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