Fetal lower urinary tract obstruction - sepeap

Seminars in Fetal & Neonatal Medicine (2007) 12, 464e470
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/siny
Fetal lower urinary tract obstruction
David Lissauer, Rachel K. Morris, Mark D. Kilby*
Division of Reproductive and Child Health, Birmingham Women’s Hospital,
University of Birmingham, Birmingham, B15 2TG, UK
KEYWORDS
Vesico-amniotic
shunting;
Lower urinary tract
obstruction;
Posterior urethral
valves
Summary Fetal lower urinary tract obstruction affects 2.2 per 10 000 births. It is a consequence
of a range of pathological processes, most commonly posterior urethral valves (64%)
or urethral atresia (39%). It is a condition of high mortality and morbidity associated with progressive
renal dysfunction and oligohydramnios, and hence fetal pulmonary hypoplasia. Accurate
detection is possible via ultrasound, but the underlying pathology is often unknown. In
future, magnetic resonance imaging (MRI) may be increasingly used alongside ultrasound in
the diagnosis and assessment of fetuses with lower urinary tract obstruction. Fetal urine analysis
may provide improvements in prenatal determination of renal prognosis, but the optimum
criteria to be used remain unclear. It is now possible to decompress the obstruction in utero via
percutaneous vesico-amniotic shunting or cystoscopic techniques. In appropriately selected
fetuses intervention may improve perinatal survival, but long-term renal morbidity amongst
survivors remains problematic.
ª 2007 Elsevier Ltd. All rights reserved.
Introduction
Fetal lower urinary tract obstruction (LUTO) can be a consequence
of a range of pathological processes. The most
common anomaly is posterior urethral valves (PUVs), and
these account for approximately half of cases presenting
with ultrasound features of LUTO. 1 Urethral obstruction is
another common cause of urethral atresia. 2 The affected
fetus is typically male; females with LUTO often demonstrate
more complex morbid pathologies such as cloacal
plate anomalies, including megacystis microcolon syndrome
(dysfunctional smooth muscle in bladder and distal bowel).
* Corresponding author. Tel.: þ44 121 627 2778; fax: þ44 121 415
4837.
E-mail address: m.d.kilby@bham.ac.uk (M.D. Kilby).
LUTO is a disease of high mortality and morbidity. It is
associated with cystic renal dysplasia and abnormal renal
(glomerular and tubular) function. Progressive renal dysfunction
may lead to severe oligohydramnios, predisposing
the fetus to pulmonary hypoplasia and positional limb
abnormalities. 3
Animal models have suggested that decompressing the
obstruction may modify the pathogenesis, 4,5 and prenatal
in-utero therapy has been considered in ‘selected’ cases
in an attempt to improve survival and attenuate the secondary
developmental complications. Current therapies
include percutaneous vesico-amniotic shunting and inutero
percutaneous cystoscopy. However, prenatal counselling
in this situation is difficult, as the modalities used
to assess fetal renal function have uncertain prognostic
value, and the effectiveness of therapy remains to be
established.
1744-165X/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.siny.2007.06.005

Fetal lower urinary tract obstruction 465
Incidence
Population-based data from the English ‘Northern Region
Congenital Anomaly Register’ showed that LUTO affects 2.2
per 10 000 births. Between 1984 and 1997, 113 cases were
registered, the underlying pathology being identified by
postnatal investigation or autopsy. PUV was found in 64%
(1.4/10 000 births), urethral atresia in 39% (0.7/10 000
births), ‘prune-belly syndrome’ in 4%, and remained unidentified
in 4%. 6
Natural history and pathophysiology
Several studies of the natural history of LUTO have been
performed, and they consistently demonstrate high mortality
rates and poor renal outcomes (Table 1). The studies
have identified that the high mortality is predominantly due
to pulmonary hypoplasia associated with severe oligohydramnios
mid-trimester. 7 In the series reported by Mahoney
et al., when oligohydramnios was present the mortality
rate was as high as 80%, and surviving fetuses had significant
renal morbidity, with 25e30% developing end-stage
chronic renal impairment necessitating dialysis or transplantation.
8 This accounts for 60% of all paediatric renal
transplants. 9
As well as the degree of oligohydramnios, poor outcome
is also predicted by earlier presentation 10 and the finding of
associated structural and/or chromosomal abnormalities.
Animal models have helped further our understanding of
these associations. Harrison’s group utilized a fetal lamb
model in which they induced complete urethral obstruction
at 95e105 days. This resulted in severe hydronephrosis,
hydroureter, megacystis, urinary ascites, and significant
pulmonary hypoplasia. Decompression in utero resulted in
some resolution of the urinary tract dilatation. However,
the expected cystic and dysplastic renal changes central
to the pathophysiology in humans were not demonstrated
in this model. 4,5 The failure to demonstrate a causative relationship
between obstruction and cystic renal dysplasia
led to subsequent experiments in which unilateral urethral
obstruction was introduced at 60 days in fetal lambs. These
demonstrated renal dysplastic changes on the obstructed
side, the severity of which correlated with the length of
time of obstruction. 11
The applicability of these animal models to humans
remains controversial. Experimentally, the obstruction is
not introduced from the commencement of renal development,
and most congenital obstruction is partial, not
complete. It has also proved difficult to reproduce the
histological changes of renal dysplasia seen in humans, so it
remains possible that obstruction may not be the sole cause
of the renal dysplasia seen in bladder outlet obstruction. 12
Diagnosis and assessment
Ultrasound
Ultrasound can accurately detect fetal lower urinary tract
obstruction 13,14 with a sensitivity of 95% and a specificity of
80%. 13 The sensitivity of ultrasound screening for these abnormalities
is improved because anomalies of the renal tract
and kidneys are also associated with secondary findings,
such as oligohydramnios.
Assessment of the fetal genitourinary tract is a part of
all routine ultrasound examinations. When abnormalities
are detected, this should lead to a detailed assessment
focusing on amniotic fluid volume, renal size and parenchyma,
the collecting system, and bladder size. 15 Dilatation
of the renal pelvis and fluid-filled areas as small as 1e2 mm
may be visualized in utero using high-resolution real-time
ultrasound. 16
Ultrasonography may allow differentiation of obstructive
and non-obstructive causes of megacystis, with the
association of increased echogenicity and oligohydramnios
in the presence of bladder distension being predictive of an
obstructive aetiology. Similarly, in cases of hydronephrosis,
Oliveira et al. showed that oligohydramnios and megacystis
were predictive of an obstructive aetiology, with the
sensitivity and specificity of the combination of both variables
being 60 and 98% respectively. 17 However, ultrasound
is of limited value in determinng the underlying aetiology
causing the LUTO. 13
Table 1
Reference
Summary of studies showing the natural history of lower urinary tract obstruction a
Number
of cases
Mortality (%)
Cystic renal
disease/chronic
renal failure in
Anumba study (%)
Pulmonary
hypoplasia (%)
Thomas et al., 1985 46 18 33 56 30 56
Mahoney et al., 1985 47 40 63 45 40 e
Nakayama et al., 1986 48 11 45 37 48 e
Hayden et al., 1988 49 14 64 e 36 43
Reuss et al., 1988 50 43 72 36 10 42
Anumba et al., 2005 6 113 75 (prenatal detection,
includes TOP);
53 (postnatal detection)
67 (detection
before 24 weeks);
40 (detection
after 24 weeks)
26 (without
shunting);
25 (with
shunting)
Total/mean values 239 58 47 31 41
a Reproduced from Studd et al. 51 with permission.
Associated
structural or
chromosomal
anomalies (%)
23

466 D. Lissauer et al.
An important prognostic feature on ultrasound diagnosis
is the presence of significant oligohydramnios, which if
present prior to 24 weeks is associated with a higher prevalence
of pulmonary hypoplasia and eventual renal dysplasia
and impairment. 18 However, this is only predictive if the
liquor volume is reduced chronically.
In addition, the presence of macro/microcystic change
within the renal parenchyma on ultrasound examination is
associated with a high rate of histologically demonstrable
renal dysplasia and severe renal impairment at birth. 19
However, the inability to detect renal cysts on ultrasound
does not predict that dysplastic renal disease is not present.
Magnetic resonance imaging (MRI)
The advent of single-shot fast-spin echo (SSFSE) techniques
has enable MRI to be used in prenatal diagnosis, including
assessment of the urinary system. 20 Cassart et al. in 2004
found that in 16 third-trimester fetuses with suspected urinary-tract
abnormalities following ultrasound, the addition
of MRI examination modified the diagnosis in five cases. 21
MRI is reported as being of particular benefit when used
in addition to ultrasonography of the fetal urinary tract if
the resolution of ultrasound is impaired by oligohydramnios.
22 Amnioinfusion is useful in these situations to aid
visualization with ultrasound, but results are more limited
towards term. 23 However, amnioinfusion is an invasive procedure
which may result in complications such as premature
rupture of membranes, amnionitis, fetal heart rate
abnormalities, or even embolisms, whereas MRI is a lessinvasive
alternative. 24
In future MRI is likely to be used increasingly alongside
ultrasound in the diagnosis of LUTO.
In-utero percutaneous cystoscopy
Difficulties establishing the cause of obstructive uropathy
with ultrasound have led to a search for alternative
techniques. Percutaneous fetal cystoscopy is being utilized
as a means of allowing better diagnosis of the cause of the
obstruction, to enhance prognostication, and to allow the
application of novel therapeutic techniques. Two groups
have demonstrated the feasibility of this technique, enabling
visualization of the ureteral orifices, bladder neck
and urethra, as well as instrumentation of the urethra. 1,25
It can improve diagnostic accuracy when combined with ultrasound,
and the extension of its use to provide alternative
therapeutic approaches will be discussed later. 25
Antenatal assessment
It is mandatory to perform a detailed anomaly scan,
determine fetal sex, and offer fetal karyotyping (due to
the high incidence of karyotypic abnormalities) in cases of
obstructive uropathy. Allocation of fetal gender may allow
diagnosis to be further elucidated. Posterior urethral valves
and urethral atresia have a very high prevalence in male
fetuses. In the presence of severe oligohydramnios, amnioinfusion
may occasionally be required to allow accurate
evaluation of fetal structures. If a normal karyotype is
confirmed in a fetus with LUTO, and no other congenital
anomalies are present, consideration of in-utero treatment
may be justified. Other prognostic indicators such as the
appearance of the kidneys and liquor volume are evaluated.
Renal function may need to be assessed to ensure that any
intervention will benefit the fetus. Several methods have
been utilized, including fetal urine, serum or amniotic fluid
analysis, and finally renal biopsy.
It is important to differentiate true urethral obstruction
from the megacystis-mega-ureter-microcolon syndrome
(MMIHS), a rare disorder characterized by a functional
intestinal obstruction/hypomobility and enlarged nonobstructed
bladder. It is more common in females, and has
a very poor prognosis. As it can be difficult to differentiate
on ultrasound, it is important to consider this diagnosis
carefully in a female with LUTO but normal liquor volume. In
general, it is not beneficial to consider in-utero shunting for
these pregnancies.
Assessment of fetal renal function
Fetal urine
Assessment of fetal renal function may be helpful prognostically
and can be performed by fetal urinary analysis.
There are many studies examining the relationship between
a range of fetal urinary metabolites and subsequent
renal function, but most are of small size and utilize
different ‘normal’ ranges, making direct comparison difficult.
No consensus has yet been reached on the optimum
approach.
Urinary sodium can be used as an index of renal
tubular function, with values 100 mmol/L have
been shown to be highly predictive of fetal or perinatal
death from terminal renal or pulmonary failure. 26,27 The
b2-Microglobulin has also been used as an index of fetal
glomerular filtration rate (GFR) and in the prediction of
postnatal GFR. b 2 -Microglobulin is a low-molecular-weight
protein that is freely filtered by the fetal glomeruli;
>99.9% is reabsorbed and metabolized in the proximal tubules
in a normally functioning kidney. However, in renal
disease it is postulated that damage to the tubules results
in the excretion of b 2 -microglobulin in the urine. 28,29
A b 2 -microglobulin >13 mg/L has been reported to be invariably
fatal, 30 and a value of >6 has been suggested as
poor prognostic factor when evaluating the benefits of
intervention. 31
Sequential urine analysis allows assessment of ‘fresh’
urine and renal reserve, and has been shown to improve
prognostic accuracy. In cases of severe renal damage, the
expected decrease in hypertonicity with repeated samples
is not observed. Conversely, some fetuses may be identified
where, despite initially high absolute values, their electrolytes
improve on sequential samples, and this may indicate
a salvageable kidney. 26,27
Fetal serum and fetal renal biopsy
Fetal serum monitoring has been utilized to assess fetal
renal function. Serum creatinine cannot be used, as creatinine
crosses the placenta and is filtered by the mother.
However, serum microglobulins such as a 1- microglobulin,
retinol binding protein, and b 2 -microglobulin, due to their
molecular weight, cannot cross the placenta but are still

Fetal lower urinary tract obstruction 467
filtered by the fetal glomerulus. They have been suggested
as potential measures of fetal renal function. 32 Serum monitoring
can be used even after the placement of a shunt if
there is insufficient urine for urine sampling, but its measurement
is associated with the risks of cordocentesis.
Fetal renal biopsy is possible by ultrasound-guided fineneedle
aspiration, but is rarely performed as it has a low
success rate in obtaining fetal tissue. 33
Therapeutic options
Animal models suggesting that potentially reversing the
obstruction in LUTO may optimize renal function, maximize
amniotic fluid volume and prevent pulmonary hypoplasia, 4
have paved the way for interventions attempting to decompress
human fetal urinary tract obstruction and thus improve
prognosis and survival.
Open fetal surgery
The initial approach adopted involved open hysterotomy.
Harrison et al. performed the first successful in-utero
decompression for hydronephrosis in 1981. 34 The maternal
morbidity associated with open surgery, and associated fetal
risks of preterm labour and neurological sequelae, have
led to the development of alternative minimally invasive
techniques. 35,36 No new cases of open fetal surgery have
been reported since 1988. 37
Vesico-amniotic shunting
Ultrasound-guided percutaneous vesico-amniotic shunting
is the most commonly used method to relieve urinary tract
obstruction. This technique involves the placement of
a double pig-tailed catheter under ultrasound guidance
and local anaesthesia, with the distal end in the fetal
bladder and the proximal end in the amniotic cavity to
allow drainage of fetal urine (Fig. 1).
Amnioinfusion is often recommended prior to shunt
insertion in cases of severe oligohydramnios to allow space
for insertion. The use of colour doppler allows the umbilical
arteries to be delineated as they course round the fetal
bladder.
In 1986, the International Fetal Surgery Register
audited 73 fetuses with ultrasound evidence of LUTO
that had been treated with vesico-amniotic shunts. 38
Overall survival rates of 41% were demonstrated. It was
suggested that better patient selection through further
prognostic testing prior to intervention could further improve
survival rates.
In 1997 Coplen reviewed 169 cases of successful
percutaneous shunt placements over 14 years. 39 Overall
survival was found to be 47%, with 40% of survivors having
end-stage renal disease. Coplen concluded that limiting intervention
to fetuses with good prognosis would improve
survival and result in a lower incidence of renal failure
in survivors. Notably, shunt-related complications were
common, occurring in 45% of cases, which may necessitate
further shunts being placed. These included shunt blockage
(25%), shunt migration (20%), preterm labour and miscarriage,
amniorrhexis, chorioamnionitis, and iatrogenic
gastroschisis. Fetal extremities becoming entangled in
the intra-amniotic portion of the shunt may cause physical
displacement of the shunt from the fetal bladder. Following
displacement, urine may flow through the defect in the
bladder to cause urinary ascites. This can result in massive
fetal abdominal distension with serious sequelae, and may
require further abdominal shunts until the bladder defect
has healed.
Figure 1 Technique for placing the Harrison double-pig-tailed catheter under sonographic guidance. Reproduced from Harrison
et al. 52 with permission.

468 D. Lissauer et al.
Fetal cystoscopy
This technique offers opportunities for cystoscopic therapies
to be delivered. It was first described under maternal
general anaesthesia, 40 but has now been performed under
local anaesthesia. 41 Therapeutic options include mechanical
or laser endoscopic ablation of posterior urethral valves
and the positioning of urethral vesico-amniotic shunts. In
2003 Welsh et al. reported the successful treatment of
6/10 fetuses by hydroablation or guide-wire passage; five
of these fetuses survived. 25 It has been postulated that direct
valve ablation may be advantageous in that it allows
restoration of normal fetal bladder dynamics. 42 This may
be beneficial, as there are concerns that the fetal urinary
diversion from stenting, with the resulting chronic bladder
decompression, may cause aberrant detrusor contractions
and voiding dysfunction in children with PUV. 43
Systematic review and meta-analysis of
prenatal bladder drainage
In 2003 Clark et al. conducted a systematic review and
meta-analysis to estimate the effect of prenatal bladder
drainage on perinatal survival in fetuses with LUTO. 44
Vesicocentesis, vesico-amniotic shunting, and open fetal
bladder surgery were included. The review identified 16
observational studies that included nine case series (147
fetuses) and seven controlled series (197 fetuses). The review
demonstrated that, despite this form of fetal therapy
having been practised for more than 25 years, there is
a lack of high-quality evidence to reliably inform clinical
practice. There were no randomized controlled trials,
many studies were observational series without control
data, and the methodological quality was deemed to be
relatively poor. Meta-analysis showed that in-utero vesico-amniotic
drainage appeared to improve overall perinatal
survival as compared to the non-drainage group (OR
2.5; 95% CI 1.0e5.9; P < 0.03). However, subgroup analysis
indicated that this improved survival was predominantly
noted in fetuses with a defined ‘poor prognosis’ (defined
on ultrasound appearance and/or fetal urinalysis) where
there appeared to be marked improvement (OR 8.0; 95%
CI, 1.2e52.9; P < 0.03). The findings of the meta-analysis
must be interpreted with caution, as the uncontrolled observational
studies from which the analysis was drawn may
be liable to selection bias and could overestimate the
effect of the therapy. The review could also not comment
on the timing and indications for intervention. Further
research in the form of a randomized controlled trial is required
to assess the short- and long-term effects of this
intervention.
Long-term outcome
Long-term follow up of 19 boys with PUV in whom no
intrauterine intervention was carried out showed that 32%
were uraemic, 21% had moderate renal failure, and 48% had
not been checked since adolescence. In 40% there were
signs of bladder dysfunction; however, all were continent.
Fertility was compromised in those who were uraemic. 45
Biard et al. recently reported their experience of longterm
clinical outcomes in 20 male fetuses with oligohydramnios
and LUTO who were treated prenatally; 31 45% had
acceptable renal function, 22% had mild renal impairment,
and 33% had end-stage renal failure requiring transplantation.
Growth and developmental abnormalities were common,
with 50% having growth below the 25th centile, and
50% of the children also reported ongoing respiratory problems
or musculoskeletal abnormalities. Positive findings
were that good cognitive development was seen. With appropriate
medical and surgical care, a majority achieved
acceptable social continence, and quality-of-life measures
were not significantly different from those in a healthy
population.
While intervention may apparently reduce perinatal
mortality, the improvement of long-term renal sequelae
remains problematic.
The percutaneous shunting in lower urinary
tract obstruction trial (PLUTO)
The systematic examination of the literature by Clarke
et al. 44 described above confirmed the scarcity of highquality
evidence to inform decision-making around vesicoamniotic
shunting. A randomized controlled trial which
hopes to answer the dilemma surrounding the role of vesico-amniotic
shunting in moderate to severe LUTO is now
in progress. The PLUTO (Percutaneous Shunting in Lower
Urinary Tract Obstruction) trial funded by Wellbeing for
Women is a multicentre trial within the UK, and will hopefully
be extended later to Europe. It is hoped that over a 5-
year period 200 women will be recruited. Recruitment is
based on a pragmatic approach. Rather than rigid entry criteria,
recruitment is based on the ‘uncertainty principle’.
That is, as long as the fetus is male with evidence of
LUTO without other abnormalities, and the clinical team
is substantially uncertain which treatment (shunt versus
no shunt) should be offered for the fetus at the current
time, that fetus is eligible to be randomized. The trial
also contains a prospective registry for those who fit the entry
criteria but the fetal medicine specialist is not uncertain
or the mother does not wish to be randomized. Further information
can be obtained at www.pluto.bham.ac.uk.
Conclusion
Lower urinary tract obstruction is a heterogeneous condition
associated with a high mortality and morbidity.
Ultrasound offers accurate diagnosis of obstruction, but
the underlying aetiology often remains unknown until after
birth. Fetal urine analysis may improve the prenatal
determination of renal prognosis, but the optimum criteria
to be used remain unclear. It is now possible in utero to
decompress the obstruction via percutaneous vesicoamniotic
shunting or cystoscopic techniques. In appropriately
selected fetuses intervention may improve perinatal
survival, but long-term renal morbidity amongst survivors
remains problematic. It is hoped that the PLUTO trial will
help clarify the uncertainty which remains regarding the
efficacy of percutaneous shunting.

Fetal lower urinary tract obstruction 469
Practice points
Lower urinary tract obstruction (LUTO) is a disease
of high mortality and morbidity.
Diagnosis may be made at second-trimester
ultrasound.
Prognosis is related to amniotic fluid volume,
presence of renal cysts, and other congenital or
structural anomalies.
Intervention is available in the form of vesicoamniotic
shunting, but the efficacy of this is not
proven.
Research directions
The efficacy and long-term safety of vesicoamniotic
shunting (PLUTO trial).
The predictive accuracy of fetal urinalysis.
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