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Abstract

Approximately 15% of couples are affected with subfertility, of which up to 20% remain unexplained. Uterine cavity abnormalities can be a contributing cause of subfertility and recurrent implantation failure. Uterine cavity assessment has been suggested as a routine investigation in the evaluation of subfertile women. Traditionally, hysterosalpingography has been the most commonly used technique in the evaluation of infertility. Transvaginal ultrasound scan allows visualization of the endometrial lining and cavity, and has been used as a screening test for the assessment of uterine cavity. Abnormal uterine findings on a baseline scan can be further evaluated with saline hysterosonography, which is highly sensitive and specific in identifying intrauterine abnormalities. Hysteroscopy is considered as the definitive diagnostic tool to evaluate any abnormality suspected on hysterosalpingography, transvaginal ultrasound scan or saline hysterosonography during routine investigation of infertile patients. Minimally invasive hysteroscopes have minimized the pain experienced by patients during the procedure and made it feasible to use hysteroscopy as a routine outpatient examination. Following recurrent IVF failure there is some evidence of benefit from hysteroscopy in increasing the chance of pregnancy in the subsequent IVF cycle, both in those with abnormal and normal hysteroscopic findings. Various possible mechanisms have been proposed for this beneficial effect, but more randomized controlled trials are needed before its routine use in the general subfertile population can be recommended.

Keywords

hysteroscopy infertility IVF outpatient hysteroscopy recurrent implantation failure hysterosalpingography saline hysterosonography subfertility transvaginal ultrasound scan

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Release date: November 30, 2010; Expiration date: November 30, 2011

Learning objectives

Upon completion of this activity, participants should be able to:

Examine the role of hysterosalpingography, transvaginal ultrasound, and saline hysterosonography in assessing the uterine cavity in women with subfertility

Identify the advantages of hysteroscopy in the diagnosis and management of subfertility

Approximately 15% of couples are affected with subfertility, which is defined as the inability to conceive after 12 months of regular unprotected sexual intercourse. Female factors are identified in approximately 50% of couples and up to 20% of cases of subfertility remain unexplained.

The main investigations in women are mainly focused on the assessment of ovulation, which includes basal hormonal profile and mid-luteal progesterone level, and tests to check tubal patency. However, structural abnormalities of the uterus may affect reproductive outcome by interfering with implantation and causing spontaneous miscarriage. Uterine cavity abnormalities can be a contributing cause of subfertility in 10% of women, and abnormal uterine findings are reported in as many as 50% of women with recurrent implantation failure [1]. In view of the possibility that uterine abnormalities can contribute to subfertility and recurrent implantation failure, uterine cavity assessment has been suggested as a routine investigation in the evaluation of subfertile women.

Methods of assessment of uterine cavity

Hysterosalpingography

Traditionally hysterosalpingography (HSG) has been the most commonly used technique in the evaluation of infertility. It gives reliable information about the patency and morphology of the fallopian tubes. It is also helpful in evaluating uterine cavity abnormalities [2 –4]. HSG is an indirect means of showing the interior of the uterus and tubes. Endometrial polyps or fibroids are shown as filling defects or uterine wall irregularities. HSG can also show intrauterine adhesions and congenital anomalies as it enables clinicians to visualize the general configuration of the cavity.

When compared with hysteroscopy HSG is considered to have a high sensitivity (60–98%), but a low specificity (15–80%) in detecting uterine abnormalities and is, therefore, associated with relatively high false-positive and false-negative rates [1 –4]. One of the studies comparing HSG with hysteroscopy reported a sensitivity of 81% and a specificity of 80% with a false-negative rate of 9% and a false-positive rate of 22% [2]. Another study conducted to assess the diagnostic reliability of hysteroscopy and HSG, demonstrated HSG to have a sensitivity of 79% and a specificity of 82%, with an 18% false-positive rate and a 19% false-negative rate. They concluded that even though HSG is mainly used for the assessment of tubal patency, it has a secondary role in the assessment of the uterine cavity [3].

The differential diagnosis of intrauterine filling defects includes polyps, endometrial hyperplasia, submucosal fibroids, intrauterine adhesions and uterine septa. These findings necessitate secondary investigation in the form of hysteroscopy to confirm and possibly treat the pathology. HSG results may also be influenced if the procedures are performed at different phases of the menstrual cycle due to the variable trophic changes of the endometrium. False-positive findings can be caused by air bubbles, mucus and menstrual debris that could mimic filling defects. False-negative findings can result from an excessive amount of contrast media in the uterus obliterating shadows caused by small endometrial lesions [2]. As a result, approximately 10–35% of women undergoing fertility investigations, who have a normal cavity at HSG, have been reported to have abnormal hysteroscopic findings [3,4]. In addition, HSG does not provide information about trophic, inflammatory and infectious lesions that may be responsible for poor reproductive outcome in nearly 25% of subfertile women [2]. In view of the low-positive predictive value and low specificity of the HSG, Golan et al. suggested HSG should be replaced by the diagnostic hysteroscopy as a first-line infertility investigation [4].

Transvaginal ultrasound scan

Transvaginal ultrasound scan (TVS) allows visualization of the endometrial lining and cavity, and has been used as a screening test for the assessment of uterine cavity. TVS is an integral part of IVF treatment and is a procedure with which women have become familiar; furthermore it is very well tolerated. Baseline periovulatory TVS has been reported to have positive predictive values as high as 85–95% [5,6]. It also allows examination of the ovaries to diagnose any ovarian cyst or polycystic ovaries, adding valuable information required prior to IVF. In comparison with hysteroscopy, TVS was reported to have 84.5% sensitivity, 98.7% specificity, 98% positive predictive value and 89.2% negative predictive value [7]. However, TVS may not diagnose submucosal fibroids in the presence of multiple fibroids, distinguish between a hyperplasic endometrium and a large polyp, or differentiate between an arcuate and a septate uterus. Abnormal uterine findings on a baseline scan can be further evaluated with saline hysterosonography (SHG).

Saline hysterosonography

The use of TVS in conjunction with saline infusion improves the delineation of the uterine cavity and, therefore, is an alternative to HSG and hysteroscopy as a screening test. This is also known as saline infusion sonography. Randolph et al. were the first to perform transabdominal ultrasound scan during saline infusion into the uterine cavity [8]. SHG has been found to be highly sensitive, specific and accurate in identifying intrauterine abnormalities such as polyps, submucosal fibroids, adhesions, septa and uterine anomalies [7,9 –11]. A recent prospective study compared the incidence of uterine cavity abnormalities in patients referred for either infertility or abnormal uterine bleeding by SHG showed that significantly more patients in the abnormal bleeding group had intracavitary abnormalities such as polyps, submucous fibroids and adhesions whereas significantly more uterine anomalies were found in the infertility group [12]. One of the studies comparing SHG with hysteroscopy reported 87.5% sensitivity, 100% specificity, 100% positive predictive value and 91.6% negative predictive value for the detection of any cavity abnormality with SHG as compared with hysteroscopy [7].

According to the American College of Obstetricians and Gynaecologists guidelines, SHG should be performed on day 5–10 of the menstrual cycle [13]. The diagnosis of specific disorders of the intrauterine cavity is directly dependent on the phase of the menstrual cycle when the ultrasonographic examination is performed; for example, while endometrial polyps are best seen during the proliferative phase, submucosal fibroids, uterine anomalies and adhesions are best observed during the secretory phase. Intracavitary saline infusion during SHG makes it possible to examine the uterine cavity at any stage of the menstrual cycle.

Furthermore, SHG can be easily performed in the office setting and is well tolerated. It gives valuable information on the ovaries and can detect adnexal pathology, such as hydrosalpinges, ovarian cysts and polycystic ovarian morphology. Abnormal findings detected by SHG can then be confirmed and treated with therapeutic hysteroscopy prior to IVF.

Other imaging modalities

3D ultrasound scan

Patients with uterine malformations seem to have an impaired pregnancy outcome even as early as their first pregnancy. Hysteroscopic treatment may restore an almost normal prognosis for the outcome of their pregnancies with term delivery rates of approximately 75% and live birth rates of approximately 85% [14]. The advent of transvaginal 3D ultrasonography has enabled the accurate, noninvasive, outpatient diagnosis of congenital uterine anomalies. It has enabled large-scale screening and morphological analysis of congenital uterine anomalies [15,16]. A prospective study comparing 3D hysterosonography with diagnostic hysteroscopy for the evaluation of intrauterine lesions in women with suspected intrauterine abnormality on TVS or HSG reported that 3D hysterosonography reached a sensitivity of 91.9% and specificity of 98.8%, with a positive predictive value of 97.1% and a negative predictive value of 96.5%, compared with hysteroscopy [17], thus confirming its diagnostic accuracy.

MRI

MRI is especially accurate in the diagnosis of congenital uterine anomalies, it is noninvasive and avoids the risk of irradiation, but its main disadvantages include high cost and limited availability. Thus its role in the evaluation of uterine cavity prior to IVF remains minor [18].

Hysteroscopy

Hysteroscopy before IVF

Hysteroscopy is the gold standard for the investigation of uterine cavity, particularly when a pathology is suspected. It is a safe test for the direct and accurate diagnosis of intrauterine abnormalities. It permits direct visualization of the uterine cavity, revealing the nature, location, shape, size and vascular pattern of any uterine cavity abnormalities, such as polyps, submucosal fibroids, differences in endometrial thickness and adhesions. It also allows a directed biopsy and therapeutic intervention for the treatment of any pathology. Thus hysteroscopy is performed as a definitive diagnostic tool to evaluate any abnormality suspected on HSG, TVS or SHG in routine investigation of infertile patients [6,7,19].

The main disadvantage of traditional hysteroscopy is the need for anesthesia, its relative invasiveness and the associated cost. However, the progressive reduction in the diameter of new hysteroscopes over the last few years has minimized the pain experienced by patients during the procedure and made the use of mini hysteroscope (outpatient hysteroscope) feasible as a routine outpatient examination. Placido et al. conducted a study of 950 patients attending for infertility treatment and compared traditional hysteroscopy (rigid hysteroscope 2.9 mm) with flexible or mini hysteroscopy (1.6 mm) for uterine cavity assessment and the associated pain scores [18]. Both of these instruments allowed operative intervention in case of any abnormal finding. Clear visualization of the uterine cavity, findings of uterine abnormality and operating times were similar in both groups, whereas the mean pain scores as a Visual Analog Scale were significantly lower in the flexible hysteroscopy group.

There is an ongoing debate regarding the value of routine hysteroscopy prior to IVF and currently there is no conclusive evidence of its benefit. The NICE guidelines suggest that women should not be offered hysteroscopy on its own as part of the initial investigation for infertility unless clinically indicated [20], whereas the European Society of Human Reproduction and Embryology guidelines for infertility investigations suggest hysteroscopy could be useful for confirmation and treatment of suspected uterine pathology [101].

Recently, Bosteels and colleagues conducted a systemic review to look at the available evidence on the effectiveness of hysteroscopy in improving pregnancy rates in subfertile women without other gynecological symptoms [21]. The authors found that hysteroscopic removal of endometrial polyps with a mean diameter of 16 mm detected by ultrasound doubles the pregnancy rate when compared with diagnostic hysteroscopy and polyp biopsy in patients undergoing intrauterine insemination within 3 months of the surgical intervention. The authors also highlighted that randomized controlled studies on hysteroscopic treatment of intrauterine adhesions are lacking. Hysteroscopy in the cycle preceding a subsequent IVF attempt nearly doubles the pregnancy rate in patients with at least two failed IVF attempts compared with starting IVF immediately. The authors concluded that more randomized controlled trials are needed before routine use of hysteroscopic surgery in the general subfertile population can be recommended.

Hysteroscopy following recurrent IVF failure

The success of IVF treatment is low [22]. Failure of IVF treatment is generally due to embryonic, uterine or transfer factors, but remains un explained in most cases [23]. A number of interventions have been proposed to improve IVF outcome, many of which may not be evidence-based and their efficacy is uncertain [24 –26]. One of the common investigations proposed following IVF failure is to re-evaluate the uterine cavity.

There have been several studies that evaluated the benefit of hysteroscopy in women who had two or more failed IVF cycles. In an attempt to examine the impact of hysteroscopy following failed IVF on the outcome of the subsequent IVF cycle, a systematic review of the existing evidence was conducted by El-Toukhy and colleagues in 2008 [27]. In total, 1691 participants were included in five studies: 841 participants in the hysteroscopy group and 850 in the control group. Meta-analyses of the results of these studies demonstrated evidence of benefit from hysteroscopy in increasing the chance of pregnancy in the subsequent IVF cycle (pooled relative risk: 1.75, 95% CI: 1.51–2.03; p < 0.00001). The number needed to treat (NNT) to achieve an additional pregnancy was six (95% CI: 5–8). Furthermore, the hysteroscopy group was sub divided according to the hysteroscopy findings and the pregnancy rate for those who had a normal uterine cavity were pooled to examine whether diagnostic hysteroscopy alone influences the outcome of the subsequent IVF attempt compared with the control group. The results demonstrated a significant improvement in the outcome of the normal hysteroscopy subgroup (relative risk: 1.63, 95% CI: 1.35–1.98; p < 0.001) [27].

A more recent prospective matched case–control study was conducted by Makrakis and colleagues to evaluate hysteroscopic findings and estimate the effect of hysteroscopy on achieving a pregnancy in women with a history of two implantation failures following IVF [28]. A total of 1475 with 414 matched pairs of women with a similar history who either had or did not have a hysteroscopy were compared. In all, 37% of the study population had abnormal hysteroscopic findings and 22% had unsuspected findings. Subsequent IVF treatment demonstrated significantly increased clinical and ongoing pregnancy rates in women who had a hysteroscopy compared with those who had no hysteroscopy (clinical pregnancy rate: 35 vs 25%, 95% CI: 0.46–0.84; ongoing pregnancy rate: 29 vs 22%, 95% CI: 0.50–0.94).

This positive impact on IVF outcome could be attributed to the ability of hysteroscopy to reliably detect and potentially treat intrauterine pathologies encountered during the procedure, such as intrauterine adhesions, endometrial polyps, submucous fibroids, endometritis or uterine malformations that could interfere with implantation [21,29]. Correction of most of these abnormalities and restoration of a normal uterine cavity is possible during outpatient hysteroscopy with reported good outcome, similar to that achieved in patients with a normal hysteroscopy [30 –32].

In addition, introduction of the hysteroscope through the cervical canal into the uterine cavity could facilitate future embryo transfers [27]. Hysteroscopy also allows inspection of the uterine cavity for the presence of subtle shape malformations, such as arcuate or subarcuate uterine configuration and measurement of uterine cavity length [27]. Knowledge of the details of the uterine cavity shape and length could make it easier to deposit the embryo at an optimum depth within the cavity [33,34]. Finally, 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 [35], which in turn may influence the likelihood of implantation [36 –39].

Conclusion & future perspective

Transvaginal ultrasound scan, HSG and SHG can all be used as screening tests for the uterine cavity assessment before IVF, especially following failed IVF. When abnormality in the uterine cavity is suspected, hysteroscopy is the preferred diagnostic and therapeutic modality and, therefore, is considered the gold standard test in the assessment of uterine cavity. Robust clinical trials are needed before we can routinely use hysteroscopy prior to IVF, but there is emerging evidence to support the role of hysteroscopy in women who have had two or more failed IVF cycles. The results of an ongoing large multicentric randomized controlled trial to assess the benefit of hysteroscopy on success of IVF treatment will provide important evidence-based data on this important step in patient care [40].

With improved technology and instrumentation, we predict that mini hysteroscopy and 3D SHG will become routine outpatient investigations for infertility patients in the next 5–10 years.

Executive summary

Approximately 15% of couples are affected with subfertility and up to 20% of subfertility cases remain unexplained.

Uterine cavity abnormalities can be a contributing cause of subfertility and recurrent implantation failure.

Hysterosalpingography

Hysterosalpingography gives reliable information about the patency and morphology of the fallopian tubes and is also helpful in evaluating uterine cavity abnormalities.

Hysterosalpingography is associated with relatively high false-positive and false-negative rates and a low positive predictive value.

Transvaginal ultrasound scan

Transvaginal ultrasound scan allows visualization of the endometrial lining and cavity, and has been reported to have a positive predictive value and is very well tolerated.

Abnormal uterine findings on a baseline scan can be further evaluated with saline hysterosonography (SHG).

Saline hysterosonography

SHG is less invasive and less expensive than hysteroscopy, with the additional advantage of evaluation of the uterine cavity.

SHG has been found to be highly sensitive, specific and accurate in identifying intrauterine abnormalities.

Hysteroscopy

Miniature outpatient hysteroscopes have minimized the pain experienced by the patients during the procedure, making it feasible to use it as a routine outpatient examination.

When hysteroscopy is performed following two or more failed IVF cycles, there is some evidence for an increase in the chance of pregnancy in the subsequent IVF cycle in patients with abnormal as well as normal hysteroscopic findings. Various possible mechanisms have been suggested for this beneficial effect.

There is a large multicentric randomized controlled trial underway to assess the benefit of hysteroscopy on the success rate of subsequent IVF treatment.

Footnotes

CME Author

Desiree Lie, MD, MSEd, Clinical Professor; Director of Research & Faculty Development, Department of Family Medicine, University of California, Irvine at Orange

Disclosure: Désirée Lie, MD, MSEd, has disclosed the following relevant financial relationship:

Served as a nonproduct speaker for: ‘Topics in Health’ for Merck Speaker Services

Authors and Disclosures

Jyotsna Pundir, ACU, Guy's & St Thomas’ NHS Trust, London, UK.

Disclosure: Jyotsna Pundir has disclosed no relevant financial relationships.

Tarek El Toukhy, ACU, Guy's & St Thomas’ NHS Trust, London, UK.

Disclosure: Tarek El Toukhy has disclosed no relevant financial relationships.

Editor

Elisa Manzotti, Editorial Director, Future Science Group, London, UK.

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

Uterine cavity assessment prior to IVF

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Uterine Cavity Assessment Prior to IVF

Abstract

Keywords

Methods of assessment of uterine cavity

Hysterosalpingography

Transvaginal ultrasound scan

Saline hysterosonography

Other imaging modalities

3D ultrasound scan

MRI

Hysteroscopy

Hysteroscopy before IVF

Hysteroscopy following recurrent IVF failure

Conclusion & future perspective

Footnotes

Uterine cavity assessment prior to IVF

References