Contents

Abstract

Congenital malformations of the uterus, also termed Müllerian duct anomalies (MDA), are an uncommon, but often treatable, cause of infertility. Estimates of its frequency vary widely owing to different patient populations, nonstandardized classification systems, and differences in diagnostic data acquisition. Because normal pregnancies can occur in women with MDA and the anomalies are mostly discovered in cases of patients presenting with infertility, the reported prevalence of MDA in the general population is probably underestimated.

J. Roos, MD

Institute of Radiology, Luzerner Kantonsspital, CH-6000, Luzern, Switzerland

G. Milosevic, MD • R.A. Kubik-Huch, MD, MPH (*) Institute of Radiology, Kantonsspital Baden AG, CH-5404, Baden, Switzerland

e-mail: rahel.kubik@ksb.ch

M. Heubner, MD

Department of Gynaecology and Obstetrics, Kantonsspital Baden AG, CH-5404, Baden, Switzerland

1\ Clinical Background

1.1\ Epidemiology

Congenital malformations of the uterus, also termed Müllerian duct anomalies (MDA), are an uncommon, but often treatable, cause of infertility. Estimates of its frequency vary widely owing to different patient populations, nonstandardized classification systems, and differences in diagnostic data acquisition. Because normal pregnancies can occur in women with MDA and the anomalies are mostly discovered in cases of patients presenting with infertility, the reported prevalence of MDA in the general population is probably underestimated.

The overall published data suggest a prevalence range of uterovaginal anomalies of around

1–10% (Acién 1997; Ashton et al. 1988; Homer et al. 2000; Raga et al. 1997; Saleem 2003; Simón et al. 1991; Troiano and McCarthy 2004; Chan et al. 2011a) in the general population among women with normal and abnormal fertility. Arcuate and septate uteri appear to be the most common malformations in an unselected population (Dreisler and Stampe 2014). While conceiving is a minor problem for the majority of women with MDA, the risk of pregnancy loss is truly associated with MDA. Its prevalence in women with repeated miscarriage is considered to be around 5–13% (Homer et al. 2000; Raga et al. 1997; Chan et al. 2011a; Clifford et al. 1994; Nahum 1998; Raziel et al. 1994) and up to 25% in women with combined infertility and recurrent miscarriage (Chan et al. 2011a). No racial predilection is noted in the literature.

1.2\ Clinical Presentation

Mild forms of MDA, especially arcuate uteri, may never be diagnosed. Major forms of MDA may become clinically evident at different ages depending on their specific characteristics and associated disorders. The distribution among the different classes of MDA and their clinical presentations is summarized in Table 1. In the newborn/infant age,

an initial presentation of a palpable abdominal or pelvic mass due to a uterine or/and vaginal obstruction causing intraluminal fluid retention is possible. In the adolescent age group, a delayed menarche or primary amenorrhea with or without fluid retention in the uterus (hematometra) and/or vagina (hematocolpos) may present as a painful intra-abdominal tumor in case of obstruction or complete obliteration. Some patients also have cyclical pain, usually due to retrograde menstruation through the fallopian tubes. The most common MDA often become significant for the first time in the childbearing age. Patients can present with various problems of infertility, repeated spontaneous abortions, premature delivery, fetal intrauterine growth retardation, and difficulties during delivery like breech presentation or transverse lie (Zlopasa et al. 2007).

By understanding the defective embryological development, one can understand the potential for the presence of associated congenital malformations of other organ systems. Most frequently, renal malformations like renal agenesis or ectopia can occur. Much less frequent are bony malformations – most of them occur in a complex of varying symptoms – like abnormal scapula, supernumerary or fused ribs, vertebral malsegmentation, fusion of the vertebral column (i.e., Klippel–Feil syndrome), and radiocarpal hypoplasia. The nonrandom association

of MDA, renal agenesis/ectopia, and cervicothoracic somite dysplasia are subsumed under the so-called MURCS associations (Pittock et al. 2005). Although other malformations such as cardiac defects have been described, it remains unclear if some of the associated malformations are caused in the same development field or if early exposure to teratogenic agents was causative (Pittock et al. 2005). The literature does not show increased mortality for patients carrying an MDA compared to the general population, whereas the morbidity may be increased in some specific types of MDA causing obstructed Müllerian systems with the presence of hematosalpinx (retention of blood in the fallopian tubes), hematocolpos (retention of blood in the vagina), or retrograde menses causing the potential problem of endometriosis.

Once an MDA is suggested based on evidence from patient history and physical examination, the next diagnostic step includes an imaging workup, which often detects the underlying anomaly and guides further (surgical) interventions. Apart from the precise anatomic evaluation of the female genital tract, attention should be paid to associated malformations (e.g., of ureter or pelvic vessels), as this additional information might impact upon therapeutic measures, especially reconstructive or corrective surgery.

1.3\ Embryology

The understanding of the embryogenesis of the urogenital female tract is of paramount importance to understand the pathogenesis of the different types of MDA. The female reproductive system develops from the two paired Müllerian ducts (synonym: paramesonephric ducts) that start off in the embryonal mesoderm lateral to each Wolffian duct (synonym: mesonephric duct). The paired Müllerian ducts develop in medial and caudal directions, and the cranial part remains nonfused and forms the fallopian tubes. The caudal part fuses to a single canal forming the uterus and the upper two thirds of the vagina. This is called lateral fusion. In a process called

vertical fusion, the intervening midline septum of both ducts undergoes regression. The caudal part of the vagina arises from the sinovaginal bulb and fuses with the lower fused Müllerian ducts. The ovaries originate from the gonadal ridge, a completely­ different tissue than the mesoderm, forming both the urinary and genital systems. Hence, associated malformations of the kidney, but not of the ovaries, are frequently observed together with MDA. Pathogenesis of Müllerian duct anomalies can be basically classified into the presence of agenesis, hypoplasia, and defects in vertical and lateral fusion of the paired ducts.

In1988,theAmericanSocietyforReproductive

Medicine (ASRM; formerly known as American Fertility Society) (1988) presented a consensus in classification of uterovaginal anomalies and published a schematization system that is widely accepted among specialists. Other used classification systems are referenced (Buttram and Gibbons 1979; Rock and Schlaff 1985; Rock 2000). A more recent classification was proposed in 2013 by the

European Society of Human Reproduction and Embryology (ESHRE) and the European Society

for Gynaecological Endoscopy (ESGE)

(Grimbizis et al. 2013), in an attempt to improve the characterization of anomalies which did not fit into any group of the older classifications. Its reliability in clinical practice and effect on reproductive outcome still warrant further scientific evaluation, as it has been reported to lead to possible overdiagnosis and unnecessary operative treatment of septate uteri in cases which would have been classified as normal or arcuate uteri according to the ASRM classification (Ludwin and Ludwin 2015).

Although most Müllerian duct anomalies occur sporadically, there is a known association with in utero exposure to teratogenic agents such as diethylstilbestrol (DES) or thalidomide (Kaufman et al. 2000). Currently there are no known specific patterns of inheritance.

1.4\ Pathology

Whatever steps in embryogenesis are defective, different types of MDA can occur. The ASRM