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Congenital uterine anomalies affecting reproduction

Best Practice & Research Clinical Obstetrics & Gynaecology, 2, 24, pages 193 - 208

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.

Keywords: Müllerian anomaly, paramesonephric duct, unicornuate, bicornuate, didelphys, arcuate, septate.

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 6thweek of development. 1 The female reproductive structures develop in close association with the primordial kidneys, as discussed in more depth below. 2

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. 3 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 Wt1.4 and 5

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. 6 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. 7

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. 8 Mutations in the HOX genes in mice have been shown to result in significant reproductive anomalies. 9

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. 10 This rubric was subsequently revised by the American Society for Reproductive Medicine in 1988. 11 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).

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Fig. 1 Arcuate uterus. Reproduced with permission - Emans SJ, Laufer MR, Goldstein DP: Pediatric and Adolescent Gynecology (Fifth edition), Philadelphia: Lippincott Williams & Wilkins Publishing Company, 2005, p 369, fig 10-55.

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). 12 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.

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Fig. 2 Bicornuate uterus – complete. Reproduced with permission - Emans SJ, Laufer MR, Goldstein DP: Pediatric and Adolescent Gynecology (Fifth edition), Philadelphia: Lippincott Williams & Wilkins Publishing Company, 2005, p 369, fig 10-53.

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Fig. 3 Bicornuate uterus – partial. Reproduced with permission - Emans SJ, Laufer MR, Goldstein DP: Pediatric and Adolescent Gynecology (Fifth edition), Philadelphia: Lippincott Williams & Wilkins Publishing Company, 2005, p 369, fig 10-54.

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. 13

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Fig. 4 Unicornuate uterus. Reproduced with permission - Emans SJ, Laufer MR, Goldstein DP: Pediatric and Adolescent Gynecology (Fifth edition), Philadelphia: Lippincott Williams & Wilkins Publishing Company, 2005, p 368, fig 10-48.

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Fig. 5 Unicornuate uterus with communicating horn. Reproduced with permission - Emans SJ, Laufer MR, Goldstein DP: Pediatric and Adolescent Gynecology (Fifth edition), Philadelphia: Lippincott Williams & Wilkins Publishing Company, 2005, p 367, fig 10-43.

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Fig. 6 Unicornuate uterus with noncommunicating horn containing endometrium. Reproduced with permission - Emans SJ, Laufer MR, Goldstein DP: Pediatric and Adolescent Gynecology (Fifth edition), Philadelphia: Lippincott Williams & Wilkins Publishing Company, 2005, p 367, fig 10-44.

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Fig. 7 Unicornuate uterus with noncommunicating horn without endometrium. Reproduced with permission - Emans SJ, Laufer MR, Goldstein DP: Pediatric and Adolescent Gynecology (Fifth edition), Philadelphia: Lippincott Williams & Wilkins Publishing Company, 2005, p 367, fig 10-46.

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Fig. 8 Unicornuate uterus with noncommunicating horn. Reproduced with permission - Emans SJ, Laufer MR, Goldstein DP: Pediatric and Adolescent Gynecology (Fifth edition), Philadelphia: Lippincott Williams & Wilkins Publishing Company, 2005, p 367, fig 10-45.

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.14 and 15Rarely, segmental septa have been described, leading to partial communications within a partitioned uterus. 16 Impaired apoptosis associated with the Bcl-2 regulatory protein has been implicated in failed regression of the uterine septum. 17

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Fig. 9 Septate uterus – complete. Reproduced with permission - Emans SJ, Laufer MR, Goldstein DP: Pediatric and Adolescent Gynecology (Fifth edition), Philadelphia: Lippincott Williams & Wilkins Publishing Company, 2005, p 369, fig 10-56.

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. 18 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).19 and 20

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Fig. 10 Uterus didelphys with complete vaginal septum. Reproduced with permission - Emans SJ, Laufer MR, Goldstein DP: Pediatric and Adolescent Gynecology (Fifth edition), Philadelphia: Lippincott Williams & Wilkins Publishing Company, 2005, p 368, fig 10-50.

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Fig. 11 Obstructed hemivagina with ipsilateral renal agenesis (OHVIRA). Reproduced with permission - Emans SJ, Laufer MR, Goldstein DP: Pediatric and Adolescent Gynecology (Fifth edition), Philadelphia: Lippincott Williams & Wilkins Publishing Company, 2005, p 369, fig 10-52.

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. 21 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.22, 23, and 24

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Fig. 12 Vaginal agenesis with rudimentary uterine horns (MRKH). Reproduced with permission - Emans SJ, Laufer MR, Goldstein DP: Pediatric and Adolescent Gynecology (Fifth edition), Philadelphia: Lippincott Williams & Wilkins Publishing Company, 2005, p 366, fig 10-37.

Incidence

The overall incidence of müllerian anomalies in the general population is often quoted to be between 2% and 3%. 25 Calculating the exact incidence of müllerian anomalies in the general population, however, has proven challenging. 26 Part of this difficulty lay in the fact that many such women with müllerian anomalies have no adverse outcomes and escape clinical detection. Hysteroscopic and hysterosalpingographic studies have, in general, tended to overestimate the prevalence of Müllerian anomalies in the general population as such investigations are biased towards patients with pelvic pain, abnormal uterine bleeding or infertility. 27

Several studies, however, have attempted to estimate the prevalence of müllerian anomalies and to delineate their frequency among subtypes but at the same time minimise these biases. In a study of 679 women with normal reproductive outcomes evaluated with laparoscopy or laparotomy prior to tubal ligation followed up with hysterosalpingography 5 months after sterilisation, the incidence of congenital uterine anomalies was 3.2%. 28 In another attempt to limit selection biases, a meta-analysis examined 22 studies of fertile but otherwise unselected patients undergoing universal uterine screening, whether by routine uterine evaluation at the time of hysteroscopic tubal occlusion, sterilisation or intrauterine assessment after cesarean delivery. This study concluded that 1 in 594 fertile, asymptomatic women are affected by uterine malformations. 27

Among women with adverse reproductive outcomes, the prevalence of such anomalies is higher, as would be expected. The incidence of müllerian anomalies among women with recurrent first trimester miscarriage is estimated to be between 5% and 10%, and as high as 25% in those women with recurrent second trimester loss. 29 Approximately 3.5% of infertile women possess a congenital uterine malformation, suggesting that uterine anomalies are 21 times more prevalent among infertile women than among those with normal fertility. 27 Pooling the results of studies examining fertile, asymptomatic patients and infertile, symptomatic patients, the overall incidence for congenital müllerian malformations in the general population has been estimated at 0.5%, or 1 in 201 women. 27 Studies vary widely regarding the incidence of distribution among the various subtypes of anomalies, although septate uterus is often quoted as the most common uterine anomaly encountered, while MRKH is often cited as the rarest. 30

Inheritance

Müllerian anomalies are most typically noted asde novocongenital abnormalities without significant hereditary distinction. Familial aggregates of such conditions, however, have rarely been reported. 31 Hand–foot–genital syndrome is one such rare disorder, associated with bilateral great toe and thumb hypoplasia along with varying degrees of incomplete müllerian duct fusion. 32 Abnormal karyotypes are said to be found in 7.7% of women with congenital uterine anomalies. 33 Given the low frequency of biological relatives affected with müllerian malformations, such anomalies are most consistent with a multifactorial, polygenic pattern of occurrence. 34 As stated above, familial studies involving müllerian defects are challenging given that many women with anomalies have no symptoms and enjoy both fruitful and uneventful reproductive lives.

Presentation

Congenital uterine anomalies are often incidentally discovered in the workup for common obstetrical complications and gynaecologic complaints. Often müllerian anomaly patients do not present in childhood or adolescence but rather in adulthood, when repeated pregnancy loss, persistent menstrual irregularities or issues related to fertility lead to an unexpected diagnosis. 35 Müllerian anomalies associated with obstruction, such as MRKH, unicornuate uterus with rudimentary horn, or uterine didelphys with obstructed hemivagina, often present with pelvic pain secondary to haematometra, haematocolpos or endometriosis. 25 Such pain may be either cyclic or non-cyclic, and located in the pelvis or vagina, depending on the patient's anatomy. Patients with hydro- or haematocolpos may present with a painful mass on bimanual examination, or with infection secondary to vaginal microperforations. 20

Non-obstructive anomalies may be discovered on routine gynaecologic examination. Patients with segmental hypoplasia or agenesis often present with primary amenorrhoea. Similarly, hypomenorrhoea may occur if there is present but minimal endometrium. For conditions associated with longitudinal vaginal septa, such as uterine didelphys, patients may report dyspareunia or bleeding despite use of a single tampon (given that two, one for each hemi-vagina, are typically required during menses). 36

Often, patients with müllerian anomalies escape clinical detection until issues of child-bearing arise (see obstetrical outcomes below). Patients may be concerned that such uterine anomalies pose increased risk for ovarian malignancy; however, there does not appear to be any association between uterine anomalies and the development of ovarian neoplasia. 37

Diagnosis

While diagnosis can often be made based on clinical presentation, a nuanced delineation of uterine anatomy is often possible only with the aid of imaging modalities. Several radiologic tools are available to assist in the diagnosis of congenital anomalies of the female reproductive tract. Ultrasound, whether through the trans-abdominal, trans-vaginal or trans-perineal approach, provides valuable information regarding both internal and external uterine contour while at the same time allowing for evaluation of the kidneys and confirming presence of the ovaries. Timing the study with the secretory phase provides more accurate visualisation of the endometrium. 38 Cases in which the endometrial echo is separated by a longitudinal division from the fundus towards the cervix suggest duplication, whereas cases in which the interstitial portion of the fallopian tube cannot be identified suggest agenesis. Three-dimensional ultrasound, where available, allows for definition of the uterine and surrounding anatomy and offers a non-invasive, reliable method for differentiating similar internal anomalies with variable external appearance, such as bicornuate and septate uterus.12, 39, 40, and 41

Hysterosalpingography (HSG) is an excellent method of evaluating the uterine cavity; however, definitive diagnosis often requires evaluation of the external uterine contour, which is poorly defined by HSG. For example, HSG correctly diagnoses only 55% of septate versus bicornuate uteri; the addition of ultrasonography improves diagnosis to 90%. 42 HSG, moreover, can be quite uncomfortable if not performed under anesthesia and this fact should especially be taken into account in the pediatric population.

Magnetic resonance (MR) imaging, less invasive than laparoscopy but both sensitive and specific for nearly all anomalies, has become for some the new ‘gold standard’ for definition of uterine and surrounding anatomy. 43 MR imaging is helpful in delineating endometrium, detecting uterine horns, as well as in defining aberrant gonadal location or renal anatomy. 44 While not necessary for every patient with a müllerian anatomy, MR imaging proves useful for those patients with more complex disorders and for those at higher risk for associated anomalies.

Associated anomalies

As mentioned above, a close embryologic relationship exists between the mesonephric and paramesonephric ducts. As the mesonephric duct enters the cloaca, it induces the formation of the ureteric bud, a diverticulum that will then differentiate into the embryologic kidney. Thus, defects in the development of the müllerian structures can also lead to defects in renal anatomy, whether it is ectopic location, aberrant anatomy or complete agenesis. 45 Numerous studies have confirmed a frequent coincidence of müllerian malformations with renal anomalies. In their original study, Buttram and Gibbons concluded that 31% of patients with müllerian anomalies had coincident urinary anomalies, with congenital absence of a kidney being the most common disturbance. 10 While cases of septate, arcuate and bicornuate uteri are more rarely associated with renal anomalies, unicornuate uterus, didelphic uterus and MRKH (those anomalies often associated with unilateral obstruction) are not infrequently associated with renal agenesis or other renal defects. In a study specifically looking at urinary tract anomalies associated with unicornuate uterus, 40.5% of those patients with unicornuate uterus had a renal anomaly, the most frequent of which was renal agenesis contralateral to the unicornuate uterus. 46 Other associated anomalies include horseshoe kidney, double renal pelvis, unilateral medullary sponge kidney, or ectopic ureteral orifices. 47 Whether through MRI, CT scan, ultrasound or intravenous pyelogram, radiologic evaluation of the kidneys should be undertaken when an obstructive müllerian anomaly is encountered. Although more rare, several case reports and studies have described renal anomalies in patients with the symmetric subtypes of müllerian malformations.48 and 49

Patients with unilateral rudimentary uteri or complete agenesis, in addition to exhibiting renal anomalies, may also be discovered to have variation in their gonadal tissue, whether it is ectopic location or complete absence of the gonad on the affected side. Although such occurrences may be found in women with normal uteri, the incidence is reported to be as high as 20% when the uterus is absent and 42% in cases of unicornuate uterus. 50 MR imaging subsequent to exogenous ovarian stimulation is one novel approach to locate ectopic ovaries and can have important implications for those women undergoing assisted reproduction therapies (ARTs). The ovaries in such patients may be found in the upper abdomen, at the level of the pelvic brim or in the inguinal canal. 51

Fertility

In general, the reproductive challenges associated with patients having müllerian anomalies lies in pregnancy maintenance rather than conception. The absolute exceptions to this rule are those disorders, such as MRKH syndrome, in which the uterus may be absent or insemination infeasible secondary to an absent upper vagina. Controversy exists over the impact of intrauterine defects and their impact on the potential for implantation. Earlier studies suggested that women with müllerian anomalies undergoingin vitrofertilisation (IVF) for myriad infertility diagnoses had similar clinical pregnancy rates as women with normal uteri undergoing IVF.52 and 53Other, more recent, studies have called into question whether subtle factors affecting the intrauterine milieu, such as small residual septa subsequent to metroplasty, have detrimental effects on implantation. 54 One study examining ART pregnancy rates in sterile women with untreated uterine malformations compared with the general sterile population did reveal significantly lower implantation and pregnancy rates. 55 As with any patient undergoing assisted reproduction, care should be taken to optimise the endometrial cavity and restore normal anatomy prior to any major treatment.

Reproductive outcomes

Except in those anomalies affecting normal sexual functioning (e.g., MRKH and vaginal septa), the reproductive challenges faced by patients with müllerian malformations are typically attributed to pregnancy maintenance rather than conception. Uterine anomalies have been associated with an increased incidence of spontaneous abortion, malpresentation, placental abruption, intrauterine growth restriction (IUGR), prematurity, operative delivery, retained placenta and foetal mortality.56, 57, and 58Various theories have been put forth to explain jeopardised outcomes associated with müllerian abnormalities, but in truth such outcomes are still poorly understood and require further research. Several researchers have theorised regarding why anomalous uteri might be associated with such dismal obstetrical outcomes. The three main aetiologies put forth in order to explain adverse outcomes are diminished muscle mass, abnormal uterine blood flow and cervical insufficiency.

In patients with müllerian anomalies associated with diminished uterine size, gestational capacity is said to be jeopardised by the presence of only half the full complement of uterine musculature. 59 It is postulated that the myometrium of congenitally abnormal uteri are thinner than normal, and that, in addition, their mural thickness diminishes as gestation advances, causing inconsistencies over different aspects of the uterus; rare cases of intrapartum uterine rupture in patients with no prior uterine surgeries have been reported.60 and 61It is unclear whether this diminished muscle mass plays a role in second trimester abortion, premature delivery and increased rates of operative deliveries and cesarean section. 2 High maternal serum alphafetoprotein in the absence of foetal structural abnormalities or multiple pregnancy has been said to be associated with thin uterine walls, leading some authors to suggest careful inspection of uterine wall contour and thickness in this scenario.13 and 62

Anomalous vasculature has also been put forth as a potential cause for adverse obstetric outcomes associated with müllerian malformations. Disturbance in the uterine blood flow, caused by absent or abnormal uterine or ovarian vessels, could potentially explain the IUGR and increased rates of spontaneous abortions seen in such patients. Should uteroplacental blood flow be compromised, impaired foetal nutrition, diminished foetal size and higher incidence of first trimester abortion might occur. 59 In a study in which the vascular configuration of uteri were mapped radiographically prior to removal at hysterectomy and subsequent linked to the patients' reproductive histories, a correlation between anomalous ascending uterine arteries and an increased rate of abortion and IUGR was observed compared to those patients with normal uterine vasculature. 63 It is thus possible, given the anatomy of the patients in question, that an absent uterine artery on one side could play an important role in the complexities observed in those müllerian anomalies involving hemi-uteri.

Lastly, the cervix has been implicated in poor reproductive outcomes in the setting of uterine malformations, even when there is no ostensible anomaly in the cervix itself. Various researchers have postulated an abnormal ratio of muscle fibres to connective tissue in uterine cervices associated with abnormal müllerian development.64 and 65Together with this loss of connective tissue, asymmetric downward forces exerted by the anomalous uterus have been presumed to lead to increased pressure during pregnancy, leading to untimely relaxation of the congenitally hypermuscular cervix in response to such forces. 66 Given the concern over cervical incompetence associated with uterine malformations, several researchers have claimed dramatic success in studies in which prophylactic cerclages were placed for patients with uterine malformations; no studies, however, have been randomised, and all have lacked appropriate controls.67 and 68

As stated above, septate uterus is often cited as the most common uterine malformation. Significant variation in the quoted rates of pregnancy complications for septate uterus exists between studies. Septal tissue, with its decreased vascular supply and abnormal overlying endometrium, has been blamed as the aetiology of pregnancy loss and other obstetrical complications associated with septate uterus. 69 Pregnancy losses associated with septate uterus typically occur between 8 and 16 weeks' gestation, which has been attributed, as in other müllerian anomalies, to jeopardised implantation dynamics.70 and 71

Several studies cite profound rates of adverse obstetrical outcomes associated with uterine septa, with foetal survival rates of 6–28% and a rate of spontaneous miscarriage as high as 60% or greater.33, 58, 72, and 73While such data may overstate the extent of reproductive compromise associated with this condition, the implications for pregnancy can be severe. 14 Fortunately, however, the uterine septum is the most treatable of all müllerian malformations. In patients in whom a uterine septum has been discovered subsequent to pregnancy complications such as recurrent miscarriage or preterm birth, hysteroscopic metroplasty has become the indicated treatment of choice. 74 Whereas abdominally approached metroplasty carried with it significant morbidity and subsequent obstetric implications, hysteroscopic metroplasty is a relatively safe, simple procedure with a growing body of evidence to support improvement in live-birth rate in patients affected by recurrent abortion who have undergone metroplasty.70 and 75A recent prospective controlled study compared fecundity rates of women with septate uterus with unexplained fertility who underwent hysteroscopic metroplasty to women with idiopathic infertility. Patients with septate uterus and no other cause of infertility had significantly higher probability of conceiving subsequent to metroplasty (38.6% vs. 20.4%) as well as exhibiting higher rates of live birth (34.1% vs. 18.9%). 76

While treatment for women with septate uterus who have suffered adverse reproductive outcomes has been widely acknowledged, it remains more controversial whether uterine septa, which are incidentally detected prior to child-bearing, should be prophylactically removed prior to attempting conception. 54 For those patients undergoing workup for infertility or beginning the process of assisted reproduction, we strongly recommend treatment of uterine septa, both given the importance of optimising the uterine cavity prior to expensive interventions and in terms of minimising adverse obstetrical outcomes once pregnancy is achieved. For fertile patients in whom a uterine septum is discovered, a candid discussion between patient and physician regarding the risks and benefits to intervention prior to further pregnancy is warranted.

Debate exists on whether resection of the cervical portion of the septum at the time of uterine metroplasty has implications for cervical incompetence once pregnancy has been achieved.77 and 78At present, given the lack of compelling evidence for subsequent cervical incompetence and increased ease of the procedure with removal, we recommend resection of the cervical septum when surgically feasible.

One would assume, based on the minimal deviation from normal anatomy represented by arcuate uterus, that patients with this malformation enjoy reproductive outcomes relatively similar to those women with normal uteri. Some have even argued that this should be considered a normal variant rather than a classified malformation. Interestingly, however, several studies have implicated arcuate uterus as being associated with poor obstetric outcomes, although such claims remain controversial, given the retrospective nature of such reports and the variability in reported numbers between studies. Cited rates of live birth vary widely, from as low as 45% to as high as 82.7%.56 and 79We are inclined to believe, based on our own experience and our understanding of the arcuate anatomy, the more optimistic reproductive data. Women with such anomalies do not benefit from surgical intervention in the absence of other anomalies, and such patients should be reassured of their high likelihood for successful reproduction.

Unicornuate uterus, with its compromised uterine mass and sometimes associated uterine horns, brings with it considerable reproductive hurdles. Unicornuate uterus has been implicated in IUGR, miscarriage, malpresentation, preterm labour and cervical incompetence. 57 In our recent review of 290 patients with unicornuate uterus, 175 patients conceived to carry a total of 468 pregnancies. In sum, 2.7% of pregnancies were ectopic, 24.3% ended in first trimester abortion and 9.7% ended in second trimester loss. Rates of intrauterine foetal distress (IUFD), preterm delivery and term births were 10.5%, 20.1% and 44.0%, respectively, with a total live-birth rate of 49.9%. 80

Unicornuate uteri are often further complicated by the presence of uterine horns containing functional endometrium. Gynaecologic problems, as stated above, include endometriosis, haematometra, haematosalpinx and pelvic pain. The uterine horn, moreover, serves as a liability for ectopic pregnancy, both in the communicating and non-communicating subtypes. Numerous case reports in the literature involve patients presenting with acute abdomen secondary to ruptured rudimentary horn containing ectopic pregnancy. 46 Rupture is such a high risk given that most patients are asymptomatic prior to rupture, and there often exists no communication with the vagina. In cases where the uterine horn contains endometrium, even when asymptomatic, we feel the data support laparoscopic removal in order to prevent retrograde menses, endometriosis, horn gestations and other such complications.81 and 82

Obstetrical outcomes are generally reported to be better in cases of bicornuate uterus than in unicornuate uterus, perhaps given the significant variation in bicornuate uterine anatomy, subtypes of which involve a partially fused central uterine cavity. A 36% abortion rate and 23% preterm delivery rate have been quoted, but may still overstate the extent of obstetric compromise given selection bias and escaped detection of many asymptomatic patients. 75 In patients with repeated pregnancy loss in whom other causes have been excluded, laparoscopic or abdominal metroplasty serves as a viable treatment modality to improve obstetric outcomes.83 and 84We do not recommend metroplasty at the time of diagnosis for patients with primary infertility, given that fertility rates are not significantly reduced from the norm and successful pregnancies without intervention are common. Where feasible, we favour laparoscopic over abdominal metroplasty given decreased recovery time and minimisation of adhesion formation as well as the potential for lower rates of infection and less blood loss. 85 Patients should be counselled regarding the need for subsequent cesarean section, given the significant risk of uterine rupture during labour after such procedures.

As with most of the other müllerian anomalies, uterine didelphys has a relatively good prognosis for achieving pregnancy; an infertility rate of 13% has been reported from a study of 49 women with a mean follow-up of 9 years. 86 A review of 114 patients with untreated uterine didelphys who had a total of 152 pregnancies exhibited a mean miscarriage rate of 32.9% and preterm delivery rate of 28.9%, with a live-birth rate quoted as 56.6%. 75 Again, we feel such studies represent ‘worst-case scenarios’, given that the patients included in such studies are those most likely to have the poorest outcomes. As above, Strassman re-unification should not routinely be undertaken, except in circumstances of repeated pregnancy loss or preterm delivery in the absence of other aetiologies. Resection of a vaginal septum associated with uterine didelphys should be undertaken if associated with obstruction, dyspareunia or infertility.

Given their unique anatomy, patients with MRKH syndrome face significant reproductive challenges. Most patients with this anomaly have at least one normal ovary; ovulation induction, retrieval and subsequent transfer to a gestational carrier offer the opportunity for patients with MRKH to have genetically related offspring. Research has suggested that congenital absence of the uterus and vagina are not commonly transmitted to offspring in MRKH surrogate pregnancies. 87 Uterine transplantation remains a hypothetical treatment of the future, with only one failed human attempt documented in the literature. 88 Animal models for such transplantation, however, have enjoyed some degree of success and continue to be researched.89 and 90

To summarise, it is important to recognise the wide variation in degree of uterine anomalies and the unique impact of each anomaly on female reproductive success; counselling should be catered to the patient's unique anatomy. The clinician should keep in mind the embryologic origins of congenital uterine malformations, for such knowledge, combined with the appropriate application of modern imaging techniques, can lead to the diagnosis of other associated anomalies. Such patients can present with adverse gynaecologic or obstetric symptoms, but it is important to remember that many women with congenital müllerian anomalies likely enjoy reproductive success without ever being labelled with a diagnosis. It is our hope that this discussion of the various reproductive outcomes associated with each müllerian anomaly will assist in the counselling of such patients, and allow for the appropriate selection of surgical candidates for malformations amenable to correction.

Conflict of interest

The authors can identify no potential conflicts of interest, neither financial nor any other, involved in the writing or publication of this article.

Practice points

 

  • Müllerian anomalies have significant gynaecologic, obstetric and psychological implications for affected women and their families
  • A thorough diagnostic approach should be undertaken both to define the patient's specific malformation and to delineate associated anomalies involving the gonads and kidneys
  • Reproductive outcomes vary widely based on the degree of malformation, but müllerian malformations in general do greatly increase adverse obstetrical outcomes without significantly affecting the ability to conceive
  • Historically, studies have likely overestimated the degree of reproductive compromise secondary to selection bias
  • The cause of adverse obstetrical outcomes is poorly understood, but may be secondary to abnormal uterine vasculature, decreased cervical connective tissue or decreased uterine musculature
  • Surgical correction of uterine septa is a safe and effective procedure for optimising the uterine cavity prior to ART and for patients with previous adverse obstetric outcomes
  • Metroplasty for bicornuate and didelphic uteri remains controversial, although may be indicated for patients with repeatedly poor outcomes
  • Removal of uterine horns is indicated in the event that they contain functional endometrium
Research agenda

 

  • Genetic bases of congenital uterine malformations
  • The biologic and chemical aetiology of adverse obstetric outcomes associated with congenital uterine anomalies
  • Viability of uterine transplantation
  • Further refinement of corrective surgical approaches

References

  • 1 T.W. Sadler. Langman's medical embryology. 6th ed. (Williams & Wilkins, Baltimore, 1990)
  • 2 M. Akar, D. Bayar, S. Yildiz, et al. Reproductive outcome of women with unicornuate uterus. Aust N Z J Obstet Gynaecol. 2005;45(2):148-150
  • 3 P.M. Motta, S.A. Nottola, S. Makabe. Natural history of the female germ cell from its origin to full maturation through prenatal ovarian development. Eur J Obstet Gynecol Reprod Biol. 1997;75(1):5-10
  • 4 D.T. Maclaughlin, P.K. Donahoe. Sex determination and differentiation. N Engl J Med. 2004;350(4):367-378
  • 5 J. Brennan, B. Capel. One tissue, two fates: molecular genetic events that underlie testis versus ovary development. Nat Rev Genet. 2004;5(7):509-521
  • 6 F.F. Marshall, D.S. Beisel. The association of uterine and renal anomalies. Obstet Gynecol. 1978;51(5):559-562
  • 7 R.C. Northcutt, P.B. Underwood. Congenital absence of the vagina: embryology, diagnosis and management: report of five cases. Med Ann Dist Columbia. 1966;35(6):316-319
  • 8 H.S. Taylor. The role of HOX genes in the development and function of the female reproductive tract. Semin Reprod Endocrinol. 2000;18(1):81-89
  • 9 H. Du, H.S. Taylor. Molecular regulation of müllerian development by Hox genes. Ann N Y Acad Sci. 2004;1034:152-165
  • *10 V. Buttram, W. Gibbons. Müllerian anomalies: a proposed classification (an analysis of 144 cases). Fertil Steril. 1979;32(1):40-46
  • *11 American Fertility Society. The American Fertility Society classification of adnexal adhesions, distal tubal occlusion, tubal occlusion secondary to tubal ligation, tubal pregnancies, müllerian anomalies and intrauterine adhesions. Fertil Steril. 1988;49(6):944-955
  • 12 R.N. Troiano, S.M. McCarthy. Müllerian duct anomalies: imaging and clinical issues. Radiology. 2004;233(1):19-34
  • 13 Y. Jayasinghe, A. Rane, H. Stalewski, et al. The presentation and early diagnosis of the rudimentary uterine horn. Obstet Gynecol. 2005;105(6):1456-1467
  • 14 P.K. Heinonen. Complete septate uterus with longitudinal vaginal septum. Fertil Steril. 2006;85(3):700-705
  • 15 B. Haddad, C. Louis-Sylvestre, P. Poitout, et al. Longitudinal vaginal septum: a retrospective study of 202 cases. Eur J Obstet Gynecol Reprod Biol. 1997;74(2):197-199
  • *16 P.C. Lin, K.P. Bhatnagar, G.S. Nettleton, et al. Female genital anomalies affecting reproduction. Fertil Steril. 2002;78(5):899-915
  • 17 D.M. Lee, R. Osathanondh, J. Yeh. Localization of Bcl-2 in the human fetal müllerian tract. Fertil Steril. 1998;70(1):135-140
  • 18 P.E. Patton. Anatomic uterine defects. Clin Obstet Gynecol. 1994;37(3):705-721
  • 19 P. Vercellini, R. Daguati, E. Somigliana, et al. Asymmetric lateral distribution of obstructed hemivagina and renal agenesis in women with uterus didelphys: institutional case series and a systematic literature review. Fertil Steril. 2007;87(4):719-724
  • *20 N.A. Smith, M.R. Laufer. Obstructed hemivagina and ipsilateral renal anomaly (OHVIRA) syndrome: management and follow-up. Fertil Steril. 2007;87(4):918-922
  • 21 T.N. Evans, M.L. Poland, R.L. Boving. Vaginal malformations. Am J Obstet Gynecol. 1981;141(8):910-920
  • 22 C.A. Salvatore, O. Lodovicci. Vaginal agenesis: an analysis of ninety cases. Acta Obstet Gynecol Scand. 1978;57(1):89-94
  • 23 L. Fedele, S. Bianchi, G. Frontino, et al. Laparoscopic findings and pelvic anatomy in Mayer–Rokitansky–Kuster–Hauser syndrome. Obstet Gynecol. 2007;109(5):1111-1115
  • 24 G.W. Bates, W.L. Wiser. A technique for uterine conservation in adolescents with vaginal agenesis and a functional uterus. Obstet Gynecol. 1985;66(2):290-294
  • *25 J.S. Sanfilippo, N.G. Wakim, K.N. Schikler, et al. Endometriosis in association with uterine anomaly. Am J Obstet Gynecol. 1986;154(1):39-43
  • 26 A.M. Propst, J.A. Hill 3rd. Anatomic factors associated with recurrent pregnancy loss. Semin Reprod Med. 2000;18(4):341-350
  • *27 G.G. Nahum. Uterine anomalies: how common are they, and what is their distribution among subtypes?. J Reprod Med. 1998;43(10):877-887
  • 28 C. Simón, L. Martinez, F. Pardo, et al. Müllerian defects in women with normal reproductive outcome. Fertil Steril. 1991;56(6):1192-1193
  • 29 P. Acien. Incidence of müllerian defects in fertile and infertile women. Hum Reprod. 1997;12(7):1372-1376
  • 30 L.P. Shulman. Müllerian anomalies. Clin Obstet Gynecol. 2008;51(1):214-222
  • 31 J. Battin, D. Lacombe, J.J. Leng. Familial occurrence of hereditary renal adysplasia with müllerian anomalies. Clin Genet. 1993;43(1):23-24
  • *32 J.L. Simpson. Genetics of the female reproductive ducts. Am J Med Genet. 1999;89(4):224-239
  • 33 J.H. Harger, D.F. Archer, S.G. Marchese, et al. Etiology of recurrent pregnancy loss and outcome of subsequent pregnancies. Obstet Gynecol. 1983;62(5):574-581
  • 34 S. Elias, J.L. Simpson, S.A. Carson, et al. Genetic studies in incomplete müllerian fusion. Obstet Gynecol. 1984;63(3):276-279
  • 35 L.L. Breech, M.R. Laufer. Müllerian anomalies. Obstet Gynecol Clin North Am. 2009;36(1):47-68
  • 36 B.W. Rackow, A. Arici. Reproductive performance of women with müllerian anomalies. Curr Opin Obstet Gynecol. 2007;19(3):229-237
  • 37 J.S. Noumoff, S. Heyner, M. Farber. The malignant potential of congenital anomalies of the paramesonephric ducts. Sem Reprod Endocrinol. 1986;4(1):67-74
  • 38 U. Nicolini, M. Bellotti, B. Bonazzi, et al. Can ultrasound be used to screen uterine malformations?. Fertil Steril. 1987;47(1):89-93
  • 39 M.H. Wu, C.C. Hsu, K.E. Huang. Detection of congenital müllerian duct anomalies using three-dimensional ultrasound. J Clin Ultrasound. 1997;25(9):487-492
  • 40 F. Raga, F. Bonilla-Musoles, J. Blanes, et al. Congenital müllerian anomalies: diagnostic accuracy of three-dimensional ultrasound. Fertil Steril. 1996;65(3):523-528
  • 41 T. Ghi, P. Casadio, M. Kuleva, et al. Accuracy of three-dimensional ultrasound in diagnosis and classification of congenital uterine anomalies. Fertil Steril. 2008; Aug 8: Epub ahead of print
  • 42 K.L. Reuter, D.C. Daly, S.M. Cohen. Septate versus bicornuate uteri: errors in imaging diagnosis. Radiology. 1989;172(3):749-752
  • *43 J.S. Pellerito, S.M. McCarthy, M.B. Doyle, et al. Diagnosis of uterine anomalies: relative accuracy of MR imaging, endovaginal sonography, and hysterosalpingography. Radiology. 1992;183(3):795-800
  • 44 M.B. Doyle. Magnetic resonance imaging in müllerian fusion defects. J Reprod Med. 1992;37(1):33-38
  • 45 P. Oppelt, M. von Have, M. Paulsen, et al. Female genital malformations and their associated abnormalities. Fertil Steril. 2007;87(2):335-342
  • *46 L. Fedele, S. Bianchi, B. Agnoli, et al. Urinary tract anomalies associated with unicornuate uterus. J Urol. 1996;155(3):847-848
  • 47 D.P. Thompson, H.B. Lynn. Genital anomalies associated with solitary kidney. Mayo Clin Proc. 1966;41(8):538-548
  • 48 C.M. March, R. Israel. Hysteroscopic management of recurrent abortion caused by septate uterus. Am J Obstet Gynecol. 1987;156(4):834-842
  • 49 R.F. Valle, J.J. Sciarra. Hysteroscopic treatment of the septate uterus. Obstet Gynecol. 1986;67(2):253-257
  • 50 W. Ombelet, G. Verswijvel, E. de Jonge. Ectopic ovary and unicornuate uterus. N Engl J Med. 2003;348(7):667-668
  • 51 H. Dabirashrafi, K. Mohammad, N. Moghadami-Tabrizi. Ovarian malposition in women with uterine anomalies. Obstet Gynecol. 1994;83(2):293-294
  • 52 S. Marcus, T. al-Shawaf, P. Brinsden. The obstetric outcome of in vitro fertilization and embryo transfer in women with congenital uterine malformation. Am J Obstet Gynecol. 1996;175(1):85-89
  • 53 R.R. Guirgis, P. Shrivastav. Gamete intrafallopian transfer (GIFT) in women with bicornuate uteri. J In Vitro Fert Embryo Transf. 1990;7(5):283-284
  • 54 R. Pabuccu, V. Gomel. Reproductive outcome after hysteroscopic metroplasty in women with septate uterus and otherwise unexplained infertility. Fertil Steril. 2004;81(6):1675-1678
  • 55 N. Lavergne, J. Aristizabal, V. Zarka, et al. Uterine anomalies and in vitro fertilization: what are the results?. Eur J Obstet Gynecol Reprod Biol. 1996;68(1-2):29-34
  • 56 F. Raga, C. Bauset, J. Remohi, et al. Reproductive impact of congenital müllerian anomalies. Hum Reprod. 1997;12(10):2277-2281
  • 57 A.W. Cohen, G. Chhibber. Obstetric complications of congenital anomalies of the paramesonephric ducts. Semin Reprod Endocrinol. 1986;4(1):59-66
  • 58 L.K. Green, R.E. Harris. Uterine anomalies: frequency of diagnosis and associated obstetric complications. Obstet Gynecol. 1976;47(4):427-429
  • 59 D.M. Moutos, M.D. Damewood, W.D. Schlaff, et al. A comparison of the reproductive outcome between women with a unicornuate uterus and women with a didelphic uterus. Fertil Steril. 1992;58(1):88-93
  • 60 G.G. Nahum. Uterine anomalies, induction of labor, and uterine rupture. Obstet Gynecol. 2005;106(5):1150-1152
  • 61 R. Achiron, O. Tadmor, R. Kamar, et al. Prerupture ultrasound diagnosis of interstitial and rudimentary uterine horn pregnancy in the second trimester: a report of two cases. J Reprod Med. 1992;37(1):89-92
  • 62 J. Zaidi, J. Carr. Rupture of pregnant rudimentary uterine horn with fetal salvage. Acta Obstet Gynecol Scand. 1994;73(4):359-360
  • 63 R.C. Burchell, F. Creed, M. Rasoulpour, et al. Vascular anatomy of human uterus and pregnancy wastage. Br J Obstet Gynaecol. 1978;85(9):698-706
  • 64 J.W. Roddick, J.C. Buckingham, D.N. Danforth. The muscular cervix – a cause of incompetency in pregnancy. Obstet Gynecol. 1961;17:562-565
  • 65 M. Blum. Comparative study of serum C.A.P. activity during pregnancy in malformed and normal uterus. J Perinat Med. 1978;6(3):165-168
  • 66 C. Nwosu, C. Soffronaff, C. Bolton. A new look at the etiology of cervical incompetence. Int J Gynaecol Obstet. 1975;13:201
  • 67 A. Golan, R. Langer, S. Wexler, et al. Cervical cerclage – its role in the pregnant anomalous uterus. Int J Fertil. 1990;35(3):164-170
  • 68 H. Abramovici, J.H. Faktor, B. Pascal. Congenital uterine malformations as indication for cervical suture in habitual abortion and premature delivery. Int J Fertil. 1983;28(3):161-164
  • 69 H. Dabirashrafi, M. Bahandori, K. Mohammad, et al. Septate uterus: new idea on the histologic features of the septum in this abnormal uterus. Am J Obstet Gynecol. 1995;172(1):105-107
  • 70 H.A. Homer, T.C. Li, I.D. Cooke. The septate uterus: a review of management and reproductive outcome. Fertil Steril. 2000;73(1):1-14
  • 71 G.B. Candiani, L. Fedele, D. Zamberletti, et al. Endometrial patterns in malformed uteri. Acta Eur Fertil. 1983;14(5):311-318
  • 72 P.K. Heinonen, S. Saarikoski, P. Pystynen. Reproductive performance of women with uterine anomalies. Acta Obstet Gynecol Scand. 1982;61(2):157-162
  • 73 A. Golan, R. Langer, I. Bukovsky, et al. Congenital anomalies of the müllerian system. Fertil Steril. 1989;51(5):747-755
  • 74 A.H. DeCherney, J.B. Russell, R.A. Graebe, et al. Resectoscopic management of müllerian fusion defects. Fertil Steril. 1986;45(5):726-728
  • 75 G.F. Grimbizis, M. Camus, B.C. Tarlatzis, et al. Clinical implications of uterine malformations and hysteroscopic treatment results. Hum Reprod Update. 2001;7(2):161-174
  • 76 A. Mollo, P. De Franciscis, N. Colacurci, et al. Hysteroscopic resection of the septum improves the pregnancy rate of women with unexplained infertility: a prospective controlled trial. Fertil Steril. 2008; June 18: Epub ahead of print
  • 77 J.A. Rock, C.P. Roberts, J.S. Hesla. Hysteroscopic metroplasty of the class Va uterus with preservation of the cervical septum. Fertil Steril. 1999;72(5):942-945
  • 78 M.E. Parsanezhad, S. Alborzi, A. Zarei, et al. Hysteroscopic metroplasty of the complete uterine septum, duplicate cervix, and vaginal septum. Fertil Steril. 2006;85(5):1473-1477
  • 79 P. Acien. Reproductive performance of women with uterine malformations. Hum Reprod. 1993;8(1):122-126
  • *80 D. Reichman, M.R. Laufer, B.K. Robinson. Pregnancy outcomes in unicornuate uteri: a review. Fertil Steril. 2009;91(5):1886-1894
  • 81 M. Canis, J. Wattiez, J.L. Pouly, et al. Laparoscopic management of unicornuate uterus with rudimentary horn and unilateral extensive endometriosis: case report. Hum Reprod. 1990;5(7):819-820
  • 82 F. Nezhat, C. Nezhat, O. Bess, et al. Laparoscopic amputation of noncommunicating rudimentary horn after hysteroscopic diagnosis: a case study. Surg Laparosc Endosc. 1994;4(2):155-156
  • 83 R. Sinha, C. Mahajan, A. Hegde, et al. Laparoscopic metroplasty for bicornuate uterus. J Minim Invasive Gynecol. 2006;13(1):70-73
  • 84 D.E. Lolis, M. Paschopoulos, G. Makrydimas, et al. Reproductive outcome after Strassman metroplasty in women with a bicornuate uterus. J Reprod Med. 2005;50(5):297-301
  • 85 S. Alborzi, N. Asadi, J. Zolghardri, et al. Laparoscopic metroplasty in bicornuate and didelphic uteri. Fertil Steril. 2008; Aug 1: Epub ahead of print
  • 86 P.K. Heinonen. Clinical implications of the didelphic uterus: long-term follow-up of 49 cases. Eur J Obstet Gynecol Reprod Biol. 2000;91(2):183-190
  • 87 J.C. Petrozza, M.R. Gray, A.J. Davis, et al. Congenital absence of the uterus and vagina is not commonly transmitted as a dominant genetic trait: outcomes of surrogate pregnancies. Fertil Steril. 1997;67(2):387-389
  • 88 M. Brännström. Uterine transplantation: a future possibility to treat women with uterus factor infertility?. Minerva Med. 2007;98(3):211-216
  • 89 C.A. Wranning, R.R. El-Akouri, K. Groth, et al. Rejection of the transplanted uterus is suppressed by cyclosporine A in a semi-allogeneic mouse model. Hum Reprod. 2007;22(2):372-379
  • 90 M. Brännström, C.A. Wranning. Uterus transplantation: how far away from human trials?. Acta Obstet Gynecol Scand. 2008;87(11):1097-1100

Footnotes

a Department of Obstetrics and Gynecology, Brigham Women's Hospital, Boston, MA, USA

b Department of Surgery, Chief of Gynecology, Children's Hospital of Boston, Boston, MA, USA

c Department of Obstetrics and Gynecology, Division of Fertility and Reproductive Endocrinology, Brigham and Women's Hospital, Boston, MA, USA

Corresponding author. Children's Hospital Boston, 300 Longwood Avenue, Boston MA 02115, USA.