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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

RECURRENT IMPLANTATION FAILURE : an evidence-based approach

Prof T C LI

Professor of Reproductive Medicine & Surgery

Sheffield, England

Istanbul, June 2010

outline
Outline
  • Definition
  • Endometrial factors
  • Causes of endometrial abnormality
  • How to investigate
  • Treatment options
recurrent implantation failure
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
a consensus on definition is urgently needed6

A consensus on definition is urgently needed

Working Party

Consensus Meeting

slide8

BASIC IMPLANTATION

PHYSIOLOGY

endometrium

embryo

uterine nk cells rif
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)
causes of endometrial abnormality
Causes of Endometrial Abnormality
  • uterine cavity pathology
causes of endometrial abnormality16
Causes of Endometrial Abnormality
  • uterine cavity pathology
  • Structural uterine anomalies
slide19
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%
slide21

Classification of congenital uterine anomalies

American Fertility Society. Fertil Steril 1988;49:944–955.

causes of endometrial abnormality22
Causes of Endometrial Abnormality
  • uterine cavity pathology
  • Structural uterine anomalies
  • Endocrine aberrations
endocrine aberrations
Endocrine Aberrations
  • High Oestrogens
  • High BMI
  • High androgens
slide25

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

androgens
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
the prognostic value of free androgen index fai in recurrent miscarriage
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

causes of endometrial abnormality28
Causes of Endometrial Abnormality
  • uterine cavity pathology
  • Structural uterine anomalies
  • Endocrine aberrations
  • Excess of inhibitors of implantation
why does the presence of hydrosalpinges adversely affect ivf pregnancy rate

Why does the presence of hydrosalpinges adversely affect IVF pregnancy rate ?

Hydrosalpingeal fluid impairs endometrial function

hydrosalpinges and leukaemia inhibitory factor lif expression in the endometrium
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

hydrosalpinges and integrin expression v 3 in the endometrium
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

investigation protocol

INVESTIGATIONPROTOCOL

ENDOMETRIAL FACTORS CAUSING RIF

endometrial factors
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
hysteroscopy
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

recommended management of rif
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
slide40

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

life style modification high bmi
Life style modification – high BMI
  • Diet
  • Exercise
  • Pharmacological agents
  • Bariatric surgery

C

endometrial scratch 1
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)
endometrial scratch 2
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)
endometrial scratch 3
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

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