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45. Draaken M, Reutter H, Schramm C, Bartels E, Boemers TM, Ebert AK, etal. Microduplications
at 22q11.21 are associated with non-syndromic classic bladder exstrophy. Eur J Med Genet.
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46. Lundin J, Söderhäll C, Lundén L, Hammarsjö A, White I, Schoumans J, etal. 22q11.2 microduplication in two patients with bladder exstrophy and hearing impairment. Eur J Med Genet.
2010;53(2):61–5.
47. Lundin J, Markljung E, Baranowska Körberg I, Hofmeister W, Cao J, Nilsson D, etal. Further
support linking the 22q11.2 microduplication to an increased risk of bladder exstrophy and
highlighting LZTR1 as a candidate gene. Mol Genet Genomic Med. 2019;7(6):e666.
48. Draaken M, Knapp M, Pennimpede T, Schmidt JM, Ebert AK, Rösch W, etal. Genome-wide
association study and meta-analysis identify ISL1 as genome-wide signicant susceptibility
gene for bladder exstrophy. PLoS Genet. 2015;11(3):e1005024.
49. Guo C, Sun Y, Guo C, MacDonald BT, Borer JG, Li X.Dkk1in the peri-cloaca mesenchyme
regulates formation of anorectal and genitourinary tracts. Dev Biol. 2014;385(1):41–51.
50. Wang C, Wang J, Borer JG, Li X.Embryonic origin and remodeling of the urinary and digestive outlets. PLoS One. 2013;8(2):e55587.
51. Kasprenski M, Michaud J, Yang Z, Maruf M, Benz K, Jayman J, etal. Urothelial differences in the exstrophy-epispadias complex: potential implications for management. J Urol.
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52. Rubenwolf PC, Eder F, Ebert AK, Hofstaedter F, Woodhouse CRJ, Roesch WH.Persistent
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N. Fernandez et al.
Bladder Exstrophy-Epispadias Complex:
Prenatal Diagnosis andCounseling
JulianaGebb, LisaPilchman, andJulieS.Moldenhauer
Introduction
The bladder exstrophy-epispadias complex (BEEC) describes a spectrum of rare
congenital genitourinary malformations that includes epispadias, classic bladder
exstrophy (CBE), and cloacal exstrophy (CE) in order of increasing severity.
Optimal care of affected infants and children requires a large multidisciplinary team
providing coordinated management, typically in specialized centers. Identication
of fetuses affected with BEEC helps to optimize prenatal counseling, maternal care,
and delivery planning such that neonates can be born in centers with the appropriate
subspecialists available for immediate evaluation and complex management.
Prenatal diagnosis of BEEC presents a challenge due to the rarity of the complex,
but also because nuanced ndings can be missed or inappropriately characterized.
In older studies, prenatal identication of BEEC through routine ultrasound was
reported to be very low at 10% [1]; however, more recent single- and multiinstitutional studies have demonstrated an approximately 46–47% prenatal diagnosis rate of classic bladder exstrophy [2, 3]. When looking at diagnosis over time,
however, the rate has increased, from around 30% in the early 2000s to 61% from
2015 to 2020 [2]. The prenatal diagnosis of CE has been more common, ranging
from 78% to 82%, likely due to the more extreme anomalies [2, 4].
2
J. Gebb (*) · J. S. Moldenhauer
Richard D.Wood Jr. Center for Fetal Diagnosis and Treatment, Children’s Hospital of
Philadelphia, Philadelphia, PA, USA
Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA
e-mail: gebbj@chop.edu; moldenhauerj@chop.edu
L. Pilchman
Children’s Hospital Los Angeles, Los Angeles, CA, USA
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2025
A. R. Shukla, R. S. Joshi (eds.), Bladder Exstrophy and Epispadias,
https://doi.org/10.1007/978-3-031-91238-2_2
15
16
J. Gebb et al.
A prenatal diagnosis of BEEC is not considered to be life-limiting, with 1-year
survival rates reported to be 90–100% [1]. However, surgical intervention is required
in all cases, and many patients require multiple surgeries. There are currently no in
utero interventions available for the treatment of BEEC.Accuracy of the prenatal
diagnosis of BEEC helps to provide improved parental counseling and delivery
venue optimization, timely referral to pediatric subspecialists, and assistance to
families in preparation for a neonate that will require complex care and often prolonged hospitalization.
Prenatal Imaging
Ultrasound is the most utilized fetal imaging modality for anatomic assessment as it
is safe, cost-effective, and accessible even in remote settings. With improving technology, fetal malformations can now be diagnosed at earlier gestational ages.
Genitourinary malformations can be suspected in the rst trimester at the time of a
standard nuchal translucency screening ultrasound between 12 and 14weeks gestation [5–7]. At this early gestational age, fetal gender is determined based on the
direction that the genital tubercle points. More detailed anatomic evaluation of the
fetus typically occurs at 18–22weeks of gestation with well-established standard
guidelines and reporting requirements [8–10]. Additionally, in cases with omphalocele and/or open spina bida, elevation of the maternal serum alpha-fetoprotein at
16weeks may be present prior to the mid-trimester scan [11, 12]. The gestational
timing of prenatal screening and imaging techniques employed in the prenatal diagnosis of BEEC are presented in the Table2.1.
Assessment of the external fetal genitalia that occurs in the mid-trimester can
better evaluate the appearance of the penis/scrotum and the labia, allowing for
fetal phenotypic sex determination. An abnormal appearance of the genitalia,
ambiguous genitalia, or discrepancy between phenotypic sex and genetic sex falls
under disorders of sex development and requires further evaluation. Parental
counseling regarding fetal sex determination should include options for invasive
and non-invasive methods. Cell-free fetal DNA screening is a non-invasive method
that involves a maternal blood draw to evaluate fetal DNA circulating in the
maternal plasma that originates from the trophoblast and is available beginning at
9–10weeks gestation [13]. It is considered diagnostic with regard to fetal sex
determination [14]. The ability to further diagnose specic disorders of sex development is limited with cffDNA and requires additional testing. Amniocentesis is
an invasive testing option available for sex determination in the mid-trimester and
is associated with a procedure-related pregnancy loss rate of approximately
0.1–0.3% [15, 16]. Third trimester amniocentesis can also be performed for those
receiving a late diagnosis and is not associated with a risk for pregnancy loss, but
complications such as preterm premature rupture of membranes and placental
abruption can lead to preterm delivery [17]. A more complete genetic assessment,
including the use of genome sequencing, could also be performed on the amniotic
uid specimen.
2 Bladder Exstrophy-Epispadias Complex: Prenatal Diagnosis andCounseling
17
Table 2.1
Imaging Ultrasound
Screening Cell-free fetal DNA
Denitive
genetic
testing
Prenatal imaging and screening pertinent to diagnosing BEEC
First trimester Second trimester
Estimate of
gestational age
Nuchal translucency
measurement
(10–14weeks)
Detailed rst trimester
anatomy (12weeks
0days–13weeks
6days)
Available from 9 to
10weeks
Chorionic villus
sampling (10–13weeks)
Pregnancy loss
rate~0.1–0.3%
Third trimester
Ultrasound
18–22weeks detailed
anatomic evaluation
Fetal echocardiogram Fetal
MRI MRI
Cell-free fetal DNA Cell-free fetal DNA
Maternal serum alphafetoprotein (15–20weeks)
Levels elevated ≥2.5 MoM
associated with open neural
tube defects with a
detection rate of 65–80%
Amniocentesis (15–23weeks)
Pregnancy loss
rate~0.1–0.3%
Ultrasound
Anatomic
evaluation
Evaluation of
growth and
amniotic uid
echocardiogram
Amniocentesis
(≥24weeks)
Complication rate
1.2–7.2%
As described in more detail in the section on prenatal imaging (Chap. 4), ndings
of classic bladder exstrophy include: (1) non-visualization of the fetal bladder over
30–60min with normal appearance of the kidneys and amniotic uid; (2) low-set
umbilical cord with abdominal bulge below; (3) splayed pubic bones; (4) anteriorly
displaced “target” sign (anal dimple); (5) genital abnormalities; and (6) umbilical
cord insertion-to-genital tubercle length below the fth centile [18–21]. Findings in
cloacal exstrophy include the ndings of classic bladder exstrophy as well as: (1)
sub-umbilical omphalocele; (2) “elephant trunk-like” appearance of the prolapsed
ileum between the two hemi-bladders; (3) absence of “target” sign implicating anal
atresia; and (4) spinal defects that can range from vertebral anomalies to tethered
cord to various forms of open and closed spina bida [22, 23]. Additional ndings
may include renal anomalies in one-third of cases as well as lower limb and brain
anomalies associated with spina bida [24].
Detailed anatomic survey should therefore focus not only on the fetal pelvis,
bladder, genitalia, and anus/rectum but should also fully evaluate other structures
such as the spine, brain, limbs, kidneys, and abdominal wall. In cases of CE, the
thoracic circumference is also an important consideration given the risk of pulmonary hypoplasia in the presence of large omphaloceles and/or signicant scoliosis.
Ultrafast fetal MRI can aid ultrasound in differentiating complex anatomical
18
J. Gebb et al.
differences and can provide lung volumes [4, 25]. Although the association with
congenital heart disease is typically low, fetal echocardiography is generally recommended, as there are reports of cardiac disease in conjunction with BEEC.
Prenatal Counseling
As with any prenatally diagnosed congenital anomaly, disclosure of ndings, discussion regarding the diagnosis and long-term outcomes, and presentation of pregnancy
management options are included in prenatal counseling. Long-term outcomes in
BEEC vary widely, depending on the specic diagnosis, as below. In general, pregnancy management options include continuation with a plan for multidisciplinary
maternal and neonatal care or termination. Gestational age limitations and methods
of termination are dictated by state laws and local practice patterns. After a prenatal
diagnosis of BEEC, the rates of termination of pregnancy vary widely based on geographic location and may be as low as 8% or as high as 100% [26, 27].
Parents should be offered the opportunity to consult with pediatric subspecialists, including urology, surgery, neurosurgery, and neonatology, in the prenatal
period. Delivery venue will largely be dictated by the availability of pediatric subspecialists to care for the neonate. Therefore, parents should be referred to specialty
centers to optimize delivery and neonatal care planning. Additionally, expectant
parents may benet from participation in a parent support group or psychosocial
support resources, as high rates of caregiver mental health disorders and stress have
been reported [28, 29].
Epispadias
Epispadias has traditionally been prenatally diagnosed as one of the ndings in fetal
classic bladder exstrophy. Cases of isolated epispadias are rarer and may be missed
on prenatal ultrasound. Kidneys and amniotic uid typically appear normal and
remain as such throughout the pregnancy. The appearance of the external fetal genitalia in isolated epispadias most commonly will be deemed ambiguous, prompting
additional evaluation, as it implies an underlying disorder of sex development. At a
minimum, a prenatal diagnosis of ambiguous genitalia warrants determination of
fetal genotypic sex. Fetal imaging might suggest a shortened phallus in males or a
bid clitoris in females, which could be easily missed if a clear image of the
perineum is not obtained in utero. The anogenital distance (AGD), visualization of
the fetal vagina, and identication of the fetal uterus have also been proposed as
additional sonographic markers to determine phenotypic sex [30–33]. Incorrect
determination of fetal sex can have a negative impact on maternal well-being and
infant care [34].
In cases of isolated epispadias, the goal is to optimize cosmetic and functional
outcomes, including reproductive outcomes and continence. For male infants, we
counsel that parents will have to refrain from attempting circumcision after birth to
2 Bladder Exstrophy-Epispadias Complex: Prenatal Diagnosis andCounseling
19
avoid injury to the penis and urethra and so that the foreskin can be used during the
surgical repair. Maternal prenatal care follows a typical course, and the mode of
delivery is anticipated to be vaginal, with cesarean delivery reserved for routine
obstetric indications. Delivery venue should be optimized to allow availability of
the appropriate pediatric subspecialists to evaluate the neonate; however, the treatment of epispadias is not urgent, and surgery will not usually be undertaken until at
least 6months of age, allowing for postnatal consultation well after discharge from
the hospital.
Classic Bladder Exstrophy
Outcomes in cases of classic bladder exstrophy have improved greatly but continue to
require complex multidisciplinary care that is best undertaken at a center with a high
volume of cases. Prenatally, the kidneys appear normal, and the amniotic uid is generally normal throughout pregnancy. Urinary reux tends to develop after bladder
reconstruction occurs, but prior to bladder closure, there is no reux and there is a low
risk of urinary tract infections. At birth, the exposed bladder mucosa is protected from
abrasion from a diaper by covering it with a smooth covering such as clear doublebacked transparent dressing such as Tegaderm™, plastic wrap, or hydrogel sheets that
can retain moisture. The anus is anteriorly displaced, but this does not cause functional concerns in most situations. Anal atresia or rectal stenosis/prolapse has been
reported in 1.8% of patients with classic bladder exstrophy, and these may require
intervention; however, rectal prolapse often resolves after the bladder closure [35].
Inguinal hernias are common and are addressed surgically if present. Genital reconstruction may be performed at the time of bladder closure, as in the complete primary
repair of exstrophy, or later in a staged repair. Females often have normal sexual function and reproductive outcomes but may have vaginal stenosis. Males often have difculties with reproduction due to low sperm count and ejaculation volume.
In the setting of fetal bladder exstrophy, maternal prenatal care follows a typical
course, and mode of delivery is anticipated to be vaginal, with cesarean delivery
reserved for routine obstetric indications. Delivery venue should be optimized to
allow availability of the appropriate pediatric subspecialists to evaluate the neonate.
Cloacal Exstrophy
The prognosis in cloacal exstrophy cases is poorer due to the involvement not only
of the bladder but also of the intestines and the spine. The combination of structural
differences associated with cloacal exstrophy is often referred to as the OEIS
(Omphalocele—Exstrophy of the Cloaca—Imperforate Anus—Spinal Defects)
Complex. Surgical management involves multiple procedures over many years.
Initial surgeries include repair of the omphalocele with colostomy creation and
reapproximation of the posterior bladder plates. Closure of open spinal dysraphism
20
J. Gebb et al.
may occur before this or at 3months of age for closed defects. These infants often
have long-term nutritional challenges due to short gut physiology. Only once the
infant has grown and is thriving, often at 1–2years of age, is there an attempt to
close the bladder plate with osteotomies of the iliac bones to internally rotate the
pelvis. Due to the combination of minimal hindgut, as well as spinal dysraphism,
pull-through procedures are rare and have a very poor success rate for becoming
clean (7%) or achieving continence (1%) [36].
After these initial procedures, other major urologic reconstruction procedures
may be necessary, and genital reconstruction surgery is also undertaken. Because of
the complicated condition and need for staged surgical repair, consultation with the
parents includes the discussion of the possibility of long-term urologic complications and bowel incontinence.
Additionally, if there is a presence of spina bida, counseling includes a discussion of the associated neuromuscular weakness that can lead to talipes and
difculty with ambulation, as well as compromise to the nerves that innervate the
bladder, bowel, and external genitalia. In cases of open spina bida, Arnold-Chiari
II malformation is often present and can lead to the need for treatment of hydrocephalus after birth. When hydrocephalus is severe, or if there are complications
from ventriculoperitoneal shunting, neurocognitive outcome may be affected.
Maternal prenatal care should follow a typical course. Prior reports have suggested an increased association with fetal growth restriction and in utero fetal death
[37, 38]. Therefore, serial ultrasounds to monitor fetal growth throughout the pregnancy are recommended. Antenatal surveillance to monitor fetal well-being should
also be considered. Oligohydramnios can also develop over the course of the pregnancy given the association with inherent renal abnormalities, requiring close monitoring of amniotic uid throughout the pregnancy. There is an increased risk for
prematurity associated with CE, with median gestational age at delivery reported to
be 36weeks [4, 39]. The most optimal mode of delivery is unknown. However, in
the setting of liver-containing omphalocele and/or open neural tube defect, cesarean
delivery should be considered. Delivery should occur in a center with experience
caring for these complex neonates.
BEEC Variants
Approximately 10% of fetuses with BEEC will have anatomic variations from the
classic forms [40–43]. It is therefore critical to tailor counseling to the individual
ndings for each fetus. Reported variants include epispadias with bladder prolapse,
pseudoexstrophy, superior vesical ssure, duplicate exstrophy/duplicate bladder,
covered exstrophy, and covered cloacal exstrophy [40].
In all cases of BEEC and variants, pediatric urology and surgery (as appropriate)
consultations should be obtained to discuss in detail the planned postnatal evaluation,
surgical interventions, and reported outcomes, including quality of life assessments.
Psychosocial support of expectant parents of fetuses with congenital anomalies is an
integral part of many fetal centers and greatly benets this population.
2 Bladder Exstrophy-Epispadias Complex: Prenatal Diagnosis andCounseling
21
Prenatal Management
Prenatal diagnosis of BEEC does not typically alter obstetric management or delivery timing in cases of epispadias and CBE. However, preterm delivery occurs commonly in CE. Serial growth scans are recommended for prenatally diagnosed
BEEC.Evaluation of the amniotic uid and fetal kidneys is warranted, although
they remain normal in the vast majority of fetuses with epispadias and CBE. Renal
differences and oligohydramnios are more commonly seen with CE, requiring serial
monitoring throughout pregnancy. Additionally, antenatal surveillance should be
considered in cases of CE, as fetal death in utero has been reported. Delivery at term
in a specialty center is recommended to facilitate postnatal evaluation and management. Vaginal delivery is offered, with cesarean reserved for normal obstetric indications except in cases with a concomitant open spina bida or large omphalocele,
for whom cesarean is recommended.
Genetic Counseling
In approximately 98.5% of cases with BEEC, the nding is isolated with neurodevelopmental outcomes similar to the general population [24, 44]. Although karyotype and microarray are generally normal, duplication of 22q11.21 has been
associated with classic bladder exstrophy, and invasive prenatal genetic testing is
offered [45]. Even when genetic testing is normal, prenatal diagnosis can determine
fetal sex, which can aid in counseling and postnatal management in cases with
ambiguous genitalia. Moreover, the systematic application of modern genetic testing with microarray and next-generation sequencing techniques in large BEEC
cohorts has begun to identify putative disease-causing genes and regions in the
human genome for both Mendelian and multifactorial phenotypes [24]. Two recent
studies of BEEC/CBE using whole exome sequencing of trios revealed numerous
de novo variants and inherited variants that require further study [46–48].
The recurrence risk for future pregnancies is 1.4% [44]. Because the BEEC spectrum is rarely associated with an underlying genetic diagnosis, genetic evaluations
in subsequent pregnancies, such as chorionic villus sampling or amniocentesis, are
not informative. The application of IVF with preimplantation genetic diagnosis also
has limited utility for couples planning future pregnancies after an affected child.
Diagnosis of BEEC in subsequent pregnancies is largely limited to imaging studies
in the late rst trimester and second trimester.
Conclusion
The prenatal diagnosis of BEEC spectrum continues to be challenging and is largely
limited to imaging techniques. Counseling, education, and support can assist expectant parents to prepare to care for a surgically complex neonate. Optimization of
long-term childhood outcomes remains the goal of prenatal diagnosis.
22
J. Gebb et al.
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