The following review seeks to summarise the current data regarding reproductive outcomes associated with congenital uterine anomalies. Such malformations originate from adverse embryologic events ranging from agenesis to lateral and vertical fusion defects. Associated renal anomalies are common both for the symmetric and asymmetric malformations. While fertility is minimally impacted upon by müllerian anomalies in most cases, such malformations have historically been associated with poor obstetric outcomes such as recurrent miscarriage, second trimester loss, preterm delivery, malpresentation and intrauterine foetal demise (IUFD). The following review delineates the existing literature regarding such outcomes and indicates therapies, where applicable, to optimise the care of such patients.
Müllerian anomalies serve as a fascinating prism through which to examine both the embryologic development and normal functioning of the female reproductive tract. For patients suffering from such anomalies, however, their anatomy often puts them at odds with their own reproductive goals. Deviation in the development of the female reproductive organs from the norm has been shown to impact greatly on fertility, obstetrical outcomes and gynaecologic health. Moreover, such müllerian anomalies often bring with them adverse psychological effects for those women discovered to have such variant anatomy. There exists a wide range of müllerian anomalies associated with varying degrees of reproductive challenges. It is thus imperative that the obstetrician gynaecologist has a keen understanding of such anomalies and the ways in which they impact upon female reproductive functioning. Such an understanding, informed by the most current evidence-based data, allows for thorough, accurate counselling and efficient, effective treatment.
Embryology
Delineating the embryologic development of the female reproductive organs provides critical insight into understanding the various aberrant phenotypes of müllerian anomaly patients. Whereas genetic sex in humans is determined at the time of fertilisation, the male or female phenotype is not exhibited until after the 6 th week of development. The female reproductive structures develop in close association with the primordial kidneys, as discussed in more depth below.
Gonadal development begins as primordial germ cells originate among the endodermal cells in the dorsal wall of the yolk sac, where they appear during the 4th week of development. They then migrate along the dorsal mesentery of the hindgut, ultimately arriving at the genital ridge by the 6th week of development. The ovaries ultimately descend by differential growth from their position of origin near the kidneys to their eventual home in the true pelvis. Several genes have now been identified as playing crucial roles in the development of the ovary, including EMX2, Igf1r/Irr/Ir, LHX9, M33, SF1 and Wt1.
Early on, developmental phenotype continues to be sex-indifferent, allowing for the appearance of both the mesonephric (wolffian) and paramesonephric (müllerian) ducts from 5 to 8 weeks of gestation. In the absence of production of müllerian-inhibiting substance (MIS) from the sertoli cells of the developing testis, however, the müllerian ducts give rise to the uterus, fallopian tubes, cervix and upper vagina. During this time the wolffian ducts regress; however, they are suggested to act as a guide in the downward growth of the müllerian ducts. From week 8 to week 18, the müllerian duct undergoes a process of elongation, fusion, canalisation and septal resorption that will ultimately give rise to the above-mentioned female reproductive structures. Around 12 weeks, the caudal portion of the müllerian ducts fuse to form the uterovaginal canal; subsequent internal canalisation of each duct produces two channels divided by a septum; this septum is then re-absorbed in a cephalad direction by 20 weeks, forming the uterus and upper vagina. The unfused upper portions of the two müllerian ducts remain as the fallopian tubes.
The lower vagina arises from the sinovaginal bulbs after fusion with the caudal-most portion of the two müllerian ducts, allowing for the creation of a vaginal plate. This vaginal plate then undergoes central degeneration, allowing for complete canalisation by 20 weeks.
Although much work is still needed in determining the genetic basis for müllerian embryologic development, the HOX series of genes have been identified as playing a critical role in determining the positional identity along the axis of the developing paramesonephric duct. HOX genes are thought to be a family of regulatory genes encoding transcription factors essential during embryonic development: Hoxa9 is expressed at high levels in areas that will ultimately become the fallopian tube; Hoxa10 is predominantly expressed in the developing uterus; Hoxa11 is expressed in the primordia of the lower uterine segment and cervix. Mutations in the HOX genes in mice have been shown to result in significant reproductive anomalies.
The various müllerian anomalies can be understood by failure of any one of the above-mentioned steps of müllerian embryologic development. Agenesis of the müllerian duct results in congenital absence of the vagina with variable uterine development (Mayer–Rokitansky–Kuster–Hauser syndrome [MRKH]). Lateral fusion deficits, the most common müllerian defects, can result either from failure of fusion of the two müllerian ducts or lack of septal resorption after fusion has occurred. Vertical defects result in defective fusion of the caudal müllerian duct with the sinovaginal bulbs, leading to cervical agenesis or vaginal septa.
Classification system
In 1979, Buttram and Gibbons proposed a classification system for müllerian anomalies based on the type and degree of failure of normal development of the female genital tract. This rubric was subsequently revised by the American Society for Reproductive Medicine in 1988. Although by no means exhaustive, the utility of this classification system lies in its provision of a standardised nomenclature, allowing for physicians to more accurately codify, and therefore treat, patients with müllerian anomalies. Fig. 1 represents the various subtypes of müllerian anomalies; the various subtypes are briefly described here; the reproductive outcomes for each anomaly are discussed below in further detail (reproductive outcomes).
Bicornuate uterus
Bicornuate uterus results from incomplete fusion of the two müllerian ducts, leading to varying degrees of separation between two uterine cavities. In its most mild form, arcuate uterus results ( Fig. 1 ), in which a slight midline septum corresponds with a minimal fundal cavity indentation (arbitrarily defined as 1 cm or greater). At the other extreme, complete bicornuate uterus results ( Fig. 2 ), in which two uterine horns are divided down to the internal os of the cervix with no communication between the two uterine cavities. Partial bicornuate uterus ( Fig. 3 ) lies between these two extremes, with a more profound indentation between the two uterine horns than in arcuate uterus but with lateral fusion and a central cavity prior to the level of the internal os.
Unicornuate uterus
Unicornuate uterus, much like bicornuate uterus, represents a lateral fusion defect; however, in this scenario the defect is asymmetric. One cavity is typically normal, with a fallopian tube and cervix, whereas the defective side exhibits varying degrees of disrupted development. There are four variations of the unicornuate uterus: an isolated unicornuate uterus with no contralateral structure ( Fig. 4 ) and three variations in which an anlage, or rudimentary horn, is present contralateral to the unicornuate uterus. This rudimentary horn may have a cavity that is either in communication with ( Fig. 5 ) or sealed off from ( Fig. 6 ) the primary uterine cavity, or it may have failed to canalise entirely and is without a cavity ( Fig. 7 ). The uterine horn may or may not be fused to the dominant uterine structure ( Fig. 8 ). Although typically asymptomatic, both subtypes involving canalised rudimentary horns can contain functional endometrium that is shed cyclically.
Septate uterus
Septate uterus can be conceived as a failure one step beyond bicornuate uterus in the embryologic cascade of events. Such anomalies occur when lateral fusion of the two müllerian ducts has occurred, allowing for a normal-appearing uterine surface, however, with failure of resorption of the internal septum between the two uterine cavities ( Fig. 9 ). This failure of resorption can be complete, wherein two cavities separated by a fibromuscular division, continuous from fundus to internal os, preclude any communication between the two, or can be incomplete, with a central caudal cavity divided cephalad into two upper compartments by a vestigial uterine septum. The presence or absence of a longitudinal vaginal septum is independent of this uterine classification. Rarely, segmental septa have been described, leading to partial communications within a partitioned uterus. Impaired apoptosis associated with the Bcl-2 regulatory protein has been implicated in failed regression of the uterine septum.
Uterine didelphys
Complete failure of fusion of the two müllerian ducts results in duplication of the cervix in addition to the uterus ( Fig. 10 ). Although such duplication usually is limited to the uterus and cervix, duplication of other structures, such as the vulva, bladder, urethra, vagina and anus, may also occur. Patients with uterine didelphys do not always by definition have symmetric anatomy, however, and often present earlier for clinical evaluation due to problems such as obstructed hemivagina ( Fig. 11 ), which usually occurs on the side of a renal anomaly and is referred to as OHVIRA (obstructed hemivagina with ipsilateral renal anomaly).
Müllerian agenesis
The MRKH syndrome refers to the congenital absence of the vagina ( Fig. 12 ) with associated variable uterine development resulting from müllerian agenesis or hypoplasia, which affects between 1 in 4000 and 1 in 10 000 women. The uterus and cervix in such patients are often absent; however, 7–10% of such women have a rudimentary uterus with functional endometrium, and as many as 25% have cavitated müllerian remnants.
Classification system
In 1979, Buttram and Gibbons proposed a classification system for müllerian anomalies based on the type and degree of failure of normal development of the female genital tract. This rubric was subsequently revised by the American Society for Reproductive Medicine in 1988. Although by no means exhaustive, the utility of this classification system lies in its provision of a standardised nomenclature, allowing for physicians to more accurately codify, and therefore treat, patients with müllerian anomalies. Fig. 1 represents the various subtypes of müllerian anomalies; the various subtypes are briefly described here; the reproductive outcomes for each anomaly are discussed below in further detail (reproductive outcomes).
Bicornuate uterus
Bicornuate uterus results from incomplete fusion of the two müllerian ducts, leading to varying degrees of separation between two uterine cavities. In its most mild form, arcuate uterus results ( Fig. 1 ), in which a slight midline septum corresponds with a minimal fundal cavity indentation (arbitrarily defined as 1 cm or greater). At the other extreme, complete bicornuate uterus results ( Fig. 2 ), in which two uterine horns are divided down to the internal os of the cervix with no communication between the two uterine cavities. Partial bicornuate uterus ( Fig. 3 ) lies between these two extremes, with a more profound indentation between the two uterine horns than in arcuate uterus but with lateral fusion and a central cavity prior to the level of the internal os.
Unicornuate uterus
Unicornuate uterus, much like bicornuate uterus, represents a lateral fusion defect; however, in this scenario the defect is asymmetric. One cavity is typically normal, with a fallopian tube and cervix, whereas the defective side exhibits varying degrees of disrupted development. There are four variations of the unicornuate uterus: an isolated unicornuate uterus with no contralateral structure ( Fig. 4 ) and three variations in which an anlage, or rudimentary horn, is present contralateral to the unicornuate uterus. This rudimentary horn may have a cavity that is either in communication with ( Fig. 5 ) or sealed off from ( Fig. 6 ) the primary uterine cavity, or it may have failed to canalise entirely and is without a cavity ( Fig. 7 ). The uterine horn may or may not be fused to the dominant uterine structure ( Fig. 8 ). Although typically asymptomatic, both subtypes involving canalised rudimentary horns can contain functional endometrium that is shed cyclically.
Septate uterus
Septate uterus can be conceived as a failure one step beyond bicornuate uterus in the embryologic cascade of events. Such anomalies occur when lateral fusion of the two müllerian ducts has occurred, allowing for a normal-appearing uterine surface, however, with failure of resorption of the internal septum between the two uterine cavities ( Fig. 9 ). This failure of resorption can be complete, wherein two cavities separated by a fibromuscular division, continuous from fundus to internal os, preclude any communication between the two, or can be incomplete, with a central caudal cavity divided cephalad into two upper compartments by a vestigial uterine septum. The presence or absence of a longitudinal vaginal septum is independent of this uterine classification. Rarely, segmental septa have been described, leading to partial communications within a partitioned uterus. Impaired apoptosis associated with the Bcl-2 regulatory protein has been implicated in failed regression of the uterine septum.
Uterine didelphys
Complete failure of fusion of the two müllerian ducts results in duplication of the cervix in addition to the uterus ( Fig. 10 ). Although such duplication usually is limited to the uterus and cervix, duplication of other structures, such as the vulva, bladder, urethra, vagina and anus, may also occur. Patients with uterine didelphys do not always by definition have symmetric anatomy, however, and often present earlier for clinical evaluation due to problems such as obstructed hemivagina ( Fig. 11 ), which usually occurs on the side of a renal anomaly and is referred to as OHVIRA (obstructed hemivagina with ipsilateral renal anomaly).
