Abstract
A structurally normal and functionally competent uterus is essential for the process of reproduction including sperm transport, embryo implantation, fetal development and growth, and the process of labour and birth. Any uterine abnormalities including congenital anomalies may adversely influence some of these uterine functions, precluding a successful pregnancy. Congenital uterine anomalies are deviations from normal anatomy resulting from embryological maldevelopment of the Mullerian ducts and are not uncommon. While most of these anomalies are asymptomatic and are associated with normal reproductive outcome, some may be associated with adverse reproductive outcomes.
1 Introduction
A structurally normal and functionally competent uterus is essential for the process of reproduction including sperm transport, embryo implantation, fetal development and growth, and the process of labour and birth. Any uterine abnormalities including congenital anomalies may adversely influence some of these uterine functions, precluding a successful pregnancy. Congenital uterine anomalies are deviations from normal anatomy resulting from embryological maldevelopment of the Mullerian ducts and are not uncommon. While most of these anomalies are asymptomatic and are associated with normal reproductive outcome, some may be associated with adverse reproductive outcomes.
2 Development of Normal Uterus and Anomalies
Normal development of the female reproductive tract involves a series of complex processes characterized by the differentiation, migration, fusion and subsequent canalization of the Mullerian duct system (Figure 10.1). Uterine anomalies result when these processes are interrupted [1, 2]. The primordial germ cells that develop at around the fourth week of life among the endodermal cells in the dorsal wall of the yolksac migrate to the primitive gonads. The primitive gonads appear on the gonadal ridge medial to mesonephros, and subsequently Wolffian and Mullerian ducts develop. By the seventh week, sex determining region-Y (SRY) antigen in male fetus differentiate the primitive gonad into testis, which secretes anti-Mullerian hormone (AMH) and testosterone, which allows Mullerian duct to regress and Wolffian duct to develop into male internal genitalia. Absence of the SRY gene in female embryos allows the gonads to develop into ovaries. The subsequent lack of AMH causes regression of the Wolffian ducts and allows the Mullerian ducts to develop into fallopian tubes, the uterus and upper vagina, while the lack of androgens permits differentiation of the indifferent external genitalia into the labia majora, labia minora and the clitoris. The lower tip of the fused Mullerian ducts makes contact with the urogenital sinus, causing proliferation of the endodermal sinovaginal bulbs, which form the vaginal plate. This then canalizes to form the vagina with the upper portion derived from Mullerian duct and lower portion from the sinovaginal bulbs. Mullerian development occurs separately from gonadal development, and women with Mullerian anomalies usually have normal ovaries and ovarian hormone production. By contrast, Mullerian development occurs in close association with the development of the urinary tract, and renal anomalies are occasionally identified in those with Mullerian anomalies.
Fig. 10.1 Congenital malformations of the female genital tract
There are three phases of Mullerian duct development (Table 10.1)
1. Organogenesis – developmental defect leads to agenesis or aplasia – Mayer Rokitansky Kuster Hauser (MRKH) Syndrome if bilateral agenesis and Unicornuate uterus if unilateral agenesis.
2. Fusion
a. Horizontal fusion (lower segments of paired Mullerian duct fuse to form uterus, cervix and upper vagina). Varying degrees of fusion defect causes bicornuate uterus and didelphys.
b. Vertical fusion (between the descending Mullerian duct and ascending sinovaginal bulbs to form vaginal canal). Fusion defects cause an imperforate hymen or a transverse vaginal septum
3. Septal resorption of the horizontally fused Mullerian ducts – failure of resorption leads to septate uterus.
While certain types of congenital malformation are the result of a clear disturbance in one stage of embryologic development, others are the result of disturbances in more than one stage of normal formation. The combination of malformations, which occur at different stages of development, seems to be the reason for the extremely wide anatomical variations and the large observed number of combinations of congenital malformation of the female genital tract (Figure 10.1).
Table 10.1 Phases of Mullerian duct development and defects
3 Classification of Uterine Anomalies
While different classification systems have been proposed for Mullerian anomalies, the classification described by the American Society of Reproductive Medicine (ASRM; formerly known as the American Fertility Society [AFS]) remains the most widely used [3]. This classification is based on the extent of failure of Mullerian development and divides anomalies into groups with similar clinical manifestations, management requirements and prognosis. However, this classification is not without limitations; for example, it does not include combined or complex anomalies (obstructive-like cervical or vaginal aplasias), which are often incorrectly identified, and inaccurately reported. There has been criticism on arcuate uterus being included as separate class as well.
The European Society of Human Reproduction and Embryology (ESHRE) and the European Society for Gynaecological Endoscopy (ESGE), recognizing the clinical significance of female genital anomalies, have established a common working group under the name CONUTA (CONgenital UTerine Anomalies), with the goal of developing a new updated classification system [4]. The ESHRE/ESGE classification system is based on anatomy. Anomalies are classified into the following main classes, expressing uterine anatomical deviations deriving from the same embryological origin: U0, normal uterus; U1, dysmorphic uterus; U2, septate uterus; U3, bicorporeal uterus; U4, hemi-uterus; U5, aplastic uterus; U6, for still unclassified cases. Main classes have been divided into subclasses expressing anatomical varieties with clinical significance. Cervical and vaginal anomalies are classified independently into subclasses having clinical significance. Embryological origin has been adopted as the secondary basic characteristic in the design of the main classes. Cervical and vaginal anomalies are classified in independent coexistent subclasses according to increasing severity of the anatomical deviation (C0 to C4 and V0 to V4); the less severe variants are placed in the beginning, the more deformed types at the end, with C0 being normal cervix and C4 being cervical aplasia and with V0 being normal vagina and V4 being vaginal aplasia. Arcuate uterus is considered as a normal variant and is not included in this classification. While it seems that the new system fulfils the needs and expectations of a large group of experts in the field, the practical usefulness of this classification system is yet to be tested.
4 Prevalence
The reported population prevalence rates in individual studies have varied between 0.06% and 38% and the observed wide variation is possibly due to the assessment of different study populations and the use of different diagnostic techniques [5]. The lack of universally agreed-upon standardized classification systems and invasive nature of the gold standard diagnostic tests (combined laparoscopy and hysteroscopy) has made difficult to assess the true population prevalence of congenital uterine anomalies in the past. The advent of 3D ultrasound with its ability to define both internal and external contours of the uterus has made the diagnosis of uterine anomalies easier and less invasive. Recently two well-conducted systematic reviews have evaluated the prevalence of uterine anomalies, categorizing the diagnostic tests used into optimal and suboptimal tests [5, 6].
Chan et al. (2011) evaluated the prevalence of congenital uterine anomalies in the unselected population and in women with a history of infertility, including those undergoing in vitro fertilization (IVF) treatment, miscarriage, infertility and recurrent miscarriage combined, and preterm delivery [5]. In their review they classified investigations, as proposed by Saravelos et. al. (2008), into optimal tests that are capable of accurately identifying and classifying congenital uterine anomalies (3D transvaginal ultrasound, laparoscopy or laparotomy with hysteroscopy or hysterosalpingogram [HSG], magnetic resonance imaging [MRI] and saline sono-hysterography) and suboptimal tests that can identify and differentiate most but not all anomalies (2D transvaginal ultrasound, hysteroscopy, HSG and clinical assessment at the time of Caesarean section). In an overall pooled sample of more than 89,000 women from 94 studies, the authors reported prevalence of different types of uterine anomalies in various population subtypes depending on whether they were subjected to optimal or suboptimal tests (Table 10.2). Overall, 5.5% (95% confidence interval [CI], 3.5–8.5) of the unselected population were shown to have a uterine anomaly diagnosed by an optimal test. The prevalence was not increased in women with infertility (8.0%; 95% CI, 5.3–12.0, P = 0.239) when compared with the unselected population. Women with a history of miscarriage (13.3%; 95% CI, 8.9–20; P = 0.011) and miscarriage in association with infertility (24.5%; 95% CI, 18.3–32.8; P = 0.001) were all shown to have significantly higher rates of uterine anomalies than the unselected population. The prevalence of congenital uterine anomalies diagnosed by optimal tests in women with two or more miscarriages (10.9%; 95% CI, 3.6–33.3) was not significantly different (P = 0.572) from those with three or more miscarriages (15.4%; 95% CI, 10.3–23). The prevalence of all uterine anomalies in various populations diagnosed by suboptimal tests was found to be consistent with those diagnosed by optimal tests (Table 10.2). The observed higher rate of major congenital uterine anomalies in the high-risk groups, with the exception of isolated subfertility, suggests a causal role in poor reproductive outcome.
Table 10.2 The prevalence of uterine anomalies in different study populations stratified by the accuracy of the diagnostic test used to classify uterine anomalies
| Population | Diagnostic test | Prevalence of all anomalies % (95% CI) | Arcuate % (95% CI) | Canalization defects % (95% CI) | Unification Defects | Others % (95% CI) | ||
|---|---|---|---|---|---|---|---|---|
| Bicornuate % (95% CI) | Unicornuate % (95% CI) | Didelphys% (95% CI) | ||||||
| Unselected | Optimal | 5.5 (3.5–8.5) | 3.9 (2.1–7.1) | 2.3 (1.8–2.9) | 0.4 (0.2–0.6) | 0.1 (0.1–0.3) | 0.3 (0.1–0.6) | 0.1 (0–2.2) |
| Suboptimal | 4.6 (2.3–9.1) | 2.2 (0.9–5.2) | 0.2 (0–0.9) | 0.2 (0–0.7) | 0.2 (0.1–0.5) | 0.1 (0.1–0.2) | 2.5 (1.6–3.7) | |
| Infertility | Optimal | 8.0 (5.3–12.0) | 1.8 (0.8–4.1) | 3.0 (1.3–6.7) | 1.1 (0.6–2.0)* | 0.5 (0.3–0.8)* | 0.3 (0.2–0.5) | 0.9 (0.4–1.8) |
| Suboptimal | 6.1 (3.9–9.5) | 5.8 (3.4–10.1) | 2.7 (1.5–4.6)* | 0.8 (0.5–1.4) | 0.8 (0.5–1.2) | 0.4 (0.2–0.9) | 1.0 (0.4–2.4) | |
| Miscarriage | Optimal | 13.3 (8.9–20)* | 2.9 (0.9–9.6) | 5.3 (1.7–16.8)* | 2.1 (1.4–3)* | 0.5 (0.3–1.1)* | 0.6 (0.3–1.4) | 0.9 (0.1–12.6) |
| Suboptimal | 15.8 (11.9– 20.9)* | 8.9 (6.4–12.4)* | 4.3 (2.3 – 8.2)* | 2.8 (1.6–5)* | 0.5 (0.3–0.9) | 0.6 (0.2–1.6) | 4.5 (2–9.8)* | |
| Mixed infertility & recurrent miscarriage | Optimal | 24.5 (18.3–32.8)* | 6.6 (2.8–15.7) | 15.4 (12.5–19)* | 4.7 (2.9–7.6)* | 3.1 (2–4.7)* | 2.1 (1.4–3.2)* | 0.3 (0–2.3) |
| Suboptimal | 31.8 (20.7–48.8) | No study found | None diagnosed | None diagnosed | 4.5 (1.5–14.1) | None diagnosed | 27.3 (17.2–43.3)* | |
Subgroup analyses showed that the specific anomalies, which were increased in the high-risk populations of miscarriage, are mainly canalization or resorption defects, namely subseptate or septate uteri, and unification or fusion defects. Of note, based on studies employing optimal tests, the most commonly diagnosed uterine anomaly in the unselected or general population was the arcuate uterus. The arcuate uterus is, however, no more prevalent in any of the high-risk groups studied than in the unselected population. The canalization defect was the most common anomaly in all of the high-risk groups (Table 10.2).
5 Diagnosis
While most uterine anomalies are asymptomatic and detected incidentally, accurate diagnosis and correct classification is important for appropriate counselling of women about their potential prognosis and risks associated with reproduction and for planning any intervention with a view to improve the reproductive outcome. Accurate evaluation of the internal and external contours of the uterus is the key in making a diagnosis and correctly classifying a uterine anomaly. Considering this, the gold standard test is the combination of laparoscopy and hysteroscopy as you can directly visualize both the external and internal uterine contours. However, imaging modalities such as ultrasonography, HSG, sonohysterogram and MRI are less invasive modes of screening and classifying various uterine anomalies [5]. HSG is an excellent method of evaluating the uterine cavity but definitive diagnosis requires evaluation of the external uterine contour, which is poorly defined by HSG. While conventional transvaginal ultrasound and HSG are good in screening for uterine anomalies, 3D ultrasound and MRI could correctly classify the type of anomaly [7, 8].
Conventional transvaginal ultrasound is minimally invasive and a less expensive way of assessing uterine morphology and ruling out uterine anomalies [9]. Timing the ultrasound study in the second half of menstrual cycle (secretory phase) provides more accurate visualization of the endometrium and is therefore more appropriate for evaluating the uterus for congenital anomalies. Visualization of double endometrial complex on a transverse plane is indicative of a uterine anomaly (Figure 10.2B), which could be a bicornuate, septate, subseptate or arcuate uterus. Systematic scanning through longitudinal plane of uterus may reveal a uterine complex which then disappears while moving to the opposite side, followed by appearance of a second uterine complex suggesting that the uterus may be bicornuate. The transverse plane provides more information and widely placed double endometrial echoes especially at the upper portion of uterus towards fundus and an indentation at the fundus on an oblique plane (if obtainable) are typical of a bicornuate uterus. However, 3D ultrasound through its unique feature of providing the coronal plane of uterus (Figure 10.2C) facilitates simultaneous visualization of both external (serosal surface) and internal (endometrial) contours of the uterine fundus and can correctly classify the uterine anomaly into bicornuate, septate or subseptate or arcuate uterus [10]. Uterus didelphys, although rarer, also shows two endometrial complexes in the transverse plane of conventional 2D scan whilst 3D ultrasound and the clinical demonstration of two cervices confirm the diagnosis. Two uterine horns may be symmetrical or asymmetrical and two separate vaginas may be seen on speculum examination. In cases of unicornuate uterus, a normal-looking long axis of the uterus is seen on one side in the pelvis with no or a rudimentary uterine shadow on the other side. A rudimentary or severely hypoplastic uterine horn is seen as isoechoic pear-shaped structure with or without a central thin echogenic endometrial line. On the transverse plane, at the level of the fundus, a beak-like projection from the endometrial shadow (cornua) is seen on one side. 3D ultrasound, again, is confirmatory, demonstrating a banana-shaped uterine cavity and single interstitial portion of fallopian tube in the coronal plane. Saline infusion sonography has been suggested as a method for diagnosing rudimentary horns as saline can be clearly seen in the unicornuate uterus, with no passage into the rudimentary horn.
