Practice Essentials
The exstrophy-epispadias complex (EEC) comprises a spectrum of increasingly complex congenital anomalies, including epispadias, classic bladder exstrophy, and cloacal exstrophy. Each of these anomalies is thought to result from the same embryologic defect, and each has several described variants.
The prevailing theory regarding the development of EEC is failure of mesodermal ingrowth to reinforce the cloacal membrane. [1] The cloacal membrane is a bilaminar layer of endodermal and ectodermal tissue located at the caudal aspect of the germinal disk of the developing lower abdominal wall. During weeks 4 and 5 of gestation, in normal development, mesenchymal ingrowth between these layers forms the lower abdominal muscles and the bony pelvis. Continued descent of this urorectal septum results in fusion with the cloacal membrane and separation of the primitive cloaca into the urogenital sinus and the hindgut.
Perforation of the cloacal membrane should occur after fusion with the urorectal septum at approximately week 6 of development. Failure of mesenchyme to migrate between the ectodermal and endodermal layers of the lower abdominal wall leads to instability of the cloacal membrane, raising the risk of premature rupture. The timing and degree of premature rupture of this membrane result in the spectrum of conditions seen in EEC, with cloacal exstrophy the earliest defect and epispadias a later insult.
It has been suggested that the premature rupture of the membrane before its caudal translocation leads to this complex of infraumbilical anomalies. Rupture of the cloacal membrane after complete separation of the genitourinary (GU) and gastrointestinal (GI) tracts results in classic bladder exstrophy. However, rupture prior to descent of the urorectal septum allows externalization of the lower urinary tract and the distal GI tract (cloacal exstrophy). [2]
Cloacal exstrophy must be distinguished from the condition of persistent cloaca or cloacal malformation. The latter terms refer to the most extreme form of anorectal malformation (ARM) in female infants. This complex anomaly involves incomplete separation of the urinary tract, genital tract, and hindgut. No abdominal wall defect is present in persistent cloaca.
Epispadias is a variant that displays normal bladder formation but incomplete urethral tubularization distal to the bladder neck. It is more frequently noted in males. [3]
For neonates with exstrophy and epispadias, general supportive care appropriate for the overall condition and associated anomalies should be instituted. (See Treatment.) For patients with cloacal exstrophy, nutrition is important and is often started early. Antibiotic therapy is usually started after delivery and continued through the early postoperative period.
Surgical techniques used in the treatment of EEC include the following:
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Modern staged repair of exstrophy (MSRE)
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Complete primary repair for classic bladder exstrophy (CPRE)
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Kelly Repair
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Urinary diversion for classic bladder exstrophy
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Closure for cloacal exstrophy
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Gender reassignment
Pathophysiology
The elusiveness of a well-defined multifactorial pathogenesis is reflected in the varied potential multisystem defects seen in EEC. In epispadias, a late-stage premature rupture of the cloacal membrane, only the urethra distal to the bladder neck is incompletely formed. Cloacal exstrophy, however, is an early event and thus affects concomitant anomalies to the most severe degree, representing the most challenging end of the EEC spectrum. Affected anomalies may involve the GI, GU, central nervous, and musculosketal systems. In the most common presentation, classic bladder exstrophy, the lower urinary tract, genitalia, and the musculosketal system are usually affected.
Etiology
Most EEC cases appear sporadic; however, genetic analyses have identified potential causes. Possible explanations include an unbalanced translocation between the long arm of chromosome 9 and the Y chromosome resulting in a 9q34.1-qter deletion; mutations in a group of homeobox genes, including HLXB9 and the HOX family (which affect mesodermal development), may represent candidate genes. [4]
Offspring of patients with EEC have a 1 in 70 risk (500 times that of the general population) of being affected. Nevertheless, familial occurrence has been uncommon in large series. [5] The heritability of cloacal exstrophy has not been established, because no offspring have been reported.
Other risk factors have been suggested through analysis of periconception factors and pregnancy courses. In one study from Israel, large doses of progesterone in the early part of the first trimester were associated with a 10-fold increase in exstrophy births. In another large series of children with exstrophy conceived using assisted reproductive techniques, a 7.5-fold increase in incidence was noted when in vitro fertilization (IVF) was used. [6] Advancing parental age has emerged as a possible risk factor; in a clinical and molecular analysis of 232 families, the average maternal age was 34 years (average parental age, 32 years), and 49% of children with exstrophies were born from first pregnancies. [7]
Currently, the environmental factors most closely linked to cloacal exstrophy are periconception maternal exposure to smoking and maternal smoking during the first trimester. [8]
At present, 22q11.2 duplication is the genetic variant most commonly associated with bladder exstrophy-epispadias complex. [9]
Two clear needs arise from these findings:
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Optimizing the periconception and first-trimester periods, the times at which any insult to organogenesis is greatest
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Understanding the shifting societal views toward family planning (with first-time parents advancing in age) and the need for assisted-reproductive technologies
Epidemiology
In the United States, the prevalence of classic bladder exstrophy is 2.15 per 100,000 births; male epispadias occurs in 1 in 117,000 births, female epispadias in 1 in 484,000 births, and cloacal exstrophy in 1 in 200,000-400,000 births. [10, 11]
An international prospective epidemiologic survey placed the incidence of bladder exstrophy at 1 per 46,000 live births. [12]
For classic bladder exstrophy, the male-to-female ratio is 2.3:1, rising as high as 6:1 in some series. These conditions seem to be more common in Whites than in other races.
Overall, however, the incidence of exstrophy live births is decreasing. With improvements in imaging modalities and antenatal diagnosis, elective termination occurs in 23% of cases, and as many as 50% of pregnancies with exstrophy abort spontaneously. [13]
Prognosis
Cloacal exstrophy is one of the most significant congenital birth defects still compatible with life. Historically, it was associated with significant mortality, and reconstruction of this condition was not attempted until the 1970s. Mortality is rare with exstrophy and epispadias, thanks to advances in surgical technique and in the care of critically ill neonates. Recognition of the importance of early recognition and parenteral nutritional support has allowed successful reconstruction and improved the survival of children with EEC, even those with cloacal exstrophy.
Survival rates after surgical treatment are excellent. With respect to bladder function or continence, reports vary according to the type of reconstruction performed. [14, 15, 16] Objective and subjective evidence indicates that many exstrophic bladders do not function normally after reconstruction and may deteriorate over time.
Continence rates of 75-90% have been reported after staged reconstruction in classic bladder exstrophy, but more than one continence procedure may be required (eg, bladder-neck reconstruction, bladder augmentation, bladder-neck sling, or artificial urinary sphincter). Many of these patients require clean intermittent catheterization (CIC) through the urethra or a continent stoma because they are unable to void spontaneously to completion. Less encouraging results also have been reported.
Continence results after staged reconstruction are poor (< 25%) in patients with cloacal exstrophy, most likely because of abnormal bladder innervation in many patients. Experience with rectal reservoirs (ureterosigmoidostomy and variants) for exstrophy continence demonstrates rates higher than 95%, but they present long-term malignancy risks. [17] Continent reconstruction with intestinal bladder augmentation and CIC has a success rate greater than 90%.
With regard to sexual function, males are generally able to have erections, but most report inadequate phallus length or residual curvature. Often, genital reconstruction is required in later adolescence or young adulthood to achieve more desired cosmesis. Females report normal sexual function and typically undergo vaginal reconstruction after puberty for more normal-appearing genitalia. [18]
With respect to fertility and childbearing, retrograde ejaculation or iatrogenic obstruction of the ejaculatory ducts or vas deferens after surgical reconstruction may result in abnormal semen analysis. Antegrade ejaculation may be preserved after single-stage repair, but abnormal semen parameters are common. However, fertilization, with viable pregnancy, has been achieved by male patients with classic bladder exstrophy, though assisted-reproductive technologies are commonly used and needed by patients with cloacal exstrophy. [19]
Females with an anteriorly located cervix are typically fertile and able to have successful pregnancies. [20] In fact, in one series of 83 female patients with exstrophy, all were able to become pregnant who wanted to. [21] Cesarean delivery is recommended to avoid injury to the continence mechanism. Postpartum uterine prolapse is common as a result of the inherent structural defects in the pelvis—most significantly, the paucity of the urogenital diaphgram musculature (levator ani) anteriorly to the genital hiatus.
With regard to psychosocial concerns, education, employment, and social relationships generally are not affected substantially in adults with a history of bladder exstrophy and epispadias. [22, 23] Age-appropriate adaptive behaviors may be delayed in children with chronic medical conditions. [24] One study revealed below-average daily living skills and socialization but above-average self-esteem. Children may need support in disclosing their condition to new peers. In most instances, the earlier the age at which continence is achieved, the better patients tend to do in adolescence and into young adulthood.
Multiple anomalies associated with cloacal exstrophy can have a significant impact on daily life. Patients may be affected by permanent colostomy, the need for CIC, and impaired ambulation, though most gait disturbances correct by early childhood.
Patient Education
EEC is a complex anomaly that often requires several surgical procedures and necessitates lifelong medical follow-up care. Patients and families should be counseled regarding the complexity of the anomaly, the need for multiple procedures, and the long-term expectations for continence, sexual function, and fertility.
The risks, benefits, and alternatives of urinary tract reconstruction must be explained carefully to the family members, and they must accept responsibility for daily care of the patient (eg, CIC after bladder augmentation) before surgery can proceed.
The exstrophy-epispadias community is a close-knit one offering support to newly diagnosed young patients and their families. Additionally, a great wealth of patient education materials can now be found online (eg, www.bladderexstrophy.com) and even in mobile applications (eg, the "We the BE" app).
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Open bladder plate and urethra with bifid clitoris in female patient with classic bladder exstrophy. Note low-set umbilicus and anteriorly displaced anus. Courtesy of Richard Rink, MD.
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Male with classic bladder exstrophy. Note low-set umbilicus and short, broad, upturned phallus. Distance between phallus and scrotum is abnormal. Courtesy of Richard Rink, MD.
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External view in female patient with epispadias. Labia are separated anteriorly. Courtesy of Richard Rink, MD.
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Female patient with epispadias with labia retracted. Clitoris is bifid, and urethra is open dorsally. Courtesy of Richard Rink, MD.
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Penopubic epispadias in male patient. Typical spadelike configuration of glans penis with incomplete foreskin, dorsal urethral plate, and open bladder neck. Courtesy of Richard Rink, MD.
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46,XY newborn with cloacal exstrophy. Very large omphalocele is present, and hemibladders flank exstrophic cecal plate. Phallus is small and bifid, with hemiglans and hemiscrotum located just distal to bladder. Courtesy of Martin Kaefer, MD.
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Lipomeningocele in same newborn shown in Image 6, 46,XY newborn with cloacal exstrophy. Courtesy of Martin Kaefer, MD.
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Superior vesical fissure variant of exstrophy. Genitalia are normal. Patent urachus is considered in differential diagnosis, although opening is well below umbilicus. Rectus abdominis and pubic abnormalities are found in exstrophic variant but not with patent urachus. Courtesy of Richard Rink, MD.
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Female with covered exstrophy. Umbilicus is very low, pubic bones are widely separated, and rectus muscles are divergent. Bladder is intact, but patient has undergone bladder neck reconstruction to achieve urinary continence. External genitalia are normal. Courtesy of Elizabeth Yerkes, MD.
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Typical appearance of pelvis in patient with exstrophy-epispadias complex with wide separation of pubic symphysis.
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Bilateral vesicoureteral reflux and small-capacity bladder after initial exstrophy closure. Contrast escapes readily through incompetent bladder neck.
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Use of plastic wrap to protect delicate bladder mucosa in newborn with bladder exstrophy. Courtesy of Richard Rink, MD.
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Subtotal prolapse of bladder wall through patulous bladder neck after bladder closure in female with cloacal exstrophy. Bladder mucosa appears healthy, and urine is draining freely. Courtesy of Richard Rink, MD.
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Male infant with cloacal exstrophy. Note large omphalocele with separated hemibladders and genitalia with protruding ileocecal segment yielding classic "elephant trunk" deformity. Courtesy of John P Gearhart, MD.
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Young male with left hemiglans loss after complete primary repair for classic bladder exstrophy (CPRE). Courtesy of John P Gearhart, MD.
