الفهرس 
Introduction and Aim of the work
Aim of the workOnly 14 pages are availabe for public view
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Abstract
Review of literature and Introduction Optimal outcomes in assisted reproductive therapy (ART) require thorough evaluation of the uterine cavity to diagnose lesions that may lead to failed implantation. Adoption of routine office hysteroscopy (OH) before In-Vitro Fertilization (IVF) to diagnose and treat intrauterine cavitary lesions is still debatable both from evidence and cost perspectives.
On the other hand, three-dimensional ultrasound (3D-US) examination of the uterus allows non-invasive simultaneous assessment of the three orthogonal planes which are not obtained by two-dimensional ultrasound (2D-US). Furthermore, 3D volumes can be stored for later offline analysis and this leads to less discomfort of the patient.
Materials and Methods:
This is a prospective cohort clinical hospital-based study. The study was registered (NCT02598921; NCT02597816, www.clinicaltrials.gov). Women attending the infertility outpatient clinic and IVF center of a single university affiliated hospital (Women’s Health Hospital, Assiut University, Egypt) between October 2013 and July 2014 were considered for enrollment.
group І women were considered eligible if they had history of primary infertility, had normal uterine cavity on HSG and were selected for IVF therapy. While group ІІ women were included if they have suspected congenital uterine anomalies on HSG, primary infertility and were selected for IVF. Women with known diagnosis of uterine abnormality by prior office hysteroscopy, or prior 3D-US were excluded from the study.
group І included 120 women, who were examined by 3 diagnostic modalities; 2D-US, 3D-US and OH (as a gold standard test). group ІІ included 38 women with suspected congenital uterine anomalies on basis of HSG diagnosis, they were examined by 3D-US followed by OH or combined hysteroscopy/laparoscopy as a gold standard.
All women were appointed a sonographic examination twice; mid-luteal of the preceding cycle (because thickened endometrium allows for better diagnosis of müllerian anomalies (Chan, Jayaprakasan, Zamora, et al., 2011) and after cessation of the menstrual flow (for better visualization of polyps (Seshadri, Khalil, et al., 2015).
Sonographic examinations (2D and 3D) were performed by the same sonographer using Medison SonoAce X8 (Medison Co., Seoul, Korea) with a 3D/4D volumetric 12mm endo-cavitary, trans-vaginal route, probe (3D4-9ES, 4-9 MHz frequency) using an average frequency of 6.5 MHz. The scan view is 90 degrees. The volumes were analyzed off-line using MPV and MSV of the mid-coronal plane of the uterus. For multi-planar display of the mid-coronal plane, Z technique was utilized as described by Abuhamad et. al.(Abuhamad et al., 2006).
group І women were followed to their IVF to compare IVF outcome, in terms of implantation and clinical pregnancy rates, between subjects with free uterine cavity and subjects with treated intrauterine abnormalities.
Results:
In group І women, OH revealed intrauterine lesions in 34 women (28.3%). More abnormalities were reported among women with prior IVF failure as compared to those scheduled for their first trial (14/40; 35% versus 20/80; 25%, respectively). However, this difference was not statistically significant (P=0.25).
30 of these lesions were diagnosed by 3D-US and 21 by 2D-US. Sensitivity, specificity, PPV, NPV and overall accuracy for 2D-US were 61.8%, 93%, 77.8%, 86% and 84.2% respectively. Most of the lesions (9/13) that were missed by 2D-US were minimal (4 arcuate uteri and 5 polyps with mean ± SD, cm: 1.02 ± 0.28). The overall agreement between 2D-US and Office Hysteroscopy was moderate (κ = 0.58, 95% CI = 0.42-0.75).
While 3D-US had 88.2% sensitivity, 96.5% specificity, 90.9% PPV, 95.4% NPV, and 94.2% overall accuracy. The overall agreement between 3D-US and OH was near-perfect (κ = 0.86, 95% CI = 0.75-0.96).
Both techniques had the same perfect accuracy for sub-mucosal fibroids (100%) and the lowest accuracy for intrauterine adhesions. Furthermore, both modalities were not perfect for detecting small polyp size. Both missed the small polyp size ≤1.1cm. Also, no significant statistical difference was noted between the means of the size of missed polyps by 2D-US and 3D-US (1.02 vs 0.83 cm; p> 0.05).
Irregular menstrual periods (metrorrhagia) (aOR = 24.96, 95% CI=2.71 – 230.04, P =0.005) and history of a prior endometrial procedure (hysteroscopic myomectomy, polypectomy, and metroplasty) (aOR = 9.16, 95% CI=2.13 –39.3, P=0.002) were significant clinical predictors in multivariate analysis to have an intrauterine lesion.
selective hysteroscopic evaluation of women, based on abnormal 2D-US and/or clinical predictors; irregular menstrual periods and prior endometrial procedure, would have a NPV of 92.8 % and would miss only 6 cases ; 4 arcuate uteri and 2 endometrial polyps (0.6 and 0.8 cm in size). This selective strategy would be comparable to global screening of women using OH in terms of diagnostic accuracy (McNemar P=0.61). When cost modeling analysis was conducted to compare global OH screening to selective OH evaluation based on the presence of abnormal 2D-US findings and/or clinical predictors, the cost of global screening was $7598.8/detected case, and the cost of selective screening would be $2845/detected case (considering OH cost of $2153 (according to Medicare 2015 National Fee Estimate).
Only Sixty six women were available for follow up. Out of these women, 20 (30.3 %) had lesions that were treated prior to IVF. The overall implantation rate (IR) and CPR were 16% and 36.4% respectively. Both groups (women with treated lesions and women with free cavity) have comparable implantation rate. However, women with treated abnormalities were more likely to have higher clinical pregnancy rate (55% vs 28%, P=0.04) than women with normal cavity, but after adjustment in a regression analysis, they became comparable. The endometrial thickness at day of hCG trigger is the only predictor that was mostly correlated with improved clinical pregnancy rate (Adjusted Odds ratio = 1.70, 95% CI=1.14 – 2.55, P=0.01).
In group ІІ women (n=38), 3 groups of congenital uterine anomalies were diagnosed based on the gold standard test: arcuate uterus (n=12, 31.5%), septate uterus (n=22,58%) and bicornuate uterus(n=4, 10.5%). 3D-US showed perfect diagnostic accuracy (100%) and perfect concordance (κ = 1.00, 95% CI = 1.00-1.00) with in identifying all anomalies in the 3 groups.
The overall agreement between HSG and the gold standard was moderate (κ = 0.44, 95% CI = 0.21-0.67). And, for the individual anomalies; arcuate and septate uterus, similar moderate level of agreement was yielded by HSG (κ = 0.6, 95% CI = 0.36-0.80; κ = 0.54, 95% CI = 0.34-0.73, respectively).
For septate uterus, 8 cases were misdiagnosed by HSG as arcuate uterus (8/22; 36%) while for bicornuate uterus; HSG misdiagnosed all of them as septate.
Based on a scenario economic analysis, screening for subtle uterine septum in women with HSG diagnosis of arcuate uterus prior to IVF was more cost effective than No 3D-US strategy. After 2 IVF cycles, 3D-US screening strategy resulted in cumulative live birth rate (LBR) , costs per one LB and costs per infertile couple of 48%, $45,872 and $22,019, respectively compared to 33%, $73,310 and $24,192 in No 3D-US strategy.
Conclusions:
Three-dimensional ultrasound is superior to two-dimensional ultrasound in the detection of hidden endometrial abnormalities in women with normal HSG. With the exception of uterine septum, this statistical superiority is needed to be interpreted cautiously from clinical practice point of view.
Most of the lesions missed by two-dimensional ultrasound in the IVF work-up are expected to be minimal without evidence to affect implantation.
Prioritizing women with abnormal two-dimensional ultrasound, irregular menstrual periods and/or prior endometrial surgery for office hysteroscopy evaluation, could yield a satisfactory cost-effective pre-IVF protocol to clinicians adopting the use of office hysteroscopy in their practice.
In infertile women with congenital anomalies, three-dimensional ultrasound averts the need to endoscopy to differentiate between common uterine anomalies and offers the preoperative confirmation of the anomaly that should be surgically corrected.