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Abnormalities of the uterus may be congenital or acquired and typically present with menstrual dysfunction, pelvic pain, infertility, or pregnancy wastage. Congenital anomalies have a heterogeneous genetic basis, and WT1, Pax2, WNT2, PBX1, and HOX genes are potentially involved (Hutson, 2014).
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Various classification schemes for female reproductive tract anomalies exist, but the most commonly used system was proposed by Buttram and Gibbons (1979) and adapted by the American Society for Reproductive Medicine (former American Fertility Society, 1988). Within this system, six categories organize similar embryonic developmental defects (Table 18-4). Acien (2009) and Rock (2010) have described types of uterovaginal and cervical malformations that do not adapt to the usual classification systems. Such anomalies are best described and drawn in detail in a patient’s medical record for future reference.
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Most cases are diagnosed during evaluation for obstetric or gynecologic problems, but in the absence of symptoms, most anomalies remain undiagnosed. Because nearly 57 percent of women with uterine defects have successful fertility and pregnancy, the true incidence of congenital müllerian defects may be significantly understated. Nahum (1998) found that the prevalence of uterine anomalies in the general population was 1 in 201 women or 0.5 percent. Dreisler and colleagues (2014) found uterine anomalies in nearly 10 percent of 622 women from the general population undergoing saline infusion sonography.
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Anatomic uterine defects have long been recognized as a cause of obstetric complications. Recurrent pregnancy loss, preterm labor, abnormal fetal presentation, and prematurity constitute the major reproductive problems encountered. Cunningham and colleagues (2014a) provide a full discussion of specific müllerian abnormalities and their obstetric importance. Müllerian defects are also associated with renal anomalies in 30 to 50 percent of cases, and defects include unilateral renal agenesis, severe renal hypoplasia, horseshoe kidney, pelvic kidney, and ectopic or duplicate ureters (Sharara, 1998). Spinal anomalies have been reported in 10 to 12 percent of cases and include wedge, supernumerary, or asymmetric and rudimentary vertebral bodies (Kimberley, 2011). The combination of müllerian and renal aplasia and cervicothoracic somite dysplasia has been described as MURCS association (Duncan, 1979). An association with Klippel-Feil syndrome has also been reported. Other anomalies associated with vaginal agenesis include ear anomalies and hearing loss, with the latter reported to be as high as 25 percent. The pattern of associated anomalies suggests an embryologic link (Kimberley, 2011).
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Müllerian anomalies may be discovered during routine pelvic examinations, infertility evaluation, or surgery for other indications. Depending on clinical presentation, diagnostic tools may include hysterosalpingography (HSG), sonography, MR imaging, laparoscopy, and hysteroscopy. Each tool has limitations, but they may be used in combination to completely define anatomy. In women undergoing fertility evaluation, HSG is commonly selected for uterine cavity and tubal patency assessment. That said, HSG poorly defines the external uterine contour and can delineate only patent cavities. In other clinical settings, sonography is initially performed. Transabdominal views may help to maximize the viewing field, but transvaginal sonography (TVS) provides better image resolution. Saline infusion sonography (SIS) improves delineation of the endometrium and internal uterine morphology, but only with a patent endometrial cavity. Three-dimensional (3-D) sonography can provide uterine images from virtually any angle. Thus, coronal images can be constructed and are essential in evaluating both internal and external uterine contours. Sonography is ideally completed during the luteal phase when the secretory endometrium provides contrast from increased thickness and echogenicity (Caliskan, 2010). Several investigators have reported good concordance between 3-D TVS and MR imaging of müllerian anomalies, but MR imaging is currently preferred for imaging complex defects (Bermejo, 2010; Ghi, 2009). MR imaging provides clear delineation of both the internal and external uterine anatomy and has a reported accuracy of up to 100 percent in the evaluation of müllerian anomalies (Fedele, 1989; Pellerito, 1992). Moreover, complex anomalies and commonly associated secondary diagnoses such as renal or skeletal anomalies can be concurrently evaluated. In some women undergoing an infertility evaluation, hysteroscopy and laparoscopy may be selected to assess for müllerian anomalies; screen for endometriosis, which is often coexistent; and exclude other tubal or uterine cavity pathologies (Puscheck, 2008; Saravelos, 2008).
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Segmental Müllerian Hypoplasia or Agenesis
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Some form of müllerian aplasia, hypoplasia, or agenesis affects 1 in every 4000 to 10,000 females and is a common cause of primary amenorrhea (American College of Obstetricians and Gynecologists, 2009). Uterine agenesis follows failed development of the lower portion of the müllerian ducts during embryogenesis and usually leads to absence of the uterus, cervix, and upper part of the vagina (Oppelt, 2006). Variants may display absence of the upper vagina but presence of the uterus. Normal ovaries are found, and affected individuals otherwise develop as phenotypically normal females and present with primary amenorrhea.
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Females with vaginal atresia lack the lower portion of the vagina, but otherwise have normal pubertal maturation and external genitalia (Fig. 18-11). Embryologically, the urogenital sinus fails to contribute its expected caudal portion of the vagina (Simpson, 1999). As a result, the lower portion of the vagina, usually one-fifth to one-third of the total length, is replaced by 2 to 3 cm of fibrous tissue. In some individuals, however, vaginal atresia may extend to near the cervix.
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Since most affected women have normal external genitalia and upper reproductive tract organs, vaginal atresia does not often become apparent until menarche. Adolescents generally present shortly after physiologic menarche with cyclic pelvic pain due to hematocolpos or hematometra. On physical examination, the hymeneal ring is normal. But proximal to the ring, only a vaginal dimple or small pouch is found. A rectoabdominal examination confirms midline organs. Additionally, sonographic or MR imaging will display upper reproductive tract organs. Of these, MR imaging is the most accurate diagnostic tool, as the length of the atresia, the amount of upper vaginal dilatation, and the presence of the cervix can be identified. Presence of the cervix in such cases distinguishes vaginal atresia from müllerian agenesis. Laparoscopy, however, is often necessary when anatomy cannot be fully evaluated with radiographic studies. Treatment follows that for müllerian agenesis.
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Because of the common müllerian source, women with congenital absence of the cervix typically also lack the upper vagina. The uterus, however, usually develops normally (see Fig. 18-11). In addition to agenesis, Rock (2010) has described various forms of cervical dysgenesis.
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Women with cervical agenesis initially present similarly to patients with other reproductive tract obstructive anomalies, that is, with primary amenorrhea and cyclic abdominal or pelvic pain. If a functional endometrium is present, a patient may have a distended uterus, and endometriosis may have developed secondary to retrograde menstrual flow. A single midline uterine fundus is the norm, although bilateral hemiuteri have also been described (Dillon, 1979).
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Radiographic studies, sonography, and MR imaging aid anatomy delineation. If imaging demonstrates an obstructed uterus, hysterectomy has been recommended by some (Rock, 1984). In contrast, Niver (1980) and others report creation of an epithelialized endocervical tract and vagina. Significant morbidity, including infection, recurrent obstruction requiring hysterectomy, and death due to sepsis, however, has been reported with establishment of such a vaginal-uterine connection (Casey, 1997; Rock, 2010). Alternatively, conservative management with GnRH antagonists or agonists or with combination oral contraceptive pills may be used to suppress retrograde menses and possible endometriosis until a patient is ready for reproduction options (Doyle, 2009). Thus, the uterus may be retained for possible reproductive potential. Thijssen and associates (1990) reported a successful pregnancy using zygote intrafallopian tube transfer in a patient with cervical agenesis. Gestational surrogacy offers another viable option for these women.
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Congenital absence of both the uterus and vagina is termed müllerian aplasia, müllerian agenesis, or Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS). In classic müllerian agenesis, patients have a shallow vaginal pouch, measuring only 1 to 2 inches deep. In addition, the uterus, cervix, and upper part of the vagina are absent. Typically, normal ovaries persist, given their separate embryonic source, and a portion of the distal fallopian tubes is present. Most patients with müllerian agenesis have only small rudimentary müllerian bulbs without endometrial activity. However, in 2 to 7 percent of women with this condition, active endometrium develops and patients typically present with cyclic abdominal pain (American College of Obstetricians and Gynecologists, 2009). Surgical excision of symptomatic rudimentary bulbs is required. With müllerian agenesis, traditional conception is impossible, but pregnancy may be achieved using oocyte retrieval, fertilization, and gestational surrogacy.
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Evaluation for associated congenital renal or other skeletal anomalies is essential in individuals with müllerian hypoplasia or agenesis. As noted, approximately 15 to 36 percent of women with uterine agenesis also have defects of the urinary system, and 12 percent may have scoliosis. Skeletal malformations observed include spina bifida, sacralization (partial fusion of L5 to the sacrum), sacral bone lumbarization (nonfusion of the first and second sacral segments), and cervical vertebral anomalies. As noted earlier, MURCS syndrome displays müllerian duct aplasia, renal aplasia, and cervicothoracic somite dysplasia (Oppelt, 2006). Cardiac malformations and neurologic disturbances play a lesser role and include ventricular septal defects and unilateral hearing problems. Fifty to 60 percent of women with müllerian agenesis have secondary malformations and thus are regarded as having a complex multiorgan and multisystem syndrome.
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One treatment goal for most of these women is creation of a functional vagina. This may be accomplished conservatively or surgically. There are several conservative approaches, and each attempts to progressively invaginate the vaginal dimple to create a canal of adequate size. Graduated hard glass dilators were initially recommended by Frank (1938). Ingram (1981) modified the Frank method by affixing the dilators to a bicycle seat mounted upon a stool. This affords patients hand mobility for other activities during the 30 minutes to 2 hours spent each day for passive dilation (American College of Obstetricians and Gynecologists, 2009). Currently, firm silicon dilators are available through several medical vendors. A vagina may also be created with repeated coitus. Overall, vaginal dilatation techniques are successful in forming a functional vagina in as many as 90 percent of cases (Croak, 2003; Roberts, 2001).
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Surgical procedures are seen by many as a more immediate solution to creation of a neovagina, and several methods have been reported. The method used most commonly by gynecologists is the McIndoe vaginoplasty (McIndoe, 1950). As illustrated in Section 43-25, a canal is created within the connective tissue between the bladder and rectum. A split-thickness skin graft obtained from the patient’s buttocks or thigh is then used to line the neovagina.
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Modifications of the McIndoe procedure include substitution of buccal mucosa, human amnion, or absorbable adhesion barriers as the neovaginal lining (Ashworth, 1986; Lin, 2003; Motoyama, 2003). Similarly, cutaneous or musculocutaneous flaps have been employed to line the neovagina (Williams, 1964). Also, the Davydov procedure pulls pelvic peritoneum from the pelvis into the newly created vaginal space and then to the introitus. However, bladder and ureteric injuries and vesicovaginal fistula are potential complications (Davydov, 1969).
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All of these methods require a commitment to scheduled postoperative dilatation to avoid significant vaginal stricture (Breech, 1999). Accordingly, these procedures should be considered only if the patient is mature and willing to adhere to a postoperative regimen of regular intercourse or manual dilatation with dilators.
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To avoid these postoperative requirements, pediatric surgeons more frequently use a segment of bowel to create the vagina. These colpoplasties most commonly use sigmoidal or ileal segments and require abdominal entry and bowel anastomosis. Many patients complain of a persistent vaginal discharge from the gastrointestinal mucosa. Kapoor (2006) reported on 14 such sigmoid vaginoplasties and noted good cosmetic results and no cases of colitis, stenosis, or excessive mucus.
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Alternatively, the Vecchietti procedure uses an initial abdominal surgery to create an apparatus for passive vaginal dilatation. A synthetic sphere, attached to two wires, is placed in the vagina dimple. The wires are guided through the potential neovaginal space and into the peritoneal cavity, and then exit onto the anterior abdominal wall. The wires are placed on continuous tension, which is increased daily to stretch the blind vaginal pouch (Vecchietti, 1965).
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To address uterine agenesis, uterine transplantation from a deceased donor has been described and entailed uterine harvest and revascularization. The donor uterus was supplied by its uterine and internal iliac vessels, which were anastomosed to the recipient’s external iliac vessels (Ozkan, 2013). This patient with MRKH syndrome resumed menses, conceived following in vitro fertilization, but failed to sustain the gestation (Erman Akar, 2013). More work is likely to come in this area of research.
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Failure of one müllerian duct to develop and elongate results in a unicornuate uterus. This anomaly is common, and Zanetti (1978) found an incidence of 14 percent in a series of 1160 uterine anomalies. With unicornuate uterus, a functional uterus, normal cervix, and normal round ligament and fallopian tube are found on one side. On the contralateral side, müllerian structures develop abnormally, and agenesis or more frequently a rudimentary uterine horn is identified. A rudimentary horn may communicate or more commonly not communicate with the unicornuate uterus. In addition, the endometrial cavity of the rudimentary horn may be obliterated or may contain some functioning endometrium. Active endometrium in a noncommunicating horn will eventually be symptomatic with cyclic unilateral pain and possibly with hematometra.
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Women with a unicornuate uterus have an increased incidence of infertility, endometriosis, and dysmenorrhea (Fedele, 1987, 1994; Heinonen, 1983). On physical examination, the uterus is often markedly deviated, but imaging is frequently needed to further define horn anatomy. In addition, renal sonography is performed, as 40 percent of women with a unicornuate uterus also have some degree of renal agenesis, usually ipsilateral to the anomalous side (Rackow, 2007). If anatomy is unclear, then MR imaging is selected to add information.
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Women with unicornuate uterus have impaired pregnancy outcomes. A review of studies reveals a spontaneous abortion rate of 36 percent, a preterm delivery rate of 16 percent, and a live birth rate of 54 percent (Rackow, 2007). Other obstetric risks include malpresentation, fetal-growth restriction, fetal demise, and prematurely ruptured membranes (Chan, 2011; Reichman, 2009).
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The pathogenesis of pregnancy loss associated with unicornuate uterus is incompletely understood, but reduced uterine capacity or anomalous distribution of the uterine artery has been suggested (Burchell, 1978). Moreover, cervical incompetence may contribute to the risk for premature delivery and second-trimester abortion. Accordingly, a unicornuate uterus is suspected in any woman with a history of pregnancy loss, premature delivery, or abnormal fetal lie.
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No surgeries are currently available to enlarge the unicornuate uterus cavity. Some obstetricians recommend prophylactic cervical cerclage, but adequate trials assessing outcome are lacking. Selection of a gestational surrogate may circumvent these anatomic limitations. Other patients, however, seem to carry their pregnancies longer with each subsequent gestation and may eventually reach fetal viability prior to labor.
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Pregnancy may also occur in the rudimentary horn. In noncommunicating horns, this is thought to result from the intraabdominal transit of sperm from the contralateral fallopian tube. Pregnancy in a cavitary horn regardless of communication is associated with a high rate of uterine rupture, typically prior to 20 weeks (Rolen, 1966). Because of the high maternal morbidity secondary to intraperitoneal hemorrhage, preconceptional excision of a cavitary rudimentary horn is reasonable (Heinonen, 1997; Nahum, 2002). With a rudimentary horn pregnancy, excision is indicated. Laparotomy is typical, but laparoscopy is feasible with suitable skills and well-selected cases (Kadan, 2008; Spitzer, 2009).
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If the rudimentary horn is obliterated, removal is not routinely recommended. Salpingectomy or salpingo-oophorectomy on the side with the rudimentary horn, however, has been suggested to prevent ectopic pregnancy in women with a unicornuate uterus, although the ectopic pregnancy risk is low.
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A didelphic uterus results from failed fusion of the paired müllerian ducts. This anomaly is characterized by two separated uterine horns, each with an endometrial cavity and uterine cervix. A longitudinal vaginal septum runs between the two cervices in most cases. Heinonen (1984) reported that all 26 women with uterine didelphys in his series had a longitudinal vaginal septum. Occasionally, one hemivagina is obstructed by an oblique or transverse vaginal septum (see Fig. 18-10) (Hinckley, 2003).
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Uterine didelphys should be suspected if a longitudinal vaginal septum or if two separate cervices are discovered. Imaging is recommended to confirm the diagnosis as outlined on page 418.
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Pregnancies develop in one of the two horns, and of the major uterine malformations, the didelphic uterus has a good reproductive prognosis. Compared with the unicornuate uterus, although the potential for uterine growth and capacity appears similar, uterine didelphys probably has an improved blood supply from collateral connections between the two horns. Alternatively, improved fetal survival may be secondary to earlier diagnosis, which favors earlier and more intensive prenatal care (Patton, 1994). Heinonen (2000) followed 36 women with uterus didelphys long term and found that 34 of 36 women (94 percent) who wanted to conceive had at least one pregnancy, and they produced 71 pregnancies. Of these pregnancies, 21 percent were spontaneously aborted, and 2 percent were ectopic. The rate for fetal survival was 75 percent; for prematurity, 24 percent; for fetal-growth restriction, 11 percent; for perinatal mortality, 5 percent; and for cesarean delivery, 84 percent. In this series, pregnancy located more often (76 percent) in the right horn than in the left. Because the spontaneous abortion rate mirrors that of women with normal uterine cavities, surgical procedures in response to pregnancy loss are rarely indicated. Thus, surgery should be reserved and only considered for highly selected patients in whom repeated late-trimester losses or premature delivery has occurred with no other apparent etiology.
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This anomaly is caused by incomplete fusion of the müllerian ducts. It is characterized by two separate but communicating endometrial cavities and a single uterine cervix. Failed fusion may extend to the cervix, resulting in a complete bicornuate uterus, or may be partial, causing a milder abnormality. Women with a bicornuate uterus can expect reasonable success—approximately 60 percent—in delivering a living child. As with many uterine anomalies, premature delivery is a substantial obstetric risk. Heinonen and colleagues (1982) reported a 28-percent abortion rate and a 20-percent incidence of premature labor in women with a partial bicornuate uterus. Women with a complete bicornuate uterus had a 66-percent incidence of preterm delivery and a lower fetal survival rate.
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Radiologic discrimination of bicornuate uterus from the septate uterus can be challenging, however, it is important because septate uterus is easily treated with hysteroscopic septal resection. Widely diverging horns seen on HSG may suggest a bicornuate uterus. An intercornual angle >105 degrees suggests bicornuate uterus, whereas one <75 degrees indicates a septate uterus. However, MR imaging is necessary to define fundal contour. With this, an intrafundal downward cleft measuring ≥1 cm is indicative of bicornuate uterus, whereas a cleft depth <1 cm indicates a septate uterus. Use of 3-D sonography also allows internal and external uterine assessment. Thus, sonography and HSG seem acceptable imaging techniques in the initial investigation. When the presumptive diagnosis is a septate uterus, laparoscopy may be performed for a definitive diagnosis and before hysteroscopic resection of the septum is initiated.
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Surgical reconstruction of the bicornuate uterus is infrequently done but has been advocated in women with multiple spontaneous abortions in whom no other causative factors are identified. Strassman (1952) described the surgical technique that unified equal-sized endometrial cavities (Fig. 18-12). Reproductive outcome after unification generally has been good. In 289 women, preoperative pregnancy loss was more than 70 percent. Following surgery, more than 85 percent of pregnancies resulted in delivery of a viable infant. The actual benefit of metroplasty for a bicornuate uterus, however, has not been tested in a controlled clinical series. As in surgery for uterine didelphys, metroplasty is reserved for women in whom recurrent pregnancy loss occurs with no other identifiable cause.
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Following fusion of the müllerian ducts, failure of their medial segments to regress can create a permanent septum within the uterine cavity. Its contours can vary widely and depend on the amount of persistent midline tissue. The septum can project minimally from the uterine fundus or can extend completely to the cervical os. Moreover, septa can develop segmentally, resulting in partial communications of the partitioned uterus (Patton, 1994). The histologic structure of septa ranges from fibrous to fibromuscular.
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The true incidence of these anomalies is not known because they are usually detected only in women with obstetric complications. Although this defect does not predispose to increase rates of preterm labor or cesarean delivery, septate uterus is associated with a marked increase in spontaneous abortion rates (Heinonen, 2006). Woelfer and associates (2001) reported a first-trimester spontaneous abortion rate for septate uterus of 42 percent. Moreover, early pregnancy loss is significantly more common with a septate than with a bicornuate uterus (Proctor, 2003).
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This extraordinarily high pregnancy wastage likely results from partial or complete implantation on a largely avascular septum, from distortion of the uterine cavity, and from associated cervical or endometrial abnormalities. Based on operative experience for septal defects, the blood supply to the fibromuscular septum appears markedly reduced compared with normal myometrium. In addition to spontaneous abortion, septate uterus may rarely cause fetal malformation, and Heinonen (1999) described three newborns with a limb-reduction defect born to women with septate uterus.
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Diagnosis of the septate uterus follows guidelines established for the bicornuate uterus and includes HSG and/or sonography. Historically, abdominal metroplasty for septate uterus was shown to dramatically decrease fetal wastage and ultimately improve fetal survival rates (Rock, 1977; Blum, 1977). Two main disadvantages to metroplasty include the requirement of cesarean delivery to prevent uterine rupture in subsequent pregnancy and the high rate of postoperative pelvic adhesion formation and subsequent infertility.
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Currently, hysteroscopic septum resection is an effective and safe alternative to treat women with septate uterus (Section 44-17). Typically, operative hysteroscopy is combined with concurrent laparoscopic surveillance to reduce the risk of uterine perforation. After the initial case reports by Chervenak and Neuwirth (1981), many investigators have confirmed satisfactory live birth rates with the procedure (Daly, 1983; DeCherney, 1983; Israel, 1984). In a retrospective review, Fayez (1986) evaluated reproductive outcome in women who had either an abdominal metroplasty or hysteroscopic septoplasty. They noted an 87-percent live birth rate in the hysteroscopic group compared with a 70-percent rate in the abdominal group. Similarly, Daly and associates (1989) reported impressive results after hysteroscopic surgery. Proponents of hysteroscopic resection describe reduced rates of pelvic adhesions, shortened postoperative convalescence, lowered operative morbidity, and avoidance of mandatory cesarean delivery (Patton, 1994).
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An arcuate uterus displays only mild deviation from normal uterine development. Anatomic hallmarks include a slight midline septum within a broad fundus, sometimes with minimal fundal cavity indentation. Most clinicians report no impact on reproductive outcomes. Conversely, Woelfer and colleagues (2001) found excessive second-trimester losses and preterm labor. Surgical resection is indicated only if excessive rates of pregnancy loss are encountered and other etiologies for recurrent spontaneous abortion have been excluded.
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Diethylstilbestrol-Induced Reproductive Tract Abnormalities
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Diethylstilbestrol (DES), a synthetic nonsteroidal estrogen, was prescribed to an estimated 3 million pregnant women in the United States from the late 1940s through the early 1960s. Early reports claimed the drug was useful in treating abortion, preeclampsia, diabetes, hot flushes, and preterm labor (Massé, 2009). It was ineffective for these indications. Almost 20 years later, Herbst and coworkers (1971) found that DES exposure in utero was linked to the development of a “T-shaped” uterus and an increased incidence of clear cell adenocarcinomas of the vagina and cervix. The risk of this vaginal malignancy approximates 1 in 1000 exposed daughters. Daughters also have increased risks of developing vaginal and cervical intraepithelial neoplasia, suggesting that DES exposure could affect gene regulation (Herbst, 2000). DES has also been shown to suppress the WNT4 gene and alter Hox gene expression in mouse müllerian ducts. This provides a plausible molecular mechanism for the uterine abnormalities, vaginal adenosis, and rarely, carcinoma observed in exposed patients (Massé, 2009).
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During normal development, the vagina is originally lined by a glandular epithelium derived from the müllerian ducts. By the end of the second trimester, this layer is replaced by squamous epithelium extending up from the urogenital sinus. Failure of the squamous epithelium to completely line the vagina is termed adenosis. Although variable, it typically appears red, punctate, and granular. Common symptoms include vaginal irritation, discharge, and metrorrhagia—in particular, postcoital bleeding. Moreover, adenosis is frequently associated with vaginal clear cell adenocarcinoma.
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Genitourinary malformations following DES exposure in utero have also been noted and include those of the cervix, vagina, uterine cavity, and fallopian tubes. Transverse septa, circumferential ridges involving the vagina and cervix, and cervical collars (“cockscomb cervix”) have been found. Women with cervicovaginal abnormalities are more likely to have uterine anomalies, such as smaller uterine cavities, shortened upper uterine segments, and “T-shaped” and irregular cavities (Barranger, 2002). Fallopian tube abnormalities include shortened and narrowed dimensions and absent fimbria.
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Males exposed to DES in utero also have structural abnormalities. Cryptorchidism, testicular hypoplasia, microphallus, and hypospadias have been reported (Hernandez-Diaz, 2002).
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Women exposed to DES, in general, have impaired conception rates (Senekjian, 1988). Reduced fertility in these women is poorly understood but is associated with cervical hypoplasia and atresia. Of those who do conceive, the incidences of spontaneous pregnancy loss, ectopic pregnancy, and preterm delivery are increased, again particularly in those with associated structural abnormalities (Goldberg, 1999). Now, more than 50 years after DES use was proscribed, most affected women are past childbearing age, but higher rates of earlier menopause and breast cancer have been reported (Hatch, 2006; Hoover, 2011).