What is the role of hysteroscopy for the management of women

undergoing IVF?

Ulun ULUG, M.D.

Assoc. Professor of Ob/Gyn

Bahceci IVF Centers

Istanbul, Turkey

Why all the embryos transferred to uterine cavity do not implant ?Human reproduction is NOT efficientThe implantation rates vary between 25 to 50% among the most

established IVF centers 1) The embryo itself does not have enough morphologic or genetic quality2) Endometrial receptivity has reduced capacity for the implantation process3) Both

Our current scope of infertility treatment

Reduced endometrial receptivity

Altered hormonal environment caused by ovarian stimulation for harvesting oocytes

Missmatch of window of implantation during embryo transferDifficult embryo transferMorphologic problems related to uterine cavityUnknown ?

Morphologic problems related to uterine cavity

CongenitalBenign Acquired

Congenital abnormalities of Uterine Cavity

• Bicornuate uterus• Unicornuate uterus• Didelphys uterus• Septate uterus• Arcuate uterus

Benign conditions of uterine cavity

Submucous fibroidsPolyps

Acquired problems related to uterine cavity

EndometritisSynechiaThin endometriumAdenomyosis ?

Assessment of endometrial receptivityHistoryTransvaginal ultrasonographySaline infusion sonographyHSGMRHysteroscopyBiopsy (endometrial receptivity assay)

Up to date, there is no adeqaute test with 100% sensitivity for the measurement of endometrial receptivity

The accuracy of HSG in assessment of the uterine cavity in infertile patients has been reported to be rather disappointing. The sensitivity and specificity are described to be 79%- 98% and 15% - 82% (Gaglione et al, Golan et al)

Hysteroscopy is the gold standard test for assesing uterine cavity (Pundir and El Toukhy)

It is generally performed as a definitive diagnostic tool to evaluate abnormal findings on HSG or saline HS performed during the course of investigation of subfertile women (Ayıda et al)

• Hysteroscopy should not be considered as a routine investigation in the infertile couple (RCOG)

• Hysteroscopy should be reserved for further evaluation and treatment of abnormalities defined by less invasive methods such as HSG and sonohysterography (ASRM)

NOT FIRST LINE DIAGNOSTIC TEST ? ? ?

Prevelance of unsuspected uterine cavity abnormalities diagnosed by hysteroscopy prior to first IVF (Fatemi et al)

%

Polyps 5.8

Fibroid 0.7

Adhesions 2.2

Septum 1.9

Combined 0.3

10 %

Prevelance of unsuspected uterine cavity abnormalities diagnosed by hysteroscopy in patients with failed IVF cycles (Demirol and Gurgan)

%

Polyps 15.7

Adhesions 8.524 %

Uterine shape decision during hysteroscopy by different clinicians (Smit et al)

Hysteroscopy should be done routinely during the work up of infertile coupleYESImaging modalities do not have

high sensitivityAt least 10% of women suffering

infertility has endometrial abnormality

NOImaging modalities have high

specificityInvasive procedureComplicationsNot cost effective

Hysteroscopy should be done routinely for the women undergoing IVF

YESImaging modalities do not have

high sensitivityAt least 10% of women suffering

infertility has endometrial abnormality

May be cost effectiveMay augment endometrial

receptivity

NOImaging modalities have high

specificityInvasive procedureComplications

Cost effectiveness of routine hysteroscopic screening (Decision analytic model) (Kasius et al)

Routine Hysteroscopy before IVF

RoutineHyst

Hystersocopy after failed IVF

Failed Hyst

No hysteroscopy NoHyst

Why Should be Hysteroscopy performed routinely ?

Hysteroscopy is a diagnostic tool for the evaluation of infertilityHysteroscopy is a screening method for diagnosis before IVF

treatmentHysteroscopy is a treatment modality for the correction or

augmentation of endometrial receptivity

Hysteroscopy should be done for the correction or restoration of endometrial receptivity

YESImaging modalities do not have

high sensitivityAt least 10% of women suffering

infertility has endometrial abnormality

May be cost effectiveMay augment endometrial

receptivity

Septate uterusEndometrial polypSynechiaSubmucous FibroidEndometrial injury

?

The effectiveness of hysteroscopy in improving pregnancy rates in subfertile women without other gynaecological symptoms: a systematic review

Scarce evidence on the effectiveness of hysteroscopic surgery in subfertile women with polyps, fibroids, septate uterus or intrauterine adhesions indicates a potential benefit. More randomized controlled trials are needed before widespread use of hysteroscopic surgery in the general subfertile population can be justified

Bosteels et al

Submucous fibroids and reduced implantation

Abnormal uterine contractilityFocal endometritisAndrogen secretionVascular disturbances

Narijan et alIVF following resection

PR

Normal cavity 21%

Resection of Fibroid 48.2%

Shokeir et alSpontaneous following resection

PR

No resection 28.2%

Resection 63.4%

Submucous Fibroids and Hysteroscopy

Endometrial polyp and Infertility

Inflammatory state was found in polyps among infertile patients (Mollo et al)

Vascular changes found in polys were related with endometritis (Carvallho et al)

Reduced COX-2 and VGEF expression (Xiao et al)Localised disturbances in cellular immune environment (El-

Hammameh et al)

Endometrial polyps affect uterine receptivity (Rackow et al)

Endometrial polyps and IVF outcomeRemove or not remove ?• There is no RCT comparing IVF outcome among women endometrial

polyp diagnosed before or during controlled ovarian stimulation (Afifi et al)

• In retrospective series, regardless of size no impact of endometrial polyp was detected among women undergoing IVF (Tiras et al)

• Polyps larger than 15/20 mm could have deleterious effect (Isikoglu et al, Lass et al)

SEPTATE UTERUS

Reproductive outcome is poorSpontaneous abortion 26%-94% Premature labor 9%-33%Fetal survival 10%-75%Spontaneous abortion after metroplasty 5.9%

(Toriano et al., 2004)

Uterine anomalies and pregnancy outcome

• 105 women with uterine anomaly vs 182 women with normal shaped uterus:

• Highest incidence of early spontaneous abortion in septate uterus

• Highest incidence of preterm labor in arcuate and bicornuate uterus

(Zlopasa G. 2007)

tr= trimester, pr= pregnancy(Zlopasa G, 2007)

Pregnancy outcome before and after hysteroscopic treatment of anomaly in 25 women

Outcome Before Treatment

After treatment

1st tr loss 34 (77.3) 18 (34.6) <0.001

2nd tr loss 7 (15.9) 3 (5.8)

Total pr loss 41 (93.2) 21 (40.4) <0.001

Term Deliveries

0 23 (44.2)

Hysteroscopic resection of the septum improves the pregnancy rate of women with unexplained infertility: a prospective controlled trial (Mollo et al)

Spontaneous follow-up

Septate, subseptate and arcuate uterus decrease pregnancy and live birth rates after IVF(Tomazevic et al)Septum and Subseptate Pregancy rates

No hysteroscopy 9.6%

Hysteroscopic resection 43.6%

Arcuate uterus Pregnancy rates

No hysteroscopy 20.9%

Hyteroscopic resection 35.5%

Septum and Subseptate Live birth rates

No hysteroscopy 1.9%

Hysteroscopic resection 38.6%

Septum and Subseptate Live birth rates

No hysteroscopy 3.0%

Hysteroscopic resection 30.4%

The outcome of singleton pregnancies after IVF/ICSI in women before and after hysteroscopic resection of a uterine septum compared to normal controls (Ben-Frangez et al)

106 women who had hysteroscopic septum resection conceived following IVF/ICSI

Compared to controlsIncreased miscarriage rates before resection compared to controls Comparable miscarriage after hysteroscopic resection

Hysteroscopy prior to the first IVF cycle:A systematic review and meta analyisis (Pundir et al)

Does diagnostic or operative hysteroscopy increase the pregnancy rate in patients with history of failed IVF cycles?

The benefit of hysteroscopy could extend beyond correction of uterine pathology

1. Easier embryo transfer, more accurate embryo placement2. Enhanced endometrial receptivity secondary to endometrial

stimulation

Local Endometrial Injury (LEI) to overcome recurrent IVF failure:meta analysis (Potdar et al)

Local Endometrial Injury (LEI)

Endometrial epithelial and stromal changes at the molecular level (Zhou et al)

Altered endometrial cell gene expression (Dekel et al, Kalma et al, Qin et al)

Upregulated

Laminin alpha 4

MMP-1

Mucin-1 transmembrane

Phospholipase A2

Uroplakin 1B

Facilitates endometrium for embryo implantation

Local Endometrial Injury (LEI)

• Increase in local production of pro-inflammatory cytokines and growth factors (Engert et al, Minas et al)

Decidualisation, trophoblast invasion and regulatingendometrial development

Increased Levels of

TNF alpha

Interleukins 6-10-11-15

Epidermal Groth Factor

LIF

Hysteroscopy for women with hydrosalpinx where abdominal approach contraindicatedEssure insertionLegendre et al43 womenPR 40.7%

IR 29.3%

LBR 25.9%

Ozgur et al27 womenPR 47.6%

LBR 23.8%

ConclusionHysteroscopy has a major role among women undergoing IVFIt has both diagnostic and therapeutic utilitiesCorrection of anomalies destorting uterine cavity could have any

benefit on the outcome but needs more relevant dataIntracavitary lesions such as polyp and fibroid not only distorts

endometrium but cause inflammatory and immunologic reactions that may affect embryo implantation

Local endometrial injury can be resulted by hysteroscopeRelevant data indicates that hysteroscopy previous to IVF increase

outcome Pre IVF hsyteroscopy among women who had previous failed cycles

has more addiditive impact on outcome compared to women who had no previous IVF cycie

Conclusion

Dr. Ulun Uluğ

Dr. Selen Sezginsoy

Dr. Emre Bakırcıoğlu

Dr. Çiğdem Çizmeci

Lab:

Oya Yetiş

Habib Aslan

Munevver Serdaroğulları

Sinan Yıldız

Nurse Staff:

Hatice Özkan

Yasemin Köroğlu

Didem Yıldız

Ebru Köse

Hatice Duymaz

Gülseven Alıcı

Cennet Işık