Surgical management of Recurrent Implantation Failure

Prof TC Li Chinese University of Hong Kong

Outline

What is recurrent implantation failure? Where is the problem? Surgical management – evidence based approach

IVF failure

Implantation failure

Are they the same?

IVF Failure Cycle cancellation Poor ovarian response Fertilisation failure Implantation failure Miscarriage after ultrasound confirmation of pregnancy

IVF Failure Cycle cancellation Poor ovarian response Fertilisation failure Implantation failure Miscarriage after ultrasound confirmation of pregnancy

Implantation failure is a of IVF failure

Failure to achieve a clinical pregnancy following the transfer of at least four good quality embryos in 3 or more ET cycles in

women aged <40 years

Outline

What is recurrent implantation failure? Where is the problem? Surgical management – evidence based approach

clinician Embryologist

Where is the problem? Clinic perspective

us? Clinic?

Where is the problem? patient’s perspective

uterus Embryo

Where is the problem? Scientific perspective

Problem IVF

Tubal Highly effective

sperm Highly effective

oocyte Effective

Uterus Hopeless

Where is the problem?

There is a good chance that the problem lies in the uterus

Outline

What is recurrent implantation failure? Where is the problem? Surgical management – evidence based approach

Levels of evidence Level 1+ : high quality meta-analyses of RCTs or RCT with a low risk of bias Level 1- : meta-analyses or RCTs or RCT with a high risk of bias Level 2 : systematic review of case-control or cohort studies or well conducted case-control or cohort studies Level 3: case reports or case series Level 4: expert opinion

Uterine factors Level of evidence

Treatment

I Hysteroscopy

I Removal of Submucous fibroid

I Removal of Hydrosalpinx II Removal of Polyp II Endometrial scratch

II Removal of Septum IV Removal of Intramural fibroid

IV Removal of IU adhesions

Bosteels, J. et al. Hum Reprod Update 2010 16:1-11

Outcome: Clinical pregnancy

RR = 1.7 (95% CI:1.5-2.0)

Hysteroscopy

Trophy Study

TROPHY Study

Multicenter RCT 8 hospitals in Europe Women with 2-4 unsuccessful IVF cycles who had normal USS of uterine cavity Hysteroscopy group (n=350) and control group (n=352); hysteroscopy in the month preceding IVF

Conclusion

Hysteroscopy before IVF in women with a normal USS of the uterine cavity and a history of unsuccessful IVF treatment does not improve the livebirth rate

Insight study

inSIGHT Study

Multicenter RCT 22 hospitals in Netherlands Women with a normal TVS of the uterine cavity and no previous hysterocopy Undergoing first IVF Hysteroscopy group (n=373) or immediate IVF group (n=377)

Results

Conclusion

Routine hysteroscopy does not improve livebirth rates in infertile women with a normal TV scan of the uterine cavity scheduled for a first IVF treatment. Women with a normal TV scan should not be offered routine hysteroscopy

Bosteels, J. et al. Hum Reprod Update 2010 16:1-11

Outcome: Clinical pregnancy

RR = 1.7 (95% CI:1.5-2.0)

Hysteroscopy

26

“3D USS combined with SIS is especially

accurate”

3D ultrasound of abnormal uteri

27

Implications on practice Routine Hysteroscopy no longer a necessity for women with RIF, provided careful ultrasound assessment of the uterus and its cavity has been made There is no evidence that treatment of subtle endometrial pathology improves outcome The role of 3D saline infusion sonography (SIS), a more refined method of assessing uterus and its cavity, is currently being examined in a prospective RCT in Guy’s Hospital

Uterine factors Level of evidence

Treatment

I Hysteroscopy

I Removal of Submucous fibroid

I Removal of Hydrosalpinx II Removal of Polyp II Endometrial scratch

II Removal of Septum IV Removal of Intramural fibroid

IV Removal of IU adhesions

Submucous fibroid lowers implantation, pregnancy and live birth rate

Level 1+ evidence

Submucous fibroid

Removal of submucous fibroid improves outcome

Level 1- evidence

Uterine factors Level of evidence

Treatment

I Hysteroscopy

I Removal of Submucous fibroid

I Removal of Hydrosalpinx II Removal of Polyp II Endometrial scratch

II Removal of Septum IV Removal of Intramural fibroid

IV Removal of IU adhesions

Hydrosalpinges

In women with repeated implantation failure, it is prudent to exclude and remove hydrosalpinges

Hydrosalpinges and IVF

The live birth rate of patients with hydrosalpinges undergoing IVF is only one-half that of women who do not have hydrosalpinges

Level 1+ evidence

Strandell et al 1999 Human Reprod 14:2762

Hydrosalpinx and IVF outcome : a prospective randomized multicentre trial in Scandinavia on salpingectomy prior to IVF

Strandell et al 1999 Human Reprod 14:2762

Group Patient PR miscarriage Live birth

Salpingectomy 112 36.6% 16.2% 28.6% No salpingectomy

92 23.9% 26.3% 16.3%

PR, p=0.067 LB, p=0.045

Level 1+ evidence

Salpingectomy prior to IVF in women with hydrosalpinges improves pregnancy, implantation and live birth rates

Good prognosis - salpingostomy

Poor prognosis – salpingectomy

Salpingectomy or Salpingostomy?

SALPINGOSTOMY: GOOD PROGNOSTIC

FEATURES

small hydrosalpinx no/minimal peri-tubal adhesions normal mucosa normal/thin wall partial occlusion

Uterine factors Level of evidence

Treatment

I Hysteroscopy

I Removal of Submucous fibroid

I Removal of Hydrosalpinx II Removal of Polyp II Endometrial scratch

II Removal of Septum IV Removal of Intramural fibroid

IV Removal of IU adhesions

Bosteels, J. et al. Hum Reprod Update 2010 16:1-11

Endometrial polyps

Hysteroscopic polypectomy

doubles CPR in women undergoing

IUI

Level 2 evidence

Uterine factors Level of evidence

Treatment

I Hysteroscopy

I Removal of Submucous fibroid

I Removal of Hydrosalpinx II Removal of Polyp II Endometrial scratch

II Removal of Septum IV Removal of Intramural fibroid

IV Removal of IU adhesions

Endometrial scratch in unexplained RIF

“Moderate-quality evidence indicates that endometrial injury …is associated with an

improvement in live birth and clinical pregnancy rates in women with more than 2 previous ET”

2015

Uterine factors Level of evidence

Treatment

I Hysteroscopy

I Removal of Submucous fibroid

I Removal of Hydrosalpinx II Removal of Polyp II Endometrial scratch

II Removal of Septum IV Removal of Intramural fibroid

IV Removal of IU adhesions

The Outcome of singleton pregnancies after IVF/ICSI in women before and after hysteroscopic resection of

a uterine septum compared to normal controls Ban-Frangez et al, Euro J Obstet Gynae & Reprod Biol 2009

Retrospective Control Study

Miscarriage rate

Miscarriage rate in matched controls

P value

Large septum, not removed

83.3% 16.7% <0.001

Small septum, not removed

78.9% 23.7% <0.001

Large septum removed 30.6% 20.4% NS Small septum removed 28.1% 19.3% NS

Level II evidence

Uterine septum

Uterine factors Level of evidence

Treatment

I Hysteroscopy

I Removal of Submucous fibroid

I Removal of Hydrosalpinx II Removal of Polyp II Endometrial scratch

II Removal of Septum IV Removal of Intramural fibroid

IV Removal of IU adhesions

Intra-mural fibroid Not apparently distorting the cavity

Intramural fibroid reduces implantation rate

Effect of large intramural fibroids (>5 cm) Hart R et al Hum Reprod 2001 16: 2411

IVF Outcome Implantation rate reduced from 20.2 to 11.9 % (p=0.018)

Pregnancy rate reduced from 34.1 % to 23.3 % (p=0.016)

Ongoing PR reduced from 28.3 to 15.1 % (p=0.003)

Large intramural myoma negatively affects outcome after IVF

There is insufficient evidence that removal of intra-mural fibroids improves

implantation rate

Metwally M, Farquhar C, Li TC (2011) Is another meta-analysis on the effects of intramural

fibroids on reproductive outcome needed? RBM Online 23: 2-14

In women with recurrent implantation failure,

intra-mural fibroids of >5cm should be removed

Level IV evidence

Uterine factors Level of evidence

Treatment

I Hysteroscopy

I Removal of Submucous fibroid

I Removal of Hydrosalpinx II Removal of Polyp II Endometrial scratch

II Removal of Septum IV Removal of Intramural fibroid

IV Removal of IU adhesions

Intra-uterine adhesion

There is no firm evidence to show treatment of this condition improves outcome, but it seems logical to remove the adhesions covering the endometrium

Level IV evidence

How often is there a uterine cause for RIF?

~20%

The clinical characteristics of women with recurrent implantation failure

Coughlan et al, 2014

~80% no obvious uterine pathology

Level III evidence

Summary Uterine factors cannot usually be overcome by IVF treatment Surgery may be helpful in ~20% of recurrent implantation failure (RIF) New evidence suggests women with RIF and normal ultrasound of uterine cavity do not benefit from routine Hysteroscopy Emerging evidence suggest that 3D SIS is an accurate and useful investigation in RIF

Thank You