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 of 14 studies Camus et al, 1999
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 IVFclinical pregnancy rates From Vercellini et al. Hum Reprod 2014
Adenomysosis and outcome of IVFmiscarriage 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 Endometrial injury YES NO From Potdar et al. RBM Online 2012
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 Hysteroscopy improves implantation only if an intracavitary lesion is corrected 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 COST EFFECTIVE 2000 Euro per additional live birth NOT COST EFFECTIVE 15800 Euro per additional live birth From Kasius et al. Hum Reprod 2011
Hunches are usually wrong, hunches of expert authorities in the field are usually wrong as well Piet Borst WE NEED EVIDENCE
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 From Smit et al. Fertil Steril 2013 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.
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??