Clinical predictors of chronic kidney disease in congenital lower urinary tract obstruction.

Congenital lower urinary tract obstruction is associated with oligohydramnios and significant perinatal mortality and long-term chronic kidney disease. The counseling of families facing this diagnosis, especially when prenatal intervention is proposed, is fraught with ambiguity. This review aims to equip the provider with the current evidence behind the conventional and novel biomarkers predictive of chronic kidney disease. The relevant clinical predictors are categorized by when they are identified, antenatally or postnatally, and as either anatomic or chemical. They are considered for their prognostic value and the challenges in obtaining them, specifically the risk to the fetus in the case of prenatal biomarkers. Serum creatinine in infancy is the traditional chemical biomarker of kidney function and continues to be a consistent predictor of future serum creatinine. ß-2 microglobulin may provide earlier information regarding fetal glomerular and tubular function and is also predictive of long-term serum creatinine. Renal parenchymal area is an anatomic surrogate of nephron mass that is used in both prenatal and postnatal settings. Understanding the anatomic and chemical biomarkers is essential for future refinement of the staging algorithm used to distinguish which patients may benefit from early in utero intervention.

Prenatal incision of ureterocele causing bladder outlet obstruction: a multicenter case series.

We reviewed data from a cohort of fetuses with ureterocele diagnosed and operated prenatally in four fetal therapy centers. Inclusion criteria were (1) ureterocele confirmed on detailed fetal ultrasound examination, (2) absence of additional fetal malformations, and (3) fetal intervention to decompress the ureterocele with local institutional review boards' approval. Data on sonographic follow-up, obstetrical, neonatal outcome, and postnatal evaluation were collected. Ten cases of prenatally treated ureterocele are described. Six cases benefited from a fetoscopy for laser incision and decompression, two cases had an ultrasound guided puncture before resorting to a fetoscopy with laser incision, one case had a balloon catheterization under ultrasound guidance, and one case had an ultrasound-guided opening of the ureterocele with a laser fiber passed through a 20-gauge needle. Mean gestational age at diagnosis was 21.6 GW. Two cases underwent termination of pregnancy. The remaining eight cases recovered normal amniotic fluid volume and delivered a liveborn child at a mean gestational age of 38.6 GW with normal creatinine levels during the first week of life. Prenatal incision provided complete treatment of severely obstructive ureteroceles in 80% of the cases and allowed improvement of urinary electrolytes, renal size and echogenicity, bladder filling in all survivors, and recollection of normal amniotic fluid volume, in case of oligoanhydramnios. © 2017 John Wiley & Sons, Ltd.

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

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.

Development of an animal model to study congenital urinary obstruction.

PURPOSE: We outline the development of a reliable model of obstructive uropathy in fetal lambs highlighting our understanding of the critical time points for interventions and the variability of any such model. We identify some discoveries that may have clinical implications. METHODS: The model requires 60-day-gestation fetal lambs. In lambs, glomerulogenesis is complete by 90 days gestation. (Term is 145 days.) The ability to develop a reliable method of creating bladder outlet obstruction in females, ligating both the urethra and urachus was critical. The lambs are bred to an accuracy of ±24 h. RESULTS: Creating the model at 50-60 days gestation, produces different expressions of renal dysplasia in groups of lambs undergoing identical interventions at the same stage of gestation. Early complete urethral obstruction can produce the Potter phenotype. An appropriately timed vesico-amniotic shunt preserves renal development, producing a shrunken, non-compliant bladder. Shunting the normal fetal bladder at 80 days gestation produces a similar bladder. Provision of a low-pressure valve in the shunt preserves bladder development and compliance. Using a high-pressure shunt produces results similar to non-shunted lambs. DISCUSSION: We developed a reliable animal model for obstructive uropathy. Being alert to peripheral results can lead to new findings.

Outcomes of fetuses with lower urinary tract obstruction treated with vesicoamniotic shunt: a single-institution experience.

PURPOSE: The purpose of this manuscript was to examine the outcomes of patients with lower urinary tract obstruction (LUTO) treated with vesicoamniotic shunt (VAS) to improve the quality of prenatal consultation and therapy. METHODS: The medical records of all patients diagnosed with LUTO at our center between January 2004 and March 2012 were reviewed retrospectively. RESULTS: Of 14 male fetuses with LUTO, all with characteristic ultrasound findings, 11 underwent intervention. One patient received vesicocentesis alone, while 10 had VAS. Two fetuses additionally underwent cystoscopy (one with attempted valve ablation), and two had peritoneoamniotic shunts. Of 16 total VAS, 13 were placed successfully, 8 dislodged (median 7 days), and 1 obstructed (84 days). Two fetuses suffered in utero demise, and two have unknown outcomes. LUTO was confirmed in six of eight live-born fetuses. One patient died in the neonatal period, while seven survived. All six available at follow-up (median 3.7 years), had significant genitourinary morbidity. Five patients had chronic kidney disease, but only one has required dialysis and transplant. Three had respiratory insufficiency, and one required a tracheostomy. CONCLUSION: Despite significant perinatal and long-term morbidity, VAS offers patients faced with a poor prognosis an improved chance of survival. Our results underscore the need for further research into the diagnosis and treatment of LUTO.

Valved shunt as a treatment for obstructive uropathy: does pressure make a difference?

PURPOSE: A valved ventriculo-peritoneal shunt (V-P shunt) as a vesico-amniotic shunt (V-A shunt) preserves the filling/emptying cycle and normal bladder development in fetal lambs with bladder outlet obstruction. The optimal pressure for such shunts is unknown. MATERIALS AND METHODS: We created obstructive uropathy in 60-day gestation fetal lambs. A V-A shunt was placed 3 weeks later, using a low-pressure (Group L: 15-54 mmH2O) or a high-pressure (Group H: 95-150 mmH2O) V-P shunt. We included non-shunted (obstructive uropathy, Group O) and control lambs (Group C). All were delivered at 130 days. Bladder volumes, bladder thickness, renal and bladder histology were compared. RESULTS: Seventeen lambs had an obstructive uropathy created. Five Group L (four survived), four Group H (three survived) and five Group O survived. Body weight and crown-to-rump lengths of the three groups were not significantly different. Group H lambs had a dilated urachus, urinary ascites and severe ureteral dilatation similar to Group O lambs. There were four Group C lambs. Bladder volume was 10, 15 and 1,150 ml in Group H, 115 ± 67.9 ml in Group L, 128 ± 99.8 ml in Group O and 24.5 ± 3.84 ml in Group C. Unlike Group O lambs, Group L did not have urinary ascites, urinomas or renal dysplasia. CONCLUSION: Low-pressure shunts preserved both bladder volume and renal development. High-pressure shunts did neither.

Bladder development following bladder outlet obstruction in fetal lambs: optimal timing of fetal therapy.

BACKGROUND: Lower urinary tract obstruction causes both renal failure and bladder dysfunction after birth. This study examined the early bladder wall changes after creating an obstructive uropathy focusing on bladder wall thickness and muscle integrity. METHODS: We created obstructive uropathy in fetal lambs at 60 days' gestation, ligating the urethra and urachus. The fetuses (n = 28) were delivered at 48 hours and 3, 4, 5, 7, and 14 days after obstruction and at term (145 days' gestation). Sham-operated lambs were used as controls (n = 20). Histology samples were stained using α-smooth muscle actin) immunohistochemistry and also hematoxylin-eosin, Masson trichrome, and colloidal Fe stain. RESULTS: The bladder wall initially expanded and stretched. By day 4, the bladder wall became thicker. Histologically, the bladder in obstructed lambs demonstrated a prominent submucosal fibrotic change by 7 days. The mean bladder wall thickness at 14 days after obstruction was thicker than controls, and fibrosis was prominent. CONCLUSION: The initial changes in the bladder wall were expansion of the muscle component followed by fibrosis. The bladder wall thickness dramatically increased 4 to 7 days after obstruction. We conclude that shunting operations to preserve bladder function may be needed earlier than expected.

In utero treatment for bladder outlet obstruction using robot assisted laparoscopic techniques.

PURPOSE: Bladder outlet obstruction can have devastating consequences. Given the poor outcome, intervention in utero has been advocated in an attempt to salvage pulmonary and renal function. We evaluated whether laparoscopic decompression of the obstructed bladder could be performed efficiently by adapting current robot assisted laparoscopic techniques to access the fetus in utero. MATERIALS AND METHODS: At 95 days of gestation 20 fetal sheep underwent ligation of the urethra and urachus. Two to 5 days later robot assisted laparoscopic vesicostomy was performed. Ultrasound of the kidneys and bladder was performed before each procedure. At 135 days of gestation the urinary tract was evaluated to assess the adequacy of bladder decompression and a patent vesicostomy. RESULTS: After 48 hours of undergoing ligation all fetuses had bilateral moderate hydronephrosis and a markedly distended bladder. In the first 10 fetuses vesicostomy could not be completed laparoscopically due to limited visualization. Additional modifications in trocar placement and gas infusion allowed vesicostomy to be completed laparoscopically in the last 8 fetuses in 2.5 to 4 hours. Urinary tract decompression and a patent vesicostomy were observed in all of these fetuses postoperatively. CONCLUSIONS: We developed specific modifications in current robot assisted laparoscopic techniques and instrumentation to allow the treatment of bladder outlet obstruction in utero. This procedure may be performed efficiently and it may provide advantages over conventional surgery for fetal intervention.

Fetal serum beta2-microglobulin before and after bladder shunting: a 2-step approach to evaluate fetuses with lower urinary tract obstruction.

PURPOSE: The evaluation of renal function in fetuses with lower urinary tract obstruction by analysis of electrolytes and beta2-microglobulin in fetal urine has limitations. We measured fetal serum beta2-microglobulin before and after bladder shunting to evaluate renal function. MATERIALS AND METHODS: A total of 12 fetuses with lower urinary tract obstruction underwent vesicoamniotic shunting. In addition to the standard evaluation of urinary electrolytes and beta2-microglobulin, fetal renal status was assessed by pre-shunt and post-shunt fetal serum beta2-microglobulin. RESULTS: At 2 to 4 weeks after shunting 2 of the 12 fetuses had persistent oligohydramnios, demonstrated increased values of serum beta2-microglobulin and were confirmed to have renal dysplasia. In the remaining 10 fetuses there was reaccumulation of amniotic fluid for a minimum of 4 weeks after shunting. Serum beta2-microglobulin values increased after shunting in 4 fetuses, all of which developed renal failure, whereas serum beta2-microglobulin did not change or was decreased after shunting in 6, of which 4 had normal renal function at latest followup. CONCLUSIONS: Urinary electrolytes, urinary beta2-microglobulin and pre-shunt serum beta2-microglobulin, whether increased or normal, failed to be predictive of potential response to prenatal intervention. Serial samples of fetal blood may provide distinction between patients who do and do not respond to prenatal treatment of lower urinary tract obstruction.

PLUTO trial protocol: percutaneous shunting for lower urinary tract obstruction randomised controlled trial.

OBJECTIVES: The primary objective is to determine whether intrauterine vesicoamniotic shunting for fetal bladder outflow obstruction, compared with conservative, noninterventional care, improves prenatal and perinatal mortality and renal function. The secondary objectives are to determine if shunting for fetal bladder outflow obstruction improves perinatal morbidity, to determine if improvement in outcomes is related to prognostic assessment at diagnosis and, if possible, derive a prognostic risk index and to determine the safety and long-term efficacy of shunting. DESIGN: A multicentre randomised controlled trial (RCT). SETTING: Fetal medicine units. POPULATION: Pregnant women with singleton, male fetus with isolated lower urinary tract obstruction (LUTO). METHODS: Following ultrasound diagnosis of LUTO in a male fetus and exclusion of other structural and chromosomal anomalies, participation in the trial will be discussed with the mother and written information given. Consent for participation in the trial will be taken and the mother randomised via the internet to either insertion of a vesicoamniotic shunt or expectant management. During pregnancy, both groups will be followed with regular ultrasound scans looking at viability, renal measurements and amniotic fluid volume. Following delivery, babies will be followed up by paediatric nephrologists/urologists at 4-6 weeks, 12 months and 3 and 5 years to assess renal function via serum creatinine, renal ultrasound and need for dialysis/transplant. MAIN OUTCOME MEASURES: The main outcome measures will be perinatal mortality rates and renal function at 4-6 weeks and 12 months measured via serum creatinine, renal ultrasound and need for dialysis/transplant. FUNDING: Wellbeing of Women. ESTIMATED COMPLETION DATE: September 2010. TRIAL ALGORITHM: [flowchart: see text].

Radiotelemetered urodynamics of obstructed ovine fetal bladders: correlations with ex vivo cystometry and renal histopathology.

OBJECTIVE: To test the hypothesis that fetal bladder outlet obstruction (BOO) in sheep causes abnormal urodynamics correlating with the initiation of renal pathology, as most boys with posterior urethral valves (PUV) have bladder dysfunction when assessed after birth. MATERIALS AND METHODS: Male ovine fetuses at 94 days of gestation were assigned to BOO (four) or sham control (five) groups. In BOO fetuses, radiotelemetry catheters were inserted transurachally and intraperitoneally, and the urethra was partly occluded. In two sham controls catheters were inserted directly through the bladder wall; the remaining three had sham surgery only. Radiotelemetered cystometry was recorded daily where possible. At the end of the experiment (9 days), ex vivo cystometry, bladder contractility studies and renal tract histology were assessed. RESULTS: Ultrasonography showed dilated renal tracts only in BOO fetuses; three of four BOO fetuses had renal cortical cysts. The control fetuses with bladder catheters died in utero, so urodynamics were recorded only in fetuses with BOO. The baseline filling/storage detrusor pressures increased slightly (by a mean of 5 mmHg) during the first 4 days of BOO, thereafter returning to those at the outset. There were marked changes in the patterns of bladder activity from 1 to 9 days. The frequency and duration of 'voiding' increased; as such the higher sustained pressures of emptying activity were progressively extended and the periods of low pressure filling/storage accordingly shortened. The patterns among individual fetuses with BOO were not substantially different, except that the one with the non-cystic kidneys had a more moderate frequency and duration of voiding. Ex vivo compliance and contractility showed no consistent differences in detrusor compliance or contractility between BOO and sham bladders. CONCLUSION: In this fetal model of PUV, there was a progressive increase in the duration and frequency of sustained elevated 'voiding' pressures, with no change in bladder compliance. Fetal kidneys were sensitive to these altered dynamics, with the formation of cortical cysts by 9 days after initiating BOO.

Ca2+ regulation in detrusor smooth muscle from ovine fetal bladder after in utero bladder outflow obstruction.

PURPOSE: We characterized intracellular Ca(2+) regulation in fetal bladders following outflow obstruction by examining the Ca(2+) response to agonists in smooth muscle cells. MATERIALS AND METHODS: Severe bladder outflow obstruction was induced in male fetal sheep by placing a urethral ring and urachal ligation midway through gestation at 75 days. Fetuses were examined 30 days after surgery. Intracellular Ca(2+) in single smooth muscle cells isolated from the bladder wall was measured with epifluorescence microscopy using fura-2(AM) during exposure to agonists, such as carbachol and adenosine triphosphate, and to other activators, such as caffeine and KCl. RESULTS: Detrusor smooth muscle cells from obstructed bladders had resting intracellular Ca(2+) similar to that in sham operated controls. The maximal response to carbachol was decreased following obstruction (p <0.05). Construction of dose-response curves also demonstrated higher EC(50) (p <0.05). However, these changes were not mirrored by caffeine evoked Ca(2+) release, which was not significantly different between the obstruction group and sham operated controls. Kinetic analysis of carbachol transients further revealed an attenuated maximal rate of increase in obstructed bladders (p <0.01). The magnitude of intracellular Ca(2+) to purinergic neurotransmitter adenosine triphosphate was also found to be smaller in cells from obstructed bladders (p <0.05), although transmembrane influx by high K depolarization was not significantly affected. CONCLUSIONS: Muscarinic and purinergic pathways were down-regulated in fetal detrusor muscle following outflow obstruction. These major functional receptors appeared to be more susceptible to obstruction than other Ca(2+) regulators. Their impairment may contribute to the compromised contractile function seen in in utero bladder outflow obstruction.

Successful outcome following prenatal intervention in a female fetus with bladder outlet obstruction.

Bladder outlet obstructions are a diverse and heterogeneous group of developmental abnormalities that generally involve obstruction of the proximal urethra in the male fetus. Indications for prenatal intervention are few and are usually restricted to the male fetus because bladder outlet obstruction in female fetuses is usually caused by complex cloacal development anomalies. We report on a female fetus with an enlarged bladder and a dilated proximal urethra (known as typical keyhole sign). A vesicoamniotic shunt was performed despite non-reassuring prognostic factors, but the procedure resulted in a successful outcome. We propose that in selected cases of bladder outlet obstruction, fetal intervention should be considered even when the fetus is female.

A preliminary study of natural-fill radiotelemetered ovine fetal cystometry.

OBJECTIVE: To determine whether fetal cystometric studies by radiotelemetry are feasible in the fetal lamb, and potentially suitable for chronically monitoring fetal bladder pressures in an experimental fetal model of bladder outlet obstruction (BOO), as in utero BOO (e.g. caused by posterior urethral valves) results in significant postnatal bladder dysfunction but the pathophysiological progression of fetal bladder maldevelopment remains poorly understood. MATERIALS AND METHODS: The procedure required fetal sheep surgery and anaesthesia. Radiotelemetry implants comprised catheters that transmitted pressure fluctuations to an implant body; data were then transmitted using radio frequency to a receiver that passed this information to a computer. Four fetuses were used with different methods of catheter placement to optimize the technique. RESULTS: Recordings were possible in three of the four sheep; during observation there were: (i) quiet periods with no abdominal or bladder pressure rises; (ii) synchronous activity in the bladder and abdomen; and (iii) discriminate activity, associated with intravesical activity only. Four patterns of discriminate bladder activity were observed, defined as void, immature void, staccato activity and 'unstable' type activity. CONCLUSIONS: Radiotelemetry cystometry for long-term monitoring is feasible in the experimental fetus without causing death or morbidity, or inhibiting growth. The method can discriminate reproducible patterns of detrusor activity. Recorded 'voiding' types were consistent between experiments and as reported in other fetal animal studies.

Prenatal bladder drainage in the management of fetal lower urinary tract obstruction: a systematic review and meta-analysis.

OBJECTIVE: To estimate the effect of prenatal bladder drainage on perinatal survival in fetuses with lower urinary tract obstruction. DATA SOURCES: Relevant articles were identified by searching the databases MEDLINE (1966-2002), EMBASE (1988-2002), and the Cochrane library (2000;4). METHODS OF STUDY SELECTION: Studies were selected if the effect of prenatal bladder drainage (vesicocentesis, vesicoamniotic shunt, or open fetal bladder surgery) on perinatal survival was reported in fetuses with ultrasonic evidence of lower urinary tract obstruction. Study selection, quality assessment, and data abstraction were performed independently and in duplicate. TABULATION, INTEGRATION, AND RESULTS: Sixteen observational studies that included nine case series (147 fetuses) and seven controlled series (195 fetuses) were identified. Study characteristics and quality were recorded for each study. Data on the effect of bladder drainage on perinatal survival were abstracted. Where controlled data were available, 2 x 2 tables were generated to compare the effects of bladder drainage versus no bladder drainage on perinatal survival. Pooled odds ratios (ORs) were used as summary measures of effect, and the results were stratified according to predicted fetal prognoses (based on ultrasound features and fetal urinary electrolytes). Among controlled studies, bladder drainage appeared to improve perinatal survival relative to no drainage (OR 2.5; 95% confidence interval [CI] 1.1, 5.9; P =.03). However, this observation was largely because among the subgroup of fetuses with a poor prognosis there was a marked improvement (OR 8.1; 95% CI 1.2, 52.9; P =.03). Improved perinatal outcome was also suggested in those fetuses considered to have a good prognosis (OR 2.8; 95% CI 0.7, 10.8; P =.13). CONCLUSION: There is a lack of high quality evidence to reliably inform clinical practice regarding prenatal bladder drainage in fetuses with ultrasonic evidence of lower urinary tract obstruction. The limited available evidence suggests that prenatal bladder drainage may improve perinatal survival in these fetuses, particularly those with poor predicted prognoses. Further research in the form of a multicenter randomized controlled trial is required to assess the short- and long-term effects of this intervention.

Neurotransmission and viscoelasticity in the ovine fetal bladder after in utero bladder outflow obstruction.

Fetal bladder outflow obstruction, predominantly caused by posterior urethral valves, results in significant urinary tract pathology; these lesions are the commonest cause of end-stage renal failure in children, and up to 50% continue to suffer from persistent postnatal bladder dysfunction. To investigate the physiological development of the fetal bladder and the response to urinary flow impairment, we performed partial urethral obstruction and complete urachal ligation in the midgestation fetal sheep for 30 days. By electrical and pharmacological stimulation of bladder strips, we found that muscarinic, purinergic, and nitrergic mechanisms exist in the developing fetal bladder at this gestation. After bladder outflow obstruction, the fetal bladder became hypocontractile, producing less force after nerve-mediated and muscarinic stimulation with suggested denervation, and also exhibited greater atropine resistance. Furthermore, fetal bladder urothelium exerted a negative inotropic effect, partly nitric oxide mediated, that was not present after obstruction. Increased compliance, reduced elasticity, and viscoelasticity were observed in the obstructed fetal bladder, but the proportion of work performed by the elastic component (a physical parameter of extracellular matrix) remained the same. In addition to denervation, hypocontractility may result from a reduction in the elastic modulus that may prevent any extramuscular components from sustaining force produced by detrusor smooth muscle.

Ultrasound-guided laser treatment for fetal bladder outlet obstruction resulting from ureterocele.

In a case of severe bilateral hydronephrosis in a female fetus associated with ureterocele at 28 weeks, under local anesthetic, ultrasound-guided neodymium:yttrium-aluminum-garnet laser was used to perforate the ureterocele and successfully overcome the obstruction. There was no recurrence of obstruction, and renal function was normal postnatally.

Effects of in utero bladder outflow obstruction on fetal sheep detrusor contractility, compliance and innervation.

PURPOSE: Congenital bladder outflow obstruction caused by posterior urethral valves is a common cause of end stage renal failure in boys. We hypothesized that fetal bladder outflow obstruction perturbs detrusor contractility and innervation and bladder storage volume-pressure relationships. MATERIALS AND METHODS: Severe bladder outflow obstruction was induced in male fetal sheep by placing a urethral ring and urachal ligation midway through gestation at 75 days. Fetuses were examined 30 days after surgery, when urinary tract dilatation, enlarged bladders and histologically abnormal kidneys were documented. Isolated strips of bladder detrusor from sham operated and obstructed fetuses were subjected to electrical field stimulation, carbachol, KCl and alpha-beta methylene-adenosine triphosphate. Whole bladder storage characteristics were determined by filling cystometry and bladder innervation was investigated by immunohistochemistry and Western blot. RESULTS: Tension-frequency contractility studies showed that obstructed fetal bladder strips were significantly hypocontractile versus sham operated controls in response to electrical field stimulation and the specific agonists carbachol, KCl and alpha-beta methylene-adenosine triphosphate. Hypocontractility was greater with nerve mediated stimulation than with carbachol, suggesting relative denervation. Reduced innervation was confirmed by S100 and protein gene product 9.5 immunohistochemistry and by measuring a significant reduction in protein gene product 9.5 protein expression using Western blot. Filling cystometry showed that obstructed fetal bladders appeared more compliant (Delta V/Delta P, where Delta V is the change in volume and Delta P is the change in pressure) with larger capacity, more flaccidity and yet retained stress relaxation. CONCLUSIONS: In response to severe experimental fetal bladder outflow obstruction the bladder becomes large and hypocontractile, and has aberrant innervation.