Fetal bladder outlet obstruction: Embryopathology, in utero intervention and outcome

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Journal of Pediatric Urology (2016) xx, 1e8

Review article

Fetal bladder outlet obstruction: Embryopathology, in utero intervention and outcome Chelsea Children’s Hospital at the Chelsea & Westminster Hospital Foundation Trust, London SW10 9NH, UK Correspondence to: M.K. Farrugia, Chelsea Children’s Hospital at the Chelsea & Westminster Hospital Foundation Trust, 369 Fulham Road, London SW10 9NH, UK [email protected] (M.-K. Farrugia) Keywords Fetal bladder outlet obstruction; Fetal lower urinary tract obstruction; Vesicoamniotic shunt; Fetal cystoscopy; Congenital renal anomalies; Posterior urethral valves Received 8 March 2016 Accepted 17 May 2016 Available online xxx

Marie-Klaire Farrugia Summary Fetal bladder outlet obstruction (BOO), most commonly caused by posterior urethral valves (PUV), remains a challenging and multi-faceted condition. Evolving techniques, and refinement in ultrasound, optics and instrumentation, have increased our rate of prenatal diagnosis, and enabled valve ablation not only in smaller newborns, but also in fetuses. Long-term outcome studies have raised our awareness of the silent damage caused by bladder dysfunction and polyuria and encouraged their proactive management. In spite of our best efforts, the proportion of boys with PUV who progress to chronic and end-stage renal disease (ESRD) has not changed in the last 25 years. Evidence suggests a reduction in perinatal mortality following prenatal intervention,

probably resulting from amelioration of oligohydramnios at the crucial time of lung development between 16 and 28 weeks’ gestation, but no improvement in postnatal renal outcome. There are no bladder functional outcome studies in patients who have undergone prenatal intervention and hence the long-term effect of in utero defunctionalisation of the bladder is not known. This aim of this review is to revisit the embryopathology of fetal BOO, in particular the renal and bladder structural and functional changes that occur with in utero obstruction. The effect of earlier prenatal diagnosis, and therapy, on postnatal outcome is also explored and compared with outcomes published for traditional postnatal treatment.

Introduction

Embryopathology

The incidence of congenital lower urinary tract obstruction is estimated to be 2.2 in 10,000 births, with up to 62% being diagnosed prenatally. About 20% of cases are associated with other structural or chromosomal anomalies [1]. The most common underlying diagnoses are posterior urethral valves (PUV), urethral atresia or the Prune Belly Syndrome (PBS) [2]. The incidence of PUV appears to be stable with a total prevalence of 3.34 (2.95e3.72) per 10,000 births. Less common causes of congenital BOO include anterior urethral valves/anterior urethral diverticulum; prolapsed ureterocoele; syringocoele; megalourethra; megacytis-microcolonhypoperistalsis syndrome; obstruction by a hydrocolpos in females with cloacal anomalies; or rarely obstruction by a tumour such as a sacro-coccygeal teratoma. The 17th Report of the UK Renal Registry published in 2014 confirmed obstructive uropathy as the second commonest cause (18%) of paediatric endstage renal disease (ESRD) after renal dysplasia  reflux (34%). The percentage of children with obstructive nephropathy was 18.0% between 2009 and 2013 [3].

The earliest descriptions of PUV are credited to Morgagni (1717) and Langenbeck (1802), who commented on valve-like folds in autopsy specimens. Tolmatschew described the valves as “overgrowths of the normally present folds and ridges in the urethra”, disputed by Bazy, who suggested that the valves were a persistence of the urogenital membrane that separated the anterior and posterior urethra prior to the process of canalisation [4]. Lowsley noted that the PUV originated from the same connective tissue that encased the ejaculatory ducts as they coursed through the prostate, and went on to attach to the entire circumference of the urethra. The fibres were stratified, rather than transitional, epithelium, suggesting an origin from the mesonephric ducts. Thus the putative origin of PUV as an anomaly of the insertion of the mesonephric ducts into the prostatic urethra [4]. In 1919, Young et al. attempted to unify these theories by offering a classification of PUV: type 1 valves, the most common, were composed of a ridge coursing anterior from the distal verumontanum, dividing into two leaflets and attaching to the anterior urethra; type 2

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Please cite this article in press as: Farrugia M-K, Fetal bladder outlet obstruction: Embryopathology, in utero intervention and outcome, Journal of Pediatric Urology (2016), http://dx.doi.org/10.1016/j.jpurol.2016.05.047

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2 valves, the most rare, extended from the proximal verumontanum toward the internal sphincter and bladder neck; type 3 valves attached to the entire circumference of the urethra with a central opening. This anatomical distinction was challenged by Dewan et al. in the early 1990s, who argued that the obstruction was caused by a membrane rather than valves, hence the term “congenital obstructive urethral membrane” (COPUM). Dewan et al. proposed two distinct causes of posterior urethral obstruction: COPUM and Cobb’s collar, based on their relationship to the verumontanum. COPUM was thought to be an oblique membrane intimately associated with the distal verumontanum, and Cobb’s collar (or congenital urethral stricture) a transverse membrane located distal to the external urethral sphincter. The Prune Belly Syndrome (PBS) or Triad Syndrome, as described by Eagle and Barrett [5], is thought to be caused by an “abnormal angulation” of the urethra in a region where the prostate has incompletely developed, and this may in itself impair urine flow [6,7], rather than complete mechanical obstruction. However, a PBS phenotype may be seen in cases with urethral atresia, which may support the hypothesis that early BOO with massive bladder distension or ascites can result in atrophy of the abdominal wall musculature, induce renal dysplasia and impair testicular descent. The appearance of urethral atresia has been described as a completely obstructed membrane below the verumontanum with a hypoplastic distal urethra.

M.-K. Farrugia Distal urethral obstruction is less common and may be caused by “anterior urethral valves” (AUV), which are thought to be the edges of a ruptured syringocele (cystic dilatation of Cowper’s Gland, which may also be a cause of BOO). The megacystis-microcolon syndrome (MMS), a generalised disorder of peristalsis with absent ganglion cells in the bladder wall, can also manifest as congenital BOO [8,9]. The effect of congenital BOO on the rest of the urinary tract is less well understood and has led to the development of a number of animal models [10]. Obstructive nephropathy is typically characterised by small cortical cysts, fewer layers of glomeruli than normal (renal hypoplasia) and a disorganised medulla (renal dysplasia). It is debated whether the kidney malformations are secondary to impairment of fetal urine flow or are manifestations of a primary defect which affects the development of the entire urinary tract, from the kidney to the urethra [11] e the likelihood is a combination of both. Evidence from the fetal lamb model suggests that damage caused by urethral and urachal occlusion is greater the earlier in gestation obstruction is initiated and the longer it is maintained [12,13]. Early on in the obstructive process, bladder detrusor muscle architecture and function is maintained, but the effect on the obstructed kidneys is more acute, with evidence of hydronephrosis, cortical cysts with glomerular tufts and dilated medullary ducts (Fig. 1). On prolonged obstruction, the bladder wall becomes “thinned”

Figure 1 Appearance of the fetal urinary tract following 1 week urachal and urethral obstruction in the fetal lamb at midgestation. (A) dilated fetal bladder with (B) hydronephrosis. Histology of a sham kidney (C) with an intact cortex and nondilated nephrons in contrast to an obstructed kidney (D) exhibiting cortical cysts, glomerular tufts and dilated tubules. Data adapted from Farrugia MK, MD Thesis (University of London, 2008).

Please cite this article in press as: Farrugia M-K, Fetal bladder outlet obstruction: Embryopathology, in utero intervention and outcome, Journal of Pediatric Urology (2016), http://dx.doi.org/10.1016/j.jpurol.2016.05.047

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Fetal bladder outlet obstruction and poorly contractile [13,14]. Radiotelemetered urodynamics in the ovine model showed a gradual increase in baseline detrusor pressure over the first few days of obstruction, with increased frequency and duration of fetal voiding [12,15]. Edouga et al. investigated the renal effects of in utero shunting following 30 days of BOO in the fetal lamb. The appearance of obstructed kidneys ranged from mild hydronephrosis to severe dysplasia, and they were noted to have 20% less glomeruli. Shunted kidneys were less hydronephrotic and had a higher number of glomeruli. The authors concluded that urinary diversion before the end of nephrogenesis could allow the recovery of this process [16]. Kitagawa et al. explored the effects of shunting on the developing ovine bladder, and showed that shunted bladders had a significantly reduced volume (4 mL vs. 16 mL), and were non-compliant and fibrotic with distorted muscle layers [17]. The negative effects of shunting were improved using a pressure-limited (similar to a ventriculo-peritoneal) shunt. Shunting, however, did preserve lung volumes compared with shams [18e20]. Fetal BOO is known to affect lung development. Although metanephric urine production begins at 12 weeks’ gestation, fetal urine only makes a significant contribution to amniotic fluid after 18 weeks’ gestation, when urine output increases from 5 mL/h to 51 mL/h at 40 weeks’ gestation [21]. Amniotic fluid is essential to bronchial branch development in the lungs, in particular during the canalicular phase between 16 and 28 weeks’ gestation, hence oligohydramnios secondary to BOO has a devastating effect on the developing lungs [22]. Three mechanisms have been proposed to explain the pulmonary hypoplasia associated with oligohydramnios: extrinsic compression, lack of fetal breathing movements and lack of pulmonary distension.

Prenatal diagnosis Ultrasound remains the most common modality for evaluating fetal BOO. Prenatal magnetic resonance Imaging (MRI) also has been used but there is currently no evidence to suggest it is superior to ultrasound at establishing the cause of obstruction. The fetal kidneys and bladder are identifiable on prenatal scanning by 12 weeks’ gestation. Fetal megacystis noted in the first trimester, defined by a longitudinal bladder diameter of 7 mm or more, often regresses spontaneously. Liao et al. showed that the incidence of chromosomal defects was higher with a bladder diameter of 7e15 mm (23.6%) than >15 mm (11.4%), and that a dilated bladder >15 mm was less likely to resolve spontaneously and hence was more suggestive of fetal BOO [23]. The prenatal ultrasound appearance of BOO secondary to urethral obstruction is that of a distended thick-walled bladder and a dilated posterior urethra, the combination of which gives a “key-hole” appearance [21] (Fig. 2). Associated hydroureteronephrosis may be asymmetrical and up to 15% of PUV cases are associated with unilateral hydroureteronephrosis [24]. It is difficult to make a clear judgement on the degree of prenatal renal dysplasia, although the presence of oligohydramnios and bilateral renal cortical cysts are statistically significant predictors of

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Figure 2 Antenatal ultrasound scan on a 21-week gestation fetus with bilateral hydroureteronephrosis (A) and a distended bladder and dilated posterior urethra (“key-hole” sign) (B).

poor postnatal renal function. Specifically, oligohydramnios has a specificity ranging from 67% to 75% and renal cortical cysts a specificity of 89% for predicting poor renal function (serum creatinine >1.2 mg/dL) at 1 year of age [25]. As the precise cause of fetal BOO cannot be evaluated by ultrasound, Welsh et al. and Ruano et al. evaluated the utility of fetoscopy at establishing the cause of obstruction. They determined an increased sensitivity for diagnosing PUV by direct visualisation of PUV versus other causes of BOO with fetoscopy (83.3e100%) over ultrasound (62.5e63.6%) [26,27]. The utility of fetal urine analysis to further gauge the degree of renal impairment has controversial results. As nephrogenesis progresses, the concentration of sodium in the urine falls, and that of creatinine, calcium and ammonia rises significantly. Fetal urinalysis including sodium (>95th centile for gestation), chloride, calcium (>95th centile for gestation), osmolality and b2microglobulin (13 mg/dL) have been used to predict fetal renal outcome. However, a systematic review evaluating the utility of fetal urine analyses in predicting postnatal renal function, showed that elevated fetal urine concentrations of sodium, calcium and b2-microglobulin were not significantly predictive of poor postnatal renal function [28]. Analysis of serial bladder aspirations at 48e72 h intervals may be more representative of renal

Please cite this article in press as: Farrugia M-K, Fetal bladder outlet obstruction: Embryopathology, in utero intervention and outcome, Journal of Pediatric Urology (2016), http://dx.doi.org/10.1016/j.jpurol.2016.05.047

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reserve than the analysis of a single urine sample from an obstructed fetal bladder [29]. The first urine sample may have been present in the bladder for a long time, and is thought to be a poor representation of function. The second urine sample reflects urine from the dilated upper urinary tract that has drained into the bladder, whereas the third sample is thought to represent fresh urine, better reflecting the renal function expected after relief of obstruction [30]. Luton et al. evaluated fetal b2-microglobulin as an index of histological injury to the kidney. b2-microglobulin was measured in serum and urine from 27 fetuses with BOO and compared with findings on kidney examination following termination of pregnancy. Increased serum b2microglobulin correlated with a decreased number of glomeruli and the presence of renal hypoplasia and dysplasia. Elevated b2-microglobulin levels in the urine correlated only to a decreased number of glomeruli [31]. A more recent study by Klein et al. successfully used fetal urinary peptides to predict postnatal outcomes in BOO. They identified 12 urinary proteins (PUV12) that predicted likelihood for poor renal function postnatally in fetuses with PUV, with higher specificity and sensitivity than traditional fetal urine analysis and ultrasound [32].

Fetal intervention Fetal bladder decompression was introduced in the hope that it would reduce the pressure effects on the developing kidneys and hence improve postnatal renal outcome. Traditionally, case selection has been based on the algorithm introduced by Johnson in 1994, whereby a candidate for prenatal intervention would have a normal male karyotype in the absence of other fetal anomalies that would adversely affect prognosis, and maternal oligo/anhydramnios or decreasing amniotic fluid volumes. Three serial vesicocentesis taken at 48e72 h intervals and showing a pattern of decreasing hypertonicity were thought to indicate potential salvage and identify fetuses that could benefit from intervention [33]. More recently, Ruano et al. proposed a standardised prenatal evaluation to select patients for in utero diversion, based on three stages of obstruction [34]. Expectant management is recommended in stage I, whereby fetuses have normal amniotic fluid levels (after 18 weeks) and “normal fetal renal function”

Table 1

(favourable urine biochemistry and no evidence of fetal renal cysts/dysplasia). In Stage II, fetuses have oligohydramnios and severe bilateral hydronephrosis but normal renal function: this group is said to benefit from fetal intervention, with the objective of preventing severe pulmonary hypoplasia and possibly further deterioration of renal function. Fetal intervention was not recommended for Stage III (oligohydramnios and severe bilateral hydronephrosis but with signs of abnormal renal function [ultrasound findings of renal cortical cysts and/or renal dysplasia and/or unfavourable urine biochemistry]) [34]. This information, summarised in Table 1, is helpful when counselling parents, some of whom may request intervention in spite of the poor prognosis. In countries offering prenatal medical terminations, this evaluation would also enable parents to come to terms with this alternative decision. Termination is more prevalent in first trimester diagnosis, when the megacystis may be associated with chromosomal anomalies and carry a poorer prognosis [35]. Two main techniques are currently being used in specialised centres. The most common is vesico-amniotic shunting (VAS), whereby a double pigtail stent is introduced percutaneously via a trocar, under ultrasound guidance and maternal local anaesthetic. Examples of popular shunts are the Rocket and Harrison shunts, in which the pigtails are orientated perpendicular to each other to decrease the risk of dislodgement (Fig. 3). Amnioinfusion is often performed to provide an interface between the amnotic cavity and the fetal abdomen to improve visualisation. The second technique is fetal cystoscopy, performed under both maternal and fetal analgesia. A trocar is placed inside the fetal bladder under ultrasound guidance. The fetoscope (1.2e3.5 mm) is then advanced into the fetal bladder in an antegrade fashion and valves visualised and ablated using guide wires, hydro-ablation or YAG laser [36]. Trans-urethral stenting via the fetal bladder also has been reported e this technique involves antegrade insertion of a Double-J stent (over a guide wire) between the bladder and amniotic cavity [37,38] (Fig. 4). Several studies have been published reporting outcomes of VAS in small cohorts, and these results were summarised in a meta analysis by Clarke et al. in 2003 [39]. Sixteen observational studies that included nine case series (147 fetuses) and seven controlled series (195 fetuses) were identified. Bladder drainage appeared to improve perinatal survival relative to no drainage. However, a sub-group

Fetal Intervention Guideline (adapted from Ruano et al. [34]).

Degree of bladder outlet obstruction

Stage 1

Stage 2

Stage 3

Fetal intervention

Not indicated

May prevent pulmonary hypoplasia but not renal impairment

Amniotic fluid Fetal kidneys Renal dysplasia/ cortical cysts Fetal urine biochemistry

Normal Normal Absent

Indicated to prevent pulmonary hypoplasia and potentially further renal damage Low/reduced Hyperechogenic Absent

Reduced/absent Hyperechogenic Present

Favourable

Favourable

Unfavourable

Please cite this article in press as: Farrugia M-K, Fetal bladder outlet obstruction: Embryopathology, in utero intervention and outcome, Journal of Pediatric Urology (2016), http://dx.doi.org/10.1016/j.jpurol.2016.05.047

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Fetal bladder outlet obstruction

Figure 3 The Rocket KCH Fetal Bladder Drain, measuring 5 cm in length in the coiled position. The forming wire aids insertion via a trans-abdominal trocar and is then removed, allowing the coils to reform, thus preventing dislodgement.

analysis indicated that improved survival was predominantly in fetuses with a defined “poor prognosis”. There were no outcome data available regarding progression to ESRD [39]. Holmes et al. reported the outcome on 36 fetuses shunted at a mean gestational age of 22 weeks. The mean age of children at follow-up was 54.3 months. Of 14 fetuses who turned out to have PUV, eight boys survived (43% mortality), of whom five (63%) progressed to ESRD before puberty. The rate of progression to ESRD was therefore no different from that quoted in historical studies following postnatal management [40]. The lack of renal outcome data led to the much anticipated Percutaneous vesicoamniotic shunting versus conservative management for Lower Urinary Tract Obstruction (PLUTO) trial, a multicentre randomised study comparing outcomes of VAS versus conservative management in fetal BOO. Planned sample size was 150 but enrolment stopped after 31 cases because of difficulty recruiting [41]. Primary outcome was survival at 28 days, and there were no eligibility criteria related to gestational age at intervention or volume of amniotic fluid. Pregnancies were randomised to VAS (n Z 16) or conservative (n Z 15) management. Most fetuses had oligohydramnios (10 VAS, 9 conservative). Shunting was performed at a median of 20 (16e22) weeks. There was no significant difference in preterm labour, number of live births (12), mean birth weight (2.8 kg) and number of babies requiring ventilation in the neonatal period (6 VAS, 7 conservative). Complications of VAS were three premature rupture of membranes (PROM); three dislodged shunts; and one blocked shunt. Only one of these fetuses, whose shunt was successfully replaced, survived. Eight shunted and four conservatively managed babies survived to 28 days e all deaths resulted from pulmonary

5 hypoplasia in the early neonatal period. One further baby in each group died from renal failure before 1 year of age. Seven babies were alive at 2 years in the VAS group (2 normal renal function, 5 moderate impairment; one patient had serious cognitive impairment) and three in the conservative group (2 moderate impairment and 1 ESRD) (Table 2). The trial concluded that “survival seemed to be higher in the fetuses receiving VAS, but the size and direction of the effect remained uncertain, such that benefit could not be conclusively proven. Results suggest that the chance of newborn babies surviving with normal renal function is very low irrespective of whether or not VAS is done”. Because all neonatal deaths in the trial were from pulmonary hypoplasia, the reduction in perinatal mortality with VAS probably results from amelioration of oligohydramnios at the crucial time of lung development. Clinical outcomes at 1e2 years was poor in both groups e suggesting that the renal parenchymal damage had already taken place at the time or diagnosis and is irreversible [41]. Sananes et al. reported the 2-year outcome of 50 fetal cystoscopies offered to male fetuses with BOO with oligohydramnios and favourable urine biochemistry, at a mean gestational age of 19.4 (14e29) weeks [42]. The cause of obstruction was visualised and PUV fulgurated using Nd:YAG laser; patients with urethral atresia or stenosis were not treated. BOO recurred in six fetuses (20%) and three were lasered a second time (2 survived). PROM occurred in 22% and mean gestational age at delivery was 32.4 weeks. There were 18 survivors (34.8%) at 2 years, of whom 75% had normal renal function. The authors concluded that fetal cystoscopy can accurately diagnose the cause of fetal BOO and hence select appropriate candidates for therapeutic intervention [42]. Martinez et al. performed laser PUV ablation by fetal cystoscopy in 20 cases at a median 18.1 weeks’ gestation. The fetal urethra was accessed in 19 and successful decompression performed in 16. Nine patients (45%) terminated, 11 (55%) delivered at mean 37 (29e40) weeks. No pulmonary hypoplasia was reported, and all babies were alive at 15e110 months, of whom three (27%) were in renal failure [43]. A further multicentre caseecontrol study compared fetal cystoscopy with VAS [44]. Cases managed in two centres (111) between 1990 and 2013 were divided into three groups: fetal cystoscopy (34), VAS (16) and no intervention (61). A trend for normal renal function was reported with fetal cystoscopy but not in the VAS group. In PUV cases, fetal cystoscopy was effective in improving both the 6-month survival rate and renal function while VAS was

Figure 4 Fetal cystoscopic view of the bladder neck (A) and insertion of a trans-urethral stent (B, C). Reproduced with permission.

Please cite this article in press as: Farrugia M-K, Fetal bladder outlet obstruction: Embryopathology, in utero intervention and outcome, Journal of Pediatric Urology (2016), http://dx.doi.org/10.1016/j.jpurol.2016.05.047

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only associated with improvement in the 6-month survival rate with no effect on renal function [44]. Although fetal cystoscopy is feasible when undertaken in specialist centres, it must be noted that this procedure is more invasive than VAS and carries a risk of further complications, in particular a 10% urological fistula rate following fetal laser ablation [45]. However, it has the advantage of relieving the BOO without an indwelling device, which may cause iatrogenic damage to the bladder [17], as well as reducing oligohydramnios.

Postnatal outcome Renal outcome Studies exploring the long-term renal outcome of prenatal BOO diagnosis (without in utero intervention) have revealed conflicting results. Whereas some studies suggest that diagnosis before 24 weeks’ gestation [46,47], and prenatal diagnosis overall, are associated with a higher mortality and a higher rate of CRF [2], others suggest that prenatal diagnosis is in fact beneficial to outcome. Sarhan et al. compared the outcome of 310 patients and reported development of CRF in 30% overall: 19% diagnosed prenatally vs. 40% in the postnatal group [48]. A long-term study by Kousidis et al. suggested that prenatal diagnosis had little impact on mortality or ESRD in the first decade of life, as this appeared to be largely predetermined by renal dysplasia and the severity of intrauterine obstruction. However, the prenatally diagnosed patients who survived with intact renal function beyond 10 years appeared to have a better functional outcome into their twenties than that of patients presenting postnatally [49]. In a further study with a mean follow-up of more than 10 years, however, Ylinen et al. observed no significant difference in progression to compromised renal function (35% prenatal and 26% postnatal diagnosis) [50]. Matsell et al. reported that patients who progressed to ESRD were more likely to be diagnosed antenatally, had a younger gestational age and were more likely to have oligohydramnios or renal cortical cysts [51]. As discussed in the earlier section, to

Table 2

date fetal intervention has not changed the long-term renal outcome significantly.

Bladder outcome Publications on bladder outcome in prenatally diagnosed patients or those who have undergone prenatal intervention are scarce. Abbo et al. compared the outcome of 38 prenatally diagnosed and 31 postnatally diagnosed boys, with PUV revealing no significant difference in the incidence of voiding dysfunction (27% vs. 31%) at 7.2 years’ follow-up. Boys in the prenatal group, however, were more likely to have recurrent febrile UTIs (35% vs. 10%, p Z 0.01) [52]. The long-term outcome of bladders defunctionalised in utero is not known. Evidence from the ovine model suggests that shunted bladders become non-compliant and fibrotic with distorted muscle layers, but there are no histological data available from human bladders. Although the numbers are small, Freedman et al. reported a high proportion of bladder augmentation (75%) in boys found to have PUV following in utero shunting [53]. No bladder functional outcome data are available following fetal cystoscopy; it is hoped that preservation of bladder cycling may be an advantage of this procedure.

Ethics Several ethical questions are being raised as fetal surgery develops, including basic Hippocratic principles of patients’ autonomy and doctors’ duty of competence moving the boundaries among experimental surgery, therapeutic innovation and standard care. In addition, the technical success of a fetal intervention can only rarely fully predict the postnatal outcome. Managing uncertainty regarding long-term morbidity and the possibility for fetal therapy to change the risk of perinatal death into that of severe disability remains a critical factor affecting women’s choice for termination as an alternative to fetal therapy. The emotional burden of this decision-making process is significant and requires attentive counselling and appropriate support [54].

Summary of the PLUTO trial results [41].

Number of patients Oligohydramnios Gestation at VAS VAS complications

Gestational age at delivery Preterm labour (<37 weeks) Mean birth weight Required ventilation Survival to 28 days Survival to 2 years

Vesico-amniotic shunt (VAS)

Conservative

16 10 20 (16e22) weeks 3 PROM, 3 dislodged and 1 blocked shunt (1 fetus survived) 28 weeks 7 2.8 kg 6 8 7 (2 normal renal function, 5 moderate renal impairment; one patient had serious cognitive impairment)

15 9 e e

28 weeks 8 2.8 kg 7 4 3 (2 moderate impairment and 1 ESRD)

Please cite this article in press as: Farrugia M-K, Fetal bladder outlet obstruction: Embryopathology, in utero intervention and outcome, Journal of Pediatric Urology (2016), http://dx.doi.org/10.1016/j.jpurol.2016.05.047

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Fetal bladder outlet obstruction

Summary The prevalence of fetal BOO, in particular that of PUV and PBS, has not changed over the last 20 years, but prenatal detection is improving. Prenatal decompression by means of VAS or fetal cystoscopic ablation is being undertaken in a number of specialised centres, and is feasible as early as the first trimester of pregnancy. Evidence suggests a reduction in perinatal mortality following shunting, probably because of amelioration of oligohydramnios at the crucial time of lung development between 16 and 28 weeks’ gestation. There is no conclusive evidence, however, that prenatal diagnosis, and indeed prenatal intervention, has altered postnatal renal outcome, as one-third of these children progress to CRF regardless. There are no bladder functional outcome studies in patients who have undergone prenatal intervention and hence the long-term effect of in utero defunctionalisation of the bladder is not known. In conclusion, detailed informed consent including the balance of risks to the mother and fetus versus what is known of long-term outcome following intervention, must be considered when considering an invasive in utero procedure. Future outcome studies ought to include bladder functional and neurodevelopmental outcomes, as well as renal function.

Conflict of interest None.

Funding None.

Acknowledgements Pramod Reddy (Cincinnati Children’s Hospital Medical Centre); Makrina Savvidou (Chelsea & Westminster Hospital, London) and Gowri Paramasivam (Queen Charlotte’s and Chelsea Hospital, London) for their assistance with the prenatal intervention text and images.

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Please cite this article in press as: Farrugia M-K, Fetal bladder outlet obstruction: Embryopathology, in utero intervention and outcome, Journal of Pediatric Urology (2016), http://dx.doi.org/10.1016/j.jpurol.2016.05.047