An Overview of Uterine Factors That Influence
Implantation !
Bulent Urman, M.D.!
Dept. of Obstetrics and Gynecology!
Koc University School of Medicine!
Assisted Reproduction Unit, American Hospital, ISTANBUL!
Uterine factors that influence implantation!
• Structural uterine anomalies!
• Polyps and fibroids!
• Hydrosalpinx!
• Adenomyosis!
• Chronic Endometritis!
• The cases of endometrial injury and hysteroscopy!
• Thin endometrium!
Structural uterine anomalies!
• Arcuate uterus!
• Septate uterus!
• Dysmorphic uterus!
• Unicornuate, bicornuate, didelphyic!
The impact of septate and subseptate/arcuate uteri on the success of IVF!
From Tomazevic et al. RBM Online 2010!
Prevalence of uterine anomalies and their impact on early pregnancy in women conceiving after assisted
reproduction treatment !
!
Jayaprakasan et al. Ultrasound Obstet Gynecol 2011!
Structural uterine anomalies!
• No randomized study evaluated the effect of
hysteroscopic correction on PR either spontaneously or with IVF!
Dysmorphic uterus!
Dysmorphic uterus!
• Problems with universal agreement on the diagnosis!
• What is the appropriate treatment?!
• What is the impact of hysteroscopic cavity enlarging procedures on uterine volume, endometrial receptivity and PR?!
Grading the evidence!
Endometrial polyps!
• The mechanism by which EPs may affect fertility in ART is also unclear !
• If an EP is detected during an ART cycle, various
management options have been reported, including: !
• expectant management!
• cancelation of the cycle and embryo cryopreservation polypectomy and transfer in a subsequent cycle!
• polypectomy without cycle cancelation. !
Endometrial polyps!
• The evidence regarding the effectiveness of polypectomy prior to ART treatment remains insufficient and demands further research !
• It is generally accepted that small polyps (<10 mm) are not deterimental to ART outcome!
• Larger polyps should be removed!
FIBROIDS!
Am J Obstet Gynecol 2008
The effect of non-cavity-distorting fibroids on IVF outcome !
From Sunkara et al. Hum Reprod 2010
The effect of non-cavity-distorting fibroids on IVF outcome-first treatment cycles only! !
From Sunkara et al. Hum Reprod 2010
Effect of fibroid removal!
Hydrosalpinx!
Effect of untreated hydrosalpinx!
Camus et al, 1999!
of 14 studies
Effect of removal of hydrosalpinx !
• Odds of pregnancy = 1.75 (1.1-2.9)!
• Odds of ongoing pregnancy = 2.13 (1.2-3.7)!
• Embryo implantation = 1.34 (0.9-2.1)!
• Ectopic pregnancy=0.42 (0.1-2.1)!
• Miscarriage=0.49 (0.2-1.5) !
Cochrane review!
Johnson et al. 2002!
Hydrosalpinx and salpingectomy!
• Laparoscopic surgical treatment should be considered for all women with hydrosalpinx who are scheduled to undergo IVF!
• Tubal occlusion and salpingectomy show similar efficacy. !
• Whenever laparoscopy is not recommended for the presence of pelvic adhesions, Essure® seems to be the most effective option for management of hydrosalpinx before IVF. !
• Transvaginal aspiration and tubal sclerotherapy are available alternatives but their effectiveness is limited by the high
recurrence rate of hydrosalpinx following treatment. !
Adenomyosis!
Universal agreement on diagnosis ??!
• USG!
• Doppler!
• MRI!
Adenomysosis and outcome of IVF- clinical pregnancy rates!
From Vercellini et al. Hum Reprod 2014!
Adenomysosis and outcome of IVF- miscarriage rates!
From Vercellini et al. Hum Reprod 2014!
Asymptomatic adenomyosis and outcome of IVF!
From Benaglia et al. RBM Online 2014 !
Detrimental effect of adenomyosis and potential improvement with GnRHa!
Galliano et al. HRU 2015!
Chronic endometritis!
A representative photomicrograph of CD138+ PC (a, solid arrows) and CD20+
B-cell (b) infiltration in the human endometrium with CE. Note that endometrial epithelial cells physiologically express CD138 mainly on the basal side of the plasma membranes (a, open arrows). !
!
Pathogenesis of CE!
From Kitaya et al. Am J Reprod Immunol 2016!
Diagnosis!
Hysteroscopy" "endometrial biopsy "
"immunohistochemical staining for plasma cells!
• Does it really exist?!
• Is it a distinct clinical entity or an incidental finding?!
• Is there a proven specific treatment for the condition?!
Chronic endometritis-outcome after treatment!
Live birth rate!
From Cicinelli et al. HR 2015!
Chronic endometritis is a significant finding in patients with RIF and should be treated!
Group 1-Patients with chronic endometritis (confirmed by immunohystochemistry) on biopsy!
Group 2-Patients who did not have chronic endometritis!
Group 3-Patients who did not undergo endometrial biopsy !
From Johnston-McAnanny et al. Fertil Steril 2010!
Chronic endometritis has no effect on IVF outcome!!
From Kasius et al. Fertil Steril 2012!
Endometrial injury and/or hysteroscopy!
From Potdar et al. RBM Online 2012!
Endometrial
injury! YES! NO!
Does local injury to the endometrium before IVF cycle really affect treatment outcome? ! Results of a randomized placebo controlled trial !
Baum et al. Gynecol Endocrinol 2012!
!
The effect of endometrial injury on ongoing pregnancy rate in unselected subfertile women undergoing in vitro fertilization: a
randomized controlled trial !
!
From Yeung et al. Human Reproduction 2014!
Hysteroscopy!
• Before the first IVF cycle in all women!
• In women with implantation failure regardless of US findings!
• Only in women with abnormal ultrasound findings!
Fertility enhancing effects of hysteroscopy!
• Dilatation of the cervical canal!
• Facilitation of an otherwise difficult ET!
• Evaluation of the cavity!
• Treatment of lesions if present!
• Fertility enhancement due to instrumentation at hysteroscopy!
Is it cost effective to do hysteroscopy in
every patient undergoing IVF?!
Hysteroscopy improves implantation regardless of
abnormal findings!
Endometrial injury effect!
COST EFFECTIVE!
2000 Euro per additional live birth!
Hysteroscopy improves implantation only if an
intracavitary lesion is corrected!
NOT COST EFFECTIVE!
15800 Euro per additional live birth!
Uterine instrumentation during hysteroscopy could cause a degree of endometrial injury and provoke an
immunological reaction that involves the release of cytokines and growth factors, which in turn may
influence the likelihood of implantation !
From Kasius et al. Hum Reprod 2011!
WE NEED EVIDENCE!
Hunches are usually wrong, hunches of expert authorities in the field are usually wrong as well !
Piet Borst!
!
RBM Online 2013!
Problems associated with hysteroscopic cavity evaluation!
• Inter/intra-observer agreement regarding both normal and abnormal findings!
• The significance of abnormal findings is not clear!
• Whether treatment improves implantation rates is unknown!
Observer agreement in the evaluation of the uterine cavity prior to IVF!
From Kasius et al. Hum Reprod 2011!
Agreement on the diagnosis of septate uterus!
Seventy-eight observers from 24 different countries assessed 8 hysteroscopy recordings. The interobserver agreement on
uterine shape variations septate and arcuate was fair (intraclass correlation coefficient 1⁄4 0.27).
The agreement among
international experts on the
hysteroscopic diagnosis of the septate uterus was found to be poor. !
!From Smit et al. Fertil Steril 2013!
Hysteroscopy in couples
with implantation failure!
Endometrial injury and/or hysteroscopy!
From Potdar et al. RBM Online 2012!
TROPHY Study!
• RCT 700 couples with 2-4 failed cycles randomized to
hysteroscopy or no hysteroscopy in the cycle preceding IVF!
• Live birth rate!
• Hysteroscopy group 31%!
• No hysteroscopy group 29%!
From El Thouky et al. ESHRE 2014!
Endometrial thickness!
Figure 2: Difference in means and 95% confidence intervals
0.4 mm
Figure 3: Odds ratio and 95% confidence intervals
OR=1.4 (1.24-1.58) !
Momeni et al. J Hum Reprod Sci 2011!
Other factors!
• Molecular factors that affect receptivity!
• Receptive vs nonreceptive endometrium-gene expression profiles!
• Deciudual phenotype!
• What happens in extreme cases??!
