Exstrophy and Epispadias 

Updated: May 03, 2022
Author: Chad B Crigger, MD, MPH; Chief Editor: Marc Cendron, MD 

Overview

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:

  • Modern staged repair of exstrophy (MSRE)
  • Complete primary repair for classic bladder exstrophy (CPRE)
  • Kelly Repair
  • Urinary diversion for classic bladder exstrophy
  • Closure for cloacal exstrophy
  • 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:

  • Optimizing the periconception and first-trimester periods, the times at which any insult to organogenesis is greatest
  • 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).

 

Presentation

History

Accurately diagnosing exstrophy-epispadias complex (EEC) is important for proper counseling of families, especially given that patients with cloacal exstrophy tend to face more health-related issuse in their lifetimes. Antenatal diagnosis facilitates appropriate planning to optimize postnatal medical and surgical management. Historically, ultrasonography (US) has been the most helpful tool for antenatal diagnosis and relies on the presence (or absence) of key findings, as shown below.

Antenatal US findings suggestive of EEC include the following:

  • Repeated failure to visualize the bladder on US
  • Lower-abdominal-wall mass located on the anterior abdominal wall
  • Low-set umbilical cord
  • Abnormal genitalia or inability to accurately determine genitalia
  • Increased pelvic diameter

Additional antenatal US findings suggestive of cloacal exstrophy include the following:

Despite vast improvements in fetal US (fUS), only an estimated 15% of patients have been diagnosed antenatally with fUS alone; findings may be incompletely identified.

The advent of fetal magnetic resonance imaging (fMRI) has added a valuable adjunct for achieving an accurate antenatal diagnosis when fUS is unclear. The ability to compare the point of umbilical cord insertion on fMRI with that on fUS has greatly increased the rate of correct diagnosis and the ability to differentiate between cloacal and bladder exstrophy.[25]

Classic bladder exstrophy and cloacal exstrophy are obvious to all in the delivery room. Variants of EEC exist, including skin-covered bladder exstrophy, duplicate bladders, superior vesical fistula, and epispadias with major bladder prolapse.[26] Most exstrophy variants and epispadias are also identifiable at birth. Unrecognized female epispadias may present as persistent childhood incontinence. Unrecognized split-symphysis variants of exstrophy may be identified in childhood only because of persistent incontinence or a waddling gait.

Physical Examination

General findings

Patients with classic bladder exstrophy or epispadias typically appear as term infants. Patients with cloacal exstrophy, however, are often preterm. They may have respiratory immaturity necessitating mechanical ventilation.

Abdominal findings

In classic bladder exstrophy (see the images below), the bladder is open on the lower abdomen, with mucosa fully exposed through a triangular fascial defect. The abdominal wall appears long because of a low-set umbilicus on the upper edge of the bladder plate. The distance between the umbilicus and the anus is foreshortened. The rectus muscles diverge distally, attaching to the widely separated pubic bones. Indirect inguinal hernias are frequent (>80% of males, >10% of females) because of wide inguinal rings and the lack of an oblique inguinal canal.

Open bladder plate and urethra with bifid clitoris 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.
Male with classic bladder exstrophy. Note low-set 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.

In epispadias, the pubic symphysis is still generally widened, though to a lesser degree than in classic bladder exstrophy or cloacal exstrophy. The rectus muscles are divergent distally.

Nearly all patients with cloacal exstrophy have an associated omphalocele (see the images below). The bladder is open and separated into two halves, flanking the exposed interior of the cecum. Openings to the remainder of the hindgut and to one or two appendices are evident within the cecal plate. Terminal ileum may prolapse as a "trunk" of bowel onto the cecal plate.

46,XY newborn with cloacal exstrophy. Very large o 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.
Male infant with cloacal exstrophy. Note large omp 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.

In exstrophy variants, the pubic symphysis is widely separated, and the rectus muscles diverge distally. The umbilicus is low or elongated. A small superior bladder opening or a patch of isolated bladder mucosa may be present. The intact bladder may be externally covered by only a thin membrane. Isolated ectopic bowel segments have been reported.

Patent urachus is a differential diagnosis for the superior vesical fissure variant of exstrophy-epispadias (see the image below). However, patent urachus lacks the typical musculoskeletal abnormalities of exstrophy and is open at the umbilicus. Superior vesical fissure is infraumbilical.

Superior vesical fissure variant of exstrophy. Gen 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.

Genital findings

(In describing the anatomy of the penis, the terms dorsal and ventral refer to a normal phallus in the erect state. The dorsal surface is in continuity with the abdominal wall, and the ventral surface is in continuity with the scrotum.)

In classic bladder exstrophy in males, the phallus is short (~50% shorter) and broad (~30% wider) with upward curvature (dorsal chordee).[27] The glans lies open and flat like a spade, and the dorsal component of the foreskin is absent. The urethral plate extends the length of the phallus without a roof. The bladder plate and urethral plate are in continuity, with the verumontanum and ejaculatory ducts visible within the prostatic urethral plate. The anus is anteriorly displaced with a normal sphincter mechanism.

In classic bladder exstrophy in females, the clitoris is uniformly bifid with divergent labia superiorly. The open urethral plate is in continuity with the bladder plate. The vagina is anteriorly displaced. The anus is anteriorly displaced with a normal sphincter mechanism.

In male epispadias (see the image below), the phallus is short and broad with upward curvature (dorsal chordee). The glans lies open and flat like a spade, and the dorsal component of the foreskin is absent. The urethral meatus is located on the dorsal penile shaft, anywhere between the penopubic angle and the proximal margin of the glans. The prepuce is usually deficient dorsally but may be intact in the mild forms of the condition.

Penopubic epispadias in male patient. Typical spad 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.

In female epispadias (see the images below), the clitoris is most often bifid with divergent labia superiorly. The dorsal aspect of the urethra is open distally. The urethra and bladder neck are patulous and may allow visualization of bladder. Bladder mucosa may prolapse through the bladder neck.

External view in female patient with epispadias. L External view in female patient with epispadias. Labia are separated anteriorly. Courtesy of Richard Rink, MD.
Female patient with epispadias with labia retracte Female patient with epispadias with labia retracted. Clitoris is bifid, and urethra is open dorsally. Courtesy of Richard Rink, MD.

In cloacal exstrophy, the penis is generally quite small and bifid, with a hemiglans located just caudal to each hemibladder. Infrequently, the phallus may be intact in the midline. In females, the clitoris is bifid, and two vaginas are present. The anus is absent.

In exstrophy variants, the genitalia generally are intact (see the image below), though epispadias can occur.

Female with covered exstrophy. Umbilicus is very l 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.

Musculoskeletal findings

The abnormal pelvis is a hallmark of atypical anatomy seen in EEC.

In classic bladder exstrophy, the pubic symphysis is widely separated by an average of 4.8 cm, with an overall 30% shortening of bone length, a 12º external rotation of the posterior segment of the pelvis, and an 18º external rotation of the anterior segment. Divergent rectus muscles remain attached to the pubis. External rotation of the innominate bones results in a waddling gait in ambulatory patients but usually corrects after treatment and does not appear to result in orthopedic problems later in life.

In cloacal exstrophy, the same defects are seen but are more severe: The average pubic diastasis exceeds 6 cm, there is an overall 43% decrease in bone length. As many as 65% of patients have a clubfoot or another major lower-extremity deformity. As many as 80% of patients have vertebral anomalies.

In split-symphysis variants of exstrophy, the pubic symphysis is widely separated (see the image below), and the rectus muscles are divergent.

Typical appearance of pelvis in patient with exstr Typical appearance of pelvis in patient with exstrophy-epispadias complex with wide separation of pubic symphysis.

The maldevelopment of the bony pelvis influences the pelvic floor. Three-dimensional (3D) computed tomography (CT) imaging of children with exstrophy revealed that the levator ani muscles are positioned more posteriorly and the urogenital diaphragm is less concave. The paucity of anterior pelvic-floor musculature and the lack of a conical shape drive the surgical technique employed in reconstructing the bony pelvis and the pelvic floor (see Surgical Care).

Neurologic findings

In cloacal exstrophy, spinal dysraphism (eg, tethered cord, myelomeningocele, or lipomyelomeningocele) is present in some form in 64-100% of patients, with 80% of lesions found in the lumbar region.[2, 28]  Vertebral anomalies other than dysraphism are also common and include hemivertebrae with associated scoliosis (seen in 40% of patients, though the scoliosis does not appear to progress in most instances).[29] In view of the high incidence of spinal and vertebral anomalies, MRI evaluation of a newborn with cloacal exstrophy is warranted, with neurosurgical involvement as needed. 

Gastrointestinal anomalies

Within EEC, gastrointestinal (GI) anomalies are more commonly seen in patients with cloacal exstrophy, nearly all of whom have some defect. GI defects include omphalocele (88-100% of cases), short-bowel syndrome (25% of cases), and duplication anomalies, gastroschisis, malrotation, duodenal atresia, and exstrophied colonic segments (46% of cases).[30, 31, 28] Imperforate anus is also very common, with an incidence approaching 100% in patients with cloacal exstrophy. The wide range of these GI anomalies presents a significant potential for morbidity, underlying the importance of optimal perioperative nutrition. 

Other urologic anomalies

Anomalies of the upper urinary tract are common, occurring in as many as 41-66% of patients with cloacal exstrophy. Particular attention to identifying and understanding the patient's upper tract anatomy is vital: Unilateral renal agenesis, pelvic kidney, or hydronephrosis is seen in as many as 48% of cases, with multiple concomitant renal anomalies in 16% of cases.[32] Less frequently reported defects include horseshoe kidney, fusion anomalies, and ureteral abnormalities (eg, megaureter and duplication). 

Complications

Inguinal hernias are common, arising from incomplete formation of the lower abdominal wall, abnormal pelvic floor musculature, and bony pelvis, which results in a lack of obliquity of the inguinal canal. Hernias have been reported in nearly 90% of males with exstrophy but only 10% of females.[33] It is recommended to explore the inguinal canals at the time of exstrophy closure. 

Bladder-plate irritation (from direct exposure and desiccation with insufficient moistening care) can result in bladder polyps. If such polyps are present before closure, they are hamartomatous polyps and should be removed before closure if numerous. If, however, they present after closure (eg, failure and at the time of secondary closure), metaplastic elements may be seen in 50% of cases (most commonly, cystitis glandularis). In view of the potential risk of adenocarcinoma, patients should be routinely screened with urine cytology and cystoscopy as they enter adulthood. 

 

DDx

Diagnostic Considerations

Other problems to be considered include the following:

  • Patent urachus
  • Persistent cloaca
  • Gastroschisis 
  • Isolated omphalocele
 

Workup

Laboratory Studies

Before complex reconstruction of the urinary tract, it is important to obtain information about the patient's baseline renal function. In patients with cloacal exstrophy, losses from the terminal ileum short-gut physiology can result in significant electrolyte abnormalities. Any derangements in electrolyte balance or renal function should be addressed, and corrected if possible, prior to surgery.

Imaging Studies

A complete imaging series that includes plain films, ultrasonography (US), and, if needed, magnetic resonance imaging (MRI) helps determine the severity of associated defects and facilitates early involvement of consulting services (eg, pediatric orthopedic surgery, pediatric neurosurgery, and pediatric general surgery). 

Baseline examination of the kidneys with US is recommended for all patients with exstrophy because increased bladder pressure after bladder closure can lead to hydronephrosis and upper urinary tract deterioration. Congenital upper urinary tract anomalies are uncommon with classic exstrophy and epispadias but are present in approximately one third of patients with cloacal exstrophy (eg, ectopic pelvic kidney, renal agenesis, or hydronephrosis).

Spinal US or radiography may be helpful. Myelodysplasia should be excluded in newborns with cloacal exstrophy. This can be accomplished by means of US early in life. In cloacal exstrophy, MRI is recommended to help identify occult abnormalities that may predispose to symptomatic spinal cord tethering.

Bilateral vesicoureteral reflux (VUR) is present in nearly all patients with classic bladder exstrophy. Voiding cystourethrography (VCUG) is performed in early childhood to assess bladder capacity in preparation for reconstructive continence surgery. Evaluation of the bladder neck and proximal urethra is recommended in patients with epispadias to facilitate the planning of surgical management.

Histologic Findings

Histologic studies are not routinely performed. However, basic science and clinical investigations have revealed interesting histopathologic differences between samples from exstrophy bladders and samples from normal age-matched controls.[34]  Specifically, there is an increased ratio of extracellular matrix to muscle within the bladder wall; in particular, the amount of type III collagen is increased. This ratio seems to approach a more normal range (ie, relative increase in muscle) after successful bladder closure. Exstrophied bladders also have fewer myelinated nerve fibers than unaffected bladders do.[35]

 

Treatment

Medical Care

For neonates with exstrophy and epispadias, general supportive care appropriate for the overall condition and any associated anomalies should be instituted. For patients with cloacal exstrophy, nutrition is important (and often challenging); accordingly, parenteral nutrition is often started early.

In the period between delivery and reconstruction, the bladder template should be gently irrigated with saline to moisten it and then covered with plastic wrap (see the image below). Moistened or impregnated gauze is irritating to the delicate bladder mucosa and should therefore be avoided. Mist tents may be used to protect exposed tissue.

Use of plastic wrap to protect delicate bladder mu Use of plastic wrap to protect delicate bladder mucosa in newborn with bladder exstrophy. Courtesy of Richard Rink, MD.

Antibiotic therapy is usually started after delivery and continued through the early postoperative period. Daily administration of prophylactic antibiotics may be continued in the weeks after bladder closure; however, surgeons' philosophies on this matter vary widely. Infections may be related to poor emptying and are to be prevented in light of the high incidence of vesicoureteral reflux (VUR).

Latex precautions should be instituted; there is a high incidence of latex sensitization in patients with exstrophy-epispadias complex (EEC).

Surgical Care

Reconstruction of EEC remains one of the greatest challenges facing the pediatric urologist. Many modifications in surgical procedures have improved outcomes. Longitudinal prospective assessment of the two main current surgical approaches (staged procedure and total reconstruction) is critical for optimizing functional and cosmetic outcomes.

Complete primary reconstruction is now more than 20 years old and may be accomplished through various methods; however, each approach is in a constant state of minor modification. Data on this approach continue to mature and are updated almost yearly.[36, 37, 38, 39, 40, 41] Analysis of each experience focuses on daytime continence with volitional voiding, need for further surgical procedures, and complication rates. In experienced hands, the safety and efficacy of the different approaches are comparable.

Goals of therapy include provision of urinary continence with preservation of renal function and reconstruction of functional and cosmetically acceptable genitalia. Creation of a neoumbilicus is also important to many of these patients.

Surgical techniques used in the treatment of EEC include the following:

  • Modern staged repair of exstrophy (MSRE) [42]
  • Kelly repair (radical soft-tissue mobilization [RSTM])
  • Complete primary repair for classic bladder exstrophy (CPRE)
  • Urinary diversion for classic bladder exstrophy
  • Closure for cloacal exstrophy
  • Gender reassignment

Staged functional closure for classic bladder exstrophy

MSRE, the traditional surgical approach, comprises a series of staged operations. Initial bladder closure is completed within 72 hours of birth for classic bladder exstrophy. If this is delayed, pelvic osteotomies are required to facilitate successful closure of the abdominal wall and to allow placement of the bladder and the posterior urethra deep into the pelvis within a closed and supportive pelvic ring. If at any point the pelvis is deemed to be immobile, even within 72 hours of life, pelvic osteotomy should be performed. Additionally, osteotomy is mandatory in all cloacal exstrophies.

Epispadias repair with urethroplasty is performed at age 6-12 months. This allows enough increase in bladder outlet resistance to improve the bladder capacity.

Bladder-neck reconstruction (typically a modified Young-Dees-Leadbetter repair) is performed at age 8-10 years, or after the child has participated in an intensive voiding improvement program to prepare for life after surgery and has demonstrated a willingness to participate in his or her care. This allows continence and correction of VUR. Multiple modifications have been proposed. The procedure is delayed until bladder capacity is adequate; better results are reported with a capacity greater than 100 mL.

Chua et al retrospectively studied a modification of staged exstrophy repair aimed at incorporating the advantages of CPRE by avoiding concurrent epispadias repair and adding bilateral ureteral reimplantation and bladder-neck tailoring (staged repair of bladder exstrophy with bilateral ureteral reimplantation [SRBE-BUR]) at the initial repair.[43] They found SRBE-BUR to be a safe alternative for exstrophy-epispadias repair, preventing penile tissue loss and yielding long-term outcomes comparable to those of CPRE.

Kelly repair

RSTM, also referred to as the Kelly repair, has been suggested as an alternative approach to staged reconstruction of bladder exstrophy.[44, 45] RSTM has been performed not only as the second part of a two-step strategy (after bladder closure) but also as part of a combined procedure that includes delayed bladder closure and RSTM in a single stage without pelvic osteotomy.[46]

Complete primary repair for classic bladder exstrophy

Compared with MSRE, CPRE is a newer approach to exstrophy closure. Primary bladder closure, urethroplasty, and genital reconstruction are performed in a single stage in newborns. This procedure involves complete penile disassembly in males and mobilization of the urogenital complex in females. Hypospadias is a common outcome in males and requires subsequent reconstruction. 

The goal is early bladder cycling. A small subset of patients have achieved continence without bladder-neck reconstruction.

In a study of 34 boys treated with a modified penile disassembly technique (15 with bladder exstrophy who underwent CPRE, 11 with penopupic epispadias after previous closure of bladder exstrophy, and eight with isolated complete epispadias), Anwar et al found the modified technique to yield acceptable cosmetic results.[47] Preservation of the distal urethral plate along with both hemiglandes avoided shortening and prevented the occurrence of hypospadias.

Urinary diversion for classic bladder exstrophy

Urinary diversion was the original surgical treatment of choice. Diversion may be performed in a patient with an extremely small bladder plate not suitable for functional closure.[48] In Europe, early diversion has been widely used, with success for most exstrophy patients. Long-term follow-up is required in these patients; metabolic disturbances are common and increased rates of malignancy have been reported.

Closure for cloacal exstrophy

Treatment of myelodysplasia and gastrointestinal (GI) anomalies has priority over management of urinary and genital anomalies.

Prompt omphalocele closure in the neonatal period is recommended to safeguard against untimely rupture; however, this is only performed after neurosurgical concerns are addressed. At the time of initial omphalocele closure, one of the following three pathways is typically employed for intestinal diversion and hindgut management:

  • Ileostomy creation with hindgut resection
  • Ileostomy placement with hindgut mucous fistula
  • Cecal tubularization with end-colostomy creation

Historically, initial intestinal diversion relied on ileostomy with hindgut resection; however, this gave rise to several unintended consequences. First, the procedure induced short-gut syndrome universally and made later reconstruction of the GI tract less likely. Second, high-output ileostomy predisposed children to increased hospitalization with recurrent dehydration and electrolyte derangements.[28] The induced acidosis secondary to high ileostomy output adversely impacts calcium homeostasis and directly modulates the growth hormone (GH)–insulinlike growth factor (IGF)-1 axis, blunting the release of GH. In the long term, this is associated with growth-related morbidity in patients with cloacal exstrophy.[49]

Consequently, there has been a paradigm shift in initial intestinal diversion and hindgut management. At present, the preferred method of bowel management is cecal tubularization with end-colostomy creation to eliminate short-gut syndrome and facilitate intestinal pull-through procedures.[32] Typically, GI reconstruction is performed 1-2 years after initial fecal diversion; however, if this reconstruction is combined with bladder closure, approximation of the pubis is paramount for successful bladder, abdominal-wall, and bowel reconstruction. Typically, the success of these reconstructions depends on pelvic reconstruction with osteotomies.

Closure can be either staged or performed in a single stage, depending on the overall condition of the child, the severity of the abdominal-wall defect, and the width of the pubic diastasis. If a large omphalocele is present, successful closure of the abdomen and the bladder in a single stage may be difficult to accomplish.

The first stage involves separation of the GI and genitourinary (GU) tracts, closure of the colon, creation of a colostomy, and closure of the omphalocele. The bladder plates are brought together in the midline.

Because virtually all of these patients have some element of short-gut syndrome, the hindgut should be incorporated into the GI tract to maximize absorptive surface area. Ileostomy should be avoided, because of the high incidence of recurrent hospitalizations for dehydration and severe electrolyte abnormalities. The choice between rectal pull-through and permanent colostomy is based on the surgeon's preference and the projected potential for social fecal continence.[50]

Subsequent bladder closure is carried out as in surgical management of classic bladder exstrophy. The principles of complete primary repair have been applied at this point as well. Consideration may be given to continent diversion as the second stage, on the basis of poor potential for volitional voiding and continence.

Because of the more severe pubic diastasis, pelvic osteotomies are required. Staged pelvic osteotomy (SPO) with gradual closure of the pelvis may be needed in severe cases.[51] In a study comparing SPO before bladder closure with combined pelvic osteotomy (CPO) at the time of closure in cloacal exstrophy patients, Inouye et al found that SPO reduced preoperative diastasis more than CPO did, without appearing to incur increased rates of complication, closure failure, or incontinence.[52]

In the past, surgical management of the pelvis in cloacal exstrophy relied on a single surgical procedure. Currently, however, the usual practice at the authors' hospital has evolved to multiple staged repairs with mandatory osteotomy. With this approach, any extreme diastasis is gradually reduced before definitive soft-tissue closure is attempted.

Approximately 2-3 weeks before abdominal-wall closure, it is standard procedure for cloacal exstrophy patients to have combined bilateral anterior innominate and vertical iliac osteotomies, followed by placement of an external fixator device. At the time of bladder closure, the pubis is further brought into apposition with screw-and-rod or screw-and-plate devices. A review of historical trends of osteotomy by Haney et al revealed an increasing prevalence of CPO since 1990, with a concomitant increase in success rates.[53]

Gender reassignment

Gender assignment is an important part of the process and requires special consideration. It may require consultation from pediatric endocrinology, child psychology, or pediatric psychiatry. All gender assignment decisions should only be made after karyotyping, thorough discussion, and appropriate parental counseling.

Given the typical wide separation of the penile bodies and demure penile bodies in boys with cloacal exstrophy, initial reports advocated universal gender reassignment of 46,XY boys to functional females.[54] This view drove early principles in management, including bilateral orchiectomy along with phallic reconstruction as a functional clitoris and vaginoplasty, either early or delayed.

The long-term effects of this practice are a topic of intense debate. Patients living longer with this condition offer a glimpse into the psychosocial implications of this practice and the potential role of genotype and intrauterine hormonal milieu. In one cohort of 29 males with cloacal exstrophy who underwent female gender reassignment, all 29 demonstrated a predominant male shift in psychosexual development despite not experiencing any pubertal hormonal surges.[55] Other series, however, have demonstrated no differences in behavior or psychosocial issues, though there was one reported case of masculinization in a 46,XY gender-converted patient that was due to an ectopic testis.[56, 57]

Cloacal exstrophy is now included as a subset of differences (disorders) of sex development.[58] Multidisciplinary evaluation and both early and long-term counseling should be offered. Current attitudes favor assigning gender that is concordant with karyotype, if possible. At the authors' institution, no gender reassignment procedures have been performed for more than 25 years. 

Intraoperative concerns

Multiple or lengthy surgical procedures with exposure to latex antigens increase the risk of latex sensitization or allergy.[40] Approximately 30% of patients with bladder exstrophy have demonstrated symptoms of latex allergy, and 70% reveal sensitization (elevation of specific immunoglobulin E [IgE] antibody) to latex antigens. For practical purposes, all patients with EEC should be considered to be latex-sensitive.

Full latex precautions are recommended in the operating room, beginning with preparation for the first operative procedure. Potential latex-containing materials in the operating room include gloves, catheters, drains, masks, anesthesia materials, bandages, and thromboembolic stockings. Polyvinyl chloride and silicone are acceptable alternatives. Latex allergy should be considered seriously in the event of intraoperative anaphylaxis. The offending agent should be removed and the surgical procedure aborted if necessary.

Treatment includes cardiopulmonary resuscitation with fluids, epinephrine, steroids, and histamine blockade. In those with a known latex allergy, premedication with steroids and histamine H1 and H2 blockers should be considered.

Postoperative Care

Postoperatively, nutrition and immobilization are key to ensure proper healing. Nutritional support is mandatory for patients with cloacal exstrophy. Patients with classic bladder exstrophy may also have early difficulties feeding because of the body position in traction.

One large series out of Johns Hopkins assessed predictors of successful primary closure in exstrophy and reported that a staged closure, along with the use of pelvic osteotomy, predicted successful closure[59] ; after bladder closure, postoperative immobilization was crucial to success.

Several techniques for immobilization have been described, including mummy wraps, spica casts, Bryant traction, and Buck traction. Spica casts and mummy wraps do not provide adequate immobilization and therefore may lead to increased failure of pelvic reconstruction (success rates of 49% and 57%, respectively, in primary closures); however, the combination of Buck traction and external fixation offers a 95% chance of successful primary closure (97% in repeated closures). Bryant traction is now less used and of mainly historical interest; it has been employed in newborn closures that do not require osteotomy.

Another key aspect of postoperative care is ensuring that the bladder is completely dry to ensure healing. Typically, the bladder and kidneys are drained fully with multiple stents catheters during the first few weeks after closure.

Complications

In the treatment of complex congenital anomalies, the distinction between technical complications and problems inherent to the anomaly is not always obvious.

Failure of closure may occur. If the bladder plate is adequate, reclosure with pelvic osteotomies is recommended. In this instance, bladder closure and epispadias repair are performed in one stage. Urinary diversion is an alternative therapy.

A vesicocutaneous fistula or urethrocutaneous fistula may form after primary closure or urethral reconstruction. If spontaneous closure does not occur, surgical repair is required.

Loss of the hemiglans (see the image below) or corporal body has been reported as a result of CPRE and is a catastrophic complication of this technique.[60, 61]

Young male with left hemiglans loss after complete Young male with left hemiglans loss after complete primary repair for classic bladder exstrophy (CPRE). Courtesy of John P Gearhart, MD.

Minor orthopedic complications (eg, transient nerve and muscle palsies, delayed ileal union, and superifical pin-site infection or inflammation) may occur after osteotomy or immobilization; they are typically self-limiting.

Upper urinary tract deterioration (documented by increased dilation of the ureters and renal collecting system) is a potential complication. Causes include excessive outlet resistance and high pressure in a small-capacity reservoir and persistent VUR.

Abnormal bladder function may result in poor emptying. Clinical problems related to poor emptying include recurrent febrile infections, epididymitis, bladder stones, acute urinary retention, and rupture of the native bladder.

Bladder prolapse is a potential complication. The posterior bladder wall may prolapse through the patulous bladder neck after primary closure (see the image below). Recurrent prolapse, congestion, ischemia of bladder mucosa, or failure of ureteral drainage warrants early surgical correction.

Subtotal prolapse of bladder wall through patulous 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.

Malignancy is a rare late complication of bladder exstrophy and is more common in untreated patients whose bladders are left exstrophic for many years. Adenocarcinoma is the most common of these malignancies, from the precursor cystitis glandularis, which is caused by chronic irritation and inflammation of exposed mucosa of the exstrophic bladder. Squamous cell carcinoma and rhabdomyosarcoma have also been reported.

Adenocarcinoma may develop adjacent to the ureterointestinal anastomosis in patients with urinary diversions that mix the urinary and fecal streams. This malignancy was reported in more than 10% of patients in one series.[62] Patients younger than 25 years with ureterosigmoidostomy have a 7000-fold greater risk of adenocarcinoma of the colon than the general population (mean latency, 10 years).

Complications of short-gut syndrome are as follows:

  • Paucity of hindgut and, in many cases, limited small intestine can result in electrolyte abnormalities in patients with cloacal exstrophy
  • Dehydration is particularly a concern during an acute GI illness with diarrhea
  • Nutritional supplementation may be required

Adjuncts for continence, including augmentation cystoplasty and catheterizable urinary diversion, present unique complications, including mucus overproduction, bladder calculi, chronic bacterial colonization, and epithelial polyps. Another long-term issue that may arise from augmentation cystoplasty is chronic metabolic acidosis.[16, 63] With time, the stoma created for urinary diversion may stenose, prolapse, necrose, or leak, requiring revision.

Regardless of the specific surgical approach followed, successful primary bladder closure is the primary goal. A failed closure is devastating for the patient and family, and the consequences are substantial. Patients who experience a failed primary closure are subject to more operations and hence increased exposure to general anesthesia. Although a failed bladder closure in classic bladder exstrophy has a negative impact on ultimate urinary continence, a failed closure in cloacal exstrophy has a less pronounced impact on continence specifically, in that most of these patients will require additional continence procedures regardless of the primary outcome.[64, 65]

The ramifications of failed closure extend beyond the additional operations required and include a substantial degree of financial morbidity. Goldstein et al performed a cost analysis in cloacal exstrophy patients and found that with a successful primary repair, it costs approximately $196,000 to reach continence, whereas after a failed primary bladder closure, the cost of achieving continence rises to $407,000.[66]

Diet

Some young patients with cloacal exstrophy are seriously affected by short-gut syndrome and may depend on long-term supplemental parenteral nutrition for growth and development.

Activity

After surgery, the patient must be kept immobile. Modified Buck traction with external fixation is now the preferred method at the authors' institution and has emerged as the best modality for ensuring proper healing of a pelvic reconstruction. Alternatively, spica casts, lower-extremity mummy wraps, and Bryant traction may be used, depending on the performance of osteotomies and on institutional protocols, but lower success rates are to be expected.

In childhood, the patient may have a waddling gait because of abnormal pelvic rotation, but activity is unrestricted, and no long-term orthopedic sequelae occur.

Consultations

The following consultations may be appropriate:

  • Neonatologist for the special needs of a premature newborn and the care of a child with multiple anomalies
  • Pediatric gastroenterologist, if needed, for the patient with cloacal exstrophy to manage the short-gut physiology with parenteral and modified external feeding
  • Pediatric urologist or surgeon with special interest and expertise in the management of EEC
  • Neurosurgeon for patients with cloacal exstrophy with myelodysplasia
  • Orthopedic surgeon if lower-extremity anomalies are present and if pelvic osteotomies are required for bladder closure
  • Child psychiatrist if gender conversion is considered; counseling should be offered to children struggling with incontinence and with concerns regarding how their bodies look or function differently from peers' bodies; counseling is recommended before major reconstruction for continence; teen and young adult males appear to be at increased risk for suicidal behaviors and other psychopathology when compared with unaffected peers [67]

Long-Term Monitoring

Remaining urinary drainage catheters are removed as part of outpatient follow-up care. Prophylactic antibiotics are continued.

Lifelong follow-up care with a urologist is important to monitor for urinary tract infections, deterioration in bladder function, or damage to the kidneys and to direct appropriate surgical or medical therapy. Patients with cloacal exstrophy require long-term follow-up care with a neurosurgeon, an orthopedic surgeon, and a general surgeon.

Counseling for school-age children may be offered preemptively or as concerns arise. Because of the potential long-term implications of exstrophy, patient education is critical. Exstrophy support groups are established at several major medical centers.

 

Medication

Medication Summary

Antibiotics are given to prevent urinary tract infections in patients with exstrophy and epispadias.

Broad-spectrum antibiotics

Class Summary

These agents are used for prevention of perioperative tissue infection due to preoperative colonization of urinary tract or multiple indwelling catheters.

Ampicillin (Marcillin, Omnipen, Polycillin)

Bactericidal activity against susceptible organisms. Started at birth in classic bladder exstrophy or cloacal exstrophy and continued through early postoperative period.

Gentamicin (Garamycin)

Aminoglycoside antibiotic for gram-negative coverage. Started at birth in classic bladder exstrophy or cloacal exstrophy and continued through early postoperative period.

Prophylactic antibiotics

Class Summary

These agents are used for prevention of urinary tract infection in light of vesicoureteral reflux and possible inefficient bladder emptying.

Amoxicillin (Trimox, Amoxil, Biomox)

First-line choice for prophylaxis in newborns. Interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria. Used as prophylaxis in certain PO, GI, or genitourinary procedures.

Trimethoprim-sulfamethoxazole (Bactrim, Septra, Cotrim)

Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. Switch from amoxicillin to TMP-SMZ after 2 mo; can dispense larger supply, making refills more convenient; susp contains 20 mg TMP and 100 mg SMZ per 5 mL; prophylactic dose is one half therapeutic dose.