embryos in either fresh or frozen cycles in women aged less than 40 years

  5. A consensus on definition is urgently needed

  6. A consensus on definition is urgently needed Working Party Consensus Meeting

  7. WHY SHOULD IMPLANTATION FAIL TO TAKE PLACE ?

  8. BASIC IMPLANTATION PHYSIOLOGY endometrium embryo

  9. Evidence of endometrial abnormality in women with RIF

  10. Uterine NK cells & RIF • 37% of women with RIF had increase number of uNK cells (Ledee-Bataille, 2004) • Women with recurrent miscarriage had increase number of uNK cells compared with control subjects; women with RIF had even higher number of uNk cells (Sheffield data)

  11. Causes of Endometrial Abnormality • uterine cavity pathology

  12. Causes of Endometrial Abnormality • uterine cavity pathology • Structural uterine anomalies

  13. Outcome of pregnancies in women with uterine leiomyomas identified by sonography in the first trimester. Benson et al, 2001 • miscarriage rate • Control n=715 7% • Fibroid n=143 14% • Multiple fibroids n=55 24%

  14. What is the abnormality?

  15. Classification of congenital uterine anomalies American Fertility Society. Fertil Steril 1988;49:944–955.

  16. Causes of Endometrial Abnormality • uterine cavity pathology • Structural uterine anomalies • Endocrine aberrations

  17. Endocrine Aberrations • High Oestrogens • High BMI • High androgens

  18. Impact of high BMI on miscarriage: spontaneous and assisted conceptions

  19. In a donor oocyte programme, embryo recipents with high BMI had a higher miscarriage rate than receipents with normal BMI Bellver et al 2003 Fertil Steril 79:1136-40

  20. ANDROGENS • Comparison of LH timed plasma samples showed that women with RM (n=43) had higher FAI than fertile control (n=10) • androgen levels were negatively correlated with uterine fluid PP14 concentrations Okon et al,1998

  21. The Prognostic Value of Free Androgen Index (FAI) in Recurrent Miscarriage 229 cases with FAI ≤ 5 Miscarriage Rate = 40% 25 cases with 5 < FAI ≤ 9 Miscarriage Rate = 64% P=0.007 9 cases with FAI > 9 Miscarriage Rate = 78% Cocksedge et al. (2008) Human Reproduction 23, 797-802

  22. Causes of Endometrial Abnormality • uterine cavity pathology • Structural uterine anomalies • Endocrine aberrations • Excess of inhibitors of implantation

  23. Why does the presence of hydrosalpinges adversely affect IVF pregnancy rate ? Hydrosalpingeal fluid impairs endometrial function

  24. Hydrosalpinges and Leukaemia inhibitory factor (LIF) expression in the endometrium • LIF expression in the mid-luteal phase endometrium of infertile women (n=10) with hydrosalpinges was significantly lower than control fertile subjects • Salpingectomy resulted in increase of LIF expression in 8/10 subjects with hydrosalpinges Seli et al 2005 Human Reprod 20:3012

  25. Hydrosalpinges and integrin expression (αvβ3) in the endometrium • Integrin (αvβ3)expression in the mid-luteal phase endometrium of women with hydrosalpinges was significantly lower than control subjects • Salpingectomy resulted in increase of integrin (αvβ3)expression Meyer et al 1997 Human Reprod 12:1393 Bildirici et al 2001 Human Reprod 16:2422

  26. INVESTIGATIONPROTOCOL ENDOMETRIAL FACTORS CAUSING RIF

  27. Endometrial factors • Hysteroscopy - intra-uterine pathology • TVS/ MRI - Structural uterine anomalies • Hormone profile - Endometrial defects secondary to endocrine aberrations • HSG - hydrosalpinges • Endometrial Biopsy – uNK cells

  28. HYSTEROSCOPY • RCT by Demirol & Gurgan (2004) • 421 women with 2 or more IVF failures • 56 out of 210 (26%) women with normal HSG had intrauterine leisons detected by office hysteroscopy, and treated • The subsequent pregnancy rate in the treated group (30.4%) and the group with normal hysteroscopy (32.5%) was significantly higher than the group who did not undergo hysteroscopy (21.6%) A

  29. TREATMENT STRATEGIES

  30. RECOMMENDED MANAGEMENT OF RIF • Designated clinic and personnel • Detailed reproductive history and treatment outcome, structured sheet • Review Life style factors • Investigations according to an agreed clinic protocol • Multi-disciplinary approach

  31. Salpingectomy A

  32. SUBMUCOUS FIBROID B

  33. C

  34. The outcome of singleton pregnancies after IVF/ICSI in women before and after hysteroscopic resection of a uterine septum compared to normal controlsBan-Frangez et al, European J Obstet Gynae & Reprod Biol 2009 Retrospective Control Study

  35. SEPTUM TRANSECTION C

  36. Intrauterine adhesiolysis (scissors) C

  37. Life style modification – high BMI • Diet • Exercise • Pharmacological agents • Bariatric surgery C

  38. Novel Treatment

  39. ENDOMETRIAL SCRATCH -1 • RCT of repeated endometrial biopsies in the cycle immediately preceding IVF treatment significantly increased (~doubled) the implantation, pregnancy and live birth (28%, 67% & 49%) rates in women who had one or more IVF failure compared with control subjects (14%, 30% and 23%) (Barash et al 2003)

  40. ENDOMETRIAL SCRATCH - 2 • Cohort study of repeated endometrial biopsies in the cycle immediately preceding IVF treatment significantly increased the implantation & pregnancy (11% & 30%) rates in 60 women who had more than 4 fresh embro transfer compared with 57 control subjects (4% & 12%) (Raziel et al 2007)

  41. Endometrial Scratch -3 • RCT • 115 women with at least two implantation failures • Endometrial biopsy in the luteal phase of cycle preceding IVF/ICSI Karimzadeh et al, 2009 Aust NZJ Obstet Gynaecol 49: 677-80

  42. Endometrial scratch

  43. Summary • Definition • Endometrial / uterine factors • How to investigate • How to manage • Endometrial Scratch • Need for consensus • Need for more evidence

  44. THANKYOU

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