Modern Assessment of the Uterine Cavity and Fallopian Tubes in the Era of High-Efficacy ART

Summary

The high efficacy of modern ART and the increase in non-infertile patients who are using ART for family building in the U.S. call into question the relevance of the standard, one-size-fits-all infertility evaluation. Herein we explore whether all patients presenting for ART need uterine cavity and tubal assessment and what tests are most appropriate, efficient, and cost-effective in current times.

Capsule

ART is highly effective and often indicated in non-infertile couples. New, less-invasive diagnostic modalities are available for evaluation of the uterine cavity and fallopian tubes. Given this, it is time to individualize diagnostic evaluation of patients planning ART.

Introduction

Many modalities for assessment of the uterine cavity and fallopian tubes pre-date high efficacy ART and should be re-evaluated in the modern patient. This is particularly true among the growing population of non-infertile women undergoing embryo transfer, e.g., to enable PGT, for isolated male factor, for ‘reciprocal IVF’ among same-sex female partners, or for women serving as gestational carriers.

Ultrasound has emerged as a potentially more efficient and less invasive tool for assessing both the uterine cavity and fallopian tubes. Saline ultrasound has emerged as similarly accurate and less invasive than diagnostic hysteroscopy. Proprietary contrast agents are increasingly used, especially in Europe, and may make for easier sonographic demonstration of tubal patency. However, operator and assessor skill significantly impact the utility of ultrasound for tubal assessment.

Herein we discuss currently available tools for uterine cavity and fallopian tube assessment in the era of high efficacy ART, with particular attention to appropriate evaluation of patients for whom anatomic pathology is not particularly suspected.

Pathology of the uterine cavity and ART

Uterine cavity abnormalities occur in 16.9% of women presenting with infertility, and nearly 40% of women presenting with abnormal uterine bleeding, most commonly in the form polyps (13%), submucous fibroids (2.9%), and adhesions (0.2%) (1).

Endometrial polyps are common (prevalence estimates ranging widely from 6–32% in women undergoing hysteroscopy prior to ART) and may have a negative impact on fertility (2). A small RCT showed higher pregnancy rates after polypectomy vs. diagnostic hysteroscopy with polyp biopsy in 215 infertile patients undergoing up to four cycles of IUI (63.4% vs. 28.2%, relative risk 2.1 95% CI 1.5–2.9) (3). While the benefit of polypectomy prior to embryo transfer remains unproven, endometrial polyps have been suggested to negatively impact endometrial receptivity (4) and polypectomy is generally thought to be safe and to have the potential to improve fertility outcomes (2) (5). One study reported an increased rate of biochemical pregnancies when endometrial polyps were left untreated in patients undergoing IVF (18.3% in the polyp group compared with 9.6% in the non-polyp group (p = .01); odds ratio = 2.12; 95% confidence interval, 1.09–4.12) (6). However, it is important to note that the prevalence of endometrial polyps in patients with normal menses (fertile or non-infertile) is unknown, as is the impact of polyps on live birth rates following embryo transfer and whether polypectomy improves live birth rates from embryo transfer (7) (2).

Other uterine cavity abnormalities have been shown to affect pregnancy rates in patients conceiving without ART. A study by Hooker et al demonstrated a significant increase in median time to conception leading to live birth in patients with intrauterine synechiae vs. women without (15 months vs. 5.0 months (HR 0.54 (5% CI: 0.30–0.97)) (8). Additionally, while there is lack of consensus regarding the management of intramural fibroids in the setting of infertility (9) (10), there is general consensus around the benefit of hysteroscopic resection of cavity distorting fibroids from a fertility perspective. While level I evidence is lacking, this practice likely improves outcomes (11) (12). Less common uterine abnormalities, such as Mullerian anomalies, also have a significant impact on obstetrical outcomes. Specifically, they can lead to recurrent miscarriage, preterm labor, breech presentation, intrauterine growth restriction, and abnormal placentation (13).

Uterine cavity assessment

Consensus is lacking as to the most appropriate first line diagnostic methodology to assess the uterine cavity prior to embryo transfer. This is particularly true for non-infertile patients undergoing ART. The gold standard of uterine cavity evaluation has historically been hysteroscopy; however, other tests, may be similarly accurate, less invasive, and less expensive.

Transvaginal ultrasound

Transvaginal ultrasound (TVUS) provides quick and inexpensive assessment of uterine anatomy. For the diagnosis of polyps specifically, TVUS has a wide range of reported diagnostic accuracy. TVUS is reported to have a sensitivity from 19–100%, specificity of 53–100%, positive predictive value (PPV) of 70–100%, and negative predictive value (NPV) of 87–97% (14). Adding color-flow doppler increased both sensitivity and specificity of TVUS for diagnosis of endometrial polyps (15) (16). For diagnosing uterine malformations, reported sensitivity of plain vaginal ultrasound was 44%. A very wide range of sensitivity (0–97%) has been reported for diagnosis of intrauterine adhesions using plain TVUS (17), suggesting that operator/assessor expertise and ultrasound resolution impact the ability of TVUS to detect adhesions without instillation of contrast.

The diagnostic accuracy of TVUS for uterine cavity defects also varies with menstrual cycle timing. One study reported low (28.2%) sensitivity during days 1–4 of the cycle, with improved detection during days 16–19. No lesion <1cm was detected by TVUS during the follicular phase (days 1–12) (18). TVUS provides excellent assessment of the myometrium and adnexal structures, including antral follicle count, making it indispensable to the pre-ART evaluation. Nevertheless, its sensitivity for uterine cavity assessment is suboptimal (1).

Sonohysterography or Saline Infusion Sonography

Sonohysterography (SHG), also known as Saline Infusion Sonography (SIS), involves instillation of saline into the uterine cavity during TVUS. First introduced in the late 1990s, this test outperforms TVUS and hystersalpingography (HSG) in its ability to diagnose uterine cavity defects (19) (20) (21), with high (>90%) PPV and NPV (1) (17) (22). The distension of the cavity with saline allows better visualization of the endometrial canal (21). SIS improved detection of intrauterine pathology from 67% to 87% relative to TVUS (23). For diagnosis of endometrial polyps, a recent meta-analysis concluded improved diagnostic accuracy of SIS over TVUS without saline infusion (24). A Cochrane meta-analysis did not find a significant difference in accuracy between 2D- and 3D-SIS in detecting endometrial polyps and myomas. Both methods approach the accuracy of diagnostic hysteroscopy in subfertile women (25).

That said 3D-SIS technology provides diagnostic advantages, even over hysteroscopy. 3D-SIS allows visualization of the whole uterus in three orthogonal planes, including the coronal view (Figure 1). The method is accurate and expedient in determining the appropriate surgical approach to myomas with submucosal components (Figure 2). Further, in experienced hands, it may be used for mapping and classification of severity of adhesions (26) (Figure 1B). 3D-SIS provides an accurate, reliable, and non-invasive tool for the classification of common congenital uterine malformations. Visualization of the external uterine contour constitutes a significant advantage of SIS over both diagnostic hysteroscopy and HSG, as it allows differentiation between bicornuate and septate pathology (Figure 1C). SIS also provides optimal ability to discern between normal, arcuate, and septate configurations -- diagnoses that are frequently debated by clinicians (27). The newest application of 3D-SIS is the calculation of uterine cavity volume using dedicated software (28). Further research is needed to determine the potential benefit of this parameter.

Figure 1: Three-dimensional saline infusion sonohysterography (3D-SIS) coronal view of uteri.

3D-SIS allows accurate assessment of the whole uterus and uterine cavity, allowing more comprehensive assessment than traditional methods like hysteroscopy and HSG, which are limited only to uterine cavity.

• Render modes: LEFT COLUMN: greyscale and Volume Contrast Imaging, CENTER COLUMN: HDlive, a.k.a. virtual hysteroscopy; RIGHT COLUMN: Automatic Volume Calculation software (SonoAVC)
• Cases: TOP ROW (A): Normal uterus with normal uterine cavity shape and volume; MIDDLE ROW (B): Intrauterine synechiae and small uterine cavity volume due to presence of adhesions; BOTTOM ROW (C): Septate uterus with endometrial polyp in left part of uterine cavity.

Figure 2: Three-dimensional saline infusion sonohysterography (3D-SIS) in assessment of submucosal myoma.

This method can determine suitability of submucosal myomas to hysteroscopic resection because it allows assessment of myoma penetration into myometrium, distance between myoma and uterine surface, and myoma size.

Hysteroscopy

Hysteroscopy has long been considered the gold standard and definitive method for diagnosis and treatment of intrauterine pathology (1) (29). This procedure provides direct visualization and the immediate treatment of abnormalities to restore normal anatomy, as well as the ability to obtain tissue samples for diagnosis. This test can be performed in the operating room with general anesthesia or sedation, or in the office with or without local anesthetic or sedation (30). Yet, there is important evidence indicating low inter-rater reliability of diagnostic hysteroscopy, which calls into question the method’s status as the gold standard (31, 32). Furthermore, diagnostic hysteroscopy is limited in its ability to discern among normal, arcuate, and the septate pathology (27, 33). While hysteroscopy has the benefit of incorporating diagnosis with immediate treatment (30), it may be more costly and invasive and may cause more pain and discomfort than SIS or HSG (1).

One study randomized subjects without a prior ‘uterine factor’ diagnosis, and without suspicion for intracavitary pathology based on TVUS and HSG, to hysteroscopy vs. no hysteroscopy prior to IVF/ICSI. The authors found that 43% of patients in the hysteroscopy group had abnormal uterine pathology, which was resected in real time. The clinical pregnancy rate was significantly higher in the hysteroscopy group (odds ratio, OR 2.77; 95% CI, 1.53–5.00) (34). However, this RCT was not prospectively registered and evaluated a small sample for each individual class of pathology. Another study compared patient preference between SIS and hysteroscopy. Patients reported a lower pain score with SIS; however, hysteroscopy was still preferred (35). Immediate treatment allows patients to avoid multiple steps, which can avoid delay in fertility treatment. A recent RCT compared SIS to office hysteroscopy in 100 patients planning embryo transfer and found that office hysteroscopy had similar (short) procedure times and patient satisfaction but fewer delays in initiation of fertility treatment and fewer secondary procedures were required (36).

On the other hand, discomfort, cost, and diagnostic limitations must be weighed heavily in considering generalization of diagnostic hysteroscopy in the evaluation of infertility and in patients planning embryo transfer. Physicians in Europe have launched the “Campaign Against Painful Hysteroscopy” and in 2020 sent an open letter to the Department of Health and Social Care in the United Kingdom (37). The largest and best quality RCTs, showed no improvement in IVF live birth rate following diagnostic hysteroscopy with treatment of detected abnormalities in patients with a normal TVUS of the uterine cavity either prior to first IVF (33) or in patients with a history of 2–4 prior embryo transfers without pregnancy (38). Based on these data, routine hysteroscopy in women with normal transvaginal ultrasound should not be offered prior to embryo transfer. Rather, SIS represents a highly accurate, cost-effective, patient friendly diagnostic modality in this setting.

Importance of Fallopian Tube Assessment in Patients Considering ART

While ruling out defects of the uterine cavity remains the keystone of diagnostic evaluation prior to embryo transfer in the era of highly effective ART, determining patency and normal caliber of fallopian tubes also plays an important role. Confirming patency remains vital in determining whether ART is indicated in the first place. 80% of couples desiring pregnancy will conceive within 1 year, and 50% of couples who do not conceive in the first year and are diagnosed with infertility will be pregnant in the second year without ART (39). Moreover, for women less than 40 years old with at least one patent fallopian tube, the cumulative pregnancy rate is over 50% after 6 cycles of intrauterine insemination, and up to 75% if further cycles of intrauterine insemination are undertaken (39).

Assessment of fallopian tube caliber warrants consideration even for patients who have clear indication(s) for IVF and embryo transfer. For such patients, fallopian tube patency is irrelevant. However, the presence of hydrosalpinx(ges) is associated with significantly lower IVF success rates. Since laparoscopic salpingectomy returns IVF success rates to those of patients without hydrosalpinges, diagnosis and treatment are crucial (40–42).

What follows is a discussion of how fallopian tubes should be assessed in the era of high-efficacy ART.

From X-ray hysterosalpingography, and laparoscopy with dye, to modern ultrasound

There are various tubal patency tests, which may be applied during fertility workup, with variable sensitivity and specificity, inter-rater reproducibility, invasiveness, and costs. The most traditional tests are X-ray hysterosalpingography (HSG) and laparoscopy with transcervical dye instillation. In the U.S., HSG is recommended as a first line test in the setting of infertility (1, 40). Laparoscopy with dye allows for direct visualization of fallopian tubes, pelvic cavity, and specific comorbidities including adhesions and endometriosis and is considered a reference for accuracy (39) (43) (44). Due to its invasive nature, laparoscopy is reserved for those women needing surgical treatment of suspected pelvic pathology or as a confirmatory tool in women with occluded tubes, especially when tubal surgery is planned (44). In the U.S., HSG remains the most utilized tool to assess for tubal patency, caliber, and para tubal loculations, despite suboptimal sensitivity (65%) and specificity (83%) (39). Pelvic pain, allergy, and exposure to radiation are drawbacks of HSG (45) (46). Infection is also a concern, but its incidence is exceedingly low (<0.5%). Overall complication rates of HSG were 1.8% where water-based contrast was used and 5.4% with oil-based contrast (47). Lastly, HSG requires X-ray, which is not available in all clinics and may necessitate referral to a hospital or radiology center.

The popularity of ultrasound-based tubal patency tests – known as hysterosalpingo-contrast sonography (HyCoSy) – is increasing, particularly in Europe (44), with notably slow uptake in the U.S. European authors have noted thatwith incorporation of HyCoSy, modern transvaginal ultrasound holds potential to become a ‘one-stop shop’ for comprehensive fertility assessment allowing targeted investigation of the uterus, myometrium, endometrium, uterine cavity, ovaries, follicle count, and fallopian tubes, including tubal patency assessment (44, 48)(38). The addition of tubal assessment to SIS is associated with minimal or no additional cost (particularly if air or saline contrast agent(s) are used). However, many fertility specialists, particularly in the U.S., are not familiar with ultrasonographic assessment of the fallopian tubes and how 3D imaging and Doppler have potential to increase the accuracy, reliability, as well as tolerability, and safety of tubal patency testing.

Evolving contrast agents for ultrasound tubal patency testing

Normal saline is a cheap, non-commercial contrast agent with many advantages. Because it is negative (anechoic), saline is an excellent agent for visualization of the uterine cavity; however, it cannot optimally delineate the fallopian tubes (44) (48). Saline infusion is sufficient to confirm that at least one tube is patent, by visualization of saline in the pouch of Douglas after infusion. Better contrasts to depict the fallopian tubes are those that generate hyperechoic (positive) images of medium flow through the tubes to the abdominal cavity. Since hyperechoic contrasts reduce the ability to identify hyperechoic intracavitary and endometrial lesions, it is reasonable to instill first saline for cavity assessment, then hyperechoic contrast for fallopian tube assessment.

Until recently, the only ultrasonographic contrast method for tubal patency approved by FDA and available in the U.S. was air/saline hysterosalpingo-contrast sonography (air/saline-HyCoSy). In this method, saline as anechoic component, and air bubbles as hyperechoic component, are infused simultaneously or alternately using the same equipment as for saline infusion sonohysterography (49). The main limitation of this method is that moving air bubbles and saline do not generate a clear and steady visualization of the tubes; therefore, an accurate and reliable diagnosis may require a high degree of expertise on the part of the interpreter. The most important diagnostic limitation of air/saline HyCoSy is low PPV/high false positive rate for tubal occlusion (50). Furthermore, the test is often inconclusive (44) (48). A strength of air/saline HyCoSy is that the method has a high NPV, i.e. that diagnostic accuracy of (a) patent tube(s) is high. Due its high NPV (low rate of false diagnoses of patent tube(s)) and low cost, HyCoSy deserves strong consideration for initial assessment of tubal patency.

Several commercial hyperechoic contrast agents have been proposed to increase accuracy of tubal patency testing. However, microbubble contrast agents: Echovist^® (galactose microparticles; Bayer Schering Pharma AG, Berlin, Germany) and SonoVue^® (sulfur hexafluoride; Bracco International BV, Amsterdam, The Netherlands), respectively, did not significantly increase diagnostic accuracy (43). Further, Echovist^® has been removed from the market due to allergic reactions, while SonoVue is still available for off-label use. Foam as contrast has recently been introduced for sonographic assessment of fallopian tube patency (51). The ExemFoam^® (hydroxyethylcellulose, glycerol and purified water; GynaecologIQ, Delft, The Netherlands) is the first such commercial agent. The contrast was launched ten years ago in the European market. In 2019, it became the first FDA-approved contrast agent for assessing tubal patency (52). HyCoSy method with use of foam is called HyFoSy (hysterosalpingo-foam sonography). Finally, as a considerably cheaper alternative, HyLiFoSy (hysterosalpingo-lignocaine foam sonography), using foam contrast created with widely accessible Lidocaine gel, air, saline, and power Doppler, has been described (53). As with microbubble contrast agents, the use of commercial foam contrast did not improve upon the diagnostic accuracy of HyCoSy in the hands of experienced practitioners, because air/saline-HyCoSy has close to perfect NPV (44). Therefore, HyCoSy stands as an excellent option, particularly in low-resource settings once appropriate training is completed.

2D and 3D HyFoSy, and Doppler HyFoSy

HyFoSy with 2-dimensional-transvaginal sonography is a basic option (Figure 3A) with foam offering potentially improved fallopian tube visualization (51). HyFoSy with 3-dimensional or Doppler imaging was described by expert users and suggested as a good option to standardize image acquisition without the need for skilled probe movements to include the fallopian tubes and ostia (44). For intermediate skill-level operators, 2D/3D HyFoSy with automatic scanning may be a better option, since it is less operator-dependent and less time-consuming. The first study evaluating inter-rater reproducibility of HyCoSy/HyFoSy recently showed that agreement in the diagnosis of tubal patency was only moderate with 2-D sonogaraphy using foam (κ = 0.55) and air/saline (κ = 0.67) but was very good with power Doppler (κ = 0.95) (54).

Figure 3: Ultrasound tubal patency testing with foam (HyFoSy):

Doppler techniques objectively confirm the contrast flow and generate easy to interpret pictorial documentation of exam.

• (A) 2D-HyFoSy in grey scale (LEFT) and tissue Doppler imaging (CENTER and RIGHT);
• (B) 3D-HyFoSy in grey scale (LEFT), HDlive render mode (CENTER and RIGHT);
• (C) 3D-HyFoSy and power Doppler. Power Doppler generates a highly useful sign called flaming tubes sign and makes diagnosis very easy to interpret for low and medium experienced users (53).

The same group assessed the diagnostic accuracy of these methods in comparison to laparoscopy (44) (55). 2D air/saline HyCoSy and 2D/3D HyFoSy showed no significant differences in diagnostic accuracy of tubal patency relative to one another, and both methods had significantly lower accuracy than laparoscopy with dye instillation. However, the addition of Doppler with high-definition flow imaging improved the accuracy of HyFoSy to the level of laparoscopy. The addition of Doppler increased PPV, i.e. it reduced the odds of falsely diagnosing tubal occlusion in the setting of patency. With 2D and 3D HyFoSy alone, a thin sonogram of the tubes close to 1 mm is obtained in grayscale, and its flow is sometimes inconclusive. With Doppler HyFoSy, the flow of foam generates a thick (>0.5 cm) colored sonogram around the tubes. Thus, inconclusive impressions of flow in the gray scale may be confirmed by adding of Doppler (Figure 3). In summary, without Doppler, both HyFoSy and HyCoSy are less accurate than laparoscopy with dye instillation; however, Doppler improves accuracy for both HyFoSy and HyCoSy to that of laparoscopy. While data directly comparing the diagnostic accuracy of Doppler HyCo/HyFoSy to HSG are unavailable, indirect comparisons indicate that both methods are similarly accurate to HSG (44) (43). A recent RCT in which infertile subjects were managed based on the results of HyFoSy vs. HSG, showed non-inferiority of HyFoSy to HSG in terms of live birth within 12 months (46 vs 47%) (56).

HyCoSy and HyFoSy are generally well-tolerated (57) (58), and pre procedure analgesia may further reduce the rate moderate to severe procedure-related pain (28). Initially there were no significant complications after more than 350 000 procedures with ExemFoam (59) (60) (61). Recently, one case of diffuse skin immune reaction, diagnosed as cutaneous small-vessel vasculitis, was the first reported case of hypersensitivity reaction to ExemFoam and occurred in the setting of contrast intravasation (61). However, complications may be under-reported. The first case of intravasation during air/saline HyCoSy was described after two decades of its use (62).

Potential Therapeutic Benefit of HyCoSy / HyFoSy

It has been described that ‘flushing’ of the fallopian tubes in the setting of HSG is associated with an increase in naturally conceived pregnancies (63, 64). A higher rate of pregnancy has been reported using oil-based vs. water-based contrast for HSG (41% vs. 34%) (65) (66). Original studies with commercial contrasts agents for tubal patency testing and flushing for sonographic fallopian tube assessment have been performed with disclosed support from the manufacturers (45) (67) and have shown 5% increase in ongoing pregnancy rate in short term (80% vs. 75%) (68) and in long-term follow-up (45). A recent RCT indicated that basic HyFoSy (without 3D or power Doppler) was less painful but led to similar pregnancy outcomes relative to HSG (69). However, independent studies without risk of commercial bias and with different methodologies of tubal patency testing and flushing are needed. Flushing with air/saline may also increase the rate of natural pregnancies.

Assessment of Fallopian Tube Caliber

For patients with one patent tube and unilateral hydrosalpinx, surgical management increases odds of conceiving without IVF (70). For those patients with indication for ART, the presence of hydrosalpinx(ges) has a clear negative prognostic influence and should be mitigated surgically prior to embryo transfer (71). RCTs comparing IVF outcomes with or without surgical management of hydrosalpinges, found surgery to be effective, returning success rates to those of patients without hydrosalpinges (40–42).

Classic studies evaluating surgical management of hydrosalpinx prior to embryo transfer relied predominantly upon ultrasound diagnosis of hydrosalpinx. While plain ultrasound suffers from low sensitivity (72, 73), specificity of TVUS for hydrosalpinx, is high. It is not known whether surgical management increases the chances of an embryo to successfully implant, in the case of hydrosalpinx(ges) that are visible with contrast instillation (as in HSG, SIS, HyCoSy, or HyFoSy), but not visible on plain TVUS. While the AIUM state that hydrosalpinx is not an absolute contraindication to HyCoSy (74), most original studies consider the presence of hydrosalpinx(ges) as a relative contraindication to HyCoSy (75, 76). For this reason, many practitioners perform plain TVUS prior to instillation of contrast and stop the procedure without performing HyCoSy, if a hydrosalpinx is suspected based on TVUS findings. Contrast instillation may increase infection risk in the setting of hydrosalpinx, but risk of procedure related pelvic inflammatory disease remains exceedingly low. Many practitioners administer prophylactic antibiotics prior to HSG if hydrosalpinx is suspected based on history or administer post procedure antibiotics if an HSG is diagnosed incidentally, which may further reduce infection risk (47). The prevalence of unsuspected, clinically relevant hydrosalpinx(ges) that would be diagnosed on HSG or HyCoSy but not on plain TVUS is not known. However, it is likely quite low, particularly among the population of non-infertile patients planning ART. Therefore, while it is reasonable to undertake HSG to rule out hydrosalpinx in patients planning embryo transfer, when tubal factor is suspected (with consideration for antibiotic prophylaxis), or even in the setting of unexplained infertility, it is our recommendation not to perform HSG routinely among non-infertile patients, in whom no tubal pathology is suspected, and in whom TVUS/SIS do not raise suspicion for dilated fallopian tube(s).

Conclusion

In the setting of high efficacy ART, particularly when embryo transfer is planned to a non-infertile patient, data provide insufficient guidance for patients and practitioners regarding optimal assessment and treatment of the uterine cavity and fallopian tubes. Success rates from ART are high and seem to be approaching an asymptote. Therefore, there is heightened relevance of even the smallest improvements in the odds of achieving live birth following embryo transfer.

Higher quality studies are needed to confirm whether and to what extent modern ART outcomes are improved by identification and treatment of uterine cavity defects – especially polyps, which are highly prevalent (7) (2). This is even more true among the growing population of non-infertile patients undergoing ART. In the absence of data to guide us, we must consider the high prevalence of uterine cavity defects and that their removal is safe and may be cost effective (2) (77). Bearing in mind the high cost of ART and of donor sperm, as well as the medical risks undertaken in the ART process, we recommend evaluating the uterine cavity with SIS prior to embryo transfer in all patients.

Historically, it was recommended to perform diagnostic hysteroscopy routinely on all patients prior to ART (78, 79). Hysteroscopy has been considered by some as first line in patients with recurrent implantation failure (80) (81); however, recent RCT data contradict this practice (38). In clinics where office hysteroscopy is available, it has been argued to use this modality more broadly, and even as first line, since enables efficient treatment without delay (36); however, again, recent RCT data did not show a benefit in terms of live birth for patients undergoing hysteroscopy prior to first IVF (33). SIS has demonstrated diagnostic accuracy approaching that of hysteroscopy (23) (17, 82) (83) (82) and also enables visualization of the external uterine contour, myometrium and adnexae. Therefore, we recommend SIS, rather than diagnostic hysteroscopy, as the first line cavity assessment prior to embryo transfer in most settings and for most patients. The use of diagnostic hysteroscopy should be limited.

Fallopian tubes should be assessed for patency to determine the most appropriate first line treatment for infertility. While HSG with or without laparoscopy have been historically undertaken, recent data indicate that sonographic tubal assessment with contrast infusion has excellent accuracy and tolerability, particularly when performed at experienced centers. 3D rendering and high-frequency Doppler increase accuracy. While uptake of this diagnostic modality has been slow in the U.S., it holds potential as a ‘one-stop shop’ for comprehensive assessment of pelvic anatomy in the infertile patient and may increase natural fecundity similar to HSG. It is our opinion that 3D ultrasound training should be standard within Reproductive Endocrinology and Infertility (REI) training programs. Consideration should also be given for HyCoSy training. This modality holds potential to reduce reliance upon HSG, which though generally safe, entails an extra step with associated discomfort and cost.

The decision of whether and what tubal assessment is needed to rule out hydrosalpinx, in patients planning embryo transfer with no tubal pathology suspected, is a complex one, particularly in the current era of high-efficacy ART, where even small improvements in odds of success are at a premium. Studies demonstrating benefit with surgical treatment of hydrosalpinges were predominantly based on plain ultrasound diagnosis, and the prevalence of unsuspected hydrosalpinges that can be seen only with contrast instillation is likely low, particularly in a non-infertile population. Therefore, while it remains important to rule out hydrosalpinges prior to embryo transfer in patients with suspected tubal pathology, and even in patients with unexplained infertility, we recommend against the use of HSG prior to embryo transfer in non-infertile patients in whom tubal pathology is not suspected based on history and TVUS/SIS.

In the era of highly-efficacy ART, the future of diagnostic evaluation for infertility has turned in large part towards genetic, genomic, metabolomic, and proteomic evaluation of embryos, endometrium, and even sperm. Still, most sub-fertile couples prefer natural conception, and many maintain a good prognosis for achieving live birth without costly, invasive ART. Saline infusion sonohysterography is a highly sensitive tool for identification of uterine cavity defects (and provides the ability to simultaneously assess the myometrium and ovaries, including antral follicle count). The addition of air infusion with 3D image acquisition and high frequency doppler holds great potential to make transvaginal ultrasound a simple, cost-effective, one-stop shop for comprehensive anatomic assessment in the infertile female. Office hysteroscopy, where available, has advantages in its ability to treat uterine cavity defects in real time but did not show a benefit in terms of live birth.

Given the high cost and high success of IVF with PGT in the U.S., even small increases in the chances of achieving live birth are at a premium. Even so, unnecessary, unproven, and uncomfortable diagnostic tests and procedures should be avoided, and cost-effective, evidence-based modalities should be prioritized, as highlighted by the ongoing debate of ‘add-ons’ to IVF (84, 85). As reviewed here, the available evidence indicates that appropriate contemporary practice prior to embryo transfer includes ruling out significant uterine cavity defects and hydrosalpinges using sonographic techniques followed by individualized surgical treatment of any significant pathology that is uncovered. HSG and diagnostic hysteroscopy are likely over-used, particularly in a non-infertile population. Practitioners should increase their skills in performing and interpreting 3D-SIS prior to ART, and REI fellowship programs should incorporate training in the performance and interpretation of 3D-SIS. Hysteroscopic management of specific lesions should be individualized, and additional studies are needed to provide proof of the dogma that removal of the most common, minor intracavitary findings is truly beneficial before ART.