Sage Journals: Discover world-class research

Abstract

Congenital uterine anomalies are not uncommon. Many are asymptomatic and have been associated with normal and adverse reproductive outcomes. The interference of these anomalies with a patient's fertility is an interesting but still debatable issue, and the proper management of infertile women with many forms of these anomalies remains controversial. The current literature regarding the frequency and probable causes of infertility among women with congenital uterine anomalies is insufficient to allow any robust conclusions to be drawn. Diagnostic and selection bias, a lack of objective diagnostic criteria for the different anomaly types and heterogeneity of study designs have contributed to the conflicting results from different studies of the prevalence of these anomalies among the infertile and fertile populations. However, emerging evidence from recent literature suggests causal associations between these anomalies (particularly the septate uterus) and infertility, and demonstrates significant improvements in the fecundity of women with septate uteri and otherwise unexplained infertility after hysteroscopic metroplasty. This review provides a critical update of the state of knowledge regarding congenital uterine anomalies, our current understanding of their effect on fertility and discusses how they can be managed from the reproductive perspective.

Keywords

congenital fertility malformation Müllerian anomalies pregnancy reproductive outcome uterine anomalies

The uterus is responsible for many of the most crucial steps in the process of reproduction. Sperm migration, embryo implantation, fetal nourishment, development and growth, and finally, the process of labor and birth are all reliant on the existence of a structurally normal and functionally competent uterus. Congenital uterine anomalies may affect some or all of these uterine functions, precluding a successful pregnancy. These anomalies are not uncommon but many are asymptomatic and have been associated with both normal and adverse reproductive outcomes [1 –6]. However, at the individual level, their effect on fertility and pregnancy outcomes can be devastating. Furthermore, the proper management of infertile women with these anomalies remains controversial. In addition, these anomalies may be isolated or may be part of a complex syndrome affecting other organs and can therefore have other implications; for example, Müllerian agenesis, renal anomalies and cervicothoracicsomite dysplasia (MURCS association) and vertebra/anus/cardiac/trachea/esophagus/radius/renal/limb (VATER/VACTERL) anomalies syndrome are associated with unicornuate uterus with noncommunicating horn [7,8]. In particular, the association of congenital uterine anomalies with those of the urinary tract is well recognized; up to 40% of patients with a unicornuate uterus and 80% of those with uterus didelphys were found to also have renal anomalies [9 –13]. Furthermore, auditory defects were reported in over 22% of patients with Müllerian anomalies [14].

The interference of uterine anomalies with a patient's fertility is an interesting but still debatable issue. This review aims to provide an update of the state of knowledge regarding congenital uterine anomalies, our current understanding of their effect on fertility and we discuss how they can be managed from the reproductive perspective.

Normal & abnormal uterine development

Normal development

During week 6 of fetal life, the primitive gonads appear on the urogenital ridge, medial to the mesonephros [15,16], and the mesonephric (Wolffian) and paramesonephric (Müllerian) ducts develop. It has been suggested that Wolffian ducts act as a precursor/inducer for Müllerian formation [17] or as a guide in the downward growth of the Müllerian ducts [18]. By the seventh week, the SRY gene (the sex-determining region of the Y-chromosome) in male embryos stimulates gonadal differentiation into testes; these produce androgens and anti-Müllerian hormone, which promote the development of male internal genitalia from the Wolffian ducts, cause regression of Müllerian structures and cause virilization of the indifferent external genitalia. Conversely, absence of the SRY gene in female embryos allows the gonads to develop into ovaries. The subsequent lack of anti-Müllerian hormone causes regression of the Wolffian ducts and allows Müllerian 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. Müllerian development occurs separately from gonadal development, and women with Müllerian anomalies usually have normal ovaries and ovarian hormone production [19]. By contrast, Müllerian development occurs in close association with the development of the urinary tract, and renal anomalies are commonly identified in those with Müllerian anomalies [9 –13].

By the sixth week of fetal development, Müllerian ducts arise from longitudinal invaginations of the coelomic epithelium on the anterolateral surface of the urogenital ridges. The ducts develop bidirectionally – the proximal segments remain unfused to form the fallopian tubes while the distal segments progress caudomedially and join in the midline to form the uterovaginal primordium. By week 10, the latter contacts the dorsal wall of the urogenital sinus forming the Müllerian tubercle. Internal canalization of the Müllerian ducts then takes place. The fused caudal portions become divided by a septum, which then regresses in a caudocephalic direction (or bidirectionally [20 –23]) and is eventually resorbed to form the uterus with its normally developed configuration and triangular-shaped endometrial cavity, and also form the cervix and upper vagina. In addition to inducing Müllerian development, the Wolffian ducts form the sinovaginal bulbs, which, together with the Müllerian tubercle, form the vaginal plate [24,25]. By the 18th week, the core of the vaginal plate degenerates, forming the lumen of the lower vagina, and this process is complete by week 20 [26,27].

Abnormal development

Congenital uterine anomalies may result from: failure of one or both Müllerian ducts to develop (e.g., agenesis, hypoplasia or unicornuate uterus without rudimentary horn); failure of one or both ducts to canalize (e.g., rudimentary uterus or a unicornuate uterus with rudimentary horn); failure of migration, or abnormal fusion, of the ducts (e.g., uterus didelphys or bicornuate uterus); and failure of resorption of the intervening septum (e.g., a septate uterus or arcuate uterus) [28 –31]. The latter two groups constitute lateral fusion defects, which is the most common category of Müllerian defects [32]. In addition, vertical fusion defects may result from the abnormal fusion of Müllerian ducts with the urogenital sinus or from problems with vaginal canalization [33].

However, the most complex malformations are the mesonephric anomalies [17,34]. Wolffian ducts are a precursor/inducer of Müllerian development and are necessary for lower vaginal formation, and by providing the ureteral buds from their distal ends, they play a crucial role in renal development; hence, mesonephric anomalies are mostly associated with uterine malformations and also with the ipsilateral blind hemivagina and renal anomalies (mostly renal agenesis, but also cystic renal dysplasia, ectopic ureters and duplicate collecting systems [35 –40]). The ipsilateral blind hemivagina may or may not communicate with the bicornuate/septate uterus (with or without communicating uteri) depending on the coexistence of cervical/cervicovaginal atresia [12,33] or may be associated with uterus unicornis with a rudimentary horn in cases of additional atresia or hypoplasia of the corresponding hemiuterus [41,42].

Classification of congenital uterine anomalies

The first classification was introduced by Strassmann in 1907 [43]. Since then, there have been several classifications based on:

The degree of failure of Müllerian development and fusion [44 –47];

The flaws in vertical and lateral fusion leading to the occurrence of obstructive/nonobstructive and symmetrical/asymmetrical anomalies [48 –50];

Using precise aspects such as the presence of communicating/noncommunicating bicornuate or septate uteri [51];

The embryologic origin of different elements of the genitourinary tract [34,52 –54];

The anatomical structures of the female genital organs (e.g., vagina, cervix, uterus, adnexa-associated malformation [VCUAM] classification [55]).

There is no universally accepted standard classification for congenital uterine anomalies [33]; however, the classification described by the American Society of Reproductive Medicine (ASRM; formerly known as the American Fertility Society [AFS]) [47] remains the most widely used. This classification is based on the extent of failure of Müllerian development and divides anomalies into groups with similar clinical manifestations, management requirements and prognosis (Table 1) [28]. However, this classification is not without shortcomings; for example, it does not include combined/complex anomalies (i.e., rudimentary uterus [52,56], cervical atresia [57], unilateral cervicovaginal atresia in a didelphys uterus [54] and utero-, cervico-and/or vaginal septation [58 –60]), which are often incorrectly identified, inappropriately treated and sometimes inaccurately reported. Nor does this classification consider the accuracy of the methods used for detecting the anomaly [61 –72]. Furthermore, it does not specify criteria for making the diagnosis of each anomaly or group of anomalies [73,74].

Table 1.

The classification of Müllerian anomalies by the American Society of Reproductive Medicine.

Class	Description
I	Müllerian agenesis or hypoplasia (segmental, partial or complete):
Ia	– Vaginal
Ib	– Cervical
Ic	– Fundal
Id	– Tubal
Ie	– Combined
II	Unicornuate uterus (agenesis or hypoplasia of one of the two Müllerian ducts):
IIa	– With a communicating rudimentary horn
IIb	– With a noncommunicating rudimentary horn
IIc	– With a rudimentary horn with no cavity
IId	– With an absent rudimentary horn
III	Didelphys uterus (failure of lateral fusion of the vagina and uterus Müllerian ducts)
IV	Bicornuate uterus (incomplete fusion of the uterine horns at the level of the fundus):
IVa	Complete
IVb	Partial
V	Septate uterus (absent or incomplete resorption of the uterovaginal septum):
Va	– Complete
Vb	– Partial
VI	Arcuate uterus (a mild indentation at the level of the fundus from a near-complete resorption of the uterovaginal septum)
VII	Diethylstilbestrol-exposed uterus (T-shaped uterus resulting from diethylstilbestrol exposure of the patient in utero)

Adapted with permission from [28].

Troiano and McCarthy suggested that the AFS classification should function as a framework for describing anomalies, and that clinicians who are faced with complex/combined anomalies should describe them according to their component parts rather than categorizing them into the class that most approximates the dominant feature [75]. This approach was adopted by Acien et al. in their revised ‘Clinical and embryological classification of the malformations of the female genital tract’ (Table 2), which could lead to a better understanding of complex malformations before deciding on the best therapeutic approach [34]. The same approach was adopted by Oppelt et al. with the VCUAM classification (Table 3) [55], which describes anomalies by relating them to their anatomical origin, making it possible to identify complex anomalies in a precise fashion that makes it easier to provide suitable clinical care for affected patients [76]. These classifications are yet to be widely accepted among clinicians.

Table 2.

Clinical and embryological classification of the malformations of the female genital tract.

Class	Description
1	Agenesis or hypoplasia of a whole urogenital ridge: unicornuate uterus with uterine, tubal, ovarian and renal agenesis on the contralateral side
2	Mesonephric anomalies with absence of the Wolffian duct opening to the urogenital sinus and absence of the ureteral bud sprouting (and, therefore, renal agenesis occurs); the ‘inductor’ function of the Wolffian duct on the Müllerian duct is also failing and uterovaginal duplicity plus blind hemivagina ipsilateral with the renal agenesis is usually observed, which is clinically presented as:
2a	– Large unilateral hematocolpos†;
2b	– Gartner's pseudocyst on the anterolateral wall of the vagina†;
2c	– Partial reabsorption of the intervaginal septum, seen as a ‘buttonhole’ on the anterolateral wall of the normal vagina, which allows access to the genital organs on the renal agenesis side;
2d	–Vaginal or complete cervicovaginal unilateral agenesis, which is ipsilateral with the renal agenesis and with no communication or with communication between both hemiuteri (communicating uteri)
3	Isolated Müllerian anomalies affecting:
3a	– Müllerian ducts: the most common uterine malformations including unicornuate (generally, with a uterine rudimentary horn), bicornuate, septate and didelphys uterus;
3b	– Müllerian tubercle: cervicovaginal atresia and segmentary anomalies such as a transverse vaginal septum;
3c	– Both Müllerian tubercle and ducts: (uni- or bilateral) Mayer-Rokitansky-Kuster-Hauser syndrome
4	Anomalies of the urogenital sinus: cloacal anomalies and others
5	Malformative combinations: Wolfian, Müllerian and cloacal anomalies

†

These types of malformations can associate with a vaginal ectopic ureter and interseptal or interuterine communication.

Adapted with permission from [34].

Table 3.

The VCUAM classification: descriptions of the individual malformations relative to the organ.

Class	Description
Vagina (V)
0	Normal
1a	Partial hymenal atresia
1b	Complete hymenal atresia
2a	Incomplete septate vagina (50%)
2b	Complete septate vagina
3	Stenosis of the introitus
4	Hypoplasia
5a	Unilateral atresia
5b	Complete atresia
S1	Sinus urogenitalis (deep confluence)
S2	Sinus urogenitalis (middle confluence)
S3	Sinus urogenitalis (high confluence)
C	Cloacae
+	Other
#	Unknown
Cervix (C)
0	Normal
1	Duplex cervix
2a	Unilateral atresia/aplasia
2b	Bilateral atresia/aplasia
+	Other
#	Unknown
Uterus (U)
0	Normal
1a	Arcuate
1b	Septate (<50% of the uterine cavity)
1c	Septate (>50% of the uterine cavity)
2	Bicornate
3	Hypoplastic uterus
4a	Unilaterally rudimentary or aplastic
4b	Bilaterally rudimentary or aplastic
+	Other
#	Unknown
Adnexa (A)
0	Normal
1a	Unilateral tubal malformation, ovaries normal
1b	Bilateral tubal malformation, ovaries normal
2a	Unilateral hypoplasia/gonadal streak (including tubal malformation, if appropriate)
2b	Bilateral hypoplasia/gonadal streak (including tubal malformation, if appropriate)
3a	Unilateral aplasia
3b	Bilateral aplasia
+	Other
#	Unknown
Associated malformation (M)
0	None
R	Renal system
S	Skeletal
C	Cardiac
N	Neurologic
+	Other
#	Unknown

VCUAM: Vagina, cervix, uterus, adnexa-associated malformation.

Adapted with permission from [55].

Etiological factors

The etiology of congenital uterine anomalies is poorly understood, and there are many theories involving genetic, environmental and pharmacologic factors. The role of genetic factors remains unclear. Normal karyotyping was found in 92% of women with Müllerian anomalies while 7.7% of these women had abnormal karyotypes [77]. Several genes have been implicated in the development of Wolffian and Müllerian ducts (e.g., Pax2, Pax8, Limi1 and Emx2), although most data were derived from mouse models [17,78]. A strong association between Müllerian anomalies and auditory defects was reported [14,79] but a possible mutation contributing to this association could not be identified. Conversely, the BCL-2 gene (which is involved with regulating apoptosis) has been implicated in the persistence of the uterine septum, suggesting apoptosis as a potential mechanism by which regression of the uterine septum takes place [80].

Genetic patterns of inheritance have been described in the expression of Müllerian anomalies [81]. Hammoud et al. found that first-degree relatives of women with Müllerian anomalies had a 12-fold higher risk of developing an anomaly, indicating a strong familial tendency; however, owing to different phenotypic expressions of uterine anomalies among members of the same family, a specific genetic etiology for each type of anomaly was considered to be unlikely [82]. Ergun et al. reported a rare familial aggregation of septate uteri among three sisters [83], while Mikkila et al. described the X-linked laterality sequence in a family where the obligate female carriers had a uterine septum, which may be a gene-carrier manifestation [84]. However, the infrequent and sporadic nature of the majority of these anomalies suggests a polygenic or multifactorial mechanism [2]. During early pregnancy, exposure to extrauterine and intrauterine environmental factors, such as ionizing radiation (e.g., x-rays and ?-rays), intrauterine infections (e.g., rubella) or drugs with teratogenic effects (e.g., thalidomide and diethylstilbestrol), has been implicated in the causation of fetal genital tract defects [1,85].

Effect of congenital uterine anomalies on fertility

The association between uterine anomalies and adverse pregnancy outcomes, particularly recurrent miscarriage, is well recognized [4,5,86 –90]; however, the role of these anomalies in infertility, remains unclear [4,89 –92]. To establish whether congenital uterine anomalies have an effect on fertility, the following need to be assessed:

Potential mechanisms whereby uterine anomalies may exert an effect on fertility – this is important for establishing the plausibility of such an effect;

Possible associations between uterine anomalies and infertility – such associations would be existent if the prevalence of these anomalies was found to be higher among the infertile than the fertile population, or if infertility was more likely among those who have these anomalies;

Probable underlying causation (cause–effect relationship) where the presence of uterine anomalies would lead to infertility; consequently, treating these anomalies would improve fertility prospects.

Potential mechanisms for an effect on fertility

Several theories have been postulated to explain the potential adverse effects of congenital uterine anomalies on fertility and reproductive outcome. The evidence to support these theories, particularly with the milder anomalies (e.g., arcuate and subseptate uteri) is deficient and lacking. This is compounded by the fact that Müllerian defects can permit an absolutely normal obstetric outcome [5]. The role of the mechanical factors in cases of severe congenital uterine anomalies (e.g., Müllerian agenesis and cervical atresia) is evident [88]; these factors may also play an important role in cases of less severe anomalies (e.g., bicornuate and septate uteri) that are likely to impact on uterine capacity and the arrangement of uterine musculature (and may consequently cause cervical incompetence). However, such effects are likely to cause adverse pregnancy outcomes rather than impairment of fertility [31,93].

Embryo implantation is affected by the morphology, thickness and vascularity of the endometrium, and by the shape and integrity of the uterine cavity; these factors are likely to be altered with congenital uterine anomalies [94]. Therefore, these anomalies can affect endometrial receptivity, resulting in implantation failure that manifests as early pregnancy loss or infertility [90]. Furthermore, congenital absence of the endometrium has been reported [95]. Uterine septa were found in 9.7% of women who had experienced preclinical miscarriage after IVF [96], and improved results with IVF after hysteroscopic metroplasty were reported [97]. This suggests that a uterine septum may be an important factor predisposing to implantation failure and early pregnancy wastage.

The uterine septum is thought to consist of fibroelastic tissue with inadequate vascularization and an altered relationship between the myometrial and endometrial vasculatures; hence the poor response of the endometrial mucosa covering the septum to estrogen, causing poor proliferation and estrogenic maturation [98,99]. As a result, implantation may be compromised or the decidual growth may be inadequate, causing infertility or early pregnancy loss. It has been suggested that removing the septum may eliminate an unsuitable site for implantation, improve endometrial function, expand uterine capacity and dramatically enhance the reproductive outcome in selected patients [89]. Conversely, Dabirashrafi et al. found significantly less connective tissue, a greater proportion of muscle tissue and more vessels in the septum [100]. The authors suggested that pregnancy wastage is caused by poor decidualization and placentation owing to the reduced amounts of connective tissue, as well as by higher or uncoordinated contractility owing to the increased muscle content. It also has been suggested that estrogen and progesterone receptor deficiencies in the malformed uteri may further increase abnormal uterine contractility, which may impede implantation or cause early fetal wastage. Pellerito et al. performed MRI in patients with a septate uterus and found a muscular septal component, and this was confirmed by histological examination of biopsy specimens [62].

Several studies have suggested that the effects on fertility caused by congenital uterine anomalies could be mediated through other infertility factors. Sorensen found that infertility patients with mild Müllerian anomalies were three-times more likely than those with normal uterine cavities to also have oligo/amenorrhea (58.6 vs 19.6%, respectively; p < 0.01), which, in these cases, was almost three-times more likely to be idiopathic (82.4 vs 30%; p < 0.01) [101]. It has been suggested that a defect in steroid receptor proteins in the congenitally deformed uterus may be responsible for these patients' eugonadotropic oligo/amenorrhea. Ugur et al. found that in infertility patients, polycystic ovaries were more common among those with Müllerian anomalies (29.9 vs 20.1%; p < 0.01) [102], particularly in those with septate and bicornuate uteri. Endometriosis was found in 26.1 [30], 35 [103] and 43% [104] of women with septate uteri, reflecting a possible role for the uterine septum in the pathogenesis of endometriosis in these cases. However, there is little conclusive evidence to support these hypotheses.

Possible associations with infertility

The exact prevalence of congenital uterine anomalies is uncertain [88 –90]. Accurate assessment and comparison of the prevalence of these anomalies among the infertile and fertile populations in order to detect associations between these anomalies and infertility (if any) is compounded by several sources of bias. The use of different techniques with variable diagnostic accuracies, the lack of universally accepted objective diagnostic criteria for each anomaly, the inconsistency in interpreting the classification of uterine anomalies and the heterogeneity of the populations examined by various studies have all contributed to the difficulty in determining the true prevalence of congenital uterine anomalies [2 –4,69,74,75,89,105,106].

Diagnostic accuracy

Saravelos et al. evaluated the accuracy of the diagnostic procedures used for assessing congenital uterine anomalies [106]. The authors examined studies that have compared hysterosalpingography (HSG) [66 –67,71,107 –112], 2D-ultrasound scan (USS) [67,108,111 –113], hysterosonography [66,67,71,108 –110,112], 3D-USS [63,64,72,114 –116] and MRI with hysteroscopy. They calculated the diagnostic accuracy [117] for each procedure and then classified these procedures accordingly (Box 1). They concluded that hysteroscopy combined with laparoscopy, hysterosonography and 3D-USS are highly accurate in assessing and classifying congenital uterine anomalies and that they can be used as diagnostic tools. They found 2D-USS to be the least accurate method but, if used in conjunction with HSG, the accuracy is increased and it could serve as a valuable screening tool. They suggested that MRI could potentially be used for screening and possibly for diagnosing uterine anomalies, but the authors recommended that more studies should be conducted in order to evaluate its diagnostic accuracy.

Box 1.

Classification of the investigative procedures used for assessing congenital uterine anomalies according to diagnostic accuracy.

Class Ia

Investigations capable of accurately identifying congenital uterine anomalies and classifying them into appropriate subtypes (accuracy >90%):

– Hysteroscopy and laparoscopy

– Hysterosonography (sensitivity: 93%; specificity: 99%; accuracy: 97%)

– 3D-USS (sensitivity: 100%; specificity: 100%; accuracy: 100%)

Class Ib

Investigations capable of accurately identifying congenital uterine anomalies (accuracy >90%) without being able to classify them into appropriate subtypes:

– Hysteroscopy alone

Class II

Investigations capable of identifying congenital uterine anomalies with an accuracy of <90%:

– Hysterosalpingography (sensitivity: 78%; specificity: 90%; accuracy: 86%)

– 2D-USS (sensitivity: 56%; specificity: 99%; accuracy: 84%)

Class III

Investigations of which the accuracy in diagnosing congenital uterine anomalies is uncertain:

– MRI

– Physical examination during pregnancy or delivery

USS: Ultrasound scan.

Adapted with permission from [106].

Hysterosalpingography is a useful screening tool for providing information regarding the uterine cavity [28] and for diagnosing malformations with more aggressive morphological expressions [67]. However, since it does not evaluate the external uterine contour, HSG cannot reliably differentiate between septate and bicornuate uteri [70,75,89]. 2D-USS allows quantification of the observations but has low sensitivity (only identifies approximately half of the uterine anomalies), although it also has a low false-positive rate and its diagnosis is likely to be correct [75,118]. However, there are no universally accepted USS diagnostic criteria for congenital uterine anomalies. Hysterosonography has the advantage of improving the delineation of the internal uterine contour [119] and appears to be accurate, not only in diagnosing, but also in categorizing uterine anomalies into appropriate groups [112,120,121]. 3D-USS has a very high accuracy rate in diagnosing and classifying uterine anomalies [114], with high reproducibility (interobserver variability of only 1% [68]); therefore, introducing appropriate universally accepted diagnostic criteria and a classification of uterine anomalies using 3D-USS could improve the homogeneity of diagnoses. MRI offers a sensitive noninvasive approach of assessing the internal and external uterine contours [62,122,123] and could therefore replace invasive procedures such as laparoscopy for the diagnosis of a ‘double uterus’ [124]. However, owing to the lack of evidence, more studies are required to confirm its diagnostic accuracy.

Hysteroscopy is accurate in identifying congenital uterine anomalies and is often used to establish a definitive diagnosis following an abnormal HSG finding [28,67,88]. However, it does not allow for evaluation of the external uterine contour and is often inadequate in differentiating between different anomaly types; diagnostic laparoscopy is required for the correct differentiation between bicornuate and septate uteri, and this combination (hysteroscopy/laparoscopy) is considered as the gold-standard diagnostic investigative method for evaluating congenital uterine anomalies [4,28,88,90,119]. Hysteroscopy combined with laparoscopy also offers the advantage of concurrent treatment (e.g., resection of uterine septum). However, since there are no strict diagnostic criteria, this exclusively relies on the subjective impression of the clinician [74].

Diagnostic criteria

There are no universally accepted diagnostic criteria for the different types of congenital uterine anomalies. This and the low accuracy of the techniques used for making diagnoses in many of the studies has resulted in wide discrepancies in the reported prevalence of these anomalies; for example, using HSG angles of less than 75° and more than 105° between the uterine horns has been suggested to diagnose the septate and bicornuate uteri, respectively [28,75]. However, the majority of angles of divergence between the horns fall within this range and considerable overlap between these anomalies are noted [61].

Similarly, some authors [75,88,122] consider the uterus to be septate rather than bicornuate if the fundal indentation of the external contour (identified by USS) is greater than 5 mm above the interostial line, while others [28,74,114] have used a cut-off of 10 mm to differentiate between the two anomalies. A threshold of 10 mm of fundal indentation has also been used in laparoscopy [75]. Furthermore, an angle of less than 60° between the two indenting medial margins of the fundus has been used to distinguish between septate and bicornuate uteri. Using these criteria, 92% sensitivity and 100% specificity for diagnosing bicornuate uteri have been reported [113], yet the value of these criteria remains unclear. In addition, measurement of the serosal–endometrial thickness along the uterine fundal border in longitudinal sections has been used as a criterion to aid diagnosis [28]. However, there is no evidence in the literature of such criteria that describe the subseptate uterus and differentiate it from the arcuate deformity. Using MRI, the criteria used to distinguish bicornuate from septate uteri are often similar to those used for USS: a 10 mm threshold of fundal indentation, an intracornual distance of greater than 4 cm or an angle greater than 60° between the two indenting medial margins of the fundus [28].

Using office hysteroscopy, without the use of anesthesia, Bettocchi et al. proposed three criteria for differentiating between septate and bicornuate uteri: presence of vascularized tissue, sensitivity of the tissue based on its innervation and its appearance at incision (if suspected to be a septum) [73]. The authors reported successful office hysteroscopic metroplasty in 93.1% of patients, and in 83% of those who had laparoscopy, the diagnosis of a suspected bicornuate uterus was confirmed. However, further evaluation of the diagnostic accuracy using these criteria is required.

Prevalence among the general (fertile) populations

In addition to diagnostic bias, the difficulty in determining the true prevalence of these anomalies among the fertile population may relate to selection bias. Various studies have used different population samples to assess the prevalence of uterine anomalies (e.g., women undergoing sterilization [5,6,125] or being investigated for nonobstetric reasons [118], such as pelvic pain, abnormal uterine bleeding [126] or suspected fibroids [74]). These samples may not be representative of the fertile population, and such bias may result in overestimation of the prevalence of these anomalies among the fertile population.

The effect of these biases is likely to have been reflected in the wide discrepancy between the reported figures for the prevalence of congenital uterine anomalies from different studies (from < 0.5% [105,118] to almost, or over, 10% [3,74,126,127], with a number of studies reporting figures of approximately 2–4% [5,6,30,128] and others of approximately 5–6% [125,129 –131]); the lower figures were reported by studies that relied on 2D-USS or HSG [5,6,30,118,128], while the higher figures were reported by those that used 3D-USS, hysterosonography or hysteroscopy [74,125,126,130,131], reflecting the biasing effect of using different diagnostic methodologies among studies. Similarly, Nahum estimated the prevalence of congenital uterine anomalies to be 0.5% among the general and 0.17% among the fertile populations (an extremely low prevalence, which could be related to the inclusion of studies that have relied on physical examination after delivery for assessing the morphology of the uterine cavity) [105], while Grimbizis et al. calculated a prevalence of approximately 4.3% among the general population [4], but the estimate of Troiano and McCarthy was closer to 1% [75]. After considering the accuracy of the diagnostic methods used, Saravelos et al. estimated the prevalence of congenital uterine anomalies among the general population to be approximately 6.7% (range: 6.0–7.4%) based on class I studies (using 3D-USS, hysterosonography and hysteroscopy with and without laparoscopy), while their estimate was approximately 2.4% based on class II studies (using 2D-USS and HSG) [106]. The authors attributed the lower prevalence reported by class II studies to be due to possible underdiagnosis. They calculated an overall prevalence of 4.6% among the general population.

Similarly, diagnostic bias is likely to have impacted on the reported prevalence of the different uterine anomalies. This could explain the wide variation in the reported prevalence between studies, particularly of the milder forms of anomaly, such as arcuate uterus, for which estimates range from single figures [6,30,118,128] to over two-thirds of the reported anomalies [74,126,131]. This also explains the difficulty in differentiating between the septate and bicornuate uteri in cases of a ‘double uterus’ appearance observed in earlier studies, which was then overcome by adding laparoscopy to assess the outer uterine contour or by using 3D-USS [74,126,131]. Nahum reported the following distribution of prevalence: 7% for arcuate, 34% for septate, 39% for bicornuate, 11% for didelphic, 5% for unicornuate, and 4% for hypoplastic/aplastic uteri [105]. By contrast, Grimbizis et al. reported a higher prevalence for arcuate (~20%) and septate (~35%) uteri followed by bicornuate (~25%) uteri; these were the most common anomalies, while unicornuate (~10%), didelphys (~8%) and Müllerian agenesis (~3%) were less common [4]. Recently, Saravelos et al. found that the most common anomaly was the arcuate, followed by the septate then bicornuate uterus (following the inverse sequence of the embryological events that occur during uterine formation) at a ratio of approximately 17:7:1 [106]. In the latter review, this discrepancy may be explained by the inclusion of studies that used 3D-USS or hysterosonography, which have a higher diagnostic accuracy and are capable of detecting mild forms of anomaly such as an arcuate uterus, which is likely to be missed by HSG and 2D-USS, which were used by the earlier studies.

Prevalence among the infertile population

Similarly, the exact prevalence of congenital uterine anomalies among the infertile population is unknown. Diagnostic bias is likely to have occurred owing to the use of different investigative methods. In addition, selection bias may have impacted on the quoted prevalence reported by different studies owing to the use of different infertility definitions and/or different inclusion criteria (e.g., duration of infertility [5]; primary/secondary infertility [108,110,132]; any cause/tubal/unexplained infertility [133,134]; women undergoing infertility investigation/IVF [64,115,126]; and/or women with oligomenorrohea/polycystic ovaries [101,102]). However, selection and diagnostic biases per se do not fully explain the extreme variation in the prevalence of uterine anomalies among the infertile population reported by different studies, which range from approximately 1% [132] (which could be attributed to inadequate assessment of uterine morphology in earlier studies) to figures between one- and two-thirds of the samples examined [64,110,114,115,134] (which may be related to selective sampling in these studies or to the inclusion of cases of past recurrent pregnancy loss, which are more likely to have uterine anomalies). However, most studies reported figures between 5 and 20% [3,67,70,102,108,119,126,133], and the higher figures tend to have been reported by the more recent studies.

Nahum estimated the prevalence of congenital uterine anomalies among the infertile population to be 3.5% (which is over 20-fold higher than the author's estimated prevalence among the fertile population [0.17%]) [105]. Grimbizis et al. calculated a similar incidence (3.4%) among the infertile population [4]; however, their estimated prevalence among the general population was much higher than Nahum's estimate of the prevalence among the fertile population (4.3 vs 0.17%, respectively). In addition to the effect of using different diagnostic methodologies, this could also be attributed to the different characteristics of the population groups in the reporting studies that were included in each review. Saravelos et al. estimated the prevalence of uterine anomalies among the infertile population to be approximately 7.3% (range: 6.7–7.9%) based on class I studies (studies of hysterosonography, 3D-USS and hysteroscopy with/without laparoscopy), while their estimate based on class II studies (studies of 2D-USS or HSG) was approximately 10.8% (a higher prevalence that may be related to selective sampling) [106]. Their overall estimate of the prevalence of uterine anomalies among the infertile population was approximately 8.1% (a higher estimate than those of earlier reviews, which could be related to the inclusion of studies that used more accurate diagnostic methods). The authors found the prevalence of uterine anomalies among the infertile and general populations to be comparable based on class I studies (7.3 vs 6.7%). However, when class II studies were included, the prevalence among the infertile population was higher than that among the general population (8.1 vs 4.6%); although this must be interpreted with caution in view of the potential effect of diagnostic bias, especially in class II studies.

Nahum found significant differences in the distributions of different anomaly types between the fertile and infertile populations [105]. Compared with the fertile group, there were higher proportions of aplastic/hypoplastic (15 vs 3%) and unicornuate (11 vs 4%) uteri among the infertile group, while the bicornuate (25 vs 41%) and didelphic (8 vs 12%) uteri were proportionately under-represented and the septate and arcuate uteri had similar distributions among the two groups. These distributions are likely to have been influenced by selection and/or diagnostic biases. Grimbizis et al. found their distribution estimate of uterine anomalies to be closer to reality (septate was estimated to be most prevalent [~35%] followed by bicornuate [~25%] then arcuate [~20%], unicornuate [~10%] and, finally, didelphys [~8%] uteri) [4]. Similarly, Saravelos et al. found the septate uterus to be the most common uterine anomaly among the infertile population but this was followed by the arcuate then bicornuate uteri (at a ratio of ~4:2:1), which differs from their findings in the general population where the arcuate uterus was twice as common as the septate uterus [106]. The authors suggested possible associations between the septate, unicornuate and hypoplastic uteri and infertility (since they found their prevalence to be relatively higher among the infertile compared with the general population, with the septate uterus being 3.5-fold higher among the infertile population [3.9 vs 1.1%, respectively]).

Comparison of the prevalence among the fertile & infertile populations

To uphold such a comparison and to consequently establish whether congenital uterine anomalies have an effect on fertility, a number of principals need to be set:

To demonstrate the effect (if existent) of uterine anomalies on fertility; their prevalence among the fertile, rather than general, population is more relevant;

The common causes of infertility should be ruled out in the infertile population, or otherwise clearly stated, since these coincidental factors may confound the observed prevalence of uterine anomalies among the infertile population;

The arcuate uterus is considered by many as a ‘normal variant’, while others consider this to have an adverse effect on reproductive outcome; therefore, for the purpose of assessing an association with infertility, the prevalence of uterine anomalies among the different populations should be estimated including and excluding the arcuate uterus;

Different types of uterine anomalies may have different associations with infertility and studying the prevalence of specific anomaly types is more important and more clinically relevant than studying the overall prevalence;

The effect of diagnostic bias on the results of the reporting studies on the prevalence of uterine anomalies among different populations should be considered.

First, to assess the possible association of a variable with infertility, it is best to carry out a comparison between the prevalence of that variable among fertile women who have had a pregnancy and the prevalence among infertile women, regardless of whether they have or have not sought medical advice. For this reason, using a group of women with nonobstetric causes for investigation (e.g., abnormal uterine bleeding) as the comparison group for the purpose of assessing the association of uterine anomalies with infertility would appear to be inappropriate (also in view of potential associations of such causes with uterine anomalies and/or infertility). Furthermore, studies of the prevalence of uterine anomalies among the fertile population that include women following giving birth or those attending hospitals for sterilization, exclude those whose pregnancies have all ended in miscarriages. Yet from the purpose of assessing the exclusive association between uterine anomalies and infertility, this exclusion seems to be appropriate given the well-recognized association between these anomalies and recurrent miscarriage.

Second, the infertility of a proportion of women in the group used for estimating the prevalence of uterine anomalies among the infertile population may be related to one or more of the common infertility causes. The occurrence of these causes in those cases may be totally incidental or there may be an association between these causes and uterine anomalies (further discussed in the section titled ‘Potential mechanisms for an effect on fertility’). Therefore, for the purpose of assessing an exclusive effect (if any) of uterine anomalies on fertility, common infertility causes need to be ruled out in the group used to estimate their prevalence among the infertile population, otherwise these causes should be sought and clearly stated, which may help to establish associations between these infertility causes and uterine anomalies.

Third, the arcuate uterus has the same embryological origin and requires the same therapy as the subseptate uterus but, since it appears extremely unified and seems to behave benignly, it was considered in the AFS classification as a separate entity. For those reasons, the arcuate uterus is considered, by many, as a normal variant [105,135]. Raga et al. found that women with an arcuate uterus had a live-birth rate of 82.7% and concluded that this has no impact on reproduction [5]. Nahum suggested that the arcuate uterus does not predispose to infertility [105]. Saravelos et al. considered the arcuate uterus not to have a role in infertility since they found its prevalence among infertile and general populations to be comparable (2.1 vs 2.4%, respectively) [106]. Conversely, other studies implied associations between the arcuate uterus and recurrent miscarriage and concluded that its impact on reproductive outcome should not be underestimated [74]. Tur-Kaspa et al. found the arcuate uterus to be more common among infertile women relative to those with abnormal uterine bleeding (15 vs 6.4%), suggesting an association with infertility [126]. In addition to this controversy, the classification as having an arcuate or subseptate uterus depends on the estimation of the severity of midline uterine abnormality, which is subjective [4]. Thus, until the effect of an arcuate uterus (especially on fertility) is further clarified, the prevalence of uterine anomalies among different populations should be estimated, including and excluding the arcuate uterus.

Fourth, in addition to the variation in the overall prevalence of uterine anomalies between different populations, as mentioned previously, several studies found that the distribution of different anomaly types (and, consequently, their relative frequencies) also varies between populations. Furthermore, other studies suggested that different uterine anomaly types may be associated with different patterns of adverse reproductive outcome. (Woelfer et al. found that women with subseptate uteri had a significantly higher proportion of first-trimester loss, while those with arcuate uteri had a significantly greater proportion of second-trimester loss and preterm labor [74]. This finding could suggest a different mechanism of miscarriage for these two types of uterine anomalies [106]). In addition, the occurrence of adverse reproductive outcome was also found to be related to the extent of distortion of the uterine anatomy associated with any one specific anomaly type – Salim et al. found that among women with arcuate and subseptate uteri, the length of the remaining uterine cavity was significantly shorter and the distortion ratio was significantly higher in those who had adverse pregnancy outcomes compared with the low-risk group [131]. Furthermore, the surgical therapy required and subsequent prognosis varies between different uterine anomaly types (this was the basis for the AFS classification). Therefore, different types of uterine anomalies may have different associations with infertility, and determining the prevalence of specific anomaly types among the fertile and infertile populations may be more important and more clinically relevant than the overall prevalence.

Fifth, the effect of diagnostic bias on the reporting studies regarding the prevalence of congenital uterine anomalies among the different populations has been discussed previously in this article.

None of the earlier published reviews regarding the prevalence of congenital uterine anomalies among fertile and infertile populations have considered all of these principals. This may explain the conflicting results and the continuing controversy as to the effect of these anomalies on fertility. Acien recorded hardly any difference between the prevalence of uterine anomalies among the general population and infertile women [3]. Nevertheless, this review has limitations and is likely to have been influenced by diagnostic bias in view of the investigative methods used. Furthermore, in almost half of the reported cases that were included in the review, the diagnostic methods used were not clearly stated [136,137]. In addition, the lack of a standard classification system and the fact that the populations studied may not be representative of the fertile population are further biasing factors in that review. Nahum found a significant difference between the prevalence of uterine anomalies among fertile and infertile populations, suggesting an association with infertility [105]. Studies in this review included subjects that seem to be representative of these populations, but the major shortcoming is related to diagnostic bias resulting from the inclusion of studies that relied on less accurate methods for detecting/classifying uterine anomalies (explaining the very low prevalence of uterine anomalies among the fertile population reported in that review). Grimbizis et al. excluded studies with seriously deficient methodology [136,137] and reported a similar prevalence of uterine anomalies among the general and infertile populations (4.3 and 3.4%, respectively); they concluded that Müllerian defects have no impact on women's fertility [4]. However, these figures are likely to be influenced by selection bias owing to the inclusion of studies of women with nonobstetric causes and those with recurrent miscarriage (which explains the relatively higher prevalence of uterine anomalies among the general population reported in this review). Furthermore, the potential effects of diagnostic bias in the studies included in this review have not been adequately explored.

Saravelos et al. appear to have adequately considered the effect of potential bias resulting from using different diagnostic procedures [106]. They estimated the prevalence of uterine anomalies among the general population as 4.6% overall (6.7 and 2.4% based on class I and II studies, respectively), while their estimate among the infertile population was 8.1% (7.3 and 10.8%, respectively). This clearly highlights the marked influence of using different diagnostic procedures on the observed prevalence of uterine anomalies. However, selection bias is likely to have influenced these estimates; six out of the 12 studies (including all class Ia studies [Box 1]) used subjects with nonobstetric causes or recurrent miscarriage. From the fertility perspective, the prevalence of uterine anomalies among the general population reported in this article is likely to be an overestimation. Similarly, many of the studies included in the review used highly selected subjects in the infertile populations. However, the review provides significant results regarding the distribution of different anomaly types among both populations: the prevalence of septate uterus was over three-times higher among the infertile population, and unicornuate, bicornuate and hypoplastic uteri were also more common among the infertile relative to general population, suggesting associations between these forms of uterine anomalies and infertility.

Infertility among women with congenitally malformed uteri

The frequency and likely causes of infertility, particularly the incidence of unexplained infertility, among women with congenital uterine anomalies relative to women with normal uteri could provide information relating to the impact of these anomalies on fertility. However, there is an evident lack of data regarding the fertility of women with congenital uterine anomalies. Acien found that 19.3% of women with uterine anomalies were infertile – an incidence comparable to that of a control group and is close to the reported approximate 15% incidence among the general population [86]. The author found that the incidence of unexplained infertility among infertile women with uterine anomalies (29.4%) was comparable to that among the infertile population as a whole [138 –141]. These data do not support the concept of uterine anomalies as an infertility factor. Conversely, Grimbizis et al. found that among infertile women with septate uteri, the incidence of unexplained infertility in the subgroup that had had a previous pregnancy (40%) was much higher than that in those with primary infertility (3.8%) [31], suggesting a role for the septate uterus in delayed conception in cases of secondary infertility. Other studies have also associated the septate uterus with infertility [103,142]. In addition, several studies suggested associations between uterine anomalies and infertility factors (e.g., idiopathic oligo/amenorrhea, polycystic ovaries and endometriosis [101 –104]), implying potential links between uterine anomalies and infertility.

Several studies of assisted conception among infertile women with and without uterine anomalies demonstrated similar implantation and pregnancy rates in the two populations. Marcus et al. found that 79.2% of infertile patients with uterine anomalies became pregnant after a mean of 2.1 IVF attempts per patient, regardless of the type of uterine anomaly they had, yet those with uncorrected uterine anomalies were more likely to have a poor pregnancy outcome compared with their counterparts with normal uteri [143]. In addition, Guirgis and Shrivastav reported a pregnancy rate of 57.1% among patients with a bicornuate uterus who were treated with gamete intrafallopian transfer procedures after a mean of 2.1 attempts per patient [144]. Conversely, in a study of women who had preclinical miscarriages after IVF, Dicker et al. suggested the incomplete uterine septum to be an important infertility factor, predisposing to implantation failure and early pregnancy wastage [96]. Furthermore, Syrop et al. and La Sala et al. demonstrated that approximately 18% of patients in whom IVF-embryo transfer repeatedly failed had important previously unsuspected endouterine anomalies, suggesting a potential role of uterine anomalies in the failure of IVF-embryo transfer [145,146].

Probable underlying causation of infertility

If there were to be a cause–effect relationship between congenital uterine anomalies and infertility, then correction of these anomalies would be associated with significant improvements in subsequent fertility prospects. There is strong evidence to support the effectiveness of hysteroscopic metroplasty in cases of uterine anomalies with earlier poor reproductive outcome, with decreases in miscarriage ranging from 88 to 14%, and 80% of these will have a term livebirth after metroplasty compared with 3% before metroplasty [4,88 –90]. However, for cases of primary infertility, metroplasty is a controversial and much debated issue [4,147]. Owing to the lack of robust evidence based on randomized trials among infertile women with uterine anomalies to compare those who have had metroplasty versus those with no treatment, the proper management of these women remains contentious [90]. Since removal of the septum may potentially prevent miscarriage and preterm birth, if these women are to conceive, it has been argued that metroplasty should be considered in these cases [88,137,148,149]. However, since many women with septate uteri can still have reasonable pregnancy outcomes and since there is no established causal relationship between the septate uterus and infertility, the controversy remains as to whether infertile women who have a septate uterus should undergo metroplasty [150,151].

Several relatively small studies suggest that women with septate uteri and primary infertility may benefit from metroplasty [31,103,104,152 –158], although the improvement observed in pregnancy and term live-birth rates is relatively modest (29.5%) [142]. These rates are significantly higher in women after metroplasty who previously suffered recurrent pregnancy loss, which highlights the difference in fertility between the two populations [88,103,142]. Daly et al. reported a pregnancy rate of 53.8% in infertile patients after septum resection [153]. Similarly, Goldenberg et al. reported a pregnancy rate of 54% after hysteroscopic metroplasty in patients with a uterine septum and primary infertility [157]. In their view, the chances of conception in these patients appear to be similar to those of the general infertile population with or without septum resection. They concluded that a uterine septum per se is not an infertility factor, but hysteroscopic metroplasty may be indicated for improving pregnancy outcome in these women.

However, heterogeneity, small sample sizes, retrospective design, self-control design and the absence of control groups makes the interpretation of results from these studies difficult. In addition, results of assisted conception studies were inconsistent. Marcus et al. found similar implantation and pregnancy rates after IVF in women with untreated septate uteri and those of the general infertile population, suggesting that metroplasty would not be useful in these patients without prior reproductive failure [143]. Lavergne et al. found significantly lower implantation and pregnancy rates after IVF in infertile women with untreated uterine anomalies relative to the general infertile population [159]. In addition, when patients were divided into groups according to the treatment received, the difference was found to be annulled when patients had metroplasty. It was suggested that IVF is less successful in women with a septate uterus relative to those who have had metroplasty, and this procedure was recommended for before undergoing IVF [159].

Furthermore, emerging evidence from recent studies demonstrates significant improvements in the fecundity of women with a septate uterus and otherwise unexplained infertility after hysteroscopic metroplasty. In a prospective self-control study of women with septate uteri and unexplained infertility, Pabuccu and Gomel reported a pregnancy rate of 41% after metroplasty [142]. The authors suggested that such a percentage supports the idea of the existence of a ‘subtle factor’ that is able to impair implantation in these patients. In addition, in a prospective controlled study of women with a septate uterus and otherwise unexplained infertility who underwent hysteroscopic metroplasty, Mollo et al. reported significantly higher pregnancy (38.6 vs 20.4%; p = 0.016) and live-birth rates (34.1 and 18.9%; p < 0.05) in the study group than in the control group of women with unexplained infertility [160]. Using survival analysis, the authors found that the probability of conception within 12 months was significantly higher (p < 0.05) in patients who underwent metroplasty than in women with unexplained infertility (fecundity rates of 4.27 and 1.92 person-months were observed, respectively). In addition, in a prospective controlled study of patients who had complete uterine septum with a double cervix and vagina who either underwent metroplasty or no treatment, Lin et al. reported significantly higher cycle fecundity (33.4 vs 12.2%; p = 0.046) and term delivery (88.9 vs 14.3%; p = 0.001) among those who underwent metroplasy relative to the untreated group [161]. Despite the fact that the latter two studies were not randomized trials comparing treated and untreated women with septate uteri, these studies provide the best evidence to date for a causal association between the septate uterus and infertility.

Conclusion

The effect of congenital uterine anomalies on fertility has been a much debated subject. Diagnostic and selection bias, a lack of objective diagnostic criteria and an appropriate classification system of different anomaly types, and heterogeneity of study design have contributed to the conflicting results from different studies regarding the prevalence of these anomalies among the infertile and fertile populations. When the accuracy of the diagnostic procedures used was taken into account, it appeared that the prevalence of the septate uterus was over three-times higher (and those of unicornuate and hypoplastic uteri were also higher) among infertile women than in the general population, suggesting associations with infertility. Furthermore, recent evidence reveals significant improvements in pregnancy and livebirth rates and a significantly higher probability of conception and cycle fecundity among women with septate uteri and otherwise unexplained infertility, who underwent hysteroscopic metroplasty relative to women with unexplained infertility and also relative to those with an untreated septate uterus. Despite the fact that this is not based on randomized trials comparing treated and untreated women with septate uteri, this evidence is the best evidence to date for a causal association between the septate uterus and infertility. It may be that uterine anomalies are more closely related to recurrent miscarriage then infertility. However, based on current evidence, infertile women who have no apparent cause for infertility should be offered an investigative procedure (e.g., 3D-USS, hysterosonography or hysteroscopy) and those who are found to have a congenitally malformed uterus (particularly septate uterus) should be counseled regarding the potential association with infertility and should be offered hysteroscopic metroplasty (particularly in women with prolonged infertility, women older than 35 years of age and those who are planning to pursue assisted conception).

Future perspective

We believe that a diagnostic method for detecting congenital uterine anomalies (e.g., 3D-USS or hysterosonography) will be a standard part of the infertility work-up. Infertile women who are found to have a uterine septum will be routinely offered hysteroscopic metroplasty, which will be most often carried out as an office procedure.

Executive summary

Background

The interference of congenital uterine anomalies with fertility is still a debatable issue and the proper management of infertile women with these anomalies remains controversial.

Normal uterine development

The Wolffian ducts may act as a precursor/inducer for Müllerian duct formation or as a guide in the downward growth of the Müllerian ducts.

In female embryos, absence of the SRY gene allows the gonads to develop into ovaries, and the subsequent lack of anti-Müllerian hormone and androgens causes regression of the Wolffian ducts and allows Müllerian ducts to develop into fallopian tubes, the uterus and the upper vagina.

Abnormal uterine development

Müllerian anomalies may result from the failure or malformation of some or all of a series of events including: Müllerian duct formation, elongation, fusion, canalization and septal resorption.

Lateral fusion defects are the most common category of Müllerian anomalies, but the most complex malformations tend to be the mesonephric anomalies.

Classification of uterine anomalies

There is no universally accepted standard classification for anomalies of the female reproductive tract, but the American Fertility Society (AFS) classification remains the most widely used.

The AFS classification system should function as a framework for the description of anomalies, rather than as an exhaustive list of all possible anomaly types.

Etiological factors

The etiology of congenital uterine anomalies is poorly understood and there are many theories involving genetic, environmental and pharmacologic factors. The pattern of familial clustering of uterine anomalies suggests a polygenetic or multifactorial mechanism.

Potential mechanisms for an effect on fertility

Several theories have been postulated, but the evidence in many cases, particularly for the milder forms of uterine anomalies, is deficient and lacking.

Mechanical factors are likely to have an important role in the effect of uterine anomalies on fertility, particularly in cases of severe congenital uterine anomalies.

The endometrial morphology, thickness and vascularity are likely to be altered in cases of congenital uterine anomalies.

Congenital uterine anomalies can affect endometrial receptivity, resulting in implantation failure that manifests as recurrent early pregnancy loss or infertility.

The effect of congenital uterine anomalies on fertility may be mediated through other infertility factors.

Prevalence of congenital uterine anomalies

The true and exact prevalence of congenital uterine anomalies is uncertain, and there are wide discrepancies between the reported figures from different studies.

Difficulties in determining the true prevalence of congenital uterine anomalies relate to the variation in diagnostic accuracy of the techniques used, the lack of objective diagnostic criteria, the inconsistency in interpreting the classification system, the asymptomatic nature of many anomalies, the selective sampling in many studies and the heterogeneity of the populations studied.

Hysteroscopy combined with laparoscopy, 3D-ultrasound and hysterosonography are highly accurate in diagnosing and classifying uterine anomalies; if 2D-ultrasound is used in conjunction with hysterosalpingography, it can serve as a valuable screening tool. The potential role of MRI requires further evaluation.

Potential association with infertility

The current literature on the frequency and probable causes of infertility among women with congenital uterine anomalies is too limited to draw any robust conclusions.

The existent prevalence literature provides conflicting results and conclusions. For accurate assessment and comparison of the prevalence of uterine anomalies among the infertile and fertile populations, a number of principals relating to the sampling of populations, study design and methodology need to be considered.

Evidence form the recent literature indicates that the prevalence of the septate uterus is markedly higher among the infertile population relative to the general population, suggesting an association with infertility.

Possible causal relationship with infertility

There is an apparent lack of robust evidence, based on trials among infertile women with uterine anomalies, to compare fertility prospects in women after undergoing metroplasty versus those with no treatment, and the proper management of these women remains contentious.

Emerging evidence from more recent prospective controlled studies demonstrates significant improvements in the fecundity of women with a septate uterus and otherwise unexplained infertility after hysteroscopic metroplasty relative to women with unexplained infertility and a normal uterus, suggesting a causal association between the septate uterus and infertility.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

References

Papers of special note have been highlighted as:

of interest

of considerable interest

Lin

Bhatnagar

Nettleton

Nakajima

: Female genital anomalies affecting reproduction. Fertil. Steril. 78, 899–915 (2002).

Propst

Hill

3rd : Anatomic factors associated with recurrent pregnancy loss. Semin. Reprod. Med. 18, 341–350 (2000).

Acien

: Incidence of Mullerian defects in fertile and infertile women. Hum. Reprod. 12, 1372–1376 (1997).

Grimbizis

Camus

Tarlatzis

Bontis

Devroey

: Clinical implications of uterine malformations and hysteroscopic treatment results. Hum. Reprod. Update 7, 161–174 (2001).

Raga

Bauset

Remohi

: Reproductive impact of congenital Mullerian anomalies. Hum. Reprod. 12, 2277–2281 (1997).

Simon

Martinez

Pardo

: Mullerian defects in women with normal reproductive outcome. Fertil. Steril. 56, 1192–1193 (1991).

10.

Hofstetter

Concin

Marth

Rinne

Erdel

Janecke

: Genetic analyses in a variant of Mayer-Rokitansky-Kuster-Hauser syndrome (MURCS association). Wien. Klin. Wochenschr. 120(13–14), 435–439 (2008).

11.

Nunes

Karandikar

Cooper

Jaganathan

Irani

: VATER/VACTERL syndrome (vertebra/anus/cardiac/trachea/esophogus/radius/renal/limb anomalies) with a noncommunicating functioning uterine horn and a unicornuate uterus: a case report. Fertil. Steril. 91(5), 1957.E11–E12 (2009).

12.

Fedele

Bianchi

Agnoli

Tozzi

Vignali

: Urinary tract anomalies associated with unicornuate uterus. J. Urol. 155, 847–848 (1996).

13.

Oayvum

Coakley

Hedvig

: Association of renal agenesis and Mullerian duct anomalies. J. Comput. Assist. Tomogr. 24, 829–834 (2000).

14.

Barakat

: Association of unilateral renal agenesis and genital anomalies. Case Rep. Clin. Pract. Rev. 3, 57–60 (2002).

15.

Acien

Sanchez-Ferrer

Mayol-Belda

: Unilateral cervico-vaginal atresia with ipsilateral renal agenesis. Eur. J. Gynecol. Reprod. Biol. 117(2), 249–251 (2004).

16.

Oppelt

von Have

Paulsen

: Female genital malformations and their associated abnormalities. Fertil. Steril. 87, 335–342 (2007).

17.

Rabinson

Orvieto

Shapira

Brownstein

Meltzer

Tur-Kaspa

: Mullerian anomalies, hearing loss, connexin 26 mutations. Fertil. Steril. 85, 1824–1825 (2006).

18.

Lin

Bhatnagar

Nettleton

Nakajima

: Female genital anomalies affecting reproduction. Fertil. Steril. 78, 899–915 (2002).

19.

Motta

Nottola

Makabe

: Natural history of the female germ cell from its origin to full maturation through prenatal ovarian development. Eur. J. Obstet. Gynecol. Reprod. Biol. 75, 5–10 (1997).

20.

Hannema

Hughes

: Regulation of Wolffian duct development. Horm. Res. 67, 142–151 (2007).

21.

Marshall

Beisel

: The association of uterine and renal anomalies. Obstet. Gynecol. 51, 559–562 (1978).

22.

Clinical Gynecologic Endocrinology and Infertility. (6th Edition). Speroff

Glass

Kase

(Eds). Lippincott Williams & Wilkins, PA, USA (1999).

23.

McBean

Brumsted

: Septate uterus with cervical duplication: a rare malformation. Fertil. Steril. 62, 415–417 (1994).

24.

Balasch

Moreno

Martinez-Romans

: Septate uterus with cervical duplication and longitudinal vaginal septum: a report of three new cases. Eur. J. Obstet. Gynecol. Reprod. Biol. 65, 241–243 (1996).

25.

Muller

Musset

Netter

Solal

Vinourd

Gillet

: Etat du haut appareil urinaire chez les porteuses de malformations uterines: etude de 133 observations. Presse Med. 75, 1331–1336 (1967).

26.

Acien

Sanchez-Ferrer

: Mullerian anomalies ‘without a classification’: from the didelphys-unicollis uterus to the bicervical uterus with or without septate vagina. Fertil. Steril. 91, 2369–2375 (2009).

27.

Bok

Drews

: The role of the Wolffian ducts in the formation of the sinus vagina: an organ culture study. J. Embryol. Exp. Morphol. 73, 275–295 (1983).

28.

Acien

: Embryologic observations of the female genital tract. Hum. Reprod. 7, 437–445 (1992).

29.

Larsen

: Development of the urogenital system. In: Human Embryology. Churchill Livingstone, NY, USA 235–279 (1993).

30.

Moore

Persaud

: The urogenital system: the development of the genital system. In: The Developing Human: Clinically Oriented Embryology (6th Edition). Saunders, PA, USA 303 (1998).

31.

Letterie

: Structural Abnormalities and Reproductive Failure: Effective Techniques of Diagnosis and Management. Blackwell Science, NY, USA (1998).

32.

Devi Wold

Pham

Arici

: Anatomic factors in recurrent pregnancy loss. Semin. Reprod. Med. 24, 25–32 (2006).

33.

Ashton

Amin

Richart

Neuswirth

: The incidence of asymptomatic uterine anomalies in women undergoing transcervical sterilization. Obstet. Gynecol. 72, 28–30 (1988).

34.

Grimbizis

Camus

Clasen

: Hysteroscopic septum resection in patients with recurrent abortions and infertility. Hum. Reprod. 13, 1188–1193 (1998).

35.

Iverson

DeCherney

Laufer

: Clinical manifestations and diagnosis of congenital anomalies of the uterus. In: UpToDate. Rose

(Ed.). Waltham, MA, USA (2007).

36.

Rackow

Arici

: Reproductive performance of women with Mullerian anomalies. Curr. Opin. Obstet. Gynecol. 19, 229–237 (2007).

37.

Acien

Sanchez-Ferrer

: Complex malformations of the female genital tract. New types and revision of classification. Hum. Reprod. 19, 2377–2384 (2004).

38.

Constantian

: Ureteral ectopia, hydrocolpos and uterus didelphys. JAMA 197, 54–56 (1966).

39.

Currarino

: Single vaginal ectopic in the Gartner duct cyst with ipsilateral renal hypoplasia and dysplasia (or agenesis). J. Urol. 128, 988–993 (1982).

40.

Gilsanz

Cleveland

: Duplication of the Mullerian ducts and genitourinary malformations. Part I: the value of excretory urographs. Part II: analysis of malformations. Radiology 144(4), 793–796 (1982).

41.

Gotoh

Koyanagi

: Clinicopathological and embryological considerations of single ectopic ureters opening into Gartner's duct cyst: a unique subtype of single vaginal ectopia. J. Urol. 137, 969–972 (1987).

42.

Gruenwald

: The relation of the growing Mullerian duct to the Wolffian duct and its importance for the genesis of malformations. Anat. Rec. 81, 1–19 (1941).

43.

Magee

Lucey

Fried

: A new embryologic classification for urogynecologic malformations: the syndromes of mesonephric duct induced Mullerian deformities. J. Urol. 121, 265–267 (1979).

44.

Heinonen

: Unicornuate uterus and rudimentary horn. Fertil. Steril. 68, 224–230 (1997).

45.

Shukunami

Tsunezawa

Kotsuji

: Unicornuate uterus with a noncommunicating cavitary, laterally dislocated rudimentary horn presenting with adenomyosis, associated with ipsilateral renal agenesis. Arch. Gynecol. Obstet. 264, 88–89 (2000).

46.

Strassmann

: Die operative Vereinigung eines doppelten Uterus. Zentralbl. Gynakol. 43, 1322–1335 (1907).

47.

Jarcho

: Malformations of the uterus. Am. J. Surg. 714, 106–166 (1946).

48.

Fenton

Singh

: Pregnancy associated with congenital abnormalities of the female reproductive tract. Am. J. Obstet. Gynecol. 63, 744–755 (1952).

49.

Buttram

Jr Gibbons

: Mullerian anomalies: a proposed classification. (An analysis of 144 cases). Fertil. Steril. 32, 40–46 (1979).

50.

The American Fertility Society classifications of adnexal adhesions, distal tubal occlusion, tubal occlusion secondary to tubal ligation, tubal pregnancies, Mullerian anomalies and intrauterine adhesions. Fertil. Steril. 49, 944–955 (1988).

51.

Pinsonneault

Goldstein

: Obstructing malformations of the uterus and vagina. Fertil. Steril. 44, 241–247 (1985).

52.

Rock

Schlaff

: The obstetric consequences of uterovaginal anomalies. Fertil. Steril. 43, 681–692 (1985).

53.

Jones

Jr : Mullerian anomalies. Hum. Reprod. 13, 789–791 (1998).

54.

Toaff

Lev-Toaff

Toaff

: Communicating uteri: review and classification with introduction of two previously unreported types. Fertil. Steril. 41, 661–679 (1984).

55.

Acien

Arminana

Garcia-Ontiveros

: Unilateral renal agenesis associated with ipsilateral blind vagina. Arch. Gynecol. 240, 1–8 (1987).

56.

Acien

: Unicornuate uterus with two cavitated, non-communicating rudimentary horns? Letter to the editor. Hum. Reprod. 16, 393–395 (2001).

57.

Acien

: Obstructive Mullerian anomalies. Letter to the editor. Am. J. Obstet. Gynecol. 186, 854 (2002).

58.

Oppelt

Renner

Brucker

: The VCUAM (vagina cervix uterus adnex-associated malformation) classification: a new classification for genital malformations. Fertil. Steril. 84, 1493–1497 (2005).

59.

Sadik

Taskin

Sehirali

: Complex Mullerian malformation: report of a case with a hypoplastic non-cavitated uterus and two rudimentary horns. Hum. Reprod. 17, 1343–1344 (2002).

60.

Deffarges

Haddad

Musset

Paniel

: Utero-vaginal anastomosis in women with uterine cervix atresia: long-term follow-up and reproductive performance. A study of 18 cases. Hum. Reprod. 16, 1722–1725 (2001).

61.

Wai

Zekam

Sanz

: Septate uterus with double cervix and longitudinal vaginal septum. A case report. J. Reprod. Med. 46, 613–617 (2001).

62.

Pavone

King

Vlahos

: Septate uterus with cervical duplication and a longitudinal vaginal septum: a Mullerian anomaly without a classification. Fertil. Steril. 85, 494.E9–E10 (2006).

63.

Dunn

Hantes

: Double cervix and vagina with a normal uterus and blind cervical pouch: a rare Mullerian anomaly. Fertil. Steril. 82, 458–459 (2004).

64.

Reuter

Daly

Cohen

: Septate versus bicornuate uteri: errors in imaging diagnosis. Radiology 172, 749–752 (1989).

65.

Pellerito

McCarthy

Doyle

Glickman

DeCherney

: Diagnosis of uterine anomalies: relative accuracy of MR imaging, endovaginal ultrasound, and hysterosalpingography. Radiology 183, 795–800 (1992).

66.

Jurkovic

Geipel

Gruboeck

Jauniaux

Natucci

Campbell

: Three-dimensional ultrasound for the assessment of uterine anatomy and detection of congenital anomalies: a comparison with hysterosalpingography and two-dimensional sonography. Ultrasound Obstet. Gynecol. 5, 233–237 (1995).

67.

Raga

Bonilla-Musoles

Blanes

Osborne

: Congenital Mullerian anomalies: diagnostic accuracy of threedimensional ultrasound. Fertil. Steril. 65, 523–528 (1996).

68.

Sheth

Sonkawde

: Uterine septum misdiagnosed on hysterosalpingogram. Int. J. Gynaecol. Obstet. 69, 261–263 (2000).

69.

Brown

Coddington

Schnorr

Toner

Gibbons

Oehninger

: Evaluation of outpatient hysteroscopy, saline infusion hysterosonography, and hysterosalpingography in infertile women: a prospective, randomized study. Fertil. Steril. 74, 1029–1034 (2000).

70.

Soares

Barbosa dos Reis

Camargos

: Diagnostic accuracy of sonohysterography, transvaginal sonography, and hysterosalpingography in patients with uterine cavity diseases. Fertil. Steril. 73, 406–411 (2000).

71.

Salim

Jurkovic

: Assessing congenital uterine anomalies: the role of threedimensional ultrasonography. Best Pract. Res. Clin. Obstet. Gynaecol. 18, 29–36 (2004).

72.

Salim

Woelfer

Backos

Regan

Jurkovic

: Reproducibility of three-dimensional ultrasound diagnosis of congenital uterine anomalies. Ultrasound Obstet. Gynecol. 21, 578–582 (2003).

73.

Braun

Grau

Pons

Enguix

: Is hysterosalpingography able to diagnose all uterine malformations correctly? A retrospective study. Eur. J. Radiol. 53, 274–279 (2005).

74.

Guimaraes Filho

Mattar

Pires

Araujo Junior

Moron

Nardozza

: Comparison of hysterosalpingography, hysterosonography and hysteroscopy in evaluation of the uterine cavity in patients with recurrent pregnancy losses. Arch. Gynecol. Obstet. 274, 284–288 (2006).

75.

Makris

Kalmantis

Skartados

Papadimitriou

Mantzaris

Antsaklis

: Three-dimensional hysterosonography versus hysteroscopy for the detection of intracavitary uterine abnormalities. Int. J. Gynaecol. Obstet. 97, 6–9 (2007).

76.

Bettocchi

Ceci

Nappi

Pontrelli

Pinto

Vicino

: Office hysteroscopic metroplasty: three ‘diagnostic criteria’ to differentiate between septate and bicornuate uteri. J. Minim. Invasive Gynecol. 14, 324–328 (2007).

77.

Woelfer

Salim

Banerjee

Elson

Regan

Jurkovic

: Reproductive outcomes in women with congenital uterine anomalies detected by threedimensional ultrasound screening. Obstet. Gynecol. 98, 1099–1103 (2001).

78.

Troiano

McCarthy

: Mullerian duct anomalies: imaging and clinical issues. Radiology 233, 19–34 (2004).

79.

Singh

Sunita

: Double uteri with cervicovaginal agenesis. Fertil. Steril. 90(5), 2016.E13–E15 (2008).

80.

Harger

Archer

Marchese

: Etiology of recurrent pregnancy losses and outcome of subsequent pregnancies. Obstet. Gynecol. 62, 574–581 (1983).

81.

Kobayashi

Behringer

: Developmental genetics of the female reproductive tract in mammals. Nat. Rev. Genet. 12, 969–980 (2003).

82.

Letterie

Vauss

: Mullerian tract abnormalities and associated auditory defects. J. Reprod. Med. 36, 765–768 (1991).

83.

Lee

Osathanondh

Yeh

: Localization of Bcl-2 in the human fetal Müllerian tract. Fertil. Steril. 70, 135–140 (1998).

84.

Sarto

Simpson

: Abnormalities of the Mullerian and Wolffian duct systems. Birth Defects Orig. Artic. Ser. 14, 37–54 (1978).

85.

Hammoud

Gibson

Peterson

Kerber

Mineau

Hatasaka

: Quantification of the familial contribution to Mullerian anomalies. Obstet. Gynecol. 111, 378–384 (2008).

86.

Ergun

Pabuccu

Atay

Kucuk

Duru

Gungor

: Three sisters with septate uteri: another reference to bidirectional theory. Hum. Reprod. 12, 140–142 (1997).

87.

Mikkila

Janas

Karikoski

Tarkkila

Simola

: X-linked laterality sequence in a family with carrier manifestations. Am. J. Med. Genet. 49, 435–438 (1994).

88.

Golan

Langer

Bukovsky

Caspi

: Congenital anomalies of the Mullerian system. Fertil. Steril. 51, 747–755 (1989).

89.

Acien

: Reproductive performance of women with uterine malformations. Hum. Reprod. 8, 122–126 (1993).

90.

Patton

: Anatomic uterine defects. Clin. Obstet. Gynecol. 37, 705–721 (1994).

91.

Homer

Cooke

: The septate uterus: a review of management and reproductive outcome. Fertil. Steril. 73, 1–14 (2000).

92.

Kupesic

: Clinical implications of sonographic detection of uterine anomalies for reproductive outcome. Ultrasound Obstet. Gynecol. 18, 387–400 (2001).

93.

Taylor

Gomel

: The uterus and fertility. Fertil. Steril. 89, 1–16 (2008).

94.

Heinonen

Pystynen

: Primary infertility and uterine anomalies. Fertil. Steril. 40, 311–316 (1983).

95.

Sanders

: Uterine factors and infertility. J. Reprod. Med. 51, 169–176 (2006).

96.

Worthen

Gonzalez

: Septate uterus: sonographic diagnosis and obstetric complications. Obstet. Gynecol. 64(Suppl. 3), 34–37 (1984).

97.

Simon

Moreno

Remohi

Pellicer

: Cytokines and embryo implantation. J. Reprod. Immunol. 39, 117–131 (1998).

98.

Berker

Taskin

: Absence of endometrium as a cause of primary amenorrhea. Fertil. Steril. 89(3), 723.E1–E3 (2008).

99.

Dicker

Ashkenazi

Dekel

: The value of hysteroscopic evaluation in patients with preclinical in-vitro fertilisation abortions. Hum. Reprod. 11, 730–731 (1996).

100.

Kirsop

Porter

Torode

Smith

Saunders

: The role of hysteroscopy in patients having failed IVF/GIFT transfer cycles. Aust. NZ J. Obstet. Gynaecol. 31, 263–264 (1991).

101.

Candiani

Fedele

Zamferletti

De Virgiliis

Carinelli

: Endometrial patterns in malformed uteri. Acta Eur. Fertil. 14, 311–318 (1983).

102.

Fedele

Bianchi

Marchini

Franchi

Tozzi

Dorta

: Ultrastructural aspects of endometrium in infertile women with septate uterus. Fertil. Steril. 65, 750–752 (1996).

103.

Dabirashrafi

Bahadori

Mohammad

: Septate uterus. New idea on the histologic features in this abnormal uterus. Am. J. Obstet. Gynecol. 172, 105–107 (1995).

104.

Sorensen

: Minor Mullerian anomalies and oligomenorrhea in infertile women. A new syndrome. Am. J. Obstet. Gynecol. 140, 636–644 (1981).

105.

Ugur

Karakaya

Zorlu

: Polycystic ovaries in association with Mullerian anomalies. Eur. J. Obstet. Gynecol. Reprod. Biol. 62, 57–59 (1995).

106.

Fedele

Arcaini

Parazzini

Vercellini

Di Nola

: Reproductive prognosis after hysteroscopic metroplasty in 102 women: life-table analysis. Fertil. Steril. 59, 768–772 (1993).

107.

Fayez

: Comparison between abdominal and hysteroscopic metroplasty. Obstet. Gynecol. 68, 399–403 (1986).

108.

Nahum

: Uterine anomalies. How common are they, and what is their distribution among subtypes? J. Reprod. Med. 43, 877–887 (1998).

109.

Saravelos

Cocksedge

: Prevalence and diagnosis of congenital uterine anomalies in women with reproductive failure: a critical appraisal. Hum. Reprod. Update 14, 415–429 (2008).

110.

Considers the diagnostic accuracy of the methods used to detect congenital uterine anomalies. It also provides evidence for an association between some of these anomalies, particularly between the septate uterus and infertility.

111.

Raziel

Arieli

Bukovsky

Caspi

Golan

: Investigation of the uterine cavity in recurrent aborters. Fertil. Steril. 62, 1080–1082 (1994).

112.

Alatas

Aksoy

Akarsu

Yakin

Aksoy

Hayran

: Evaluation of intrauterine abnormalities in infertile patients by sonohysterography. Hum. Reprod. 12, 487–490 (1997).

113.

Keltz

Olive

Kim

Arici

: Sonohysterography for screening in recurrent pregnancy loss. Fertil. Steril. 67, 670–674 (1997).

114.

Alborzi

Dehbashi

Khodaee

: Sonohysterosalpingographic screening for infertile patients. Int. J. Gynaecol. Obstet. 82, 57–62 (2003).

115.

Traina

Mattar

Moron

Neto

LCA

Matheus

EDE

: Diagnostic accuracy of hysterosalpingography and transvaginal sonography to evaluate uterine cavity diseases in patients with recurrent miscarriage. Rev. Bras. Ginecol. Obstet. 26, 527–533 (2004).

116.

Valenzano

Mistrangelo

Lijoi

: Transvaginal sonohysterographic evaluation of uterine malformations. Eur. J. Obstet. Gynecol. Reprod. Biol. 124, 246–249 (2006).

117.

Nicolini

Bellotti

Bonazzi

Zamberletti

Candiani

: Can ultrasound be used to screen uterine malformations? Fertil. Steril. 47, 89–93 (1987).

118.

Hsu

Huang

: Detection of congenital Mullerian duct anomalies using three dimensional ultrasound. J. Clin. Ultrasound 25, 487–492 (1997).

119.

Radoncic

Funduk-Kurjak

: Three-dimensional ultrasound for routine check-up in in vitro fertilization patients. Croat. Med. J. 41, 262 (2000).

120.

Makris

Skartados

Kalmantis

Mantzaris

Papadimitriou

Antsaklis

: Evaluation of abnormal uterine bleeding by transvaginal 3-D hysterosonography and diagnostic hysteroscopy. Eur. J. Gynaecol. Oncol. 28, 39–42 (2007).

121.

Altman

: Practical Statistics for Medical Research. Chapman & Hall, London, UK (1991).

122.

Byrne

Nussbaum-Blask

Taylor

: Prevalence of Mullerian duct anomalies detected at ultrasound. Am. J. Med. Genet. 94, 9–12 (2000).

123.

Hamilton

Larson

Lower

Hasnain

Grudzinskas

: Routine use of saline hysterosonography in 500 consecutive, unselected, infertile women. Hum. Reprod. 13, 2463–2473 (1998).

124.

Alborzi

Dehbashi

Parsanezhad

: Differential diagnosis of septate and bicornuate uterus by sonohysterography eliminates the need for laparoscopy. Fertil. Steril. 78, 176–178 (2002).

125.

Ventolini

Zhang

Gruber

: Hysteroscopy in the evaluation of patients with recurrent pregnancy loss: a cohort study in a primary care population. Surg. Endosc. 18, 1782–1784 (2004).

126.

Fedele

Dorta

Brioschi

Massari

Candiani

: Magnetic resonance evaluation of double uteri. Obstet. Gynecol. 74, 844–847 (1989).

127.

Fischetti

Politi

Lomeo

Garozzo

: Magnetic resonance in the evaluation of Mullerian duct anomalies. Radiol. Med. 89, 105–111 (1995).

128.

Nguyen

Harford

Trott

: Evaluating Mullerian anomalies as a cause of recurrent pregnancy loss. Delaware Med. J. 69, 209–212 (1997).

129.

Cooper

Houck

Rigberg

: The incidence of intrauterine abnormalities found at hysteroscopy in patients undergoing elective hysteroscopic sterilization. J. Reprod. Med. 28, 659–661 (1983).

130.

Tur-Kaspa

Gal

Hartman

: A prospective evaluation of uterine abnormalities by saline infusion sonohysterography in 1,009 women with infertility or abnormal uterine bleeding. Fertil. Steril. 86, 1731–1735 (2006).

131.

Maneschi

Zupi

Marconi

: Hysteroscopically detected asymptomatic Mullerian anomalies. Prevalence and reproductive implications. J. Reprod. Med. 40, 684–688 (1995).

132.

Nasri

Setchell

Chard

: Transvaginal ultrasound for diagnosis of uterine malformations. Br. J. Obstet. Gynaecol. 97, 1043–1045 (1990).

133.

Sorensen

: Estimated prevalence of Mullerian anomalies. Acta Obstet. Gynecol. Scand. 67, 441–445 (1988).

134.

Jurkovic

Gruboeck

Tailor

Nicolaides

: Ultrasound screening for congenital uterine anomalies. Br. J. Obstet. Gynaecol. 104, 1320–1321 (1997).

135.

Salim

Regan

Woelfer

Backos

Jurkovic

: A comparative study of the morphology of congenital uterine anomalies in women with and without a history of recurrent first trimester miscarriage. Hum. Reprod. 18, 162–166 (2003).

136.

Tulandi

Arronet

McInnes

: Arcuate and bicornuate uterine anomalies and infertility. Fertil. Steril. 34, 362–364 (1980).

137.

Vasiljevic

Ganovi

Jovanovi

Markovi

: Diagnostic value of hysterosalpingography and laparoscopy in infertile women. Srp. Arh. Celok. Lek. 124, 135–138 (1996).

138.

Nickerson

: Infertility and uterine contour. Am. J. Obstet. Gynecol. 129, 268–273 (1997).

139.

Heinonen

Saarikoski

Postynen

: Reproductive performance of women with uterine anomalies. Acta Obstet. Gynecol. Scand. 61, 157–162 (1982).

140.

Rock

Schlaff

: The obstetric consequences of uterovaginal anomalies. Fertil. Steril. 43, 681–691 (1985).

141.

Semmens

: Congenital anomalies of female genital tract. Functional classification based on review of 56 personal cases and 500 reported cases. Obstet. Gynecol. 19, 328–350 (1962).

142.

Hull

Glazener

Kelly

: Population study of causes, treatment, and outcome of infertility. BMJ 291, 1693–1697 (1985).

143.

Templeton

Fraser

Thompson

: The epidemiology of infertility in Aberdeen. BMJ 301, 148–152 (1990).

144.

School of Public Health, University of Leeds; Centre for Health Economics, University of York; Research Unit, Royal College of Physicians: The management of subfertility. Effective Health Care 1(3), 1–24 (1992).

145.

Thonneau

Marchand

Tallec

: Incidence and main causes of infertility in a resident population (1,850,000) of three French regions (1988–1989). Hum. Reprod. 6, 811–816 (1991).

146.

Pabuccu

Gomel

: Reproductive outcome after hysteroscopic metroplasty in women with septate uterus and otherwise unexplained infertility. Fertil. Steril. 81, 1675–1678 (2004).

147.

Marcus

Al-Shawaf

Brinsden

: The obstetric outcome of in vitro fertilization and embryo transfer in women with congenital uterine malformation. Am. J. Obstet. Gynecol. 175, 85–89 (1996).

148.

Guirgis

Shrivastar

: Gamete intrafallopian transfer (GIFT) in women with bicornuate uteri. J. In Vitro Fert. Embryo Transfer 7, 283–284 (1990).

149.

Syrop

Sahakian

: Transvaginal sonography detection of endometrial polyps with fluid contrast augmentation. Obstet. Gynecol. 79, 1041–1043 (1992).

150.

La Sala

Montanari

Dessanti

Cigarini

Sartori

: The role of diagnostic hysteroscopy and endometrial biopsy in assisted reproductive technologies. Fertil. Steril. 70, 378–380 (1998).

151.

Acien

: Evidence-based management of recurrent miscarriage. Surgical management. Int. Congr. Series 1266, 335–342 (2004).

152.

Choe

Baggish

: Hysteroscopic treatment of septate uterus with neodymium-YAG laser. Fertil. Steril. 57, 81–84 (1992).

153.

Colacurci

De Placido

Perino

Mencaglia

Gubbini

: Hysteroscopic metroplasty. J. Am. Assoc. Gynecol. Laparosc. 5, 171–174 (1998).

154.

Fedele

Bianchi

Frontino

: Septums and synechiae: approaches to surgical correction. Clin. Obstet. Gynecol. 49, 767–788 (2006).

155.

Heinonen

: Complete septate uterus with longitudinal vaginal septum. Fertil. Steril. 85, 700–705 (2006).

156.

Perino

Mencaglia

Hamou

Cittadini

: Hysteroscopy for metroplasty of uterine septa: report of 24 cases. Fertil. Steril. 48, 321–323 (1987).

157.

Daly

Maier

Soto-Albers

: Hysteroscopic metroplasty: six years' experience. Obstet. Gynecol. 73, 201–205 (1989).

158.

Querleu

Brasme

Parmentier

: Ultrasound-guided transcervical metroplasty. Fertil. Steril. 54, 995–998 (1990).

159.

Marabini

Gubbini

Stagnozzi

Stefanetti

Filoni

Bovicelli

: Hysteroscopic metroplasty. Ann. NY Acad. Sci. 734, 488–492 (1994).

160.

Pabuccu

Atay

Urman

Ergun

Orhon

: Hysteroscopic treatment of septate uterus. Gynaecol. Endosc. 4, 213–215 (1995).

161.

Goldenberg

Sivian

Sharabi

Mashiach

Lipitz

Seidman

: Reproductive outcome following hysteroscopic management of intrauterine septum and adhesions. Hum. Reprod. 10, 2663–2665 (1995).

162.

Colacurci

De Placido

Mollo

Carravetta

De Franciscis

: Reproductive outcome after hysteroscopic metroplasty. Eur. J. Obstet. Gynecol. Reprod. Biol. 66, 147–150 (1996).

163.

Lavergne

Aristizabal

Zarka

Erny

Hedon

: Uterine anomalies and in vitro fertilization: what are the results? Eur. J. Obstet. Gynecol. Reprod. Biol. 68, 29–34 (1996).

164.

Mollo

De Franciscis

Colacurci

: Hysteroscopic resection of the septum improves the pregnancy rate of women with unexplained infertility: a prospective controlled trial. Fertil. Steril. 91, 2628–2631 (2009).

165.

Despite the lack of randomization, this controlled study provides some of the best evidence to date for a causal association between the septate uterus and infertility.

166.

Lin

Zhu

Liang

Zhang

: Reproductive outcome following resectoscope metroplasy in women having a complete uterine septum with double cervix and vagina. Int. J. Gynecol. Obstet. 105, 25–28 (2009).

167.

Despite the lack of randomization, this controlled study provides some of the best evidence to date for a causal association between the septate uterus and infertility.

Congenital Uterine Anomalies and their Impact on Fertility

Abstract

Keywords

Normal & abnormal uterine development

Normal development

Abnormal development

Classification of congenital uterine anomalies

Etiological factors

Effect of congenital uterine anomalies on fertility

Potential mechanisms for an effect on fertility

Possible associations with infertility

Diagnostic accuracy

Diagnostic criteria

Prevalence among the general (fertile) populations

Prevalence among the infertile population

Comparison of the prevalence among the fertile & infertile populations

Infertility among women with congenitally malformed uteri

Probable underlying causation of infertility

Conclusion

Future perspective

Footnotes

References