Bladder Exstrophy

Bladder exstrophy (BE) is a rare congenital anomaly caused by failure of the lower abdominal wall and bladder to close during fetal development. This leads to eversion of the bladder structures and portions of the urethra through a midline defect of the anterior abdominal wall (1).

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It is estimated that BE occurs in 1:30,000-1:50,000 births (1). Males are more likely than females to be affected by bladder exstrophy; some studies report a 6:1 male-to-female ratio while others report a much lower male-to-female ratio of 1.3:1 (2).

The pathogenesis of BE is unclear (1). It has been suggested that classical BE results from premature rupture of the cloacal membrane after the 7^th week of embryonic development; by this time there has already been complete separation of the genitourinary and gastrointestinal tracts. Abnormal migration of the mesoderm within the layers of the cloacal membrane has been proposed as the mechanism leading to instability and thus premature rupture of the membrane (2). There is not currently a consensus on whether BE is part of a continuum of disease including epispadias and cloacal exstrophy (2-5).

The etiology of BE is not well understood. A variety of factors have been suggested to increase risk of BE: male gender; advanced paternal age; Caucasian ethnicity (6); smoking; alcohol; rubella infection; in vitro fertilization; insufficient folic acid intake (7); high parity; advancing maternal age; and exposure to medications including misoprostol; heparin; diazepam; valproic acid (1). However, most cases are sporadic. There is limited data on the impact of environmental factors on the development of BE. There has not been a specific gene identified, however multiple genetic aberrations have been reported in the literature with an unclear causal relationship (1). Trisomy 21 and other chromosomal abnormalities have been reported in those with BE (7).

BE is the most common presentation of the epispadias-exstrophy complex (EEC) (1). As outlined above (see pathogenesis) there is not currently a consensus on whether BE is a distinct disorder or part of a spectrum of disease including epispadias and cloacal exstrophy (2-5). BE is sometimes seen in the omphalocele-bladder exstrophy-imperforate anus-spinal defects (OEIS) complex. Other variant forms of BE have been described (1).

In males and females with BE, structural anomalies of the pubic symphysis and inferior displacement of the umbilicus have been noted (1). Occasionally, renal anomalies are seen including unilateral agenesis and horseshoe kidney (2). In males, epispadias, undescended testes, and anterior displacement of the anus sometimes occur (1). In females, the clitoris may be cleft, and uterine and vaginal duplication has been reported. One study reported 1 out of 46 individuals with BE to also have spine defects or imperforate anus (2). Some of these abnormalities may be difficult to identify with ultrasound.

A recurrence risk of approximately 1% has been reported for BE however most cases are sporadic. To date a specific gene has not been identified; this suggests a polygenic inheritance with unknown environmental influence (1). One study reported that 1 in 70 offspring of parents affected by BE or epispadias will also have BE (8).

Diagnosis of BE is usually made by prenatal ultrasound. Ultrasound criteria for BE include: absent bladder with normal appearing kidneys; persistent lower abdominal bulge between the umbilical arteries; low insertion of umbilical cord; abnormal widening of the iliac crests; and small phallus (10-12). A short umbilical cord insertion-to-genital tubercle length, defined as <5^th percentile for gestational age, may help diagnose bladder exstrophy before 18 weeks gestation (13, 14). Genitalia are often ambiguous and sex assignment by ultrasound is not possible.

If the fetal bladder is not visualized given adequate filling time, typically 30 minutes, and non-visualization of the fetal bladder persists despite normal amniotic fluid and kidneys, suspicion for BE should be raised (11). The use of color Doppler can help identify the umbilical arteries and umbilical cord insertion and is useful as a landmark of the bladder (12).

Elevations in maternal serum alpha protein can be seen (1). 3-dimensional ultrasound may aid in the diagnosis, and MRI may be considered to further assess the gastrointestinal tract, spine and genitalia. Karyotype/microarray with cell free fetal DNA reserved for patients who decline invasive testing may also be used to exclude chromosome defects determine genetic fetal sex (9).

The differential diagnosis of BE may also include epispadias, cloacal exstrophy, the OEIS complex, and Pentalogy of Cantrell. Thus attention to associated structures including the intestines, anal dimple, omphalocele, spinal abnormalities, diaphragm, and heart is warranted (1). Renal anomalies should remain on the differential diagnosis, as absent bladder can be a sign of such conditions. These include bilateral renal agenesis, bilateral polycystic kidneys, and bilateral dysplastic kidneys (10-12). In BE, the kidneys and ureters are typically normal. If the abdominal wall and bladder are noted to be closed, complete epispadias should be considered (10). In mono-chorionic twin gestations, an absent bladder should raise concern for twin-to-twin transfusion syndrome.

Once the diagnosis of BE has been made, the fetus should be reevaluated periodically to assess growth and presence or absence of associated abnormalities. Invasive testing for karyotype or microarray and fetal sex can be considered. Delivery should take place in a center which is prepared for neonatal evaluation and treatment.  

With advancement in prenatal detection and surgical intervention, the prognosis of BE has improved. However multiple reconstructive surgeries are typically required (1). BE does not appear to be associated with an increased risk of stillbirth with a reported rate of BE occurring in 1:10,000 stillbirths (2). Similarly, BE does not appear to be associated with prematurity; one study reported a prematurity rate of 5% among infants with BE (15). Given the significant impact on quality of life and potential for significant urinary and sexual dysfunction, some families may opt for termination of pregnancy. Case series from Europe have reported termination rates of up to 80% for pregnancies complicated by BE (16). In women with BE, there is minimal data on fertility and obstetric outcomes.  Fertility is often impaired. If conception is accomplished pregnancy is high risk for complications including miscarriage, intrauterine fetal demise, pelvic organ prolapse, urinary retention, cesarean delivery, and surgical concerns including abnormal anatomy and postpartum hemorrhage (17). Later in life, there appears to be an increased risk of urinary tract malignancy in individuals with BE (1).

Antenatally, women with suspected BE should be managed by a multidisciplinary team with the objective of providing appropriate counseling on postnatal management and outcomes, as the prognosis of BE has significantly improved over recent years. This team should include perinatologists, pediatric urologists, and neonatologists. Families will then be able to make an informed reproductive decision. In addition, the caring provider will be able to schedule serial ultrasounds and genetic testing. Clarification of fetal sex will further aid some families in decision-making regarding continuation of the pregnancy as male infants may require more surgical intervention (9). Psycho-social support is also of utmost importance (1).

Delivery should occur in a tertiary care center with a neonatal intensive care unit and pediatric urology (10). Surgical reconstruction is challenging, with an end-goal of preserved renal and sexual function and voided continence. Multiple variations in surgical management have been described in the literature however the traditional surgical approach involves a staged reconstruction over multiple procedures (18). Utilizing this approach, the bladder is primarily closed during the first 48 hours of life. If early closure occurs the pubic rami can often be closed without necessitating pelvic osteotomies (10). The following stages occur later in the infancy period and involve urethral reconstruction and repair of epispadias. The final stage involves bladder neck reconstruction and ureteral reimplantation (18).

^{1.         Siffel C, Correa A, Amar E, Bakker MK, Bermejo-Sanchez E, Bianca S, et al. Bladder exstrophy: an epidemiologic study from the International Clearinghouse for Birth Defects Surveillance and Research, and an overview of the literature. Am J Med Genet C Semin Med Genet. 2011;157C(4):321-32.}

^{2.         Martinez-Frias ML, Bermejo E, Rodriguez-Pinilla E, Frias JL. Exstrophy of the cloaca and exstrophy of the bladder: two different expressions of a primary developmental field defect. Am J Med Genet. 2001;99(4):261-9.}

^{3.         Carey JC. Exstrophy of the cloaca and the OEIS complex: one and the same. Am J Med Genet. 2001;99(4):270.}

^{4.         Cadeddu JA, Benson JE, Silver RI, Lakshmanan Y, Jeffs RD, Gearhart JP. Spinal abnormalities in classic bladder exstrophy. Br J Urol. 1997;79(6):975-8.}

^{5.         Hendren WH. Cloaca, the most severe degree of imperforate anus: experience with 195 cases. Ann Surg. 1998;228(3):331-46.}

^{6.         Boyadjiev SA, Dodson JL, Radford CL, Ashrafi GH, Beaty TH, Mathews RI, et al. Clinical and molecular characterization of the bladder exstrophy-epispadias complex: analysis of 232 families. BJU Int. 2004;94(9):1337-43.}

^{7.         Ludwig M, Ching B, Reutter H, Boyadjiev SA. Bladder exstrophy-epispadias complex. Birth Defects Res A Clin Mol Teratol. 2009;85(6):509-22.}

^{8.         Shapiro E, Lepor H, Jeffs RD. The inheritance of the exstrophy-epispadias complex. J Urol. 1984;132(2):308-10.}

^{9.         Goyal A, Fishwick J, Hurrell R, Cervellione RM, Dickson AP. Antenatal diagnosis of bladder/cloacal exstrophy: challenges and possible solutions. J Pediatr Urol. 2012;8(2):140-4.}

^{10.       Gearhart JP, Ben-Chaim J, Jeffs RD, Sanders RC. Criteria for the prenatal diagnosis of classic bladder exstrophy. Obstet Gynecol. 1995;85(6):961-4.}

^{11.       Mallmann MR, Mack-Detlefsen B, Reutter H, Pohle R, Gottschalk I, Geipel A, et al. Isolated bladder exstrophy in prenatal diagnosis. Arch Gynecol Obstet. 2019;300(2):355-63.}

^{12.       Lee EH, Shim JY. New sonographic finding for the prenatal diagnosis of bladder exstrophy: a case report. Ultrasound Obstet Gynecol. 2003;21(5):498-500.}

^{13.       Fishel-Bartal M, Perlman S, Messing B, Bardin R, Kivilevitch Z, Achiron R, Gilboa Y. Early diagnosis of bladder exstrophy: quantitative assessment of a low-inserted umbilical cord. J Ultrasound Med. 2017;36(9):1801-1805.}

^{14.       Gilboa Y, Katorza E, Kedem A, Spira M, Achiron R. Measurement of the fetal umbilical cord insertion-to-genital tubercle length in early gestation: in utero sonographic study. J Ultrasound Med. 2011;30(2):237-41.}

^{15.       Ahn JJ, Shnorhavorian M, Katz C, Goldin AB, Merguerian PA. Early versus delayed closure of bladder exstrophy: A National Surgical Quality Improvement Program Pediatric analysis. J Pediatr Urol. 2018;14(1):27 e1- e5.}

^{16.       Wiesel A, Queisser-Luft A, Clementi M, Bianca S, Stoll C, Group ES. Prenatal detection of congenital renal malformations by fetal ultrasonographic examination: an analysis of 709,030 births in 12 European countries. Eur J Med Genet. 2005;48(2):131-44.}

^{17.       Deans R, Banks F, Liao LM, Wood D, Woodhouse C, Creighton SM. Reproducitve outcomes in women with classic bladder exstrophy:  an observational cross-sectional study. Am J Obstet Gynecol. 2012;206(6):496 e1-6.}

^{18.       Pathak P, Ring JD, Delfino KR, Dynda DI, Mathews RI. Complete primary repair of bladder exstrophy: a systematic review. J Pediatr Urol. 2020.}

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