Diagnosis of septate uterus

Abstract

The septate uterus is the most common structural uterine anomalies and it is associated with the poor reproductive outcome. It is believed to be the result of the failure in resorption of the tissue connecting the 2 paramesonephric ducts prior to the 20th embryonic week. The true prevalence of uterine septum is difficult to ascertain, as many uterine septal defects are asymptomatic. The septate uterus is usually diagnosed during an infertility evaluation and affects reproductive health by impairing fertility and increasing adverse pregnancy outcomes. The variations in uterine and cervical/vaginal anomalies collectively referred to as Müllerian anomalies. No consistent gold standard for the diagnosis of Müllerian anomalies exists. The preferred diagnostic method for Müllerian anomalies is two-dimensional ultrasound, other methods such as three-dimensional ultrasound, magnetic resonance imaging, hysterosalpingo contrast sonography, hysterosalpingography, hysteroscopy, and laparoscopy are also used to improve accuracy.

Uterine anomalies have long been recognized as a cause of obstetric complications. Uterine anomalies are first described by Cruveilhier and Von Rokitansky in the 19th century^[1] . Congenital uterine malformations are defined as deviations from normal anatomy resulting from the embryological maldevelopment of the Müllerian, or paramesonephric ducts. The most common types of malformations of the reproductive system are congenital uterine anomalies resulting from Müllerian fusion defects^[2].

Among the different types of structural uterine anomalies, the septate uterus is the most common^[3-4] and is associated with the poorest reproductive outcome^[5-8]. However, it is also the most amenable to simple and successful hysteroscopic treatment. This paper reviwed the septate uterus and its diagnostic methods.

1. Embryology and histology

Congenital malformations of the female genital tract are defined as deviations from normal anatomy resulting from the embryological maldevelopment of the Müllerian, or paramesonephric ducts. At approximately 5 to 6 weeks of embryonic life, the paramesonephric ducts arise from the urogenital ridge of the embryo as an invagination of the celomic epithelium. The ducts grow immediately downward to fuse in the midline at approximately 9 weeks. Then, the remainder of the vagina is formed by the union of the fused paramesonephric ducts with the endodermal bulbs of the urogenital sinus. This process is completed by 12 to 14 weeks of gestation^[9]. The paramesonephric ducts progress to normal female development in the absence of Müllerian-inhibiting factor.

A uterine septum is believed to be the result of the failure of resorption of the tissue connecting the 2 paramesonephric ducts prior to the 20th embryonic week. Unlike the uterine septum, the arcuate uterus, which is the mildest form of resorption failure, is not considered clinically relevant.

Initially, it was believed that the septum is composed of predominantly fibrous tissue. Then, biopsy specimens and magnetic resonance imaging (MRI) revealed the septum to be primarily composed of muscle fibers with less connective tissue^[10-11]. In general, the septum is composed of fibromuscular tissue which is vascularized by adjacent myometrial vessels^[9]. The results of one study^[12] that used transvaginal color and pulsed Doppler sonography as well as three dimensional (3D) sonography to evaluate uterine septa showed septal vascularity in 71% of patients, suggesting that most uterine septa carry myometrial vessels. The high levels of uncoordinated activity in septal muscular tissue may explain most obstetric problems.

2. Epidemiology and genetics

The prevalence of septate uterus varies in different populations, including women with normal fertility, infertility, and repeated pregnancy loss. The true prevalence of septate uterus is difficult to ascertain, as many uterine septal defects are asymptomatic. The literature^[13] indicates that the prevalence of uterine anomalies is 5.5% in the unselected population, 8% in the infertile women, 13.3% in women with miscarriage, and 24.5% in infertile women with a history of miscarriage. The specific anomalies, which are increased in these high-risk populations, are mainly canalization defects. However, some canalization defects may be diagnosed as arcuate uterus and vice versa, and some cases of septate uterus, particularly those with a large septum extending to the cervix, may be misdiagnosed as bicornuate uterus, even with the use of optimal tests^[14] . It is necessary to differentiate these anomalies from septate uterus to better direct appropriate surgical intervention for septate uterus. In 2006, Rai R and Regan L^[12] reported that septate uterus is the most common uterine anomaly, with an estimated prevalence of 2% to 3% in women of reproductive age.

It has also been reported that the origin of nearly all uterine malformations is consistent with a polygenic/multifactorial etiology^[15-16]. In 1997, Ergün A, et al^[16] reported a rare, familial aggregation of different degrees of septate uteri among 3 sisters. Mikkilä SP, et al^[15] described a family in which 2 male cousins had an X-linked laterality sequence (XLLS) with caudal manifestations, and the obligate carrier females had uterine septum and hypertelorism. Further support for a genetic basis was provided by Lee DM, et al^[17], who reported that an altered expression of the BCL-2 gene in uterine septum may prevent apoptosis and uterine septum regression.

3. Classification

To describe the variations in uterine and cervical/vaginal anomalies, collectively referred to as Müllerian anomalies, several classifications have been proposed since the 19th century^[18-23]. All of these have been based on embryology and the development of Müllerian ducts to support accurate diagnosis and enable comparisons between cases. However, most of these classifications have applied imprecise terminology and failed to properly characterize the anomalies. According to the definition of septate configurations by the American Society for Reproductive Medicine (ASRM), the parameters are not strict. In the latest ASRM classification, the following parameters are included for septate uterus: partial septate uterus, normal/arcuate uterus, Robert’s uterus, complete septate uterus with duplicated cervices and longitudinal vaginal septum, complete septate uterus with septate cervix, longitudinal vaginal septum, and complete septate uterus with duplicated cervices and obstructed right or left hemivagina^{[18-19, 24]}. Following the most recent European Society of Human Reproduction and Embryology-European Society for Gynecological Endoscopy (ESHRE-ESGE) classification, Class U2, or septate uterus, incorporates all cases of septate uterus with normal fusion and abnormal absorption of the midline septum. Septate uterus is defined as a uterus with normal outline and an internal indentation at the fundal midline exceeding 50% of the uterine wall thickness. This indentation is characterized as septum, and it may partly or completely divide the uterine cavity, including, in some cases, the cervix and/or vagina^[23].

Class U2 is further divided into 2 subclasses according to the degree of the uterine corpus deformity: 1) Class U2a, or partial septate uterus, characterized by the existence of a septum partly dividing the uterine cavity above the level of the internal cervical os. 2) Class U2b, or complete septate uterus, characterized by a septum fully dividing the uterine cavity up to the level of the internal cervical os. Patients with complete septate uterus (Class U2b) may or may not have cervical (such as septate uterus with double cervix)/vaginal defects (see cervical/vaginal anomalies).

A complete septate uterus may be associated with a longitudinal vaginal septum. Uterus didelphys, in which the uterine horns are separated, may also have duplicated cervices and is typically associated with a longitudinal septum. Therefore, a complete septate uterus associated with a longitudinal vaginal septum must be differentiated from uterus didelphys^[25].

4. Diagnosis methods

The accurate diagnosis and classification of congenital uterine anomalies are required especially when a septate uterus is suspected, and the patient may benefit from interventional therapeutic approaches. There exists no consistent gold standard method for diagnosing Müllerian anomalies. In the past, direct visualization of the exterior and interior of the uterus using laparoscopy and hysteroscopy was required. At present, the initial diagnostic method for Müllerian anomalies usually entails two-dimensional ultrasound (2D-US), and three-dimensional ultrasound (3D-US), MRI, hysterosalpingo-contrast sonography, hystero-salpingography (HSG), hysteroscopy, and laparoscopy are also used^[26]. In the past, combined laparoscopic and hysteroscopic examinations were considered the gold diagnostic standard for assessing congenital uterine anomalies, establishing a correct diagnosis, and applying the principle of “seeing and treating”^[27].

With the development of radiologic methods, the diagnosis of a septate uterus is typically made using radiographic rather than surgical techniques.

HSG can detect a septate uterus and evaluate the size and extent of a septum^[28]. There are several advantages regarding the application of HSG in the diagnostic approach, including the concomitant assessment of tubal patency. Furthermore, the procedure can be repeated after operative intervention to assess the surgical outcome and possible complications. However, the main disadvantage of HSG is that it cannot reliably differentiate a septate from a bicornuate uterus^[29], and thus the diagnostic accuracy of HSG is low for distinguishing between these 2 uteris^{[25, 30-32]}. It has also been reported that HSG may miss minor septal defects^[3]. Procedurally related pain has been reported by up to 72% of patients who underwent HSG during an infertility investigation^[4]. When there is evidence of tubal disease or if there is immunologic evidence of Chlamydia trachomatis, the procedure may be complicated by pelvic inflammatory disease^[5]. Additionally, during the procedure, the ovaries are exposed to radiation, but one study^[6] has indicated that the level of radiation exposure is well within established margins of safety.

Hysteroscopy has been shown to be superior to HSG in diagnosing intrauterine abnormalities, including septal defects. During the procedure, any abnormal endometrial lesions can be biopsied or removed simultaneously. The use of hysteroscopy has facilitated treatment at the same time as diagnosis (in accordance with the principle of “seeing and treating”)^[12]. However, hysteroscopy has several disadvantages. Firstly, hysteroscopy does not provide information on the external uterine fundal contour so that the distinction between a septate and a bicornuate uterus cannot always be properly made. Secondly, if a complete septate with double cervix is presented, and the hysteroscopy is inserted into 1 cervix only, a false diagnosis of unicornuate uterus may be made^[33].

In the past, HSG was the initial diagnostic test performed to assess the evidence for a Müllerian anomaly in patients complaining of infertility or adverse pregnancy outcomes. However, as previously mentioned, the diagnostic accuracy of HSG is low for distinguishing between septate and bicornuate uteri^{[25, 30-32]}. In a series study^[14] of 117 females found that 3D-US combined with saline infusion demonstrated 100% accuracy. MRI can detect septate uterus with 100% accuracy, but its routine use in clinical practice remains controversial as it is time-consuming and expensive^[33-35]. Other literature^[36] has reported that MRI is an accurate method for diagnosing Müllerian abnormalities generally, but it demonstrates only 70% accuracy in the diagnosis of septate uterus. In conclusion, these diagnosis methods have some shortcomings, and thus their application is relatively limited.

Ultrasound is useful in making the diagnosis of septate uterus^[37-38], as it has the potential for the accurate classification of congenital uterine abnormalities, including the differentiation of septate from bicornuate uteri. Considering the fact that 25% to 30% of patients present with subfertility, sonohysterography may be useful in providing additional information regarding tubal factors^[39].

3D-US has good reproducibility, provides additional and more reliable images, and allows for the evaluation of the cervix and the vagina^{[23, 40-42]}. Three-dimensional transvaginal ultrasound (3D-TVUS) is a safe, painless, noninvasive examination that is readily available, relatively low cost, and, most importantly, can be used to explore the areas where a hysteroscope cannot reach. 3D-TVUS can accurately measure uterine length, uterine width, uterine height, interostial distance, uterine fundal myometrial thickness, uterine septum length, and postoperative uterine fundal internal indentation depth. Therefore, it has unique advantages over other diagnostic methods.

Laparoscopy is recommended to complete the evaluation of patients with infertility, including assessment and possible concomitant treatment of tubal disease and such as endometriosis^[34]. Laparoscopy may also be of value in aspirating excessive intra-abdominal irrigation fluid and safer during hysteroscopic metroplasty. Although laparoscopy can evaluate the external contour of the uterus and the peritoneal structures, it is an invasive examination which cannot evaluate the thickness of the uterine wall and completely depends on the experience and subjective evaluation of the examiner^[23].

5. 3D-US and septate uterus

Several diagnostic techniques are used for diagnosing uterine anomalies. The first is conventional 2D-TVUS^[43]. 2D-US is routinely used as the first approach in the diagnosis of uterine anomalies. However, making the distinction between the different types of anomalies is difficult with 2D-US^{[40, 44]}. With conventional 2D-US, 2 cavities can be easily detected in women presenting with septate uterus, with little detection of other features. With 3D-US, the contribution of the coronal plane enables an accurate diagnosis, and the relationship between the cavity and the fundus becomes obvious. Furthermore, with 3D-US, the volume of the cavity can be calculated, and vascularization of the septum can be assessed^[33-34]. In addition, the use of 3D-US permits ultrasound volumes to be permanently stored, enabling further reexamination and evaluation of the diagnosis^[35].

During 3D-TVUS, a high-frequency and endocavity US transducer are placed in close proximity to the target pelvic organs, with excellent image resolution. 3D-TVUS can display multiplanar views, including the coronal plane. It supports the simultaneous visualization of all 3 orthogonal planes, which is often unattainable with transabdominal sonography (TAS) or 2D-TVUS. The coronal view clearly illustrates the endometrial-myometrial junctional zone, the entire cervical canal, the cornual angles, and the fallopian tube ostia. 3D-TVUS must be performed during the mid-luteal phase when it can capture more informative and accurate data than at other periods and be performed over a longer time with better image quality. The findings of 3D-TVUS may also provide the surgeon with a detailed overview of the intracavitary status. 3D-TVUS can help to avoid possible errors by surgeons. 3D-TVUS data can be used for uterine cavity assessment preoperatively in order to contribute to surgical planning, as patients may be better informed of the current condition of their endometrial cavities and potential courses of treatment. The data retrieved preoperatively can inform intraoperative judgement with the aim to minimize risks and complications during surgery and to achieve the best possible results for patients.

6. Differential diagnosis

A complete septate uterus may be associated with a longitudinal vaginal septum. Uterus didelphys is a malformation in which the uterine horns are separated and the cervices are duplicated, and it is typically associated with a longitudinal vaginal septum. Therefore, complete septate uterus associated with a longitudinal vaginal septum must be differentiated from uterus didelphys^[25]. To distinguish a septate from a bicornuate uterus, it is important to assess both the outer and inner uterine contours. The septate uterus is defined as a uterus having a normal outline with an internal indentation at the fundal midline exceeding 50% of the uterine wall thickness. On the contrary, a bicorporeal uterus is defined as a uterus having an abnormal fundal outline characterized by the presence of an external indentation at the fundal midline exceeding 50% of the uterine wall thickness^[23]. This indentation may partly or completely divide the uterine corpus including, in some cases, the cervix and/or vagina^[23]. A study^[45] reported on a case of combined bicornuate/septate configuration of the uterus in which the external fundus had an indentation consistent with bicornuate shape, but at hysteroscopy, a septum dividing the endometrial cavities was discovered.

The arcuate uterus is difficult to classify. It is important to differentiate between septate and arcuate uterus for better direct surgical intervention. The coronal plane of the uterus obtained by 3D-US is usually used to distinguish between these 2 types of uterine morphology. The ASRM recommends considering a uterus as septate when there is both an indentation depth >1 cm and an indentation angle <90°, while a normal/arcuate uterus should have both an indentation depth <1 cm and an indentation angle >90°^[25].

It is important to note, however, that some canalization defects may be diagnosed as an arcuate uterus and vice versa. Similarly, some cases of septate uterus, particularly those with a large septum extending to the cervix, may be misdiagnosed as bicornuate uteri even with the use of optimal tests. It is necessary to differentiate these anomalies from septate uterus to better direct surgical intervention in patients with a septate uterus.

7. Conclusion

The septate uterus is the most common structural uterine anomalies. It affects reproductive health by impairing fertility and increasing adverse pregnancy outcomes. Therefore, the accurate diagnosis is required, especially when the patient benefits from interventional therapeutic approaches.

The use of hysteroscopy has facilitated treatment at the same time as diagnosis, but it does not provide information on the external uterine fundal contour. Laparoscopy can evaluate the external contour of the uterus and the peritoneal structures, but it is an invasive examination which cannot evaluate the thickness of the uterine wall. HSG can detect a septate uterus, but diagnostic accuracy of HSG is low for distinguishing between a septate and a bicornuate uterus. Ultrasound is useful in making the diagnosis of a septate uterus. 2D-US is routinely used as the first approach in the diagnosis of uterine anomalies. However, making the distinction between the different types of anomalies is difficult with 2D-US. With 3D-US, the contribution of the coronal plane enables an accurate diagnosis, and the relationship between the cavity and the fundus becomes obvious.

Although no consistent gold standard for the exact diagnosis of Müllerian anomalies exists, ultrasound has the potential for accurate classification, including the differentiation of septate from other types of structural uterine anomalies, which still needs further research.

Funding Statement

This work was supported by the National Key Research and Development Program of China (2018YFC1004800).

Conflict of Interest

The authors declare that they have no conflicts of interest to disclose.

AUTHORS’CONTRIBUTIONS

ZHANG Baiyun Conceptualized, drafted, edited and submitted the manuscript; WU Si Conceptualized, drafted, reviewed and revised the manuscript; ZHAO Xingping Collected data, reviewed and revised the manuscript; ZHU Xiuting Reviewed and revised the manuscript; XU Dabao Conceptualized, reviewed and revised the manuscript. All authors have approved the final version of this manuscript.

Note

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